Updated: Dec 15, 2009
Primary amenorrhea is the failure of menses to occur by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 13, menses has not occurred and the onset of puberty, such as breast development, is absent, a work-up for primary amenorrhea should start. For information on secondary amenorrhea, see Amenorrhea, Secondary.
Menstruation is the cyclic, orderly sloughing of the uterine lining, due to the interactions of hormones produced by the hypothalamus, pituitary, and ovaries.
Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.
The hypothalamic central nervous system discharges gonadotropin-releasing hormone (GnRH), which is transported to the anterior pituitary, where it stimulates the gonadotrophs. In response to stimulation, these cells in turn secrete the gonadotropins follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Furthermore, these tropic hormones stimulate the gonads to synthesize and secrete sex steroids. Hormone release in the hypothalamus-pituitary-ovarian (HPO) axis is regulated by a negative feedback on gonadotrophs in the anterior pituitary and by indirect inhibition at the level of the hypothalamus. Stimulation and negative inhibition complete the pathway between the hypothalamus, pituitary, and ovaries. Any disruption in this axis may result in amenorrhea. A systematic approach to understand pathophysiology of amenorrhea involves defining the level of primary dysfunction.
Hypothalamic dysfunction results in decreased or inhibited GnRH secretion, which affects the pulsatile release of LH and FSH, causing anovulation.
A common cause of amenorrhea is functional hypothalamic amenorrhea.1 It is characterized by abnormal hypothalamic GnRH secretion, decreased gonadotropin pulsations, low or normal LH concentrations, absent LH surges, abnormal follicular development, and low serum estradiol. Serum FSH concentrations are usually in the normal range, with high FSH to LH ratio.2 This can be caused by eating disorders, exercise, or high levels of prolonged physical or mental stress. This can also include major psychiatric disorders such as depression. For further information, see Medscape’s Eating Disorders and Depression Resource Centers.
Congenital GnRH deficiency leads to low gonadotropin levels. When this occurs with anosmia, it is diagnosed as Kallman syndrome. Kallman syndrome may be associated with midline facial defect, renal agenesis, and neurologic deficiency. Most often, it occurs as X-linked recessive disorder. Autosomal dominant and autosomal recessive inheritances are possible but less common. For detailed information, see Gonadotropin-Releasing Hormone Deficiency in Adults.
Evidence suggests a negative correlation between body fat and menstrual abnormalities. A critical body fat level must be present to have a functioning reproductive system. The excessive exercise in which these athletes engage increases the effects of the associated nutritional deficiency. This synergism causes severe suppression of GnRH, leading to the low estradiol levels. The female athletic triad is characterized by disordered eating, amenorrhea, and osteoporosis as defined by the American College of Sports Medicine.1 A 2009 study by DeSouza et al found that about half of exercising women could be amenorrheic.3
Anorexia nervosa is a serious psychiatric disease with severe medical complications including primary amenorrhea (15%), osteopenia (52%), and osteoporosis (35%).4
Functional causes of amenorrhea include severe chronic disease, rapid weight loss, malnutrition, depression or other psychiatric disorders, recreational drug abuse, and psychotropic drug use.
A deficiency in FSH and LH may be a result of GnRH receptor gene mutations. Mutations in the FSH beta gene have been associated with amenorrhea. These women have low FSH and estradiol levels and high LH levels. Primary amenorrhea caused by hyperprolactinemia is a rare condition characterized by the onset of thelarche and pubarche at appropriate ages but arrest of pubertal development before menarche.5 Hyperprolactinemia is associated with suppression of the GnRH from the hypothalamus and subsequent inhibition of LH and FSH, suppressed gonadal function and galactorrhea. Prolactinomas are the most common cause of persistent hyperprolactinemia, accounting for 40-50% of pituitary tumors.6
Pituitary tumors may suppress gonadotropin secretion such as in Cushing disease or hypothalamic tumors, craniopharyngioma, or germinoma. Brain injury or cranial irradiation may also result in amenorrhea. Other pituitary causes include empty sella syndrome, pituitary infarct, hemachromatoses, and sarcoidosis.
