{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T12:20:54Z","timestamp":1791634854973,"version":"4.3.4"},"reference-count":122,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Reproductive function depends upon an operational hypothalamo\u2013pituitary\u2013gonadal (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 &gt;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.<\/jats:p>","DOI":"10.3390\/ijms22158217","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"8217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Mechanisms of Central Hypogonadism"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0689-9195","authenticated-orcid":false,"given":"Thomas","family":"Barber","sequence":"first","affiliation":[{"name":"Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK"},{"name":"Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6997-3439","authenticated-orcid":false,"given":"Ioannis","family":"Kyrou","sequence":"additional","affiliation":[{"name":"Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK"},{"name":"Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK"},{"name":"Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK"},{"name":"Centre for Sport, Exercise and Life Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV2 2DX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Kaltsas","sequence":"additional","affiliation":[{"name":"National and Kapodistrian University of Athens, 10679 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Grossman","sequence":"additional","affiliation":[{"name":"Green Templeton College, University of Oxford, Oxford OX2 6HG, UK"},{"name":"Barts and the London School of Medicine, University of London, London E1 2AD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpal","family":"Randeva","sequence":"additional","affiliation":[{"name":"Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK"},{"name":"Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK"},{"name":"Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4070-8164","authenticated-orcid":false,"given":"Martin","family":"Weickert","sequence":"additional","affiliation":[{"name":"Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK"},{"name":"Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK"},{"name":"Centre for Sport, Exercise and Life Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry CV2 2DX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"T135","DOI":"10.1530\/JME-15-0257","article-title":"60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH","volume":"56","year":"2016","journal-title":"J. Mol. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/B978-0-444-59602-4.00009-5","article-title":"Central regulation of the hypothalamo-pituitary-thyroid (HPT) axis: Focus on clinical aspects","volume":"Volume 124","author":"Fliers","year":"2014","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.psyneuen.2016.12.017","article-title":"Stress-related and basic determinants of hair cortisol in humans: A meta-analysis","volume":"77","author":"Stalder","year":"2017","journal-title":"Psychoneuroendocrinology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/pchj.278","article-title":"Early life stress predicts cortisol response to psychosocial stress in healthy young adults","volume":"8","author":"Zhang","year":"2019","journal-title":"Psych J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/cphy.c150017","article-title":"Euthyroid Sick Syndrome","volume":"6","author":"Lee","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1177\/0004563217739930","article-title":"Biochemistry of the menopause","volume":"55","author":"Honour","year":"2018","journal-title":"Ann. Clin. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1080\/10253890290027912","article-title":"Stress and reproduction: Central mechanisms and sex differences in non-rodent species","volume":"5","author":"Tilbrook","year":"2002","journal-title":"Stress"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.cnur.2018.04.006","article-title":"Male and female hypogonadism","volume":"53","year":"2018","journal-title":"Nurs. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.2047-2927.2012.00008.x","article-title":"Male hypogonadism: An extended classification based on a developmental, endocrine physiology-based approach","volume":"1","author":"Rey","year":"2013","journal-title":"Andrology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"459","DOI":"10.4103\/1008-682X.148719","article-title":"Clinical management of infertile men with nonobstructive azoospermia","volume":"17","author":"Esteves","year":"2015","journal-title":"Asian J. Androl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1097\/01.med.0000436185.36717.76","article-title":"Male hypogonadism and skeletal health","volume":"20","author":"Irwig","year":"2013","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1159\/000175839","article-title":"Current guidelines for the diagnosis of testosterone deficiency","volume":"37","author":"Arver","year":"2009","journal-title":"Adv. Manag. Testosterone Defic."