ArticlePDF AvailableLiterature Review

Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)

  • The Center for Human Reproduction. New York, N.Y.
  • Center for Human Reproduction

Abstract and Figures

With infertility populations in the developed world rapidly aging, treatment of diminished ovarian reserve (DOR) assumes increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances with DOR, and is now utilized by approximately one third of all IVF centers world-wide. Increasing DHEA utilization and publication of a first prospectively randomized trial now warrants a systematic review. PubMed, Cochrane and Ovid Medline were searched between 1995 and 2010 under the following strategy: [ and ]. Bibliographies of relevant publications were further explored for additional relevant citations. Since only one randomized study has been published, publications, independent of evidence levels and quality assessment, were reviewed. Current best available evidence suggests that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. DHEA over time also appears to objectively improve ovarian reserve. Recent animal data support androgens in promoting preantral follicle growth and reduction in follicle atresia. Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA may, thus, represent a first agent beneficially affecting aging ovarian environments. Others can be expected to follow.
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REVIEW Open Access
Dehydroepiandrosterone (DHEA) supplementation
in diminished ovarian reserve (DOR)
Norbert Gleicher
and David H Barad
Background: With infertility populations in the developed world rapidly aging, treatment of diminished ovarian
reserve (DOR) assumes increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to
improve pregnancy chances with DOR, and is now utilized by approximately one third of all IVF centers world-
wide. Increasing DHEA utilization and publication of a first prospectively randomized trial now warrants a
systematic review.
Methods: PubMed, Cochrane and Ovid Medline were searched between 1995 and 2010 under the following
strategy: [<dehydroepiandrosterone or DHEA or androgens or testosterone > and <ovarian reserve or diminished
ovarian reserve or ovarian function >]. Bibliographies of relevant publications were further explored for additional
relevant citations. Since only one randomized study has been published, publications, independent of evidence
levels and quality assessment, were reviewed.
Results: Current best available evidence suggests that DHEA improves ovarian function, increases pregnancy
chances and, by reducing aneuploidy, lowers miscarriage rates. DHEA over time also appears to objectively
improve ovarian reserve. Recent animal data support androgens in promoting preantral follicle growth and
reduction in follicle atresia.
Discussion: Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new
concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA may, thus,
represent a first agent beneficially affecting aging ovarian environments. Others can be expected to follow.
Casson and associates were first to suggest therapeutic
benefits from supplementation with dehydroepiandros-
terone (DHEA) in women with diminished ovarian
reserve (DOR) [1]. They also suggested that, in micro-
nized form, the androgen offers potential for postmeno-
pausal steroid replacement, adjunctive to estrogen [2];
that its conversion may not be symmetrical, favoring
androgens over estrogen, with testosterone increasing
and estradiol remaining low [2]; that DHEA has immu-
nomodulatory effects [3], now therapeutically explored
in autoimmune diseases [4,5], that vaginally adminis-
tered DHEA, while delivering equivalent hormone, sub-
stantially diminishes bioconversion comparatively to oral
micronized products [6], and that abnormally low
adrenal DHEA secretion is potentiated by ovarian
hypertstimulation with gonadotropins [7].
They also reported that DHEA is well tolerated and
increases IGF-1 levels [8]. A main focus of this groups
work was, thus, the compensation of adrenal cortical
changes in aging women with DHEA [9].
Their initial therapeutic use of DHEA in patients with
DOR [1] was motivated by observed increases in IGF-1
after DHEA supplementation [8]. Since growth hormone
had been suggested to improve oocytes yields via IGF-1,
they hypothesized that DHEA may be able to achieve
similar effects. Though demonstrating improvement in
oocytes yields [1], their initial paper went unnoticed for
years, and initiated no follow up studies.
It was left to a 43 year old infertility patient to redis-
cover their paper, searching the literature for remedies
to overcome DOR. She, in a first in vitro fertilization
(IVF) cycle, had produced only a single egg and embryo,
and was advised to consider oocyte donation [10]. This
* Correspondence:
Center for Human Reproduction (CHR) and Foundation for Reproductive
Medicine, New York, NY, USA
Full list of author information is available at the end of the article
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
© 2011 Gleicher and Barad; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
lay-person, reviewing the medical literature, amongst
various suggested treatment options for improving low
egg counts, chose DHEA because it was the only medi-
cation in the United States (US) available without pre-
scription (DHEA in the U.S. is considered a food
In a second IVF cycle she produced three oocytes/
three embryos. Her oocyte and embryo yields after that
increased from cycle to cycle (Figure 1). In the ninth
IVF cycle, now age 44, gonadotropin dosages had to be
reduced because of concerns about potential ovarian
hyperstimulation, she still produced 17 oocytes (16
embryos) in that cycle alone.
Following nine consecutive all-freeze IVF cycles, her
change in ovarian function under DHEA supplementa-
tion (unknown to her physicians until after her 6th
cycle) initiated the prospective investigation of DHEA
[10]. Above noted initial patient will here be referred to
as index patient.Six years following this patientsself-
administration of DHEA, a recent survey of IVF centers
concluded that approximately one third of all IVF cen-
ters world-wide have started DHEA supplementation in
women with DOR [11].
Because patients, largely, were not willing to enter
randomization, a clinical trial of DHEA in the US (Clini- ID# NCT00419913) had to be abandoned.
Considering the usually limited time for conception left
for DOR patients, this cannot surprise. A multicenter
European trial involving centers in Austria, Switzerland
cancelled U.S. trial, had to be abandoned for the same
reasons. Only recently did an Israeli group, for the first
time, succeed in completing a small, prospectively ran-
domized study [12]. All other DHEA studies published
so far relied on other study designs.
An excellent recent study in a mouse model also
offers considerable support for DHEA supplementation.
This study very convincingly demonstrates the critical
importance of androgens in regulating ovarian develop-
ment and function [13]. In very elegantly designed
experiments, Sen and Hammer demonstrated that
androgens promote preantral follicle growth, while pre-
venting follicular atresia. Androgens, long considered
antagonistic to normal follicle development, thus, sud-
denly assume a central role in follicular development
and female fertility [13]. Noting the previously referred
to preferential conversion of DHEA to testosterone [2],
these observations offer a potential mechanism by which
DHEA supplementation improves ovarian function.
As only one, small prospectively randomized study,
addressing DHEA supplementation with DOR, has so
far been published (12), this review presents a compre-
hensive summary of all published data, indiscriminate of
studyformatand/orqualityassessment. Limitations of
presented data are, however, discussed in detail.
Search strategy, study selection, data collection and
We searched PubMed, Cochrane and Ovid Medline
between 1995 and 2010 for all publications under the
following key words: Dehydroepiandrosterone or DHEA;
androgens or testosterone; ovarian reserve or diminished
ovarian reserve; ovarian function or diminished ovarian
function. In addition, we explored the bibliographies of
all relevant publications for further relevant citations,
which had not been detected via the original search. So
identified publications were also in detail reviewed by
the authors, including their relevant citations. A total of
114 publications were, thus, reviewed for this publica-
tion, with 64 being cited in this manuscript. The 50
manuscripts reviewed but not referenced in the review
either contained no relevant information in regards to
the topic of this review and/or only recited data of ear-
lier published manuscripts, which are included in the
reference list of this manuscript.
