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Quest Diagnostics

Hypogonadism

Test codes: 457, 470, 509, 571, 615, 746, 866, 899, 873, 4212, 5363, 5616, 7573, 8658, 14596,14966, 15983,16122, 30289, 30740, 30741, 35167, 36170, 37073, 38149, 40049  

Male hypogonadism is a clinical syndrome caused by low testosterone and/or sperm production.1

The syndrome can occur in 3 forms: primary, secondary, and combined (Table 1).1 All 3 forms are characterized by low T and impaired sperm production. Primary hypogonadism (hypergonadotropic hypogonadism) is caused by abnormalities of the testes and is also characterized by high gonadotropin levels: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Secondary hypogonadism (hypogonadotropic hypogonadism) is caused by abnormalities of the hypothalamus and/or pituitary and, in contrast to primary hypogonadism, is characterized by low or normal gonadotropin levels. In combined hypogonadism, gonadotropin levels vary depending on whether primary or secondary hypogonadism predominates. 

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a Combined primary and secondary hypogonadism but classified (ie, primary or secondary) according to the predominant gonadotropin hormonal pattern.1

b High-prevalence conditions of low testosterone for which serum testosterone measurements are suggested.1

 

 

In men diagnosed with hypogonadism, additional diagnostic evaluation is recommended to determine the cause or  causes, which are classified as organic or functional (Table 1).1 Organic causes include congenital, structural, or destructive disorders that permanently affect the testes and/or hypothalamic-pituitary-testicular (HPT) axis. The clinical presentation of organic hypogonadism is usually severe, and testosterone supplements are almost always necessary.

Functional causes of male hypogonadism include aging and comorbidities associated with aging, such as obesity, insulin resistance, type 2 diabetes, some medications (eg, glucocorticoids, gonadotropin hormone-releasing hormone [GnRH] agonists, and anti-androgens), and drugs of abuse (eg, opioids, anabolic steroids, cannabis, alcohol), excessive exercise, organ failure, and renal, endocrine, sleep, and systemic disorders. Functional causes suppress gonadotropins and T, but to a lesser degree than organic causes; they are potentially reversible by removing the cause (eg, liver transplantation in terminal liver failure, weight loss in obesity, weight gain in anorexia nervosa, discontinuing medications affecting the HPT axis).1 In general, patients with functional hypogonadism present with milder symptoms compared to those with organic hypogonadism. However, severe symptoms can occur in patients with the most advanced forms of functional impairment, who develop significant hypotestosteronemia for a long time.

The clinical features of hypogonadism depend on when the disorder causing hypogonadism begins and can be classified into 3 groups: prenatal, prepubertal, and postpubertal.

Prenatal hypogonadism

Patients with prenatal hypogonadism usually have ambiguous genitalia that can be categorized as complete, intermediate, or mild.

Prepubertal hypogonadism

Patients with prepubertal hypogonadism usually have delayed puberty, appear younger than their age, have small testes and phallus, and have problems developing muscle mass. The most revealing clinical signs are in Table 2.

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a Defined as a lower body segment (floor to pubis) more than 2 cm longer than the upper body segment (pubis to crown) and an arm span more than 5 cm longer than the vertical length. Eunuchoidism is due to a delay in epiphyseal closure, an event under testosterone, and, more importantly, estradiol control. Eunuchoid proportions are a highly specific sign of prepubertal hypogonadism.

 

 

Postpubertal hypogonadism

For patients with postpubertal hypogonadism, clinical presentation depends on the degree and duration of low blood T. A common cause of abrupt decreases in T is androgen deprivation therapy for prostate cancer. These patients have an immediate reduction of libido and erectile function, and have low energy, hot flashes, insomnia, depression, changes in body composition with decreased lean and increased fat mass, and reduced bone mineral density with increased risk of fragility fractures.

Most patients with hypogonadism of this age group do not experience such a sudden decrease in serum T and develop a gradual decline in energy, libido, and erectile function. Primary and secondary sexual characteristics do not regress to prepubertal levels; therefore, phallus, sexual hair, muscle mass, and bone mineral density do not diminish significantly for several months. Also, testicular size does not change significantly unless the patient is affected by primary hypogonadism. However, as T and its metabolite estradiol are essential for acquiring and maintaining bone mass, osteoporosis eventually develops, increasing the risk of fragility fractures.

Gynecomastia is more frequent in patients with primary hypogonadism because high gonadotropins increase testicular aromatase expression.

Testosterone stimulates erythrocytosis by increasing erythropoietin and suppressing hepcidin; therefore, men with androgen deficiency may have mild hypoproliferative normocytic, normochromic anemia. Clinical manifestations reported by hypogonadal men overlap with those seen in elderly, obese, or chronically ill patients, including sarcopenia, low energy, depressed mood, fragility fractures, and low libido.

Differentiating chronic diseases from hypogonadism requires diagnosing hypogonadism using a strict syndromic approach based on (1) clinical symptoms and (2) unequivocally and consistently low serum T concentrations.

