Endocrine Abstracts

Hypogonadotrophic hypogonadism (HH) is the only form of infertility that is directly treatable with hormone replacement, either in the form of gonadotrophin injections, or pulsatile GnRH if the underlying defect is hypothalamic and pituitary function is intact. However, men with HH face a complex and confusing journey to access treatment: misinformed that they are irredeemably infertile, struggling to find a clinician with relevant experience and authorisation to prescribe gonadotrophins, or even denied funding outright as not explicitly commissioned by local NHS structures. Despite its physiological elegance, GnRH is not available in the UK and many other countries. Indeed, for men with adult-onset HH, fertility is often restored by substituting hCG for testosterone (T). The hCG dose is titrated to achieve normal range serum T levels (levels within the testes are upto 100x higher), without abnormally raising estradiol level or haematocrit. However, hCG-alone rarely achieves sperm in the ejaculates of men with congenital HH (CHH), even after 10 years’ treatment; these men require combined hCG and FSH treatment. Nevertheless, almost ¼ fail to develop sperm in the ejaculate even after 12–36 months’ combined therapy. For those having smaller testes (<4 ml) and history of bilateral cryptorchidism – evidencing absent perinatal minipuberty, during which Sertoli cell proliferation would normally occur– prognosis is even poorer; only ⅓ developing sperm. Outcomes are slightly better when serum FSH levels >4 IU/l are achieved, but a more radical approach re-thinks the gonadotrophin initiation sequence. Classical regimens begin with an arbitrary phase of hCG-monotherapy before introducing FSH; a sequence largely informed by regulatory requirements of drug-licensing studies and lacking scientific underpinning. Having missed minipuberty, CHH males have a depleted population of immature Sertoli and germ cells, and their testis should logically receive a phase of FSH-mediated cell-proliferation prior to these cells being matured through exposure to hCG-stimulated T.