Filter

Refine by Access

Refine by Date

—
  • Print
  • Save

Search Results

You are looking at 1 - 10 of 11 items for

  • Author: David J Handelsman x
  • Refine by Access: All content x
Clear All Modify Search
Free access

Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays

Lam P Ly and David J Handelsman

Background: The growing interest in measuring blood free testosterone (FT) is constrained by the unsuitability of the laborious reference methods for wider adoption in routine diagnostic laboratories. Various alternative derived testosterone measures have been proposed to estimate FT from either additional assay steps or calculations using total testosterone (TT) and sex hormone-binding globulin (SHBG) measured in the same sample. However, none have been critically validated in large numbers of blood samples.

Methods: We analyzed a large dataset comprising over 4000 consecutive blood samples in which FT as well as TT and SHBG were measured. Dividing the dataset into samples with blood TT above and below 5 nM, using a bootstrap regression modeling approach guided by Akaike Information Criterion for model selection to balance parsimony against reduction of residual error, empirical equations were developed for FT in terms of TT and SHBG.

Results: Comparison between the empirical FT equations with the laboratory FT measurements as well as three widely used calculated FT methods showed the empirical FT formulae had superior fidelity with laboratory measurements while previous FT formulae overestimated and deviated systematically from the laboratory FT values.

Conclusion: We conclude that these simple, assumption-free empirical FT equations can estimate accurately blood FT from TT and SHBG measured in the same samples with the present assay methods and have suitable properties for wider application to evaluate the clinical utility of blood FT measurements.

Restricted access

Recombinant growth hormone and insulin-like growth factor I do not alter gonadotrophin stimulation of the baboon testis in vivo

Bronwyn A Crawford and David J Handelsman

Crawford BA, Handelsman DJ. Recombinant growth hormone and insulin-like growth factor I do not alter gonadotrophin stimulation of the baboon testis in vivo. Eur J Endocrinol 1994;131:405–12. ISSN 0804–4643

In vitro studies indicate a physiological role for insulin-like growth factor I (IGF-I) in paracrine regulation of testicular function and recent clinical studies suggest a potential role for growth hormone (GH) and/or IGF-I in the treatment of hypogonadotrophic states in males. This study aimed to examine the effects of pretreatment with recombinant human GH (rhGH) or rhIGF-I on the response to gonadotrophins of the non-human primate testis in vivo. Using a balanced Latin square design with repeated measures, six prepubertal male hamadryas baboons (Papio hamadryas hamadryas) were treated in a cross-over sequence for periods of 18 days with daily im injections of rhGH (0.4 IU·kg−1 · day−1), rhIGF-I (0.1 mg·kg−1 · day−1) or saline with a 2-week washout period between each treatment. A single im injection of hCG (1500 IU) increased serum testosterone (p = 0.0002) but neither rhGH nor rhIGF-I influenced the timing or magnitude of this response (p > 0.5). A single im dose of FSH (75 IU) stimulated immunoreactive inhibin (p = 0.01) but also was unaffected in magnitude or timing by pretreatment with rhGH or rhIGF-I (p> 0.2). Circulating IGF-I levels were increased independently by hCG (p = 0.01) and FSH (p < 0.0001) administration. These findings indicate that neither GH nor IGF-I pre-treatment enhance acute gonadal responses to gonadotrophin stimulation of the prepubertal non-human primate testis in vivo. These findings suggest that GH or IGF-I treatment of hypogonadotrophic men without somatotrophin deficiency is unlikely to be beneficial.

David J Handelsman, Andrology Unit, Royal Prince Alfred Hospital, Departments of Medicine and Obstetrics and Gynaecology, University of Sydney, Sydney 2006, Australia

Restricted access

Identification of human semen insulin-like growth factor-I/somatomedin-C immunoreactivity and binding protein

Robert C. Baxter, Janet L. Martin, and David J. Handelsman

Abstract. Human seminal plasma (SP) samples have been tested for insulin-like growth factor-I/somatomedin-C (IGF-I/SM-C) immunoreactivity. Gel chromatography of SP at neutral pH indicated that all immunoreactive IGF-I/SM-C was present at a higher molecular weight than the free peptide from plasma, while in 1 m acetic acid, a major peak of immunoreactivity was seen at an apparently lower molecular weight than the free peptide, together with a peak with molecular weight about 40000. This latter peak contained a binding protein which, on Scatchard analysis, was shown to have a single class of binding site, Ka = 1.2 × 1010 l/mol. The low molecular weight peak material was displaced from monoclonal and polyclonal IGF-I/SM-C antibodies parallel to standard preparations. Its elution on gel chromatography later than plasma IGF-I/SM-C was shown by re-chromatography to be due to physical retardation on the column, rather than a lower molecular weight. As acid-ethanol extraction of SP samples failed to remove binding activity, samples from patients were all subjected to acid gel chromatography before assay. The mean IGF-I/SM-C content in 5 normal men was 20.7 ± 3.7 (sd) ng/ml while that for 4 azoospermic subjects was 9.2 ± 3.7 ng/ml. A hyposomatotrophic subject with normal sperm density and low serum IGF-I/SM-C had an SP IGF-I/SM-C value in the normal range. This study indicates that human semen contains protein-bound immunoreactive IGF-I/SM-C which is at least in part of testicular origin, and apparently not growth hormone-dependent.

