Biomedical subjects

D J Handelsman

Publications and source records attributed to D J Handelsman.

At least 55 records · Page 3Linked to original sources

PubMed1999

Ethnicity and migration as determinants of human prostate size.

The roles of ethnicity and migration in determining the size of human prostate zones during midlife were explored. Prostate size was measured by planimetric ultrasound in 163 men residing in Sydney who were either Australian non-Chinese (AR; n = 116) or Chinese migrants (ACM; n = 47) and had lived in Australia for a median of 7.3 yr (range, 0.2-25 yr). These were compared with Chinese men residing in China (CR; n = 210). Central and total prostate volumes were estimated by a single observer using the same equipment at both sites. After adjustment for age, central and total prostate volumes were significantly smaller, and plasma prostate-specific antigen and 5alpha-dihydrotestosterone (DHT) concentrations and International Prostate Syndrome Scores were significantly lower, in CR compared with either ACM or AR, whereas the scores of the latter two groups were similar. Almost all of the population difference in total prostate volumes could be accounted for by differences in central prostate volumes. The strongest correlates of age-adjusted prostate volume were prostate-specific antigen and DHT, the latter presumably reflecting the quantitative importance of prostatic stromal type II 5alpha-reductase activity to circulating DHT concentrations. Sex hormone-binding globulin concentrations were significantly higher in CR and significantly lower in ACM compared with those in AR, but the significance of these observations is unclear. These findings highlight the importance of the central zone of the prostate as well as provide evidence for an environmental factor influencing prostate growth. This factor operates over a relatively short time period compared with the evolution of prostate disease. Hence, this study provides evidence that ethnicity and geographical factors, such as migration, can influence the growth of the normal human prostate during midlife and may facilitate future studies of the origins and pathogenesis of human prostate disease.

Adult↗

PubMed1999

Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate.

Estrogens play an important role in prostate physiology and neonatal exposure to estrogens has profound effects on the mature structure and hormonal sensitivity of rodent prostate. We aimed to determine the long-term effects of neonatal estrogens on the ductal architecture, morphology and hormonal sensitivity of the mature mouse prostate. Newborn mice (day 1-2) were administered a single injection (s.c.) of estrogens (estradiol benzoate (EB), diethylstilbestrol (DES)) with or without concomitant anti-estrogens (tamoxifen (TAM) or ICI 182 780 (ICI)) TAM or ICI alone, GnRH-antagonist (GnRH-A) or vehicle. At 7 weeks of age, ventral prostates (VP) were microdissected to estimate branch tip numbers and processed for stereologic analysis of volume fractions and diameters of various tissue components. Estrogens induced permanently reduced branching morphogenesis leading to reduced VP weights and these effects were fully reproduced by GnRH-A, consistent with an indirect effect. Stereologically, neonatal estrogens induced epithelial and stromal hyperplasia and significantly reduced (P<0.05) the diameters of VP glandular tubules and lumen compared with controls and these regressive effects were not reversed either by TAM or ICI. These studies confirm that a single neonatal dose of both DES and EB produces imprinting in the mature mouse prostate and indicate that neonatal estrogen effects involve both direct as well as indirect effects. In addition, both TAM and ICI act as partial agonists to the estrogen receptor in the ventral prostate of neonatal mouse.

Animals↗

PubMed1998

Testing the gonadal regression-cytoprotection hypothesis.

