The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms. Testosterone, as one of the most critical sex hormones, is essential for the development of the reproductive system, maintenance of reproductive function, and the overall health of males. The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes. Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis. We also examined the specific effects of these genes on the occurrence, development, and treatment of common male diseases, including late-onset hypogonadism, erectile dysfunction, male infertility, and prostate cancer.
Testosterone/metabolism* ; Humans ; Male ; Circadian Clocks/genetics* ; Circadian Rhythm Signaling Peptides and Proteins/metabolism* ; Circadian Rhythm/physiology* ; Hypogonadism/metabolism* ; Erectile Dysfunction/metabolism* ; Infertility, Male/metabolism* ; Prostatic Neoplasms/metabolism* ; Men's Health

Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. It is a major transformational period of life, whose timing is strongly affected by genetic makeup of the individual, along with various internal and external factors. Although the exact mechanism for initiation of the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. We developed a classification of the mechanisms involved in male puberty that allowed placing many genes into physiological context. These include (i) hypothalamic development during embryogenesis, (ii) synaptogenesis where gonadotropin releasing hormone (GnRH) neurons form neuronal connections with suprahypothalamic neurons, (iii) maintenance of neuron homeostasis, (iv) regulation of synthesis and secretion of GnRH, (v) appropriate receptors/proteins on neurons governing GnRH production and release, (vi) signaling molecules activated by the receptors, (vii) the synthesis and release of GnRH, (viii) the production and release of gonadotropins, (ix) testicular development, (x) synthesis and release of steroid hormones from testes, and (xi)the action of steroid hormones in downstream effector tissues. Defects in components of this system during embryonic development, childhood/adolescence, or adulthood may disrupt/nullify puberty, leading to long-term male infertility and/or hypogonadism. This review provides a list of 598 genes involved in the development of HPT axis and classified according to this schema. Furthermore, this review identifies a subset of 75 genes for which genetic mutations are reported to delay or disrupt male puberty.
Adolescent ; Male ; Humans ; Adult ; Child ; Gonadotropin-Releasing Hormone ; Gonadotropins/metabolism* ; Hypogonadism ; Testis/metabolism* ; Puberty/physiology* ; Sexual Maturation

In men, obesity and metabolic complications are associated with lower serum testosterone (T) and dihydrotestosterone (DHT) and an increased risk of, and mortality from, multiple chronic diseases in addition to cardiovascular disease (CVD). The causal interrelationships between these factors remain a matter of debate. In men with untreated congenital and lifelong forms of hypogonadotropic hypogonadism, there appears to be no increased risk. Men with Klinefelter's syndrome have an increased risk of various types of cancers, as well as CVD, which persist despite T therapy. In the absence of pathology of the hypothalamic-pituitary-gonadal axis, the effect of modest reductions in serum T in aging men is unclear. The prevalence of low serum T concentrations is high in men with cancer, renal disease, and respiratory disease and is likely to be an indicator of severity of systemic disease, not hypogonadism. Some population-based studies have found low serum T to be associated with a higher risk of deaths attributed to cancer, renal disease, and respiratory disease, while others have not. Although a meta-analysis of longitudinal studies has shown an association between low serum T and all-cause mortality, marked heterogeneity between studies limited a firm conclusion. Therefore, while a decrease in T particularly occurring later in life may be associated with an increase in all-cause and specific types of mortality in men, the differential effects, if any, of T and other sex steroids as compared to health and lifestyle factors are unknown at the current time.
Age Factors ; Cardiovascular Diseases/metabolism* ; Cause of Death ; Dihydrotestosterone/metabolism* ; Humans ; Hypogonadism/metabolism* ; Klinefelter Syndrome/metabolism* ; Male ; Mortality ; Obesity/metabolism* ; Testosterone/metabolism*

Epidemiological studies hint at a beneficial influence of endogenous circulating testosterone (T), or its metabolite dihydrotestosterone (DHT), such that men with lower concentrations of T or DHT appear to have poorer health outcomes including frailty, diabetes, cardiovascular disease, and mortality. Small interventional studies of T have shown favorable effects on surrogate outcome measures, but a large randomized controlled trial (RCT) with the prespecified outcome of cardiovascular events has not been performed and would be logistically demanding. In the absence of such a definitive RCT, there is a controversy about the cardiovascular risks of T-therapy fuelled by contradictory findings from retrospective analyses of insurance databases of men prescribed T. The US Testosterone Trials (T-Trials) are the largest published RCTs of T-therapy in older men with symptoms or signs of hypogonadism and circulating T <9.54 nmol l⁻¹ at baseline. The T-Trials showed a modest benefit of T-therapy over a 12-month period on sexual function, a significant benefit in bone density and for anemia and neutral effect on cognition. The T-Trials cardiovascular sub-study was designed to determine the effects of T in these older men, and there was a statistically significant difference in the increase in noncalcified plaque volume in the T-treated group compared to placebo, but it is difficult to interpret these results due to differences in baseline coronary plaque burden (>50% difference) between the treatment and placebo arms of the subset involved. Therefore, there continues to be ongoing uncertainty over the effect of T-therapy on the cardiovascular system in men.
Age Factors ; Androgens/therapeutic use* ; Cardiovascular Diseases/metabolism* ; Dihydrotestosterone/metabolism* ; Hormone Replacement Therapy ; Humans ; Hypogonadism/metabolism* ; Male ; Protective Factors ; Risk Factors ; Testosterone/therapeutic use*

