Guideline sources The following summarized guidelines for the evaluation and management of male hypogonadism are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2023), the Italian Society of Endocrinology (SIE/SIAMS 2022), the European Academy of Andrology (EAA 2020), and the Endocrine Society (ES 2020; 2018). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Indications for screening: As per EAU 2023 guidelines: Obtain screening for late-onset hypogonadism (including in patients with T2DM) only in symptomatic patients. A https://web.pathway.md/diseases/recBbq16MFvJGGAZh 1/10 6/29/23, 6:18 AM Male hypogonadism Pathway Do not use structured interviews or self-reported questionnaires for systematic screening for late-onset hypogonadism because of the low specificity. D As per EAA 2020 guidelines, do not obtain universal screening for hypogonadism in middle- aged or older males by structured interviews or questionnaires and/or random total testosterone measurements. D As per ES 2018 guidelines, do not obtain routine screening for male hypogonadism in the general population. D Diagnostic criteria: As per EAU 2023 guidelines: Use a total testosterone value of 12 nmol/L (3.5 ng/mL) as a reliable threshold to diagnose late-onset hypogonadism. A Consider using a free testosterone value < 225 pmol/L as a possible cut-off to diagnose late- onset hypogonadism. C As per SIAMS 2022 guidelines: View a value of LH 9.4 IU/L in the presence of low total or calculated free testosterone as suggestive of primary hypogonadism. Consider measuring follicular-stimulating hormone to differentiate between primary and secondary hypogonadism if LH concentration is < 9.4 IU/L. B Consider establishing a diagnosis of compensated hypogonadism in the presence of LH 9.4 IU/L and normal testosterone or calculated free testosterone concentrations. E As per EAA 2020 guidelines, diagnose functional hypogonadism only on the basis of the presence of clinical symptoms or signs of testosterone deficiency in combination with consistently low morning serum testosterone concentrations. B Show 2 more As per ES 2018 guidelines: Diagnose hypogonadism in patients with symptoms and signs of testosterone deficiency and unequivocally and consistently low serum total testosterone and/or free testosterone concentrations (when indicated). B Consider obtaining further evaluation in patients with hypogonadism to identify the etiology of hypothalamic, pituitary, and/or testicular dysfunction. C 2. Diagnostic investigations Testosterone levels: As per EAU 2023 guidelines, obtain measurement of total testosterone in the morning (7-11 am) and in the fasting state with a reliable laboratory assay. A Show 4 more As per SIAMS 2022 guidelines: Obtain measurement of total testosterone in all patients with clinical manifestations consistent with hypogonadism and adopt a threshold of 12.0 nmol/L to define low total testosterone. B https://web.pathway.md/diseases/recBbq16MFvJGGAZh 2/10 6/29/23, 6:18 AM Male hypogonadism Pathway Consider measuring sex hormone-binding globulin during diagnostic workup to calculate free testosterone in all patients with clinical manifestations consistent with hypogonadism and adopt a threshold < 220 pmol/L to define low calculated low free testosterone. C As per EAA 2020 guidelines: Obtain measurement of serum total testosterone with a well-validated assay on fasting morning (before 11 am) blood samples obtained on two different days to confirm the clinical diagnosis of functional hypogonadism. B Measure or calculate free testosterone in addition to total testosterone in patients with conditions altering sex hormone-binding globulin and when total testosterone concentrations are in the borderline range (~ 8-12 nmol/L) if the clinical suspicion of hypogonadism is strong. B As per ES 2018 guidelines, obtain measurement of fasting total testosterone concentrations on two separate mornings in patients with suspected hypogonadism. E Show 4 more LH/FSH levels: As per EAU 2023 guidelines, obtain measurement of LH and FSH serum levels to differentiate between primary and secondary hypogonadism. A As per SIAMS 2022 guidelines: Obtain measurement of LH in all patients with clinical manifestations consistent with hypogonadism. B Consider measuring