Male hypogonadism occurs when the body fails to produce an adequate amount of the sex hormone testosterone. Patients can be born with hypogonadism, or it can develop later in life. The effects and treatment options for hypogonadism depend on the cause and the point in life when it occurs. Testosterone is naturally much higher in people assigned males at birth than in people assigned females at birth.
Testosterone is mainly produced by the Leydig cells of the testes, although the adrenal glands also make small quantities. In addition, your adrenal glands produce dehydroepiandrosterone (DHEA), which the body transforms into testosterone or estrogen.
Studies show that age-specific testosterone levels in men have been slowly declining for several decades. This decline appears to be related to the overall worse health status of men due to increased rates of obesity, decreased physical activity, poor nutrition, and increased environmental toxins.
The level of testosterone changes throughout a man's life based on age and the body's needs. Testosterone levels usually decrease by about 1% annually, beginning around age 30. However, hypogonadism occurs when testosterone levels become too low.
Causes of Hypogonadism
Hypogonadism is defined as testosterone deficiency plus associated symptoms. The cause of hypogonadism can be either primary (testes) or secondary (problem with the pituitary or hypothalamus in the brain). In primary hypogonadism, the testes do not function properly. Causes of primary hypogonadism include:
- Genetic and developmental disorders
- Infection
- Iron excess
- Liver and kidney disease
- Radiation to the testes
- Surgery
- Trauma
- Certain autoimmune disorders
Secondary hypogonadism occurs when the pituitary gland or hypothalamus fails to properly signal the testes to produce testosterone. Causes of secondary hypogonadism include:
- Taking medicines, such as glucocorticoids and opiates
- Genetic problems
- Infections
- Nutritional deficiencies
- Iron excess
- Radiation to the pituitary or hypothalamus
- Surgery
- Trauma
- Tumors
- Anorexia nervosa
Effects of Hypogonadism and Potential Treatments Depend on Patient Age
Fetal Development
Around week seven of embryonic development, the sex-related gene on the Y chromosome initiates testicular development in male infants. The testicles then begin producing testosterone, which triggers the development of internal and external reproductive organs. If the body does not produce enough testosterone during fetal development, there may be impaired growth of the external sex organs. When there is insufficient testosterone, a genetically male child may have female genitals, ambiguous genitals, or underdeveloped male genitals.
Fetal exposure to testosterone can have long-lasting effects on human behavior. For example, higher fetal testosterone exposure leads to males who compete more aggressively regardless of their counterpart's level of aggressiveness. Research in this area is ongoing.
Puberty
At puberty, the testes increase testosterone production. During the teen years, testosterone helps boys develop male features such as body and facial hair, a deeper voice, increased sex drive, and muscle size and strength. In addition, testosterone stimulates sperm production and increases height and the size of the penis, testes, and prostate gland. Ejaculation becomes possible in mid-adolescence, and fertility is attained later in adolescence.
Depending on the timing, hypogonadism can delay or interrupt puberty or cause incomplete or lack of normal development. In addition, it can cause the development of breast tissue or excessive growth of the arms and legs in relation to the trunk.
Adulthood
Hypogonadism in adulthood can alter certain masculine physical characteristics and impair normal reproductive function. Early signs and symptoms of adult hypogonadism include decreased sex drive, decreased energy, and depression.
Later symptoms of adult hypogonadism may include erectile dysfunction, decreased muscle mass, breast tissue development, and osteoporosis. Severe hypogonadism can cause mental and emotional changes, difficulty concentrating, and hot flashes.
During adulthood, testosterone is essential for the production of sperm. In addition, testosterone signals your body to make red blood cells, ensures your bones and muscles stay strong, and enhances sex drive and a sense of well-being.
Hypogonadism is more prevalent in obese men, older men, and men with type 2 diabetes. An estimated 35% of men older than 45 and 30–50% of men with type 2 diabetes or obesity have hypogonadism. Signs and symptoms of low testosterone in adults include:
- Reduced sex drive
- Erectile dysfunction (fewer and weaker erections)
- Lowered sperm count and infertility
- Breast enlargement and tenderness
- Depressed mood
- Increased irritability, inability to concentrate
- Less muscle and decreased strength
- Increased body fat
- Anemia (low iron)
- Loss of bone strength
Testosterone Testing and Ranges
A total testosterone test (most common) measures free and testosterone attached to proteins. The American Urological Association considers 450–600 ng/dL a normal testosterone range. A 2017 study of over 9,000 men found that the total testosterone range for males aged 19 to 39 is 264–916 ng/dL. The normal range in most laboratories is 300 –800 ng/dL.
