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Reproductive Endocrinology |
Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114
Address correspondence and requests for reprints to: Ann E. Taylor, Reproductive Endocrine Unit, National Center for Fertility Research, Massachusetts General Hospital, Bartlett Hall Extension, Fruit Street, Boston, Massachusetts 02114.
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Abstract |
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Sixty-one women with PCOS defined by oligomenorrhea and hyperandrogenism and 24 normal women in the early follicular phase had LH samples obtained every 10 min for 8–12 h. Pool LH levels from the frequent sampling studies were within the normal range in the 9 PCOS patients (14.8%) who were studied within 21 days after a documented spontaneous ovulation. Excluding these post-ovulatory patients, 75.0% of the PCOS patients had an elevated pool LH level (above the 95th percentile of the normal controls), and 94% had an elevated LH to FSH ratio.
In the anovulatory PCOS patients, pool LH correlated positively with 17-OH progesterone (R = 0.30, P = 0.03), but not with estradiol, estrone, testosterone, androstenedione, or DHEA-S. Pool LH and LH to FSH ratio correlated positively with LH pulse frequency (R = 0.40, P = 0.004 for pool LH, and R = 0.39; P = 0.005 for LH/FSH). There was also a strong negative correlation between pool LH and body mass index (BMI) (R = -0.59, P < 10-5). The relationship between BMI and LH secretion in the PCOS patients appeared to be strongest with body fatness, as pool LH was correlated inversely with percent body fat, whether measured by skinfolds (R = -0.61, P < 10-5), bioimpedance (R = -0.55, P < 10-4), or dual energy x-ray absorptiometry (DEXA) (R = -0.70, P = 0.001; n = 18 for DEXA only). By DEXA, the only body region that was highly correlated with pool LH was the trunk (R = -0.71, P = 0.001).
The relationship between body fatness and LH secretion occurred via a decrease in LH pulse amplitude (R = -0.63, P < 10-5 for BMI; R = -0.58, P < 10-4 for bioimpedance; and R = -0.64, P = 0.004 for whole body DEXA), with no significant change in pulse frequency with increasing obesity (R = -0.17, P = 0.23 for BMI).
In conclusion: 1) the prevalence of gonadotropin abnormalities is very high in women with PCOS selected on purely clinical grounds, but is modified by recent spontaneous ovulation; 2) the positive relationship between LH pulse frequency and both pool LH and LH to FSH ratio supports the hypothesis that a rapid frequency of GnRH secretion may play a key etiologic role in the gonadotropin defect in PCOS patients; 3) pool LH and LH pulse amplitude are inversely related to body mass index and percent body fat in a continuous fashion; and 4) the occurrence of a continuous spectrum of gonadotropin abnormalities varying with body fat suggests that nonobese and obese patients with PCOS do not represent distinct pathophysiologic subsets of this disorder.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An increased prevalence of obesity in PCOS patients has long been appreciated (15, 16). Several recent studies (2, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26), but not all (3, 27, 28) have demonstrated a negative correlation of LH values with obesity and/or insulin resistance. However, only one (26) of these studies assessed pulsatile gonadotropin secretion with sufficient intensity to evaluate the relationship between obesity and LH pulse amplitude and frequency. In that study, small numbers of patients were studied at the extremes of body weight (body mass index < 23 or > 30), and all had a baseline gonadotropin defect. While the study concluded that the lean patients had an increased LH pulse amplitude, but no difference in frequency compared with the obese patients, the spectrum of gonadotropin abnormalities across a spectrum of body weight in PCOS patients remains unknown. In addition, none of the studies has assessed the relationship between gonadotropin secretion and body composition.
We have previously hypothesized that an increased GnRH pulse frequency could result in the increased mean LH levels and the normal to decreased FSH levels observed in patients with PCOS (6), based on studies in GnRH deficient men in whom an increase in the frequency of exogenous GnRH administration resulted in a progressive increase in LH and the LH/FSH ratio (29). This frequency hypothesis has not previously been evaluated in PCOS patients, nor has it been assessed relative to body weight or body composition.
