Primary Hypogonadism

Primary hypogonadism is a condition where the testes fail to produce enough testosterone or sperm, affecting male development, sexual function, and overall health at any stage of life.

Table of contents

• What is Primary Hypogonadism?
• Causes of Primary Hypogonadism
• Signs and Symptoms
• Diagnosis
• Treatment Options

What is Primary Hypogonadism?

Primary hypogonadism, also called hypergonadotropic hypogonadism, occurs when the sex glands in males—the testes—do not function properly.^[1] This condition results in the body not making enough of the male hormone testosterone (the hormone that helps develop male characteristics) or not producing enough sperm, or both.^[1] In this form of the condition, the problem lies directly in the testes themselves, not in the brain centers that normally control them.^[2]

The condition differs from secondary hypogonadism, where the issue originates in the hypothalamus or pituitary gland (parts of the brain that send signals to the testes).^[2] In primary hypogonadism, sperm production is typically more significantly affected than testosterone production because of extensive damage to the seminiferous tubules (the structures in the testes where sperm are made).^[17]

This disorder can be present from birth or develop later in life due to injury or infection.^[1] The effects and what can be done about them depend on the cause and at what point in life the condition develops.^[4]

• Testes
• Seminiferous tubules
• Leydig cells

Causes of Primary Hypogonadism

Primary hypogonadism can be either congenital (present from birth) or acquired later in life.^[3] Understanding the cause is important for determining the best treatment approach.

The most common form of congenital primary hypogonadism is Klinefelter syndrome, a genetic disorder that occurs when a male is born with an additional X chromosome.^[17] This condition is seen in approximately 1 in 1,000 male births.^[17] Men with this syndrome often have damage to the seminiferous tubules and Leydig cells (the cells that produce testosterone), resulting in decreased size of the testes as well as low sperm counts and testosterone levels.^[17] Another congenital cause is Turner syndrome, though this primarily affects females.^[3]

Acquired primary hypogonadism develops when a person is exposed to a substance, experiences trauma, or contracts a disease or infection that damages the testes.^[17] Common causes include certain autoimmune disorders, genetic and developmental disorders, infections, iron excess (hemochromatosis), liver and kidney disease, radiation exposure to the testes, surgery, and trauma.^[3]

Medications can also cause acquired primary hypogonadism. Common medication causes include glucocorticoids (steroid medicines), ketoconazole (an antifungal medicine), and alkylating agents used in cancer treatment, such as cyclophosphamide, chlorambucil, cisplatin, and busulfan.^[17]

Signs and Symptoms

The signs and symptoms of primary hypogonadism depend greatly on when the condition begins—during development in the womb, before puberty, or during adulthood.^[1]

During Fetal Development

If the body doesn’t produce enough testosterone while a baby is developing in the womb, it can affect the outer sex organs.^[4] Depending on when the condition starts and how much testosterone is present, a baby whose genes are male may be born with female genitals, genitals that are neither clearly male nor clearly female (called ambiguous genitals), or male genitals that don’t develop fully.^[1]

Before and During Puberty

Primary hypogonadism that occurs in the first 10 years of life can delay puberty or cause incomplete or lack of usual development.^[1] It can interfere with muscle mass growth, the voice getting deeper, growth of body and facial hair, and growth of the penis and testicles.^[1] Boys with this condition may experience excessive growth of the arms and legs in relation to the trunk of the body and development of breast tissue, called gynecomastia.^[1] Children with primary hypogonadism do not progress through puberty normally, and girls don’t menstruate or develop breasts, while overall growth is slowed.^[6]

In Adulthood

In adults, primary hypogonadism can change certain physical traits and affect the ability to have children.^[1] Early symptoms might include less sex drive, less energy, and depression.^[1] Over time, men with primary hypogonadism can develop difficulty getting and keeping an erection (called erectile dysfunction), problems having children (called infertility), less hair growth on the face and body, decrease in muscle mass, development of breast tissue, and loss of bone mass (osteoporosis).^[1]

Other symptoms that may occur include depressed mood, difficulties with concentration and memory, increased body fat, decreased motivation, hot flashes, and shrinking testicles.^[7] Severe primary hypogonadism can also cause mental and emotional changes similar to those of menopause in women.^[4]

