What should be included in the differential diagnoses of amenorrhea with delayed puberty?

Updated: Oct 14, 2019
  • Author: Kristi A Tough DeSapri, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Amenorrhea with delayed puberty

Puberty is considered delayed when no breast development is evident at 13 years, pubic hair is absent at 14 years, and menarche is absent at 15 years (which is 2 standard deviations above the mean age for menarche). The most common cause of delayed puberty is constitutional delay. Another common reason for delayed puberty is ovarian failure, which is also termed hypergonadotropic hypogonadism. Elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) characterize hypergonadotropic hypogonadism with low estrogen production.

The most common example of hypergonadotropic hypogonadism is found in Turner syndrome, which is caused by a 45,X karyotype. Clinical manifestations of Turner syndrome include a webbed neck, short stature, broad shield-like chest, anomalous auricles, and hypoestrogenemia resulting in sexual immaturity.

Gonadal dysgenesis fits the same pattern of high FSH and LH and low estradiol (E2) levels. Gonadal dysgenesis is caused by a mosaic karyotype with an abnormal X chromosome, with loss of part of an X chromosome or translocation, or with a normal karyotype (46,XX) and streak ovaries.

Individuals with Perrault syndrome have gonadal dysgenesis, a normal karyotype, and neurosensory deafness. Swyer syndrome is illustrated by a phenotypically immature female with a 46,XY karyotype without testis-determining factor on the Y chromosome and with failure to produce anti-müllerian hormone.

Patients with Swyer syndrome have normal female external genitalia, a patent vagina, and a normal uterus. The gonads are testes. They have no breast development, in contrast to individuals with androgen insensitivity. Another rare cause of hypergonadotropic hypogonadism is gonadotropin-resistant ovary syndrome, which is characterized by FSH-resistant ovaries.

Acquired causes of hypergonadotropic hypogonadism can result from high-dose alkylating chemotherapy and radiation treatments to the pelvis. An elevated erythrocyte sedimentation rate (ESR) and anti-ovarian antibody levels may suggest autoimmune oophoritis, but such tests are rarely needed. Autoimmune oophoritis is an exclusionary diagnosis. Like all forms of hyperandrogenic hypogonadotropic amenorrhea, these conditions are not reversible.

Hypogonadotropic hypogonadism occurs when FSH and LH levels are low. Hypogonadotropic hypogonadism may present prior to or after the completion of puberty. The most common causes of hypogonadotropic hypogonadism include chronic illness, starvation, excessive exercise, anorexia nervosa, depression, stress, and marijuana use. Hypogonadotropic hypogonadism involves slowed gonadotropin-releasing hormone (GnRH) release caused by multifactorial components of decreased body fat and increased beta endorphins.

Chronic illness can affect pubertal development adversely by interfering with metabolism through malabsorption and poor nutrition (eg, Crohn disease, diabetes mellitus, hypothyroidism and hyperthyroidism, cystic fibrosis, anorexia nervosa, excessive exercise).

Tumors in the CNS can compress the portal vessels and impede the flow of GnRH from the hypothalamus to the pituitary gland. Pituitary adenomas, craniopharyngiomas, and meningiomas are examples of slow-growing nonmetastatic tumors that are uncommon causes of hypogonadotropic hypogonadism. Anterior pituitary prolactinomas releasing prolactin hormone are the most common pituitary tumors to cause hypogonadotropic hypogonadism.

Other acquired disorders can disrupt pituitary function by destructive means, such as ischemia, infiltration, and obstruction. Head trauma, cranial aneurysms, and infiltrative processes (eg, sarcoidosis, syphilis, tuberculomas) are examples of conditions that can disrupt pituitary function.

Abnormal development of the hypothalamus can result in hypogonadotropic hypogonadism. Kallmann syndrome is a form of hypogonadotropic hypogonadism with associated anosmia and pubertal delay and a normal response to exogenous gonadotropins. Kallmann syndrome occurs during embryonic development when GnRH-secreting neurons fail to migrate from the olfactory area to the hypothalamus. The gene KAL1 codes for the protein associated with normal migration. Other syndromes associated with hypothalamic dysfunction include Prader-Willi syndrome and Laurence-Moon-Biedl syndrome.

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