D-Chiro-Inositol improves testosterone levels in older hypogonadal men with low-normal testosterone: a pilot study.

BACKGROUND: Several recent journal articles report that D-chiro-inositol (DCI), primarily known as insulin second messenger, influences steroidogenesis. In particular, new evidence is arising on DCI ability to regulate aromatase expression and testosterone biosynthesis. In this regard, DCI administration could represent a good therapeutic opportunity in case of reduced levels of testosterone. Older men generally have lower testosterone concentrations than younger men, and recent randomized controlled trials have examined whether testosterone treatment might improve health outcomes in this age group. There is limited information about the safety of testosterone replacement therapy in these men, hence DCI could represent an interesting alternative for future trials. Therefore, this study aims to evaluate the effect of DCI treatment on testosterone levels in older male patient. RESULTS: Ten older men with basal low testosterone levels were enrolled in this study. Patients took 600 mg of DCI, two-times per day, for 30 days. We evaluated hormonal and glycaemic parameters, weight, waist circumference, and Body-Mass Index at baseline (T0) and after 30 days (T1). Finally, all patients also filled in the standardized International Index of Erectile Function questionnaire and performed the Handgrip test at T0 and T1. Men receiving DCI showed increased androgen and reduced oestrogen concentrations, and improved glycaemic profiles. DCI was also associated with reduced weight, Body-Mass Index, waist circumference, and improved grip strength and self-reported sexual function. All these effects led to the improvement of sexual function and physical strength. CONCLUSIONS: In this pilot study, DCI treatment improved the levels of testosterone and androstenedione at the expense of oestrogens in elder men with low basal levels of these hormones without adverse effects. TRIAL REGISTRATION: Clinicaltrials.gov: D-chiroinositol Administration in Hypogonadal Males, NCT04708249.

RéSUMé: CONTEXTE: Plusieurs articles de revues récents rapportent que le D-chiro-inositol (DCI), principalement connu sous le nom de second messager de l'insuline, influence la stéroïdogenèse. En particulier, de nouvelles preuves apparaissent sur la capacité du DCI à réguler l'expression de l'aromatase et la biosynthèse de la testostérone. À cet égard, l'administration de DCI pourrait représenter une bonne opportunité thérapeutique en cas de réduction des taux de testostérone. Les hommes d'âge avancé ont généralement des concentrations de testostérone plus faibles que celles d'hommes plus jeunes, et de récents essais contrôlés randomisés ont examiné, si le traitement par testostérone pourrait améliorer dans ce groupe d'âge les résultats en matière de santé. Il existe peu d'informations sur l'innocuité de cette thérapie de remplacement de la testostérone chez ces hommes ; le DCI pourrait ainsi constituer une intéressante alternative pour de futurs essais. Par conséquent, la présente étude vise à évaluer l'effet du traitement par DCI sur les taux de testostérone chez les hommes d'âge avancé. RéSULTATS: Dix hommes d'âge avancé ayant un faible taux basal de testostérone ont été recrutés dans la présente étude. Les patients ont pris 600 mg de DCI, deux fois par jour, pendant 30 jours. Nous avons évalué les paramètres hormonaux et glycémiques, le poids, le tour de taille et l'indice de masse corporelle au départ (T0) et après 30 jours (T1). Enfin, tous les patients ont également rempli le questionnaire normalisé de l'indice international de la fonction érectile et ont effectué le test de force de préhension (handgrip test) à T0 et T1. Les hommes prenant le DCI ont présenté des concentrations augmentées d'androgènes et réduites d'œstrogènes, ainsi qu'une amélioration des profils glycémiques. La prise de DCI était également associée à une réduction du poids, de l'indice de masse corporelle, du tour de taille, et à une amélioration de la force de préhension et de la fonction sexuelle autodéclarée. Tous ces effets ont conduit à une amélioration de la fonction sexuelle et de la force physique. CONCLUSIONS: Dans cette étude pilote, le traitement par DCI a amélioré les taux de testostérone et d'androstènedione au détriment des œstrogènes chez des hommes d'âge avancé ayant de faibles taux de base de ces hormones, sans effets indésirables.

