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Original Studies |
Division of Endocrinology and the Center for Research in Reproduction (J.C.M.), University of Virginia, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: C. L. Pastor, M.D., Box 511, 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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The data indicate that E2 and P can inhibit the activity of the hypothalamic GnRH pulse generator in women with PCOS. However, higher plasma concentrations of P were required to reduce GnRH/LH pulse frequency in PCOS compared to controls, suggesting an insensitivity of the GnRH pulse generator to suppression by E2 and P. These results suggest that an abnormality in the regulation of hypothalamic GnRH secretion is present in PCOS and may be a factor in the etiology of the disorder in adolescence.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present report we have pursued studies aimed to test the hypothesis that the sensitivity of the GnRH pulse generator to P suppression of pulse frequency is diminished in women with PCOS. In the first study, women with PCOS and normal controls were given E2 and P, in concentrations similar to those present during the midluteal phase of an ovulatory cycle, for a period of 21 days. The aim was to determine whether the time course and/or magnitude of suppression of GnRH pulse frequency by P in the presence of E2 were different in normal women and those with PCOS. In the second protocol we used data obtained in the initial study and administered E2 in constant dosage and varying amounts of P to women with PCOS and to normal controls. The goal was to determine whether women with PCOS required higher concentrations of P to reduce the frequency of pulsatile GnRH secretion.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-four women [age, 29 ± 2.7 yr; body mass index
(BMI), 34.1 ± 1.8 kg/m2] with clinical and
laboratory features of PCOS and 20 normal women volunteers (age,
27 ± 1.4 yr; BMI, 25.8 ± 2.4 kg/m2) with
regular menstrual cycles were studied. The patients with PCOS were
diagnosed on the basis of a history of oligo/amenorrhea, infertility,
and/or hirsutism. Both patients with PCOS and normal controls were
screened by measurements of LH, FSH, PRL, dehydroepiandrosterone
sulfate, 17-hydroxyprogesterone, E2, T, T4 or
TSH, fasting insulin, and hCGß. Results of screening data are shown
in Table 1
. All subjects with PCOS and
normal volunteers had normal values on the screening tests, with the
exception that plasma insulin, LH, and T levels were elevated in the
PCOS patients. Patients were taking no medications, and any prior oral
contraceptive use had been discontinued at least 3 months before the
study. For the studies described below, PCOS patients were studied at
least 60 days after the last episode of menstrual bleeding. Normal
volunteers were screened through a previous cycle to determine their
cycle day. Both protocols 1 and 2 were begun on days 8–10 of the cycle
to obtain a hormonal milieu, plasma E2, P, and LH pulsatile
secretion, which was as similar as possible to that expected to be
found in the patients with PCOS. Informed consent was obtained from all
patients, and the studies were approved by the human investigation
committee of the University of Virginia Health Sciences Center and the
General Clinical Research Center (GCRC) protocol review board.
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Protocol 1. This study was designed to assess the degree and time course of action of midluteal concentrations of E2 and P in suppressing gonadotropin secretion. Ten women with PCOS and five normal volunteers participated in the study. Patients were admitted to the GCRC either the evening before or at least 1 h before an iv heparin lock was placed in a forearm vein and blood sampling began. At 0800 h, sampling began (every 10 min for LH and FSH, every 2 h for E2, P, and T) and was continued for a total of 12 h. A dose of 25 ng/kg GnRH (Factrel, Wyeth Ayerst, Philadelphia, PA) was given iv after 8 h, and a dose of 250 ng/kg GnRH was given after 10 h of sampling. Upon completion of blood drawing, a vaginal ultrasound was performed, and ovarian size and the diameter of the lead follicle were measured. Meals were taken throughout the study at standard times. The above studies were performed on day 1 (before); days 5, 10, and 20 (E2 and P administration); and day 28 (7 days after discontinuing E2 and P). Upon completion of sampling on day 1, E2 and P were administered to achieve midluteal concentrations for 21 days. E2 was given by two Estraderm (0.1-mg patches, Ciba, Summit, NJ) worn continuously and changed every third day. P was given every 8 h by vaginal suppositories (50 mg P in polyethylene glycol matrix). An ultrasound was also performed on day 34, 13 days after E2 and P were stopped. One patient in the PCOS group had hormonal evidence of recent ovulation (elevated P) on day 1, and data were excluded from analysis. A second patient was not compliant with the protocol after day 10 (low plasma P and/or E2), and one normal volunteer developed sinusitis and discontinued the study on day 11. The data from these two individuals were excluded from analysis after day 10.
