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You are in: eMedicine Specialties > Medicine, Ob/Gyn, Psychiatry, and Surgery > Obstetrics/gynecology

Amenorrhea
Last Updated: May 17, 2005

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AUTHOR INFORMATION

Section

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Author: Lawrence M Nelson, MD, MBA, Head of Gynecologic Endocrinology Unit, Investigator, Sec
Women's Health Research, Developmental Endocrinology Branch, National Institutes of Health
Coauthor(s): Vladimir Bakalov, MD, Clinical Associate, Developmental Endocrinology Branch, Natio
Child Health and Human Development, National Institutes of Health; Carmen Pastor, MD, Associate
Section of Women's Health Research, National Institutes of Health
Lawrence M Nelson, MD, MBA, is a member of the following medical societies: American College of
and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gyne
Obstetrics, Endocrine Society, and Society for Experimental Biology and Medicine
Editor(s): Thomas Michael Price, MD, Associate Professor of Reproductive Endocrinology, Duke U
Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; A David B
PhD, Professor, Department of Obstetrics and Gynecology, University of Hawaii, Chubu Hospital; Fr
Gaupp, MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital; and
Shulman, MD, Professor of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern
Chief, Division of Reproductive Genetics, Department of Obstetrics and Gynecology, Prentice Wome
Northwestern Memorial Hospital
Disclosure

INTRODUCTION

Section 2 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Primary amenorrhea is defined as the failure of menses to occur by age 16 years. Sec
amenorrhea is defined as the cessation of menses once they have begun. Oligomenorrhea is define
occurring at intervals longer than 35 days. No consensus has been reached regarding the point at w
oligomenorrhea becomes amenorrhea. Some authors suggest the absence of menses for 6 months
amenorrhea, but the basis for this recommendation is unclear. Practically speaking, a woman aged 2
experiences loss of an established regular menstrual pattern should have an evaluation to seek the

This article addresses the evaluation and treatment of women with amenorrhea who have no eviden
excess. Women with amenorrhea who do have evidence of androgen excess, such as hirsutism, viri
ambiguity, should be evaluated differently from women with amenorrhea alone.

Pathophysiology: Regular and predictable menstrual cycles occur if the ovarian hormones estradio
progesterone are secreted in an orderly fashion in response to stimulation by the hypothalamus and
Circulating estradiol stimulates growth of the endometrium. Progesterone, produced by the corpus lu
after ovulation, transforms proliferating endometrium into secretory endometrium. If pregnancy does
secretory endometrium breaks down and sheds during the ensuing menstrual period.

Amenorrhea occurs if the hypothalamus and pituitary fail to provide appropriate gonadotropin stimula
resulting in inadequate production of estradiol or in failure of ovulation and progesterone production.
also occur if the ovaries fail to produce adequate amounts of estradiol despite normal and appropria
stimulation by the hypothalamus and pituitary. In some cases, the hypothalamus, pituitary, and ovarie
functioning normally, yet amenorrhea occurs because of adhesions in the endometrial cavity or an o
cervicovaginal outflow tract.
Frequency:

In the US: Each year, approximately 5% of menstruating women experience 3 months of sec
amenorrhea.

Internationally: No evidence indicates that the prevalence of amenorrhea varies according to

or ethnic group. However, local environmental factors related to nutrition and the prevalence o
undoubtedly have an effect. For instance, the age of the first menses varies by geographic loc
demonstrated by a World Health Organization study comparing 11 countries, which reported a
menarche of 13-16 years across centers.

Mortality/Morbidity: The regular occurrence of menses is a sign of good health. It means that the h
pituitary-ovarian axis is functioning normally to produce ovarian hormones and support ovulation. Th
as both an endocrine organ and a reproductive organ. When menstrual cycle regularity is lost, this m
are not functioning normally in either their endocrine role or their reproductive role. Loss of menstrua
been associated with reduced bone density and increased fracture rates. Thus, loss of menstrual reg
associated morbidity and may contribute to increased mortality.

Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androg
progesterone. These sex hormones play an important role in building and maintaining bone m
menarche has been associated with a 3-fold increase in the risk of wrist fracture. Menstrual cy
longer than 31 days has been associated with a 2-fold increase in wrist fracture. Similar corre
the risk of hip fracture, a potentially fatal occurrence.

Regular menses is also a sign that the ovaries support ovulation and that they contain a norm
primordial follicles. Primordial follicles are composed of an oocyte surrounded by a single laye
cells. The number of primordial follicles in the human ovary peaks during the fifth gestational m
approximately 7 million. After this initial finite pool is in place, no additional primordial follicles
some cases, loss of menstrual regularity is an early sign of declining fertility and impending pr
failure. Also in some cases, this follicle depletion progresses to cause irreversible infertility. Ap
of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian

Race: No evidence suggests that the incidence of either primary or secondary amenorrhea is related
Sex: Amenorrhea occurs only in women.

