A Randomized, Double-Blinded, Placebo-Controlled Phase II Trial of Recombinant Human Leukemia Inhibitory Factor (RhuLIF, Emfilermin, AM424) to Prevent …

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J Clin Endocrin Metab. First published ahead of print November 8, 2012 as doi:10.1210/jc.2012-3071

ORIGINAL E n d o c r i n e

ARTICLE R e s e a r c h

A Randomized Double-Blinded Placebo-Controlled Trial on the Effect of Dehydroepiandrosterone for 16 Weeks on Ovarian Response Markers in Women with Primary Ovarian Insufficiency Tracy Wing Yee Yeung, Raymond Hang Wun Li, Vivian Chi Yan Lee, Pak Chung Ho, and Ernest Hung Yu Ng Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China

Context: Preliminary reports have shown encouraging effects of dehydroepiandrosterone (DHEA) in women with poor ovarian reserve undergoing assisted reproduction and primary ovarian insufficiency (POI), although data from randomized controlled trials are limited. The present study assesses the effect of DHEA on ovarian response markers in women with POI. Objective: The objective of the study was to evaluate whether DHEA for 16 wk would improve ovarian response markers in women with POI. Design: This was a randomized, double-blinded, placebo-controlled study. Setting: The study was conducted at a tertiary reproductive unit. Patients: Twenty-two women with unexplained POI participated in the study. Interventions: Eligible subjects were randomized into the DHEA group (n ! 10), who received DHEA (LiveWell, 25 mg three times a day), or the placebo group (n ! 12), who received placebo for 16 wk according to a computer-generated randomization list. Ovarian response markers included serum anti-Mullerian hormone (AMH), FSH levels, and antral follicle count (AFC) as well as follicles of 10 mm or greater in diameter, and hormonal profiles were measured at 4-wk intervals until 4 wk after completion of treatment. Any returns of menses and side effects from treatment were recorded. Main Outcome Measures: The primary outcome was serum AMH level. Results: No significant change in serum AMH and FSH levels had been detected throughout the study. AFC and ovarian volume were significantly higher at wk 12 and 20, respectively, in the DHEA group. Significantly more women having at least one follicle of 10 mm or greater at wk 12, 16, and 20 were found in the DHEA group. Serum testosterone and DHEA sulfate levels along with higher estradiol levels were significantly higher in the DHEA group. Conclusion: This randomized, double-blinded, placebo-controlled trial found higher AFC and ovarian volume at wk 12 and 20, respectively, in the DHEA group, although there were no significant changes in serum AMH and FSH levels. Further trials using a longer duration of DHEA should be considered to evaluate the long-term effect of DHEA in women with POI. (J Clin Endocrinol Metab 98: 0000 – 0000, 2013)

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2013 by The Endocrine Society doi: 10.1210/jc.2012-3071 Received August 13, 2012. Accepted October 11, 2012.

Abbreviations: AFC, Antral follicle count; AMH, anti-Mullerian hormone; BMD, bone mineral density; CV, coefficient of variation; DHEA, dehydroepiandrosterone; DHEA-S, DHEAsulfate; E2, estradiol; POI, primary ovarian insufficiency.

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Copyright (C) 2012 by The Endocrine Society