A recent conference on PCOS (30) proposed minimum consensus criteria for the definition of PCOS requiring the presence of menstrual dysfunction (oligo- or amenorrhea) and hyperandrogenism (clinical or biochemical) in the absence of other identifiable diseases. Therefore, neither polycystic ovarian morphology by ultrasonography nor an identifiable biochemical abnormality are required to meet these diagnostic criteria. The current study was designed to determine the prevalence and determinants of the defect of gonadotropin secretion in a large population of PCOS patients defined by these broad clinical criteria. Our results provide further evidence that body fatness and LH pulse amplitude, by an as yet unknown mechanism, are strongly related across the broad spectrum of PCOS patients.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PCOS was defined by chronic oligoamenorrhea (fewer than 9 menses/yr) or amenorrhea plus clinical or biochemical evidence of hyperandrogenism (30). Ovarian morphology by ultrasound and elevated LH levels were not required for inclusion. Late onset congenital adrenal hyperplasia was excluded by a peak 17-OH progesterone response 60 min. after iv 0.25 mg ACTH (Cosyntropin, Organon Inc., West Orange, NJ) of less than 4 ng/mL (31) when the progesterone level was less than 1 ng/mL. All patients were between 16 and 42 yr old and had a serum prolactin level less than 25 ng/mL and a TSH between 0.4 and 5.5 IU/mL. Except for one patient with hypertension whose beta-blocker was held for 3 days before the study, all were otherwise healthy and had been off all medications (except for stable thyroid hormone replacement) for at least 2 months before the study.
Control subjects
Normal women were between the ages of 18 and 41 and had been on no medications for at least 3 months before the study. All normal subjects were healthy, had Ferriman-Gallwey hirsutism scores (32) less than 10, and had regular 26–34 day menstrual cycles. All had a documented ovulatory progesterone level above 2 ng/mL in the luteal phase before their study. All studies were performed in the early follicular phase between 1 and 7 days after the onset of menses.
All subjects. Obesity was defined by a BMI (weight in kg divided by height in m2) above 27 (33). Subjects were recruited from the Reproductive Endocrine Associates clinic at Massachusetts General Hospital, or by posted advertisements, and all gave their informed consent. Obese control subjects and nonobese PCOS patients were actively recruited, and thus the results of this study do not reflect the distribution of body weight in the population of either normal control women or patients with PCOS. The study was approved by the Institutional Review Board of the Massachusetts General Hospital.
Protocol
All subjects underwent a medical history and physical examination upon entry into the study, including clinical assessment of hirsutism by the method of Ferriman and Gallwey (32). Subjects had a pelvic ultrasound examination performed on the same machine (Toshiba Sonolayer L, SAL-778 with a transvaginal 5 MHz probe) and interpreted by a single technologist (J.M.A.) to evaluate ovarian morphology and to identify a dominant follicle or corpus luteum. Ovarian volume was calculated as length x width x height in cm divided by 2. Polycystic ovarian morphology was defined as a peripheral array of follicles with at least 8 follicles of 6–8 mm detectable in a single plane. When films were of inadequate quality to accurately count small follicles (secondary to abdominal gas, obesity, or a substitue ultrasonographer), they were not scored.
On the day of admission to the General Clinical Research Center, height and weight were measured using standardized techniques. In all normal women and 58 of the PCOS patients, skinfold measurements were performed 3 times at each of 4 sites (biceps, triceps, suprailiac, and subscapular) (34). Percent body fat was determined from age and sex adjusted tables of the sum of the mean skinfolds at each site (35). In addition, in all normal women and 57 of the PCOS patients, percent body fat was also calculated by bioelectrical impedance (RJL Systems, Clinton Turnpike, MI). Total body resistance and reactance were measured in hydrated (nonfasting) supine patients, and percent body fat was calculated from those values and age, height, weight, and sex by a computer program supplied by the manufacturer (36). Lastly, a subset of PCOS patients (n = 25) underwent whole body dual energy X-ray absorptiometry (DEXA) (Hologic QDR-2000, Waltham, MA) to determine total body fat as well as truncal fat (37).
