Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series

P.R. Casson1, M.S. Lindsay, M.D. Pisarska, S.A. Carson and J.E. Buster

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine,6550 Fannin, Suite 801, Houston, Texas 77030, USA


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In patients with poor response to ovarian stimulation with gonadotrophins, growth hormone (GH) is sometimes used to increase paracrine insulin-like growth factor-1 (IGF-1) effect. We postulated that dehydroepiandrosterone (DHEA) administration to poor responders would augment gonado-trophin effect via a similar mechanism. Baseline ovarian stimulation response to a cycle with DHEA in five healthy non-smoking women <41 years old was compared with day 3 FSH <20 mIU/ml. All had documented poor response to vigorous gonadotrophin administration. After day 2 ultrasounds, DHEA-sulphate (DHEA-S), FSH, human chorionic gonadotrophin (HCG), and testosterone were measured, and the women were given 80 mg/day of oral micronized DHEA for 2 months. While still on DHEA, they underwent ovarian stimulation with FSH given i.m. twice a day, and HCG (10 000 IU) at follicular maturity, followed by intrauterine insemination. Cycle parameters assessed were peak oestradiol, and peak oestradiol/ampoule. The DHEA/ovarian stimulation cycles occurred between 4 and 24 months after the control cycles. After 2 months DHEA treatment, DHEA-S increased to 544 ± 55 µg/dl, and testosterone increased to 67.3 ± 6.1 ng/dl. All five subjects (six cycles; one subject had two DHEA cycles) had increased responsiveness; peak oestradiol concentrations increased from 266.3 ± 69.4 pg/ml to 939.8 ± 418.9 pg/ml. The oestradiol/ampoule ratio increased in all six cycles, by a mean of 2.94 ± 0.50 fold (P = 0.012). One of the cycles resulted in a delivered twin pregnancy. In this small series, DHEA improved response to ovarian stimulation even after controlling for gonadotrophin dose. Supplemental DHEA treatment during ovarian stimulation may represent a novel way to maximize ovarian response.

Key words: androgens/dehydroepiandrosterone/gonadotrophins/ovarian stimulation/poor responders


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In recent years, the widespread application of assisted reproductive technology has revolutionized the treatment of all forms of infertility. With few exceptions, however, assisted reproductive technology depends on ovarian stimulation and concurrent multiple oocyte development, induced by administration of large quantities of exogenous gonadotrophins. Unfortunately for some infertile women, gonadotrophin administration results in desultory ovarian response. While this is commonly due to diminished ovarian reserve, as indicated by advanced age and/or elevated basal day 3 FSH concentrations, a subset of these patients are <41 years old and have normal FSH concentrations.

To overcome this problem several strategies have been reported, with limited success. These include gonadotrophin-releasing hormone (GnRH) flare protocols (Padillo et al., 1996; Hugues and Durnerin, 1998Go), high dose gonadotrophin administration (Hofmann et al., 1993Go), oestrogen pre-treatment down-regulation (Check et al., 1990Go), and concomitant growth hormone (GH) administration (Homburg et al., 1991). GH is thought to amplify intra-ovarian insulin-like growth factor-I (IGF-I) paracrine effect, which is expressed by granulosa cells and enhances gonadotrophin action (Adashi et al., 1991Go). However, the clinical utility of combined GH/ovarian stimulation is limited; responses, while present, are not dramatic, and recombinant GH is extravagantly expensive.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEA-S) are ubiquitous steroids of primarily adrenocortical reticularis zonal origin. These hormones circulate in high amounts in female reproductive life; however, concentrations fall progressively with age (Orentreich et al., 1984Go), leading to speculation that replacement of DHEA and DHEA-S in the elderly may have age-retardant effects (Casson et al., 1998).

Two lines of circumstantial evidence support use of exogenous DHEA to augment ovarian stimulation in women aged 35–40 years who are poor responders. First, well controlled studies demonstrate marked augmentation of serum IGF-I concentrations with oral administration of physiological DHEA (Morales et al., 1994Go; Diamond et al., 1996Go; Casson et al., 1998aGo). Second, in vivo, DHEA is a steroid prohormone for ovarian follicular sex steroidogenesis (Haning et al., 1993Go). On this basis, we postulated that in patients <41 years old, with previously demonstrated poor response and normal FSH concentrations, administration of oral DHEA in combination with gonadotrophin stimulation would result in enhanced ovarian response. Therefore, we designed and executed the following prospective case series repeated here.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
With approval of our Institutional Review Board, five women with unexplained infertility were identified from our tertiary clinical infertility practice. All were <41 years old, had day 3 FSH concentrations <20 mIU/ml, had unexplained infertility, and had had previous poor response to vigorous gonadotrophin stimulation (peak oestradiol attained was <500 pg/ml, the number of mature follicles was <=2). All had documentation of the most recent gonadotrophin cycle, meeting the above criteria of poor response. One patient subsequently had an additional DHEA–ovarian stimulation cycle, which was also included in the analysis.

