Continuing Education Activity

Male hypogonadism, acquired or congenital, can be caused by defects that interfere with the hypothalamic-pituitary-testicular axis. It is essential to distinguish between primary hypogonadism (which originates in the testes) and secondary hypogonadism (which originates in the hypothalamus or pituitary gland). Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, and reduced testicular volume. This activity reviews the evaluation and management of male hypogonadism and describes which patients are most likely to benefit from screening. This activity highlights the role of the interprofessional team in improving care for patients with male hypogonadism.

Objectives:

• Describe the etiology of male hypogonadism.
• Explain the pathophysiology of male hypogonadism.
• Review the evaluation of male hypogonadism.
• Describe interprofessional team strategies for improving care coordination and communication to patients with male hypogonadism.

Introduction

Nintey-five percent of the total testosterone in males is synthesized in the Leydig cells of the testis. Defects, whether acquired or congenital, that interefere with interactions in the hypothalamic-pituitary-testicular axis can cause male hypogonadism It is essential to distinguish between primary hypogonadism (which originates in the testes) and secondary hypogonadism (which originates in the hypothalamus or pituitary). Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, and reduced testicular volume. The normal range for early morning testosterone in a male is between 300 ng/dL to 1000 ng/dL[1]. Hypogonadism is diagnosed when the morning serum testosterone level is less than 300 ng/dL. However, clinical judgment can be exercised in the diagnosis of hypogonadism for patients with persistent symptoms of testosterone deficiency despite having testosterone levels are in the normal range [2]. Of note, total testosterone less than 405.9 ng/dL is below the fifth percentile[3]. Elderly males should aim for testosterone levels between 500 and 800 ng/dL while young adults should aim for testosterone levels between 600 and 900 ng/dL.

Etiology

Hypogonadism can be due to congenital or acquired causes. Ambiguous genitalia, micropenis, and bilateral cryptorchidism are all signs of testosterone deficiency in pre-pubertal males. Karyotype testing is done in young adults to rule out conditions such as Turner syndrome and Klinefelter syndrome which can result in testosterone deficiency. Some causes of primary hypogonadism include Klinefelter’s syndrome, undescended testicles, mumps orchitis, hemochromatosis, cancer treatment, and normal aging. Causes of secondary hypogonadism include Kallman syndrome, pituitary disorders, HIV, obesity, surgery, trauma, and stress-induced hypogonadism[4].

Epidemiology

Hypogonadism is often under-reported. According to some studies approximately 40% of men over the age of 45 and 50% of men in their 80s are hypogonadal[5][6]. Testosterone levels have been found to decrease by 100 ng/dL every ten years[7]. There appears to be no relationship between racial and ethnic groups with hypogonadism.

Pathophysiology

Testosterone production by testicular Leydig cells depends on stimulation from the anterior pituitary gland which secretes pulses of luteinizing hormone (LH) into the circulation. When LH binds to its receptors on Leydig cells, it causes cAMP levels to rise. Increased levels of cAMP drives the expression of two proteins: StAR (the steroidogenic acute regulatory protein) and CYP11A1 (the cholesterol sidechain clevage enzyme). StAR promotes the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane while CYP11A1 promotes the conversion of cholesterol to pregnenolone, the precursor of all steroid hormones. Pregnenolone can undergo 17 alpha-hydroxylation to 17 OH pregnenolone which is converted to DHEA, dehydroepiandrosterone[8]. DHEA is then converted into androstenediol in order to make testosterone.  Primary hypogonadism is when the testicular steroidogenesis is insufficient to synthesis adequate levels of testosterone while secondary hypogonadism is when signaling to the testis (either from the pituitary, through LH, or from the hypothalamus, through GnRH) is unable to stimulate sufficient Leydig cell testosterone production. 

History and Physical

Symptoms highly suggestive of androgen deficiency in men include reduced sexual desire, decreased spontaneous erections, loss of axillary and pubic hair, declining testicular volume, hot flashes, low or zero sperm count. Other less suggestive symptoms include depressed mood, poor concentration, increased body fat, decreased physical performance, reduced muscle mass.

