Preprint · Jan 2026
Hypothalamic–Pituitary–Gonadal Axis Monitoring in Clinical Trials of Myostatin Pathway Inhibitors: A Scoping Review
By Phong DTN, Chang H, LE MH et al.
Background: Myostatin (GDF-8), a TGF-β superfamily member synthesized predominantly in skeletal muscle, has long been regarded as a muscle-specific negative regulator of skeletal muscle mass. A landmark study published in Science (Ongaro et al., January 2025) identified a direct skeletal muscle-to-pituitary endocrine axis, whereby circulating myostatin drives follicle-stimulating hormone (FSH) synthesis in anterior pituitary gonadotropes via ACVR2A/B and TGFBR1. Deletion of myostatin in mice resulted in impaired ovarian folliculogenesis, reduced ovulation, smaller testes, and significantly lower intratesticular testosterone. This discovery raises an important clinical concern: pharmacological inhibition of myostatin, deployed to augment skeletal muscle mass in conditions such as sarcopenia, muscular dystrophy, spinal muscular atrophy, and cancer cachexia, may simultaneously disrupt the hypothalamic–pituitary–gonadal (HPG) axis. Objectives: This scoping review aims to: (1) systematically map the extent to which HPG axis parameters — including FSH, LH, testosterone, estradiol, progesterone, inhibin A/B, and follistatin — have been measured, reported, or omitted across all registered clinical trials of pharmacological myostatin/ActRII inhibitors in humans; (2) characterize the reproductive endocrine risk profiles by agent class, indication, and patient age; and (3) identify evidence gaps and provide a framework for standardized HPG monitoring in future trials. Methods: The review will follow the PRISMA Extension for Scoping Reviews (PRISMA-ScR) and the JBI methodological framework. Multi-database searches will be conducted across PubMed/MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science, ClinicalTrials.gov, and EudraCT. No language or date restrictions will be applied. Two independent reviewers will screen and extract data using a standardized PCC-based charting form. Results will be presented as a narrative synthesis and structured evidence map. Expected contribution: This review will produce the first systematic evidence map documenting the extent of HPG axis monitoring omission across the global myostatin inhibitor clinical trial pipeline, and will generate specific recommendations for reproductive endocrine safety monitoring in future programs spanning pediatric, reproductive-age, and geriatric populations.