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4103\/aja.aja_44_18","article-title":"Secondary male hypogonadism: A prevalent but overlooked comorbidity of obesity","volume":"20","author":"Tinahones","year":"2018","journal-title":"Asian J. Androl."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ando.2012.03.040","article-title":"Male acquired hypogonadotropic hypogonadism: Diagnosis and treatment","volume":"73","author":"Salenave","year":"2012","journal-title":"Ann. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Practice Committee of the American Society for Reproductive Medicine (2018). Electronic address, a.a.o. Management of nonobstructive azoospermia: A committee opinion. Fertil. Steril., 110, 1239\u20131245.","DOI":"10.1016\/j.fertnstert.2018.09.012"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"756069","DOI":"10.1155\/2015\/756069","article-title":"Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas","volume":"2015","author":"Vargas","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1111\/cen.13015","article-title":"The prevalence of structural pituitary abnormalities by MRI scanning in men presenting with isolated hypogonadotrophic hypogonadism","volume":"84","author":"Dalvi","year":"2016","journal-title":"Clin. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.clineuro.2016.01.029","article-title":"Hypopituitarism patterns among adult males with prolactinomas","volume":"144","author":"Peng","year":"2016","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1136\/pmj.76.898.513","article-title":"Young male with headache, blindness, and hypogonadism. Diagnosis: Craniopharyngioma presenting with hypogonadotrophic hypogonadism","volume":"76","author":"Kashyap","year":"2000","journal-title":"Postgrad. Med. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1055\/s-0042-124355","article-title":"Hypogonadotropic hypogonadism in non-functioning pituitary adenomas: Impact of intervention","volume":"125","author":"Monteiro","year":"2017","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101475","DOI":"10.1016\/j.beem.2020.101475","article-title":"Kallman syndrome and central non-obstructive azoospermia","volume":"34","author":"Thakker","year":"2020","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12610-017-0057-8","article-title":"Hypogonadotropic hypogonadism in men with hereditary hemochromatosis","volume":"27","author":"Grandpre","year":"2017","journal-title":"Basic Clin. Androl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.5489\/cuaj.10050","article-title":"CUA Guideline: The workup of azoospermic males","volume":"4","author":"Jarvi","year":"2010","journal-title":"Can. Urol. Assoc. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147893","DOI":"10.1155\/2012\/147893","article-title":"Genetics of isolated hypogonadotropic hypogonadism: Role of GnRH receptor and other genes","volume":"2012","author":"Beate","year":"2012","journal-title":"Int. J. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00439-020-02147-1","article-title":"Genetics of congenital hypogonadotropic hypogonadism: Peculiarities and phenotype of an oligogenic disease","volume":"140","author":"Cangiano","year":"2021","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/ejhg.2008.206","article-title":"Kallmann syndrome","volume":"17","author":"Dode","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"81","DOI":"10.6061\/clinics\/2013(Sup01)09","article-title":"Hypogonadotropic hypogonadism revisited","volume":"68","author":"Fraietta","year":"2013","journal-title":"Clinics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1242\/dev.139444","article-title":"Development of the neurons controlling fertility in humans: New insights from 3D imaging and transparent fetal brains","volume":"143","author":"Casoni","year":"2016","journal-title":"Development"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1210\/er.2018-00116","article-title":"Clinical management of congenital hypogonadotropic hypogonadism","volume":"40","author":"Young","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E136","DOI":"10.1210\/jc.2011-2041","article-title":"Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: Pathophysiological and genetic implications","volume":"97","author":"Hughes","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/OGX.0b013e3181641278","article-title":"A review of Kallmann syndrome: Genetics, pathophysiology, and clinical management","volume":"63","author":"Fechner","year":"2008","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_32","first-page":"113","article-title":"Update on the genetics of idiopathic hypogonadotropic hypogonadism","volume":"9","author":"Topaloglu","year":"2017","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/353529a0","article-title":"A gene deleted in Kallmann\u2019s syndrome shares homology with neural cell adhesion and axonal path-finding molecules","volume":"353","author":"Franco","year":"1991","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/molehr\/gan027","article-title":"The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome","volume":"14","author":"Chorich","year":"2008","journal-title":"Mol. Hum. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1210\/jc.2002-021981","article-title":"X chromosome-linked Kallmann syndrome: Clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene","volume":"88","author":"Massin","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.fertnstert.2015.07.1142","article-title":"Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: Evidence for the involvement of an alternatively spliced isoform","volume":"104","author":"Goncalves","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1242\/dev.00334","article-title":"FGF signaling through FGFR1 is required for olfactory bulb morphogenesis","volume":"130","author":"Hebert","year":"2003","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fendo.2013.00019","article-title":"PROK2\/PROKR2 signaling and Kallmann syndrome","volume":"4","author":"Dode","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_39","first-page":"1580","article-title":"Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism","volume":"86","author":"Beranova","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1399-0004.2008.01107.x","article-title":"CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome","volume":"75","author":"Jongmans","year":"2009","journal-title":"Clin. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1210\/jc.2010-0176","article-title":"Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency","volume":"95","author":"Trarbach","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"E943","DOI":"10.1210\/jc.2012-4116","article-title":"Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes","volume":"98","author":"Balasubramanian","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1530\/EJE-17-0065","article-title":"Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)","volume":"178","author":"Bonomi","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_44","first-page":"248","article-title":"De novo SOX10 nonsense mutation in a patient with Kallmann syndrome, deafness, iris hypopigmentation, and hyperthyroidism","volume":"48","author":"Wang","year":"2018","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.metabol.2017.10.012","article-title":"Kallmann syndrome: Phenotype and genotype of hypogonadotropic hypogonadism","volume":"86","author":"Stamou","year":"2018","journal-title":"Metabolism"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.ajhg.2013.03.024","article-title":"Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness","volume":"92","author":"Pingault","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1016\/j.fertnstert.2013.01.149","article-title":"Identification of HESX1 mutations in Kallmann syndrome","volume":"99","author":"Newbern","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_48","unstructured":"Short, R.V. (1976). Ciba Foundation Symposium, Ciba Foundation."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3109\/07853899309164164","article-title":"Lactational infertility in family planning","volume":"25","author":"Short","year":"1993","journal-title":"Ann. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1055\/s-0039-3400956","article-title":"Kisspeptin and Prolactin","volume":"37","author":"Grattan","year":"2019","journal-title":"Semin. Reprod. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1365-2265.1982.tb01603.x","article-title":"Opiate mediation of amenorrhoea in hyperprolactinaemia and in weight-loss related amenorrhoea","volume":"17","author":"Grossman","year":"1982","journal-title":"Clin. Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1023\/A:1026229810876","article-title":"Prolactin, psychological stress and environment in humans: Adaptation and maladaptation","volume":"6","author":"Sobrinho","year":"2003","journal-title":"Pituitary"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1111\/j.1365-2265.2011.04136.x","article-title":"Recurrence of hyperprolactinaemia following discontinuation of dopamine agonist therapy in patients with prolactinoma occurs commonly especially in macroprolactinoma","volume":"75","author":"Barber","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s11102-019-01009-y","article-title":"Prolactinomas in males: Any differences?","volume":"23","author":"Shimon","year":"2020","journal-title":"Pituitary"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"136","DOI":"10.7861\/clinmedicine.13-2-136","article-title":"Erectile dysfunction in general medicine","volume":"13","author":"Grant","year":"2013","journal-title":"Clin. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11102-019-00997-1","article-title":"Pathology of prolactinomas: Any predictive value?","volume":"23","author":"Lopes","year":"2020","journal-title":"Pituitary"},{"key":"ref_57","first-page":"72","article-title":"Factors influencing disconnection hyperprolactinemia and reversal of serum prolactin after pituitary surgery in a non-functioning pituitary macroadenoma","volume":"23","author":"Kumran","year":"2016","journal-title":"Malays. J. Med. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1210\/jcem-60-3-599","article-title":"Mechanism of the inhibitory action of dopamine and somatostatin on prolactin secretion from human lactotrophs in culture","volume":"60","author":"Ishibashi","year":"1985","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/j.1365-2265.2011.04226.x","article-title":"Disconnection hyperprolactinaemia in nonadenomatous sellar\/parasellar lesions practically never exceeds 2000 mU\/l","volume":"76","author":"Korevaar","year":"2012","journal-title":"Clin. Endocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1592\/phco.29.1.64","article-title":"Antipsychotic-induced hyperprolactinemia","volume":"29","author":"Bostwick","year":"2009","journal-title":"Pharmacotherapy"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000499694","article-title":"Pitfalls in the diagnostic evaluation of hyperprolactinemia","volume":"109","author":"Vilar","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.psym.2013.08.008","article-title":"Psychotropic-induced hyperprolactinemia: A clinical review","volume":"55","author":"Ajmal","year":"2014","journal-title":"Psychosomatics"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s10552-016-0758-x","article-title":"Antidepressant use and circulating prolactin levels","volume":"27","author":"Reeves","year":"2016","journal-title":"Cancer Causes Control"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2165\/11533140-000000000-00000","article-title":"Antidepressant-induced hyperprolactinaemia: Incidence, mechanisms and management","volume":"24","author":"Coker","year":"2010","journal-title":"CNS Drugs"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Srikantha, M., and Butterworth, R. (2009). Pharmacological hyperprolactinaemia. BMJ Case Rep.","DOI":"10.1136\/bcr.01.2009.1432"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s11102-008-0106-6","article-title":"Drugs and prolactin","volume":"11","author":"Molitch","year":"2008","journal-title":"Pituitary"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1136\/bmj.283.6285.194","article-title":"Amenorrhoea, galactorrhoea, and hyperprolactinaemia induced by methyldopa","volume":"283","author":"Arze","year":"1981","journal-title":"Br. Med. J. (Clin. Res. Ed.)"},{"key":"ref_68","first-page":"E96","article-title":"Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia","volume":"270","author":"Kelley","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1530\/EJE-18-0270","article-title":"Mechanisms of Endocrinology: Endocrinology of opioids","volume":"179","author":"Fountas","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1210\/jc.2010-1692","article-title":"Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline","volume":"96","author":"Melmed","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"bqaa204","DOI":"10.1210\/endocr\/bqaa204","article-title":"The importance of leptin to reproduction","volume":"162","author":"Childs","year":"2021","journal-title":"Endocrinology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrn.2018.7","article-title":"Leptin and brain-adipose crosstalks","volume":"19","author":"Caron","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"549","DOI":"10.14310\/horm.2002.1649","article-title":"The impact of adipose tissue-derived factors on the hypothalamic-pituitary-gonadal (HPG) axis","volume":"14","author":"Tsatsanis","year":"2015","journal-title":"Hormones"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1515\/hmbci-2014-0017","article-title":"Role of the adipocyte-derived hormone leptin in reproductive control","volume":"19","author":"Allen","year":"2014","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"43537","DOI":"10.1038\/srep43537","article-title":"Adipokines (leptin, adiponectin, resistin) differentially regulate all hormonal cell types in primary anterior pituitary cell cultures from two primate species","volume":"7","author":"Peinado","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"146574","DOI":"10.1016\/j.brainres.2019.146574","article-title":"Leptin actions through the nitrergic system to modulate the hypothalamic expression of the kiss1 mRNA in the female rat","volume":"1728","author":"Petrine","year":"2020","journal-title":"Brain Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5240","DOI":"10.1523\/JNEUROSCI.0405-09.2009","article-title":"The ventral premammillary nucleus links fasting-induced changes in leptin levels and coordinated luteinizing hormone secretion","volume":"29","author":"Donato","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"R5","DOI":"10.1677\/joe.0.140R005","article-title":"The distribution of hypothalamic nitric oxide synthase mRNA in relation to gonadotrophin-releasing hormone neurons","volume":"140","author":"Grossman","year":"1994","journal-title":"J. Endocrinol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"154229","DOI":"10.1016\/j.metabol.2020.154229","article-title":"The effect of underweight on female and male reproduction","volume":"107","author":"Boutari","year":"2020","journal-title":"Metabolism"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1159\/000126413","article-title":"IGFBP-1: A metabolic signal