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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2099
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1309-1316
Copyright © 2006 by The Endocrine Society

Inverse Relationship between Luteinizing Hormone and Body Mass Index in Polycystic Ovarian Syndrome: Investigation of Hypothalamic and Pituitary Contributions

Yanira L. Pagán1, Serene S. Srouji1, Yarisie Jimenez, Anne Emerson, Sabrina Gill and Janet E. Hall

Reproductive Endocrine Unit (Y.L.P., S.S.S., Y.J., A.E., S.G., J.E.H.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Obstetrics and Gynecology (S.S.S.), Center for Reproductive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Janet E. Hall, M.D., Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: jehall{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Patients with polycystic ovarian syndrome (PCOS) have increased LH relative to FSH, but LH is modified by body mass index (BMI).

Objective: The objective of the study was to determine whether the impact of BMI on neuroendocrine dysregulation in PCOS is mediated at the hypothalamic or pituitary level.

Participants/Interventions/Setting: Twenty-four women with PCOS across a spectrum of BMIs underwent frequent blood sampling, iv administration of GnRH (75 ng/kg), and sc administration of the NAL-GLU GnRH antagonist (5 µg/kg) in the General Clinical Research Center at an academic hospital.

Main Outcome Measures: LH pulse frequency and LH response to submaximal GnRH receptor blockade were used as measures of hypothalamic function; LH response to GnRH was used as a measure of pituitary responsiveness.

Results: BMI was negatively correlated with mean LH, LH/FSH, and LH pulse amplitude. There was no effect of BMI on LH pulse frequency. Percent inhibition of LH was decreased in PCOS, compared with normal women (53.9 ± 1.5 vs. 63.1 ± 4.1, respectively; P < 0.01), suggesting an increase in the amount of endogenous GnRH, but was not influenced by BMI. Pituitary responsiveness to GnRH was inversely correlated with BMI (peak LH, R = –0.475, P < 0.02; and LH area under the curve R = –0.412, P < 0.02).

Conclusions: LH pulse frequency and quantity of GnRH are increased in PCOS, but there is no influence of BMI on either marker of hypothalamic function. The pituitary response to a weight-based dose of GnRH is inversely related to BMI in PCOS. These studies suggest that the effect of BMI on LH is mediated at a pituitary and not a hypothalamic level in PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SINCE THE INITIAL description of the association of sclerocystic disease of the ovary with menstrual dysfunction, clinical hyperandrogenism, and infertility (1), a vast body of literature has been generated in an attempt to understand both the clinical spectrum and pathophysiology of the disorder that is now termed polycystic ovarian syndrome (PCOS). When defined by the presence of oligomenorrhea and hyperandrogenism, 75% of women with PCOS have an LH level that is above the normal range for women in the early follicular phase and 94% have an increased LH to FSH ratio (2). Women with polycystic ovarian morphology and regular cycles have higher androgen and insulin levels but normal gonadotropins when compared with regularly cycling women who do not have this ovarian morphology (3). Taken together, these findings suggest that gonadotropin dysfunction plays a key role in anovulatory PCOS.

Recent ovulation (2) or progesterone exposure (4) transiently reduces the LH/FSH level in oligomenorrheic women with PCOS. A decrease in LH has also been observed in obese compared with lean PCOS patients (5, 6, 7). It was initially hypothesized that altered gonadotropin dynamics in the setting of obesity suggested specific subgroups of patients with PCOS with distinct pathophysiologies (8, 9). However, further studies have demonstrated an inverse relationship between LH and body weight that is continuous across a wide spectrum of body weights in PCOS patients (2, 10), supporting the model of an intrinsic neuroendocrine abnormality in all oligomenorrheic PCOS patients that is modified by obesity.

There is evidence that both hypothalamic and pituitary mechanisms contribute to the gonadotropin dysfunction in PCOS. Increased LH pulse frequency has been documented (2, 10, 11, 12, 13, 14), suggesting an increase in the frequency of hypothalamic GnRH stimulation, whereas increased pituitary responsiveness to GnRH (11, 12, 13) suggests a pituitary defect. Previous studies have shown that LH pulse frequency is not affected by body mass index (BMI) (2, 10), whereas LH pulse amplitude is reduced in obese compared with lean patients with PCOS in most (2, 6, 7, 10) although not all studies (15). Whereas these findings might suggest that obesity exerts its effects on gonadotropin dynamics at a pituitary site, the effect on LH pulse amplitude could be secondary to a reduction in GnRH pulse amplitude as a function of BMI. Several studies have assessed pituitary responsiveness in relation to BMI using pharmacological doses of GnRH between 10 and 100 µg (5, 6, 10, 15, 16), but none have adjusted the dose of GnRH for the wide variations in subject weights, a critical consideration, given the exquisite sensitivity of LH secretion to GnRH dose (17, 18).