Age: A large study by Treolar et al (1967) demonstrated that by age 20 years, women have establish
regular and persistent patterns of menstrual cycle length with little variation on an individual basis. R
and predictable menstrual cycle length then continues until age 40 years.

According to the findings from the Treolar et al study, fewer than 2 menses in a 90-day interval (>95t
woman aged 20-40 years is distinctly abnormal. Further, more than 3 menses in a 90-day interval in
also distinctly abnormal. Finally, menstrual bleeding for more than 10 days in women in this age grou
distinctly abnormal.

As women age, a remarkably steady decline occurs in mean menstrual cycle length. The shortening
be physiologically linked in some way to the well-established decline in the number of primordial folli
the pool as women age.

While the overall median menstrual cycle length is 28 days, cycle length gradually declines from age
40 years. At age 20 years, the median cycle length is 29 days, and by age 40 years, this has decline
Further shortening of the menstrual cycle length is a well-recognized early sign of impending menop

In the first year after menarche, the fifth percentile for menstrual cycle length is 23 days and th
is 90 days. By the fourth year after menarche, the 95th percentile for cycle length has decline
approximately 50 days. Menstrual cycle length is certainly more variable for females in their te
women aged 20-40 years. However, by 7 years after menarche, cycles are more stable; the fi
cycle length is 27 days, and the 95th percentile is 38 days.

In the year preceding menopause, the fifth percentile for cycle length is 25 days and the 95th
approximately 150 days. Four years before menopause, the fifth percentile for cycle length is
95th percentile for cycle length is significantly more regular, at approximately 40 days. Menstr
certainly more variable during the years preceding the menopausal transition than during the

40 years.

CLINICAL

Section 3 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: Loss of menstrual regularity is an indication for a careful review of systems. The menstrual
viewed as a vital sign. Loss of menstrual regularity may be the first clear symptom heralding the ons
illness or systemic disease. Viewing the menstrual cycle as a vital sign may lead to earlier diagnosis
intervention for, several potentially life-threatening disorders. An arbitrarily defined duration of ameno
pass before taking corrective action.

Amenorrhea can be due to pregnancy, anatomic defects of the outflow tract, ovarian disorders, and p
hypothalamic disorders. In some cases, the cause is functional, meaning that the hypothalamic gona
releasing hormone (GnRH) pulse generator has shut down the reproductive system in its role as an
metabolic and psychogenic stress. Attributing the loss of menstrual regularity to a recent stressful life
tempting; however, this approach can delay the detection of significant pathology that can have long
consequences. One study has shown that one third of control women report a significant stressful lif
preceding year.

Pregnancy is the most common cause of amenorrhea. Determining whether the patient is sexually a
she is using contraceptive methods is important. In some cases, the hormonal contraception itself m
of the amenorrhea.

Often, time constraints do not permit practitioners to obtain a thorough history and review of symptom
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 prepara
visit. In other cases, patients may be asked to keep a menstrual calendar and return in 3 months for
The importance of the ovary as an endocrine organ that helps maintain bone density should be stres
to help ensure her return.

In cases of primary amenorrhea, inquiring about other aspects of growth and pubertal development i
absence of any breast development or pubertal growth spurt by age 14 years in girls is distinctly abn
requires investigation. Breast development, pubertal growth spurt, and adrenarche are delayed or ab
with hypothalamic pituitary failure. A distinguishing factor in the case of isolated ovarian insufficiency
adrenarche occurs normally, while estrogen-dependent breast development and the pubertal growth
or delayed.

Disorders of the outflow tract

o

A history of otherwise normal growth and pubertal development in association with prim

suggests the possibility of a congenital outflow tract abnormality such as imperforate h

of the vagina, cervix, or uterus. These findings are also compatible with the complete a
resistance syndrome.
o

Prior history of a surgical procedure involving the endometrial cavity, especially if perfo
presence of infection, raises the possibility of uterine synechiae (Asherman syndrome)

Ovarian disorders
o

Symptoms of vaginal dryness, hot flashes, night sweats, or disordered sleep may be a
insufficiency or premature ovarian failure. The presence of these symptoms in young w
timely further evaluation.

Prior history of chemotherapy or radiation therapy may be associated with ovarian failu

A distinguishing factor in the case of isolated ovarian insufficiency or failure and primar
that adrenarche occurs normally while estrogen-dependent breast development and th
spurt are absent or delayed.

Hypothalamic/pituitary disorders
o

Associated galactorrhea, headaches, or reduced peripheral vision could be a sign of in

These symptoms require immediate further evaluation.

A history of hemorrhage after childbirth can lead to failure of regular menses to return.
indication of postpartum pituitary necrosis. Failure of lactation is an even earlier sign. D
condition early is important because of the possible development of associated central
insufficiency, a potentially fatal condition.

An impaired sense of smell in association with primary amenorrhea and failure of norm
development may be related to isolated gonadotropin deficiency, as is observed in pers
Kallmann syndrome.