Protocol 2. This study was aimed to assess the dose-response relationship between suppression of LH pulse frequency and plasma P in both normal women and women with PCOS. Fourteen women with PCOS and 15 normal volunteers participated in the study. One patient with PCOS performed the study twice (3.5 months apart) using different concentrations of P. The study was performed over 7 days based on the results in protocol 1, in which midluteal concentrations of P revealed differences between days 5 and 10 in LH pulse frequency in normal cycling women and those with PCOS. Patients were admitted to the GCRC, an iv heparin lock was placed in a forearm vein, and 1 h later, sampling was initiated. The same samples were obtained as described for protocol 1, except that in 9 subjects (3 PCOS and 6 controls), the GnRH iv injection (25 ng/kg) was not given until after 12 h, and blood sampling was continued for 2 h to complete the 14-h study. Sampling began at either 0800 h (15 subjects; 7 PCOS and 8 Controls) or 2000 h (14 subjects; 7 PCOS and 7 controls), with the same starting time used on both days 1 and 7 of the study. Meals were taken at standard times. Upon completion of sampling on day 1, E2 was administered as described for protocol 1, and P was given every 8 h by vaginal suppositories. These suppositories contained amounts of P (between 4–75 mg/suppository) that would produce different concentrations of plasma P. P doses were administered in random order. Both E2 and P were continued through the completion of sampling on day 7 and were discontinued upon completion of the study. Three subjects (2 controls and 1 PCOS) were given Estraderm patches only to assess the effects of E2 alone over 7 days on LH pulse secretion.
Hormonal measurements
Hormone levels were measured in duplicate by immunoassays. Plasma LH, FSH, and PRL were measured by immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA); the assay sensitivity was 1.0 mIU/mL for LH and FSH, and 1.5 ng/mL for PRL. Intraassay coefficients of variation (CVs) were 4.0%, 5.6%, and 3.3%; interassay CVs were 7.2%, 7.3%, and 6.9%, respectively. Samples from one study subject were run in the same assay. Plasma insulin was also measured by RIA (Coat a Count, Diagnostic Products Corp., Los Angeles, CA; sensitivity, 2 µIU/mL; intraassay CV, 5.0%; interassay CV, 7.2%).
Dehydroepiandrosterone sulfate was measured by chemiluminescence enzyme (Immunolite, Diagnostic Products Corp.; assay sensitivity, 25 µg/dL; intraassay CV, 8.1%; interassay CV, 13.0%).
P, T, E2, and 17-hydroxyprogesterone were measured by RIA (Coat-a-Count; sensitivities, 0.1 ng/mL, 10 ng/mL, 10 pg/mL, and 8 ng/mL; intraassay CVs, 4.9%, 6.1%, 6.4%, and 5.0%; interassay CVs, 4.8%, 6.7%, 6.8%, and 5.4%, respectively).
Data analysis
Data are presented as the mean ± SE. The number of LH pulses and pulse amplitude were measured by the computer algorithm Cluster (32), using parameters of threshold change corresponding to a t statistic of 2.45 for both the peak upstroke and the peak downstroke. If the increment in LH was less than 1.0 IU/L, it was not considered a pulse in subsequent analyses. Missing values represented less than 0.5% of the total and were not replaced.
