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David J Handelsman

Publications and source records attributed to David J Handelsman.

At least 55 records · Page 3Linked to original sources
PubMed2003

Luteinizing hormone receptor-mediated effects on initiation of spermatogenesis in gonadotropin-deficient (hpg) mice are replicated by testosterone.

Testosterone (T) is an absolute requirement for spermatogenesis and is supplied by mature Leydig cells stimulated by LH. We previously showed in gonadotropin-deficient hpg mice that T alone initiates qualitatively complete spermatogenesis bypassing LH-dependent Leydig cell maturation and steroidogenesis. However, because maximal T effects do not restore testis weight or germ cell number to wild-type control levels, additional Leydig cell factors may be involved. We therefore examined 1). whether chronic hCG administration to restore Leydig cell maturation and steroidogenesis can restore quantitatively normal spermatogenesis and testis development and 2). whether nonandrogenic Leydig cell products are required to initiate spermatogenesis. Weanling hpg mice were administered hCG (0.1-100 IU i.p. injection three times weekly) or T (1-cm subdermal Silastic implant) for 6 weeks, after which stereological estimates of germinal cell populations, serum and testicular T content, and testis weight were evaluated. Human CG stimulated Leydig cell maturation and normalized testicular T content compared with T treatment where Leydig cells remained immature and inactive. The maximal hCG-induced increases in testis weight and serum T concentrations were similar to those for T treatment and produced complete spermatogenesis characterized by mature, basally located Sertoli cells (SCs) with tripartite nucleoli, condensed haploid sperm, and lumen development. Compared with T treatment, hCG increased spermatogonial numbers, but both hCG and T had similar effects on numbers of spermatocytes and round and elongated spermatids per testis as well as per SC. Nevertheless, testis weight and germ cell numbers per testis and per SC remained well below phenotypically normal controls, confirming the involvement of non-Leydig cell factors such as FSH for quantitative normalization of spermatogenesis. We conclude that hCG stimulation of Leydig cell maturation and steroidogenesis is not required, and that T alone mostly replicates the effects of hCG, to initiate spermatogenesis. Because T is both necessary and sufficient for initiation of spermatogenesis, it is likely that T is the main Leydig cell secretory product involved and that additional LH-dependent Leydig cell factors are not essential for induction of murine spermatogenesis.

Androgens↗
PubMed2003

Physiological testosterone replacement and arterial endothelial function in men.

OBJECTIVE: The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long-term physiological androgen replacement therapy, at trough and peak testosterone levels. PATIENTS AND DESIGN: We recruited nine hypogonadal men (aged 35 +/- 4 years) receiving androgen replacement therapy, each treated with 800 mg testosterone (T) depot preparations every 6 months. MEASUREMENTS: Serum lipid and hormone levels and arterial reactivity were measured, prior to (trough T) and 2-4 weeks following testosterone administration (peak T). Each subject therefore served as their own control. Vessel diameter was measured by ultrasound at rest, during reactive hyperaemia [leading to flow-mediated dilatation (FMD), an endothelium-dependent response] and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). RESULTS: Serum T (13 +/- 2 nmvs. 27 +/- 3 nm for trough and peak serum T, respectively, P < 0.001; normal adult male range 11-35 nm), and free T (195 +/- 23 pmvs. 510 +/- 93 pm, P < 0.005) significantly increased following subcutaneous depot T administration, as did serum oestradiol (100 +/- 10 pmvs. 175 +/- 9 pm, P = 0.001; normal adult male range < 250 pm). There was a significant decrease in FMD (3.6 +/- 1.1%vs. 3.0 +/- 0.8%, P < 0.01), but GTN responses were similar (9.5 +/- 0.8%vs. 10.4 +/- 1.0%, P > 0.2). Lipid, blood pressure and vessel diameter measurements were also similar before and after testosterone administration. CONCLUSION: Physiological replacement of testosterone is associated with decreased endothelium-dependent dilatation, in hypogonadal men.

Adult↗
PubMed2003

Sertoli and germ cell development in hypogonadal (hpg) mice expressing transgenic follicle-stimulating hormone alone or in combination with testosterone.