follicular-stimulating hormone to differentiate between primary and secondary hypogonadism if LH concentration is < 9.4 IU/L. C As per EAA 2020 guidelines, obtain measurement of LH in addition to morning total testosterone in all patients with suspected functional hypogonadism to differentiate between the primary and secondary causes. B As per ES 2018 guidelines, measure serum LH and FSH concentrations in patients with hypogonadism to distinguish between primary (testicular) and secondary (pituitary/hypothalamic) hypogonadism. B Prolactin levels: consider measuring prolactin levels in patients with low sexual desire (or other suggestive signs/symptoms) and low/low-normal testosterone. B Pituitary imaging: Obtain pituitary MRI in patients with secondary hypogonadism, with elevated prolactin levels or specific symptoms of a pituitary mass and/or presence of other anterior pituitary hormone deficiencies. A Obtain pituitary MRI in patients with severe secondary hypogonadism (total testosterone < 6 nmol/L). B Assessment of concomitant causes: assess for concomitant diseases, drugs, and substances possibly interfering with testosterone production/action. A Evaluation before testosterone therapy: https://web.pathway.md/diseases/recBbq16MFvJGGAZh 3/10 6/29/23, 6:18 AM Male hypogonadism Pathway As per EAU 2023 guidelines, elicit a family history to exclude VTE before initiating testosterone therapy. A Show 2 more As per SIAMS 2022 guidelines: Consider eliciting a detailed family, personal and clinical history of VTE before initiating testosterone replacement therapy. C Consider assessing the global cardiovascular risk and associated morbidities, including hematocrit level, before initiating testosterone replacement therapy. C As per EAA 2020 guidelines, consider eliciting a detailed personal and family history of VTE and risk factors for VTE before initiating testosterone replacement therapy. C Show 2 more 3. Medical management Discontinuation of contributing medications: As per EAU 2023 guidelines, withdraw concomitant drugs likely to impair testosterone production, when possible. B As per EAA 2020 guidelines, consider withdrawing/modifying drugs potentially interfering with testosterone production (such as opioids, anabolic steroids, and corticosteroids), when clinically permissible. C Management of underlying cause: Treat organic causes of hypogonadism (such as pituitary masses, hyperprolactinemia) when indicated. A Consider offering unilateral or bilateral orchidopexy, if technically feasible in patients with unilateral or bilateral undescended testis with biochemical hypogonadism and/or spermatogenic failure (infertility). C Indications for testosterone therapy: As per EAU 2023 guidelines, initiate testosterone replacement therapy in patients with hypogonadism to restore serum testosterone concentration to the average normal range for young males. B Show 4 more As per SIAMS 2022 guidelines, initiate testosterone replacement therapy in all symptomatic patients with hypogonadism, after the exclusion of contraindications, if a reversal of the condition cannot be expected in a reasonable timeframe. B Show 7 more As per EAA 2020 guidelines: Initiate testosterone replacement therapy to improve libido, erectile function, and sexual satisfaction in patients with hypogonadism with sexual/erectile dysfunction. A Do not initiate testosterone replacement therapy for the following purposes: https://web.pathway.md/diseases/recBbq16MFvJGGAZh 4/10 6/29/23, 6:18 AM Male hypogonadism Pathway weight reduction in patients with obesity D improvement of glycometabolic control in patients with T2DM and/or metabolic syndrome D improvement of morbidity and/or mortality of several chronic diseases including human immunodeficiency virus infection/acquired immune deficiency syndrome, HF, obstructive pulmonary disease, CKDs, bowel inflammatory diseases or prevention of long-term outcomes of patients chronically treated with corticosteroid or opioid therapy, in the absence of symptomatic hypogonadism D reduction of fracture risk in patients with high fracture risk D improvement of exercise capacity/physical function in frail patients D anti-aging therapy in > 65 years old patients D improvement of depressive symptoms D improvement of cognitive