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Ovulation After Glucocorticoid Suppression of Adrenal Androgens in the Polycystic Ovary Syndrome Is Not Predicted by the Basal Dehydroepiandrosterone Sulfate Level¹

Departments of Obstetrics/Gynecology (R.A., V.Y.B., E.S.K., G.A.H., L.R.B.), and Medicine (R.A.), The University of Alabama at Birmingham, Birmingham, Alabama 35233

Address correspondence and requests for reprints to: Ricardo Azziz, M.D., M.P.H., The University of Alabama at Birmingham, Department of Obstetrics and Gynecology, 618 South 20th Street, OHB 549, Birmingham, Alabama 35233-7333. E-mail: razziz{at}uabmc.edu

	Abstract

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Adrenal androgen (AA) excess, primarily in the form of dehydroepiandrosterone sulfate (DHEAS), affects over 50% of women with the polycystic ovary syndrome (PCOS). Nonetheless, it is unclear what role AA excess plays in the PCOS-associated oligo-ovulation. We have hypothesized that AAs are important in the maintenance of the ovulatory dysfunction of women with PCOS and AA excess, which can be improved by glucocorticoid suppression. To test our hypothesis we prospectively studied 36 unselected women, ages 18–40 yr, with PCOS; i.e. oligomenorrhea (cycles > 35 days in length), and clinical/biochemical evidence of hyperandrogenism (i.e. hirsutism and/or hyperandrogenemia), after the exclusion of related disorders. After informed consent, all patients underwent an acute ACTH-(1–24) stimulation test, measuring androstenedione, dehydroepiandrosterone (DHEA) and cortisol (F), and were then treated with dexamethasone 0.5 mg/day for four cycles. Ovulatory function was assessed before and during treatment using a basal body temperature calendar and day 22–24 progesterone (P4) levels. If patients were anovulatory (P4 < 4 ng/mL), a withdrawal bleed was induced by the administration of 100 mg P4 in oil i.m. Before and during treatment the levels of total and free testosterone (T), sex hormone-binding globulin, androstenedione, DHEA, DHEAS, cortisol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were monitored. With therapy, all patients demonstrated a significant decrease in all androgens (-40-60%), a 24% increase in sex hormone-binding globulin, and no change in LH/FSH. Mean body weight increased by over 4 kg (4.4%) during treatment. Of the 138 cycles monitored, 78% remained anovulatory. Twenty-five percent, 17%, 14%, and 20% of the first, second, third, and fourth treatment cycles, were ovulatory, respectively (P = 0.381). Of the 36 patients studied, 18 (50%) did not demonstrate a single ovulatory cycle (i.e. a day 22–24 P4 level > 4 ng/mL); and of the remaining, 10 (28%) had only one, five (14%) had two, and three (8%) had three ovulatory cycles. There were no significant differences either in physical features, basal hormones, adrenal response to ACTH stimulation, or hormonal levels at the end of treatment, between those women ovulating and those not. Finally, there were no differences in ovulatory response to dexamethasone therapy between women with (n = 14) and without (n = 22) DHEAS excess (i.e. DHEAS > 2750 ng/mL). In conclusion, the data from this prospective study do not suggest that continuous dexamethasone suppression results in consistent ovulation in any PCOS patient, regardless of basal DHEAS levels. Furthermore, this treatment is associated with significant side-effects, notably weight gain. Finally, these data suggest that, while AA may be an important risk factor for PCOS, once the syndrome is established, they play a limited role in the associated ovulatory dysfunction.

	Introduction

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ANDROGEN excess in women results in a number of symptoms including hirsutism, acne, and oligo- or anovulation. In polycystic ovary syndrome (PCOS), the vast majority of patients demonstrate an ovarian source for their high androgen secretion. Nonetheless, approximately 50–70% of PCOS patients also have excessive adrenal androgen (AA) levels (1, 2, 3). Overall, the role of adrenal hyperandrogenism in producing the PCOS-associated oligo-ovulation is unclear, as both dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are relatively weak androgens, in comparison to testosterone (T) (4). However, because DHEAS circulates in a concentration approximately 10,000 times that of T (4), excess levels of that AA may result in clinically relevant hyperandrogenicity. Circulating DHEAS has been found to be the precursor for almost 50% of the follicular fluid T in women treated with menotropins (5). These data would suggest that excess circulating DHEAS results in elevated levels of intrafollicular T. In turn, elevated intrafollicular androgens have been associated with an increased incidence of follicular atresia, polycystic-like ovaries, and ovulatory dysfunction (6, 7). Overall, it is highly probable that AA excess in PCOS plays a role in the associated oligo-ovulation.

