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Original Studies |
Department of Reproductive Medicine, School of Medicine 0633, University of California, San Diego, La Jolla, California 92093-0633
Address all correspondence to (no reprints available): Samuel S. C. Yen, Department of Reproductive Medicine, School of Medicine 0633, University of California, 9500 Gilman Drive, BSB5046A, La Jolla, California 92093-8856.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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Our results showed that BMI, an indicator of relative adiposity, had a significant negative impact on 24-h mean LH pulse amplitude (r = -0.63, P < 0.001) and the peak increment of LH in response to GnRH stimulation (r = -0.41; P = 0.02) for PCOS but not NC women. In contrast, 24-h LH pulse frequency was uniformly increased (40%) in PCOS as compared with NC women independent of BMI. In PCOS women, the blunting of pulse amplitude with increasing BMI resulted in a decline in 24-h mean LH levels (r = -0.63, P < 0.001) and the ratio of LH/FSH (r = -0.44, P = 0.02) not seen in NC. With BMI <30 kg/m2, 24-h mean LH values for PCOS women were greater than the normal range for NC in 95% (18/19) of cases, whereas 24-h LH levels failed to discriminate PCOS from NC women in 43% (6/14) of obese (BMI >30 kg/m2) PCOS women. Thus, the diagnostic value of LH determinations is retained for PCOS women with BMI <30 kg/m2. For screening purposes, the mean of two LH values in samples collected at 30-min intervals was found to have a discriminatory power equal to that of the 24-h mean.
These findings suggest that 1) BMI negatively influences LH pulse amplitude in PCOS women principally by an effect at the pituitary level; 2) accelerated LH pulse frequency in PCOS women is not influenced by BMI and represents a basic component of hypothalamic dysfunction in PCOS women; and 3) BMI does not influence gonadotropin secretion in normal cycling women. Thus assessments of basal LH levels and the LH/FSH ratio in hyperandrogenic anovulatory women are clinically meaningful when BMI is taken into account. Investigations to define the factor(s) that link adiposity and the attenuation of LH pulse amplitude in PCOS women would add further understanding of this complex neuroendocrine-metabolic disorder.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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However, when basal LH measurements were used as clinical markers of PCOS, a significant number of patients failed to exhibit an elevated LH and hence LH/FSH ratio (19, 20, 21). This issue prompted an NICHHD-sponsored consensus conference on diagnostic criteria for PCOS in 1990, and the recommendation that LH and the LH/FSH ratio are not required for the diagnosis of PCOS (21). However, several recent studies (22, 23, 24, 25, 26) confirmed and extended earlier observations (27, 28, 29, 30) that in women with PCOS there is a negative influence of obesity on LH values. An important question then arises: does adiposity suppress LH pulsatile secretion in women with PCOS? Because these studies lack sufficient intensity and/or duration of sampling to assess LH pulse amplitude and frequency, we recently addressed this issue by examining 24-h pulse parameters in obese and lean PCOS women and body mass index (BMI)-matched controls (13). Although an unequivocal attenuation of LH pulse amplitude occurs in obese PCOS women, the relationship between LH pulsatility and adiposity across a spectrum of BMI in PCOS women remains to be defined. We report here the results of such an assessment with the aim of providing both a clinical reference and a pathophysiological basis for the heterogeneity of inappropriate gonadotropin secretion in PCOS women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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Thirty three women with the diagnosis of PCOS and 32 women of similar age and BMI with regular menstrual cyclicity (NC) were studied. Data on these subjects has been presented in a previous study of leptin levels in PCOS women (31). The age range of the subjects was 17–36 yr; BMI ranged from 19–42 kg/m2. The diagnosis of PCOS was based on perimenarcheal onset of oligomenorrhea, elevated serum levels of androstenedione (A) and/or testosterone (T), and ultrasound evidence of bilateral enlarged polycystic ovaries. All subjects were euglycemic, euthyroid, and had normal PRL levels. They were nonsmokers and had not been on any medications for at least 3 months before the study. In PCOS subjects, late-onset congenital adrenal hyperplasia was excluded by a normal 17-hydroxyprogesterone (17-OHP) level 60 min after an ACTH stimulation test. The protocol for this study was approved by the Committee on Investigations Involving Human Subjects of the University of California, San Diego (UCSD), and written informed consent was obtained from each participant.