Every published study, addressing DHEA supplemen-
tation in infertile women with DOR, was reviewed and
is cited in this manuscript. No selection of materials for
Figure 1 Oocyte and embryo counts in index patient.The
patient underwent nine consecutive IVF cycles and increased
oocytes and embryo yields from cycle to cycle, starting with one
egg and embryo, respectively, and ending up with 17 oocytes and
16 embryos in her ninth cycle. Gonadotropin stimulation was
reduced in her last cycle for concerns about possible ovarian
hyperstimulation. The patients advised us of her DHEA
supplementation only after her sixth cycle. The figure is modified
from Barad and Gleicher, with permission, [10].
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 2 of 12
inclusion or exclusion, therefore, took place. All publica-
tions were reviewed by both authors, who agreed with
analysis and interpretation of data.
IRB approval
tions, no Institutional Review Board (IRB) approval was
required for this study. All materials from the authors
own center had previously been accumulated (and pub-
lished) after appropriate IRB review.
Clinical experience
Increase in oocytes and embryo yields
Casson et al. did not claim direct DHEA effects on DOR
ovaries. They, instead, suggested that DHEA supplemen-
tation appears to augment ovarian stimulation with
gonadotropins in poor responders, resulting in improved
oocytes yields [1]. Likely due to their small study popu-
lation, their paper failed to elicit follow up until pre-
viously noted index patient, five years later, rediscovered
their publication [10].
Like the paper by Casson et al [1], the index patients
experience initially suggested that improvements from
DHEA supplementation were primarily quantitative
(better oocyte yields), and even greater than originally
reported by the Baylor group. Moreover, the index
patients longitudinal experience over nine IVF cycles
also demonstrated continuous improvements in oocyte
(and embryo) numbers with increasing length of DHEA
Cumulative DHEA effects over time, in turn, sug-
gested possible effects on follicle recruitment or, as
previously reported by the Baylor group, a synergistic
effect between DHEA and gonadotropins [8]. One,
therefore, at that point could conclude that DHEAsup-
plementation, potentially, may not only offer improving
oocyte numbers, but also improving ovarian reserve
(OR). Since the Baylor group had only attempted to
address the problem of poor response to ovarian sti-
mulation [1], this conclusion represented a significant
expansion of the concept underlying the utilization of
Concentrating on DHEA effects on OR significantly
changed concepts since OR, defined by size and quality
of remaining follicles within ovaries [14,15], presumed
DHEA effects on ovaries beyond just one stimulation
cycle. DHEA would then not only have to impact oocyte
and embryo numbers but also oocyte and embryo qual-
ity and, therefore, ultimately, pregnancy success. In
absence of prospectively randomized studies, and with
use of other study formats, conclusions, of course, have
to be drawn cautiously.
Improvements in oocytes and embryo quality
The first 25 DOR patients, supplemented with DHEA in
paired analysis of pre- and post-DHEA cycles, confirmed
significant increases in oocytes and embryo numbers,
previously observed in the index patient [16]. They,
however, also demonstrated improved embryo quality,
including better embryo grades, average embryo scores
and, most importantly, better embryo numbers available
for transfer.
Since low embryo numbers are a principle characteris-
tic of DOR, this observation further supported the
hypothesis that DHEA may also positively affect preg-
nancy chances. Uniformity of quantitative and qualita-
tive IVF outcome improvements (Table 1) also
encouraged such thought.
Improvements in pregnancy rates
In a subsequently larger cohort of 89 DOR patients,
supplemented with DHEA for up to four months, and
in 101 controls, DHEA patients demonstrated shorter
time to pregnancy and higher pregnancy rates (cumula-
tive clinical pregnancies, 28.1% vs. 10.9%; 95% CI 1.2-
11.8; p < 0.05), despite prognostically more favorable
controls (more oocytes, P < 0.01; normal day-3 embryos,
P < 0.05; and more embryos transferred, P < 0.05).
Moreover, study patients were also older (41.6 ± 0.4 vs.
40.0 ± 0.4 years) [17].
DHEA thus improved all outcome parameters, even
though patient selection was biased against such find-
ings. This study for the first time also suggested primacy
of egg and embryo quality over egg and embryo
[Though not part of here reported literature review, we
find it noteworthy that, concomitantly, Edward Ryans
Table 1 Comparisons of pre- and post-DHEA cycles in 25
women with DOR*
Pre-DHEA Post-DHEA p-value
Cycle cancellations (%) 32.0 4.3 0.02
Number oocytes 3.4 ± 0.5 4.4 ± 0.5 <0.05
Fertilized oocytes (n) 1.4 ± 0.3 3.0 ± 0.5 <0.001
(%) 39 67 <0.001
Day 3 blastomeres 3.4 ± 0.4 4.7 ± 0.5 0.01
embryo grade 2.9 ± 0.1 3.4 ± 0.1 0.02
Cumulative embryoscore/oocytes 8.4 ± 1.5 16.1 ± 1.6 0.001
Number of transferred embryos 1.4 ± 0.2 2.4 ± 0.3 0.005
Normal day 3 embryos 1.2 ± 0.2 2.7 ± 0.4 0.001
* 25 patients were evaluated in their respective IVF cycle outcomes pre- and
post-DHEA. This study design potentially biases outcome against positive
DHEA effects since patients who entered DHEA supplementation after a prior
failed IVF cycle, quite obviously, reflected, in view of their prior IVF treatment
failure, a negatively selected patient population. Pre- and post DHEA cycles
occurred at ages 39 ± 0.8 and 40.4 ± 0.8 years, respectively, also mildly
biasing the study against positive DHEA findings. Post-DHEA patients were on
supplementation 17.6 ± 2.13 weeks by time of second IVF cycle. Data
extracted from Barad and Gleicher [16].
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 3 of 12
Toronto West Fertility Center had started utilizing
DHEA in women with DOR. This group in subsequent
years in a number of abstracts reported significantly
improved clinical pregnancy rates in hundreds of IVF
and insemination cycles, using varying ovarian stimula-
tion protocols (Ryan E, Personal communication, 2009).
In cooperation with Robert F Casper from Torontos
Mount Sinai Hospital and University of Toronto, they
more recently reported on 47 patients with prior clomi-
phene citrate failures who, supplemented with 75 mg
DHEA daily for at least 60 days prior to inseminations,
with stimulation by either clomiphene citrate or letrozole
in combination with FSH. Controls were 46 women,
matched by age and baseline FSH, without supplementa-
tion. DHEA patients demonstrated significantly higher
antral follicle counts, significantly improved pregnancy
rates (29.8 vs. 8.7%; CI 1.3-14.8) and live births (21.3%
and 6.5%, respectively) [18], numbers remarkably similar
to those earlier reported from our center [17].]
From Turkey, Sönmezer and associates reported on 19
poor respondersto ovarian stimulation [19]. After
DHEA, this group experienced significant decreases in
cycle day-3 estradiol levels, increased large follicle num-
bers, MII oocytes, top quality day-2 and day-3 embryos,
reduced cycle cancellations and improved pregnancy
rates per patients (47.4% vs. 10.5%, P < 0.001) and per
embryo transfer (44.4% vs. 0.0%, P < 0.01).
