ArticlePDF AvailableLiterature Review

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

July 2016
Physiological Reviews 96(3):873-909

DOI:10.1152/physrev.00023.2015

Authors:

The University of Western Australia

Across the Western World there is an increasing trend to postpone childbearing. Consequently, the negative influence of age on oocyte quality may lead to a difficulty in conceiving for many couples. Furthermore, lifestyle factors may exacerbate a couple’s difficulty in conceiving due mainly to the metabolic influence of obesity; however, the negative impacts of low peripheral body fat, excessive exercise, the increasing prevalence of sexually transmitted diseases, and smoking all have significant negative effects on fertility. Other factors that impede conception are the perceived increasing prevalence of the polycystic ovary syndrome, which is further exacerbated by obesity, and the presence of uterine fibroids and endometriosis (a progressive pelvic inflammatory disorder) which are more prevalent in older women. A tendency for an earlier sexual debut and to have more sexual partners has led to an increase in sexually transmitted diseases. In addition, there are several genetic influences that may limit the number of oocytes within the ovary; consequently, by postponing attempts at childbearing, a limitation of oocyte number may become evident, whereas in previous generations with earlier conception this potentially reduced reproductive life span did not manifest in infertility. Environmental influences on reproduction are under increasing scrutiny. Although firm evidence is lacking however, dioxin exposure may be linked to endometriosis, phthalate exposure may influence ovarian reserve, and bisphenol A may interfere with oocyte development and maturation. However, chemotherapy or radiotherapy is recognized to lead to ovarian damage and predispose the woman to ovarian failure.

. Differences between fallopian tube and uterine secretion for mammalian embryos Component Oviduct Uterus

…

Intra-and extra-ovarian factors that are associated with the pathology PCOS that may negatively influence oocyte and subsequent embryo quality. [From Qiao and Feng (237), with permission from Oxford University Press.]

…

The effects of bisphenol A during early stages of oogenesis and the final stages of maturation (metaphase I and metaphase II). [From Machtinger and Orbvieto (207), with permission from Elsevier.]

…

Figures - uploaded by Roger Hart

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Content uploaded by Roger Hart

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PHYSIOLOGICAL ASPECTS OF FEMALE FERTILITY:

ROLE OF THE ENVIRONMENT, MODERN

LIFESTYLE, AND GENETICS

Roger J. Hart

School of Women’s and Infants Health, University of Western Australia & Fertility Specialists of Western

Australia, Subiaco, Perth Western Australia

LHart RJ. Physiological Aspects of Female Fertility: Role of the Environment, Modern

Lifestyle, and Genetics. Physiol Rev 96: 873–909, 2016. Published June 1, 2016;

doi:10.1152/physrev.00023.2015.—Across the Western World there is an in-

creasing trend to postpone childbearing. Consequently, the negative inﬂuence of age on

oocyte quality may lead to a difﬁculty in conceiving for many couples. Furthermore,

lifestyle factors may exacerbate a couple’s difﬁculty in conceiving due mainly to the metabolic

inﬂuence of obesity; however, the negative impacts of low peripheral body fat, excessive exercise,

the increasing prevalence of sexually transmitted diseases, and smoking all have signiﬁcant nega-

tive effects on fertility. Other factors that impede conception are the perceived increasing preva-

lence of the polycystic ovary syndrome, which is further exacerbated by obesity, and the presence

of uterine ﬁbroids and endometriosis (a progressive pelvic inﬂammatory disorder) which are more

prevalent in older women. A tendency for an earlier sexual debut and to have more sexual partners

has led to an increase in sexually transmitted diseases. In addition, there are several genetic

inﬂuences that may limit the number of oocytes within the ovary; consequently, by postponing

attempts at childbearing, a limitation of oocyte number may become evident, whereas in previous

generations with earlier conception this potentially reduced reproductive life span did not manifest

in infertility. Environmental inﬂuences on reproduction are under increasing scrutiny. Although ﬁrm

evidence is lacking however, dioxin exposure may be linked to endometriosis, phthalate exposure

may inﬂuence ovarian reserve, and bisphenol A may interfere with oocyte development and matu-

ration. However, chemotherapy or radiotherapy is recognized to lead to ovarian damage and

predispose the woman to ovarian failure.

I. INTRODUCTION 873

II. PHYSIOLOGY 874

III. PATHOLOGICAL PROCESSES,... 878

IV. LIFESTYLE INFLUENCES... 888

V. ENVIRONMENTAL INFLUENCES... 893

VI. CONCLUSION 900

I. INTRODUCTION

The most powerful inﬂuence relating to a woman’s chance

of conceiving is her age. Female age has physiological and

genetic inﬂuences on conception, relating to a reduced ovar-

ian follicular pool, perturbations in ovulation, and an in-

crease in meiotic errors within the oocyte. Indeed, in some

instances, age could be considered a lifestyle decision; how-

ever, in most instances this is not the case, as with increasing

societal and professional pressures upon women childbear-

ing is increasingly postponed into the 30s, whereas in pre-

vious generations starting a family in the 20s was the norm.

This has resulted in the increasing recourse to fertility treat-

ment; indeed, 1 in 25 children in Australia are born as a

result of in vitro fertilization (IVF) treatment, and it is be-

lieved the ﬁgure reaches 1 in 7 for women over 37 years of

age (239), when the treatment is much less successful (FIG-

URE 1).

This delay in childbearing has provided a window of op-

portunity for various lifestyle, pathological, and genetic

perturbations to exert their inﬂuence further to reduce a

couple’s chance of conceiving. The lifestyle factors that

have a detrimental impact on reproduction relate mainly to

the metabolic inﬂuence of obesity; however, the negative

impacts of low peripheral body fat, excessive exercise, the

increasing prevalence of sexually transmitted diseases, and

smoking all have signiﬁcant negative effects on female fe-

cundity at a population level.

Other factors that are believed to be exerting an increas-

ing negative inﬂuence upon female conception are the

greater prevalence of the polycystic ovary syndrome,

which is further exacerbated by obesity. Furthermore,

the incidence of uterine myomas (ﬁbroids) and endome-

triosis (a progressive pelvic inﬂammatory disorder) are

more prevalent in older women. A tendency for an earlier

sexual debut and to have more sexual partners has led to

Physiol Rev 96: 873–909, 2016

Published June 1, 2016; doi:10.1152/physrev.00023.2015

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an increase in notiﬁcations of sexually transmitted dis-

eases, a well-established cause of infertility. In addition,

there are several genetic inﬂuences that may limit the

“ovarian reserve,” an expression of the total number of

oocytes within the ovary; consequently, by postponing

attempted childbearing a limitation in ovarian reserve

may become evident, whereas in previous generations

with earlier conception this propensity to a limited repro-

ductive lifespan was not revealed.

Environmental inﬂuences upon reproduction are under in-

creasing scrutiny; however, the ﬁrm evidence to date is lack-

ing. There are suggestions that dioxin exposure may be

linked to endometriosis and phthalate exposure may inﬂu-

ence ovarian reserve, and bisphenol A may interfere with

oocyte development and maturation, although very good

evidence exists to relate the exposure to chemotherapy and

radiotherapy to gonadal damage.

The purpose of this review is to attempt to cover the sub-

stantial ﬁeld of female fertility and to try to address the

inﬂuences of lifestyle and the environment on female infer-

tility, and to provide a limited insight into genetic inﬂuences

on female reproduction, from follicular development to im-

plantation and early pregnancy.

II. PHYSIOLOGY

A. Folliculogenesis

Follicular development originates in utero during the sec-

ond trimester of pregnancy by the rapid mitosis of the pri-

mordial germ cells into up to a maximum of ⬃6 million

oogonia at 20 wk of gestation; from this point onwards the

dominant activity is atresia. Indeed, there will only be 1

million germ cells surviving at birth (243). This ﬁnite re-

serve of primordial germ cells originates in the yolk sac

endoderm and migrates to the gonadal ridge, and upon

arrival enter the ﬁrst meiotic division and become primary

oocytes, and constitute the “ovarian reserve” [follicles that

can subsequently be recruited for ovulation (20)]. These

germ cells are essential for the formation and maintenance

of the ovary, and in their absence the gonad degenerates

into cordlike structures (215, 243). These primary oocytes

are maintained at this arrested state of meiosis until the time

of the surge in luteinizing hormone (LH) that presages ovu-

lation. The oocyte is arrested in prophase I of meiosis by

high levels of cAMP (323). In addition to the germ cells, the

primordial follicle consists of somatic cells derived from the

primitive gonad which develop into the ﬂattened granulosa,

theca, and interstitial cells. As described, this so-called fol-

licular reserve of 6-7 million oocytes at 20 wk of gestation

(20, 22) will continually deplete throughout the woman’s

life, the rate of which may be accelerated by factors such

as genetic inﬂuences such as Turner’s syndrome or Frag-

ile X premutation carrier status (67), virological expo-

sures such as the mumps virus (71), environmental expo-

sure such as treatment with chemotherapy or radiother-

apy (138), ovarian surgery (6), negative lifestyle factors

such as smoking (308), and also in relation to autoim-

mune causes (367).

With the use of rodent models, factors involved in the reg-

ulation of the recruitment of these primordial follicles into a

developing population of follicles for a menstrual cycle have

been explored. Once puberty commences, Kit ligand and

leukemia inhibitory factor (LIF) have been identiﬁed as sig-

niﬁcant promoters of the follicular transition (210, 237,

323). Kit ligand is expressed on the granulosa cells of the

developing primordial follicle, with its receptor on the

membrane (oolema) of the primary oocyte, and LIF is se-

creted from the early granulosa cells. LIF secretion is be-

lieved to regulate the local signaling involved with primor-

dial follicle activation by promoting Kit ligand expression

(323). In addition, oocyte-derived factors bone-morpho-

genic protein 15 (BMP-15) and growth differentiation fac-

tor-9 (GDF-9) are involved in the promotion of primordial

< 22 23-24 25-26 27-28 29-30 31-32 33-34 35-36 37-38 39-40 41-42 43-44 ≥ 45

Percentage live birth rate

Age group (years)

FIGURE 1. Age-speciﬁc live delivery rates per initiated

autologous fresh cycle by two-year age groups, Australia

and New Zealand, 2013. The highest live delivery rates

were for women aged between their mid-20s to early-30s.

For women aged 45 or older, only one live delivery resulted

from every 80 initiated cycles compared with one live de-

livery from every four initiated cycles in women aged be-

tween 25 and 34. [From Macaldowie et al. (206), with

permission.]

ROGER J. HART

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follicle maturation (70, 255); in addition, granulosa cell

anti-Müllerian hormone (AMH) secreted by the granulosa

cells of small antral follicles appears to act as a restraint (51,

184). Other paracrine signals involved in primordial follicle

activation include basic ﬁbroblast growth factor (bFGF),

nobox and Foxo3, and insulin (176, 243). For a detailed

description of the local factors involved in follicle and

oocyte development, please refer to Sobinoff et al. (323) and

Kristensen et al. (184) (FIGURE 2). The ﬂattened granulosa

cells become cuboidal during the transition into a primary

follicle under the inﬂuence of transcription factor Foxl2; the

oocyte increases in diameter and develops a zona pellucida.

This recruitment into primary follicles commences during

fetal life and continues until the menopause.

B. Ovulation

The development and recruitment of these primordial folli-

cles is regulated by paracrine and autocrine signals involv-

ing the transforming growth factor-

␤

(TGF-

␤

) superfamily,

which includes TGF-

␤

, inhibins, activins, follistatins, bone

morphogenic proteins, growth factors, and AMH (184).

Then the follicle transitions to the gonadotrophin-depen-

dent antral follicle to the preovulatory stage; the whole

process takes ⬃6 months (129). The gradual maturational

change from the primordial follicle characterized by the

cuboidal granulosa cells, through the preantral stage (up to

0.2 mm in size), involves proliferation and maturational

changes and multi-layering within the granulosa and theca

cells, and the development of an antrum within the follicle.

With the development of the antrum, the follicle becomes

responsive to gonadotrophins, which takes several months

to complete (129, 243). The granulosa cell basal lamina is

traversed by many gap junctions that allow communication

and nutrition to surrounding granulosa cells and across the

zona pellucida to the oocyte. The innermost layers of gran-

ulosa cells become differentiated as cumulus cells. In con-

trast, the theca cells have a greater vascular supply and are

responsible for androgen synthesis, under LH stimulation.

This acts as the substrate for the granulosa cell synthesis of

estradiol, primarily under follicular stimulating hormone

(FSH) control, the so-called “two-cell two gonadotrophin

hypothesis” (21, 89). Both granulosa and theca cells secrete

growth factors that modulate follicle maturation; the acti-

vators include Kit ligand, FGF-2, KGF, LIF, BMPs, and

GDF-9, and the inhibitors include AMH, Foxl2, and

Foxo3A (for a detailed description, see Ref. 243). The pre-

antral follicle transition to the antral stage is modulated by

AMH and stimulated by activins and GDF-9, and then as

described the antral follicle becomes responsive to FSH

(243).

Gonadotrophin stimulation of the ovary requires integ-

rity of the hypothalamic-pituitary-ovary axis and appro-

priate peripheral signals that inﬂuence hypothalamic

function. Gonadotrophin releasing hormone (GnRH)

neurons arise alongside the olfactory nerves and migrate

during embryological development to the hypothalamus

and send neuronal projections from the arcuate nucleus

to the median eminence where they release GnRH into

the capillaries of the hypophysial-portal vessels (194).

The GnRH then binds to the GnRH receptor on the an-

terior pituitary initiating the synthesis and secretion of

LH and FSH (194). The control of hypothalamic secre-

tion of GnRH is complex, relying on a complex interplay

of ovarian feedback, primarily by inhibin B and estradiol

and neuroendocrine signals modulated by systemic met-

abolic signals. Kisspeptins have the strongest inﬂuence

over GnRH release via the kisspeptin receptor, coded for

by GPR54, and are also integral to the timing and onset

of puberty (232, 259; for detailed description, see Pinilla

et al., Ref. 259). The kisspeptin neurons also express the

FIGURE 2. Diagrammatic representation of primordial

follicle activation, oocyte maturation, and oocyte activa-

tion. A: the follicular activation of the dormant primordial

follicle occurs in response to cytokine growth factors

(e.g., Kit and LIF) and is characterized by oocyte growth

and granulosa cell differentiation/proliferation. B: oocyte

maturation occurs in response to the LH surge, resulting

in meiotic resumption and arrest at metaphase II. C:

oocyte activation occurs in ovulated oocytes after fertil-

ization, resulting in the completion of MII, extrusion of the

second polar body, and male/female pro-nuclear forma-

tion. Images are not to scale. [From Sobinoff et al. (323),

with permission from Oxford University Press.]

PHYSIOLOGICAL ASPECTS OF FEMALE FERTILITY

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neuropeptides neurokinin B (NKB) and dynorphin which

modulate the GnRH secretion (123). Other neuropep-

tides integral to GnRH pulsatility are

␣

melanocyte-stim-

ulating hormone (

␣

MSH), produced by proopiomelano-

cortin and cocaine and amphetamine-regulated tran-

script (POMC/CART), and the agouti-related protein

(AgRP), an antagonist of

␣

MSH, produced by the neuro-

peptide Y (NPY)/AgRP neurons (for review, see Navarro

and Kaiser, Ref. 232). These neuropeptides are integral

in the coordination of the reproductive and metabolic

axes through their action in the hypothalamus (232); the

neuropeptides derived from POMC/CART neurons exert

a potent anorectic action, thus decreasing food intake

and body weight, whereas AgRP and NPY have the op-

posite (orexigenic) effect, inducing food intake. In addi-

tion, these neurons express receptors for leptin (secreted

by adipose tissue, anorexogenic, and a stimulus for

GnRH activity), insulin, and gherlin (secreted by the gut,

orexigenic, and a suppressor of GnRH activity). Further-

more, neuronal projections from the premammillary ven-

tral nucleus which can be stimulatory (glutamatergic) or

inhibitory (GABAergic) are responsive to peripheral lep-

tin signals, leading to a complex relation of reproductive

responses to metabolic signals (232).

After the antral stage of development, granulosa cell es-

tradiol production increases by granulosa cell prolifera-

tion, increased vascularity, and an increased supply of

theca cell androgens. Inhibin A secretion from larger fol-

licles increases, promoting androgen secretion from

theca cells, and there is a reduction of activin A secretion

from larger follicles. Activin A acts to inhibit androgen

secretion and promote oocyte developmental competence

(5). As preantral follicle development progresses, there is

an increase in FSH and LH receptor expression, aroma-

tase activity, and inhibin and progesterone production

(180).

The oocyte-derived BMPs and GDF-9 inhibit the premature

luteinization of the follicle, which commences after the re-

lease of the oocyte at ovulation. Inhibin A secretion via

pituitary feedback leads to a reduction in FSH secretion;

hence, larger, or dominant follicles, will have higher con-

centrations of FSH and LH receptors and will continue to

have higher aromatase activity and hence estradiol secre-

tion.

Prior to ovulation, FSH induces expression of LH and

progesterone receptors on the surface of the granulosa

cells. The transformation to luteinization of the domi-

nant follicle is initiated by the surge in LH and is often

preceded by a slight rise in serum progesterone. The pro-

cess of ovulation involves rapid expansion of the domi-

nant follicle (1–4 mm/day), and ovulation results when

tumor necrosis factor-

␣

(TNF-

␣

)-stimulated collagenase

weakens the apical surface epithelium of the ovary and

follicle rupture results (228). The corpus luteum is com-

posed of theca and granulosa cells, endothelial, immune

cells, macrophages, T and B lymphocytes, and ﬁbroblast

cells and secretes up to 40 mg of progesterone per day, in

addition to estradiol and androgens (82, 83, 275). The

LH surge must last more than 24 h to initiate resumption

of oocyte meiosis and breakdown of the granulosa cell-

oocyte gap junctions as well as to promote luteinization

of the granulosa cells, ovulation, and the initiation of

corpus luteum function (82, 83). It is believed that stim-

ulation of the granulosa progesterone receptor is also a

prerequisite for ovulation (66). The granulosa-lutein

cells express the enzyme aromatase and produce estradiol

in addition to progesterone, and the theca-lutein cells

have P450C17 activity and generate the androgen pre-

cursors for granulosa cells (82), and are also believed to

secrete progesterone (83). Granulosa cell steroidogenic

acute regulatory protein (StAR) expression is substan-

tially increased around the time of ovulation, induced by

LH (171). StAR is essential for the movement of choles-

terol carried by low-density lipoprotein into the inner

membrane of the mitochondria where it becomes a sub-

strate for P450scc to commence steroidogenesis (171).

