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.

The present study tests the hypothesis that specific endocrine, metabolic, and anthropometric features distinguish obese women with polycystic ovary syndrome (PCOS) who resume ovulation in response to calorie restriction and weight loss from those who do not. Fifteen obese (body mass index 39 +/- 7 kg/m(2)) hyperandrogenemic oligoovulatory patients undertook a very low calorie diet (VLCD), wherein each lost > or =10% of body weight over a mean of 6.25 mo. Body fat distribution was quantitated by magnetic resonance imaging. Hormones were measured in the morning at baseline, after 1 wk of VLCD, and after 10% weight loss. To monitor LH release, blood was sampled for 24 h at 10-min intervals before intervention and after 7 days of VLCD. Responders were defined a priori as individuals exhibiting two or more ovulatory cycles in the course of intervention, as corroborated by serum progesterone concentrations > or =18 nmol/l followed by vaginal bleeding. At baseline, responders had a higher sex hormone-binding globulin (SHBG) concentration but were otherwise indistinguishable from nonresponders. Body weight, the size of body fat depots, and plasma insulin levels declined to a similar extent in responders and nonresponders. Also, SHBG increased, and the free testosterone index decreased comparably. However, responders exhibited a significant decline of circulating estradiol concentrations (from 191 +/- 82 to 158 +/- 77 pmol/l, means +/- SD, P = 0.037) and a concurrent increase in LH secretion (from 104 +/- 42 to 140 +/- 5 U.l(-1).day(-1), P = 0.006) in response to 7 days of VLCD, whereas neither parameter changed significantly in nonresponders. We infer that evidence of retention of estradiol-dependent negative feedback on LH secretion may forecast follicle maturation and ovulation in obese patients with PCOS under dietary restriction.

Neck circumference a good predictor of raised insulin and free androgen index in obese premenopausal women: changes with weight loss.

OBJECTIVE: Severe obesity can be associated with evidence of androgen excess and insulin resistance, which are features of the metabolic and polycystic ovary syndromes (PCOS). In this study, we examined the association between clinical and biochemical features of these syndromes and assess changes with weight loss. DESIGN: A consecutive series of 107 severely obese premenopausal women presenting for obesity surgery. MEASUREMENTS: Pre-operative assessment included details of clinical comorbidity, anthropometric measures and biochemical measures, including fasting insulin, glucose, lipid profile and sex hormone analysis. Changes in these measures for 42 of 52 (81%) patients at 1 year post surgery are reported. RESULTS: Neck circumference and younger age were independent predictors of higher free androgen index (FAI) (combined r2 = 0.36). If neck circumference is not included, then younger age, higher body mass index and raised fasting insulin levels were all independent predictors of FAI (r2 = 0.29). Waist to hip ratio showed no predictive value (r = 0.14). Neck circumference was also a good clinical predictor of menstrual irregularity, hirsutism, infertility, insulin resistance and the PCOS. Neck circumference of less than 39, 39-42 and greater than 42 cm reflect a low, intermediate and high risk of the metabolic and PCOS syndromes in obese premenopausal women. For 42 patients who were followed for 1 year after surgery, the weight loss was associated with reduction of FAI, less insulin resistance and improved menstrual regularity and resolution of the PCOS in 11 of 12 cases. CONCLUSIONS: Neck circumference is a good predictive measure of hyperinsulinaemia and raised androgens in obese premenopausal women. weight loss following surgery improves ovarian function and vasculopathic risk.

Effects of weight loss on QT interval in morbidly obese patients.

BACKGROUND: obesity causes structural changes to the heart that may influence its function. Furthermore, morbid obesity is associated with an acquired prolongation of the QTc interval that may lead to potentially hazardous arrhythmias. The present study investigated the effect of body weight loss following vertical banded gastroplasty (VBG) on the QTc interval. METHODS: 17 morbidly obese patients, scheduled for elective VBG, were studied before the operation and 8-10 months postoperatively, when each patient had achieved a weight loss of >/= 25% of the preoperative body weight. RESULTS: 15 patients achieved significant body weight loss of >/= 25% within the first 8-10 postoperative months (P <0.001).This weight loss, corresponding to an excess weight loss of 48.7% and a mean body mass index (BMI) reduction from 49.7 kg/m2 to 36.6 kg/m2, was followed by significant shortening of the QTc interval from 428 msec to 393 msec (P <0.001). CONCLUSIONS: The significant postoperative weight loss following VBG was accompanied by shortening of the QTc interval. This effect is expected to reduce the incidence of fatal conditions associated with the long QT syndrome, such as malignant ventricular arrhythmias and sudden death, and therefore improve morbidity and mortality.

Central administration of transforming growth factor-alpha and neuregulin-1 suppress active behaviors and cause weight loss in hamsters.

Transforming growth factor-alpha (TGF-alpha) is a candidate output signal of the hypothalamic circadian pacemaker. TGF-alpha is expressed in the suprachiasmatic nucleus (SCN) of rats, hamsters, and rhesus macaques [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5., X. Li, N. Sankrithi and F.C. Davis, Transforming growth factor-alpha is expressed in astrocytes of the suprachiasmatic nucleus in hamster: role of glial cells in circadian clocks, Neuroreport, 13 (2002) 2143-7., Y.J. Ma, M.E. Costa and S.R. Ojeda, Developmental expression of the genes encoding transforming growth factor alpha and its receptor in the hypothalamus of female rhesus macaques, Neuroendocrinology, 60 (1994) 346-59., Y.J. Ma, M.P. Junier, M.E. Costa and S.R. Ojeda, Transforming growth factor-alpha gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation, Neuron, 9 (1992) 657-70.]. TGF-alpha reversibly inhibits wheel-running activity during long-term infusions into the third ventricle of hamsters (2 weeks, intracerebroventricular or ICV) [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5.], and this effect appears to be mediated by the epidermal growth factor receptor (EGFR or ErbB-1) [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5.]. Here, we demonstrate that this inhibitory effect is not restricted to wheel-running behavior or to mediation by the EGFR. Using direct observation, we found the effects of long-term TGF-alpha infusion (ICV, 12 mul/day, 3.3 muM) to be more general than previously reported. Other active behaviors such as grooming and feeding were reversibly inhibited and hamsters showed dramatic weight loss as a result of reduced feeding (34% of body weight over 19 days). TGF-alpha did not disrupt a non-behavioral rhythm, the rhythm in pineal melatonin. Wheel-running activity was also inhibited by another epidermal growth factor-like (EGF-like) peptide, neuregulin (NRG-1), that binds to different ErbB receptors. Like TGF-alpha, NRG-1 caused a significant weight loss. We also show that an acute injection of TGF-alpha inhibits activity (ICV, 5 mul, 3.3 muM over 2 min), with inhibition and recovery occurring over a few hours. Although the results are consistent with the proposed [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5.] role for EGF-like peptides in the daily regulation of activity, the actions of these peptides might also contribute to the behavioral etiology of diseases in which EGF-like peptides are expressed.