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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4179-4183
Copyright © 1997 by The Endocrine Society

Original Studies

Resistance of Gonadotropin Releasing Hormone Drive to Sex Steroid-Induced Suppression in Hyperandrogenic Anovulation1

Tammy L. Daniels and Sarah L. Berga

Departments of Obstetrics, Gynecology, and Reproductive Sciences and Psychiatry, The University of Pittsburgh School of Medicine, Magee-Womens Hospital and Research Institute, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Sarah L. Berga, M.D., Departments of Obstetrics, Gynecology, and Reproductive Sciences and Psychiatry, The University of Pittsburgh School of Medicine, Magee-Womens Hospital and Research Institute, 300 Halket Street, Pittsburgh, Pennsylvania 15213. E-mail: pixie+{at}pitt.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Women with hyperandrogenic anovulation (HAA) exhibit increased GnRH drive, as evidenced by a faster LH pulse frequency that slows in response to progestin-induced opioidergic tone. To determine whether increased GnRH-LH drive in HAA reflects altered sex steroid exposure caused by chronic anovulation or is an intrinsic hypothalamic attribute, we compared the pulsatile LH response to oral contraceptive (OC)-induced suppression in seven women with HAA, with that of seven eumenorrheic women (EW). LH levels were determined at 10-min intervals for 12 h after 19–21 days of OC use and 5–7 days after cessation. Testosterone, androstenedione, estradiol, FSH, and LH levels were determined at weekly intervals before, during, and after OC use.

LH pulse number/12 h was higher (P < 0.001) in HAA during and after OCs, when compared with that of EW. Mean LH was increased in HAA before, during, and after OCs. Testosterone, androstenedione, and estradiol levels were higher in HAA before OCs, but they decreased to similar levels during OC use in both groups. FSH concentrations were similar before and during OCs but rose more after cessation of OCs in EW. These findings indicate that GnRH drive in HAA is resistant to OC-induced suppression and, therefore, could be an intrinsic hypothalamic attribute.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
WOMEN WITH hyperandrogenic anovulation (HAA) have increased LH levels caused by both increased LH pulse frequency and LH pulse amplitude (1, 2, 3, 4). We previously showed that the LH pulse frequency of women with HAA slowed in response to progestin exposure (5). These latter data suggested that the increased LH pulse frequency observed in women with HAA could be a consequence of the anovulatory state, that is, caused by infrequent progesterone exposure. Alternatively, the increased LH pulse frequency could signal an intrinsic increase in GnRH drive. Theoretically, a persistently faster GnRH pulse frequency would increase LH and decrease FSH (6, 7). Whereas chronically elevated LH pulsatility would promote hyperandrogenism, the resulting subthreshold levels of FSH would be insufficient to sustain folliculogenesis and ovulation. Increased GnRH pulse frequency likely would manifest as both increased LH pulse amplitude and LH pulse frequency. Given these considerations, we hypothesized that the increased LH/FSH ratio characteristic of HAA (8) is caused by an intrinsic increase in the frequency of the GnRH pulse generator.

To test this hypothesis, we examined LH pulse patterns after withdrawal from combined estrogen and progestin suppression. The GnRH pulse generator was suppressed by administering a standard oral contraceptive (OC), containing 35 µg ethinyl estradiol and 1 mg norethindrone, for 3 weeks. This artificial and prolonged luteal phase was simulated in seven women with HAA and seven eumenorrheic women (EW). In a previous study, this regimen significantly suppressed the LH secretory profile in EW, and we presumed that it would affect women with HAA similarly. The rationale for studying LH pulse patterns 5–7 days after cessation of OCs is that a previous study showed that, by day 7 of the pill-free interval, a normal LH pulse pattern was found, even in long-term OC users (9). We reasoned that if LH pulse frequency 5–7 days after cessation of OCs were the same in HAA and EW, then this finding would indicate that the increase in LH pulsatility in HAA was a consequence of anovulation and infrequent exposure to progesterone. Alternately, if the LH pulse frequency were increased in HAA relative to that of EW after steroid withdrawal, then this finding would suggest an intrinsic increase in GnRH drive in HAA.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental subjects

