The Efficacy and Adverse Events of Testosterone Replacement Therapy in Hypogonadal Men: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials

Ponce, Oscar J.; Spencer‐Bonilla, Gabriela; Alvarez‐Villalobos, Neri Alejandro; Serrano, Valentina; Ospina, Naykky M Singh; Rodríguez-Gutiérrez, René; Salcido‐Montenegro, Alejandro; Benkhadra, Raed; Prokop, Larry J.; Bhasin, Shalender; Brito, Juan P.

doi:10.1210/jc.2018-00404

Cited by 115 publications

(90 citation statements)

References 33 publications

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“…Greater effects on libido and sexual activity than on erectile function were observed . These data are in line with most recent meta‐analyses on sexual function, which also showed that TRT is effective when T is <10.4 nmol/L (<300 ng/dL) or12 nmol/L (350 ng/dL) and ineffective in men with T > 12 nmol/L (>350 ng/dL) . In addition, a recent meta‐analysis on men with functional hypogonadism suggested that TRT alone may modestly (International index of erectile function—Erectile function domain [IIEF‐EFD] 2‐3 points; effect size 0.30) improve mild (IIEF‐EFD score 22‐25), but not more severe (IIEF‐EFD score < 22) ED .…”

Section: Treatment Outcomessupporting

confidence: 86%

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males

et al. 2020

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Background Evidence regarding functional hypogonadism, previously referred to as ‘late‐onset’ hypogonadism, has increased substantially during the last 10 year. Objective To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. Methods Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well‐validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%‐50% represent relative contraindications for TRT. Prostate‐specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. Conclusion TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long‐term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision‐making.

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Section: Treatment Outcomessupporting

confidence: 86%

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males

et al. 2020

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“…Testosterone is well-known to increase circulating hemoglobin, hematocrit, and erythrocyte count, [1][2][3][4][5][6] and erythrocytosis is a well-recognized adverse effect of testosterone treatment. Accordingly, the Endocrine Society guideline recommends monitoring of hemoglobin and hematocrit in hypogonadal men receiving testosterone therapy.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials

et al. 2020

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Background Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. Objective To determine whether testosterone affects circulating leukocytes and platelets in men. Methods Secondary analyses of two randomized testosterone trials were performed: the 5α‐reductase (5aR) and OPTIMEN trials. In 5aR trial, 102 healthy men, 21‐50 years (mean age 38), received a long‐acting GnRH agonist, and 50, 125, 300, or 600 mg/week testosterone enanthate (TE) plus placebo or 2.5 mg/day dutasteride for 20 weeks. In OPTIMEN, 78 functionally limited men, ≥65 years (mean age 72) with protein intake ≤ 0.83 g kg−1 day−1, were randomized to controlled diets with 0.8 g kg−1 day−1 protein or 1.3 g kg−1 day−1 protein plus placebo or TE (100 mg/week) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated. Results In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/µL, P < .001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/µL, P < .001), monocyte (−20.2, 24.5, 90.6, and 143.9 cells/µL, P < .001), platelet (−7.3, 8.4, 8.7, and 8.9 × 103 cells/µL, P = .033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77 × 103 cells/µL, P vs placebo = 0.004). Conclusions Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic, and safety implications.

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“…1,69 ES also noted that the US regulatory agency required labelling to warn of a possible increased risk of cardiovascular events with the use of testosterone, but the European regulatory agency concluded that there was no consistent evidence of increased risk of coronary heart disease associated with testosterone therapy in hypogonadal men. 1,69 ES also noted that the US regulatory agency required labelling to warn of a possible increased risk of cardiovascular events with the use of testosterone, but the European regulatory agency concluded that there was no consistent evidence of increased risk of coronary heart disease associated with testosterone therapy in hypogonadal men.…”

Section: Cardiovascular Safetymentioning

confidence: 99%

“…US Endocrine Society notes that no randomized controlled trial large enough to determine effects of testosterone therapy on major cardiovascular events has been undertaken. 1,69 ES also noted that the US regulatory agency required labelling to warn of a possible increased risk of cardiovascular events with the use of testosterone, but the European regulatory agency concluded that there was no consistent evidence of increased risk of coronary heart disease associated with testosterone therapy in hypogonadal men. 1 ESA concluded that the evidence regarding testosterone therapy and cardiovascular outcomes is inconclusive.…”

Section: Cardiovascular Safetymentioning

confidence: 99%

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care

Yeap

2018

Clinical Endocrinology

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US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age‐standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone‐binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre‐existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required.

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The Efficacy and Adverse Events of Testosterone Replacement Therapy in Hypogonadal Men: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials

Abstract: In hypogonadal men TRT improves sexual desire, erectile function, and sexual satisfaction, however it increases the risk of erythrocytosis.

Cited by 115 publications

References 33 publications

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males

Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care

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