Free access

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

Ashraf Aminorroaya, Sharyn Kelleher, Ann J Conway, Lam P Ly, and David J Handelsman

Objective: Androgen deficiency (AD) leads to bone loss and contributes to osteoporotic fractures in men. Although low bone mineral density (BMD) in AD men is improved by testosterone replacement, the responses vary between individuals but the determinants of this variability are not well defined.

Design and methods: Retrospective review of dual energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur in men with established AD requiring regular androgen replacement therapy (ART). After a DEXA scan all men were treated with testosterone implants (800 mg, ~6 month intervals). Patients were classified as having a congenital, childhood, or post-pubertal onset, as well as according to the adequacy of treatment prior to their first DEXA scan as untreated, partially treated or well treated.

Results: Men with AD requiring regular ART (n = 169, aged 46.3±1.1 years, range 22–84 years) underwent a DEXA scan prior to being treated with testosterone implants (800 mg, ~6 month intervals). In cross-sectional analysis at the time of the first DEXA scan untreated men (n = 24) had significantly reduced age-adjusted BMD at all four sites (L1–L4, femoral neck, Ward’s triangle and trochanter). Well-treated men (n = 77) had significantly better age-adjusted BMD at all four sites compared with those who were partially treated (n = 66) or untreated (n = 24) with their age-adjusted BMD being normalized. In a longitudinal assessment of men (n = 60) who had two or more serial DEXA scans, at the second DEXA scan after a median of 3 years, men who were previously partially treated (n = 19) or untreated (n = 11) had proportionately greater improvements in BMD, significantly for Ward’s triangle (P = 0.025) and the trochanter (P = 0.044) compared with men (n = 30) previously well treated.

Conclusions: The present study demonstrates a positive relationship between adequacy of testosterone replacement and BMD in men with overt organic AD. Additionally, the BMD of well-treated AD men approximates that of age-matched non-AD controls. The greatest BMD gains are made by those who have been either untreated or partially treated, and optimal treatment over time (median 3 years) normalizes BMD to the level expected for healthy men of the same age.

Free access

Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy

Vita Birzniece, Margot A Umpleby, Anne Poljak, David J Handelsman, and Ken K Y Ho

Objective

In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women.

Design

Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation.

Outcome measures

The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1.

Results

Testosterone treatment significantly reduced LRa by 7.1±2.5% and Lox by 14.6±4.5% (P<0.05). The concentration of liver transaminases did not change significantly, while that of serum SHBG fell within the normal range by 16.8±4.0% and that of IGF1 increased by 18.4±7.7% (P<0.05). The concentration of peripheral testosterone increased from 0.4±0.1 to 1.1±0.2 nmol/l (P<0.05), without exceeding the upper normal limit. There was no change in energy expenditure and fat and carbohydrate utilization.

Conclusions

Hepatic exposure to unesterified testosterone by oral delivery stimulates protein anabolism by reducing protein breakdown and oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified testosterone holds promise as a simple novel treatment of protein catabolism and muscle wasting.

Restricted access

Short-term exposure to insulin-like growth factors stimulates testosterone production by testicular interstitial cells

John S. M. De Mellow, David J. Handelsman, and Robert C. Baxter

Abstract. The effect of short-term exposure to the insulin-like growth factors (IGF-I and IGF-II) on testosterone production by rat testicular interstitial cells in primary culture has been examined. Both peptides, when present during a 1-h pre-incubation period, increased human chorionic gonadotropin (hCG)-stimulated testosterone release over the following 16-h period. The effect of exposure to IGFs was most marked on maximally hCG-stimulated testosterone release. Maximal stimulation following IGF exposure was 80– 85% above that seen without IGFs, and the IGF effect was half-maximal at 1.5–2 μg/l of IGF-I or IGF-II. Pre-incubation with IGFs did not alter the concentration of hCG (0.1 μg/l) at which half-maximal stimulation of testosterone release was seen. Increasing cell density had a marked effect on the testosterone production rate per 105 cells, and the stimulatory effect of IGFs was only seen at relatively high cell density (2.8 × 105 cells/ml). Varying the period of pre-incubation with IGFs between 0.5 and 16 h, it was found that a 1-h period gave maximal stimulation. We conclude that a short exposure to IGFs is capable of increasing hCG-stimulated steroidogenesis in Leydig cells, and postulate that this effect may be part of an intratesticular paracrine control mechanism.