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rimary ovarian insufficiency (POI) is characterized by the triad of amenorrhea for at least 4 months, sex steroid deficiency, and two recordings of serum FSH in the menopausal range in a woman aged younger than 40 yr (1). Previously used terms including premature menopause or premature ovarian failure should be avoided because the term premature arbitrarily confined the disorders in which menses stop before the age of 40 yr (2); and as supposed to menopause in which the cessation of ovarian function is permanent, up to 50% of women with POI has varying and unpredictable ovarian function and about 5–10% of women conceive spontaneously after the diagnosis (3). It affects about 1% of women aged younger than 40 yr, 0.1% of under the age of 30 yr, and 0.01% under the age of 20 yr (4). Women with POI not only experience estrogen deficiency but also suffer from the loss of ovarian androgens due to atrophy of ovarian cortex (5). They have to face major difficulties with fertility and conception (6) as well as long-term health risks associated with estrogen deficiency. Women are counseled to have long-term hormonal replacement and resort to oocyte/embryo donation, adoption, or remain childless owing to the very limited and unpredictable ovarian function. Dehydroepiandrosterone (DHEA) is an endogenous steroid produced mainly in the zona reticularis of adrenal cortex and ovarian theca cells in women. It has been implicated in ovarian follicular steroidogenesis and is believed to increase follicular IGF-I, which promotes folliculogenesis (7) and potentiates gonadotropin effects (8). Previous studies have shown preliminary success in using DHEA to improve ovarian response to gonadotrophins, leading to spontaneous pregnancies or improved outcomes in assisted reproductive techniques (8 –12). Mamas and Mamas (39) published their preliminary results that after DHEA supplementation, women with POI had reduced serum FSH and successful live births either achieved spontaneously or after mild ovarian stimulation and intrauterine tuboperitoneal insemination. The encouraging effects of DHEA in improving ovarian function, even in women with POI, prompted some centers to use DHEA in routine management of these women. However, such practice was not supported by evidence from randomized controlled trials. The present study aims at filling this gap by assessing the effect of DHEA on ovarian reserve. Although endocrine tests like anti-Mullerian hormone (AMH), FSH, and ultrasound markers like antral follicle count (AFC) and ovarian volume have been widely used and regarded as ovarian reserve markers, none of these tests can directly measure the number of nongrowing primordial follicles in ovaries, which constitute the genuine ovarian reserve. These markers should therefore be more appropriately referred as ovarian response markers.

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Materials and Methods Study design and protocol Women who presented with secondary amenorrhea and were diagnosed with primary POI were recruited from the Department of Obstetrics and Gynaecology, University of Hong Kong. Inclusion criteria included the following: 1) age younger than 40 yr; 2) secondary amenorrhea; 3) serum FSH level greater than 30 IU/liter on two occasions of at least 6 wk apart; 4) normal karyotype of 46XX; and 5) negative FMR1 gene mutation. Patients were excluded if they had any of the following: 1) a history of ovarian cystectomy or oophorectomy; 2) having received cytotoxic chemotherapy; 3) having received pelvic irradiation; 4) a diagnosis of autoimmune disease; 5) a history of taking testosterone or DHEA supplement; or 6) pregnancy. The study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster and was registered under Hong Kong Clinical Trial Center (HKCTR1148). All women were fully counseled and written consents were obtained before their participation. Women who were taking hormonal replacement therapy at the time of recruitment were asked to withhold them for a minimum of 2 months. Baseline investigations for ovarian response markers including serum AMH, FSH levels, AFC, and ovarian volume were performed. Serum estradiol (E2), testosterone, DHEA-sulfate (DHEA-S), SHBG, IGF-I, and liver enzymes were also measured.

Assignment and masking Women were randomized according to a computer-generated randomization list generated by a research nurse not involved in the subjects’ clinical management. The hospital pharmacy packaged the DHEA and placebo capsules according to the randomization list and labeled the drug packs with subject numbers only. The placebo capsules were identical in appearance with the DHEA capsules. Physicians, research nurses involved in the trial, and the study subjects were all blinded to the assignment.

