The basic tenet of this investigation was that obesity is not a prerequisite in the development of polycystic ovary syndrome (PCOS), as indicated by the fact that 50% of PCOS women are not obese. Further, obesity itself is a disease entity with the common manifestation of insulin resistance/hyperinsulinemia with PCOS. Given recent evidence that insulin and GH may have gonadotropin-augmenting effects, we have determined the common and distinguishing features of neuroendocrine-metabolic dysfunctions of lean [body mass index (BMI), < 23 kg/m2] and obese (BMI, > 30 kg/m2) women with the classical form of PCOS. Insulin sensitivity, as determined by rapid i.v. glucose tolerance testing; 24-h dynamics of insulin/glucose levels, somatotropic [GH/GH-binding protein/insulin-like growth factor I (IGF-I)/IGF-binding proteins (IGFBP)], and LH axes; and their downstream effects on ovarian steroids were simultaneously assessed in eight lean PCOS and eight obese PCOS patients and an equal number of BMI-matched normal cycling controls. Our results show that insulin sensitivity was reduced 50% (P < 0.01) in lean PCOS from that in lean controls. There was a further decrease in obese controls (P < 0.01) and a 2-fold greater reduction (P < 0.001) in obese PCOS than in obese controls, suggesting that insulin resistance (IR) is a common lesion in PCOS, and that obesity contributes an additional component to IR in obese PCOS. Consistent with the degree of IR, the manifestation of compensatory hyperinsulinemia in lean PCOS was incipient, being evident only in response to meals (P < 0.05), and became overt during the 24-h fasting/feeding phases of the day in obese control (P < 0.001) with a 2- to 3-fold greater elevation (P < 0.001) in obese PCOS. An enhanced early insulin response to glucose occurs equally in obese control (P < 0.01) and obese PCOS (P < 0.05), but not in their lean counterparts. Considering the more profound IR and the associated hyperglycemia in obese PCOS, the magnitude of the early insulin release is inadequate, suggesting that beta-cell dysfunction exists in obese PCOS. Remarkable differences in the somatotropic axis were also observed; although 24-h GH pulse frequency and levels of IGF-I and IGFBP-3 were unaltered by either PCOS or obesity, the 24-h mean GH pulse amplitude was increased by 30% (P < 0.01) in lean PCOS in the presence of normal levels of high affinity GHBP and normal GH response to GHRH. In distinct contrast, the somatotropic axis in both obese control and obese PCOS was profoundly modified, with attenuation of GH pulse amplitude (P < 0.001) and GH response to GHRH (P < 0.001), resulting in a state of hyposomatotropinism with a more than 50% reduction (P < 0.001) of 24-h mean GH levels. In addition, GHBP levels were elevated 2-fold and were correlated inversely with GH (r = -0.81) and positively with insulin (r = 0.75) concentrations. IGFBP-I levels were suppressed in both obese groups, with a 4-fold greater reduction in obese PCOS than that in obese controls. Thus, the downstream effects of hyperinsu...

A study was initiated to delineate the neuroendocrine characteristics of hyperandrogenic adolescent girls with the aim of discerning features that may relate to the pubertal onset of the polycystic ovarian syndrome. Thirteen 11- to 18-yr-old girls with mild to moderate signs of hyperandrogenism (HA) and increased ovarian volume and 28 age-matched normal girls were recruited for the study. LH pulsatility and FSH levels were analyzed based on serum concentrations measured with sensitive immunofluorometric assays in samples taken at 10-min intervals for 24 h under basal conditions, GnRH antagonist (Nal-Glu) suppression, and dexamethasone suppression. Adrenal and ovarian contributions to serum cortisol, dehydroepiandrosterone, androstenedione, testosterone (T), estrone (E1), estradiol (hourly), 17-hydroxypregnenolone, and 17-hydroxyprogesterone (17PO) concentrations were compared during basal and suppression conditions and after gonadotropin and adrenal stimulations by bolus GnRH (10 micrograms) and CRF (1 microgram/kg). The progression from sleep-augmented pulsatile LH secretion to higher LH levels during wake than sleep observed during normal pubertal development occurred 2 yr earlier in the HA group. The number of LH pulses was significantly higher in the HA group during both sleep and waking, whereas pulse amplitude was higher only during the awake time. Thus, mean LH was 2.0-fold higher during the awake time and only 