Frequent blood sampling for LH occurred through an indwelling 18-gauge catheter every 10 min. In the PCOS patients, sampling was performed from 2000 h to 0800 h (12 h) as they had previously been shown to have no diurnal variation in gonadotropin secretion (6). In the normal women, in whom early follicular phase sleep slowing is a well-documented phenomenon (38), blood sampling was performed from 1600 to midnight, and the subjects were kept awake until sampling was complete. The morning after completion of their frequent sampling study, all subjects had a fasting 0800 blood sample for estradiol, estrone, progesterone, testosterone, androstenedione, DHEA-S, and 17-OH progesterone.
Assays
LH, FSH, estradiol, estrone, progesterone, testosterone, DHEA-S, 17-OH progesterone, and testosterone were measured by radioimmunoassays that have been previously validated (12, 39, 40, 41, 42). Androstenedione was measured after extraction from serum in a radioimmunoassay using a polyclonal antiserum provided by P. N. Rao, Ph.D., Southwestern Foundation for Biomed Research, San Antonio, TX. The sensitivity of the assay is 0.6 ng/mL, and the intra- and interassay coefficients of variation are both less than 10%.
A serum pool was created from equal aliquots of each sample of the frequent sampling study to assess integrated LH and FSH levels during the study. 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 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. The 10 replicates of the pool were used to determine the coefficient of variarion (CV) of LH in the patient’s samples in the same assay.
Pulse analysis
Pulsatile secretion of LH was determined statistically as previously described (6, 38). A pulse was identified in the frequent sampling series when the peak minus the nadir exceeded 3 times the assay CV (see above) and at least 1 IU/L. 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 24 h was calculated from the number of pulses identified and the duration of sampling.
Statistical analysis
Because many of the variables were not normally distributed, nonparametric tests were used for all analyses. For each variable tested, normal and PCOS women were compared by the Mann-Whitney U test. With 12 biochemical variables being analyzed, a P value of 0.0042 (0.05 divided by 12, the Bonferroni correction) was required for formal acceptance of statistical significance. This is a conservative estimate of significance given the anticipated a priori differences between the patients and controls for many of these variables. For correlation analyses, the Spearman rank order correlation test was used. Lastly, multivariate analysis was performed to determine the contributions of cycle day, fatness, and pulse frequency to the pool LH level.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 24 normal controls (13 nonobese and 11 obese) and 61
PCOS patients (24 nonobese and 37 obese) completed the frequent
sampling studies. PCOS and normal women did not differ by age, but PCOS
patients had increased Ferriman-Gallwey hirsutism scores and were less
likely to be African American compared with the normal group (Table 1
). Ultrasound examinations were adequate for
interpretation of morphology in 89% of patients, all of whom had
polycystic ovarian morphology. In spite of directed recruitment of
obese normal women, the obese PCOS patients were more obese than the
normal women.
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Impact of recent ovulation on gonadotropin secretion in PCOS
Nine of the PCOS patients, all of whom met the oligo-ovulatory
criteria for the diagnosis of PCOS, were studied within 21 days after a
spontaneous ovulation. Ovulation was documented in 3 subjects by a
serum progesterone level above 4 ng/mL on the day of study (2 obese and
1 nonobese). Six additional patients (2 obese and 4 nonobese) were
studied between 1 and 7 days after the onset of menses after ovulation
was documented by a serum progesterone level of more than 6 ng/mL (5
patients) and/or by ultrasound. The 9 PCOS patients with documented
ovulation did not differ significantly from the anovulatory PCOS
patients in terms of body weight or hirsutism scores (Table 2), but they tended to have lower androgen levels. Two
of these subjects had been amenorrheic for over 1 yr before the
study.
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, Fig. 1). Because progesterone exposure has previously been
shown to suppress LH pulse frequency and random LH levels in PCOS
patients (43, 44, 45), these nine women were considered separately in
subsequent analyses.
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The pool LH and LH/FSH ratio, but not pool FSH, were significantly
elevated in the 52 anovulatory PCOS patients (19 nonobese and 33 obese)
compared with normal women (Table 2, Fig. 1). In the normal group, the
upper 95th percentile of pool LH was 11.8 IU/L and the LH to FSH ratio
was 0.94. This ratio is lower than previously described for normal
women because of the inclusion of only the early follicular phase, when
FSH levels are highest. Using these criteria, a full 75% of the
anovulatory PCOS patients had an elevated serum LH, and 94% had an
elevated LH to FSH ratio. The frequency distribution of pool LH levels
was continuous with no visual or statistical evidence for 2 or more
distinct populations of subjects.
