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From the Clinical Research Centers |
Division of Endocrinology and the Center for Research in Reproduction, University of Virginia, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: C. A. Eagleson, M.D., Box 800746, Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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At baseline women with PCOS had higher LH pulse amplitude, response to GnRH, T, androstenedione, and insulin and lower sex hormone-binding globulin concentrations (P < 0.05). Most hormonal parameters were not altered by 4 weeks of flutamide, except T in controls and E2 and FSH in PCOS patients, which were lower. Of note, flutamide alone had no effect on LH pulse frequency or amplitude, mean plasma LH, or LH responsiveness to exogenous GnRH. After the addition of E2 and P for 7 days, both PCOS patients and normal controls had similar reductions in LH pulse frequency (4.0 ± 0.7 and 5.8 ± 0.7 pulses/12 h, respectively). This contrasts with our earlier results in the absence of flutamide, where a plasma P level of less than 10 ng/mL had minimal effects on LH pulse frequency in women with PCOS, but was effective in controls. These results suggest that although the elevated LH pulse frequency in PCOS may in part reflect impaired sensitivity to E2 and P, continuing actions of hyperandrogenemia are important for sustaining the abnormal hypothalamic sensitivity to feedback inhibition by ovarian steroids.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A common feature in women with PCOS is increased LH pulse frequency and amplitude, although wide variations in the prevalence of elevated LH levels are reported with a range between 30–90% (9, 10, 11, 12, 13, 14, 15). This may in part reflect the timing of blood sampling in relation to length of time since last ovulation. Taylor et al. (15) showed that when a woman with PCOS spontaneously ovulates, plasma LH remains in the normal range for approximately 3 weeks. Evidence regarding the importance of excess LH in elevation of ovarian androgen secretion originates from studies using GnRH agonists to desensitize LH secretion (16). After GnRH agonist therapy, plasma LH levels are reduced together with androstenedione and testosterone, supporting a role for LH in controlling abnormal ovarian androgen production. Recent studies using different paradigms have revealed reduced sensitivity of LH suppression (specifically pulse frequency) by estradiol (E2) and progesterone (P) (17, 18). Thus, impaired sensitivity of the GnRH pulse generator to inhibition by ovarian steroids may in part be responsible for the increased LH pulse frequency seen in PCOS, although the mechanism(s) of the reduced sensitivity is unclear.
Data from both humans and animal models suggest that exposure to androgens early in life may result in abnormal gonadotropin secretion. When LH secretion in women with classic congenital adrenal hyperplasia and late-onset 21- hydroxylase deficiency is compared, only women with the classic form, in which there is early exposure to androgens, exhibit elevation of basal LH and LH responses to a GnRH agonist (19). However, the effects of androgens on LH secretion are concentration dependent, as marked androgen elevations in adults are associated with decreased LH pulsatility (20, 21, 22). Animal studies also support an effect of early androgenic exposure on gonadotropin secretion. When female rhesus monkeys are exposed to T propionate prenatally, they subsequently develop abnormal gonadotropin secretion with elevated levels of LH (23). In a recent study, female lambs were exposed to T in utero, which resulted in several features similar to those present in women with PCOS. During subsequent adolescence, the lambs developed enlarged cystic ovaries, hyperandrogenemia, irregular menstrual cycles, elevated plasma LH, and increased LH pulse frequency (24). Interestingly, the androgenized lambs also exhibited impaired feedback to E2 and P, consistent with observations in women with PCOS.
The goal of the present study was to further evaluate the effects of elevated plasma androgens on LH secretion and LH pulse frequency in women with PCOS. Therefore, we tested the hypothesis that antiandrogen therapy would modify LH pulse frequency and the reduced hypothalamic sensitivity to estrogen and progesterone feedback.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ten women (age, 28 ± 2 yr) with clinical and laboratory features of PCOS and nine normal controls (age, 28 ± 2 yr) were studied. The women with PCOS were diagnosed on the basis of a history of oligomenorrhea, amenorrhea, hirsutism, acne, and/or infertility using NIH consensus criteria. All women were screened with LH, FSH, E2, total T, dehydroepiandrosterone sulfate, P, fasting insulin/glucose, PRL, T4, and hCGß. PCOS patients were also screened for elevated 0800 h 17-hydroxyprogesterone levels. The women were not taking medication, and any hormonal medication was discontinued for a minimum of 90 days before the study. Women with PCOS were studied at least 60 days after their last menstrual bleeding. Normal controls were studied between days 8 and 10 of their menstrual cycle (admissions 1 and 2) to approximate plasma E2 and P and LH pulse frequency present in women with PCOS.