OBJECTIVETo evaluate the efficacy and safety of testosterone undecanoate (TU) in the treatment of late-onset hypogonadism (LOH) by meta-analysis.

METHODSWe searched Pubmed (until April 1, 2014), Embase (until March 28, 2014), Cochrane Library (until April 17, 2014), CBM (from January 1, 2001 to February 2, 2014), CNKI (from January 1, 2001 to February 2, 2014), Wanfang Database (from January 1, 2000 to February 2, 2014), and VIP Database (from January 1, 2000 to Febru ary 2, 2014) for randomized controlled trials of TU for the treatment of LOH. We evaluated the quality of the identified literature and performed meta-analysis on the included studies using the Rveman5. 2 software.

RESULTSTotally, 14 studies were included after screening, which involved 1 686 cases. Compared with the placebo and blank control groups, TU treatment significantly increased the levels of serum total testosterone (SMD = 6.22, 95% CI 3.99 to 8.45, P < 0.05) and serum free testosterone (SMD = 4.35, 95% CI 1.86 to 6. 85, P < 0.05) but decreased the contents of luteinizing hormone (WMD = -2.23, 95% CI -4.03 to -0.42, P < 0.05), sex hormone binding globulin (WMD = 2.00, 95% CI 1.38 to 2.63, P < 0.05). TU also remarkably reduced the scores of Partial Androgen Deficiency of the Aging Males (WMD = -9.49, 95% CI -12.96 to -6.03, P < 0.05) and Aging Males Symptoms rating scale (WMD = -2.76, 95% CI -4.85 to -0.66, P <0.05) but increased the hemoglobin level (SMD = 2.35, 95% CI 0.29 to 4.41, P < 0.05) and packed-cell volume (SMD = 4.35, 95% CI 1.36 to 7.33, P < 0.05). However, no significant changes were shown in aspertate aminotransferase, alanine transaminase, prostate-specific antigen, or prostate volume after TU treatment (P > 0.05).

CONCLUSIONTU could significantly increase the serum testosterone level and improve the clinical symptoms of LOH patients without inducing serious adverse reactions. However, due to the limited number and relatively low quality of the included studies, the above conclusion could be cautiously applied to clinical practice.

Androgens ; therapeutic use ; Hemoglobin A ; metabolism ; Humans ; Hypogonadism ; blood ; drug therapy ; Luteinizing Hormone ; blood ; Male ; Prostate-Specific Antigen ; Randomized Controlled Trials as Topic ; Sex Hormone-Binding Globulin ; metabolism ; Testosterone ; adverse effects ; analogs & derivatives ; blood ; pharmacology

Hemochromatosis is an inherited genetic disorder of iron metabolism which can also occur as a secondary result of iron-overload. It leads to organ damage such as cardiomyopathy, liver cirrhosis, hypogonadism, and diabetes. This paper discusses a case of secondary hemochromatosis associated with repeated transfusions, presenting as asymptomatic hypoparathyroidism and subclinical hypothyroidism with multiple organ involvement. The 29-year-old female, who had severe aplastic anemia, received multiple transfusions totaling approximately 1,400 units of red blood cells over 15 years. During her routine laboratory examination, hypocalcemia was detected with decreased intact parathyroid hormone and increased thyroid stimulating hormone. Serum ferritin, iron, and total iron binding capacity had increased to 27,583.03 ng/mL, 291 microg/dL, and 389 microg/dL, respectively. She had unusually bronze skin and computed tomography revealed iron deposition in the thyroid, liver, and heart. Multiorgan involvement as seen in this case is rare in hemochromatosis associated with secondary transfusions. To the best of the author's knowledge, this is the first case report in Korea of hypoparathyroidism and subclinical hypothyroidism due to iron deposition in the parathyroid and thyroid gland.
Adult ; Anemia, Aplastic ; Cardiomyopathies ; Erythrocytes ; Female ; Ferritins ; Heart ; Hemochromatosis* ; Humans ; Hypocalcemia ; Hypogonadism ; Hypoparathyroidism* ; Hypothyroidism* ; Iron ; Korea ; Liver ; Liver Cirrhosis ; Metabolism ; Parathyroid Hormone ; Skin ; Thyroid Gland ; Thyrotropin

