Luteinizing hormone (LH) and chorionic gonadotropin (CG) are glycoproteins fundamental for sexual development and reproduction. Since they act on the same receptor (LHCGR), there is a general consensus that LH and hCG are equivalent. However, separate evolution of LHβ and hCGβ subunits occurred in primates, resulting in two molecules sharing ∼85% identity and regulating different physiological events. Pituitary, pulsatile LH production results in a ∼90 min half-life molecule targeting the gonads, to regulate gametogenesis and androgen synthesis. Trophoblast hCG, the “pregnancy hormone”, exists in several isoforms and glycosylation variants with long half-lives (hours), angiogenic potential, and acts on luteinized ovarian cells as a progestational. The different molecular features of LH and hCG lead to hormone-specific LHCGR binding and intracellular signaling cascades. In ovarian cells, LH action is preferentially exerted through kinases, pERK1/2 and pAKT, resulting in irreplaceable proliferative/anti-apoptotic signals and partial agonism on progesterone production in vitro. In contrast, hCG displays notable cAMP/PKA-mediated steroidogenic and pro-apoptotic potential, which is masked by estrogen action in vivo. In vitro data are confirmed by large dataset from assisted reproduction, since the steroidogenic potential of hCG positively impacts on the number of retrieved oocytes, while LH impacts pregnancy rate (per oocyte number). Interestingly, Leydig cell in vitro exposure to hCG results in qualitatively similar cAMP/PKA and pERK1/2 activation as compared to LH, as well as testosterone. The supposed equivalence of LH and hCG is debunked by such data highlighting their sex-specific functions, thus deeming it an oversight caused by incomplete understanding of clinical data.

Background: Human reproduction is regulated by the combined action of the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH) on the gonads. Although FSH is largely used in female reproduction, in particular in women attending assisted reproductive techniques to stimulate multi-follicular growth, its efficacy in men with idiopathic infertility is not clearly demonstrated. Indeed, whether FSH administration improves fertility in patients with hypogonadotropic hypogonadism, the therapeutic benefit in men presenting alterations in sperm production despite normal FSH serum levels is still unclear. In the present review, we evaluate the potential pharmacological benefits of FSH administration in clinical practice. Methods: This is a narrative review, describing the FSH physiological role in spermatogenesis and its potential therapeutic action in men. Results: The FSH role on male fertility is reviewed starting from the physiological control of spermatogenesis, throughout its mechanism of action in Sertoli cells, the genetic regulation of its action on spermatogenesis, until the therapeutic options available to improve sperm production. Conclusion: FSH administration in infertile men has potential benefits, although its action should be considered by evaluating its synergic action with testosterone, and well-controlled, powerful trials are required. Prospective studies and new compounds could be developed in the near future.

Testosterone (T) deficiency remains a poorly understood issue in men with Human Immunodeficiency Virus (HIV). We investigated the gonadal status in HIV-infected men in order to characterize T deficiency and to identify predictive factors for low serum T. We performed a cross-sectional, observational study on 1325 consecutive HIV male outpatients, most of them having lipodystrophy. Serum total T<300 ng/dL was used as the threshold for biochemical T deficiency. Morning serum total T, luteinizing hormone (LH), estradiol, HIV parameters, and body composition parameters by CT-scan and Dual-Energy-X-ray-Absorptiometry were measured in each case. Sexual behavior was evaluated in a subset of 247 patients. T deficiency was found in 212 subjects, especially in the age range 40–59, but was frequent even in younger patients. T deficiency occurred mainly in association with low/normal serum LH. Adiposity was higher in subjects with T deficiency (p<0.0001) and both visceral adipose tissue and body mass index were the main negative predictors of serum total T. Osteoporosis and erectile dysfunction were present in a similar percentage in men with or without T deficiency. Premature decline of serum T is common (16%) among young/middle-aged HIV-infected men and is associated with inappropriately low/normal LH and increased visceral fat. T deficiency occurs at a young age and may be considered an element of the process of premature or accelerated aging known to be associated with HIV infection. The role of HIV and/or HIV infection treatments, as well as the role of the general health state on the gonadal axis, remains, in fact, to be elucidated. Due to the low specificity of signs and symptoms of hypogonadism in the context of HIV, caution is needed in the diagnosis of hypogonadism in HIV-infected men with biochemical low serum T levels.

Polycystic ovary syndrome (PCOS) is a common female endocrine disorder characterized by phenotypes ranging from hyperandrogenism to metabolic disorders, more prevalent in people of African/Caucasian and Asian ancestry. Because PCOS impairs fertility without diminishing in prevalence, it was considered an evolutionary paradox. Genome-Wide Association Studies identified 17 single nucleotide polymorphisms (SNPs) associated with PCOS, with different allele frequencies, ethnicity-related, in 11 susceptibility loci. In this study we analyze the PCOS phenotype-genotype relationship in silico, using SNPs of representative genes for analysis of genetic clustering and distance, to evaluate the degree of genetic similarity. 1000 Genomes, HapMap, and Human Genome Diversity Project databases were used as source of allele frequencies of the SNPs, using data from male and female individuals grouped according to their geographical ancestry. Genetic clustering was calculated from SNPs data by Bayesian inference. The inferred ancestry of individuals was matched with PCOS phenotype data, extracted from a previous meta-analysis. The measure of genetic distance was plotted against the geographic distance between the populations. The individuals were assigned to five genetic clusters, matching with different world regions (Kruskal-Wallis/Dunn's post test; P < .0001), and converging in two main PCOS phenotypes in different degrees of affinity. The overall genetic distance increased with the geographic distance among the populations (linear regression; R(2) = 0.21; P < .0001), in a phenotype-unrelated manner. Phenotype-genotype correlations were demonstrated, suggesting that PCOS genetic gradient results from genetic drift due to a serial founder effect occurred during ancient human migrations. The overall prevalence of the disease supports intralocus sexual conflict as alternative to the natural selection of phenotypic traits in females.

Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.

Purpose: The relationship between probiotics and levothyroxine (LT₄) requirement has not yet been investigated. The aim of this study was to assess whether a mixture of highly charged Lactobacilli and Bifidobacteria (VSL#3^®) is able to influence LT₄ metabolism acting on the gut microbiota. Methods: A prospective, randomized, single-blind, controlled, investigator-started clinical trial was carried out. Patients with primary hypothyroidism were randomly assigned to the study (VSL#3^® + LT₄) and the control group (LT₄). A 2-month treatment phase was followed by 2 months of follow-up. Clinical examination, blood tests for thyroid function and for peripheral tissue markers of thyroid hormones (PTM) were performed monthly. LT₄ dose adjustments were performed when necessary. Results: Thirty-nine patients were enrolled in the study group and 41 in the control group. No difference in thyroid function [thyroid-stimulating hormone (TSH), free triiodothyronine (fT₃), and free thyroxine (fT₄)] and PTM was found between groups and among visits. FT₃/fT₄ ratio was directly correlated to TSH at each visit in both groups, with the exception of the first evaluation of probiotics-treated subjects (rho = 0.287, p = 0.076). LT₄ daily dose adjustments occurred more frequently in the control than in the study group (p = 0.007), despite no differences in the mean LT₄ daily dose. In particular, LT₄ doses were increased six times in the control group and decreased four times in the study group. Conclusion: VSL#3^® does not directly alter thyroid functional compensation. A probiotics-mediated influence on thyroid hormones homeostasis is suggested since probiotics supplementation could be able to prevent serum hormonal fluctuations. ClinicalTrials.gov ID: Registration number NCT03095963.