Amenorrhea

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Background

Amenorrhea is the absence of menstrual bleeding.[1] Amenorrhea is a normal feature in prepubertal, pregnant, and postmenopausal females. In females of reproductive age, diagnosing amenorrhea is a matter of first determining whether pregnancy is the etiology. In the absence of pregnancy, the challenge is to determine the exact cause of absent menses.[2]

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 workup for primary amenorrhea should start.

Secondary amenorrhea is defined as the cessation of menses sometime after menarche has occurred. Oligomenorrhea is defined as menses occurring at intervals longer than 35 days.

No consensus has been reached regarding the point at which oligomenorrhea becomes amenorrhea. Some authors suggest the absence of menses for 6 months constitutes amenorrhea, but the basis for this recommendation is unclear. For a postmenarchal girl or a reproductive-aged woman to experience a menstrual cycle interval of more than 90 days is statistically unusual. Practically speaking, this should be an indication for an evaluation to seek the cause.

Pathophysiology

The menstrual cycle is an orderly progression of coordinated hormonal events in the female body that stimulates growth of a follicle to release an egg and prepare a site for implantation if fertilization should occur. Menstruation occurs when an egg released by the ovary remains unfertilized; subsequently, the soggy decidua of the endometrium (which was primed to receive a fertilized egg) is sloughed in a flow of menses in preparation for another cycle.

The menstrual cycle can be divided into 3 physiologic phases: follicular, ovulatory, and luteal. Each phase has a distinct hormonal secretory milieu. Consideration of the target organs of these reproductive hormones (hypothalamus, pituitary, ovary, uterus) is helpful for identifying the disease process responsible for a patient’s amenorrhea.

Follicular phase

In physiologic terms, the first day of menses is considered the first day of the menstrual cycle. The following 13 days of the cycle are designated the follicular phase. As levels of progesterone, estradiol, and inhibin decline 2-3 days before menses, the pituitary begins to release higher levels of follicle-stimulating hormone (FSH), which recruits oocytes for the next menstrual cycle. The hypothalamus is the initiator of the follicular phase via gonadotropin-releasing hormone (GnRH).

The GnRH pump in the hypothalamus releases GnRH in a pulsatile fashion into the portal vessel system surrounding the anterior pituitary gland. GnRH interacts with the anterior pituitary gland to stimulate release of FSH in the follicular phase. FSH is secreted into the circulation and communicates with the granulosa cells surrounding the developing oocytes.

As FSH increases during the early portion of the follicular phase, it meshes with granulosa cells to stimulate the aromatization of androgens into estradiol. The increase in estradiol and FSH leads to an increase in FSH-receptor content in the many developing follicles.

Over the next several days, the steady increase of estradiol (E2) levels exerts a progressively greater suppressive influence on pituitary FSH release. Only one selected lead follicle, with the largest reservoir of estrogen, can withstand the declining FSH environment. The remaining oocytes that were initially recruited with the lead follicle undergo atresia. Immediately prior to ovulation, the combination of E2 and FSH leads to the production of luteinizing-hormone (LH) receptors on the granulosa cells surrounding the lead follicle.

During the late follicular phase, estrogen has a positive influence on LH secretion, instead of suppressing pituitary LH secretion as it does early in the follicular phase. To have this positive effect, the E2 level must achieve a sustained elevation for several days. The LH surge promotes maturation of the dominant oocyte, the release of the oocyte and then the luteinization of the granulosa cells and the surrounding theca cells of the dominant follicle resulting in progesterone production.

The appropriate level of progesterone arising from the maturing dominant follicle contributes to the precise timing of the midcycle surge of LH. E2 promotes uterine endometrial gland growth, which allows for future implantation.

Ovulatory phase

Ovulation occurs approximately 34-36 hours after the onset of the LH surge or 10-12 hours after the LH peak and 24-36 hours after peak E2 levels. The rise in progesterone increases the distensibility of the follicular wall and enhances proteolytic enzymatic activity, which eventually breaks down the collagenous follicular wall.

After the ovum is released, the granulosa cells increase in size and take on a yellowish pigmentation characteristic of lutein. The corpus luteum then produces estrogen, progesterone, and androgens and becomes increasingly vascularized.

Luteal phase

The lifespan and steroidogenic capacity of the corpus luteum depends on continued LH secretion from the pituitary gland. The corpus luteum secretes progesterone that interacts with the endometrium of the uterus to prepare it for implantation. This process is termed endometrial decidualization.

In the normal ovulatory menstrual cycle, the corpus luteum declines in function 9-11 days after ovulation. If the corpus luteum is not rescued by human chorionic gonadotropin (hCG) hormone from the developing placenta, menstruation reliably occurs 14 days after ovulation. If conception occurs, placental hCG interacts with the LH receptor to maintain luteal function until placental production of progesterone is well established.

Puberty

At birth, female infants have a predetermined number of primordial follicles that are arrested during meiosis 1 at the diplotene stage of prophase until stimulation at puberty. Until puberty, the hypothalamus is in a quiescent state. At approximately age 8 years, GnRH is synthesized in the hypothalamus and released. The adrenal cortex begins to produce dehydroepiandrostenedione to initiate the start of adrenarche (ie, the development of sexual hair).