New Territory for an Old Disease: 5-Alpha-Reductase Type 2 Deficiency in Bulgaria.

Disorders/differences of sexual development (DSD) are a group of conditions, some of which can be clinically indistinguishable mainly due to their phenotypic variability. Defining the molecular basis of their wide spectrum is still in progress. The diagnosis of 5-alpha-reductase type 2 (5α-reductase-2) deficiency is difficult especially in newborns and pre-pubertal individuals, and as a result its frequency might be underestimated. In the present study, we describe the clinical characteristics and molecular defects in 3 nonrelated 5α-reductase-2 deficiency patients of Bulgarian descent. Sequencing analysis revealed the mutations p.Y188CfsX9 and p.G196S, and MLPA analysis showed a deletion of exon 1 in the SRD5A2 gene. The observed genetic substitutions were not detected in 76 additionally screened unrelated controls, but a heterozygous healthy carrier of the p.R171S mutation was found. This is the first study on the molecular basis of 5α-reductase-2 deficiency in Bulgaria. It suggests that the carrier frequency of mutations in the SRD5A2 gene might be noteworthy worldwide. There is no correlation between cultural aspects, location, and/or population size and the number of different mutations in SRD5A2 detected, and more efforts should be made to determine the prevalence of this condition in different geographic areas. Our study supports the importance of genetic testing in 46,XY DSD patients, especially in countries or regions where 5α-reductase-2 deficiency has not been reported so far.

Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.

BACKGROUND: A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy. METHODS: Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort. RESULTS: Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance. CONCLUSIONS: These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.

Influence of the body weight on the onset and progression of puberty in boys.

BACKGROUND: Unlike in girls, the data on the relationship between pubertal development and body weight in boys are controversial. METHODS: We measured the height, body weight, body mass index (BMI), pubic hair stages, testicular volume, penis length and circumference of 4030 boys, aged between 7 and 19 years. According to their body weight, the investigated children and adolescents were divided in four groups at each age: underweight boys (BMI <12th percentile), boys with normal weight (12th-84.99th percentile), overweight boys (85th-94.99th percentile) and boys with obesity (BMI ≥95th percentile), and their data were compared. RESULTS: The onset of puberty occurred when the boys' weight gained 40.33±9.03 kg (median 39.00) and BMI was 18.62±3.12 kg/m2 (median 17.80), whereas the late stage was reached at weight of 62.44±10.39 kg (median 61.00) and BMI 21.47±2.84 kg/m2 (median 21.20). Earlier maturing boys were heavier than their coevals, whereas underweight boys developed puberty later. CONCLUSIONS: The onset and progression of puberty in boys are in a significant positive relationship with weight and BMI. Moreover, in the overweight boys pubertal development begins and comes to the late stage earlier in comparison with normal weight children, whereas in those who are underweight a delay at every stage of the development is observed.

A Novel SRY Gene Mutation p.F109L in a 46,XY Female with Complete Gonadal Dysgenesis.

46,XY complete gonadal dysgenesis (CGD) is a disorder of sexual development that can result from different mutations in genes associated with sex determination. Patients are phenotypically females, and the disease is often diagnosed in late adolescence because of delayed puberty. Here, we present the clinical and molecular data of a 46,XY female CGD patient with gonadoblastoma with dysgerminoma and incidentally found inherited thrombophilia. The clinical significance of the described de novo SRY gene mutation c.325T>C (p.F109L) is discussed. This case report supports the critical role of the HGM domain in the SRY gene and the need of a multidisciplinary approach for CGD patients.

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

BACKGROUND: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

Does an Association between the Idiopathic Left-Sided Varicocele and Eye Colour Exist?

