Dr. Rachna Agarwalis a graduate and postgraduate from the prestigious All India Institute of Medical Sciences, New Delhi.She has over 40 publications, with 25 in indexed international journals. She has co-authored two books—Jaypee’s VideoAtlas of Surgical Techniques in Gyneocology and Obstetrics and Step by Step Non-Descent Vaginal Hysterectomy. She wasproject facilitator of WHO Global Survey (2008)—Asia on Maternal and Perinatal health: mode of delivery and pregnancyoutcomes and WHO RHL-EBM trial (2009). She has made several scientific presentations at international, national andregional conferences. She is also on the panel of reviewers for the international journals. She was past Joint Secretary of theAssociation of Obstetrics and Gynaecology of Delhi (2011) and Joint Secretary NARCHI Delhi branch (2014–2016). Herarea of interest includes gynecology, oncology and high-risk pregnancy.
Introduction We conducted a randomized, double-blinded,placebo-controlled study, to evaluate the effect of dehy-droepiandrosterone (DHEA), on diminished ovarianreserve (DOR).
Materials and Methods Twenty patients with DORreceived DHEA (oral 25 mg three times a day). Post-sup-plementation 12 weeks, D2/3 age-specific follicle-stimu-lating hormone (FSH), anti-mullerian hormone (AMH)levels, and antral follicle count (AFC), were repeated toevaluate response. Spontaneous pregnancy rates and regu-larization of menstrual cycles were also studied as sec-ondary outcome.
Results Predominant risk factors were age[35 years(28 %) and poor responders to ovarian stimulation (23 %).There was significant improvement of AMH levels(1.15±1.49 vs. 1.53±1.62) found before and aftersupplementation in the DHEA group. When the AMHvalues between DHEA and placebo group were compared,pre- and post-supplementation, no significant differencewas found. There was decrease in FSH levels and increasein AFC value post-supplementation in both DHEA andplacebo groups which was not statically significant. DHEAsupplementation benefited clinically, as evidenced by the improvement in the menstrual abnormality spontaneousconception in two cases each.
Conclusions A significant improvement in AMH levelspre- and post-supplementation of DHEA was noted. Thesame was not seen for FSH and AFC values.
Keywords : Diminished ovarian reserve, Dehydroepiandrosterone, FSH, Anti-mullerian hormone, Antral follicle count
Poor ovarian response reflecting diminished ovarianreserve (DOR) still remains among the foremost chal-lenging problems in artificial reproductive medicine. It isestimated that despite of all protocol, 5–18 % of all IVFcycles are ended because of poor ovarian response [1–3].The treatment of diminished ovarian reserve is debatable.The possible options for fulfilling parenthood for suchcouples are limited, like in vitro fertilization with donoroocyte or adoption. Since this may not be sociallyacceptable or sometimes economically feasible, alternateoptions need to be explored. It has been proposed based onvarious studies that oral administration of Dehy-droepiandrosterone (DHEA), a food supplement foundnaturally in wild yam and soy products, may improveovarian response and pregnancy rates in reduced ovarianreserve [4,5]. DHEA ovarian impact needs to be reas-sessed, as so far only few and small double-blinded ran-domized case control studies has been done in this regard,with limited statistical significance and those too in thesetting of in vitro fertilization [1–3].
We planned a randomized, double-blinded, placebo-controlled study, to evaluate the effect of DHEA ondiminished ovarian reserve (DOR) and its impact onobjective parameters such as serum anti-mullerian hor-mone (AMH), age-specific follicle-stimulating hormone(FSH) and Antral follicle count (AFC).
The study (2012–2014) was approved by the hospital ethicscommittee, and an informed consent from all the partici-pants obtained. Our centre does not have IVF and assistedreproduction facilities. The inclusion criteria for enrolled inthe study were patients (age group 18–45 years) of infer-tility (primary or secondary), with high-risk factors forDOR and rest of the infertility workup was normal (tubaland male factor), who screened positive for any of the testsof diminished ovarian reserve (Fig.1)[6,7]. Women withpolycystic ovarian disorder, premature ovarian failure (FSH levels[30 mIU/ml), hormone-dependent disorders(e.g., breast cancer), diagnosed liver disease, diabetes orpsychiatric illness were excluded.
