eMedicine Specialties > Pediatrics: Surgery > Gynecology

Amenorrhea

Author: Kenneth M Bielak, MD, Clinic Director of Family Practice Center, Associate Professor, Department of Family Medicine, University of Tennessee at Knoxville
Coauthor(s): Gayla S Harris, MD, Associate Professor, Department of Obstetrics and Gynecology, University of Tennessee Medical Center
Contributor Information and Disclosures

Updated: Mar 12, 2008

Introduction

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 This article reviews the physiologic aspects of menstruation and presents an approach for ascertaining the etiology of amenorrhea. Only the main components of amenorrhea are highlighted. Many minor components of physiology are important but cannot be discussed in the context of this overview.

Pathophysiology

The menstrual cycle is an orderly progression of hormonal events in the female body that results in the release of an egg. 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. When one diagnoses the disease processes responsible for amenorrhea, consideration of the target organs of these reproductive hormones (hypothalamus, pituitary, ovary, uterus) is helpful.

Menstrual Cycle

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.

The gonadotropin-releasing hormone (GnRH) pump located 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 release FSH in the follicular phase. FSH is secreted into the circulation and interacts with the granulosa cells surrounding the developing oocytes.

As FSH increases during the early portion of the follicular phase, it interacts 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 mid-cycle 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.

The menstrual cycle is a complex but coordinated system of hormonal changes and organ responses. The main directive of the menstrual cycle is to stimulate growth of a follicle to release an egg and prepare a site for implantation if fertilization should occur. Absence of fertilization results in the timely release of the prepared endometrium, which is termed menses.

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 12.8 years, with a range of 9-16 years.

Clinical Details

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 preforming detailed physical examination is essential.3 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;4 therefore, ascertaining the patient's sexual development is the key to differentiating these conditions.

See the Algorithms for Evaluation of Amenorrhea below to determine the most logical course leading to a specific diagnosis.

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.

Physical examination

Physical examination begins with vital signs, including height and weight, and with sexual maturity ratings. Physical examination findings include the following:

  • Generalized findings
    • Anorexia - Cachexia, bradycardia, hypotension, hypothermia, yellow skin (carotenemia), body mass index (BMI) of less than 18
    • Pituitary tumor - Funduscopic changes, visual field impairment, cranial nerve signs
    • Polycystic ovarian (PCO) syndrome - Acne, acanthosis nigricans, hirsutism, BMI of more than 30 (common) 
    • Inflammatory bowel disease - Fissure, skin tags, occult blood found on rectal examination
    • Gonadal dysgenesis (eg, Turner syndrome) - Webbed neck, increased carrying angle, lack of breast development
  • Breast findings
    • Galactorrhea - Breast palpation
    • Delayed puberty - Underdeveloped with sparse pubic hair
    • Gonadal dysgenesis (eg, Turner syndrome) - Undeveloped breasts with normal growth of pubic hair
  • Pubic hair and external genitalia findings
    • Hyperandrogenism - Pubic hair distribution, excess facial hair
    • Androgen insensitivity syndrome - Absent or sparse axillary and pubic hair with breast development
    • Delayed puberty - Without breast development
    • Adrenal or ovarian tumors - Clitoromegaly, virilization
    • Pelvic fullness - Pregnancy, ovarian mass, genital anomalies
  • Vaginal findings
    • Imperforate hymen - Distension or bulging of the external vagina
    • Agenesis (Rokitansky-Hauser syndrome) - Foreshortened vagina with a rudimentary or absent uterus, normal pubic hair
    • Androgen insensitivity syndrome - Foreshortened vagina without uterus, absent pubic hair
  • Uterine findings: If the uterus is enlarged, pregnancy must be excluded.
  • Cervical findings
    • Assess the vaginal canal, the effect of estrogen on the vaginal mucosa, and mucus secretion.
    • The presence of mucus suggests that the ovaries are producing E2 (unopposed by progesterone).
    • Clear, abundant mucus after cycle day 20 suggests anovulation.
    • A lack of mucus and a dry, pale vagina suggest that E2 is not in production.

