Androgen Replacement

[Michael Scally MD]

[OA] Androgen Treatment in Adolescent Males With Hypogonadism

During adolescence, androgens are responsible for the development of secondary sexual characteristics, pubertal growth, and the anabolic effects on bone and muscle mass. Testosterone is the most abundant testicular androgen, but some effects are mediated by its conversion to the more potent androgen dihydrotestosterone (DHT) or to estradiol.

Androgen deficiency, requiring replacement therapy, may occur due to a primary testicular failure or secondary to a hypothalamic-pituitary disorder. A very frequent condition characterized by a late activation of the gonadal axis that may also need androgen treatment is constitutional delay of puberty.

Of the several testosterone or DHT formulations commercially available, very few are employed, and none is marketed for its use in adolescents. The most frequently used androgen therapy is based on the intramuscular administration of testosterone enanthate or cypionate every 3 to 4 weeks, with initially low doses. These are progressively increased during several months or years, in order to mimic the physiology of puberty, until adult doses are attained. Scarce experience exists with oral or transdermal formulations.

Preparations containing DHT, which are not widely available, are preferred in specific conditions. Oxandrolone, a non-aromatizable drug with higher anabolic than androgenic effects, has been used in adolescents with preserved testosterone production, like Klinefelter syndrome, with positive effects on cardiometabolic health and visual, motor, and psychosocial functions. The usual protocols applied for androgen therapy in boys and adolescents are discussed.

Rey RA, Grinspon RP. Androgen Treatment in Adolescent Males With Hypogonadism. Am J Mens Health. 2020;14(3):1557988320922443. doi:10.1177/1557988320922443 SAGE Journals: Your gateway to world-class research journals

 

[Michael Scally MD]

Dose-Response Relationships Between Gonadal Steroids and Bone, Body Composition, and Sexual Function

Context: Most labs set the lower limit of normal for testosterone at the 2.5th percentile of values in young or age-matched men, an approach that does not consider the physiologic changes associated with various testosterone concentrations.

Objective: To characterize the dose-response relationships between gonadal steroid concentrations and measures regulated by gonadal steroids in older men.

Design, participants, and intervention: 177 men ages 60-80 were randomly assigned to receive goserelin acetate plus either 0 (placebo),1.25, 2.5, 5, or 10 grams of a 1% testosterone gel daily for 16 weeks, or placebos for both medications (controls).

Primary outcomes: Changes in serum C-telopeptide (CTX), total body fat by dual energy x-ray absorptiometry (DXA), and self-reported sexual desire.

Results: Clear relationships between the testosterone dosage (or the resulting testosterone levels) and a variety of outcome measures were observed. Changes in serum CTX exceeded changes in the controls in men whose testosterone levels were 0-99, 100-199, 200-299 ng/dL, or 300-499 ng/dL whereas increases in total body fat, subcutaneous fat, and thigh fat exceeded controls when testosterone levels were 0-99 or 100-199 ng/dL. Sexual desire and erectile function were indistinguishable from controls until testosterone levels were <100 ng/dL.

Conclusion: Changes in measures of bone resorption, body fat, and sexual function begin at a variety of testosterone concentrations with many outcome measures remaining stable until testosterone levels are well below the stated normal ranges. In light of this variation, novel approaches for establishing the normal range for testosterone are needed.

Finkelstein JS, Lee H, Burnett-Bowie SM, et al. Dose-Response Relationships Between Gonadal Steroids and Bone, Body Composition, and Sexual Function in Aging Men [published online ahead of print, 2020 Jun 1]. J Clin Endocrinol Metab. 2020;dgaa318. doi:10.1210/clinem/dgaa318 Dose-Response Relationships Between Gonadal Steroids and Bone, Body Composition, and Sexual Function in Aging Men

 

[Michael Scally MD]

Importance of Total and Measured Free Testosterone in Diagnosis of Male Hypogonadism: Immunoassay Versus Mass Spectrometry

Purpose - To meet clinicians’ request for adequate results and reliable reference ranges for testosterone, this study was planned with the aims (i) to verify the reliability of the reference interval for total testosterone (TT) declared by immunoassay manufacturer and adopted by laboratory, (ii) to compare results for serum TT obtained by immunoassay and LC–MS/MS and (iii) to verify if the cutoff values for low TT and measured free testosterone (FT), defined by Endocrine Society Guidelines for diagnosis of hypogonadism, are applicable to our study group.

