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Insulin‐like peptide 3 (INSL3) is a peptide biomarker secreted specifically by the mature Leydig cells of the testes. It is constitutive, has low within‐individual variance, and effectively measures the functional capacity of Leydig cells to make testosterone. In young adult men there is a large 10‐fold range of serum INSL3 concentration, persisting into old age, and implying that later hypogonadal status might be programmed in early life. To determine whether maternal exposure to environmental endocrine disrupting compounds (EDCs) influences adult serum INSL3 concentration, using a retrospective paradigm, INSL3 was measured in young adult male rats (80–90 days) from the F1 generation of females maternally exposed to varied doses of bisphenol A (BPA), butylparaben, epoxiconazole, and fludioxonil as single compounds, as well as estrogenic and anti‐androgenic mixtures of BPA and butylparaben, and di(2‐ethylhexyl) phthalate and procymidone respectively. A mixture of BPA and butylparaben significantly reduced circulating INSL3 concentration in adult male progeny. The remaining compounds or mixtures tested, though sufficient to induce other effects in the F1 generation were without significant effect. Maternal exposure to low concentrations of some EDCs may be a contributing factor to the variation in the Leydig cell biomarker INSL3 in young adulthood, though caution is warranted translating results from rats to humans. [ABSTRACT FROM AUTHOR]

Background: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell‐produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin‐like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes. Objectives: To characterize insulin‐like peptide 3 as a biomarker to assess gonadal status in aging men. Methods and materials: A large European multicenter (European Male Aging Study) cohort of community‐dwelling men was analyzed to determine how insulin‐like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters. Results and discussion: Insulin‐like peptide 3 declines cross‐sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin‐like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin‐like peptide 3 is negatively dependent on luteinizing hormone and sex hormone‐binding globulin and positively dependent on follicle‐stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin‐like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin‐like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European‐wide reference range for insulin‐like peptide 3 (95% confidence interval) adjusted for increasing age. Conclusion: Insulin‐like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin‐dependent short‐term regulation and within‐individual variation in testosterone. [ABSTRACT FROM AUTHOR]

Background: Insulin‐like peptide 3 (INSL3) is a constitutive, secreted peptide produced in the male uniquely by the Leydig cells of the testes. It is a biomarker for Leydig cell functional capacity, which is a measure of the numbers and differentiation status of these steroidogenic cells and lacks the biological and technical variance of the steroid testosterone. This retrospective study was carried out to examine the relationship between seminal parameters and the Leydig cell compartment, and secondarily to assess other factors responsible for determining Leydig cell functional capacity. Methods: INSL3 was assessed together with seminal, anthropometric, and hormonal parameters in a Swedish cohort of 18‐year‐old men, representing the average population, and in a smaller, more heterogeneous cohort of men visiting an Australian infertility clinic. Results and discussion: Average INSL3 concentration at 18 years is greater than that reported at younger or older ages and indicated a large 10‐fold variation. In neither cohort was there a relationship between INSL3 concentration and any semen parameter. For the larger, more uniform Swedish cohort of young men, there was a significant negative relationship between INSL3 and BMI, supporting the idea that adult Leydig cell functional capacity may be established during puberty. In both cohorts, there was a significant relationship between INSL3 and FSH, but not LH concentration. No relationship was found between INSL3 and androgen receptor trinucleotide repeat polymorphisms, reinforcing the notion that Leydig cell functional capacity is unlikely to be determined by androgen influence alone. Nor did INSL3 correlate with the T/LH ratio, an alternative measure of Leydig cell functional capacity, supporting the view that these are independent measures of Leydig cell function. [ABSTRACT FROM AUTHOR]

