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 guis...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/15/8217 |
| _version_ | 1797525521543725056 |
|---|---|
| author | Thomas M. Barber Ioannis Kyrou Gregory Kaltsas Ashley B. Grossman Harpal S Randeva Martin O. Weickert |
| author_facet | Thomas M. Barber Ioannis Kyrou Gregory Kaltsas Ashley B. Grossman Harpal S Randeva Martin O. Weickert |
| author_sort | Thomas M. Barber |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:14:07Z |
| format | Article |
| id | doaj.art-7a556796fa33461fb5f2e719967c6487 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:14:07Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7a556796fa33461fb5f2e719967c64872023-11-22T05:45:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215821710.3390/ijms22158217Mechanisms of Central HypogonadismThomas M. Barber0Ioannis Kyrou1Gregory Kaltsas2Ashley B. Grossman3Harpal S Randeva4Martin O. Weickert5Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UKWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UKNational and Kapodistrian University of Athens, 10679 Athens, GreeceGreen Templeton College, University of Oxford, Oxford OX2 6HG, UKWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UKWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UKReproductive 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.https://www.mdpi.com/1422-0067/22/15/8217hypogonadismprolactinleptinKallmann syndromestress |
| spellingShingle | Thomas M. Barber Ioannis Kyrou Gregory Kaltsas Ashley B. Grossman Harpal S Randeva Martin O. Weickert Mechanisms of Central Hypogonadism International Journal of Molecular Sciences hypogonadism prolactin leptin Kallmann syndrome stress |
| title | Mechanisms of Central Hypogonadism |
| title_full | Mechanisms of Central Hypogonadism |
| title_fullStr | Mechanisms of Central Hypogonadism |
| title_full_unstemmed | Mechanisms of Central Hypogonadism |
| title_short | Mechanisms of Central Hypogonadism |
| title_sort | mechanisms of central hypogonadism |
| topic | hypogonadism prolactin leptin Kallmann syndrome stress |
| url | https://www.mdpi.com/1422-0067/22/15/8217 |
| work_keys_str_mv | AT thomasmbarber mechanismsofcentralhypogonadism AT ioanniskyrou mechanismsofcentralhypogonadism AT gregorykaltsas mechanismsofcentralhypogonadism AT ashleybgrossman mechanismsofcentralhypogonadism AT harpalsrandeva mechanismsofcentralhypogonadism AT martinoweickert mechanismsofcentralhypogonadism |