The data were analyzed using nonparametric Wilcoxon one-sample and two-sample rank sum comparison tests. Nonparametric Bootstrap was used for determining the confidence interval. In addition, in protocol 2, regression analyses were performed to determine whether the suppression of LH pulse frequency by increasing concentrations of P was different from zero and to compare the slopes of the lines between normal controls and women with PCOS. Regressions were performed using the SAS (SAS Institute, Cary, NC) general linear models procedure (proc GLM) specifying a simple linear model. To determine whether slopes were different between the groups, a linear model was fit with an interaction term. If the interaction term was statistically significant, then the group-specific slopes were considered significantly different.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Plasma steroid concentrations on each of the 5 study days are
shown in Table 2. Plasma E2
and P were similar in both PCOS patients and normal controls on day 1,
and plasma E2 was not different after the application of
E2 patches. Similarly, plasma P concentrations were similar
in the two groups on day 1 and were elevated (mean values in the
midluteal range) during administration of vaginal suppositories every
8 h. Examination of the 2-h plasma P values revealed that after
insertion of the suppository, plasma P peaked between 2–4 h later, was
declining at 6 h, and approximated basal by 8 h. This
provided a plasma P profile consisting of three peaks per 24 h,
with concentrations being elevated for approximately 4 h, and
nadir values being 50–70% of peak values. Plasma T was higher in PCOS
patients, and during administration of E2 and P, it fell to
approximately 50% of basal values by day 20, but remained elevated
compared to levels in normal volunteers (P <
0.05).
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, a–d.
Mean plasma LH values were higher in women with PCOS (11.1 ± 2.4
IU/L) than in controls (3.0 ± 0.9 IU/L), but fell rapidly to
3.3 ± 0.7 IU/L on day 5, thereafter plateauing at approximately
30% of basal values. In normal controls, mean LH also fell, but was
not significantly lower than basal until day 20. LH values began to
increase in both groups on day 28. LH pulse amplitude was also higher
in PCOS women (6.1 ± 0.8 vs. 3.2 ± 0.4 IU/L) on
day 1 and was not suppressed until day 10 (2.6 ± 0.5), when
values were similar to those in normal controls (2.0 ± 0.6 IU/L),
and did not change further in either group through days 20 and 28,
respectively. LH pulse frequencies were similar in the two groups on
day 1 (6.7 ± 0.3 and 5.8 ± 0.5 pulses/8 h) and had fallen
by approximately 50% by day 5 in both groups. In normal women, LH
pulse frequency continued to fall to 1.0 ± 0.3 and 1.5 ±
0.9 pulses/8 h on days 10 and 20. In contrast, pulse frequency
plateaued after day 5 in patients with PCOS (3.5 ± 0.8 and
2.4 ± 0.9 pulses/8 h) on days 10 and 20, respectively. After
cessation of E2 and P, LH pulse frequency increased to
basal values in both groups by day 28. Mean plasma FSH values were also
higher in PCOS on day 1, which may reflect the fact that normal women
began the study on days 8–10 of the cycle, when FSH values are
declining. Plasma FSH fell in both groups; it was lower than basal by
day 5 in PCOS (2.0 ± 0.6 mIU/mL) and by day 20 in normal
volunteers (0.9 ± 0.2 IU/L). After withdrawal of E2
and P, mean FSH rose markedly in both groups (5.1 ± 0.8 and
4.7 ± 0.9 IU/L on day 28 in PCOS and normal subjects,
respectively) and was similar to or higher than levels present on day
1.
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. In normal
volunteers, the dominant follicle (days 8–10 of the cycle, 14.3
± 0.5 mm) decreased during administration of E2 and P to
6 ± 1.4 mm on day 20. After cessation of E2 and P, an
increase in follicular size occurred in the other ovary; follicular
diameter was 13 ± 1.5 mm 13 days after discontinuing
E2 and P (n = 4). In patients with PCOS, initial
follicular sizes were similar in both ovaries (6.4 ± 0.4 and
6.3 ± 0.9 mm) and did not change during administration of
E2 and P. After cessation of steroids, follicular size
increased in one ovary, reaching 11.8 ± 1.1 mm in diameter 13
days later.