Over one-third of cells within the corpus luteum are en-

dothelial cells representing the signiﬁcant degree of vas-

cularization the corpus luteum has undergone, induced

primarily through the expression of vascular epithelial

growth factor (VEGF). The immune cells are responsible

for the secretion of cytokines, primarily interleukin

(IL)-1

␤

and TNF-

␣

, which modulate steroidogenesis

(82). Estradiol production by the granulosa-lutein cells is

stimulated by LH and insulin-like growth factor I (IGF-

I), not by FSH. In the absence of human chorionic gonad-

otrophin (hCG) secreted by a developing embryo or ex-

ogenously administered, there is a substantial reduction

of StAR expression (84), mirrored in the serum proges-

terone level and reductions in P450scc and 3

␤

hydroxys-

teroid dehydrogenase (HSD) (responsible for conversion

of pregnenolone to progesterone) (83). Luteolysis leads

to reductions in progesterone, estradiol, and inhibin A

which through hypothalamic-pituitary-ovarian feedback

initiates a further wave of follicular recruitment via in-

creased GnRH pulses and the falling steroids precipitate

menstruation. The process of luteolysis is not well under-

stood, however, apoptosis is a signiﬁcant feature, al-

though the percentage of cells with apoptotic markers is

low (358), and it involves breakdown of the extracellular

matrix by matrix metalloproteinases (159).

At the time of embryo implantation, trophoblast produc-

tion of hCG prevents the regression of the corpus luteum by

increasing StAR expression within the granulosa and theca-

lutein cells, increasing the vascular supply to the corpus

luteal cells and a reduction in luteolysis by inhibition of the

pro-apoptotic protein Bax and an increase in macrophages

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that are believed to be essential for the vascular support of

the corpus luteum (50, 83, 333).

C. Fertilization and Early Embryonic

Development

After release of the oocyte and cumulus cell complex from

the ovary to the ﬁmbriae of the fallopian tube, the oocyte is

fertilized in the ampulla of the distal end of the fallopian

tube. The process of binding of the acrosomal membrane of

a sperm that has undergone the acrosome reaction and ca-

pacitation to the zona pellucida (a glycoprotein matrix sur-

rounding the oocyte) initiates release of cortical granules

within the oocyte. The binding of the sperm to the zona

pellucida precipitates a hardening of the zona preventing

polyspermic fertilization of the oocyte (the zona reaction),

intracellular calcium oscillations commence, and meiosis II

is completed by extrusion of the second polar body. In

addition, the sperm acrosome contains several lytic en-

zymes and zona pellucida binding proteins (241). The

mechanism of sperm-oocyte binding to the four zona pellu-

cida sperm binding proteins (ZP1 to 4) and the prevention

of polyspermic fertilization is still subject to debate (for

further discussion, see Clift and Schuh, Ref. 62), as from

animal studies there are believed to be several other sub-

stances involved in the sperm-oocyte fusion, such as sperm

ADAMs (consisting of a disintegrin and a metalloprotei-

nase) and their oocyte integrin ligands, and the sperm pro-

teins IZUMO1 and SPESP1 (98). The increase in calcium

within the oocyte is a trigger for the development of the

female pronucleus and the sperm DNA, which is tightly

packed with protamines, undergoes decondensation, and is

wrapped around nucelosomes and forms the male pronu-

cleus (62). In addition, global DNA demethylation occurs in

male pronucleus; this is active and rapid, and in the female

pronucleus this is passive and slower, and epigenetic repro-

gramming commences. Roughly 150 genes are considered

“imprinted” in that their methylation pattern (to suppress

the expression of a gene) is determined by the parent of

origin of the gene, and they retain their methylation pattern

(260). Mitochondria that originate in the sperm are de-

stroyed in early embryonic development, to prevent mito-

chondrial heteroplasmy (73).

Under the inﬂuence of the microtubules of the sperm aster

(a star-shaped structure derived from the centriole of the

mid-piece of the sperm), the pronuclei migrate towards the

center of the oocyte (296). Syngamy is the point at which

the pronuclei come together and break down completing

fertilization, and subsequently the centrioles duplicate and

migrate around the zygote nucleus to form opposite poles of

the ﬁrst mitotic spindle and commence the ﬁrst cleavage

(296). Early embryonic cleavage and development is regu-

lated by mRNA transcripts and proteins within the

ooplasm, and by cell division over the subsequent days with

activation of the embryonic genome develops to a blasto-

cyst of ⬃100 blastomeres (196).

D. Fallopian Tube Function

The fallopian tube is derived from the Müllerian duct and

averages 11 cm in length; however, it is made of four dis-

tinct regions with differing functional signiﬁcance: the in-

fundibulum and ﬁmbria (for oocyte capture), the ampullary

region (fertilization occurs at the junction with the isth-

mus), the isthmus, and interstitial portion of the fallopian

tube (regulating the release of the embryo into the endome-

trial cavity), and each region has differing secretions for the

nutrition of the early embryo and for capacitation and sus-

tenance of the sperm (294). The tube is responsible for the

transport and nutrition of the gametes and early embryo, by

muscular contractions and ciliary action (204). As de-

scribed, it is the site of fertilization and for the collection of

the released oocyte, and its secretory activity, cyclical mor-

phology, and contractility are related to the hormonal en-

vironment. In the early stages of embryo development, the

fallopian tube secretion is low in glucose and has relatively

high levels of pyruvate and lactate, the inverse of the uterine

environment (see TABLE 1), a fact that is mirrored in the

development of commercial embryo culture media for IVF

treatment to mimic the in vivo early embryo environment

by using sequential culture media as the embryo develop to

the blastocyst stage (191). For a detailed review of the phys-

iology of the fallopian tube, please refer to References 7, 16,

191.

E. Implantation

The endometrium is prepared for implantation under the

inﬂuence of estrogen and progesterone; however, only ap-

proximately half of all embryos that are generated will im-

plant and proceed to a successful on-going pregnancy (368).

The window of implantation is limited to a receptive win-

Table 1. Differences between fallopian tube and uterine

secretion for mammalian embryos

Component Oviduct Uterus

Glucose concentration, mM 0.5 3.15

Pyruvate concentration, mM 0.32 0.10

Lactate concentration, mM 10.5 5.2

Oxygen concentration, % 8 1.50

Carbon dioxide concentration, % 12 10

pH 7.5 7.1

Glycine concentration, mM 2.77 19.33

Alanine concentration, mM 0.5 1.24

Serine concentration, mM 0.32 0.8

From Lane and Gardner (191), with permission.

PHYSIOLOGICAL ASPECTS OF FEMALE FERTILITY

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dow between 7 and 10 days after ovulation when the endo-

metrium has undergone secretory morphological changes in

preparation for implantation with the development of api-

cal epithelial protrusions-pinopodes (236, 265) and is pro-

tected against blastocyst attachment until the appropriate

time by Muc-1 and facilitated by

␣

␤

and

␣

␤

integrin

expression (134). Implantation is characterized by three

phases: apposition, adhesion, and invasion into the decidu-

alized endometrium. Decidualization describes the mor-

phological and functional changes occurring within the en-

dometrial stromal cells in response to progesterone in prep-

aration for embryo implantation. Apposition of the

blastocyst trophectoderm occurs with the inner cell mass

directed towards the epithelium. Factors that are believed to

be important in implantation and the appropriate endome-

trial changes are as follows: LIF, IL-1, colony stimulating

factor, L-selectin, Wnt, Hoxa10/11, heparin binding epider-

mal growth factor, and bone morphogenic protein 2, in

addition to cell adhesion molecules and glycoproteins, and

it is believed that signaling from the embryo is crucial to

trigger this process of endometrial decidualization (for a

detailed review, see Refs. 54, 85, 134). The trophoblast cells

then degrade the extracellular matrix and invade into the

endometrial epithelium, basal lamina, and the stroma and

placental formation commences.

III. PATHOLOGICAL PROCESSES, THEIR

IMPLICATIONS, AND THERAPEUTIC

OPTIONS

A. Folliculogenesis

1. Genetic

Premature ovarian insufﬁciency (POI) occurs in ⬃1% of

women and is deﬁned as the cessation of menstrual cycles

under 40 years of age in the presence of an elevated serum

FSH measured on two separate occasions (128). The causes

may be genetic (107), environmental, infective (subsequent

to mumps infection), associated with autoimmune condi-

tions, metabolic [due to biochemical damage in the presence

of galactossaemia (174)], and subsequent to cancer therapy

(138) or surgery (230); however, in the majority of cases no

cause is determined (128). A positive family history exists in

10–15% of cases with the suggestion that inheritance is

autosomal dominant sex-linked or X-linked with incom-

plete penetrance (357). For a detailed review of the genetic

mutations associated with premature ovarian insufﬁciency,

please see Fortuno and Labarta (107). There are in excess of

20 genes on the X chromosome, particularly involving the

critical region of the short arm of the X chromosome be-

tween Xp21.1 and Xp22.1.22 and the long arm regions

Xq13.3-Xq21.1 and Xq26-Xqter (107), and well over 50

autosomal genes related to POI.

Possibly the most common genetic cause of POI is Turner

syndrome (347) characterized by the loss of all, or part of an

X chromosome, occurring in ⬃1 in 3,000 female births

(336). Approximately half due to X chromosome mono-

somy and the majority of the remainder due to mosaicism

(336). This is a condition with several phenotypic features

characterized by short stature, cardiac and renal abnormal-

ities, hypothyroidism, webbed-neck, and otological and

ophthalmological abnormalities are all common in child-

hood (336). The ovarian insufﬁciency commonly found in

this condition relates to disruption of the BMP15 gene locus

located at Xp11.2, within a critical region related to ovar-

ian failure (254, 391). Spontaneous puberty occurs in ap-

proximately one quarter of girls, more commonly in mosa-

ics; however, premature ovarian failure is universal.

Another common genetic cause of POI is related to the

fragile X mental retardation protein, occurring in 3–15% of

patients with POI (373). In this condition there is an expan-

sion of the CGG triplet repeats of the FMR1 gene at

Xq27.3, and in the presence of more than 200 repeats the

condition fragile X syndrome occurs. This is a severe form

of mental retardation and autism; however, in the presence

of the premutation of 55 and 200 triplet repeats, premature

ovarian failure results (373).

The fertility options for women with premature ovarian

insufﬁciency are essentially restricted to oocyte donation

treatment only. This is a reliable and effective treatment

provided the woman has been assessed as medically ﬁt and

suitable for assisted reproduction and she has adequate

uterine and endometrial development, which may be lack-

ing in some women with POI (150).

This therefore raises the specter of attempts to preserve

fertility in women where it would be expected that there is

a premature depletion of oocytes; such as in Turner syn-

drome or galactossaemia for instance. Attempts have been

made by the freezing of ovarian cortical tissue for young

adolescent girls or by the collection of stimulated mature

oocytes as part of an IVF cycle for older girls; however, due

to the restricted oocyte number, these techniques are not

routine and have had to date limited success (150) but may

offer promise in the future (242). Furthermore, when a

woman with Turner syndrome commences fertility treat-

ment in view of the associated increased risk of cardiovas-

cular-related mortality in pregnancy, they should be cared

for under specialized care, and indeed, Turner syndrome

should be considered a relative contraindication to preg-

nancy (266).

B. Ovulation

1. Hypogonadotrophic hypogonadism

Insufﬁcient ovarian stimulation with gonadotrophins LH

and FSH results in the condition of hypogonadotrophic

hypogonadism (HH), either due to insufﬁcient hypotha-

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lamic GnRH stimulation of the pituitary or due to insufﬁ-

cient secretion due to pituitary compromise. After exclusion

of excessive exercise, extreme stress, or an eating disorder,

and after ensuring pituitary function, other than secretion

of LH and FSH, is normal, and pituitary imaging is normal

the condition is considered idiopathic HH (IHH) (194). The

most common cause of GnRH insufﬁciency is the failure of

migration of the GnRH secretory neurons to the forebrain

which may also result in olfactory disorder (Kallman’s syn-

drome); in the absence of olfactory, the condition is de-

scribed as normosmic IHH (354). The inheritance is either

X-linked (KAL genes), autosomal dominant or autosomal

recessive, and the condition is usually detected in adoles-

cence with a delay or absence of pubertal development, with

in excess of 20 genes implicated in this condition to date

(194). Kallman’s syndrome is characterized by HH and

anosmia and is most commonly caused by mutations of the

KAL-1, KAL-2, and KAL-6 and are all implicated in inter-

ference with the neuronal migration associated with HH

and anosmia, in addition to other abnormalities (354). Mu-

tations of the GnRH1 gene encoding GnRH are very rare;

however, mutations of the GnRHR gene (4q13.2–3) encod-

ing the GnRH receptor are more common and lead to vari-

able expression of the phenotype (354). The KISS1 gene

encodes kisspeptins which stimulates GnRH release, its re-

ceptor is coded for by the GPR54 gene, and hence muta-

tions of either gene will lead to variable expression of IHH

either in childhood or adulthood. In addition, the TAC3

gene codes for NK3R which also stimulates GnRH neurons,

mutations of which lead to perturbed GnRH secretion and

hence insufﬁcient LH and FSH secretion. In addition, mu-

tations in the leptin gene, Ob, the LH and FSH

␤

subunits,

LHB and FSHB, are rare but are associated with hypogo-

nadism. For a more detailed review of the genetics associ-

ated with IHH and Kallman’s syndrome, see Valdes-Socin

et al. (354) and Layman (194).

2. Hyperprolactinemia

Other central causes of HH can be caused by systemic dis-

ease, medication (such as opioids and psychotropic medica-

tion), hypothalamic or pituitary compression, or inﬁltra-

tion; however, the most common cause is probably hyper-

prolactinemia. Hyperprolactinemia may be caused by

physiological states such as pregnancy, breastfeeding,

stress, exercise, and some medications as well as patients

with chronic hypothyroidism. Kidney disease may predis-

pose a patient to hyperprolactinemia due to reduced clear-

ance and altered prolactin metabolism. As prolactin secre-

tion is suppressed by hypothalamic dopamine secretion,

interruption or compression of the pituitary stalk by a non-

prolactin-secreting pituitary tumor will lead to hyperpro-

lactinemia. Furthermore, prolactin secreting adenomas, ei-

ther a micro (⬍10 mm) or a macro adenoma (⬎10 mm in

size), lead to prolactin inhibition of gonadotrophin secre-

tion and anovulation (214).

3. Polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is a collection of

signs and symptoms related to ovarian dysfunction, found

within a phenotypically heterogeneous group of women. It

is classically described by the Rotterdam criteria (285) as a

syndrome consisting of two of three criteria related to in-

frequent or absent ovulation, a morphological description

of the ovaries by ultrasound assessment, and hyperandro-

genism. Other groups suggest that the excessive androgen

secretion is the most signiﬁcant underlying pathology as this

is believed to lead to ovarian dysfunction and the longer

term metabolic consequences these women experience

(140), and they consequently adopt a more stringent deﬁ-

nition of PCOS (19, 382).

The etiology of PCOS is unclear with putative causes

being a genetic predisposition modulated by hyperinsu-

linemia or the early life environment, as there is very

good evidence from animal models for a programming

effect of early life exposure to androgens (1). The pheno-

type of PCOS is modulated by the presence of obesity,

which also exacerbates the metabolic features of PCOS

(226). From genome-wide association studies (GWAS),

potential loci for PCOS have been identiﬁed at 9q22.32,

8p23.1, and 11p14.1 and single-nucleotide polymor-

phisms (SNPs) of the gonadotrophin receptors and the

androgen receptor (102), and several other SNPs have

been identiﬁed (18). A SNP at 11p14.1 was associated

with PCOS and elevated serum LH concentration, a fre-

quently observed feature in PCOS. Other genes believed

to be associated with the development of PCOS relate to

genes involved with insulin signaling and the epidermal

growth factor receptor (for review, see Ref. 18). There is

evidence from both human and animal studies that sup-

raphysiological maternal androgen levels may lead to

disordered folliculogenesis in female offspring with a

PCOS phenotype (1, 106, 281). Animal models of PCOS

have been generated with rodents (363), sheep (281), and

monkeys (1) by early life exposure to supraphysiological

androgens, leading to the development in the female of

offspring of hyperandrogenism, hyperinsulinemia, LH

hypersecretion, and ovulatory disorder. In humans, evi-

dence from early life exposure to hyperandrogenemia in

conditions such as congenital adrenal hyperplasia can

lead to the development of PCOS like features (24). How-

ever, the impact of variations in maternal androgens

within the normal physiological range is less well under-

stood. One study measured maternal circulating total

serum testosterone concentration at 18 wk of gestation

and demonstrated a signiﬁcant positive association with

early follicular phase circulating AMH in female off-

spring in adolescence (147), but not PCOS per se (151).

Serum AMH is secreted from the granulosa cells within

preantral and small antral follicles and is elevated in both

adolescents (142) and women with a polycystic ovarian

morphology and PCOS (257). During normal pregnancy,

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the fetus is protected from maternal androgens by pla-

cental aromatase. However, it is possible that placental

dysfunction may expose the fetus to higher concentra-

tions of androgens, or with the suppression of sex hor-

mone binding globulin by hyperinsulinemia the concen-

tration of free testosterone maybe increased. The associ-

ation of bisphenol A (BPA) as a potential environmental

cause of PCOS is discussed in section V.

It is believed that oocyte developmental competence and

the embryos resulting from fertilization are altered in

women with PCOS, compared with women without

PCOS (91). There are multiple serum and follicular fac-

tors that are reportedly altered in women with PCOS that

may be responsible for this poor embryonic development

and reduced implantation (summarized by Qiao and

Feng, see FIGURE 3 and TABLE 2), although it is not clear

whether this is associated with an increase in the rate of

embryo aneuploidy (268). Not only is the systemic and

follicular environment different in PCOS, the gene ex-

pression proﬁle of oocytes derived from women with

PCOS are distinctly different (91). These genes relate to

signal transduction, transcription, RNA and DNA pro-

cessing, and the regulation of the cell cycle [summarized

by Dumesic and Abbott (91)]. Of particular importance

in the acquisition of oocyte developmental competence is

GDF-9 expression, which is reduced in the oocytes of

women with PCOS (342).