We screened the pharmacological effects of a 50% ethanol extract of Yacon tubers and leaves on spermatogenesis in rats. As a result, we found that Yacon tuber extracts increased sperm number and serum testosterone level in rats. It has been reported that the crude extract of Yacon tubers and leaves contain phenolic acids, such as, chlorogenic acid, ferulic acid and caffeic acid by HPLC/MS analysis. We were interested in the contributions made by phenolic acid, particularly chlorogenic acid of Yacon tuber extract to the spermatogenic activity. After administering Yacon tuber extract or chlorogenic acid to rats for 5 weeks, numbers of sperm in epididymis were increased by 34% and 20%, respectively. We also administered ferulic acid, which has been reported to be a metabolite of chlorogenic acid and a constituent of Yacon tuber extract to investigate its spermatogenic activity in rats. Yacon tuber extract and ferulic acid increased sperm numbers by 43% and 37%, respectively. And, Yacon tuber extract, and chlorogenic acid showed significantly inhibition effect of testoeterone degradation in rat liver homogenate. We considered that the spermatogenic effect of Yacon tuber extract might be related to phenolic compounds and their inhibitory effect of testosterone degradation. Yacon showed the possibility as ameliorable agents of infertility by sperm deficiency and late onset hypogonadism syndrome with low level of testosterone.
Animals ; Chlorogenic Acid ; Epididymis ; Ethanol ; Hypogonadism ; Infertility ; Liver ; Male ; Metabolism* ; Phenol ; Rats ; Sperm Count ; Spermatogenesis ; Spermatozoa ; Testosterone*

OBJECTIVETo investigate the effect of the method of tonifying the kidney and activating blood circulation on the testosterone secretion index (TSI) in late-onset hypogonadism (LOH) male patients with kidney deficiency and its possible mechanisms.

METHODSWe screened 60 LOH male patients with kidney deficiency based on the scores on Partial Androgen Deficiency in Aging Males (PADAM), the levels of serum total testosterone (TT) and luteinizing hormone (LH), and TSI (TT/LH). We randomly divided the patients into a Nan Geng Ning (NGN) group (n = 40, aged 55.02 +/- 11.37 years) and a control group (n = 20, aged 54.56 +/- 12.12 years) to be treated orally with NGN decoction and testosterone undecanoate capsules, respectively, both for 12 consecutive weeks. We obtained the scores on psychological status, physical status and sexual function and observed the changes in serum TT, LH and TSI after 4, 8 and 12 weeks of treatment.

RESULTSCompared with the baseline, both the NGN and control groups showed a significant reduction after 12 weeks of medication in the LH level ([5.32 +/- 2.08] vs [4.89 +/- 1.46] IU/L and [5.36 +/- 2.07] vs [4.81 +/- 1.75] IU/L, P < 0.05), psychological status score (5.2 +/- 1.3 vs 2.7 +/- 1.4 and 4.8 +/- 2.2 vs 2.9 +/- 1.2, P < 0.05), physical status score (6.9 +/- 2.5 vs 2.9 +/- 1.6 and 7.1 +/- 2.7 vs 3.1 +/- 1.5, P < 0.05) and sexual function score (10.2 +/- 3.3 vs 4.5 +/- 2.9 and 9.8 +/- 3.1 vs 4.8 +/- 3.0, P < 0.05), but a remarkable increase in the TT level ([11.13 +/- 0.69] vs [14.55 +/- 0.75] nmol/L and [10.99 +/- 0.74] vs [14.74 +/- 0.83] nmol/L, P < 0.05) and TSI ([2.14 +/- 0.65] vs [2.99 +/- 0.72] nmol/IU and ([2.05 +/- 0.73] vs [3.11 +/- 0.65] nmol/IU, P < 0.05). However, no significant differences were found between the NGN and control groups at 12 weeks in LH ([4.89 +/- 1.46] vs [4.81 +/- 1.75] IU/L, P > 0.05), TT ([14.55 +/- 0.75] vs [14.74 +/- 0.83] nmol/L, P > 0.05), TSI ([2.99 +/- 0.72] vs [3.11 +/- 0.65] nmol/IU, P > 0.05), psychological status score (2.7 +/- 1.4 vs 2.9 +/- 1.2, P > 0.05), physi- cal status score (2.9 +/- 1.6 vs 3.1 +/- 1.5, P > 0.05) and sexual function score (4.5 +/- 2.9 vs 4.8 +/- 3.0, P > 0.05). There were no adverse events in either of the two groups throughout the whole experiment.

