Primary Hypogonadism: What Is It and What Can Be Done?

Hypogonadism occurs when you have low levels of sex hormones (testosterone in males) due to the underproduction by the gonads (testes in males). Men with hypogonadism have lower-than-normal amounts of testosterone in their bodies.

Primary hypogonadism specifically refers to low testosterone levels caused by the underproduction of the hormone by your testes, as opposed to secondary or tertiary hypogonadism, which are caused by problems with your pituitary gland or hypothalamus, respectively.

Primary hypogonadism can develop due to genetic conditions or other conditions that develop later in life, such as some infections or testicular injuries.

Testosterone is the main androgen (male) sex hormone. And low levels can cause many problems in your body.

Signs and symptoms of hypogonadism in adult men may include:

• Fewer spontaneous or morning erections

• Persistent fatigue

• Low sex drive

• Increased body fat

• Noticeably smaller testicles

• Difficulty achieving or maintaining an erection

• Thinning or loss of pubic hair and body hair

• Decreased muscle mass or difficulty gaining muscle

• Reduced ability to exercise for long durations

• Loss of muscle strength

• Hot flashes

• Depression

• Mood swings or irritability

• Trouble focusing or poor mental clarity

• Reduced appetite

• Swelling or enlargement of breast tissue (gynecomastia)

• Low red blood cell count (anemia)

In children and adolescents, primary hypogonadism can cause problems with development, such as:

• Micropenis

• Genitals that don’t appear clearly male or female

• Undescended testicles

• Delayed puberty

Low testosterone is also associated with an increased risk of osteoporosis. Some people have both low testosterone and metabolic or cardiovascular conditions, such as diabetes and heart problems, due to overlapping risk factors.

Three glands work together to ensure that your testosterone levels stay within a normal range. Collectively, these glands and their respective hormones are known as the hypothalamic–pituitary–gonadal axis. Here’s how they work together:

• A gland in your brain called the hypothalamus produces gonadotropin-releasing hormone (GnRH).

• This hormone stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from your pituitary gland.

• The hormone FSH stimulates your testicles to produce sperm, while LH stimulates the release of testosterone from special cells in your testicles called Leydig cells.

Hypogonadism can occur due to problems in any step of this chain. It’s named based on where in this chain the problem leading to low testosterone occurs:

• Primary hypogonadism develops when GnRH and LH production are normal, but testicular dysfunction leads to the underproduction of testosterone in response to LH.

• Secondary hypogonadism develops when low testosterone originates from problems with the release of LH and FSH.

• Tertiary hypogonadism develops when low testosterone develops due to a problem with GnRH levels. It’s also sometimes referred to as secondary hypogonadism.

Any condition that damages cells in your testicles may lead to primary hypogonadism.

The following are some of the specific causes of primary hypogonadism.

Congenital or Genetic Conditions

Many congenital or genetic conditions can lead to primary hypogonadism. Some of the most common examples include:

• Klinefelter syndrome. Klinefelter syndrome, or 47,XXY karyotype, is among the most common genetic causes of primary hypogonadism. Most males have an X and a Y sex chromosome, but males with Klinefelter syndrome have an extra X chromosome.

• Cryptorchidism. Undescended testicles are one of the most common genital problems in newborns. They often correct themselves without treatment but may need surgery. There’s evidence that cryptorchidism is associated with hypogonadism later in life.

• Anorchia or testicular agenesis. Anorchia is the complete absence of testicular tissue, and testicular agenesis is incomplete development. The adrenal glands produce weak androgens, but not enough to maintain normal male testosterone levels. People with these conditions may have drastically lower than normal testosterone levels.

• Enzyme defects in testosterone synthesis. Enzyme defects in testosterone synthesis are a group of conditions that cause an impairment in the enzymes that allow your testicles to produce testosterone.

Acquired and Other Causes

Other causes of primary hypogonadism include:

• Orchitis. Orchitis is a testicular infection. Mumps orchitis is the most common type of testicular infection.

• Testicular trauma or testicular torsion. Testicular torsion is when the spermatic cord twists around itself and cuts off a testicle’s blood supply. Any loss of blood supply or trauma to your testicles can impair their ability to make testosterone.