The orderly progression of puberty begins with breast budding (thelarche), accelerated growth, and menses (menarche). Pubarche, which is independent from GnRH function, typically occurs between breast budding and accelerated growth but may occur anywhere along the puberty timeline. In the United States, the average age of girls at menarche is 12.6 years, with a range of 9-15 years. (Age 15 years is 2 standard deviations above the mean, while age 16 years is 3 standard deviations above.)

Menarche and sustained menstrual cycles requires normal function of the endocrine axis comprising the hypothalamus, pituitary, and ovaries (see the image below). Any disruption in this axis may result in amenorrhea. Defining the level of primary dysfunction is critical in determining the pathophysiology of amenorrhea.


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Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.

Types of amenorrhea based on HPO axis etiology

Hypothalamic amenorrhea

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.[3] 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.[4]

Functional hypothalamic amenorrhea 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. Hypothyroidism, hyperthyroidism, sarcoidosis, galactosemia or any severe chronic medical condition may result in amenorrhea.[5]

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 is an 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 levels and menstrual abnormalities. A critical body fat level must be present for the reproductive system to function normally.

In some female athletes, the synergistic effects of excessive exercise and disordered eating cause severe suppression of GnRH, leading to low estradiol levels. The female athletic triad, as defined by the American College of Sports Medicine, is characterized by disordered eating, amenorrhea, and osteoporosis.[3] A 2009 study by DeSouza et al found that about half of exercising women could be amenorrheic.[6]

Anorexia nervosa is a serious psychiatric disease with severe medical complications including primary amenorrhea (15%), osteopenia (52%), and osteoporosis (35%).[7]

Functional causes of amenorrhea include severe chronic disease, rapid weight loss, malnutrition, depression or other psychiatric disorders, recreational drug abuse, and psychotropic drug use.

Pituitary amenorrhea

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.[8]

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.[9]

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 age 9-10 years.

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.[3] 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 years, 1 in 1,000 women by age 30 years, 1 in 250 women by age 35 years, and 1 in 100 women by age 40 years.[10] 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 permutation 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 permutation, the number of CGG repeats ranges from 55-200. Approximately 21% of permutation carriers have POF/POI compared with 1% in the general population.[11] Autoimmune oophoritis occurs in 3-4% of POI cases.[12]

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.

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 Swyer syndrome, the fetus has a 46,XY karyotype but with mutations of the SRY gene such that the testes never form and antimüllerian hormone is not produced.

As a result, these individuals 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 gonads 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 involving 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.[13] The first sign is primary amenorrhea. It affects 1 of 4500 women. It can be associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects.[13]

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).[3]

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.[14]

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.[15]

Etiology

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.

Causes of primary amenorrhea

First and fore most, it is imperative to rule out pregnancy. Additional diagnoses of primary amenorrhea usually result from a genetic or anatomic abnormality. The relative prevalence of primary amenorrhea (percentages rounded to the nearest tenth) includes hypergonadotropic hypogonadism (48.5% of cases), hypogonadotropic hypogonadism (27.8%), and eugonadism (pubertal delay with normal gonadotropins; 23.7%).[16]

The hypergonadotropic hypogonadism category includes patients with abnormal sex chromosomes (ie, Turner syndrome), who make up 29.7% of all primary amenorrhea cases, and those with normal sex chromosomes. The latter group includes both patients who are 46,XX (15.4%) and those who are 46,XY (3.4%).

Hypogonadotropic hypogonadism includes the following:

Congenital abnormalities that can cause hypogonadotropic hypogonadism include the following:

Endocrine disorders that can cause hypogonadotropic hypogonadism include the following:

Tumors that can cause hypogonadotropic hypogonadism include the following:

Eugonadism may result from anatomic abnormalities or intersex disorders. Anatomic abnormalities include congenital absence of the uterus and vagina (CAUV; 16.2%) and cervical atresia (0.4%). Intersex disorders include androgen insensitivity (1.5%), 17-ketoreductase deficiency (0.4%), and inappropriate feedback (5.3%).

Causes of secondary amenorrhea

Disorders associated with a low or normal FSH, which account for 66% of cases of secondary amenorrhea, include the following[17] :

Disorders in which the FSH is high (12%) include the following:

Disorders associated with a high prolactin level comprise 13% of cases. Anatomic disorders (ie, Asherman syndrome) account for 7%.

Hyperandrogenic states as a cause of secondary amenorrhea (2%) include the following:

Epidemiology

The incidence of primary amenorrhea in the United States is less than 1%.[18] Each year, approximately 5-7% of menstruating women in the US experience 3 months of secondary amenorrhea

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.

Recent increases in the rates of childhood obesity around the world may also contribute to earlier onset of menarche and increased prevalence of obesity-related menstrual disorders, especially in areas where obesity is more prevalent.[19] Exposure to environmental toxins, namely hormonally active endocrine disruptors, may also result in increased rates of menstrual and reproductive disorders in endemic areas.[20]

Prognosis

Loss of menstrual regularity has been associated with an increased risk of wrist and hip fractures related to reduced bone density, even without the development of amenorrhea. A later menarche and menstrual cycle intervals longer than 32 days have both been associated with increased fracture rates in later years. Young women with ovarian insufficiency that is unresponsive to therapy require hormone replacement to maintain bone density.

Adolescence is a critical period for bone accretion as over half of peak bone mass is achieved during the teenage years.[21] Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone, all of which 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.[22]

In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, follicle depletion progresses to cause irreversible infertility. Approximately 10% of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian failure or primary ovarian insufficiency.