Using both clinical symptoms and unequivocally and consistently low serum T concentrations to diagnose hypogonadism, as Endocrine Society guidelines recommend,1,2 population studies found that the prevalence of hypogonadism in men ages 40 to 80 years is between 2% and 12.3%.3-6 These estimates are lower than those where only clinical (24%)4 or biochemical (12.8% and 29%)4,7 approaches were used. 

LOH is a form of functional hypogonadism (FH) that was once thought to be the male equivalent of female climaterium and caused by decreased Leydig cell functionality that occurred with aging.

In LOH, testosterone (T) levels decrease as a patient ages, but the decrease is modest: 0.4% to 1.4% per year for total T (TT) and 1.3% to 2.7% for free T (FT).8 The European male aging study (EMAS) defined LOH as a condition with TT levels <320 and FT levels <6.3 ng/dL, with at least 3 sexual symptoms: decreased frequency of morning erections, erectile dysfunction, and decreased frequency of sexual thoughts. Using these criteria, the prevalence of LOH among men ages 40 to 80 is 2.1% and increases as a function of aging, from 0.1% in men ages 40 to 49 to 5.1% in men ages 70 to 79.9

According to EMAS, most of the decline in TT and FT observed in older individuals is due to comorbidities common in the geriatric population: the prevalence of hypogonadism increases 13-fold among men with obesity and 9-fold among men with chronic disease.10 In addition, serum T is 30% lower in obese men than in normal-BMI men at any age, representing more than the entire age-dependent T decrease between 40 and 80.11 These studies suggest that most of the T decrease observed in elderly individuals is due to comorbidities rather than a primary condition of the hypothalamic-pituitary-testicular (HPT) axis. In most individuals with LOH, gonadotropins are in the normal range, suggesting that the condition is caused by a central disorder.

The Endocrine Society recommends diagnosing hypogonadism based on (1) clinical symptoms and (2) unequivocally and consistently low serum T concentrations.1,2 The guidelines emphasize testing for low T in patients presenting with signs and symptoms compatible with hypogonadism and in patients affected by conditions associated with a high prevalence of low T that can be addressed by T supplementation (Table 3). The Endocrine Society does not recommend the routine use of case-detection questionnaires that rely on self-reporting to help diagnose hypogonadism because evidence does not strongly support their performance.12-14

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The most useful analytes for diagnosing hypogonadism are total testosterone (TT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). TT reflects the status of T production by the testes. If TT is low, measurement of LH and FSH can help determine if hypogonadism is primary (characterized by elevated gonadotropins) or central (low or inappropriately normal gonadotropins). Specimens for TT measurement should be collected between 7:00 AM and 10:00 AM, because levels peak in the morning, especially among younger men. Also, because levels can fluctuate from day to day, a second test is recommended to confirm hypogonadism before initiating treatment.1

For screening purposes, professional societies recommend measuring TT by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is more sensitive and reliable than TT measured by immunoassay (IA). However, TT measured by IA is acceptable in follow-up visits, when the patient has started testosterone replacement therapies (TRT) and TT levels are expected to be in the mid-normal range. Free testosterone (FT) by equilibrium dialysis should be measured when TT is near the lower limit of normal or alterations in sex hormone-binding globulin (SHBG) (Table 4) that could affect TT are suspected.1

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Once the biochemical diagnosis reveals whether the patient is affected by primary or secondary hypogonadism, the physician will be able to determine the etiology of the condition by following established clinical protocols.

Quest Diagnostics offers testosterone tests and panels for diagnosing hypogonadism, distinguishing primary vs secondary hypogonadism, identifying organic or functional causes of hypogonadism, and monitoring and managing TRT (Table 5).1,15,16 Panel components may be ordered separately.

ACTH, adrenocorticotropin hormone; FT, free testosterone; FT4, free thyroxine; LC/MS (LC-MS/MS), liquid chromatography/tandem mass spectrometry; MS, mass spectrometry; PSA, prostate-specific antigen; SHBG, sex hormone binding globulin, TRT, testosterone replacement therapy; TT, total testosterone.

 

Click the table to open in a new window.

a  This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by FDA. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

b  Laboratory tests can provide 3 measurements of testosterone: free, bioavailable, and total. These measurements incorporate the 3 major forms of circulating testosterone: unbound (free), weakly bound to albumin, and tightly bound to SHBG. TT is the total concentration of bioavailable (free and weakly bound testosterone) and SHBG-bound testosterone.

c  As an alternative to FT measurement by dialysis, FT levels can be estimated from a formula based on TT, SHBG, and albumin measurements (test code 14966).1 Quest uses a modified Vermeulen equation25 that accurately reflects FT as if it were measured by equilibrium dialysis1; however, FT measurement by dialysis is preferred (test code 36170).

d  Direct immunoassays cannot accurately measure low serum testosterone levels found in hypogonadal men. For higher specificity, sensitivity, and precision testing of low TT, clinicians should consider using LC-MS/MS-based assays, preferably those certified by the Centers for Disease Control and Prevention (CDC).1 The LC-MS/MS tests (test codes 15983, 36170) have been certified by the CDC Hormone Standardization Program.26

It depends. If FH is due to a reversible condition, treatment consists of removing the offending agent: for instance, one of the drugs listed in Table 1 that affect the physiology of the hypothalamic-pituitary-testicular (HPT) axis.

