Hypogonadism in Men: Underdiagnosed and Undertreated

MAY 18, 2007
Francisco Badar, MD, Vijay Mirmira, MD, MPH, and Nikhil Hemady, MD, FAAFP, North Oakland Medical Center, Pontiac, Mich

Francisco Badar, MD
Resident Family Medicine Residency Program

Vijay Mirmira, MD, MPH
Resident Family Medicine Residency Program

Nikhil Hemady, MD, FAAFP
Associate Residency Director and Vice Chairman Department of Family Medicine

North Oakland Medical Center Pontiac, Mich

Hypogonadism results from impaired physiologic functioning of the gonads and is characterized by a low serum testosterone level, with deleterious effects on end organs. It is classified as primary (hyper­gonadotropic) or secondary (hypogonadotropic) hypogonadism, depending on where in the hypothalamic-pituitary-testicular axis the dysfunction occurs. Prevalence increases with age, and up to 4 million American men are estimated to be affected. Clinical manifestations vary by age and are usually subtle when associated with adult-onset disease, which may explain the underdiagnosis of this condition. Total serum testosterone level is the initial diagnostic test. Other studies that help determine the etiology and guide appropriate therapy include measurement of serum follicle-stimulating hormone, luteinizing hormone, and prolactin levels. Testosterone replacement therapy is indicated in symptomatic men with low levels of serum testosterone, although benefits in elderly men are uncertain.

Practice points
Most men are not likely to complain of symptoms of hypogonadism because of the nonspecific nature of these signs or symptoms.

Hypogonadism can manifest as testosterone deficiency, infertility, or both. n Laboratory evaluation includes a measurement of testosterone concentration, gonadotropin and prolactin levels, as well as semen analysis.

Before starting testosterone replacement therapy, measuring hemoglobin, hematocrit, and prostate-specific antigen levels, as well as a digital rectal examination are recommended in all patients.

Hypogonadism is estimated to affect approximately 2 million to 4 million men in the United States and is destined to become more prevalent with the growing numbers of older Americans, since incidence increases with age. The condition is defined by low serum testosterone levels secondary to reduced testicular function resulting from a disturbance in the hypothalamic-pituitary-testicular axis. The adult male testis has 2 primary functions, spermatogenesis and testosterone production; hence, testicular dysfunction can manifest as reduced spermatogenesis, decreased testosterone production, or both. Clinical manifestations vary by age of onset.

Hypogonadism is classified into 2 categories, depending on the site of dysfunction. When the problem is at the level of the testes, it is termed primary or hypergonadotropic hypogonadism. Secondary or hypogonadotropic hypogonadism arises from a dysfunction in the hypothalamic-pituitary axis. In both forms, serum testosterone levels and sperm counts are reduced. However, serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone are increased in the primary form but are normal or reduced in the secondary form.

Clinical Features
Hypogonadism can manifest as testosterone deficiency, infertility, or both. Signs and symptoms of this condition depend on whether it occurred before or after the onset of puberty. Features in the prepubertal male include delayed puberty, stunted skeletal muscle development, reduced body hair, high-pitched voice, small testes, short penis, gynecomastia, and long arms and legs (caused by delayed epiphyseal closure).

In postpubertal males, clinical features may be nonspecific and less obvious than in young males, because testosterone-dependent physical attributes, such as hair distribution, genital development, and muscle mass, develop normally and function properly despite the decreased androgen levels.1,2 Features in adults include depression, fatigue, loss of libido, impotence, oligospermia or azoospermia, decreased muscle mass, osteoporosis, and hypoproliferative anemias.2,3

Illustrative Case
A 67-year-old man presents with complaints of fatigue, weakness, and a decreased libido over the past year. He reports no other symptoms, such as cold or heat intolerance, headaches, visual changes, or recent weight loss. He drinks a glass of red wine on weekends. He denies being depressed and says he is in good health. He is married and has a daughter. Physical examination is unremarkable. Initial laboratory evaluation shows a normal complete blood cell count and metabolic panel. His thyroid-stimulating hormone (TSH) level is normal, but serum total testosterone concentration is low at 300 ng/dL. Serum FSH and luteinizing hormone levels were within normal range. This is a typical case of nonspecific signs of hypogonadism that may easily elude a diagnosis. In a case like this, obtaining the serum testosterone, TSH, FSH, and luteinizing hormone levels initially may be of benefit.