Methods - Sera from anonymous young/middle-aged male blood donors were selected for the study. TT was measured by immunoassay and LC–MS/MS. SHBG was measured by immunoassay and used with albumin concentration to calculate FT according to Vermeulen’s formula.

Results - The reference interval declared by the manufacturer and adopted by the lab was validated. The two methods for TT evaluation correlated very well. TT and FT lower limits at 5th and 2.5th percentile are below the cutoffs reported in the literature for the diagnosis of hypogonadism.

Conclusions - The immunoassay currently used in our lab can be considered an adequate tool for TT, but it’s essential that clinical data agree with the biochemical ones, particularly in the presence of TT values between the lower limit of reference range and the cutoff values recommended by scientific societies.

Agretti, P., Pelosini, C., Bianchi, L. et al. Importance of total and measured free testosterone in diagnosis of male hypogonadism: immunoassay versus mass spectrometry in a population of healthy young/middle-aged blood donors. J Endocrinol Invest (2020). https://doi.org/10.1007/s40618-020-01304-7

 

[Michael Scally MD]

[OA] Testosterone Replacement Therapy In Puberty

This review focuses on testosterone replacement therapy during puberty in males. Delayed puberty may be an extreme of normal puberty, but such cases are difficult to distinguish from organic diseases of the hypothalamic-pituitary-gonadal axis.

Substitutive testosterone treatment allows complete pubertal development in young adolescents with early onset hypogonadotropic hypogonadism or hypergonadotropic hypogonadism, using low doses followed by progressive escalation and then long-term therapy.

In boys with constitutional delay of growth and puberty (CDGP), short courses of testosterone therapy accelerate growth and sexual maturation, before the start of physiological puberty.

Though few data have been published, we discuss the clinical use of these treatments in adolescents, testosterone preparations used, effects of the sex steroid therapy and outcomes.

Bouvattier C, Young J. Testosterone replacement therapy in puberty. Current Opinion in Endocrine and Metabolic Research 2020. Testosterone replacement therapy in puberty - ScienceDirect

 

[Michael Scally MD]

Endocrinological and Symptomatic Characteristics of Patients with Late-Onset Hypogonadism Classified by Functional Categories Based on Testosterone and Luteinizing Hormone Levels

Objectives: To define the characteristics of patients with late-onset hypogonadism based on endocrinological findings.

Methods: We assessed age, body mass index, laboratory/endocrinological profiles and symptom-specific questionnaire scores of 967 men with late-onset hypogonadism symptoms.

The patients comprised four groups by testosterone and luteinizing hormone concentrations: normal group, compensated hypogonadism group, primary hypogonadism group and secondary hypogonadism group.

We compared characteristics between the normal group and compensated hypogonadism group in men with normal testosterone concentration, and the primary hypogonadism group and secondary hypogonadism group in hypogonadal men after age adjustment.

Results: The normal group, compensated hypogonadism group, primary hypogonadism group and secondary hypogonadism group accounted for 83.6%, 3.4%, 0.8% and 12.2% of patients, respectively.

Despite age adjustment, serum dehydroepiandrosterone sulfate and insulin-like growth factor 1 concentrations were significantly lower in the compensated hypogonadism group than the normal group. Only the Aging Males' Symptoms scale mental subscore was significantly different.

Serum testosterone and dehydroepiandrosterone sulfate concentrations were significantly lower in the primary hypogonadism group than the secondary hypogonadism group. Only the Aging Males' Symptoms scale sexual subscore was significantly different.

Conclusions: Most patients with late-onset hypogonadism symptoms are in the normal group, with secondary hypogonadism being much more frequent than primary hypogonadism. Current symptomatic differences among these groups are minor. Classifying patients by testosterone and luteinizing hormone levels might provide useful information for follow up.

Ishikawa K, Tsujimura A, Miyoshi M, et al. Endocrinological and symptomatic characteristics of patients with late-onset hypogonadism classified by functional categories based on testosterone and luteinizing hormone levels [published online ahead of print, 2020 Jun 25]. Int J Urol. 2020;10.1111/iju.14296. doi:10.1111/iju.14296 Error - Cookies Turned Off

 

[Michael Scally MD]

[OA] The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use

The U.S. Food and Drug Administration (FDA) has approved dozens of hormone therapy products for men and women, including estrogen, progesterone, testosterone, and related compounds. These products have been reviewed for safety and efficacy and are indicated for treatment of symptoms resulting from hormonal changes associated with menopause or other endocrine-based disorders.

