[Show abstract][Hide abstract] ABSTRACT: Two distinct types of Leydig cells emerge during the development of eutherian mammals. Fetal Leydig cells (FLCs) appear shortly after gonadal sex differentiation, and play a crucial role in masculinization of male fetuses. Meanwhile, adult Leydig cells (ALCs) emerge after birth and induce the secondary male-specific sexual maturation by producing testosterone. Previous histological studies suggested that FLCs regress completely soon after birth. Furthermore, gene disruption studies indicated that androgen signaling is dispensable for FLC differentiation, but indispensable for postnatal ALC differentiation. Here, we performed lineage tracing of FLCs using a fetal Leydig cell enhancer of the Ad4BP/SF-1 (Nr5a1) gene, and found that FLCs persist in the adult testis. Given that postnatal FLCs expressed androgen receptor (AR) as well as luteinizing hormone (LH) receptor (LuR), the effects of AR disruption on FLCs and ALCs were analyzed by crossing AR knockout (ARKO) mice with FLC-specific EGFP mice. Moreover, to eliminate the influence of elevated LH levels in ARKO mice, LuR knockout (LuRKO) mice and AR/LuR double-knockout mice were analyzed. The proportion of ALCs to postnatal FLCs was decreased in ARKO mice, and the effect was augmented in the double-knockout mice, suggesting that androgen signaling plays important roles in ALCs, but not in FLCs. Finally, AR knockout was achieved in an FLC-specific manner (FLCARKO mice), but the FLC number and gene expression pattern appeared unaffected. These findings support the conclusion that FLCs persist as an androgen-independent Leydig subpopulation in the postnatal testis.
[Show abstract][Hide abstract] ABSTRACT: Secondary hypogonadism is common in ageing men; its natural history and predisposing factors are unclear.
1) To identify factors which predispose eugonadal men (T ≥10.5nmol/L) to develop biochemical secondary hypogonadism (T<10.5nmol/L, LH≤9.4U/L) and secondary hypogonadal men to recover to eugonadism. 2) To characterize clinical features associated with these transitions.
Prospective observational general population cohort survey.
Clinical research centres.
3369 community-dwelling men aged 40-79 yr in eight European centres.
Observational follow-up of 4.3 years.
Subjects were categorised according to change/no change in biochemical gonadal status during follow-up into persistent eugonadal (n=1909), incident secondary hypogonadal (n=140), persistent secondary hypogonadal (n=123) and recovered from secondary hypogonadism to eugonadism (n=96). Baseline predictors and changes in clinical features associated with incident secondary hypogonadism and recovery from secondary hypogonadism were analysed by regression models.
The incidence of secondary hypogonadism was 155.9/10,000/year, while 42.9% of men with secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by obesity [BMI≥30kg/m(2): odds ratio (OR)=2.86 (95% confidence interval 1.67;4.90); p<0.0001], weight gain [OR=1.79 (1.15;2.80);p=0.011] and increased waist circumference [OR=1.73 (1.07;2.81); p=0.026 and 2.64 (1.66;4.21);p<0.0001, for waist circumference 94-102 and ≥102 cm, respectively]. Incident secondary hypogonadal men experienced new/worsening sexual symptoms [low libido, erectile dysfunction and infrequent spontaneous erections]. Recovery from secondary hypogonadism was predicted by non-obesity [OR=2.28 (1.21;4.31); p=0.011], weight loss [OR=2.24 (1.04;4.85); p=0.042], normal waist circumference [OR=1.93 (1.01;3.70); p=0.048], younger age [<60yr OR=2.32 (1.12;4.82); p=0.024] and higher education [OR=2.11 (1.05;4.26); p=0.037], but symptoms did not show significant concurrent improvement.
Obesity-related metabolic and lifestyle factors predispose older men to the development of secondary hypogonadism, which is frequently reversible with weight loss.
The Journal of Clinical Endocrinology and Metabolism 05/2015; 100(8):jc20151571. DOI:10.1210/jc.2015-1571 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 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 helps him/her to chose the correct assay method to serve his/her diagnostic and research needs.
European Journal of Endocrinology 04/2015; 173(2). DOI:10.1530/EJE-15-0338 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation.
A family with five affected members, including a phenotypically female, but genotypically male (46,XY) patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities were studied genetically. Cell trafficking studies as well as signaling studies of mutated receptor were performed.
The 5 affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frame-shift affecting most of the C-terminal intracellular domain. In vitro studies showed that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small molecule agonist treatment or stimulated intracellularly by co-expression of a yoked-hCG.
This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.
European Journal of Endocrinology 03/2015; 172(6). DOI:10.1530/EJE-14-1095 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND 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.
Human Reproduction Update 02/2015; 21(3). DOI:10.1093/humupd/dmv008 · 10.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this. Objective: To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, BMI and insulin resistance on this risk. Methods: 3369 community-dwelling men aged 40-79 years were recruited for participation in EMAS. MetS was defined by the updated NCEP ATP III criteria. Testosterone and E2 levels were measured by liquid and gas chromatography/mass spectrometry respectively. Logistic regression was used to assess the association between sex steroids and incident MetS. Results: 1651 men without MetS at baseline were identified. During follow-up 289 men developed incident MetS, while 1362 men did not develop MetS. Men with lower baseline total T levels were at higher risk for developing MetS (Odds ratio (OR)=1.72, p<0.001), even after adjustment for SHBG (OR=1.43, p=0.001), BMI (OR=1.44, p<0.001) or HOMA-IR (OR=1.64, p<0.001). E2 was not associated with development of MetS (OR=1.04; p=0.56). However, a lower E2/T ratio was associated with a lower risk of incident MetS (OR=0.38; p<0.001), even after adjustment for SHBG (OR=0.48; p<0.001), BMI (OR=0.60; p=0.001) or HOMA-IR (OR=0.41; p<0.001). Conclusions: In men, lower T levels, but not E2, are linked with an increased risk of developing MetS, independent of SHBG, BMI or insulin resistance. A lower E2/T ratio may be protective against developing MetS.