Patient Education

For patients with ovarian insufficiency that persists despite appropriate evaluation and treatment, careful counseling is warranted to stress the need for ongoing attention to the factors that help maintain bone density. Hormone replacement therapy is important for these patients. Other factors to consider are the need for adequate calcium and vitamin D intake (1200-1500 mg/d of elemental calcium and 1000 IU/d of vitamin D) and the need for 20-30 minutes of weight-bearing exercise each day.

For patient education information, see the Women's Health Center, Eating Disorders Center, and Pregnancy and Reproduction Center, as well as Amenorrhea, Anorexia Nervosa, Birth Control Overview, and Birth Control FAQs.

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.

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.

Hemachromatosis may manifest as weakness, lassitude, weight loss, and a change in skin color.

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.[23]

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.[24]

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-Wili syndrome[25] or leptin deficiency,[26] 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.[27]

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 downregulated 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.[28]

Drugs

When taking the medication history, consider the following:

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[29] and thalassemia[30] are associated with amenorrhea.

Type 1 and type 2 diabetes may both be associated with disordered menses.[31]

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.[32]

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.[33]

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, parchmentlike 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 (testicular feminization), 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 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.

Approach Considerations

In most cases, clinical variables alone are not adequate to define the pathophysiologic mechanism disrupting the menstrual cycle. The clinician must be concerned with an array of potential diseases and disorders involving many organ systems. However, the history and physical findings help in selecting tests.

Thyroid-stimulating hormone (TSH), prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) measurements are always the first line of testing. If hirsutism is predominant upon examination, include androgen testing: measure testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17-OH progesterone to determine the organ of cause (eg, adrenal gland vs ovary).

If the history or physical findings suggest a chronic disease process, indicated tests may include of the erythrocyte sedimentation rate (ESR), liver function tests, blood urea nitrogen (BUN) determination, creatinine determination, and urinalysis.

If the history and physical findings suggest a delay in puberty, assessing FSH and LH levels and determining bone age are important in differentiating pubertal delays as a cause.

Testing in secondary amenorrhea

Pregnancy is the most common cause of secondary amenorrhea. A pregnancy test (measurement of serum or urinary human chorionic gonadotropin) is recommended as a first step in evaluation of a secondary amenorrhea.

After pregnancy testing, all women who present with 3 months of secondary amenorrhea should have a diagnostic evaluation initiated at that visit. As stated by Speroff et al, "Few problems in gynecologic endocrinology are as challenging or taxing to the clinician as amenorrhea. The clinician must be concerned with an array of potential diseases and disorders involving, in many instances, unfamiliar organ systems, some carrying morbid and even lethal consequences for the patient."[40]

A complete blood cell count, urinalysis, and serum chemistries should be evaluated to help rule out systemic disease. Serum prolactin, FSH, estradiol, and thyrotropin levels should also be measured routinely in the initial evaluation of amenorrhea once pregnancy has been excluded.

Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs. Magnetic resonance imaging can detect hypothalamic/pituitary lesions. Hysterosalpingography and hysteroscopy are indicated in cases of possible Asherman syndrome.

Hormonal Studies

Hormonal studies may include assays of prolactin, FSH, LH, estradiol, thyroid hormones, or androgens.

Prolactin

Prolactin levels in excess of 200 ng/mL are not observed except in the case of prolactin-secreting pituitary adenoma (prolactinoma). In general, the serum prolactin level correlates with the size of the tumor. For more details, see Hyperprolactinemia.

Psychotropic drugs, hypothyroidism, stress, and meals can also raise prolactin levels. Repeatedly elevated prolactin levels require further evaluation if the cause is not readily apparent.

FSH, LH, and estradiol

An FSH level of approximately 40 mIU/mL is indicative of ovarian insufficiency. However, this is assay-dependent and some patients have a lower menopausal level of FSH; check the reference range for the laboratory where the test is performed. If a repeat value in 1 month confirms this finding and amenorrhea still persists, then the diagnosis of premature ovarian failure/primary ovarian insufficiency is confirmed.

LH levels are elevated in cases of 17,20 lyase deficiency, 17-hydroxylase deficiency, and premature ovarian failure.

Serum estradiol levels undergo wide fluctuations during the normal menstrual cycle. During the early follicular phase of the menstrual cycle, levels may be lower than 50 pg/mL. During the preovulatory estradiol surge, levels in the range of 400 pg/mL are not uncommon. In healthy menopausal women, estradiol levels are routinely lower than 20 pg/mL.

Thyroid hormones

Disorders of the thyroid gland may result in menstrual irregularities; however, for it to present as primary amenorrhea is uncommon. Measure thyrotropin and free thyroxine (T4)if symptoms of hypothyroidism or hyperthyroidism are present.

Androgens

Checking levels of testosterone and dehydroepiandrosterone sulfate helps identify hyperandrogenic conditions resulting in amenorrhea. For more details, see Polycystic Ovarian Syndrome.

Imaging Studies to Consider

Ultrasonography

Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs. However, a report of absence of the uterus on ultrasonography does not always mean that the patient does not have a uterus. In primary amenorrhea in association with estrogen deficient states, the uterine fundus may be underdeveloped and may not be readily visible at the time of ultrasonography to less experienced examiners. With proper estrogen replacement, it may reach the normal size.

Pelvic ultrasonography may be helpful in determining ovarian morphology as well. However, in most cases of amenorrhea without androgen access, the information obtained with ovarian ultrasonography does not change clinical management.