Wiser and associates most recently presented the first
prospectively randomized study of DHEA supplementa-
tion with DOR ( ID # NCT01145144)
(12). While small (17 study and 16 control patients),
DHEA patients demonstrated improved embryo quality
over time (P = 0.04), with increasing length of DHEA
supplementation and significantly higher live birth rates
(23.1 vs. 4.0%; P = 0.05).
While in our opinion the study was underpowered
since the authors counted 55 IVF cycles in 33 patients,
thus including repeat IVF cycles without evidence of
adjustments via the randomization schedule, it, never-
theless, has to be considered a milestone in view of
prior failed attempts to conduct such studies.
Premature versus physiologic DOR
When DOR patients were separated into those with age-
dependent DOR and women with so-called premature
ovarian aging (POA) [17], also given the acronym occult
primary ovarian insufficiency (OPOI) (20), DHEA sup-
plementation proved similarly effective in both groups,
though POA patients did mildly better. The beneficial
effects of DHEA increased with length of DHEA supple-
mentation, documented by increasing discrepancy in
cumulative pregnancy rates between the groups over
time (Figure 2) [17].
This confirmed initial observations in the index
patient [10]. DHEA effects occur relatively quickly
(apparently within ca. 2 months) but peak only after 4-5
months of DHEA supplementation. Our center, there-
fore, supplements DHEA for at least six weeks prior to
IVF cycle starts, though even longer pretreatment may
be used in younger patient.
Surprising numbers of spontaneously conceived preg-
nancies during these waiting periods suggest that
DHEA, alone, can in DOR patients raise fecundity [17].
Figure 2 Cumulative pregnancy rates in women with DOR with and without DHEA supplementation. The figure demonstrates on the left
side cumulative pregnancy rates in DHEA and control patients with POA (for definition see text). The right side of the figure demonstrates
cumulative pregnancy rates in women above age 40 years. Both patient populations demonstrate similar treatment benefits for DHEA, though
POA patients appear to have a slight pregnancy advantage, further confirmed in later data presentations. Modified with permission from Barad
et al [17].
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 4 of 12
Premature ovarian failure (POF)/primary ovarian
insufficiency (POI)
POA/OPOI has to be differentiated from outright pre-
mature ovarian failure (POF), also called primary ovar-
ian insufficiency (POI) [20]. Mamas and Mamas claimed
a small case series of five alleged POF/POI patients,
who spontaneously conceived while on DHEA [21].
Intriguing in concept, the report should, however, be
viewed with caution since three of the five reported
patients do not qualify for a diagnosis of POF/POI and,
likely, more resemble POA/OPOI patients [22]. Mamas
and Mamas, however, reiterated their claim [23] and in
a personal communication advised us of additional preg-
nancies in DHEA supplemented POF/POI patients
(Mamas L, Personal communication, ESHRE Annual
Meeting, Amsterdam, The Netherlands, July 2009).
Anecdotally, we recently recorded, after 4 months of
DHEA supplementation, a spontaneous pregnancy in a
38 year old woman with POF/POI (highest recorded FSH
100.0 mIU/mL). A registered clinical trial of DHEA in
POF/POI patients ( ID#NCT00948857)
is currently underway at our center but is not expected
to yield results for at least two more years.
Effects on embryo ploidy, miscarriage risk and live birth
In her last IVF cycle the index patient offered to have 10
of her embryos investigated for aneuploidy [10].
Only one was euploid. Limitations in current methods
of preimplantation genetic screening (PGS) restrict
applications of PGS in women with DOR since small
embryo numbers mostly preclude PGS [24]. In 2007, a
small pilot study demonstrated in 100 percent of DHEA
treated but only 53 percent of control IVF cycles at least
one euploid embryo (p < 0.05) [25]. Patient selection
was again biased against DHEA since DHEA supple-
mented women were older than controls and, therefore,
should have demonstrated higher aneuploidy rates.
Though offering statistically significant results, study
results of this pilot also had to be viewed cautiously
because of small study numbers and potential biases
and patient selection. Better numbers and superior
selection of controls in a more recently published study
permitted for more reliable results, which confirmed sig-
nificant decreases in aneuploidy after DHEA supplemen-
tation [26].
In absence of adequate PGS numbers, close statistical
associations between aneuploidy and spontaneous preg-
nancy loss [27] offered an indirect way to investigate the
issue. In a combined effort with Edward Ryans Toronto
center, enough DHEA pregnancies had been established
to allow for a statistically robust analysis of miscarriage
rates. As at least 60 percent of miscarriages are asso-
ciated with chromosomal abnormalities [27], a DHEA
effect on ploidy should be statistically reflected in lower
miscarriage rates, and this was, indeed, confirmed [28].
Depending on statistical method utilized, pregnancy
loss after DHEA supplementation was reduced by 50 to
80 percent in comparison to national U.S. IVF preg-
nancy rates, a conclusion further strengthened by the
following: (i) Miscarriage rates in Toronto and New
York were practically identical (15.2 and 15.0%, respec-
tively); (ii) The U.S. national IVF registry, used as con-
trol population, in contrast to DHEA patients, included
only relatively few DOR patients. Women with DOR are
known to demonstrate significantly increased miscar-
riage rates in comparison to other infertility etiologies
Makeup of controls, therefore, biased the study against
findings favoring DHEA supplementation; (iii) The com-
bined miscarriage rate of 15.1 percent in DHEA pre-
treated patients at both IVF centers is reflective of
spontaneous miscarriage rates for normal, fertile popula-
tions [30]; (iv) DHEA effects on miscarriage rates were
small under age 35 years but increased progressively
after that age (Figure 3).
Increasing aneuploidy with advancing female age, of
course, would suggest increasing effectiveness of DHEA
with advancing female age. A beneficial DHEA effect on
embryo ploidy, therefore, appears likely, and seems to
increase with age.
Recent data further support these conclusions (Figure
4): Miscarriage rates, even with most severe DOR, are
very low after DHEA supplementation. Between non-
detectable anti-Müllerian hormone (AMH) of <0.1 and
0.4 ng/mL they remain equal to those seen in normally
fertile women, increase at AMH 0.41 - 1.05 ng/mL to
over 50 percent of all pregnancies established,
Figure 3 Age-stratified miscarriage rates in DHEA
supplemented DOR patient in comparison to national U.S. IVF
pregnancies. DHEA pretreated patients demonstrated significantly
lower miscarriage rates at all ages. The difference was, however,
relatively small under age 35 years and progressively increased after
that age. Modified with permission from Gleicher et al [28].
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 5 of 12
representing the expected rate in DOR patients [29],
only to fall off again above AMH 1.05 ng/mL [31]. With
miscarriage rates, likely due to DHEA supplementation,
being very low under AMH 0.4 and above 1.05 ng/mL,
the question arises why this effect is not also seen at
AMH levels of 0.41-1.05 ng/mL?
Trying to find an answer, we investigated 39 sponta-
neous pregnancies in DOR patients on DHEA, con-
ceived before they reached their first IVF cycle. Figure 4
depicts miscarriage rates of spontaneous in comparison
to IVF pregnancies, demonstrating that spontaneous
pregnancies experienced at all low AMH levels almost
identically high miscarriage rates around approximately
50 percent of all pregnancies established. They, thus,
demonstrate expected pregnancy loss rates for DOR
patients [29], and do not seem to benefit from DHEA
supplementation like IVF pregnancies.
