Amenorrhea: Evaluation and Treatment TARANNUM MASTER-HUNTER, M.D., University of Michigan Medical School, Ann Arbor, Michigan DIANA L. HEIMAN, M.D., University of Connecticut School of Medicine, Hartford, Connecticut A thorough history and physical examination as well as laboratory testing can help narrow the differential diagnosis of amenorrhea. In patients with primary amenorrhea, the presence or absence of sexual development should direct the evaluation. Constitutional delay of growth and puberty commonly causes primary amenorrhea in patients with no sexual development. If the patient has normal pubertal development and a uterus, the most common etiology is con- genital outflow tract obstruction with a transverse vaginal septum or imperforate hymen. If the patient has abnormal uterine development, müllerian agenesis is the likely cause and a karyotype analysis should confirm that the patient is 46,XX. If a patient has secondary amenor- rhea, pregnancy should be ruled out. The treatment of primary and secondary amenorrhea is based on the causative factor. Treatment goals include prevention of complications such as osteoporosis, endo- metrial hyperplasia, and heart disease; preservation of fertility; and, in primary amenorrhea, progression of normal pubertal development. (Am Fam Physician 2006;73:1374-82, 1387. Copyright 2006 Ameri- can Academy of Family Physicians.)
A handout on amenor-rhea, written by the authors of this article, is provided on page 1387.
Primary amenorrhea can be diag- ination of patients with amenorrhea (Table 22,6-8). Many algorithms exist for the evalu-
ondary sexual characteristics but ation of primary amenorrhea; Figure 11,7,9,10 no menarche by 16 years of age. If is one example. Laboratory tests and radi-
a patient has no secondary sexual character-
ography, if indicated, should be performed
to evaluate for suspected systemic disease. If
rhea can be diagnosed as early as 14 years of secondary sexual characteristics are present, age. Secondary amenorrhea is the absence pregnancy should be ruled out. Routine radi-of menses for three months in women with ography is not recommended, however.7 previously normal menstruation and for nine
Figure 21-3,6 is an algorithm for the evalu-
orrhea. Secondary amenorrhea is more com-
is pregnancy. After pregnancy is ruled out,
Pubertal changes typically occur over a the initial work-up should be based on
three-year period and can be measured using patient history and physical examination Tanner staging.4 The normal progression of findings. Prolactin levels should be checked female puberty is illustrated in Table 1.4,5 in most patients. The risk of amenorrhea is The normal menstrual cycle involves a com-
lower with subclinical hypothyroidism than
plex interaction between the hypothalamic-
with overt disease. However, the effects of
pituitary-ovarian axis and the outflow tract. subclinical hypothyroidism on menstrua-Any disruption in this interaction can cause tion and fertility are unclear, and abnormal amenorrhea.
thyroid hormone levels can affect prolactin levels; therefore, physicians should consider
Physicians should conduct a comprehensive (TSH) levels.3,11,12 A study13 of 127 women patient history and a thorough physical exam-
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2006 American Academy of Family Physicians. For the private, noncom-
r ioaf n
t he Web site. All other rights res w
Amenorrhea SORT: KEY RECOMMENDATIONS FOR PRACTICE
A female patient with primary amenorrhea and sexual development, including pubic hair,
should be evaluated for the presence of a uterus and vagina.
Women with secondary amenorrhea should receive pregnancy tests.
Women with polycystic ovary syndrome should be tested for glucose intolerance.
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1313 or http://www.aafp.org/afpsort.xml.
Table 1 Normal Female Pubertal Development
Elevation of papil a only; no pubic hair
The rights holder did not grant the American
Academy of Family Physicians the right to sublicense this material to a third party.
For the missing item, see the original print version of this publication. Information from references 4 and 5.April 15, 2006 ◆ Volume 73, Number 8American Family Physician 1375 Amenorrhea
7.5 percent of participants had abnormal prolactin levels tive progestogen challenge test signifies an outflow tract and 4.2 percent had abnormal TSH levels.
abnormality or inadequate estrogenization. An estrogen/
If TSH and prolactin levels are normal, a progestogen progestogen challenge test (Table 33,14) can differentiate
challenge test (Table 33,14) can help evaluate for a patent the two diagnoses. A negative estrogen/progestogen chal-outflow tract and detect endogenous estrogen that is lenge test typically indicates an outflow tract obstruc-affecting the endometrium. A withdrawal bleed usually tion. A positive test indicates an abnormality within the occurs two to seven days after the challenge test.3 A nega-
hypothalamic-pituitary axis or the ovaries.