Computerized random number table for 40 packets wasgenerated (Fig.1). The patients were allocated precodedpackets in a consecutive manner, as they were enrolled inthe study. Oral DHEA supplementation was given at thedosage of 25 mg three times a day for duration of 12 weeksto one group and placebo to the other in a double-blindmanner. Patients were followed up weekly for the first2 weeks for tolerance and side effects, every fortnightlythereafter to ensure compliance. After 12 weeks, serumD2/3 FSH, serum AMH levels, and AFC were repeated intheir fourth cycle. Spontaneous pregnancy rates, if any,during the course of supplementation were also recorded.Regularization of menstrual cycles in patients with previ-ous menstrual problems was also studied as a secondaryoutcome.
The study groups were matched, regarding age, BMI, pri-mary and secondary infertility, and the two groups werecomparable. Nonparametric tests were applied to obtainbetween the group comparison (Mann–Whitney test) andwithin the group comparison (Wilcoxon signed-rank test).Repeated measure ANOVA was applied to obtain thebetween and within the group comparisons for FSH levels.
Forty women fulfilled the inclusion criteria and fit into thediagnosis of DOR, making the prevalence rate of 6.3 % (40out of 633) at our centre (Table1). The predominant riskfactors in our study population (n=40) were age[35 years (28 %) and poor responders to ovarian stimu-lation (23 %). The percentage prevalence of POA women\38 years with DOR was 85 % (n=34). The mean age(35.8 vs. 30.4 years) and duration of infertility (10.5 vs.6.6 years) were more in cases of secondary infertility whencompared to cases of primary infertility in DHEA andplacebo group (Table2).
After the completion of supplementation, the values ofFSH, AFC, and AMH from pre- and post-supplementationwere compared (Table3). It was seen that there is adecrease in the mean value of FSH in both groups, but itwas not statistically significant (p=0.899). When thepost-supplementation values between DHEA and placebogroup were compared, it was also not statistically
Diminished ovarian reserve (DOR), one of the recently recognized causes of infertility, is a natural process bywhich follicular pool diminishes with time, as women ages.The prevalence of DOR is said to be around 10 % in thein fertile population [1].
Conventional modalities of treatment in high-incomecountries would suggest IVF with donor oocyte as the nextstep in DOR. However, there is a need for cheaper alterna-tives to the expensive IVF treatment in low-income healthcare settings. Few small randomized prospective studiessuggest that Dehydroepiandrosterone (DHEA) improvesovarian function, ovarian reserve, increases chances of livebirth, by reducing miscarriage and aneuploidy [5,6,9,10].The rationale suggested is that oocytes, in their resting stagewithin the unrecruited primordial follicles, do not really age[4]. Once recruited, they enter into an age-dependent ovarianenvironment, where follicle maturation takes place. Thequality of this environment deteriorates uniformly as womenage and affects the segregation process of meiosis resultingin aneuploidies. DHEA probably acts by altering and reju-venating this ovarian environment and hence preventing theaging of the follicles.
There have been many studies reporting the role ofDHEA in DOR mainly in the setup of ART and IVF set-ting, where oocyte retrieval has been used principally as apredictor of improvement. Barad and Gleicher [4,6]reported improvement in quality and quantity of oocytes,and embryos retrieved post-DHEA supplementation. Son-mezer evaluated DHEA in the intracytoplasmic sperminjection (ICSI) cycles. DHEA potentiated the effect ofgonadotropins, in increasing the number and quality ofoocytes, embryo quality, and increased pregnancy anddecreased cancelation rate [2]. Contrarily, a recent meta-analysis based on 22 publications and 3 controlled studiesindicated insufficient evidence for supporting the role ofDHEA in IVF cycles [7]. We designed this randomized,double-blinded, placebo-controlled study to further evalu-ate the effects of DHEA in diminished ovarian reserve.