Treatment and monitoring Each woman received 16 wk of either DHEA (GNC LiveWell, Pittsburgh, PA) capsule at 25 mg three times a day or matching placebo capsules. All women were assessed before the start of treatment and were followed up at 4-wk intervals until 4 wk after stopping treatment. Serial transvaginal scans were performed by T.Y. using a 7-MHz vaginal probe (Voluson 730; GE Healthcare, Madison, WI) to determine AFC (2–9 mm) in both ovaries and to measure the volume of the ovaries. The length, height, and width of each ovary were measured in the sagittal and coronal planes, and then the ovarian volume was obtained using a formula for the volume of an ellipsoid (!/6 " length " height " width). The total ovarian volume was the sum of the right and left ovarian volumes. The intraobserver coefficient of variation (CV) for AFC and ovarian volume was 7% and less than 10%, respectively. Blood was collected for serum AMH, FSH, E2, testosterone, DHEA-S, SHBG, IGF-I, and liver function. Serum samples were stored at #20 C until assayed as a whole batch. Any return of menses or side effects were recorded. Serum AMH was measured using AMH Gen II ELISA (Beckman Coulter, Fullerton, CA); IGF-I was measured using Quantikine ELISA human IGF-I (R&D Systems, Minneapolis, MN), and E2, testosterone, DHEA-S, and SHBG were measured using Beckman Coulter Access 2 Immunoassay system.

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The intra-assay CVs were 3.4 –5.4% for AMH, 3.5– 4.3% for IGF-I, less than 12–21% for E2, 1.67–3.93% for testosterone, 1.6 – 8.3% for DHEA-S and 4.5– 4.8% for SHBG. The interassay CV were 4.0 –5.6% for AMH, 7.5– 8.1% for IGF-I, 4.22– 7.08% for testosterone, 3.7–11.3% for DHEA-S and 5.2–5.5% for SHBG. Detection range was 0.08 –22.5 ng/ml for AMH, 0.007– 6 ng/ml for IGF-I, 0.1–16 ng/ml for testosterone, 2–1000 "g/dl for DHEA-S and 0.33–200 nmol/liter for SHBG.

Statistical analysis The primary outcome measure was the serum AMH level. We have chosen serum AMH as our primary outcome measure because it is produced by granulosa cells of small growing follicles, whose number and thus the serum concentration should be reflective of the ovarian reserve (13). Secondary outcome measures included serum FSH level, AFC, total ovarian volume, ovarian follicles of 10 mm or greater and hormonal profiles including serum E2, testosterone, DHEA-S, SHBG, and IGF-I. Based on our previous data in patients with newly diagnosed POI, the mean serum AMH concentration was 2.65 pmol/liter (0.37 ng/ml) with a SD of 1.8 pmol/liter (0.25 ng/ml) (14). Assuming a doubling of mean serum AMH levels in the DHEA

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group being clinically significant, nine women would be required in each arm to give a test of significance of 0.05 and a power of 0.8. 22 subjects were recruited to allow for possible dropouts. Statistical comparisons were carried out with the intention to treat and per-protocol approaches by Student’s t test, Mann-Whitney U test, #2 test, and Fisher’s exact test where appropriate using the Statistical Program for Social Sciences (version 19.0; SPSS Inc., Chicago, IL). A two-sided P $ 0.05 was taken as statistically significant.

Results Participant flow Between June 2010 and June 2011, 63 women with POI were screened, and 29 fulfilled the selection criteria and were counseled to participate. Twenty-two women were recruited and randomized. One woman from the DHEA group at wk 4 and one woman from the placebo group at wk 12 withdrew their consents due to personal reasons.

FIG. 1. Consolidated Standards of Reporting Trials 2010 flow diagram.

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One woman from the DHEA group was excluded after 4 wk because she was found to be 8 wk pregnant, i.e. she conceived before the administration of DHEA (Fig. 1).

DHEA-S levels were significantly higher in the DHEA group from wk 4 to wk 16. No significant difference was detected in the SHBG and IGF-I levels between the two groups.