Magnetic resonance imaging

MRI of the pituitary and hypothalamus is often indicated in the evaluation of amenorrhea. Request imaging of the hypothalamic/pituitary area specifically, rather than a study of the entire brain. This achieves higher resolution. MRI is indicated in the following circumstances:

Questionnaires

Several validated tools are available to measure dietary intake, mood disorder, and eating disorders. These tools include the following:

Progesterone Withdrawal Test

Prior to the development of readily available assays to measure serum levels of estradiol, the progesterone challenge test was used as a bioassay with which to demonstrate estrogen effect at the level of the endometrium. Progesterone has been shown to predictably induce a withdrawal bleed if the circulating serum estradiol level is at least 50 pg/mL. However, the progesterone withdrawal test can provide inappropriately reassuring information that may delay the etiology of ovarian insufficiency.

The progesterone withdrawal test is no substitute for evaluating ovarian health. Demonstrating the presence of normally functioning ovaries requires the concurrent measurement of serum estradiol and FSH.

Algorithms for Evaluation of Amenorrhea

Amenorrhea with delayed puberty

Obtain studies of thyroid function (thyroid-stimulating hormone [TSH] and thyroxine [T4]) and bone age. If TSH levels are elevated and T4 levels are low, the cause is hypothyroidism. If the bone age is delayed, the cause is constitutional delay.

If the bone age is normal, obtain LH, FSH, and prolactin levels. If LH and FSH levels are elevated, obtain a karyotype.

If the karyotype is 45,X, the cause is gonadal dysgenesis (ie, Turner syndrome). Amenorrhea can also occur when 1 of the 2 X chromosomes is abnormal, such as a ring chromosome, or if a partial loss of the p or q arm of the X chromosome occurs. If the karyotype is 46,XX, the primary cause is ovarian failure from pure gonadal dysgenesis.

Perform an autoimmune workup. Consider an etiology of autoimmune oophoritis, effects of radiation therapy or chemotherapy, 17-alpha-hydroxylase deficiency, or resistant ovary syndrome. Check for neurosensory loss.

If the karyotype is 46,XY, the cause is Swyer syndrome. The patient has streak gonads and neither testosterone nor Müllerian inhibitory factor (MIS) is produced; thus, the patient has a female phenotype and does not enter puberty. These gonads have an increased incidence of malignant transformation and should be removed.

If LH and FSH levels are low or within the reference range and bone age is normal, obtain a head MRI. If head MRI findings are abnormal, the cause is pituitary tumor, pituitary destruction, or hypothalamic disease

If prolactin levels are elevated, obtain a head MRI. If head MRI findings are abnormal, the cause is pituitary tumor or a brain lesion disrupting the pituitary stalk. If the MRI finding is normal, the cause may be marijuana use or psychiatric medicine, specifically dopamine antagonist medications, which lead to a decrease in prolactin inhibiting factor and a subsequent increase in serum prolactin levels.

If head MRI findings are normal with normal history and physical examination findings, the etiology may be drug use, an eating disorder, athleticism, or psychosocial stress.

If head MRI findings are normal but clinical evaluation and screening study findings are abnormal, chronic disease can be excluded.

Amenorrhea with normal puberty with uterus present

Obtain a pregnancy test. If the pregnancy test result is positive, refer the patient to the appropriate specialist. If the pregnancy test result is negative, obtain TSH, prolactin, FSH, and LH levels.

If the TSH level is elevated, the diagnosis is hypothyroidism. If the prolactin level is elevated, the diagnosis is hyperprolactinemia. Causes include prolactinoma, CNS tumors, and medications. MRI is indicated.

If the FSH level is low, obtain head MRI. If MRI findings are abnormal, consider hypothalamic disease, pituitary disease, or pituitary tumor. If MRI findings are normal, proceed with clinical evaluation to exclude chronic disease, anorexia nervosa, marijuana or cocaine use, and social or psychological stresses.

If FSH is elevated, premature ovarian failure is the diagnosis. Obtain a karyotype. If the karyotype is abnormal, mosaic Turner syndrome may be present. If the karyotype is normal (46,XX), the cause is premature ovarian failure. An association with fragile X syndrome may be observed.[43] If fragile X syndrome is present, family members should be offered genetic testing.

Consider premature ovarian failure due to the following:

If TSH, prolactin, and FSH levels are within reference range, perform a progestin challenge test. If withdrawal bleeding occurs, consider anovulation secondary to PCO syndrome. If no withdrawal bleed occurs, proceed with estradiol (E2) priming, followed by a progestin challenge.

If the challenge does not induce menses, consider Asherman syndrome, outlet obstruction, or endometrial thinning secondary to elevated androgens (PCO syndrome) or hypothalamic amenorrhea with decreased estrogen production.

If the challenge induces menses, a hypothalamic dysfunction with low circulating E2 is present. Acquired hypothalamic causes of amenorrhea after puberty has been achieved is a diagnosis of exclusion. The FSH and LH levels may be low or may be below the reference range. The causes include eating disorders, caloric restriction, exercise, stress, and medications.

If hirsutism and/or acne are present, check testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxy (17-OH) progesterone level. If the testosterone and DHEAS levels are within the reference range or are moderately elevated, perform a progesterone challenge. If withdrawal bleeding occurs, the diagnosis is PCOS. If the 17-OH progesterone level is elevated, the diagnosis is adult-onset adrenal hyperplasia.