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Mean data for parameters of LH pulsatile secretion, responses to
exogenous GnRH, plasma FSH, and plasma steroids are shown for both
controls and patients with PCOS in Table 3. Both groups had similar concentrations
of E2 and P, LH (mean, pulse amplitude, and pulse
frequency), mean FSH, and responses to exogenous GnRH on day 1 of the
study. Plasma T was increased in patients with PCOS. On day 7, mean
values for E2 and P were again similar in the two groups,
whereas T remained elevated in PCOS patients, although values were
lower than those on day 1. Data showing the patterns of LH secretion in
one normal control and one PCOS subject with similar concentrations of
plasma P are shown in Figs. 3 and 4, respectively. Data showing LH pulse
frequency in the two groups as a function of the day 7 plasma P level
are shown in Fig. 5, and the change (fall
in number of LH pulses per 8 h between days 1 and 7) and percent
fall are shown in Fig. 6. Mean LH (Table 3) fell in both groups between days 1 and 7, whereas the amplitude of
spontaneous LH pulses increased, although the latter did not achieve
statistical significance. In contrast, LH pulse frequency fell
significantly in normal controls and was lower on day 7 than that in
patients with PCOS (P < 0.0001). Responses to
exogenous GnRH tended to increase in both groups on day 7, but were
only significantly different in controls (25 ng/kg dose). The reduction
in LH pulse frequency exceeded 45% of the basal level in all normal
controls, whereas in only two patients with PCOS did LH pulse frequency
decrease by a similar degree, and both received the highest
concentrations of P (mean, 13.6 and 14.9 ng/mL, respectively). A review
of the data indicated that although the overall reduction in LH pulse
frequency was greater in normal control subjects, this was more marked
at lower concentrations of P (Fig. 6). The data were subsequently
reanalyzed in groups in which plasma P was less than 10 ng/mL
(controls, n = 10; PCOS, n = 12) and less than 5 ng/mL
(controls, n = 7; PCOS, n = 6) respectively. When analyzed in
these groupings, both mean LH frequency on day 7 and the reduction and
percent reduction in LH pulses per 8 h were lower in normal
controls (P < 0.001 for P levels <10 ng/mL;
P < 0.05 for P levels <5 ng/mL). The regression
analyses showed that the slope of the line for both the fall and
percent fall in LH pulse frequency was different from zero in normal
controls (P < 0.01 for P levels <10 ng/mL), but not
in patients with PCOS. Analyses of the slopes of the reduction in LH
pulse frequency in controls and PCOS showed no difference for the
overall groups, but were different when P values of less than 10 ng/mL
were analyzed (P < 0.05). In summary, subanalyses into
groupings by P concentration showed that basal parameters in terms of
LH pulse frequency and plasma steroids were the same in the two groups
(P levels <10 and <5 ng/mL), but normal controls suppressed LH pulse
frequency at lower concentrations of plasma P than individuals with
PCOS. Two patients with PCOS suppressed LH pulse frequency into the
same range as that seen in normal controls in the presence of high
concentrations of P (>13 ng/mL for 7 days in this study). This is in
accord with the results observed in protocol 1, in which lower
concentrations of P for a longer duration suppressed LH pulse frequency
by similar degrees in patients with PCOS and in normal controls.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The studies reported here were aimed to determine whether the disorder of PCOS is associated with reduced sensitivity of the GnRH pulse generator to the inhibitory feedback action of E2 and P. The results from protocol 1 showed that during exposure to midluteal concentrations of E2 and P for 20 days, both normal subjects and women with PCOS suppressed mean LH, LH pulse amplitude, and frequency to a similar degree by day 20, although values tended to remain higher in women with PCOS. The time course of suppression, however, appeared to be more rapid in normal women, and both mean LH and LH pulse frequency were lower by day 10. These data suggested that women with PCOS may be relatively insensitive to the action of P.