The ovulatory disorder is frequently exacerbated by hy-

perinsulinemia, which is present in well over 50% of

women with PCOS (225), and is further accentuated by

central obesity, and hence lifestyle modiﬁcation pro-

grams should be the ﬁrst intervention strategy (88). The

elevated endogenous serum insulin promotes ovarian an-

drogen secretion, via IGF-I receptor activation of theca

cell androgen secretion (317) and perturbs folliculogen-

esis (292). Second-line therapies consist of using the in-

sulin sensitizer metformin, which leads to a reduction in

androgen secretion, by effects on steroidogenic acute reg-

ulatory protein and 17

␤

-hydroxylase, and inhibits FSH

and induces aromatase activity in granulosa cells (277).

Speciﬁcally metformin increases insulin sensitivity by de-

creasing gluconeogenesis and lipogenesis and enhancing

glucose uptake by the liver, skeletal muscle, and adipose

tissue (231). Other approaches are the use of the selective

estrogen receptor modulator clomiphene citrate which

leads to increased pituitary FSH secretion, exogenously

administered FSH itself on an incrementally increasing

regime according to response (311), and the use of aro-

matase inhibitors which lead to increased pituitary FSH

secretion by negative feedback in response to the reduced

estradiol production (155, 197, 220–222). A systematic

review of the pharmacological interventions for women

with PCOS was performed in 2011 and updated in 2015,

and the ﬁndings are listed below (9, 341) (see TABLE 3).

The purpose of these therapies is to induce monofollicu-

lar ovulation in the anovulatory woman, or to overcome

a subtle progesterone deﬁciency in the luteal phase of the

menstrual cycle, under strict ultrasound and serial serum

estradiol assessment to ensure single follicle development

and adequate endometrial thickness, and to prevent con-

ceiving a multiple gestation (23). This approach often

requires the initiation of ovulation when the dominant

follicle size has reached 18 mm, by the use of exogenously

administered hCG, as an LH substitute, due to the close

homology of the beta chains (37). However, women with

PCOS may ultimately be required to undergo IVF treat-

ment, either as they have been unsuccessful with the

treatment to date or they are required to embark on IVF

FIGURE 3. Intra- and extra-ovarian factors that are as-

sociated with the pathology PCOS that may negatively

inﬂuence oocyte and subsequent embryo quality. [From

Qiao and Feng (237), with permission from Oxford Uni-

versity Press.]

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treatment as either their fallopian tubes are compromised

or their partner has suboptimal semen parameters. If a

woman embarks on IVF treatment, she is at particular

risk of developing an idiosyncratic reaction called ovar-

ian hyperstimulation syndrome (OHSS) (267).

OHSS is triggered by the systemic release of inﬂamma-

tory cytokines, particularly VEGF which leads to endo-

thelial cell damage and increased vascular permeability

and the rapid development of ascites, and potentially

pleural and pericardial effusion (338). OHSS is a signif-

icant cause of morbidity and in Australia and New Zea-

land is reported to complicate 0.6% of IVF cycles (206).

Adjuvant therapies that have been demonstrated to sig-

niﬁcantly reduce the incidence are the use of an GnRH

antagonist for pituitary downregulation (378), particu-

larly with the use of an GnRH agonist trigger (381), the

VEGF receptor blocker cabergoline (338), and by comb-

ing the ovarian stimulation with metformin administra-

tion (346). Other strategies include using low doses of

gonadotrophin drugs for stimulation or omitting com-

pletely (8), cancelling the IVF cycle prior to oocyte re-

trieval, omitting the gonadotrophin drugs for a few days–

“coasting” (75) and not proceeding to an embryo trans-

Table 2. Factors in serum and follicular ﬂuid of patients with PCOS with an impact on the quality of the oocytes and embryos, oocyte

fertilization, and the outcome of pregnancy

Factors Serum Level

Follicular

Fluid

Level

Oocyte

Quality

Fertilization

Rate

Embryo

Quality

Pregnancy

Rate

Activin 22

AMH 111or 21or ⬃or 21or ⬃1or ⬃

Epidermal growth factor 1

Fibroblast growth factor 1or 21or 2⬃or 2⬃⬃

Follistatin 11

Brain-derived neurotrophic factor 1

Bone morphogenic protein-15 11 1 1

Estradiol 222 2 2

Follicular ﬂuid meiosis-activating sterol 11 ⬃⬃

Growth differentiation factor-9 12

Homocysteine 112 2 2

Insulin-like growth factorsI&II 222

IGF binding protein 112

Interleukin-12 22 2 2

Interleukin-13 22 2 2

InhibinA&B 2or ⬃⬃

Corticotrophin releasing hormone 22

Leptin 112 2 22

Leukemia inhibitory factor 22 2 2 2

Malondialdehyde 112 2 2

Matrix metalloproteinase 2/9 1or ⬃

Nerve growth factor 1or 2

Renin 221 1 1

Resistin ⬃⬃⬃ ⬃ ⬃

Reactive oxygen species 12 2 2 2

Soluble Fas 222

sFas ligand 112

Superoxide dismutase 2or ⬃2or ⬃

Total antioxidant capacity 222 2 22

Testosterone 112

Tissue metalloproteinase1&2 2or ⬃

Tumor necrosis factor 112 2 22

Vascular endothelial growth factor 2or 12or 12 2or ⬃22

Visfatin 1⬃

1, Increases or positive impact; 2, decreases or negative impact; ⬃, similar; blank, no data. All data are as

compared with controls patients without PCOS. [Modiﬁed from Qiao and Feng (237), with permission from

Oxford University Press.]

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fer (so-called “freeze-all” approach) (284). A further

innovation is to use a different stimulation approach

called in vitro maturation of oocytes (IVM) where no

ﬁnal trigger for oocyte maturation is administered prior

to oocyte retrieval and oocyte maturation is performed in

the laboratory with some centers reporting similar preg-

nancy rates as their standard IVF approach (362) without

the risk of OHSS. The evidence for some of the therapeu-

tic interventions employed for women with OHSS is not

robust and hence for the prevention of OHSS clinicians

are advised to follow guidelines provided by con-

sensus statements after systematic review of the literature

(189).

The deranged metabolic environment frequently present in

women with PCOS is believed to lead to altered decidual

trophoblast invasion, placental development and endovas-

cular changes at the site of implantation (247), and in-

creased circulating markers of oxidative stress (229). Pro-

portionate to the degree of hyperinsulinemia and hyperan-

drogenemia, women with PCOS have abnormalities of

homocysteine metabolism (130), correctable with adequate

folate intake. Other systemic changes prevalent in women

with PCOS, inﬂuencing conception and miscarriage, are an

elevated serum plasminogen activator inhibitor-1 (124) and

an abnormal expression of some molecular markers with

the endometrium, including insulin-like growth factor

binding protein-1, glycodelin, homeobox protein (HOXA

10), and a endometrial progesterone resistance (53, 249,

295, 306). The consequences of this disturbed systemic and

endometrial environment is a reduced chance of concep-

tion, an increased risk of miscarriage, and in pregnancy a

predisposition to growth restriction, preeclampsia, and pre-

maturity (41, 87, 269).

C. Fallopian Tube Function

1. Disorders of ciliary action

The fallopian tube as a conduit for sperm and embryos

relies on effective cilial activity to perform these tasks. The

fallopian tube cilia can be affected by the environment,

mainly related to infection and inﬂammation; however, a

primary disorder of ciliary structure and function will also

lead to impaired tubal transport and a predisposition to

ectopic gestation implantation and subfertility. Primary cil-

iary dyskinesia (PCD) is associated with recurrent respira-

tory tract infections and potentially situs invertus. This is a

very heterogeneous condition as there exist many differing

structural and functional defects within the cilia, related to

as yet many unidentiﬁed genetic defects; however, over 20

genetic mutations related to axonemal-dynein function

have been identiﬁed (188) and in addition mutations within

the retinitis pigmentosa GTPase regulator on the X chro-

mosome have been found in men with this condition and

PCD. Due to the tissue speciﬁc expression of the multiple

genes responsible for PCD, not all women with the respi-

ratory phenotype of PCD have impaired fallopian tube

ciliary function, and spontaneous conceptions have been

reported (99).

Table 3. Pharmacological options for women with PCOS who are trying to conceive

Evidence Statement Level of Evidence

Clomiphene citrate should be the ﬁrst-line pharmacological therapy to improve fertility outcomes in women

with PCOS and anovulatory infertility, with no other infertility factors.

The risk of multiple pregnancy is increased with clomiphene citrate use, and monitoring is recommended. PP

Metformin should be combined with clomiphene citrate to improve fertility outcomes rather than

persisting with further treatment with clomiphene citrate alone in women with PCOS who are

clomiphene citrate resistant, anovulatory, and infertile with no other infertility factors.

Metformin could be used alone to improve ovulation rate and pregnancy rate in women with PCOS who

are anovulatory, have a body mass index ⫽30 kg/m, and are infertile with no other infertility factors.

If one is considering using metformin alone to treat women with PCOS who are anovulatory, have a body

mass index ⫽30 kg/m, and are infertile with no other infertility factors, clomiphene citrate should be

added to improve fertility outcomes.

Gonadotrophins should be the second-line pharmacological therapy. B

Laparoscopic surgery in women who are overweight or obese is associated with both intraoperative and

postoperative risks.

Letrozole, under caution, could be offered as a pharmacological treatment for ovulation induction

indicated for infertile anovulatory women with polycystic ovary syndrome with no other infertility factors.

A, body of evidence can be trusted to guide practice; B, body of evidence can be trusted to guide practice

in most situations; C, body of evidence provides some support for recommendation but care should be

taken in its application; PP, evidence not sought. A practice point has been made by the guideline

development group where important issues arose from discussion of evidence-based or clinical consensus

recommendations. Adapted from Evidence Based Guidelines for the Assessment and Management of

Polycystic Ovary Syndrome. Melbourne, Australia: Jean Hailes for Women’s Health on behalf of the PCOS

Australian Alliance, 2015.

ROGER J. HART

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Cystic ﬁbrosis (CF) is a condition characterized by ab-

normal mucus secretion due to being homozygous, or a

compound heterozygote, for one of the ⬎1,900 muta-

tions in the CF transmembrane regulator gene, limiting

chloride and bicarbonate secretion (3). In addition to the

associated symptoms of ovulatory disorder relating to

poor general health and low body fat levels, CF is asso-

ciated with female subfertility due to a direct effect on the

epithelial cells of the reproductive tract, although not

directly on cilial action. The thick cervical mucus impairs

sperm penetration, although it is believed that the effect

on the uterine cavity and the fallopian tube function is

less signiﬁcant (3), although the inﬂuence on bicarbonate

metabolism may lead to problems with sperm capacita-

tion within the fallopian tube (55).

2. Inﬂammatory disorders: endometriosis and

infection

Inﬂammation within the fallopian tube due to extrinsic

infection, salpingitis, or salpingitis isthimica nodosa

(nodular thickening or scarring of the fallopian tubes

within the isthmic fallopian tube) may lead to an activa-

tion of an inﬂammatory cascade via the innate immune

system, within the tubal ﬂuid and leading to fallopian

tube damage from the inﬂammatory response, and inhi-

bition of ciliary beat frequency (250). Salpingitis may

lead to distal occlusion of the fallopian tube and perma-

nent deciliation. The most common cause of salpingitis is

pelvic inﬂammatory disease (PID), due to sexually trans-

mitted infection. Hence, the risk factors for PID are mul-

tiple sexual partners, young age, smoking, and illicit

drugs (223). The most common infection agent is Chla-

mydia trachomatis (CT), and it is believed that genetic

polymorphisms within the Toll-like receptor genes may

increase the susceptibility to upper genital tract infection,

as not all women with cervical chlamydial infection will

have detectable infection within the endometrium and

fallopian tubes (223). CT appears to initiate a fallopian

tube inﬂammatory response via the innate immune in-

ﬂammatory response and also an adaptive T-cell re-

sponse (76), and ongoing chlamydial infection is com-

mon (204), leading to continued inﬂux of inﬂammatory

cells, damage to host epithelium, scarring, and ultimately

ﬁbrosis and progressive tubal scarring. Furthermore, CT

causes a direct cytotoxic effect on the fallopian tube mu-

cosa (204). With increased screening of young women by

cervical swabs for CT, and commencement of prompt

treatment of early cervical infection in most Western

countries, it is proposed that this will lead to a reduction

in the incidence of PID, and consequently fallopian tube

damage (244). Other fallopian tube pathogenic organ-

isms include Neisseria gonorrhoea, which was tradition-

ally the most common responsible pathogen in Western

countries. In many instances the pelvic infection and the

resulting fallopian tube damage may be exacerbated by

the anaerobic bacterial agents often associated with bac-

terial vaginosis (223).

Endometriosis is another pathological pelvic inﬂammatory

process that is known to inhibit ciliary beat frequency

(203), and in severe disease leads to signiﬁcant pelvic scar-

ring and pelvic anatomy distortion, and hence is associated

with doubling in the incidence of ectopic pregnancy (152),

in addition to the negative impact on endometrial receptiv-

ity (discussed later). PCOS has also been associated with a

doubling of the rate of ectopic pregnancies, although no

mechanism has been proposed (140).

3. Other gynecological conditions

Gross anatomical distortion of the fallopian tubes, either

due to extrinsic compression by large uterine ﬁbroids and

ovarian cysts, or by mechanical distortion of the fallopian

tube itself by severe adhesions, ﬁbrosis due to chronic in-

ﬂammation may lead to compromise of the fallopian tube

contractility and potentially cilial function. The implica-

tions of ﬁbroids for conception and the therapeutic options

for intervention have undergone systematic review (186),

and a summary of the most recent review of the literature is

listed in TABLE 4. The medical and surgical interventions for

women trying to conceive with endometriosis have under-

gone systematic review, and the overview published in 2014

(44) is summarized in TABLE 5.

Table 4. Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines for the management of ﬁbroids,

derived after systematic review of the literature

The majority of studies relate to the impact of ﬁbroids on fertility outcomes of women undergoing IVF treatment

1) Subserosal ﬁbroids (the majority of the ﬁbroid is on the exterior of the uterus) do not appear to have an effect on fertility outcomes.

2) Intramural ﬁbroids (within the muscle wall of the uterus) may be associated with reduced fertility and an increased miscarriage

rate; however, there is insufﬁcient evidence to determine whether myomectomy will improve fertility outcomes.

3) Submucosal ﬁbroids (a portion of the ﬁbroid is within the endometrial cavity) are associated with reduced fertility and an increased

miscarriage rate; hysteroscopic resection of submucosal ﬁbroids is likely to improve fertility outcomes. (Quality of studies is poor,

and further research is required.)

The size of the ﬁbroid, the number, and their location within the uterus may impact on the utility of myomectomy.

Adapted from the RANZCOG guidelines, on behalf of the CREI Consensus Expert Panel on Trial evidence group.

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D. Embryonic Development

The human embryo is prone to chromosomal errors dur-

ing development. It is believed that at the blastocyst stage

(reached at the 5th or 6th day after fertilization) that

three-quarters of embryos of a 30-yr-old woman will be

normal; however, at 40 years of age, only 40% are nor-

mal (109). The centrosome, responsible for the subse-

quent spindle and microtubule development within the

embryo, is derived from the sperm, hence men with sig-

niﬁcant impairment in spermatogenesis, and oligosper-

mia, may be responsible for higher rates of aneuploidy

(the gain or loss of whole chromosomes) within the sub-

sequent embryo (209, 339). However, the most common

cause of embryo aneuploidy is related to female age as the

oocyte has been in a stage of arrested meiotic develop-

ment in prophase since early fetal life, hence as a woman

ages and is exposed to reactive oxygen species within the

environment, there is a progressive loss of cohesion mol-

ecules that hold sister chromatids together, the incidence

of aneuploidy increases exponentially (114), particularly

the chiasmata proximal to the telomere (208). This is

exacerbated by deterioration in cytoplasmic mitochon-

dria and mRNA stores (369). This all leads to the subse-

quent substantial increase in the rate of miscarriage with

increasing age (FIGURE 4).

A signiﬁcant initiator of aneuploidy which is independent

of maternal age is the lack of chromosomal recombina-

tion in the fetal stages of meiosis. To prevent chromo-

some missegregation, it is essential that at least one cross-

over (recombination) is formed by recombination of each

Table 5. Medical and surgical interventions for women with endometriosis seeking fertility treatment

Intervention Inﬂuence of Intervention

Number of

Studies

Grade Quality of

Evidence Assessment of Studies

Ovulation suppression versus

placebo (4)

There is no evidence of beneﬁt in

the use of ovulation

suppression in subfertile

women with endometriosis

who wish to conceive.

11 (557

patients)

Low Lack of explanation for

allocation

concealment and

blinding.

Long downregulation of pituitary

with a GnRH agonist versus no

agonist (5)

The administration of GnRH

agonists for a period of 3–6

months prior to IVF in women

with endometriosis increases

the odds of clinical pregnancy

fourfold.

3 (165

patients)

Very low Included studies

lacked blinding and

explanation of

allocation

concealment. There

was some

imprecision.

Excisional versus ablative surgery

for endometriomata (3)

Excisional surgery for

endometriomata provides a

more favorable outcome than

drainage and ablation with

regard to subsequent

spontaneous pregnancy in

women. However, in women

who may subsequently

undergo fertility treatment,

insufﬁcient evidence exists to

determine the favored surgical

approach.

2 (88

patients)

Low Included studies

lacked blinding and

there was some

imprecision.

Laparoscopic ablation or excision

versus diagnostic laparoscopy

(2)

Laparoscopic surgery for mild

and moderate endometriosis

was associated with a doubling

live birth rate than diagnostic

laparoscopy alone.

3 (528

patients)

Moderate Two studies did not

adequately describe

randomization; one

study was at high

risk of attrition bias.

Extract adapted from Brown and Farquhar (44).