If the testosterone level or DHEAS is 2 or more times higher than the reference range, consider PCOS, hyperthecosis, or an androgen-secreting tumor of the ovary or adrenal gland

Amenorrhea with genital tract abnormalities

Obtain a pelvic sonography. If the uterus is absent and the vagina foreshortened, obtain a karyotype. If the karyotype is 46,XY, obtain testosterone levels.

If testosterone levels are within reference range or are high (male range), the cause is androgen insensitivity or 5-alpha-reductase deficiency. Surgical gonad removal is recommended in patients with androgen insensitivity. If testosterone levels are within reference range or are low (female range), the cause is testicular regression or gonadal enzyme deficiency. Surgical gonad removal is recommended.

If the karyotype is 46,XX, the cause is Müllerian agenesis (ie, Rokitansky-Kuster-Hauser syndrome).

Approach Considerations

Treatment is determined by the etiology of the amenorrhea and the desires of the patient. Ideally, treatment should be directed at correcting the underlying pathology. In the case of outflow tract abnormalities (eg, imperforate hymen), surgery may be indicated. In other cases, correcting the underlying pathology should restore normal ovarian endocrine function and prevent the development of osteoporosis.

Dopamine agonists are effective in treating hyperprolactinemia. In most cases, this treatment restores normal ovarian endocrine function and ovulation.

Hormone replacement therapy is required to achieve peak bone density in patients whose underlying pathology cannot be reversed to restore normal endocrine function. In conditions leading to estrogen deficiency, hormone replacement therapy is required to maintain bone density, and it may have other possible health benefits in patients whose underlying pathology cannot be reversed to restore normal endocrine function.

Women with evidence of hyperandrogenism and disordered menses have many other medical issues that must be addressed (eg, polycystic ovarian syndrome).

Gonadotropin therapy or the use of pulsatile gonadotropin-releasing hormone (GnRH) therapy may be required to induce ovulation in patients with infertility whose underlying pathology cannot be reversed.

Other than pregnancy, constitutional delay, anovulation, and chronic illness, most other disorders that cause amenorrhea may require referral to a subspecialist for treatment. Many of the treatment methods require surgery or specific therapies. For the adolescent with constitutional delay and anovulation, the goal should be the restoration of ovulatory cycles. If ovulatory cycles are not spontaneously restored, estrogen-progestin therapy is indicated.

Osteoporosis prevention

Evidence is mounting that loss of menstrual regularity is a risk factor for later development of osteoporosis and hip fractures. Both patients and clinicians need to view the ovary as an important endocrine organ that helps maintain healthy bones. Excessive delay in the evaluation and treatment of disordered menses can contribute to osteoporosis. At some point, failure to promptly evaluate for the presence of ovarian insufficiency could become a medicolegal pitfall.

Many patients are deficient in their body stores of vitamin D, reflected by a serum 25-hydroxy vitamin D level less than 30 nmol/L. If this is the case, patients should be treated for 8-12 weeks with high-dose vitamin D, 50,000 IU/week, for repletion. Once the 25-OH-D level is greater than 30 nmol/L, 1000 IU/d of vitamin D may be instituted.

Emotional health concerns

Primary amenorrhea and the potential for impaired fertility affect the emotional health of the adolescent and her family. Adolescence encompasses a broad spectrum of emotional maturity, which needs to be considered in assessment and treatment. For the adolescent girl, a reproductive disorder impacts her developing sense of self, body-image, and sexuality, which, in turn, can affect her self-esteem and relationships with others.

Because of the sexual nature of a reproductive disorder, feelings of embarrassment, inadequacy, or protectiveness can make it difficult for families. Families should be encouraged to be open and honest regarding the condition and discouraged from keeping the diagnosis a secret.

The family is an emotional unit and a family systems approach to deal with health issues is most appropriate. Parents must first deal with their own feelings about the condition before they can help their child. They must also be provided with tools to build an ongoing conversation with their child. Physicians need to be culturally sensitive because in some cultures a woman's identity in adulthood as a mother could play a crucial role in her life. The objective is to help the adolescent girl formulate positive self-esteem and body image, despite impaired fertility.

Treatment of Common Causes

In the overall management of females with amenorrhea, remembering the most likely causes that may present in an outpatient setting is helpful. The following information is a guide to managing the most common causes.

Although the differential diagnosis for amenorrhea is broad, most patients who present in an outpatient setting with primary or secondary amenorrhea have 1 of 5 common medical problems: PCOS, hypothalamic amenorrhea, hyperprolactinemia, ovarian failure, or thyroid dysfunction.

For women with strictly primary amenorrhea, Müllerian abnormalities are second to premature ovarian failure as the most likely diagnosis. The management options of the most common causative processes are below. Unusual and uncommon causative factors of amenorrhea, such as sarcoidosis, require referral and evaluation by a specialist and are not reviewed below.

Polycystic ovarian syndrome

PCOS is characterized by oligomenorrhea or amenorrhea, an excess androgen hormone environment, and polycystic-appearing ovaries on ultrasonography.[44] A high body mass index (BMI) and insulin resistance also play an important role in the pathogenesis of PCO syndrome. Women with PCO syndrome have lifelong increased risks of developing adult-onset diabetes mellitus, hypertension, lipid disorders, hypothyroidism, and endometrial cancer.[45]

If pregnancy is not desired, monthly withdrawal bleeding should be induced. Both cyclic progesterone (10-12 days per month) and oral contraceptives can accomplish monthly withdrawal bleeding; however, oral contraceptives use different mechanisms to control other aspects of PCOS. Oral contraceptives decrease LH secretion, leading to lower androgen production and improvement in acne and hirsutism. Oral contraceptives atrophy the endometrial lining, decreasing the risk of endometrial hyperplasia and endometrial cancer.