Impact of obesity
There was a striking inverse relationship between BMI and pool LH
in the anovulatory PCOS patients (Fig. 2). One hundred
percent of nonobese PCOS patients had a pool LH above the 95th
percentile of the normal group, whereas only 61% of the obese patients
had pool LH values above the normal range. Because there was also a
negative correlation between BMI and pool FSH, 100% of the nonobese
patients and 91% of the obese PCOS patients had an elevated LH to FSH
ratio. This relationship was continuous across the wide range of BMI
seen in the studied subjects.
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Pulsatile gonadotropin dynamics
The anovulatory PCOS patients had significantly higher LH pulse
amplitude and frequency compared with the normal group of women, as
expected (Table 2). Of the anovulatory PCOS patients, 28.8% had an
elevated LH pulse amplitude and 19.2% had an elevated LH pulse
frequency above the 95th percentile of the controls. The LH pulse
frequency was significantly correlated with the pool LH and the LH to
FSH ratio in both the PCOS patients and the controls (Fig. 3) (Pool LH: R = 0.40, P = 0.004
for PCOS; R = 0.59, P = 0.002 for controls; LH
to FSH: R = 0.39, P = 0.005 for PCOS; R =
0.49, P = 0.02 for controls).
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).
There was a similar negative correlation of LH pulse amplitude with BMI
in the normal women (R = -0.61, P = 0.002).
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Sex steroids and gonadotropin secretion
In the anovulatory PCOS patients, baseline 17 OH progesterone
levels were weakly positively correlated with pool LH (R = 0.30,
P = 0.03), LH to FSH ratio (R = 0.36,
P = 0.009), and LH pulse amplitude (R = 0.36,
P = 0.009), but not pulse frequency (R = 0.08,
P = 0.58). In the normal women there was a positive
correlation of baseline testosterone and androstenedione levels with LH
pulse amplitude (R = 0.71, P < 0.001 for
testosterone and R = -0.44, P = 0.03 for
androstenedione), but this was not apparent in the PCOS patients. There
was no correlation of estradiol, estrone, androstenedione, or DHEA-S
with pool LH, LH to FSH ratio, LH pulse amplitude or frequency in
either the patients or the controls (Table 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent ovulation
Unlike the anovulatory subjects, the 9 PCOS patients studied within 21 days after spontaneous ovulation each had pool LH levels within the normal range. From the current study design, it can not be determined whether the normal LH levels permitted ovulation or whether the ovulation normalized the LH levels. However, 2 of the patients had been amenorrheic for more than 1 yr before that study, indicating that they are not merely a less severe subgroup of PCOS patients. In addition, in these patients the Ferriman-Gallwey hirsutism scores, as a marker of prolonged androgen exposure, and the ovarian volumes were elevated and indistinguishable from the remainder of the PCOS patients. The PCOS patients who had recently ovulated had serum androgen levels intermediate between normal and anovulatory PCOS values. Thus, recent spontaneous ovulation might be able to acutely normalize LH secretion and subsequent androgen secretion in PCOS patients, as has previously been demonstrated in individual cases (45). Because previous studies demonstrated suppression of LH and androgens after endogenous (46, 47, 48) or exogenous progestin exposure (43, 44, 46), the patients who had recently ovulated were excluded from subsequent analyses.
The evidence that spontaneous ovulation might be sufficient to acutely normalize gonadotropin secretion in PCOS patients is in contrast to recent reports that exogenous physiologic steroid replacement therapy or supraphysiologic oral contraceptives are unable to completely reverse the gonadotropin defect of PCOS (49, 50). The apparent ability of spontaneous ovulation, but not steroid replacement alone, to normalize gonadotropin dynamics suggests that other ovarian factors might be required for normal hypothalamic-pituitary feedback. Alternatively, normalization of gonadotropin dynamics could have occurred spontaneously by an unknown mechanism, permitting the subsequent ovulation to occur.