We recently created a novel transgenic (tg) model to examine the specific gonadal actions of FSH, distinct from LH effects, by expressing tg-FSH in gonadotropin-deficient hypogonadal (hpg) mice. Using this unique in vivo paradigm, we now describe the postnatal cellular development in seminiferous tubules selectively stimulated by tg-FSH alone or combined with testosterone (T). In the alphabeta.6 line, tg-FSH stimulated the maturation and proliferation ( approximately 2-fold) of Sertoli cells in hpg testes. Total Sertoli cell numbers were also significantly increased (1.5-fold) independently of FSH effects by T treatment alone. Selective FSH activity in alphabeta.6 hpg testes increased total spermatogonia numbers 3-fold, which established a normal spermatogonia/Sertoli cell ratio. FSH also elevated meiotic spermatocyte numbers 7-fold, notably at pachytene (28-fold), but induced only limited numbers of postmeiotic haploid cells (absent in hpg controls) that arrested during spermatid elongation. In contrast, T treatment alone had little effect on postnatal spermatogonial proliferation but greatly enhanced meiotic progression with total spermatocytes increased 12-fold (pachytene 53-fold) relative to hpg testes, and total spermatid numbers 11-fold higher than tg-FSH hpg testes. Combining tg-FSH and T treatment had no further effect on Sertoli or spermatogonia numbers relative to FSH alone but had marked additive and synergistic effects on meiotic cells, particularly pachytene (107-fold more than hpg), to establish normal meiotic germ cell/Sertoli cell ratios. Furthermore, tg-FSH had a striking synergistic effect with T treatment on total spermatid numbers (19-fold higher than FSH alone), although spermatid to Sertoli cell ratios were not fully restored to normal, indicating elevated Sertoli cell numbers alone are insufficient to establish a maximal postmeiotic germ cell capacity. This unique model has allowed a detailed dissection of FSH in vivo activity alone or with T and provided compelling evidence that FSH effects on spermatogenesis are primarily via Sertoli and spermatogonial proliferation and the stimulation of meiotic and postmeiotic germ cell development in synergy with and dependent on T actions.

Animals↗
PubMed2003

Androgens and cardiovascular disease.

Globally, cardiovascular disease will continue causing most human deaths for the foreseeable future. The consistent gender gap in life span of approximately 5.6 yr in all advanced economies must derive from gender differences in age-specific cardiovascular death rates, which rise steeply in parallel for both genders but 5-10 yr earlier in men. The lack of inflection point at modal age of menopause, contrasting with unequivocally estrogen-dependent biological markers like breast cancer or bone density, makes estrogen protection of premenopausal women an unlikely explanation. Limited human data suggest that testosterone exposure does not shorten life span in either gender, and oral estrogen treatment increases risk of cardiovascular death in men as it does in women. Alternatively, androgen exposure in early life (perinatal androgen imprinting) may predispose males to earlier onset of atherosclerosis. Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in the progression of cardiovascular disease, highlighting the need to better understand androgen receptor (AR) coregulators, nongenomic androgen effects, tissue-specific metabolic activation of androgens, and androgen sensitivity. Novel therapeutic targets may arise from understanding how androgens enhance early plaque formation and cause vasodilatation via nongenomic androgen effects on vascular smooth muscle, and how tissue-specific variations in androgen effects are modulated by AR coregulators as well as metabolic activation of testosterone to amplify (via 5alpha-reductase to form dihydrotestosterone acting on AR) or diversify (via aromatization to estradiol acting upon estrogen receptor alpha/beta) the biological effects of testosterone on the vasculature. Observational studies show that blood testosterone concentrations are consistently lower among men with cardiovascular disease, suggesting a possible preventive role for testosterone therapy, which requires critical evaluation by further prospective studies. Short-term interventional studies show that testosterone produces a modest but consistent improvement in cardiac ischemia over placebo, comparable to the effects of existing antianginal drugs. By contrast, testosterone therapy has no beneficial effects in peripheral arterial disease but has not been evaluated in cerebrovascular disease. Erectile dysfunction is most frequently caused by pelvic arterial insufficiency due to atherosclerosis, and its sentinel relationship to generalized atherosclerosis is insufficiently appreciated. The commonality of risk factor patterns and mechanisms (including endothelial dysfunction) suggests that the efficacy of antiatherogenic therapy is an important challenge with the potential to enhance men's motivation for prevention and treatment of cardiovascular diseases.