Metformin is presently offered to improve ovulation.[46] There is no evidence that metformin improves live birth rates, although some studies have shown it to be associated with improved clinical pregnancy.[47] Further research is needed to determine whether metformin should be used for the prevention of the long-term development of adult-onset diabetes mellitus, cardiovascular disease, and lipid disorders.[48] Patients should be strongly encouraged to maintain a weight-to-height ratio within the reference range and to regularly exercise because both are first-line therapies used to control PCO syndrome.[49]

Hypothalamic amenorrhea

Hypothalamic amenorrhea is most common in patients who exercise to excess and/or have eating disorders, caloric restriction, and psychogenic stress. Hypothalamic amenorrhea is best treated using behavioral modification and a multidisciplinary team approach, depending on the root cause.

An interdisciplinary team approach that involves nutritionists, clinicians, counselors, and family members is most effective.[50] After correcting the behavior that leads to hypothalamic amenorrhea, most women resume normal pulsatile release of GnRH and subsequent normal menstrual cycling.[50]

Women with severe anorexia nervosa may not resume normal menstrual cycling after weight gain.[51, 52] A BMI of less than 15 kg/m2 requires immediate intervention by an eating disorder specialist. Hospitalization may be indicated. This group of women may need hormone replacement and monitoring of bone density.[53] Weight gain may be the most important factor in bone recovery.[54] Gonadotropin therapy may be needed for conception.

Patients with hypothalamic amenorrhea caused by excessive exercise may refuse to correct or change their behavior. This is especially true for professional, competitive college, or elite athletes participating in "leanness" sports. Although controversial, consideration should be given to correcting their low estradiol (E2) level by prescribing oral contraceptives.[55, 56] Many athletes may request to use oral contraceptives continuously to limit or avoid menses.[57]

Functional hypothalamic amenorrhea due to stress is a diagnosis of exclusion. An occult eating disorder and caloric restriction must be ruled out as a compounding factor.[58] Behavioral modification is the first-line treatment. Although controversial, consideration should be given to correcting the low E2 by prescribing oral contraceptives.[55, 56] If oral contraceptive therapy is initiated, it can be intermittently stopped to determine if the GnRH pump has regained pulsatile function. An increase in BMI is associated with the best long-term recovery.[59]

Hyperprolactinemia

Hyperprolactinemia with a normal TSH level requires an MRI to determine the presence of a tumor, microadenomas or macroadenomas, and other organic CNS lesions. Microadenomas and prolactinomas less than 1 cm in diameter are slow growing and are mostly found in the premenopausal population. Treatment should be considered to reverse hypoestrogenemic symptomatology, improve fertility, and/or eliminate bothersome galactorrhea.

Symptomatic hyperprolactinemia from a pituitary disorder should first be treated by dopamine agonists such as bromocriptine (Parlodel) and cabergoline (Dostinex). Pergolide has been associated with heart value abnormalities; it should not be used and was withdrawn from the US market in March, 2007.

Macroadenomas may also be treated with dopamine agonists initially. Occasionally, larger lesions fail to respond to medical therapy or present with acute vision changes. Referral with subsequent surgery or radiation is indicated. The recurrence rate after surgery can be as high as 50%. Patients with hyperprolactinemia associated with medications (eg, antipsychotics, metoclopramide) should consider discontinuation or switching of the causative medication if medically possible.

Some pituitary and hypothalamic tumors may require surgery and, in some cases, radiation therapy.

Hypergonadotropic hypogonadism

In a patient who fails to enter puberty, hypergonadotropic hypogonadism (gonadal failure) is most often associated with Turner syndrome or other gonadal dysgenesis disorders, such as Swyer syndrome. An X chromosome deletion (Turner syndrome), ring formation, partial deletion, or translocation is the most common diagnosis in this setting. A karyotype is required to detect any Y-containing chromatin.

Patients who have a Y chromosome have a 25% chance of developing a gonadal tumor. The gonads should immediately be removed.[60] These gonads are nonfunctioning; therefore adult height and bone mass are not affected by their presence. Hormone replacement therapy (HRT) should be offered to allow completion of puberty in a controlled fashion, similar to her peers, and should facilitate maximum bone density development.[61] Turner syndrome is associated with ear and renal disease; evaluation of these organ systems is indicated.

Premature ovarian failure after puberty occurs in 1% of adult women. Treatment should be decided on an individual basis. Some patients may require estrogen replacement therapy (ERT) for hot flashes and other symptomatic menopausal issues. Long-term E2 use should be individualized.[62] A small number of women with repetitively elevated FSH levels may have a resumption of cycles for a short period before proceeding to complete menopause. No medications or therapies have been found to induce normal cycling; its occurrence is sporadic, spontaneous, and not inducible.

Ovarian failure that occurs in patients younger than 30 years requires a karyotype to detect any Y chromatin and an evaluation of the fragile X area of the X chromosome. A strong family history of premature ovarian failure may require a referral for evaluation of GALT and autoimmune regulatory gene (AIRE) mutations and other autosomal disorders.[63] Documentation of a fragile X area requires other family members to receive genetic counseling. With a normal karyotype, evaluation of other autoimmune disease should be considered, including antithyroid and antiadrenal antibody titers.[64] Bone density should be monitored and treated appropriately using hormonal or nonhormonal therapy.