The purpose of the present study was to further investigate the mechanisms underlying the effect of obesity on gonadotropin dynamics in PCOS by determining whether the effect of BMI is mediated at a hypothalamic or pituitary level. We have previously shown that incomplete GnRH receptor blockade using a GnRH antagonist can be used to provide an estimate of the overall amount of endogenous GnRH secreted (19, 20) and have now combined this with assessment of LH pulse frequency to determine the effect of BMI at the hypothalamic level in PCOS. The LH response to a weight-adjusted dose of GnRH that has previously been shown to result in recreation of normal cycle dynamics in GnRH-deficient subjects (18) was used to assess the effect of BMI at the pituitary.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty-four otherwise healthy women with PCOS were recruited for this study. PCOS was defined as the presence of clinical or biochemical evidence of hyperandrogenism and oligomenorrhea (fewer than nine menstrual periods per year). Clinical hyperandrogenism was defined by a Ferriman-Gallwey score of more than 10 (21), whereas biochemical hyperandrogenism was documented with an elevated total testosterone. Late-onset congenital adrenal hyperplasia was excluded by the presence of a normal 17-hydroxyprogesterone level in a baseline morning sample (22). None of the subjects required ACTH stimulation testing to exclude this diagnosis. All subjects were between the ages of 18 and 40 yr and had normal thyroid function, prolactin, renal function, and complete blood count with liver function tests less than twice the upper limit of normal. Subjects with a known history of significant drug allergy (urticaria, bronchospasm, or systemic symptoms) to other medications were excluded from the NAL-GLU GnRH antagonist portion of this study.

Subjects were recruited from the Reproductive Endocrine Associates clinic at Massachusetts General Hospital or by posted advertisements, and all gave their written informed consent. The study was approved by the Institutional Review Board of the Massachusetts General Hospital.

Protocol

At the time of admission, subjects had a negative ß-HCG and progesterone less than 2 ng/ml (0.63 nmol/liter). An ultrasound was performed around the time of admission to determine the presence of a corpus luteum and was used, in addition to hormonal data, to assist in the exclusion of women who had spontaneously ovulated at the time of the study. A corpus luteum was defined as a complex cyst with an irregular wall and/or internal echoes. The ultrasounds were all performed on the same machine (Sonolayer L, SAL-778 with a transvaginal 5 MHz probe; Toshiba, Tokyo, Japan) by a single technologist. The study was delayed for any subject in whom ovulation had occurred and any subject who had had menses in the 7 d before the scheduled admission to permit recovery from the potential suppressive effect of progesterone on LH (2, 4).

Upon admission to the General Clinical Research Center, height, weight, bioelectrical impedance assay (BIA), and waist (at the iliac crest) to hip ratio (WHR) were measured. An iv catheter was inserted for blood drawing. Blood was sampled every 10 min for 8 h. All samples were assayed for LH, and FSH was analyzed in hourly samples. A weight-adjusted dose of GnRH (75 ng/kg) was then administered, and LH was monitored in blood samples every 10 min for 1 h and then every 30 min for the following 5 h. A 75 ng/kg dose of GnRH was chosen because this is the dose that recapitulates normal cycle dynamics in GnRH-deficient women and results in ovulation and fertility in patients with both GnRH deficiency and PCOS (18, 23). The following morning, 16 h after GnRH administration, a submaximal dose of the NAL-GLU GnRH antagonist (5 µg/kg) was administered sc. LH was measured at 30-min intervals for 2 h before and 8 h after administration of the antagonist. On the second day, a 75-g oral glucose tolerance test (OGTT) was also performed after an overnight fast. Blood samples for glucose and insulin levels were drawn at 0, 60, and 120 min.

Assays

Serum LH, FSH, and estradiol were measured using a two-site monoclonal nonisotopic system (AxSYM; Abbott Laboratories, Abbott Park, IL) as previously described (24, 25). A serum pool was created from equal aliquots of each sample of the frequent sampling study (h 0–8). For the determination of pulsatile LH secretion, the serum pool of the entire study was first run in the LH assay to determine the volume of the serum to be used in the assay so that all LH measurements fell in the linear portion of the standard curve. Each sample was then measured at this volume, and at least 10 samples of the pool were included throughout the same assay to determine the coefficient of variation (CV) of the patient’s samples in the assay in which the study was run. The sensitivity of the LH assay was 1.2 IU/liter. The intra- and interassay CVs were less than 7%. The sensitivity of the FSH assay was 1.2 IU/liter, and the intra- and interassay CVs were less than 6 and less than 8%, respectively. LH and FSH are expressed in international units per liter, as equivalents of the second International Reference Preparation pituitary standards (World Health Organization 68/40 and World Health Organization 78/541 for LH and FSH, respectively). The lower limit of detection of the estradiol assay was 10 pg/ml (36.7 pmol/liter) and the interassay CVs were less than 10% at concentrations spanning the reported range. Progesterone was assayed using an automated chemiluminescent enzyme immunoassay system (Immulite; Diagnostic Products Corp., Los Angeles, CA). The sensitivity of the assay was 0.2 ng/ml (0.063 nmol/liter) and the interassay CV was less than 16%. Serum testosterone was measured using the Coat-A-Count RIA kit (Diagnostic Products Corp.), with an intra- and interassay CV of less than 10% and a lower limit of detection of 4 ng/dl (138.7 pmol/liter). 17-Hydroxyprogesterone was measured using the Coat-A-Count kit (Diagnostic Products Corp.) with an interassay CV of less than 10%. Glucose was measured using the glucose oxidase method (Beckman Instruments, Fullerton, CA). Insulin was measured using an automated chemiluminescent enzyme immunoassay (Immulite 2000; Diagnostic Products Corp.), with a sensitivity of 2 µU/ml and interassay CV of less than 6%. SHBG was measured by a chemiluminescent enzyme immunometric assay (Immulite; Diagnostics Products Corp.) with an intraassay CV of less than 7% and an interassay CV less than 8%.