Sarcoidosis can manifest insidiously, with development of mild fatigue, malaise, anorex
and fever. Because 90% of patients with sarcoidosis have pulmonary involvement at so
disorder, cough and dyspnea may be present.

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

Functional impairment of the hypothalamic GnRH pulse generator

o

Dieting with excessive restriction of energy intake, especially fat restriction, may lead to
menstrual regularity and associated bone loss. In extreme cases, the process may adv
nervosa, a potentially fatal condition. Associated symptoms are an intense fear of fatne
image that is heavier than observed. Eating disorders can be restrictive in nature or ca

eating/purging type.
o

Major psychiatric disorders such as depression, obsessive-compulsive disorder, or sch

disrupt the menstrual cycle. Symptoms associated with these conditions may be detec
of systems.

Autoimmune adrenal insufficiency, a potentially fatal condition, often manifests as vagu

symptoms. Loss of menstrual regularity may be the first clear symptom indicating a nee
evaluation to detect this condition.

Loss of menstrual regularity may herald the onset of other autoimmune endocrine diso
hyperthyroidism, hypothyroidism, or autoimmune lymphocytic hypophysitis. The same
endocrine disorders such as Cushing syndrome or pheochromocytoma. A careful revie
may help uncover these disorders.

Strenuous exercise related to a wide variety of athletic activities can be associated with
development of amenorrhea. Elicit a history regarding the type of exercise activity and
week.

o
o
o

Abuse of drugs such as cocaine and opioids have central effects that may disrupt the m
Malnutrition and cirrhosis associated with alcoholism may cause loss of menstrual regu
AIDS, HIV disease, or other types of immune-deficiency states may induce systemic in
chronic disease and loss of menstrual regularity.
Occult malignancy with progressive weight loss and a catabolic state may lead to loss
regularity. A careful review of systems may help uncover such a disorder.

Physical: Physical examination should begin with an overall assessment of nutritional status and ge
Measure height and weight and seek evidence for chronic disease or cachexia.

Hypothermia, bradycardia, hypotension, and reduced subcutaneous fat can be observed in persons
anorexia nervosa. In cases of frequent vomiting, look for possible dental erosion, reduced gag reflex
palate, subconjunctival hemorrhage, and metacarpophalangeal calluses or bruises.

Examine the skin for evidence of androgen excess, such as hirsutism and acne. Acanthosis n
present in association with androgen excess related to insulin resistance.

Skin examination findings can also give clues to other endocrine disorders. Vitiligo or increase
of the palmar creases may herald primary adrenal insufficiency. Thin, parchmentlike skin, stria
of easy bruising may be signs of Cushing syndrome. Warm, moist skin radiating excessive he
of hyperthyroidism.

Large pituitary tumors can cause visual-field cuts by impinging on the optic tract. In some cas
field cuts can be detected by simple confrontational testing.

Assess the state of breast development. Also examine the breasts for galactorrhea. In some c
discharge can be expressed, yet the condition is not true galactorrhea. If the discharge is inde

be confirmed by finding fat globules in the fluid using low-power microscopy.

Examine for the presence of axillary and pubic hair. These are a marker of adrenal and ovaria
secretion. In cases of panhypopituitarism, sources of androgen are low and pubic and axillary
Also, some women develop the combination of autoimmune premature ovarian failure and au
primary adrenal insufficiency. These women are also markedly androgen-deficient and have s
pubic hair. The same is true for persons with androgen insensitivity syndrome (testicular femin
hydroxylase deficiency, and 17,20-desmolase deficiency.

In cases of primary amenorrhea with otherwise normal pubertal development, pelvic examina
detect imperforate hymen, a transverse vaginal septum, or cervical or uterine aplasia.

Pelvic examination findings can provide physical evidence indicating the adequacy of estroge
Thin and pale vaginal mucosa with absent rugae is evidence of estrogen deficiency. The pres
mucus with spinnbarkeit is good evidence of estrogen effect. However, evidence of estrogen e
physical examination findings can be misleading in some cases because estrogen is being pr
result of higher than normal follicle-stimulating hormone (FSH) levels (compensated ovarian in
Women with well-established premature ovarian failure often have intermittent ovarian follicle
produces enough estrogen to have vaginal and cervical effects.

Measuring the clitoris is an effective method for determining the degree of androgen effect. Th
can be determined by measuring the glans of clitoris in the anteroposterior and transverse dia
index greater than 35 mm2 is evidence of increased androgen effect. A clitoral index greater th
evidence of virilization.

Ovarian enlargement may be found upon pelvic examination in cases of autoimmune oophori
hydroxylase deficiency, or 17,20-desmolase deficiency. In these disorders, inadequate negativ
supplied by the ovary permits excessive gonadotropin stimulation that may cause ovarian enl
multiple follicular cysts. In some cases, these disorders manifest with an acute onset of pain r
torsion.

