History
An adequate history includes childhood growth and development and other areas, including height and weight charts and age at thelarche and menarche. Ascertaining the age at menarche of the patient's mother and sisters is advisable because the age at menarche in family members can occur within a year of the age in others. The duration and flow of menses, cycle days, day and date of last menstrual period, presence or absence of molimina (breast soreness and mood change immediately before menses) are necessary pieces of information.
Any history of chronic illness, trauma, surgery, and medications is also important. A sexual history should be obtained in a confidential manner. Information regarding substance use, exercise, diet, home and school situations, and psychosocial issues should be elicited. A comprehensive review of symptoms should include vasomotor symptoms, hot flashes, virilizing changes, galactorrhea, headache, fatigue, palpitations, nervousness, hearing loss, and visual changes.
Primary amenorrhea
Assessment of the adolescent patient requires a sensitive, age-appropriate approach. Clinicians need to consider the psychosocial age and emotional maturity of the patient, rather than simply 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 years 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 girls 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.
Secondary amenorrhea
Loss of menstrual regularity is an indication for a careful review of systems. The menstrual cycle should be viewed as a vital sign. Loss of menstrual regularity may be the first clear symptom heralding the onset of a major illness or systemic disease. Viewing the menstrual cycle as a vital sign may lead to earlier diagnosis of, and intervention for, several potentially life-threatening disorders. The clinician need not wait for an arbitrarily defined duration of amenorrhea to pass before taking corrective action.
Amenorrhea can be due to pregnancy, anatomic defects of the outflow tract, ovarian disorders, and pituitary or hypothalamic disorders. In some cases, the cause is functional, meaning that the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator has shut down the reproductive system in its role as an integrator of metabolic and psychogenic stress.
Attributing the loss of menstrual regularity to a recent stressful life event is tempting; however, this approach can delay the detection of significant pathology that can have long-term health consequences. One study has shown that one third of women in a control group report a significant stressful life event in the preceding year.
Pregnancy is the most common cause of amenorrhea. Determining whether the patient is sexually active and whether she is using contraceptive methods is important. In some cases, hormonal contraception itself may be the cause of the amenorrhea.
Taking a careful patient history is paramount in deciphering potential etiologies of secondary amenorrhea. Often, time constraints do not permit practitioners to obtain a thorough history and review of symptoms on the first visit. Scheduling a repeat visit to permit a more thorough evaluation may be necessary.
Another option is to use standardized history-taking instruments to collect this information in preparation for a return visit. In other cases, patients may be asked to keep a menstrual calendar and return in 3 months for reassessment. The importance of the ovary as an endocrine organ that helps maintain bone density should be stressed to the patient to help ensure proper follow-up.
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.
Prior history of a surgical procedure involving the endometrial cavity, especially if performed in the presence of infection, raises the possibility of uterine synechiae (Asherman 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. A prior history of chemotherapy or radiation therapy may be associated with ovarian failure.
Autoimmune oophoritis may be associated with autoimmune adrenal insufficiency, a potentially fatal condition that often manifests as vague and nonspecific symptoms. Loss of menstrual regularity may be the first clear symptom indicating a need for further evaluation to detect this condition.
PCOS is one of the most common causes of secondary amenorrhea. The two most commonly used definitions of PCOS are the Rotterdam criteria [29] and the Androgen Excess and PCOS (AE-PCOS) Society criteria. [30] Both recognize menstrual cycle irregularity and polycystic-appearing ovaries on ultrasonographic examination as defining characteristics of PCOS, but the Rotterdam criteria does not require androgen expression, while the AE-PCOS Society criteria requires increased androgen expression or serum elevations. In 2012, a National Institutes of Health committee on PCOS sided with the broad diagnosis set forth by the Rotterdam committee.
Hypothalamic/pituitary disorders
Associated galactorrhea, headaches, or reduced peripheral vision could be a sign of an anterior pituitary adenoma. These symptoms require immediate further evaluation. However, secondary amenorrhea may be the only overt symptom of a small prolactinoma.
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.
Neurosarcoidosis can infiltrate the hypothalamus and/or pituitary and cause hypogonadotropic hypogonadism, leading to disrupted menses. 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.
Hemochromatosis may manifest as weakness, lassitude, weight loss, and a change in skin color.
Anti-CLTA 4 antibodies for immunotherapy may lead to hypophysitis with resultant amenorrhea. [80]
A history of hemorrhage after childbirth with subsequent failure of regular menses to return may be an indication of postpartum pituitary necrosis (Sheehan syndrome). Failure of lactation is an even earlier sign. Detecting this condition early is important because of the possible development of associated central adrenal insufficiency, a potentially fatal condition.
Functional hypothalamic impairment
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.
Orthorexia is characterized by obsession with eating healthy or organic foods, often to the detriment of a patient’s health. This is currently classified as an “eating disorder not otherwise specified” in the DSM-IV-TR. Patients with orthorexia may also restrict specific nutrients and calories from their diet and develop amenorrhea and its long-term health consequences, namely, low bone mineral density. [31]
Major psychiatric disorders such as depression, obsessive-compulsive, or schizophrenia may cause amenorrhea. Symptoms associated with these conditions may be detected upon review of systems. In these cases, secondary amenorrhea may be due to the psychiatric disorder itself, as these are chronic disease states, or amenorrhea may be related to necessary medications, such as antipsychotic or antiepileptic drugs.