Causes of Hypogonadism
There are many etiologies for primary (Table 1) and secondary (Table 2) hypogonadism. Klinefelter’s syndrome is the most common cause of hypogonadism, but it remains undiagnosed in about three fourths of patients.4 The syndrome is characterized by primary testicular failure from sex chromosome aneuploidy, which results in an extra X chromosome. Patients will have features of hypogonadism but are also prone to developing venous leg ulcers, varicose veins, and venous thromboembolism caused by hypofibrinolysis secondary to androgen deficiency. Diabetes and autoimmune disorders are also prevalent in Klinefelter’s syndrome.

Barr body analysis is a useful screening test for Klinefelter’s syndrome; chromosome analysis is used for diagnostic confirmation. Lifelong testosterone replacement therapy is recommended to correct the testosterone deficiency, but it has no effect on infertility.5 Genetic counseling is recommended for all patients with hypogonadism.

Other congenital causes of hypogonadism include cryptorchidism, chromosomal abnormalities (46,XY/XO and the 47,XYY karyotypes), mutation in the FSH receptor gene, disorders of androgen biosynthesis, and myotonic dystrophy. Viral infections, such as mumps, can cause orchitis and lead to infertility but are rarely associated with testosterone deficiency.

Chemotherapeutic drugs (especially alkylating agents), glucocorticoids, long-term opioid therapy, and heavy alcohol consumption can all reduce testosterone levels.6,7

Data indicate that patients with the metabolic syndrome have an increased prevalence of hypogonadism.8 Chronic illnesses, such as cirrhosis, chronic renal failure, and HIV infection, are associated with primary and secondary hypogonadism as a result of a direct testicular effect as well as reductions in gonadotropin levels.2,9

Be sure to rule out hemochromatosis and hyperprolactinemia in any man with secondary hypogonadism.1 Numerous cases of primary and secondary hypogonadism of varying severity with unknown etiology, termed idiopathic hypogonadism, have been identified.7 Kallmann’s syndrome is a form of hypogo­­nadotropic hypogonadism that is accompanied by nongonadal features, such as anosmia, red-green color blindness, cleft lip/palate, urogenital tract problems, and hearing loss.10

Hypogonadism in aging men, sometimes referred to as “andropause,” affects an estimated 30% of men aged 60 to 70 years and 70% of men aged 70 to 80 years.11 The merits and potential harms of androgen replacement therapy in the elderly are a subject of ongoing debate.12,13

Diagnosis
Most men with hypogonadism are unlikely to present to their physician complaining of signs and symptoms of hypogonadism because of the nonspecific nature of these symptoms. Hence, physicians should be familiar with the often subtle symptoms and include questions in the history that may elicit such findings.

The history should include specific questions about sexual function, including any type of sexual dysfunction, loss of libido, impotence, or decreased ejaculate volume; testicular trauma or damage (eg, from orchitis or systemic chemotherapy); and current medication use. A history of anosmia or hyposmia suggests Kallmann’s syndrome, whereas a history of other central endocrine deficiencies suggests secondary hypogonadism.

Physical examination should include documentation of Tanner stage (Table 3); amount and distribution of hair, including facial, axillary, and pubic hair; secondary sexual characteristics; and a search for gynecomastia. Findings of galactorrhea in a man with hypogonadism suggest hyperprolactinemia.

Testicular length and width should be measured with calipers or a Prader orchidometer. Firm, small testes suggest damage to the testicular germinal epithelium before puberty; soft, small testes point to postpubertal damage.2 Klinefelter’s syndrome is suggested by tall stature (especially disproportionately long legs), eunuchoid body habitus, gynecomastia, and behavioral abnormalities.