Laboratory evaluation

The history and physical findings help in selecting tests in a female patient with amenorrhea. Possible tests include endocrinologic and chemical tests to detect chronic disease processes.

If the history and physical findings suggest an ovarian-axis problem with normal puberty, thyroid-stimulating hormone (TSH), prolactin, FSH, and LH measurements are the first line of testing. If hirsutism is predominant upon examination, include androgen testing of 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, the following may be indicated including measurement of the erythrocyte sedimentation rate (ESR), liver function tests, 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.

To evaluate the CNS, a coned view of the sella turcica or MRI of the pituitary is indicated. Many specialists prefer MRI.

Primary and Secondary Amenorrhea

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, and Turner syndrome (45,XO). The remaining diagnoses should be considered in patients with both primary and secondary amenorrhea.

The causes of amenorrhea are listed below. 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.

Causes of amenorrhea

  • Generalized pubertal delay
    • Constitutional delay
    • Hypergonadotropic hypogonadism
      • Turner syndrome
      • Gonadal dysgenesis with mosaic karyotype
      • Pure gonadal dysgenesis (Perrault syndrome, Swyer syndrome)
      • Gonadotropin-resistant ovary syndrome
      • Acquired causes (eg, high-dose alkylating chemotherapy, pelvic radiation, autoimmune oophoritis)
    • Hypogonadotropic hypogonadism
      • Chronic conditions (eg, starvation, excessive exercise, depression, psychological stress, marijuana use, Crohn disease, cystic fibrosis, sickle cell disease, thalassemia major, human immunodeficiency virus [HIV] infection, renal disease, thyroid disease, diabetes mellitus, anorexia nervosa)
      • Slow-growing CNS tumors (eg, adenomas, craniopharyngiomas, meningiomas, pituitary microadenomas)
      • Abnormal hypothalamic development (eg, Kallmann syndrome, Prader-Willi syndrome, and Laurence-Moon-Biedl syndrome)
      • Acquired miscellaneous disorders (eg, infiltration disorders [sarcoidosis, Langerhans cell histiocytosis, syphilis, tuberculomas], ischemia disorders [caused by trauma, aneurysm, obstruction of the aqueduct of Sylvius] and destruction [concentrated, high-dose exposure to radiation])
  • Normal puberty with estrogen expressed: Associated with hyperandrogenicity (eg, PCO syndrome, late-onset 21-hydroxylase deficiency [nonclassic congenital adrenal hyperplasia], immaturity of the hypothalamic-pituitary-ovarian axis, Cushing disease, androgen-producing ovarian or adrenal tumors, ovarian stromal hypertrophy)
  • Normal puberty with prior estrogen expression but no current estrogen expression
    • Hypergonadotropic hypogonadism (eg, premature ovarian failure, high-dose alkylating chemotherapy or pelvic radiation occurring after puberty, autoimmune oophoritis)
    • Hypogonadotropic hypogonadism
      • Chronic conditions that occur after puberty (eg, starvation, excessive exercise, depression, psychological stress, marijuana use, Crohn disease, cystic fibrosis, sickle cell disease, thalassemia major, HIV infection, renal disease, thyroid disease, diabetes mellitus, anorexia nervosa)
      • Slow-growing CNS tumors (eg, adenomas, craniopharyngiomas, meningiomas, pituitary microadenomas)  
      • Acquired miscellaneous disorders (eg, infiltration disorders [sarcoidosis, Langerhans cell  histiocytosis, syphilis, tuberculomas], ischemia disorders [caused by trauma, aneurysm] and destruction [concentrated, high-dose exposure to radiation])
  • Anomalies of the genital tract
    • Müllerian agenesis (eg, Mayer-Rokitansky-Kuster-Hauser syndrome5 ) breast present with rudimentary or absent uterus
    • Congenital or acquired anatomic obstruction (eg, imperforate hymen, transverse vaginal septum, Asherman syndrome, endometrial destruction due to severe infection or surgery)
    • Androgen insensitive syndrome (absent uterus with normal breast development)