A general physical examination may undercover unexpected findings that are indirectly relate
menstrual regularity (eg, discovery of hepatosplenomegaly, which may lead to detection of a c
disease).

Causes: Amenorrhea can be divided into 2 groups, (1) amenorrhea without evidence of associated
and (2) amenorrhea with evidence of androgen excess (eg, hirsutism, virilization, sexual ambiguity).
the causes of amenorrhea associated with androgen excess, see Polycystic Ovarian Syndrome.
Causes of amenorrhea without associated androgen excess

Pregnancy

Anatomic defects of outflow tract

Intrauterine adhesions (Asherman syndrome)

Imperforate hymen

Transverse vaginal septum

Aplasia of the vagina, cervix, or uterus: Congenital absence of the uterus can be an iso
can occur in association with the complete androgen resistance syndrome, also known
feminization.

Ovarian causes
o

Prodromal premature ovarian failure: This is a state of ovarian insufficiency in which FS

elevated and menses are irregular but not to the degree required to make a diagnosis
ovarian failure. It is also referred to as overt ovarian insufficiency. For a more in-depth d
Ovarian Insufficiency.

Karyotypically normal spontaneous premature ovarian failure: For an in-depth discussi

Failure.

Turner syndrome

Pure gonadal dysgenesis: The term "pure" here refers to the fact that the syndrome se
purely affected the gonad. No associated dysmorphic findings exist as are noted in Tur
which is often referred to as gonadal dysgenesis. Pure gonadal dysgenesis can occur
46,XX or a 46,XY karyotype.

Autoimmune oophoritis

17,20-desmolase deficiency or 17-hydroxylase deficiency

Radiation or chemotherapy

Galactosemia

FSH receptor mutation

Pituitary causes
o

Prolactinoma

o
o
o
o
o

Other pituitary tumors (Cushing syndrome, acromegaly, thyrotropin)

Postpartum pituitary necrosis (Sheehan syndrome)
Autoimmune hypophysitis
Pituitary radiation
Sarcoidosis

o
o

Hemachromatosis
Hypothalamic causes
Tumors such as craniopharyngioma or teratoma
Infiltrative disorder such as sarcoidosis
Kallmann syndrome

Functional causes
o Anorexia/bulimia
o Chronic disease
o Weight loss
o Malnutrition
o Depression or other psychiatric disorders
o Recreational drug abuse
o Psychotropic drug use
o Excessive exercise
o Idiopathic
DIFFERENTIALS

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Adnexal Tumors
Adrenal Adenoma
Adrenal Carcinoma
Androgen Excess
Anorexia Nervosa
Anovulation
Anxiety Disorders
Benign Lesions of the Ovaries
C-17 Hydroxylase Deficiency
Cushing Syndrome
Depression
Follicle-Stimulating Hormone Abnormalities
Germ Cell Tumors
Hydatidiform Mole
Hyperthyroidism
Hypopituitarism (Panhypopituitarism)
Imperforate Hymen
Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism
Leydig Cell Tumors
Luteinizing Hormone Deficiency
Luteinizing Hormone-Releasing Hormone Deficiency
Menopause
Ovarian Failure
Ovarian Insufficiency
Ovarian Polycystic Disease

Section 4 of 10

Pituitary Macroadenomas
Pituitary Microadenomas
Polyglandular Autoimmune Syndrome, Type I
Polyglandular Autoimmune Syndrome, Type II
Polyglandular Autoimmune Syndrome, Type III
Pregnancy Diagnosis
Prolactinoma
Pseudo-Cushing Syndrome

WORKUP
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab Studies:

In most cases, clinical variables alone are not adequate to define the pathophysiologic mecha
women who present with 3 months of secondary amenorrhea should have a diagnostic evalua
Speroff et al, "Few problems in gynecologic endocrinology are as challenging or taxing to the
must be concerned with an array of potential diseases and disorders involving, in many instan
carrying morbid and even lethal consequences for the patient."

Perform a pregnancy test. Once pregnancy is excluded, a thorough history, review of symptom
important. If the history and physical examination findings do not reveal the cause of the ame
urinalysis, and serum chemistries should be evaluated to help rule out systemic disease. Seru
thyrotropin levels should also be measured routinely in the initial evaluation of amenorrhea on

Prolactin

Prolactin levels in excess of 200 ng/mL are not observed except in the case of prolactin
(prolactinoma). In general, the serum prolactin level correlates with the size of the tumo

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

Follicle-stimulating hormone
o

An FSH level of approximately 40 mIU/mL is indicative of ovarian insufficiency. Howeve

patients have a lower menopausal level of FSH; check the reference range for the labo

If a repeat value in 1 month confirms this finding (taking in consideration the above lab
patient has experienced at least 4 months of amenorrhea, then the diagnosis of prema

If the FSH level is 20-40 mIU/mL in a patient with disordered menses, then the diagnos
known as prodromal premature ovarian failure.