Spontaneous pregnancies were, of course, conceived
after shorter exposure to DHEA than IVF pregnancies
since, as noted above, our centers DOR patients are at
least for six weeks on DHEA supplementation before an
IVF cycle is initiated. Patients who conceive sponta-
neously on DHEA during this waiting period,there-
fore, by definition, had shorter DHEA exposure times.
This observation then leads to the conclusion that
shorter exposure times may be enough to raise fecundity
but may not suffice to positively affect ploidy and mis-
carriage rates.
Predicting the effectiveness of DHEA
AMH levels are predictable of treatment outcomes after
DHEA utilization [31,32]. Table 2 summarizes how
AMH levels relate to chance of conception and live
births in IVF pregnancies: Even with complete absence
of detectable AMH, an approximately five percent preg-
nancy chance per IVF cycle can be obtained. Since mis-
carriage rates are very low, pregnancy and live birth
rates are very close. Outcomes remain the same up to
AMH 0.4 ng/mL, when clinical pregnancy chances
approximately double. Live birth rates remain, however,
unchanged since at AMH 0.41-1.05 ng/mL spontaneous
pregnancy wastage increases. Above those AMH levels
pregnancy chances greatly improve and miscarriage risk
recedes once again to much lower levels [31].
separation between poorer and better live birth chances:
Up to AMH 1.05 ng/mL the chance of live birth per
treatment cycle is only approximately 5 percent. Above
that, chances are significantly improved [31].
AMH increases in parallel to length of DHEA supple-
mentation, and this increase is more pronounced in
younger POA than older DOR patients [32] (Figure 5).
Moreover, improvements in AMH are statistically highly
predictive of pregnancy success [32] but do not yet
allow for accurate prediction of who will and will not
conceive with DHEA supplementation. AMH responses
to DHEA, however, facilitate proper informed consent,
particularly important in view of recent ethics guidelines
on fertility treatments in poor prognosis patients [33].
Treatment protocols, side effects and complications
Except for the previously noted studies by the Baylor
group, few other pharma studies have address DHEA
utilization, and those were usually restricted to postme-
nopausal women [34]. Building on the Baylor groups
work, the index patient supplemented with micronized
DHEA. She utilized over-the-counter products, which
have been found inconsistent [35]. Though products are
now, likely, improved, we primarily utilize pharmaceuti-
cal grade, compounded DHEA, by prescription at a
dosage of 25 mg TID. Other authors, including Wiser et
al in their recently published clinical trial [12], have
used the same dosage of DHEA.
No studies on maximal dosaging of DHEA have, how-
ever, been reported, nor have delivery systems been
compared. The Baylor group demonstrated distinct
Figure 4 Spontaneous pregnancy loss in spontaneous and IVF
pregnancies at various AMH levels. The figure depicts at various
AMH levels in the left column IVF pregnancies (IVF), as previously
reported [Gleicher et al. (31)], and in the right column
spontaneously conceived pregnancies (SP). Each column represents
100% of all pregnancies established, separated for live births (black
section), voluntary termination of pregnancy (TOP; usually for
aneuploidy) and spontaneous miscarriages (SAB). The figure
demonstrates that at very low AMH levels (0.40 ng/mL) and at
AMH 1.06 ng/mL. IVF pregnancies led to significantly higher live
birth rates than spontaneously conceived DHEA pregnancies.
Lowest pregnancy and live birth rates were observed with IVF and
spontaneously between AMH 0.41-1.05 ng/mL, with no
spontaneous DHEA pregnancies at all at AMH 0.81-1.05 ng/mL.
While in IVF pregnancies miscarriage rates were clearly reduced at
very low and at higher AMH, miscarriages appeared unaffected
(~50%) in spontaneously conceived pregnancies.
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 6 of 12
advantages from micronized and orally delivered DHEA
Side effects at these dosages are small and rare, and
primarily relate to androgen effects.
They include oily skin, acne vulgaris and hair loss.
More frequently, patients comment on improved energy
levels and better sex drive. In over 1,000 patients sup-
plemented with DHEA, we did not encounter a single
complication of clinical significance. A recent paper
from Israel reported a posttraumatic seizure after one
month of DHEA supplementation in attempts to
improve oocytes yields [36]. Except for the anecdotal
association, there appears no clinical significance to this
report. Even long-term therapy of DHEA, in similar
dosages as described here, has been demonstrated safe
DHEA was recently listed amongst drugs with orphan
indicationsin fertility therapy [38]. Our center, never-
theless, requires a DHEA-specific informed consent
before treatment start.
Two other indications for DHEA supplementation are
currently still under investigation in randomized, pla-
cebo controlled trials. Those are unexplained infertility
( ID#NCT00650754) and POF/POI
( ID# NCT00948857).
How does DHEA affect OR?
How DHEA improves OR, IVF parameters, pregnancy
chances and decreases miscarriage rates is, ultimately,
still unknown. Improved embryo ploidy may, at least in
part, explain improvements in miscarriage rates, sponta-
neous pregnancies and pregnancies after IVF since this
would suggest a method of pharmacological embryo
Hodges et al suggested that treatments can be devel-
oped which will reduce the risk of age-related aneu-
ploidy by influencing meiotic chromosome segregation
[39]. Major disturbances in chromosome alignments on
the meiotic spindle of oocytes (congression failure),
responsible for aneuploidy, result from the complex
interplay of signals regulating folliculogenesis, and
increase the risk of non-disjunction errors. Discussed in
more detail below, DHEA may, indeed, represent a first
such treatment!
Other DHEA effects have, however, also to be consid-
ered: The Baylor group suspected increased ovarian
IGF-1 to be responsible for observed DHEA effects
[1,8]. IGF-1, indeed, appears reduced in poor responders
Androgens, in general, may enhance ovarian function:
Already a few decades ago, androgens were in the
Table 2 Effectiveness of DHEA supplementation in IVF pregnancies based on preconception AMH levels
DHEA effects Reference
Pregnancies/live births at all AMH levels; Not even undetectable levels of AMH, therefore, preclude pregnancies/live births; [31]
Pregnancies lowest
at AMH levels <0.1 (undetectable) -0.4 ng/mL, intermediate
at AMH 0.41-1.05 ng/ML and high
AMH 1.06 ng/
Spontaneous miscarriage rates lowest
at AMH 0.4 ng/mL and 1.06 ng/mL; Highest
at AMH 0.41-1.05 ng/mL; [31]
Live births rates uniformly low
at AMH <0.1-1.05 ng/mL and high
at AMH 1.6 ng/mL; [31]
AMH increases in parallel with length of DHEA supplementation; [32]
This increase is more pronounced in younger POA than older DOR patients; [32]
Improvement in AMH levels with DHEA supplementation is highly predictive of pregnancy success [32]
Approximately 5% per cycle, 10% cumulative;
Approximately 10% per cycle and 17% cumulative;
Approximately 28% per cycle and 42% cumulative;
Approximately <15%;
Approximately 50%;
Approximately 4% per cycle, 7% cumulative;
Approximately 22% per cycle, 32% cumulative;
Date extracted from Gleicher et al [31].