In recent decades, an increasing number of health care providers and patients have turned to custom-formulated, or compounded, drug preparations as an alternative to FDA-approved drug products for hormone-related health concerns. These compounded hormone preparations are often marketed as “bioidentical” or “natural” and are commonly referred to as compounded bioidentical hormone therapy (cBHT).

In light of the fast-growing popularity of cBHT preparations, the clinical utility of these compounded preparations is a substantial public health concern for various stakeholders, including medical practitioners, patients, health advocacy organizations, and federal and state public health agencies.

This report examines the clinical utility and uses of cBHT drug preparations and reviews the available evidence that would support marketing claims of the safety and effectiveness of cBHT preparations. It also assesses whether the available evidence suggests that these preparations have clinical utility and safety profiles warranting their clinical use and identifies patient populations that might benefit from cBHT preparations in lieu of FDA-approved BHT.

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy; Donald R. Mattison, Ruth M. Parker, and Leigh Miles Jackson, Editors. Washington, DC: The National Academies Press; 2020. https://www.nap.edu/catalog/25791/the-clinical-utility-of-compounded-bioidentical-hormone-therapy-a-review

 

[Michael Scally MD]

Circulating Sex Steroid Measurements of Men by Mass Spectrometry Are Highly Reproducible after Prolonged Frozen Storage

Long-term studies investigating hormone-dependent cancers and reproductive health often require prolonged frozen storage of serum which assumes that the steroid molecules and measurements are stable over that time. Previous studies of reproducibility of circulating steroids have relied upon flawed historical rather than contemporaneous controls.

We measured serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) in 150 randomly selected serum samples by liquid chromatography-mass spectrometry (LC-MS) from men 70 years or older (mean age 77 years) in the CHAMP study.

The original measurements in 2009 were repeated 10 years later using the identical serum aliquot (having undergone 2-4 freeze-thaw cycles in the interim) in 2019 together with another never-thawed aliquot of the same serum sample.

The results of all three sets of measurements were evaluated by Passing-Bablok regression and Bland-Altman difference analysis. Serum androgens (T, DHT) and estrogens (E2, E1) measured by LC-MS display excellent reproducibility when stored for 10 years at -80 C without thawing. Serum T and DHT displayed high level of reproducibility across all three sets of measurements. Multiple freeze-thaw cycles over those storage conditions do not significantly affect serum T, DHT and E1 concentrations but produce a modest increase (21%) in serum E2 measurements.

Handelsman DJ, Desai R, Seibel MJ, Le Couteur DG, Cumming RG. Circulating Sex Steroid Measurements of Men by Mass Spectrometry Are Highly Reproducible after Prolonged Frozen Storage. J Steroid Biochem Mol Biol. 2020;197:105528. doi:10.1016/j.jsbmb.2019.105528 Circulating Sex Steroid Measurements of Men by Mass Spectrometry Are Highly Reproducible after Prolonged Frozen Storage - ScienceDirect

 

[Michael Scally MD]

Effects of Testosterone on Serum Concentrations, Fat-Free Mass, and Physical Performance by Population

Testosterone (T) administration (TA) increases serum T and fat-free mass (FFM). Although TA-mediated increases in FFM may enhance physical performance, the data are largely equivocal, which may be due to differences in study populations, the magnitude of change in serum T and FFM, or the performance metrics.

This meta-analysis explored effects of TA on serum T, FFM, and performance. Association between increases in serum T and FFM were assessed, and if changes in serum T or FFM, study population, or the performance metrics affected performance was determined. A systematic review of double-blind randomized trials comparing TA versus placebo on serum T, FFM, and performance was performed.

Data were extracted from 20 manuscripts. Effect sizes (ES) were assessed using Hedge’s g and a random effects model. Data are presented as ES (95% CI).

No significant correlation between changes in serum T and FFM was observed (p=0.167). Greater increases in serum T, but not FFM, resulted in larger effects on performance. Larger increases in testosterone [7.26(0.76,13.75)] and FFM [0.80(0.20,1.41)] were observed in young males, but performance only improved in diseased [0.16(0.05,0.28)] and older males [0.19(0.10,0.29)].

TA increased lower body [0.12(0.07,0.18)], upper body [0.26(0.11,0.40)], and handgrip [0.13(0.04,0.22)] strength, lower body muscular endurance [0.38(0.09,0.68)], and functional performance [0.20(0.00,0.41)], but not lower body power or aerobic endurance.