associated with exercise-induced amenorrhoea","volume":"57","author":"Jenkins","year":"1993","journal-title":"Neuroendocrinology"},{"key":"ref_81","first-page":"3673","article-title":"Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels","volume":"84","author":"Isidori","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/cen.12092","article-title":"The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism","volume":"78","author":"Kumar","year":"2013","journal-title":"Clin. Endocrinol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/MOU.0000000000000762","article-title":"The role of leptin and obesity on male infertility","volume":"30","author":"Khodamoradi","year":"2020","journal-title":"Curr. Opin. Urol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1515\/hmbci-2016-0014","article-title":"Male gonadal axis function in patients with type 2 diabetes","volume":"26","author":"Costanzo","year":"2016","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"789653","DOI":"10.1155\/2012\/789653","article-title":"Androgens and adipose tissue in males: A complex and reciprocal interplay","volume":"2012","author":"Mammi","year":"2012","journal-title":"Int. J. Endocrinol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1210\/jc.2010-2724","article-title":"Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity","volume":"96","author":"Dandona","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"926937","DOI":"10.1155\/2013\/926937","article-title":"LPS-induced inflammation potentiates the IL-1beta-mediated reduction of LH secretion from the anterior pituitary explants","volume":"2013","author":"Herman","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/j.1365-2265.2012.04401.x","article-title":"Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men","volume":"78","author":"Gautier","year":"2013","journal-title":"Clin. Endocrinol."},{"key":"ref_89","first-page":"116","article-title":"The relationship between testosterone and molecular markers of inflammation in older men","volume":"28","author":"Maggio","year":"2005","journal-title":"J. Endocrinol. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"E700","DOI":"10.1210\/jc.2011-2387","article-title":"Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia","volume":"97","author":"Burney","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.janh.2017.02.001","article-title":"The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis","volume":"3","author":"Brook","year":"2017","journal-title":"J. Anesth. Hist."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1093\/pm\/pnx048","article-title":"Are prescription opioids driving the opioid crisis? Assumptions vs facts","volume":"19","author":"Rose","year":"2018","journal-title":"Pain Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/978-3-319-69535-8_6","article-title":"Pain medications and male reproduction","volume":"1034","author":"Drobnis","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1210\/clinem\/dgz022","article-title":"Opioids and their Endocrine effects: A systematic review and meta-analysis","volume":"105","author":"Bruin","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1365-2265.1981.tb00363.x","article-title":"The opioid control of LH and FSH release: Effects of a met-enkephalin analogue and naloxone","volume":"14","author":"Grossman","year":"1981","journal-title":"Clin. Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1365-2265.1981.tb00202.x","article-title":"The effect of naloxone on pulsatile gonadotrophin release in normal subjects","volume":"14","author":"Moult","year":"1981","journal-title":"Clin. Endocrinol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1007\/s40279-017-0709-z","article-title":"Effects of anabolic androgenic steroids on the reproductive system of athletes and recreational users: A systematic review and meta-analysis","volume":"47","author":"Christou","year":"2017","journal-title":"Sports Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"R47","DOI":"10.1530\/EJE-15-0080","article-title":"MECHANISMS IN ENDOCRINOLOGY: Medical consequences of doping with anabolic androgenic steroids: Effects on reproductive functions","volume":"173","author":"Nieschlag","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/add.12850","article-title":"Prolonged hypogonadism in males following withdrawal from anabolic-androgenic steroids: An under-recognized problem","volume":"110","author":"Kanayama","year":"2015","journal-title":"Addiction"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.fertnstert.2014.02.002","article-title":"Anabolic steroid-induced hypogonadism: Diagnosis and treatment","volume":"101","author":"Rahnema","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neubiorev.2019.02.014","article-title":"Supraphysiologic-dose anabolic-androgenic steroid use: A risk factor for dementia?","volume":"100","author":"Kaufman","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s11102-019-00958-8","article-title":"Pituitary pathology in traumatic brain injury: A review","volume":"22","author":"Sav","year":"2019","journal-title":"Pituitary"},{"key":"ref_103","first-page":"831","article-title":"Isolated gonadotropic deficiency after multiple concussions in a professional soccer player","volume":"138","author":"Auer","year":"2013","journal-title":"Dtsch. Med. Wochenschr."