Luteinizing hormone: Luteinizing hormone is elevated in cases of 17-20 lyase deficiency, 17-h
ovarian failure.

Estradiol
o

Generally, when considering measurement of the estradiol level, concomitantly draw a

levels within the reference range can be found intermittently despite the presence of w
Finding a concomitantly elevated FSH level brings this to light.

Serum estradiol levels undergo wide fluctuations during the normal menstrual cycle. Du
menstrual cycle, levels may be lower than 50 pg/mL. During the preovulatory estradiol
are not uncommon. In healthy menopausal women, estradiol levels are routinely lower

Testosterone and dehydroepiandrosterone sulphate: Ordering these tests is not necessary in

excess.

Thyrotropin and free thyroxine (T4)

Imaging Studies:

Ovarian causes: The information obtained with ovarian ultrasound imaging does not change c
amenorrhea, and ovarian ultrasound should be reserved for investigational use.

MRI for pituitary or hypothalamic causes

o

MRI of the pituitary and hypothalamus is often indicated in the evaluation of amenorrhe

Request imaging of the hypothalamic/pituitary area specifically, rather than a study of t

resolution.

MRI is indicated in the following circumstances:

Associated headaches or visual-field cuts
Profound estrogen deficiency with otherwise unexplained amenorrhea
Hyperprolactinemia

Other Tests:

Progesterone withdrawal test

o

The development of accurate and reasonably priced hormonal assays has called into q
challenge test. The authors do not recommend performing the test as part of the diagn
on the progesterone challenge test results can cause a delay in the diagnosis of poten

Prior to the development of readily available assays to measure serum levels of estrad
used as a bioassay with which to demonstrate estrogen effect at the level of the endom
100 mg of progesterone in oil has been shown to predictably induce a withdrawal bleed
is at least 50 pg/mL. However, the progesterone withdrawal test can provide inappropr
delay the diagnosis of ovarian insufficiency and, possibly, other conditions.

A 1990 report by Rebar and Connolly demonstrated that nearly 50% of women with pre
withdrawal bleed in response to progestin. These patients have intermittent ovarian fol
despite the presence of extremely elevated FSH and luteinizing hormone levels.

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

Minnesota Nutrition Data Systems evaluation: This can be used to assess dietary intake. This
energy, protein, fat, and carbohydrate content.

Beck Depression Inventory: This can be used to assess the patient's mood.

Modifiable Activity Questionnaire and Paffenbarger Questionnaire: The Modifiable Activity Que
Paffenbarger Questionnaire (Kohl, 1988) can be used to assess the patient's level of physical

Multidimensional eating disorder inventory for anorexia and bulimia (Garner, 1983)

The bulimia test, revised, ie, the BULIT-R (Thelen, 1991)

Procedures:

Hysterosalpingography and hysteroscopy are indicated in cases of possible Asherman syndro

Surgical repair is indicated in disorders of the outflow tract.

TREATMENT

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical Care: Medical care needs are defined by the etiology of the menstrual cycle disturbance an
treatment should be directed at correcting the underlying pathology. In the case of outflow tract abno
other cases, correcting the underlying pathology should restore normal ovarian endocrine function a
osteoporosis. Likewise, correcting the underlying pathology should restore ovulation and permit wom
maintain fertility.

Dopamine agonists are effective in treating hyperprolactinemia. In most cases, this treatment
function and ovulation (see Prolactinoma).

Hormone replacement therapy is required to maintain bone density in patients whose underly

restore normal endocrine function.

Gonadotropin therapy or the use of pulsatile GnRH therapy is required to induce ovulation for
underlying pathology cannot be reversed.

Women with evidence of hyperandrogenism and disordered menses have many other medica
Polycystic Ovarian Syndrome).

Surgical Care: Some pituitary and hypothalamic tumors may require surgery and, in some cases, ra
Macroadenomas). Asherman syndrome requires hysteroscopic lysis of the intrauterine adhesions. T
outflow tract abnormalities depends on the specific clinical situation (see Imperforate Hymen).

Consultations: The causes of menstrual cycle disturbance leading to the development of amenorrh
cases, the situation is best addressed by a multidisciplinary team. For example, a patient with compl
feminization) would benefit from the involvement of experts in endocrinology, human genetics, psych

General internal medicine specialist: In certain cases in which an underlying chronic disease p
internist may be needed.

Medical endocrinologist: In cases of pituitary/hypothalamic tumor, other endocrine disorders (

adrenal insufficiency) may be involved. Generally, the expertise of a medical endocrinologist i
patients who require neurosurgery to treat the underlying condition. In cases of hyperthyroidis
of a medical endocrinologist is required to treat the underlying pathology.

Geneticist: With hereditary causes of amenorrhea, such as Kallmann syndrome, a geneticist's

extended family and in counseling patients regarding the disorder.

Psychiatrist: Cases of major depression, anorexia nervosa, bulimia nervosa, or other major ps
with a psychiatrist (see Anorexia Nervosa).