Spontaneous abortion, %

2220 2624 3028 3432 36 4038 4442 46 5048 5452

Patient Age

FIGURE 4. Spontaneous abortion rates for assisted reproductive

technology pregnancies conceived with freshly fertilized embryos by

source of oocytes used and maternal age. The solid line indicates

pregnancies conceived with the patient’s oocytes, and the dashed

line indicates pregnancies conceived with donor oocytes. [From

Schieve et al. (298), with permission from Wolters Kluwer Health,

Inc.]

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pair of homologous chromosomes (for review, see Ma-

cLennan et al., Ref. 208). It is estimated that ⬃30% of

Down syndrome births are as a result of lack of recom-

bination between homologous chromosomes 21, as the

most common chromosomes prone to lack crossover

within fetal oocytes are chromosomes 21 and 22 (58).

Furthermore, the distance from the centromere that the

single cross-over are located also determines the risk of

aneuploidy, and again appears independent of maternal

age. Chiasmata close to the telomere are at greatest risk

of being lost as there exists less cohesion between the

chromosomes predisposing to missegregation.

Embryonic mosaicism is a common ﬁnding resulting from

abnormal chromosome segregation either within meiosis or

mitosis due to 1) a failure of the process whereby microtu-

bules pull the divided chromosomes towards their respec-

tive spindles prior to cytokinesis and cell division “non-

disjunction”; 2) “anaphase lag” whereby a chromatid is not

incorporated into the nucleus during mitosis, thus creating

two-cell lines, one monosomic for the chromosome and the

other disomic for the chromosome; and 3) chromosomal

gain by “endo-replication” (339). A further process that

leads to a mosaic embryo is uniparental disomy where an

embryo has two copies of either a maternally derived or

paternally derived chromosome, rather than one from each

(339). The earlier in development that mosaicism develops,

the more signiﬁcant is the implication for the developing

embryo; however, it is possible that abnormal cells can be

forced away from the embryo, effectively being “selected

against” (330, 339).

The recent innovation of embryo morphokinetics using

time-lapse imaging systems for use with IVF laboratories

has enabled scientists to document abnormal embryonic

development (216). However, individual laboratories

will have differing culture systems, hence may have dif-

ferent ﬁndings, although the staging system proposed by

Meseguer is one of the most widely used (216). This

group demonstrated that the most predictive parameters

of embryo implantation potential were the time between

division to two cells and division to three cells, the time

between division to three cells and subsequent division to

four cells, and the time of division to ﬁve cells (114, 216).

They also demonstrated that the abnormal features of

uneven blastomere size at the two-cell stage and abrupt

cell division to three or more cells, and multi-nucleation

at the four-cell stage resulted in embryos that would not

implant. Incorporation of these features into a random-

ized controlled trial to improve IVF outcomes demon-

strated an increased on-going pregnancy rate and re-

duced miscarriage rate when embryos were selected using

this algorithm (287).

The abnormal embryo may also display an abnormal me-

tabolism that can be detected within the culture media

within the IVF laboratory, either by proteomics of the se-

cretome or by metabolomics to study the rate of consump-

tion of carbohydrates, oxygen, and amino within the cul-

ture media and consequently assist with improved embryo

selection during IVF treatment (114, 115).

E. Implantation

1. Systemic

It is generally believed that severe systemic illness, such as

sepsis or severe renal disease, will prevent embryonic im-

plantation, although infection is an unusual cause of early

pregnancy failure (315, 318). A comprehensive list of all

systemic conditions that have been demonstrated to have a

signiﬁcant negative inﬂuence on embryonic implantation is

difﬁcult to compile; however, conditions such as unstable

diabetes (64), subclinical hypothyroidism (356), periodon-

tal disease (144), and uncontrolled celiac disease (343) have

been demonstrated to reduce rates of conception, and it is

believed that low serum vitamin D (199) and active auto-

immune conditions (304) are also associated with a reduced

chance of conception, and strategies to control these condi-

tions may improve conception chances. Due to their high

prevalence and ease of correction of the abnormality, celiac

disease and subclinical hypothyroidism are discussed fur-

ther.

2. Celiac disease

In a population of women experiencing unexplained infer-

tility or recurrent miscarriage, celiac disease is ﬁve times

more prevalent than in the general population (343). A

meta-analysis of patients with celiac disease found that the

risk of miscarriage is 40% greater with increased risks in the

pregnancy for growth restriction and premature delivery,

and the effect is tempered if a gluten-free diet is observed

(343).

3. Subclinical hypothyroidism

Overt thyroid disorder must be appropriately managed

prior to conception; however, more subtle perturbations in

thyroid function are also associated with reproductive dis-

order. Approximately 1 in 25 women have subclinical hy-

pothyroidism, and thyroid antibodies are present in up to

one in eight of women (153). The presence of thyroid anti-

bodies in a woman with normal thyroid function is believed

to be associated with difﬁculty conceiving, recurrent im-

plantation failure of embryos, and early pregnancy loss,

potentially due to an unrecognized thyroid hormone deﬁ-

ciency or due to a potential autoimmune cause (359). Treat-

ment of subclinical hypothyroidism is believed to poten-

tially improve embryo development and is recommended

for women prior to conception; however, whether to treat a

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woman prior to conception, who is euthyroid in the pres-

ence of thyroid antibodies, is contentious (77).

4. Thrombophilia

It has been unclear whether an inherited thrombophilia

leading to microthrombi within the decidua are associ-

ated with implantation failure of the embryo as the inter-

villous spaces are not developed until 10 wk of gestation

(164). Although it is tempting to speculate that perturba-

tions in the clotting system may inﬂuence implantation

and early embryonic development, for example, factor

XII gene expression is increased in endometrial stromal

cells during in vitro decidualization, this is believed to

lead to an activation of the kallikrein-kininogen-kinin

system during the implantation of human embryos (175).

Furthermore, plasminogen activator inhibitor (PAI-1) is

a signiﬁcant regulator of the thrombotic/ﬁbrinolytic pro-

cess in early pregnancy and is elevated in insulin resistant

women with PCOS (17). Other changes within the clot-

ting process around the time of embryo implantation are

an increase in tissue factor, an activation of the extrinsic

coagulation cascade, and an increase in requirement for

methylation from folic acid. Hence, inherited abnormal-

ities of the clotting system such as the prothrombin gene

mutation, factor V Leiden, methyltetrahydrofolate re-

ductase (MTHFR), and protein S and C and anti-throm-

bin III would be expected to have a signiﬁcant inﬂuence

on implantation and the early pregnancy (164). Although

the appropriate treatment is not clear, except for women

with the anti-cardiolipin syndrome, where appropriate

treatment must commence at conception is widely ac-

cepted (274).

Due to the effect of heparin on modulating endometrial

receptivity and potentially improving implantation, in

addition to its inhibition of factor Xa and thrombin, it

has been proposed as a treatment for women with im-

plantation failure undergoing IVF treatment (264). Hep-

arin reduces the expression of E-cadherin and promotes

trophoblast invasion and proliferation into the endome-

trial cells potentially improving implantation (95). A sys-

tematic review of women with recurrent implantation

failure undergoing IVF demonstrated that use of adjunct

low-molecular-weight heparin improved live birth rates,

and the rate of miscarriage was substantially reduced

compared with the control group (264). The authors ad-

vised caution with the interpretation of the results due to

the low numbers in the studies.

5. Natural killer cells

There has been substantial interest in the assessment of

blood and uterine natural killer cell populations in

women with poor embryo implantation (305). Evidence

would appear to suggest that women with unexplained

implantation failure may have an abnormal population

of natural killer (NK) cells in the blood and in the endo-

metrium in the mid-luteal phase of the menstrual cycle

(293), although strategies to improve the systemic and

endometrial environment to facilitate conception have

not been proven (305).

6. Endometrial and myometrial (endometriosis,

leiomyomas, hydrosalpines, PCOS, obesity,

endometrial polyps)

As evidenced by IVF success rates, embryonic implantation

potential is decreased in the presence of endometriosis (25),

leiomyomas (145), dilated fallopian tubes (hydrosalpines)

(332), and PCOS (346) and have been linked to reduced

endometrial expression of HOXA10 and HOXA11 (48). In

addition, women with endometriosis have reduced expres-

sions of endometrial integrin

␣

␤

and LIF, hypermethyl-

ation leading to silencing of the HOXA10 gene and endo-

metrial progesterone resistance (48) leading to a reduction

in the chance of conception which may potentially be im-

proved by surgical intervention (90) or by use of prolonged

downregulation with a GnRH analog prior to the initiation

of an IVF cycle (291). Similarly to integrin

␣

␤

expression

normalizing with surgical intervention in the presence of

endometriosis (200), the surgical removal of hydrosalpin-

ges (salpingectomy) will restore the expression of integrin

␣

␤

and LIF improving conception (332). Leiomyomas are

common benign smooth muscle tumors of the myome-

trium, if they distort the endometrial cavity, a submucosal

leiomyoma, implantation may be inhibited by a purely me-

chanical method. However, leiomyomas located in the

body of the uterus (myometrium), intramural leiomyomas,

may also mechanically inhibit conception implantation, but

overlying endometrial atrophy and an altered endometrial

environment has been demonstrated (48). Surgical inter-

vention is believed to improve implantation potential for

women with a submucosal leiomyoma; however, the case

for treating small intramural leiomyomas to improve con-

ception has yet to be proven (186). Due to the estrogenic

stimulation required for the growth of leiomyomas, it has

been speculated that their growth may be associated with

environmental estrogenic stimulation, such as bisphenol A

(BPA) (309); however, an observational study of the expo-

sure to BPA, phthalates, and ﬁve ultraviolet ﬁlters was un-

able to conﬁrm any direct association (262).

The endometrium of women with PCOS is abnormal as it is

exposed to lower levels of serum progesterone in the luteal

phase, the consequences of ovulatory disorder prevalent in

women with PCOS. Furthermore, the endometrium is po-

tentially exposed to elevated levels of serum IGF-I and se-

rum androgens (140). Elevated IGF-I can lead to endome-

trial hyperplasia and a predisposition to endometrial malig-

nancy; however, in contrast, the high serum androgens,

often present in women with PCOS, can induce endometrial

atrophy and amenorrhea. In addition, there is an increase in

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estrogen receptor

␣

, an increase in 17

␤

hydroxysteroid de-

hydrogenase type 1, and a reduction in type 2 (promoting a

greater local concentration of estradiol), in association with

a degree of progesterone resistance promoting endometrial

hyperplasia and leading to a decrease in fertility (306). In

women with PCOS, there is a decreased endometrial secre-

tory phase expression of selectins, integrin

␣

␤

, and

HOXA10 reducing the implantation potential of an em-

bryo (306). A compounding factor for many women with

PCOS is obesity which has a synergistic effect to reduce the

chance of conception (29), leading to a greater perturbation

in endometrial gene expression (29), as demonstrated by the

association of an increase in BMI being associated with a

reduced chance of conception using the oocyte donor model

(81) [for a review, see Schulte et al. (302)]. However, life-

style interventions with diet and exercise will lead to alter-

ations in endometrial gene expression (348), although it is

not clear whether the improved conception rates noted due

to lifestyle interventions are due to an endometrial effect, an

oocyte effect, or a combination of both.

Common benign overgrowths of the endometrium known

as endometrial polyps may interfere with sperm transport

and embryo implantation to mechanically inhibit concep-

tion, but they may promote the abnormal expression of

markers of implantation; upon surgical removal of the en-

dometrial polyps, documented increases in endometrial se-

cretion of IGFBP-1, TNF-

␣

, and osteopontin have been

noted, assisting implantation (31).

7. Embryonic

With the advent of genetic testing of blastomeres from em-

bryos of women undergoing IVF treatment, it has become

evident that a signiﬁcant cause of embryos failing to implant

is due to chromosomal rearrangements developing within

the embryo as described above (114). With the ability to

perform a low-resolution genome-wide survey of either sin-

gle blastomeres from a three-day-old embryo or by the

study of several cells from the trophectoderm of a ﬁve- or

six-day-old blastocyst, it has become evident that in addi-

tion to the common occurrence of aneuploidy within the

embryo, usually arising during meiosis, the embryo is pre-

disposed to segmental chromosomal imbalances (372)

which arise during programmed DNA breakage and repair

by homologous recombination during prophase I of meiosis

(360). These rearrangements may lead to a failure to de-

velop and implant, but also lead to phenotypic variability

and hence ultimately genome evolution [for a detailed de-

scription of the origin of chromosomal rearrangement, see

Voet et al. (360)]. Hence, in IVF programs the majority of

apparently morphologically normal embryos fail to implant

as aneuploidy is such a frequent occurrence, occurring more

frequently in an older woman, and a woman with a history

of failed embryonic implantation (371).

A less frequent cause of unsuccessful embryo development

and implantation, or implantation then subsequent early

pregnancy failure, is the prevalence of a chromosomal

translocation within either one of the couple trying to con-

ceive. The prevalence of a chromosomal translocation

within a couple with a history of failed implantation under-

going IVF treatment is 1.4%, substantially less than the

4.1% prevalence within couples with a history of recurrent

miscarriages (329), but signiﬁcantly greater than the 0.2

and 0.3% prevalence in neonatal and general infertility pa-

tients, respectively (329). Chromosomal translocations

within a phenotypically normal prospective parent can be

either a balanced reciprocal translocation, whereby there is

an mutual exchange of genetic material from the distal end

of two different chromosomes, or a Roberstonian translo-

cation, wherein there is a fusion of the long arm of two of

the acrocentric chromosomes (chromosomes 13, 14, 15, 21,

and 22) and a resulting loss of the short arms. In both

instances, the gametes resulting from these chromosomes

can be “balanced” containing the appropriate amount of

genetic material, or “unbalanced” and contain an excess or

deﬁcit of genetic material leading to miscarriage or a risk of

congenital malformations in the offspring.

F. Early Pregnancy Failure

The causes of early pregnancy failure overlap with the

causes of embryo implantation failure and hence are not

reiterated here. The discussion is limited to a description of

possible associations of genetic variations which may inﬂu-

ence implantation and predispose to early pregnancy loss.

1. Genetic polymorphisms

Genetic polymorphisms associated with recurrent early

pregnancy loss suggest that genes regulating oxidative stress

may be involved (353). Single nucleotide polymorphisms of

genes associated with oxygen free radical metabolism,

ABCB1,COMT,GPX4, and OGG1, have been reported to

lead to a doubling of the risk of recurrent miscarriage (177).

In addition, polymorphism of genes that regulate the com-

plement cascade, such as membrane cofactor protein and

C4 binding protein, have a putative role in recurrent early

pregnancy loss (353). HLA-G, part of the major histocom-

patibility complex class I group, has been linked to the

success of IVF and is believed to have an immune modula-

tory role, and potentially lower expression of HLA-G is

associated with reduction in embryo implantation and early

pregnancy failure (353).

MTHFR is responsible for the synthesis of 5-methyltetra-

hydrofolate required to allow the conversion of homocys-

teine to methionine. Patients with the 677TT genotype are

reported to have up to a threefold increased risk of recur-

rent early pregnancy loss (233).

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Due to the putative belief that an imbalance of the tolerant

[T helper cell1 (Th1)] over the prorejection [T helper cell 2

(Th2)] cytokines within the adaptive immune system for

women predisposed to reproductive failure these cytokines

have been studied. Of note, Th1 cytokines include IL-2 and

interferon-

␥

(INF

␥

), and Th2 include IL-4, IL-5, IL-6, IL-

10, and IL-13. Several haplotypes leading to a reduction in

serum IL-18 levels have been associated with a signiﬁcant

increase in recurrent early pregnancy loss (4).

IV. LIFESTYLE INFLUENCES INFLUENCING

OVULATION, FALLOPIAN TUBE

FUNCTION, IMPLANTATION, AND

MISCARRIAGE

A. Delayed Childbearing

It is well established that oocyte quality deteriorates with

advancing reproductive age, in addition to an increase in

ovulatory disorder, a reduction in ovulatory frequency, an

impaired luteal phase and also premature recruitment of

follicles, all leading to reduced conception rates.

1. Ovulatory frequency

As a woman ages, in line with a progressive reduction in

follicle number, there is a progressive reduction in ovula-

tory frequency. This situation is also applicable to the

woman with premature ovarian insufﬁciency where there is

a reduction in functioning granulosa cells, leading to a re-

duction in secretion of inhibin B, further leading to a reduc-

tion in pituitary feedback there is an increase in late follic-

ular phase and then early follicular phase FSH secretion

(45, 46). This may lead to premature initiation of follicular

recruitment and early ovulation, or if there are no follicles

to recruit, a low rise in inhibin B and estradiol and a pro-

longed anovulatory menstrual cycle. Further follicular de-

pletion leads to an increase in the frequency of anovulatory

cycles. One study demonstrated that in the last 10 cycles

before the menopause, approximately only one-third of the

cycles will be ovulatory (190). The consequent impact on

the chances of conception are the fact that that with prema-

ture follicular recruitment the timing of intercourse may be

more difﬁcult to plan and with impaired estradiol and pro-

gesterone secretion by the corpus luteum in the luteal phase,

“luteal phase insufﬁciency” (245), there will be a further

impediment to embryo implantation, often compounded by

a poorer quality oocyte.

2. Oocyte quality

The deterioration in oocyte quality is related to a predispo-

sition to the generation of aneuploid embryos caused by

chromosomal segregation errors and abnormal spindle de-

velopment, epigenetic modiﬁcations (120), and a deteriora-

tion of the oocyte cytoplasm (ooplasm), related to a de-

crease in mitochondria, a reduction in their quality and an

increase in oxidative stress within the ooplasm (2), which

can lead to promote free radical formation leading to the

modiﬁcation of intracellular proteins, lipids, and nucleic

acids macromolecules (92) and alterations in mRNA (108).

Consequently, female fertility starts to rapidly decline in a

woman beyond 37 years of age, as manifest by the success

rates of IVF treatment (206) and also by measures of natu-

ral fertility (192). The causes of the age-related decline in

embryo quality are detailed below.

A)ANEUPLOIDY. As described previously as the woman’s age

increases, the chiasmata more proximal to the telomere be-

come more susceptible to missegregation as there is believed

to be less cohesion between the sister chromatids, due to an

age-related loss in cohesin and shugoshin cohesions pro-

teins, as they are produced in fetal life and deteriorate with

time and exposure to reactive oxygen species (ROS) (136,

208). Another reported peculiarity of the human oocyte is

the slow meiotic spindle formation compared with the

mouse, and consequent predisposition to spindle instability

and anaphase lag whereby due to slow segregation of the

chromosomes an aneuploid chromosomal constitution may

arise upon cytokinesis (154). Furthermore, a reduction in

supply of ATP from a progressive reduction in mitochon-

drial function will lead to a reduction in spindle formation,

microtubular activity, and polar body extrusion, promoting

aneuploidy.