Germinal damage is an almost universal accompaniment of cancer treatment as the result of bystander damage to the testis from cytotoxic drugs and/or irradiation. Cancer treatment for the most common cancers of the reproductive age group in men has improved such that most are now treated with curative intent, and many others are treated with likelihood of prolonged survival, so that the preservation of fertility is an important component of posttreatment quality of life. This has led to the consideration of developing adjuvant treatments that may reduce the gonadal toxicity of cancer therapy. One dominant hypothesis has been based on the supposition that the immature testis was resistant to cytotoxin damage. Hence, if hormonal treatment were able to cause spermatogenic regression to an immature state via an effective withdrawal of gonadotrophin secretion, the testis might be maintained temporarily in a protected state during cytotoxin exposure. However, clinical studies have been disappointing but have also been unable to test the hypothesis definitively thus far, due to the inability to completely suppress gonadotrophin secretion. Similarly, experimental models have also given conflicting results and, at best, a modest cytoprotection. To definitively test this hypothesis experimentally, we used the fact that the functionally hpg mouse has complete gonadotrophin deficiency but can undergo the induction of full spermatogenesis by testosterone. Thus, if complete gonadotrophin deficiency were an advantage during cytotoxin exposure, then the hpg mouse should exhibit some degree of germinal protection against cytotoxin-induced damage. We therefore administered three different cytotoxins (200 mg/kg procarbazine, 9 mg/kg doxorubicin, 8 Gy of X irradiation) to produce a range of severity in testicular damage and mechanism of action to either phenotypically normal or hpg mice. Testis weight and homogenization-resistant spermatid numbers were measured to evaluate the potential protective effects on spermatogenesis. Although the three cytotoxins produced a range of severity of spermatogenic damage, there was no evidence of cytoprotection in the hpg mice that were completely gonadotrophin deficient at the time of treatment. These findings cast doubt on the validity of the hypothesis that spermatogenic regression via gonadotrophin withdrawal can protect the mouse testis against cytotoxin-mediated spermatogenic damage.

Animals↗

PubMed1998

Vascular reactivity is impaired in genetic females taking high-dose androgens.

OBJECTIVE: To assess the vascular effects of high-dose androgen treatment in genetic females. BACKGROUND: Male gender is an independent risk factor for coronary artery disease, suggesting either a protective effect of estrogens and/or a deleterious effect of androgens. We have recently demonstrated that androgen deprivation is associated with enhanced vascular reactivity in adult men, however, the effects of androgen excess on vascular function in humans has not been reported previously. METHODS: We studied vascular reactivity in two groups of genetic females: 12 female-to-male transsexuals receiving long-term high-dose androgens, and 12 healthy female control subjects, matched for age and smoking history. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (leading to flow-mediated dilatation [FMD], which depends on normal endothelial function) and after sublingual nitroglycerin (NTG), an endothelium-independent dilator. RESULTS: Testosterone levels were higher (15.2+/-8.7 vs. 1.9+/-1.3 mmol/L, p < 0.001) and high-density lipoprotein cholesterol levels were lower (1.2+/-0.2 vs. 1.6+/-0.4 mmol/L, p=0.02) in the transsexuals compared with the control subjects. In each group, nine of 12 subjects were current or ex-smokers, leading to impaired FMD in both groups (5.1+/-3.7% in the transsexuals vs. 6.9+/-4.1% in controls, p=0.28). The NTG response was significantly decreased in the transsexuals (15.9+/-4.9% vs. 22+/-5.8% in controls, p=0.01), independent of the effects of age, cholesterol or vessel size. CONCLUSIONS: Long-term treatment with high-dose androgens is associated with impaired vascular reactivity in genetic females, consistent with a deleterious effect of androgen excess on arterial physiology.

Adult↗

PubMed1998

Androgen therapy in chronic renal failure.

Chronic renal failure, dialysis and transplantation have major effects on male reproductive health because of the impairment of spermatogenesis, steroidogenesis and sexual function. Hypothalamo-pituitary testicular dysfunction in uraemia is manifest clinically as delayed growth and puberty, sexual dysfunction, androgen deficiency, impaired spermatogenesis and infertility. Apart from renal anaemia, there are at present no proven indications for androgen therapy in chronic renal failure. This chapter reviews the basis and scope for various clinical applications of gonadotropin and androgen therapy as an adjunct to the standard medical care of chronic renal failure. The therapeutic possibilities implied by experimental and clinical findings suggesting that uraemic hypogonadism may be a functional state of gonadotropin deficiency are emphasized.