Laboratory and Imaging Studies
Serum testosterone
Testosterone circulates mostly in the bound form, with 30% bound to sex hormone–binding globulin (SHBG) and 68% bound to albumin. The remaining 2% is in a free form2 and is the biologically active testosterone. Measurement of total serum testosterone level is reliable, widely available, and relatively inexpensive to obtain and is therefore considered the initial diagnostic test for hypogonadism.1,2 In certain situations, however, total testosterone values can be misleading. For example, SHBG levels are reduced in obesity, hypothyroidism, and type 2 diabetes, resulting in misleadingly low total testosterone values. Conversely, SHBG levels increase with age, causing total testosterone to increase.2,14 A free-testosterone level measured by equilibrium dialysis is helpful in such situations, especially in patients with no clinical features of hypogonadism. Serum testosterone levels follow a diurnal pattern and peak at around 8 am, making this the best time for measurement. Abnormal levels should be confirmed with repeat testing.

Gonadotropins
Testing serum FSH and luteinizing hormone values is the next step in the workup of a patient with a low testosterone concentration. Elevated levels of these gonadotropins suggest primary hypogonadism, whereas low or low-normal values suggest a secondary cause. Measurement of prolactin level is recommended in patients with secondary hypogonadism.2 Normal testosterone levels in a man with a low sperm count and increased FSH and luteinizing hormone levels may be the result of damage to the seminiferous tubules.

Semen analysis
Semen analysis is valuable for assessing spermatogenesis. Healthy men produce 20 million sperm/mL of ejaculate, with more than 60% of the ejaculated sperm being motile. Men with primary hypogonadism usually have slightly decreased sperm counts and significantly impaired sperm motility.14

Genetic testing
Barr body analysis is a useful screening test for Klinefelter’s syndrome. Peripheral leukocyte karyo­typing is used to confirm the diagnosis.4

Magnetic resonance imaging
Magnetic resonance imaging (MRI) is used for the evaluation of the hypothalamic-pituitary axis in patients with acquired secondary hypogonadism. The most recent update of the consensus guideline from the American Association of Clinical Endocrinologists recommends pituitary MRI scanning in patients with a testosterone level of 150 ng/mL or less, even if they are asymptomatic.2 MRI is also indicated in men with secondary hypogonadism and elevated prolactin levels (to rule out a pituitary adenoma), central hypothyroidism, and symptoms of a pituitary tumor (eg, headache, visual changes). Olfactory system abnormalities in patients with Kallmann’s syndrome can also be detected by MRI.15

Treatment
Testosterone replacement therapy is indicated in symptomatic men with low levels of serum testosterone. Factors that need to be considered before beginning testosterone replacement therapy in men are etiology (ie, primary or secondary), patient age, benefits versus risks, and contraindications. Reversible causes of hypogonadism should be sought and treated appropriately, since treatment of illnesses outside the control of the hypothalamic-pituitary-testicular axis will usually improve testosterone levels.16

Benefits of testosterone replacement
The benefits of testosterone replacement in elderly men are unclear, but therapy can be considered in symptomatic older men with a total testosterone level less than 200 ng/dL.2,17,18 There is no consensus on goal of total testosterone levels in older men, although the lower end of the normal reference range (300-450 ng/dL) is probably prudent.19 Adjusting testosterone therapy to alleviate symptoms is difficult, since nonspecific symptoms may be caused by other underlying conditions in the geriatric population. Once placed on testosterone therapy, elderly patients should be closely monitored for adverse effects, such as the development or progression of testosterone-dependent disease (eg, prostate cancer).

