Changes in plasma leptin during the menstrual cycle.

OBJECTIVE: To measure the plasma concentration of leptin, which is expressed in ovarian follicles and may have a reproductive function, in healthy women during the menstrual cycle. DESIGN: This study included nine women with regular menstrual cycles (mean+/-S.E.M. age 28+/-2 years: body mass index 23.9+/-1.8 kg/m2). From the onset of menses, fasting blood samples were collected every 1-2 days throughout the menstrual cycle. As a control, plasma leptin was measured in six postmenopausal women and six men every other day for 28 days. RESULTS: In menstruating women, plasma leptin increased from 14.9+/-2.9 ng/ml in the early follicular phase to 20.4+/-4.2 ng/ml (P<0.01) at the midluteal phase and returned to the baseline by the subsequent menses. In contrast, leptin concentrations did not change significantly in postmenopausal women or men. The changes in plasma leptin during the menstrual cycle were not related to changes in sex hormones. CONCLUSIONS: The cause of the increase in plasma leptin during the late follicular and luteal phases of the menstrual cycle is not clear. It may be attributed to augmented adipocyte production of leptin in response to increased caloric intake or hypothalamic release of neuropeptide Y. or to release of leptin from mature ovarian follicles. Leptin may have a role in regulating the menstrual cycle and preparing the body for the metabolic demands of pregnancy.

Physiological insulinemia acutely modulates plasma leptin.

Whether insulin acutely regulates plasma leptin in humans is controversial. We examined the dosage-response and time-course characteristics of the effect of insulin on leptin in 10 men (age 42+/-2 years [mean+/-SE]; BMI 29.3+/-2.0 kg/m2). Each individual underwent four 9-h euglycemic clamps (insulin at 20, 40, 80, and 400 mU x m[-2] x min[-1) and a control saline infusion. Although plasma glucose and insulin levels remained constant, leptin diminished from 9.1+/-3.0 to 5.9+/-2.1 ng/ml (P < 0.001) by the end of the control experiment. Conversely, plasma leptin showed a dosage-dependent increase during the insulin infusions that was evident within 30-60 min. The insulin-induced increase in leptin was proportionately lower in obese insulin-resistant men. Free fatty acids (FFAs) decreased during insulin and did not change during saline infusions. ED50 (the dose producing half-maximal effect) for insulin's effect on leptin and FFA was similar (138+/-36 vs. 102+/-24 pmol/l, respectively; P=0.11). To further define the role of physiological insulinemia, we compared the effect of a very low dosage insulin infusion (10 mU x m[-2] x min[-1]) with that of a control saline infusion in another group of 10 men (mean age 39+/-3 years; BMI 27.1+/-1.0 kg/m2). Plasma leptin remained stable during that insulin infusion, but fell by 37+/-2% in the control experiment. Thus physiological insulinemia can acutely regulate plasma leptin. Insulin could mediate the effect of caloric intake on leptin and could be a determinant of its plasma concentration. Inadequate insulin-induced leptin production in obese and insulin-resistant subjects may contribute to the development or worsening of obesity.

Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity.

Plasma leptin shows a nocturnal rise and a pulsatile pattern. This work was undertaken to determine the effects of gender and obesity on this pattern. Twenty-four-hour leptin profiles were evaluated in 31 subjects [17 male, 14 female; age: 36 +/- 2 yr (mean +/- SEM); body mass index: 27.5 +/- 1.0 kg/m2]. Plasma leptin profiles were higher in obese (body mass index > 27 kg/m2) than in lean subjects and higher in women than in men, regardless of fat mass. Leptin showed diurnal rhythmicity with peaks between 2200-0300 (median: 0120) and nadirs between 0800 and 1740 (median: 1033). Spectral analysis revealed 2 components (periodicities: 24 and 12 h) with higher relative amplitudes in lean than in obese subjects. The relative diurnal amplitude also was higher in men than in women, controlling for adiposity. Insulinemia, female sex, and age were negative determinants of diurnal rhythm relative amplitude. Pulse analysis revealed 3.6 +/- 0.3 pulses/24 h, occurring mostly 2-3 h after meals. Pulse frequency correlated negatively with fat mass and insulinemia (Spearman's r = -0.54 and -0.37, respectively; P < 0.05 for each). Thus, obesity is associated not only with higher leptin levels but also with blunted diurnal excursions and dampened pulsatility. This abnormal rhythmicity may contribute to leptin resistance in obesity. The significance of the sexual dimorphism in the diurnal amplitude is unclear, but it may be related to leptin's putative role as a metabolic signal to the reproductive axis.

The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women.

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, glucose intolerance, and obesity. High levels of the lipostatic hormone, leptin, have also been reported in this condition. The purpose of the present study was to examine the effect of an oral contraceptive (OC) of low androgenicity containing desogestrel on glucose tolerance in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on leptin concentrations. Sixteen nondiabetic hyperandrogenic women, aged 29 +/- 1 yr with a body mass index (BMI) of 36.8 +/- 1.8 kg/m2, underwent an oral glucose tolerance test before and after 6 months of therapy with the OC. Free testosterone decreased and sex hormone-binding globulin increased after therapy (P < 0.001). Glucose tolerance deteriorated significantly, and two women developed diabetes. Body weight, BMI, and leptin did not change significantly. Leptin correlated with BMI before (r = 0.56; P = 0.02) and after (r = 0.51; P = 0.04) treatment, but not with glucose, insulin, total and free testosterone, or sex hormone-binding globulin before or after treatment. In conclusion, 1) glucose tolerance should be monitored in hyperandrogenic women using OC, even those of low androgenicity; and 2) changes in androgenic/estrogenic status had no effect on the leptin concentration, suggesting that its sexual dimorphism is not related to sex steroids.

PIP: Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, and glucose intolerance--all of which, in turn, have been linked to high levels of the lipostatic hormone, leptin. This study investigated the effect of an oral contraceptive (OC) containing a progestin of low androgenicity on glucose tolerance and insulinemia in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on plasma leptin levels. 16 nondiabetic hyperandrogenic US women (mean age, 29 years) with a mean body mass index of 36.8 kg/sq. m underwent oral glucose tolerance testing before and after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Treatment was associated with significant decreases in free testosterone and increased sex hormone-binding globulin (p 0.001). Glucose tolerance deteriorated moderately but significantly. After 6 months of treatment, 5 women had normal glucose tolerance, 9 had impaired glucose tolerance, and 2 developed non-insulin-dependent diabetes mellitus. There were no significant changes in serum insulin concentrations, body weight, body mass index, or leptin, but leptin levels were highly correlated with body mass index both before and after treatment. The data suggest that the sexual dimorphism of leptin is not caused by differences in sex hormones. Even when OCs containing low androgenic progestins are prescribed, women at high risk for diabetes should receive regular glucose tolerance tests.

Sexual dimorphism in plasma leptin concentration.

Leptin, the obese (ob) gene product, is thought to be a lipostatic hormone that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure. The determinants of plasma leptin concentration were evaluated in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8-79.6 ng/mL (geometric mean, 12.4), were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women had still higher leptin levels than men of similar age, and their levels were not different from those in younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Thus, our data indicate that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. Leptin's sexual dimorphism suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function.