Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine,6550 Fannin, Suite 801, Houston, Texas 77030, USA
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: androgens/dehydroepiandrosterone/gonadotrophins/ovarian stimulation/poor responders
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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, 1998), high dose gonadotrophin administration (Hofmann et al., 1993
), oestrogen pre-treatment down-regulation (Check et al., 1990
), 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., 1991
). 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., 1984), 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 3540 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., 1994; Diamond et al., 1996
; Casson et al., 1998a
). Second, in vivo, DHEA is a steroid prohormone for ovarian follicular sex steroidogenesis (Haning et al., 1993
). 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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., 1994; Diamond et al., 1996
; 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., 1993
) 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., 1998). Dexamethasone suppression of elevated endogenous DHEAS concentrations did not improve outcome in IVF (Rein et al., 1996
), but the addition of suppressive doses of this drug did improve outcome in clomiphene-resistant ovulatory subjects (Trott et al., 1996
). 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 3540 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 |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Buster, J.E., Casson, P.R., Straughn, A.B. et al. (1992) Postmenopausal steroid replacement with micronized dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies. Am. J. Obstet. Gynecol., 166, 11631170.[ISI][Medline]
Casson, P.R., Carson S.A., Buster J.E. et al. (1998a) Replacement dehydroepiandrosterone in elderly: rationale and prospects for the future. Endocrinologist, 8, 187194.[ISI]
Casson, P.R., Santoro, N.F., Elkind-Hirsch, K. et al. (1998b) Postmenopausal dehydroepiandrosterone (DHEA) administration increases free insulin-like growth factor-I (IGF-I) and decreases high density lipoprotein (HDL): a six month trial. Fertil. Steril., 70, 107110.[ISI][Medline]
Castracane, V.D., Stewart, D.R., Gimpel, T. et al. (1998) Maternal serum androgens in human pregnancy: early increases within the cycles of conception. Hum. Reprod., 13, 460464.[ISI][Medline]
Check, J.H., Nowroozi, K., Chase, J.S. et al. (1990) Ovulation induction and pregnancies in 100 consecutive women with hypergonadotropic amenorrhea. Fertil. Steril., 70, 107110.
Diamond, P., Cusan, L., Gomez, J.L. et al. (1996) Metabolic effects of 12-month percutaneous dehydroepiandrosterone replacement therapy in postmenopausal women. J. Endocrinol., 150, 543550.
Haning, R.V. Jr., Hackett, R.J., Flood, C.A. et al. (1993) Plasma dehydroepiandrosterone sulfate serves as a prehormone for 48% of follicular fluid testosterone during treatment with menotropins. J. Clin. Endocrinol. Metab., 76, 13011307.[Abstract]
Hedon, B., Out, J.H., Hughes, J.N. et al. (1995) Efficacy and safety of recombinant follicle stimulating hormone (Puregon®) in infertile women pituitary-suppressed with triptorelin undergoing in-vitro fertilization: a prospective, randomized, assessor-blind, multicentre trial. Hum. Reprod., 10, 31022106.[Abstract]
Hofmann, G.E., Toner, J.P., Muasher, S.J. et al. (1993) High-dose follicle stimulating hormone (FSH) ovarian stimulation in low responder patients for in-vitro fertilization J. In Vitro Fert. Embryo Trans., 6, 285289.
Homburg, R., Eshel, A., Abdulla, H.I. et al. (1988) Growth hormone facilitates ovulation induction by gonadotrophins. Clin. Endocrinol., 29, 113115.[ISI][Medline]
Hugues, J. and Durnerin, I. (1998) Revisiting gonadotrophin-releasing hormone agonist protocols and management of poor ovarian responses to gonadotrophins. Hum. Reprod. Update, 4, 83101.
Ibrahim, Z.H., Lieberman, B.A., Matson, P.L. et al. (1991) The use of biosynthetic growth hormone to augment ovulation induction with buserelin acetate/human menopausal gonadotrophin during ovarian stimulation for in vitro fertilization in women with a poor ovarian response. Fertil. Steril., 55, 202205.[ISI][Medline]
Morales, A.J., Nolan, J.J., Nelson, J.C. et al. (1994) Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. Clin. Endocrinol. Metab., 78, 13601367.
Orentreich, N., Brind, J.L., Rizer, R.L. et al. (1984) Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J. Clin. Endocrinol. Metab., 59, 551555.[Abstract]
Padilla, S.L., Dugan, K., Maruschak, V. et al. (1996) Use of the flare-up protocol with high dose human follicle stimulating hormone and human menopausal gonadotrophins for in vitro fertilization in poor responders. Fertil. Steril., 65, 796799.[ISI][Medline]
Rein, M., Jackson, K., Sable, D. et al. (1996) Dexamethasone during ovulation induction for in-vitro fertilization: a pilot study. Hum. Reprod., 11, 253255.[Abstract]
Trott, E., Plouffe, L., Hansen, K. et al. (1996) Ovulation induction in clomiphene-resistant anovulatory women with normal dehydroepiandrosterone sulfate levels: beneficial effects of the addition of dexamethasone during the follicular phase. Fertil. Steril., 66, 484486.[ISI][Medline]
Submitted on February 8, 1999; accepted on June 7, 2000.