Testosterone Pellets in Women: Revisiting Safety and Clinical Outcomes.

Abstract

Testosterone is the most abundant biologically active gonadal steroid in women, yet its therapeutic role remains controversial. Current guidelines restrict its use to hypoactive sexual desire disorder (HSDD) with transdermal formulations, while subcutaneous pellets are used off-label in clinical practice despite unresolved concerns about pharmacokinetics, efficacy, and safety. The objective of this study is to critically evaluate the pharmacokinetics, clinical efficacy, and safety of subcutaneous testosterone pellets in peri- and postmenopausal women. A structured narrative review was conducted using PubMed/MEDLINE, covering studies published from January 1980 to August 2025. Other databases were not systematically searched. Search terms included "testosterone", "pellets", "implants", "subcutaneous", "women", and "menopause", combined with Boolean operators. Eligibility criteria comprised original pharmacokinetic or clinical studies in women, defined by STRAW+10 when available, reporting outcomes on pharmacokinetics, efficacy, or safety. Narrative synthesis was chosen due to heterogeneity in design, dosing, comparators, and outcome definitions. From 455 records, 38 studies were included. Pellets provided sustained release over four to six months with supraphysiologic early peaks (>100-250 ng/dL) and wide interindividual variability. The only randomized controlled trial showed improved sexual activity, orgasm, and satisfaction at 24 weeks with testosterone plus estradiol implants. Observational cohorts reported improvements in sexual function (Female Sexual Function Index, Female Sexual Distress Scale-Revised, and satisfying sexual events), mood, energy, and bone density, but findings are limited by non-randomized designs, lack of blinding, and conflicts of interest. Safety data, dominated by practice-based registries, indicated mild androgenic events (acne and hair growth) and rare transient voice changes; signals of reduced breast cancer incidence were reported but derive from cohorts without adequate adjustment for confounders, precluding causal inference. Data on cardiovascular, metabolic, and endometrial outcomes remain sparse and inconsistent. Testosterone pellets provide long-term delivery but at the cost of supraphysiologic peaks, dosing variability, and reliance on observational evidence. Reported benefits for sexual function and well-being are hypothesis-generating, while safety cannot be confirmed. Until adequately powered randomized trials with standardized formulations are conducted, pellet use should remain individualized, off-label, and accompanied by structured monitoring rather than routine adoption.