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Abstract

Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea). It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 and 1:1,000 women by age 30. The most severe forms present with absent pubertal development and primary amenorrhea (50% of these cases due to ovarian dysgenesis), whereas forms with post-pubertal onset are characterized by disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion. As in the case of physiological menopause, POF presents by typical manifestations of climacterium: infertility associated with palpitations, heat intolerance, flushes, anxiety, depression, fatigue. POF is biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea). Beyond infertility, hormone defects may cause severe neurological, metabolic or cardiovascular consequences and lead to the early onset of osteoporosis. Heterogeneity of POF is also reflected by the variety of possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. POF has a strong genetic component. X chromosome abnormalities (e.g. Turner syndrome) represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation.
BioMed Central
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Orphanet Journal of Rare Diseases
Open Access
Review
Premature ovarian failure
Paolo Beck-Peccoz*
1
and Luca Persani
2
Address:
1
Dipartimento di Scienze Mediche, Università di Milano, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena,
Via F. Sforza 35, 20122-Milano, Italia and
2
Dipartimento di Scienze Mediche, Università di Milano, IRCCS Istituto Auxologico Italiano, Via Zucchi
18, 20095 Cusano (Milano), Italia
Email: Paolo Beck-Peccoz* - paolo.beckpeccoz@unimi.it; Luca Persani - luca.persani@unimi.it
* Corresponding author
Abstract
Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche
(primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 years
(secondary amenorrhea). It is a heterogeneous disorder affecting approximately 1% of women <40
years, 1:10,000 women by age 20 and 1:1,000 women by age 30. The most severe forms present
with absent pubertal development and primary amenorrhea (50% of these cases due to ovarian
dysgenesis), whereas forms with post-pubertal onset are characterized by disappearance of
menstrual cycles (secondary amenorrhea) associated with premature follicular depletion. As in the
case of physiological menopause, POF presents by typical manifestations of climacterium: infertility
associated with palpitations, heat intolerance, flushes, anxiety, depression, fatigue. POF is
biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high
levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea). Beyond infertility,
hormone defects may cause severe neurological, metabolic or cardiovascular consequences and
lead to the early onset of osteoporosis. Heterogeneity of POF is also reflected by the variety of
possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. POF has a strong
genetic component. X chromosome abnormalities (e.g. Turner syndrome) represent the major
cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several
candidate genes, the cause of POF remains undetermined in the vast majority of the cases.
Management includes substitution of the hormone defect by estrogen/progestin preparations. The
only solution presently available for the fertility defect in women with absent follicular reserve is
ovum donation.
Disease name and synonyms
Premature ovarian failure (POF; POF1: OMIM 311360);
Hypergonadotropic ovarian failure; Menopausa precoce.
Included diseases
POF2 (OMIM #300511); POF3 (OMIM #608996)
Definition
Premature ovarian failure is defined as a primary ovarian
defect characterized by absent menarche (primary amen-
orrhea) or premature depletion of ovarian follicles/
arrested folliculogenisis before the age of 40 years (sec-
ondary amenorrhea) [1,2].
Published: 06 April 2006
Orphanet Journal of Rare Diseases 2006, 1:9 doi:10.1186/1750-1172-1-9
Received: 02 March 2006
Accepted: 06 April 2006
This article is available from: http://www.OJRD.com/content/1/1/9
© 2006 Beck-Peccoz and Persani; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Orphanet Journal of Rare Diseases 2006, 1:9 http://www.OJRD.com/content/1/1/9
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Epidemiology
POF affects approximately: one in 10,000 women by age
20; one in 1,000 women by age 30; one in 100 women by
age 40 [3]. The familial form of POF is rare, representing
4 to 31% of all cases of POF [4-6].
Etiology
The causes of POF are extremely heterogeneous. Acquired
forms such as those occurring after treatments for neo-
plastic diseases or autoimmune diseases account for many
cases [1]. POF has a strong genetic component with X
chromosome abnormalities playing a primary role mainly
in the cases with ovarian dysgenesis [7-10]. A gene (or
genes) for POF (POF1) was localised to Xq21.3–Xq27 on
the basis of deletions in various patients and families. A
second gene (or genes) for POF (POF2) implicated by the
analysis of balanced X/autosomal translocations has been
localised to Xq13.3–q21.1. Despite the description of sev-
eral candidate genes [11-16], the cause of POF still
remains undetermined in the majority of the cases (idio-
pathic). This idiopathic form of POF can show sporadic
and familial forms.
