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    • Topic 1

      AMENORRHEA
      Background:
      Amenorrhea is the absence of menstrual bleeding. 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.
      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.


      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. 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. 
      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. 
      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.
       Anorexia nervosa is a serious psychiatric disease with severe medical complications including primary amenorrhea (15%), osteopenia (52%), and osteoporosis (35%).
      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. 
      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. 
      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. 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. POI is hypergonadotropic hypogonadism, characterized by oligomenorrhea, estrogen deficiency, and its associated symptoms such as hot flashes, vaginal dryness, dyspareunia, and insomnia.  
      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. Autoimmune oophoritis occurs in 3-4% of POI cases. 
      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. 


      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. 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. 

      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). 
      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. 
      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. 


      Etiology:
      Amenorrhea can be divided into 2 groups: 
      (1) amenorrhea without evidence of associated androgen excess
       (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 foremost, 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%).
      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
      Endocrine disorders
      Tumor
      Systemic illness (2.6%)
      Eating disorder (2.3%)

      Congenital abnormalities that can cause hypogonadotropic hypogonadism include the following:
      Isolated GnRH deficiency (8.3%)
      Forms of hypopituitarism (2.3%)
      Congenital central nervous system (CNS) defects (0.8%)
      Constitutional delay (6%)

      Endocrine disorders that can cause hypogonadotropic hypogonadism include the following:
      Congenital adrenal hyperplasia (CAH) (0.8%)
      Cushing syndrome (0.4%)
      Pseudohypoparathyroidism (0.4%)
      Hyperprolactinemia (1.9%)

      Tumors that can cause hypogonadotropic hypogonadism include the following:
      Unclassified pituitary adenoma (0.8%)
      Craniopharyngioma (1.1%)
      Unclassified malignant tumor (0.4%)
      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 :
      Weight loss/anorexia
      Nonspecific hypothalamic disorder
      Chronic anovulation including Polycystic Ovarian Syndrome
      Hypothyroidism
      Cushing syndrome
      Pituitary tumor, empty sella, Sheehan syndrome

      Disorders in which the FSH is high (12%) include the following:
      46XX, spontaneous Primary Ovarian Insufficiency
      Premature ovarian failure due to abnormal karyotype (45,XO)
      Pure gonadal dysgenesis
      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:
      Polycystic ovarian syndrome (PCOS)
      Ovarian tumor
      Nonclassic Congenital Adrenal Hyperplasia (CAH)
      Undiagnosed



      Presentation:
      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 (Diagnostic and Statistical Manual of mental disorders). 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. 
      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. 
      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] or leptin deficiency, 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. 
      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. 


      Drugs:
      When taking the medication history, consider the following:
      Abuse of drugs such as cocaine and opioids have central effects that may disrupt the menstrual cycle
      Use of antiepileptics is associated with amenorrhea
      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] and thalassemia are associated with amenorrhea.
      Type 1 and type 2 diabetes may both be associated with disordered menses. 
      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. 
      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. 
      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.