Androgens↗
PubMed2003

Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment.

Long-term glucocorticoid therapy in men is associated with loss of bone and muscle mass as well as a decrease in serum testosterone. We tested the effect of two androgens, testosterone and its minimally aromatizable analog nandrolone, on muscle mass (dual x-ray absorptiometry), muscle strength (knee flexion and extension by isokinetic dynamometry), bone mineral density (BMD), and quality of life (Qualeffo-41 questionnaire) in 51 men on a mean daily prednisone dose of 12.6 +/- 2.2 mg. Men were randomized, double blind, to testosterone (200 mg mixed esters), nandrolone decanoate (200 mg), or placebo given every fortnight by im injection for 12 months. At 12 months, both androgens increased muscle mass (mean change from baseline +3.5%, +5.8%, and -0.9% in testosterone, nandrolone, and placebo groups, respectively, P < 0.0001) and muscle strength (P < 0.05). Lumbar spine BMD increased significantly only in men treated with testosterone (4.7 +/- 1.1%, P < 0.01). There was no significant change in hip or total body BMD. Testosterone, but not nandrolone or placebo, improved overall quality of life (P < 0.001). These results suggest that androgen therapy may have a role in ameliorating adverse effects of glucocorticoid therapy such as muscle and bone loss and aromatization is necessary for androgen action on bone but not on muscle.

Anabolic Agents↗
PubMed2003

Contraceptive efficacy of a depot progestin and androgen combination in men.

WHO studies provided proof of concept for hormonal male contraception using a prototype androgen-alone regimen. Combined testosterone plus progestin regimens offer more practical promise, but no contraceptive efficacy studies have been completed. The objective of this study was to establish the proof of principle for depot hormonal androgen/progestin combination as a male contraceptive. We performed a contraceptive efficacy study of 55 healthy men in stable fertile relationships seeking a change in contraceptive method. Testosterone (four 200-mg implants, every 4 or 6 months) and 300 mg depot medroxyprogesterone acetate, im, every 3 months were administered. Once sperm output was suppressed (<1 million/ml for 2 consecutive months), men entered a 12-month contraceptive efficacy period, ceasing other contraception. The main outcome measure was contraceptive failure (pregnancy) rate. No pregnancies occurred in 426 person-months (35.5 person-years; 95% confidence limits for contraceptive failure rate, 0-8%/annum), superior to the first year failure rate of condoms, the only reversible male method. Sperm density fell rapidly, so 94% of men entered the efficacy phase by 3 months, with only 2 of 55 (3.6%) men not sufficiently suppressed to enter efficacy. A few men treated with testosterone implants at 6-month intervals demonstrated androgen deficiency symptoms and/or escape of gonadotropin and spermatogenic suppression between months 5 and 6; after a protocol amendment, all men receiving testosterone implants at 4-month intervals avoided androgen deficiency or loss of gonadotropin and sperm output suppression. Recovery was complete (median, 3.6 months to sperm reappearance and 5.0 months to 20 million sperm/ml) in all but one man with an incidental testicular disorder. Discontinuations were for protocol-related reasons (n = 15) or altered personal circumstances (n = 12), but there were no serious adverse effects related to drug exposure. The first male contraceptive efficacy study using a prototype depot androgen/progestin combination demonstrates high contraceptive efficacy with satisfactory short-term safety and recovery of spermatogenesis. Further studies of purpose-developed products are required to extend the overall safety and efficacy experience with depot androgen/progestin combinations, the most promising approach to hormonal male contraception.

Adolescent↗
PubMed2003

The short-term effects of high-dose testosterone on sleep, breathing, and function in older men.