In accordance with the presumption that AAs play a role in the ovulatory dysfunction of women with PCOS, a number of investigators have noted a beneficial effect of glucocorticoid administration on ovulation. The use of corticosteroid suppression for the treatment of ovulatory dysfunction was first reported in 1953 (8, 9). Subsequently, a number of investigators have reported improved menstrual regularity in 30–66% of oligo-ovulatory patients treated with glucocorticoids only (10, 11, 12, 13) and has recently been reviewed (14). Nonetheless, it should be noted that earlier reports primarily determined changes in menstruation, without further documentation of ovulatory function. Furthermore, although most patients studied were oligomenorrheic, they did not necessarily meet the diagnostic criteria for PCOS.

We now have hypothesized that AA excess is acting to maintain the ovulatory dysfunction of some/all women with PCOS, and that it is possible to predict which patients would respond to glucocorticoid suppression by their basal AA levels or the response of AAs to acute ACTH stimulation. To test these hypotheses, we prospectively studied the impact of dexamethasone (DEX), 0.5 mg/day for 4 cycles, on the ovulatory function of 36 patients with PCOS.

	Materials and Methods

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Subjects

We prospectively recruited unselected women, age range 18–40 yr, with PCOS. PCOS was defined according the criteria set forth in the National Institute for Child Health and Human Development consensus conference of 1990 (15). In brief, all patients demonstrated evidence of oligo-ovulation and hyperandrogenism (defined by the presence of hirsutism and/or hyperandrogenemia) after the exclusion of related disorders. We defined hirsutism as a score of 6 or greater using a modification of the Ferriman-Gallwey (F-G) scoring method (16). We recently reported that 7.6% of 369 consecutive unselected women demonstrated an F-G score of 6 or more (17). Hyperandrogenemia was defined as a total or free T, or androstenedione (A4) above the 95th percentile of age-matched normal controls. Based on 44 consecutive healthy eumenorrheic nonhirsute women, ages 18–40 yr, these values are as follows: total T > 89 ng/dL (3.08 nmol/L), free T > 0.66 ng/dL (0.023 nmol/L), and A4 > 2.97 ng/mL (10.4 nmol/L), as previously reported (18).

To be included in this study all patients had to have a history of menstrual cycles more than 40 days in length and either a monophasic basal body temperature (BBT) chart and/or a day 22–24 P4 level of less than 4 ng/mL, within the preceeding 3 months. Patients were excluded if they: a) were menopausal or pregnant; b) desired oral contraception; or c) had used hormonal therapy within the preceeding 3 months. All patients were advised to use a barrier contraceptive during the study if they were sexually active and did not desire pregnancy.

All patients completed a standardized history form and underwent a full physical exam, including the determination of the waist-to-hip ratio (WHR), as previously described (19). We excluded hyperprolactinemia and thyroid dysfunction by the measurement of a basal prolactin and a high-sensitivity TSH measurement, respectively; nonclassic adrenal hyperplasia by the measurement of a basal 17-hydroxyprogesterone measure less than 2 ng/mL (6.0 nmol/L) (20); and Cushing’s syndrome and androgen-secreting tumors, using clinical and hormonal parameters, as previously reported (21). Patients were studied, as outlined below, according to the guidelines of the Institutional Review Board of the University of Alabama at Birmingham, after written informed consent.

Study protocol

After confirmation of oligo-ovulation, patients were treated with DEX 0.5 mg/day for four treatment cycles. During each treatment cycle, ovulatory function was assessed using a basal body temperature calendar and day 22–24 P4 levels. If patients were found to be anovulatory (i.e. P4 < 4 ng/mL) during a treatment cycle, they then received 100 mg P4 in oil i.m., to induce a withdrawal bleed, while the DEX therapy was continued.

Before therapy, patients underwent an acute ACTH stimulation test (see below). Additional blood was obtained immediately before beginning DEX therapy and at the end of therapy, after their fourth menses (or withdrawal bleed). All samples were obtained in the morning (0700–1000 hr) and in the fasting state, and serum was separated and stored at -20 C. until assayed. In addition, patients were weighed at each visit.

Acute 1–24 ACTH stimulation

All studies were performed between 0800 and 1000 hr in the fasting state, in the follicular phase (days 3–8) of the menstrual cycle. In the event the patient was amenorrheic, tests were performed after a withdrawal bleed induced by P4 in oil. DEX was not administered before the study, in order to assess the resting basal steroid levels. Three baseline samples were obtained 15 min apart and mixed (0-min sample). Immediately afterwards 0.25 mg ACTH-(1–24) (Cortrosyn, Organon Co., Orange, NJ) was administered i.v. over 60 sec, and blood was sampled 60 min later. The serum was separated and stored at -20 C. until assayed.