Based on these results, a dose-response study was performed (protocol 2) in which a constant dose of E2 and varying doses of P were administered to both groups for 7 days. By starting the study on cycle days 8–10 in normal women, a similar basal milieu of E2 and P was present in both groups, although T levels were elevated in women with PCOS. LH pulse frequency was suppressed to a greater degree in normal controls than in women with PCOS when exposed to mean P concentrations of less than 10 ng/mL. With the exception of one normal control who received a low dose of P (plasma P, 0.9 ng/mL), there was no overlap between the groups. In five patients (three controls and two PCOS) who received higher concentrations of P (11–14 ng/mL), the reductions in LH pulse frequency were similar, suggesting that the GnRH pulse generator is responsive to high doses of P in PCOS. In summary, these data suggest that the hypothalamic GnRH pulse generator is more sensitive to inhibition of firing frequency by lower doses of P in normal controls than in women with PCOS.
A preliminary study (44) has also suggested that PCOS may be associated with a relative insensitivity to the feedback actions of P. After treatment with a combined oral contraceptive (30 µg ethinyl estradiol and 1 mg norethindrone) for 21 days, LH pulse frequency was higher in women with PCOS, both during and after oral contraceptives were discontinued. Together with the findings of the present study, the data suggest that the increased plasma LH and persistently rapid GnRH/LH pulsatile secretion in PCOS are not simply a consequence of the low levels of P due to anovulation, but reflect an underlying insensitivity of the hypothalamic GnRH pulse generator to E2/P inhibition. If such insensitivity was present during pubertal maturation, it could account for the perimenarchal abnormalities seen in hyperandrogenemic adolescents who appear to exhibit early manifestations of PCOS. Venturoli studied 13 adolescents over 3 yr and identified individuals with elevated LH, LH pulse frequency, and plasma androgens (45). Of these, only 3 of 7 attained ovulatory cycles, after which LH secretion and androgen levels were normalized. In the other 4, the increased LH pulse frequency and hyperandrogenemia were maintained. Longer term studies (27) have indicated that adolescent hyperandrogenemia appears to be a progenitor of anovulation, hyperandrogenism, and reduced fertility seen in adult life. In hyperandrogenemic adolescents (46), daytime LH levels were higher than those in age-matched normal controls. In a detailed study of 18-yr-old subjects with hirsutism and oligomenorrhea, Apter et al. (26) showed that LH pulse frequency was increased, and mean LH and plasma androgens were 2-fold higher than those in normal controls. These studies have indicated abnormalities of LH secretion in adolescents and suggest that the normal events involved in initiating cyclic ovulation after puberty have not been established. The pubertal increases in GnRH frequency and amplitude are known to induce some follicular maturation and ovarian steroid secretion, albeit at low levels (47). If these low plasma levels of E2 and P were adequate to slow the GnRH pulse generator, selective secretion of FSH could ensue and promote follicular maturation. In subsequent cycles of follicular maturation, progressively more ovarian steroid production would be expected with each cycle, establishing the normal relationships between ovarian steroids and GnRH pulsatile secretion seen in women with regular cyclic ovulation. If adolescents destined to develop PCOS are relatively resistant to the inhibitory effects of low concentrations of E2 and P, these events may not occur, leading to reduced FSH secretion and impaired follicular maturation. Maintaining GnRH secretion at 1 pulse every 60–90 min would increase LH and ovarian androgen production, and moderately elevated androgens have been reported during irregular anovulatory cycles in adolescents (45). This proposed sequence of events remains speculative in part, but provides a potential mechanism by which abnormalities of regulation of pulsatile GnRH secretion during pubertal maturation may lead to persistent GnRH secretion and the elevated pulsatile LH pattern seen in hyperandrogenemic adolescents.