LH pulse frequency
When frequent blood sampling protocols are used, investigators have uniformly demonstrated an increase in LH pulse amplitude in PCOS patients compared with normal women. Many, but not all, authors have also demonstrated an increase in LH pulse frequency in agreement with the current study. The failure of some investigators to identify a frequency defect in their cohort of PCOS subjects is likely attributable to sampling too infrequently or for too short a time period, although a difference in pulse detection algorithms is also possible. Most studies performed with sampling intervals longer than 10 min or durations shorter than 8 h did not demonstrate an increased LH pulse frequency in PCOS patients compared with normal follicular phase women (4, 8, 23, 27, 28). Conversely, 2 out of 3 studies that sampled at least every 10 min for at least 12 h conclusively demonstrated an increased LH pulse frequency in PCOS (6, 7, 9).
The demonstration of an increased LH pulse frequency in PCOS is important as it indicates that at least a portion of the gonadotropin defect in this disorder occurs at the hypothalamic level. The lack of relationship between obesity and LH pulse frequency implies that the frequency defect is present in the entire spectrum of PCOS subjects and is likely to be a defining property of the syndrome. We have previously hypothesized that an increased pulse frequency can drive the exaggerated gonadotropin secretion and increased LH to FSH ratio in PCOS patients (6, 29). The current study supports this hypothesis by confirming the expected positive correlation between GnRH-induced LH pulse frequency and pool LH and LH to FSH ratio in a large number of PCOS patients.
Sex steroids
Our study reveals a positive relationship between pulsatile LH secretion and serum 17-OH progesterone levels in PCOS patients. This observation is strengthened by its verification in all three of the related variables of pool LH, LH to FSH ratio, and LH pulse amplitude, suggesting that circulating LH levels may contribute to the increased 17-OH progesterone secretion seen in PCOS women (42). This relationship is supported by similar findings in smaller groups of hyperandrogenic women (26, 51) and by recent evidence that metformin therapy suppresses basal and GnRH agonist stimulated 17-OH progesterone levels in association with suppression of both insulin and LH levels in PCOS women (52).
Previous studies of gonadotropin defects in women with PCOS have demonstrated a correlation of serum LH levels with estrone and estradiol (1, 26, 53), LH to FSH ratio with free estradiol (54) or estrone administration (55), and LH pulse frequency with serum estradiol (6), all in small numbers of subjects. Based on these observations, investigators have suggested that estrogen may contribute to the gonadotropin abnormality in PCOS. In contrast, the frequently sampled LH data in this study shows no relationship of either estradiol or estrone with any of the parameters of pulsatile LH secretion in all subjects as a group or in the PCOS or the normal women separately. These discrepancies with previous studies may be explained by the larger number of subjects, by the statistical rigor applied, or by the use of a broader definition of PCOS in the current study. It is also possible that a relationship would have been observed if free estrogen levels were measured (54).
Body fat
BMI correlates strongly and inversely with pool LH and LH amplitude but not with LH pulse frequency in PCOS patients. This latter finding is consistent with a recent report in 8 very lean and 8 very obese PCOS subjects (26) and further demonstrates that the correlation of gonadotropin secretion and obesity is strongly related to percent body fat, in particular truncal fat, and is continuous across the entire spectrum of obesity, not just in the extreme groups. These data suggest the gonadotropin dynamics are modified by obesity rather than that lean and obese PCOS patients represent distinct etiologic subsets.