Figure 5 AMH in POA and DOR patients over time of DHEA
exposure. As the figure demonstrates, AMH increases significantly
with length of DHEA treatment (————). This effect is more
pronounce in young POA patients (---) than older DOR patients
(......). Modified with permission from Gleicher et al [32].
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 7 of 12
mouse reported to increase follicle recruitment [41].
Increasing intrafollicular androgens augments granulose
cell AMH and inhibin-B production [42].
Androgen receptors have been described in ovarian
stroma and granulose cells of primordial follicles, pri-
mary follicles and at more advanced stages of folliculo-
genesis [43]; and ovarian androgens but not estrogens
correlate with systemic inflammation during ovarian sti-
mulation with gonadotropins [44].
Frattarelli and Peterson reported that day three testos-
terone levels below 20 ng/dL are associated with poorer
IVF pregnancy rates [45]. They later reported an asso-
ciation with IVF stimulation parameters but not with
pregnancy chance [46]. Iranian investigators recently
reported that testosterone on day 14 after embryo trans-
fer is predictive of pregnancy chance [47]. Lossl et al
published contradictory papers, one claiming [48] and
one refuting [49] that treatment with aromatase inhibi-
tors (increasing androgens) improves embryo quality.
Contradictory results have also been reported by French
investigators in regards to short-term transdermal tes-
tosterone administration, with Massin et al reporting no
benefit [50], and the Balaschs group in two publications
stressing beneficial effects on ovarian resistance [51,52].
demonstrated that transdermal testosterone appears to
improve ovarian response to stimulation and IVF out-
come in low responders [53].
The, likely, most important study in support of essen-
tial androgen effects on follicle development and normal
female fertility was recently, however, reported by Sen
and Hammes [13]. These two authors were encouraged
towards their study by previously reported observations
in global androgen receptor knockout (ARKO) female
mice, characterized by reduced androgen signaling, and
subfertility. The mice also demonstrate defective follicu-
logenesis, decreased antral follicle counts and corpora
lutea, exhibit higher granulose cell apoptosis, are resis-
tant to ovarian stimulation with gonadotropins and
often develop POF.
While androgen excess in animal and human experi-
ence has widely been associated with excessive and unre-
gulated follicle formation, Sen and Hammes suspected
that androgen signaling via androgen receptors may actu-
ally be important for normal follicle development and
function. Since androgen receptors are widely expressed
in different cell types, they decided to determine which
androgen receptor - expressing cells contribute to ovar-
ian function and fertility in female ARKO mice.
Using this elegant mouse model they concluded that
almost all reproductive phenotypes they observed in glo-
bal ARKO mice can be explained by lack of androgen
receptor expression in granulose cells. Granulosa cell -
specific androgen receptors, indeed, appear to promote
preantral follicle growth and to prevent follicle atresia.
The authors, therefore, concluded that androgen recep-
tors (and by extension androgens) are essential for nor-
mal follicle development and female fertility [13].
Speculating about the future
A new concept of age-related declining fecundity
IVF has revolutionized infertility care since it offers
tools to maximize pregnancy chances while minimizing
multiple pregnancy risks [54]. Even in association with
DOR IVF has radically changed the clinical outlook,
with pregnancy and live birth rates in women at even
advanced reproductive ages constantly improving
[31,32,55]. In the US women above age 40, now, repre-
sent the most rapidly growing age group giving birth
Since young women with normal age-appropriate OR
conceive quickly, POA and/or DOR patients, due to
their lower pregnancy chances, disproportionally accu-
mulate in infertility centers, needing more IVF cycles.
The mean age of newly presenting patients at our center
during 2009 was above 39.5 years. Premature or age-
dependent DOR represented close to 90 percent of IVF
cycle activity (Figure 6). DOR is, therefore, assuming
increasing clinical importance, and potentially effective
clinical approaches, like DHEA, are attracting wide
Pharmaceuticals, stimulating ovaries, have been at the
center of clinical and research interests in reproductive
medicine for the last five decades. All agents developed
and/or investigated affect follicle maturation, though
only during final stages, the so-called gonadotropin-sen-
sitive last two weeks. Here reviewed DHEA effects, in
contrast, appear to affect folliculogenesis at much earlier
If confirmed, these observations on DHEA could open
ovarian stimulation to radically new horizons, for the
first time directing pharmacological interventions
towards earlier stages of in vivo follicle maturation.
Declining female fecundity with advancing age is
based on diminishing follicle numbers and deteriorating
egg quality [14,15,56]. While declines in follicle numbers
are undisputed, the here presented DHEA experience
raises, however, questions about the widely held under-
standing that declining egg quality with advancing
female age is caused by aging oocytes.
Young women with prematurely DOR exhibit most
typical signs of ovarian aging, such as elevated FSH, low
AMH and ovarian resistance to stimulation, but do not
demonstrate increased aneuploidy [57]. Their oocytes
thus, quite obviously, are functionally not behaving old
enough to lead to aneuploidy, while oocytes from older
women, indisputably, demonstrate increased aneuploidy
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 8 of 12
We previously noted that DHEA supplementation
apparently significantly reduces these age-related
increases in aneuploidy [25,26], and, therefore, also
reduces age-associated increases in miscarriages
[28,31]. In absence of healthy and genetically normal
oocytes both of these findings are inconceivable.
DHEA is, therefore, either able to revert older,
already damaged oocytes, into youngeroocytes, in
itself a rather unlikely proposition, or one has to con-
clude that, contrary to current dogma [15,56], oocytes
in their resting stages within unrecruited primordial
follicles do not really age.
Once recruited, they, however, enter age-dependent
ovarian environments where follicle maturation takes
place. These ovarian environments can be of different
quality and will, uniformly, deteriorate as women age.
As proposed by Hodges et al, these environments affect
segregation processes during meiosis, giving rise to
increased aneuploidy at older ages. Hodges and associ-
ates, however, also pointed out that these envriron-
ments, and with it aneuploidy and miscarriage rates,
may be open to pharmacologic manipulation [39].
Here presented DHEA data, therefore, support the
concept that ovarian environments, but not resting
oocytes, age as women grow older. Under such a con-
cept here described DHEA effects are perfectly under-
standable. DHEA levels, indeed, peak in humans
between ages 20 and 30 years, and then decline by
approximately 2 percent per year, to reach nadirs of 10
to 20 percent around age 80 years [58].
In some women, aneuploidy may, thus, simply, repre-
sent a reversible DHEA deficiency. Others may lack yet
to be determined components of healthy ovarian
environments and, therefore, may benefit from other
Proven correct, one can expect a significant expansion
of the females reproductive lifespan as science learns
how to reconstitute ovarian environments, mimicking
conditions of younger ages. Since even menopausal
ovaries still contain follicles and oocytes [14], at least
theoretically, childbirth may be expandable into the 50s.
In the Squirrel monkey, older animals, immediately
prior to cessation of reproduction, still demonstrate an
abundance of well-differentiated granulosa cells [58].
