INSULIN, SOMATOTROPIC, AND LUTEINIZING-HORMONE AXES IN LEAN AND OBESEWOMEN WITH POLYCYSTIC-OVARY-SYNDROME - COMMON AND DISTINCT FEATURES

The basic tenet of this investigation was that obesity is not a prereq uisite in the development of polycystic ovary syndrome (PCOS), as indi cated by the fact that 50% of PCOS women are not obese. Further, obesi ty itself is a disease entity with the common manifestation of insulin resistance/hyperinsulinemia with PCOS. Given recent evidence that ins ulin and GR may have gonadotropin-augmenting effects, We have determin ed the common and distinguishing features of neuroendocrine-metabolic dysfunctions of lean [body mass index (BMI), < 23 kg/m(2)] and obese ( BMI, > 30 kg/m(2)) women with the classical form of PCOS. Insulin sens itivity, as determined by rapid iv glucose tolerance testing; 24-h dyn amics of insulin/glucose levels, somatotropic [GH/GH-binding protein/i nsulin-like growth factor I (IGF-I/IGF-binding proteins (IGFBP)], and LH axes; and their downstream effects on ovarian steroids were simulta neously assessed in eight lean PCOS and eight obese PCOS patients and an equal number of BMI-matched normal cycling controls. Our results sh ow that insulin sensitivity was reduced 50% (P < 0.01) in lean PCOS fr om that in lean controls. There was a further decrease in obese contro ls (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 comp onent to IR in obese PCOS. Consistent with the degree of IR, the manif estation of compensatory hyperinsulinemia in lean PCOS was incipient, being evident only in response to meals (P < 0.05), and became overt d uring 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 PCO S, An enhanced early insulin response to glucose occurs equally in obe se control (P < 0.01) and obese PCOS (P < 0.05), but not in their lean counterparts. Considering the more profound IR and the associated hyp erglycemia in obese PCOS, the magnitude of the early insulin release i s inadequate, suggesting that beta-cell dysfunction exists in obese PC OS. Remarkable differences in the somatotropic axis were also observed ; although 24-h GH pulse frequency and levels of IGF-I and IGFBP-3 wer e unaltered by either PCOS or obesity, the 24-h mean GH pulse amplitud e was increased bg 30% (P < 0.01) in lean PCOS in the presence of norm al levels of high affinity GHBP and normal GH response to GHRH. Tn dis tinct 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 o f 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 w ere correlated inversely with GH (r = -0.81) and positively with insul in (r = 0.75) concentrations. IGFBP-1 levels were suppressed in both o bese groups, with a 4-fold greater reduction in obese PCOS than that i n obese controls. Thus, the downstream effects of hyperinsulinemia on the somatotropic axis may include up-regulation of hepatic production of GHBP, suppression of IGFBP-1 (r = 0.82) and sex hormone-binding glo bulin (r = -0.69) levels, and a more than a-fold increase in ratios of IGF-I/IGFBP-1 and estradiol-testosterone/sex hormone-binding globulin , thereby increasing their bioavailabilities. In contrast, LH pulsatil ity was unaffected by obesity alone. An accelerated LR pulse frequency was evident in both lean and obese PCOS (P < 0.001), whereas the mean 24-h LH pulse amplitude was increased in lean (P < 0.001), but not ob ese, PCOS patients. These events resulted in a 3-fold increase in 24-h mean LH levels in lean PCOS and a 2-fold increase in obese PCOS. Thus , increased LH pulse frequency and augmented LH response to GnRH are c haracteristic of PCOS, independent of obesity, and the presence of obe sity in PCOS is associated with an attenuated LH pulse amplitude, not accounted for by obesity per se, Positive relationships were identifie d for serum levels of 17-hydroxyprogesterone, androgens, and estrogens with insulin and the ratio of IGF-I/IGFBP-1 for the obese groups, GH pulse amplitude for the lean groups, and LH for both lean and obese gr oups. In conclusion, the results of this study are consistent with our basic tenet that the neuroendocrine-metabolic dysregulation in PCOS i n the absence of the confounding influence of obesity may be viewed as the pathophysiology underlying the ''authentic syndrome'' and that ob esity constitutes a modifier of the syndrome. Although IR and LH hyper pulsatility are common features of PCOS, the coupling of enhanced GH p ulsatility in lean PCOS and of hyperinsulinemia and insulin-mediated i ncreased bioavailability of IGFs in obese PCOS as cogonadotropins may contribute to the genesis and maintenance of hyperandrogenic chronic a novulation and polycystic ovarian morphology.