Hormonal determinations

Baseline samples before and at the end of therapy were assayed for cortisol (F), A4, DHEA, T, SHBG, DHEAS, luteinizing hormone (LH) and FSH. DHEA, A4, and F were also measured in the 0–60-min samples of the acute ACTH stimulation test samples. Serum samples on all patients were batched for analysis, and hormonal assays were performed at one time.

DHEAS, A4, and 17-HP were measured by direct RIA, using commercially available kits (17-HP: Diagnostic Products Corp., Los Angeles, CA; DHEAS and A4: Diagnostics Systems, Webster, TX), as previously described (22). Progesterone was measured by a chemiluminescent assay (Chiron Diagnostics, Boston, MA), with an intra-assay coefficients of variance (CVs) of 5.7% and 8.4%, and interassay CVs of 7.7% and 7.0%. FSH and LH were measured by immunoradiometric assays (Nichols Institute Diagnostics, San Juan Capistrano, CA) with interassay CVs of 10.4% and 7.5% for FSH, and 5.8% and 4.1% for LH. SHBG activity was measured by diffusion equilibrium dialysis using Sephadex G-25 and ³[H]-T as the ligand, and free T was calculated as previously described (23). Total testosterone, cortisol, and DHEA were measured by in-house RIAs, as previously described (18, 24).

Statistical analysis

A P < 0.05 was considered significant. A statistical software package was used (Kiwkstat-Winks 4.5 professional, TexasSoft, Cedar Hill, TX) to perform Student’s t test on the continuous data and paired t test for comparisons of variables at baseline to 4 months, Mann-Whitney (nonparametric comparison) for discrete data, and -square on the discontinuous variables.

	Results

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A total of 44 patients were recruited into the study. Of these, 8 (18.2%) discontinued treatment before their third cycle, secondary to difficulty making the necessary visits or poor compliance (n = 5), weight gain or swelling (n = 2), and skin eruption (n = 1). Thirty-six patients completed the study, and their characteristics before treatment are depicted in Table 1. There were no significant differences in mean age, body mass index (BMI), WHR, F-G score, race, or basal DHEAS between those patients completing and not completing the study (i.e. 27.3 ± 7.8 yr vs. 26.1 ± 5.6 yr; 32.9 ± 8.0 kg/M²vs. 36.5 ± 6.0 kg/M²; 0.83 ± 0.07 vs. 0.83 ± 0.07, 10.3 ± 4.1 vs. 10.9 ± 3.3, 8.3% vs. 12.5% nonwhite, and 2508 ± 1274 ng/mL vs. 3041 ± 810 ng/mL, respectively).

Of the potential 144 treatment cycles, no day 22–24 P4 levels were obtained in six [one, third cycle; five, fourth cycles (one, due to conception in the third cycle)]. These cycles were excluded from analysis. One patient had all her P4 measurements performed in an outside laboratory, per her request, and these cycles were included in the analysis. Of the 138 cycles monitored, 5 (3.6%) demonstrated a day 22–24 P4 level of at least 4 ng/mL and less than 8 ng/mL, and 25 (18%) demonstrated a P4 level of at least 8 ng/mL. Overall, the remainder of cycles monitored (108/138 or 78%) were anovulatory. Twenty-five percent (9/36), 17% (6/36), 14% (5/35), and 10% (3/31) of the first, second, third, and fourth treatment cycles, were ovulatory, respectively. These differences in ovulatory rates per treatment cycle were not significant (multiple square = 3.074, P = 0.381).

Of the 36 patients studied, 18 (50%) did not demonstrate a single ovulatory cycle (i.e. a day 22–24 P4 level > 4 ng/mL). Of the remaining 18 women, 10 (28%) patients had only one ovulatory cycle, 5 (14%) had two ovulatory cycles, three (8%) had three ovulatory cycles, and none of the patients had four ovulatory cycles (Fig. 1). It should be noted that one of the patients conceived during her third ovulatory cycle, the only pregnancy documented during the course of this study.

View larger version (26K): [in this window] [in a new window]   Figure 1. Histogram demonstrating the percent of PCOS patients with (Hi-DHEAS) and without (Lo-DHEAS) adrenal androgen excess, and combined (i.e. All), who ovulated during only one, only two, and only three of the four treatment cycles of dexamethasone suppression (0.5 mg/day). Note that none of the patients ovulated all four treatment cycles.

Hormonal response to DEX therapy

In response to DEX administration, the basal levels of DHEAS, DHEA, A4, total and free T decreased by 65%, 41%, 55%, 44%, and 52%, respectively; while mean SHBG increased by 24%, and the LH/FSH ratio did not change (Table 1). In turn, mean body weight increased over 4 kg (4.4%) during the four cycles of treatment, with little change in the overall BMI. There were no differences between those women ovulating and those not for the hormonal levels at the end of four treatment cycles, nor in the net difference (data not shown).

