Reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) neurons play a central role in this axis through production of GnRH, which binds to ...a membrane receptor on pituitary gonadotrophs and stimulates the biosynthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Multiple factors affect GnRH neuron migration, GnRH gene expression, GnRH pulse generator, GnRH secretion, GnRH receptor expression, and gonadotropin synthesis and release. Among them anosmin is involved in the guidance of the GnRH neuron migration, and a loss-of-function mutation in its gene leads to a failure of their migration from the olfactory placode to the hypothalamus, with consequent anosmic hypogonadotropic hypogonadism (Kallmann syndrome). There are also cases of hypogonadotropic hypogonadim with normal sense of smell, due to mutations of other genes. Another protein, kisspeptin plays a crucial role in the regulation of GnRH pulse generator and the pubertal development. GnRH is the main hypothalamic regulator of the release of gonadotropins. Finally, FSH and LH are the essential hormonal regulators of testicular functions, acting through their receptors in Sertoli and Leydig cells, respectively. The main features of the male HPG axis will be described in this review.
Spermatogenesis and folliculogenesis involve cell-cell interactions and gene expression orchestrated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH regulates the ...proliferation and maturation of germ cells independently and in combination with LH. In humans, the requirement for high intratesticular testosterone (T) concentration in spermatogenesis remains both a dogma and an enigma, as it greatly exceeds the requirement for androgen receptor (AR) activation. Several data have challenged this dogma. Here we report our findings on a man with mutant LH beta subunit (LHβ) that markedly reduced T production to 1-2% of normal., but despite this minimal LH stimulation, T production by scarce mature Leydig cells was sufficient to initiate and maintain complete spermatogenesis. Also, in the
(
) knockout (LuRKO) mice, low-dose T supplementation was able to maintain spermatogenesis. In addition, in antiandrogen-treated LuRKO mice, devoid of T action, the transgenic expression of a constitutively activating
(
) mutant was able to rescue spermatogenesis and fertility. Based on rodent models, it is believed that gonadotropin-dependent follicular growth begins at the antral stage, but models of FSHR inactivation in women contradict this claim. The complete loss of FSHR function results in the complete early blockage of folliculogenesis at the primary stage, with a high density of follicles of the prepubertal type. These results should prompt the reassessment of the role of gonadotropins in spermatogenesis, folliculogenesis and therapeutic applications in human hypogonadism and infertility.
SummaryThe recent onslaught of mass spectrometry (MS) to measurements of steroid hormones, including demands that they should be the only acceptable method, has confused clinicians and scientists who ...have relied for more than 40 years on a variety of immunoassay (IA) methods in steroid hormone measurements. There is little doubt that MS methods with their superior specificity will be the future method of choice in many clinical and research applications of steroid hormone measurement. However, the majority of steroid measurements are currently, and will continue to be, carried out using various types of IAs for several reasons, including their technical ease, cost and availability of commercial reagents. Speedy replacement of all IAs with MS is an unrealistic and unnecessary goal, because the availability of MS measurements is limited by cost, need of expensive equipment, technical demands and lack of commercial applications. Furthermore, IAs have multiple well-known advantages that vindicate their continuing use. The purpose of this article is to elucidate the advantages and limitations of the MS and IA techniques from two angles, i.e. promotion of MS and defence of IA. The purpose of the text is to give the reader an unbiased view about the current state and future trends of steroid analysis and to help him/her choose the correct assay method to serve his/her diagnostic and research needs.
Spermatogenesis is a concerted sequence of events during maturation of spermatogonia into spermatozoa. The process involves differential gene-expression and cell-cell interplay regulated by the key ...endocrine stimuli, i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-stimulated testosterone. FSH affects independently and in concert with testosterone, the proliferation, maturation and function of the supporting Sertoli cells that produce regulatory signals and nutrients for the maintenance of developing germ cells. Rodents are able to complete spermatogenesis without FSH stimulus, but its deficiency significantly decreases sperm quantity. Men carrying loss-of-function mutation in the gene encoding the ligand (
) or its receptor (
present, respectively, with azoospermia or suppressed spermatogenesis. Recently, the importance of high intratesticular testosterone concentration for spermatogenesis has been questioned. It was established that it can be completed at minimal intratesticular concentration of the hormone. Furthermore, we recently demonstrated that very robust constitutive FSHR action can rescue spermatogenesis and fertility of mice even when the testosterone stimulus is completely blocked. The clinical relevance of these findings concerns a new strategy of high-dose FSH in treatment of spermatogenic failure.
Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult ...populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed 'mini-puberty' precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic-pituitary-testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates.
Pubmed, Scopus, Web of Science and Google Scholar databases were searched between December 2012 and October 2014. Studies published in languages other than English or German were excluded, as were data in abstract form only. Studies available on primates were primarily examined and compared with available data from specific animal models with emphasis on rodents.