Ovarian causes of primary amenorrhea
Gonadal dysgenesis most commonly occurs in Turner syndrome (45, X). Accelerated loss of the germ cells in the gonads occurs. The gonads usually contain only fibrous tissue and are called streak gonads. Gonadotropin levels, especially the FSH levels, are high during early childhood and after 9-10 years of age. Additional anomalies associated with Turner syndrome include short stature, webbed neck, coarctation of the aorta (10%), renal abnormalities (50%), hypertension, pigmented nevi, short forth metacarpal and metatarsals, Hashimoto thyroiditis, obesity, and osteoporosis.1 Depletion of ovarian follicles causes amenorrhea.
Spontaneous 46,XX primary ovarian insufficiency (POI), (also known as premature ovarian failure [POF] and premature menopause) affects 1 in 10,000 women by age 20, 1 in 1,000 women by age 30, 1 in 250 women by age 35, and 1 in 100 women by age 40.7 POI is hypergonadotropic hypogonadism, characterized by oligomenorrhea, estrogen deficiency, and its associated symptoms such as hot flashes, vaginal dryness, dyspareunia, and insomnia. For more detailed information, see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
The fragile X premutation accounts for approximately 6% of cases of overt POI. It is caused by an increased number of CGG repeats in the FMR1 gene located on the long arm of the X-chromosome. In the premutation, the number of CGG repeats ranges from 55-200. Approximately 21% of premutation carriers have POF/POI compared with 1% in the general population.8 Autoimmune oophoritis occurs in 3-4% of POI cases.9
Amenorrhea is also seen in pure 46,XX gonadal dysgenesis and in 46,XY gonadal dysgenesis. These women have significantly elevated FSH levels due to the absence of ovarian follicles and reduction in negative feedback on FSH from estradiol and inhibin A and B.
46,XY gonadal dysgenesis (Swyer syndrome): The early stages of testicular formation require the action of several genes, of which one of the earliest and most important is the sex-determining region of the Y chromosome (SRY). In patients with mutations of the SRY gene, the testes never form and antimüllerian hormone is not produced. As a result, these patients have a vagina, uterus, and fallopian tubes. Germ cells in the ovaries are lost before birth. The streak gonads must be surgically removed because of the increased risk for developing germ cell tumor. Pure gonadal dysgenesis occurs when the syndrome affects the gonad only and no other dysmorphic features are noted.
Polycystic ovarian syndrome (PCOS) usually presents as secondary amenorrhea, but in some cases may present as primary amenorrhea. See Polycystic Ovarian Syndrome for more information.
Congenital and anatomical abnormalities
A uterus and patent vaginal tract are needed for normal menstrual flow to occur. Female reproductive tract abnormalities account for about one fifth of primary amenorrhea cases. Cyclic pelvic pain is common in girls with disorders of the reproductive tract that have outflow obstruction. Imperforate hymen causes an outflow obstruction. These patients can have blood in the vagina that collects and can result in a perirectal mass. Transverse vaginal septum can be anywhere along the tract between the hymenal ring and cervix.
Vaginal agenesis, or müllerian dysgenesis (also known as Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome) is caused by agenesis or partial agenesis of the müllerian duct system. It is characterized by congenital aplasia of the uterus and upper two thirds of the vagina in women showing normal development of the secondary sexual characteristics and a normal 46,XX karyotype.10 The first sign is primary amenorrhea. It affects 1 of 4500 women. It could be associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects.10
Receptor and enzyme defects
Congenital adrenal hyperplasia as a result of 17 alpha-hydroxylase deficiency (CYP17) causes an excess of deoxycortisone to be produced and deficiency of cortisol and adrenal and gonadal sex steroids. Patients with this disorder who experience primary amenorrhea can be either genotypic males (XY) or females (XX).1
Vanishing testes syndrome is characterized by genotypic males 46,XY whose gonads do not develop completely. As a result, no testosterone, estrogen, or müllerian-inhibiting substance is produced. These patients appear phenotypically female. The diagnosis is made from the findings of gonadal failure with lack of pubertal progression, high-serum FSH and LH concentrations, and male karyotype.