Study protocol
The study was approved by the human investigation committee of the University of Virginia Health Systems and the General Clinical Research Center advisory committee. Informed consent was obtained from all patients. Subjects were admitted to the General Clinical Research Center 2 h before sampling, and blood samples were obtained through an indwelling iv forearm heparin lock over a 13-h period. At 0600 h, a blood sample was drawn for fasting insulin, androstenedione, and sex hormone-binding globulin (SHBG) determinations. During each admission, LH and FSH were determined every 10 min, and E2, P, and T were determined every 2 h. GnRH (25 ng/kg) was given iv 1 h before completion of sampling to evaluate responses to GnRH. After the first admission, patients were given flutamide at a dose of 250 mg twice daily for 5 weeks (Eulexin, Schering AG, Kenilworth, NJ). Nine, 11, and 13 days later, all subjects had blood samples for P determination to confirm ovulatory cycles in normal controls and absence of ovulation in PCOS patients. Liver function tests were measured on day 13. The second admission occurred between days 8 and 10 of the subsequent menstrual cycle for normal controls and on day 28 in women with PCOS. Blood sampling and GnRH dosage were identical to those at the first admission. All patients were then given 2 E2 patches (0.1 mg/day changed every 3 days; Estraderm, Novartis Pharmaceuticals, East Hanover, NJ) and P vaginal suppositories every 8 h (10–20 mg P in polyethylene glycol matrix) for 7 days. During this week flutamide was continued. The third admission occurred on the seventh day of E2 and P, and the sampling protocol was identical to the first 2 admissions. With each admission, sampling began either at 0800 h (7 subjects; 1 normal control and 6 PCOS) or 2000 h (12 subjects; 8 normal controls and 4 PCOS). The same starting time was used in all studies for each patient. Four additional normal controls were studied, but were not included in data analysis (3 took at least 1 of the medications incorrectly, and 1 had low hematocrit on the third admission). Two additional PCOS were studied, but were not included in the results because their plasma P levels suggested that they ovulated during the study.
Hormonal measurements
All samples from an individual woman were analyzed in duplicate in the same assay for each hormone. Plasma LH and FSH were measured by chemiluminescence (Nichols Institute Diagnostics, San Juan Capistrano, CA). The assay sensitivities were 0.01 and 0.02 mIU/mL for LH and FSH, respectively; intraassay coefficients of variation (CVs) were 11% and 6%, and interassay CVs were 10% and 10%, respectively. E2, P, and T were measured by RIA (Diagnostics Systems Laboratories, Inc., Webster, TX; sensitivity, 4.7 pg/mL, 0.12 ng/mL, and 0.08 ng/mL; intraassay CV, 8%, 9%, and 7%; interassay CV, 14%, 18%, and 15% for E2, P, and T, respectively). Androstenedione, estrone, and insulin were also measured by RIA (Diagnostics Systems Laboratories, Inc.; sensitivity, 30 pg/mL, 1.2 pg/mL, and 1.3 µIU/mL; intraassay CV, 4%, 8%, and 6%; interassay CV 8%, 14%, and 12%, respectively). SHBG was measured by immunoradiometric assay (Diagnostics Systems Laboratories, Inc.). Sensitivity was 3 nmol/L, intraassay CV was 7%, and interassay CV was 10%. Samples with measured values below the assay sensitivity were assigned the value of the assay’s sensitivity.
Data and statistical analysis
Data are presented as the mean ± SEM. P < 0.05 was considered statistically significant. LH pulses and amplitude were identified and characterized using the computer algorithm Cluster, with parameters of threshold change corresponding to a t statistic of 2.45 for both peak upstroke and downstroke (25, 26). If the increment in LH was less than 1.0 IU/L, it was not considered a pulse in subsequent analysis. Missing values represented less than 0.1% of the total and were not replaced.