The possible interrelation between male reproductive disorders and iris pigmentation is poorly understood. We have found a link between eye colour and the existence of adolescent varicocele. Therefore, we aimed to extend our investigation on the relationship between the eye colour and varicocele in adult men. 231 andrology outpatients from Caucasian origin were included in the study. The presence of varicocele, sperm disturbances, and the iris pigment of the patients were investigated. Left-sided varicocele was found in 93 adults. In the group of light-eyed men the prevalence of varicocele was significantly lower than among the dark-eyed men (15% versus 59.5%, P < 0.001). No associations were found between the eye colour and disturbances in semen parameters in males with varicocele (P = 0.419) and in those without varicocele (P = 0.586). The present results in adult men suggest that the prevalence of varicocele could be associated with the iris pigment. A possible genetic linkage between the eye colour and the susceptibility to some disorders like varicocele could not be excluded. However, the iris pigmentation seems not to have a direct relationship with the sperm disturbances.

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.

Androgen receptor (CAG)n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects mainly females. Therefore, interrelations between the reproductive and immune system have been assumed. Considering the complex influence of hormones and receptors, we aimed to investigate the influence of androgens and androgen receptor (AR) polymorphism in women with SLE. One hundred and sixteen patients and 44 healthy women were investigated. Testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone-sulphate (DHEAS) concentrations and AR (CAG)n polymorphism were determined. SLE patients had significantly lower levels of total and free testosterone and DHEAS in comparison with the controls. No differences in the CAG repeat length between the groups were established. Women with two alleles carrying more than 22 CAG repeats had significantly higher levels of SHBG (101.51 ± 61.81 vs. 69.22 ± 45.93 nmol/l, p = 0.015) and DHEAS (3.11 ± 2.65 vs. 2.11 ± 3.06 µmol/l, p = 0.007) and a tendency to higher testosterone concentrations (2.35 ± 2.10 vs. 1.71 ± 1.70 nmol/l, p = 0.056) in comparison with other women. The CAG repeat length in the relatively longer (CAG)n allele was inversely related to the Systemic Lupus International Collaborating Clinics/ACR index (r = -0.258, p = 0.009). In conclusion, the androgen receptor (CAG)n polymorphism is not related to the development of SLE, but it could modulate the severity of the lupus chronic damages as well as the androgen levels in women.

Acne vulgaris is associated with intensive pubertal development and altitude of residence--a cross-sectional population-based study on 6,200 boys.

UNLABELLED: Acne vulgaris is a chronic inflammatory disease with a complex pathogenesis that affects predominantly adolescents. The aim of the study was to investigate the interrelations between the presence of acne and several variables associated with somatic growth, pubertal maturation, and environmental conditions (altitude and regions of residence). A population sample of 6,200 clinically healthy boys (0-19 years) was examined and the presence of acne was determined. Height, weight, testicular volumes, penile length and circumference, as well as pubic hair were also measured. The prevalence of moderate and severe acne in the whole group was 7.74 %, while in the age group 12-19 years, it was 19.31 %. Twelve-15-year-old boys with acne were taller and heavier than the ones without. They also had increased penile length and circumference as well as larger testicular volumes. Somatometric and pubertal characteristics of 17-19-year-old boys with and without acne were similar. The prevalence of the disease did not differ between the rural and urban inhabitants. However, the acne frequency decreased with the increasing of the altitude where the boys lived. CONCLUSIONS: Our results showed that the development of acne vulgaris in male adolescents was associated with an intensive growth and pubertal maturation, while obesity per se did not play an important role. Of particular interest was the association between the prevalence of acne and the altitude of residence.

Sperm disturbances in metabolic syndrome: what we actually know.