Expression of different marker genes in rodents provides evidence that at least two distinct progenitor lineages give rise to the fetal LC (FLC) population, one arising from the coelomic epithelium and the other from specialized vascular-associated cells along the gonad-mesonephros border. There is general agreement that the formation and functioning of the FLC population in rodents is gonadotrophin-responsive but not gonadotrophin-dependent. In contrast, although there is in primates some controversy on the role of gonadotrophins in the formation of the FLC population, there is consensus about the essential role of gonadotrophins in testosterone production. Like the FLC population, adult Leydig cells (ALC) in rodents arise from stem cells, which have their origin in the fetal testis. In contrast, in primates the ALC population is thought to originate from FLC, which undergo several cycles of regression and redifferentiation before giving rise to the mature ALC population, as well as from differentiation of stem cells/precursor cells. Despite this difference in origin, both in primates and rodents the formation of the mature and functionally active ALC population is critically dependent on the pituitary gonadotrophin, LH. From studies on rodents considerable knowledge has emerged on factors that are involved besides LH in the regulation of this developmental process. Whether the same factors also play a role in the development of the mature primate LC population awaits further investigation.
Distinct populations of LC develop along the life span of males, including fetal, neonatal (primates) and ALC. Despite differences in the LC lineages of rodents and primates, the end product is a mature population of LC with the main function to provide androgens necessary for the maintenance of spermatogenesis and extra-gonadal androgen actions.
Formation of G protein-coupled receptors (GPCRs) into dimers and higher order oligomers represents a key mechanism in pleiotropic signaling, yet how individual protomers function within oligomers ...remains poorly understood. We present a super-resolution imaging approach, resolving single GPCR molecules to ∼8 nm resolution in functional asymmetric dimers and oligomers using dual-color photoactivatable dyes and localization microscopy (PD-PALM). PD-PALM of two functionally defined mutant luteinizing hormone receptors (LHRs), a ligand-binding deficient receptor (LHRB−) and a signaling-deficient (LHRS−) receptor, which only function via intermolecular cooperation, favored oligomeric over dimeric formation. PD-PALM imaging of trimers and tetramers revealed specific spatial organizations of individual protomers in complexes where the ratiometric composition of LHRB− to LHRS− modulated ligand-induced signal sensitivity. Structural modeling of asymmetric LHR oligomers strongly aligned with PD-PALM-imaged spatial arrangements, identifying multiple possible helix interfaces mediating inter-protomer associations. Our findings reveal that diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile.
Background: GPCRs form complex oligomers whose role in signaling is poorly understood.
Results: Super-resolution imaging of functionally asymmetric oligomers reveals diverse functional and structural organizations and the ability to alter signal responses.
Conclusion: GPCR oligomers may fine-tune receptor signaling by altering the functional role of individual protomers.
Significance: Distinct oligomers could be exploited pharmacologically to improve efficacy, selectivity, and/or specificity.
The investigators sought evidence-based criteria for identifying late-onset hypogonadism in men between the ages of 40 and 79 years on the basis of the association between symptoms and a low ...testosterone level. The data suggest that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter.
The data suggest that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms with a total testosterone level of less than 11 nmol per liter and a free testosterone level of less than 220 pmol per liter.
The clinical importance of an age-related reduction in the testosterone level
1
–
3
remains controversial.
4
,
5
Because of the uncertainty regarding the nature of testosterone deficiency in aging men,
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–
9
recent guidelines have suggested that so-called late-onset hypogonadism be regarded as a clinical and biochemical state with advancing age, characterized by particular symptoms and a low level of serum testosterone.
10
,
11
However, few data on hypogonadism in aging men are available
4
,
8
,
12
because of the lack of evidence regarding the exact criteria for identifying testosterone deficiency in older men who do not have pathological hypogonadism.
6
,
13
Although a familiar array . . .
Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by ...limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo, we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a ligand-dependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology.
Context: The cause of declining testosterone (T) in aging men and their relationships with risk factors are unclear.
Objective: The objective of the study was to investigate the relationships between ...lifestyle and health with reproductive hormones in aging men.
Design: This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40–79 yr from a prospective cohort study in eight European countries.
Results: Four predictors were associated with distinct modes of altered function: 1) age: lower free T (FT; −3.12 pmol/liter·yr, P < 0.001) with raised LH, suggesting impaired testicular function; 2) obesity: lower total T (TT; −2.32 nmol/liter) and FT (−17.60 pmol/liter) for body mass index (BMI; ≥ 25 to < 30 kg/m2) and lower TT (−5.09 nmol/liter) and FT (−53.72 pmol/liter) for BMI 30 kg/m2 or greater (P < 0.001–0.01, referent: BMI < 25 kg/m2) with unchanged/decreased LH, indicating hypothalamus/pituitary dysfunction; 3) comorbidity: lower TT (−0.80 nmol/liter, P < 0.01) with unchanged LH in younger men but higher LH in older men; and 4) smoking: higher SHBG (5.96 nmol/liter, P < 0.001) and LH (0.77 U/liter, P < 0.01) with increased TT (1.31 nmol/liter, P < 0.001) but not FT, compatible with a resetting of T-LH-negative feedback due to elevated SHBG.
Conclusions: Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment. These changes are differentially linked to specific risk factors. Some risk factors operate independently of but others interact with age, in contributing to the T decline. These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men.
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