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Nicholas Russell and Mathis Grossmann

Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may in fact be dependent on its aromatization to estradiol (E2). In men, E2 circulates at concentrations exceeding those of postmenopausal women, and estrogen receptors are expressed in many male reproductive and somatic tissues. Human studies contributing evidence for the role of E2 in men comprise rare case reports of men lacking aromatase or a functional estrogen receptor alpha, short-term experiments manipulating sex steroid milieu in healthy men, men with organic hypogonadism or men with prostate cancer treated with androgen deprivation therapy (ADT) and from observational studies in community-dwelling men. The collective evidence suggests that, in men, E2 is an important hormone for hypothalamic–pituitary–testicular axis regulation, reproductive function, growth hormone insulin-like growth factor-1 axis regulation, bone growth and maintenance of skeletal health, body composition and glucose metabolism and vasomotor stability. In other tissues, particularly brain, elucidation of the clinical relevance of E2 actions requires further research. From a clinical perspective, the current evidence supports the use of testosterone as the treatment of choice in male hypogonadism, rather than aromatase inhibitors (which raise testosterone and lower E2), selective androgen receptor modulators and selective estrogen receptor modulators (with insufficiently understood tissue-specific estrogenic effects). Finally, E2 treatment, either as add-back to conventional ADT or as sole mode of ADT could be a useful strategy for men with prostate cancer.

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Mathis Grossmann and Thomas Hugh Jones

Clinicians commonly encounter middle-aged and older men who present with functional hypogonadism, that is, with clinical features compatible with androgen deficiency and lowered serum testosterone, but without evidence of organic hypothalamic-pituitary-testicular axis pathology. Whether, and when, testosterone therapy should be offered to such men remains uncertain and controversial, in part due to the lack of definitive evidence regarding long-term patient-important health outcomes with testosterone treatment. In this debate, we address this controversy and provide two opposing points of view on the role of testosterone treatment in older men with functional hypogonadism.

Free access

Ada S Cheung, Alistair J Tinson, Stefan V Milevski, Rudolf Hoermann, Jeffrey D Zajac, and Mathis Grossmann

Objective

Hypogonadism from androgen deprivation therapy (ADT) for prostate cancer causes adverse body composition changes associated with insulin resistance and decreased quality of life (QoL). Our objective was to assess whether adverse body composition changes improve after cessation of ADT.

Design

Prospective case–control study in a tertiary referral hospital. Thirty-four men newly commencing ADT (cases, median age: 67.6 years (interquartile range: 64.6–72.0)) and 29 age-matched (70.6 years (65.3–72.9)) prostate cancer controls not on ADT were assessed 2 years after cessation of ADT (median: 4.4 years).

Methods

Serum testosterone, body composition, handgrip strength, frailty and QoL were measured. Using a mixed model, the mean adjusted differences (MADs (95% CI)) between groups from baseline to study end are reported.

Results

Twenty-seven cases and 19 controls completed the study. Median duration of ADT was 2.3 years (interquartile range: 1.8–3.1). Two years after cessation of ADT, total testosterone remained lower (MAD: −3.4 nmol/L (−6.3 to −0.5), P < 0.022), fat mass (2214 g (490–3933), P = 0.025) and insulin resistance (homeostasis model assessment of insulin resistance: 0.69 (0.31–1.07), P < 0.001) remained higher in cases, whereas lean mass (−1450 g (−2259 to −640), P < 0.001) and physical component of QoL remained lower than controls (−11.9 (−16.4 to −7.4), P < 0.001).

Conclusion

Two years after ADT cessation, metabolically adverse changes in body composition, increased insulin resistance and reduced QoL persisted. This may be related to incomplete testosterone recovery. Persisting adverse effects need to be considered in the risk to benefit assessment of ADT and proactive mitigation should continue after cessation of treatment.

Free access

Ada S Cheung, Rudolf Hoermann, Philippe Dupuis, Daryl Lim Joon, Jeffrey D Zajac, and Mathis Grossmann

Objective

While androgen deprivation therapy (ADT) has been associated with insulin resistance and frailty, controlled prospective studies are lacking. We aimed to examine the relationships between insulin resistance and frailty with body composition and testosterone.

Design

Case–control prospective study.

Methods

Sixty three men with non-metastatic prostate cancer newly commencing ADT (n=34) and age-matched prostate cancer controls (n=29) were recruited. The main outcomes were insulin resistance (HOMA2-IR), Fried’s frailty score, body composition by dual x-ray absorptiometry and short physical performance battery (SPPB) measured at 0, 6 and 12months. A generalised linear model determined the mean adjusted difference (95% CI) between groups.