Androgen insensitivity syndrome occurs when patients are resistant to testosterone. It is an X linked disease. Patients appear as phenotypically normal females. The testes, located internally and sometimes in the labia or inguinal area, do make müllerian-inhibiting hormone, so all müllerian structures, fallopian tubes, uterus, and upper third of the vagina are absent.
Gonadotropin resistance is rare, but inactivating mutations of the receptors for LH and FSH can cause anovulatory amenorrhea.11
Aromatase deficiency is also a rare disorder. Aromatase catalyzes the conversion of androgen to estrogen. When estrogen synthesis cannot occur, increased levels of testosterone result and virilization of the female occurs. Often, girls have cystic ovaries and resultant amenorrhea.12
Hypothyroidism, hyperthyroidism, sarcoidosis, galactosemia or any severe chronic medical condition may result in amenorrhea.13
The incidence of primary amenorrhea in the United States is less than 1%.14
No evidence indicates that the prevalence of amenorrhea varies according to national origin or ethnic group. However, local environmental factors related to nutrition and the prevalence of chronic disease undoubtedly have an effect. For instance, the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.
Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone. These sex hormones play an important role in building and maintaining bone mass. Late menarche has been associated with a 3-fold increase in the risk of wrist fracture.15
No evidence suggests that the incidence of primary amenorrhea is related to race.
Amenorrhea occurs only in women.
Assessment of the adolescent patient requires a sensitive, age-appropriate approach. Clinicians need to consider the psychosocial age and emotional maturity of the patient, in contrast to the chronological age, when examining the adolescent. The physician should find out how much the patient knows by asking her about her understanding of why she is being seen and what she has been told. The subsequent step is to find out how much the patient wants to know by asking about her concerns and letting questions emerge.
Absence of spontaneous menstruation before age 16 is an indication for a careful review of systems. The menstrual cycle should be viewed as a vital sign. Inquiring about other aspects of growth and pubertal development is important. An absence of any breast development or pubertal growth spurt by age 13-14 years in girls is distinctly abnormal and requires investigation. Breast development, pubertal growth spurt, and adrenarche are delayed or absent in persons with hypothalamic pituitary failure. A distinguishing factor in the case of isolated ovarian insufficiency or failure is that adrenarche occurs normally, while estrogen-dependent breast development and the pubertal growth spurt are absent or delayed.
Pregnancy could be the cause for primary amenorrhea. Determining whether the patient is sexually active and whether she is using contraceptive methods is important. See Medscape's Pregnancy Resource Center.
- Disorders of the outflow tract: A history of otherwise normal growth and pubertal development and cyclic pelvic pain in association with primary amenorrhea suggests the possibility of a congenital outflow tract abnormality such as imperforate hymen or agenesis of the vagina, cervix, or uterus. These findings are also compatible with the complete androgen resistance syndrome.
- Ovarian disorders
- Symptoms of vaginal dryness, hot flashes, night sweats, or disordered sleep may be a sign of ovarian insufficiency or premature ovarian failure. The presence of these symptoms in young women demands further evaluation in a timely manner.
- Prior history of chemotherapy or radiation therapy may be associated with ovarian failure.
- A distinguishing factor in the case of isolated ovarian insufficiency or failure and primary amenorrhea is that adrenarche occurs normally while estrogen-dependent breast development and the pubertal growth spurt are absent or delayed.
- Hypothalamic/pituitary disorders
- Associated galactorrhea, headaches, or reduced peripheral vision could be a sign of intracranial tumor such as prolactinoma. These symptoms require immediate further evaluation.
- An impaired sense of smell in association with primary amenorrhea and failure of normal pubertal development may be related to isolated gonadotropin deficiency, as is observed in persons with Kallmann syndrome.
- Sarcoidosis can manifest insidiously, with development of mild fatigue, malaise, anorexia, weight loss, and fever. Because 90% of patients with sarcoidosis have pulmonary involvement at some stage of the disorder, cough and dyspnea may be present.
- Hemachromatoses may manifest as weakness, lassitude, weight loss, and a change in skin color.
- Functional impairment of the hypothalamic GnRH pulse generator
- Dieting with excessive restriction of energy intake, especially fat restriction, may lead to amenorrhea and associated bone loss. In extreme cases, the process may advance to anorexia nervosa, a potentially fatal condition. Associated symptoms are an intense fear of fatness and a body image that is heavier than observed. Eating disorders can be restrictive in nature or can be of a binge-eating/purging type.