For opioids, probably the most frequent pharmacologic cause of FH, resuming activity of HPT axis requires significant time. If the patient is young and affected by severe symptoms, TRT is justified and should be continued if associated with symptomatic improvements. A 2017 study showed that TRT in patients affected by opioid-induced hypogonadism was associated with an increase in median T of 262.5 ng/dL and an improvement of common hypogonadal symptoms that included libido, erectile function, body composition, and quality of life (P <0.05).17

Other reversible causes of FH include obesity and type 2 diabetes (T2DM) (Table 1). Studies have demonstrated that indirect measures, such as lifestyle changes in obese individuals or improved hemoglobin A1c (HbA1c) control in individuals with T2DM, effectively increase serum TT concentrations and reduce erectile dysfunction (ED). For instance, weight loss is associated with (proportionate) increases in TT18 and improvement in ED,19 and improved glycemic control is associated with increases in T levels.20

The decision of whether to treat individuals with FH who are unable to modify their lifestyle can be informed by recent studies that support TRT effectiveness21 and cardiovascular22 safety. The Testosterone trials (T-trials) showed that older men with FH who are receiving TRT experience a (modest) improvement in libido, sexual satisfaction, and sexual activity and a lesser improvement in erectile function (compared to libido). The T-trials also showed that hemoglobin increases by ~1 g/dL with the correction of baseline anemia.23 TRT in older men also increases volumetric trabecular bone mineral density (BMD), estimated bone strength, and areal BMD increase.24 However, T-trials did not show a significant positive effect on vitality and physical or cognitive function.21

The Transverse study, which was published in 2023 and powered to assess the cardiovascular (CV) safety of TRT, suggests that this treatment is not associated with increased CV risk for 2 years of treatment.22 Based on these results, if the presence of FH is confirmed by biochemistry and clinical presentation, a physician can initiate a course of TRT after discussing the benefits and side effects with the patient. The patient should be monitored and TRT discontinued if no response is present after 6 to 12 months.

Alternative treatments to lifestyle modifications and TRT, for instance use of clomiphene or human chorionic gonadotropin (HCG), have not been tested in properly powered clinical trials and are not recommended in clinical practice.       

References

  1. 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;103:1715-1744.
  2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.
  3. Tajar A, Forti G, O'Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95:1810-1818.
  4. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92:4241-4247.
  5. Araujo AB, O'Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89:5920-5926.
  6. Liu YJ, Shen XB, Yu N, et al. Prevalence of late-onset hypogonadism among middle-aged and elderly males in China: results from a national survey. Asian J Androl. 2021;23:170-177.
  7. Haring R, Ittermann T, Volzke H, et al. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male. 2010;13:247-257.
  8. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. 2008;93:2737-2745.
  9. Tajar A, Huhtaniemi IT, O'Neill TW, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab. 2012;97:1508-1516.
  10. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363:123-135.
  11. Huhtaniemi I. Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment. Asian J Androl. 2014;16:192-202.
  12. Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49:1239-1242.
  13. Moore C, Huebler D, Zimmermann T, et al. The Aging Males' Symptoms scale (AMS) as outcome measure for treatment of androgen deficiency. Eur Urol. 2004;46:80-87.
  14. Smith KW, Feldman HA, McKinlay JB. Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men. Clin Endocrinol (Oxf). 2000;53:703-711.
  15. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37:151-171, xi.
  16. American Association for Clinical Chemistry. Estradiol testing in men. Last reviewed June 2020. Accessed May 25, 2023. https://www.aacc.org/advocacy-and-outreach/optimal-testing-guide-to-lab-test-utilization/a-f/estradiol-testing-in-men
  17. Raheem OA, Patel SH, Sisul D, et al. The Role of Testosterone Supplemental Therapy in Opioid-Induced Hypogonadism: A Retrospective Pilot Analysis. Am J Mens Health. 2017;11:1208-1213.
  18. Corona G, Rastrelli G, Monami M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 2013;168:829-843.
  19. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA. 2004;291:2978-2984.
  20.  Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93:1834-1840.
  21. Snyder PJ, Ellenberg SS, Farrar JT. Testosterone Treatment in Older Men. N Engl J Med. 2016;375:90.
  22.  Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023
  23. Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med. 2017;177:480-490.
  24. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med. 2017;177:471-479.
  25. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666-3672. doi:10.1210/jcem.84.10.6079
  26. Centers for Disease Control and Prevention. HoSt/VDSCP certified participants. Testosterone in serum; 2023. Accessed June 7 2023. https://www.cdc.gov/labstandards/csp/pdf/hs/CDC_Certified_Testosterone_Assays-508.pdf

 

This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

 

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