Androgen treatment of male hypogonadism in older males

The treatment of primary and secondary hypogonadism with testosterone is well established. Recently, there has been increased awareness that low testosterone levels also occur in chronically ill persons and aging males. Because of sex hormone binding globulin changes, it is more appropriate to make the diagnosis using either free or bioavailable testosterone. A small number of controlled studies have suggested that testosterone replacement in older men improves libido, quality of erections, some aspects of cognition, muscle mass, muscles strength, and bone mineral density. It also decreases fat mass and leptin levels. A number of screening questionnaires for the andropause have been developed. Insufficient numbers of older men have been treated with testosterone to characterize the true incidence of side effects. There is a desperate need for well designed, large controlled trials to establish the value or otherwise of testosterone treatment in older males.     

Fundamental aspects of hypogonadism in the aging male

With aging in men, serum testosterone levels decline progressively and the prevalence of hypogonadism increases; these changes are associated with alterations in androgen-regulated physiological functions. In young hypogonadal men, similar alterations improve with testosterone replacement. In older men, short-term testosterone treatment trials suggest benefits (eg, on body composition and bone mineral density), without significant adverse effects. Therefore, androgen deficiency may contribute to physiological decline with aging, and testosterone therapy is reasonable for older men with clinical manifestations of androgen deficiency and low testosterone levels. However, the long-term benefits and potential risks (eg, for prostate disease) of testosterone treatment in older men are unknown.     

Photoperiodic suppression of gonadotrophin secretion in castrated male hamsters

Male golden hamsters were transferred from long to short days and castrated on the day of transfer (Group SP0) or 1, 2 or 3 weeks afterwards (Groups SP1, SP2 & SP3). Animals in Group LP were castrated and maintained on long days. After 7 weeks of short days, plasma levels of LH and FSH were low in Groups SP1, SP2, and SP3. In Group SP0 LH output was also low and FSH secretion, although greater than in Groups SP1, SP2 and SP3, was lower than in the long-day controls (Group LP). This photoperiodic control of gonadotrophin secretion in castrated hamsters raises doubts about the significance of hypothetical alterations in hypothalamo-pituitary sensitivity to sex steroids.     

New advances in the treatment of hypogonadism in the aging male

The signs and symptoms of low testosterone in the aging male include erectile dysfunction, decreased libido, mood disturbances such as depression, loss of muscle mass, osteoporosis, and increase in body fat. Many of these signs and symptoms were previously believed to be part of the normal aging process, and only recently has treatment of low testosterone in the aging male been shown to provide long-term physical and mental improvement. In the past, oral and injectable testosterone delivery methods had disadvantages that limited their use, but the introduction of transdermal testosterone patches has allowed testosterone to be delivered into the circulation in a consistent fashion. Long-term use of these patches over the last 3 to 10 years has been effective in maintaining sexual function and bone and muscle mass, and from short-term studies it does not appear that testosterone treatment puts men at risk for the development of prostate cancer. A new topical gel formation (Testim) has been designed to provide consistent transdermal absorption of testosterone over 24 hours after a single dose.     

Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism

BACKGROUND: No randomized study exists comparing the effects of different modes of androgen substitution on bone mineral density (BMD). METHODS: We performed a prospective, randomized, trial assigning 53 hypogonadal men to the following treatment groups: mesterolone 100 mg p.o. daily, testosterone undecanoate 160 mg p.o. daily, testosterone enanthate 250 mg i.m. every 21 days, or a single subcutaneous implantation of 1,200 mg crystalline testosterone. The BMD was determined by peripheral quantitative computed tomography. RESULTS: At baseline, men with secondary hypogonadism (n = 33) had a lower BMD (-1.52 +/- 0.23 SDS; Z-scores) than men with primary hypogonadism (n = 20, -0.87 +/- 0.23 SDS, p < 0.01). In men with primary hypogonadism, the BMD increased dose dependently (crystalline testosterone +7.0 +/- 1.3%, testosterone enanthate +4.8 +/- 0.2%, testosterone undecanoate +3.4 +/- 2.5%, mesterolone +0.8 +/- 1.6%) after 6 months of therapy. Only secondary hypogonadal men treated with testosterone enanthate experienced an increase of the BMD. CONCLUSIONS: In primary hypogonadal men the BMD responds dose dependently to testosterone substitution, whereas in secondary hypogonadism only testosterone enanthate treatment significantly increased the BMD.     

Genetic analyses of male breast cancer in Israel

Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) germline mutations: 11 individuals from high-risk families and 20 patients unselected for family history of cancer. Two patients of the high-risk group (18.2%) displayed germline mutations: one harbored the 185delAG BRCA1 mutation, and the other the 6174delT mutation in BRCA2. None of the unselected patients displayed any mutation. In 2 patients, complete mutation analysis of the BRCA2 gene did not reveal any disease-associated mutations. We conclude that the predominant Jewish germline mutations in BRCA1/BRCA2 contribute to male breast cancer in Israel, primarily in Ashkenazi individuals with a family history of cancer.     

Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male

Of the gonadal steroids in the male, testosterone is the most important regulator of gonadotrophin secretion. However, whether testosterone affects gonadotrophin secretion directly or whether it must first be aromatized to estrogens is controversial. We have reported extensively on the endocrine and anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS 20267 in adult female rats. In these animals, both inhibitors potently and selectively inhibit estrogen biosynthesis. Thus these agents can be effectively used in studying estrogen-dependent processes. CGS 16949A was administered for 14 days to adult male rats, over a dose range which in females suppresses estradiol and elevates LH. In male rats a suppression of estradiol was seen, however, there was no significant effect on either serum LH or on the weights of androgen-dependent organs. CGS 16949A, when administered to healthy men at a dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol and significant elevations of plasma FSH and testosterone. Dose-dependent suppression of serum estradiol and an increase in serum testosterone and LH are seen after administration of single oral doses of CGS 20267. These results indicate that in the male rat, inhibition of aromatization of testosterone to estrogens does not influence gonadotrophin secretion whereas in men the negative feedback exerted by testosterone on gonadotrophin secretion is dependent on the aromatization of testosterone to estrogens.     

Testicular responsiveness to human chorionic gonadotrophin during transient hypogonadotrophic hypogonadism induced by androgenic/anabolic steroids in power athletes

Serum concentrations of testosterone, 17-hydroxyprogesterone, estradiol and several other unconjugated and sulphated steroids were analyzed before and after a single dose of hCG in 6 power athletes, who had used high doses of testosterone and anabolic steroids for 3 months. The study was carried out 3 weeks after cessation of drug use, but the study subjects were still characterized by hypogonadotrophic hypogonadism. The mean concentrations of serum LH and FSH were 2.6 +/- 0.3 and 1.1 +/- 0.03 mIU/ml (mean +/- SEM), respectively, and the concentrations of several precursors and metabolites of testosterone were lower than those before drug use. In contrast, circulating concentrations of steroid sulphates were not decreased, with the exception of dehydroepiandrosterone sulphate. After hCG injection serum testosterone and 5 alpha-dihydrotestosterone concentrations increased significantly, whereas no increases in estradiol and 17-hydroxyprogesterone concentrations were observed. These results demonstrate that during transient hypogonadotrophism in adult men, the testicular responsiveness to a single injection of hCG is similar to that in prepubertal boys without any sign of steroidogenic lesion at the 17,20-desmolase step. Therefore, the appearance of the possibly estradiol-mediated inhibition at the level of C21-steroid side-chain splitting in testosterone biosynthesis seems to be dependent on priming by gonadotrophins.     

Hormonal responses to gonadotrophin releasing hormone during testicular development in male African green monkeys

Reproductive development in male African green monkeys was characterized by evaluating both luteinizing hormone (LH) and testosterone (T) before and after gonadotrophin releasing hormone (GnRH) stimulation in relation to the physical maturation of the testis. There were LH responses to GnRH at all ages studied, but the failure of some animals to respond at earlier ages suggested developmental changes in the responsiveness of the pituitary. The T secretion developed progressively but did not reach adultlike characteristics until approximately 44 months of age, at which time sperm could be demonstrated in ejaculated semen.     

Genome analyses substantiate male mutation bias in many species

In many species the mutation rate is higher in males than in females, a phenomenon denoted as male mutation bias. This is often observed in animals where males produce many more sperm than females produce eggs, and is thought to result from differences in the number of replication-associated mutations accumulated in each sex. Thus, studies of male mutation bias have the capacity to reveal information about the replication-dependent or replication-independent nature of different mutations. The availability of whole genome sequences for many species, as well as for multiple individuals within a species, has opened the door to studying factors, both sequence-specific and those acting on the genome globally, that affect differences in mutation rates between males and females. Here, we assess the advantages that genomic sequences provide for studies of male mutation bias and general mutation mechanisms, discuss major challenges left unresolved, and speculate about the direction of future studies.     

Effects of male hypogonadism on regional adipose tissue fatty acid storage and lipogenic proteins

Testosterone has long been known to affect body fat distribution, although the underlying mechanisms remain elusive. We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. Twelve men with chronic hypogonadism and 13 control men matched for age and body composition: 1) underwent measures of body composition with dual energy x-ray absorptiometry and an abdominal CT scan; 2) consumed an experimental meal containing [(3)H]triolein to determine the fate of meal FA (biopsy-measured adipose storage vs. oxidation); 3) received infusions of [U-(13)C]palmitate and [1-(14)C]palmitate to measure rates of direct free (F)FA storage (adipose biopsies). Adipose tissue lipoprotein lipase, acyl-CoA synthetase (ACS), and diacylglycerol acetyl-transferase (DGAT) activities, as well as, CD36 content were measured to understand the mechanism by which alterations in fat storage occur in response to testosterone deficiency. Results of the study showed that hypogonadal men stored a greater proportion of both dietary FA and FFA in lower body subcutaneous fat than did eugonadal men (both p<0.05). Femoral adipose tissue ACS activity was significantly greater in hypogonadal than eugonadal men, whereas CD36 and DGAT were not different between the two groups. The relationships between these proteins and FA storage varied somewhat between the two groups. We conclude that chronic effects of testosterone deficiency has effects on leg adipose tissue ACS activity which may relate to greater lower body FA storage. These results provide further insight into the role of androgens in body fat distribution and adipose tissue metabolism in humans.