Results

Compared with controls over 12months, men receiving ADT had reductions in mean total testosterone level (14.1–0.4nmol/L, P<0.001), mean adjusted gain in fat mass of 3530g (2012, 5047), P<0.02 and loss of lean mass of 1491g (181, 2801), P<0.02. Visceral fat was unchanged. HOMA2-IR in the ADT group increased 0.59 (0.24, 0.94), P=0.02, which was most related to the increase in fat mass (P=0.003), less to lean mass (P=0.09) or total testosterone (P=0.088). Frailty increased with ADT (P<0.0001), which was related to decreased testosterone (P=0.028), and less to fat mass (P=0.056) or lean mass (P=0.79). SPPB was unchanged.

Conclusions

ADT is associated with increased insulin resistance and frailty within 12months of commencement, independently of confounding effects of cancer or radiotherapy. Insulin resistance appears to be mediated by subcutaneous or peripheral sites of fat deposition. Prevention of fat gain is an important strategy to prevent adverse ADT-associated cardiometabolic risks.

Free access

Aye N Tint, Rudolf Hoermann, Henry Wong, Elif I Ekinci, Richard J MacIsaac, George Jerums, Jeffrey D Zajac, and Mathis Grossmann

Objective

Low circulating testosterone levels have been associated with increased mortality in men. We hypothesized that the prognostic role of testosterone in men with type 2 diabetes mellitus (T2DM) is influenced by its carrier protein sex hormone-binding globulin (SHBG).

Design

We conducted a prospective cohort study at a tertiary referral centre.

Methods

In total, 531 men with T2DM presenting to a diabetes clinic in 2004–2005 were followed prospectively until death, or July 31, 2014, and a survival analysis was performed. The main outcome measure was all cause mortality.

Results

Over a mean (s.d.) follow up of 7.6 years (2.6) 175 men (33%) died. In Cox proportional hazard models both higher SHBG (Hazard Ratio (HR) 1.012 (95% CI 1.002–1.022), P=0.02) and lower calculated free testosterone (cFT) (HR 0.995 (95% CI 0.993–0.998), P=0.001) were risk factors for all cause mortality independently of age, BMI, presence of macro- and microvascular disease, duration of T2DM, hemoglobin, renal function, insulin use, C-reactive protein and homeostatic model of insulin resistance. By contrast, the inverse association of total testosterone (TT) with mortality weakened after these adjustments (P=0.11). SHBG remained associated with mortality (P<0.001) both if substituted for or added to TT in the multivariable model. In the fully adjusted model, an increase of SHBG by 17.3 nmol/l (1 s.d.) increased mortality by 22% and a decrease in cFT by 81 pmol/l (1 s.d.) increased mortality by 45%.

Conclusions

The association of SHBG with mortality in men with T2DM is novel. Whether SHBG acts via regulation of testosterone, has intrinsic biological roles, or is a marker of poor health requires further study.

Free access

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.

Restricted access

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.

Restricted access

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

Objective

Most men undergoing androgen deprivation therapy (ADT) for prostate cancer experience hot flushes. Current treatments have low or limited evidence of efficacy. It is likely that oestradiol depletion is the mediator of these hot flushes, and transdermal oestradiol might be an effective treatment.

Design

This is a 6-month randomised, placebo-controlled trial with the hypothesis that oestradiol would reduce hot flush frequency and intensity and improve quality of life (QoL).

Methods

Seventy-eight participants receiving ADT were randomised to 0.9 mg of 0.1% oestradiol gel per day or matched placebo. Hot flush frequency and severity were assessed by 7-day diary at baseline, month 1, month 3, and month 6. QoL was assessed by validated questionnaire.

Results

Oestradiol reduced daily hot flush frequency, with a mean adjusted difference (MAD) of –1.6 hot flushes per day (95% CI: –2.7 to –0.5; P = 0.04). The effect on weekly hot flush score was non-significant, with a MAD –19.6 (95% CI: –35.5 to –3.8; P = 0.11). On per protocol analysis, E2 significantly reduced daily hot flush frequency, with a MAD of –2.2 hot flushes per day (95% CI: –3.2 to –1.1; P = 0.001), and weekly hot flush score, with a MAD of –27.0 (–44.7 to –9.3; P = 0.02). Oestradiol had no significant effect on QoL.

Conclusion

We confirmed our hypothesis of a clinical effect of assignment to oestradiol to reduce hot flush frequency in men with castrate testosterone due to ADT. Transdermal oestradiol could be considered for men with burdensome hot flushes in whom other treatments have failed as long as the risk of breast effects and fat gain are considered.

Restricted access

Nicholas Russell, Ali Ghasem-Zadeh, Rudolf Hoermann, Ada S Cheung, Jeffrey D Zajac, Cat Shore-Lorenti, Peter R Ebeling, David J Handelsman, and Mathis Grossmann

Objective

In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T.

Design

This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling.

Methods

78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers.

Results

For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm3 (95% CI: −0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm3 (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers.

Conclusion

Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.

Restricted access

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.