Baseline characteristics No significant difference was found between the two groups with regard to age, body mass index, duration of POI [defined as the time between the confirmed diagnosis (history of amenorrhea $4 months and two FSH results at menopausal range under the age of 40 yr) and the time of the baseline blood tests and ultrasound scans] and serum FSH level at diagnosis (Table 1). A comparable percentage of the women had received hormone replacement therapy, which had been withheld for a minimum of 2 months before the start of the study as a washout period. Baseline hormonal profiles, AFC, and total ovarian volume were comparable between the groups, and no subject had follicles 10 mm or larger at the start of study. Endocrine profile Median serum AMH levels were undetectable in both groups throughout the 20-wk study period. It was only detectable at very low levels in one woman in the DHEA group (up to 0.11 ng/ml) and two women in the placebo group (up to 0.14 ng/ml). No significant difference was detected in the serial serum FSH levels between the two groups (Fig. 2). The median serum E2 levels were significantly higher in the DHEA group at wk 12 at 114 pmol/liter compared with 73 pmol/liter in the control group. The testosterone and

Ultrasound findings Median AFC was significantly higher in the DHEA group than that in the control group at wk 12 [2.00 (range 1–5) vs. 1.00 (range 0 –2), respectively, P ! 0.034]. Median total ovarian volume was significantly higher in the DHEA group than that in the control group at wk 20 (3.79 vs. 2.02 cm3, respectively, P ! 0.033) (Fig. 3). Median percentage changes of total ovarian volume followed a similar pattern with an increase starting at wk 16 and became statistically significant at wk 20 [224% (range 109 –529%) vs. 47% (range #56 to 147%), P ! 0.006] (Fig. 4). There was no follicle 10 mm or larger in any subject at baseline and 4 wk after the intervention. Overall, a higher proportion of women in the DHEA group had follicles 10 mm or larger, ranging from 11 to 33% from wk 8 onward (Fig. 5). Return of menses Twenty-five percent of the women in the placebo group and 11.1% in the DHEA group experienced irregular return of menses, and there was no significant difference between the groups. Side effects No major adverse effects were reported during the study period. Up to 22% of subjects in the DHEA group com-

TABLE 1. Baseline characteristics, hormonal profile, and ultrasound findings of a randomized comparison between the DHEA and placebo groups Age (yr) BMI (kg/m2) Duration of POI (months) FSH at diagnosis (IU/liter) Previous use of HRT Baseline serum levels AMH (ng/ml) FSH (IU/liter) Estradiol (pmol/liter) Testosterone (ng/ml) DHEA-S ("g/dl) SHBG (nmol/liter) IGF-I (ng/ml) Baseline USG findings AFC Total ovarian volume (cm3) Follicles $10 mm

DHEA group (n ! 9) 35.9 % 3.26 21.4 % 3.34 30 (2– 81) 79.2 % 35.1 4/9 (44.0%)

Placebo group (n ! 12) 33.4 % 4.74 21.1 % 4.08 43 (6 –132) 81.8 % 33.7 11/12 (91.7%)

P value 0.196a 0.961a 0.477b 0.783a 0.46c

0 (0) 101.9 % 49.8 89 (73–268) 0.27 % 0.12 160.0 % 68.7 47.3 % 16.8 145.4 % 56.6 0 (0 –2) 1.50 (0 –2.2) 0

0 (0 – 0.13) 91.6 % 32.6 73 (73–109) 0.56 % 0.37 157 % 107 50.6 % 26.0 150.0 % 60 0 (0 –2) 1.51 (0.6 –2.9) 0

0.209b 0.678a 0.320b 0.694a 0.967a 0.708a 0.611a 0.327b 0.413b 1.0c

Data expressed as mean % SD or median (range) or number (percentage) as appropriate. P $ 0.05 was considered as statistically significant. BMI, Body mass index; HRT, hormone replacement therapy; USG, ultrasound. a

Student’s t test.

b

Mann-Whitney U test.

c

# 2 test.

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FIG. 2. Box-and-whisker plots of hormone concentrations for women randomized into groups using 16 wk of DHEA (shaded box) and placebo (open box). Boxes indicate 25th and 75th percentiles, with the horizontal line representing the median values. Whiskers span the range between the fifth and the 95th percentiles of the data. The x-axis represents the time of the blood taking after the DHEA/placebo use. Statistically significant differences are defined as P $ 0.05 and are indicated by an asterisk.