TA elicits increases in serum T and FFM in younger, older and diseased males; however, the performance-enhancing effects of TA across studies were small, observed mostly in muscular strength and endurance, and only in older and diseased males.

Varanoske AN, Margolis LM, Pasiakos SM. Effects of testosterone on serum concentrations, fat-free mass, and physical performance by population: a meta-analysis. Journal of the Endocrine Society 2020. Effects of testosterone on serum concentrations, fat-free mass, and physical performance by population: a meta-analysis

 

[Michael Scally MD]

An Audit of the Measurement and Reporting of Male Testosterone Levels in UK Clinical Biochemistry Laboratories

Introduction: A number of guidance documents have been published in recent years for diagnosis and management of hypogonadism (HG). Laboratory practice has a major role in supporting guidelines with accurate and precise total serum testosterone (TT) methods and standardised pre- and post-analytical protocols. Our study investigated whether laboratory practice currently supports the management guidelines for HG.

Methods: An internet-based questionnaire-survey of senior laboratory biochemists (UK/Republic of Ireland) was conducted (April-May 2018). Questions reflected sampling, laboratory practice, reference ranges and reporting of results. The results were analysed in conjunction with data obtained from the UK National External Quality Assurance Service (UK NEQAS) on assay performance.

Results: Analyses of 96 laboratory surveys returned the following: 74 laboratories stated that optimal sampling time was communicated to users; 81 laboratories used immunoassays; 76 laboratories included reference ranges for adult men (31 had dual/multiple age-related intervals).

Wide variability in lower/upper limits was evident in the common immunoassays; the majority of reference ranges were from manufacturers (50.0%) or historical (18.8%). Action limits based on TT levels were used by 64 laboratories, but 63 did not report a borderline range as suggested by guidelines.

Protocols for cascading tests based on TT were evident in 58 laboratories, with 50 laboratories offering estimated free testosterone; Interpretative comments were provided by 67 laboratories, but no references were made to management guidelines. Data from UK NEQAS demonstrated considerable variation in testosterone assay performance.

Conclusions: Our survey has highlighted inconsistencies that could lead to HG (and other conditions requiring TT measurement) not being managed appropriately. The results from this survey and from UK NEQAS reinforce the requirement for action to be considered regarding the standardisation of testosterone assays and harmonisation of laboratory practice.

Livingston M, Downie P, Hackett G, Marrington R, Heald A, Ramachandran S. An Audit of the Measurement and Reporting of Male Testosterone Levels in UK Clinical Biochemistry Laboratories [published online ahead of print, 2020 Jul 10]. Int J Clin Pract. 2020;e13607. doi:10.1111/ijcp.13607 https://onlinelibrary.wiley.com/doi/abs/10.1111/ijcp.13607

 

[Michael Scally MD]

[OA] Critical Evaluation of Different Available Guidelines for Late-Onset Hypogonadism

Background Late-onset hypogonadism (LOH) is a syndrome characterized by clinical and biochemical evidence of low testosterone levels with advancing age. In recent years, several guidelines, position statements and other recommendations have become available. It is unclear whether similar indications are reported in these documents.

Objective To review similarities and differences among available documents on the management of hypogonadism, with a special focus on LOH.

Materials and methods PubMed, Google and international societies websites were searched on March 2020 for documents published in the last 10 years on the management of hypogonadism and LOH.

Results Nine documents were found, each developed by:

(a) the American Urological Association;

(b) the British Society for Sexual Medicine;

(c) the Canadian Medical Association;

(d) the Endocrine Society;

(e) the Endocrine Society of Australia;

(f) the European Academy of Andrology;

(g) the European Association of Urology;

(h) the International Consultation for Sexual Medicine; and

(i) the International Society for the Study of Aging Male.

Discussion Despite similar principles, differences were found both for the diagnostic workup and follow-up. Particularly, discrepancies were reported both for total and free testosterone levels for diagnosis and for total testosterone for monitoring.

Conclusion Available documents differ in terms of specific recommendations for the management of hypogonadism and LOH. Given the relevant clinical implications of adequate management of these disorders, future guidelines should report more consistent measures to be adopted in clinical practice.

Giagulli VA, Castellana M, Lisco G, Triggiani V. Critical evaluation of different available guidelines for late-onset hypogonadism. Andrology 2020;n/a. Error - Cookies Turned Off

 

[Michael Scally MD]

Variation in Levels of Serum Testosterone in Monthly Samples

Introduction & Objectives: It is well known that testosterone deficiency syndrome is related to increased insulin resistance, increased visceral fat, and erectile dysfunction. Therefore, the testosterone level is an important issue of men`s health.