The different causes of POF are illustrated as follows:
• Iatrogenic origin (surgery, chemotherapy, radiations);
• Autoimmune, including polyglandular autoimmune
syndrome, as well as autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy (APECED) due to
mutations in AIRE gene);
• Infections (e.g. herpes zoster, cytomegalovirus);
• Chromosome X defects:
Turner syndrome
Fragile X syndrome (FMR1 gene premutation)
• Monogenic defects
Syndromic defects:
Congenital disorders of glycosylation (CDG, formerly
named carbohydrate-deficient glycoprotein syndromes)
(recessive)
Galactosemia (recessive)
Blepharophimosis-ptosis-epicanthus inversus syn-
drome (BPES) (female-limited, dominant)
Pseudohypoparathyroidism (PHP) type Ia (parental
imprinting : maternal inheritance)
Isolated defects:
Follicle stimulating hormone (FSH) receptor mutations
(FSHR), (recessive)
Luteinizing hormone (LH) receptor mutations (LHR),
(recessive)
FOXL2 (transcription factor involved in BPES) muta-
tions (female-limited defect, dominant)
Bone morphogenetic protein 15 (BMP15) mutations
(female-limited defect, heterozygous mutation)
• Idiopathic
Defects in some of these candidate genes may present
with different phenotypes. FOXL2 defects may present
either with BPES type 1 (without POF) or with BPES type
2 (with POF), condition designated as POF3 [14]. Rarely,
FOXL2 mutations may be associated with POF in the
absence of eyelid/palpebral alterations (isolated POF)
[17,18]. Depending on the degree of FSH resistance, FSHR
defects are associated with primary [12] or secondary
amenorrhea [13,19]. Mutations in LHR have been
described in women with secondary amenorrhea (charac-
terized by elevated serum LH/FSH ratio and cystic follicles
at ultrasound) belonging to pedigrees of male patients
with Leydig hypoplasia [20]. Two of the candidate genes
are located on the X chromosome. FMR1 gene (Xq27.3)
mutations or pre-mutations are typically associated with
secondary amenorrhea in female relatives of male patients
with mental retardation [8]. BMP15 gene (Xp11.2) defect
has so far been described in two sisters with primary
amenorrhea and heterozygous for the mutation. This
defect represents an unusual example of a X-linked disease
in which affected females inherit the mutation from their
unaffected father [15].
Clinical description
The symptoms can vary considerably from patient to
patient and the disorder may occur abruptly or spontane-
ously or it may develop gradually over several years. The
most severe forms of hypergonadotropic ovarian failure
present with absent pubertal development and primary
amenorrhea [2,21]. The clinical picture is characterized by
absent menarche and pubertal delay results in absent sex-
ual maturation and reduced growth velocity. In the
female, pubertal delay is defined as the absence of mam-
mary and pubic hair development and menarche at 13
years. Moderate hirsutism may be seen due to the action
of androgens originating from adrenals.
About half of the cases of primary amenorrhea are due to
ovarian dysgenesis, which is revealed by the finding of
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streak ovaries accompanied by uterus hypoplasia at ultra-
sound. In the other patients, follicles (<10 mm) may be
found at histological evaluation such as in the case of
FSHR mutations [22]. In these cases, almost normal
pubertal development may be seen.
Post-pubertal onset of ovarian failure represents the large
majority of the cases [1]. This is characterized by second-
ary amenorrhea associated with premature follicular
depletion or arrested folliculogenisis. As in the case of
physiological menopause, POF is clinically characterized
by typical manifestations of climacterium such as palpita-
tions, heat intolerance, flushes, night sweats, irritability,
anxiety, depression, sleep disturbance, decreased libido,
hair coarseness, vaginal dryness, fatigue.
Female infertility is an obvious and presently irreversible
consequence of POF. Importantly, POF and prolonged
lack of estrogen treatment may lead to the early onset of
osteopenia and osteoporosis. Moreover, sexual hormone
defects represent an important risk factor for frequent and
severe neurological, metabolic or cardiovascular disorders
such as Alzheimer's disease, hypercholesterolemia or
ischemic diseases.
Hypergonadotropic ovarian failure may be part of other
syndromic features (see the causes of POF): Autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy,
Blepharophimosis-ptosis-epicanthus inversus syndrome,
Carbohydrate-deficient glycoprotein syndromes, Galac-
tosemia, Turner) and PHP I.
PHP I is associated with mutation in the GNAS gene
encoding Gs protein alpha [23]. The diagnosis of PHP I is
based on the findings of resistance to several peptide hor-
mones acting through the adenylyl cyclase/cAMP path-
way. The key findings are elevated parathyroid hormone
(PTH) with low/normal calcemia, high thyrotropin (TSH)
with normal thyroid hormone levels, growth hormone
deficiency and high gonadotropins in patient with
delayed puberty and skeletal abnormalities (Albright
osteodystrophy). PHP I syndrome occurs when the
mutant allele is inherited from the mother, due to the
imprinting of the paternal GNAS allele in the affected tis-
sues.
The early diagnosis of familial POF will provide the
opportunity to predict the likelihood of early menopause,
and allow other reproductive choices to be made, such as
freezing embryos or having children earlier. As POF has
cumulative negative effects over time, it is important for
clinicians to make a timely diagnosis and begin appropri-
ate strategies for symptom management, emotional sup-
port, and risk reduction.
Diagnostic methods
Both primary and secondary forms of ovarian failure are
biochemically characterized by low levels of gonadal hor-
mones (estrogens and inhibins) and high gonadotropins
(LH and FSH) (hypergonadotropic amenorrhea). The ele-
vation of FSH is usually more marked than that of LH and
an FSH value >30 U/L is indicative of ovarian failure.