Anemia↗

PubMed1997

Arterial reactivity is enhanced in genetic males taking high dose estrogens.

OBJECTIVES: We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. BACKGROUND: Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. METHODS: We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. RESULTS: Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). CONCLUSIONS: Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.

Adult↗

PubMed1997

An analysis of testosterone implants for androgen replacement therapy.

OBJECTIVE: To review 13 years of experience using fused crystalline testosterone implants for androgen replacement therapy in order to identify pattern of usage (including continuation rates) and adverse events emerging during therapy and factors associated with adverse events including implant extrusions. DESIGN: Retrospective review of prospectively collected data on characteristics of patients and implant procedures performed as well as adverse events reported during routine follow-up. PATIENTS: Over 13 years 973 implant procedures using fused crystalline testosterone implants were performed in 221 men. MEASUREMENTS: Continuation rates and adverse events such as extrusions, bleeding, infection or others were recorded and analysed in relationship to characteristics of the patient and the implant procedure performed. RESULTS: Overall rate of adverse events (108/73, 11.1%) was significantly related to increased numbers of implants (4.2 +/- 0.1 vs 4.0 +/- 0.03, P = 0.031) and higher levels of physical activity at work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%) which was related to occupational classification (P = 0.033) and increasing work activity (P = 0.044) and occurred more frequently than by chance in multiple (16 vs 3.3 expected) rather than single (65 vs 76.1 expected) episodes. Bleeding (22/973, 2.3%) was significantly associated with an increased number of implants (4.5 +/- 0.2 vs 4.0 +/- 0.03, P = 0.020) but even in the worst cases (3/22) it was of minor clinical importance. Infection was rare (6/973, 0.6%) but occurred more among thinner men. The overall continuation rate was 92.7% increasing from 86% after the first implantation to > 99% after the tenth implant. CONCLUSIONS: This study demonstrates the very satisfactory clinical acceptability of testosterone pellet implants for androgen replacement therapy within a single unit with experienced operators. The only regular adverse effect is extrusion, which may be related to mechanical factors such as habitual work activity but also possibly procedural factors. Other adverse effects such as bleeding, infection and fibrosis were rare. An improved method of implant delivery would enhance this old but durable technology.

Adult↗

PubMed1997

Estimating familial and genetic contributions to variability in human testicular function: a pilot twin study.

The biological basis for the remarkably wide variation in sperm output between and within men remains unclear. Although some contributing factors have been identified, the familial and genetic contributions to variation in human sperm output have been little studied, although such sources of variation are known to be significant in experimental animals. In order to identify such familial and genetic factors in a classical twin study design, we recruited monozygotic and dizygotic twins aiming to study the degree of resemblance between genetically identical and non-identical twins in sperm output, testis size and testicular endocrine function. From an approach to 160 twin pairs on the Australian Twin Register database, eventually 17 pairs of male twins (11 monozygotic and six dizygotic) participated in this study. Sperm concentration and output, right testis size and SHBG all exhibited a strong familial effect but a genetic component could not be confirmed. Total and free testosterone exhibited a genetic component. Although identifying for the first time a clear familial component to normal human spermatogenesis, this study had insufficient power to determine whether there was a genetic component, nor could its design distinguish between genetic or shared (early) environmental determinants for these familial effects. Implications for future twin studies of human testicular function including stronger recruitment strategies, multi-centre studies and surrogate variables for human spermatogenesis are suggested.

Adult↗

PubMed1997

Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian high school students.