plained of increased acne compared with 8.3% in the placebo group, and up to 22% in DHEA group and 16.7% in placebo group had a nonpersisting mild elevation of liver enzymes. There was no significant difference between two groups. Subgroup analyses Subgroup analyses were performed within the DHEA group (n ! 9) to identify the characteristics among those

who responded to DHEA with a return of menses and/or follicles of 10 mm or larger. Compared with women who remained amenorrheic throughout the study period (n ! 6), women who had a return of menses (n ! 3) had a lower serum FSH level at initial diagnosis (33.3 % 9.61 IU/liter vs. 110 % 39.5 IU/ liter, P ! 0.041). They also had significantly lower serum FSH at wk 8 (59.9 % 34.6 IU/liter vs. 117.3 vs. 25.9 IU/ liter, P ! 0.036) and wk 12 (37.2 % 7.44 IU/liter vs. 109.4

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FIG. 3. Box-and-whisker plots of AFC (left panel) and total ovarian volume (right panel) for women randomized into groups using 16 wk of DHEA (shaded box) and placebo (open box). Boxes indicate 25th and 75th percentiles, with the horizontal line representing the median values. Whiskers span the range between the fifth and the 95th percentiles of the data. The x-axis represents the time of the ultrasound monitoring after DHEA/ placebo use. Statistically significant differences are defined as P $ 0.05 and are indicated by an asterisk.

vs. 41.8 IU/liter, P ! 0.028). In addition, serum estradiol level was significantly higher at wk 12 [312 pmol/liter (range 233–390) vs. 89 pmol/liter (range 79 –129), P ! 0.025]. There were no significant differences in other baseline characteristics, other hormonal parameters, AFC, and ovarian volume in the women who responded or not to DHEA. All parameters were comparable between women who had at least one follicle larger than 10 mm (n ! 4) and those who had not (n ! 5). All the above analyses were repeated by per protocol approach and the results (not shown) were essentially the same.

Discussion To the best of our knowledge, this is the first randomized, double-blinded, placebo-controlled study to detect any

FIG. 4. Percentage differences in ovarian volume compared with baseline presented at 4-wk intervals. Statistically significant differences are defined as P $ 0.05 and are indicated by an asterisk.

improvement in ovarian response markers in women with POI after 16 wk of DHEA and monitor the change in these markers 4 wk after stopping DHEA. We could not find any significant improvement in serum AMH and FSH levels throughout the whole study period. AFC and ovarian volume were significantly higher at wk 12 and 20, respectively, in the DHEA group. More women having at least one follicle 10 mm or larger at wk 12, 16, and 20 were found in the DHEA group. Significantly higher serum testosterone and DHEA-S levels were achieved in the DHEA group from wk 4 to wk 16, confirming the compliance of subjects in taking the drugs. A recent systematic review and meta-analysis demonstrated that total testosterone concentrations are reduced in women with spontaneous POI compared with the agematched controls (15). It has previously been shown that accumulation of androgens in the micro milieu of the primate ovary plays a critical role in early follicular development and granulosa cell proliferation (16, 17). Androgens promote recruitment and initiation of primordial

FIG. 5. Percentage of women having at least one follicle greater than 10 mm during the 20 wk.