Ultrasound frequently reveals small ovaries without evi-
dence of growing follicles. In the cases with primary
amenorrhea, gonadal dysgenesis is documented by the
finding of streak ovaries. Histological examination of
biopsies performed during pelvic laparoscopy in the case
of hypoplastic ovaries (0.20–0.30 ml on ultrasound) may
reveal the presence of primary follicles. Forms of POF
linked to the finding of ovarian cysts may be due to LH
resistance (LHR mutations) which presents with second-
ary amenorrhea. In contrast to what is generally found in
POF, defects in LH receptor are typically associated with a
serum LH elevation (> 10 U/L) more pronounced than
that of serum FSH. The evaluation of other peptide factors
of ovarian origin, such as inhibin B and anti-mullerian
hormone (AMH), may be useful to determine the follicu-
lar reserve when POF is suspected. Low levels of inhibin B
may predict follicular depletion before the large FSH rise.
Karyotype evaluation and other cytogenetic investigations
are useful to identify major X chromosome abnormalities.
Differential diagnosis
The differential diagnosis is based on the exclusion of
other causes of primary and secondary amenorrhea
(absence of menstruation for more than 6 months).
Parameters useful for the exclusion of each of the follow-
ing conditions are illustrated:
• Pregnancy: high chorionic gonadotropin (CG) levels.
• Iatrogenic causes (surgery, anti-neoplastic treatments,
radiations, antidopaminergic drugs): complete anamnes-
tic investigation.
• Hypothalamic-pituitary disease (pituitary tumors,
hyperprolactinemia, Kallmann syndrome, ....): high prol-
actin (PRL) and low/normal gonadotropin levels, altera-
tions at imaging of brain/sella region.
• Hypothalamic amenorrhea (induced by stress, intensive
exercise, anorexia, weight loss, fasting, severe diseases,):
low/normal gonadotropin levels.
• Polycystic ovaries: alterations at ovarian ultrasound,
normal gonadotropin and high androgen levels.
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• Enzymatic defects of steroidogenesis (e.g. 21-hydroxy-
lase deficiency): alterations at physical and adrenal ultra-
sound, normal gonadotropin, high androgen and
adrenocorticotropic hormone (ACTH) levels.
• Endocrine disorders, such as hyperthyroidism, hypothy-
roidism, Cushing syndrome: complete clinical/biochemi-
cal evaluations, normal gonadotropin levels.
• Only in patients with primary amenorrhea:
- vaginal/uterus anatomical abnormalities, such as Roki-
tanski syndrome or Asherman syndrome: alterations at
physical examination/pelvic ultrasound, normal gonado-
tropin levels.
- disorders of sexual differentiation (e.g. resistance to
androgens): alterations at physical/ultrasound examina-
tion, evaluation of karyotype, measure androgen/anti-
mullerian hormone levels.
Genetic counseling
Genetic counseling is nowadays recommended for several
reasons, when a genetic form of POF is suspected or iden-
tified.
Counseling is of particular importance in POF cases from
families with X-linked mental retardation (Fragile X syn-
drome). Fragile X syndrome is due to CGG expansion
(>55 repeats) at the 5'UTR of FMR1 gene (Xq27.3). The
expansion of CGG repeats is associated with gene silenc-
ing resulting in male mental retardation and in POF with
secondary amenorrhea in female carriers [8].
Genetic investigations may be useful for the early diagno-
sis of genetic defects underlying POF, when a female is
born from a family with other female members affected
with POF. Pedigree studies on affected families showed a
mode of inheritance suggestive of autosomal dominant
sex-limited transmission or X-linked inheritance with
incomplete penetrance. In families with POF, the risk of
other females developing POF will depend on the mode
of inheritance and the mode of transmission. With auto-
somal dominant inheritance, the risk of POF will be 50%
with either maternal or paternal transmission. However,
with X-linked inheritance and paternal transmission this
risk may be as high as 100%. These risks will be smaller
with incomplete penetrance. If a POF patient appears to
be a sporadic case, the risk of other female relatives devel-
oping POF will probably be equal to the risk in the general
population.
All women who experience POF before the age of 30 years
should perform a blood test for chromosomal assessment.
Older women should discuss the option of chromosomal
studies, as identification of abnormality may influence
other family members, sisters or daughters, who carry the
same defect in term of planning pregnancies. Carriers of
the genetic defect may be advised for early pregnancy or
oocyte collection and preservation.
Antenatal diagnosis
Not relevant at present.
Management
Patients with POF have infertility and hormone deficits.
At present, fertility cannot be restored if the diagnosis is
made after complete follicular depletion. In some cases,
early diagnosis by genetic investigation may instead lead
to advice for early conception or oocyte harvesting and
preservation. Hormone defect may be substituted by
estrogen/progestin preparations. The only solution pres-
ently available for the fertility defect in women with
absent follicular reserve is represented by ovum donation.
Unresolved questions
In most of the isolated defects the cause is still unknown.
Several candidate genes have been identified, but causa-
tive mutations have been found in a strict minority of
patients [7,11,15,16]. The prevalence of some genetic
defects remains to be determined (e.g. BMP15 mutations).
Though one paper described auto-antibodies against
FSHR in a series of women with POF [24], auto-antigens
and specific auto-antibodies for the diagnosis of autoim-
mune forms of isolated POF remain to be determined.