Procedures
Studies were conducted in regularly cycling controls during the early follicular phase (days 2–5) of their menstrual cycle and in PCOS women on a random day. In no case had recent ovulation occurred in PCOS women as evidenced by retrospective measurement of serum progesterone levels on the day of the study. Subjects were admitted to the General Clinical Research Center (GCRC) of the UCSD Medical Center at 0700 h after an overnight fast. Blood samples were drawn through an indwelling iv catheter every 10 min for 24-h beginning at 0800 h. Subjects refrained from napping and drinking caffeinated beverages during the study and received standard meals at 0800 h, 1200 h, and 1700 h and a 200-kcal snack at 2200 h. The total caloric content of meals was adjusted to 30 kcal/kg body weight with a nutrient composition of 15% protein, 55% carbohydrate, and 30% fat and a caloric division of 1/5, 2/5, and 2/5 for breakfast, lunch, and dinner, respectively. Subjects were allowed to sleep from 2300–0700 h. Serum LH concentrations were determined at 10-min intervals, and concentrations of FSH, sex hormone binding globulin (SHBG), and steroid hormones on 0800-h fasting samples. Serum insulin and plasma glucose levels were measured hourly and at 30 min after each meal. Each individual’s samples were analyzed in the same assay in duplicate. Pituitary responses to iv bolus GnRH (10 µg) were determined at 1800 h after completion of the 24-h study. Blood samples were obtained before (-20, -10, and 0 min) and after (10, 20, 30, 40, 60, 90, 120, 150, and 180 min) GnRH administration. Serum LH concentrations were determined on each sample.
Insulin sensitivity (SI) was assessed in a subset of 28 PCOS and 29 control subjects by a modified rapid iv glucose tolerance test (32). After an overnight fast of 10 h, an iv line was established in each forearm, and baseline samples were drawn at -10 and 0 min before administration of an iv bolus of glucose (0.3 g/kg 50% dextrose) over 1 min in the opposite arm. At 20 min after the glucose injection, an iv bolus of regular insulin (0.03 units/kg for women with a BMI <28 kg/m2 and 0.05 units/kg for those with a BMI >28 kg/m2) was injected over 20 sec, and the line immediately flushed with saline. Blood samples were then drawn at 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min. Plasma glucose and serum insulin concentrations were determined for each sample.
Data analysis
SI was analyzed by the MINMOD computer program (copyright RN Bergman) (32). LH pulsatile activity was analyzed using the Cluster pulse detection algorithm (33). A cluster configuration of 2 x 1 and t statistics of 2.1 x 2.1 were chosen to minimize false positive and false negative errors. Dose-dependent intrasample variance was assessed by employing a second-degree polynomial regression of SD as a function of hormone concentration. Pulse number/24-h, mean pulse amplitude (the difference in concentration between the preceding nadir and the pulse peak), and 24-h mean concentration were determined for each subject.
Assays
Serum LH and FSH concentrations were measured by RIA with intra- and interassay coefficients of variation (CVs), respectively, of 5.4% and 8.0% for LH and 3.0% and 4.6% for FSH. Serum insulin levels were measured by a double-antibody RIA with an assay sensitivity of 15 pmol/L, and intra- and interassay CVs of 7% and 9%, respectively. Plasma glucose concentrations were determined by the glucose oxidase method (Yellow Springs Instrument Co., Yellow Springs, OH) with an intraassay CV less than 2% and an interassay CV of 3%. SHBG was measured by a time-resolved immunofluorometric assay (Delfia SHBG kit; Wallac, Gaithersburg, MD) with intra- and interassay CVs of 7% and 9%, respectively. Serum concentrations of estrone (E1), estradiol (E2), A, T, and 17-OHP were measured by established RIAs with intraassay CVs less than 7%.
