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The biochemical confirmation of adult male hypogonadism: Global perspectives from the International Society of Andrology

Year: 2023

Type: article

Abstract: The function of the hypothalamic-pituitary-testicular (HPT) axis during all epochs of life is to regulate androgenization and maintain fertility through repeated incremental and decremental feedforward (stimulatory) and feedback (inhibitory) signaling among its neural and hormonal components.1 Male hypogonadism is the clinical syndrome that results from failure to secrete sufficient testosterone (T) and/or produce spermatozoa of adequate quality or quantity due to the culmination of single, sequential or simultaneous pathophysiological abnormalities in the HPT axis.2-4 This definition is simple to apply when the cause of HPT axis failure is obvious ("organic hypogonadism", e.g. due to pituitary tumor causing secondary hypogonadism or due to Klinefelter syndrome causing primary hypogonadism); however, many chronic illnesses can dysregulate the HPT axis, decrease T and impair fertility ("functional hypogonadism"). These chronic illnesses include specific non-metabolic disorders such as chronic obstructive pulmonary disease, heart failure with preserved ejection fraction, acquired immunodeficiency syndrome, alcoholic liver disease and chronic kidney disease; but therapy is not recommended because randomized controlled trials of androgen therapy in these disorders show no or very modest benefits.5 On the other hand, emerging evidence shows that chronic metabolic disorders such as obesity, metabolic syndrome, and type 2 diabetes mellitus may be responsive to T replacement therapy (TRT),6 and lifestyle modifications partially repair the HPT defects.7 Similarly, data are accumulating regarding the usefulness of TRT to improve distance walked, mood, hemoglobin and sexual function in generally healthy men with age-related functional hypogonadism,8, 9 a condition that is characterized by multiple regulatory defects in the entire HPT axis.1, 10 Therefore, applying the definition of male hypogonadism is complicated because the clinical syndrome is not specific, and overlaps with features of aging and many chronic metabolic and nonmetabolic disorders. Multiple guidelines exist to help steer the clinical assessment of male hypogonadism, including the evaluation of a constellation of symptoms and signs, the decision regarding whom to treat according to the risk compared to benefit, and the treatment target.2-4 These regional and national guidelines are required because of differences in the patient population and the type of symptoms; varying diagnostic and therapeutic thresholds among clinicians; and patient and prescriber preference for and availability of certain androgen formulations. Despite these differences, there is universal agreement that the clinical suspicion of male hypogonadism should be confirmed by laboratory measurement of serum T since no reliable biological marker of T action exists. In this issue of the Journal, Jayasena et al.11 address how the biochemical confirmation of hypogonadism should proceed for nonspecialist clinicians. These recommendations are on behalf of the Society of Endocrinology and the Association of Clinical Biochemistry and Laboratory Medicine, both based in the United Kingdom. The authors recommend that total T be measured (and free T calculated when sex hormone binding globulin is below the reference range) in men with symptoms consistent with male hypogonadism using morning, fasting blood samples obtained from men who are not acutely ill and after a good night's rest. Low T requires confirmation with a repeat measurement. They also recognize that the assessment of hypogonadism in night shift workers is complicated and warrants specialist referral because the diurnal rhythm of T is primarily driven by sleeping patterns and not endogenously by circadian factors.12 This is an important caveat, not addressed by other guidelines because 15%–20% of working men in North and South America, Asia, Africa and Oceania are regular or occasional night shift workers.13 The latter disproportionately complain of symptoms such as poor sleep, lack of energy, and sexual dysfunction that trigger an evaluation for male hypogonadism, and simply measuring T in a blood sample taken before 11 AM without regard to prior sleep patterns may not be interpretable. This position statement provides guidance relevant to all men, including shift workers, within and outside of United Kingdom. Nevertheless, gaps in knowledge exist that need to be addressed from a global perspective. The prevalence of male hypogonadism in large areas of Africa, Asia and South America has not been studied systematically.14 It may differ depending on the prevalence of the underlying iatrogenic causes, such as cancer treatments and opioid use; or possible metabolic causes, such as obesity and type 2 diabetes mellitus.14 The T threshold to define age-related functional hypogonadism and the target for such therapy has been investigated in cohorts that are overwhelming Caucasian in origin,9, 15 which may not be generalizable to all men since the regulation of the HPT axis may differ among races.16 The impact of aging and chronic diseases on the HPT axis needs to be deciphered in geographically diverse and multiethnic populations. For comparisons across geographically diverse and multiethnic populations to occur, hormone assays must be accurate to a known standard. So far, this is being conducted exclusively by the CDC HoSt program, which has certified laboratories in United States, Europe, and Asia: https://www.cdc.gov/labstandards/csp/hs_certified_participants.html. The laboratories certified have almost all relied upon liquid chromatography tandem mass spectrometry technology, which is a methodology that is expensive and labor-intensive. Existing harmonized reference ranges have been exclusively developed in the United States and Europe; their applicability to other parts of the world is uncertain.17 The feasibility of harmonized reference ranges in less well-resourced regions of the world seems problematic when such ranges have not yet been developed in the United Kingdom. Nevertheless, the guidance provided by Jayenson et al.11 is valuable to reduce the variability in assessing T and is applicable throughout the world. Understanding where male hypogonadism stands compared with other andrological conditions such as erectile dysfunction, infertility, and lower urinary tract syndrome in different parts of the world will help define priorities. Such an undertaking is being conducted by the International Society of Andrology. All authors have read and approved the manuscript. The authors declare no conflicts of interest.

Source: Clinical Endocrinology

DOI: 10.1111/cen.14941

Authors: Giovani Corona, Dimitrios G. Goulis, Peter Y. Liu

Institutions: Azienda USL di Bologna, Aristotle University of Thessaloniki, University of California, Los Angeles, The Lundquist Institute, Harbor–UCLA Medical Center

Language: English

Topic: Hormonal and reproductive studies

Subfield: Endocrinology, Diabetes and Metabolism

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,330