Free testosterone is unbound, not attached to other molecules. Since it is not linked to sex hormone-binding globulin (SHBG) or albumin, free testosterone enters the body's cells unimpeded. In addition, free testosterone functions as a signaling molecule that regulates metabolism and other cellular processes.
Free testosterone is a valuable measurement when SHBG levels are low, causing total testosterone to decrease as well. Free testosterone would provide more accurate information regarding testosterone levels in this scenario. In addition, total testosterone may tell you your body's androgen hormone production isn't properly functioning, but free testosterone levels can help pinpoint possible causes of hypogonadal symptoms.
Testosterone Treatment and Therapies
The treatment for hypogonadism is testosterone replacement therapy (TRT). While TRT is the treatment of choice, potential reversible causes of hypogonadism, such as obesity, should be addressed first. Testosterone therapy aims to improve symptoms associated with testosterone deficiency and maintain sex characteristics. The target range for total testosterone in men is 450 ng/dL to 600 ng/dL. Routine monitoring of testosterone levels should occur every 6 to 12 months.
Testosterone therapy is available in multiple forms, including:
- Oral capsules
- Topical gels and solutions
- Transdermal patch
- Intranasal gel
- Injectable
- Implantable pellets
Each available form of testosterone therapy has strengths and weaknesses. For example, topical forms of testosterone are easy to use; however, they present a risk of transference to non-patients. Injectable delivery has extended dosing periods and reliable physiologic effects but is not an option for patients averse to needles. New oral capsule formulations report many advantages and are equally effective as other delivery modes.
Absolute contraindications to TRT include:
- Breast cancer
- Polycythemia (increased red blood cells)
- Prostate cancer
- Prostate-specific antigen (PSA) > 4 ng/mL
- Nodules upon digital rectal examination
Side effects of TRT may include snoring, benign prostatic hyperplasia, mood changes, acne, blood clots, breast enlargement, and polycythemia (increased number of red blood cells).
Polycythemia while on TRT is an independent risk factor for major adverse cardiovascular events and stroke if the patient's hematocrit (the proportion of red blood cells in the blood) reaches or exceeds 52% during the first year of TRT. The polycythemia risk increases with longer-acting testosterone modalities, such as injectables. Patients being treated with testosterone should have their hematocrit and hemoglobin levels monitored regularly.
Landmark Testosterone Studies
A large study of more than 9,000 men was used to establish harmonized total testosterone reference ranges in men, enabling clinicians to make correct hypogonadism diagnoses. Researchers obtained testosterone samples from men who had already had their testosterone analyzed. The samples were then measured using a higher-order sophisticated measuring technique. Age-specific testosterone reference ranges were then calculated. For example, the harmonized normal range for testosterone in a non-obese population of men 19-39 years is 264–916 ng/dL.
A recent landmark study found that TRT did not result in a higher incidence of major adverse cardiac events in middle-aged and older men with hypogonadism. The study enrolled 5,246 men aged 45 to 80 with either preexisting or high risk of cardiovascular disease. Patients received either 1.62% testosterone gel daily or a placebo gel through the skin.
A 2018 study of almost 150,000 men > 40 with low testosterone found that TRT was not associated with an increased risk for prostate cancer. No association was found between testosterone's cumulative dose or formulation and prostate cancer.
The Testosterone Trials consisted of seven coordinated studies in 788 men with an average age of 72. The trials aimed to determine the effectiveness of increasing testosterone levels in older men with low testosterone levels. For example, researchers learned that TRT increased the median testosterone level from a deficient level at baseline to normal for young men after three months of treatment and maintained that level for at least one year. The studies also provided information on TRT's effect on sexual activity and function, mood and depressive symptoms, bone mineral density, and more.