B)OOCYTE MITOCHONDRIAL FUNCTION. Mitochondria are ma-

ternally inherited, and the oocyte has the largest number of

mitochondria (⬃200,000) and copies of mitochondrial

DNA (mtDNA) of any cell. They are essential ROS scaven-

gers and for the generation of ATP for the cellular processes

including cortical granule extrusion, polar body formation,

spindle formation, chromosome segregation, and cytokine-

sis. As the selection of mitochondria and mtDNA during

oocyte development is a random process, the possibility

arises for the ampliﬁcation of mutated mtDNA during

oocyte maturation and mitochondrial expansion (32).

Upon fertilization mtDNA replication ceases, leading to a

progressive dilution of mtDNA within the blastomeres dur-

ing embryonic development, until blastulation when repli-

cation can resume. A reduced pool of mtDNA within the

oocyte has been associated with a reduced fertilization po-

tential (276) and also a reduced ovarian reserve (213). Fur-

thermore, ageing is associated with an adverse effect on the

mitochondria [reviewed by Schatten (297)], leading to an in

increase in mtDNA damage and mutations with mtDNA,

structural abnormalities with the mitochondria, a reduction

in ATP synthesis, and an increase in ROS production (57,

297). Putative methods to improve mitochondrial function

are the oral administration of CoQ10 (32), an electron

transporter involved in the transport of electrons within the

respiratory chain within the mitochondria (32), to assist

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mitochondrial function or even to introduce donor ooplasm

to “rejuvenate” an oocyte. In the area of embryonic screen-

ing within IVF cycles, it is now feasible to combine an

assessment of aneuploidy within the blastocyst with an as-

sessment of mtDNA content within blastomeres by mi-

croarray analysis (183).

C)EMBRYO METABOLISM. Evidence from animal studies sug-

gest that the metabolism of the developing embryo may

differ according to the age of the mother, as there were

measured differences in the embryo culture media of em-

bryos generated from older mice, compared with those gen-

erated from younger mice (212). If this is translated into

humans, this may lead to a reduced implantation potential

for such embryos independent of aneuploidy. In this murine

model, the offspring were growth restricted, which if repli-

cated in humans may have signiﬁcant implications for the

child’s long-term health and development (212). To date,

there is limited data to suggest an adverse outcome for

children born from IVF (146). However, these children may

be predisposed to cardiometabolic disorder, which is also

associated with a fetus not reaching its growth potential

(157), which is an interesting observation in view of these

animal model ﬁndings, as IVF conceived children tend to be

born to a population of older mothers than naturally con-

ceived children (146).

D)EPIGENETIC ALTERATIONS. There is some evidence of an

alteration in DNA methylation patterns within oocytes de-

rived from older female animals (120), and there is one

report of an alteration of DNA methylation patterns within

metaphase II oocytes derived from women over 38 years of

age compared with women under 35 years of age (133), and

there are reports of a reduction in histone protein deacety-

lation in the metaphase I and II surplus oocytes derived

from older women (355), and an alteration in the expres-

sion of ubiquilin in metaphase II oocytes (131). Hence, the

consensus view is that oocytes derived from older women

may be at risk of epigenetic modiﬁcation (120).

3. Fallopian tube function

The incidence of ectopic pregnancy increases as a woman

ages, although it is unclear whether this is directly related to

an age-related change in fallopian tube function (273).

B. Dietary Restriction and Over-exercise

As described earlier, an alteration of food intake can have

profound effects on the complex interplay of hormones re-

leased by the gastrointestinal system and neuropeptides in-

ﬂuencing follicular development (97). It is well established

that calorie restriction and excessive exercise lead to a re-

duction in the frequency of ovulation, poor endometrial

development, amenorrhea, and subfertility, with even rec-

reational levels of activity potentially leading to abnormal-

ities of gonadotrophin secretion and ovulatory disorder

without inducing amenorrhea (79). This is due to a suppres-

sion of the hypothalamic-pituitary ovarian axis, due to a

reduction in the systemic stimulatory signals of GnRH re-

lease. As described previously, an alteration of food intake

can have profound effects on the complex interplay of hor-

mones released by the gastrointestinal system and neuro-

peptides inﬂuencing follicular development (97). Interest-

ingly, body weight in late adolescence is an important pre-

dictor of fecundity in later life, as women within the Nurses’

Health Study (117) who were underweight at 18 years of

age (BMI under 18.5 kg/m

) took an average 25% longer

than normal weight women at 18 years of age to conceive,

suggesting adolescence is a critical time for the program-

ming of the reproductive axis.

The negative consequences of exercise on the chance of

conception are demonstrated by an observational study of

women undergoing their ﬁrst IVF cycle which showed that

women who exercised for four or more hours per week

were 40% less likely to have a live birth, twice as likely to

have implantation failure, and were more likely to miscarry

(227).

1. Leptin

Leptin is of particular importance in the regulation of the

reproductive axis, as evidenced by restoration of gonado-

trophin secretion with recombinant leptin administration

to over-exercising and underweight women leading to a

restoration of LH pulsatility, ovulation, and menstrual cy-

clicity (364). As adequate GnRH secretion is essential for

normal gonadotrophin secretion, a perturbation in GnRH

pulsatility may lead to impaired ovulation, inadequate

maintenance of a corpus luteum, and hence may predispose

a woman to infertility and early pregnancy loss (337), and

appropriate weight gain may lead to restoration of ovula-

tory cycles (111).

2. Insulin

Circulating concentrations of insulin are related to adipos-

ity, and concentrations are lower in amenorrheic and regu-

larly exercising women with functional hypothalamic

amenorrhea (FHA), and are associated with a reduction in

leptin secretion, although insulin does not have a direct

action on GnRH pulsatility as GnRH neurons do not ap-

pear to express insulin receptors.

3. Gherlin

Ghrelin secretion from the gastrointestinal tract is maximal

when the stomach is empty, it has an inhibitory effect on LH

secretion, and serum levels are greater in regularly exercis-

ing (78), underweight (113), women with functional hypo-

thalamic amenorrhea with abnormal eating habits (300)

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leading to disordered ovulation as a consequence of the LH

suppression.

4. Protein YY

Protein YY (PYY) infusion in humans is an appetite sup-

pressor (28), and although animal studies suggest a degree

of sexual dimorphism in the response to PYY, it is believed

that in humans the action of PYY is suppressive on the

reproductive axis (65). Interestingly, in adolescent girls

with anorexia nervosa, the fasting concentrations of PYY

have been reported to be three times greater than those of

girls without anorexia, suggesting that PYY may play a role

in the suppression of appetite and the suppression of the

reproductive axis (219).

C. Stress

Due to central neuronal corticotrophin releasing hormone

(CRH) projection to GnRH cells and CRH-induced

␤

-en-

dorphin inhibition of GnRH secretion, stress may exert a

modulating effect on subsequent pituitary LH and FSH pul-

satility (33, 60), which may be overcome by modiﬁed be-

havior restoring ovulation (35). Higher daily reported stress

levels in a cohort of normal healthy women were associated

with a reduction in serum estradiol, LH, and luteal phase

progesterone concentrations as well as a predisposition to

anovulation (299). Furthermore, while it is known that an

elevated serum cortisol concentration is related to FHA,

women with FHA who resume ovulation have serum corti-

sol concentrations similar to eumenorrheic women, sug-

gesting that by reducing stress levels by therapeutic inter-

ventions normal ovulation may return (34). The Nurses’

Health Study demonstrated that working longer hours

(over 40 h/wk) and also lifting heavy loads were associated

with increased time to conceive, suggesting a relation to

tiredness or stress may impact upon conception (116).

D. Obesity

Women who are overweight are less likely to ovulate (240)

and spontaneously conceive (256), and upon conception,

they have an increased risk of miscarriage and are predis-

posed to an adverse pregnancy outcome (15). Obesity ap-

pears to alter the follicular ﬂuid environment (282), the

ooplasm of the oocyte, and leads to a reduction in fertiliza-

tion and impairs embryonic development (92). Evidence

derived from mouse models would suggest that obesity

leads to slower growth and delayed maturation of the

oocyte, epigenetic modiﬁcations, increased granulosa cell

apoptosis, and mitochondrial dysfunction within the

oocyte (92, 327, 380). Hence, maternal obesity may exert

germ-line effects by affecting oocyte quality and the meth-

ylation of imprinted genes, and in the mouse model, this has

led to altered methylation patterns within metabolism-re-

lated genes in the oocytes and the liver of the offspring of

obese mice (72, 118). From mouse studies it has been dem-

onstrated that maternal obesity leads to a deterioration in

blastocyst development compared with matched controls;

this effect can be overcome by intervention (218). To help

to determine whether there is an element of harm inﬂicted

on the oocyte or embryo by exposure to metabolic derange-

ment rather than the intrauterine environment, in an ele-

gant series of experiments, embryos were transferred from

diabetic mice (377) or mice that had been fed a high-fat diet

(202). In this study the embryos that were transferred from

the diabetic mice were more prone to develop intrauterine

growth restriction and congenital malformations, and

when the oocytes from the high-fat diet fed mice were ana-

lyzed, there was a greater incidence of oocyte aneuploidy

and mitochondrial damage (202, 377). A retrospective hu-

man study also demonstrated phenotypic differences in

oocyte morphology, embryonic metabolism, and the rate of

embryonic development in embryos derived from over-

weight women (195).

Population data suggest that obesity is associated with ad-

verse obstetric outcomes such as preeclampsia, gestational

diabetes, premature delivery and stillbirth (303), and con-

genital malformations in the offspring (331). Although it is

believed that an improvement in obstetric and neonatal out-

comes may be achieved by weight loss (13), not all studies

agree (135). The use of bariatric surgery for obesity treat-

ment is associated with a reduced rate of gestational diabe-

tes and large-for-gestational-age infants. However, it is as-

sociated with an increase in the incidence of small-for-ges-

tational-age infants, a shorter pregnancy, and potentially an

increased risk of stillbirth or neonatal death. Despite the

potential concern for nutritional deﬁciencies after bariatric

surgery, a recent study reported that there was no signiﬁ-

cant effect of bariatric surgery on the overall risk of con-

genital malformations (168); however, a delay in attempt-

ing to conceive for at least a year post surgery is a recom-

mendation (132).

In the Nurses’ Health Study (117), every 5 kg increase in

body weight from the age of 18 years of age was associated

with a 5% increase in the median time to conceive, but

women who gained more than 20 kg since 18 years of age

took on average an extra 1.4 months to conceive, compared

with women who maintained their weight. Interestingly, of

particular detriment to conception was being underweight

at 18 years of age but overweight at the time of attempt to

conceive, where this led to a doubling of the time to con-

ception (117), similar to data derived from the Danish Birth

Cohort (272).

Several studies demonstrate the beneﬁt of weight loss as

part of a structured weight loss program upon the chance of

conception for overweight women, and also as part of their

IVF treatment (61, 314). In a systematic review of 11 stud-

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ies that met the search criteria weight loss on the outcome of

subsequent IVF treatment, losing weight by either diet and

lifestyle changes (7 studies), nonsurgical medical interven-

tions (1 study), or bariatric surgery (2 studies) led to a

signiﬁcant increase in the natural conception rate, an in-

crease in the number of embryos available for transfer as

well as the subsequent pregnancy rate, and a decrease in the

miscarriage rate (314). Due to the difﬁculty in completing

such studies, the overall quality of the studies was reported

as weak, although all interventions led to signiﬁcant im-

provements in pregnancy or live birth rates in overweight or

obese women, with several studies reporting an improve-

ment in spontaneous pregnancy rates. Due to the heteroge-

neity within the studies, a quantiﬁcation of the beneﬁt was

not possible; however, the greatest improvements in out-

comes was reported for women embarking on a multidisci-

plinary structured program of dietary and lifestyle interven-

tion (314).

Of particular importance in relation to obesity is that

women with PCOS, which is characterized by hyperinsulin-

emia and hyperandrogenism (231), are particularly predis-

posed to weight gain (340), exacerbating their risk of ob-

stetric, perinatal, and neonatal complications in addition to

an increase in congenital malformations (87). In general,

women with PCOS are at a greater risk of miscarriage than

women without features of PCOS; in addition, they are at

greater risk of gestational diabetes, preeclampsia, and pre-

mature labor in pregnancy, and the perinatal mortality rate

is greater for infants born to women with PCOS (87, 139).

In later life, women with PCOS were twice as likely to have

a non-injury-related hospital admissions, three times more

likely to develop type II diabetes, four times more likely to

be obese, and were signiﬁcantly more likely to have cere-

brovascular and cardiovascular disease, suffer a thrombo-

embolic event, and have a hospital admission for a mental

health condition than a woman without a diagnosis of

PCOS (139). Furthermore, as it is believed hyperinsulin-

emia is present in 75% of lean women with PCOS and 95%

of overweight women with PCOS (328), the reproductive,

metabolic, and psychological consequences of PCOS are

further exacerbated by weight gain (231).

Overweight women take longer to conceive through natural

conception (166), and overweight women who require IVF

treatment to conceive are less likely to conceive and more

likely to miscarry than women of normal weight (279). The

ideal way to determine whether the negative inﬂuence of

obesity on conception is related to a negative inﬂuence on

the oocyte or to the endometrium is to use the egg donation

model. Whilst one large retrospective study of young nor-

mal weight oocyte donors demonstrated a negative trend

upon conception related to an increasing BMI amongst re-

cipients (30), a recent systematic review of six data sources

demonstrated that there was no negative inﬂuence of obe-

sity upon implantation, clinical pregnancy, miscarriage

rate, and live birth (169). This may suggest the primary

inﬂuence may relate more to oocyte quality rather than an

endometrial effect. To study this thoroughly, a study con-

trolling for the body mass index of the donor is required.

The effect of obesity on the endometrium is to alter the

expression of over 150 endometrial genes, primarily related

to transcription and biosynthesis, to reduce the chance of

conception (29). The beneﬁt of preconception intervention

was demonstrated in an RCT of a preconception structured

lifestyle modiﬁcation program for women with PCOS, in-

cluding a combination of calorie restriction, weight loss

medication, and exercise, that led to a signiﬁcant improve-

ment in metabolic features, ovulation rates, and trend to-

wards an increased live birth rate (198).

Obesity is associated with an increased risk of miscarriage

in women undergoing IVF treatment (279), although as

described above this may primarily be due to an oocyte

effect, rather than an endometrial effect. However, in over-

weight women with PCOS, it is believed that integral to the

endometrial defect is insulin resistance leading to decreased

expression of

␣

␤

3 integrin, HOXA10, and IGFBP-1 and

increased androgen receptor expression (302), leading to an

increased risk of miscarriage [for review, see Schulte et al.

(302)]. Consequently, therapies to address the insulin resis-

tance such as weight loss (61), and use of the insulin sensi-

tizer metformin (248), have been employed to reduce the

risk of miscarriage. The practice guidelines from the system-

atic review of the nonpharmacological interventions for

women with PCOS was performed in 2011 and updated in

2015 and the ﬁnding are listed in TABLE 6 (9, 341).

E. Cigarette Smoking

Cigarette smoking has a profound effect on fertility for both

the male and the female (80, 270); despite this, many

women continue to smoke while attempting to conceive and

even when undergoing IVF treatment (127). In one study, if

both partners smoked, the woman’s chance of conceiving

was one-ﬁfth of those couples where neither partners

smoked; despite this, the authors cite data that 20% of

women in the United States are believed to smoke in the 3

months prior to starting to try to conceive (263). For a

cigarette smoking woman, all aspects of fertility are im-

paired (80), as the smoke contains heavy metals, polycylic

hydrocarbons, nitrosamines, and aromatic amines (80, 86)

[for review, see Dechanet et al. (80) and Camlin et al. (49)].

1. Ovarian function

In animal models cigarette smoking leads to a depletion of

primordial follicles (49), further loss of follicles throughout

folliculogenesis, impaired cumulus oocyte complex expan-

sion (361) and impaired granulosa cell function, granulosa

cell steroid production, impaired oocyte meiosis (49), and a

predisposition to aneuploidy within the oocyte (201). It is

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unclear how these translate for the woman that smokes

cigarettes while attempting to conceive; however, it is

known that smoking leads to a reduction in ovarian reserve

and an advancement of the age of menopause for the

woman (167, 301), potentially due to the inﬂuence of poly-

cyclic hydrocarbons which are activated into more toxic

metabolites by the liver (49, 271). Further human studies

have demonstrated that oocytes derived from cigarette

smoking women undergoing IVF treatment have a greater

number of immature oocytes (385), an increased thickness

of the zona pellucida (310), with follicles containing higher

level of markers of oxidative stress within the follicular ﬂuid

(252), and within the cumulus (316).

Women embarking on an IVF cycle have a reduced ovarian

response if they had been recent cigarette smokers (112).

With the use of the smoking mouse model, the ovaries of

cigarette smoke-exposed mice were smaller, contained

fewer primordial and primary follicles, and resulted in

fewer oocytes at the time of ovulation (321).

2. Fallopian tube function

Smoking is the main lifestyle and environmental agent that

negatively inﬂuences fallopian tube function. Rhesus mon-

key and mouse studies suggest that smoking exposure re-

duces fallopian tube blood ﬂow (224) and smooth muscle

contraction (234), impairs ﬁmbrial oocyte collection (181)

and tubal motility, and reduces the number of ciliated cells

within the fallopian tube and their beat frequency [reviewed

by Shao et al. (307)]. Human studies of fallopian tube func-

tion are challenging to perform; however, it is believed that

there is a close similarity between the rodent and human

fallopian tube physiology assisting with our understanding

of fallopian tube physiology (307). However, it is still un-

clear what is the cause of an ectopic embryo implantation,

as it may be mechanical due to obstruction, due to a change

in fallopian tube histology, or an abnormal expression of

hormone receptors within the tube (307). Indeed, it is be-

lieved that smoking more than 20 cigarettes a day increases

the risk of a fallopian tube ectopic gestation fourfold (43,

100). This epidemiological evidence, combined with the

many animal studies, of the inﬂuence of cigarette smok-

ing on fallopian tube function suggests that the agents, or

their metabolites, within cigarette smoke are a substan-

tial contributing cause of female infertility and ectopic

gestation (80).