Table 2 History and Physical Examination Findings Associated with Amenorrhea Patient history Exercise, weight loss, current or previous chronic il ness,
Previous central nervous system chemotherapy or radiation
Psychosocial stressors; nutritional and exercise history
Family history Genetic defects
Menarche and menstrual history (mother and sisters)
Constitutional delay of growth and puberty
Constitutional delay of growth and puberty
Physical examination Anthropomorphic measurements; growth chart
Constitutional delay of growth and puberty
Dysmorphic features (e.g., webbed neck, short stature,
Striae, buffalo hump, significant central obesity, easy bruising,
hypertension, or proximal muscle weakness
Transverse vaginal septum; imperforate hymen
Undescended testes; external genital appearance; pubic hair
Review of systems Anosmia
Outflow tract obstruction or mül erian agenesis
Galactorrhea; headache and visual disturbances
Signs and symptoms of hypothyroidism or hyperthyroidism
Information from references 2 and 6 through 8.1376 American Family Physician Volume 73, Number 8 ◆ April 15, 2006Amenorrhea Evaluation of Primary Amenorrhea
History and physical examination completed for a patient with primary amenorrhea
Figure 1. algorithm for the evaluation of primary amenorrhea. (FSH = follicle-stimulating hormone; lH = luteinizing Information from references 1, 7, 9, and 10.
Gonadotropin levels can further help determine the are present, they should be removed because of the high
source of the abnormality. Elevated follicle-stimulat-
risk of malignant transformation after puberty.1
ing hormone (FSH) or luteinizing hormone (LH) levels
If a patient has normal secondary sexual characteris-
suggest an ovarian abnormality (hypergonadotropic tics, including pubic hair, the physician should perform hypogonadism). Normal or low FSH or LH levels suggest MRI or ultrasonography to determine if a uterus is a pituitary or hypothalamic abnormality (hypogonado-
present. Müllerian agenesis (the congenital absence of
tropic hypogonadism). Magnetic resonance imaging a vagina and abnormal uterine development [usually (MRI) of the sella turcica can rule out a pituitary rudimentary]) causes approximately 15 percent of pri-tumor. Normal MRI indicates a hypothalamic cause of mary amenorrhea.16 The etiology is thought to involve amenorrhea.3
embryonic activation of the antimüllerian hormone, causing malformation of the female genital tract.7,17
Differential Diagnosis of Primary Amenorrhea
Patients may have cyclic abdominal pain if there is endo-
Causes of primary amenorrhea should be evaluated in the metrial tissue in the rudimentary uterus, mittelschmerz, context of the presence or absence of secondary sexual or breast tenderness. An absent or truncated vagina and characteristics. Table 43,6,15 includes the differential diag-
an abnormal adult uterus confirm müllerian agenesis.
Karyotype analysis should be performed to determine if the patient is genetically female.8
PRESENCE OF SECONDARY SExuAl CHARACTERISTICS
If the patient has a normal uterus, outflow tract
If a patient with amenorrhea has breast development and obstruction should be considered. An imperforate hymen minimal or no pubic hair, the usual diagnosis is androgen or a transverse vaginal septum can cause congenital out-insensitivity syndrome (i.e., patient is phenotypically female flow tract obstruction, which typically is associated with but genetically male with undescended testes). A karyotype cyclic abdominal pain from blood accumulation in the analysis is needed to determine proper treatment. If testes uterus and vagina.1 If the outflow tract is patent, the
April 15, 2006 ◆ Volume 73, Number 8American Family Physician 1377 Amenorrhea Evaluation of Secondary Amenorrhea
Patient presenting with secondary amenorrhea; negative pregnancy test
Normal MRI: hypogonadotropic hypogonadism (Table 4)
Figure 2. algorithm for the evaluation of secondary amenorrhea. (TSH = thyroid-stimulating hormone; MRI = magnetic
resonance imaging; FSH = follicle-stimulating hormone; lH = luteinizing hormone.)