Amenorrhea with Delayed Puberty

Hypergonadotropic hypogonadism

Puberty is considered delayed when no breast development is evident at 13.5 years, pubic hair is absent at 14 years, and menarche is absent at 16 years. 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 FSH and 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 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. 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. Elevated 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

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 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. Kallman syndrome occurs during embryonic development when GnRH secreting neurons fail to migration 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, amenorrhea with normal puberty is associated with hirsutism. The most common cause in this setting is PCO syndrome. PCO syndrome 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.6  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. See Polycystic Ovarian Syndrome for an in-depth discussion of this entity.

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. 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 an 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.

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 (see Amenorrhea with 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 E2. Clinically significant infections that destroy the endometrial lining can also result in primary or secondary amenorrhea.

Algorithms for Evaluation of Amenorrhea

Algorithm for evaluation of amenorrhea with delayed puberty

Obtain the following laboratory results: thyroid function; bone age; and LH, FSH, and prolactin levels.

  • If TSH levels are elevated and thyroxine (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,XO, 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.

Algorithm for evaluation of 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.7  If fragile X syndrome is present, family members should be offered genetic testing.
    • Consider premature ovarian failure due to autoimmune oophoritis, exposure to radiation or chemotherapy, resistant ovary syndrome, or 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 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)
    • 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 is present, check testosterone, DHEAS, and 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 PCO syndrome.
    • 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 PCO syndrome, hyperthecosis, or an androgen-secreting tumor of the ovary or adrenal gland

Algorithm for evaluation of 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).

Management of Amenorrhea

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. Reassure patients because the diagnosis of amenorrhea can cause tremendous anxiety.

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 varies, most patients who present in an outpatient setting with primary or secondary amenorrhea have 1 of 5 common medical problems: PCO syndrome, 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.

PCO syndrome

PCO syndrome is characterized by oligomenorrhea or amenorrhea, an excess androgen hormone environment, and polycystic-appearing ovaries on ultrasonography.6  High BMIs 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.8   

If pregnancy is not desired, monthly withdrawal bleeding should be induced. Both cyclic progesterone (7-14 d per month) and oral contraceptives can accomplish monthly withdrawal bleeding; however, oral contraceptives use different mechanisms to control other aspects of PCO syndrome. 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.9  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.10  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 tocontrolPCOsyndrome.11
 
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. An interdisciplinary team approach that involves nutritionists, physicians, counselors, and family members is most effective.12  After correcting the behavior that leads to hypothalamic amenorrhea, most women resume normal pulsatile release of GnRH and subsequent normal menstrual cycling.13  
 
Women with severe anorexia nervosa may not resume normal menstrual cycling after weight gain.14,15  A BMI of less than 15 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.16  Weight gain may be the most important factor in bone recovery.17 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 E2 by prescribing oral contraceptives.18,19 Many athletes may request to use oral contraceptives continuously to limit or avoid menses.20      
 
Functional hypothalamic amenorrhea due to stress is a diagnosis of exclusion. A physician must rule out an occult eating disorder and caloric restriction as a compounding factor.21 Behavioral modification is the first-line treatment. Although controversial, consideration should be given to correcting the low E2 by prescribing oral contraceptives.18,19  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.22

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 recently 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.   
 
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 gonad should immediately be removed.23  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. 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 E 2 use should be individualized.24 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.25  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.26  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. Further information can be found in the eMedicine articles Hypothyroidism and Hyperthyroidism.

For excellent patient education resources, visit eMedicine's Women's Health Center, Eating Disorders Center, and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Amenorrhea, Anorexia Nervosa, Birth Control Overview, and Birth Control FAQs.