Thyroid dysfunction

Patients with hypothyroidism and hyperthyroidism should undergo a standard work-up and therapy. Treatment in most cases is straightforward.

Diet and Activity

Women with findings suggestive of an eating disorder should be evaluated by a multidisciplinary team with special expertise in these disorders. Nutritional counseling alone is inadequate therapy for these women.

In some cases, nutritional deficiencies induced by dieting and exercise can cause amenorrhea even in the absence of a psychiatric disorder. Strict fat restriction often plays a role. Frequently, simply explaining the need to balance energy expenditure with energy intake resolves the problem. In this situation, nutritional counseling may be all that is required.

More than 8 hours of vigorous exercise a week may cause amenorrhea. As noted above, in some cases this resolves with appropriate adjustment of the diet.

Consultations

The causes of menstrual cycle disturbance leading to the development of amenorrhea are so diverse that in some complex cases, the situation is best addressed by a multidisciplinary team. For example, a patient with complete androgen resistance (testicular feminization) would benefit from the involvement of experts in endocrinology, human genetics, psychiatry, and reproductive surgery.

With hereditary causes of amenorrhea, such as Kallmann syndrome, a geneticist's expertise can be helpful in counseling patients and their families regarding the disorder

In cases of pituitary/hypothalamic tumor, other endocrine disorders (eg, central hypothyroidism, central adrenal insufficiency) may be involved. Generally, the expertise of a medical endocrinologist is required to assist in the treatment of patients who require neurosurgery to treat the underlying condition. In cases of hyperthyroidism or Cushing syndrome, the expertise of a medical endocrinologist is required to treat the underlying pathology.

Cases of major depression, anorexia nervosa, bulimia nervosa, or other major psychiatric disorders warrant consultation with a psychiatrist.

In some unusual cases, such as with vaginal agenesis, consult with a reproductive surgeon with extensive experience in the specific disorder.

In many cases, exercise-induced amenorrhea is due to an imbalance in energy intake and expenditure. Nutritional counseling to increase energy intake without reducing exercise is a means of reversing the underlying pathology. Women who are underweight or who appear to have nutritional deficiencies should receive nutritional counseling and can be referred to a multidisciplinary team specializing in eating disorders.

In certain cases in which an underlying chronic disease process is present, the insights of an internist may be needed.

Long-Term Monitoring

The need for ongoing care is defined by the mechanism disrupting the menstrual cycle and the patient's desires.

See patients with primary ovarian insufficiency annually to monitor their ovarian hormone replacement and to detect the development of associated conditions that may be related to the original pathogenic mechanism that led to the disruption of the menstrual cycle.

See patient every 3-6 months for the first 2 years to monitor ovarian hormone replacement and to detect the development of associated conditions that may be related to the original pathogenic mechanism that led to the disruption of the menstrual cycle.

Medication Summary

For primary amenorrhea, hormone therapy, consisting of an estrogen and a progestin, is recommended for women with estrogen deficiency.[65] Girls with primary amenorrhea typically do not have symptoms of estrogen deficiency. However, with inadequate estrogen exposure over time, these patients are at increased risk for developing osteoporosis and possibly other health issues.

Young women in whom secondary sex characteristics have failed to develop fully should be exposed initially to very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen consists of an estrogen with a dosage equivalent to 25 mcg/day of transdermal estradiol (approximately 0.3 mg of conjugated equine estrogen) given unopposed (ie, no progestogen) daily for 6 months with incremental dose increases at 6-month intervals until the required maintenance dose is achieved.

Gradual dose escalation allows time to balance estrogen supplementation with need to grow in height, develop secondary sexual characters, and often results in optimal breast development. It also allows time for the young woman to adjust psychologically to her physical maturation.[66]

Cyclic progestogen therapy, given 12-14 days per month, should be instituted once vaginal bleeding begins.

Parenteral estrogen (transdermal or vaginal) is the preferred route of administration because it avoids first-pass liver metabolism. Moreover, it is less likely to increase sex hormone–binding globulin (SHBG) and has little or no effect on circulating lipids, coagulation parameters, or C-reactive protein. However, no long-term controlled studies are available to compare the efficacy and safety of one method over another. Therefore, the choice of therapy should follow consideration of the patient's preferences and the physician's experience.

The role of androgen replacement is unclear at this time and is the subject of ongoing investigation.[67]

For secondary amenorrhea, dopamine agonists are the only medical therapy specifically approved to reverse an underlying pathology that leads to amenorrhea. In most cases, dopamine agonists effectively reduce hyperprolactinemia.

Gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH) therapy is indicated in women who desire fertility yet remain anovulatory because of an unresolved hypothalamic/pituitary disorder.

Once the diagnosis is established, for some women with oligomenorrhea or amenorrhea who do not wish to become pregnant, oral contraceptives may be a good choice to restore menstrual cyclicity and provide estrogen replacement. The absence of pregnancy should be documented before oral contraceptive therapy is begun.

In patients with amenorrhea or oligomenorrhea withdrawal bleeding should be induced with an injection of progesterone or the administration of 5-10 mg of medroxyprogesterone for 10 days.

