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D J Handelsman

Publications and source records attributed to D J Handelsman.

At least 19 recordsLinked to original sources
PubMed2007

Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study.

BACKGROUND: Androgens have striking effects on skeletal muscle, but the effects on human cardiac muscle function are not well defined, neither has the role of metabolic activation (aromatization, 5alpha reduction) of testosterone on cardiac muscle been directly studied. OBJECTIVE: To assess the effects of testosterone and nandrolone, a non-amplifiable and non-aromatizable pure androgen, on cardiac muscle function in healthy young men. DESIGN: Double-blind, randomized, placebo-controlled, three-arm parallel group clinical trial. SETTING: Ambulatory care research centre. PARTICIPANTS: Healthy young men randomized into three groups of 10 men. INTERVENTION: Weekly intramuscular injections of testosterone (200 mg mixed esters), nandrolone (200 mg nandrolone decanoate) or matching (2 ml arachis oil vehicle) placebo for 4 weeks. MAIN OUTCOME MEASURES: Comprehensive measures of cardiac muscle function involving transthoracic cardiac echocardiography measuring myocardial tissue velocity, peak systolic strain and strain rates, and bioimpedance measurement of cardiac output and systematic vascular resistance. RESULTS: Left ventricular (LV) function (LV ejection fraction, LV modified TEI index), right ventricular (RV) function (ejection area, tricuspid annular systolic planar motion, RV modified TEI index) as well as cardiac afterload (mean arterial pressure, systemic vascular resistance) and overall cardiac contractility (stroke volume, cardiac output) were within age- and gender-specific reference ranges and were not significantly (P < 0.05) altered by either androgen or placebo over 4 weeks of treatment. Minor changes remaining within normal range were observed solely within the testosterone group for: increased LV end-systolic diameter (30 +/- 7 vs. 33 +/- 5 mm, P = 0.04) and RV end-systolic area (12.8 +/- 1.3 vs. 14.6 +/- 3.3 cm(2), P = 0.04), reduced LV diastolic septal velocity (Em, 9.5 +/- 2.6 vs. 8.7 +/- 2.0 cm/s, P = 0.006), increased LV filling pressure (E/Em ratio, 7.1 +/- 1.6 vs. 8.3 +/- 1.8, P = 0.02) and shortened PR interval on the electrocardiogram (167 +/- 13 vs. 154 +/- 12, P = 0.03). CONCLUSION: Four weeks of treatment with testosterone or nandrolone had no beneficial or adverse effects compared with placebo on cardiac function in healthy young men.

Adult↗
PubMed2006

Influence of demographic factors and sport type on growth hormone-responsive markers in elite athletes.

CONTEXT: GH-responsive markers of the IGF system and of collagen turnover hold promise as the basis of a GH doping test. OBJECTIVE: The purpose of this study was to determine the influence of age, gender, body mass index (BMI), ethnicity, and sporting type on GH-responsive serum markers in a large cohort of elite athletes from different ethnic backgrounds. DESIGN: The study was designed as a cross-sectional study. PARTICIPANTS: A total of 1103 elite athletes (699 males, 404 females), aged 22.2 +/- 5.2 yr, from 12 countries and 10 major sporting categories participated in this study. MAIN OUTCOME MEASURES: Serum IGF-I, IGF binding protein-3 (IGFBP-3), acid labile subunit (ALS), and collagen markers [N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), N-terminal propeptide of type III procollagen (PIIINP)] were measured. RESULTS: There was a significant negative correlation (r = -0.14 to -0.58, P < 0.0005) between age and each of the GH-responsive markers. Serum IGF-I, IGFBP-3, and ALS were all lower (P < 0.05), whereas the collagen markers PINP, ICTP, and PIIINP were higher (P < 0.05) in men than in women. Multiple regression analysis indicated that age, gender, BMI, and ethnicity accounted for 23-54% of total between-subject variability of the markers. Age and gender cumulatively accounted for 91% of the attributable variation of IGF-I and more than 80% for PINP, ICTP, and PIIINP. Gender exerted the greatest effect on ALS (48%), and BMI accounted for less than 12% attributable variation for all markers. The influence of ethnicity was greatest for IGFBP-3 and ALS; however, for the other markers, it accounted for less than 6% attributable variation. Analysis of 995 athletes indicated that sporting type contributed 5-19% of attributable variation. CONCLUSIONS: Age and gender were major determinants of variability of GH-responsive markers except for IGFBP-3 and ALS. Ethnicity is unlikely to confound the validity of a GH doping test based on IGF-I and these collagen markers.