Free access

Effects of estradiol on fat in men undergoing androgen deprivation therapy: a randomized trial

Nicholas Russell, Rudolf Hoermann, Ada S Cheung, Jeffrey D Zajac, David J Handelsman, and Mathis Grossmann

Objective

Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone.

Design

Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass.

Methods

Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass.

Results

Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123–292), P  < 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124–1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0–1.6), P= 0.15; gynoid fat, MAD 147 g (95% CI: 2–293), P = 0.08; visceral fat, 53 g (95% CI: 1–105) P = 0.13; and subcutaneous fat, MAD 65 g (95% CI: 5–125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41–286), P = 0.04.

Conclusion

Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.

Free access

Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets

Flora F Ip, Irene di Pierro, Ross Brown, Ilona Cunningham, David J Handelsman, and Peter Y Liu

Objectives

Testosterone formulations that have more steady-state pharmacokinetics, such as subcutaneously implanted testosterone pellets, may cause less erythrocytosis than i.m. injections of shorter acting androgen esters. We, therefore, sought to define the prevalence, predictors, and proximate basis (role of erythropoietin) for polycythemia (hematocrit >0.50) in hypogonadal men receiving testosterone implants long term.

Design

A cross-sectional study was conducted in an academic andrology center with a longitudinal subgroup analysis.

Patients

A total of 158 hypogonadal men aged 14–84 years (mean age 46.7 years) treated on average for 8 years (range 0–21 years).

Measurements

Trough blood testosterone and hematocrit. Serial serum erythropoietin concentrations were measured in 16 volunteers.

Results

Positive univariate associations between polycythemia (hematocrit >0.50) and log(testosterone) (odds ratio (OR) 24.7, 95% confidence interval (CI): 4.3, 141.2, P<0.01) and age (OR 1.1, 95% CI: 1.0, 1.1, P=0.03) and a borderline relationship with current smoking (OR 4.2, 95% CI: 0.9, 20.0, P=0.08) were unveiled. A sensitivity analysis using alternate definitions of polycythemia was performed to capture all potential covariants. Multivariate regression analysis incorporating all potential covariants disclosed the independent OR of developing polycythemia (after adjusting for smoking and age) for log(testosterone) to be 15.0 (95% CI: 2.5, 90.8). Duration of testosterone therapy did not alter the risk of polycythemia. A direct relationship between testosterone and erythropoietin was observed (P=0.05).

Conclusions

Higher trough serum testosterone concentrations but not duration of treatment predict the development of polycythemia in men receiving long-acting depot testosterone treatment.

Free access

Short-term effects of transdermal estradiol in men undergoing androgen deprivation therapy for prostate cancer: a randomized placebo-controlled trial

Nicholas Russell, Rudolf Hoermann, Ada S Cheung, Michael Ching, Jeffrey D Zajac, David J Handelsman, and Mathis Grossmann

Objective

There is increasing recognition that, in men, some biological actions attributed to testosterone (TS) are mediated by estradiol (E2). This study used two low doses of daily transdermal E2 gel to assess the effects on circulating E2 concentrations in men with prostate cancer with suppressed endogenous E2 production arising from androgen deprivation therapy (ADT). Secondarily, we aimed to assess short-term biological effects of E2 add-back without increasing circulating TS.

Design

28-day randomised, placebo-controlled trial.

Methods

37 participants were randomised to either 0.9 or 1.8 mg of 0.1% E2 gel per day or matched placebo gel. Fasting morning serum hormones, quality of life questionnaires, and treatment side effects were evaluated at baseline, days 14 and 28. Hot flush diaries and other biochemical measurements were completed at baseline and study end.

Results

Transdermal E2 significantly raised serum E2 from baseline to day 28 compared to placebo in the 0.9 mg dose group (median: 208 pmol/L; interquartile range: 157–332) and in the 1.8 mg dose group (median: 220 pmol/L; interquartile range: 144–660). E2 treatment reduced hot flush frequency and severity as well as beta carboxyl-terminal type 1 collagen telopeptide.

Conclusion

In men with castrate levels of E2 and TS, daily transdermal E2: 0.9–1.8 mg increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. E2 treatment reduced hot flushes and bone resorption. Larger studies will be required to test whether low-dose E2 treatment can mitigate ADT-associated adverse effects without E2-related toxicity.

Free access

Recovery of male reproductive endocrine function after ceasing prolonged testosterone undecanoate injections

David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn G A Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Wittert

Context

The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective

The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Materials and Methods

Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later.

Results

In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since the last injection.

Conclusions

After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.