Testosterone replacement therapy has been shown to increase lean body mass and bone mineral density and improve mood and cognition,2,20 but it has little effect on depression in older men with low testosterone levels.21 Although there is no evidence that testosterone therapy increases the risk of prostate cancer in the elderly, monitoring is prudent.17 Studies have shown either only a mild increase or no increase in prostate-specific antigen (PSA) levels in older men at up to 2 years of follow-up.22,23

Risks of therapy
Risks of testosterone replacement therapy include increased hematocrit, thrombogenicity, and platelet aggregation, along with an infrequent incidence of sleep apnea, gynecomastia, acne, and infertility; the latter reverses on treatment discontinuation. 2,16,17 Because transdermal and intramuscular testosterone delivery is not associated with liver function abnormalities, routine monitoring of liver enzymes is unnecessary when using either type of administration.17 Reduced fertility caused by the downregulation of gonadotropins is a known side effect of androgen replacement therapy.24 Absolute contraindications include prostate cancer (past, current, or when suspicion is high), hematocrit above 55%, breast cancer, and obstructive-but not nonobstructive-uropathy. Relative contraindications are high hematocrit (50%-55%), gynecomastia, and sleep apnea.12,16

Choosing the mode of administration
Factors that need to be considered when choosing among the different modes of available therapies include convenience, acceptability, and cost (Table 4). Oral agents are the least expensive form but can cause significant hepatotoxicity and are, therefore, rarely used in the United States. The injectable depot preparations, testosterone enanthate (Delatestryl) and cypionate (Depo-Testosterone), are given once every 2 to 3 weeks, but they produce inconsistent serum levels and thus variable clinical responses.25 Transdermal formulations-skin patch (Androderm, Testoderm TTS), scrotal patch (Testoderm), and gel (AndroGel, Testim)-have the advantage of producing serum levels that mimic circadian testosterone levels.25 Gel formulations are associated with less skin irritation than patches. Buccal tablets also produce physiologic testosterone levels.26 Testosterone implants, such as pellets (Testopel), are useful for younger patients requiring long-term testosterone replacement. In such cases, 4 to 5 pellets are implanted under the skin, providing a daily steady release of testosterone for 5 to 6 months.27

Follow-up visits every 3 to 4 months should be scheduled to assess for subjective improvement in the symptoms of hypogonadism as well as any worsening of sleep apnea or prostatic hypertrophy.16,17

Monitoring therapy
Before starting testosterone replacement therapy, measurement of hemoglobin, hematocrit, and PSA levels, and a digital rectal examination are recommended for all patients. Periodic PSA monitoring should be done, but the optimal frequency has not been determined. Any change in PSA level or digital rectal examination findings should prompt further evaluation for prostate cancer.17,19

Monitoring of the lipid profile is optional, given that the most frequently used forms of testosterone therapy (transdermal and injectable) have minimal effects on serum cholesterol.28,29 Serum testosterone levels are checked 1 month after therapy is begun and periodically thereafter. There is no consensus on target testosterone levels, but the middle to low end of the normal range is usually advocated.19

Testosterone therapy should be adjusted based on clinical response.2,17 No changes are needed in patients showing clinical improvement, even if their testosterone levels are at the low end of normal. In patients whose testosterone levels are at the low end of normal and have no clinical response, the dosage should be increased; those who have not responded to the maximal dose of transdermal therapy should be switched to an intramuscular form.17

Conclusion
Physicians and patients often disregard the importance of hypogonadism, despite consequences that can range from mood disturbances and sexual dysfunction to osteoporosis and cardiovascular disease. A comprehensive history and thorough physical examination will help determine the cause and severity of the condition. Distinguishing between primary and secondary hypogonadism is vital to guide treatment. Laboratory evaluation begins with a measurement of testosterone concentration and may also include a determination of gonadotropin and prolactin levels, as well as semen analysis. Androgen replacement therapy can improve sexual functioning and mood, optimize bone density and prevent osteoporosis, and possibly lower the patient’s risk for cardiovascular disease. In older men who are at risk for prostate cancer, PSA levels should be measured before starting therapy and then periodically during treatment.