Abuse of anabolic-androgenic steroids (AAS) is reportedly increasing in prevalence and spreading from sportsmen to cosmetic and recreational use, though there are few accurate estimates of the extent of AAS use outside North America. In order to identify the prevalence of, and risk factors for, 'ever' (lifetime) or 'recent' (within last month) use of AAS among Australian high school students, 13,355 students (51.3% male, median age 13.8 years) in 203 schools constituting a stratified random sample of all high schools in New South Wales and Victoria completed a self-report questionnaire about drug use. Lifetime ('ever') use of AAS was reported by 213 boys (3.2%; 95% CI, 2.7-3.6%) and 74 girls (1.2%; 95% CI, 0.9-1.5%). Factors associated with 'ever' use were truancy [odds ratio (OR) 17.7 (95% CI, 9.4-31.6) for 7 or more truant days compared with no trauncy over the last fortnight], unsupervised recreation [OR 8.4 (5.9-11.9) for 6 or more compared with 2 or fewer nights per week], speaking only a non-English language at home [OR 7.75 (4.4-13.1)], Aboriginality [OR 3.4 (2.0-5.5)], male gender [OR 2.8 (2.1-3.7)], higher student income [OR 2.3 (1.7-3.0)], overseas born [OR 2.2 (1.6-3.0)] and low level of social support [OR 2.5 (1.7-3.5)]. Use of AAS within the last month ('recent') was reported by 113 boys (1.7%; 95% CI, 1.4-2.0%) and 28 girls (0.4%; 95% CI, 0.3-0.6%) and virtually identical risk factor patterns except ORs were uniformly higher. We conclude that AAS abuse is relatively uncommon among Australian high school students but has distinctive and strong socio-economic and cultural predictors. Further studies of the behavioural epidemiology of AAS abuse are required to clarify the origins and significance of our findings and to identify potentially effective interventions.

Absenteeism↗

PubMed1997

Sperm output of healthy men in Australia: magnitude of bias due to self-selected volunteers.

Controversial claims, based on a meta-analysis aggregating 61 heterogeneous observational studies, have been made that human sperm output has decreased by 50% over the last six decades and that this trend may be due to global pollution. If true, such effects should be evident in all areas of the globe; however, longitudinal studies within single centres in Europe and America have produced conflicting results and there are no reports from the southern hemisphere. We therefore reviewed semen analyses obtained from 1980-1995 from 689 healthy men volunteering for screening either as potential sperm donors for a donor insemination programme (n = 509) or to participate in five male contraception research studies (studies no. 1-5, n = 180). All were recruited through the Andrology Unit of the Royal Prince Alfred Hospital, Sydney, by the same doctors using standard methods of recruiting, screening and laboratory examination throughout the period 1980-1995. Recruitment was by advertising without regard to marital or fertility status except in two contraceptive efficacy studies (no. 1 and no. 3) where participants had to be in a stable relationship requiring contraception. Analysing the first semen sample individually or when grouped by year of ejaculation, there was no significant difference in sperm concentration over time or between years or according to year of birth. During the second half of this period, 180 consecutive volunteers were recruited by the same doctors and staff for five male contraception studies. The median sperm concentration for studies no. 1 (103 x 10(6) ml) and no. 2 (142 x 10(6) ml) were significantly (P < 0.05) higher than for studies no. 3-5 (84, 67 and 63 x 10(6) ml, respectively) and for potential sperm donors (median 69 x 10(6) ml). The inconsistency of these estimates illustrates the magnitude of bias (up to 100%) in sperm output that may occur in recruiting groups of self-referred volunteers within a single centre. This highlights the invalidity of extrapolating similar findings on sperm output of self-selected volunteers to the general male community or in using such study groups to characterize sperm output in supposedly 'normal' men.

Adult↗

PubMed1997

Growth and hormone characteristics of pubertal development in the hamadryas baboon.

The semi-longitudinal collection of growth measurements in male and female hamadryas baboons has enabled documentation of the timing of puberty and the development of sexually dimorphic growth patterns in body weight, crown-rump length (CRL), limb lengths, and muscle mass. In addition, another sexually dimorphic characteristic appears to be the presence of a pubertal growth spurt in body weight, and possibly CRL, in male but not female baboons. Serum testosterone levels rose during male development; however, there was a progressive decrease in dehydroepiandrosterone sulfate levels indicating the absence of adrenarche. Insulin-like growth factor-I (IGF-I) and its major binding protein, IGFBP-3, both rose during pubertal development; however, a simultaneous rise in the IGF-I:IGFBP-3 molar ratio suggests other factors may enhance the bioactivity of IGF-I during puberty. A distinct rise in serum osteocalcin levels was also associated with puberty in male baboons. These growth and hormonal changes during puberty in the hamadryas baboon indicate that this species provides a close primate model for human puberty.

