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Testosterone is a naturally occurring androgenic-anabolic steroid that is produced in the Leydig cells of the gonads. The preoptic area and the medial basal region of the hypothalamus monitor testosterone levels and secrete gonadotropin-releasing hormone (GnRH) in a pulsatile manner to the pituitary gland.

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The periodicity and amplitude of GnRH secretion determine the pattern of secretion of the gonadotrophins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from the gonadotroph cells of the anterior pituitary.1 In particular, LH controls testosterone production and FSH controls sperm production.

Only 1% to 2% of testosterone circulates freely in the blood; the remaining 98% to 99% is bound to albumin (40%–50%) and to sex hormone-binding globulin (SHBG) (50%–60%). Testosterone binds strongly to SHBG; therefore, it is largely the free and albumin-bound testosterone that is available for biologic action.2

As men age, there is a rise in FSH and LH and a decline in testosterone, assuming normal operation of the feedback pathway by which low testosterone level signals the hypothalamic-pituitary axis to release FSH and LH. This natural aging process is what affects a man’s total testosterone levels over time.3

Testosterone controls sexual differentiation (stabilization of the Wolfian ducts) and is active on skeletal muscle, libido, and sexual function.

Primary hypogonadism

Primary hypogonadism (hypergonadotropic hypogonadism) is a term used to refer to the decrease in testosterone and sperm production. Sperm is made in the seminiferous tubules affected by FSH secretion. FSH regulates spermatogenesis in the basal aspect of the plasma membrane of Sertoli cells in the testis.

If testosterone production is low, secondary to dysfunction of the Leydig cells in the testes, this condition is called primary hypogonadism. The diagnosis of primary hypogonadism is made by testing total serum testosterone concentration; testosterone will be below normal, and the serum LH and FSH concentrations typically will be above normal.

Secondary hypogondism

Secondary hypogonadism (hypogonadotropic hypogonadism) is caused by low testosterone levels secondary to insufficient stimulation of the Leydig cells by LH. In a man with secondary hypogonadism, the serum testosterone concentration and the sperm count are subnormal, and the serum LH and FSH concentrations are normal or reduced.

Secondary hypogonadism is usually caused by hypothalamic and pituitary disorders or lesions; hyperprolactinemia; or Kallmann syndrome, which leads to a GnRH deficiency.4

Causes of low testosterone

The primary cause of decreased testosterone production is a natural decline in rate of production. In the third decade of life, men start losing about 1% of testosterone production per year, unless there is disease of the hypothalamic-pituitary-testicular axis. It has been suggested, but not proven, that neuronal GnRH outflow in healthy men is reduced by 33% to 50% between the second and eighth decades of life.

Feedback from testosterone induces a slowing of the hypothalamic pulse generator and a subsequent reduction in the frequency of the LH pulsatile release. LH binds to the LH receptor on the plasma membrane of Leydig cells in the testes, resulting in the synthesis of the enzymes of testosterone.

An increase in stress can have a direct effect on the testes and stimulate the release of glucocorticoids, which can suppress testosterone levels. Obesity, tobacco and alcohol use, obstructive sleep apnea, diabetes, chromosomal abnormalities, HIV/AIDS, disease, and illness can all affect a man’s testosterone levels.

Low testosterone can also be caused by Klinefelter syndrome and other chromosomal abnormalities, mutation in the FSH and LH receptor genes, cryptorchidism, variocele, mytonic dystrophy and disorders of androgen synthesis.

Some medications may cause a decrease in serum testosterone as well, including suramin (Germanin), ketoconazole (Nizoral), glucocorticoids and alkylating agents. Chronic opioid use is a common cause of low testosterone and will be discussed in detail later in this report.

The symptom most associated with hypogonadism is low libido. Other common signs include fatigue, decreased muscle mass, erectile dysfunction, and weight gain (Table 1).5

Table 1. Signs and symptoms of low testosterone

Reduced libido Erectile dysfunction
Decreased muscle mass Decline in mental function
Fatigue Loss of bone mineral densit
Insulin resistance Moodiness/irritability
Increased body fat Metabolic syndrome
Hair loss Atherosclerosis
Breast discomfort/gynecomastia Hot flushes
Sleep disturbance Decreased vitality