Bonomi, Marco

Cangiano, Biagio

Quinton, Richard

English

AIR Universita degli studi di Milano

Frontiers in EndocrinologyOPEN ACCESSEDITED AND REVIEWED BYRichard Ivell,University of Nottingham, United Kingdom*CORRESPONDENCEBiagio Cangianob.cangiano@auxologico.itMarco Bonomim.bonomi@auxologico.itRichard Quintonrichard.quinton@nhs.netRECEIVED 02 January 2024ACCEPTED 15 January 2024PUBLISHED 31 January 2024CITATIONCangiano B, Bonomi M and Quinton R (2024)Editorial: Functional acquiredhypogonadotropic hypogonadism in males.Front. Endocrinol. 15:1364634.doi: 10.3389/fendo.2024.1364634COPYRIGHT© 2024 Cangiano, Bonomi and Quinton. This isan open-access article distributed under theterms of the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and that theoriginal publication in this journal is cited, inaccordance with accepted academicpractice. No use, distribution or reproductionis permitted which does not comply withthese terms.TYPE EditorialPUBLISHED 31 January 2024DOI 10.3389/fendo.2024.1364634Editorial: Functional acquiredhypogonadotropichypogonadism in malesBiagio Cangiano1,2*, Marco Bonomi1,2* and Richard Quinton3,4,5*1Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy,2Department of Endocrine and Metabolic Medicine, IRCCS Istituto Auxologico Italiano, Milan, Italy,3Department of Endocrinology, Diabetes & Metabolism, Newcastle-upon-Tyne Hospitals, Newcastle-upon-Tyne, United Kingdom, 4Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom, 5Department of Metabolism, Digestion &Reproduction, Imperial College London, London, United KingdomKEYWORDSfunctional hypogonadotropic hypogonadism, testosterone, obesity, metabolicsyndrome, relative energy deficit, genetics, chronic diseaseEditorial on the Research TopicFunctional acquired hypogonadotropic hypogonadism in malesAdult-onset isolated hypogonadotropic hypogonadism (HH) is an heterogeneouscondition associated with signs and symptoms that can significantly impact on patients’quality of life through gynecomastia, osteoporosis, anaemia, sexual dysfunction andimpaired fertility, and may also be linked with other chronic conditions such asosteoporosis, depression and cardiometabolic disease.HH is classically divided into organic (due to structural or genetic damage) and“functional” (FHH - related to comorbidities, aging and/or medication) forms, with thelatter being particularly prevalent among patients with chronic diseases. These conditionsdiffer for the potential reversibility of the disease and the pathogenic mechanisms, but also(as recent data here reviewed by Grande et al.) in relation to different effects on biochemicalpathways, including glucose metabolism and ketogenesis. These data support the view thatthis form of hypogonadism should be considered and addressed not only in relation to lowtestosterone levels, but also for its ancillary features related to the underlying disease (1).Although relative FHH due to energy deficit is now increasingly recognized in males (2)as well as females, that associated with diabesity is the by far most prevalent form. Even ifclinical trials of testosterone treatment in FHH have reported improvements in lipid profile,body composition, insulin sensitivity and glycemic control in dysmetabolic patients, thistherapy can be associated with unacceptable degrees of erythrocytosis (3), particularlywhere there is a concomitant obstructive sleep apnoea. Indeed, data from the T-trialssuggest that the greatest functional improvements may accrue to men with baselineanaemia (4).There is still no consensus as to whether any form of FHH should be treated withtestosterone, or other hormonal therapies, such as aromatase inhibitors (AI) or selectiveestrogen receptor modulators (SERM) as part of routine clinical care. This is because of thepotential for complete reversibility of the condition, including restoration of fertility (whichcannot be achieved by testosterone treatment) with lifestyle measures alone. Moreover, thefrontiersin.org01Cangiano et al. 10.3389/fendo.2024.1364634improvements in fertility and sexuality observed with these AI andSERM may be marginal (5, 6) in addition to a potential negativeimpact of AI on bone density (6).The pathogenetic mechanism of FHH is also a matter of debate,and there are different hypotheses. In dysmetabolic forms, forexample, estrogen excess due to adipose aromatization wasinitially thought to cause hypogonadism through negativefeedback. However, despite the biochemical responsiveness of themale hypothalamo-pituitary-testicular axis in obesity and chronicdisease to blockade of estrogen secretion or action (5, 6), theimpairment of gonadotropin secretion in FHH is