Amenorrhea an Approach to Diagnosis

8/11/2019 Amenorrhea an Approach to Diagnosis

1/8

June 1, 2013 Volume 87, Number 11 www.aafp.org/afp American Family Physician 781

Amenorrhea: An Approach to Diagnosis

and ManagementDAVID A. KLEIN, MD, MPH, San Antonio Military Medical Center, San Antonio, TexasMERRILY A. POTH, MD, Uniformed Health Services University of the Health Sciences, Bethesda, Maryland

Many underlying conditionscan lead to amenorrhea. Eachof these conditions is asso-ciated with varying clinical

sequelae; thus, it is important to consider abroad differential diagnosis to avoid miss-ing rare or emergent pathology. Primaryamenorrhea is dened as the failure to reachmenarche. Evaluation should be under-taken if there is no pubertal development by13 years of age, if menarche has not occurredve years after initial breast development,

or if the patient is 15 years or older.1-3

Sec-ondary amenorrhea is characterized as thecessation of previously regular menses forthree months or previously irregular men-ses for six months. 1,2 In contrast, a normalmenstrual cycle typically occurs every 21 to35 days.2

Primary amenorrhea is often, but notexclusively, the result of chromosomal irregu-larities that lead to primary ovarian insuf-ciency (e.g., Turner syndrome) or anatomicabnormalities (e.g., Mllerian agenesis). Mostpathologic cases of secondary amenorrhea

can be attributed to polycystic ovary syn-drome (PCOS), hypothalamic amenorrhea,hyperprolactinemia, or primary ovarianinsufciency. 1,4,5

EvaluationIt is helpful to consider the possible causesof amenorrhea categorically. These includeanatomic defects in the outow tract; pri-mary dysfunction of the ovary; disruptionof hypothalamic or pituitary function; sys-temic disease affecting the hypothalamic-

pituitary-gonadal axis; and pathology ofother endocrine glands 2 (Table 11,2,4-11).A detailed history, examination, and lab-

oratory analysis will identify most causes(Table 2) .1,2,6,7,11 In all cases, pregnancy shouldrst be excluded. 1,2,6,7,11 The initial evaluativesteps are similar; however, a major differ-ence is the need to determine the presenceor absence of the uterus in patients withprimary amenorrhea (Figures 11,2,5-8,10,11 and 2 1,2,4,6-8,10,11). It is important to considerall causes of secondary amenorrhea in theevaluation of primary amenorrhea.

Although amenorrhea may result from a number of different conditions, a systematic evaluation including a detailedhistory, physical examination, and laboratory assessment of selected serum hormone levels can usually identify theunderlying cause. Primary amenorrhea, which by denition is failure to reach menarche, is often the result of chromo-somal irregularities leading to primary ovarian insufciency (e.g., Turner syndrome) or anatomic abnormalities (e.g.,Mllerian agenesis). Secondary amenorrhea is dened as the cessation of regular menses for three months or the ces-sation of irregular menses for six months. Most cases of secondary amenorrhea can be attributed to polycystic ovarysyndrome, hypothalamic amenorrhea, hyperprolactinemia, or primary ovarian insufciency. Pregnancy should beexcluded in all cases. Initial workup of primary and secondary amenorrhea includes a pregnancy test and serum lev-els of luteinizing hormone, follicle-stimulating hormone, prolactin, and thyroid-stimulating hormone. Patients withprimary ovarian insufciency can maintain unpredictable ovarian function and should not be presumed infertile.Patients with hypothalamic amenorrhea should be evaluated for eating disorders and are at risk for decreased bonedensity. Patients with polycystic ovary syndrome are at risk for glucose intolerance, dyslipidemia, and other aspectsof metabolic syndrome. Patients with Turner syndrome (or variant) should be treated by a physician familiar with theappropriate screening and treatment measures. Treatment goals for patients with amenorrhea may vary considerably,and depend on the patient and the specic diagnosis. ( Am Fam Physician. 2013;87(11):781-788. Copyright 2013American Academy of Family Physicians.)

Patient information:A handout on amenor-rhea, written by theauthors of this article, isavailable at http://www.aafp.org/afp/2013/0601/p781-s1.html. Access tothe handouts is free andunrestricted.

Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright 2013 American Academy of Family Physicians. For the private, noncocial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.

Scan the QR code belowwith your mobile devicefor easy access to thepatient information hand-out on the AFPmobile site.