- Major psychiatric disorders such as depression, obsessive-compulsive disorder, or schizophrenia may cause amenorrhea. Symptoms associated with these conditions may be detected upon review of systems.
- Autoimmune adrenal insufficiency, a potentially fatal condition, often manifests as vague and nonspecific symptoms. Amenorrhea may be the first clear symptom indicating a need for further evaluation to detect this condition.
- Amenorrhea may herald the onset of other autoimmune endocrine disorders such as hyperthyroidism, hypothyroidism, or autoimmune lymphocytic hypophysitis. The same is true for other endocrine disorders such as Cushing syndrome or pheochromocytoma. A careful review of symptoms may help uncover these disorders.
- Strenuous exercise related to a wide variety of athletic activities can be associated with the development of amenorrhea. Elicit a history regarding the type of exercise activity and its duration per week.
- Abuse of drugs such as cocaine and opioids have central effects that may disrupt the menstrual cycle.
- AIDS, HIV disease, or other types of immune-deficiency states may induce systemic infection leading to chronic disease and amenorrhea.
- Occult malignancy with progressive weight loss and a catabolic state may lead to loss of menstrual regularity. A careful review of systems may help uncover such a disorder.
Before physical examination, the clinician should engage the adolescent in a discussion to assess her emotional maturity and establish a relationship. As questions emerge, the clinician should share age-appropriate information about the condition, giving the opportunity to respond to the patient’s emotions. After careful preparation and with privacy, the physical and pelvic examination should come later in the assessment.
- Physical examination should begin with an overall assessment of nutritional status and general health. Measure height and weight and seek evidence for chronic disease or cachexia.
- Hypothermia, bradycardia, hypotension, and reduced subcutaneous fat can be observed in persons with severe anorexia nervosa. In cases of frequent vomiting, look for possible dental erosion, reduced gag reflex, trauma to the palate, subconjunctival hemorrhage, and metacarpophalangeal calluses or bruises.
- Skin examination findings can also give clues to other endocrine disorders. Vitiligo or increased pigmentation of the palmar creases may herald primary adrenal insufficiency. Thin, parchmentlike skin, striae, and evidence of easy bruising may be signs of Cushing syndrome. Warm, moist skin radiating excessive heat may be a sign of hyperthyroidism.
- Examine the skin for evidence of androgen excess, such as hirsutism and acne. Acanthosis nigricans may be present in association with androgen excess related to insulin resistance.
- Large pituitary tumors can cause visual-field cuts by impinging on the optic tract. In some cases, these visual-field cuts can be detected by simple confrontational testing.
- Assess the state of breast development. Also examine the breasts for galactorrhea. In some cases, breast discharge can be expressed, yet the condition is not true galactorrhea. If the discharge is indeed milk, this can be confirmed by finding fat globules in the fluid using low-power microscopy.
- Examine for the presence of axillary and pubic hair. These are a marker of adrenal and ovarian androgen secretion. In cases of panhypopituitarism, sources of androgen are low and pubic and axillary hair is sparse. In addition, some women develop the combination of autoimmune premature ovarian failure and autoimmune primary adrenal insufficiency. These women are also markedly androgen-deficient and have scant axillary and pubic hair. The same is true for persons with androgen insensitivity syndrome (testicular feminization), 17-hydroxylase deficiency, and 17,20-desmolase deficiency.
- In cases of primary amenorrhea with otherwise normal pubertal development, pelvic examination may help detect imperforate hymen, a transverse vaginal septum, or cervical or uterine aplasia.
- Pelvic examination findings can provide physical evidence indicating the adequacy of estrogen production. Thin and pale vaginal mucosa with absent rugae is evidence of estrogen deficiency.
- Measuring the clitoris is an effective method for determining the degree of androgen effect. The clitoral index can be determined by measuring the glans of clitoris in the anteroposterior and transverse diameter. A clitoral index greater than 35 mm2 is evidence of increased androgen effect. A clitoral index greater than 100 mm2 is evidence of virilization.