1.6-fold higher during sleep in the HA group compared to the normal group. The elevation of FSH in HA was small relative to that of LH, resulting in an increased LH/FSH ratio (P < 0.008). The HA group had higher concentrations of 17PO (1.8-fold), androstenedione (1.9-fold), T (2.4-fold), and E1 (1.7-fold) than the normal group (all P < 0.001), with no alteration in circadian rhythm. These elevated steroid levels were significantly correlated with LH levels in the basal state and decreased in proportion to the change in LH during Nal-Glu suppression. During adrenal suppression with dexamethasone, concentrations of cortisol, dehydroepiandrosterone, and 17-hydroxypregnenolone decreased in both groups (P < 0.001), but significant suppression of 17PO, T, and E1 occurred only in the normal girls, indicating the ovarian origin of the increased levels of these steroids with enhanced expression of 17 alpha-hydroxylase activity in HA girls.(ABSTRACT TRUNCATED AT 400 WORDS)

Recently, we reported that hyperandrogenism in adolescent girls is accompanied by augmented LH pulsatility and elevated LH/FSH ratio with increased ovarian volume. Together with higher concentrations of 17-hydroxyprogesterone, androstenedione, testosterone, and estrone that are ovarian in origin, these neuroendocrine features are identical to those seen in adult women with polycystic ovary syndrome. In the present study, we report the metabolic characteristics of these hyperandrogenic adolescent girls. The GH insulin-like growth factor I (IGF-I)-binding protein (BP)-3 axis, insulin sensitivity, and insulin-IGFBP-1/insulin sex hormone binding globulin axes were evaluated in 13 adolescent girls (ages 11-18 yr) with mild to moderate signs of hyperandrogenism (HA) and 28 age-matched normal girls. Insulin sensitivity was assessed by a frequent-sample iv glucose tolerance test (ivGTT, 0.3 g/kg). Twenty-four hour blood samples were obtained at 10-min intervals and were used to determine GH pulsatility (20-min samples), IGFBP-3 levels (0800-0900 h), and fluctuations of insulin, IGFBP-1, and IGF-I (hourly samples) during feeding and fasting phases of the day. In addition, GH responses to GHRH stimulation (1 microgram/kg) were assessed. Fasting insulin concentrations, but not plasma glucose levels, were significantly elevated in the HA group compared with those in the normal group (256 +/- 35 vs. 103 +/- 24 pmol/L, P = 0.0008), as were insulin responses to ivGTT and meals (P < 0.01) and 24-h mean insulin concentrations (P < 0.01). Thus, hyperinsulinemia with normal fasting glucose levels in HA girls may reflect insulin resistance, as suggested by the increased ratio of insulin and glucose (P < 0.001). All measures of insulin were correlated with body mass index (BMI); however, insulin remained significantly higher in the HA group after correcting for BMI, suggesting that decreased insulin sensitivity was related to other factors in addition to BMI. Twenty-four hour IGFBP-1 concentrations showed a diurnal pattern with an inverse relationship to insulin, and 24-h mean concentrations were lower in the HA group (0.35 +/- 0.13 vs. 0.76 +/- 0.09 micrograms/L, P = 0.02). Reduced sex hormone binding globulin levels were also inversely related to insulin levels (P = 0.0007). In contrast, GH pulsatile characteristics and IGF-I/IGFBP-3 levels, as well as GH responses to GHRH, were similar between the groups.(ABSTRACT TRUNCATED AT 400 WORDS)

To delineate the activity of the GnRH pulse generator during pubertal transition, 40 healthy girls 7-18 yr of age were studied. Ten were prepubertal (PP), 7 were in early puberty (EP), and 23 were in late puberty (LP, all postmenarcheal). Serum concentrations of LH and FSH were measured with immunofluorometric assays, which have a sensitivity about 100-fold that of RIA, in samples taken at 10-min intervals for 24 h during basal conditions, during Nal-Glu antagonist suppression, and in response to GnRH stimulation (10 micrograms). Serum levels of androstenedione, testosterone, and estradiol were measured with RIA. A pulsatile pattern of LH and FSH secretion was found in girls of all ages. PP girls had irregular LH pulses with low amplitudes during the daytime, but increased amplitude LH and FSH pulses were evident within 1 h after sleep-onset. Older PP girls had more regular and higher amplitude pulses throughout sleep than younger PP girls. The sleep-related LH and FSH pulses in PP girls were abolished with Nal-Glu GnRH antagonist treatment, reflecting