Adolescent↗
PubMed2006

Follicle-stimulating hormone increases primordial follicle reserve in mature female hypogonadal mice.

Ovarian primordial follicle reserve is considered hormonally independent or subject to depletion by FSH-driven follicle recruitment. To explore specific in vivo effects of FSH on early follicle populations in the absence of luteinizing hormone (LH) activity, we examined mature hypogonadal (hpg), gonadotrophin-deficient mice expressing transgenic (tg) human FSH. Sustained expression of tg-FSH (5.3 +/- 0.3 IU/l) increased ovary weights fourfold and significantly elevated total primordial follicle numbers twofold in tg-FSH hpg (4209 +/- 457) relative to non-tg hpg (2079 +/- 391) and wild-type (2043 +/- 195) age-matched ovaries. Absolute primary follicle numbers in tg-FSH hpg ovaries were similar to non-tg hpg and wild-type ovaries. Furthermore, tg-FSH quantitatively increased secondary and antral follicles in hpg ovaries to numbers equivalent to wild-type, but did not induce ovulation, indicating a selective FSH response without LH. Circulating inhibin B and inhibin A levels were significantly increased in tg-FSH hpg females compared with hpg controls, and inhibin B correlated with antral number, consistent with FSH-driven antral follicle formation. These findings revealed that sustained pituitary-independent FSH activity, in the absence of endogenous gonadotrophins, promotes an increase in primordial follicle reserve despite also stimulating follicular growth in mature females. Therefore, the tg-FSH hpg ovary presents a novel paradigm to evaluate specific gonadotrophin effects on follicle reserve and recruitment.

Animals↗
PubMed2005

Sexual activity, fertility and contraceptive use in middle-aged and older men: Men in Australia, Telephone Survey (MATeS).

BACKGROUND: With limited information regarding fertility and sexual activity in the older population, men's behaviour, attitudes and concerns were explored in a representative population of middle-aged and older men using the Men in Australia, Telephone Survey (MATeS). METHODS: A stratified random national sample of 5990 men participated in a standardized computer-assisted telephone interview. Equal numbers in the age strata 40-49, 50-59, 60-69 and >or=70 years were surveyed with findings census-standardized to the national population. Broad aspects of men's health and well-being, including reproductive health, were explored. RESULTS: The majority of men were sexually active in the last 12 months (age-standardized proportion, 78.3%) with approximately 37% of men aged >or=70 years still continuing sexual activity. Overall, 12.2% of men had never fathered children, of whom most (7.7%) had chosen not to have children. Questioning on failed attempts to produce a pregnancy suggested an involuntary infertility rate of 7.6%. The age-standardized vasectomy rate was 25.1%, with 5.6% of vasectomized men having no children. Although 9.2% of vasectomized men regretted sterilization, only 1.4% had undergone vasectomy reversal. CONCLUSIONS: Continuing sexual activity, fertility and contraception needs in middle-aged and older men suggests that education and service delivery must be more appropriately directed to an ageing population.

Adult↗
PubMed2005

Erythropoietin administration does not influence the GH--IGF axis or makers of bone turnover in recreational athletes.