Self-assessment test
1. All these conditions can cause primary hypogonadism, except:
A. Klinefelter’s syndrome
B. Kallmann’s syndrome
C. Varicocele
D. HIV infection

2. Which of these features is NOT associated with a postpubertal onset of hypogonadism?
A. Gynecomastia
B. Decreased muscle mass
C. Oligospermia
D. Fatigue

3. Which laboratory finding is LEAST characteristic of primary hypogonadism?
A. Slight decrease in sperm count
B. Significant impairment of sperm motility
C. Elevated FSH
D. Decreased luteinizing hormone

4. All these complications are proven risks of testosterone replacement therapy, except:
A. Increased thrombogenicity
B. Sleep apnea
C. Prostate cancer
D. Infertility

5. Which testosterone replacement therapy is the option most likely to produce fluctuating levels of serum testosterone?
A. Intramuscular injection
B. Skin patch
C. Scrotal patch
D. Gel

(Answers at end of reference list)

References
1. Grant NN, Anawalt BD. Male hypogonadism in the primary care clinic. Prim Care. 2003;30:743-763, vii.

2. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients-2002 update. Endocr Pract. 2002;8:440-456.

3. Liu PY, Swerdloff RS, Wang C. Relative testosterone deficiency in older men: clinical definition and presentation. Endocrinol Metab Clin North Am. 2005;34:957-972, x.

4. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88:622-626.

5. Lanfranco F, Kamischke A, Zitzmann M, et al. Klinefelter’s syndrome. Lancet. 2004;364:2732-2783.

6. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.

7. Snyder PJ. Causes of primary hypogonadism in males. UpToDate [online serial]. 2005. Available at http://patients.uptodate.com/topic. asp?file= r_endo_m/4572&title=Male hypogonadism.

8. Makhsida N, Shah J, Yan G, et al. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol. 2005;174:827-834.

9. Poretsky L, Can S, Zumoff B. Testicular dysfunction in human immunodeficiency virus-infected men. Metabolism. 1995;44:946-953.

10. Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998;19:521-539.

11. Hijazi RA, Cunningham GR. Andropause: is androgen replacement therapy indicated for the aging male? Annu Rev Med. 2005;56: 117-137.

12. Vermeulen A. Androgen replacement therapy in the aging male-a critical evaluation. J Clin Endocrinol Metab. 2001;86:2380-2390.

13. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87:589-598.

14. Snyder PJ. Clinical features and diagnosis of male hypogonadism in adults. UpToDate [online serial]. 2005. Available at http:// patients.uptodate.com/topic.asp?file=r_endo_m/5198&title=Male  hypogonadism.

15. Madan R, Sawlani V, Gupta S, et al. MRI findings in Kallmann syndrome. Neurol India. 2004;52:501-503.

16. Sadovsky R, Althof S. Men’s sexual issues. Clin Fam Pract. 2004; 6:863-915.

17. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004; 350:482-492.

18. Harman SM, Metter EJ, Tobin JD, et al, for the Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86: 724-731.

19. Snyder PJ. Hypogonadism in elderly men-what to do until the evidence comes [editorial]. N Engl J Med. 2004;350:440-442.

20. Mittan D, Lee S, Miller E, et al. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab. 2002;87:3656-3661.

21. Seidman SN, Spatz E, Rizzo C, et al. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry. 2001;62: 406-412.

22. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60:1451-1457.

23. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 1997;82:3793-3796.

24. Bagatell CJ, Bremner WJ. Androgens in men-uses and abuses. N Engl J Med. 1996;334:707-714.

25. Schubert M, Minnemann T, Hubler D, et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab. 2004;89:5429-5434.

26. Wang C, Swerdloff R, Kipnes M, et al. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab. 2004;89: 3821-3829.

27. Kelleher S, Howe C, Conway AJ, et al. Testosterone release rate and duration of action of testosterone pellet implants. Clin Endocrinol (Oxf). 2004;60:420-428.

28. Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89:2085-2098.

29. Snyder PJ, Peachey H, Berlin JA, et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med. 2001;111:255-260.

Answers: 1. B; 2. A; 3. D; 4. C; 5. A.



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