Statistical analyses
Non-Gaussian–distributed variables were log10 transformed to achieve normality. This applied to insulin sensitivity, 24-h mean insulin and LH levels, and 24-h mean LH pulse amplitude. Results for PCOS and NC women were compared by group t tests. Relationships between variables were sought by Pearson product-moment correlations and stepwise multivariate linear regression analysis with forward selection. When more than five correlations were performed, a protected P value of 0.01 was used to reduce false positive assignment of significance to no more than 1/100. Results are expressed as the mean ± SE. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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When compared with euandrogenic NC of similar age and BMI, PCOS
women displayed elevated (P < 0.0001) serum 17-OHP, A,
T, and E1 levels (Table 1
).
Serum concentrations of SHBG were decreased (P <
0.01), and the ratios of E1/SHBG, E2/SHBG, and
T/SHBG, reflecting nonprotein bound steroid levels, were increased
(P < 0.01) in PCOS women. PCOS women displayed 2-fold
elevations (P < 0.0001) of 24-h mean insulin levels,
increased 24-h mean glucose levels (P < 0.02), and a
50% reduction in SI (P < 0.01).
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Twenty four-hour LH pulse frequency was accelerated by 
40%
(P < 0.0001) in the PCOS group as compared with the NC
group (Table 2). This was accompanied by
an 80% elevation (P < 0.001) of 24-h mean LH pulse
amplitude and 2-fold higher (P < 0.0001) 24-h mean LH
levels. FSH levels for PCOS women did not differ from NC. Thus, the
augmentation of LH levels alone accounted for a 2.6-fold higher
(P < 0.001) LH/FSH ratio in the PCOS group. Pituitary
LH sensitivity was enhanced in PCOS women as evidenced by a 3-fold
greater peak increment (P < 0.0001) of LH in PCOS than
in NC women in response to GnRH (10 µg bolus) stimulation.
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The relationships of LH pulsatility features with BMI for PCOS and
NC women are shown in Fig. 1. Twenty
four-hour LH pulse frequency was uniformly elevated in PCOS as compared
with NC women independent of BMI, with minimal overlap between the two
groups. In contrast, mean LH pulse amplitude for PCOS but not NC women
was inversely dependent on BMI (r = -0.63, P <
0.001). At a BMI of 20 kg/m2, mean LH pulse amplitude was
elevated 2.5-fold in PCOS women. Thereafter, LH pulse amplitude
decreased with increasing BMI. This relationship was continuous until
BMI reached 40 kg/m2, when LH pulse amplitude for PCOS
women became indistinguishable from that of NC women.
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). Using a BMI
of 30 kg/m2 as a reference point, 24-h mean LH levels for
PCOS women with BMI 
30 kg/m2 overlapped with the 95%
confidence interval for NC women in only 5% (1/19) of cases, whereas
43% (6/14) of PCOS women with BMI >30 kg/m2 were within
the 95% confidence interval. The ability to discriminate PCOS from NC
women on the basis of LH measurements using single 0800-h values and
the mean of the two values at 0800 h and 0830 h was also
evaluated. As shown in Table 3, although
a single measurement of LH was not as effective as the 24-h mean in
distinguishing PCOS from NC women, the mean of two samples drawn at
30-min intervals had a discriminatory power equivalent to that of the
24-h mean.
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). FSH levels did not relate to BMI for
either PCOS or NC women, whereas the ratio of LH/FSH was negatively
correlated with BMI for PCOS women only (r = -0.44;
P = 0.02) (Fig. 3).
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Levels of 17-OHP for PCOS but not NC women were positively related to 24-h mean LH levels (r = 0.52, P = 0.006) and pulse amplitude (r = 0.52, P = 0.007), independent of BMI. Twenty four-hour mean LH levels, mean pulse amplitude, and pulse frequency were not related to serum concentrations of A, T, E1, E2 or the ratios of T/SHBG, E1/SHBG, or E2/SHBG for either PCOS or NC women.