Diagnosis

Finding primary hypogonadism early can help prevent problems from delayed puberty in children and protect against osteoporosis and other conditions in adults.^[9] Diagnosis requires both the presence of low blood testosterone levels and the presence of symptoms consistent with low testosterone.^[2]

A healthcare provider will perform a physical exam and look at sexual development to see if pubic hair, muscle mass, and the size of the testes are typical for the patient’s age.^[9] Blood tests are used to measure testosterone levels. Testosterone levels are typically highest in the morning, so blood testing is usually done between 8 and 10 a.m.^[9] The test is typically done on more than one day to confirm low testosterone.^[9]

The American Urology Association considers low blood testosterone to be less than 300 nanograms per deciliter (ng/dL) for adults, though some researchers feel that levels below 250 ng/dL are low.^[7] Hypogonadism is usually diagnosed when the morning serum testosterone level is less than 300 ng/dL on at least two occasions.^[2]

If tests show low testosterone, further testing can help determine if it is primary or secondary hypogonadism. These studies might include measuring luteinizing hormone (LH) levels.^[14] In primary hypogonadism, LH levels are typically greater than 10 ng/mL, indicating that the brain is trying to stimulate the testes but the testes are not responding properly.^[14] Additional tests may include semen analysis, pituitary imaging, and gene studies.^[9]

Treatment Options

Patients with primary hypogonadism are typically treated with sex hormone replacement.^[10] The goals of treatment are to promote the development of and maintain secondary sexual characteristics and normal sexual function, to build and sustain normal bone and muscle mass, and to assist in the proper adjustment of individuals with the condition.^[10]

Testosterone Replacement Therapy

Testosterone replacement can raise testosterone levels and help ease the symptoms of primary hypogonadism, including less desire for sex, less energy, less facial and body hair, and loss of muscle mass and bone mass.^[9] Studies suggest that testosterone replacement therapy may improve sexual function, depressive symptoms, bone density, and lean body mass.^[15]

There are several different ways to receive testosterone replacement therapy. Testosterone taken by mouth is not often used because it can cause serious liver problems and doesn’t keep testosterone levels even.^[9] The U.S. Food and Drug Administration has approved one oral testosterone replacement that is absorbed by the lymph system and might not cause liver problems.^[9]

Available forms of testosterone therapy include intramuscular injections (shots given into the muscle), transdermal patches (patches worn on the skin), transdermal gels (gels applied to the skin), buccal patches (patches applied to the upper gum), and subcutaneous pellets (small pellets placed under the skin).^[11] The method of treatment should take into consideration patient preference, how the medication works in the body, potential for medication interactions, side effects specific to each form, treatment burden, and cost.^[15]

A typical regimen for boys starting puberty involves testosterone injections starting at 50 mg monthly, gradually increasing to 200-250 mg every 2 weeks, which is a typical adult replacement dose.^[10] Adult testosterone doses can be adjusted to maintain testosterone concentrations in the normal adult range.^[10]

Monitoring During Treatment

Anyone taking testosterone replacement should have a medical checkup and blood tests several times during the first year of treatment and yearly after that.^[9] This is to see how well the treatment works and to watch for side effects. Healthcare providers should monitor patients for symptom improvement, potential adverse effects, and adherence to treatment.^[15] Blood testosterone, hematocrit (the percentage of red blood cells in the blood), and prostate-specific antigen levels should be measured at baseline and at least annually in men 40 years or older receiving testosterone replacement therapy.^[15]

Fertility Considerations

In patients with primary hypogonadism caused by damage to the testes, fertility is generally not possible.^[10] Testosterone replacement therapy does not restore fertility or stimulate testicular growth in men with this condition.^[10] However, men with secondary hypogonadism may have fertility potential with different treatments.^[10]

Potential Side Effects

Potential side effects of testosterone replacement include erythrocytosis (too many red blood cells), increases in prostate-specific antigen and worsening of prostate disorders, skin effects including acne and skin irritation, and worsening of existing obstructive sleep apnea.^[11] Additionally, testosterone administration leads to the suppression of sperm production.^[11]