endogenous GnRH pulse activities. The PP group had the most pronounced amplification of LH secretion with sleep yielding a sleep-wake ratio of 4, which decreased to 2 in the EP group and to 1 in the LP group. The emergence of regular daytime LH pulses along with a further amplification of pulsatile activity during sleep was closely related to the onset of breast development. By the age of 16 yr, an LH secretory pattern characteristic of adult women in the early follicular phase, i.e. a decrease in LH concentration during sleep, was established. Mean 24-h LH concentrations increased 40-fold from PP to LP consequent to a 9-fold increase in pulse amplitude and a 4-fold increase in pulse number (both P < 0.0001). Mean FSH concentrations (24 h), which were 20-fold higher than corresponding LH concentrations in the PP group, increased only 3-fold from the PP to the LP group. FSH pulse secretion appears to be predominantly GnRH dependent in PP girls in contrast to girls after ovarian activation, as indicated by the increased FSH responses to both GnRH antagonist suppression and GnRH stimulation in the PP as compared to the EP and LP groups. We conclude that the GnRH pulse generator is functionally active in prepubertal girls with selective expression of LH and FSH pulses after the onset of sleep. The onset of puberty is associated with a greater increase in LH pulse amplitude than frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

The satiety factor leptin is expressed in several reproductive tissues, but its role in the control of reproductive physiology is not well understood. We studied leptin concentrations in the sera and follicle fluids of 52 women [body fat mass percentage (BFM%) range, 19.6 -38.8%] undergoing pituitary down-regulation and ovarian hyperstimulation for in vitro fertilization (IVF) treatment. Fasting serum samples were collected 1) at maximal suppression before the initiation of gonadotropin treatment, 2) at maximal ovarian hyperstimulation, 3) at the time of oocyte retrieval, and 4) 16 days later when all subjects were under exogenous luteal support using 600 mg progesterone daily. Follicular fluid (FF) was obtained at oocyte retrieval from two representative preovulatory follicles in both ovaries. During ovarian hyperstimulation there was a significant 60% increase in serum leptin concentrations from 10.9 Ϯ 1.1 (SEM) to 15.7 Ϯ 1.5 ng/mL (P Ͻ 0.01) between suppression and maximal hyperstimulation, demonstrating that the ovarian functional state can affect serum leptin concentrations. A serum leptin increase of 22-198% during ovarian hyperstimulation was evident in 43 subjects, whereas in 9, leptin concentrations remained unchanged. A positive correlation between leptin change and BFM% (r ϭ 0.55; P Ͻ 0.0005) was observed in the 43 leptin responders. The follicular fluid leptin level was similar to that in serum. In separate linear regression analysis, BFM% contributed to 59 -64%, body mass index to 46 -56%, and weight to 46 -55% (all P Ͻ 0.001) of the variability in leptin concentrations at the 4 time points. The 20-fold increase in serum estradiol concentrations during IVF was not significantly correlated with changes in leptin concentrations. On the contrary, the relative serum leptin increase was negatively associated with the ovarian response to hyperstimulation, as revealed by the numbers of follicles (b ϭ Ϫ0.28; r 2 ϭ 8.1%; P Ͻ 0.05) and oocytes retrieved (b ϭ Ϫ0.39; r 2 ϭ 15.2%; P Ͻ 0.01). This relationship was further reflected in a positive correlation between the percent increases in leptin and FSH concentrations (r ϭ 0.39; P Ͻ 0.01). The significant relationship of high leptin and reduced ovarian response was also maintained when the cumulative dose of FSH was used as a covariable. Reduced ovarian response was not a function of body mass index, BFM%, basal leptin levels, or insulin concentrations. Fasting serum insulin concentrations remained unchanged in response to IVF, but were positively correlated to serum leptin concentrations at all four time points.Our data suggest that leptin production may be influenced by the ovarian functional state. During IVF a high relative leptin increase is associated with adiposity and a reduced ovarian response. These observations support the possibility that high leptin concentrations might reduce ovarian responsiveness to gonadotropins. Hence, leptin might explain in part why obese individuals require higher amounts of gonadotropins than lean subjects to achiev...