Hypogonadotropic hypogonadism (HH) is a condition characterized by insufficient sex hormone production. This occurs when the brain’s hypothalamus or pituitary gland, which regulate hormone production, do not function properly. Unlike other forms of hypogonadism, the primary issue in HH stems from these brain regions, impacting sexual development and reproductive function.
Understanding Hypogonadotropic Hypogonadism
The body’s reproductive system is regulated by the hypothalamic-pituitary-gonadal (HPG) axis. This axis starts in the hypothalamus, which releases Gonadotropin-Releasing Hormone (GnRH). GnRH then stimulates the pituitary gland to produce Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH).
These hormones, called gonadotropins, travel to the gonads (testes in males, ovaries in females). In males, LH stimulates testosterone production, and FSH supports sperm production. In females, FSH promotes ovarian follicle growth, and both LH and FSH stimulate estrogen and progesterone production, regulating the menstrual cycle. In HH, the hypothalamus or pituitary gland malfunctions, leading to low GnRH, LH, or FSH, and consequently, reduced sex hormone production.
Causes of Hypogonadotropic Hypogonadism
Hypogonadotropic hypogonadism can arise from genetic, acquired, or idiopathic (unknown) causes. Genetic forms, known as congenital hypogonadotropic hypogonadism (CHH), involve inherited gene defects affecting GnRH-producing neurons or pituitary cells. Kallmann syndrome is a common genetic cause, characterized by HH and an impaired sense of smell due to abnormal GnRH neuron development. Other genetic mutations can also lead to HH.
Acquired forms of HH develop after birth from damage or dysfunction of the hypothalamus or pituitary gland. Causes include tumors (e.g., pituitary adenomas), head trauma, radiation therapy, or infections. Chronic illnesses like hemochromatosis, sarcoidosis, severe stress, extreme exercise, and substance use (e.g., opioids, alcohol) are also linked to acquired HH. When no specific cause is identified after investigation, it is classified as idiopathic hypogonadotropic hypogonadism (IHH).
Recognizing the Signs
The signs of hypogonadotropic hypogonadism vary by sex and age of onset. If HH occurs before or during puberty, it causes delayed or absent sexual development. Girls may have a lack of breast development and absent menstrual periods (amenorrhea). Boys might experience little to no enlargement of the testes and penis, lack of facial or body hair growth, and a voice that does not deepen. Short stature and, in some genetic cases like Kallmann syndrome, an inability to smell (anosmia) may also occur.
When HH develops in adulthood, after puberty, symptoms differ. Both men and women may experience low libido and infertility. Men might notice muscle loss, weight gain, and breast enlargement. Women may experience irregular or absent menstrual periods, hot flashes, and changes in energy and mood. Prolonged sex hormone deficiency can also lead to decreased bone density, increasing fracture risk.
Diagnosis and Treatment Approaches
Diagnosis of hypogonadotropic hypogonadism starts with a medical history and physical examination, assessing for delayed or incomplete sexual development. Blood tests measure hormone levels, including Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), and sex hormones like testosterone or estradiol. In HH, low sex hormone levels are seen with low or normal LH and FSH, distinguishing it from primary hypogonadism where gonadotropin levels are high. Additional blood tests, such as prolactin and thyroid hormone levels, may rule out other pituitary conditions. Imaging studies, particularly an MRI of the brain and pituitary gland, identify structural abnormalities like tumors.
Genetic testing may be considered for congenital HH or suspected genetic syndromes like Kallmann syndrome. A GnRH stimulation test, where GnRH is administered and LH/FSH levels are monitored, helps differentiate between hypothalamic and pituitary causes.
Treatment for HH replaces deficient hormones and addresses patient goals, such as inducing puberty or restoring fertility. For inducing puberty and maintaining secondary sexual characteristics, hormone replacement therapy is standard. Males receive testosterone via injections, patches, or gels to mimic pubertal development and maintain adult hormone levels. Females receive estrogen, often with progestin, through pills or patches to induce breast development, menstruation, and preserve bone density.
When fertility is desired, especially in adults, different strategies are used because sex steroid replacement alone does not restore fertility. For men, gonadotropin therapy, using injections of human chorionic gonadotropin (hCG) and sometimes FSH, stimulates testosterone and sperm production. This treatment can be lengthy but is effective in restoring spermatogenesis. For women, gonadotropin therapy or pulsatile GnRH injections can stimulate ovulation. Genetic counseling may also be recommended for individuals with congenital HH before fertility treatments.