Fourteen women, 20–38 yr old, with body mass index (BMI) ranging from 19–30 kg/m2, participated after informed consent was obtained. This study was approved by the Institutional Review Board of Magee-Womens Hospital and the University of Pittsburgh. There were seven women with HAA, as evidenced by serum androstenedione levels >= 250 ng/dL or a total testosterone concentration >= 2.1 nmol/L, and seven EW. The following criteria were used to establish the diagnosis of HAA: 1) oligomenorrhea with no more than six menses annually since menarche; 2) no evidence of 21-hydroxylase deficiency, as determined by normal levels of 17-hydroxyprogesterone (10); and 3) normal TSH and PRL values. Serum progesterone levels were measured the day before beginning OCs, to ensure that women with HAA had not ovulated recently. Serum progesterone levels in HAA averaged 1.7 nmol/L ± 0.3.

HAA and EW subjects were matched for age, height, weight, and BMI. To ensure that they were ovulatory before starting OCs, EW were required to have midluteal progesterone levels greater than 30 nmol/L. The mean ± SE progesterone in EW was 50.1 nmol/L ± 9.4. HAA women had a negative urine ßhCG, to rule out pregnancy, before starting OC pills containing 35 µg ethinyl estradiol and 1 mg norethindrone. EWs started OCs on day 7 after last menses. No subjects had medical conditions that would contraindicate the use of OCs, and none had taken OCs for at least 4 weeks before initiation of the study.

Protocol

Participants were admitted to the General Clinical Research Center by 0800 h. An indwelling iv catheter was inserted into the nondominant forearm. Subjects then were permitted to rest for at least 30 min before venous sampling began. Meals were served at standard times. Subjects were not permitted to nap or to have caffeinated beverages during the sampling period. Blood samples were obtained at 10-min intervals for 12 h on days 19, 20, or 21 of OC use and on days 5, 6, or 7 after cessation.

Subjects also presented to the Magee-Womens Clinical Research Center for weekly venipuncture. Blood samples were drawn before initiation of OCs and on days 7, 14, and 21 of OC use and day 7 after cessation.

Assays

LH levels were determined in duplicate by a highly sensitive immunofluorometric assay (Delfia, hLH Spec, Wallac, Inc., Gaithersburg, MD) with a sensitivity of 0.05 IU/L. The interassay coefficient of variation (CV) was 8.9%, and the intraassay CV was 3.4%. All samples from a given participant were run in the same assay. FSH levels were determined in duplicate by immunofluorometric assay (Delfia, hFSH, Wallac, Inc.). The between-assay CV was 3.5%, and the within-assay CV was 2.6%.

Total testosterone was measured in duplicate in each sample using an RIA (Coat-A-Count, DPC, Los Angeles, CA). The between- and within-assay CVs were 11.9% and 3.8%, respectively. Serum androstenedione levels were also determined in duplicate by RIA (Coat-A-Count, DPC), with an interassay CV of 8.8% and intraassay CV of 3.0%. Estradiol was measured in duplicate in each sample by RIA (Coat-A-Count, DPC). Interassay and intraassay CVs were 9.9% and 2.6%, respectively.

Ethinyl estradiol levels were determined by gas chromatography/mass spectrometry on day 21 of OC exposure for all subjects (PPD Pharmaco, Richmond, VA). The validation range for this assay was 2.00–1000 pg/mL. The intraassay CV at 40 pg/mL was 2%, and the interassay CV at 40 pg/mL was 2.8%.

Data analysis

LH pulse number and amplitude were determined by a computer-assisted algorithm, Cluster, using a peak width of 2, a nadir width of 1, a t-statistic of 3 for upstroke and downstroke, and a quadratic equation based on assay CV to estimate variance (11).

Group t tests were used to determine whether differences existed between the groups for the parameters of age, height, weight, BMI, and ethinyl estradiol. LH pulse parameters, during and after OC use, were analyzed by a mixed, two-factor ANOVA with repeated measures. The levels of LH, FSH, estradiol, total testosterone, and androstenedione in both groups (before, during, and after OC use) were compared by a mixed, five-factor ANOVA with repeated measures. Group and paired t tests were used to identify post hoc significance. Change scores were determined to quantify OC-induced suppression, and group t tests were used to compare the degree of suppression between groups.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
As shown in Table 1Go, there were no group differences between HAA and EW in age, height, weight, BMI, or ethinyl estradiol levels. Ethinyl estradiol levels were assessed to ensure that biochemical differences between the two groups were not attributable to pharmacokinetic differences occasioned by giving a standard OC to all participants.