- Ovarian enlargement may be found upon pelvic examination in cases of autoimmune oophoritis, 17-hydroxylase deficiency, or 17,20-desmolase deficiency. In these disorders, inadequate negative feedback supplied by the ovary permits excessive gonadotropin stimulation that may cause ovarian enlargement with multiple follicular cysts. In some cases, these disorders manifest with an acute onset of pain related to ovarian torsion.
- A general physical examination may undercover unexpected findings that are indirectly related to the loss of menstrual regularity (eg, discovery of hepatosplenomegaly, which may lead to detection of a chronic systemic disease).
Amenorrhea can be divided into 2 groups, (1) amenorrhea without evidence of associated androgen excess and (2) amenorrhea with evidence of androgen excess (eg, hirsutism, virilization, sexual ambiguity). For a review of the causes of amenorrhea associated with androgen excess, see Polycystic Ovarian Syndrome.
Primary amenorrhea is usually caused by genetic or anatomic abnormality.
Causes of amenorrhea without associated androgen excess
- Anatomic defects of outflow tract
- Imperforate hymen
- Transverse vaginal septum
- Aplasia of the vagina, cervix, or uterus: Congenital absence of the uterus can be an isolated finding or it can occur in association with the complete androgen resistance syndrome, also known as testicular feminization.
- Ovarian causes
- Karyotypically normal spontaneous primary ovarian insufficiency or premature ovarian failure (For an in-depth discussion, see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure.)
- Turner syndrome
- Pure gonadal dysgenesis: The term pure refers to the fact that the syndrome seems to have purely affected the gonad. No associated dysmorphic findings exist as are noted in Turner syndrome, which is often referred to as gonadal dysgenesis. Pure gonadal dysgenesis can occur with either a 46,XX or a 46,XY karyotype.
- Autoimmune oophoritis
- 17,20-desmolase deficiency or 17-hydroxylase deficiency
- Radiation or chemotherapy before puberty
- FSH receptor mutation
- Pituitary causes
- Other pituitary tumors (Cushing syndrome, acromegaly, thyrotropin secreting tumor)
- Autoimmune hypophysitis
- Pituitary radiation
- Hypothalamic causes
- Tumors such as craniopharyngioma or teratoma
- Infiltrative disorder such as sarcoidosis
- Kallmann syndrome
- Functional causes
- Chronic disease
- Weight loss
- Depression or other psychiatric disorders
- Recreational drug abuse
- Psychotropic drug use
- Excessive exercise
The following are causes of primary amenorrhea (percentages rounded to the nearest tenth).16
- Hypergonadotropic hypogonadism (48.5%)
- Abnormal sex chromosomes (Turner syndrome [29.7%])
- Normal sex chromosomes (46,XX [15.4%]; 46,XY [3.4%])
- Hypogonadotropic hypogonadism (27.8%)
- Congenital abnormalities
- Isolated GnRH deficiency (8.3%)
- Forms of hypopituitarism (2.3%)
- Congenital central nervous system (CNS) defects (0.8%)
- Constitutional delay (6%)
- Acquired lesions
- Congenital adrenal hyperplasia (CAH) (0.8%)
- Cushing syndrome (0.4%)
- Pseudohypoparathyroidism (0.4%)
- Hyperprolactinemia (1.9%)
- Unclassified pituitary adenoma (0.8%)
- Craniopharyngioma (1.1%)
- Unclassified malignant tumor (0.4%)
- Systemic illness (2.6%)
- Eating disorder (2.3%)
- Congenital abnormalities
- Eugonadism (23.7%)
- Congenital absence of the uterus and vagina (CAUV) (16.2%)
- Cervical atresia (0.4%)
- Intersex disorders
- Androgen insensitivity (1.5%)
- 17-ketoreductase deficiency (0.4%)
- Inappropriate feedback (5.3%)
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amenorrhea, primary amenorrhea, secondary amenorrhea, hypothalamic amenorrhea, pituitary amenorrhea, menstruation, absence of menstruation, gonadotropin-releasing hormone, GnRH, follicle-stimulating hormone, FSH, luteinizing hormone, LH, hypothalamus-pituitary-ovarian axis, HPO