Animals↗

PubMed1997

Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and injection volume.

We studied healthy men who underwent blood sampling for plasma nandrolone, testosterone and inhibin measurements before and for 32 days after a single i.m. injection of 100 mg of nandrolone ester in arachis oil. Twenty-three men were randomized into groups receiving nandrolone phenylpropionate (group 1, n = 7) or nandrolone decanoate (group 2, n = 6) injected into the gluteal muscle in 4 ml of arachis oil vehicle or nandrolone decanoate in 1 ml of arachis oil vehicle injected into either the gluteal (group 3, n = 5) or deltoid (group 4, n = 5) muscles. Plasma nandrolone, testosterone and inhibin concentrations were analyzed by a mixed-effects indirect response model. Plasma nandrolone concentrations were influenced (P < .001) by different esters and injection sites, with higher and earlier peaks with the phenylpropionate ester, compared with the decanoate ester. After nandrolone decanoate injection, the highest bioavailability and peak nandrolone levels were observed with the 1-ml gluteal injection. Plasma testosterone concentrations were also influenced (P < .001) by the ester and injection site, with the most rapid, but briefest, suppression being due to the phenylpropionate ester, whereas the most sustained suppression was achieved with the 1-ml gluteal injection. Plasma inhibin concentrations were also significantly influenced by injection volume and site, with the lowest nadir occurring after the nandrolone decanoate 1-ml gluteal injection. Thus, the bioavailability and physiological effects of a nandrolone ester in an oil vehicle are greatest when the ester is injected in a small (1 ml vs. 4 ml) volume and into the gluteal vs. deltoid muscle. We conclude that the side-chain ester and the injection site and volume influence the pharmacokinetics and pharmacodynamics of nandrolone esters in an oil vehicle in men.

Adolescent↗

PubMed1997

Use of filter paper for sample collection and transport in steroid pharmacology.

Field studies of androgen pharmacology are complicated by the necessity to collect, process, and store blood samples in a central facility. We have assessed the feasibility of using capillary blood spots collected by fingerprick and dried on filter paper for pharmacokinetics and pharmacodynamic measurements with nandrolone and testosterone RIAs modified for extracts from capillary blood spots. Assays on punched spots of 7.9-mm diameter (14.9 microL of dried blood) permitted accurate quantification of testosterone down to 0.4 nmol/L from a single spot and nandrolone down to 0.9 nmol/L from two spots. Stability of the steroids in dried blood spots to adverse environmental conditions, notably increased temperatures, was investigated both in the laboratory and in field studies of dried spots sent through the postal system. Storage or postal transport under moderate conditions appeared to have no deleterious effects on apparent androgen concentrations. However, under extreme conditions of storage at 50 degrees C for a week or more, or transport to a very hot tropical location, a rise in the final concentration of nandrolone, and, to a lesser extent, testosterone when corrected for tracer recovery, was noticed. These effects were largely due to apparent susceptibility of tritiated tracer, but not unlabeled androgen, to thermal degradation. In a pilot pharmacological study involving intramuscular injection of 100 mg of nandrolone decanoate in 1 mL of arachis oil, nandrolone concentrations in concurrently collected plasma as well as venous and capillary blood spots showed good agreement. Testosterone concentrations in contemporaneously collected plasma and venous blood spots also showed very good agreement. We propose that these methods may allow patients and experimental subjects to self-collect samples at remote or field locations for convenient mailing to a central laboratory for androgen assay. Applications of this methodology are now under way.