Information from references 1 through 3 and 6.
physician should continue an evaluation similar to that stitutional delay of growth and puberty is indistinguish-for secondary amenorrhea (Figure 21-3,6).1
able from that associated with hypothalamic or pituitary failure.10 Watchful waiting is appropriate for constitu-
AbSENCE OF SECONDARY SExuAl CHARACTERISTICS
tional delay of growth and puberty. Kallmann syndrome,
Diagnosis of patients with amenorrhea and no second-
which is associated with anosmia, also can cause hypogo-
ary sexual characteristics is based on laboratory test nadotropic hypogonadism.18results and karyotype analysis. The most common cause
Hypergonadotropic hypogonadism (elevated FSH and
of hypogonadotropic hypogonadism (low FSH and LH LH levels) in patients with primary amenorrhea is caused levels) in primary amenorrhea is constitutional delay of by gonadal dysgenesis or premature ovarian failure. growth and puberty.16,17 A detailed family history also Turner’s syndrome (45,XO karyotype) is the most com-may help detect this etiology, because it often is familial. mon form of female gonadal dysgenesis. Characteristic Hypogonadotropic hypogonadism associated with con-
physical findings include webbing of the neck, widely
1378 American Family Physician Volume 73, Number 8 ◆ April 15, 2006Amenorrhea
Table 3 guidelines for Progestogen and Estrogen/Progestogen Challenge Tests Progestogen challenge test Medroxyprogesterone acetate (Provera) Estrogen/progestogen challenge test Conjugated equine estrogen (Premarin) Information from references 3 and 14.
spaced nipples, and short stature. Mosaicism occurs prolactinemia. Medications usually raise prolactin levels in approximately 25 percent of patients with Turner’s to less than 100 ng per mL.15 When hyperprolactinemia syndrome.19 These patients often have a more normal is not related to tumor, physicians should identify and phenotype with spontaneous onset of puberty and men-
treat or eliminate the underlying cause. Table 43,6,15 lists
arche. Other rare causes of pure gonadal dysgenesis can common etiologies of hyperprolactinemia. occur with a 46,XY or XX karyotype.7
If asymptomatic microadenomas (smaller than 10
mm) are found on MRI, repeat prolactin measurements
Differential Diagnosis of Secondary Amenorrhea
and imaging should be performed to monitor for pro-
After pregnancy, thyroid disease, and hyperprolactinemia gression. Microadenomas are slow growing and rarely are eliminated as potential diagnoses, the remaining malignant. Treatment of microadenomas should focus causes of secondary amenorrhea are classified as nor-
on management of infertility, galactorrhea, and breast
mogonadotropic amenorrhea, hypogonadotropic hypo-
discomfort. A dopamine agonist can help improve
gonadism, and hypergonadotropic hypogonadism; each symptoms and fertility. Bromocriptine (Parlodel) is is associated with specific etiologies (Table 43,6,15).
effective, but cabergoline (Dostinex) has been shown to be superior in effectiveness and tolerability.20 Mac-
roadenomas may be treated with dopamine agonists or
Other clinical signs of thyroid disease are usually noted removed with transsphenoidal resection or craniotomy, before amenorrhea presents. Mild hypothyroidism is if necessary. more often associated with hypermenorrhea or oligo-menorrhea than with amenorrhea. Treatment of hypo-
thyroidism should restore menses, but this may take Two common causes of normogonadotropic amenor-several months.12
rhea are outflow tract obstruction and hyperandrogenic chronic anovulation. The most common cause of out-
flow obstruction in secondary amenorrhea is Asherman’s
A patient with markedly elevated prolactin levels, galac-
syndrome (intrauterine synechiae and scarring, usually
torrhea, headaches, or visual disturbances should receive from curettage or infection).3 Hysterosalpingography, imaging tests to rule out a pituitary tumor. Adenomas hysteroscopy, or sonohysterography can help diagnose are the most common cause of anterior pituitary dys-
Asherman’s syndrome. Other causes of outflow tract
function.15 A prolactin level more than 100 ng per mL obstruction include cervical stenosis and obstructive (100 mcg per L) suggests a prolactinoma, and MRI fibroids or polyps. should be performed. If tumor is excluded as the cause,
Polycystic ovary syndrome (PCOS) is the most com-
medications (e.g., oral contraceptive pills, antipsychotics, mon cause of hyperandrogenic chronic anovulation. antidepressants, antihypertensives, histamine H2 block-
The National Institutes of Health diagnostic criterion for
ers, opiates) are the next most common cause of hyper-
PCOS21 is chronic anovulation and hyperandrogenism
April 15, 2006 ◆ Volume 73, Number 8American Family Physician 1379 Amenorrhea
Table 4 Causes of Amenorrhea Hyperprolactinemia Hypergonadotropic hypogonadism Hypogonadotropic hypogonadism (continued) Normogonadotropic Hypogonadotropic hypogonadism
Nonclassic congenital adrenal hyperplasia
Constitutional delay of growth and puberty*
Severe depression or psychosocial stressors
*—Causes of primary amenorrhea only.Information from references 3, 6, and 15.