Our data raise the possibility that an obesity-associated factor suppresses GnRH pulse amplitude or pituitary LH responsiveness, but not pulse frequency. The even stronger negative correlation of LH with percent body fat suggests that the factor may be related to adipose tissue volume. The mechanisms by which an obesity-associated factor might influence pulsatile LH secretion have yet to be determined. These mechanisms might include a hypothalamic effect to decrease the amount of GnRH per bolus, or a pituitary effect suppressing the LH response to GnRH. Insulin receptors have been identified on pituitary cells (56), and the hyperinsulinemia of obesity may operate at a pituitary level to dampen LH pulse amplitude (57). Alternatively, another fat-associated factor, such as leptin, with a hypothalamic or pituitary site of action could mediate a feedback effect on LH secretion. This hypothesis is supported by a recent report that PCOS patients have increased serum leptin levels compared with weight matched normal women (58). The decreased circulating LH levels in obese patients could be explained by an increase in renal gonadotropin clearance that is unique to PCOS women and not seen in normal obese women. Short-term fasting has been shown to significantly increase renal LH excretion in men and in obese post-menopausal women (59). However, our subjects were ingesting their normal diets and had not fasted before the study. Although differences in LH clearance with obesity have not yet been reported (60, 61), it seems unlikely that a change in clearance would influence the LH pulse peak or amplitude, as seen in the current study, even if increased clearance could reduce the pool LH level.
If an obesity-associated factor suppresses LH secretion, obese PCOS patients may have an underlying gonadotropin defect that is masked by their obesity. If so, weight loss should result in an increase in LH secretion. Several studies have demonstrated either no change or a decrease in LH levels after interventions such as weight loss (62) or suppression of insulin secretion (51, 63, 64, 65) in PCOS patients. However, these intervention studies also demonstrate an increase in the frequency of menses and of ovulation. Thus, it is possible that the observed decrease in LH levels is attributable to the post-ovulatory state rather than to suppression of insulin levels. Intriguingly, one study that achieved significant weight loss (50–60 lb. each) in 5 reproductive age amenorrheic women using long-term fasting demonstrated a tripling of the LH response to a GnRH test after weight loss and fasting (66), consistent with our findings that leaner subjects had a greater LH pulse amplitude.
In summary, we have demonstrated that gonadotropin abnormalities are a key component of PCOS even in patients meeting the broadest clinical definition of this disorder, confirming previous studies in more restricted patient populations. We have also shown that these gonadotropin abnormalities are modified by recent spontaneous ovulation and by body weight. These influences would contribute to differences in the prevalence of gonadotropin abnormalities seen in different studies of PCOS subjects that included patients of different body weights with or without progestin pretreatment. The addition of an elevated LH to FSH ratio as a selection factor for PCOS patients would also increase the prevalence of gonadotropin frequency abnormalities, as we have demonstrated a strong positive correlation of LH to FSH with LH pulse frequency. The continuous inverse relationship between increased LH pulse amplitude and body fatness suggests that LH and obesity are not independent contributors to the PCOS phenotype. Rather than suggest two distinct subtypes of PCOS, one associated with primary excess gonadotropin secretion and one associated with obesity and hyperinsulinemia, our data indicate a more complex interrelated model of PCOS.
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Acknowledgments |
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Footnotes |
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Received September 20, 1996.
Revised March 26, 1997.
Accepted April 18, 1997.
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References |
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S.K. Blank, C.R. McCartney, and J.C. Marshall The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2006; 12(4): 351 - 361. [Abstract] [Full Text] [PDF]
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C. R. McCartney, K. A. Prendergast, S. Chhabra, C. A. Eagleson, R. Yoo, R. J. Chang, C. M. Foster, and J. C. Marshall The Association of Obesity and Hyperandrogenemia during the Pubertal Transition in Girls: Obesity as a Potential Factor in the Genesis of Postpubertal Hyperandrogenism J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1714 - 1722. [Abstract] [Full Text] [PDF]