Background: It has recently been suggested that the hypergonadotropic hypogonadism characterizing Klinefelter syndrome (KS) might not be due to a steroidogenic dysfunction per se, but mainly to an altered testosterone (T) secretion into the bloodstream. However, the Leydig cell functionality remains incompletely studied in KS, and new markers should be considered. Previous data indicated that chronic hCG stimulation influences the production of both insulin‐like peptide 3 (INSL3) and 25‐hydroxy‐vitamin D (25‐VD) in eugonadal men. Aim of the study: To evaluate INSL3 and 25‐VD serum levels, as markers of Leydig cell functionality, in association with sex steroids, after an acute hCG test in a group of KS patients and healthy volunteers. Methods: A retrospective analysis of a prospective case‐control clinical trial was carried out. KS patients (n = 11) and age‐matched healthy controls (n = 11) provided a basal blood sample (V0) immediately followed by a single intramuscular injection of hCG 5000 IU. Blood samples were taken in the following five days (V1‐V5). Results: At baseline, INSL3 was lower in KS patients compared with controls (P =.007). When adjusted for INSL3 levels, the production of steroids was similar between KS patients and controls. 25‐VD was in the insufficient range both in KS patients and in controls and was not different (P =.064). Acute hCG stimulation increased neither INSL3 nor 25‐VD in both KS patients and controls. In controls, an inverse correlation was detected between INSL3 levels and body mass index (P =.020) and waist circumference (P =.020). Conclusions: INSL3 secretion is independent from steroidogenesis, and its production is mostly not influenced by acute hCG stimulation both in KS men and in controls. INSL3 serum levels should be considered as a marker of Leydig cell differentiation and numbers rather than steroidogenesis. 25‐VD serum levels are also not increased by a single acute hCG administration, which was not able to restore the normal concentrations of 25‐VD. [ABSTRACT FROM AUTHOR]

The relaxin family of peptide hormones and their cognate GPCRs are becoming physiologically well-characterized in the cardiovascular system and particularly in female reproductive processes. Much less is known about the physiology and pharmacology of these peptides in male reproduction, particularly as regards humans. H2-relaxin is involved in prostate function and growth, while insulin-like peptide 3 (INSL3) is a major product of the testicular Leydig cells and, in the adult, appears to modulate steroidogenesis and germ cell survival. In the fetus, INSL3 is a key hormone expressed shortly after sex determination and is responsible for the first transabdominal phase of testicular descent. Importantly, INSL3 is becoming a very useful constitutive biomarker reflecting both fetal and post-natal development. Nothing is known about roles for INSL4 in male reproduction and only very little about relaxin-3, which is mostly considered as a brain peptide, or INSL5. The former is expressed at very low levels in the testes, but has no known physiology there, whereas the INSL5 knockout mouse does exhibit a testicular phenotype with mild effects on spermatogenesis, probably due to a disruption of glucose homeostasis. INSL6 is a major product of male germ cells, although it is relatively unexplored with regard to its physiology or pharmacology, except that in mice disruption of the INSL6 gene leads to a disruption of spermatogenesis. Clinically, relaxin analogues may be useful in the control of prostate cancer, and both relaxin and INSL3 have been considered as sperm adjuvants for in vitro fertilization.Linked Articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. [ABSTRACT FROM AUTHOR]

Objective Plasma androgen levels are inversely associated with health in men, the age-related decline of which may result from factors other than ageing per se. This study aimed to determine the effects of demographic, physical and lifestyle factors on age-related androgen status in men. Design An observational survey of a regionally representative male population residing in the North West regions of Adelaide, Australia. Participants Study sample includes 1195 men aged 35–81 years with a response rate of 45·1%. Measurements Plasma levels of total testosterone (TT), bioavailable testosterone (BT), SHBG, insulin-like peptide 3 (INSL3), and gonadotrophins were measured along with an extensive list of demographic, physical and lifestyle factors including body composition, muscle strength and biomarkers of chronic diseases, physical activity, nutrition and smoking behaviour. Results Low TT was mostly associated with high abdominal fat and triglycerides and low muscle strength rather than ageing per se. Low BT was associated with increased age followed by high whole body fat percentage. BT and TT levels were higher in unmarried men and smokers. SHBG levels increased with age, but were also inversely associated with insulin and triglycerides. The Leydig cell specific factor INSL3 was the strongest biomarker associated with both TT and BT. Conclusions Factors associated with low androgen status variably include high body fat percentage, low muscle strength and biomarkers of the metabolic syndrome. Reducing exposure to factors that adversely affect androgen status may improve the general health of ageing men by mechanisms yet to be defined. [ABSTRACT FROM AUTHOR]

