A narrative review proposes kisspeptin stimulation as the first viable way to tell whether low testosterone originates in the hypothalamus or pituitary.
Journal: Andrology | Published: 2025-01-20 | Type: Narrative Review | PMID: 39834030 Authors: Pierret et al., Section of Endocrinology and Investigative Medicine, Imperial College London Funding/COI: Publicly funded (NIHR, MRC, BBSRC). Two authors — Abbara and Dhillo — consult for Myovant Sciences Ltd; Dhillo also consults for KaNDy Therapeutics, both companies with commercial interests in hormonal disorders.
Clinicians currently cannot directly measure GnRH in the hypothalamic-pituitary portal vessels, which means secondary hypogonadism (pituitary failure) and tertiary hypogonadism (hypothalamic failure) are routinely conflated and treated as a single entity. This review argues that kisspeptin — the neuropeptide that drives GnRH pulses — could serve as a functional probe: inject it, measure the gonadotropin response, and infer whether the hypothalamus is intact. The authors apply this logic across six disorder categories: age-related and obesity-related hypogonadism, structural brain pathology, hyperprolactinemia, congenital hypogonadotropic hypogonadism vs. constitutional delay of puberty, functional hypothalamic amenorrhea, and relative energy deficiency syndrome.
This is a narrative review, not a systematic review or meta-analysis. There is no PROSPERO registration, no explicit search strategy reported, and no formal risk-of-bias assessment of cited studies. The authors selectively synthesize existing evidence — much of it from their own group at Imperial College London — to build a case for kisspeptin's diagnostic potential. The review does not present new data.
The mechanistic framework is coherent and grounded in established HPG axis physiology. But the diagnostic claims rely on small, mostly proof-of-concept human trials. Many cited studies have sample sizes in the tens. The clinical differentiation proposals are largely theoretical: the postulated sensitivity differences between hypothalamic and primary hypogonadism have not been validated in adequately powered prospective cohorts.
This is a well-argued hypothesis paper from a credible group, not a practice-changing finding. If kisspeptin stimulation testing actually works as a clinical diagnostic tool, it would address a real problem — clinicians today cannot easily tell whether hypogonadism originates in the hypothalamus or the pituitary, and the distinction matters for treatment. But "could" does not mean "does." The evidence base cited is thin, the diagnostic thresholds are undefined, and the commercial consulting relationships of the senior authors are worth noting. Worth following as a research direction; not evidence to act on.