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  		Table 1. Characteristics (mean ± SE) of seven eumenorrheic women (EW) and seven women with hyperandrogenic anovulation (HAA)

 
LH pulse frequency was higher in HAA, as compared with EW, during and after OCs. Figure 1Go displays representative LH pulse profiles in two women with HAA and two EW. As shown in Fig. 2Go, women with HAA had an LH pulse no./12 h of 6.3 ± 0.8 during OCs and 11.7 ± 0.6 after OCs, whereas EW had an LH pulse no./12 h of 1.6 ± 0.5 during OCs and 5.6 ± 1.0 after OCs. LH pulse frequency was higher in HAA during OC use (P < 0.001) and after cessation (P < 0.001). LH pulse amplitude was similar in HAA, as compared with EW, both during OC use (HAA: 4.3 IU/L ± 0.8, and EW: 2.4 IU/L ± 0.8) and after cessation of OCs (HAA: 2.4 IU/L ± 0.3, and EW: 2.2 IU/L ± 0.3). The decrease in LH pulse amplitude observed in the HAA group after cessation of OCs was significant (P < 0.05), however. Women with HAA had a greater mean LH during (4.8 IU/L ± 1.0) and after (6.4 IU/L ± 0.7) OC use, when compared with that of EW during (1.2 IU/L ± 0.2) and after (3.0 IU/L ± 0.6) (P < 0.01).



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  		Figure 1. Representative 12-h LH pulse profiles in two women with HAA ( right) and in two EW (left).

 


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  		Figure 2. Mean (± SE) of LH pulse #/12 h in seven EW and seven women with HAA during and after OC use. *, EW != HAA (P < 0.001).

 
Weekly gonadotropin, androgen, and estradiol levels are displayed in Fig. 3Go. LH levels increased in both groups during the first 7 days of OC use and then declined on days 14 and 21 but rose again after cessation (P < 0.001). LH levels were higher at all time points in HAA (P < 0.001). FSH levels (shown in Fig. 3Go, panel 2) were comparable in both groups before initiating OCs. During OC use, FSH was suppressed to similar levels in both groups (P < 0.001). After cessation, FSH levels rose in both groups; but the rise was greater in EW, as compared with HAA (P < 0.05).



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  		Figure 3. Mean (± SE) of LH, FSH, estradiol, total testosterone, and androstenedione (Adione) concentrations for 5 consecutive weeks before, during, and after OC use in seven EW ({circ}) and in 7 women with HAA (•).

 
Estradiol levels were higher in HAA (57 pg/mL ± 5.0) than EW (28.8 pg/mL ± 3.2) before OCs (P < 0.001) but were similar by day 21 of OC exposure (HAA: 23 pg/mL ± 2.0, and EW: 20 pg/mL ± 0.0). Total testosterone levels were higher in HAA (2.9 nmol/L ± 0.3), when compared with EW (1.0 nmol/L ± 0.2), before beginning OCs (P < 0.001); but they were suppressed to the same level (HAA 0.9 nmol/L ± 0.2 and EW 0.7 nmol/L ± 0.0) during OC use. Total testosterone and estradiol rose slightly in both groups after cessation, but total testosterone levels remained within normal limits (<=1.2 nmol/L) in five of seven women with HAA. Androstenedione levels in HAA were approximately twice those seen in EW before, during, and after OCs (P < 0.001). However, by day 21 of OC exposure, androstenedione levels in HAA were suppressed an average of 45% (paired P < 0.05) and in EW 52.4% (paired P < 0.001). Androstenedione levels were suppressed to within the normal range (<=250 ng/dL) by day 21 of OC use in five of seven women with HAA.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The finding that LH pulse frequency is higher in women with HAA during and after sex steroid exposure supports the hypothesis that the GnRH pulse generator in HAA is intrinsically faster. Although LH pulse frequency was suppressed by OC use in HAA and EW, the suppressive effects of OCs on LH pulse frequency in HAA were significantly less than in EW. A likely explanation for this observation is an intrinsic increase in GnRH drive. A faster GnRH pulse frequency, supplied exogenously, increased the LH/FSH ratio in hypogonadal men (6, 7). This relationship also holds in women (12, 13). Thus, an intrinsically more rapid GnRH pulse frequency could explain the increased LH/FSH ratio characteristic of women with HAA. Not only would a persistently rapid GnRH pulse generator cause increased LH secretion that then could induce theca cell hyperplasia and promote excess androgen secretion, it also could suppress FSH levels below the threshold needed to sustain folliculogenesis and permit ovulation. The greater rise in FSH levels in EW, as compared with HAA after steroid withdrawal, supports this interpretation.