OBJECTIVE: Measurement of biochemical markers of the IGF-system and of collagen turnover is a potential approach to detect GH abuse in sport. These markers are increased in patients on dialysis treated with recombinant human erythropoietin (r-HuEPO), mimicking the effects of GH. The aim was to determine whether r-HuEPO induces similar effects on the IGF-system and collagen turnover in healthy athletes. SUBJECTS AND MEASUREMENTS: Young male Caucasian recreational athletes were administered 50 U/kg r-HuEPO (n=14) or placebo (n=16) three times a week for 25 days, followed by a 4-week wash-out period. IGF-I, IGFBP-3, the acid labile subunit (ALS), N-terminal propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III collagen (PIIINP) were measured in samples collected at baseline (two samples), after 10, 22 and 24 days of r-HuEPO treatment and at the end of the 4-week wash-out period. RESULTS: Treatment with r-HuEPO resulted in approximately threefold elevation of serum EPO and marked elevation of markers of erythropoiesis. There was no significant treatment effect of r-HuEPO compared to baseline on IGF-I, IGFBP-3, ALS, PINP, ICTP or PIIINP. CONCLUSIONS: r-HuEPO administration did not change markers of the IGF-system and of collagen turnover in young healthy male athletes. Therefore, use of r-HuEPO in athletes should not affect the validity of a GH doping test using these GH-responsive markers.

Adult↗
PubMed2004

Validation of an ultrasensitive and specific immunofluorometric assay for mouse follicle-stimulating hormone.

Sensitive and specific measurement of FSH is critical to research in reproductive biology, and the increasing availability of transgenic mouse models has created a need for a robust, sensitive, and specific mouse (m) FSH assay. The present study evaluated a time-resolved immunofluorometric assay (IFMA) for mFSH using monoclonal antibody to human (h) FSHbeta as a capture antibody and a biotinylated polyclonal antibody to rat alpha subunit as a detection probe, with signaling amplified by europium-labeled streptavidin. The mFSH IFMA lowered the detection limit 34-fold (5 vs. 170 pg/sample) compared with standard mFSH RIA. The mFSH IFMA demonstrated parallelism of response to dilutions of castrated mouse serum and rat FSH but no cross-reactivity with hFSH and mLH or hLH, whereas the RIA demonstrated nonparallel cross-reactivity with hFSH. The IFMA has a wide analytical range, with a good precision profile for within- and between-assay reproducibility. Because the IFMA is a sandwich-type assay with strict dimer-specificity by design, the lower readings and recovery obtained were compared with the RIA when both assays used a pituitary-purified mFSH assay standard that contained isolated or fragmented subunits as well as intact dimeric FSH. When used with mouse serum sample, the mFSH IFMA demonstrated the expected increases following orchidectomy as well as markedly enhanced sensitivity to very low levels of endogenous mFSH in gonadotropin-deficient mice. Furthermore, the IFMA measured mFSH with fidelity in both intact and orchidectomized male mice without any interference from transgenic hFSH. The greatly enhanced sensitivity, specificity, and technical convenience of this mFSH IFMA will allow wider application of FSH measurements to very small blood samples in immature and mature mice as well as transgenic models.

Animals↗
PubMed2004

Sperm output of older men.

BACKGROUND: Declining fertility of couples from the fourth decade of life is largely attributable to the drop in female fertility. However, increasing numbers of men, whose fertility theoretically lasts until death, are seeking fertility treatment at older ages, yet there is little information on sperm production and function past the age of 50 years. The few studies of such older men have examined men attending fertility clinics, and therefore willing to provide semen samples, but the participation bias of such recruitment hinders extrapolation to the unselected general male population. METHODS: We have taken the opportunity to study a convenience sample of 55 healthy, non-infertile men ranging in age from 52 to 79 years old who provided semen samples as part of a prostate cancer screening project. They were compared with a control group (n = 409) of younger (< 52 years) men from among 567 volunteers screened as potential sperm donors for an artificial insemination program. RESULTS: Older men had lower semen volume (mean semen volume 1.8 versus 3.2 ml; P < 0.0001) and total sperm output (median 74 versus 206 million sperm per ejaculate; P < 0.0001), whereas sperm density (median 64 versus 73 million sperm/ml; P = 0.12) was non-significantly decreased. Older men had more abnormal sperm morphology with decreasing numbers of normal forms (mean 14% versus 25%; P < 0.0001) and reduced vitality (mean 51% versus 80%; P < 0.0001), as well as increased numbers of cytoplasmic droplets (median 1 versus 0; P < 0.0001) and sperm tail abnormalities (30% versus 17%; P < 0.0001). Sperm head or neck abnormalities were no different between the groups. CONCLUSIONS: While neither study group may be representative of the general male population, these findings suggest that sperm production, reflected in sperm output but not sperm density, as well as sperm morphology and viability are diminished in this population of healthy, non-infertile older men.

