Objective
To determine the effect of lipid/heparin versus saline infusion, with or without concurrent euglycemic hyperinsulinemia on serum FSH and LH. Obesity is associated with hyperlipidemia, insulin resistance, and relative hypogonadotropic hypogonadism. We hypothesized that acutely elevated fatty acids and insulin would impair gonadotropin secretion.
Methods
Regularly cycling women and men who were non-obese underwent a crossover 6-hour infusion study over 4 visits. Participants received infusions of: saline-control, lipid/heparin, insulin and lipid/heparin plus insulin. Serum FSH and LH were measured by immunoassay.
Results
In women (n=10), infusion of lipid plus insulin significantly reduced LH, from 4.6 (3.7-5.4) [mean (95% confidence interval)] to 3.3 (2.3-4.4); p=0.03 and FSH from 3.9 (3.2-4.6) to 3.1, (2.3-3.8) IU/L; p=0.03 compared to saline-control. Similarly, in men (n=10), LH, 3.3 (2.4-4.1) IU/L and FSH, 2.1 (1.4-2.8) IU/L were significantly reduced after the combined infusion, (2.2 (1.3-3.1) IU/L and 1.5 (0.8-2.1) IU/L; p=0.03, p=0.02, respectively). Neither lipid nor insulin alone significantly impacted gonadotropin levels compared to saline-control.
Conclusions
Hyperinsulinemia combined with elevated lipids acutely suppresses LH and FSH, providing a possible mechanism underlying the relative hypogonadotropic hypogonadism of obesity. Effects of insulin on the hypothalamic-pituitary-gonadal axis may be dependent on the concomitant metabolic environment.
E2 priming seems to improve hypothalamic-pituitary-ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility.
Background
A high-throughput, sensitive, specific, mass spectrometry-based method for quantitating estrone (E1), estradiol (E2), and testosterone (T) in postmenopausal human serum has been developed for clinical research. The method consumes 100 ul human serum for each measurement (triplicates consume 300 ul) and does not require derivatization. We adapted a commercially available 96-well plate for sample preparation, extraction, and introduction into the mass spectrometer on a single platform.
Methods
Steroid extraction from serum samples and mass spectrometer operational parameters were optimized for analysis of estradiol and subsequently applied to other analytes. In addition to determining the limit of detection (LOD) and limit of quantitation (LOQ) from standard curves, a serum LOQ (sLOQ) was determined by addition of known steroid quantities to serum samples. Mass spectrometric method quantitative data were compared to results using a state-of-the-art ELISA (enzyme-linked immunosorbent assay) using stored serum samples from menopausal women.
Results
The LOD, LOQ, sLOQ was (0.1 pg, 0.3 pg, 1 pg/ml) for estrone, (0.3 pg, 1 pg, 3 pg/ml) for estradiol, and (0.3 pg, 1 pg, 30pg/ml) for testosterone, respectively. Mass spectrometry accurately determined concentrations of E2 that could not be quantified by immunochemical methods. E1 concentrations measured by mass spectrometry were in all cases significantly lower than the ELISA measurements, suggesting immunoreactive contaminants in serum may interfere with ELISA. The testosterone measurements broadly agreed with each other in that both techniques could differentiate between low, medium and high serum levels.
Conclusions
We have developed and validated a scalable, sensitive assay for trace quantitation of E1, E2 and T in human serum samples in a single assay using sample preparation method and stable isotope dilution mass spectrometry.
Dietary administration with omega-3 PUFA decreased serum FSH levels in NW but not in obese women with normal ovarian reserve. This effect is intriguing and is directionally consistent with murine data whereby higher dietary omega-3 PUFA extends reproductive lifespan. Our results imply that this nutritional intervention should be tested in women with diminished ovarian reserve in an attempt to delay ovarian aging.
A brief, low-dose estrogen intervention, combined with a LNG-IUS, led to significant improvement of some common perimenopausal symptoms. Such a "minimalist" approach to management of the perimenopause holds promise for reducing common, bothersome perimenopausal symptoms while maintaining effective contraception.
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