• Radiation therapy. Radiation therapy can damage cells in your testicles and impair testosterone production. This may occur if you receive high dosages of pelvic radiation to treat cancer.

• Toxic exposures. Exposure to heavy metals, some medications, and some chemicals can potentially affect testosterone production. For example, many chemotherapy medications have the potential to reduce serum testosterone levels (levels of testosterone in your blood).

• Chronic illnesses. Some conditions, like severe chronic kidney disease, can lead to reduced testosterone levels. Underlying medical conditions may contribute to primary or other forms of hypogonadism.

• Testicular cancer. Testicular cancer itself can impair your testosterone levels. The most common treatment for testicular cancer is the removal of a testicle. If both testicles are removed, you may need medications to maintain testosterone levels.

• Idiopathic primary testicular failure. If no clear cause can be identified, your doctor may tell you that you have idiopathic testicular failure, meaning the cause of your low testosterone isn’t clear.

Secondary Hypogonadism Causes

As mentioned above, secondary hypogonadism is caused by problems with the pituitary gland that lead to low LH levels. Some potential causes include:

• Kallmann syndrome

• Pituitary tumors such as hyperprolactinemia, which often aren’t cancerous

• Pituitary surgery complications

• Radiation therapy to your head or neck

Learn more about secondary hypogonism.

Anybody can develop hypogonadism, but some people may be at a higher risk due to factors such as:

• Personal history of undescended testes

• Genetic conditions such as Klinefelter syndrome

• History of mumps orchitis or other testicular infections

• Being unvaccinated for mumps

• History of testicular injury or trauma

• Exposure to radiation, especially to the pelvis

• Older age, as male hypogonadism becomes more common with age

• Heavy alcohol use or liver disease

• Chronic kidney disease

• Taking certain medications associated with testicular damage

• Anabolic steroid use

A diagnosis of male hypogonadism usually starts by visiting your primary healthcare provider or a specialist in endocrinology. They will:

• Consider your symptoms

• Perform a physical exam to look for abnormalities with your testicles or scrotum, as well as complications of low testosterone

• Review your medical history

If your doctor suspects you may have low testosterone, the next step will likely be to measure your hormone levels with a blood test. Typically, healthcare providers measure total T on two separate mornings.

We offer at-home testosterone testing kits where you can measure your testosterone and LH levels and have them analyzed by a licensed professional without going to a clinic in person. If your testosterone levels are low, you can talk to a medical professional through our telehealth service. You’ll go through a medical evaluation to identify the cause and talk through considering testosterone therapy.

Your doctor will likely also want to measure your LH and FSH levels to differentiate primary from secondary hypogonadism.

In people with primary hypogonadism, LH and FSH are typically elevated because your body produces more of these hormones in response to low levels of testosterone in your blood. Low levels of these hormones suggest that low testosterone has a secondary cause.

You may also receive many other types of tests to confirm the diagnosis, rule out other conditions, or monitor for complications.

You may receive other blood tests to look for certain genetic mutations or measure levels of:

• Free testosterone levels

• Total testosterone levels

• Sex hormone-binding globulin (SHBG) levels

• Prolactin (to detect pituitary tumors called hyperprolactinemia)

• GnRH

• Estrogen (estradiol)

• Iron levels, if a condition called hemochromatosis is suspected

• Prostate-specific antigen (PSA) levels if prostate cancer is suspected

In some cases, you may receive:

• A bone mineral density (DEXA) scan if you’re at risk of osteoporosis

• Semen analysis to measure sperm count and other markers of fertility

• Imaging such as MRI or ultrasound

• Sleep studies to look for conditions like sleep apnea

Many of the causes of primary hypogonadism aren’t curable. Once a healthcare provider confirms low T from testicular failure is causing symptoms, men are typically treated with testosterone replacement therapy (TRT). But there are other options to consider, too. 

