Embryo Quality May Be Associated With Serum Inhibin B Levels but Not With Serum or Follicular Fluid Levels of Other Components of the Activin-Follistatin-Inhibin Axis.

OBJECTIVE: We investigated the potential associations of embryo quality with serum and/or follicular fluid (FF) concentrations of the molecules of the activin-follistatin-inhibin (AFI) axis and antimüllerian hormone and aimed to identify molecules that could predict a positive assisted reproductive technology (ART) outcome. METHODS: In this cross-sectional study, we measured AFI hormone and antimüllerian hormone levels in the serum and FF of follicles (n = 101) obtained from healthy oocyte donors who underwent an assisted reproductive technology course (n = 32). After egg retrieval, embryos were characterized as good or bad quality according to the European Society of Human Reproduction and Embryology criteria. Women were divided into 3 groups (<50%; 50%-66.7%; and >66.7%) according to the percentage of good quality embryos obtained. RESULTS: There was no difference between good and bad quality embryos in any of the molecules measured in FF. Moreover, there was no difference in the parameters measured in the serum among women according to the percentage of good quality embryos (ie, suitable for transfer or freezing) except for inhibin B, which tended to increase along with a good quality embryo rate (55.6 ± 7.9 vs 95.3 ± 14.3 vs 113.9 ± 36.9; P = .045). CONCLUSIONS: Among the molecules of the AFI axis, only serum but not FF inhibin B levels were marginally associated with good quality embryo rates.

PCSK9 and ANGPTL3 levels correlate with hyperlipidemia in HIV-lipoatrophy, are regulated by fasting and are not affected by leptin administered in physiologic or pharmacologic doses.

BACKGROUND: Medications leveraging the leptin, PCSK9, ANGPTL3 and FABP4 pathways are being developed for the treatment of insulin resistance and/or lipid disorders. To evaluate whether these pathways are independent from each other, we assessed the levels of PCSK9, ANGPTL3 and FABP4, in normal subjects and subjects exhibiting HIV and highly active antiretroviral therapy (HAART) induced metabolic syndrome with lipoatrophy and hypoleptinemia. Studies were performed at baseline and during food deprivation for three days with either a placebo or leptin administration at physiological replacement doses to correct fasting induced acute hypoleptinemia and in pharmacological doses. METHODS: PCSK9, ANGPTL3, FABP4 levels and their correlations to lipoproteins-metabolites were assessed in randomized placebo controlled cross-over studies: a) in 15 normal-weight individuals undergoing three-day admissions in the fed state, in complete fasting with placebo and in complete fasting with leptin treatment in physiologic replacement doses (study 1), b) in 15 individuals day baseline in a fed and three fasting admissions for three days with leptin administered in physiologic, supraphysiologic and pharmacologic doses (study 2), c) in 7 hypoleptinemic men with HIV and HAART-induced lipoatrophy treated with leptin or placebo for two months in the context of a cross over randomized trial (study 3). RESULTS: Circulating ANGPTL3, PCSK9 and FABP4 were markedly elevated in HIV-lipoatrophy and not affected by leptin treatment. PCSK9 levels correlated with lipids and markers of lipid utilization and lipolysis. ANGPTL3 levels correlated with HDL particles and their lipid composition. FABP4 levels were negatively associated with HDL diameter (HDL-D) and composition. PCSK9 and ANGPTL3 levels decreased during food deprivation by ~65 % and 30 % respectively. Leptin administration at physiologic, supraphysiologic and pharmacologic doses did not affect PCSK9, ANGPTL3 and FABP4 levels. CONCLUSIONS: PCSK9, ANGPTL3 and FABP4 levels are associated with markers of lipid metabolism and are higher in HIV-lipoatrophy. PCSK9 and ANGPTL3 but not FABP4 decrease in response to food deprivation. PCSK9 and ANGPTL3 regulation is leptin-independent, suggesting independent pathways for lipid regulation. Thus, combining treatments of leptin with PCSK9 and/or ANGPTL3 inhibitors for metabolic diseases should have additive effects and merit further investigation. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov no. NCT00140231, NCT00140205, NCT00140244.

Circulating profile of Activin-Follistatin-Inhibin Axis in women with hypothalamic amenorrhea in response to leptin treatment.

BACKGROUND: Chronic energy deficiency observed in women that exercise strenuously affects reproductive function, often leading to hypothalamic amenorrhea (HA). In such conditions, hypoleptinemia and robust changes in the Activin-Follistatin-Inhibin Axis (AFI) are observed. Treatment with leptin restores menstruation in many (60% responders) but not all (40% non-responders) women, suggesting that leptin is not the only regulator of reproductive function related to energy balance. In this work, we aimed to identify differences in hormonal profiles between leptin responders and non-responders among women with HA, with particular focus on the AFI axis. METHODS: AFI axis and reproductive hormones (LH, FSH, Estradiol, ΑΜΗ) were measured in blood in: a) An open-label interventional study, b) a randomized placebo-controlled trial, both investigating responders versus non-responders/women with HA treated with leptin. RESULTS: Women with HA that responded to leptin treatment have higher circulating levels/peak values of Inhibin A, Estradiol (E2), higher LH/FSH ratio and a trend to lower AMH compared with non-responders. CONCLUSIONS: Components of the AFI axis are associated with improvement of reproductive function in women with HA treated with leptin. ΑΜΗ may serve as a marker of ovarian recovery under HA treatment.