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Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Hudson J 1 , Cruickshank M 1 , Quinton R 2 , Aucott L 1 , Wu F 3 , Grossmann M 4 Show all authors , Bhasin S 5 , Snyder PJ 6 , Ellenberg SS 6 , Travison TG 7 , Brock GB 8 , Gianatti EJ 9 , van der Schouw YT 10 , Emmelot-Vonk MH 11 , Giltay EJ 12 , Hackett G 13 , Ramachandran S 14 , Svartberg J 15 , Hildreth KL 16 , Antonic KG 17 , Tenover JL 18 , Tan HM 6 , Ho Chee Kong C 19 , Tan WS 20 , Marks LS 21 , Ross RJ 22 , Schwartz RS 16 , Manson P 1 , Roberts SA 23 , Skovsager Andersen M 24 , Velling Magnussen L 24 , Aceves-Martins M 1 , Gillies K 1 , Hernández R 25 , Oliver N 26 , Dhillo WS 26 , Bhattacharya S 27 , Brazzelli M 1 , Jayasena CN 28

Affiliations 

  • 1 Health Services Research Unit, University of Aberdeen, Aberdeen, UK
  • 2 Translational & Clinical Research Institute, University of Newcastle, Newcastle upon Tyne, UK
  • 3 Division of Diabetes, Endocrinology & Gastroenterology, University of Manchester, Manchester, UK
  • 4 University of Melbourne Austin Health, Heidelberg, VIC, Australia
  • 5 Department of Medicine, Harvard Medical School, Boston, MA, USA
  • 6 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • 7 Division of Gerontology, Boston, MA, USA
  • 8 Department of Surgery, Western University and Omega Fertility Center, London, ON, Canada
  • 9 Department of Endocrinology, Fiona Stanley Hospital, Murdoch, WA, Australia
  • 10 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  • 11 Department of Geriatrics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  • 12 Department of Psychiatry, Leiden University Medical Centre, Leiden, Netherlands
  • 13 School of Health and Life Sciences, Aston University, Birmingham, UK
  • 14 Department of Chemical Pathology, University Hospitals Birmingham, Birmingham, UK
  • 15 Division of Internal Medicine, Section of Endocrinology, University Hospital of North Norway, Tromsø, Norway; Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway
  • 16 Division of Geriatric Medicine, University of Colorado School of Medicine, Aurora, CO, USA
  • 17 Department of Endocrinology, University Medical Centre, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
  • 18 Geriatric Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA; School of Medicine, Stanford University, Stanford, CA, USA
  • 19 School of Medicine, Taylor's University, Subang Jaya, Malaysia
  • 20 MD Anderson Cancer Center, University of Texas, Houston, TX, USA
  • 21 David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  • 22 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
  • 23 Centre for Biostatistics, University of Manchester, Manchester, UK
  • 24 Department of Endocrinology, University of Southern Denmark, Odense, Denmark
  • 25 Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
  • 26 Faculty of Medicine, Imperial College London, London, UK
  • 27 School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
  • 28 Faculty of Medicine, Imperial College London, London, UK. Electronic address: c.jayasena@imperial.ac.uk
Lancet Healthy Longev, 2023 Oct;4(10):e561-e572.
PMID: 37804846 DOI: 10.1016/S2666-7568(23)00169-1

Abstract

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment.

METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005.

FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory).

INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity.

FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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