Blood Chemical Analysis↗

PubMed1996

Cyclic adenosine 3',5'-monophosphate-independent regulation of cytosolic calcium in Sertoli cells.

We have examined the cAMP-independent regulation of cytosolic calcium concentration in rat Sertoli cells using the effect of vasoactive hormones, known as testicular paracrine regulators operating via the non-cAMP pathway, on cytosolic calcium. Calcium concentrations were estimated with dual excitation fluorimetry, using freshly isolated, fura-2/AM-loaded cells. No increase in the cellular cAMP concentration was detected after stimulation with angiotensin II (AII), vasopressin, PGF2 alpha, or atrial natriuretic peptide. Whereas both AII and vasopressin evoked a rise in cytosolic calcium from a basal level of 81.4 +/- 4 to 142.5 +/- 18 and 154.4 +/- 11 nM, respectively, PGF2 alpha had only a minimal effect (98 +/- 5 nM), and atrial natriuretic peptide no effect (86.6 +/- 9 nM). The effect of AII on calcium was blocked by the the selective AT2, but not by the AT1, receptor antagonist, indicating the selective presence on Sertoli cells of AT2 AII receptor. Similarly, the vasopressin-induced calcium response was blocked by vasopressin V1, but not by V2 receptor antagonist, consistent with the presence of V1 receptor subtype in these cells. Removal of extracellular calcium or blockade of calcium channels did not inhibit the calcium increase due to AII and vasopressin, suggesting the involvement of intracellular calcium. Thapsigargin increased the basal cytosolic calcium concentration to 137 +/- 10 nM. Depletion of intracellular calcium stores with thapsigargin before stimulation with AII or vasopressin abolished both the AII-mediated and the vasopressin-mediated calcium rise in the presence as well as the absence of extracellular calcium, indicating that the increase in calcium is predominantly derived from the thapsigargin-sensitive endoplasmic reticulum. This study indicates that calcium homeostasis of Sertoli cells might also be regulated by cAMP-independent metabolism apart from the well known cAMP-dependent pathway. Furthermore, our findings support the idea that angiotensin and vasopressin might be important paracrine regulators of Sertoli cells functions.

Angiotensin II↗

PubMed1996

Androgens regulate circulating levels of insulin-like growth factor (IGF)-I and IGF binding protein-3 during puberty in male baboons.

To examine the role of androgens in initiating the pubertal rise in circulating insulin-like factor-I (IGF-I) levels, a longitudinal study of puberty in 13 male hamadryas baboons was conducted over 3 yr. The five control baboons commenced puberty (initial testicular enlargement) at a mean +/- SE age of 4.2 +/- 0.4 yr. Another eight baboons were castrated prepubertally; of those four received testosterone pellets (dose equivalent: 12.5-50 mg every 6 weeks) implanted se from the time of puberty. Body weight, crown-rump length, and limb length measurements, synchronized to pubertal onset, suggest that a pubertal growth spurt occurs in male baboons. Control baboons had a marked rise (4- to 5-fold; P < 0.0001) in circulating IGF-I levels; maximum IGF-I levels (168 +/- 9 nmol/L) were reached 42 months after the onset of puberty (mean chronological age 7.5 yr). Castrated baboons had no significant rise in IGF-I levels, however, administration of testosterone resulted in a close approximation of the normal pubertal rise in IGF-I (maximum values 140 +/- 8 nmol/L), confirmed by comparison of fitted sigmoid curves (r2 > 0.99; chronological age ED50 controls, 4.4 +/- 0.1 yr and castrate + testosterone, 4.3 +/- 0.1 yr). Serum IGF binding protein-3 levels paralleled the rise in IGF-I consistent with a common regulatory mechanism. In another study, castration of four sexually mature male baboons aged 11.12 +/- 1.16 yr had no effect on serum IGF-I levels (P = 0.5). This indicates that androgens are the predominant determinant of circulating IGF-I in the male baboon, and that this is an uniquely pubertal phenomenon.