Aged↗
PubMed2004

Testosterone release rate and duration of action of testosterone pellet implants.

OBJECTIVE: Testosterone pellets are a highly effective subdermal depot administered at regular intervals with the timing individualized depending upon return of the patient's characteristic androgen deficiency symptoms. Yet the in vivo testosterone release rate and effective duration of action of these pellets has been little studied systematically. DESIGN: Analysis of prospectively collected data from three randomized controlled clinical trials. Collection of extruded pellets. PATIENTS: Androgen-deficient men (n = 136) undergoing long-term androgen replacement therapy with a standard dose (800 mg) of testosterone pellets implanted subdermally at intervals from 5 to 7 months. MEASUREMENTS: Testosterone release rate of pellets, consisting of pure crystalline testosterone without excipients, is estimated by measuring the dry weight lost by pellets (n = 179) over their time in situ. The effective duration of the standard regimen, and the influence of extrusion and patient or procedural characteristics on it, was estimated by timing of return for re-implantation due to recurrence of the patient's familiar androgen deficiency symptoms. RESULTS: The loss of dry weight of intact (n = 112) pellets was strongly correlated with time in situ (r2 = 0.969) providing an estimate of daily testosterone release rate per 200 mg pellet of 1.34 +/- 0.02 mg/pellet/day (95% CI 1.30-1.37 mg/day) for the first 3 months. After 756 implantations of the standard dose, men return for re-implantation at 5.8 calendar months following no or only a single pellet extrusion, but the time to return was significantly shorter after multiple extrusions. No patient or procedural features influenced the timing of return. Among men with primary hypogonadism, increases in plasma LH and FSH were more sensitive than plasma total or free testosterone to changes in testosterone delivery following an extrusion. CONCLUSION: Testosterone pellet implants release testosterone at a steady rate of 1.3 mg/200 mg implant/day (95% CI). The duration of action is about 6 months in an uncomplicated cycle with timing of return shortened by extrusions only in the 3.6% of procedures followed by multiple extrusions. No other patient or procedural features influenced duration of action. Among men with an intact hypothalamo-pituitary unit, plasma gonadotropins are more sensitive than blood total or free testosterone to reduced testosterone delivery following an extrusion.

Adolescent↗
PubMed2004

Blood testosterone threshold for androgen deficiency symptoms.

There are few systematic studies of the relationship between blood testosterone concentrations and the symptoms of overt androgen deficiency. Because most testosterone preparations are relatively short-term, the rapid changes in blood testosterone concentrations they cause make it difficult to define any testosterone threshold. By contrast, subdermal testosterone implants provide stable blood testosterone concentrations over days to weeks, while gradually declining to baseline over 5-7 months. Hence, this provides an opportunity to define a blood testosterone threshold for androgen deficiency symptoms by observing androgen-deficient men as their familiar androgen deficiency symptoms return as testosterone pellets slowly dissolve. Among 52 androgen-deficient men who underwent 260 implantations over 5 yr, at the time of return of androgen deficiency symptoms the blood total and free testosterone concentrations were highly reproducible within individuals (F = 0.8, P = 0.49 and F = 1.4, 0.24, respectively) but varied markedly between men (F = 167 and F = 138, both P < 0.001), indicating that each person had a consistent testosterone threshold for androgen deficiency symptoms that differed markedly between individuals. The most reported symptoms of androgen deficiency were lack of energy, lack of motivation, and reduced libido. The symptomatic threshold was significantly lower in men with secondary hypogonadism compared with men with primary or mixed hypogonadism (total, 9.7 +/- 0.5 nmol/liter vs. 11.7 +/- 0.4 nmol/liter and 10.2 +/- 0.3 nmol/liter, P = 0.006; free, 146 +/- 10 pmol/liter vs. 165 +/- 6 pmol/liter and 211 +/- 18 pmol/liter, P = 0.002) but was not affected by the underlying cause of hypogonadism or by specific symptoms of any severity. Despite a wide range in individual thresholds for androgen deficiency symptoms, the mean blood testosterone threshold corresponded to the lower end of the eugonadal reference range for young men. The implications of these observations for the development of more specific quality-of-life measures, as well as for other potential androgen deficiency states such as chronic diseases and aging, remain to be determined.