Androgen therapy may precipitate obstructive sleep apnea in men. Despite increasing androgen use in older men, few studies have examined sleep and breathing. Randomized, double-blind, placebo-controlled studies examining effects of testosterone simultaneously on sleep, breathing, and function in older men are not available. Seventeen community-dwelling healthy men over the age of 60 yr were randomized to receive three injections of im testosterone esters at weekly intervals (500 mg, 250 mg, and 250 mg) or matching oil-based placebo and then crossed over to the other treatment after 8 wk of washout. Polysomnography, anthropometry, and physical, mental, and metabolic function were assessed at baseline and after each treatment period. Testosterone treatment reduced total time slept ( approximately 1 h), increased the duration of hypoxemia ( approximately 5 min/night), and disrupted breathing during sleep (total and non-rapid eye movement respiratory disturbance indices both increased by approximately seven events per hour) (all P < 0.05). Despite expected effects on body composition (increase in total and lean mass, reduction in fat mass, P < 0.05, bioimpedance method), upper airway dimensions did not change (acoustic reflectometry). Driving ability (computer simulation), physical activity (accelerometry, Physical Activity Scale in the Elderly), quality of life (SF36, Functional Outcomes of Sleep Questionnaire), mood (Profile of Mood States Questionnaire), sleepiness (Epworth, Stanford scales), and insulin resistance (homeostasis model) also were not changed by treatment. Short-term administration of high-dose testosterone shortens sleep and worsens sleep apnea in older men but did not alter physical, mental, or metabolic function. These changes did not appear to be due to upper airway narrowing. Further study of longer-term lower-dose androgen therapy on sleep and breathing is needed to evaluate its safety in older men.

Aged↗
PubMed2003

Estimating the contribution of the prostate to blood dihydrotestosterone.

The prostate strongly expresses type 2 5 alpha-reductase, which avidly converts on entry most testosterone (T) to 5 alpha-dihydrotestosterone (DHT). However, the quantitative contribution of the prostate to blood DHT is uncertain. We evaluated prostatic contribution to blood DHT by comparing the blood DHT concentrations in androgen-deficient patients with or without a prostate while they were receiving standard dose of T replacement. Androgen-deficient males (ADM) and female to male (F2M) transsexuals were studied in 2 centers, with both groups receiving either testosterone ester injections (250 mg mixed T esters) every 1 wk (Amsterdam) or 800 mg subdermal T implantation (Sydney). Among 39 Dutch patients, F2M (n = 21) were younger and smaller in physique than ADM (n = 18). One week (+/-1 d) after an injection, plasma DHT concentrations were 1.6 +/- 0.2 (F2M) vs. 1.4 +/- 0.2 (ADM) nmol/liter (P = 0.47), but the postinjection time interval to blood sampling was shorter in F2M (5.9 +/- 0.4 vs. 7.2 +/- 0.3 d; P = 0.01). Covariance adjustment for time since last injection, age, and physique did not change the lack of significant difference in postinjection plasma DHT concentration. The rapid and wide excursions in plasma T concentrations after an im T ester injection make the timing of blood sampling critical. To remove confounding by this variable, the experiment was repeated at a second site in similar patients, but using a depot T that achieves steady-state delivery for prolonged periods. Among 29 Australian patients, before and 1 month after subdermal implantation of 800 mg T, plasma DHT concentrations were not significantly different between groups [F2M, 1.1 +/- 0.1 (n = 14); ADM, 1.3 +/- 0.1 (n = 15); P = 0.28]. Correction for covariates, including age, height, weight, body surface area, and body mass index, did not influence the lack of significant difference between treated groups. As both modes of T administration yielded similar plasma DHT concentrations regardless of the presence of a prostate, this study indicates that the normal human prostate is not a major contributor to circulating blood DHT concentrations.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2003

Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin.