There is not a clear explanation for why the GnRH pulse generator of women with HAA would pulse at a higher frequency. We previously demonstrated that progestin exposure produced the expected slowing in LH pulse frequency in HAA and that it did so by inducing opioidergic tone (5). Thus, opioidergic neuromodulation of GnRH seems intact in HAA. Decreased central dopaminergic neuroregulation has been suggested as a cause of elevated LH and PRL levels observed in women with polycystic ovary syndrome (PCOS) (14). However, bromocriptine therapy did not alter LH levels when given to PCOS (15, 16). Further, LH levels in women with PCOS were unaltered by disulfiram (given to block central dopamine synthesis), metoclopramide (given as a dopamine receptor blocker), or iv administered dopamine (17, 18). Thus, available data do not support the notion that derangements in the neuroregulation of GnRH explain the more rapid GnRH-LH pulsatility observed in women with HAA.

Decrements in insulin levels and improvements in insulin action, produced by either weight loss (19) or the administration of insulin sensitizers (20), also did not alter LH pulse patterns. Neither metformin (21) nor troglitazone (22) altered basal or stimulated LH and FSH levels when given for 12 weeks. Further, Dunaif and Graf (23) showed that acute hyperinsulinemia (induced by a hyperinsulinemic, euglycemic clamp) had no effect on gonadotropin secretion in PCOS. Although Velasquez (24) and Nestler (25) found that metformin use reduced insulin and LH levels in women with PCOS, there are no data showing that insulin sensitizers alter LH pulsatility.

An alternate explanation for the rapid GnRH-LH pulsatility is that fetal ovarian or adrenal androgen exposure has imprinted the developing central nervous system. Plant (26) showed that when neonatal monkeys are gonadectomized, the LH pulse frequency of males is faster than that of females. If this explanation held for women with HAA, however, then there must be fetal androgen exposure of either adrenal or ovarian origin or both. Recent data suggest that the fetal ovary does secrete during late gestation (27). Further, women with virilizing congenital adrenal hyperplasia (CAH) hypersecrete LH, when compared with normal women or those with adult-onset CAH (28), but LH pulse frequency was not determined. Women with adult-onset CAH have an LH pulse frequency intermediate between that of EW and PCOS (29). Taken together, these data are consistent with the notion that an endowed tendency toward excess fetal androgen secretion could cause an intrinsic increase in GnRH pulse frequency in HAA.

Cyclic OC therapy only partially suppressed androgen secretion in HAA. Testosterone levels were suppressed to the same extent in HAA and EW, but androstenedione levels remained higher in HAA. Higher androstenedione levels could reflect increased adrenal androgen contribution or lesser suppression of LH by OC use in HAA. Extended, continuous, duration of OC use might achieve even greater suppression of gonadotropins and androgens (30). Because OC therapy did not significantly compromise insulin action in HAA (31), OC use can be used to reduce phenotypic sequelae of excess androgen exposure, to prevent menometrorrhagia and endometrial hyperplasia from chronic anovulation, and possibly to reduce the risk of cardiovascular disease (32).


   Acknowledgments
 
We would like to thank Ms. Christine Contis for her technical expertise; Ms. Teresa Ferguson, R.N., for her assistance in recruiting subjects; and R. Kazer (M.D.), T. Plant (Ph.D.), and A. Zeleznik (Ph.D.) for intellectual input. Also we would like to recognize the nurses and staff of the General Clinical Research Center and the Magee-Womens Clinical Research Center for their assistance and attention to detail.


   Footnotes
 
1 Supported in part by NIH RO1-MH/HD-50748 (to S.L.B.) and RR-00056 (to the General Clinical Research Center at the University of Pittsburgh School of Medicine). Presented in part at the 10th International Congress of Endocrinology, Abstract P2–612, June 12–15, 1996, San Francisco, CA. Back

Received June 3, 1977.

Revised August 6, 1997.

Accepted August 20, 1997.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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