3. Fertilization and embryonic development

The effects of cigarette smoking exposure on the oocyte

of women undergoing IVF treatment appears to consist

of the development of a thicker zona pellucida compared

with nonsmokers (310), a potential cause of the reported

reduction in fertilization rate with IVF (185), and de-

layed embryo morphokinetic cleavage events in couples

undergoing ICSI treatment (110), which as previously

discussed may reduce embryo implantation. Further-

more, the oocyte derived from a cigarette smoking

woman may have delayed maturation and be at risk of

meiotic errors (385), leading to an increased risk of the

development of an aneuploid embryo (384). Rodent

studies also suggest slower rates of embryonic develop-

ment with reduced cell numbers and implantation rates

upon exposure to cigarette smoke (224).

Table 6. Lifestyle management for women with PCOS who are trying to conceive: recommendations after systematic review

Evidence Statement Level of Evidence

Lifestyle management, including diet and exercise programs, should be used throughout the life span

in women PCOS to optimize health generally and to alleviate PCOS clinical severity including

infertility.

In women with PCOS and body mass index ⫽30 kg/m with due consideration given to age-related

infertility, intensive (frequent multidisciplinary contact) lifestyle modiﬁcation alone (and not in

combination with pharmacological ovulation induction therapy) should be the ﬁrst-line therapy for

3–6 months to determine if ovulation is induced.

Pharmacological ovulation induction should not be recommended for ﬁrst-line therapy in women with

PCOS who are morbidly obese (body mass index ⫽35 kg/m) until appropriate weight loss has

occurred either through diet, exercise, bariatric surgery, or other appropriate means.

Pharmacological ovulation induction could be second-line therapy, after intensive lifestyle modiﬁcation

has been undertaken.

Morbid obesity increases risks during pregnancy and should be regarded as a relative

contraindication to assisted fertility.

Psychological factors should be considered and managed in infertile women with PCOS, to optimize

engagement and adherence with lifestyle interventions.

C, body of evidence provides some support for recommendation, but care should be taken in its application; PP,

evidence not sought. A practice point has been made by the guideline development group where important

issues arose from discussion of evidence-based or clinical consensus recommendations. Adapted from

Evidence Based Guidelines for the Assessment and Management of Polycystic Ovary Syndrome. Melbourne,

Australia: Jean Hailes for Women’s Health on behalf of the PCOS Australian Alliance, 2015.

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4. Implantation

It is widely believed that cigarette smoking has a detrimen-

tal effect on implantation, as the recipient in an oocyte

donation program will have less chance of conceiving if she

smokes, proportionate to the amount of cigarettes smoked

(319). With the use of animal models and cultures of human

endometrial cells, the effect of inhalation of cigarette smoke

upon the endometrium can be analyzed (80). It appears that

the inﬂuence of cigarette smoke may lead to anti-estrogenic

effects on the developing endometrium, altered angiogene-

sis within the endometrium, inﬂuence on trophoblast inva-

sion, and altered gene expression within the endometrium

(80). The actual inﬂuences are determined by the individual

compounds and the dose to which the endometrium is ex-

posed. Human placental trophoblastic cell lines exposed to

compounds within cigarette smoke have been reported to

lead to altered expression of epidermal growth factor (387),

matrix metalloproteases (121), alterations of hCG secretion

(40), L-selectin expression (383), in addition to increased

apoptosis, altered cellular architecture, and reduced cy-

totrophoblast invasion (80, 122). Cigarette smoking

women are exposed to high levels of cadmium and lead, and

these metals have been found within the endometrium of

cigarette smokers, correlating with the number of cigarettes

smoked and the duration of smoking (289).

5. Miscarriage

Smoking is believed to increase the risk of miscarriage by

⬃1% per cigarette smoked (258), with the overall adjusted

relative risk of miscarriage being 1.23, with a nonsigniﬁcant

increased risk of miscarriage associated with passive smok-

ing (258). The cause of the increased miscarriage risk is

likely to be multifactorial. One large study that analyzed the

effect of cigarette smoking on the miscarriage of chromo-

somally normal conceptions demonstrated a tendency to-

wards an increased likelihood of miscarriage in this group

(179), suggesting an endometrial effect in addition to the

potential for an increased risk of aneuploidy described

above (384).

F. Periodontal Disease

There is increasing evidence of an association of poor oral

health with a number of clinically important medical con-

ditions (370). Periodontal disease is a chronic infectious and

inﬂammatory disease of the gums and supporting tissues

and has been associated with cardiovascular disease, type 2

diabetes, respiratory disease, kidney disease, and adverse

pregnancy outcomes (105, 235, 312, 313, 370). It is be-

lieved that up to 10% of the population have severe peri-

odontal disease. Several studies suggest that successful

treatment of periodontal disease may alter or modify in-

ﬂammatory markers (74) and improve endothelial and vas-

cular function after therapy (345), and it is believed to be a

modiﬁable factor that may lead to improvements in long-

term health (235, 344). An observational study of the prev-

alence of periodontal disease in pregnant women suggested

that periodontal disease may also be a factor limiting a

woman’s time to conceive (143). The mechanism proposed

was that it caused a low-grade inﬂammation reducing em-

bryo implantation, as pregnant woman with periodontal

disease took, on average, an extra 2 mo to conceive, a

negative inﬂuence on conception of the same order of mag-

nitude as obesity.

In summary, the main lifestyle factors that may have a neg-

ative impact on a woman’s fertility are smoking and obe-

sity. Fortunately, evidence suggests that smoking cessation

will improve the chance of conception, and embarking on a

supervised weight loss program will improve the chances of

conceiving for the overweight woman. Unfortunately, the

age-related decline in oocyte quality for a woman leads

many women to seek fertility treatment using an oocyte

donor. Potential future interventions of ovarian rejuvena-

tion may offer some of these women in the future alterna-

tive options.

V. ENVIRONMENTAL INFLUENCES

AFFECTING

It is suspected that potentially the most signiﬁcant of the

common environmental inﬂuences that may impact upon

female fertility relate to endocrine disrupting chemicals

(EDCs). EDCs are ubiquitous chemicals that interfere with

hormone action, and almost all pregnant women in the

United States have measurable quantities within their bod-

ies (375). Evidence derived from environmental disasters

where toxic chemical have leaked into the environment has

demonstrated that permanent changes can occur to the en-

docrine system and conﬁrms that environmental chemicals

can act as EDCs. However, for many years there has been

substantial controversy around the subject of environmen-

tal EDCs at lower levels of environmental exposure, as

many stakeholders have been involved in investigating the

subject, often with potential for bias, for example, the

chemical industry has a vested interest in proving safety,

and in contrast the media have at times generated sensa-

tional reports. The Endocrine Society published an updated

systematic review in 2015 that endeavored to analyze the

literature in a very balanced manner with regard to any

potential conﬂict of interest of the investigators, any ten-

dency towards negative or positive ﬁndings bias (depending

on the source of funding for the research), and being mind-

ful of the extrapolation of animal studies to the human

situation (125).

EDCs have numerous potential mechanisms of actions in

addition to traditional receptor activation and generally do

not have a predictable dose-response curve, and the same

chemical may have agonistic or antagonistic properties at

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different concentrations and at different sites. Furthermore,

they are frequently additive with other EDCs, of which

there are believed to be in excess of 800 chemicals, and also

they may have several active metabolites, and the effect

of the EDC may depend on the timing of exposure (26,

392). Consequently, it is often difﬁcult to determine the

properties of many substances with potential endocrine dis-

rupting actions. EDCs interfere with the action of hormones

either at a hormone receptor or they may alter the number

of hormone receptors within a cell, and if these inﬂuences

happen at a critical stage of development, the changes may

be permanent. Due to single-nucleotide polymorphisms,

some individuals may be more susceptible than others. In

addition, it is possible that some EDCs may cause epigenetic

changes leading to a transgenerational effect by DNA meth-

ylation, histone modiﬁcation, and inﬂuence on micro-RNA

expression (125). A further complicating factor when ana-

lyzing the effects of EDCs is that the EDC may act on the

receptors of several hormones, and depending on the levels

of exposure studied, the outcome may vary as each organ

may have a different threshold for disruption (125). To

study the endocrine disrupting nature of a substance in the

United States, the Endocrine Disruptor Screening Program

employs two series of assays (Tox21 and ToxCast) to study

thousands of chemicals and their signaling pathways.

Animal studies offer several advantages when studying the

effects of EDCs as many biological processes are conserved

across several species; furthermore, they enable the investi-

gator to control the dosing of exposure, the timing of expo-

sure, limit any interference from other chemicals and con-

trol for many variables, and potentially perform the study

over a relatively short period of time. However, the limita-

tions of using animals as experimental subjects are that the

action in the animal may differ from their actions on hu-

mans. Many EDCs have additive effects, and this may am-

plify the effect of the particular chemical studied which may

not be evident in an animal study. In addition, replicating

the “human timing of exposure” or “window of vulnera-

bility” in animal studies can be difﬁcult, and in animal

studies it may be required to use higher doses of an EDC for

a shorter period of time, rather than prolonged low level of

exposure as is often found in the human situation (374).

Therefore, it is believed that observational human studies

may provide useful epidemiological data; however, chal-

lenges that may be faced are that the particular EDC expo-

sure may be difﬁcult to identify and quantify and may be

reliant on human recall, plus eliminating confounding fac-

tors may be difﬁcult in a long-term epidemiological study

(374).

The main endocrine disrupting chemicals are BPA, the

phthalates and their esters, the pesticide Atrazine, and the

polychlorinated biphenyls (PCBs) and DDT/DDE. They are

brieﬂy described below, and their actions are described in

greater detail where they inﬂuence fertility.

1) BPA is a synthetic chemical widely used in the manufac-

ture of plastics and resins for many years, and the main

route of exposure is within the diet and through transder-

mal contact. In many countries its use in the manufacture of

plastic bottles has been phased out. However, BPA along

with phthalates are frequently measurable within urine

(182), serum (141), follicular ﬂuid (187), umbilical cord

blood (162), and the amniotic ﬂuid (162). Of particular

concern was the ﬁnding that the amniotic ﬂuid concentra-

tions of BPA were ﬁve times greater than serum, presumably

due to fetal renal clearance (162). The methods of action of

BPA are that it can bind to the nuclear receptors for ER

␣

and ER

␤

, with differing afﬁnities for each which may lead

to differing agonist/antagonist responses, although it is be-

lieved that the majority of its action is through other mech-

anisms, such as through intracellular signal transduction

pathways independent of the nuclear hormone receptors,

modiﬁcation of cytochrome P-450 enzyme expression

and activity, alterations in the level and activity of sex

hormone binding globulin, and epigenetic modulation by

the silencing of promoters by methylation [for review, see

Wetherill et al. (365)]. In addition, BPA is believed to

impair mitochondrial function and promote oxidative

stress in high doses in rat studies (178). It is reported that

more BPA is produced than any other chemical with ⬃15

billion pounds produced in 2013 (125). Interestingly, the

United States Environmental Protection Agency safety

level is set at 50

␮

g·kg

⫺1

·day

⫺1

, whereas the European

Food Safety Authority tolerable daily intake is 4

␮

g·kg

⫺1

·day

⫺1

. However, it is reported in the The Endo-

crine Society’s Second Scientiﬁc Statement on Endocrine-

Disrupting Chemicals that BPA is believed to have effects

at or below these levels (125).

2) Phthalates and their esters are plasticizers to provide

ﬂexibility to materials and are present widely within the

home and hospital environment and are also used in per-

sonal care products, such as cosmetics. As they are nonco-

valently bound, they leach into the environment and they

are detectable and hence they are ubiquitous within the

environment (125).

3) Many pesticides have been suspected of being EDCs.

Atrazine is a widely employed herbicide used in commercial

crop growing in the United States, is persistent with its

metabolites in ground and surface water for many years,

and is detectable within drinking water (125).

4) PCBs were banned in 1979; however, they bioaccumu-

late within the environment and are stored in body fat, and

some PCBs have thyroidogenic, estrogenic, and antiandro-

genic actions (125).

5) DDT is an insecticide with a long half-life which was

widely used prior to being banned in the United States in

1972 due to being linked to several cancers, and as with

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PCBs, DDT is persistent within the environment due to its

long half-life and bioacumulates in fat (125). The conse-

quences of substances that are stored in fat tissue are often

difﬁcult to determine, as the measurable levels in the blood

are low, however, the substances may be released rapidly

within the body during periods of weight loss.

The effects of EDCs on reproduction has recently under-

gone an updated systematic review by the Endocrine Society

and published in October 2015, and several summary state-

ments are derived from this review (125).

A. Folliculogenesis and Ovulation

1. Premature ovarian insufﬁciency

Environmental causes of premature ovarian insufﬁciency

(POI) are not well deﬁned, other than being related to che-

motherapy and radiotherapy; however, the potential for in

utero or other early life exposure to gonadotoxic chemicals

to lead to POI in later life is a possibility, although no

common environmental chemicals or EDCs have been dem-

onstrated to conclusively lead to POI (36, 125, 141). Al-

though there is evidence from a series of studies performed

on rats that a mixture of estrogenic EDCs (phthalates, pes-

ticides, chemical ultraviolet ﬁlters, bisphenol A, parabens),

exposed from day 7 of gestation to 22 days postnatally, may

lead to a reduction in the frequency of estrous in the rats,

there was no signiﬁcant difference in ovarian weight or

follicle count in this short study (163).

2. Inﬂuences on follicular development and ovulation

A)ENDOCRINE DISRUPTORS.I) BPA. With regard to folliculo-

genesis, animal studies suggest that maternal BPA exposure

may lead to disorders of meiosis in the female offspring,

increasing the risk of oocyte aneuploidy and abnormal pri-

mordial follicle development and progression through fol-

liculogenesis (160, 386).

The multiple purported effects of BPA during early stages of

oogenesis and the ﬁnal stages of maturation (metaphase I

and metaphase II) from human and animal studies are dem-

onstrated in FIGURE 5.

Studies using culture of murine ovarian tissue demonstrate

that, at exposure levels found in Chinese children, BPA may

lead to a premature activation of folliculogenesis ultimately

leading to a reduced follicular pool (388). Similar studies

have been performed in vivo using mice, rats, sheep, and

monkeys (see TABLE 7); however, there is limited data avail-

able on the effects of BPA on ovarian development and early

folliculogenesis in humans (125). Animal studies suggest

that early life exposure to BPA at higher doses appears to

accelerate the follicular development leading to cystic folli-

cles and reducing the antral follicle pool, but at lower doses

decreases all follicle stages both in in vivo animal studies

and in cultures of ovarian cells [summarized by Gore et al.

(125)].

The negative inﬂuence of BPA upon follicular growth is

believed to have several mechanisms: interference with the

aryl hydrocarbon receptor, alteration of cell cycle regula-

tors, and altered steroidogenesis (253). In animal studies

BPA-induced follicular atresia is associated with increased

markers of apoptosis (253). These animal studies appear to

be corroborated in human studies of the antral follicle count

of 209 women undergoing a fertility assessment, where

there was an association of a higher urinary BPA concen-

tration with a lower antral follicle count (326).

Both BPA and phthalates are believed to have a modulat-

ing effect on hypothalamic-pituitary action in animal

studies (52), and it is hypothesized that BPA may be

FIGURE 5. The effects of bisphenol A during early stages of oogenesis and the ﬁnal stages of maturation

(metaphase I and metaphase II). [From Machtinger and Orbvieto (207), with permission from Elsevier.]

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associated with a premature activation of the hypotha-

lamic-pituitary-ovarian axis and be related to premature

pubertal development (52).

Depending on the dose and the species studied, BPA is

believed to have several points of action to interfere with

steroidogenesis (125). Associations of higher serum BPA

have been linked with a lower estradiol response in

women undergoing IVF treatment, suggesting a negative

impact on ovarian steroidogenesis (39, 94), and in-

creased urinary concentrations of BPA have been associ-

ated with lower antral follicle counts in women undergo-

ing IVF treatment (326). Although, seemingly in con-

trast, BPA exposure has also been associated with PCOS

(1, 26, 172, 288); however, it is unclear whether this is a

causal relationship as higher serum androgen concentra-

tions are associated with delayed clearance of BPA (52),

as the ﬁnding of an increased follicular count is in direct

contrast to Souter et al. (326).

With regard to PCOS, BPA is probably the most studied

of the environmental endocrine disrupters. BPA has been

demonstrated in vitro to increase in adipocyte differenti-

ation in human and mice cell culture (42), stimulate rat

ovarian theca cells to synthesize testosterone (390), and

induce insulin resistance in offspring of rats exposed in

pregnancy (325). How these in vitro studies and the use

of animal models relate to human programming of the

disease is unclear, particularly as the “window” of expo-

sure that may program PCOS is unknown due to the

difﬁculties in studying transgenerational effects in hu-

mans. However, it is believed that the most likely vulner-

able period of exposure is in utero and the ﬁrst few years

of life (26). The reasoning proposes that animal studies of

Table 7. Effects on oocytes of prenatal and postnatal BPA exposure

Study Sample Dose

Route of

Administration Time of Exposure Results

Zhang et al. (386) Pregnant mice 0.02, 0.04, 0.08

kg body

⫺1.

day

⫺1

Oral route 12.5–18.5 day

post-coital

Inhibition of meiotic progression

to prophase I in 0.08 BPA-

treated group; decreased

mRNA expression of speciﬁc

meiotic genes; inhibition of

germ cell cyst breakdown

Hunt et al. (160) Pregnant rhesus

monkeys

400

␮

kg body

⫺1.

day

⫺1

Tubing implants GD 50–100, GD 100

to term

Disturbances in prophase

events; increase in MOFs

Susiarjo et al. (335) Pregnant mice,

offspring

400 ng/day Pellets

releasing

BPA

GD 11.5–17.5 Aberrant meiotic prophase;

increased aneuploidy in eggs

and embryos from adult

females

Rivera et al. (280) Lambs 50

␮

⫺1.

day

⫺1

Subcutaneous

injections

PND 1–14 Decreased ovarian weight;

increased primordial-to-

primary follicle transition;

increased incidence of MOFs;

increased number of small

antral atretic follicles

associated with higher p27

expression

Karavan et al. (173) Mice 10, 100

␮

g/day Subcutaneous

injections

PND 1–4 Increased incidence of MOFs;

increased total number

oocytes; increased

percentage of primordial

follicles

Rodriguez et al. (283) Rats 0.05, 20

⫺1.

day

⫺1

Subcutaneous

injections

PND 1–7 In BPA 20 group stimulation of

neonatal initial follicle

recruitment; p27 and ER

␣

increased expression;

increased proliferation rate of

granulosa cells

Chao et al. (56) Mice 20, 40

␮

g/kg Subcutaneous

injections

PND 7–14, PND 5–20

(every 5 days)

Decreased methylation pattern

of two maternal imprinted

genes; upregulated mRNA

expression of ER

␣

; decreased

primordial follicle number but

increased primary,

secondary, and antral follicle

number; abnormal spindle

assembling in meiosis

From Caserta et al. (52).