Data analysis

Free testosterone was calculated from total testosterone and SHBG (26). Pulsatile LH secretion was determined using a modification of the original Santen and Bardin algorithm (27) that has been validated in vivo (28). A pulse was identified in the frequent sampling series when the peak minus the nadir exceeded 3 times the assay CV and at least 0.3 IU/liter using the pituitary standard for LH measurements. In addition, each pulse was required to have a second point that met at least one of these two criteria. The number of pulses in 8 h was determined and expressed as a 24-h frequency.

The peak LH amplitude and area under the curve (AUC) were determined for 6 h after administration of a weight-based dose of GnRH. In the calculation of AUC, baseline differences in endogenous secretion of LH were accounted for by subtracting the mean baseline LH level from the LH values obtained after administration of exogenous GnRH.

The percent inhibition of LH was calculated in response to a 5 µg/kg dose of the NAL-GLU GnRH antagonist. The nadir of gonadotropin suppression after administration of the NAL-GLU GnRH antagonist was determined using a 3-point moving average. The nadir of LH was subtracted from the preantagonist baseline; this difference was then expressed as a percentage of baseline [(mean baseline – nadir)/baseline] x 100, as previously described (19, 29).

All variables were analyzed to determine whether they were normally distributed using SigmaStat software (SigmaStat, version 2.03; SyStat Software Inc., Point Richmond, CA). Variables that were not normally distributed were logarithmically transformed before analysis. Correlation analyses were performed using Pearson’s or Spearman’s correlation as appropriate. LH pulse frequency in PCOS women was compared with that from previously published data in 24 normal women studied in the early follicular phase (2), and percent inhibition of LH was compared with previously published results in 12 normal women, studied in the early and late follicular phases who also received 5 µg/kg of the NAL-GLU GnRH antagonist (19). A t test was used for comparison of results between PCOS and normal women.

Results are expressed as the mean ± SEM. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A total of 24 PCOS subjects were enrolled in the study and were studied between 9 and 365 d from previous menses. Two women were excluded from the GnRH antagonist portion of the study due to a history of significant drug allergies. The mean age of subjects enrolled was 27.3 ± 1.03 yr. BMI ranged from 18 to 48.1 kg/m2, with a mean of 32.94 ± 1.76 kg/m2. Percent fat, estimated by BIA, ranged from 20 to 54% with a mean of 39.1 ± 2.1 and WHR ranged from 0.76 to 1.02, with a mean of 0.864 ± 0.02. The mean hirsutism score was 16.5 ± 1.3, testosterone was 80.8 ± 7.1 ng/dl (2.8 nmol/liter) with a normal range of 5 to 63 ng/dl (0.2 to 2.2 nmol/liter), calculated free testosterone was 1.94 ± 0.17 ng/dl (normal range < 0.947 ng/dl), and estradiol was 69.04 ± 5.37 pg/ml (253.4 ± 19.7 pmol/liter) at baseline. Polycystic ovarian morphology was present in all subjects. Seven subjects met criteria for impaired glucose tolerance (fasting glucose ≥ 100 mg/dl but < 126 mg/dl or 2-h OGTT glucose ≥ 140 mg/dl but < 200 mg/dl), whereas two subjects had previously undiagnosed diabetes (fasting glucose ≥ 126 mg/dl or 2-h OGTT ≥ 200 mg/dl). BMI was inversely related to SHBG for the group as a whole (R = –0.496, P < 0.02) and positively correlated with fasting glucose (R = 0.048, P < 0.02) but was not specifically related to insulin or homeostasis model assessment (HOMA), even with exclusion of patients with impaired glucose tolerance or diabetes, presumably due to the relatively small sample size.

Impact of obesity on gonadotropin secretion in PCOS

LH levels in representative subjects at the lean and obese ends of the spectrum of BMIs are shown in Fig. 1Go and reflect the inverse relationship between LH and BMI in this patient population (Fig. 2Go). BMI was also inversely related to LH/FSH and LH pulse amplitude (Fig. 2Go). LH, LH/FSH, and LH pulse amplitude were also inversely correlated with percent fat as measured by BIA (LH, R = –0.513, P < 0.01; LH/FSH, R = –0.555, P < 0.01; LH pulse amplitude, R = –0.532, P < 0.01) and with WHR (LH, R = –0.499, P < 0.02; LH/FSH, R = –0.505, P < 0.02; LH pulse amplitude, R = –0.441, P < 0.05).


Figure 1
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  		FIG. 1. Data from representative PCOS subjects at both ends of the spectrum of BMIs during baseline frequent sampling and GnRH administration and after administration of a submaximal dose of the NAL-GLU GnRH antagonist. Note the differing y-axis scales in the two panels.

 

Figure 2
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  		FIG. 2. Inverse relationship between BMI and mean LH, LH to FSH ratio, and LH pulse amplitude in women with PCOS.

 
Impact of obesity on hypothalamic function in PCOS

Although mean LH and LH pulse amplitude were inversely correlated with BMI, LH pulse frequency, which reflects GnRH pulse frequency, was unaffected by BMI (R = –0.140, P = 0.51; Fig. 3Go). LH pulse frequency was increased in the PCOS subjects when compared with previously reported data in normal early follicular phase women (2), consistent with previous reports, and implying an increase in the frequency of pulsatile GnRH secretion in PCOS (Fig. 3Go). LH pulse frequency was not correlated with days from previous menses but was positively related to LH/FSH (R = 0.453, P < 0.03), also consistent with previous studies (2).


