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Definition of Amenorrhea

Amenorrhea occurs physiologically before menarche, during pregnancy and lactation, and in postmenopausal women. Primary amenorrhea is characterized by the absence of menstruation by the age of 16 years. Possible causes are multifactorial, including atresia of the hymen, vaginal septum, competitive sports, Ullrich-Turner syndrome, malnutrition, adrenogenital syndrome, and polycystic ovary syndrome.

Secondary amenorrhea is defined by the absence of menstruation for at least 3 months after a previously regular cycle without an existing pregnancy. It occurs in 3–5% of women in any specific year secondary amenorrhea can result from abnormal hypothalamus, pituitary, ovary, uterus, or outflow tract.

Differential Diagnoses

Endocrinology and internal medicine

Congenital adrenal hyperplasia (overproduction of androgens due to abnormal cortisol synthesis in the adrenal cortex).

Women deficient in 21-hydroxylase manifest a seemingly male phenotype, despite the presence of uterus and ovaries (female pseudohermaphroditism).

Acromegaly

Acromegaly is characterized by amenorrhea in addition to the increased size of extremities, vision problems, joint pain, and fatigue.

Sheehan’s syndrome

Sheehan’s syndrome, also known as postpartum pituitary gland necrosis is hypopituitarism characterized by the complete or partial failure of the anterior pituitary. Amenorrhea occurs in addition to other symptoms associated with FSH/LH deficiency.

Inflammatory bowel disease

Amenorrhea can occur especially during Crohn’s disease.

Diabetes mellitus I and II

Amenorrhea may occur especially in patients with poorly controlled diabetes mellitus types 1 and 2.

Hyperprolactinemia

Elevated secretion of the hormone prolactin or hyperprolactinemia may be caused by a pituitary adenoma (prolactinoma) or medications (e.g., metoclopramide).

Hypothyroidism

Amenorrhea in hypothyroidism is associated with a constellation of symptoms such as loss of libido and poor fertility. Hyperthyroidism in Graves’ disease may also be another contributing factor.

Gynecology

Endometriosis

Scattered endometrial tissue is found within or outside genital areas or extra-abdominally. In addition to menstrual ailments such as spotting, menorrhagia, metrorrhagia or hypermenorrhea, it can also result in amenorrhea.

Polycystic ovary syndrome

Multiple cysts in the ovaries lead to increased androgen production accompanied by anovulatory cycles and virilization (with a differential diagnosis of congenital adrenal hyperplasia).

Polycystic ovary syndrome may also increase the long-term risk of ovarian tumors/cancers.

Clinical symptoms are pelvic pain, palpable/visible protrusions.

Menopause praecox (or premature menopause)

A complete ovarian failure before the age of 40 may be attributed to various factors such as autoimmune or metabolic diseases, radiotherapy, and chemotherapy.

Asherman’s syndrome

Asherman’s syndrome results from the obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium. Common causes include gynecological procedures such as dilatation and curettage. It may also be caused by genital tuberculosis in endemic areas.

Psychiatric/psychosomatic conditions

Psychogenic

Menstruation may also cease due to altered lifestyle and environmental changes, e.g., travel and/or extreme changes in climate.

Anorexia nervosa

Secondary amenorrhea may occur as a result of complications of eating disorders, including anorexia nervosa and bulimia. Due to hormonal imbalance associated with increased cortisol secretion, the body creates a sort of ‘natural contraceptive protection’ because it may not be able to withstand pregnancy. Often the patients perceive this more like a relief, which complicates compliance with therapeutic interventions.

Depression

Menstruation may not occur for months or years during manifest or depressive episodes.

Side Effects

Anabolic effects

Hyperandrogenism, often combined with extreme performance sports.

Cushing’s syndrome

The most common cause of hypercortisolism is exposure to exogenous glucocorticoids. Symptoms include not only androgenization of women but also truncal obesity, peripheral muscle wasting, osteoporosis, and arterial hypertension.

Radiotherapy or chemotherapy

Irreversible damage to the ovaries leads to premature menopause.

Psychiatric medications

Exposure to tricyclic antidepressants and neuroleptics, especially risperidone, are potential risk factors for amenorrhea. Treatment with corticosteroids may increase the risk of Cushing’s syndrome.

Additional Tips

Diagnostic skills can be improved based on a few non-invasive approaches, such as medical history, physical examination, complete blood cell counts, hormone tests, and sonography.

Before any further diagnostic evaluation, however, a β-HCG-test is mandatory to exclude pregnancy!

Structural abnormalities of the uterus and outflow tract should be ruled out during the initial evaluation that should also include testing for hyperandrogenism and abnormal FSH levels. Hyperandrogenism is often suggestive of PCOS and rarely indicates 21-hydroxylase deficiency. Elevated FSH levels are commonly seen in ovarian insufficiency.

Patients with normal reproductive structure and either low or normal FSH levels should be tested for abnormally high prolactin levels following drug treatment and diagnosis of prolactinoma. Patients with normal prolactin levels should be evaluated for other causes of amenorrhea such as abnormal TSH, short stature, primary amenorrhea, eating disorders, and other chronic conditions.

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