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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.

Adult↗

No difference in pubertal growth and final height between treated hypogonadal and non-hypogonadal thalassemic patients.

BACKGROUND: Many factors can negatively affect growth in thalassemic patients, and hypogonadism has been considered as the main factor responsible for their pubertal growth failure. OBJECTIVE: To evaluate the influence of hypogonadism and its treatment on pubertal growth and final height in thalassemic patients. METHODS: We compared the growth of 28 hypogonadal thalassemic patients in whom puberty was induced to that of 25 patients in whom puberty occurred spontaneously. RESULTS: In both groups of patients we observed reduced peak height velocity (induced puberty: females 4.9 +/- 2.1, males 6.0 +/- 1.8 cm/year; spontaneous puberty: females 6.1 +/- 1.5, males 7.3 +/- 2.1 cm/year) and pubertal height gain (induced puberty: females 11.3 +/- 4.0, males 18.0 +/- 4.5 cm/year; spontaneous puberty: females 15.8 +/- 2.7, males 18.1 +/- 5.3 cm/year) and a short final height (induced puberty: females -1.8 +/- 0.7, males -2.1 +/- 1.0 SDS; spontaneous puberty: females -2.3 +/- 1.0, males -1.9 +/- 1.0 SDS). CONCLUSIONS: Poor pubertal growth is present in thalassemic patients regardless of hypogonadism. Other factors are responsible for the reduced growth spurt and the final short stature observed in these patients.

Adolescent↗

Hypogonadotropic hypogonadal men respond less well to androgen substitution treatment than hypergonadotropic hypogonadal men.

This research asked whether androgen substitution therapy is as efficacious in hypogonadotropic hypogonadal men as in hypergonadotropic hypogonadal men. Erotosexual functions of two groups of six men of each diagnostic category were compared after 5-6 years of continuous androgen treatment. Treatment regimen was the same in both groups: Parenteral testosterone esters 250 mg/2 weeks. No difference was found in erectile and ejaculatory potency, but the number of sexual acts and scores of subjective quality of sexual acts, sexual excitement, and frequency of sexual thoughts and of nonsexual parameters as vigor, fatigue, anxiety were more negative in the hypogonadotropic men. The most obvious difference between the two groups is the value of LH/FSH and presumably of LHRH. Hypogonadotropic hypogonadal men may be better treated with gonadotropins (or with pulsatile LHRH, when the hypophysis is intact) than with androgens.

Adolescent↗

Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism.

The efficacy and safety of highly purified follicle stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) was studied in 60 men with hypogonadotrophic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotrophic hypogonadism and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynaecomastia. No local reactions at injection site were observed. In conclusion, the s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.

Adult↗

Hypogonadism and methadone: Hypothalamic hypogonadism after long-term use of high-dose methadone.

OBJECTIVE: To assess the relationship between hypogonadism and long-term administration of high-dose methadone. METHODS: We present a case of a 47-year-old man with a history of heroin use and treatment with high doses of methadone (130 mg/day), who complained of gynecomastia and impotence. Baseline levels of serum luteinizing hormone (LH), serum follicle-stimulating hormone (FSH), plasma testosterone, and prolactin were determined, and then the response of gonadotropin levels to stimulation with gonadotropin-releasing hormone (GnRH) was examined at 30, 60, 90, 120, and 180 minutes. RESULTS: Basal values of testosterone, LH, and FSH were below normal levels, whereas prolactin was normal. After administration of GnRH, the patient had a suboptimal increase in LH levels and lack of a response of FSH. When the daily dose of methadone was decreased to 40 mg, the patient's libido returned, and LH, FSH, and testosterone levels increased. CONCLUSION: These findings could indicate the presence of (1) a direct effect of methadone on the hypothalamus that leads to an alteration in normal gonadotropin pulse patterns, or (2) a selective effect of methadone on the anterior pituitary that alters its response to GnRH, with either mechanism leading to a reversible, dose-related depression of testosterone levels.

Journal Article↗

Usefulness of the free alpha-subunit to diagnose hypogonadotropic hypogonadism.

