Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features

Abstract

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...

Insulin Modulation of Luteinizing Hormone Secretion in Normal Female Volunteers and Lean Polycystic Ovary Syndrome Patients

“…Previous data have shown that peripheral insulin sensitivity can already be altered in lean PCOS patients [14]. The patients reported here, diagnosed on clinical grounds and selected to be nonobese, had a normal glucose metabolism even though their insulin sensitivity tended to be lower than that of controls.…”

“…Thus, the combined actions of luteinizing hormone (LH) and insulin could result in higher levels of circulating androgens, with ensuing abnormal feedback on the pituitary [11, 12]. Gonadotropin secretion in PCOS is also abnormal and has been characterized by an increased release of LH versus FSH, higher LH peak amplitudes and a faster LH pulse frequency compared to controls [13,14,15,16]. This faster frequency can be directly related to an abnormal hypothalamic stimulation, since LH pulses recorded in the periphery mirror the coordinate activation of gonadotropin-releasing hormone (GnRH) neurons.…”

“…The precise role of insulin in the pathophysiology of gonadotropin secretion in PCOS has been regularly questioned in the past, but two recent studies in PCOS patients disclosed no association between anomalies in LH secretion and the peripheral levels of insulin, or the degree of insulin resistance [21, 22]. However, obesity has been reported to affect the neuroendocrine regulations in PCOS [14, 23], and the patients reported in these two studies were obese whereas controls were in the overweight range[21, 22]. …”

THERAPY OF ENDOCRINE DISEASE: Treatment of hirsutism in the polycystic ovary syndrome

“…Obesity is also associated with increased testosterone levels in adolescent girls presenting with stigmata of PCOS (42). It is possible that the ability of obesity to worsen the androgen balance is related to the associated insulin resistance and hyperinsulinaemia, which may be directly responsible for an increased ovarian steroidogenesis (43,44,45). The impacts of obesity on the phenotype of PCOS are multiple and involve both the expression of hyperandrogenism and ovarian dysfunction.…”

“…In any case, all pharmacological treatments can have the same efficacy in all women, who should therefore be advised on the potential long-term treatment and on the potential combination of different drugs and/or cosmetic procedures. Unfortunately, almost all studies investigating the potential efficacy of drugs on hirsutism lasted for a maximum of 6-12 months, so it is unclear how long any systemic treatment should be prolonged (43). Nonetheless, it is very common in clinical practice to meet women who have been treated for many years or decades, without attending any structured follow-up.…”