Figure 3
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  		FIG. 3. LH pulse frequency is not influenced by BMI but is increased in PCOS compared with normal women in the early follicular phase. **, P < 0.0005.

 
As with LH pulse frequency, there was no effect of BMI on the percent inhibition of LH in response to a fixed, submaximal dose of the NAL-GLU GnRH antagonist that results in incomplete GnRH receptor blockade (R = –0.049, P = 0.83; Fig. 4Go). However, the percent inhibition of LH in PCOS was less than previously reported in normal follicular phase women (19), suggesting that the increase in GnRH pulse frequency in PCOS is accompanied by an increase in the overall amount of GnRH secreted. Moreover, the increase in pulse frequency of 30% in PCOS is approximately matched by the increase in overall amount of GnRH.


Figure 4
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  		FIG. 4. The percent inhibition of LH in response to a submaximal dose of the NAL-GLU GnRH antagonist is not influenced by BMI but is lower than in normal follicular phase women. These data imply that the overall quantity of GnRH is increased in PCOS but is not affected by BMI. *, P < 0.01.

 
Impact of obesity on pituitary responsiveness in PCOS

Pituitary responsiveness, assessed using a weight-adjusted dose of GnRH, was significantly influenced by BMI. There was an inverse relationship between BMI and peak LH and LH AUC (Fig. 5Go). Peak LH was also inversely related to both BIA (R = –0.420; P < 0.05) and WHR (R = –0.501, P < 0.02); LH AUC was also inversely related to WHR (R = –0.454, P < 0.05). Pituitary responsiveness was strongly and positively correlated with mean LH (P < 0.0002), LH/FSH (P < 0.0005), and LH pulse amplitude (P < 0.0005).


Figure 5
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  		FIG. 5. Both peak LH and the LH AUC in response to a weight-based dose of GnRH are inversely related to BMI in women with PCOS.

 
Relationship to insulin and gonadal steroids

Fasting glucose, fasting insulin, and HOMA were not correlated with baseline gonadotropin secretion, markers of hypothalamic GnRH secretion or pituitary responsiveness, nor were there significant correlations between stimulated glucose or insulin and these parameters. In our study population BMI was not significantly correlated with testosterone (R = –0.033, P = 0.88), free testosterone (R = 0.202, P = 0.36), or estradiol (R = –0.103, P = 0.63). However, testosterone was positively correlated with the insulin AUC during the OGTT (R = 0.510, P < 0.02) but not with fasting insulin, glucose, or HOMA. Testosterone was also positively correlated with LH (R = 0.534; P < 0.01), LH/FSH (R = 0.552; P = 0.005), LH pulse amplitude (R = 0.618; P < 0.002), and peak LH in response to GnRH (R = 0.478; P < 0.02), whereas there was no correlation of free testosterone, estradiol, or estrone with gonadotropin levels at baseline or in response to GnRH.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study was designed to provide further insights into control of gonadotropin secretion in oligomenorrheic women with PCOS. Our goal was to determine whether the inverse relationship between LH and BMI that has previously been described is mediated at the hypothalamus or the pituitary. Our results indicate that both the frequency and overall quantity of GnRH are increased in PCOS, but neither measure of hypothalamic GnRH secretion is influenced by BMI. In contrast, BMI has an inhibitory effect on LH pulse amplitude and on the LH response to a weight-based dose of GnRH. Thus, the abnormal dynamics of LH secretion in women with PCOS are modulated by obesity at the pituitary and not at the hypothalamic level.

Abnormalities in gonadotropin secretion, characterized by increased LH and the LH to FSH ratio, have been recognized in patients with PCOS from the initial development of gonadotropin assays and their measurement in urine (30) and serum (31). The critical role of LH in ovarian hyperandrogenism in PCOS has been shown in vitro (32) and by the reductions in testosterone after acute LH suppression with a GnRH antagonist (29) and chronic LH suppression using a GnRH agonist (33). The positive correlation between testosterone and LH, LH pulse amplitude, and the LH response to GnRH in the current study is consistent with this mechanism and extends the findings in previous studies (6). Other studies that did not demonstrate significant correlations of LH with testosterone did show a correlation of LH with 17-hydroxyprogesterone, which is more proximate in the steroidogenic pathway (2, 10).

Recent studies have shed light on the inter- and intraindividual variability in gonadotropin levels in patients with PCOS by noting that LH and the LH to FSH ratio can be temporarily suppressed by recent ovulation (2) and progesterone (4) and that gonadotropins are not abnormal in women with regular ovulatory cycles and polycystic ovarian morphology (3). In the current study, we have demonstrated the additional impact of BMI as a modulator of gonadotropin secretion in PCOS. Our results confirm our previous studies (2) and those of Arroyo et al. (10) by showing a continuous inverse relationship between BMI and LH and the LH to FSH ratio in PCOS patients across a wide spectrum of BMI. These data argue against earlier suggestions that lean and obese patients with PCOS may represent discrete pathophysiological subsets with hyperandrogenism resulting from high LH in lean PCOS patients and hyperinsulinemia in obese PCOS patients (8, 9). Rather, our study suggests that abnormal gonadotropin dynamics are a key component of the pathophysiology of oligo/anovulatory PCOS but are modified by obesity. This interpretation is supported by the demonstration of enhanced LH secretion in response to short-term caloric restriction in obese patients with PCOS (34).

