What causes hypogonadotropic hypogonadism?

Causes of Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism results from impairment of the hypothalamic-pituitary-gonadal (HPG) axis, characterized by low or inappropriately normal gonadotropin levels (FSH and LH) despite low sex steroid levels. 1, 2

Congenital Causes

Idiopathic hypogonadotropic hypogonadism (IHH) represents the most common congenital form, occurring in approximately 1-10 per 100,000 live births. 3

• Kallmann syndrome accounts for approximately two-thirds of congenital cases and presents with hypogonadotropic hypogonadism accompanied by anosmia due to abnormal olfactory bulb development. 1, 3
• Normosmic IHH comprises the remaining one-third of congenital cases, presenting without olfactory defects. 1, 2
• Genetic mutations including loss-of-function mutations in GPR54 (the KiSS1-derived peptide receptor) have been identified as causing IHH by disrupting the gonadotropic axis. 4

Acquired Causes

Structural Lesions

• Pituitary tumors, particularly prolactinomas, represent the most common acquired cause of hypogonadotropic hypogonadism. 5
• Hypothalamic or infundibular tumors and cysts can disrupt GnRH neuron function or gonadotroph cell activity. 5
• Traumatic brain injury damages the hypothalamic-pituitary structures. 1, 5

Iatrogenic Causes

• Cranial or pituitary radiation therapy causes direct damage to the HPG axis, with hypothalamic/pituitary radiation doses as low as those used in cancer treatment leading to central hypogonadism. 6, 5
• Pituitary surgery can result in gonadotroph cell dysfunction. 5

Drug-Induced Causes

Exogenous testosterone or anabolic steroids provide negative feedback to the hypothalamus and pituitary, suppressing gonadotropin secretion and causing secondary hypogonadism—this is a critical and common cause in males pursuing fertility. 6, 1, 2

• Opiates are a frequently overlooked but common cause of hypogonadotropic hypogonadism. 1, 2
• GnRH agonists and antagonists suppress the HPG axis through receptor desensitization or blockade. 1
• Glucocorticoids (including Cushing syndrome) disrupt gonadotropin secretion. 1, 2
• Estrogens suppress gonadotropin release through negative feedback. 1

Systemic Diseases and Metabolic Conditions

• Type 2 diabetes mellitus and metabolic syndrome are associated with functional suppression of the HPG axis. 2
• Obesity impairs hypothalamic GnRH pulsatility and gonadotropin secretion. 2
• Hemochromatosis causes iron overload damage to the pituitary. 3, 5
• Sarcoidosis and histiocytosis X represent infiltrative disorders affecting the hypothalamic-pituitary region. 3, 5

Functional Causes

• Hyperprolactinemia (from any cause) suppresses GnRH pulsatility and gonadotropin secretion. 6, 5
• Excessive exercise and energy deficit lead to functional hypothalamic amenorrhea in women, characterized by reduced GnRH pulse frequency. 6
• Psychological stress suppresses the HPG axis through kisspeptin neuron dysfunction, bridging the stress response system with reproductive control. 6
• Chronic systemic illness causes functional suppression of gonadotropin secretion. 3

Pathophysiologic Mechanism

The fundamental defect involves reduced pulsatile GnRH secretion from the hypothalamus, which leads to decreased LH pulse frequency and reduced FSH secretion. 6, 7 This can range from complete absence of GnRH secretion to defects in amplitude, frequency, or altered bioactivity of released gonadotropins. 7

Critical Clinical Distinction

In hypogonadotropic hypogonadism, FSH and LH levels are low or inappropriately normal (not elevated) despite low testosterone or estradiol levels—this distinguishes it from primary gonadal failure where gonadotropins are markedly elevated. 1, 2, 3