Decreased ovarian reserve diagnosed in younger women(\38 years) is defined as premature ovarian aging (POA)[8]. Thus a significant number of women in our study werePOA (85 %) reflecting increased age of child bearing incareer-driven women of the present generation. The inci-dence of poor ovarian response to stimulation (9–24 %) ininfertile patients was also comparable in our study (23 %)[7]. In our study, there was significant increase in levels ofAMH, pre- and post-supplementation in the DHEA group(p=0.048), from 1.15±1.49 to 1.53±1.62 ng/ml,suggesting an improvement in ovarian reserve. Gleicher inhis study observed an improvement from 0.22±0.22 ng/ml in baseline to 0.35±0.03 ng/ml after DHEA supple-mentation in 120 subjects, an increase of 60 % in meanvalue (p=0.001) [8]. Significant improvement in AMHlevels after DHEA supplementation was also noted byYilmaz et al. [11]. We found no significant decrease inlevels of FSH and no increase in AFC, pre- and post-sup-plementation in either DHEA or placebo group. Yilmazonthe contrary, noticed a significant decrease in FSH levels (p=0.001) and increase in AFC (p=0.025) after DHEAsupplementation in 41 patients [11]. The difference couldprobably be due to the limited subjects receiving DHEA inour study.
The occurrence of two spontaneous pregnancy in theDHEA group (p=0.244), and none in placebo group, wasan interesting observation. Similar incidence of sponta-neous pregnancy while on DHEA supplementation wasreported by other authors suggesting DHEA probablecapacity in increasing fecundity [11,12]. One of them hada missed abortion at 8 weeks of gestation, and the otherresulted in full-term pregnancy. It is important to note thatboth these women were secondary infertility; this wascomparable to the results obtained by Wiser et al. [5] where14 of the clinical pregnancies observed were in secondaryinfertile women. Thus in DOR managed with DHEA,patients with previous pregnancy may have better prog-nosis than women of primary infertility.
The normalization of menstrual cycles post-DHEAsupplementation noted in three women, although not sta-tistically significant (p=0.500), was also important as thenormalization of the ovarian milieu, with associatedimprovement in the hormonal imbalance and anovulation,might have lead to regular cycles. Further research need tobe done regarding this effect of DHEA.
Facilities for IVF and ART are not available at ourcentre. We were therefore unable to quantify oocyteretrieval and embryo quality. Data regarding subsequentovulation induction or IVF cycles were not available due tolimited scope and small time frame of our study. However,evaluation of a new emerging treatment modality for DORusing prospective double-blinded randomized placebo-controlled data collection and uniform monitoring of pre-and post-DHEA supplementation responses using threeparameters (FSH, AMH and AFC) was the key strengths ofthis study. The increase in AMH values was significantsupporting the beneficial role of DHEA in DOR. DHEAsupplementation also benefited clinically, as evidenced bythe improvement in menstrual abnormalities and sponta-neous conceptions. DHEA can be one of the low-costoptions in DOR in low-income countries like ours wherefacilities for IVF and ART are very limited and costly. Itstrue potential as a sole agent for DOR remains to be testedin larger trials.
significant (p=0.235). There was significant improvement of AMH levels (1.15±1.49 vs. 1.53±1.62) found before and after supplementation in the DHEA group(p=0.048), whereas in the placebo group, although the mean value improved, but it was not found to be statisti-cally significant (p=0.776). When the AMH values between DHEA and placebo group were compared, post-supplementation (p=0.725), no significant difference was found. Although the mean value of AFC increased pre- and post-supplementation, on within the group comparison, itwas not statistically significant (p=0.092). When the post-supplementation values between DHEA and placebogroup were compared, it was also not statistically signifi-cant (p=0.097). Thus there was slight decrease in FSHlevels, increase in AMH levels, and increase in AFC valuepost-supplementation in both DHEA and placebo groups.On statistical analysis, only the increase in AMH value wasfound to be statistically significant.
There were two cases of spontaneous conception which occurred after completion of DHEA supplementation. Boththe patients had secondary infertility and had received DHEA. One patient was parous, and the other had repeatedpregnancy loss. When statistical tests were applied, it was not found to be significant (p=0.244). On follow-up, outof the two women, one had a missed abortion at 8 weeks of gestation and the other had viable conception.
Three women with menstrual abnormalities had nor-malization of the menstrual cycles at the end of 12 weeks,of which two were in DHEA group and one in placebogroup. But, this also was not found to be statistically sig-nificant (p=0.500).
All cases of DOR were reviewed for androgenic side effects as well such as acne, facial hair growth, anddeepening of voice [8]. None of the women had these orany other side effects during the period of supplementation.
