Male Hypogonadism- Low Testosterone: Treatment Choices

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Male hypogonadism: therapeutic choices and pharmacological management
Sandro LA VIGNERA, Giulia IZZO, Gian P. EMERENZIANI, Rossella CANNARELLA , Rosita A. CONDORELLI, Aldo E. CALOGERO, Antonio AVERSA


ABSTRACT

Male hypogonadism, defined as an inadequate testosterone production, recognizes a testicular (primary hypogonadism) or a hypothalamic-pituitary dysfunction (central hypogonadism), although combined forms can also occur. Moreover, it has been known that intensive exercise training might be a cause of functional hypogonadism. Many therapeutic choices are currently available, depending on the timing of hypogonadism onset and fertility issues. The aim of this review was to comprehensively supply therapeutic options and schemes currently available for male hypogonadism, including pharmacological management of primary and central forms. Evidence on testosterone formulations, human chorionic gonadotropin, selective estrogen receptor modulators, and aromatase inhibitors will be provided.

Male hypogonadism is a clinical syndrome characterized by failure of the testes to produce an adequate amount of testosterone (T) and/or a normal number of spermatozoa. It can be classified according to the site of hypothalamic-pituitary dysfunction, the involvement of testicular cell population, and the time of its onset. Also, hypogonadism can be organic or dysfunctional. The former is caused by congenital, structural or destructive disorders, whereas the latter refers to potentially reversible conditions.1 Hypogonadism is further classified into primary or central forms, based on the presence of a dysfunction at the testicular or the hypothalamic-pituitary level.1, 2 Combined hypogonadism is characterized by low serum T levels and/ or impaired spermatogenesis, with gonadotropin levels which vary depending on whether primary or secondary hypogonadism predominates. Late-onset hypogonadism (LOH) is an example of combined hypogonadism. It is a clinical and biochemical syndrome associated with advancing age characterized by symptoms indicative of androgen deficiency and a decline in serum T levels. Accordingly, several cross-sectional and longitudinal studies have shown a gradual decline in T levels with increasing age, at an average rate of 1-2% per year,3, 4 which varies among men on the basis of the presence of adiposity, pharmacological therapies, and chronic diseases. Among a cohort of 3219 participants from Europe aged 40-79 years, LOH was identified in 2.1%, whereas 17% has shown isolated T deficiency (total T<11 nmol/L [317 ng/dL]).3, 4 Finally, a new classification of hypogonadism has been proposed by using data from the European Male Ageing Study (EMAS), which presents the issue of “compensated hypogonadism,” a further clinical subgroup characterized by normal total T levels combined with higher LH values, especially in the aging population. This category of patients may develop infertility since their testicular dysfunction carries on an increased risk of low total motile sperm count, low testicular volume, and azoospermia.5

Diagnosis of male hypogonadism is established when the presence of specific symptoms and signs are associated with decreased serum T levels. So far 12.1 nmol/L (350 ng/dL or 3.5 ng/ mL) is considered the lower limit of the normal range for total T level.6 However, due to individual differences in T sensitivity, some men may exhibit symptoms of hypogonadism with total T concentrations above this threshold.6


Evidence strongly supports that low T is an important biomarker for morbidity and mortality in men. It is now clear that low T levels correlate significantly with certain conditions, such as age, obesity, poor general health, and with some diseases, such as metabolic syndrome and cardiovascular disease (CVD).7 Epidemiological studies identified T deficiency as a risk factor for CVD.8 Low levels of T may have important long-term negative health consequences, such as premature death, in presence of CVD, due to high rate of myocardial infarction, ischemic stroke, and other adverse cardiovascular events. It seems that patients with low T have a 24-124% increased risk for all-cause mortality during an average 4 to 16-year follow-up period.9, 10 Moreover, low T is significantly associated with respiratory mortality and to cancer mortality.10, 11 Lastly, normal serum T levels favor glycemic homeostasis through a better glucose uptake, utilization and disposal, and the general improvement of metabolism. For this reason, T deficiency favors hyperglycemia which, in addition to being the hallmark of diabetes mellitus, is an important component of the metabolic syndrome and increases the risk of CVD.12 T deficiency has also been shown to alter the lipid profile and to change, by causing insulin-resistance, body composition favoring the accumulation of visceral fat.13

Complications of untreated hypogonadism include worsening of sexual symptoms, bone damage, systemic symptoms, and long-term metabolic complications. This strongly highlights the importance of proper pharmacological treatment of male hypogonadism. Therefore, the aim of this review is to provide a comprehensive and updated overview of the available therapeutic options for male hypogonadism, including T, human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and their management.


Treatment of primary hypogonadism: Testosterone formulations

Oral administration

Buccal administration

Nasal administration

Subdermal administration


Transdermal testosterone
Transdermal patch
Transdermal gel/liquid solution


Intramuscular administration


Treatment of central hypogonadism

hCG
SERMs
AIs


Treatment of prepubertal male hypogonadism: the induction of puberty

Follow-up

Follow-up of primary hypogonadism

Management of central hypogonadism treatment

Exercise-related hypogonadism

Anabolic-androgenic steroids use

Treatment of the exercise-related hypogonadism


Conclusions

In conclusion, several therapeutic schemes are available for the treatment of male hypogonadism, whose choice depends on the timing of disease onset and fertility issues.
Exercise-related hypogonadism is still a controversial occurrence and it is unclear if a clinical intervention is warranted (or desired) since it is considered an adaptive condition with no reported negative health consequences. Timing of follow-up, including the assessment of serum T levels and markers of safety, depending on the drug pharmacokinetics.
 

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hCG

hCG is a glycoprotein produced by placental trophoblastic cells starting from the 10th-12th embryonic day, and it is required for the maintenance of the fetus in the first trimester. The β-subunit of hCG shares with that of LH 82% amino acid homology.31 On this basis, hCG extracted from the urine of pregnant women or produced in vitro using recombinant DNA technology is currently used for the treatment of central hypogonadism.32 It enhances T synthesis by stimulating Leydig cell function. hCG, administered by IM or subcutaneous injection, has a biological halflife of 8 hours. On the other hand, due to the above-mentioned chemical differences with LH, the latter has a half-life of only 30 minutes and, therefore, it is not used in clinical practice. Doses of hCG ranging from 2000 IU twice/week in patients with LOH33 to 1500-2000 IU three times/week in patients with central hypogonadism34, 35 have been successfully used to raise T levels for up to 24 months.35 One of the advantages of hCG administration is the increase of intra-tubular T levels, which, on the opposite, are suppressed in patients on TRT. The raise of intra-tubular T levels is better accomplished using low-dose schemes (125 IU every other day)36 and it is crucial to sustaining spermatogenesis. However, hCG at high doses has been also found compatible with the achievement of spontaneous pregnancy.35 Indeed, among 20 patients with central hypogonadism treated with 1500-2000 IU three times a week, 10 searched paternities and 7 of them achieved it naturally.35 Accordingly, hCG has been shown to stimulate the recovery of spermatogenesis in patients with central hypogonadism who have been treated with TRT.37 Treatment with hCG has been also observed to increase vitamin D levels. However, this topic requires further investigation since only few evidence is available so far.33, 38, 39
 

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*hCG, administered by IM or subcutaneous injection, has a biological halflife of 8 hours.

*CC has a half-life of 5 days and is mainly eliminated through feces

*Tamoxifen has a half-life of 7 days and is removed by the gallbladder

*Anastrozole and letrozole, both showing a half-life of 48 hours
 
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