with no other identified secondary cause. The primary fivefold; therefore, testing for glucose intolerance should etiology of PCOS is unknown, but resistance to insulin be considered.21-24is thought to be a fundamental component.21
The primary treatment for PCOS is weight loss
The diagnosis of PCOS is primarily clinical, although through diet and exercise. Modest weight loss can lower
laboratory studies may be needed to rule out other causes androgen levels, improve hirsutism, normalize menses, of hyperandrogenism (Table 56,21). Significantly elevated and decrease insulin resistance. It may take months to testosterone or dehydroepiandrosterone sulfate levels see these results, however.21 Use of oral contraceptive indicate a possible androgen-secreting tumor (ovarian pills or cyclic progestational agents can help maintain or adrenal). Levels of 17-hydroxyprogesterone can help a normal endometrium. The optimal cyclic progestin diagnose adult-onset congenital adrenal hyperplasia. regimen to prevent endometrial cancer is unknown, Cushing’s disease is rare; therefore, patients should only but a monthly 10- to 14-day regimen is recommended.21 be screened when characteristic signs and symptoms Insulin sensitizing agents such as metformin (Gluco-(e.g., striae, buffalo hump, significant central obesity, phage) can reduce insulin resistance and improve ovula-easy bruising, hypertension, proximal muscle weakness) tory function.21,25,26 are present.21,22
Patients with PCOS have excess unopposed circulat-
ing estrogen, increasing their risk of endometrial cancer Ovarian failure can cause menopause or can occur pre-threefold.21 The insulin resistance associated with PCOS maturely. On average, menopause occurs at 50 years of increases a patient’s risk of diabetes mellitus two- to age and is caused by ovarian follicle depletion. Premature
1380 American Family Physician Volume 73, Number 8 ◆ April 15, 2006Amenorrhea
Table 5 laboratory Evaluation of Hyperandrogenism Serum testosterone (normal: 20 to 80 ng per dl [0.7 to 2.8 nmol per l]) ≤ 200 ng per dL (6.9 nmol per L)
Consider hyperandrogenic chronic anovulation*
Serum dehydroepiandrosterone sulfate (normal: 250 to 300 ng per dl [0.7 to 0.8 µmol per l]) ≤ 700 ng per dL (1.9 µmol per L)
Consider hyperandrogenic chronic anovulation*
Serum 17-hydroxyprogesterone (normal: < 2 ng per ml (6.1 nmol per l])† > 4 ng per mL (12.1 nmol per L)
Consider adrenocorticotropic stimulation test to diagnose
Dexamethasone suppression test (if clinically indicated)†† Morning cortisol level > 5 µg per dL (138 nmol per L)§ *— These values are not specific for diagnosis of hyperandrogenic chronic anovulation. †—Morning level during fol icular phase of menstrual cycle. ††—For an overnight dexamethasone suppression test, the physician should administer a 1-mg dose of dexamethasone oral y between 11 p.m. and midnight and draw a single blood sample for serum cortisol testing at 8 a.m. the fol owing day. §—Morning cortisol level in a healthy patient with an intact hypothalamic-pituitary axis. There is some variability in the cutoff values that can affect sensitivity and specificity of the test. Patients should receive further testing to confirm Cushing’s disease.Information from references 6 and 21.