Both 24-h mean LH levels and pulse amplitude for PCOS but not NC women
were related positively with SI (r = 0.49,
P = 0.009 and r = 0.52, P = 0.005,
respectively) and inversely with 24-h mean insulin levels (r =
-0.56, P = 0.001 and r = -0.52,
P = 0.003, respectively). Not unexpectedly, stepwise
regression analyses indicated these relationships were dependent on the
influence of BMI on both SI (r = -0.70,
P < 0.0001) and insulin levels (r = 0.80,
P < 0.0001) (Fig. 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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The blunting effect of BMI on LH pulse amplitude in PCOS women (r
= -0.63, P < 0.001) may explain the heterogeneity of
inappropriate gonadotropin secretion observed in previous studies
(19, 20, 21), in which the effect of BMI was not accounted for. The present
study showed that at a BMI of 20 kg/m2 mean LH pulse
amplitude was elevated 2.5-fold in PCOS women from that of NC women.
Thereafter, LH pulse amplitude decreased progressively and became
indistinguishable from that of NC women when BMI reached 40
kg/m2 (Fig. 1). This BMI-dependent blunting of LH pulse
amplitude in PCOS women was accompanied by a parallel attenuation of
pituitary LH sensitivity to GnRH stimulation (Fig. 2). These findings
suggest that factors associated with obesity exert an inhibitory effect
on endogenous GnRH action at the level of the pituitary and are
operative selectively in PCOS women, but not in normal cycling
women.
The link between adiposity and blunting of pituitary LH responses to GnRH in PCOS women is unknown. In this study, LH levels and pulse amplitude for PCOS women were inversely related to both 24-h insulin levels and the degree of insulin resistance, however these relationships were not independent of the strong influence of BMI based on regression analyses. It is recognized that multiple interdependent interactions may not be accurately dissected by regression analyses. Thus, a negative influence of hyperinsulinemia and insulin resistance on LH levels in PCOS women cannot be categorically excluded. However, LH levels in PCOS women were not altered during insulin infusion (35), after suppression of insulin levels by diazoxide (36), or lowering of insulin after weight-loss (37, 38). Moreover, most (39, 40, 41, 42), but not all (43), studies using metformin or troglitazone have shown reduced LH levels in conjunction with suppression of insulin levels in PCOS women, suggesting an enhancing influence of insulin on LH secretion. None of the cited studies identified an inverse relationship between insulin and LH levels. Thus, it is unlikely that insulin serves as a link between adiposity and blunting of LH pulse amplitude and pituitary LH responses to GnRH.
The increase (40%) in 24-h LH pulse frequency was relatively uniform
in PCOS women independent of BMI (Fig. 1). Because LH pulse frequency
in NC women was also not influenced by increasing BMI, these
observations suggest that factors associated with adiposity, including
leptin (31, 44, 45, 46), have no discernible effect on hypothalamic control
of GnRH pulse frequency. Thus, as previously proposed (3, 10, 11, 12, 13, 14), our
present data indicate that the accelerated GnRH pulse generator
represents a basic neuroendocrine aberration in PCOS women. Slowing of
LH pulse frequency with lowering of LH levels were found in PCOS women
when studies were performed following spontaneous ovulation, and in
response to exogenous progestin-induced withdrawal bleeding in PCOS
women (47, 48, 49). Under these circumstances, hypothalamic opioidergic
tone is increased by the feedback action of progesterone resulting in a
decreased frequency of the GnRH pulse generator, which can be reversed
by naloxone infusion (50, 51). Consequently, the endogenous
neuroendocrine milieu is desynchronized, and LH levels are reduced
contributing, in part, to the artifact of disparate reports of
inappropriate gonadotropin secretion in PCOS women (19, 20, 21).