Evaluation of: Lotti F, Corona G, Degli Innocenti S et al. Seminal, ultrasound and psychobiological parameters correlate with metabolic syndrome in male members of infertile couples. Andrology 1(2), 229-239 (2013). Male hypogonadism is considered a fundamental component of metabolic syndrome (MetS), but the data concerning sperm quality in men with MetS are still scarce. The role of MetS in male fertility is poorly investigated owing to the fact that the prevalence of metabolic syndrome increases with age and peaks at the time when reproductive plans of couples are already accomplished. However, the worldwide trend towards a younger age of MetS development, owing to the increase in obesity, and the tendency for reproduction later in life could aggravate the influence of the metabolic disturbances on male reproduction. The present article is an important step in the study of the interrelations between MetS and subfertility.

Decreased daily melatonin levels in women with systemic lupus erythematosus - a short report.

BACKGROUND: The neuroendocrine system is known to influence immunity, but the precise interactions between different hormones and autoimmune disorders remain obscure. AIMS: The present study aimed to investigate the role of daily serum melatonin concentrations in the development of systemic lupus erythematosus (SLE) in women. STUDY DESIGN: Case-control study. METHODS: One-hundred and eleven SLE female patients and 46 healthy women were included in the study. Daily serum melatonin levels were investigated in all participants. RESULTS: SLE patients showed significantly lower daily melatonin levels in comparison to healthy women during the short photoperiod (17.75±7.13 pg/mL [16.05] vs. 21.63±6.60 pg/mL [20.10], p=0.012). Hormone concentrations were inversely related to the SLE activity index (SLEDAI) (r= -0.268, p=0.004), but they did not correlate to any particular American College Rheumatology (ACR) criterion (p>0.05 for all). CONCLUSION: Daily melatonin levels were decreased in women with systemic lupus erythematosus and correlated inversely to the activity of the autoimmune disease. Further studies are needed to clarify the importance of the pineal and extrapineal melatonin secretion in patients with systemic lupus erythematosus as well as the interrelations between hormones and autoimmunity.

Growth and development of male external genitalia: a cross-sectional study of 6200 males aged 0 to 19 years.

OBJECTIVE: To provide estimates of normal variations in penile measurements and testicular volumes, and to establish reference ranges for clinical use. DESIGN: Cross-sectional, population-based study. SETTING: Schools, kindergartens, and child care centers in different parts of Bulgaria. PARTICIPANTS: A population of 6200 clinically healthy white males aged 0 to 19 years. INTERVENTIONS: The study physician chose schools, kindergartens, and child care centers randomly and examined children at random until he reached the required number. Each of the 20 age groups (age range, 0-19 years) had an equal number of males (ie, 310). MAIN OUTCOME MEASURES: The mean (SD) values and fifth, 50th, and 95th percentiles of height (Siber Hegner anthropometer), weight (beam balance), testicular volume (Prader orchidometer), penile length (rigid tape), and penile circumference (measuring tape) from birth to 19 years of age. RESULTS: Testes did not show any increase in size until the onset of puberty at age 11 years, whereas penile growth was gradual after birth. However, both penile and testicular development demonstrated peak growth from 12 to 16 years of age, which coincided with the maximal male pubertal growth spurt. Data indicate an earlier pubertal development for this study population than that for a similar population several decades ago. Significant differences between urban and rural populations regarding penile length were also noticed. CONCLUSIONS: Our study provides the contemporary reference range values for height, weight, testicular volume, and penile length and circumference of males aged 0 to 19 years. Our data show that, even by the end of 20th century, there is still some acceleration of male pubertal development. For the first time are reported somatic differences in genitalia within a population between urban and rural representatives.

Melatonin secretion and non-specific immune responses are differentially expressed in corticotropin-dependent and corticotropin-independent Cushing's syndrome.

