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Hypogonadism

What Is It, Causes, Signs and Symptoms, and More

Author: Anna Hernández, MD

Editors: Alyssa Haag, Emily Miao, PharmD, Kelsey LaFayette, DNP, RN

Illustrator: Jessica Reynolds, MS

Copyeditor: Sadia Zaman, MBBS, BSc

What is hypogonadism?

Hypogonadism is a clinical syndrome that occurs when the gonads—testes and ovaries—produce low levels of sex hormones due to a disruption of the hypothalamic-pituitary-gonadal (HPG) axis.

The release of sex hormones is under the control of the hypothalamus and the pituitary gland. The hypothalamus secretes a hormone called gonadotropin-releasing hormone, or GnRH, which travels to the nearby pituitary gland, where it stimulates the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) into the bloodstream. These hormones then stimulate the gonads to produce sex-specific hormones, mainly estrogen and progesterone in those assigned female at birth, and testosterone in those assigned male at birth. After puberty and throughout an individual’s life, sex hormone levels are regulated through a negative feedback mechanism, where rising levels of sex hormones signal the hypothalamus and pituitary to reduce the secretion of FSH and LH, thereby decreasing the release of sex hormones by the gonads. 

What causes hypogonadism?

There are two main types of hypogonadism, primary and secondary. Primary hypogonadism is caused by dysfunction of the gonads, and can be acquired or congenital. Acquired causes include radiation therapy, chemotherapy, autoimmunity, trauma to the gonads, and certain infections, like mumps orchitis. On the other hand, congenital causes include genetic disorders, like Klinefelter syndrome or Turner syndrome, both of which affect gonadal function. Regardless of the cause, the result is a decrease or complete absence of sex hormones, which means there is no negative feedback on the hypothalamic-pituitary-gonadal axis. This leads to an overproduction of the  LH and FSH gonadotropins, thus giving primary hypogonadism its other name, hypergonadotropic hypogonadism.

The second cause of hypogonadism is secondary hypogonadism, which is also called hypogonadotropic hypogonadism because there are low levels of LH and FSH. Secondary hypogonadism can occur due to hypothalamus or pituitary gland dysfunction, which leads to impaired GnRH or gonadotropin secretion. Acquired causes of secondary hypogonadism include tumors of the pituitary gland and hypothalamus; pituitary apoplexy (i.e., a sudden bleeding or impaired blood supply to the pituitary gland); and trauma to the base of the skull. Congenital causes include panhypopituitarism, which involves a decrease in all pituitary hormones, as well as Kallmann syndrome, a genetic condition marked by isolated GnRH deficiency and anosmia, or hyposmia. Finally, general causes of secondary hypogonadism include chronic illness, for instance cystic fibrosis or celiac disease; malnutrition or obesity; excessive exercise; and stress, all of which affect the way the hypothalamus and pituitary gland release hormones.

What are the signs and symptoms of hypogonadism?

Signs and symptoms of hypogonadism vary depending on whether hypogonadism occurs before or after puberty. The most common presenting feature of hypogonadism in teenagers is a delay in puberty, which generally occurs when puberty has not started by age 13 in those assigned female at birth and age 14 in those assigned male at birth. Other clinical features of hypogonadism include a high-pitched voice, sparse body hair, poorly developed muscles, small or underdeveloped genitals, and short stature due to delayed epiphyseal closure. Another presenting feature can be primary amenorrhea, which is when an individual hasn’t had their first menstruation by the age of 13 to 15. 

When hypogonadism occurs later on in life, secondary sex characteristics have typically already developed. Signs and symptoms may involve changes in mood and energy levels, decreased libido, sleep disturbances, osteoporosis, muscle atrophy, and decreased strength. In addition, there may be erectile dysfunction, infertility, oligomenorrhea or amenorrhea, as well as galactorrhea, which is when milk is discharged from the nipple outside of pregnancy or breastfeeding.

How is hypogonadism diagnosed?

Diagnosis of hypogonadism begins with a thorough medical history and physical exam, including assessment using the Tanner scale. The Tanner scale, or Tanner stages, consists of a predictable set of steps that individuals go through as they develop primary and secondary sex characteristics and become sexually mature. This scale centers on two, independent criteria: the appearance of pubic hair; and the increase in testicular volume and penile size and length in those assigned male at birth or with breast development in those assigned female at birth.

Medical history and physical exam are usually followed by measurement of serum levels of sex hormones, including testosterone, estrogen, progesterone, LH and FSH. Primary hypogonadism is diagnosed when serum LH and FSH concentrations are elevated, and estradiol or testosterone levels are low. In such cases, further diagnostic tests may include karyotyping to rule out genetic conditions, like Klinefelter or Turner syndrome. On the other hand, diagnosis of secondary hypogonadism requires decreased levels of both LH and FSH, as well as testosterone and estradiol. If secondary hypogonadism is diagnosed, further diagnostic testing may be needed to assess the underlying cause leading to hypogonadism.

How is hypogonadism treated?

Treatment of hypogonadism is directed at addressing the underlying cause, when possible. In most cases, hypogonadism can be managed with hormone replacement therapy to ensure the onset and progression of puberty, as well as improve the symptoms of hypogonadism. 

In those assigned male at birth, treatment typically involves testosterone replacement therapy either in patches, gels, pills or intramuscular injections. It’s important to note that testosterone treatment can increase the risk of edema, so it shouldn’t be used in individuals with poorly controlled heart failure. Testosterone treatment, along with estrogen treatment,  can also lead to an increase in red blood cell count, which in turn can increase the risk of developing thromboembolic events. In addition, it can worsen sleep apnea, interfere with fertility, and increase the risk of prostate cancer. In those assigned female at birth, treatment involves estrogen and progesterone replacement therapy, which can be taken in the form of pills or skin patches. The main side effect of estrogen therapy is increased risk of thromboembolic events. When taken without progesterone, unopposed estrogen therapy can also increase the risk of endometrial hyperplasia and carcinoma. Although hormone replacement therapy is effective in inducing puberty, or as lifelong replacement therapy in those with permanent hypogonadism, it does not induce fertility. If fertility is desired, pulsatile GnRH or gonadotropin therapy are usually prescribed. 

Can hypogonadism be reversed?

Certain cases of hypogonadism are transient and can be reversed, especially if they are a result of a treatable underlying disorder, such as malnutrition, excessive exercise, or stress. In addition, there have been cases of idiopathic hypogonadotropic hypogonadism that have reversed over time, although the exact reason why is still unknown.

What are the most important facts to know about hypogonadism?

Hypogonadism refers to a clinical syndrome that results in low levels of sex hormones. There are two types of hypogonadism: primary and secondary. Signs and symptoms of hypogonadism depend on the time of onset, and can include delayed puberty, primary amenorrhea, changes in mood and energy, infertility, decreased libido, and erectile dysfunction. Diagnosis of hypogonadism is based on the clinical manifestations along with lab tests to assess the levels of sex hormones in the body. Treatment involves long-term hormone replacement therapy and fertility treatments, as well as treatment of the underlying cause of hypogonadism, when possible. 

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