Whereas many studies have described gonadotropin abnormalities in PCOS, the mechanism underlying the increased LH to FSH ratio has remained unclear. The presence of hypothalamic dysfunction is suggested by the increase in LH pulse frequency that has been described in this and numerous previous studies (2, 10, 11, 12, 13, 14). The reference population used in the current study was within 5–7 d from menses, whereas the interval from previous menses was considerably longer in the PCOS subjects. Thus, it is possible that duration from progesterone exposure may contribute to the increased pulse frequency in PCOS. However, in a previous study, we found an increase in pulse frequency in PCOS relative to all stages of the follicular phase (14), and in the current study, pulse frequency was not correlated with days from previous menses. There is additional evidence that increased pulse frequency in PCOS is due, at least in part, to a decrease in the sensitivity of the GnRH pulse generator to progesterone-induced slowing (35) that may be secondary to the hyperandrogenic environment in PCOS (36).

We have previously developed the use of submaximal GnRH receptor blockade to provide a relative estimate of the overall amount of GnRH secreted (19), complementing the information derived from measurement of pulse frequency as an indicator of hypothalamic GnRH activity. The principles governing ligand-receptor interaction predict that a semiquantitative estimate of endogenous GnRH secretion can be derived from measurement of the effect of competition between the GnRH antagonist and GnRH at its receptor. As we have previously discussed (19), the use of a competitive GnRH antagonist to provide an estimate of endogenous GnRH secretion is possible only when the marker of ligand action (in this case LH) is controlled by a single secretagogue that acts at a single receptor type and when the affinity of the receptor remains constant. There is no evidence that physiological changes in GnRH stimulation or steroid feedback alter the affinity of GnRH for its receptor, consistent with our previous finding that the dose-response curve for LH inhibition in response to a range of doses of the NAL-GLU antagonist in PCOS women is parallel to that in normal women (29). Whereas there is now evidence of the existence of multiple forms of both GnRH and GnRH receptors, only the type I GnRH receptor appears to be present in the human (37, 38). Both GnRH and GnRH II can stimulate LH secretion by acting on pituitary type I GnRH receptors (39). Although the potential contribution of GnRH II to physiological gonadotropin secretion is not known, this approach would not distinguish between the two ligands for the type I GnRH receptor.

Use of competition at the receptor to assess the quantity of endogenous GnRH secretion is based on the assumption that differences in pituitary responsiveness at baseline secondary to differences in receptor density, cell number, or postreceptor signaling will be similar before and after acute GnRH receptor blockade and can be accounted for by normalizing the decrease in LH after GnRH antagonist administration to the baseline LH values. Finally, of particular importance to this study, the dose of NAL-GLU antagonist administered is calculated in relation to body weight. The percent inhibition of LH in response to incomplete GnRH receptor blockade will therefore be inversely proportional to the overall quantity of endogenous GnRH. Whereas this methodology does not permit precise quantification of GnRH secretion, it does allow comparisons to be made between PCOS and normal women and as a function of BMI.

In the current study, we have shown that the increased frequency of pulsatile GnRH secretion in PCOS is accompanied by an increase in the overall quantity of GnRH and that the increase in quantity of GnRH is of similar magnitude to the increase in pulse frequency. In a previous small study, we were unable to demonstrate an increase in the overall quantity of GnRH in PCOS, compared with normal women, likely due to the relatively small number of subjects studied (29). We previously hypothesized that the increased GnRH pulse frequency per se may contribute to the elevated LH to FSH ratio in PCOS, based on studies in animal models and GnRH-deficient subjects (14, 40). This hypothesis is supported by the positive correlation between LH pulse frequency and the LH to FSH ratio seen in this and our previous study (2). Despite our demonstration of an increase in both the frequency and overall amount of GnRH secreted in PCOS, we found no evidence of an effect of BMI on either marker of hypothalamic activity in PCOS, and thus, there is no evidence that factors related to increased BMI influence LH by affecting hypothalamic secretion of GnRH.

Many investigators have concluded that pituitary hyperresponsiveness to GnRH plays a major role in the increased LH secretion in PCOS, based on the LH response to exogenous GnRH (11, 12, 13). Comparison of results of GnRH responsiveness to our previous studies shows that the LH response to a weight-based, 75 ng/kg dose of GnRH was markedly higher in all of the subjects with PCOS than in GnRH-deficient women after 7 d of pituitary priming with pulsatile GnRH (41), confirming the importance of pituitary hyperresponsiveness in addition to GnRH hypersecretion in the gonadotropin abnormalities in PCOS. In addition, some (5, 6, 8, 10), but not all (15, 16), studies have now reported an increased LH response to GnRH in lean compared with obese patients with PCOS. However, doses used in previous studies were all in the pharmacological range (10–100 µg), and none of the previous studies adjusted the GnRH dose for the wide range of weights in the subject population, making interpretation of the results problematic. Using a weight-based dose of GnRH that is known to be physiological in GnRH-deficient women, we have shown that increasing BMI attenuates the response to GnRH. These results provide compelling evidence that the decreased LH response to GnRH in obese women is due to decreased pituitary responsiveness per se rather than an increased volume of distribution and less effective pituitary stimulus that might otherwise explain the results in response to a dose of GnRH that is not adjusted for weight.