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follicle growth and induce significant increase in the number of primary, preantral, and antral follicles through the up-regulation of IGF-I (7, 17); up-regulate FSH receptor expression in granulosa cells to potentiate the effect of FSH (7, 16, 18); and exert paracrine regulation on follicular maturation and reduce follicular atresia (7, 18). At the same time, lack of androgen has been shown to reduce the number of antral follicles and ovulated oocytes (19) as well as leading to an accelerated rate of follicular atresia (20). With the presumed important roles of androgens in folliculogenesis and reducing follicular atresia, attempts to restore androgen levels in women with POI in the hope of improving ovarian functions seem biologically plausible. There have been increasing publications on improved treatment outcomes after DHEA supplementation in poor responders undergoing in vitro fertilization as well as reports on improved serum AMH in women with diminished ovarian reserve (21) and pregnancies among women with POI (22). It becomes imperative to further investigate the potential benefits of DHEA in women with POI. The baseline AMH level in the present study were unexpectedly lower than that of the women in our previous study (14) on which we based our statistical analysis. It may be explained by the fact that women in the previous study were newly diagnosed with POI during their investigations for secondary amenorrhea, whereas women in the present study have already been diagnosed with POI for a much longer time (median 30 months, range 2–132 months). AMH is mainly secreted by the granulosa cells of preantral and early antral follicles, which are constantly being recruited from a primordial follicle pool (23). In women with POI, the primordial pools are already severely depleted at the time of diagnosis. Ongoing depletion of the remaining follicular pool in women diagnosed with POI for years may further reduce the number of preantral and early antral follicles leading to undetectable baseline AMH levels. In contrast to the reported improvement of serum AMH in women with poor ovarian reserve (21), our study was unable to detect any significant improvement of serum AMH levels after 16 wk of DHEA, and serum AMH remained largely undetectable in both groups. It has been well accepted that women are born with all the primordial follicles and additional primordial follicles cannot be produced. Even with 16 wk of DHEA, the proposed actions of androgens are not to generate new primordial follicles de novo but only to increase the proportion of follicles in the growing pool by increasing the recruitment and initiation of folliculogenesis and reduce those undergoing atresia. The pool of preantral and early antral follicles may still be too small to secret AMH in a detectable amount using the current kits despite an improvement after DHEA.

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Moreover, we would not be able to detect a doubling of AMH because the baseline level is unexpectedly undetectable, and this would be one of the weaknesses of our study. However, substantial ovarian function and spontaneous conception had been reported in some patients who underwent orthotopic transplantation of ovarian tissue after gonadotoxic treatment whom serum AMH remained very low or undetectable (24). Despite the lack of apparent improvement in serum AMH and FSH levels in the DHEA group, higher AFC and total ovarian volume had been observed. Up to 30% of patients in the DHEA group had follicles 10 mm or larger after 8 wk of DHEA compared with 17% in the placebo group. Although the variability of AFC and ovarian volume measurement is usually greater than that of AMH, and possibly more prone to observer bias, the doubleblind placebo control design in our study can minimize the potential observer bias in the ultrasound measurements. It has been suggested that DHEA is involved in regulating follicular development through increased IGF-I (8, 17). It has been shown to increase the number of primary, preantral, and antral follicles by increasing the follicular recruitment and initiation together with reduced follicular atresia. These may result in an increase in the number of follicles in the growing pools that are susceptible to stimulation by FSH. It has also been shown to potentiate the effect of FSH by the up-regulation of FSH receptors (7, 16, 18). These could lead to increased ovarian volume and proportion of women having at least one follicle 10 mm or larger as observed in the DHEA group. Although our findings did not show any changes in serum IGF-I after DHEA use, it is possible that the up-regulation of IGF-I acts locally in primordial and subsequent stages of follicles and may not be reflected in serum levels. On the other hand, it is possible that DHEA supplementation can provide an increased amount of androsteinedione to the theca cells of the remaining follicles and thus increase the estradiol production by the granulosa cells. This could be a mechanism to improve follicle growth and responsiveness. On average, women reaches menopause when the primordial follicular pool falls below 1000 (25). Although the depleted follicular pool would unlikely be revived by DHEA, its supplementation may help in maximizing the growing pool by increased recruitment and follicular activities together with reduced follicular atresia. Approximately 50% of young women with POI experience intermittent and unpredictable ovulation that can continue for many years (26 –30), and spontaneous pregnancies have been reported in 5–10% of these women (6). Maximizing the number of recruited follicles that remain in the growing pool may provide a better chance of spontaneous ovulation and pregnancy during the period of supplementa-