After informed consent, the subjects had baseline ultrasound scans on cycle day 2, and blood was drawn for serum DHEA-S, FSH, HCG, testosterone assays, and liver function tests. All subjects had regular cycles, and normal liver, thyroid and kidney function. The women were then given 80 mg/day of oral micronized DHEA (Belmar Pharmacy, Lakewood, CO, USA) for 2 months. Monthly repeat DHEA-S, testosterone, liver function tests, and ultrasound scans were performed. After 2 months of DHEA pretreatment, and while still remaining on this hormone, the subjects had a repeat ovarian stimulation cycle. The stimulation protocol was started on day 2 and consisted of two ampoules of 75 IU recombinant FSH (rFSH, Follistim®; Organon, West Orange, NJ, USA) given i.m. twice a day for 5 days. One subject (no. 2) used purified urinary FSH (Metrodin; Serono Laboratories Inc., Randolph, MA, USA) in both her control and DHEA cycles. On day 7 repeat ultrasound and oestradiol measurements were performed and rFSH dose was subsequently adjusted for maximal response. At follicular maturity (>=1 or more follicles of >=16 mm average diameter) ovulation was induced with HCG (10 000 IU i.m.), followed at 36 h by intrauterine insemination. The ovarian response to gonadotrophins was assessed with transvaginal ultrasound and with serum oestradiol concentrations at 0800 hours. To assess the differences between the control and DHEA cycles, peak oestradiol concentrations, number of follicles >15 mm average diameter, and change in peak oestradiol obtained per ampoule of gonadotrophin were compared. The fold increase in peak oestradiol concentrations and oestradiol per ampoule of gonadotrophin was also compared for the five patients (six cycles) using paired t-tests with post hoc (Bonferroni's) correction.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The six DHEA/ovarian stimulation cycles occurred between 4 and 24 months after the control ovulation induction cycles; the age range of the subjects at the time of DHEA/ovarian stimulation was 35–40 years. The subjects' baseline serum hormone values were: day 3 FSH, 10.7 ± 1.9 IU/ml (mean ± SEM); DHEA-S 122 ± 51.5 µg/dl; testosterone, 34.2 ± 2.1 ng/dl. After 2 months of DHEA supplementation serum steroid concentrations at 0800 hours were: DHEA-S, 544 ± 55 µg/dl; and testosterone, 67.7 ± 6.1 ng/dl. The subjects' control ovarian stimulation cycles had a mean peak oestradiol of 266 ± 69 pg/ml, attained with 35.4 ± 5.0 ampoules of gonadotrophins, a stimulation duration of between 7 and 11 days, and a mean number of mature follicles of 1.0. With DHEA supplementation, all five subjects had increased responsiveness to gonadotrophins. Peak oestradiol concentrations obtained were 940 ± 419 pg/ml attained with 35.6 ± 6.5 ampoules of gonadotrophin which represented 3.1 ± 6.4 fold increase over control cycles (P = 0.02). The cycle data are presented in Table IGo. The fold increase in peak oestradiol concentrations is presented in Figure 1Go. The mean number of mature follicles also increased from 1.0 to 2.2. Assuming equivalent biopotency between the gonadotrophin preparations, an assumption borne out by the literature (Hedon et al., 1995Go; Follistim, package insert), the mean oestradiol per no. of 75 IU ampoules ratio increased in all five patients (six cycles) by 2.94 ± 0.50 fold (P = 0.012). These increases are presented in Figure 2Go.


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Table I. Comparison of control and DHEA-supplemented cycles
 


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Figure 1. The fold increase in peak oestradiol concentration attained in control versus subsequent DHEA-supplemented ovarian stimulation cycles. Six cycles, performed in five subjects, are presented. The mean (± SEM) fold increase was 3.10 ± 0.69 (P = 0.02).