Hormone therapy, consisting of an estrogen and a progestin, is needed for women in whom estrogen deficiency remains because ovarian function cannot be restored. The role of androgen replacement is unclear at this time and is the subject of ongoing investigation

Estradiol (Alora, Climara, Esclim, Vivelle-dot, Estrace)

Clinical Context:  Estradiol increases synthesis of DNA, RNA, and many proteins in target tissues. Transdermal patch available as Alora (0.05, 0.075, and 0.1 mg/d, applied twice weekly), Climara (0.025, 0.05, 0.075, and 0.1 mg/d, applied once weekly), Esclim (0.025, 0.0375, 0.05, 0.075, 0.1 mg/d, applied twice weekly), and Vivelle-dot (0.037, 0.05, 0.075, 0.1 mg/d, applied twice weekly). If transdermal patch is not tolerated, oral form may be used.

Estrogens, conjugated (Premarin)

Clinical Context:  Use in patients who refuse or do not tolerate other forms of estrogen. Use oral estrogen to achieve adequate estrogenization of vaginal epithelium in young women and adequately maintain bone density.

Class Summary

Estrogens are administered transdermally, transvaginally, or orally. The appropriate dose for young women with ovarian failure or secondary amenorrhea has not been established. The authors recommend full replacement doses for young women. Generally, this is approximately twice as high as doses recommended for hormone therapy in normally postmenopausal women.

The authors prefer to administer estradiol by skin patch (100-mcg transdermal estradiol patch). This avoids the first-pass effect of oral estrogen on the liver. No controlled studies are available to compare the efficacy and safety of one method over another. Therefore, the choice of therapy should follow consideration of the patient's preferences and the physician's experience.

Medroxyprogesterone (Provera, Cycrin, Depo-Provera, Amen)

Clinical Context:  Administer cyclically 12 d/mo to prevent endometrial hyperplasia that unopposed estrogen may cause. In young women, regular withdrawal bleeding is preferable because even young women with premature ovarian failure have a 5-10% chance of spontaneous pregnancy (unlike postmenopausal women). If an expected withdrawal bleeding is absent, perform a pregnancy test (and a timely diagnosis of pregnancy will not be missed). Other causes of amenorrhea may also remit spontaneously and result in an unexpected pregnancy.

Progesterone (Prometrium)

Clinical Context:  This agent is used to prevent endometrial hyperplasia

Class Summary

Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. No long-term controlled studies compare efficacy of medroxyprogesterone with oral progesterone in protecting the endometrium from neoplasia at the doses of estrogen generally required for replacement in young women. The authors recommend use medroxyprogesterone as first-line therapy because of longer-term clinical experience with this agent.

Author

Kenneth M Bielak, MD, Clinic Director of Family Practice Center, Associate Professor, Department of Family Medicine, University of Tennessee Health Science Center College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Elizabeth Alderman, MD, Director of Fellowship Training Program, Director of Adolescent Ambulatory Service, Professor of Clinical Pediatrics, Department of Pediatrics, Division of Adolescent Medicine, Albert Einstein College of Medicine and Children's Hospital at Montefiore

Disclosure: Merck Honoraria Speaking and teaching

Gayla S Harris, MD, Associate Professor, Department of Obstetrics and Gynecology, University of Tennessee Medical Center

Disclosure: Nothing to disclose.

Karim Anton Calis, PharmD, MPH, FASHP, FCCP, Adjunct Clinical Investigator, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Clinical Professor, Medical College of Virginia, Virginia Commonwealth University School of Pharmacy; Clinical Professor, University of Maryland School of Pharmacy

Disclosure: Nothing to disclose.

Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Group, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health

Disclosure: Nothing to disclose.

Shannon D Sullivan, MD, PhD, Staff Physician, Department of Endocrinology, Washington Hospital Center

Disclosure: Nothing to disclose.

Sharon N Covington, LCSW-C, BCD, Clinical Assistant Professor, Department of Obstetrics and Gynecology, Georgetown University School of Medicine; Associate Investigator, Integrative Reproductive Medicine Unit, Reproductive Biology and Medicine Branch, National Institutes of Child Health and Human Development, National Institutes of Health; Private Practice, Covington and Hafkin and Associates; Director of Psychological Support Services, Shady Grove Fertility Reproductive Science Center

Disclosure: Nothing to disclose.

Suzanne R Trupin, MD, FACOG, Clinical Professor, Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women's Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical Center

Disclosure: Nothing to disclose.

Tamara Prodanov, MD, Research Assistant, National Institutes of Child Health and Human Development, National Institutes of Health

Disclosure: Nothing to disclose.

Vaishali Popat, MD, MPH, Clinical Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health

Disclosure: Nothing to disclose.

Wayne Wolfram, MD, MPH, Associate Professor, Department of Emergency Medicine, Mercy St Vincent Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Thomas Michael Price, MD, Associate Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Director of Reproductive Endocrinology and Infertility Fellowship Program, Duke University Medical Center

Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee Consulting; Gerson Lehrman Group Advisor Consulting fee Consulting; Adiana Grant/research funds PI

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

A David Barnes, MD, PhD, MPH, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)

Disclosure: Nothing to disclose.

Andrea L Zuckerman, MD, Assistant Professor of Obstetrics/Gynecology and Pediatrics, Tufts University School of Medicine; Division Director, Pediatric and Adolescent Gynecology, Tufts Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Richard Scott Lucidi, MD, Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Somya Verma, MD, to the development and writing of a source article.

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Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.

Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.

Primary amenorrhea flowchart.