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

Nutritionist: In many cases, exercise-induced amenorrhea is due to an imbalance in energy in

counseling to increase energy intake without reducing exercise is a means of reversing the un
underweight or who appear to have nutritional deficiencies should receive nutritional counseli
multidisciplinary team specializing in eating disorders.

Diet: Women with findings suggestive of an eating disorder should be evaluated by a multidisciplina
disorders. Nutritional counseling alone is inadequate therapy for these women.

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

Activity: More than 8 hours of vigorous exercise a week may cause amenorrhea. As noted above, in

appropriate adjustment of the diet.

MEDICATION
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Dopamine agonists are the only medical therapy specifically approved to reverse an underlying path
cases, dopamine agonists effectively reduce hyperprolactinemia (see Prolactinoma).

Gonadotropin therapy or pulsatile GnRH therapy is indicated in women who desire fertility yet remain
hypothalamic/pituitary disorder.

For some women with oligomenorrhea or amenorrhea who do not wish to become pregnant, oral con
restore menstrual cyclicity and provide estrogen replacement. Document the absence of pregnancy
begun.

In patients with amenorrhea or oligomenorrhea, induce withdrawal bleeding with an injection of prog
mg of medroxyprogesterone for 10 days. Therapy is then begun with an oral contraceptive containin
as norethindrone and levonorgestrel.

Hormone replacement therapy, consisting of an estrogen and a progestin, is needed for women in w

because ovarian function cannot be restored. The role of androgen replacement is unclear at this tim
investigation.

Drug Category: Estrogens -- Administered transdermally, transvaginally, or orally. Appropriate dos

has not been established. The authors recommend full replacement doses for young women. Gener
as doses recommended for hormone replacement therapy in normally postmenopausal women. The
by skin patch. This avoids the first-pass effect of oral estrogen on the liver. No controlled studies are
safety of one method over another. Therefore, the choice of therapy should follow consideration of th
physician's experience.

Drug Name

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

synthesis of DNA, RNA, and many proteins in target tissues. TD patc
available as Alora (0.05, 0.075, and 0.1 mg/d, applied twice weekly),
Climara (0.025, 0.05, 0.075, and 0.1 mg/d, applied once weekly),
Esclim (0.025, 0.0375, 0.05, 0.075, 0.1 mg/d, applied twice weekly),
and Vivelle-dot (0.037, 0.05, 0.075, 0.1 mg/d, applied twice weekly).
TD patch not tolerated, PO form may be used.

Adult Dose

100 mcg/d TD patch or 2 mg/d PO in cyclic regimen of q3wk on and

wk off

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; thrombophlebitis; neuroophthalmologic

vascular disease; undiagnosed vaginal bleeding; pregnancy; breast
cancer; estrogen-dependent neoplasia; chronic liver disease

Interactions

May reduce hypoprothrombinemic effects of anticoagulants

Levels may be reduced with coadministration of barbiturates, rifampin
and other agents that induce hepatic microsomal enzymes
Possible increase in corticosteroid levels when administered
concurrently
Use with hydantoins may cause spotting, breakthrough bleeding, and
pregnancy
Increase in fluid retention caused by estrogen intake may reduce
seizure control
In isolated cases, may decrease effect of TCAs and therefore cause
worsening of previously well-controlled depression (phenomenon
seems to be dose-dependent and is reversible with decrease or
discontinuation of estrogen)
Thyroid replacement or suppressive therapy may need adjustments
because estrogen increases SHBG, thus leaving less free T4 (active
hormone) available
Tobacco smoking can have antiestrogenic effect by increasing the Chydroxylation of estradiol molecule