Animals↗

PubMed1996

Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot.

Hormonally induced azoospermia induced by weekly im injections of testosterone enanthate provides effective and reversible male contraception, but more practical regimens are needed. Given our previous findings that six 200-mg pellets implanted subdermally produced more stable, physiological T levels and reduced the delivered T dose by more than 50% while maintaining equally effective suppression of sperm output with fewer metabolic side-effects than weekly 200-mg testosterone enanthate injections, we sought in this study to determine 1) whether further dose-sparing could be achieved by lower testosterone doses while maintaining efficacy and 2) the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose as a model depot progestin/androgen combination male contraceptive. Healthy volunteers were randomized into groups (n = 10) who received either of two lower T doses (two or four 200-mg T pellets) or four 200-mg T pellets plus a single im injection of 300 mg depot medroxyprogesterone acetate (DMPA). Two T pellets (400 mg, 3 mg/day) had a negligible effect on sperm output. Four T pellets (800 mg, 6 mg/day) suppressed sperm output between the second to fourth postimplant months; output returned to normal by the seventh postimplant month, although only 4 of 10 men became azoospermic or severely oligozoospermic (< 3 mol/L/mL). The addition of a depot progestin markedly increased the extent, but not the rate, of sperm output suppression, with 9 of 10 becoming azoospermic and 10 of 10 becoming severely oligozoospermic. There were no serious adverse effects during the study. Plasma total and free testosterone levels remained within the eugonadal range at all times with each treatment. Plasma epitestosterone was suppressed by all 3 regimens, consistent with a dose-dependent inhibition of endogenous Leydig cell steroidogenesis. Plasma LH and FSH measured by a two-site immunoassay were suppressed in a dose-dependent fashion by T and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either T dose. Prostate-specific antigen and lipids (total, low or high density lipoprotein cholesterol, and triglycerides) were not significantly changed in any group. Thus, a depot testosterone preparation with zero order release must be delivered at between 6-9 mg/day to provide optimal (but not uniform) efficacy at inducing azoospermia. The addition of a single depot dose of a progestin to a suboptimal testosterone dose (6 mg/day) markedly enhances the extent, but not the rate, of spermatogenic suppression, with negligible biochemical androgenic side-effects. These findings provide a basis for the use of a progestin/androgen combination depot for hormonal male contraception.

Adult↗

PubMed1996

The effects of chronic high dose androgen or estrogen treatment on the human prostate [corrected].

Prostate development and disease are androgen dependent. However, the nature of hormonal effects on the prostate of healthy young men is not clear. We, therefore, measured prostate size in males chronically exposed to high doses of androgens (AS; habitual anabolic steroid abusers; n = 15) or estrogens (E; male to female transsexuals; n = 11) and compared the results with those in age-matched healthy eugonadal men without known prostate disorders. Prostate size was measured by planimetric ultrasound as cross-sectional areas and maximal dimensions in three orthogonal dimensions with a 7.5-megahertz B-mode sector scanner biplane in a transrectal transducer at 2.5 mm steps from the base to the apex of prostate. Total prostate volume (TPV) was reconstructed from planimetric sections, central prostate volume (CPV) was calculated by the ellipsoidal formula from the appropriate three maximum dimensions, and peripheral prostate volume was determined by the difference between TPV and CPV. Compared with age-matched controls, TPV was normal (-2%) in AS (P = 0.752) and reduced by 31% in E (P = 0.002), whereas CPV was increased by 20% in AS (P = 0.002) and reduced by 46% in E (P = 0.002), and the ratio of CPV/peripheral prostate volume was increased by 77% in AS (P < 0.001) and decreased by 33% in E (P = 0.047). Blood sex hormone-binding globulin was elevated by nearly 500% in E (P < 0.001), but was reduced by 47% in AS (P = 0.003). Prostate-specific antigen was normal (-6%) in AS (P = 0.799) and decreased by 86% in E (P = 0.002). Prostatic acid phosphatase was increased by 26% in AS (P = 0.007), but was unchanged (-28%) in E (P = 0.106). Total and free testosterone levels were reduced to castrate levels in E, whereas LH, FSH, and total testosterone levels were significantly reduced in AS. We conclude that in the human prostate of young men, CPV is more hormonally sensitive than TPV, and during high dose treatment, CPV is preferentially increased by chronic androgen treatment and decreased by chronic estrogen treatment. The reduction of TPV by estrogens was less than expected if solely attributable to inhibition of endogenous gonadotropin and testosterone secretion, suggesting that estrogens also have a positive effect on the normal human prostate. The reversibility and long term significance of androgen-induced stimulation of CPV and, in particular, its relationship to the onset and severity of benign prostatic hyperplasia remain to be clarified.

