Search

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Biallelic pathogenic variants in RNF216 cause a syndrome characterized by hypogonadotropic hypogonadism, cerebellar ataxia, chorea, and cognitive impairment, a combination first described as Gordon Holmes syndrome (MIM 212840). We report 2 siblings who were referred due to absent or delayed puberty. The older sibling, a 17-year-old male, presented with absence of secondary sexual characteristics and a high-pitched voice. He had normal cognitive development and no anosmia. Clinical examination revealed Tanner stage P1/G1 and bilateral gynecomastia. Blood tests showed low gonadotropin and morning testosterone levels. His 15-year-old sister was referred due to primary amenorrhea. She had spontaneous thelarche and presented with Tanner stage P3/B3. Pituitary magnetic resonance imaging was performed on the brother due to suspicion of Kallmann syndrome, revealing a normal anterior pituitary, a hypoplastic posterior pituitary, and an extensive supratentorial leuko-encephalopathy. Whole-exome sequencing revealed a homozygous pathogenic variant in RNF216 in both affected siblings. Both parents were heterozygous carriers. RNF216 pathogenic variants cause a disorder characterized by combined neurodegeneration and reproductive dysfunction. Although neurological symptoms are typically recognized first, they often seem to follow the onset of hypogonadism. This highlights the need for awareness, as hypogonadotropic hypogonadism may be the initial manifestation of this severe neuroendocrine disorder, especially in males. [ABSTRACT FROM AUTHOR]

The article offers information on the history and role of vitamin D in preventing rickets and its potential implications in various health problems. Topics include the activation of the vitamin D receptor regulating a large number of genes, the importance of evaluating vitamin D status worldwide, and the surprising findings of high rates of deficiency in regions with abundant sunlight.

The relationship between testosterone and related hormones and cardiovascular and mortality outcomes is debated. The authors of this study obtained individual patient–level data from 9 cohort studies and aggregate data from 11 studies in total. These data enabled them to describe the associations of testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol with all-cause mortality, cardiovascular death, and incident cardiovascular events while accounting for other cardiac risk factors. Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. Purpose: To clarify associations of sex hormones with these outcomes. Data Sources: Systematic literature review to July 2019, with bridge searches to March 2024. Study Selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Data Extraction: Independent variables were testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Data Synthesis: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Limitations: Observational study design, heterogeneity among studies, and imputation of missing data. Conclusion: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668) [ABSTRACT FROM AUTHOR]

Background: Although Klinefelter syndrome (KS) is the most frequent sex‐hormone disorder, there is ongoing uncertainty about the often associated sex‐hormone deficiency, its impact on common comorbidities, and therefore about prevention and treatment. In this study, we focus on bone loss, reported to occur in over 40% of KS patients, and the impact of testosterone replacement therapy (TRT) on this comorbidity. Objectives: This single‐center retrospective cohort study in a tertiary hospital compared the effect of treatment with TRT to no TRT on evolution of bone mineral density (BMD) in KS patients. Methods: After a medical chart review, a total of 52 KS subjects were included in this study. BMD was measured by dual‐energy X‐ray absorptiometry (DXA) and expressed as T‐scores. Results: The subjects were divided into three groups, according to TRT. In the subgroup that only started TRT after baseline measurements (mean age 31 years), we observed significant gain in BMD T‐score at the lumbar spine (0.58 ± 0.60, p = 0.003; mean gain of 0.62% areal BMD per year) and total femur T‐score (0.24 ± 0.39, p = 0.041; mean gain of 0.25% areal BMD per year) after a mean follow‐up period of 7.5 years. Compared to untreated subjects, a significant difference in evolution was demonstrated at the lumbar level (+0.58 ± 0.60 vs. −0.14 ± 0.42, p = 0.007). In untreated subjects with normal testosterone levels, a loss of BMD (−0.27 ± 0.37, p = 0.029; mean loss of 0.49% areal BMD per year) at the femoral neck was measured. This decline was equal to the predicted loss seen in the general male population. Conclusion: TRT results in BMD gain in patients with KS with testosterone deficiency, mainly at the lumbar spine. However, this effect is limited (0.62% per year). Patients who were not treated with TRT because of sufficient endogenous testosterone levels, showed only the predicted age‐related bone loss during follow‐up. The need for TRT in maintaining bone health in KS should be evaluated on an individual basis according to the degree of sex steroid deficiency. [ABSTRACT FROM AUTHOR]

Background: Low testosterone levels are frequently present in men with obesity and insulin resistance. Currently available treatment options (testosterone replacement therapy or lifestyle changes) hold possible risks or are insufficient. Since low testosterone levels are closely related to obesity and type 2 diabetes, treatment modalities for these conditions could result into improvement of testosterone levels. Objectives: To summarize the available evidence on the effects of traditional and recent treatment modalities for diabetesmellitus on testosterone levels and androgendeficiency-related signs and symptoms. Materials and methods: PubMed was searched from the year 2000 till present using MESH terms: "hypogonadism," "testosterone," "testosterone deficiency," "functional hypogonadism," and the different classes of medications. Studies with observational and experimental designs on humans that evaluated the effect of antidiabetic medications on gonadotropins and testosterone were eligible for inclusion. Results: Current available data show no or only limited improvement on testosterone levels with the classic antidiabetic drugs. Studies with GLP1-receptor analogues show beneficial effects on both body weight and testosterone levels in men with low testosterone levels and obesity with or without type 2 diabetes. However, data are limited to small and heterogeneous study groups and only few studies report data about impact on and rogen-deficiency-related signs and symptoms. Discussion and conclusion: With the recent advances in the knowledge of the pathophysiological pathways in obesity, there is an enormous progress in the development of medications for obesity and type 2 diabetes. Newer incretin-based agents have a great potential for the treatment of functional hypogonadism due to obesity since they show promising weight reducing results. However, before the use of GLP1-receptor analogues can be suggested to treat functional hypogonadism, further studies are needed. [ABSTRACT FROM AUTHOR]