      Diagnostic Considerations
      Primary amenorrhea is defined either as absence of menses by age 14 years with the absence of growth or development of secondary sexual characteristics (eg, breast development) or as absence of menses by age 16 years with normal development of secondary sexual characteristics.
      Secondary amenorrhea is defined as the cessation of menstruation for at least 6 months or for at least 3 of the previous 3 cycle intervals. Because only 3 diagnoses are unique to primary amenorrhea and never cause secondary amenorrhea, differentiating primary from secondary amenorrhea does little to enhance the clinician's understanding of the etiology.
      Diagnoses unique to primary amenorrhea include vaginal agenesis, androgen insensitivity syndrome, Turner syndrome (45,X), and mosaicism. The remaining diagnoses should be considered in patients with both primary and secondary amenorrhea.
      Since regular menstruation reflects a properly functioning hypothalamic-pituitary-gonadal axis, a logical approach is to consider disorders based upon the levels of control of the menstrual cycle: uterus, ovary, pituitary, and hypothalamus.
      Amenorrhea with delayed puberty:
      Puberty is considered delayed when no breast development is evident at 13 years, pubic hair is absent at 14 years, and menarche is absent at 15 years (which is 2 standard deviations above the mean age for menarche). The most common cause of delayed puberty is constitutional delay. Another common reason for delayed puberty is ovarian failure, which is also termed hypergonadotropic hypogonadism. Elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) characterize hypergonadotropic hypogonadism with low estrogen production.
      The most common example of hypergonadotropic hypogonadism is found in Turner syndrome, which is caused by a 45,X karyotype. Clinical manifestations of Turner syndrome include a webbed neck, short stature, broad shieldlike chest, anomalous auricles, and hypoestrogenemia resulting in sexual immaturity.
      Gonadal dysgenesis fits the same pattern of high FSH and LH and low estradiol (E2) levels. Gonadal dysgenesis is caused by a mosaic karyotype with an abnormal X chromosome, with loss of part of an X chromosome or translocation, or with a normal karyotype (46,XX) and streak ovaries.
      Individuals with Perrault syndrome have gonadal dysgenesis, a normal karyotype, and neurosensory deafness. Swyer syndrome is illustrated by a phenotypically immature female with a 46,XY karyotype without testis-determining factor on the Y chromosome.
      These patients have normal female external genitalia, a patent vagina, and a normal uterus. The gonads are testes. They have no breast development, in contrast to individuals with androgen insensitivity. Another rare cause of hypergonadotropic hypogonadism is gonadotropin-resistant ovary syndrome, which is characterized by FSH-resistant ovaries.
      Acquired causes of hypergonadotropic hypogonadism can result from high-dose alkylating chemotherapy and radiation treatments to the pelvis. An elevated erythrocyte sedimentation rate (ESR) and anti-ovarian antibody levels may suggest autoimmune oophoritis, but such tests are rarely needed. Autoimmune oophoritis is an exclusionary diagnosis. Like all forms of hyperandrogenic hypogonadotropic amenorrhea, these conditions are not reversible.
      Hypogonadotropic hypogonadism occurs when FSH and LH levels are low. Hypogonadotropic hypogonadism may present prior to or after the completion of puberty. The most common causes of hypogonadotropic hypogonadism include chronic illness, starvation, excessive exercise, anorexia nervosa, depression, stress, and marijuana use. Hypogonadotropic hypogonadism involves slowed gonadotropin-releasing hormone (GnRH) release caused by multifactorial components of decreased body fat and increased beta endorphins.
      Chronic illness can affect pubertal development adversely by interfering with metabolism through malabsorption and poor nutrition (eg, Crohn disease, diabetes mellitus, hypothyroidism and hyperthyroidism, cystic fibrosis, anorexia nervosa, excessive exercise).
      Tumors in the CNS can compress the portal vessels and impede the flow of GnRH from the hypothalamus to the pituitary gland. Pituitary adenomas, craniopharyngiomas, and meningiomas are examples of slow-growing nonmetastatic tumors that are uncommon causes of hypogonadotropic hypogonadism. Anterior pituitary prolactinomas releasing prolactin hormone are the most common pituitary tumors to cause hypogonadotropic hypogonadism.
      Other acquired disorders can disrupt pituitary function by destructive means, such as ischemia, infiltration, and obstruction. Head trauma, cranial aneurysms, and infiltrative processes (eg, sarcoidosis, syphilis, tuberculomas) are examples of conditions that can disrupt pituitary function.
      Abnormal development of the hypothalamus can result in hypogonadotropic hypogonadism. Kallmann syndrome manifests with anosmia, pubertal delay, and a normal response to exogenous gonadotropins. Kallmann syndrome occurs during embryonic development when GnRH-secreting neurons fail to migrate from the olfactory area to the hypothalamus. The gene KAL1 codes for the protein associated with normal migration. Other syndromes associated with hypothalamic dysfunction include Prader-Willi syndrome and Laurence-Moon-Biedl syndrome.
      Amenorrhea with normal puberty:
      Frequently, pubertal development occurs at a normal rate, but primary amenorrhea may occur and may be associated with hirsutism. These individuals are eugonadal. The most common cause in this setting is polycystic ovarian syndrome (PCOS), which is characterized by anovulation, oligo-ovulation, androgen excess (clinical or biochemical), ultrasonographic demonstration of increased ovarian stroma and accumulation of antral follicles (polycystic appearance), and obesity.
      Ovarian hyperthecosis results in hyperandrogenicity, which is evident by signs of hirsutism, acne, and obesity and can be associated with type 2 diabetes mellitus and acanthosis nigricans. Hyperthecosis can also cause virilization, which manifests as clitoromegaly, temporal balding, and deepened voice change. 
      Another cause of hirsutism is the rare late-onset 21-hydroxylase deficiency, which is caused by mutations in the 21-hydroxylase gene that result in excessive 17-hydroxyprogesterone levels. This deficiency is also termed nonclassic congenital adrenal hyperplasia and can occur in 1-10% of women with hirsutism.
      Rarely, patients with hypothalamic amenorrhea may have hyperandrogenic/polycystic ovaries. Wang et al explored the coexistence of these 2 disorders in women with hypothalamic amenorrhea/PCOS, and found that over time, these patients may fluctuate between symptoms of hypothalamic amenorrhea and polycystic ovarian syndrome, depending on the status of their hypothalamic activity. 
      Other causes of hyperandrogenism include Cushing disease, ovarian stromal hypertrophy, and androgen-producing tumors of the ovary and adrenal glands. Exogenous anabolic steroid use should be considered in the differential for hyperandrogenic amenorrhea.
      Anovulation remains the most common cause of amenorrhea in the setting of nonvirilization. Anovulation is caused by dysfunction of the hypothalamic-pituitary-ovarian axis, which can be apparent after discontinuation of various hormonal contraception medications and can result in loss of menses for several months. It is often associated with a hypothalamic hypogonadotropic etiology.
      Idiopathic premature menopause occurs in 1% of women younger than 40 years. Premature ovarian failure can be idiopathic, secondary to chemotherapy or radiation therapy, or autoimmune in origin.
      Premature ovarian failure is more accurately termed primary ovarian insufficiency (POI) because women with spontaneous POI may have intermittent ovarian function, and, as a group, demonstrate a pregnancy rate of 5-10%. 
      Prodromal POI is a state of ovarian insufficiency in which FSH levels are elevated and menses are irregular but not to the degree required to make a diagnosis of overt POI. This is likely on a continuum with diminished ovarian reserve (a state in which women respond poorly to exogenous gonadotropin stimulation) and overt POI (a state of drastically reduced fertility).
      Hyperprolactinemia is a pituitary cause of amenorrhea in the presence of normal puberty. Hyperprolactinemia can occur as a consequence of breastfeeding, microadenomas of the pituitary, and use of psychoactive medications (eg, haloperidol, phenothiazines, amitriptyline, benzodiazepines, cocaine, marijuana) and metoclopramide (Reglan).
      Amenorrhea may be caused by thyroid disorders, including hyperthyroidism and hypothyroidism. Hypogonadotropic hypogonadism can occur from the same causes as delayed puberty. In addition, Sheehan syndrome, which results from panhypopituitarism after pituitary infarction from postpartum hemorrhage or shock, can manifest as pubertal amenorrhea.
      Amenorrhea that results from genital tract anomalies can arise from the absence of reproductive organs. Mayer-Rokitansky-Hauser syndrome is an anomaly of the genital tract characterized by vaginal agenesis. The uterus is usually absent, and the vagina is foreshortened.
      Because the ovaries function normally and produce E2, breasts are normal in shape and contour. Pubarche is also normal in this patient population; therefore, pubic hair remains normal. Mayer-Rokitansky-Hauser syndrome accounts for 15% of primary amenorrhea cases and is second to Turner syndrome as the most common cause of primary amenorrhea.
      Androgen insensitivity syndrome (previously termed testicular feminization) is present in 10% of patients with amenorrhea. Androgen insensitivity syndrome is caused by an abnormality of the androgen receptor. The gonads are testicles producing testosterone; however, testosterone has no effect because the androgen receptor is nonfunctional.
      The phenotypic appearance in patients with this condition is female, but the circulating hormonal pattern is male. Androgen insensitivity syndrome is a maternal X-linked recessive disease in which the testes remain intra-abdominal or partially descended, and pubic hair is sparse.
      Spontaneous testicular regression is a rare disorder of genetic males that results in a female phenotype with an absent uterus. In addition, certain enzyme deficiencies affecting androgen production can result in male pseudohermaphrodites. All disorders that are phenotypically female but chromosomally male (XY) require that the gonads be removed to avert cancerous changes.
      Primary amenorrhea can result from an imperforate hymen, which presents as a boggy uterus and cyclic abdominal pain. Asherman syndrome occurs after an overzealous curettage of the endometrial lining, which results in adhesions or synechiae that prevent the endometrium from responding to estradiol. The diagnosis is suggested by absence of endometrial stripe on uterine ultrasonography and confirmed by hysteroscopy evaluation or by absence of bleeding after cyclic therapy with estrogen and later progestin for several weeks.
      A case report has been published of a woman in whom persistent secondary amenorrhea developed due to intrauterine adhesions after selective embolization of the uterine arteries for control of refractory primary postpartum hemorrhage. Adverse effects of these new lifesaving technologies remain to be evaluated long term. 
      Clinically significant infections that destroy the endometrial lining can also result in primary or secondary amenorrhea.