Adolescent↗

PubMed1996

Neonatal administration of FSH increases Sertoli cell numbers and spermatogenesis in gonadotropin-deficient (hpg) mice.

We previously demonstrated that androgens alone, in the complete absence of gonadotropins, initiated qualitatively complete spermatogenesis in hypogonadal (hpg) mice. Although germ cell to Sertoli cell ratios were normal in hpg mice with androgen-induced spermatogenesis, testicular size. Sertoli cell and germ cell numbers only reached 40% of those of non-hpg mice, and Sertoli cell numbers were unaffected by androgen treatment started at 21 days of age. We postulated that these observations were due to diminished gonadotropin-dependent. Sertoli cell proliferation during perinatal life while the Sertoli cells still exhibited normal carrying capacity for mature germ cells. In order to test this hypothesis, we examined the effects of administering androgens and gonadotropins to hpg mice during the first 2 weeks of postnatal life when Sertoli cells normally continue to proliferate. The study end-points were Sertoli and germ cell numbers in hpg mice following induction of spermatogenesis by 8 weeks treatment with 1 cm subdermal silastic testosterone implants. Newborn pups (postnatal day 0-1) were injected s.c. with recombinant human FSH (rhFSH) (0.5 IU/20 microliters) or saline once daily for 14 days, with or without a single dose of testosterone propionate (TP) (100 micrograms/20 microliters arachis oil) or human chorionic gonadotropin (hCG) (1 IU/20 microliters). Untreated hpg and phenotypically normal littermates were studied as concurrent controls. At 21 days of age, all treated weaning mice received a 1 cm silastic subdermal testosterone implant and, finally, 8 weeks after testosterone implantation, all mice were killed. As expected, qualitatively complete spermatogenesis was induced in all groups by testosterone despite undetectable circulating FSH levels. Exogenous rhFSH increased testis size by 43% (P < 0.002) but a single neonatal dose of either TP or hCG reduced the FSH effect although neither TP nor hCG had any effect alone. In contrast, a single neonatal dose of TP or hCG increased final seminal vesicle size whereas FSH had no effect. FSH and TP treatment significantly increased absolute numbers of testicular spermatids compared with saline treatment, whereas hCG and TP significantly increased testicular sperm when expressed relative to testis size. Stereological evaluation of Sertoli and germ cell numbers demonstrated a rise in the absolute numbers of Sertoli and all germ cell populations induced by neonatal administration of hormones. When expressed per Sertoli cells the numbers of germ cells in the treated mice were between 85 and 90% of non-hpg controls. We conclude that exogenous FSH treatment during the first 2 weeks of postnatal life, coinciding with the natural time of Sertoli cell proliferation, increases Sertoli cell numbers and thereby the ultimate size of the mature testis and its germ cell production. Thus neonatal gonadotropin secretion may be a critical determinant of the sperm-producing capacity of the mature testis. In addition, neonatal exposure to androgens could be important for the imprinting of sex accessory organs in hpg mice, with the long-term effects of altering the sensitivity of the accessory organs to exogenous testosterone later in life.

Animals↗