BACKGROUND: This study was done to clarify the relation between melatonin secretion and the hypothalamic-pituitary-adrenal axis. MATERIAL/METHODS: In this clinical study using a follow-up approach, we investigated the circadian melatonin secretion and immune parameters of patients with corticotropin-dependent (Cushing's disease) and corticotropin-independent Cushing's syndrome. Plasma hormone concentrations, interleukin 1-beta (IL-1beta) and total immunoglobulin E (IgE) were determined before surgical treatment and during remission of the syndrome 1 year later. RESULTS: Patients with Cushing's disease showed mean nocturnal and diurnal melatonin plasma values similar to those of healthy controls. Only the midday level of patients (taken at 12:00) was significantly higher in comparison to controls (35.44+/-19.5 pg/mL vs 17.14+/-3.58 pg/mL; P<0.05). In contrast, patients with corticotropin-independent Cushing's syndrome had significantly lower mean nocturnal and significantly higher mean diurnal melatonin levels (52.8+/-17.7 pg/mL and 59.2+/-28.7 pg/mL, respectively; P<0.05 and P<0.05) as compared with corresponding values for controls (101.4+/-43.1 pg/mL and 28.9+/-11.7 pg/mL, respectively). In the last group of patients, significantly higher mean IL1beta and plasma IgE concentrations (3.30+/-1.72 pg/mL and 527.8+/-474.0 IU/mL, respectively) were observed compared with controls (1.43+/-0.95 pg/mL and 35.7+/-32.1 IU/mL, respectively) (P<0.05). Remission of the hypercortisolism in these patients resulted in restoration of circadian melatonin secretion and significant reductions in plasma IL1beta and total IgE levels. CONCLUSIONS: Our results demonstrate a specific mode of melatonin secretion and different nonspecific immune responses in the 2 investigated forms of hypercortisolism, specifically, corticotropin-dependent and corticotropin-independent Cushing's syndrome.

Adolescent varicocele: who is at risk?

OBJECTIVES: Varicocele results from the abnormal dilation of the veins of the pampiniform plexus and is the most common identifiable cause of male infertility. It can develop during puberty and thus affect the testicular growth and function. The aim of this study was to determine the prevalence and the risk factors for the development of the varicocele among Bulgarian boys. METHODS: In a prospective study, 6200 boys from 5 regions of the country aged 0 to 19 years were evaluated for varicocele. All were clinically healthy. Height, weight, testicular volumes, penile length, and penile circumference were also examined. RESULTS: Varicocele was found in 4.1% of all investigated boys, whereas in the age group 10 to 19 years, it was 7.9%. After adjustment for age, the negative factors associated with the development of the disorder were height, penile length, and penile circumference, whereas the weight and BMI had a protective role. The prevalence of varicocele demonstrated clear regional differences, and it was found significantly more often among dark-eyed boys. The incidence of the disease increased rapidly during midpuberty. CONCLUSIONS: The incidence of varicocele is related to some somatometric parameters and with the accelerated pubertal development. Longitudinal studies are needed to clarify better the relations between the adolescent varicocele and puberty.

Prevalence of cryptorchidism among Bulgarian boys.

BACKGROUND: Cryptorchidism is the most common congenital defect of the male urogenital system. It may be an important cause for male infertility. The data about its prevalence in South-eastern European countries and especially for the Balkan region are still incomplete. OBJECTIVE: The aim of the present study was to establish the prevalence of the abnormality in the Bulgarian population living in the different areas of the country. METHODS: In a population-based cross-sectional study in Bulgaria 6200 Caucasian boys (aged under 1 year to 19 years) from five regions of the country were included. One physician examined all children in order to reduce the inter-observer error. RESULTS: The prevalence of cryptorchidism was 1.52% for the total group. It was 3.2% for boys under one year of age, 2.1% for those between one and ten years and dropped significantly in older boys (0.6%). No regional or seasonal trends were established. CONCLUSIONS: Our study suggests a relatively higher prevalence of cryptorchidism in Bulgaria for children younger than one year of age, while the overall prevalence is comparable to those reported for other countries. The prevalence of cryptorchidism did not differ significantly from the prevalence reported thirty years ago.

Prevalence of micropenis among boys from different regions of Bulgaria.