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... In Mexico, 17% of women of childbearing age have infertility problems, which is equivalent to 1.4 million of couples requiring assisted reproduction techniques, 1,2 from which, 9 to 25% of the patients may show a low ovarian response defined as a poor obtention of oocytes after an ovarian stimulation. 3,4 This alteration may be associated to Premature Ovarian Insufficiency (POI) characterized by an increase of the Follicle Stimulating Hormone (FSH), and Luteinizing Hormone (LH), with diminution of Anti-Müllerian Hormone (AMH), and estrogens, including menstrual modifications before 40 years old (oligomenorrhea or amenorrhea), [5][6][7] with a prevalence of 1 out of 100 women before 40, and 1 out of 1000 women before 30. The risk varies depending on the race, from 0.1% in Japanese to 1% in Caucasians, and 1.4% in Africans and Hispanics. ...
... The risk varies depending on the race, from 0.1% in Japanese to 1% in Caucasians, and 1.4% in Africans and Hispanics. [7][8][9] Diverse POI etiopathogeneses have been described; i.e. autoimmune diseases, 10 oxidative stress, 11 genetic predisposition, 12 radiotherapy, and chemotherapy in the treatment of cancer. [13][14][15] This can lead to problems of collection and maintenance of primordial follicles, in addition to the induction of follicular atresia, and apoptosis of granulosa cells. ...
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Method
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Background • Female infertility is a complex issue encompassing a wide variety of diagnoses, many of which are caused or affected by adhesions. Objectives • The study intended to examine the rates of successful treatment of infertile women using a protocol of manual physical therapy to address underlying adhesive disease leading to infertility. Methods • The research team designed a retrospective chart review. Setting • The study took place in a private physical therapy clinic. Participants • Participants were 1392 female patients who were treated at the clinic between the years of 2002 and 2011. They had varying diagnoses of infertility, including occluded fallopian tubes, hormonal dysfunction, and endometriosis, and some women were undergoing in vitro fertilization (IVF). Intervention • All patients underwent whole-body, patient-centered treatments that used a protocol of manual physical therapy, which focused on restoring mobility and motility to structures affecting reproductive function. Outcome Measures • Improvements demonstrated in the condition(s) causing infertility were measured by improvements in tubal patency and/or improved hormone levels or by pregnancy. Results • The results included a 60.85% rate of clearing occluded fallopian tubes, with a 56.64% rate of pregnancy in those patients. Patients with endometriosis experienced a 42.81% pregnancy rate. The success rate was 49.18% for lowering elevated levels of follicle stimulating hormone (FSH), with a 39.34% pregnancy rate in that group, and 53.57% of the women with polycystic ovarian syndrome (PCOS) achieved pregnancy. The reported pregnancy rate for patients who underwent IVF after the therapy was 56.16%. The results also suggested that the treatment was effective for patients with premature ovarian failure (POF). Conclusion • The manual physical therapy represented an effective, conservative treatment for women diagnosed as infertile due to mechanical causes, independent of the specific etiology. (Altern Ther Health Med. 2015;21(3):32-40.) Amanda D. Rice, PhD, is the director of clinical studies; Kelseanne P. Breder, BA, is an intern. Both are in the research department at Clear Passage Physical Therapy in Gainesville, Florida. Kimberley Patterson, PTA, is a therapist; Leslie B. Wakefield, DPT, is a physical therapist; Evette D. Reed, PT, is a physical therapist; and Belinda F. Wurn, PT, is a clinical director. All are located in the clinical department at Clear Passage Physical Therapy. C. Richard King, III, MD, is the medical director of Clear Passage Physical Therapy. Lawrence J. Wurn, LMT, is a therapist in the clinical department and the research director in the research department at Clear Passage Physical Therapy.
... Premature ovarian failure (POF) is a primary ovarian defect characterized by premature depletion of ovarian follicles before the age of 40 years. [1] Chemotherapy-induced ovarian failure (COF) is defined as a state of impairment of both endocrine and reproductive ovarian function after exposure to chemotherapy. [2] COF is one of the etiological factors of POF. ...
Article
m We aimed to examine the potential beneficial effects of diosmin administration on cisplatin - induced premature ovarian failure (POF) in a rat model Material and Methods Twenty-eight rats were divided into four groups. Group A rats (n:7) were determined as the sham group. The remaining rats received an intraperitoneal injection of 1.5 mg/kg/day cisplatin for 10 days to create a POF model. Then, they were randomly divided into 3 subgroups. Group B was determined as POF group. Group C rats were given 100mg/kg/day diosmin for 10 days simultaneously while creating POF model. Group D rats were given 100mg/kg/day diosmin for 10 days after POF model was created. Twentieth day blood samples were taken and left ovaries were resected for examination. Results CIS-induced rats showed reduced levels of SOD, AMH and E2 compared to sham group rats (p0.05) between the sham group, group C and D. No significant (p>0.05) difference in FSH value was observed between group C, D and sham groups. There was no significant (p>0.05) difference in the number of secondary and antral follicles between group C and D compared to the sham group. Primordial follicle count was significantly higher in group C than group B (p
... However, decreased fertility and even infertility are the top POF-related concerns for women of every reproductive age. In addition, the negative effects of POF include an increased risk of cardiovascular disease, osteoporosis, and sexual dysfunction (3,4). ...