Adult↗
PubMed2002

A randomised controlled clinical trial of antibiotic impregnation of testosterone pellet implants to reduce extrusion rate.

OBJECTIVE: Testosterone pellet implantation is a safe, effective and convenient form of depot androgen replacement, with extrusion of pellets following about 10% of procedures the most frequent adverse effect. This study aimed to determine whether extrusion rate could be reduced by antibiotic impregnation of pellets immediately prior to implantation. DESIGN: Prospective, randomised, parallel-group, open-label study design in a single centre. One hundred and eighty-six androgen-deficient men (400 implantation procedures) were randomised into either a group who had their pellets soaked for approximately 2 min in gentamicin solution prior to implantation, or a control group who had the standard implantation procedure. METHODS: Extrusion, infection and/or bruising were evaluated prospectively by self-report from the participants, and retrospectively at subsequent implantation. Other variables (site, shaving, skin preparation, operator, pellet batch, bruising) were collected at implantation time. RESULTS: The extrusion rate was 20% lower (odds ratio=0.80, 95% confidence interval (CI) 0.40-1.62) but not statistically different between the two groups (extrusion rate 23/205 (11.2%) for the control group vs 18/195 (9.2%) for the antibiotic-soak group, P=0.42). One operator experienced more total (P=0.0002) and infection-related (P=0.0008) extrusions and marginally more bruising (P=0.06) than other operators. The operator effect did not appear to be explained by differences in experience or implantation style. There was a 4.6-fold excess (95% CI 1.6-18.6) of multiple (19 vs 4 expected) over single (22 vs 10 expected) and no (359 vs 386 expected) extrusions. Extrusion was not related to batch number (P=0.15), location (P=0.15), shaving (P=0.32), old or new site (P=0.59), or the presence of suppuration or not (P=0.42); however, povidone-iodine skin disinfectant had statistically fewer extrusions than mixed alcohol solution. CONCLUSIONS: Antibiotic impregnation prior to implantation does not significantly decrease testosterone pellet extrusion rate. An operator effect, not due to experience or procedural style, an excess of multiple extrusions and disinfectant effects were confirmed. Neither location, nor preparation of the site, nor pellet batch, influences extrusion rate.

Adult↗
PubMed2001

Loss of annexin II heavy and light chains in prostate cancer and its precursors.

Annexin II mRNA coding for a calcium binding protein was found to be absent in prostate cancer by subtractive hybridization and Northern analysis. In contrast to high expression in normal and benign hyperplastic glandular and basal epithelium, Annexin II heavy (p36) and light (p11) chains in 31/31 prostate cancer specimens were lost immunohistochemically. In glands involved by prostate intraepithelial neoplasia, 65% lost both chains in glandular epithelial cells, whereas basal cells were all positively stained. Southern analysis of cancer DNA showed no noticeable deletion in p36 gene. LNCaP cells treated with 5-azacytidine re-expressed p36, suggesting methylation could be responsible for the silencing.

Adult↗
PubMed2001

Androgenic anabolic steroids and arterial structure and function in male bodybuilders.