      Diagnostic strategy
      The differential diagnosis of amenorrhea is broad and can range from genetic abnormalities to endocrine disorders and psychological, environmental, and structural anomalies. To facilitate prompt and accurate diagnostic workup, obtaining a thorough history and performing a detailed physical examination is essential.
      In the differential diagnosis of primary or secondary amenorrhea, the most important step in diagnosis is to exclude pregnancy. Always consider pregnancy first. After pregnancy is excluded, an algorithmic approach is followed to narrow the diagnostic possibilities. Causes of primary and secondary amenorrhea overlap considerably; therefore, ascertaining the patient's sexual development is the key to differentiating these conditions.


      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:
      Autoimmune oophoritis
      Exposure to radiation or chemotherapy
      Resistant ovary syndrome
      Multiple endocrine neoplasm (MEN) syndrome
      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).
      Organize clinical evaluation on the basis of sexual development and basic developmental physiology. With such a vast differential diagnosis, one way to organize and memorize the causes of amenorrhea can be in its relationships with generalized pubertal delay, normal pubertal development, or abnormalities of the genital tract.


      Differential Diagnoses
      1. Anorexia Nervosa
      2. Anxiety Disorders
      3. Congenital Adrenal Hyperplasia
      4. Cushing Syndrome
      5. Depression
      6. Follicle-Stimulating Hormone Abnormalities
      7. Luteinizing Hormone Deficiency
      8. Ovarian Insufficiency
      9. Pregnancy Diagnosis
      10. Prolactinoma






      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." 
      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. 
      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.  


      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:
      Associated headaches or visual-field cuts
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