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tion. Interestingly, women who responded to DHEA supplementation with return of menses had lower FSH at first diagnosis. Whether this is suggesting women who have less depleted ovarian reserve at the start with more primordial follicles remained for DHEA to work upon would respond better would be worth exploring. However, this should be interpreted with caution in view of the small sample size. In terms of optimal duration of treatment, because it takes more than 120 d for the primordial follicles to pass through the primary follicle stage to reach preantral stage, and it takes 65 d to grow from preantral to antral follicles, a longer duration of DHEA supplementation may confer additional benefits for increased folliculogenesis. Whether a longer duration and/or higher dose of DHEA could recruit more of the remaining follicles, building up a bigger growing pool and secrete detectable amounts of serum AMH would require further investigations. Another important aspect in managing women with POI is the replacement of estrogen. Mean serum E2 levels were significantly improved after 2 months of DHEA use and reduced vaginal dryness was reported. Although increased serum E2 level was observed, whether it is sufficient for bone protection would require long-term follow-up and an objective assessment of bone mineral density (BMD) by dual-energy x-ray absorptiometry. Several randomized control trials had evaluated the effects of DHEA therapy for 26 –104 months on BMD in postmenopausal women. There were evidences of improved BMD at the lumbar spine (31–35) and hip (33, 34, 36, 37) along with the evidence of significantly increased plasma bone alkaline phosphatase and osteocalcin (38). Its effect on POI patients would definitely be worth further exploration. Traditional hormonal replacement therapy increases serum estradiol but reduces bioavailable testosterone by increasing SHBG. In contrast, DHEA supplementation increases serum estradiol and testosterone without affecting serum SHBG. This may have positive effect in sexual function, although it is beyond the scope of the present study. We have excluded women who suffered from POI due to secondary causes like previous ovarian surgery, cytotoxic chemotherapy, and pelvic irradiation, FMR1 premutation, or Turner syndrome. By including only women with idiopathic POI, we were able to look at the effect of DHEA on ovarian function in a more homogeneous group of patients. The main weakness of our study was the relatively small sample size, which was calculated based on the assumption that DHEA supplementation would lead to the doubling of serum AMH levels. Moreover, we did not check serum progesterone level on a weekly basis to

confirm ovulation and did not use ongoing pregnancy or live birth rate as the primary outcome. Successful pregnancies after DHEA supplementation had been reported in case series (22). However, it should be noted that spontaneous pregnancies occur in 5–10% of women with POI without any intervention (6). Indeed, one of our subjects was found to be 8 wk pregnant at the second visit and had already conceived before the entry to the study. Without a properly randomized control group, any beneficial effect of DHEA would remain speculative. Conclusion Although there was no significant improvement in serum AMH and FSH levels, higher AFC and total ovarian volume were found after 16 wk of DHEA in women with POI. Given the small number of women with POI encountered in most units, a larger multicentered randomized trial addressing the effect of a longer duration of DHEA on hormonal profile, ovulation rate, and ultimately ongoing pregnancy or live birth rate would be important for both patients and clinicians. Before there is further evidence supporting the benefits of DHEA on women with POI, their empirical use should not be encouraged outside a clinical trial context.

Acknowledgments The clinical trial registration number is HKCTR-1148. Address all correspondence and requests for reprints to: Tracy Wing Yee Yeung, (M.B.B.S., M.R.C.O.G., F.H.K.C.O.G., F.H.K.A.M., Department of Obstetrics and Gynecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. E-mail: [email protected] This work was supported by the Hong Kong Obstetrical and Gynaecological Trust Fund and The Department of Obstetrics and Gynaecology, University of Hong Kong. Disclosure Summary: The authors have nothing to disclose.

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