Assuming that unrecruited oocytes maintain their youth
and that aged ovarian environments can be rejuvenated,
smaller, but healthier, egg cohorts may, indeed, allow
for pregnancy into surprisingly advanced female ages.
DHEA may, therefore, represent a first compound in a
new category of pharamacological agents with potential
to rejuvenateovarian environments. Following a simi-
lar concept, Bentov et al., based on the known loss of
mitochondrial functions with advancing age, recently
suggested the use of mitochondrial nutrients, like coen-
zyme Q10 (CoQ10), after demonstrating that CoQ10
increases oocytes numbers in older mice [59]. Andro-
gens positively affect mitochondrial function [60].
A better understanding of differences in ovarian envir-
onment between younger and older women will be
needed to discover additional beneficial pharmacological
agents. The technology for such studies is being devel-
oped [61].
Utilization of DHEA outside of infertility
Ovarian aging does not only affect infertile women. Age-
dependency of fecundity is driven by the
Figure 6 Trends in patient characteristics of our centers IVF population. Panel A demonstrates mean ages for IVF patients between 2005
and year-to-date 2009. Panel B demonstrates proportional shift from younger patients (<39 years) to older women (40 years). Panel C
demonstrates that this age shift is also accompanied by a significant fall in AMH levels in younger women (ages 31-35 years) and, therefore,
increasing DOR in these younger (POA) patients. Combined, these data explain why in 2009 close to 90% of the centers population was
affected by either POA or DOR.
Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
Page 9 of 12
acknowledgment that ovaries age with expected adverse
consequences, including longer times to conception,
increased aneuploidy and increased spontaneous miscar-
riages risks.
One, therefore, can also conceive of potentially utiliz-
ing DHEA, and other pharmaceuticals able to rejuvenate
ovarian environments, in normally fertile, older women
attempting to conceive. Like supplementation with folic
acid to prevent neural tube defects [62], supplementa-
tion with DHEA may achieve favorable public health
consequences by potentially reducing aneuploidy and
spontaneous pregnancy losses in a general population.
Despite worldwide utilization of DHEA supplementation
in women with DOR, lack of enough controlled studies
is still regretful. With the small study by Wiser et al
[12] representing the only prospective clinical trial
(Level I evidence), studies of more substantial size are
all based on lower levels of evidence and, therefore,
have to be interpreted cautiously. This fact is reempha-
number of centers, including, these authorsown center.
Purists may argue that no treatments should be routi-
nely applied in clinical practice, unless based on pro-
spectively randomized studies. Recognizing that Level I
clinical trials may, at times, be too costly and/or too dif-
ficult to conduct, such an approach has, however,
recently been questioned in the academic community
Best available evidence for the utilization of DHEA sup-
plementation in improving ovarian performance in
women with DOR was reviewed. A small, recently pub-
lished clinical trial [12] and remarkable animal data [13]
offer increasingly convincing clinical and experimental
support for the use of DHEA, and possibly other andro-
gens, in women with DOR.
These newly available data add to Level II and III evi-
dence, generated by a small number of investigators,
these authors included, over the preceding six years.
Combined, these data suggest that DHEA supplementa-
tion may be effective in improving pregnancy chances in
women with DOR. Since a DOR diagnosis often leaves
limited time for treatment, patients should be given the
choice of DHEA supplementation, though with appro-
priate informed consents. Especially with severe DOR,
DHEA may, at least in some patients, make the differ-
ence between conceptions with autologous or heterolo-
gous oocytes.
Considering absence of significant side effects and, at
least within the US, availability of DHEA as a food sup-
plement, here presented data support utilization of
DHEA in association with DOR, though attempts should
be made to further define best suited patient popula-
tions for such treatment, maximally effective treatment
protocols and best delivery systems.
AMH: Anti-Müllerian hormone; ARKO: Androgen receptor knock out; CoQ10:
Coenzyme Q10; DHEA: dehydroepiandrosterone; DOR: diminished ovarian
reserve; IVF: In vitro fertilization; OPOI: Occult primary ovarian insufficiency;
OR: Ovarian reserve; PGS: Preimplantation genetic screening; POF: Premature
ovarian failure; POI: Primary ovarian insufficiency; U.S.: United States;
This study was supported by the Foundation for Reproductive Medicine and
intramural research grants from the Center for Human reproduction (CHR) -
New York. The authors wish to acknowledge and to thank E. Ryan, MD
(Toronto West Fertility Center, Toronto, Canada) and L. Mamas, MD (Athens,
Greece) for the personal communications, noted in the body of the
Author details
Center for Human Reproduction (CHR) and Foundation for Reproductive
Medicine, New York, NY, USA.
Department of Obstetrics, Gynecology and
Reproductive Sciences, Yale University School of Medicine, New Haven, CT,
Departments of Epidemiology and Social Medicine and Obstetrics,
Gynecology and Womens Health, Albert Einstein College of Medicine, Bronx,
NG and DHB contributed equally to this manuscript. Both authors read and
approved the final manuscript.
Competing interests
Unless otherwise noted, each author and spouse/life partner (if any) has
nothing to disclose. Both authors are listed as co-inventors of a U.S.
patent, which claims beneficial effects from DHEA supplementation in
women with diminished ovarian reserve on ovarian function and
pregnancy rates. Both authors are also listed as inventors on other, still
pending patent applications in regards to DHEA effects on ovarian
function, and on other patents, unrelated to the topic of this
communication. Neither author derives financial benefits from any of these
patents. Both authors received in the past research support, speaker
honoraria and travel funds from various pharmaceutical and medical
device companies, though none of these companies is related in any
fashion to the topic, covered in this manuscript.
Received: 7 March 2011 Accepted: 17 May 2011 Published: 17 May 2011
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Cite this article as: Gleicher and Barad: Dehydroepiandrosterone (DHEA)
supplementation in diminished ovarian reserve (DOR). Reproductive
Biology and Endocrinology 2011 9:67.
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Gleicher and Barad Reproductive Biology and Endocrinology 2011, 9:67
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... The zona reticularis layer of the adrenal cortex and the theca cells of the ovary create DHEA, an important prohormone, when they synthesize testosterone and estradiol from cholesterol [138]. Its levels are seen to be high, particularly in the early stages of reproduction, and to decrease with age [116,139]. Several phases of folliculogenesis have seen the identification of androgen receptors (AR) [140]. By stimulating primordial follicles in monkeys [141,142] and mouse models, androgens were found to increase the number of primary follicles [143]. ...
... Following Casson's original study, numerous studies in mice and humans with poor responders were carried out using different doses (10-80 mg per day) of DHEA administration for various lengths of time (pre-IVF treatment or concurrently with ovarian DOI: stimulation), and it was found that improved ovarian function was associated with an increase in ovarian response and a decrease in the number of atretic follicles [123,139]. When DHEA was pretreated for at least 8 weeks prior to IVF treatment, Li et al. found that the CCs of women older than 38 years produced more energy and had higher-quality oocytes [124]. ...
... DHEA can also reduce the rate of CC apoptosis in aged follicles [154]. It is believed that DHEA will improve the ovarian microenvironment and reduce agerelated embryonic aneuploidy [139]. ...
