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

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 controlled by the hypothalamus and the pituitary gland, two brain structures that regulate hormone production. The hypothalamus secretes gonadotropin-releasing hormone, or GnRH, which travels via blood vessels to the nearby pituitary gland. There, it stimulates the secretion of gonadotropins – follicle stimulating hormone (FSH) and luteinizing hormone (LH) – into the bloodstream. These hormones in turn stimulate the gonads to produce sex-specific hormones, mainly estrogen and progesterone in individuals 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: as their levels rise, they signal the hypothalamus and pituitary to reduce the secretion of FSH and LH, which in turn lowers the release of sex hormones by the gonads.  

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, such as mumps orchitis. On the other hand, congenital causes include genetic disorders affecting gonadal function such as Klinefelter syndrome or Turner syndrome. Regardless of the cause, primary hypogonadism is characterized by 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 gonadotropins (LH and FSH), which is why primary hypogonadism is also known as hypergonadotropic hypogonadism. 

On the other hand, secondary hypogonadism, also known as hypogonadotropic hypogonadism, is characterized by low levels of LH and FSH. Secondary hypogonadism occurs due to hypothalamus or pituitary gland dysfunction causing impaired GnRH or gonadotropin secretion. Acquired causes of secondary hypogonadism include tumors of the pituitary gland and hypothalamus; pituitary apoplexy (i.e., 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 (i.e., complete or partial loss of the sense of smell). Finally, general causes of secondary hypogonadism include conditions that affect hormonal release by the hypothalamus and pituitary gland, such as chronic illness (e.g., cystic fibrosis or celiac disease), malnutrition or obesity, excessive exercise, and stress. 

Signs and symptoms of hypogonadism vary depending on whether hypogonadism occurs before or after puberty. In teenagers, the most common sign of hypogonadism is delayed puberty, which occurs when puberty has not started by age 13 in those assigned female at birth and by 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 occurs when an individual hasn’t had their first menstruation by age 15.  

When hypogonadism occurs later 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 (i.e., infrequent or absent menstruation), and galactorrhea (i.e., discharge of milk from the nipple outside of pregnancy or breastfeeding). 

Diagnosis of hypogonadism begins with a thorough medical history and physical exam, including assessment using the Tanner scale. The Tanner scale, or Tanner stages, describes a predictable sequence of physical changes that individuals go through as they develop primary and secondary sex characteristics and reach sexual maturity. This scale is based on two, independent criteria: the appearance of pubic hair, and either the increase in testicular volume and penile growth in those assigned male at birth, or breast development in those assigned female at birth. 

Medical history and physical exam are usually followed by measurement of serum levels of sex hormones and gonadotropins, including testosterone, estrogen, progesterone, LH and FSH. Primary hypogonadism is diagnosed when serum LH and FSH concentrations are elevated, while 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 low or normal levels of both gonadotropins (LH and FSH) and low levels of sex hormones (testosterone and estradiol). If secondary hypogonadism is diagnosed, further diagnostic testing may be needed to identify its underlying cause. 

Treatment of hypogonadism focuses on addressing the underlying cause whenever possible. In most cases, hormone replacement therapy is used to ensure the onset and progression of puberty and to improve the symptoms of hypogonadism.  

In those assigned male at birth, testosterone replacement therapy can be administered via patches, gels, pills or intramuscular injections. It’s important to note that testosterone treatment can increase the risk of edema and should be avoided in individuals with poorly controlled heart failure. Testosterone treatment and estrogen treatment can also lead to an increase in red blood cell count, which in turn can increase the risk of thromboembolic events. In addition, testosterone treatment 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 at inducing puberty or providing lifelong treatment in permanent hypogonadism, it does not induce fertility. If fertility is desired, pulsatile GnRH or gonadotropin therapy are usually prescribed.