OBJECTIVE: In order to assess the hormonal determinants of insulin sensitivity and related components of the metabolic syndrome, we evaluated the effect of subcutaneous recombinant human chorionic gonadotropin (r-hCG; Ovidrel) on insulin sensitivity, vascular reactivity, leptin, insulin-like growth factor-I (IGF-I) and lipids in ambulant, community dwelling men >60 Years of age with serum testosterone <or= 15 nmol/l on two occasions. DESIGN: Forty eligible men were randomized to receive 250 microg (5000 IU) r-hCG subcutaneously twice each week (n=20) or placebo (n=20) injections for 3 Months, and all subjects (mean age 67 (range 60-85) Years) completed the study. METHODS AND RESULTS: Groups were well matched for height, weight, anthropometry and insulin sensitivity. Insulin sensitivity was assessed by homeostasis model (HOMA) and euglycemic hyperinsulinemic clamp at baseline and at the end of the treatment period in the first 30 men who did not have diabetes mellitus. Insulin sensitivity (HOMA and euglycemic clamp) or beta cell function (HOMA) were not significantly changed by r-hCG despite a significant increase in lean body mass (approximately 2 kg, P<0.001) and reduced fat mass (approximately 1 kg, P<0.05). Subcutaneous fat (skinfold measurements), abdominal girth and serum leptin all decreased and IGF-I tended to increase, but these changes were not significant. Recombinant hCG significantly reduced total and low density lipoprotein cholesterol, and triglycerides, but did not significantly alter high density lipoprotein cholesterol. Endothelial function (vascular reactivity) was not significantly worsened. We conclude that three-Months of treatment with r-hCG demonstrates expected hormonal effects, improved lipids and did not worsen vascular endothelial function. Insulin sensitivity was not altered despite suggestive changes in body composition. CONCLUSIONS: These findings suggest short-term metabolic and cardiovascular safety and argue against an important role for androgens in the hormonal control of insulin sensitivity in older men.

Aged↗
PubMed2002

Prospective study of effect of androgens on serum inflammatory markers in men.

OBJECTIVE: Because male sex is an independent risk factor for the severity of atherosclerosis, it is possible that androgens may be proatherogenic. There is evidence that sex hormones, particularly estrogens, regulate (or modulate) inflammation, a process integral to atherogenesis. Because levels of serum inflammatory markers predict cardiovascular outcomes, we prospectively assessed the effects of androgen therapy on these markers in older men. METHODS AND RESULTS: Levels of high-sensitivity C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured from sera collected at baseline and at the end of 2 randomized double-blind placebo-controlled trials evaluating the effects of 3 months of androgen treatment with either dihydrotestosterone (DHT) or recombinant human chorionic gonadotropin (rhCG) in healthy men aged >60 years with partial androgen deficiency (serum testosterone levels <15 nmol/L). For the DHT study (70 mg transdermally daily), 33 men completed 3 months of treatment (16 men were treated with DHT, and there were 17 controls). For the rhCG (250 microg twice weekly) study, 20 men were treated with rhCG, and there were 20 controls. In both studies, groups were well matched for age and vascular risk factors. Androgen levels (DHT and testosterone) were consistently maintained at eugonadal levels throughout the trials, with estradiol markedly increased by rhCG but not DHT. Baseline CRP levels were 0.74 to 1.49 mg/L, sVCAM-1 levels were 847 to 950 ng/mL, and sICAM-1 levels were 256 to 292 ng/mL in all groups. Neither DHT nor rhCG resulted in significant changes in CRP, sVCAM-1, or sICAM-1 compared with placebo (P>0.3 in both studies). CONCLUSIONS: Exogenous androgen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women. These data provide a measure of reassurance concerning potential adverse cardiovascular effects of androgen therapy in older men.

Aged↗
PubMed2002

Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient infertile men.

BACKGROUND: Predictors of fertility or spermatogenesis during gonadotrophin therapy of gonadotrophin-deficient men remain poorly defined. METHODS AND RESULTS: In order to evaluate potential predictors, this study evaluated 29 consecutive gonadotrophin-deficient men all desiring paternity who received 43 courses of therapy in one centre between 1982 and 1998. The Kaplan-Meier survival analysis estimates of median (SE) time to a sperm concentration of >0, >5 and >20 x 10(6)/ml were 5.5 (1.1), 12.4 (2.3) and 29.1 (1.9) months respectively. Conception occurred in 22/43 cycles (with eight men achieving two pregnancies) with a median (SE) Kaplan-Meier estimate of 20.5 (4.7) months. The median sperm concentration at conception was 5.0 (SE 2.0; range 0.0-59.5) x 10(6)/ml. Multivariate correlated Cox proportional hazards models predicting these same sperm thresholds and conception were developed by forward stepwise variable selection with verification of the model by backward stepping. Larger testicular volume, prior gonadotrophin therapy, completion of puberty, older age, the absence of adverse fertility factors and the absence of multiple pituitary hormone deficiency predicted a favourable response. Multivariate modelling suggests that the two most important predictors of sperm output are testicular volume and pubertal status. The most important potentially modifiable predictor was prior gonadotrophin therapy. The efficacy of recombinant and urinary FSH were similar. Prior androgen therapy and partner's age did not appear to be significant. CONCLUSIONS: Since prolonged treatment may be required to induce spermatogenesis, attention to these predictors may allow appropriate early use of advanced reproductive technologies.

