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Treatment of Male Hypogonadism

US Endocrinology, 2007;(1):83-8 DOI: http://doi.org/10.17925/USE.2007.00.1.88

Abstract:

Physiology
Androgens are responsible for the development and maintenance of secondary sexual characteristics, fertility, and anabolic effects of somatic tissues (lean body mass) in men.1,2 The primary androgen in circulation is testosterone. Production and secretion of testosterone is under the tonic control of leutinizing hormone (LH). LH and follicle-stimulating hormone (FSH) are secreted by the anterior pituitary and regulated by the pulsatile action of gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus. FSH, with the effects of testosterone, is responsible for spermatogenesis. Testosterone secretion is episodic and follows a distinct diurnal rhythm,1,2 with testosterone levels maximal in the morning and minimal in the evening.

Hypogonadism
Hypogonadism refers to deficiency of testosterone and spermatogenesis. Primary testicular failure is referred to as hypergonadotropic hypogonadism, where the testosterone levels are low and gonadotropins are appropriately elevated. Secondary or tertiary (hypogonadotropic) hypogonadism results from reduced secretion of gonadotropins (GnRH deficiency), and the LH and FSH levels are inappropriately low or normal with low testosterone levels. Differential diagnoses for hypogonadism are listed (see Tables 1 and 2). The clinical characteristics of testosterone deficiency are summarized in Table 3.3,4

Diagnostic Evaluation
Measurement of 08:00h serum total testosterone levels29 is an initial test used to diagnose hypogonadism. The measurement of total testosterone can be altered in conditions that affect the levels of sex-hormone-binding globulin (SHBG): obesity, nephrotic syndrome, glucocorticoids, aging, cirrhosis, anti-convulsant use, and others.4 In these conditions measurement of free or bioavailable testosterone may be helpful. Testosterone levels are affected by illness, and a diagnosis should not be made during acute illness.3 FSH and LH levels help to distinguish between primary and secondary hypogonadism. Further work to elucidate the causes of primary and secondary hypogonadism should be pursued (karyotype, prolactin levels, iron profile, other pituitary hormones, and magnetic resonance imaging (MRI) of the pituitary if indicated).

Goals of Treatment
Testosterone replacement should be given in doses sufficient to approach normal physiological serum concentrations of testosterone and its active metabolites and to avoid adverse effects on the prostate, serum lipids, cardiovascular system, liver, and lung function.5

Indications for Treatment

  • Low serum testosterone concentration, plus signs and symptoms of hypogonadism.
  • Low bone mineral density with hypogonadism.
  • Indications may also include increasing lean body mass and decreasing fat mass and improving energy and mood.

Evidence of Beneficial Effects of Testosterone Replacement Therapy

  • Improved libido and erectile function: Testosterone replacement has been shown to improve libido, frequency of sexual activity, and erectile dysfunction.6
  • Improved mood: It has also been associated with improved mood, energy, and verbal fluency.7,8
  • Changes in body composition: Testosterone replacement therapy has been associated with increased lean body mass, decreased body fat,9 increase in muscle mass,10 increased fat free mass, and decreased fat mass.11–20
  • Increase in muscle strength: Bhasin et al.26 found that T supplementation for 16 weeks in 61 hypogonadal, HIV-infected men aged 18–50 years resulted in increases in muscle volume and strength, whether accompanied by resistance training or not. However, a recent study suggested that replacing testosterone, dehydroepiandrosterone (DHEA), or dehydroepiandrosterone sulfate (DHEA-S) in men with baseline mid to high normal levels has little benefit on physical performance and potentially increases risk of side effects.25
  • Increase in bone mineral density (BMD) but no data on fracture risk: Testosterone replacement has been associated with improvement of trabecular and cortical bone density of the spine in younger and older hypogonadal men.29
  • Cardiovascular effects: A recent meta-analysis concluded that there is weak evidence to suggest that testosterone use in men with baseline low testosterone levels is not associated with important cardiovascular effects.28

Testosterone Replacement
Daily output of testosterone is about 4–7mg, with the concentrations being higher in the morning and lower in the evening22 (see Table 4). There are a variety of formulations on the market, listed below.

Oral Preparations
The first orally active, synthesized derivative of T was 17-á-methyl-T. Blood levels peak at 1.5–2 hours and serum half-life is about 150 minutes, indicating the need for several daily doses to maintain therapeutic levels. Side effects include cholestasis, peliosis, elevation of liver enzymes, and reduction of high-density lipoprotein-cholesterol.5 Fluoxymesterone is a 17- alpha-methyl testosterone steroid with fluorine in the 9-position and is longer acting than its parent steroid, but is limited by hepatotoxicity.5 Mesterolone is derived from 5-alpha-dihydrotestosterone with a methyl group in the 1-position. It is not hepatotoxic, but relatively large doses must be taken several times a day and dosing is difficult to monitor. Testosterone undecanoate is an esterified form of testosterone, which is absorbed by lymphatics, by-passing the portal system. Serum testosterone levels tend to vary within the same individual. An advantage is oral administration, but it is not yet available in the US.

Intramuscular Preparations
Two widely used formulations of testosterone esters are testosterone cypionate and enanthate. Testosterone esters lengthen the retention and duration of activity of the drug. Commonly used regimens are administration of 200mg of testosterone enanthate or cypionate once every two weeks intramuscular (IM) or 100mg weekly. Serum testosterone concentrations are supranormal initially and decline to the lower range of normal by the end of two weeks. The advantages of this formulation are that they are inexpensive (if self-administered) and allow flexibility of dosing. The disadvantages are that it is an IM injection and symptoms of energy and libido may vary depending on the serum levels of testosterone. A testosterone undecanoate injection, when given in doses of 1000mg IM, maintains normal testosterone levels in the majority of patients.3 It requires infrequent administration but a large volume (4ml) in each injection.

Transdermal Preparations Trans-scrotal Testosterone
Scrotal patches deliver approximately 4–6 mg of testosterone daily.30 Normal androgen concentrations were achieved in 80% of hypogonadal men.5 Dihydrotestosterone (DHT) levels are elevated and scrotal shaving is necessary for optimal adherence of the patch.

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