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exogenous androgen exposure and human evidence of in

utero growth restriction with subsequent catch-up

growth, leading to the subsequent development of fea-

tures of PCOS and the metabolic syndrome, suggest that

a period of vulnerability exists at this time to individuals

who may have a genetic predisposition to PCOS (26,

246). Indeed, with the use of both high- and low-dose

exposures to BPA in early postnatal life, a rodent model

of PCOS has been developed (103). From animal studies

of BPA exposure at levels of exposure found in humans,

animals tend to accrue body fat, leading to metabolic

derangement, and develop impaired ovarian function

(26), although human data are not clear (125). It is im-

portant to note that a signiﬁcant vehicle of BPA exposure

is transdermal; hence, larger individuals will tend to have

greater exposure leading to an assumption of an associ-

ation with obesity, rather than potentially being an arte-

fact of an increased surface area. It is also important to

note for substances with a high degree of transdermal

absorption that since an infant has the greatest surface

area-to-volume ratio, it will receive a greater exposure

relative to height than an adult. No epidemiological stud-

ies of early life BPA exposure into adulthood have yet

been performed, although studies suggest serum BPA

concentrations are increased in the presence of PCOS in

adulthood after controlling for BMI (172), as serum BPA

correlates to BMI; however, this association does not

demonstrate causality as, for example, the excretion of

BPA may be impaired in PCOS and hence its concentra-

tion would be artiﬁcially elevated.

II) Phthalates. There is limited information on the effects of

phthalates on follicular development. Animal studies sug-

gest that DEHP, MEHP, and DBP induce follicular arrest

and atresia in cultured rat and mice cells [summarized by

Gore et al. (125)]. Limited human data exist, although by

measuring the metabolites of phthalates in stored maternal

blood, our group demonstrated a trend toward an earlier

menarche in Western Australian girls, a degree of hypogo-

nadism with a reduction in early follicular phase serum FSH

associated with the phthalate metabolite MEHP (141). Of

particular concern was the ﬁnding that maternal exposure

to MEP, widely found in cosmetics, was associated with a

reduction in their daughters’ serum AMH in adolescence, a

marker of antral follicles (ovarian reserve) and granulosa

cell function (141). In addition, higher MEP exposure was

associated with a reduced prevalence of PCOS in adoles-

cence and reduced antral follicle count (141). A similar

ﬁnding was observed in a small study of patients with PCOS

where lower urine concentrations of mBP and mBzP were

detected in women with PCOS (352). Several in vivo and in

vitro studies have been performed on animals with phtha-

late exposure, and exposure, particularly to DEHP and

MEHP, appears to impair estradiol, progesterone, andro-

stenedione, and testosterone production [summarized by

Gore et al. (125)].

III) Pesticides. Methoxyclor (MXC) is a pesticide and an

insecticide; hence, it is present in food and water and has

been used as a replacement for dichlorodiphenyltrichloro-

ethane (DDT), and it has been reported to inhibit the re-

sponse to ovarian stimulation in mice (96), and also induces

apoptosis in baboon antral follicles by activation of the

aryl-hydrocarbon and estrogen receptor and by the activa-

tion of apoptotic cascade and via oxidative stress [summa-

rized by Gore et al. (125)]. In mice, it inhibits steroidogen-

esis at multiple points in the steroidogenic pathway, leading

to a reduced antral follicle production of estradiol, testos-

terone, and androstenedione (27). Some of the other pesti-

cides that have been studied in animals and are suspected to

have an adverse effect upon folliculogenesis include endo-

sulfan, malathion, cypermethrin, carbamate, imidacloprid,

fenvalerate, triﬂuralin, bifenthrin, and diurin, and it is sug-

gested that pesticides may alter gene expression, impair fol-

licle growth, induce atresia, and reduce oocyte quality and

impair steroidogenesis [summarized by Gore et al. (125)].

Atrazine has been associated with menstrual cycle length

irregularity, as women who drunk more than 2 cups of

unﬁltered Illinois water (where atrazine is widely used and

detectable in the drinking water) were up to six times as

likely to have menstrual irregularity as women who did not

drink the water (69), suggesting a disruption of the ovula-

tory menstrual cycle.

IV) Persistent environmental contaminants. 2,3,7,8-Tetra-

chlorodibenzo-p-dioxin (TCDD) is a dioxin and a wide-

spread persistent environmental pollutant. It has inhibitory

inﬂuences upon pubertal timing, ovarian steroidogenesis,

folliculogenesis, and ovulation in several species (165, 253),

although human data on the effect of TCDD upon repro-

duction is limited. In mice studies, TCDD and PCBs reduced

ovarian weight and induced follicular atresia (261). Al-

though, in contrast, a small observational study reported

that PCOS subjects, where antral follicle counts are usually

increased, had higher serum concentrations of some persis-

tent environmental pollutants, perﬂuorooctanoate and per-

ﬂuorooctane sulfonate (352); however, associations do not

demonstrate causality.

V) Phytoestrogens. Genistein is a phytoestrogen present in

soy, lentils, and chickpeas and appears to either promote or

inhibit follicular development on the rat ovary, depending

on the dose, strain, and age to promote, and inﬂuence sex

steroid production within the follicle and activate apoptosis

(253).

For a detailed description of the effect of environmental

exposures in ovarian function, readers are directed to Bhat-

tacharya and Keating (36) and Patel et al. (253). Trichloro-

ethylene (TCE) is commonly found in adhesives and lubri-

cants. Both TCE and its metabolites led to a reduction in

fertilization of mouse oocyte (68). Exposure to 7,12-dim-

ethylbenz[a]anthracene (DMBA), found in cigarette smoke

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and car exhaust fumes, leads to a loss of mouse or rat

follicles at all stages of development (161), and exposure to

DMBA led to altered expression of genes regulating follic-

ular development (322). A common by-product of pesti-

cide, rubber, plastic, and ﬂame retardant manufacture is

4-vinylcyclohexene (VCH). In animal studies, VCH de-

stroys primordial and small primary follicles leading to

ovarian failure (156).

B)HEAVY METALS. Heavy metals are resistant to degradation

and hence may persist in the environment for many years.

Potentially their concentration may be ampliﬁed by bioac-

cumulation within the food chain, particularly individuals

with high ﬁsh intake which may be at risk of exposure to

mercury. Some of these metals are essential for life in low

concentrations, but highly toxic in higher concentrations,

such as copper, chromium, manganese, and zinc, although

cadmium, lead, mercury, and the metalloid arsenic are non-

essential and are toxic (290). Women are exposed to these

chemicals through inhalation, drinking contaminated wa-

ter, or eating food contaminated by exposure or by bio-

accumulation. With the use of mercury-based dental amal-

gams, dental technicians may have greater exposure than

the general population as measured by urinary excretion of

the metal and are potentially at risk of a dose-dependent

reduction in fecundability for a woman actively trying to

conceive (286), as are women who have a high ﬁsh intake in

their diet (11). However, the evidence for normal environ-

mental mercury exposure interfering with ovulation is lim-

ited (59). Despite this, it is advised that women trying to

conceive should avoid processed and “fast food” and min-

imize exposure to mercury until completion of breast feed-

ing by avoiding large ﬁsh such as shark, king mackerel, and

tileﬁsh (238).

Evidence exists for some heavy metals to have a potential

epigenetic modiﬁcation inﬂuence on various cultured cell

lines (290), inﬂuencing DNA methylation leading to gene

inactivation loss of acetylation and increasing histone

methylation (12) as well as activating apoptosis, and ar-

senic is known to disrupt the cell cycle (12, 104). In

women undergoing IVF treatment, higher mercury expo-

sure has been associated with altered methylation pat-

terns within CpG sites within whole blood, and cadmium

exposure has been linked to altered methylation patterns

in Andean women from Argentina, suggesting that these

laboratory-observed inﬂuences on epigenetic modiﬁca-

tions may occur at concentrations present within the en-

vironment.

A major source of exposure to heavy metals is derived from

cigarette smoking, as the tobacco plant accumulates cad-

mium and lead from the soil and the serum concentrations

of these heavy metals have been correlated to the brand and

the number of cigarettes smoked (14).

B. Fallopian Tube Function and Inﬂammatory

Disorders

1. Endocrine disrupting chemicals

Due to the estrogen responsive nature of the development of

endometriosis, researchers have extensively studied the as-

sociation of endometriosis and endocrine disrupting chem-

icals. Dioxin exposure (47, 324) and exposure to the a

phthalate BzBP metabolite and its metabolites MBz, P and

the DEP metabolite MEP may be associated with increased

risk of endometriosis (63), although BPA exposure was not

linked in an epidemiological study of women with endome-

triosis (350). One large cross-sectional study from the

United States demonstrated an association of MBP with an

increased risk of endometriosis (366), and another did not

conﬁrm the associations of phthalate exposure with endo-

metriosis and demonstrated that MEHP had an inverse as-

sociation with the presence of endometriosis (351). Serum

levels of the organochlorine pesticide

␤

-hexachlorocyclo-

hexane have been associated with endometriosis in a cohort

of women undergoing surgical exploration for the disease

(349), and dioxin and dioxin-like compounds have for

many years been believed to be associated with the devel-

opment of endometriosis. However, the literature is con-

ﬂicting (320), although a small study that performed anal-

ysis of adipose tissue at the time of laparoscopic surgery

demonstrated an association between adipose concentra-

tions of dioxin and PCBs and the presence of endometriosis

at the time of surgery (211).

C. Embryonic Development

1. Teratogens

While not the focus of this fertility review, it is important to

mention teratogens. Teratogens are agents that an individ-

ual may be administered or self-administered, or be exposed

to in pregnancy, or around the time of conception, that may

cause a structural or functional defect to the fetus (101).

Hence, the most common preconception teratogen is prob-

ably being overweight or obese, as being overweight leads

to an increase in the incidence of neural tube defects as well

as cardiac and oro-facial abnormalities for the offspring

(101). Furthermore, the use of fertility drugs themselves and

IVF have been linked to an increase in congenital abnormal-

ities in the children born (137). Consequently, it is essential

that a treating physician aims to ensure a woman trying to

conceive is as healthy as possible at the time of conception

and she should aim to keep the use of over-the-counter and

prescribed medications in pregnancy to a minimum.

In addition to medication exposure, teratogens can consist

of infections, such as syphilis, rubella, and cytomegalovirus

exposure. They may be caused by metabolic disturbance,

such as diabetes, and may be a physical insult such as ra-

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diotherapy or exposure to a chemotherapeutic agent. How-

ever, the most common teratogens are physician-prescribed

medications, as up to two-thirds of women in the United

States are prescribed drugs in pregnancy (251). Further-

more, as the most critical window of exposure is the ﬁrst

trimester, often before the woman recognizes she is preg-

nant, it is imperative that a doctor is vigilant to this factor in

treating a woman of reproductive age and prescribes med-

ication sparingly and also manages chronic medical condi-

tions such as thyroid disorder and diabetes in an optimal

manner to reduce the fetal exposure to teratogenic medica-

tion and also to the harm of an unstable systemic illness.

The Federal Drug Administration describes drugs accord-

ing to their teratogenicity by ascribing a category (A, B, C,

D, and X), and this is readily available to clinicians for their

reference.

2. Pollutants

Organochlorine pollutants, such as polychlorinated biphe-

nyls and DDT, are persistent within the environment and

within the body and have been speculated to be associated

with an increased time to conceive for women, although this

has not been veriﬁed (170). Furthermore, review of the

literature did not demonstrate any association with oocyte

quality, fertilization rate, embryo development, or ulti-

mately the pregnancy rate for women embarking on IVF

treatment (170). Human and animal studies demonstrated

impaired steroidogenesis in granulosa cells exposed to BPA

(52), and this is borne out by women with higher serum

BPA concentrations undergoing IVF treatment whereby

they have a lower peak estradiol concentration and reduced

oocyte yield (39, 94). A recent study of hair mercury con-

centrations, a marker of dietary ﬁsh intake, in women un-

dergoing IVF treatment did not ﬁnd a relationship between

mercury levels and ovarian responsive to stimulation,

oocyte fertilization rate, embryo development, and preg-

nancy rates (376).

D. Implantation

1. Endocrine disrupting chemicals

An environmental exposure assessment of 501 couples try-

ing to conceive in the United States did not determine a

relationship between exposures to BPA and 14 phthalate

metabolites in the urine on the length of time it took a

couple to conceive, although this does not suggest that any

exposures were not in some way inﬂuencing early embry-

onic development.

A)BPA. In animal studies, BPA exposure has led to a signif-

icant reduction in embryo implantation (379). Exposure to

BPA is believed to lead to a downregulation of HOXA10

expression (217), with IVF embryo implantation failure be-

ing more common in women with higher urinary BPA levels

(93). A United States study of women with unexplained

miscarriage demonstrated that those with a serum conju-

gated BPA concentration in the highest quartile were almost

twice as likely to miscarry as those women in the lowest

quartile. The authors hypothesized that the cause was due

to a negative inﬂuence of BPA upon the endometrium or

early placentation (193), and BPA exposure has also been

associated with a predisposition to with recurrent miscar-

riage (334, 389).

B)PHTHALATES. There are conﬂicting reports on the associa-

tion of urinary and follicular ﬂuid levels of phthalates and

conception, although DEHP exposure has been associated

with increased time to conception and miscarriage in mice

studies [summarized by Gore et al. (125)].

C)PESTICIDES. Exposures to higher levels of the pesticides

DDT and DDE have been associated with subfertility and

increased risk of miscarriage in observational studies from

countries with a high environmental exposure [summarized

by Gore et al. (125)].

2. Heavy metals

Mercury does not appear to be teratogenic within the con-

centrations expected due to occupational exposure (149),

and in a study of women undergoing IVF treatment, total

hair mercury was measured and the concentration did not

correlate with any IVF treatment outcome, response to

ovarian stimulation, oocyte fertilization, embryonic devel-

opment, pregnancy rate, or live birth rate when controlled

for confounders (376).

3. Other environmental exposures

Flight attendants and health workers using ionizing radia-

tion may be at increased risk of exposure to radiation

through their work (10, 38), which may have a detrimental

impact on the developing embryo and potentially increase

the risk of miscarriage; hence, employers should develop

guidelines for the occupational exposure to ionizing radia-

tion for pregnant women.

There is also the possibility that environmental exposure to

excessive noise may have detrimental effects upon and im-

plantation and increase the risk of miscarriage (278).

In summary, there is extensive evidence derived from ani-

mal studies of a negative inﬂuence of environmental chem-

icals on many aspects of female fertility: follicular number,

ovulation, meiosis, and embryo implantation; however, the

evidence of such negative associations in humans is often

lacking and contradictory. Further epidemiological studies

may assist in the clariﬁcation of these associations. How-

ever, the inherent difﬁculty with human studies lies with the

varying human exposures, often over many years of poten-

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tial exposure, potential intergenerational inﬂuences and the

multiple confounding variables that are present when

studying fertility in a population.

VI. CONCLUSION

This review aimed to provide an overview of the processes

involved in conception, embryo implantation, and embry-

onic development. It provided an insight into the patholog-

ical conditions that may impair these processes and result in

a couple having difﬁculty conceiving and discussed revers-

ible lifestyle and environmental factors that may impact on

conception.

ACKNOWLEDGMENTS

Address for reprint requests and other correspondence: R. J.

Hart, School of Women’s and Infants Health, The Univer-

sity of Western Australia, King Edward Memorial Hospital,

374 Bagot Rd., Subiaco, Perth Western Australia 6008

(e-mail: roger.hart@uwa.edu.au).

DISCLOSURES

The author is the Medical Director of the IVF unit Fertility

Specialists of Western Australia and is a shareholder in

Western IVF.

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COVID-19 PANDEMIC AFFECTS STRESS LEVELS, LIFESTYLE, OBESITY AND MENSTRUAL REGULARITY IN FEMALE STUDENTS DURING STUDY FROM HOME

Conference Paper

Full-text available

Oct 2022

The Indonesian government has socialized social distancing policies, physical distancing and "large-scale social restrictions" in response to the COVID-19 pandemic. The policy's implementation shifts all activities to the home affecting stress, lifestyle, obesity and menstrual regularity. The goal of this study was to look at how the COVID-19 pandemic affected stress, lifestyle, obesity and menstrual regularity in female students who were studying from home. This study was carried out at STIKES Karya Husada Kediri in July- August 2020. Cross sectional observational research of an analytical nature. This study's sample consisted of 243 female students from STIKES Karya Husada Kediri who met the inclusion and exclusion criteria using stratified proportional random sampling. The questionnaires used in this study were analyzed using the Wilcoxon Ranks Test and the McNemar Test. The findings of this study revealed that during the COVID-19 pandemic, female students' stress levels (p=0.000) and lifestyle (p=0.000) increased, while obesity (p=0.023) and menstrual regularity (p=0.021) decreased. Therefore, the results of this study can be considered to create a student mental and reproductive health service program at Karya Husada Health Center (KHHC) and improve counseling guidance services in helping to overcome academic problems to minimize the impact experienced by female students due to the COVID-19 pandemic which can lead to reproductive health problems in the future.