The novel peptide hormone insulin-like peptide 3 (INSL3) is a major secretory product of the Leydig cells of the testis, and in adult men is secreted into the blood, giving rise to circulating concentrations ranging from 0.5 to 2.5 ng/mL. We studied a large randomly recruited cohort of 1183 men from South Australia, comparing serum INSL3 concentrations with age, and a variety of endocrine, cognitive and morphological parameters. While INSL3 concentration declines significantly ( p < 0.001) and continuously with age from 1.29 ± 0.47 ng/mL in young men (age 35–44 years) to 0.79 ± 0.39 ng/mL in the age group 75–80 years, there is no correlation with testosterone or components of the hypothalamo-pituitary-gonadal (HPG) axis, independent of age, nor with any other parameter measured, including thyroid or prostate status and obesity. For men exhibiting normal follicle stimulating hormone (FSH) and high luteinizing hormone (LH) levels, there was a significant inverse correlation with plasma oestradiol. Unilaterally orchidectomized men had INSL3 values intermediate between intact men and anorchid subjects, and showed inverse correlations ( p < 0.001) between INSL3 and FSH or LH concentrations, which were independent of age. Taken together, the data show that INSL3 is an independent measure of Leydig cell function (quality and number), which appears to be independent of acute control via the HPG axis. Its decline with age reflects a decline in the properties of the Leydig cell population only, and emphasizes a gonadal component in the age-related decrease in androgen production. [ABSTRACT FROM AUTHOR]

Insulin-like factor 3 (INSL3), previously known as the relaxin-like factor (RLF), is a major peptide hormone secreted from the testicular Leydig cells of adult men and circulating in the blood at a concentration of approximately 1 ng/mL. Women also produce INSL3 in the theca interna cells of ovarian follicles, but circulating levels remain below 100 pg/mL. INSL3 is structurally related to relaxin and insulin, but unlike the latter, signals through a novel G-protein-coupled receptor, LGR8. Ablation of the gene for INSL3 leads primarily to cryptorchidism because of a defect in the first, transabdominal phase of testicular descent. In the adult knockout mouse, a mild phenotype is evident in the testis and ovary. We have developed a panel of antibodies specific for INSL3 from various species, which are suitable for immunohistochemistry and, more recently, for immunoassays. INSL3 is an important marker for the mature Leydig cell phenotype, where it appears to be expressed constitutively, once the mature differentiation state is achieved. It is also an indicator of differentiation status not only for Leydig cells but also for the theca interna cells of the ovary. [ABSTRACT FROM AUTHOR]

The heterodimeric peptide hormone relaxin in most cells appears to signal through a G-protein-coupled receptor, LGR7. Whereas in artificial cell systems, made by transfection of receptor-expressing gene constructs into cells normally not presenting the receptor, classic activation of adenylate cyclase appears to be mediated by Gs, in cells naturally expressing the receptor, this type of coupling appears to be very weak. Instead, there is good evidence of other intermediate steps involving cytoplasmic components and tyrosine kinase activity. Part of the complexity of relaxin signaling is also manifest in the variable time course of cAMP production evident in the THP-1 cell line, which appears to depend on passage number and, hence, presumably on differentiation status. It is therefore important to distinguish between immediate early effects, short to mid-term responses, and long-term responses likely the consequences of specific gene upregulation. [ABSTRACT FROM AUTHOR]