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

Abstract

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.

Full text

REVIEW Open Access
Dehydroepiandrosterone (DHEA) supplementation
in diminished ovarian reserve (DOR)
Norbert Gleicher
1,2*
and David H Barad
1,3
Abstract
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.
Background
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 group’s
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: ykizawa@thechr.com
1
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
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© 2011 Gleicher and Barad; 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.

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
supplement).
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 patient’sself-
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-
calTrials.gov 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
andtheCzechRepublic,designedinfollowuptothe
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.
Methods
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
analysis
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].
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inclusion or exclusion, therefore, took place. All publica-
tions were reviewed by both authors, who agreed with
analysis and interpretation of data.
IRB approval
Sincehererevieweddatawerebasedonpriorpublica-
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.
Results
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 patient’s
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
patient’s longitudinal experience over nine IVF cycles
also demonstrated continuous improvements in oocyte
(and embryo) numbers with increasing length of DHEA
supplementation.
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
DHEA.
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
quantity.
[Though not part of here reported literature review, we
find it noteworthy that, concomitantly, Edward Ryan’s
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].
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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 Toronto’s
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 responders”to 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 (ClinicalTrial.gov 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].
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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 (ClinicalTrials.gov 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
rates
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 Ryan’s 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
[29].
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].
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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 center’s 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].
AMH1.05ng/mL,thus,representsadistinctpointof
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 group’s
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.
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advantages from micronized and orally delivered DHEA
[6].
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
[37].
DHEA was recently listed amongst drugs with “orphan
indications”in 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
(ClinicalTrials.gov ID#NCT00650754) and POF/POI
(ClinicalTrials.gov 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
selection.
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
[40].
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
a
at AMH levels <0.1 (undetectable) -0.4 ng/mL, intermediate
b
at AMH 0.41-1.05 ng/ML and high
c
≥AMH 1.06 ng/
mL;
[31]
Spontaneous miscarriage rates lowest
d
at AMH ≤0.4 ng/mL and 1.06 ng/mL; Highest
e
at AMH 0.41-1.05 ng/mL; [31]
Live births rates uniformly low
f
at AMH <0.1-1.05 ng/mL and high
g
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]
a
Approximately 5% per cycle, 10% cumulative;
b
Approximately 10% per cycle and 17% cumulative;
c
Approximately 28% per cycle and 42% cumulative;
d
Approximately <15%;
e
Approximately 50%;
f
Approximately 4% per cycle, 7% cumulative;
g
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].
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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 Balasch’s group in two publications
stressing beneficial effects on ovarian resistance [51,52].
ThemostrecentstudyonthesubjectbyKimetal
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
[55].
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
attention.
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
stages.
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
[27,29].
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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 “younger”oocytes, 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
supplementations.
Proven correct, one can expect a significant expansion
of the female’s 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 “rejuvenate”ovarian 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 center’s 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 center’s population was
affected by either POA or DOR.
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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.
Limitations
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-
sizedbymostpublicationscomingfromonlyasmall
number of centers, including, these authors’own 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
[63-65].
Conclusions
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.
Abbreviations
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;
Acknowledgements
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
manuscript.
Author details
1
Center for Human Reproduction (CHR) and Foundation for Reproductive
Medicine, New York, NY, USA.
2
Department of Obstetrics, Gynecology and
Reproductive Sciences, Yale University School of Medicine, New Haven, CT,
USA.
3
Departments of Epidemiology and Social Medicine and Obstetrics,
Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx,
NY, USA.
Authors’contributions
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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doi:10.1186/1477-7827-9-67
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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