Daily fluctuations in testosterone have been reported in many articles. However, there has been little evidence concerning monthly fluctuations in testosterone and their results are inconsistent across studies. In this study, we investigated the aforementioned issues.

Materials & Methods: We enrolled a total of 9,318 middle-aged men who had received health check-ups from 2011 to 2013. We excluded participants who had taken 5 alpha-reductase inhibitors or anti-psychotics, received androgen replacement therapy, and diagnosed with any kind of cancer. Serum testosterone was measured via radioimmunoassay and serum was collected between 7:00 and 9:00 AM. Analyses were conducted with the R statistical package.

Results: Mean age, BMI, and testosterone were 50.6±5.5 years old, 25.1±2.7kg/m2, and 5.2±1.6ng/mL, respectively. And 37.4% of participants had metabolic syndrome.

The trough testosterone level was observed in May (4.46ng/mL) and the peak level was observed in Jan (5.94ng/ mL). The relative difference ((peak – trough)/peak) was 24.9% and absolute difference (peak - trough) was 1.48ng/mL. The ratio of testosterone <3.5ng/mL was highest in May (23.4%) and lowest in Jan (3.0%) (P<.001).

After adjusting age, BMI, and the number of metabolic syndromes, the trough testosterone level was also observed in May and the peak level in Jan. (adjusted mean (95% CI)ng/mL; May, 4.390(4.239-4.542); Jan., 5.968(5.832-6.104)).

Conclusions: We found that monthly variation in levels of testosterone. In the diagnosis of testosterone deficiency, careful consideration of monthly variation in levels of testosterone would be needed. Further investigational studies would be needed to confirm our data.

Lee JH. 20 - Variation in levels of serum testosterone in monthly samples from healthy men. European Urology Open Science 2020;19:e130. Variation in levels of serum testosterone in monthly samples from healthy men - ScienceDirect

 

[Michael Scally MD]

Discontinuation of Testosterone Replacement Therapy in Patients with Late-Onset Hypogonadism: A 10-Year Observational Study

Introduction & Objectives: The efficacy and safety of testosterone replacement therapy (TRT) in male patients with late onset hypogonadism (LOH) are well documented. However, many patients discontinue medication during treatment. It is important to understand the motivations for discontinuation and to develop strategies that promote compliance. The present study evaluated the discontinuation rate of TRT in LOH patients. In addition, we investigated whether treatment types and patient characteristics influenced discontinuation.

Materials & Methods: Patients aged 40 years or older who were diagnosed with LOH (total testosterone <300 ng/dL) from 2010 to 2019 were enrolled. The duration of treatment, duration of discontinuation, retreatment rate, discontinuation rate at 1 year, and reason for discontinuation were investigated. We also evaluated the effects of treatment type and patient characteristics on the observed discontinuation rate.

Results: Of the 820 enrolled subjects, complete data were available for 640 patients. The mean duration of continuous treatment was 15 ± 7 months, the mean discontinuation period was 8.5 ± 3 months, and the retreatment rate was 65%. One year after initial treatment, the discontinuation rate was 24%.

Testosterone enanthate 250 mg (short acting injection) was associated with the highest discontinuation rate (42%), followed by Andriol Testocaps® (31.2%), testosterone gel (28.8%), and Nebido® (testosterone undecanoate 1000 mg, long-acting injection, 9.2%). The retreatment rate after discontinuation was highest for Nebido® (75%) and lowest for testosterone enanthate (51%).

The reasons for discontinuation were perceived lack of efficacy (45.4%), cost (19.5%), side effects (16.2%), symptom improvement (12.9%), and discomfort (5.8%). Older patients (>60 years) with lower T (T< 200 ng/dL) and more severe sexual dysfunction (IIEF-5≤7) taking PDE-5 inhibitors showed lower drop-out rates. The overall rate of medication change was 21.9%, with the most common switch being from testosterone enanthate, testosterone gel, or Andriol Testocaps® to Nebido®.

Conclusions: In our 10-year observational study, the discontinuation rate was 24% 1 year after initial TRT. Nebido® had the lowest discontinuation rate and the primary reason patients gave for medication cessation was lack of efficacy.