Pregnancy

X - Contraindicated in pregnancy

Precautions

Reported endometrial cancer risk among those on unopposed estrog

is approximately 2- to 12-fold greater than those who are not; appear

dependent on duration of treatment and on estrogen dose; greatest r
appears associated with prolonged use (increased risks of 15- to 24fold for 5-10 y or more); concurrent progestin therapy may offset this
risk but overall health impact in premenopausal women is unknown
Some studies suggest possible increased incidence of breast cancer
women taking estrogen therapy at higher doses or for prolonged
periods; these studies have focused on postmenopausal women;
conclusions may not be applicable to young women with ovarian failu
Counseling should help young women deficient in estrogen to feel
comfortable taking estrogens; estrogen therapy during pregnancy is
associated with an increased risk of fetal congenital reproductive trac
disorders and possibly other birth defects
Two studies have reported a 2- to 4-fold increase in risk of gallbladde
disease requiring surgery in women receiving oral estrogen
replacement therapy, similar to the 2-fold increase previously noted in
users of oral contraceptives (risk from TD estrogens not established)
Occasional blood pressure increases during therapy have been
attributed to idiosyncratic reactions to estrogens; other studies showe
slightly lower blood pressure compared with those not on therapy;
postmenopausal use does not increase risk of stroke; nonetheless,
blood pressure should be monitored at regular intervals
May lead to severe hypercalcemia in patients with breast cancer and
bone metastases; if hypercalcemia occurs, discontinue therapy and
take appropriate measures to reduce serum calcium level
Addition of a progestin to estrogens may cause adverse effects on
lipoprotein metabolism (lowering HDL and raising LDL), which could
diminish cardioprotective effect of therapy
Possible enhancement of mitotic activity in breast epithelial tissue,
although few epidemiological data are available to address this point
take complete medical and family history before initiation of therapy;
a general rule, should be prescribed for no longer than 1 y without
another physical examination
Some studies have shown that women on therapy have
hypercoagulability, primarily related to decreased antithrombin activit
effect appears dose- and duration-dependent and is less pronounced
than that associated with oral contraceptive use
Insufficient information on hypercoagulability in women with previous
thromboembolic disease; may be associated with massive elevations
plasma triglycerides, leading to pancreatitis and other complications
patients with familial defects of lipoprotein metabolism; because may
cause some degree of fluid retention, careful observation required wh
conditions that might be influenced by this factor are present (eg,
asthma, epilepsy, migraine, cardiac, renal dysfunction)
Certain patients may develop undesirable manifestations of estrogen
stimulation (eg, abnormal uterine bleeding, mastodynia); may be poo

metabolized in patients with impaired liver function and should be

administered with caution; accelerated PT, aPTT, and platelet
aggregation time; increased platelet count; increased factors II, VII
antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex,
and beta-thromboglobulin; decreased levels of antifactor Xa and
antithrombin III, decreased antithrombin III activity; increased levels o
fibrinogen and fibrinogen activity; increased plasminogen antigen and
activity
Increased thyroid-binding globulin leading to increased circulating tot
thyroid hormone, as measured by protein-bound iodine, T4 levels (by
column or by radioimmunoassay), or T3 levels by radioimmunoassay
free T4 and free T3 concentrations are unaltered
Other binding proteins may be elevated in serum (eg, corticosteroidbinding globulin and SHBG, leading to increased circulating
corticosteroids and sex steroids, respectively); free or biologically act
hormone concentrations are unchanged; other plasma proteins may
increased (eg, angiotensinogen/renin substrate, alpha1-antitrypsin,
ceruloplasmin); increases plasma HDL and HDL-2 subfraction
concentrations, reduces LDL cholesterol concentration, and increase
triglyceride levels; reduces response to metapyrone test; reduces
serum folate concentration
Long-term continuous administration of natural and synthetic estroge
in certain animal species increases frequency of carcinomas of the
breast, uterus, cervix, vagina, testis, and liver
Generally, any drug should be administered to breastfeeding women
only when clearly necessary because many drugs are excreted in
human milk; administration to breastfeeding women has been shown
decrease quantity and quality of milk
Drug Name

Estrogens, conjugated (Premarin) -- Some cannot tolerate TD patch.

Use conjugated equine estrogens to achieve adequate estrogenizatio
of vaginal epithelium in young women and adequately maintain bone
density.

Adult Dose

1.25 mg/d PO

Pediatric Dose

Contraindications

Interactions

Not established

Documented hypersensitivity; known or possible pregnancy; breast

cancer, undiagnosed abnormal genital bleeding, active
thrombophlebitis, or thromboembolic disorders; history of
thrombophlebitis, thrombosis, or thromboembolic disorders associate
with previous estrogen use (except when used in treatment of breast
prostatic malignancy)

May reduce hypoprothrombinemic effect of anticoagulants;

coadministration of barbiturates, rifampin, and other agents that indu
hepatic microsomal enzymes may reduce levels; pharmacologic and
toxicologic effects of corticosteroids may occur as a result of estroge

induced inactivation of hepatic P-450 enzyme; loss of seizure control

has been noted when administered concurrently with hydantoins
Pregnancy

X - Contraindicated in pregnancy

Precautions

Certain patients may develop undesirable manifestations of excessiv

estrogenic stimulation (eg, abnormal or excessive uterine bleeding or
mastodynia); may cause some degree of fluid retention (exercise
caution); prolonged unopposed estrogen therapy may increase risk o
endometrial hyperplasia

Drug Category: Progestins -- Stop endometrial cell proliferation, allowing organized sloughing of

controlled studies compare efficacy of medroxyprogesterone with oral progesterone in protecting the
doses of estrogen generally required for replacement in young women. The authors recommend use
therapy because of longer-term clinical experience with this agent.

Drug Name

Medroxyprogesterone (Provera, Cycrin, Depo-Provera, Amen) -Administer cyclically 12 d/mo to prevent endometrial hyperplasia that
unopposed estrogen may cause. In young women, regular withdrawa
bleeding is preferable because even young women with premature
ovarian failure have a 5-10% chance of spontaneous pregnancy (unl
postmenopausal women). If an expected withdrawal bleeding is abse
perform a pregnancy test (and a timely diagnosis of pregnancy will no
be missed). Other causes of amenorrhea may also remit spontaneou
and result in an unexpected pregnancy.