Article
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Objective The objective of this study was to compare the efficacy differences between Chinese patent medicines combined with hormone replacement therapy (HRT) in the treatment of premature ovarian failure (POF) by the Bayesian network meta-analysis (NMA) method. Methods Randomized controlled trials (RCTs) reporting Chinese patent medicine combined with HRT for POF included Medline ( via PubMed), Embase, Cochrane Library, China National Knowledge Infrastructure Database (CNKI), Wanfang Database (Wanfang), VIP Database (VIP), and China Biology Medicine Database (CBM) from the inception of the databases to July 2022. Two researchers independently screened the articles, extracted data, and evaluated the quality. The literature that met the inclusion criteria was screened out, the quality and risk of bias of the included studies were assessed according to the Cochrane 5.1 manual and RevMan 5.4, and NMA was performed using Stata 15.0 and R software. Results Sixty-four RCTs involving 5,675 individuals containing 12 oral Chinese patent medicines combined with HRT were enrolled into the current NMA. The results showed that when compared with patients using only HRT, the total clinical response rate is greater in patients using HRT combined with one of these 12 oral Chinese patent medicines. Among them, Zuogui pills + HRT [odds ratio (OR) = 3.92; 95% credible interval (CrI) = 0.86, 23.84; SUCRA = 73.76%] is most likely to be the best intervention, and the suboptimal intervention is Guishen pills + HRT (OR = 3.22, 95% CrI = 1.16, 9.44, SUCRA = 70.60%). Conclusion Chinese patent medicines combined with HRT were more effective than HRT alone in the treatment of POF. Zuogui pills are good at decreasing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and more effective in the improvement of total clinical response rate; Xuefu Zhuyu capsule is also good at decreasing FSH. Ziheche capsule is an expert in improving estradiol level; Kuntai capsule shows the lowest incidence of adverse reactions. However, the quality of the literature included in this study is relatively low, so it may affect the results of the study. Therefore, higher quality and multi-center trial would be necessary for supporting these results. Systematic review registration [ www.crd.york.ac.uk/prospero ], identifier [CRD42022350587].
... Statistics have revealed that POF affects about 1% of women under 40 years old and about 0.1% of women under the age of 30 [3]. Both environmental and genetic factors are noted to cause POF, whereas chromosomal defects (fragile X syndrome), toxins (including chemotherapy and radiotherapy), autoimmune diseases, infections, and thyroid malfunction are reported to alleviate this disorder [3,4]. In the POF patients, follicle-stimulating hormone (FSH) levels reach above 40 IU/mL while the content of anti-Mullerian hormone (AMH) declines below 1 ng/mL [5]. ...
Article
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Background The restorative effect of classical music was assessed on the cyclophosphamide-induced animal model of premature ovarian failure (POF). Methods Mozart’s piano classical music (K.448) was used for up to 4 and 8 weeks. Rats were exposed to music 6 h every day using a stereo system with a volume of 65–70 dB. Sera and ovarian tissue samples were collected for the evaluation of FSH, LH, and E2 and histopathological examination. At the same time points, samples were taken from the hypothalamus and hippocampus to monitor the expression of Ntrk2, Crh, and Pomc using real-time PCR. Mating trial was performed to evaluate the fertility status of POF rats. Results Histopathological examination revealed a significant increase (p < 0.05) in the numbers of morphologically normal follicles at all the developmental stages in POF rats after music therapy compared to the POF group (p < 0.05). Music therapy decreased FSH and LH levels to near-to-normal levels conidied with elevation of E2 (p < 0.05). Ntrk2, Crh, and Pomc expressions were down-regulated in POF rats. Music therapy increasaed the expression of Ntrk2 in the hypothalamus of POF rats (p < 0.05). In contrast, Crh and Pomc failed to reach the detection limit before intervention and four weeks after the intervention however, these genes were expressed eight weeks after music therapy. Fertility status was increased (p < 0.05) in terms of litter size in POF rats after being exposed to music compared to the non-treated POF control group (p < 0.05). Conclusion Results showed that music can exert therapeutic effects on POF rats via the alteration of sex-related hormones.
Chapter
Frailty in children with oncological diseases is evident during the diagnostic phase, therapeutic process, and also follow-up. Children with cancer are frail as a consequence of both the disease per se and the therapies, which are responsible for an inflammation status, which results in accelerated ageing (Ness et al., Cancer 121(10):1540–7, 2015, Ness et al., J Clin Oncol 31(36):4496–503, 2013, Ness et al., J Clin Oncol 36(21):2206–15, 2018). Also, the psychological burden involving children during the diagnosis and treatment phases is heavy and difficult to overcome, and the experience of such a pervasive disease may stay in the mind all life long, even when the oncologic follow-up is concluded. The improving outcome of children with cancer over the years has increased the number of childhood cancer survivors, but this conduced to an increased prevalence of frailty in these long survivors (Ness et al., J Clin Oncol 31(36):4496–503, 2013, Robison and Hudson, Nat Rev Cancer 14:61–70, 2014). Frailty in childhood cancer survivors is a phenotype characterized by reduced physical and cognitive functions with an increased incidence of chronic conditions involving different organs and systems, risks of secondary malignancies and psychological disorders (hyperactivity, inattention, anxiety and depression). These conditions result in a reduced quality of life and increase the risk of mortality. A correct lifestyle and specific interventions are fundamental to preventing the onset and progress of chronic illnesses; therefore, an adequate screening program for childhood cancer survivors is important to ameliorate clinical outcomes (Ness et al., Cancer 121(10):1540–7, 2015).