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Y. L. Pagan, S. S. Srouji, Y. Jimenez, A. Emerson, S. Gill, and J. E. Hall Inverse Relationship between Luteinizing Hormone and Body Mass Index in Polycystic Ovarian Syndrome: Investigation of Hypothalamic and Pituitary Contributions J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1309 - 1316. [Abstract] [Full Text] [PDF]
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J. C. Marshall Obesity in Adolescent Girls: Is Excess Androgen the Real Bad Actor? J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 393 - 395. [Full Text] [PDF]
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N. A. Cataldo, F. Abbasi, T. L. McLaughlin, M. Basina, P. Y. Fechner, L. C. Giudice, and G. M. Reaven Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome Hum. Reprod., January 1, 2006; 21(1): 109 - 120. [Abstract] [Full Text] [PDF]
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C. K. Welt, A. E. Taylor, J. Fox, G. M. Messerlian, J. M. Adams, and A. L. Schneyer Follicular Arrest in Polycystic Ovary Syndrome Is Associated with Deficient Inhibin A and B Biosynthesis J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5582 - 5587. [Abstract] [Full Text] [PDF]
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D.H. Abbott, D.K. Barnett, C.M. Bruns, and D.A. Dumesic Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update, July 1, 2005; 11(4): 357 - 374. [Abstract] [Full Text] [PDF]
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J. Vrbikova and D. Cibula Combined oral contraceptives in the treatment of polycystic ovary syndrome Hum. Reprod. Update, May 1, 2005; 11(3): 277 - 291. [Abstract] [Full Text] [PDF]
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 C Ortega-Gonzalez, L Cardoza, B Coutino, R Hidalgo, G Arteaga-Troncoso, and A Parra Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome J. Endocrinol., January 1, 2005; 184(1): 233 - 239. [Abstract] [Full Text] [PDF]
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G. A. R. Maciel, E. C. Baracat, J. A. Benda, S. M. Markham, K. Hensinger, R. J. Chang, and G. F. Erickson Stockpiling of Transitional and Classic Primary Follicles in Ovaries of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5321 - 5327. [Abstract] [Full Text] [PDF]
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J. M. Adams, A. E. Taylor, W. F. Crowley Jr., and J. E. Hall Polycystic Ovarian Morphology with Regular Ovulatory Cycles: Insights into the Pathophysiology of Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4343 - 4350. [Abstract] [Full Text] [PDF]
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 E. W. C. M. van Dam, F. Roelfsema, J. D. Veldhuis, S. Hogendoorn, J. Westenberg, F. M. Helmerhorst, M. Frolich, H. M. J. Krans, A. E. Meinders, and H. Pijl Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E615 - E620. [Abstract] [Full Text] [PDF]
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S. Jonard and D. Dewailly The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest Hum. Reprod. Update, March 1, 2004; 10(2): 107 - 117. [Abstract] [Full Text] [PDF]
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M.H.A. van Hooff, F.J. Voorhorst, M.B.H. Kaptein, R.A. Hirasing, C. Koppenaal, and J. Schoemaker Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years Hum. Reprod., February 1, 2004; 19(2): 383 - 392. [Abstract] [Full Text] [PDF]
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The Rotterdam ESHRE/ASRM-sponsored PCOS consensus Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Hum. Reprod., January 1, 2004; 19(1): 41 - 47. [Abstract] [Full Text] [PDF]
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 V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]
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P.-H. Ducluzeau, P. Cousin, E. Malvoisin, H. Bornet, H. Vidal, M. Laville, and M. Pugeat Glucose-to-Insulin Ratio Rather than Sex Hormone-Binding Globulin and Adiponectin Levels Is the Best Predictor of Insulin Resistance in Nonobese Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3626 - 3631. [Abstract] [Full Text] [PDF]
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S. Taponen, H. Martikainen, M.-R. Jarvelin, J. Laitinen, A. Pouta, A.-L. Hartikainen, U. Sovio, M. I. McCarthy, S. Franks, and A. Ruokonen Hormonal Profile of Women with Self-Reported Symptoms of Oligomenorrhea and/or Hirsutism: Northern Finland Birth Cohort 1966 Study J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 141 - 147. [Abstract] [Full Text] [PDF]
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C. K. Welt, A. E. Taylor, K. A. Martin, and J. E. Hall Serum Inhibin B in Polycystic Ovary Syndrome: Regulation by Insulin and Luteinizing Hormone J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5559 - 5565. [Abstract] [Full Text] [PDF]
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R. B. Barnes, A. B. Namnoum, R. L. Rosenfield, and L. C. Layman The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: Clinical studies in a patient with isolated FSH deficiency and multicystic ovaries: Case report Hum. Reprod., January 1, 2002; 17(1): 88 - 91. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3772 - 3778. [Abstract] [Full Text] [PDF]