CONCLUSIONThe method of tonifying the kidney and activating blood circulation could significantly improve the clinical symptoms of LOH with kidney deficiency and increase the patient's serum TT level and TSI. NGN decoction works on LOH by acting on the hypothalamic-pituitary-gonad axis.

Adult ; Aged ; Humans ; Hypogonadism ; diagnosis ; drug therapy ; metabolism ; Luteinizing Hormone ; blood ; Male ; Medicine, Chinese Traditional ; methods ; Middle Aged ; Phytotherapy ; Testis ; secretion ; Testosterone ; analogs & derivatives ; blood ; therapeutic use ; Treatment Outcome

OBJECTIVETo study the regulatory effect of Bushenfang on the serum testosterone (T) level of naturally aging rats and its mechanism, in order to provide a theoretical and experimental basis for the clinical treatment of late onset hypogonadism (LOH) in males.

METHODSThirty-two 18-month-old male SD rats were randomly divided into four groups of equal number, naturally aging model and low-, medium- and high-dose Bushenfang groups, and another eight 4-month-old rats were taken as normal controls. The rats of the aging model and normal control groups were treated with normal saline, while those of the low-, medium- and high-dose Bushenfang groups received intragastrically Bushenfang at 3.25, 7.50 and 15.00 g/kg, respectively, all for 3 weeks. Then the rats were sacrificed, the histomorphologic changes of the testis observed by HE staining, the serum T level measured by radioimmunoassay, and the expressions of the StAR protein, P450scc and 3beta-HSD I determined by RT-PCR.

RESULTSThe number of Leydig cells was obviously increased after Bushenfang treatment. The levels of serum T were significantly higher in the low-, medium- and high-dose Bushenfang groups ([6.74 +/- 1.56] nmol/L, [8.50 +/- 1.99] nmol/L and [12.41 +/- 2.91] nmol/L) than in the model group ([3.48 +/- 0.75] nmol/L) (P < 0.05). The three Bushenfang groups also showed a remarkable elevation in the mRNA expressions of StAR (0.74 +/- 0.29, 0.83 +/- 0.32 and 1.35 +/- 0.50), P450scc (0.72 +/- 0.36, 1.023 +/- 0.30 and 1.41 +/- 0.37) and 3beta-HSD I (0.58 +/- 0.14, 0.72 +/- 0.07 and 0.85 +/- 0.18), as compared with the models (StAR: 0.44 +/- 0.09; P450scc: 0.33 +/- 0.05; 3beta-HSD I: 0.34 +/- 0.02), with significant differences in the StAR expression between the high-dose Bushenfang and the model groups, as well as in P450scc and 3beta-HSD I expressions between the medium- and high-dose Bushenfang and the model groups (P < 0.05).

CONCLUSIONBushenfang could improve the pathological status of testicular injury and increase the expression of testosterone synthetase, which might be the mechanism behind its regulatory effect on the serum T level of aging rats.

Aging ; drug effects ; Animals ; Drugs, Chinese Herbal ; pharmacology ; Hypogonadism ; drug therapy ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Testis ; drug effects ; Testosterone ; metabolism

PURPOSE: The aim of this preliminary study was to determine the possible relationship between alkaline phosphatase (ALP) levels in the gingival crevicular fluid (GCF) and periodontal disease in men with hypergonadotropic hypogonadism (HH). MATERIALS AND METHODS: A total of 41 patients were divided into four groups. 9 with HH and periodontitis (P/HH), 11 with HH and gingivitis (G/HH), 12 with systemically healthy and periodontally healthy (H/C) and 9 with systemically healthy and periodontitis (P/C). The clinical evaluation of patients was based on the following parameters; the plaque index (PI), gingival index (GI), probing depths (PD) and attachment level (AL). The levels of ALP in the GCF were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: No significant difference could be detected in the mean clinical parameter data between the P/HH and P/C groups (p > 0.05). The periodontitis patients in both groups (P/C and P/HH) had higher mean probing depths than the H/C and G/HH patients (p < 0.001). The concentrations and total amounts of ALP in the GCF were significantly higher in both periodontitis groups compared to healthy and gingivitis groups (p < 0.01). The serum ALP levels were significantly higher in the P/HH group when compared to the other groups (p < 0.001). CONCLUSION: The findings of this study suggested that HH could be implicated as a contributing factor to the progress of periodontal disease.
Adolescent ; Adult ; Alkaline Phosphatase/*metabolism ; Gingival Crevicular Fluid/*enzymology ; Humans ; Hypogonadism/diagnosis/*enzymology ; Male ; Periodontium/*enzymology