Keywords

amenorrhea, menstrual cycle, menarche, menstrual bleeding, absence of menstrual bleeding, menstrual dysfunction, menses, absent menses, lack of menstruation, absent menstruation, abnormal menstrual cycle, primary amenorrhea, secondary amenorrhea, Turner syndrome

delayed puberty, dietary amenorrhea, emotional amenorrhea, jogger's amenorrhea, ovarian amenorrhea, pathologic amenorrhea, period, missed period, absent period, physiology of menstruation, gonadotropin-releasing hormone, GnRH, follicle-stimulating hormone, FSH, luteinizing-hormone, LH, estrogen, progesterone, follicular phase, ovulatory phase

ovulation, corpus luteum, luteal phase, human chorionic gonadotropin hormone, hCG, dehydroepiandrostenedione, adrenarche, pituitary tumor, polycystic ovary syndrome, inflammatory bowel disease, gonadal dysgenesis, galactorrhea, hyperandrogenism, androgen insensitivity syndrome, adrenal tumors, ovarian tumors, imperforate hymen, Rokitansky-Hauser syndrome

 


More on Amenorrhea

References

References

  1. ASRM. Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. Sep 2004;82 Suppl 1:S33-9. [Medline].

  2. Pletcher JR, Slap GB. Menstrual disorders. Amenorrhea. Pediatr Clin North Am. Jun 1999;46(3):505-18. [Medline].

  3. Iglesias EA, Coupey SM. Menstrual cycle abnormalities: diagnosis and management. Adolesc Med. Jun 1999;10(2):255-73. [Medline].

  4. Aloi JA. Evaluation of amenorrhea. Compr Ther. Oct 1995;21(10):575-8. [Medline].

  5. Fedele L, Bianchi S, Frontino G, Ciappina N, Fontana E, Borruto F. Laparoscopic findings and pelvic anatomy in Mayer-Rokitansky-Kuster-Hauser syndrome. Obstet Gynecol. May 2007;109(5):1111-5. [Medline].

  6. The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. Jan 2004;19(1):41-7. [Medline].

  7. Marozzi A, Vegetti W, Manfredini E, et al. Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod. Jan 2000;15(1):197-202. [Medline].

  8. Sharma ST, Nestler JE. Prevention of diabetes and cardiovascular disease in women with PCOS: treatment with insulin sensitizers. Best Pract Res Clin Endocrinol Metab. Jun 2006;20(2):245-60. [Medline].

  9. Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril. Feb 2002;77(2):209-15. [Medline].

  10. Teede HJ, Meyer C, Norman RJ. Insulin-sensitisers in the treatment of polycystic ovary syndrome. Expert Opin Pharmacother. Nov 2005;6(14):2419-27. [Medline].

  11. Norman RJ, Homan G, Moran L, Noakes M. Lifestyle choices, diet, and insulin sensitizers in polycystic ovary syndrome. Endocrine. Aug 2006;30(1):35-43. [Medline].

  12. Kreipe RE, Yussman SM. The role of the primary care practitioner in the treatment of eating disorders. Adolesc Med. Feb 2003;14(1):133-47. [Medline].

  13. Golden NH, Jacobson MS, Schebendach J, Solanto MV, Hertz SM, Shenker IR. Resumption of menses in anorexia nervosa. Arch Pediatr Adolesc Med. Jan 1997;151(1):16-21. [Medline].

  14. Jacoangeli F, Masala S, Staar Mezzasalma F, et al. Amenorrhea after weight recover in anorexia nervosa: role of body composition and endocrine abnormalities. Eat Weight Disord. Mar 2006;11(1):e20-6. [Medline].

  15. Brambilla F, Monteleone P, Bortolotti F, et al. Persistent amenorrhoea in weight-recovered anorexics: psychological and biological aspects. Psychiatry Res. Jun 15 2003;118(3):249-57. [Medline].

  16. Grinspoon S, Miller K, Coyle C, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab. Jun 1999;84(6):2049-55. [Medline].

  17. Miller KK, Lee EE, Lawson EA, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. Aug 2006;91(8):2931-7. [Medline].