Article
Background: Premature ovarian failure (POF) is a well-known cause of infertility, particularly in women under the age of 40. POF is also associated with elevated gonadotropin levels, amenorrhea and sex-hormone deficiency. Aim of the study: In this study, the therapeutic potential of autologous mesenchymal stromal cells obtained from menstrual blood (Men-MSCs) for patients with POF was evaluated. Methods: 15 POF patients were included in the study. The cultured Men-MSCs were confirmed by flow cytometry, karyotype, endotoxin and mycoplasma and were then injected into the patients' right ovary by vaginal ultrasound guidance and under general anesthesia and aseptic conditions. Changes in patients' anti-Müllerian hormone (AMH), antral follicle count (AFC), follicle-stimulating hormone (FSH), luteal hormone (LH), and estradiol (E2) levels, as well as general flushing and vaginal dryness were followed up to one year after treatment. Results: All patients were satisfied with a decrease in general flushing and vaginal dryness. 4 patients (2.9%) showed a spontaneous return of menstruation without additional pharmacological treatment. There was a significant difference in AFC (0 vs. 1 ± 0.92 count, p value ≤0.001%), FSH (74 ± 22.9 vs. 54.8 ± 17.5 mIU/mL, p-value ≤0.05%), E2 (10.2 ± 6 vs. 21.8 ± 11.5 pg/mL p-value ≤0.01%), LH (74 ± 22.9 vs. 54.8 ± 17.5 IU/L,p-value ≤0.01%) during 3 months post-injection. However, there were no significant changes in AMH (p-value ≥0.05%). There were also no significant differences in assessed parameters between 3 and 6 months after cell injection. Conclusion: According to the findings of this study, administration of Men-MSCs improved ovarian function and menstrual restoration in some POF patients.
Preprint
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Background: Primary ovarian insufficiency (POI) refers to the loss of ovarian function under the age of 40 and resultsin amenorrhea and infertility. Our previous studies have shown that transplantation of mesenchymal stem cells (MSCs) and MSC-derived exosomesin chemotherapy-induced POI mouse ovaries can reverse the POI and eventually achieve pregnancy. Based on our recent studies, MSC-derived exosomeshave almost equal therapeutic potentials as transplanted MSCs. However, it is still unclear whether exosomes can completely replace MSCs in POI treatment. For the reliable application of cell-free treatment for POI patients using exosomes, there is a need to understand whetherthere is any outcome and effectiveness differencebetween MSC and MSC-derived exosome treatment. Methods: Comparing the therapeutic effect of intravenous injection using MSCs and equal amountsof exosomesin aPOI mouse model will reveal the differencebetween the two therapeutic resources. In this study, we induced POI in C57/BL6 mice by chemotherapy (CXT) using a standard protocol. We then injected four different doses of MSCs or equal amountsof commercialized MSC-derived exosomesby retro-orbital injection post-CXT. Result: After MSC/exosome treatment, tissue and serum samples were harvested to analyze molecular changes after treatment,while other mice in parallel experiments underwent breeding experimentsto compare the restoration of fertility. Both the MSC- and exosome-treated groups had a restored estrous cycle and serum hormone levelscompared to untreated POI mice. The pregnancy rate in the MSC-treated group was 60% to 100% after treatment, while thepregnancy rate in the exosome-treated group was 30% to 50% after treatment. Interestingly, in terms oflong-term effects, MSC-treated mice still showed a 60% to 80% pregnancy rate in the second round of breeding, while the exosome-treated group became infertile again inthe second roundof breeding. Conclusions: Although there were some differences in the efficacy between MSC treatment and exosome treatment, both treatments were able to achieve pregnancy in the POI mouse model. In conclusion, we report that MSC-derived exosomes are apromising therapeutic option to restore ovarian function in POI conditions similar to treatment with MSCs.
Preprint
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Purpose Gonadotoxic effects of chemotherapy is a critical concern in Pediatric Oncology given most patients survive their cancer. Future fertility is an important concern in this population supporting the need for additional research on chemotherapy gonadotoxicity. This study’s purpose was to identify associations with premature ovarian insufficiency (POI) in pediatric patients with a history of cancer based on age, cancer type and cyclophosphamide equivalent dose (CED). Methods We retrospectively collected data on pediatric patients with cancer treated between 2008–2017. Inclusion criteria included female gender, age 0–25 at time of cancer diagnosis, diagnosis of a malignancy requiring chemotherapy, and documented ovarian hormone levels following chemotherapy completion. Results Two-hundred and forty-five female patients were identified based on age, malignancy and chemotherapy criteria.. Of these, 57 had documented ovarian hormone levels following chemotherapy. Five patients (9%) met criteria for POI. These 5 patients were all ≥ 13 years old at time of cancer diagnosis and found to have a lymphoma or solid tumor diagnosis. Conclusion We sought to analyze ovarian hormone levels for pediatric cancer survivors based on age in which chemotherapy was administered. There was a significant association between POI and age ≥ 13 years at time of cancer diagnosis. Those documented with POI received a CED between 0-28.4 gm/m², suggesting other factors contribute to ovarian dysfunction. Implications for cancer survivors As more pediatric patients are being cured of their cancer diagnoses, gonadal health and treatment-related risks continue to be important topics of research to help provide informed gonadal-preservation conversations in this vulnerable population.