Adult Dose

10 mg PO qd for first 12 d of menstrual cycle

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; cerebral apoplexy, vaginal bleeding fro

undiagnosed cause, thrombophlebitis, liver dysfunction, pregnancy,
missed abortion, breast or genital malignancies

Interactions

May decrease effects of aminoglutethimide; slightly decreases

clearance of digoxin; increases liver enzymes when coadministered
with tamoxifen; increases half-life of warfarin

Pregnancy

X - Contraindicated in pregnancy

Precautions

Be alert to earliest manifestations of thrombotic disorders (eg,

thrombophlebitis, cerebrovascular disorders, pulmonary embolism,
retinal thrombosis); if these occur or are suspected, discontinue drug
immediately
Discontinue medication pending examination with sudden, partial, or
complete loss of vision or with sudden onset of proptosis, diplopia, or
migraine; if examination reveals papilledema or retinal vascular lesio
withdraw medication
Perform physical examination (including special attention to breast,
pelvic organs, and Papanicolaou smear); may cause some degree of
fluid retention, and conditions that might be influenced by this (eg,

epilepsy, migraine, asthma, cardiac or renal dysfunction) require care

observation
In case of breakthrough bleeding, as in all cases of irregular bleeding
per vagina, bear in mind nonfunctional causes; in cases of vaginal
bleeding from an unknown cause, adequate diagnostic measures are
indicated
Carefully observe patients with history of depression and discontinue
drug if depression recurs to serious degree; carefully observe diabeti
patients receiving progestin therapy; advise pathologist of progestin
therapy when relevant specimens are submitted
Because of occurrence of thrombotic disorders (eg, thrombophlebitis
pulmonary embolism, retinal thrombosis, cerebrovascular disorders)
patients taking estrogen-progestin combinations and because
mechanism is obscure, be alert to earliest manifestation of these
disorders
Administer any drug to breastfeeding women only when clearly
necessary because many drugs are excreted in human milk; detecta
amounts of progestin have been identified in milk
Drug Name

Progesterone (Prometrium) -- Used to prevent endometrial hyperplas

Adult Dose

For women with a uterus receiving estrogen therapy: 200 mg/d PO fo

d sequentially per 28-d cycle

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; caps contain peanut oil and should nev

be used by patients allergic to peanuts; known or suspected pregnan
thrombophlebitis thromboembolic disorders, cerebral apoplexy, or
patient with a history of these conditions; severe liver dysfunction or
disease; known or suspected malignancy of breast and genital organ
undiagnosed vaginal bleeding; missed abortion; as a diagnostic test
pregnancy

Interactions

Ketoconazole inhibits metabolism by human liver microsomes (clinica

relevance unknown)

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

May cause some degree of fluid retention; thus, conditions that migh
be influenced by this factor (eg, epilepsy, migraine, asthma, cardiac o
renal dysfunction) require careful observation
Patients with history of depression should be carefully observed
Transient dizziness may occur in some patients; caution when driving
motor vehicle or operating machinery; small percentage of women m
experience extreme dizziness and/or drowsiness during initial therap
for these women, bedtime dosing is advised

FOLLOW-UP
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Outpatient Care:

The need for ongoing care is defined by the mechanism disrupting the menstrual cycle and th
ovarian insufficiency annually to monitor their ovarian hormone replacement and to detect the
that may be related to the original pathogenic mechanism that led to the disruption of the men

Complications:

Loss of menstrual regularity has been associated with an increased risk of wrist and hip fractu
even without the development of amenorrhea. A later menarche and menstrual cycle intervals
associated with increased fracture rates in later years. Young women with ovarian insufficienc
require hormone replacement to maintain bone density.

Patient Education:

For patients with ovarian insufficiency that remains after appropriate evaluation and treatment
stress the need for ongoing attention to the factors that help maintain bone density. Hormone
these patients. Other factors to consider are the need for adequate calcium intake (1200-1500
need for 20-30 minutes of weight-bearing exercise each day.

For excellent patient education resources, visit eMedicine's Women's Health Center, Eating D
Reproduction Center. Also, see eMedicine's patient education articles Amenorrhea, Anorexia
Birth Control FAQs.
MISCELLANEOUS

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

Evidence is mounting that loss of menstrual regularity is a risk factor for later development of
patients and clinicians need to view the ovary as an important endocrine organ that helps mai
the evaluation and treatment of disordered menses can contribute to osteoporosis. At some p
presence of ovarian insufficiency could become a medicolegal pitfall.

Special Concerns:

Having regular menses is a sign of good health. Blood pressure is recognized as an importan
detection of a disease process that may be silently advancing. In this sense, the menstrual cy
sign that can lead to earlier detection of the silent disease process of osteoporosis.
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NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors,
efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical
possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate
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