OBJECTIVES: The study examined arterial and cardiac structure and function in bodybuilders using androgenic anabolic steroids (AAS), compared to non-steroid-using bodybuilder controls. BACKGROUND: Adverse cardiovascular events have been reported in bodybuilders taking anabolic steroids. The cardiovascular effects of AAS, however, have not been investigated in detail. METHODS: We recruited 20 male bodybuilders (aged 35 +/- 3 years), 10 actively using AAS and 10 who denied ever using steroids. Serum lipid and hormone levels, carotid intima-media thickness (IMT), arterial reactivity, and left ventricular (LV) dimensions were measured. Vessel diameter was measured by ultrasound at rest, during reactive hyperemia (an endothelium-dependent response, leading to flow-mediated dilation, FMD), and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Arterial reactivity was also measured in 10 age-matched non-bodybuilding sedentary controls. RESULTS: Use of AAS was associated with significant decreases in high density lipoprotein cholesterol, sex hormone binding globulin, testosterone and gonadotrophin levels, and significant increases in LV mass and self-reported physical strength (p < 0.05). Carotid IMT (0.60 +/- 0.04 mm vs. 0.63 +/- 0.07 mm), arterial FMD (4.7 +/- 1.4% vs. 4.1 +/- 0.7%) and GTN responses (11.0 +/- 1.9% vs. 14.4 +/- 1.7%) were similar in both bodybuilding groups (p > 0.2). The GTN responses were significantly lower and carotid IMT significantly higher in both bodybuilding groups, however, compared with the non-bodybuilding sedentary controls (p = 0.01). CONCLUSIONS: Although high-level bodybuilding is associated with impaired vascular reactivity and increased arterial thickening, the use of AAS per se is not associated with significant abnormalities of arterial structure or function.

Adult↗
PubMed2001

Oestradiol improves arterial endothelial function in healthy men receiving testosterone.

OBJECTIVE: To assess prospectively the effects of low dose oestradiol on arterial endothelial and smooth muscle function in healthy men. Oestrogen use is associated with reduced cardiovascular disease in oestrogen-deficient women, however, the vascular effects of low-dose oestradiol in healthy men have not been investigated previously. PATIENTS AND DESIGN: Twenty-three men (aged 32 +/- 8 years) were randomized to receive depot implants of testosterone (T) alone (group 1, n = 10), or T with either 10 mg (group 2, n = 7) or 20 mg (group 3, n = 6) of oestradiol (E). MEASUREMENTS: Hormone levels, lipids and vascular reactivity were measured before, 1 month and 6 months after hormone implantation. Using high-resolution ultrasound, brachial artery diameter was measured at rest, during reactive hyperaemia (leading to flow-mediated dilatation, FMD, which is endothelium-dependent) and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). RESULTS: Oestradiol produced a dose-dependent increase in plasma oestradiol (at 1 month 96 +/- 7, 149 +/- 6, 192 +/- 23 pmol/l in the 3 groups, respectively, P < 0.001 by ANOVA for trend). Minor side-effects (gynaecomastia, nipple tenderness) indicated that 20 mg oestradiol was the maximum tolerated dose. There was also a dose-dependent increase in FMD with oestradiol dose: at 1 month, - 0.2, + 0.2 and + 1.8% for groups 1-3, respectively (P = 0.31 by ANOVA for trend); and at 6 months, - 0.8, + 0.4 and + 2.2% (P = 0.02). The rise in oestradiol levels following treatment correlated with the improvement in FMD (P = 0.01). GTN responses were similar in the 3 groups throughout the study. CONCLUSION: In healthy young men, oestradiol supplementation is associated with enhanced arterial endothelial function, a key marker of vascular health.

Adult↗
PubMed2001

Effects of androgen deficiency and replacement on prostate zonal volumes.