Article
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Premature ovarian failure (POF) causing hypergonadotrophic hypogonadism occurs in 1% of women. In majority of cases the underlying cause is not identified. The known causes include: (a) Genetic aberrations, which could involve the X chromosome or autosomes. A large number of genes have been screened as candidates for causing POF; however, few clear causal mutations have been identified. (b) Autoimmune ovarian damage, as suggested by the observed association of POF with other autoimmune disorders. Anti-ovarian antibodies are reported in POF by several studies, but their specificity and pathogenic role are questionable. (c) Iatrogenic following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. (d) Environmental factors like viral infections and toxins for whom no clear mechanism is known. The diagnosis is based on finding of amenorrhoea before age 40 associated with FSH levels in the menopausal range. Screening for associated autoimmune disorders and karyotyping, particularly in early onset disease, constitute part of the diagnostic work-up. There is no role of ovarian biopsy or ultrasound in making the diagnosis. Management essentially involves hormone replacement and infertility treatment, the only proven means for the latter being assisted conception with donated oocytes. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation hold promise in cases where ovarian failure is foreseeable as in women undergoing cancer treatments.
Article
A major challenge in this field is that mutations lead to infertility, thereby limiting the investigator’s ability to use traditional genetic linkage and association studies to identify candidate genes. However, the human genome project is starting to have a major impact on strategies used to identify genetic mutations. The density of polymorphic markers, such as single nucleotide polymorphisms, is increasing rapidly, allowing better gene mapping. In addition, easy access to the structure of genes known to be involved in reproductive disorders is allowing high-throughput screening of candidate genes. A large number of genes involved in reproduction are being identified in transgenic and gene knockout mice. As these phenotypes are characterized more thoroughly, it may be possible to better predict candidate genes in humans based on characteristic hormonal and histologic features of particular mutations. Gene microarrays have the potential to provide gene expression fingerprints associated with specific types of genetic disorders.
Article
Objective To determine the relative importance of family history as a predictor of early menopause. Design Case-control study. From a population-based survey of 10,606 women between 45 and 54 years of age, we selected 344 cases with early menopause (average age 42.2 years) and 344 age-matched controls who were still menstruating or who had a menopause after age 46 years. Subjects were interviewed about their medical and family history and blood was drawn for identification of women who were carriers for the classic or Duarte variant of galactosemia, a potential hereditary factor for early menopause. Logistic regression analysis was used to estimate the risk of an early menopause in women with and without a family history of early menopause. Results Overall 129 (37.5%) of the early menopause cases reported a family history of menopause before age 46 years in a mother, sister, aunt, or grandmother compared to 31 (9.0%) of controls yielding an odds ratio (OR) of 6.1 (95% confidence interval [CI] of 3.9 to 9.4) after adjustment for smoking history, education, parity, and body mass index. Risk for early menopause associated with family history of same was greatest: for family history in a sister, OR = 9.1 (95% CI 3.1 to 26.5); multiple relatives, OR = 12.4 (95% CI 4.4 to 34.2); and cases menopausal before age 40 years, OR = 8.4 (95% CI 2.5 to 31.2). Cases with a family history of early menopause were not more likely to have errors of galactose metabolism compared with cases without a family history or to all controls, nor did they possess Turner's stigmata such as short stature, but they were less likely to have brothers in their sibships. Conclusions Although preferential recall of family history by women with early menopause could contribute to the association between family history and early menopause observed in this study, a genetic factor is also plausible including partial deletions of the X chromosome compatible with the deficiency of male siblings in cases with family history of early menopause.
Article
The full mutation leading to the fragile X syndrome is a dynamic trinucleotide repeat located in the 5′ untranslated region of the FMR1 gene. The premutation allele contains approximately 60 to 199 repeats, is unstable, and originally not considered detrimental; that is, there did not appear to be a phenotype consequence of the long repeat tract. However, in the late 1980s and early 1990s, preliminary findings suggested that nonimpaired heterozygotes were at risk of early menopause and increased rates of twinning, both indications of ovarian failure. Once premutation carriers could be distinguished from full mutation carriers, this phenotype was found to be restricted to premutation carriers only. Based on the recent studies reviewed here, approximately 21% of premutation carriers have premature ovarian failure (POF) compared to only 1% in the general population, or a relative risk of 21. Moreover, among women with idiopathic sporadic or the more rare form of familial POF, approximately 2% and 14%, respectively, carry the premutation. To date, data supporting increased twinning rates are conflicting and need to be resolved. Neither the underlying cellular pathophysiology of POF caused by the premutation allele nor molecular mechanism underlying the presence of the long repeat tract of the premutation allele is understood. Irrespective, women who carry the premutation allele should have not only genetic counseling but also fertility counseling to ensure that they reach their goals for reproduction. Am. J. Med. Genet. (Semin. Med. Genet.) 97:189–194, 2000. 2000 Wiley-Liss, Inc.
