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

Eur J Endocrinol. 2022 Jan 28;186(3):307-318. doi: 10.1530/EJE-21-0608.


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dihydrotestosterone / blood
  • Follicle Stimulating Hormone / blood
  • Follow-Up Studies
  • Genitalia, Male / drug effects*
  • Genitalia, Male / physiology
  • Glucose Intolerance / blood
  • Glucose Intolerance / drug therapy*
  • Glucose Intolerance / physiopathology
  • Humans
  • Hypogonadism / blood
  • Hypogonadism / drug therapy*
  • Hypogonadism / physiopathology
  • Hypogonadism / rehabilitation
  • Injections
  • Luteinizing Hormone / blood
  • Male
  • Middle Aged
  • Quality of Life
  • Recovery of Function / drug effects
  • Sexual Behavior / drug effects
  • Testosterone / administration & dosage
  • Testosterone / analogs & derivatives*
  • Testosterone / blood
  • Testosterone / pharmacology
  • Withholding Treatment


  • Dihydrotestosterone
  • Testosterone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone
  • testosterone undecanoate