Taken together, our results indicate that the effect of BMI on LH secretion is mediated at a pituitary and not a hypothalamic level. However, the mechanisms that mediate this pituitary effect remain unclear. Insulin must be considered as one of the factors due to the presence of insulin resistance and hyperinsulinemia in both PCOS and obesity and due to the findings from in vitro studies that insulin stimulates both the secretion of GnRH from hypothalamic neurons (42) and secretion of LH from pituitary cells in culture (43). In the current study, we found no relationship between pituitary responsiveness and insulin resistance as assessed by HOMA, nor did we find a relationship between pituitary responsiveness and fasting or stimulated insulin secretion. Our findings are consistent with other studies in which insulin was not found to be associated with LH independent of BMI (10). Our findings are also consistent with two studies that failed to demonstrate an effect of insulin infusions on pulsatile LH secretion in women with PCOS (44, 45). Because insulin infusions are also ineffective in altering LH secretion in normal women (46), the lack of such an effect in women with PCOS is likely not due to insulin resistance.

A second potential mediating factor is leptin, which is secreted from adipocytes and is involved in regulation of body weight, energy homeostasis, and reproduction. Leptin levels are highly correlated with BMI in patients with PCOS (47, 48, 49) as they are in normal women (50). Most studies have implicated the hypothalamus as the major site of leptin feedback on the reproductive axis (50) and leptin administration increases LH pulse frequency in amenorrheic women (51). In addition to their presence in the hypothalamus, however, leptin receptors are present on pituitary gonadotropes (50). In vitro studies have suggested that the effect of leptin on LH secretion is biphasic, with stimulation of LH secretion at low levels but inhibition at higher concentrations (52). Several studies have demonstrated an inverse correlation between leptin and mean LH and LH pulse amplitude in women with PCOS (53, 54). Moreover, short-term caloric restriction in women with PCOS resulted in a marked decrease in leptin levels and a concomitant increase in LH pulse amplitude (34). Taken together, these studies suggest that leptin may mediate the effects of BMI on pituitary secretion of LH, but further studies using leptin or leptin antagonists are needed to resolve this issue.

An additional candidate to consider as a potential mediator of the effect of BMI on LH is ghrelin. In women with PCOS, ghrelin levels are inversely related to BMI (55) and insulin resistance (55, 56), as they are in normal women (57). However, ghrelin is not correlated with the LH to FSH ratio (56). In addition, studies of ghrelin administration to ovariectomized monkeys demonstrated a decrease in LH pulse frequency but no effect on pulse amplitude (58), suggesting that the effect is mediated at the hypothalamus rather than the pituitary. These data suggest that ghrelin is unlikely to be the predominant factor mediating the attenuation of LH secretion that is seen with increasing BMI.

Finally, it is important to consider potential effects of gonadal steroids on the pituitary. In the current studies, there was no correlation of estradiol or estrone with mean LH or pituitary responsiveness. We found a positive correlation of testosterone with LH and insulin AUC, supporting a role for both LH and insulin in ovarian steroidogenesis. However, neither testosterone nor free testosterone were correlated with BMI and are therefore unlikely to be implicated in the effect of BMI on LH. Our finding of a lack of correlation of BMI with testosterone or free testosterone is consistent with some (15, 59) but not all (7, 60) previous studies. It is likely that differences in patient populations account for the disparity in results in different studies because both insulin and LH are stimulatory with respect to androgen secretion but are differentially influenced by BMI.

Thus, we have now shown that in addition to an increase in the frequency of pulsatile GnRH secretion in women with PCOS, the overall quantity of GnRH is also increased. However, neither measure of hypothalamic GnRH secretion is influenced by BMI. In contrast, BMI has an inhibitory effect on LH pulse amplitude and the LH response to a weight-based dose of GnRH. Thus, the abnormal dynamics of LH secretion in women with PCOS are modulated by obesity at the pituitary and not at the hypothalamic level. Studies that further define the mechanism underlying this decrease in pituitary responsiveness with increasing BMI can help target therapeutic interventions in PCOS patients.


   Footnotes
 
This work was supported by National Institutes of Health Grants K24 HD 01290 and M01 RR 01066.

Current address for Y.L.P.: Pediatric Endocrine Unit, Research, Education, and Clinical Diabetes Center for Puerto Rico, University of Puerto Rico, School of Medicine.

Current address for S.G.: Division of Endocrinology and Metabolism, St. Paul’s Hospital, Vancouver, Canada.

The authors have nothing to declare.

First Published Online January 24, 2006

1 Y.L.P. and S.S.S. contributed equally as first authors. Back

Abbreviations: AUC, Area under the curve; BIA, bioelectrical impedance assay; BMI, body mass index; CV, coefficient of variation; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test; PCOS, polycystic ovarian syndrome; WHR, waist to hip ratio.

Received September 20, 2005.