Testosterone Replacement Therapy

Testosterone replacement therapy (TRT) involves taking a synthetic form of testosterone, such as testosterone cypionate or testosterone enanthate, to replace your body’s natural supply. It can be delivered in many ways, such as through:

• Oral medications

• Testosterone gels or patches applied to the body

• Intramuscular injection

• Gel applied to the gums and cheeks

• Nasal sprays

• Pellets implanted under the skin

Clinicians often recommend TRT to help return your testosterone levels to a normal range and treat symptoms associated with low testosterone. However, like all medications, there’s a risk of side effects, and it might not be for everybody.

Side effects such as increased estrogen levels or the development of breast tissue are often treatable by adjusting the testosterone dose. Aromatase inhibitors are occasionally used off-label. Talk to a licensed healthcare professional about testosterone replacement therapy through our telehealth service. They can evaluate whether you may be a candidate for TRT and discuss the potential benefits and risks.

Enclomiphene

Other medications such as enclomiphene citrate may also be prescribed for some men with low testosterone to increase testosterone levels. Enclomiphene falls into a class of drugs called selective estrogen receptor modulators (SERMs). It works by increasing LH and FSH levels to signal to your testicles to produce more testosterone.

Enclomiphene is not FDA-approved, and researchers are still investigating its effectiveness and long-term safety. Because enclomiphene works by increasing pituitary LH and FSH rather than directly stimulating the testes, it’s not effective for primary hypogonadism, where the testicles cannot respond to those signals.

Supportive Treatment

In some situations where testicular function is only partially impaired, such as after an infection or medication effects, treating the underlying issue may help restore testosterone levels. 

Examples include:

• Receiving treatment for testicular infections

• Making lifestyle changes, such as reducing alcohol intake

• Treating liver or kidney disease

In most congenital or destructive causes, function does not recover.

Many causes of primary hypogonadism are out of your control, so it often isn’t possible to prevent it. However, you can reduce your risk by implementing strategies such as:

• Correcting undescended testes in infancy

• Vaccinating against mumps to reduce the risk of orchitis

• Taking protective measures to avoid testicular trauma, such as wearing proper sports equipment

• Discuss fertility and hormone-preservation strategies before radiation or chemotherapy when feasible.

• Taking steps to minimize the risk of liver disease, kidney disease, obesity, type 2 diabetes, or other conditions that affect your overall health

• Avoiding exposure to toxic chemicals like pesticides and heavy metals

• Avoid anabolic steroid use

• Getting genetic counseling if you have known sex chromosome or developmental disorders in your family

Primary hypogonadism occurs in males when the testicles don’t produce a normal amount of testosterone despite elevated LH and FSH levels.

Primary hypogonadism has many potential causes, including testicular injury or some genetic conditions like Klinefelter syndrome. Some potential causes, like testicular injuries, may be treatable or somewhat treatable, but genetic causes are often manageable with TRT to help supplement your body’s testosterone production and bring your testosterone levels into a normal range.

If you suspect you may have a testosterone deficiency, it’s a good idea to talk to a medical professional. You can talk to a licensed professional online through our telehealth service without the need to go to a clinic. If you’re eligible, they can write you a prescription for TRT and advise you of the benefits and risks. 

What is primary hypogonadism, and how does it differ from secondary hypogonadism?

Primary hypogonadism is low testosterone caused by a problem that originates from your testicles (low testosterone with high LH and FSH). In contrast, secondary hypogonadism (or hypogonadotropic hypogonadism) results from pituitary or hypothalamic dysfunction (low testosterone with low or normal LH and FSH)

How common is primary hypogonadism in men?

The exact prevalence of primary hypogonadism isn’t clear. However, low testosterone in general is a very common issue, especially among older men, affecting an estimated 40 percent of men over the age of 45 and 50 percent of men in their 80s.

What levels of testosterone suggest hypogonadism?

The exact cut-off for hypogonadism varies. Many healthcare providers consider a value less than 300 ng/dL on two separate morning tests to indicate low testosterone. Diagnosis also requires consistent symptoms. 

How is primary hypogonadism treated?

Primary hypogonadism is often treated with TRT to help bring testosterone levels back into a normal range. Many of the potential causes of primary hypogonadism, such as genetic conditions, aren’t reversible, and TRT often remains the best treatment option. Because TRT suppresses sperm production, men wishing to preserve fertility should discuss alternatives.