OBJECTIVE: Differentiating constitutional delay of growth and puberty from hypogonadotropic hypogonadism is still a problem in clinical practice. Our previous study demonstrated that the peak/basal ratio of the free alpha-subunit of the glycoprotein hormones is higher in normal prepubertal boys than in male adults with hypogonadotropic hypogonadism. The objective of this study was to assess the performance of this ratio in normal male patients at different ages and levels of pubertal development, and in patients with hypogonadotropic hypogonadism, both isolated and combined with other pituitary hormone deficiencies. DESIGN: Cohort study. PATIENTS: Twenty-eight normal prepubertal males between 6 and 8 years; 20 normal prepubertal males between 9 and 13 years; 18 males with constitutional delay of growth and puberty; 26 normal pubertal males; 13 adult men with isolated hypogonadotropic hypogonadism; 21 adult men with complete hypogonadotropic hypogonadism combined with other hormone deficiencies; and 11 adult men with partial hypogonadotropic hypogonadism combined with other hormone deficiencies. MEASUREMENTS: Serum levels of free alpha-subunit immediately before (basal), and 30 and 60 min after 100 micro g intravenous GnRH were measured by immunofluorimetry. Median and P25-P75 range of the peak/basal ratio of the free alpha-subunit was determined for each group. A receiver operating characteristics curve was calculated. Results were compared using the Kruskal-Wallis test. RESULTS: The peak/basal ratio of the free alpha-subunit was higher in patients with constitutional delay of growth and puberty (7.46) than in those with isolated hypogonadotropic hypogonadism (2.73), complete combined hypogonadotropic hypogonadism (1.58), and partial combined hypogonadotropic hypogonadism (2.61; P < 0.001). A peak/basal ratio < 3.26 identified hypogonadotropic hypogonadism with 93.2% sensitivity and 94.4% specificity when compared to constitutional delay of growth and puberty. There was no statistical difference between the peak/basal ratio of prepubertal patients between 6 and 8 years (7.20), patients between 8 and 13 years (8.71), normal pubertal males (8.10) and those with constitutional delay of growth and puberty (7.46). In a group of boys with delayed puberty, a cut-off point of 3.69 defined hypogonadotropic hypogonadism with 95.6% sensitivity and 94.4% specificity. A cut-off point of 4.81 gave 100% sensitivity (88.9% specificity), and 3.09 gave 100% specificity (86.7% sensitivity). CONCLUSIONS: The peak/basal ratio of the free alpha-subunit can be used for the differential diagnosis of constitutional delay of growth and puberty and hypogonadotropic hypogonadism, irrespective of age. This distinction allows early investigation and treatment of patients with hypogonadotropic hypogonadism and reassurance for those with constitutional delay of growth and puberty.

Adolescent↗

Serum zinc, retinol and retinol-binding protein levels in cirrhotics with hypogonadism.

Levels of serum zinc, retinol and retinol-binding protein (RBP) were measured in 16 male hypogonadal cirrhotics and compared with 13 male cirrhotic patients without evidence of hypogonadism. Their ages ranged from 20 years to 76 years with a mean of 40.06 +/- 15.6 years (+/- s.e.m.) while non-hypogonadal patients had an age range of 30-55 years with a mean of 41.23 +/- 7.2 years. Mean testicular volume for hypogonadal patients was 6.69 +/- 3.5 cm3 (+/- s.e.m.) while for non-hypogonadal ones it was 12.15 +/- 6.0 cm3. Mean serum zinc level in hypogonadal patients was 4.43 +/- 0.05 mumol/l which was significantly lower than for those without hypogonadism (6.8 +/- 0.09 mumol/l). Similarly serum retinol was lower in hypogonadal patients (0.40 +/- 0.07 mumol/l) than in patients without hypogonadism (0.53 +/- 0.12), although this difference was not statistically significant. RBP was also lower in the hypogonadal patients (0.79 +/- 0.49 mumol/l) than in those without (1.36 +/- 0.74 mumol/l, P less than 0.05). It is concluded that hypogonadal cirrhotics have lower levels of serum zinc and RBP than those without hypogonadism. These deficiencies may contribute to the genesis of hypogonadism in cirrhosis of the liver and supplementation of zinc alone or with vitamin A early in the disease may retard the development of this feature of the disease.

Adult↗

Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls.