  18. Hartard M, Kleinmond C, Kirchbichler A, et al. Age at first oral contraceptive use as a major determinant of vertebral bone mass in female endurance athletes. Bone. Oct 2004;35(4):836-41. [Medline].

  19. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL. Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab. Jun 2005;90(6):3162-7. [Medline].

  20. Gidwani GP. Amenorrhea in the athlete. Adolesc Med. Jun 1999;10(2):275-90, vii. [Medline].

  21. Warren MP, Fried JL. Hypothalamic amenorrhea. The effects of environmental stresses on the reproductive system: a central effect of the central nervous system. Endocrinol Metab Clin North Am. Sep 2001;30(3):611-29. [Medline].

  22. Falsetti L, Gambera A, Barbetti L, Specchia C. Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors. J Clin Endocrinol Metab. Feb 2002;87(2):500-5. [Medline].

  23. Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol. Feb 1 1976;124(3):293-300. [Medline].

  24. Adhikary AK, Banik U, Numaga J, Suzuki E, Inada T, Okabe N. Heterogeneity of the fibre sequence in subgenus C adenoviruses. J Clin Pathol. Jun 2004;57(6):612-7. [Medline].

  25. Laml T, Preyer O, Umek W, Hengstschlager M, Hanzal H. Genetic disorders in premature ovarian failure. Hum Reprod Update. Sep-Oct 2002;8(5):483-91. [Medline].

  26. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril. Oct 2005;84(4):958-65. [Medline].

Further Reading

Keywords

amenorrhea, menstrual cycle, menarche, menstrual bleeding, absence of menstrual bleeding, menstrual dysfunction, menses, absent menses, lack of menstruation, absent menstruation, abnormal menstrual cycle, primary amenorrhea, secondary amenorrhea, Turner syndrome

delayed puberty, dietary amenorrhea, emotional amenorrhea, jogger's amenorrhea, ovarian amenorrhea, pathologic amenorrhea, period, missed period, absent period, physiology of menstruation, gonadotropin-releasing hormone, GnRH, follicle-stimulating hormone, FSH, luteinizing-hormone, LH, estrogen, progesterone, follicular phase, ovulatory phase

ovulation, corpus luteum, luteal phase, human chorionic gonadotropin hormone, hCG, dehydroepiandrostenedione, adrenarche, pituitary tumor, polycystic ovary syndrome, inflammatory bowel disease, gonadal dysgenesis, galactorrhea, hyperandrogenism, androgen insensitivity syndrome, adrenal tumors, ovarian tumors, imperforate hymen, Rokitansky-Hauser syndrome

Contributor Information and Disclosures

Author

Kenneth M Bielak, MD, Clinic Director of Family Practice Center, Associate Professor, Department of Family Medicine, University of Tennessee at Knoxville
Kenneth M Bielak, MD is a member of the following medical societies: American Academy of Family Physicians, American College of Sports Medicine, American Medical Association, and American Medical Society for Sports Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Gayla S Harris, MD, Associate Professor, Department of Obstetrics and Gynecology, University of Tennessee Medical Center
Gayla S Harris, MD is a member of the following medical societies: American Society for Reproductive Medicine
Disclosure: Nothing to disclose.

Medical Editor

Elizabeth Alderman, MD, Director of Fellowship Training Program, Director, Adolescent Ambulatory Service, Clinical Professor, Department of Pediatrics, Division of Adolescent Medicine, Albert Einstein College of Medicine and Montefiore Medical Center
Elizabeth Alderman, MD is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, North American Society for Pediatric and Adolescent Gynecology, and Society for Adolescent Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Wayne Wolfram, MD, MPH, Clinical Associate Professor, Departments of Pediatrics, Children's Hospital and University of Cincinnati
Wayne Wolfram, MD, MPH is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Pediatrics, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center
Maureen Strafford, MD is a member of the following medical societies: American Medical Women's Association, American Pain Society, American Society of Anesthesiologists, International Anesthesia Research Society, Society for Education in Anesthesia, Society for Pediatric Anesthesia, and Society of Cardiovascular Anesthesiologists
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.