function. D As per ES 2020 guidelines: Consider initiating testosterone replacement therapy as symptomatically indicated in patients with low testosterone levels. C Avoid initiating testosterone replacement therapy to improve dyslipidemia or CVD risk in patients with low testosterone levels. D As per ES 2018 guidelines, initiate testosterone replacement therapy to induce and maintain secondary sex characteristics and correct symptoms of testosterone deficiency in patients with hypogonadism. B Show 5 more Landmark trials: Testosterone Trial In men 65 years of age with serum testosterone concentration of < 275 ng/dL and symptoms suggesting hypoandrogenism, testosterone gel was superior to placebo with respect to the percentage of patients achieving an improvement of at least 50 m in 6MWD. Snyder PJ et al. N Engl J Med. 2016 Feb 18. Contraindications for testosterone therapy: As per EAU 2023 guidelines: Restrict testosterone replacement therapy to patients with a low risk for recurrent prostate cancer (preoperative PSA < 10 ng/mL, Gleason score < 7, cT1-2a), and initiate treatment after at least 1 year of follow-up with PSA level < 0.01 ng/mL. B Advise patients that safety data on the use of testosterone therapy in male patients treated for breast cancer are unknown. A As per SIAMS 2022 guidelines, do not initiate testosterone replacement therapy in patients desiring fatherhood in the near future. D Show 3 more https://web.pathway.md/diseases/recBbq16MFvJGGAZh 5/10 6/29/23, 6:18 AM Male hypogonadism Pathway As per EAA 2020 guidelines, do not initiate testosterone replacement therapy in patients with hypogonadism desiring fertility. D Show 2 more As per ES 2018 guidelines, do not initiate testosterone replacement therapy in patients planning fertility in the near future. D Show 2 more Choice of testosterone preparations: As per EAU 2023 guidelines: Select the testosterone preparation in a joint decision process, only with fully informed patients. A Offer testosterone gels rather than long-acting depot administration when starting initial treatment, thus allowing adjustment or discontinuation of therapy in case of treatment-related adverse effects. B As per SIAMS 2022 guidelines: Consider offering testosterone gels in older patients with hypogonadism, particularly in case of potentially reversible conditions. E Consider offering long-acting injectable testosterone preparations in younger patients with hypogonadism, particularly in case of irreversible conditions. E As per EAA 2020 guidelines, consider offering transdermal testosterone as the preferred preparation in the initiation of testosterone replacement therapy for functional hypogonadism. C 4. Nonpharmacologic interventions Lifestyle modifications: As per EAU 2023 guidelines, advise lifestyle improvements and weight reduction in patients with hypogonadism. B As per EAA 2020 guidelines, offer lifestyle changes, including physical exercise and weight reduction, in male patients with overweight/obesity with functional hypogonadism since weight loss may increase testosterone concentrations. B 5. Specific circumstances Patients with hypogonadotropic hypogonadism: As per EAU 2023 guidelines, initiate combined hCG and FSH (recombinant FSH, highly purified FSH) or pulsed GnRH via pump therapy to stimulate spermatogenesis in patients with hypogonadotropic hypogonadism (secondary hypogonadism), including congenital causes. A As per EAA 2020 guidelines, initiate gonadotropin therapy in patients with secondary hypogonadism only when fertility is desired. A https://web.pathway.md/diseases/recBbq16MFvJGGAZh 6/10 6/29/23, 6:18 AM Male hypogonadism Pathway 6. Patient education General counseling: Inform patients fully about the expected benefits and adverse effects of any treatment option. Select the testosterone preparation in a joint decision process, only with fully informed patients. A Provide full counseling in patients with symptomatic hypogonadism previously treated (surgically) for localized prostate cancer (currently not showing evidence of active disease) considering testosterone therapy, emphasizing the benefits and lack of sufficient safety data on long-term follow-up. B 7. Follow-up and surveillance Indications for specialist referral: refer patients with