Park HJ, Park JH, Kim KH, Kang BJ, Baek SR, Park NC. 21 - Discontinuation of testosterone replacement therapy in patients with late-onset hypogonadism: A 10-year observational study. European Urology Open Science 2020;19:e131. Discontinuation of testosterone replacement therapy in patients with late-onset hypogonadism: A 10-year observational study - ScienceDirect

 

[Michael Scally MD]

An Audit of The Measurement and Reporting of Male Testosterone Levels in UK Clinical Biochemistry Laboratories

Introduction A number of guidance documents have been published in recent years for the diagnosis and management of hypogonadism (HG). Laboratory practice has a major role in supporting guidelines with accurate and precise serum total testosterone (TT) methods and standardised pre- and post-analytical protocols. Our study investigated whether laboratory practice currently supports the management guidelines for HG.

Methods An internet-based questionnaire survey of senior laboratory biochemists (UK/Republic of Ireland) was conducted (April-May 2018). Questions reflected sampling, laboratory practice, reference ranges and reporting of results. The results were analysed in conjunction with data obtained from the UK National External Quality Assurance Service (UK NEQAS) on testosterone assay performance.

Results Analyses of 96 laboratory surveys returned the following: 74 laboratories stated that the optimal sampling time was communicated to users; 81 laboratories used immunoassays; 76 laboratories included reference ranges for adult men (31 had dual/multiple age-related intervals). Wide variability in lower/upper limits was evident in the common immunoassays; the majority of reference ranges were from manufacturers (50.0%) or historical (18.8%). Action limits based on TT levels were used by 64 laboratories, but 63 did not report a borderline range as suggested by the guidelines. Protocols for cascading tests based on TT were evident in 58 laboratories, with 50 laboratories offering estimated free testosterone; interpretative comments were provided by 67 laboratories, but no references were made to the management guidelines. Data from UK NEQAS demonstrated considerable variation in testosterone assay performance.

Conclusions Our survey has highlighted inconsistencies that could lead to HG (and other conditions requiring measurement of TT) not being managed appropriately. The results from this survey and from UK NEQAS reinforce the requirement for action to be considered regarding the standardisation of testosterone assays and harmonisation of laboratory practice.

Livingston M, Downie P, Hackett G, Marrington R, Heald A, Ramachandran S. An audit of the measurement and reporting of male testosterone levels in UK clinical biochemistry laboratories. International Journal of Clinical Practice 2020;n/a:e13607. https://doi.org/10.1111/ijcp.13607

 

[Michael Scally MD]

Pharmacoepidemiology of Testosterone: Impact of Reimbursement Policy on Curbing Off-Label Prescribing

Objectives - To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria.

Design - Analysis of testosterone prescribing data from PBS and private (non‐PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria.

Main outcome measures - New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age‐group, indication and prescriber type. Total national testosterone prescriptions (private plus PBS) was verified from an independent data supplier (IQVIA).

Results - PBS usage peaked in 2014 declining by 30% in 2017‐8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017‐18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle‐aged men without pathological hypogonadism whereas specialist initiations and prescription for adult hypogonadism or pediatric/prepubertal indications were largely unaffected.

Conclusions - The tightening of PBS criteria from 1 April 2015 to curb off‐label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions.

The continuation of off‐label testosterone prescribing for unproven indications suggests that long‐term androgen dependence is created in men without pathological hypogonadism who commence testosterone.

This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long‐term androgen dependency when trying to quit.

Handelsman DJ. Pharmacoepidemiology of testosterone: Impact of reimbursement policy on curbing off-label prescribing. Pharmacoepidemiol Drug Saf 2020;n/a. Error - Cookies Turned Off

 

[Michael Scally MD]

[OA] Testosterone Therapy: Prescribing and Monitoring Patterns of Practice in British Columbia

Introduction: Guidelines recommend that testosterone therapy (TTh) be restricted to men with a biochemical diagnosis of hypogonadism, and that therapeutic responses be titrated within the normal range.

Methods: Using four provincial longitudinal databases in British Columbia, we identified men prescribed TTh (1997-2013). We characterized the prescribing and monitoring practices of TTh in the context of serum testosterone levels drawn prior to and following initiation of TTh in a population-based setting.

Results: In our analysis of 37 741 men who received at least one TTh prescription, 48% received injectable testosterone and the vast majority were treated by general practitioners. The number of prescriptions for men increased annually, particularly after 2008; 40% discontinued their treatment after their first or second prescription, while 27% received more than 10 repeats.

The absolute percentage of pre- and post-serum testosterone levels ordered increased by 16% and 31% during the study period, respectively. However, after initiating TTh, only 36% of all the men had a followup serum testosterone level drawn. Of those with low serum testosterone levels prior to TTh, 49% remained biochemically hypogonadal following TTh, suggesting non-compliance or inadequate dosing.