Data comparing admissions for each group were analyzed using the paired nonparametric Wilcoxon rank-sum comparison tests. Data comparing PCOS to controls in each admission were analyzed with the Mann-Whitney unpaired nonparametric test. Due to limited data, adjustments for multiple comparisons within a response or for multiple responses could not be made. Regression analysis was performed to determine whether the change in LH pulse frequency (between admissions 2 and 3) as a function of increasing concentrations of P was different in normal controls and women with PCOS. The SAS (SAS Institute, Inc., Cary, NC) general linear model procedure (proc GLM) was used for the regression analysis. The model was based on ordinary least squares regression.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. At baseline, both
groups had similar plasma concentrations of E2,
estrone (E1), P, LH, FSH, and LH pulse frequency.
However, women with PCOS had higher T (0.9 ± 0.09 vs.
0.6 ± 0.05 ng/mL; P < 0.01), androstenedione
(4.6 ± 0.7 vs. 2.1 ± 0.5 ng/mL;
P < 0.005), and insulin (24.5 ± 3.1
vs. 13.3 ± 1.6 µIU/mL; P < 0.005)
and lower SHBG (56.9 ± 8.1 vs. 123.1 ± 21.2
nmol/L; P < 0.05). Although there was a trend toward
higher LH values, which did not achieve significance, women with PCOS
did have increased LH pulse amplitude and response to GnRH. After 4
weeks of flutamide treatment (admission 2), most hormonal parameters
did not change, except women with PCOS had lower mean FSH and
E2 levels, and normal controls had a reduction of
total T. Although there was no change in mean LH and LH pulse frequency
in PCOS and normal controls between admissions 1 and 2, values of both
were higher in PCOS patients compared with controls in admission 2
(P = 0.04 and P < 0.01, respectively).
LH pulse patterns in a control subject and a PCOS patient before and
after flutamide are shown in Fig. 1.
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shows the
relationship between suppression of LH (GnRH) pulse frequency and the
mean concentration of P on day 7 (study day 35). Linear regression
analysis, comparing the change in LH pulse frequency as a function of
P, revealed that the slope of LH pulse reduction vs. the
plasma P concentration on day 7 was similar for PCOS and normal
controls (slope, -0.72 vs. -0.53, respectively;
P = NS).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After 1 week of E2 and P administration, both
normal controls and PCOS had similar mean plasma levels of these
ovarian hormones. Mean plasma LH was lowered by
E2 and P due to slowing of the LH pulse
frequency, which was reduced to a similar degree in controls and PCOS
as a function of plasma P. These results stand in marked contrast to
our earlier findings using an identical study protocol performed
without flutamide pretreatment (17). In that study only a
minimal reduction of LH pulse frequency (
3 pulses/12 h) occurred
with plasma P levels below 10 ng/mL in women with PCOS, whereas
frequency fell by 60% (5.5 ± 0.6 pulses/12 h) in controls. In
Fig. 2
we superimposed the present results on those obtained in the
earlier study. In the prior study (17), there was no
association between P and LH pulse frequency reduction in PCOS
(P = NS). In contrast, normal controls had similar
reductions in LH pulse frequency (5.8 vs. 5.5 pulses/12 h,
this study vs. Ref. 17) regardless of whether
they had received flutamide (P = NS). Likewise, the
slopes for the linear regression analysis evaluating the LH pulse
reduction as a function of P were similar in normal controls treated
with and without flutamide (-0.53 vs. -0.76, respectively;
P = NS). These data suggest that blockade of androgen
action for 5 weeks restores the sensitivity of the GnRH pulse generator
to feedback inhibition by E2 and P. The results
also suggest that continuing hypothalamic exposure to hyperandrogenemia
is an important factor in sustaining the abnormal feedback inhibition
to E2 and P.