Accepted January 18, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Stein IF, Leventhal ML 1935 Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181–191
  2. Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, Hall JE 1997 Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:2248–2256[Abstract/Free Full Text]
  3. Adams JM, Taylor AE, Crowley Jr WF, Hall JE 2004 Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab 89:4343–4350[Abstract/Free Full Text]
  4. Christman GM, Randolph JF, Kelch RP, Marshall JC 1991 Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease. J Clin Endocrinol Metab 72:1278–1285[Abstract/Free Full Text]
  5. Paradisi R, Venturoli S, Pasquali R, Capelli M, Porcu E, Fabbri R, Flamigni C 1986 Effects of obesity on gonadotropin secretion in patients with polycystic ovarian disease. J Endocrinol Invest 9:139–144[Medline]
  6. Morales AJ, Laughlin GA, Butzow T, Maheshwari H, Baumann G, Yen SS 1996 Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 81:2854–2864[Abstract/Free Full Text]
  7. Holte J, Bergh T, Gennarelli G, Wide L 1994 The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women. Clin Endocrinol (Oxf) 41:473–481[Medline]
  8. Dale PO, Tanbo T, Vaaler S, Abyholm T 1992 Body weight, hyperinsulinemia, and gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct populations. Fertil Steril 58:487–491[Medline]
  9. Anttila L, Ding YQ, Ruutiainen K, Erkkola R, Irjala K, Huhtaniemi I 1991 Clinical features and circulating gonadotropin, insulin, and androgen interactions in women with polycystic ovarian disease. Fertil Steril 55:1057–1061[Medline]
  10. Arroyo A, Laughlin GA, Morales AJ, Yen SS 1997 Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab 82:3728–3733[Abstract/Free Full Text]
  11. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F 1976 Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 57:1320–1329[Medline]
  12. Batrinos ML 1993 Diagnostic dilemmas in polycystic ovarian syndrome. Ann NY Acad Sci 687:230–234[CrossRef][Medline]
  13. Patel K, Coffler MS, Dahan MH, Malcom PJ, Deutsch R, Chang RJ 2004 Relationship of GnRH-stimulated LH release to episodic LH secretion and baseline endocrine-metabolic measures in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 60:67–74[CrossRef][Medline]
  14. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley Jr WF 1988 Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 66:165–172[Abstract/Free Full Text]
  15. Dunaif A, Mandeli J, Fluhr H, Dobrjansky A 1988 The impact of obesity and chronic hyperinsulinemia on gonadotropin release and gonadal steroid secretion in the polycystic ovary syndrome. J Clin Endocrinol Metab 66:131–139[Abstract/Free Full Text]
  16. Moran C, Garcia-Hernandez E, Barahona E, Gonzalez S, Bermudez JA 2003 Relationship between insulin resistance and gonadotropin dissociation in obese and nonobese women with polycystic ovary syndrome. Fertil Steril 80:1466–1472[CrossRef][Medline]
  17. Spratt DI, Finkelstein JS, Badger TM, Butler JP, Crowley Jr WF 1986 Bio- and immunoactive luteinizing hormone responses to low doses of gonadotropin-releasing hormone (GnRH): dose-response curves in GnRH-deficient men. J Clin Endocrinol Metab 63:143–150[Abstract/Free Full Text]
  18. Martin K, Santoro N, Hall J, Filicori M, Wierman M, Crowley Jr WF 1990 Clinical review 15: management of ovulatory disorders with pulsatile gonadotropin-releasing hormone. J Clin Endocrinol Metab 71:1081A–1081G
  19. Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley Jr WF 1994 Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc Natl Acad Sci USA 91:6894–6898[Abstract/Free Full Text]
  20. Gill S, Sharpless JL, Rado K, Hall JE 2002 Evidence that GnRH decreases with gonadal steroid feedback but increases with age in postmenopausal women. J Clin Endocrinol Metab 87:2290–2296[Abstract/Free Full Text]
  21. Ferriman D, Gallwey DJ 1971 Clinical assessment of body hair growth in women. J Clin Endocrinol 21:1440–1447
  22. Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna MT, Lesser M, New MI, White PC 1992 Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 90:584–595[Medline]
  23. Gill S, Taylor AE, Martin KA, Welt CK, Adams JM, Hall JE 2001 Specific factors predict the response to pulsatile gonadotropin-releasing hormone therapy in polycystic ovarian syndrome. J Clin Endocrinol Metab 86:2428–2436[Abstract/Free Full Text]
  24. Welt CK, Adams JM, Sluss PM, Hall JE 1999 Inhibin A and inhibin B responses to gonadotropin withdrawal depends on stage of follicle development. J Clin Endocrinol Metab 84:2163–2169[Abstract/Free Full Text]
  25. Welt CK, Pagan YL, Smith PC, Rado KB, Hall JE 2003 Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition. J Clin Endocrinol Metab 88:1766–1771[Abstract/Free Full Text]
  26. Vermeulen A, Verdonck L, Kaufman JM 1999 A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84:3666–3672[Abstract/Free Full Text]
  27. Santen RJ, Bardin CW 1973 Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest 52:2617–2628[Medline]
  28. Hayes FJ, McNicholl DJ, Schoenfeld D, Marsh EE, Hall JE 1999 Free {alpha}-subunit is superior to luteinizing hormone as a marker of gonadotropin-releasing hormone despite desensitization at fast pulse frequencies. J Clin Endocrinol Metab 84:1028–1036[Abstract/Free Full Text]
  29. Hayes FJ, Taylor AE, Martin KA, Hall JE 1998 Use of a gonadotropin-releasing hormone antagonist as a physiologic probe in polycystic ovary syndrome: assessment of neuroendocrine and androgen dynamics. J Clin Endocrinol Metab 83:2343–2349[Abstract/Free Full Text]