Conclusions: Many men prescribed TTh did not continue beyond a short trial. While the practice of checking pre-and post-TTh testosterone levels has improved over the study period, it is concerning that only one-third had a followup serum testosterone level, and half remained biochemically low. Further education is required around TTh prescribing, dose titration, and monitoring to ensure both effective and safe prescribing practice.

Locke JA, Flannigan R, Günther OP, Skeldon S, Goldenberg SL. Testosterone therapy: Prescribing and monitoring patterns of practice in British Columbia [published online ahead of print, 2020 Jul 27]. Can Urol Assoc J. 2020;10.5489/cuaj.6586. doi:10.5489/cuaj.6586 Testosterone therapy: Prescribing and monitoring patterns of practice in British Columbia | Canadian Urological Association Journal

 

[Michael Scally MD]

The Causes of Adverse Changes of Testosterone Levels

Introduction As men age, progressive testosterone deficiency syndrome becomes an increasingly common problem. However, the decreased testosterone levels are not only the result of advanced age.

Areas covered PubMed search of published data on testosterone, nutritional deficiency, stress, sleep and obesity. Many factors impact the male HPG axis (the hypothalamic-pituitary-adrenal), including body weight, calorific and nutritional value of a diet, the amount and quality of sleep, as well as the level of stress. In the case of persons of healthy weight, a below-average calorific value of a diet may decrease the levels of testosterone in men. On the other hand, the same caloric deficiency in obese persons may result in a neutral or positive impact on testosterone levels.

Expert opinion Many factors, including external, environmental and internal factors, influence testosterone levels. Undoubtedly, nutritional deficiency, and particularly of such nutrients as zinc, magnesium, vitamin D, together with low polyphenols intake, affects the HPG axis. The levels of mental and oxidative stress can also adversely impact the axis. Hence, a diagnosis of the cause of disturbance in testosterone levels depends on many factors and requires a broad range of research, as well as a change of patients? lifestyle.

Wrzosek M, Woźniak J, Włodarek D. The causes of adverse changes of testosterone levels in men. Expert Review of Endocrinology & Metabolism 2020. https://doi.org/10.1080/17446651.2020.1813020

 

[Michael Scally MD]

[OA] Reflections on The T Trials

Background: This manuscript is a review and discussion of the published results of The T Trials.

Objective: To re-examine the efficacy of testosterone replacement of hypogonadal men greater than 65 years of age in The T Trials.

Materials and methods: The T Trials were a complex collection of seven double blind, placebo-controlled trials of the efficacy of testosterone as replacement therapy for older men with unequivocal hypogonadism. There were three main trials (sexual function; physical function; vitality) and four sub-trials (cognition; bone; anemia; cardiovascular). All subjects participated in the main trials while more selective inclusion/exclusion criteria existed for the sub-trials. Subjects were excluded for perceived higher risk of prostate cancer and recent myocardial or cerebral vascular events.

Results: The previously published results are reviewed here as seen in the context of this special issue on late onset hypogonadism. In the T Trials, positive benefits were seen in the sexual function, bone, and anemia trials with small but significant benefits in the vitality trial. No benefit was seen in the cognition trial, partial benefit in physical function, and a negative benefit outcome seen in the cardiovascular trial. The later trial was underpowered and the results were described as exploratory. Adverse events were relatively uncommon in the 12-month treatment phase and additional 12-month post treatment phase. The most frequent adverse effect ascribed to testosterone was erythrocytosis.

Conclusions: The T Trials studied the efficacy of testosterone replacement therapy on 788 men with low testosterone and symptoms of hypogonadism. The studies demonstrated benefits in four trials (sexual function, vitality, bone and anemia); partial benefit in the physical function trial; no effect in the cognition trial; and a negative effect in the exploratory cardiovascular trial. The T Trials were not designed to assess long-term risks of testosterone in men.

Swerdloff R, Wang C. Reflections on The T Trials [published online ahead of print, 2020 Sep 9]. Andrology. 2020;10.1111/andr.12901. doi:10.1111/andr.12901 Error - Cookies Turned Off

 

[Michael Scally MD]

Risks of Serious Injury with Testosterone Treatment

BACKGROUND - Injury causes significant morbidity and mortality that is sometimes attributed to testosterone and violence. We hypothesized that prescribed testosterone might be associated with the subsequent risk of serious injury.

