Mechanisms of Central Hypogonadism


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 (combined 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 resistance 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 (reduction 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 vulnerable, and their clinical management requires both sensitivity and empathy.

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Medical School
Additional Information: © 2021 by the authors. Li‐ censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con‐ ditions of the Creative Commons At‐ tribution (CC BY) license (http://crea‐
Uncontrolled Keywords: Hypogonadism,Kallmann syndrome,Leptin,Prolactin,Stress,Catalysis,Molecular Biology,Spectroscopy,Computer Science Applications,Physical and Theoretical Chemistry,Organic Chemistry,Inorganic Chemistry
Publication ISSN: 1422-0067
Last Modified: 14 May 2024 07:27
Date Deposited: 02 Aug 2021 08:05
Full Text Link:
Related URLs: https://www.mdp ... 0067/22/15/8217 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Review article
Published Date: 2021-07-30
Accepted Date: 2021-07-24
Authors: Barber, Thomas M.
Kyrou, Ioannis (ORCID Profile 0000-0002-6997-3439)
Kaltsas, Gregory
Grossman, Ashley B.
Randeva, Harpal S.
Weickert, Martin O.



Version: Published Version

License: Creative Commons Attribution

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