Adult↗
PubMed2002

Direct response of the murine prostate gland and seminal vesicles to estradiol.

In the prostate, testosterone action depends on conversion to bioactive metabolites dihydrotestosterone and 17beta-estradiol (E2) via the 5alpha-reductase and aromatase enzymes, respectively. Exogenous estrogen inhibits prostate growth by indirect effects caused by suppression of pituitary gonadotropins and testicular testosterone output, but direct effects are less well known. Direct effects of estrogens were evaluated using the hypogonadal (hpg) mouse model, which has postnatal deficiency in gonadotropins and testosterone but remains hormone sensitive. Mature hpg mice were implanted sc with implants filled with E2. After 6 wk, prostate lobe [anterior prostate (AP) and ventral prostate (VP)] and seminal vesicle (SV) organ volumes were significantly increased (P < 0.05) but remained smaller than wild-type mice. Analysis of the relative volumes (the proportional composition) of each tissue compartment in these organs showed significant increases in cellular and luminal volumes (P < 0.05) in AP (but not VP) and in SVs. Stromal fibroblasts proliferated, whereas smooth muscle cells were reduced in the AP and SVs. In the epithelia, basal cells proliferated and became metaplastic in the AP and VP. In the AP, luminal debris accumulated, together with an inflammatory response, but there was no evidence of malignant changes. The current study unequivocally demonstrates direct proliferative responses to E2 in the hpg mouse AP and VP lobes and SVs, characterized by discrete lobe-specific changes, including smooth-muscle regression, fibroblast proliferation, inflammation, and basal epithelial cell proliferation and metaplasia.

Animals↗
PubMed2002

A double-blind, placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency.

Despite partial androgen deficiency, the safety and efficacy of androgen therapy in older men remains controversial because controlled studies of testosterone have given equivocal results. Human chorionic gonadotropin (hCG) can be conveniently and infrequently self-administered, and it increases not only circulating testosterone but also estradiol and other testicular steroids. We evaluated the efficacy and safety of 3 months of treatment with sc recombinant hCG (r-hCG, Ovidrel) on muscle mass, strength, mobility, and physical activity in ambulant, community-dwelling men more than 60 yr old having partial androgen deficiency (testosterone < or = 15 nmol/liter, twice). Forty eligible men (mean age, 67 yr; range, 60-85 yr) were randomized to receive r-hCG (5000 IU, 250 microg) or placebo by twice weekly sc self-injection and were studied before treatment, monthly during treatment, and 1 month after treatment. All completed the study, and treatment groups were well matched. r-hCG significantly increased body weight (approximately 1 kg; P < 0.05) and lean body mass ( approximately 2 kg; P < 0.001) and reduced fat mass (approximately 1 kg, P < 0.05). However, anthropometric measures of skinfold thickness (biceps, triceps, subscapular, suprailiac) and circumferences (midarm, waist, hip, and midthigh), including the waist-hip ratio, did not change significantly. Shoulder and knee strength (peak torque), as measured by isokinetic and isometric dynamometry, was not significantly increased, nor was physical activity (accelerometry and Physical Activity Scale for Elderly self-report) or gait and balance (modified Guralnik and Frailty and Injuries: Cooperative Studies of Intervention Techniques performance batteries) altered. Total and free testosterone and estradiol were markedly (150%; P < 0.001) and stably increased, whereas LH, FSH, and urea were significantly decreased. Testis volume was significantly decreased (approximately 5 ml; P < 0.05). There were no significant changes in hemoglobin, osteocalcin, or prostate-specific antigen, and the International Prostate Symptom Score did not change. Three men developed nipple tenderness that did not progress to gynecomastia. We conclude that 3 months of treatment with twice weekly r-hCG demonstrates sustained androgenic effects on hormones and muscle mass but has no effect on muscle strength or physical functioning.

Aged↗
PubMed2002

An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH-like activity in gonadotropin-deficient transgenic mice.