ovarian failure is characterized by amenorrhea, hypoes-
secretion and disruption of the hypothalamic-pituitary-
trogenism, and increased gonadotropin levels occurring ovarian axis. The condition often is caused by excessive before 40 years of age and is not always irreversible27 weight loss, exercise, or stress. Other causes are listed (0.1 percent of women are affected by 30 years of age in Table 4.3,6,15 The mechanism of how stress or weight and one percent by 40 years of age).28 Approximately loss affects GnRH secretion is unknown.33-35 Treatment 50 percent of women with premature ovarian failure have of hypothalamic amenorrhea depends on the etiology. intermittent ovarian functioning29 with a 5 to 10 percent Women with excessive weight loss should be screened chance of achieving natural conception.
for eating disorders and treated if anorexia nervosa or
Women with premature ovarian failure have an bulimia nervosa is diagnosed. Menses usually will return
increased risk of osteoporosis and heart disease.29-31 after a healthy body weight is acheived.35 The condition also can be associated with autoim-
Young athletes may develop a combination of health
mune endocrine disorders such as hypothyroidism, conditions called the female athlete triad that includes Addison’s disease, and diabetes mellitus.27,29 Therefore, an eating disorder, amenorrhea, and osteoporosis. Men-fasting glucose, thyroid-stimulating hormone (TSH), ses may return after a modest increase in caloric intake and, if clinically appropriate, morning cortisol levels or a decrease in athletic training. Similar to patients should be measured. Other laboratory testing should be with eating disorders, athletes with continued amenor-determined based on the individual patient.32 Approxi-
rhea are at risk of bone loss. In adolescent athletes, the
mately 20 to 40 percent of women with premature ovar-
bone loss occurs during peak bone mass development
ian failure will develop another autoimmune disorder; and may not be reversible.36,37 Weight-bearing exercise therefore, if initial laboratory tests are normal, periodic may partially protect against bone loss.38 screening should be considered. Patients younger than
In patients with amenorrhea caused by eating disor-
30 years should receive a karyotype analysis to rule ders or excessive exercise, the use of oral contraceptive out the presence of a Y chromosome and the need for pills or menopausal hormone therapy may decrease removal of gonadal tissue.29 Ovarian biopsy and anti-
bone turnover and partially reverse bone loss; however,
ovarian antibody testing have not been shown to have neither therapy has been shown to significantly increase clinical benefit.27,29
bone mass.38 Bisphosphonates, traditionally used to treat postmenopausal osteoporosis, are possible terato-
gens and have not been studied as a therapy in women
Hypothalamic amenorrhea is associated with abnor-
of reproductive age. Adequate calcium and vitamin D
malities in gonadotropin-releasing hormone (GnRH) intake are recommended for these patients.
April 15, 2006 ◆ Volume 73, Number 8American Family Physician 1381 Amenorrhea
The authors thank Barbara S. Apgar, M.D., M.S., for her assistance in the
15. Pickett CA. Diagnosis and management of pituitary tumors: recent
16. Folch M, Pigem I, Konje JC. Mül erian agenesis: etiology, diagnosis, and
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series from an academic center. J Clin Endo Metab 2002;87:1613-20.
of Family Medicine at the University of Michigan Medical School, Ann
18. Traggiai C, Stanhope R. Delayed puberty. Best Pract Res Clin Endocrinol
Arbor. She received a medical degree from the University of Medicine
and Dentistry of New Jersey-New Jersey Medical School in Newark. Dr.
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Master-Hunter completed a family practice residency at the University of
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DIANA L. HEIMAN, M.D., C.A.Q., is assistant professor in the Department
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of Family Medicine at the University of Connecticut School of Medicine, Hartford. She received a medical degree from Case Western Reserve
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Address correspondence to Tarannum Master-Hunter, M.D., C.A.Q., Chelsea Family Practice, 14700 Old U.S. Hwy. 12, Chelsea, MI 48118
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over 12 months. Am J Obstet Gynecol 1997;176:1017-25. 1382 American Family Physician Volume 73, Number 8 ◆ April 15, 2006
CURRICULUM VITAE PD Dr. Med. Karin Jordan Leitende Oberärztin Universitätsklinik und Poliklinik für Innere Medizin IV Onkologie – Hämatologie Ernst-Grube-Straße 40 06120 Halle / Saale Beruflicher Werdegang Studium der Humanmedizin, „Martin-Luther-Universität“ Halle-Wittenberg; Fellowship u. a. in Newcastle und San DiegoKlinik für Onkologie und Hämatologie der „Mar