  30. McArthur JW, Ingersoll FM, Worcester J 1958 The urinary excretion of interstitial-cell and follicle-stimulating hormone activity by women with diseases of the reproductive system. J Clin Endocrinol Metab 18:1202–1215[Abstract/Free Full Text]
  31. Yen SS, Vela P, Rankin J 1970 Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 30:435–442[Abstract/Free Full Text]
  32. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ 1986 Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 62:904–910[Abstract/Free Full Text]
  33. Chang RJ, Laufer LR, Meldrum DR, DeFazio J, Lu JK, Vale WW, Rivier JE, Judd HL 1983 Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 56:897–903[Abstract/Free Full Text]
  34. Van Dam EW, Roelfsema F, Veldhuis JD, Helmerhorst FM, Frolich M, Meinders AE, Krans HM, Pijl H 2002 Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS. Am J Physiol Endocrinol Metab 282:E865–E872
  35. Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC 1998 Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 83:582–590[Abstract/Free Full Text]
  36. Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC 2000 Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 85:4047–4052[Abstract/Free Full Text]
  37. Cheng CK, Leung PC 2005 Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev 26:283–306[Abstract/Free Full Text]
  38. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR 2004 Gonadotropin-releasing hormone receptors. Endocr Rev 25:235–275[Abstract/Free Full Text]
  39. Densmore VS, Urbanski HF 2003 Relative effect of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on gonadotropin release. J Clin Endocrinol Metab 88:2126–2134[Abstract/Free Full Text]
  40. Hall JE, Taylor AE, Hayes FJ, Crowley Jr WF 1998 Insights into hypothalamic-pituitary dysfunction in polycystic ovary syndrome. J Endocrinol Invest 21:602–611[Medline]
  41. Lavoie HB, Martin KA, Taylor E, Crowley WF, Hall JE 1998 Exaggerated free {alpha}-subunit levels during pulsatile gonadotropin-releasing hormone replacement in women with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 83:241–247[Abstract/Free Full Text]
  42. Burcelin R, Thorens B, Glauser M, Gaillard RC, Pralong FP 2003 Gonadotropin-releasing hormone secretion from hypothalamic neurons: stimulation by insulin and potentiation by leptin. Endocrinology 144:4484–4491[Abstract/Free Full Text]
  43. Adashi EY, Hsueh AJ, Yen SS 1981 Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 108:1441–1449[Abstract/Free Full Text]
  44. Dunaif A, Graf M 1989 Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 83:23–29[Medline]
  45. Patel K, Coffler MS, Dahan MH, Yoo RY, Lawson MA, Malcom PJ, Chang RJ 2003 Increased luteinizing hormone secretion in women with polycystic ovary syndrome is unaltered by prolonged insulin infusion. J Clin Endocrinol Metab 88:5456–5461[Abstract/Free Full Text]
  46. Nestler JE, Clore JN, Strauss III JF, Blackard WG 1987 The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. J Clin Endocrinol Metab 64:180–184[Abstract/Free Full Text]
  47. Chapman IM, Wittert GA, Norman RJ 1997 Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters. Clin Endocrinol (Oxf) 46:175–181[CrossRef][Medline]
  48. Mantzoros CS, Dunaif A, Flier JS 1997 Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 82:1687–1691[Abstract/Free Full Text]
  49. Carmina E, Ferin M, Gonzalez F, Lobo RA 1999 Evidence that insulin and androgens may participate in the regulation of serum leptin levels in women. Fertil Steril 72:926–931[CrossRef][Medline]
  50. Moschos S, Chan JL, Mantzoros CS 2002 Leptin and reproduction: a review. Fertil Steril 77:433–444[CrossRef][Medline]
  51. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS 2004 Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 351:987–997[Abstract/Free Full Text]
  52. Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM 1997 Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 94:1023–1028[Abstract/Free Full Text]
  53. Laughlin GA, Morales AJ, Yen SS 1997 Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 82:1692–1696[Abstract/Free Full Text]
  54. Spritzer PM, Poy M, Wiltgen D, Mylius LS, Capp E 2001 Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: influence on LH and relationship with hormonal, metabolic, and anthropometric measurements. Hum Reprod 16:1340–1346[Abstract/Free Full Text]
  55. Wasko R, Komarowska H, Warenik-Szymankiewicz A, Sowinski J 2004 Elevated ghrelin plasma levels in patients with polycystic ovary syndrome. Horm Metab Res 36:170–173[CrossRef][Medline]
  56. Schofl C, Horn R, Schill T, Schlosser HW, Muller MJ, Brabant G 2002 Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 87:4607–4610[Abstract/Free Full Text]
  57. McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cummings DE 2004 Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab 89:1630–1635[Abstract/Free Full Text]
  58. Vulliemoz NR, Xiao E, Xia-Zhang L, Germond M, Rivier J, Ferin M 2004 Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 89:5718–5723[Abstract/Free Full Text]
  59. Vanky E, Kjotrod S, Salvesen KA, Romundstad P, Moen MH, Carlsen SM 2004 Clinical, biochemical and ultrasonographic characteristics of Scandinavian women with PCOS. Acta Obstet Gynecol Scand 83:482–486[CrossRef][Medline]
  60. Norman RJ, Masters SC, Hague W, Beng C, Pannall P, Wang JX 1995 Metabolic approaches to the subclassification of polycystic ovary syndrome. Fertil Steril 63:329–335[Medline]



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