moreconvincingly attributed to systemic inflammation, or a reducedneuronal sensitivity to insulin and/or leptin. Finally, it has beenshown that, in adult-onset HH, there is enrichment of rare variantsin the genes related to congenital HH, suggesting an individualpredisposition (7). However these mechanisms cannot be robustlyextended to other forms of FHH (8), including prolonged therapywith opioids, corticosteroids and dopamine-antagonists, abuse ofanabolic-androgenic steroids, relative energy deficit due to low fatmass from excessive physical endurance training, as well ashypogonadism due to various chronic diseases (9, 10). Spazianiet al. and colleagues, explore the many aspects of this elusivedefinition and the current knowledge about functional HH in amini review of this Research Topic.In fact, all these conditions are often considered as a whole,within the wider category of FHH, which intrinsically limits theunderstanding of the peculiarities in both the pathogenesis andclinical outcomes of what are clearly different diseases, that untilnow lack the due insight. Also, many other conditions associatedwith low testosterone levels are variably included or excluded fromthis great pot, such as depression and mood disorders, as well asHIV related hypogonadism (here reviewed respectively by IndirliFrontiers in Endocrinology 02et al. and De Vincentis and Rochira adding complexity tothe matter.In the age of a medicine aimed to restore not only patients’ lifeexpectancy but also their quality of life, it is important for futureresearch to focus on the clinical consequences of each functionalform of hypogonadism, and when and how to treat them.Author contributionsBC: Writing – original draft, Writing – review & editing. MB:Writing – review & editing. RQ: Writing – review & editing.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.The author(s) declared that they were an editorial boardmember of Frontiers, at the time of submission. This had noimpact on the peer review process and the final decision.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Munari EV, Amer M, Amodeo A, Bollino R, Federici S, Goggi G, et al. Thecomplications of male hypogonadism: is it just a matter of low testosterone? FrontEndocrinol (2023) 14:1201313. doi: 10.3389/fendo.2023.12013132. Grossmann M, Wittert GA. Dysregulation of the hypothalamic-pituitary-testicular axis due to energy deficit. J Clin Endocrinol Metab (2021) 106(12):e4861–715. doi: 10.1210/clinem/dgab5173. Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap B, Handelsman DJ, et al.Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyleprogramme (T4DM): A randomised, double-blind, placebo-controlled, 2-year, phase3b trial. Lancet Diabetes Endocrinol (2021) 9(1):32–45. doi: 10.1016/S2213-8587(20)30367-34. Roy CN, Snyder PJ, Stephens-Shields AJ, Artz AS, Bhasin S, Cohen HJ, et al.Association of testosterone levels with anemia in older men: A controlled clinical trial.JAMA Internal Med (2017) 177(4):480–90. doi: 10.1001/jamainternmed.2016.95405. Hill S, Arutchelvam V, Quinton R. Enclomiphene, an estrogen receptorantagonist for the treatment of testosterone deficiency in men. IDrugs:Investigational Drugs J (2009) 12(2):109–95.6. Jones TH, Dobs AS, Randeva H, Moore W, Parkin JM. Leflutrozole in maleobesity-associated hypogonadotropic hypogonadism: ph 2b double-blind randomisedcontrolled trial. Eur J Endocrinology/European Fed Endocrine Societies (2023) 189(3):297–3085. doi: 10.1093/ejendo/lvad0997. Cangiano B, Duminuco P, Vezzoli V, Guizzardi F, Chiodini I, Corona G, et al.Evidence for a common genetic origin of classic and milder adult-onset forms ofisolated hypogonadotropic hypogonadism. J Clin Med Res (2019) 8(1):126.doi: 10.3390/jcm80101268. Turner HE, Wass JA. Gonadal function in men with chronic illness. ClinEndocrinol (1997) 47(4):379–403. doi: 10.1046/j.1365-2265.1997.2611108.x9. Rasmussen JJarløCheckta, Albrethsen J, Frandsen MN, Jørgensen N, Juul A,Kistorp C. Serum insulin-like factor 3 levels are reduced in former androgen users,suggesting impaired leydig cell capacity. J Clin Endocrinol Metab (2021) 106(7):e2664–725. doi: 10.1210/clinem/dgab12910. Sharma A, Grant B, Islam H, Kapoor A, Pradeep A, Jayasena CN. Commonsymptoms associated with usage and cessation of anabolic androgenic steroids in men.Best Pract Res Clin EndocrinolMetab (2022) 36(5):1016915. doi: 10.1016/j.beem.2022.101691frontiersin.org

Editorial: Functional acquired hypogonadotropic hypogonadism in males

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Editorial: Functional acquired hypogonadotropic hypogonadism in males

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