Mechanisms of central hypogonadism

Thomas M. Barber, Ioannis Kyrou, Gregory Kaltsas, Ashley B. Grossman, Harpal S. Randeva, Martin O. Weickert

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    20 Citations (Scopus)
    42 Downloads (Pure)


    Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (com-bined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti‐related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin re-sistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic‐androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduc-tion or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vul-nerable, and their clinical management requires both sensitivity and empathy.

    Original languageEnglish
    Article number8217
    JournalInternational Journal of Molecular Sciences
    Issue number15
    Publication statusPublished - 30 Jul 2021

    Bibliographical note

    Publisher Copyright:
    © 2021 by the authors. Licensee MDPI, Basel, Switzerland.


    • Hypogonadism
    • Kallmann syndrome
    • Leptin
    • Prolactin
    • Stress

    ASJC Scopus subject areas

    • Catalysis
    • Molecular Biology
    • Spectroscopy
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Inorganic Chemistry


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