Other studies have shown a persistent increase in LH pulse frequency in PCOS (9, 10, 11, 12, 13, 14, 15), and some have suggested that prenatal androgen exposure has effects on LH secretion in adult life (19). Barnes et al. studied women with either classic congenital adrenal hyperplasia or late-onset 21-hydroxylase deficiency on the basis that only women with the classic form had been exposed to androgens early in life. The women with classic congenital adrenal hyperplasia exhibited elevated basal LH levels and enhanced LH responses to GnRH agonist stimulation compared with women with late-onset 21-hydroxylase deficiency. Recent studies in animal models also support an effect of early androgenic exposure on subsequent gonadotropin secretion. Dumesic et al. administered T propionate to pregnant female rhesus monkeys (23). The female offspring with a history of prenatal androgen exposure were compared with control female monkeys and showed significant increases in LH during the follicular and luteal phases and elevated LH/FSH compared with normal females. Other studies have found other features of PCOS in prenatally androgenized monkeys, such as delayed menarche, polycystic ovaries, and frequent infertility (32, 33). In another study, lambs were androgenized in utero by exposure to T, which resulted in increased LH pulse frequency at puberty (24). The time of pubertal onset was significantly advanced in the androgenized lambs compared with that in control female lambs. The androgenized female lambs exhibited some features similar women with PCOS, including enlarged cystic ovaries, hyperandrogenemia, and irregular or anovulatory menstrual cycles. Interestingly, they also had impaired feedback to E2 and P. Similar to our earlier observations in women with PCOS (17), administration of P to the androgenized lambs did not result in slowing of LH (GnRH) pulse frequency.
Most women with PCOS have menstrual abnormalities dating back to menarche, and a recent study showed that LH secretion is abnormal before and after menarche in adolescents with hyperandrogenemia (34). Hyperandrogenemia in adolescents is considered an early manifestation of subsequent PCOS (35, 36). As in adults with PCOS, the adolescents were found to have elevated mean LH and a persistent rapid frequency of LH pulse secretion (35). These data indicate abnormalities of LH secretion in adolescents and suggest that the normal events involved in initiating cyclic ovulation after puberty have not been established. Reduced hypothalamic sensitivity to low levels of P may provide an explanation for this perimenarchal difference in LH pulse secretion. In early puberty nocturnal increases in LH secretion occur with the onset of sleep (37, 38). Nocturnal increases in LH pulse frequency and amplitude result in subsequent small increases in E2 and P (39). Transient elevation of these ovarian steroids may play a role in establishing ovarian inhibition of GnRH pulse secretion, which is part of the mechanisms allowing selective FSH secretion and stimulation of follicular maturation. In subsequent perimenarchal cycles, further increases in ovarian steroids could then lead to the establishment of the normal relationship between ovarian steroids and GnRH secretion seen in women with regular menstrual cycles (40, 41, 42, 43). In contrast, in adolescents with hyperandrogenemia (or after exposure to androgens in utero), low levels of nocturnal E2 and P may not lead to inhibition of GnRH pulses. As a result, persistently rapid GnRH (LH) secretion could then maintain hyperandrogenemia and prevent the gonadotropin (LH/FSH) changes required for cyclic ovulation. Indeed, Apter et al. showed that 11- to 18-yr-old girls with hyperandrogenism, hirsutism, and/or oligomenorrhea had higher LH pulse frequency during both waking and sleeping hours as well as 2-fold higher mean LH compared with age-matched controls (44). Additionally, the transition from the sleep-augmented LH secretion to the adult 24-h LH pattern occurred 2 yr earlier. Reduced sensitivity of the hypothalamic GnRH pulse generator to inhibition by ovarian steroids could explain these gonadotropin abnormalities.
The results presented reveal that blockade of androgen action can restore the sensitivity of the GnRH pulse generator to E2 and P in adult women with PCOS. They also suggest that reduction of excess androgen secretion or blockade of androgen action may be an important element in restoring normal ovarian regulation of GnRH secretion in PCOS and may have a place in therapeutic regimens aimed at establishing cyclic ovulation in women with PCOS.
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Footnotes |
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2 Present address: Developmental Endocrinology Branch, National
Institute of Child Health and Human Development, National Institutes of
Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda,
Maryland 20892.
Received May 11, 2000.
Revised July 26, 2000.
Accepted August 10, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit secretion in women with hyperandrogenemic anovulation. J Clin Endocrinol Metab. 77:895–901.[Abstract]
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E. W. C. M. Van Dam, F. Roelfsema, J. D. Veldhuis, F. M. Helmerhorst, M. Frolich, A. E. Meinders, H. M. J. Krans, and H. Pijl Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E865 - E872. [Abstract] [Full Text] [PDF]
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