Evaluation

Population screening is not recommended, but patients with either HIV, end-stage renal disease, type 2 diabetes, infertility, severe COPD, or osteoporosis should be screened[9]. The Androgen Deficiency in Aging Male (ADAM) test is the initial step in diagnosis; it consists of a 10-item questionnaire to identify men who exhibit signs of testosterone deficiency[10]. Initial laboratory testing should include two early morning (8 am-10 am) measurements of serum testosterone[11]. If both levels are reduced, further testing including FSH (follicle stimulating hormone), LH, prolactin, TSH (thyroid stimulating hormone), free T4 (thyroxine), vitamin D, complete blood count, comprehensive metabolic panel, iron, transferrin, and cortisol are indicated. It is also important to measure sex hormone binding globulin (SHBG) in order to calculate the bioavailable testosterone which can be affected by obesity, type 2 diabetes, hypothyroidism, and liver disease. 

Treatment / Management

There are several options for testosterone replacement including oral, buccal, transdermal (gel, patch, solution, pellet), and intramuscular injections (add reference: Surampudi, P. et al. An Update on Male Hypogonadism Therapy. Expert Opin Pharmacother 15(9):1247-1264, 2014). Among these transdermal gels and intramuscular injections are the most widely used in the US. Testosterone gels are generally recommended due to patient preference, cost, convenience, and insurance coverage. The primary advantage of gels is the maintenance of stable serum testosterone concentrations resulting in stable libido, energy, and mood. There are various commercial prescription testosterone gel products, in varying concentrations. Gels should be applied to shoulder, upper arms, or abdomen and shouldn't be applied to the scrotum. Miller and colleagues (9) showed that the bioavailability of testosterone gel is 30 percent lower when applied to the abdomen compared to the arms or shoulders[12]. It is generally recommended that intramuscular injections of testosterone with testosterone enanthate or testosterone cypionate be given 50 to 100mg doses every week or 100 to 200mg doses every two weeks. In 2014, the FDA approved an extra-long acting intramuscular injectable form of testosterone called testosterone undecanoate which is administered at an initial dose of 750mg followed by a second dose four weeks later with subsequent doses given at ten week intervals. Testosterone undecanoate is not used as a first-line agent but rather in patients that don’t have access to other forms of treatment. 

Contraindications to androgen replacement therapy include a history of breast cancer, prostate cancer, uncontrolled heart failure, untreated obstructive sleep apnea, a pre-treatment hematocrit (Hct) over 48%, palpable undiagnosed prostate nodules, an elevated prostate specific antigen (PSA) above 4ng/mL, or an elevated PSA level above 3ng/mL in high-risk patients including African Americans as well as men that have a first-degree relative with prostate cancer[9]. 

Monitoring:

Pretreatment: Hgb, Hct, DRE (digital rectal exam), PSA level, two early morning testosterone levels, consider DEXA scan

• One month after initiating treatment: morning testosterone level
• 3 to 6 months after from the start of therapy during the first year: morning testosterone level, liver function tests (LFTs), lipid profile, PSA, DRE, Hgb, Hct
• Annually after the first year: morning testosterone level, LFTs, lipid profile, DRE, PSA, estradiol, Hgb, and Hct.

Differential Diagnosis

Differential diagnoses include hyperprolactinemia, congenital adrenal hyperplasia, anorexia nervosa, androgen insensitivity syndrome, malnutrition, Turner syndrome, Klinefelter syndrome, and 5-alpha-reductase deficiency. Kallman syndrome should be ruled out in males complaining of anosmia or hyposmia. Pituitary gland masses need to be ruled out in patients complaining of visual disturbances.

Enhancing Healthcare Team Outcomes

It is important for nurses, physicians, and pharmacists to review the risks and benefits of therapy and to be aware of the contraindications to testosterone therapy. There are conflicting trials on the cardiovascular risks of testosterone, most notably the TOM (Testosterone in Older Men) trial and the TEAAM (Testosterone's Effects on Atherosclerosis Progression in Aging Men) trial.

Outcomes: The TOM trial found that the application of testosterone gel daily after six months was associated with an increased incidence of cardiovascular events[13]. The TOM trial used a sample size of 209 men with no monitoring of serum testosterone levels. Recently, the TEAAM trial published in 2015 followed 308 men over three years and found that testosterone administration resulted in no difference in cardiovascular risk[14]. A randomized, double-blind, placebo-controlled, parallel study found that testosterone undecanoate resulted in reduced fasting glucose, waist circumference, and improved carotid intima-media thickness and high sensitivity C-reactive protein after 12 weeks of treatment[15]. (Level V)