The mechanisms underlying the reduced hypothalamic sensitivity remain unclear, however. As progestins suppress LH pulse frequency in women with PCOS (31, 32, 33), opioid modulation of the GnRH pulse generator appears to be intact, but no information is available about any change in sensitivity of this system to P. Possible candidates that may alter the sensitivity or set-point of hypothalamic mechanisms controlling GnRH secretion and/or pituitary sensitivity to GnRH include the hyperinsulinemia and hyperandrogenemia present in women with PCOS. Obese women with PCOS have higher plasma insulin levels and consequently lower plasma concentrations of sex hormone-binding globulin and insulin-like growth factor-binding protein-1 than controls. The potential roles of these changes in the etiology of PCOS, however, are unclear. Reduction of hyperinsulinemia, either by weight loss or by administration of metformin or troglitazone, resulted in a fall in plasma LH in some (15, 16), but not all (17, 18, 19), studies. Other studies have also revealed discordant results. In obese women with PCOS, hyperinsulinemia was associated with similar or lower LH levels compared to those in lean women with PCOS (48, 49). In vitro, insulin potentiated LH release in response to GnRH, but FSH was also increased (50), whereas in rats, increases in plasma insulin were not associated with increased LH responses to GnRH (51). In women with PCOS, acute elevation of insulin during a hyperinsulinemic euglycemic clamp did not alter plasma gonadotropin levels (52). Thus, data on the effects of insulin on GnRH and LH secretion remain unclear, and it is uncertain whether the increased BMI and insulin levels in the PCOS patients in the present study affected the results.
The fall in plasma LH after reduction of insulin in some studies may reflect the coexistent reduction in plasma androgen levels due to reduced enhancement of ovarian androgen secretion by insulin (53, 54). Elevated plasma androgens themselves may modify hypothalamic regulation of GnRH pulse generator activity, but again, data are not conclusive. In vitro, androgens increase the activity of the GnRH pulse generator (55). Modest or moderate hyperandrogenemia in congenital adrenal hyperplasia (CAH) may be associated with an elevation in serum LH and enhanced responses to GnRH, with restoration toward normal when androgens are reduced by therapy (20). In contrast, infusion of T so as to modestly increase plasma concentrations did not alter mean LH or LH pulsatility (56), and higher concentrations of T suppressed pulsatile LH secretion (23, 24). The androgen receptor-blocking agent flutamide reduced LH pulse amplitude, but pulse frequency and mean LH were unchanged in women with PCOS (57).
Thus, the potential roles of hyperinsulinemia and hyperandrogenemia in modifying ovarian steroid regulation of the GnRH pulse generator remain unclear. In addition, the finding of a reduced sensitivity of the GnRH pulse generator to ovarian steroids in adults with PCOS does not differentiate between acute effects and the possible actions of insulin and/or androgens at a prepubertal or peripubertal stage. Again, data are lacking in this regard, although the observation that women with CAH have elevated plasma LH levels, whereas those with late-onset CAH do not (20), suggests that the effects of a neonatal increase in androgens may only be manifest in later life, probably during the reactivation of GnRH pulse activity at puberty.
In summary, the data presented here indicate that in adult women with PCOS, the sensitivity of the hypothalamic GnRH pulse generator to P feedback is impaired. This raises the possibility that an intrinsic abnormality of the GnRH pulse generator during pubertal maturation may lead to subsequent excess LH secretion and increased ovarian androgen production. The mechanisms underlying this change in the sensitivity of the GnRH pulse generator in women with PCOS remain unclear, and further understanding of these mechanisms await the results of further investigation.
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Acknowledgments |
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Footnotes |
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Received August 27, 1997.
Revised October 28, 1997.
Accepted November 7, 1997.
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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]
activity and serum free testosterone
after reduction of insulin secretion in PCOS. N Engl J Med. 335:617–623.This article has been cited by other articles:
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,
P < 0.05 vs. controls.
) and day 7 (
) of E2 and P administration as a
function of the mean P concentration on that day. In normal controls,
day 1 equals days 8–10 of the cycle. Data for patients who received
E2 only are shown as solid squares.