OBJECTIVE: The potential use of testosterone preparations for substitution therapy for ageing men and for male contraception, in addition to the well established substitution therapy of male hypogonadism, make increased testosterone use likely. However, little clinical information is available on the effect of testosterone therapy on the prostate in hypogonadal men. DESIGN AND MEASUREMENTS: In a controlled cross-sectional study, prostate volume measured by transrectal ultrasonography, serum levels of prostate-specific antigen (PSA) and sex hormones, and uroflow parameters were determined. PATIENTS: Three groups of age-matched men were enrolled in the study: 47 newly diagnosed hypogonadal men before testosterone treatment, 78 hypogonadal men with at least 6 months of effective testosterone therapy and 75 normal men. RESULTS: Regression analysis revealed a significant positive correlation of prostate volume with age in normal men and testosterone-treated hypogonadal men, whereas no significant correlation was detected in untreated hypogonadal men. Prostate volume was significantly lower in untreated hypogonadal men (12.2 (11.0-13.5) ml) (mean (95% confidence limits)) compared to both other groups. However, no significant difference in prostate volume was detected between testosterone-treated hypogonadal men (21.3 (19.9-22.8) ml) and normal men (22.9 (21.4-24.4) ml). Similar results were obtained for PSA with comparable values in the testosterone-treated hypogonadal men (0.98 (0.88-1.10) micrograms/l) and normal men (1.02(0.91-1.14) micrograms/l), and significantly lower concentrations in the untreated hypogonadal men (0.64 (0.55-0.73) micrograms/l). No differences in uroflow parameters were detected between the three study groups. CONCLUSIONS: Effective testosterone treatment of hypogonadal men results in prostate volume and prostate-specific antigen levels comparable to age-matched normal men. Therefore, testosterone-induced prostate growth should not preclude hypogonadal men from testosterone substitution therapy.

Adult↗

Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study.

BACKGROUND: Both hypogonadism and low estrogen levels adversely affect bone health in young men. In elderly men, who are at greatest risk for osteoporotic fracture, the influence of hypogonadism on bone mineral density remains unclear, as does the relative effect of estrogen status compared to hypogonadism. OBJECTIVE: To examine the relation of hypogonadism and estrogen status to bone mineral density in elderly men. DESIGN: Community-based, prospective cohort study. SETTING: Framingham, Massachusetts. PATIENTS: Male participants of the Framingham Study. MEASUREMENTS: Total testosterone, total estradiol, and luteinizing hormone were measured in participants at all four biennial examinations from 1981 to 1989. Values from at least three of four examinations were averaged. Hypogonadism was defined as a mean testosterone level less than 10.4 nmol/L (<3.0 ng/mL) or a mean luteinizing hormone level of 20 IU/L or greater. An alternate definition of hypogonadism based only on a mean testosterone level less than 10.4 nmol/L (<3.0 ng/mL) was also used. In 1988-1989, bone mineral density was measured at the proximal femur (femoral neck, Ward triangle, and trochanter) and lumbar spine by using dual-photon absorptiometry and at the radial shaft by using single-photon absorptiometry. The association of hypogonadism with bone mineral density was examined with adjustment for confounders, including estradiol levels. A similar model that adjusted for hypogonadism was used to examine the association of estradiol level (ranked as quartiles) with bone mineral density. RESULTS: Of 448 men with bone mineral density measurements, 405 had evaluable hormone levels (mean age, 75.7 years [range, 68 to 96 years]); 71 (17.5%) of the 405 men were hypogonadal. Bone mineral density at any site did not significantly differ in hypogonadal men compared with eugonadal men (for example, bone mineral density at the femoral neck was 0.89 g/cm(2) vs. 0.87 g/cm(2), respectively; P > 0.2), even when alternate definitions of hypogonadism were used. In contrast, compared with the lowest estradiol quartile, men with higher estradiol levels had greater mean bone mineral density at all sites (for example, bone mineral density at the femoral neck was 0.84 g/cm(2), 0.88 g/cm(2), 0.86 g/cm(2), and 0.91 g/cm(2) from the lowest to the highest estradiol quartile; P for trend = 0.002). The difference in mean bone mineral density between men in the lowest and those in the highest estradiol quartile levels was similar to the effect of 10 years of aging on bone mineral density. CONCLUSIONS: In elderly men, hypogonadism related to aging has little influence on bone mineral density, but serum estradiol levels have a strong and positive association with bone mineral density.

Aged↗