FSH mediates its testicular actions via a specific Sertoli cell G protein-coupled receptor. We created a novel transgenic model to investigate a mutant human FSH receptor (FSHR(+)) containing a single amino acid substitution (Asp567Gly) equivalent to activating mutations in related glycoprotein hormone receptors. To examine the ligand-independent gonadal actions of FSHR(+), the rat androgen-binding protein gene promoter was used to direct FSHR(+) transgene expression to Sertoli cells of gonadotropin-deficient hypogonadal (hpg) mice. Both normal and hpg mouse testes expressed FSHR(+) mRNA. Testis weights of transgenic FSHR(+) hpg mice were increased approximately 2-fold relative to hpg controls (P < 0.02) and contained mature Sertoli cells and postmeiotic germ cells absent in controls, revealing FSHR(+)-initiated autonomous FSH-like testicular activity. Isolated transgenic Sertoli cells had significantly higher basal ( approximately 2-fold) and FSH-stimulated ( approximately 50%) cAMP levels compared with controls, demonstrating constitutive signaling and cell-surface expression of FSHR(+), respectively. Transgenic FSHR(+) also elevated testosterone production in hpg testes, in the absence of circulating LH (or FSH), and it was not expressed functionally on steroidogenic cells, suggesting a paracrine effect mediated by Sertoli cells. The FSHR(+) response was additive with a maximal testosterone dose on hpg testicular development, demonstrating FSHR(+) activity independent of androgen-specific actions. The FSHR(+) response was male specific as ovarian expression of FSHR(+) had no effect on hpg ovary size. These findings reveal transgenic FSHR(+) stimulated a constitutive FSH-like Sertoli cell response in gonadotropin-deficient testes, and pathways that induced LH-independent testicular steroidogenesis. This novel transgenic paradigm provides a unique approach to investigate the in vivo actions of mutated activating gonadotropin receptors.

Amino Acid Substitution↗
PubMed2002

Male reproductive ageing: human fertility, androgens and hormone dependent disease.

The waning of male virility with age, in all its ambiguities, has always intrigued humans, prompting innumerable approaches to staving it off. In modern terms, advancing age impacts on all aspects of male reproductive health sexuality, fertility and androgenization with differing extents and tempo. With ageing, male sexual function declines predominantly due to vasculogenic defects in cavernosal haemodynamics, whereas libido and ejaculation are less affected. This raises the potential for prevention and treatment of erectile dysfunction as an early clinical manifestation of atherosclerosis. After maturity, male fertility persists throughout life but decreases modestly with age presumably due to concomitant decline in sexual activity rather than in sperm output or function, although systematic population studies of the latter are difficult. Male ageing is associated with a progressive, partial and variable degree of androgen deficiency, but the clinical and public health significance remain to be established. Available evidence suggests that androgen supplementation is unlikely to prolong life expectancy but might improve quality of life through prevention of apparently age-related declines in androgen-sensitive tissues. The appropriate target population, treatment modality and objectives remain to be established by further controlled clinical studies.

Aging↗
PubMed2002

[Effects of 19-nortestosterone on sex accessory gland growth in hypogonadal mice].

OBJECTIVES: To evaluate the effects of 19-nortestosterone (NT) on the growth and development of the ventral prostate (VP), epididymis, and seminal vesicles (SV) in hypogonadal (hpg) mice. METHODS: The silastic tube filled with NT was implanted subdermally into mature hpg mice (n = 7) for five weeks. Similar silastic tubes without NT were implanted into both of hpg mouse control group (n = 7) and normal mouse group (n = 10) instead. The weights of sex accessory glands and the branch tip number of VP from all mice were evaluated. RESULTS: The weights of VP, SV, and epididymis in NT treated hpg group were significantly higher than those of hpg control group (P < 0.005); and the branching morphology of the VP showed a tendency to be normal and the development of prostate ductal tip was improved significantly. Especially, the weight of SV in NT treated hpg mice was equal to that of normal mice, while the weights of VP, epididymis and branching tip number in NT treated hpg group was still significantly lower than that of normal mice (P < 0.005). CONCLUSIONS: The NT treatment significantly stimulates the growth and development of the sex accessory gland in mature hpg mouse.

Animals↗