Autoimmune adrenal insufficiency is a rare disorder and a potentially fatal condition, often manifesting as vague and gradually evolving nonspecific symptoms such as fatigue, anorexia, and weight loss. Occasionally, an acute crisis can become life threatening, owing to the sudden interruption of a normal or hyperfunctioning adrenal or pituitary gland or a sudden interruption of adrenal replacement therapy. Clinical suspicion mandates appropriate diagnostic screening and early intervention with sodium chloride–containing fluids and hydrocortisone replacement. Long-term management of patients with adrenal insufficiency requires an experienced specialist as management can be challenging. All clinicians should have some basic knowledge of when to suspect and begin the diagnostic workup of suspected acute adrenal failure. [32]
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.
Both extreme thinness or rapid weight loss and morbid obesity or rapid weight gain may result in amenorrhea by altering pulsatile GnRH release.
History of excessive food intake may be due to Prader-Willi syndrome [33] or leptin deficiency, [34] both of which cause both extreme obesity and amenorrhea.
Women with hypothalamic amenorrhea have lower serum leptin concentrations, which may contribute to their low gonadotropin secretion. Leptin administration resulted in improvement of the reproductive axis in one study of women with functional hypothalamic amenorrhea. [35, 36]
Kisspeptin, a neural signal that acts directly on GnRH neurons to stimulate neuronal firing, and which may act downstream from leptin as an integrator of metabolic cues to the GnRH pulse generator, is also down regulated in cases of hypothalamic amenorrhea. Interestingly, exogenous administration of kisspeptin to women with hypothalamic amenorrhea acutely stimulates gonadotropin secretion, an effect similar to what is seen with leptin administration. [37]
Drugs
When taking the medication history, consider the following:
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Abuse of drugs such as cocaine and opioids have central effects that may disrupt the menstrual cycle
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Use of antiepileptics is associated with amenorrhea
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Use of birth control pills or other hormonal therapies may be associated with disordered menses
Chronic diseases
Malnutrition and cirrhosis associated with alcoholism may cause loss of menstrual regularity. AIDS, HIV disease, or other types of immune-deficiency states may induce systemic infection, lipodystrophy, or other chronic health complications, leading to loss of menstrual regularity.
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.
Sickle cell disease [38] and thalassemia [39] are associated with amenorrhea.
Type 1 and type 2 diabetes may both be associated with disordered menses. [40]
Epilepsy itself, as well as antiepileptic medications, are associated with reproductive dysfunction in women. The etiology of menstrual cycle abnormalities in epileptic females may vary and includes polycystic ovarian syndrome (PCOS), hypothalamic amenorrhea, and hyperprolactinemia. [41]
Chronic kidney disease requiring hemodialysis is associated with loss of menstrual cyclicity and vitamin D deficiency, putting patients at high risk of bone mineral density loss. [42]
Physical Examination
In the case of primary amenorrhea, 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
General physical examination
A general physical examination may identify features of many of the disorders that underlie amenorrhea. In addition, it may uncover 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).
Physical examination should begin with an overall assessment of sexual development, nutritional status, and general health. Measure height and weight and seek evidence for chronic disease, cachexia, or obesity.
In anorexia nervosa, hypothermia, bradycardia, hypotension, and reduced subcutaneous fat may be observed. Other findings include yellow skin (carotenemia) and a body mass index (BMI) of less than 18 kg/m2. In cases of frequent vomiting, look for possible dental erosion, reduced gag reflex, trauma to the palate, subconjunctival hemorrhage, and metacarpophalangeal calluses or bruises.
Examine the skin for evidence of androgen excess, such as hirsutism, hair loss, and acne. Acanthosis nigricans may be present in association with androgen excess related to insulin resistance (eg, diabetes, polycystic ovarian syndrome (PCOS). A BMI of more than 30 kg/m2 is common.
Examine for stigmata of Turner syndrome (short stature, webbed neck, low-set hairline and/or ears, pubertal delay, cubitus valgus, nail hypoplasia, short fourth metacarpal, high-arched palate, chronic otitis media, cardiac abnormalities).
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, parchment-like skin, wide purplish striae, and evidence of easy bruising may be signs of Cushing syndrome. Warm, moist skin radiating excessive heat may be a sign of hyperthyroidism.
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.
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.
Also, 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, 17-hydroxylase deficiency, and 17,20-desmolase deficiency.
Breast examination
Assess the state of breast development. Delayed puberty results in underdeveloped breasts with sparse pubic hair, whereas gonadal dysgenesis (eg, Turner syndrome) results in undeveloped breasts with normal growth of pubic hair.
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.
Pelvic examination
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. If the uterus is enlarged, pregnancy must be excluded.
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.
The presence of cervical mucus with spinnbarkeit is good evidence of estrogen effect. However, evidence of estrogen effect detected on physical examination findings can be misleading in some cases because estrogen is being produced as a result of higher-than-normal follicle-stimulating hormone (FSH) levels (compensated ovarian insufficiency). Women with well-established premature ovarian failure often have intermittent ovarian follicle function that produces enough estrogen to have vaginal and cervical effects.
Measuring the clitoris is an effective method for determining the degree of androgen effect. The clitoral index is the product of the sagittal and transverse diameters of the glans of the 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, which may cause ovarian enlargement with multiple follicular cysts. In some cases, these disorders manifest with an acute onset of pain related to ovarian torsion. Ovarian enlargement is also commonly associated with PCOS.
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Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.
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Primary amenorrhea flowchart.