hypogonadism to a urologist in case of a confirmed increase in PSA concentration > 1.4 ng/mL above baseline or confirmed PSA > 4.0 ng/mL, or a prostatic abnormality detected on DRE during the first 12 months of testosterone therapy. B Serial clinical and laboratory assessment: As per EAU 2023 guidelines, monitor testosterone and hematocrit at 3, 6, and 12 months after initiation of testosterone therapy and annually thereafter. A Show 3 more As per SIAMS 2022 guidelines: Assess clinical outcomes, including biochemical parameters (hematocrit, PSA, and testosterone), every 3-6 months during the first year and at least annually thereafter. B Consider obtaining further evaluation in the following situations: confirmed PSA > 4 ng/mL at any time, and detection of a prostatic abnormality on DREs, or substantial worsening of LUTS. C As per EAA 2020 guidelines, assess the clinical response and adverse effects to testosterone replacement therapy at 3 and 12 months after initiation of treatment and schedule clinical review at least yearly thereafter. A Show 4 more As per ES 2018 guidelines, assess response to treatment, adverse effects, and treatment adherence in patients on testosterone therapy. E Clinical findings Symptoms Past medical history Decreased energy Bone fracture https://web.pathway.md/diseases/recBbq16MFvJGGAZh 7/10 6/29/23, 6:18 AM Male hypogonadism Pathway Decreased libido COPD Depression Diabetes mellitus Erectile dysfunction Dyslipidemia Hot flashes Encephalitis Memory impairment Exposure to chemotherapy Sleeping disorder Hemochromatosis Sweating Human immunodeficiency virus infection Trouble concentrating Hypertension Medication history IBD Isolated GnRH deficiency Anabolic steroids Kallmann's syndrome Antipsychotics Klinefelter syndrome Corticosteroids Liver cirrhosis Opioids Obesity Osteoporosis Anthropomorphic exam Pasqualini's syndrome Delayed puberty Pituitary apoplexy Malnutrition Pituitary irradiation Pituitary tumor Genitourinary exam Prader-willi syndrome Ambiguous genitals Radiation therapy for previous cancer Female genitals Rheumatoid arthritis Testicular atrophy Sarcoidosis Underdeveloped male genitals Sickle cell disease Undescended testicle Tuberculosis Integument exam Vitamin D deficiency Loss of body hair Past surgical history Hematological findings Pituitary surgery Anemia Musculoskeletal exam Decrease in muscle mass Breast exam Gynecomastia Lab findings Azoospermia serum FSH serum LH serum prolactin GnRH https://web.pathway.md/diseases/recBbq16MFvJGGAZh 8/10 6/29/23, 6:18 AM Male hypogonadism Pathway serum FSH serum LH serum SHBG serum testosterone Imaging findings Pituitary mass Studies 2016 Testosterone Trial In men 65 years of age with serum testosterone concentration of < 275 ng/dL and symptoms suggesting hypoandrogenism, testosterone gel was superior to placebo with respect to the percentage of patients achieving an improvement of at least 50 m in 6MWD. Snyder PJ et al. N Engl J Med. 2016 Feb 18. References 1. Giovanni Corona, Dimitrios G Goulis, Ilpo Huhtaniemi et al. European Academy of Andrology EAA guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology. 2020 Sep;8 5 970 987. Open 2. A. Salonia, C. Bettocchi, J. Carvalho et al. EAU Guidelines on Sexual and Reproductive Health. EAU. 2023. Open 3. A M Isidori, A Aversa, A Calogero et al. Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine SIAMS and the Italian Society of Endocrinology SIE . J Endocrinol Invest. 2022 Aug 26;1 19. Open 4. Bhasin S, Brito JP, Cunningham GR et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 May 1;103 5 1715 1744. Open 5. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 6. T Mulligan, M F Frick, Q C Zuraw et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006 Jul;60 7 762 9. Open 7. Anna Ross, Shalender Bhasin. Hypogonadism: Its Prevalence and Diagnosis. Urol Clin North Am. 2016 May;43 2 163 76. Open 8. Emily J Meyer, Gary Wittert. Endogenous testosterone and mortality risk. Asian J Androl. Mar-Apr 2018;20 2 115 119. Open https://web.pathway.md/diseases/recBbq16MFvJGGAZh 9/10 6/29/23, 6:18 AM Male hypogonadism Pathway 9. G.R. Dohle Chair), S. Arver, C. Bettocchi et al. EAU Guidelines on Male Hypogonadism. EAU. 2018 Mar. Open https://web.pathway.md/diseases/recBbq16MFvJGGAZh 10/10