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The ovarian milieu, which includes increased vasculature, different growth factors, necessary hormone synthesis, and appropriate granulosa cell function, is essential for oocyte maturation. Keeping the microenvironment in a state of equilibrium is crucial for healthy ovarian function. However, as people age, their tissues rebuild less effectively, leading to an imbalance in the microenvironment’s homeostasis and ovarian fibrosis, which finally causes ovarian function to deteriorate. As a result, full restoration of ovarian microenvironment health is required to enhance ovarian function. The precise identification of the molecular pathways involved in ovarian aging can help to devise therapy techniques that can decrease ovarian decay and boost the amount and quality of oocytes available for IVF. Antioxidants, melatonin, growth hormones, and mitochondrial and cell therapy are among the available treatments. All of these treatments must be considered in light of every couple’s history and current biological parameters, and a personalized (patient-tailored) therapy program must be developed. In this chapter, we aim to give an overview on the identified mechanism involved in female reproductive aging and potential therapeutic approaches to amend reproductive efficiency.
... Previous studies have directly compared the efficacy and safety of adjuvant treatment strategies for POR [7,14,16,17]. However, traditional meta-analysis can only compare direct evidence and cannot determine the most effective treatment measures for patients with POR. ...
... This study suggests that POR patients undergoing IVF improved the conditions of early pregnancy after taking DHEA, which seems to imply an indirect increase in the clinical pregnancy rate. In some direct comparative evidence, DHEA supplementation had a positive effect on women with reduced ovarian reserve (DOR) or POR undergoing IVF/ICSI [43][44][45][46], which can improve the ovarian environment for follicle maturation [17]. Compared with placebo or untreated women, the use of DHEA improved the live-birth rate and the ongoing pregnancy rate increased by 3-14% [47]; its mechanism was through the effect on granular cell and ovarian matrix expression of androgen receptor and it also increased the quantity of follicular cavity and AMH level, thereby increasing ovarian reserve [48]. ...
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Background Assisted reproductive technology (ART) has brought good news to infertile patients, but how to improve the pregnancy outcome of poor ovarian response (POR) patients is still a serious challenge and the scientific evidence of some adjuvant therapies remains controversial. Aim Based on previous evidence, the purpose of this systematic review and network meta-analysis was to evaluate the effects of DHEA, CoQ10, GH and TEAS on pregnancy outcomes in POR patients undergoing in vitro fertilization and embryo transplantation (IVF-ET). In addition, we aimed to determine the current optimal adjuvant treatment strategies for POR. Methods PubMed, Embase, The Cochrane Library and four databases in China (CNKI, Wanfang, VIP, SinoMed) were systematically searched up to July 30, 2022, with no restrictions on language. We included randomized controlled trials (RCTs) of adjuvant treatment strategies (DHEA, CoQ10, GH and TEAS) before IVF-ET to improve pregnancy outcomes in POR patients, while the control group received a controlled ovarian stimulation (COS) regimen only. This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The surface under the cumulative ranking curve (SUCRA) was used to provide a pooled measure of cumulative ranking for each outcome. Results Sixteen RCTs (2323 women) with POR defined using the Bologna criteria were included in the network meta-analysis. Compared with the control group, CoQ10 (OR 2.22, 95% CI: 1.05 to 4.71) and DHEA (OR 1.92, 95% CI: 1.16 to 3.16) had obvious advantages in improving the clinical pregnancy rate. CoQ10 was the best in improving the live birth rate (OR 2.36, 95% CI: 1.07 to 5.38). DHEA increased the embryo implantation rate (OR 2.80, 95%CI: 1.41 to 5.57) and the high-quality embryo rate (OR 2.01, 95% CI: 1.07 to 3.78) and number of oocytes retrieved (WMD 1.63, 95% CI: 0.34 to 2.92) showed a greater advantage, with GH in second place. Several adjuvant treatment strategies had no significant effect on reducing the cycle canceling rate compared with the control group. TEAS was the least effective of the four adjuvant treatments in most pooled results, but the overall effect appeared to be better than that of the control group. Conclusion Compared with COS regimen, the adjuvant use of CoQ10, DHEA and GH before IVF may have a better clinical effect on the pregnancy outcome of POR patients. TEAS needs careful consideration in improving the clinical pregnancy rate. Future large-scale RCTs with direct comparisons are needed to validate or update this conclusion. Systematic review registration PROSPERO CRD42022304723
... This result suggests that ovarian ageing may be related to the ovarian environment and not limited to the oocyte itself. DHEA may play a role in altering this ovarian environment, thereby preventing follicle ageing (5). The role of DHEA in DOR, mainly in artificial reproduction treatment (ART) and in vitro fertilization (IVF), is to improve oocyte quality and quantity and significantly improve anti-Müllerian hormone (AMH) levels (6). ...
Diminished ovarian reserve (DOR) refers to the decline in fertility caused by the loss of normal ovarian function. DOR is associated with adverse reactions to ovarian stimulation during in vitro fertilization and embryo transfer (IVF-ET), increasing cycle cancellation rates and reducing pregnancy rates. Although it is well known that dehydroepiandrosterone (DHEA) can be used as a dietary supplement for age-related diseases, its potential has gradually been shown for many diseases. In this review, we focus on the effects of DHEA on DOR, briefly analysing its clinical benefits and limitations and describing the mechanism of function and the clinical trials conducted. Therefore, we summarize the mechanisms and indications of DHEA for DOR.
Although reproductive medical treatment has become the standard in gynecology over the past few decades, there are still significant knowledge gaps. Less than 50% of treatments lead to the desired result, a pregnancy. Therefore, many additional examinations and treatments (so-called add-ons) have been developed, which are offered to couples with an unfulfilled desire to have children in order to possibly improve the treatment results. To date, however, there is no evidence of benefits in terms of pregnancy and live birth rates for the vast majority of these add-ons. This overview article highlights the various add-ons available for patients, oocytes, embryos, and sperm based on the current study situation.
The aging process is complicated and involves diverse organ dysfunction; furthermore, the biomarkers that are able to reflect biological aging are eagerly sought after in order to monitor the system-wide decline associated with the aging process. To address this, we performed a metabolomics analysis using a longitudinal cohort study from Taiwan (N=710) and established plasma metabolomic age using a machine learning algorithm. The resulting estimation of age acceleration among the older adults was found to be correlated with HOMA-insulin resistance. In addition, a sliding window analysis was used to investigate the undulating decrease in hexanoic and heptanoic acids that occurs among the older adults at different ages. A comparison of the metabolomic alterations associated with aging between humans and mice implied that ω-oxidation of medium chain fatty acids was commonly dysregulated in older subjects. Among these fatty acids, sebacic acid, an ω-oxidation product produced by the liver, was significantly decreased in the plasma of both older humans and aged mice. Notably, an increase in the production and consumption of sebacic acid within the liver tissue of aged mice was observed, along with an elevation of pyruvate-to-lactate conversion. Taken together, our study reveals that sebacic acid and metabolites of ω-oxidation are the common aging biomarkers in both humans and mice. The further analysis suggests that sebacic acid may play an energetic role to supporting the production of acetyl-CoA during liver aging, and thus its alteration in plasma concentration potentially reflects the aging process.