METHODS - We conducted a self-matched individual-patient exposure-crossover analysis comparing injury risks before and after initiation of testosterone. We selected adults treated with testosterone in Ontario, Canada, from October 1, 2012 to October 1, 2017 (enrollment) and continued until October 1, 2018 (follow-up). The primary outcome was defined as an acute traumatic event that required emergency medical care.

RESULTS - A total of 64,386 patients were treated with testosterone, of whom 89% were men with a median age of 52 years. We identified 34,439 serious injuries during the baseline interval before starting testosterone (584 per month) and 7,349 serious injuries during the subsequent interval after starting testosterone (565 per month).

Rates of injuries were substantially above the population norm in both intervals with no significant increased risk after starting testosterone (relative risk = 1.00; 95% confidence interval: 0.96 to 1.04, P = 0.850). The unchanged risk extended to diverse patients, was observed for different formulations, and applied to all injury mechanisms. In contrast, testosterone treatment was associated with a 48% increased risk of a thromboembolic event (relative risk = 1.48; 95% confidence interval: 1.25 to 1.74, P < 0.001).

CONCLUSIONS - Testosterone treatment was associated with a substantial baseline risk of serious injury that did not increase further after starting therapy. Physicians prescribing testosterone could consider basic safety reminders to mitigate injury risks.

Yarnell CJ, Thiruchelvam D, Redelmeier DA. Risks of Serious Injury with Testosterone Treatment. The American Journal of Medicine. Redirecting

 

[Michael Scally MD]

Testosterone Therapy: Where Do the Latest Guidelines Agree and Differ?

PURPOSE OF REVIEW: The incidence of testosterone deficiency and number of men on testosterone therapy (TTh) has increased significantly over the past 3 decades. This rise has been accompanied by controversies surrounding the indications and possible adverse effects of therapy.

To better inform prescribing habits among providers, many major medical associations have devised guidelines regarding the diagnosis and management of testosterone deficiency. While these guidelines agree in many areas, there are some key differences that should be identified. This review will explore the similarities, differences, and rationale for these guidelines.

RECENT FINDINGS: Over the past 7 years, much attention has been devoted to the implications of TTh on cardiac health. All reviewed guidelines include dedicated sections discussing these implications and the society's position on prescribing testosterone considering recent findings, however, differ on specific contraindications to TTh and when to initiate therapy after a cardiovascular event. In addition, the American College of Physicians released its first guideline earlier this year which may impact prescribing habits among primary care physicians.

SUMMARY: The differences between testosterone deficiency guidelines may indicate gaps in our knowledge of testosterone deficiency and focuses of future research efforts. Prescribers should be aware of these differences and discuss all treatment options with their patients.

Pelzman DL, Hwang K. Testosterone therapy: where do the latest guidelines agree and differ? Current opinion in endocrinology, diabetes, and obesity 2020. Testosterone therapy: where do the latest guidelines agree... : Current Opinion in Endocrinology, Diabetes and Obesity

 

[Michael Scally MD]

[OA] Mechanisms Underlying the Metabolic Actions of Testosterone

The role of testosterone in improving sexual symptoms in men with hypogonadism is well known. However, recent studies indicate that testosterone plays an important role in several metabolic functions in males.

Multiple PubMed searches were conducted with the use of the terms testosterone, insulin sensitivity, obesity, type 2 diabetes, anaemia, bone density, osteoporosis, fat mass, lean mass and body composition. This narrative review is focused on detailing the mechanisms that underlie the metabolic aspects of testosterone therapy in humans.

Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor β subunit, insulin receptor substrate‐1, protein kinase B and glucose transporter type 4 in adipose tissue and adenosine 5′‐monophosphate‐activated protein kinase expression and activity in skeletal muscle.

Observational studies show that long‐term therapy with testosterone prevents progression from prediabetes to diabetes and improves HbA1c. Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor‐2 and decreases expression of the muscle growth suppressors, myostatin and myogenic regulatory factor 4.

Testosterone increases haematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations.

Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on bone.

In conclusion, testosterone exerts a series of potent metabolic effects, which include insulin sensitization, maintenance and growth of the skeletal muscle, suppression of adipose tissue growth and maintenance of erythropoiesis and haematocrit.

Dandona, P, Dhindsa, S, Ghanim, H, Saad, F. Mechanisms underlying the metabolic actions of testosterone in humans: A narrative review. Diabetes Obes Metab. 2020; 1– 11. https://doi.org/10.1111/dom.14206