Article
Ovarian failure can result from several different genetic mechanisms—X chromosomal abnormalities, autosomal recessive genes causing various types of XX gonadal dysgenesis, and autosomal dominant genes. The number and precise location of loci on the X are still under investigation, but it is clear that, in aggregate, these genes are responsible for ovarian maintenance, given that monosomy X shows germ cells that undergo accelerated atresia. Despite recent hypotheses, at present there is no evidence for a gene directing primary ovarian differentiation; this process may be constitutive. Phenotypic/karyotypic correlation and limited molecular confirmation have long shown that proximal Xp and proximal Xq contain regions of the most importance to ovarian maintenance. Terminal deletions at Xp11 result in 50% primary amenorrhea and 50% premature ovarian failure or fertility. Deletions at Xq13 usually produce primary amenorrhea. Terminal deletions nearer the telomeres on either Xp of Xq bring about premature ovarian failure more often than complete ovarian failure. The X-linked zinc finger gene (ZFX) and diaphanous 2 Drosophila homologue (DIAPH2) are the only candidate genes for ovarian maintenance that map to the X chromosome. Additional, as yet unidentified, genes along the X chromosome must be involved. The search for these genes in humans is hampered by the lack of candidate genes that map to the X chromosome, the scarcity of patients with fortuitous autosomal translocations, and small pedigrees, which hinder mapping of the loci. In addition, difficulties with human germ cell research also make it challenging to dissect genes important to ovarian development. Autosomal genes also are involved in ovarian differentiation and gonadal failure. Follicle-stimulating hormone receptor and ataxia telangiectasia are examples of autosomal genes known to cause human ovarian failure. Transgenic mouse models point to many other candidate autosomal genes, and sequencing of the human homologues in affected women should lead to the discovery of new genes responsible for human ovarian failure. Identification, functional analysis, and mapping of novel genes specifically expressed in the ovary of mice and women eventually should lead to fruitful dissection of essential genes in mammalian ovarian development and maintenance. Am. J. Med. Genet. (Semin. Med. Genet.) 89:186–200, 1999. © 2000 Wiley-Liss, Inc.
Article
To assess the occurrence of premature ovarian failure, the age-specific incidence rates of natural menopause were determined for a cohort of 1858 women born between 1928 and 1932. These women were identified as Rochester, Minnesota residents in 1950 and were followed for date and type of menopause. A total of nine experienced natural menopause before age 40 years, which represents a 1% risk of natural menopause to age 40. The annual incidence rates of natural menopause per 100,000 person-years were ten for ages 15 to 29 and 76 for ages 30 to 39. In the age group 40 to 44, the incidence of natural menopause increased greatly to 881 per 100,000 person-years at risk.
Article
Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance. By systematically searching for linkage in multiplex affected families, we mapped a locus for ODG to chromosome 2p. As the previously cloned follicle-stimulating hormone receptor (FSHR) gene had been assigned to 2p, we searched it for mutations. A C566T transition in exon 7 of FSHR predicting an Ala to Val substitution at residue 189 in the extracellular ligand-binding domain segregated perfectly with the disease phenotype. Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor. We conclude that the mutation causes ODG in these families.
Article
To determine the relative importance of family history as a predictor of early menopause. Case-control study. From a population-based survey of 10,606 women between 45 and 54 years of age, we selected 344 cases with early menopause (average age 42.2 years) and 344 age-matched controls who were still menstruating or who had a menopause after age 46 years. Subjects were interviewed about their medical and family history and blood was drawn for identification of women who were carriers for the classic or Duarte variant of galactosemia, a potential hereditary factor for early menopause. Logistic regression analysis was used to estimate the risk of an early menopause in women with and without a family history of early menopause. Overall 129 (37.5%) of the early menopause cases reported a family history of menopause before age 46 years in a mother, sister, aunt, or grandmother compared to 31 (9.0%) of controls yielding an odds ratio (OR) of 6.1 (95% confidence interval [CI] of 3.9 to 9.4) after adjustment for smoking history, education, parity, and body mass index. Risk for early menopause associated with family history of same was greatest: for family history in a sister, OR = 9.1 (95% CI 3.1 to 26.5); multiple relatives, OR = 12.4 (95% CI 4.4 to 34.2); and cases menopausal before age 40 years, OR = 8.4 (95% CI 2.5 to 31.2). Cases with a family history of early menopause were not more likely to have errors of galactose metabolism compared with cases without a family history or to all controls, nor did they possess Turner's stigmata such as short stature, but they were less likely to have brothers in their sibships. Although preferential recall of family history by women with early menopause could contribute to the association between family history and early menopause observed in this study, a genetic factor is also plausible including partial deletions of the X chromosome compatible with the deficiency of male siblings in cases with family history of early menopause.