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L. Bilo, R. Meo, R. Valentino, C. Di Carlo, S. Striano, and C. Nappi Characterization of Reproductive Endocrine Disorders in Women with Epilepsy J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2950 - 2956. [Abstract] [Full Text] [PDF]
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P.M. Spritzer, M. Poy, D. Wiltgen, L.S. Mylius, and E. Capp 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., July 1, 2001; 16(7): 1340 - 1346. [Abstract] [Full Text] [PDF]
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S. Gill, A. E. Taylor, K. A. Martin, C. K. Welt, J. M. Adams, and J. E. Hall Specific Factors Predict the Response to Pulsatile Gonadotropin-Releasing Hormone Therapy in Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2428 - 2436. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini Disruption of the Joint Synchrony of Luteinizing Hormone, Testosterone, and Androstenedione Secretion in Adolescents with Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 72 - 79. [Abstract] [Full Text]
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C. A. Eagleson, M. B. Gingrich, C. L. Pastor, T. K. Arora, C. M. Burt, W. S. Evans, and J. C. Marshall 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., November 1, 2000; 85(11): 4047 - 4052. [Abstract] [Full Text]
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M. H. A. van Hooff, F. J. Voorhorst, M. B. H. Kaptein, R. A. Hirasing, C. Koppenaal, and J. Schoemaker Insulin, Androgen, and Gonadotropin Concentrations, Body Mass Index, and Waist to Hip Ratio in the First Years after Menarche in Girls with Regular Menstrual Cycles, Irregular Menstrual Cycles, or Oligomenorrhea J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1394 - 1400. [Abstract] [Full Text]
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M. P. Rose, R. E. Gaines Das, and A. H. Balen Definition and Measurement of Follicle Stimulating Hormone Endocr. Rev., February 1, 2000; 21(1): 5 - 22. [Abstract] [Full Text]
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H.M. Buckler, W.R. Robertson, A. Anderson, M. Vickers, and A. Lambert Ovulation induction with low dose alternate day recombinant follicle stimulating hormone (Puregon) Hum. Reprod., December 1, 1999; 14(12): 2969 - 2973. [Abstract] [Full Text] [PDF]
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H. J. H. M. T. van Dessel, P. D. K. Lee, G. Faessen, B. C. J. M. Fauser, and L. C. Giudice Elevated Serum Levels of Free Insulin-Like Growth Factor I in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3030 - 3035. [Abstract] [Full Text]
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L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
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M.H.A. van Hooff, M. van der Meer, C.B. Lambalk, and J. Schoemaker Variation of luteinizing hormone and androgens in oligomenorrhoea and its implications for the study of polycystic ovary syndrome Hum. Reprod., July 1, 1999; 14(7): 1684 - 1689. [Abstract] [Full Text] [PDF]
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S. B. Seminara, J. E. Hall, A. E. Taylor, W. F. Crowley Jr., and K. A. Martin The Reproductive Endocrine Associates of the Massachusetts General Hospital: Fifteen Years of Integrated Clinical Practice and Investigation J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1912 - 1918. [Full Text]
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M. Nagamani, C. Osuampke, and M. E. Kelver Increased Bioactive Luteinizing Hormone Levels and Bio/Immuno Ratio in Women with Hyperthecosis of the Ovaries: Possible Role of Hyperinsulinemia J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1685 - 1689. [Abstract] [Full Text]
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A. E. Taylor, J. Hubbard, and E. J. Anderson Impact of Binge Eating on Metabolic and Leptin Dynamics in Normal Young Women J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 428 - 434. [Abstract] [Full Text]
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F. J. Hayes, A. E. Taylor, K. A. Martin, and J. E. Hall 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., July 1, 1998; 83(7): 2343 - 2349. [Abstract] [Full Text]
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C. L. Pastor, M. L. Griffin-Korf, J. A. Aloi, W. S. Evans, and J. C. Marshall Polycystic Ovary Syndrome: Evidence for Reduced Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Estradiol and Progesterone J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 582 - 590. [Abstract] [Full Text]
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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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, normal early follicular phase women, •, anovulatory PCOS
women, 
, PCOS women studied within 21 days of documented ovulation.
Cycle day 1 is defined as the first day of menses. The gray
shaded areas represent the 90th percentile of the 24 normal
women.
