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

Frequently, pubertal development occurs at a normal rate, but primary amenorrhea may occur and may be associated with hirsutism. These individuals are eugonadal. The most common cause in this setting is polycystic ovarian syndrome (PCOS), which is characterized by anovulation, oligo-ovulation, androgen excess (clinical or biochemical), ultrasonographic demonstration of increased ovarian stroma and accumulation of antral follicles (polycystic appearance), and obesity. [43]

Ovarian hyperthecosis results in hyperandrogenicity, which is evident by signs of hirsutism, acne, and obesity and can be associated with type 2 diabetes mellitus and acanthosis nigricans. Hyperthecosis can also cause virilization, which manifests as clitoromegaly, temporal balding, and deepened voice change. See Polycystic Ovarian Syndrome for an in-depth discussion of this entity.

Another cause of hirsutism is the rare late-onset 21-hydroxylase deficiency, which is caused by mutations in the 21-hydroxylase gene that result in excessive 17-hydroxyprogesterone levels. This deficiency is also termed non classic congenital adrenal hyperplasia and can occur in 1-10% of women with hirsutism.

Rarely, patients with hypothalamic amenorrhea may have hyperandrogenic/polycystic ovaries. Wang et al explored the coexistence of these 2 disorders in women with hypothalamic amenorrhea/PCOS, and found that over time, these patients may fluctuate between symptoms of hypothalamic amenorrhea and polycystic ovarian syndrome, depending on the status of their hypothalamic activity. [44]

Other causes of hyperandrogenism include Cushing disease, ovarian stromal hypertrophy, and androgen-producing tumors of the ovary and adrenal glands. Exogenous anabolic steroid use should be considered in the differential for hyperandrogenic amenorrhea.

Anovulation remains the most common cause of amenorrhea in the setting of nonvirilization. Anovulation is caused by dysfunction of the hypothalamic-pituitary-ovarian axis, which can be apparent after discontinuation of various hormonal contraception medications and can result in loss of menses for several months. It is often associated with a hypothalamic hypogonadotropic etiology.

Premature ovarian failure can be idiopathic, secondary to chemotherapy or radiation therapy, or autoimmune in origin. The idiopathic form occurs in 1% of women younger than 40 years.

Premature ovarian failure is more accurately termed primary ovarian insufficiency (POI) because women with spontaneous POI may have intermittent ovarian function, and, as a group, demonstrate a pregnancy rate of 5-10%. [45] (For an in-depth discussion, see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure].)

Prodromal POI is a state of ovarian insufficiency in which FSH levels are elevated and menses are irregular but not to the degree required to make a diagnosis of overt POI. This is likely on a continuum with diminished ovarian reserve (a state in which women respond poorly to exogenous gonadotropin stimulation) and overt POI (a state of drastically reduced fertility).

Hyperprolactinemia is a pituitary cause of amenorrhea in the presence of normal puberty. Hyperprolactinemia can occur as a consequence of breastfeeding, microadenomas of the pituitary, and use of psychoactive medications (eg, haloperidol, phenothiazines, amitriptyline, benzodiazepines, cocaine, marijuana) and metoclopramide (Reglan).

Amenorrhea may be caused by thyroid disorders, including hyperthyroidism and hypothyroidism. Hypogonadotropic hypogonadism can occur from the same causes as delayed puberty. In addition, Sheehan syndrome, which results from panhypopituitarism after pituitary infarction from postpartum hemorrhage or shock, can manifest as pubertal amenorrhea.

Amenorrhea that results from genital tract anomalies can arise from the absence of reproductive organs. Mayer-Rokitansky-Hauser syndrome is an anomaly of the genital tract characterized by vaginal agenesis. The uterus is usually absent, and the vagina is foreshortened.

Because the ovaries function normally and produce E2, breasts are normal in shape and contour. Pubarche is also normal in this patient population; therefore, pubic hair remains normal. Mayer-Rokitansky-Hauser syndrome accounts for 15% of primary amenorrhea cases and is second to Turner syndrome as the most common cause of primary amenorrhea.

Androgen insensitivity syndrome (previously termed testicular feminization) is present in 10% of patients with amenorrhea. Androgen insensitivity syndrome is caused by an abnormality of the androgen receptor. The gonads are testicles producing testosterone; however, testosterone has no effect because the androgen receptor is nonfunctional.

The phenotypic appearance in patients with this condition is female, but the circulating hormonal pattern is male. Androgen insensitivity syndrome is a maternal X-linked recessive disease in which the testes remain intra-abdominal or partially descended, and pubic hair is sparse.

Spontaneous testicular regression is a rare disorder of genetic males that results in a female phenotype with an absent uterus. In addition, certain enzyme deficiencies affecting androgen production can result in male pseudohermaphrodites. All disorders that are pheno typically female but chromosomally male (XY) require that the gonads be removed to avert cancerous changes.

Primary amenorrhea can result from an imperforate hymen, which presents as a boggy uterus and cyclic abdominal pain. Asherman syndrome occurs after an overzealous curettage of the endometrial lining, which results in adhesions or synechiae that prevent the endometrium from responding to estradiol. The diagnosis is suggested by absence of endometrial stripe on uterine ultrasonography and confirmed by hysteroscopy evaluation or by absence of bleeding after cyclic therapy with estrogen and later progestin for several weeks.

A case report has been published of a woman in whom persistent secondary amenorrhea developed due to intrauterine adhesions after selective embolization of the uterine arteries for control of refractory primary postpartum hemorrhage. Adverse effects of these new lifesaving technologies remain to be evaluated long term. [46]

Clinically significant infections that destroy the endometrial lining can also result in primary or secondary amenorrhea.

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