Nano-encapsulated senolytic cocktail attenuates germ cell senescence in female mice

Article

Full-text available

Apr 2025
CELL MOL LIFE SCI

Low-quality oocytes directly affect fertilization and embryonic development, contributing to infertility in women, while germ cell senescence leads to reduced germ cell numbers and decreased egg quality. Dasatinib and quercetin (D and Q), as senolytic drugs, have been extensively explored in different age-related diseases. However, their effects on in vitro cultured senescent oocytes and the molecular mechanisms underpinning ovarian aging remain elusive. Here, we report that a nano-encapsulated senolytic D + Q cocktail efficiently improves the quality of post-ovulatory aging oocyte in vitro and follicle quantity in ovaries in a cyclophosphamide (Cy)-induced premature ovarian failure (POF) mouse model. Cocktail supplementation to cultured oocytes potently reduces reactive oxygen species (ROS) levels, maintains spindle integrity, decreases fragmented oocyte frequencies, rescues mislocalized cortical granules (CGs) and mitochondrial membrane potential (MMP), and alleviates DNA damage and apoptosis. Importantly, the cocktail effectively ameliorates fertility deficits in the model. Transcriptome analysis shows cocktail administration to fertility-deficient mice not only up-regulates developmental gene expression but also reduces senescence-associated secretory phenotype (SASP) accumulation. Therefore, our nano-encapsulated D + Q cocktail is a promising reagent for assisted reproductive technology and improving reproductive outcomes in POF. Graphical Abstract

The Effect of Being Faithful, Condom Use, no Drug Behavior on the Incidence of Sexually Transmitted Infections (STIs) in UnmarriedMen Who Have Sex with Men (MSM) in Indonesia

Article

Apr 2025

Background: “BCD” habits can help homosexual people and men who have sexwith men (MSM) prevent the transmission of sexually transmitted infections (STIs)and safeguard their partners. Objective: The purpose of this study was to investigate how BCD behaviour affects the prevalence of STIs among Indonesian MSM.Methods: a cross-sectional study was conducted in 24 provinces in Indonesia fromApril to May 2023. The study population comprised MSM who had ever engaged insexual intercourse, either occasionally, once, or frequently, totaling 6,000 individuals. A sample of 3,515 participants was selected using the Respondent Driven Sampling (RDS) method. Integrated Biological and Behavior Survey (STBP) 2018-2019data was utilized. The data was analyzed using multivariate analyses with STATA14 software. Results: after controlling for the variables of pieces of information exposure and vaginal intercourse, the following behaviors were found to have a significant influence of the occurrence of STIs among MSM (p-value:0.050; AOR:1,62with 95% CI:0.96-2.73), condom use (p-value:0.050; AOR:0.37 with 95% CI:0.14-1.00), no drug use (p-value:0.040; AOR:1,67 with 95% CI:1.02-2.75). Conclusion:promoting faithful behavior towards a steady partner, consistent condom use duringsexual activity, and refraining from injections and drug use can effectively reducethe transmission of STIs among MSM.

The effect of educational intervention based on protection motivation theory in improving reproductive health protective behaviors: a quasi-experimental study

Article

Full-text available

Apr 2025
BMC Wom Health

Background Reproductive health has broad implications for individuals, families, and society. This study aims to explore how an educational intervention, centered around PMT, can enhance reproductive health protective behaviors among female students. Methods This quasi-experimental study was conducted on female students of Khomein University of Medical Sciences in Markazi Province, Iran, from December 2023 to August 2024. A random cluster sampling method was used for sampling, resulting in 51 female students being selected for the intervention group and 54 female students for the control group. The data collection tool was a researcher-developed questionnaire, which included demographic information and PMT constructs with confirmed validity and reliability. The educational intervention for the intervention group consisted of three one-hour sessions spaced one week apart, incorporating methods such as lectures, group discussions, Q&A sessions, brainstorming, role-playing exercises, as well as distribution of educational booklets. The collected data was then analyzed using various statistical methods including independent t-tests, t-tests, chi-square tests, simple linear regression, and multiple linear regression models. Results After the intervention, the mean score for all constructs in the intervention group was higher than that of the control group, except for perceived cost. A statistically significant difference was noted in the mean scores of most constructs, such as perceived susceptibility, perceived severity, perceived self-efficacy, protection motivation, fear, and behavior, between the two groups being studied (p < 0.05). Conclusion The PMT-based educational intervention has proven to be effective in promoting reproductive health protective behaviors among female students. Given the significance of infertility issues and the value of preserving fertility in young women, it is recommended to implement PMT-based educational programs to safeguard women's reproductive health.

Deciphering the association between the Life’s Essential 8 and infertility: insights into depression, inflammation, and metabolic mediation

Article

Full-text available

Feb 2025

Background The Life’s Essential 8 (LE8) score has been associated with various health outcomes, but its relationship with female infertility remains unclear. Methods This study investigated the relationship between LE8 and infertility in women aged 20-45 years using the National Health and Nutrition Examination Survey (NHANES) data from 2013 to 2020. Weighted multifactorial logistic regression models were utilized to examine the association between the LE8 factors and their two subgroups [health behavior score (HBS) and health factor score (HFS)], as well as depressive status and infertility. Nonlinear relationships were examined using weighted restricted cubic spline (RCS) regression. Subgroup analysis and mediation analysis of depression, metabolic, and inflammation further elucidated the relationships. Sensitivity analysis was conducted to ensure the robustness of the findings. Results A total of 2,182 participants were included in this study, with 304 in the infertility cohort. Multifactorial regression analysis revealed significant negative correlations between LE8 and its subgroup HFS with infertility. Among the eight subscales, scores for sleep health, body mass index, and blood glucose were significantly negatively correlated with depression, while Patient Health Questionnaire-9 (PHQ-9) scores showed a positive correlation with infertility. Weighted RCS regression modeling indicated no nonlinear relationships between LE8, depression, HFS, HBS, and infertility. Mediation analyses suggested that depression scores, systemic immune inflammation index (SII), and uric acid (UA) mediated the association between LE8 and infertility. Conclusion Higher LE8 scores, indicating better cardiovascular health, are associated with lower depression scores and reduced levels of SII and UA. These factors collectively contribute to a lower risk of infertility in women. Targeted interventions aimed at enhancing cardiovascular health may potentially mitigate infertility risk through these pathways.

A life course study of genetic and environmental influences on sustainable working life

Article

Full-text available

Feb 2025
PLOS ONE

Genetics plays a role in short- and long-term sustainable working life (i.e., not having interruptions due to sickness absences (SA), disability pensions (DP), or unemployment), but the life course effects are not known. Thus, we aimed to investigate the age-specific genetic and environmental influences on sustainable working life from young adulthood until old-age pension. We used classical twin modeling based on the genetic relatedness of mono- and dizygotic twins in a longitudinal design. The final sample (n = 49 372) of Swedish same-sex twins with known zygosity born between 1929 and 1990 (52.8% women) with detailed national register data of employment, SA, DP, unemployment, old-age pension, emigration, and death. Genetic influences for sustainable working life were 54% at ages 18–27 years, 59% at 28–37 years, 37% at 38–47 years, 69% at 48–57 years, and 34% at 58–65 years. We observed genetic influences transferred from 18–27 years to 28–37 years and to 38–47 years explaining 28% and 17% of the variance, respectively, from 28–37 years to 38–47 years 60%, and from 48–57 years to 58–65 years 47%. Unique environmental influences were 57–72% in five age groups. Age group-specific common environment explained 63% of the variance for 18–27 years, 27% for 28–37 years, 12% for 48–57 years, and 25% for 58–65 years (none for 38–47 years). From age 48–57 years, the common environment explained 24% of the variance among those aged 58–67. To conclude, stability and change in genetic effects are important for a sustainable working life across the life course. The unique environmental effects were important for the middle age groups between 28 and 57 years. Thus, society and workplaces should support health and well-being to promote a sustainable working life.

Fertility in Celiac Disease: The Impact of Gluten on Male and Female Reproductive Health

Article

Full-text available

May 2025

Celiac disease (CeD) is a chronic immune-mediated disorder of the small intestine triggered by the ingestion of dietary gluten. This narrative review aims to summarize and critically evaluate the recent literature on the association between CeD and infertility, with an emphasis on identifying patterns and inconsistencies. Previous studies have reported conflicting findings: while some demonstrate a higher prevalence of unexplained infertility in patients with CeD, others do not support this association. Overall, untreated CeD may be a contributing factor to infertility, especially unexplained cases, and a gluten-free diet (GFD) might improve fertility outcomes. However, the general prevalence of infertility in CeD patients does not appear to exceed that of the general population. This review includes evidence on both male and female infertility and examines possible pathophysiological mechanisms, including nutritional deficiencies, immune-mediated effects, and sexual dysfunction. Further high-quality prospective studies are needed to determine the true impact of CeD on reproductive health and to inform screening guidelines.

Three Novel Mutations in TUBB8 Cause Female Infertility Due to Multiple Morphological Abnormalities of the Oocyte and Early Embryo

Article

Apr 2025
REPROD SCI

Recent years have seen a global increase in infertility, affecting up to 17.5% of the population. For successful human reproduction, the proper development process of the oocyte, fertilization, and early embryo is required. Assisted reproductive technology (ART), which is the primary treatment for infertility, uses the morphology of oocytes and zygotes as parameters to predict ART outcomes. However, factors such as large perivitelline space (PVS), centrally located granular cytoplasm (CLGC), multi-pronuclei (MPN) formation, and final early embryonic development arrest often lead to repeated failure of ART treatment. Genetic analysis has identified various pathogenic genetic factors contributing to infertility, suggesting that genetic variation plays a significant role in recurrent ART treatment failure. However, maternal genes responsible for large PVS, CLGC, and MPN formation are rarely reported. In this study involving Whole Exome Sequencing (WES) and Sanger sequencing validation, three novel heterozygous missense mutations (p.M403V, p.R306H, p.H190Y) in TUBB8 were identified as being associated with large PVS, CLGC, MPN formation, and early embryonic development arrest. These mutant sites are evolutionarily conserved in different species. Additionally, in silico and in vitro experiments demonstrate that these variants disrupt the conformation, expression, and microtubule structures of the TUBB8 protein. Therefore, these findings contribute significantly to understanding TUBB8-related large PVS, CLGC, and MPN formation in the context of ARTs. This broadens our insight into the genetic connection in human reproduction and emphasizes the importance of comprehensive genetic screening and personalized intervention strategies for PVS, CLGC, and MPN formation.

Reproductive Outcomes of Women with Endometrial Fluid during IVF-ICSI Treatment: A Single-Center Experience

Article

Mar 2025
AM J REPROD IMMUNOL

Objective: To retrospectively evaluate whether endometrial fluid detected at transvaginal ultrasonography on the third day of the menstrual cycle in infertile patients undergoing in vitro fertilization/intracytoplasmic sperm injection – embryo transfer (IVF-ICSI/ET) affects pregnancy outcomes. Methods: One hundred forty-eight patients who had undergone IVF-ICSI between 2010 and 2017 were included in this study. The participants were stratified according to the presence of endometrial fluid: Group 1 (control; n=74) consisted of women without endometrial fluid and Group 2 (study; n=74) of those with endometrial fluid. Baseline sociodemographic characteristics and reproductive outcomes were compared between the groups. Results: No difference was found between the groups in terms of age, body mass index, smoking rates, duration of infertility, etiology of infertility, baseline follicle-stimulating hormone, luteinizing hormone, estradiol, thyroid-stimulating hormone, and prolactin levels, duration of stimulation, stimulation protocol, antral follicle counts, total gonadotropin doses, peak E2 and progesterone levels on the day of human chorionic gonadotropin (hCG) administration, or endometrial thickness at hCG administration and the day of transfer (p>0.05). The number of oocytes retrieved, metaphase II oocytes, two pronuclei, fertilization rates, and the rates of grade I embryos per woman, as well as pronucleus counts, were comparable between the groups (p>0.05). However, the clinical pregnancy rate (CPR) (47.3% vs 31.1%) and live birth rate (LBR) (41.9% vs 24.3%) were both significantly lower in women with endometrial fluid compared to the control group (p<0.05). Conclusion: This retrospective cohort study shows that the women with endometrial fluid in their IVF-ICSI/ET cycles exhibited lower CPR and LBR. Further prospective studies are needed to confirm the validity of our results. Keywords: endometrial fluid; ICSI; IVF; reproductive outcomes

Semaglutide ameliorates metabolic disorders in offspring via regulation of oocyte ROS of pre-pregnancy obesity mice

Article

Feb 2025
ACTA PHARMACOL SIN

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome

Article

Full-text available

Dec 2020

Background: The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of androgens. It is suggested that as a consequence metformin could improve assisted reproductive techniques (ART) outcomes, such as ovarian hyperstimulation syndrome (OHSS), pregnancy, and live birth rates. Objectives: To determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS. Search methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, LILACS, the trial registries for ongoing trials, and reference lists of articles (from inception to 13 February 2020). Selection criteria: Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment. Types of participants: women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors. Types of interventions: metformin administered before and during IVF or ICSI treatment. Primary outcome measures: live birth rate, incidence of ovarian hyperstimulation syndrome. Data collection and analysis: Two review authors independently selected the studies, extracted the data according to the protocol, and assessed study quality. We assessed the overall quality of the evidence using the GRADE approach. Main results: This updated review includes 13 RCTs involving a total of 1132 women with PCOS undergoing IVF/ICSI treatments. We stratified the analysis by type of ovarian stimulation protocol used (long gonadotrophin-releasing hormone agonist (GnRH-agonist) or short gonadotrophin-releasing hormone antagonist (GnRH-antagonist)) to determine whether the type of stimulation used influenced the outcomes. We did not perform meta-analysis on the overall (both ovarian stimulation protocols combined) data for the outcomes of live birth and clinical pregnancy rates per woman because of substantial heterogeneity. In the long protocol GnRH-agonist subgroup, the pooled evidence showed that we are uncertain of the effect of metformin on live birth rate per woman when compared with placebo/no treatment (risk ratio (RR) 1.30, 95% confidence interval (CI) 0.94 to 1.79; 6 RCTs; 651 women; I2 = 47%; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 28%, the chance following metformin would be between 27% and 51%. Only one study used short protocol GnRH-antagonist and reported live birth rate. Metformin may reduce live birth rate compared with placebo/no treatment (RR 0.48, 95% CI 0.29 to 0.79; 1 RCT; 153 women; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 43%, the chance following metformin would be between 13% and 34% (short GnRH-antagonist protocol). We found that metformin may reduce the incidence of OHSS (RR 0.46, 95% CI 0.29 to 0.72; 11 RCTs; 1091 women; I2 = 38%; low-quality evidence). This suggests that for a woman with a 20% risk of OHSS without metformin, the corresponding risk using metformin would be between 6% and 14%. Using long protocol GnRH-agonist stimulation, metformin may increase clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.32, 95% CI 1.08 to 1.63; 10 RCTs; 915 women; I2 = 13%; low-quality evidence). Using short protocol GnRH-antagonist, we are uncertain of the effect of metformin on clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.38, 95% CI 0.21 to 9.14; 2 RCTs; 177 women; I2 = 87%; very low-quality evidence). We are uncertain of the effect of metformin on miscarriage rate per woman when compared with placebo/no treatment (RR 0.86, 95% CI 0.56 to 1.32; 8 RCTs; 821 women; I2 = 0%; low-quality evidence). Metformin may result in an increase in side effects compared with placebo/no treatment (RR 3.35, 95% CI 2.34 to 4.79; 8 RCTs; 748 women; I2 = 0%; low-quality evidence). The overall quality of evidence ranged from very low to low. The main limitations were inconsistency, risk of bias, and imprecision. Authors' conclusions: This updated review on metformin versus placebo/no treatment before or during IVF/ICSI treatment in women with PCOS found no conclusive evidence that metformin improves live birth rates. In a long GnRH-agonist protocol, we are uncertain whether metformin improves live birth rates, but metformin may increase the clinical pregnancy rate. In a short GnRH-antagonist protocol, metformin may reduce live birth rates, although we are uncertain about the effect of metformin on clinical pregnancy rate. Metformin may reduce the incidence of OHSS but may result in a higher incidence of side effects. We are uncertain of the effect of metformin on miscarriage rate per woman.

Reproduction, Smell, and Neurodevelopmental Disorders: Genetic Defects in Different Hypogonadotropic Hypogonadal Syndromes

Article

Full-text available

Jul 2014

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.

EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

Article

Full-text available

Dec 2015

The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community abouthow environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, andepigeneticchanges, therebyproducingeffects inexposedindividuals as well as theirdescendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in arange that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings canbemuchbetter translated tohumanhealth. Armedwith this information, researchers, physicians, andother healthcare providers can guide regulators and policymakers as they make responsible decisions.

Assessment and management of polycystic ovary syndrome: summary of an evidence‐based guideline

Article

Nov 2011

Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis

Article

Jan 2004

Diagnostic criteria for polycystic ovary syndrome: towards a rational approach

Article

Jan 1992
Boston

Ovarian hyperstimulation syndrome

Article

Nov 2008
FERTIL STERIL

The Practice Committee of the American Society for Reproductive Medicine

Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: Evidence for perinatal masculinization of neuroendocrine function in women

Article

Nov 1994

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.(J Clin Endocrinol Metab 79:1328-1333, 1994).

Exposure to toxic environmental agents

Article

Oct 2013
OBSTET GYNECOL

Reducing exposure to toxic environmental agents is a critical area of intervention for obstetricians, gynecologists, and other reproductive health care professionals. Patient exposure to toxic environmental chemicals and other stressors is ubiquitous, and preconception and prenatal exposure to toxic environmental agents can have a profound and lasting effect on reproductive health across the life course. Prenatal exposure to certain chemicals has been documented to increase the risk of cancer in childhood; adult male exposure to pesticides is linked to altered semen quality, sterility, and prostate cancer; and postnatal exposure to some pesticides can interfere with all developmental stages of reproductive function in adult females, including puberty, menstruation and ovulation, fertility and fecundity, and menopause. Many environmental factors harmful to reproductive health disproportionately affect vulnerable and underserved populations, which leaves some populations, including underserved women, more vulne ble to adverse reproductive health effects than other populations. The evidence that links exposure to toxic environmental agents and adverse reproductive and developmental health outcomes is sufficiently robust, and the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine join leading scientists and other clinical practitioners in calling for timely action to identify and reduce exposure to toxic environmental agents while addressing the consequences of such exposure.© 2013 by The American College of Obstetricians and Gynecologists.

Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)

Article

Jan 2004

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

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