AIMS: Micropenis is a normally formed penis whose length is more than 2.5 SD below the mean penile length for age. However, the definition of this disorder depends on penile length norms. METHODS: Penile length, circumference and anthropometric values of 310 boys under one year of age from five regions in Bulgaria were investigated. RESULTS: The mean penile length for all boys was 3.55 +/- 0.46 cm, thus micropenis could be defined as a penile length below 2.40 cm. However, regional differences were observed in penile length and circumference. According to regional mean values and the appropriate definition of micropenis, only two of the children had micropenis. CONCLUSIONS: In a prospective study of Bulgarian boys we established wide regional variations of normal penile length. Consequently, the diagnostic and therapeutic approach to micropenis should consider the mono-ethnic inter-regional differences.

Relationship of adolescent gynecomastia with varicocele and somatometric parameters: a cross-sectional study in 6200 healthy boys.

PURPOSE: To evaluate the relationship of gynecomastia with varicocele and somatometric parameters in otherwise clinically healthy boys. METHODS: The relationship between gynecomastia and somatometric parameters was examined with 6200 clinically healthy boys aged 0-19 years of different socioeconomic backgrounds in various schools, kindergartens, and childcare centers. Multivariable logistic regression analysis was used to model the prevalence of gynecomastia (>or=1cm) in relation to height, weight, testicular volume, penile length and circumference, age, pubic hair Tanner stage, and residential status. RESULTS: Pubic hair Tanner stages 3 and 4 had the highest incidence of gynecomastia. Gynecomastia was found only in boys more than 10 years old and its prevalence in the age group of 10-19 years (n = 3082) was 3.93 %. In boys 10-13 years old, gynecomastia was positively correlated with varicocele, the adjusted odds ratio (OR) was 2.1 (95% confidence interval [CI] = 1.1-4.1). For the age at which gynecomastia was most prevalent (group aged 12-14 years), the adjusted OR of gynecomastia occurring in boys with varicocele, using the Cochran-Mantel-Hasenzel method of adjusting for age was 1.9 (95% CI = 1.1-3.4). Gynecomastia was negatively correlated with body mass index (BMI). In addition, it was weakly correlated with testicular volume, positively in age group 10-13 years and negatively in those 14-19 years. However no relationship was found between gynecomastia and penis size, urban/rural status, and sea level of residence. CONCLUSIONS: Adolescent gynecomastia is a mid-puberty event. It is significantly associated with varicocele and somatometric parameters including BMI and testicular volume.

Testosterone replacement therapy in male hypogonadism is not associated with increase of endothelin-1 levels.

Differences in endothelin-1 (ET-1) blood plasma levels were established between healthy men and women. Little is known about vascular effects of testosterone and the interactions between sex hormones and endothelin. In order to study the relationship between ET-1 and testosterone in more detail, we have investigated 33 male patients with various forms of hypogonadism (13 with hypergonadotropic hypogonadism and 20 with hypogonadotropic hypogonadism). Fourteen age-matched healthy males served as controls. The basal ET-1 levels in patients with hypogonadism (0.96 +/- 0.12 fmol/mL) (mean +/- SEM) were significantly higher in comparison with the controls (0.44 +/- 0.04 fmol/mL), p < 0.01. Fifteen individuals of these patients were studied during the therapy with testosterone depot 250 mg i.m. The ET-1 levels decreased in this group from 0.99 +/- 0.22 to 0.78 +/- 0.14 fmol/mL at the third and to 0.76 +/- 0.25 fmol/mL at the sixth month of the medication, respectively. The differences were not significant compared with the initial levels, but the concentrations at the sixth month of the treatment were not statistically different in comparison with the ET-1 levels of the controls. There was no significant difference in lipid data between patients before and during testosterone medication, except for the high-density lipoprotein cholesterol, which decreased at the third month of the treatment. Our results show that plasma ET-1 levels in males with hypogonadism are elevated with a tendency to decrease after testosterone administration. The optimum testosterone is not associated with enhanced cardiovascular risk as far as ET-1 plasma levels and lipids are concerned.