BACKGROUND AND OBJECTIVES: Androgens play a key role in prostate development and disease. However the effects of androgen deficiency and replacement on the prostate during mid-life are not well understood, and there is no information on their effects on prostate zonal volumes. This study aimed to define the effects of androgen deficiency and androgen replacement therapy on prostate zonal volumes (central, peripheral & total) using planimetric prostate ultrasound with particular emphasis on the central zone of the prostate, the most hormonally sensitive and fastest growing region of the prostate and the zone where nodular benign prostate hyperplasia originates. PATIENTS AND MEASUREMENTS: Central and total prostate volume were measured directly, and peripheral prostate volume calculated, by a single observer using transrectal ultrasound in 71 hypogonadal men (aged 40 +/- 2, range 18-78 years) who were compared with individually age-matched health controls without prostate or gonadal disease. Among the men with androgen deficiency, 17 men had untreated androgen deficiency (never treated or no treatment for at least 6 months) and 54 men were receiving long-term androgen replacement therapy (median 32 months, 93% > or = 6 months) with testosterone implants (n = 27), testosterone ester injections (n = 24) or other testosterone treatment (n = 3). RESULTS: Compared with individually age-matched controls, untreated androgen deficient men (n = 17) had reduced central (4.0 +/- 0.5 vs. 6.2 +/- 0.5 ml, P < 0.001) and total (23.4 +/- 2.6 vs. 29.2 +/- 1.6 ml, P < 0.001) prostate volumes whereas the reduction in peripheral prostate volume (19.4 +/- 2.1 vs. 23.0 +/- 1.3 ml, P = 0.15) was not statistically significant. Men with treated androgen deficiency (n = 54) also still had significantly reduced central (4.8 +/- 0.4 vs. 6.8 +/- 0.4, P < 0.001), peripheral prostate volume (19.6 +/- 0.8 vs. 21.6 +/- 0.7 ml, P = 0.06) and total (24.4 +/- 1.1 vs. 28.4 +/- 1.0 ml, P = 0.008) despite prolonged restoration of physiological testosterone concentrations. Neither modality of testosterone treatment nor type of hypogonadism influenced prostate zonal volumes before or after treatment. In contrast, central, peripheral and total prostate volume increased with age among healthy controls and men with androgen deficiency regardless of androgen replacement therapy. Plasma PSA concentrations were reduced in men with untreated androgen deficiency and were similar to age-matched controls in men with treated androgen deficiency. CONCLUSIONS: We conclude that, during mid-life, chronic androgen deficiency due to hypogonadism is associated with reduced central, peripheral and total prostate volumes. Reduced prostate volumes persist even during long-term maintenance of effective androgen replacement therapy with physiological testosterone concentrations until the fourth decade of life. After that, prostate volumes increase with age regardless of androgen deficiency or replacement. These findings suggest that, during mid-life, age is a more important determinant of prostate growth than ambient testosterone concentrations maintained in the physiological range. The persistently subnormal prostate volumes despite adequate androgen replacement therapy may explain the apparent paucity of cases of overt prostate disease among testosterone-treated androgen deficient men who retain protection against prostate disease despite physiological androgen replacement therapy.

Adult↗
PubMed2001

Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants.

BACKGROUND: Implantation of testosterone pellets under the lateral abdominal wall skin is an old but popular and effective form of androgen replacement therapy. Extrusion of one or more pellets remains the most frequent adverse event. OBJECTIVE: To determine whether an alternative implantation site (hip) and/or track geometry (two vs. four tracks) would reduce extrusion rates compared with the standard of a four-track abdominal site. Additionally, the study aimed to evaluate the effects of site and track geometry on other adverse effects (bruising, infection) and the pharmacology of testosterone release from the implants. DESIGN: A prospective, parallel-group unmasked study design in a single centre. The primary objective was to evaluate sites, with evaluation of track geometry a subordinate objective made necessary by anatomical differences. Accordingly, androgen deficient men requiring testosterone implantation with the standard dose (four 200 mg pellets) were randomized into one of three groups (ratio 1 : 1 : 2): a four-track abdomen site (standard), a two-track abdomen site or a two-track hip site. The pharmacological substudy was to evaluate the impact of site and track geometry on testosterone implant pharmacology by monthly hormone assays following implantation. PATIENTS: Two hundred and forty-six implantation procedures involving 96 androgen deficient men. MEASUREMENTS: The primary end-point, extrusion rate per procedure, and secondary end-points (bruising or infection post procedure) were evaluated prospectively by self-report from the participants, and verified when they returned next for implantation. The pharmacology substudy involved monthly blood sampling for hormone (total and free testosterone, LH, FSH) measurements. RESULTS: The extrusion rate was significantly higher [odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-7.1] for the hip site (15/125, 12%) compared with the abdominal site (6/121, 5%). Track geometry made no significant difference (OR = 1.05, 95% CI 0.2-5.4) to the extrusion rate. No secondary end-points (bruising, infection) were significantly different according to either site or track geometry. One operator who performed the implant procedures had significantly less primary and secondary adverse events than the other operators (P = 0.006). Neither implantation site, nor track geometry influenced pharmacokinetics [peak plasma total and free testosterone concentrations and net hormone release (area-under-curve, AUC)] or pharmacodynamics [nadir plasma LH and FSH and net suppression (AUC) in men with hypergonadotrophic hypogonadism]. CONCLUSIONS: We conclude that the hip site has a higher extrusion rate than the standard abdominal wall site but that track geometry does not increase the risk of extrusion. Neither implantation site, nor track geometry influenced either other adverse effects or the pharmacokinetics or pharmacodynamics of testosterone pellet implants.

