Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands (of the hypothalamic-pituitary-gonadal (HPA) axis) so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.
Signs and symptoms
Symptoms can vary greatly depending on the stage of life, biological sex, and etiology.
Males
During birth and early infancy, HH in males can present as normal male phenotype with or without cryptorchidism, complex genital anomaly, or normal female phenotype. Children often have small or non-palpable testes and this can present with or without genital anomaly. As individuals progress onto adolescence, they may experience absent or delayed puberty or puberty that starts but fails to progress. Adult males with HH may exhibit gynecomastia, erectile dysfunction, reduced testicular volume (absence of testicular enlargement during puberty), abnormal testicular texture and consistency, small stature, decreased libido and sexual activity, infertility due to low (oligospermia) or no (azoospermia) sperm count, loss of body hair, loss of muscle mass, hot flashes, psychological disturbances and poor sleep pattern.
Females
Females may present with low levels of estrogen and abnormal menstruation. Individuals with Turner syndrome may have short stature, dysmorphic features, gonadal dysgenesis, and delayed puberty. Other signs and symptoms associated with HH consist of intellectual disability or learning difficulties and delayed puberty including amenorrhea and absent breast and pubic hair development.
Other complications that can arise include anxiety and depression, osteoporosis and relationship problems.
Causes
There are a multitude of etiologies for HH and it can include congenital or acquired causes.
Congenital causes include the following: Disorders of Sex Development (DSD) – Turner's syndrome, Klinefelter's syndrome, Swyer's syndrome, XX gonadal dysgenesis, mosaicism, partial androgen insensitivity, complete androgen insensitivity syndrome, congenital adrenal hyperplasia, galactosemia, and testicular regression sequence. Gonadotropin resistance (e.g., due to inactivating mutations in the gonadotropin receptors) – carbohydrate-deficient glycoprotein syndrome, Leydig cell hypoplasia (or insensitivity to LH) in males, FSH insensitivity in females, and LH and FSH resistance due to mutations in the GNAS gene (termed pseudohypoparathyroidism type 1A) Myotonic Dystrophy
Acquired causes
(due to damage to or dysfunction of the gonads) include testicular torsion, ovarian torsion, vanishing/anorchia, orchitis, premature ovarian failure, ovarian resistance syndrome, trauma, surgery, autoimmunity, chemotherapy, radiation, infections (e.g., sexually-transmitted diseases), toxins (e.g., endocrine disruptors), infection, kidney disease, liver disease, iron overload, and drugs (e.g., antiandrogens, opioids, alcohol).
Diagnosis
A diagnosis can be made from the following:
History
Family history including age, healthy pubertal development of family members, and possibility of genetic disease will be evaluated. Prenatal history, such as maternal medication use, birthweight of the affected individual, childhood surgical interventions, and overall general health will also play a significant role during diagnosis. In children with delayed puberty, hypogonadism can be distinguished from constitutional delay through family history, with constitutional delay being closely associated with positive family history.
Examination
Individuals will be examined for height, weight, and any abnormal body features. Breast and genitalia examinations in presence of a chaperone may also be needed. Diagnostic imaging such ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI) can be done evaluate for any abnormalities of the internal genitalia, tumors in the pituitary gland or in the brain, and ovarian cysts for possibilities of polycystic ovarian syndrome (PCOS).