 


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Figure 2. The fold increase in peak oestradiol concentration, controlled for the number of 75 IU ampoules of gonadotrophin used (peak oestradiol/no. of ampoules) in control versus subsequent DHEA-supplemented ovarian stimulation cycles (six cycles, five subjects). The mean (± SEM) fold increase was 2.94 ± 0.50 (P = 0.012).

 
One patient conceived (cycle no. 6, Table IGo) and delivered a twin pregnancy as a result of one of the DHEA-augmented ovarian stimulation cycles; those patients who did not achieve pregnancy returned to their previous normal menstrual cycle patterns.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In these five subjects, all of whom were <41 years old, had normal FSH concentrations, yet had poor response to ovarian stimulation, it was found that concurrent oral DHEA supplementation improved gonadotrophin response by approximately two-fold. On the basis of this preliminary data, we conclude that use of adjuvant DHEA in poor responders may represent a novel way to maximize ovarian response in ovarian stimulation, and reduce gonadotrophin dose.

The mechanism by which DHEA supplementation exerts this gonadotrophin-augmentation effect is uncertain. We, and others, have shown that DHEA supplementation enhances serum free IGF-I concentrations by ~150%, probably independently of changes in GH secretion (Morales et al., 1994Go; Diamond et al., 1996Go; Casson et al., 1998). Perhaps this indicates that DHEA amplifies hepatic and end organ IGF-I response to GH, which, in the milieu of the ovarian follicle, may potentiate gonadotrophin action. Another possible mechanism by which DHEA exerts its effect is based on other work (Haning et al., 1993Go) demonstrating that circulating DHEA-S acts as a prohormone for much of ovarian follicular sex steroidogenesis. In the five subjects reported here, baseline DHEA-S concentrations were relatively low (122 ± 51.5 µg/dl). DHEA supplementation may therefore provide a more readily available pool of ovarian steroidogenic prohormone, facilitating follicular function and growth.

The literature regarding DHEAS, DHEA, and ovulation induction is scant. In natural cycles, endogenous DHEAS concentrations did not vary between luteal phases in non-conception and conception cycles (Castracane et al., 1998Go). Dexamethasone suppression of elevated endogenous DHEAS concentrations did not improve outcome in IVF (Rein et al., 1996Go), but the addition of suppressive doses of this drug did improve outcome in clomiphene-resistant ovulatory subjects (Trott et al., 1996Go). The interplay between adrenal androgens and ovarian function/stimulation is clearly complex. Supplementation of this steroid may only be beneficial in certain subgroups, such as the subjects in this case series.

The results of this study must be considered preliminary. First, it is possible that oral DHEA administration, which we have previously demonstrated is extensively metabolized to the down stream androgenic steroids, may very well result in production of a metabolite that cross reacts with the oestrogen assay used and artificially elevates serum oestradiol concentrations. However, the baseline oestradiol concentrations in these subjects were not elevated, even during concurrent DHEA supplementation. Additionally, in other studies of administration of this dose range of oral DHEA in postmenopausal women, circulating oestradiol concentrations do not appear to be increased (Casson et al., 1998).

The second contentious issue arises from the different gonadotrophin preparations used in the historical control cycles (mainly i.m. HMG) and in the study cycles (mainly i.m. rFSH). Perhaps the rFSH, by virtue of its greater purity, is more potent. However, both preparations are designed to be bioequivalent; the recombinant product simply has much less protein (Hendon et al., 1995; Follistim, package insert). Also, the gonadotrophin used in the subject with the most dramatic response (patient no. 2; purified FSH) was the same in the control and DHEA cycle. However, it may be that non-recombinant preparations of HMG contain some inhibitory substance that may worsen ovarian response, compared to rFSH. Clearly, a randomized controlled trial would address these questions.

DHEA does appear to augment ovulation induction in poor responders, particularly patients who are aged 35–40 years and have normal FSH concentrations. This effect may have great clinical potential. Not only would it allow for successful ovulation induction in patients with previous poor response, but it may, in normal patients, allow for dose reduction of gonadotrophin. The effect clearly bears further investigation.


    Acknowledgments
 
We thank Organon for their support and supply of Follistim for this study, and Belmar Pharmacy for supplying the DHEA tablets.


    Notes
 
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of Vermont, Burlington,VT 05405, USA. E-mail: pcasson{at}vtmednet.org Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on February 8, 1999; accepted on June 7, 2000.