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"R112","DOI":"10.1530\/EC-20-0117","article-title":"Traumatic brain injuries induced pituitary dysfunction: A call for algorithms","volume":"9","author":"Kluczynski","year":"2020","journal-title":"Endocr. Connect."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"827","DOI":"10.7326\/0003-4819-148-11-200806030-00005","article-title":"Brief communication: Pituitary volume and function in competing and retired male boxers","volume":"148","author":"Tanriverdi","year":"2008","journal-title":"Ann. Intern. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1089\/neu.2013.3212","article-title":"Prevalence of pituitary hormone dysfunction, metabolic syndrome, and impaired quality of life in retired professional football players: A prospective study","volume":"31","author":"Kelly","year":"2014","journal-title":"J. Neurotrauma"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1136\/bjsports-2016-097393","article-title":"What is the definition of sports-related concussion: A systematic review","volume":"51","author":"McCrory","year":"2017","journal-title":"Br. J. Sports Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"539799","DOI":"10.3389\/fpsyg.2021.539799","article-title":"Putting Stress in Historical Context: Why it is important that being stressed out was not a way to be a person 2,000 years ago","volume":"12","author":"Hutmacher","year":"2021","journal-title":"Front. Psychol."},{"key":"ref_109","first-page":"290","article-title":"Stress and personality","volume":"22","author":"Vukovic","year":"2011","journal-title":"Psychiatriki"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Siegrist, J., and Li, J. (2018). Work stress and the development of chronic diseases. Int. J. Environ. Res. Public Health, 15.","DOI":"10.3390\/ijerph15030536"},{"key":"ref_111","first-page":"252","article-title":"Functional hypothalamic amenorrhoea\u2014Diagnostic challenges, monitoring, and treatment","volume":"66","author":"Walkowiak","year":"2015","journal-title":"Endokrynol. Pol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s40618-019-01013-w","article-title":"Functional hypothalamic and drug-induced amenorrhea: An overview","volume":"42","author":"Lania","year":"2019","journal-title":"J. Endocrinol. Investig."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1210\/jc.2017-00131","article-title":"Functional hypothalamic amenorrhea: An Endocrine Society clinical practice guideline","volume":"102","author":"Gordon","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1146\/annurev.clinpsy.1.102803.144141","article-title":"Stress and health: Psychological, behavioral, and biological determinants","volume":"1","author":"Schneiderman","year":"2005","journal-title":"Annu. Rev. Clin. Psychol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s40618-014-0169-3","article-title":"Functional hypothalamic amenorrhea and its influence on women\u2019s health","volume":"37","author":"Meczekalski","year":"2014","journal-title":"J. Endocrinol. Investig."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ando.2010.02.006","article-title":"Hypothalamic amenorrhea: From diagnosis to therapeutical approach","volume":"71","author":"Genazzani","year":"2010","journal-title":"Ann. Endocrinol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1210\/jc.2018-00229","article-title":"Testosterone therapy in men with hypogonadism: An Endocrine Society clinical practice guideline","volume":"103","author":"Bhasin","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.mayocp.2017.11.006","article-title":"Testosterone and cardiovascular health","volume":"93","author":"Elagizi","year":"2018","journal-title":"Mayo Clin. Proc."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1186\/1423-0127-17-S1-S9","article-title":"Effects of taurine on male reproduction in rats of different ages","volume":"17","author":"Yang","year":"2010","journal-title":"J. Biomed. Sci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.4158\/EP171795.RA","article-title":"Sarcopenia: An Endocrine disorder?","volume":"23","author":"McKee","year":"2017","journal-title":"Endocr. Pract."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1159\/000485998","article-title":"The metabolic syndrome in central hypogonadotrophic hypogonadism","volume":"49","author":"Dwyer","year":"2018","journal-title":"Front. Horm. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1073\/pnas.0609301103","article-title":"Differential fitness costs of reproduction between the sexes","volume":"104","author":"Penn","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:37:29Z","timestamp":1760164649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":122,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22158217"],"URL":"https:\/\/doi.org\/10.3390\/ijms22158217","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]}}}