Because 24-h mean LH levels for both PCOS and NC women are highly
dependent on the combined effects of pulse frequency and amplitude
(52), accelerated pulse frequency together with elevated LH pulse
amplitude resulted in 3-fold higher 24-h mean LH levels in PCOS women
with low BMI. The blunting of LH pulse amplitude with increasing BMI
resulted in a parallel decline in 24-h mean LH levels in PCOS women not
observed in NC women. In this study, 95% of PCOS women with BMI 30
kg/m2 had 24-h mean LH levels greater than the 95%
confidence interval for NC women, whereas LH levels failed to
discriminate PCOS from NC women in 43% of obese subjects (BMI >30
kg/m2) (Fig. 1). Of clinical significance, we found that
the mean of two LH values in samples collected at a 30-min interval,
but not a single determination, had a discriminatory power equal to
that of the 24-h mean LH value (53). FSH levels for PCOS women were not
influenced by BMI, thus the decline of LH/FSH ratio with increasing
adiposity (r = -0.44, P = 0.02) was expected
(Fig. 3). Taken together, these findings suggest that elevated LH
levels will not be consistently disclosed in PCOS women with BMI
greater than 30 kg/m2. However, we propose that
measurements of LH and FSH remain clinically meaningful if the negative
influence of BMI/adiposity is taken into account. Confirmation of our
findings by studying a larger number of subjects may generate a
specific reference point for BMI or adiposity to further define the
usefulness of LH levels and LH/FSH ratios as markers for PCOS
women.
We conclude that 1) BMI/adiposity negatively influences LH pulse amplitude in PCOS women principally by an effect at the pituitary level; 2) accelerated LH pulse frequency in PCOS women is not influenced by BMI and is a defining pathophysiology of hypothalamic dysfunction in PCOS women; and 3) BMI does not influence gonadotropin secretion in normal cycling women. Thus assessments of basal LH levels and the LH/FSH ratio in hyperandrogenic anovulatory women are clinically meaningful when BMI is taken into account. Investigations to define the factor(s) that link adiposity and the attenuation of LH pulse amplitude in PCOS women would add further understanding of this complex neuroendocrine-metabolic disorder.
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Addendum |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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Acknowledgments |
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Footnotes |
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2 Clayton Foundation investigator.
Received June 4, 1997.
Accepted August 1, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAddendumReferences |
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T. L. Bützow, M. Lehtovirta, R. Siegberg, O. Hovatta, R. Koistinen, M. Seppälä, and D. Apter The Decrease in Luteinizing Hormone Secretion in Response to Weight Reduction Is Inversely Related to the Severity of Insulin Resistance in Overweight Women J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3271 - 3275. [Abstract] [Full Text]
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G. A. Laughlin, E. Barrett-Connor, D. Kritz-Silverstein, and D. von Mühlen Hysterectomy, Oophorectomy, and Endogenous Sex Hormone Levels in Older Women: The Rancho Bernardo Study J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 645 - 651. [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.-M. Huber-Buchholz, D. G. P. Carey, and R. J. Norman Restoration of Reproductive Potential by Lifestyle Modification in Obese Polycystic Ovary Syndrome: Role of Insulin Sensitivity and Luteinizing Hormone J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1470 - 1474. [Abstract] [Full Text]
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A.M. Fulghesu, F. Cucinelli, V. Pavone, F. Murgia, M. Guido, A. Caruso, S. Mancuso, and A. Lanzone Changes in luteinizing hormone and insulin secretion in polycystic ovarian syndrome Hum. Reprod., March 1, 1999; 14(3): 611 - 617. [Abstract] [Full Text] [PDF]
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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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) women against LH pulse frequency (PCOS and NC:
P = NS), LH pulse amplitude (PCOS: r = -0.63;
P < 0.001; NC: P = NS), and
24-h mean LH levels (PCOS: r = -0.63; P <
0.001; NC: P = NS). Values for LH pulse amplitude
and 24-h mean are log10 transformed. Shaded
area represents 95% confidence interval for NC (frequency:
11–22 pulses/24 h; amplitude: 2.6–9.2 IU/L; 24-h mean: 6.1–18.2
IU/L).