Total testosterone (TT), sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA) levels, and cervical length (CL) were investigated in pregnant Egyptian women with polycystic ovary syndrome (PCOS, n = 38), history of miscarriages (RM, n = 40) and without the conditions (HC, n = 40). At week 8, the RM had lower levels of TT (p = 0.000) and free androgen index (FAI) (p = 0.000) and higher SHBG (p = 0.000) and DHEA (p < 0.05) than the PCOS. Compared with the HC, they had elevated SHBG (p < 0.05) and DHEA (p = 0.001) and reduced CL (p = 0.000). TT (p = 0.001) and FAI (p = 0.000) were higher and SHBG (p = 0.000) and CL (p = 0.001) lower in the PCOS than in the HC group. At week 16, TT (p = 0.000) and FAI (p = 0.000) were higher, and SHBG (p = 0.000) and CL (p < 0.05) lower in PCOS than in RM and HC. The PCOS had elevated FAI than the RM (p = 0.000) and HC (p = 0.001) at week 20. The DHEA, SHBG and CL abnormalities in PCOS and RM may compromise pregnancy outcomes. • IMPACT STATEMENT • What is already known on this subject? Hyperandrogenaemia, low sex hormone-binding globulin (SHBG), shortened cervical length (CL) and polycystic ovary syndrome (PCOS) are the most cited risk factors for recurrent miscarriages (RM). However, the published data are inconsistent, perhaps because of the confounding effects of ethnicity and nutritional milieu. • What do the results of this study add? The study’s findings comprising ethnically and socially homogenous women demonstrate that PCOS and RM are characterised by elevated dehydroepiandrosterone (DHEA) and shortened CL, and PCOS by reduced SHBG. These abnormalities would be expected to have an adverse impact on pregnancy outcomes. • What are the implications of these findings for clinical practice and/or further research? Twenty-weeks DHEA and CL values have the potential to predict outcome risk in women with a history of RM and PCOS. Further research on other population groups is required to validate the current study’s findings.
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Objective: To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman's reproductive history. Design: Prospective register linkage study. Subjects: All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes. Main outcome measures: Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions. Results: Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20-24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age. Conclusions: Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.
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Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR), and to reduce miscarriage rates by 50-80%. Such an effect is mathematically inconceivable without beneficial effects on embryo ploidy. This study, therefore, assesses effects of DHEA on embryo aneuploidy. In a 1:2, matched case control study 22 consecutive women with DOR, supplemented with DHEA, underwent preimplantation genetic screening (PGS) of embryos during in vitro fertilization (IVF) cycles. Each was matched by patient age and time period of IVF with two control IVF cycles without DHEA supplementation (n = 44). PGS was performed for chromosomes X, Y, 13, 16, 18, 21 and 22, and involved determination of numbers and percentages of aneuploid embryos. DHEA supplementation to a significant degree reduced number (P = 0.029) and percentages (P < 0.001) of aneuploid embryos, adjusted for relevant covariates. Short term supplementation (4-12 weeks) resulted in greatest reduction in aneuploidy (21.6%, 95% CI -2.871-46.031). Beneficial DHEA effects on DOR patients, at least partially, are the likely consequence of lower embryo aneuploidy. DHEA supplementation also deserves investigation in older fertile women, attempting to conceive, where a similar effect, potentially, could positively affect public health.
Objective: To investigate the effects of T, dihydrotestosterone (DHT), and 17beta-estradiol on human ovarian stromal tissue survival in culture and to identify steroids capable of inhibiting cell death in vitro. Design: Prospective study. Setting: Academic research setting. Patient(s): Thirty women, aged 18-38 years, undergoing gynecological operations for benign conditions and eight women, aged 27-36 years, undergoing IVF because of tubal obstruction or male factor infertility. Intervention(s): Cultured tissue was exposed to T, DHT, 17beta-estradiol, or the anti-androgen casodex. Main Outcome Measure(s): Immunohistochemistry for androgen receptor (AR), Southern blot analysis of DNA fragmentation, histology, and in situ end labeling of apoptotic DNA. Result(s): Androgen receptors were detected in the ovarian stroma and granulosa cells of the primordial follicles, although they were more clearly seen in primary follicles and more advanced-stage follicles. Testosterone only marginally suppressed ovarian tissue apoptosis in vitro. DHT was more effective than T, whereas 17beta-estradiol had no notable effect on the viability of the tissue. The effects of androgens on the ovarian tissue may be mediated through ARs, since blocking the receptors with an AR antagonist reversed the suppressive effect of DHT. Conclusion(s): DHT may be useful for enhancing human ovarian tissue survival in vitro. (C) 2004 by American Society for Reproductive Medicine.
Clomiphene citrate (CC) and follicle stimulating hormone (FSH) are the two main modalities used for ovarian stimulation (OS). However, many adjuncts have been used to maximize the convenience and effectiveness of these two agents, often specifically targeted to subsets of women undergoing stimulation. Most of these adjuncts are not officially approved for these indications. Therefore educators and practitioners must take it upon themselves to assess the evidence supporting their use, and make treatment recommendations and decisions accordingly. A process was recently outlined in an editorial for Fertility and Sterility to aid in this endeavor. Decisions are based not only on randomized clinical trials (RCT), but also on other basic science and clinical evidence supporting their use. Primarily developed for treatment of prostate cancer, the usefulness of GnRH agonists in preventing premature luteinizing hormone (LH) release became immediately apparent, leading to the suggestion for routine use in all IVF cycles. Despite reduction of premature ovulation from over 20 percent to almost zero and a subsequent meta-analysis showing a two fold increase of the pregnancy rate, the principle GnRH agonist used in the USA, leuprolide acetate (LA), is still “off label” for this indication. Further benefits have been increased numbers of retrieved oocytes and embryos for fresh transfer and for cryopreservation, as well as the ability to schedule procedures for patients' or programs' convenience.
To investigate the effectiveness of treatment with transdermal testosterone gel (TTG) before controlled ovarian stimulation (COS) using GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection (ICSI). Prospective randomized controlled trial. University-affiliated infertility clinic. A total of 110 low responders, who were defined as patients who failed to produce ≤ 3 follicles with a mean diameter of ≥ 16 mm with the result that ≤ 3 oocytes were retrieved despite the use of a high gonadotropin dose (>2,500 IU) in a previous failed IVF/ICSI cycle. Patients were randomized into TTG pretreatment group or control group. For TTG pretreatment group, 12.5 mg TTG were applied daily for 21 days in the cycle preceding COS for IVF. COS results and IVF outcome. There were no differences in patients' characteristics between the two groups. Total dose and days of rhFSH used were significantly fewer in the TTG pretreatment group than in the control group. The numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were significantly higher in the TTG pretreatment group. Embryo implantation rate and clinical pregnancy rate per cycle initiated also were significantly higher in the women pretreated with TTG. No patient reported adverse effects attributed to TTG use. TTG pretreatment might be beneficial in improving both response to COS and IVF outcome in low responders undergoing IVF/ICSI.
Medical care should be based on best available evidence. While randomized controlled trials (RCT) are currently considered a gold standard of study design, they are not always available and do not represent the only study format that can lead to best available evidence. This communication argues that overvaluation of RCT and undervaluation of other study formats in establishing best available evidence hurts progress in reproductive medicine and in medicine in general. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.