Abdomen↗
PubMed2001

Estrogens and falling sperm counts.

Extravagant claims have been made repeatedly in recent years that human sperm counts are falling and that global exposure to environmental estrogens are responsible. The basis for these two distinct claims is reviewed. The claims of falling human sperm output, reviving an old debate, are prompted by a paper by Carlsen et al. (1992). This meta-analysis, however, is marred by numerous flaws that invalidate its claims. Major defects include severe heterogeneity of component studies, rendering them unsuitable for aggregation, and defective data analysis based on arithmetic mean rather than median, which showed no significant changes over time. This debate is likely to remain unresolved until valid, representative population-based studies of human sperm output can be achieved. None have been reported, or seem feasible in the near future, and so alternative strategies, based on surrogate variables for human male fertility not requiring sperm counts, need to be developed and validated. The plausible hypothesis that prenatal estrogen exposure might influence development of the human testis through effects on Sertoli cell replication and sperm carrying capacity has, however, been conclusively refuted by studies of boys born to women exposed to high doses of oral diethylstilbestrol during pregnancy. Neither fertility nor sperm output were adversely influenced by massive maternal estrogen exposure during pregnancy, although minor urogenital malformations did occur. The still wider claims of deteriorating male reproductive health, notably changes in prevalence or incidence of hypospadias or cryptorchidism, also lack convincing population-based evidence, although cancer registry data indicate a gradual increase in testis cancer in some countries. In summary, the available evidence does not support claims of falling sperm counts or any general deterioration in male reproductive health. Population-based studies of valid surrogate variables for male fertility not requiring semen analysis are needed. If population-based evidence regarding male fertility or sperm output could be generated, it is highly unlikely that prenatal estrogen exposure could be a valid explanation of any deterioration as massive maternal exposure to oral estrogen has negligible effects on male fertility or sperm output.

Estrogens↗
PubMed2001

Long-term outcomes of elective human sperm cryostorage.

BACKGROUND: Sperm cryopreservation allows men with threatened fertility to preserve their progenitive potential, but there is little data on long-term outcomes of elective sperm cryostorage programmes. METHODS AND RESULTS: Over 22 years, 930 men sought semen cryostorage in a single academic hospital, of which 833 (90%) had spermatozoa cryostored. Among 692 (74%) men surviving their illness, sperm samples were discarded for 193 (21% of all applicants, 28% of survivors) and cryostored spermatozoa were used for 64 men (7% of all applicants, 9% of survivors) in 85 treatment cycles commencing at a median of 36 months post-storage (range 12-180 months) with nearly 90% of usage started within 10 years of storage and none after 15 years. Pregnancy was most efficiently produced by intracytoplasmic sperm injection (median three cycles) compared with conventional IVF (median eight cycles) or artificial insemination (median more than six cycles; P < 0.05). A total of 141 (15%) of men had died and of these, 120 (85% of those dying) had their spermatozoa discarded; requests to prolong cryostorage were received from relatives of 21 men (2% of all applicants, 15% of deceased) of which three cases had spermatozoa transferred for use with no pregnancies reported. Sperm concentration was lower for all cryostorage groups compared with healthy sperm donor controls (P < 0.05). Following orchidectomy, men with testicular cancer had sperm density approximately half that of all other groups of men seeking cryostorage (P < 0.05), the lowering attributable to removal of one testis rather than in defects in spermatogenesis. CONCLUSION: Elective sperm cryopreservation is an effective, if sparsely used, form of fertility insurance for men whose fertility is threatened by medical treatment and is an essential part of any comprehensive cancer care programme.

Adult↗