Comparison of PCOS patients with and without AA excess

Patients were subdivided according to the level of their initial basal DHEAS. Those with DHEAS values more than 2750 ng/mL (7.46 µmol/L), the upper 95th percentile of normal as previously reported (16), were designated as having AA excess (i.e. Hi-DHEAS). We then compared Hi-DHEAS subjects (n = 14 or 39% of the total) with those patients having an initial basal DHEAS no more than 2750 ng/mL (i.e. Lo-DHEAS; n = 22). Not unexpectedly, the mean initial basal DHEAS was greater in Hi-DHEAS than Lo-DHEAS patients (Table 2).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
We have studied the role of AA excess in maintaining the oligo-ovulation of PCOS, by prospectively assessing the impact of DEX suppression (0.5 mg/day) on ovulatory function during 4 cycles in these patients. Ovulatory function was documented by basal body temperature charting and by a day 22–24 P4 level. Of 36 patients completing the protocol, only 8% had 3 ovulatory cycles, and none had 4 ovulatory cycles. Overall, 78% of cycles treated were anovulatory. Most importantly, no difference in response was observed between those patients with and those without elevated DHEAS levels. In fact, there were no obvious clinical or hormonal parameters that could be used to predict which patients were most likely to ovulate. Although this study was not specifically designed to study therapeutic value of glucocorticoid suppression alone on ovulatory function in PCOS, corticosteroid suppression may enhance the ovulatory response to clomiphene citrate, particularly in those patients with higher DHEAS levels (25).

Overall, these data suggest that once PCOS is established AAs play a limited role in maintaining the associated ovulatory dysfunction. Alternatively, AAs may be an important risk factor for the development of PCOS. For example, children with premature adrenarche are at higher risk than normal for developing PCOS (26, 27). In addition, women with 21-hydroxylase deficient nonclassic adrenal hyperplasia frequently develope PCOS-like symptomatology, including LH excess, polycystic ovaries, oligo-ovulation, and ovarian hyperandrogenemia (28). It would appear that AA excess is a factor in the development or initiation of PCOS.

Regardless of ovulatory response, DEX suppression resulted in significant suppression of all androgens in these PCOS patients, consistent with other studies (10, 29, 30, 31, 32, 33, 34). Although elevated intrafollicular levels of T appear to be associated with PCOS (6, 7), these data would suggest that solely reducing circulating T levels is insufficient to normalize ovulatory function in these women. While it may be argued that perhaps the absence of this association is secondary to a slower response of T compared to DHEAS to glucocorticoid suppression, other investigators have observed a significant reduction of T within 30 days of therapy, albeit at a greater dose of DEX (i.e. 1 mg/day) (33). Interestingly, the basal DHEAS levels remained higher in patients who had excess DHEAS at the beginning of the study, in spite of over 4 months of DEX administration. This observation would suggest that the excess DHEAS observed in many PCOS patients (42% in the present study) may be relatively independent of ACTH stimulation.

The study may be criticized for its lack of a control group (e.g. the same or a similar group of patients could have been monitored for 4 cycles, before receiving or without DEX). Nonetheless, it should be noted that all the patients included had evidence, at least by history, of long-term oligo-ovulation. It may also be argued that in our study adrenal suppression was of insufficient duration, and thus a role for excess AA in the ovulatory dysfunction of PCOS cannot wholly be excluded. However, this is unlikely because, as noted above, the four cycles of therapy with a duration of treatment generally lasting greater than 4 months were sufficient to significantly decrease all androgens. Furthermore, the highest ovulatory response occurred in the first treatment cycle (25%), although a rate not significantly different than that of cycles two, three or four. Together, these data would suggest that a longer period of treatment would not have produced a higher ovulatory response rate. Nonetheless, it should be stressed that this study was designed primarily to test the hypothesis that AA excess plays a role in maintaining the oligo-ovulation associated with PCOS, not to determine the therapeutic benefit of DEX on the ovulatory function of these patients.

In conclusion, the data from this prospective study do not suggest that continuous DEX suppression resulted in consistent ovulation in any PCOS patient, regardless of basal DHEAS levels. In addition to its limited impact on ovulatory function, glucocorticoid therapy is associated with a number of side-effects, including weight gain, glucose intolerance (35, 36), and osteoporosis (37). In fact, our patients gained an average of 4 kg during the study. Overall, these data suggest that once PCOS is established, AAs play a limited role in the associated ovulatory dysfunction, although this study cannot exclude a role for AAs in the development of the syndrome.

	Acknowledgments

 
We thank Dr. Carlos Moran for his review and suggestions.

	Footnotes

 
¹ Supported by Grant RO1-HD29364 from the National Institutes of Health, Bethesda, Maryland (R.A.)

Received August 7, 1998.

Revised October 22, 1998.

Revised December 14, 1998.

Accepted December 18, 1998.

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