2/8

Amenorrhea

782 American Family Physician www.aafp.org/afp Volume 87, Number 11 June 1, 2013

HISTORY

Patients should be asked about eating and exercise pat-terns, changes in weight, previous menses (if any), medi-cation use, chronic illness, presence of galactorrhea,and symptoms of androgen excess, abnormal thyroidfunction, or vasomotor instability. Taking a sexual his-tory can help corroborate the results of, but not replace,the pregnancy test. Family history should include age atmenarche and presence of chronic disease. Although it isnormal for menses to be irregular in the rst few yearsafter menarche, the menstrual interval is not usuallylonger than 45 days. 7,12

PHYSICAL EXAMINATION

The physician should measure the patients height,weight, and body mass index, and perform thyroid pal-pation and Tanner staging. Breast development is anexcellent marker for ovarian estrogen production. 1 Acne,virilization, or hirsutism may suggest hyperandrogen-

emia. Genital examination may reveal virilization, evi-dence of an outow tract obstruction, or a missing ormalformed organ. Thin vaginal mucosa is suggestive oflow estrogen. 7 Dysmorphic features such as a webbedneck or low hairline may suggest Turner syndrome. 13

LABORATORY EVALUATION

The initial workup includes a pregnancy test and serumluteinizing hormone, follicle-stimulating hormone, pro-lactin, and thyroid-stimulating hormone levels. If his-tory or examination suggests a hyperandrogenic state,serum free and total testosterone and dehydroepiandros-terone sulfate concentrations are useful. 14 If the patient

is short in stature, a karyotype analysis should be per-formed to exclude Turner syndrome. 1,15 If the presenceof endogenous estradiol secretion is not evident from thephysical examination (e.g., breast development), serumestradiol may be measured. 7 A complete blood count andcomprehensive metabolic panel may be useful if historyor examination is suggestive of chronic disease. 7

FURTHER TESTING

Pelvic ultrasonography can help conrm the presence orabsence of a uterus, and can identify structural abnor-malities of reproductive tract organs. If a pituitary tumoris suspected, magnetic resonance imaging (MRI) may beindicated. 8 Hormonal challenge (e.g., medroxyproges-terone acetate [Provera], 10 mg orally per day for sevento 10 days) with anticipation of a withdrawal bleed toconrm functional anatomy and adequate estrogeniza-tion, has traditionally been central to the evaluation. 2 Some experts defer this testing because its correlation

with estrogen status is relatively unreliable.1,6,13,16,17

Differential Diagnosis and TreatmentANATOMIC ABNORMALITIES

Mllerian agenesis, a condition characterized by a con-genital malformation of the genital tract, may presentwith normal breast development without menarche,and may be associated with urinary tract defects andfused vertebrae. 18 Other congenital abnormalities thatmay cause amenorrhea include imperforate hymen andtransverse vaginal septum. In these conditions, productsof menstruation accumulate behind the defect and canlead to cyclic or acute pelvic pain. Physical examination,

Table 1. Major Causes of Amenorrhea

Outow tractCongenital

Complete androgen resistanceImperforate hymenMllerian agenesisTransverse vaginal septum

AcquiredAsherman syndrome

(intrauterine synechiae)Cervical stenosis

Primary ovarian insufciencyCongenital

Gonadal dysgenesis (other thanTurner syndrome)

Turner syndrome or variantAcquired

Autoimmune destructionChemotherapy or radiation

Information from references 1, 2, and 4 through 11.

HypothalamicEating disorderFunctional (overall energy

decit)Gonadotropin deciency

(e.g., Kallmannsyndrome)

Infection (e.g., meningitis,tuberculosis, syphilis)

MalabsorptionRapid weight loss

(any cause)StressTraumatic brain injuryTumor

PituitaryAutoimmune diseaseCocaineCushing syndromeEmpty sella syndromeHyperprolactinemiaInltrative disease

(e.g., sarcoidosis)Medications

AntidepressantsAntihistaminesAntihypertensivesAntipsychoticsOpiates

Other pituitary or centralnervous system tumor

ProlactinomaSheehan syndrome

Other endocrine gland disordersAdrenal diseaseAdult-onset adrenal hyperplasiaAndrogen-secreting tumorChronic diseaseConstitutional delay of pubertyCushing syndromeOvarian tumors (androgen

producing)Polycystic ovary syndrome

(multifactorial)Thyroid disease

PhysiologicBreastfeedingContraceptionExogenous androgensMenopausePregnancy


3/8

Amenorrhea


Table 2. Findings in the Evaluation of Amenorrhea

Findings Associations

HistoryChemotherapy or radiation Impairment of specic organ (e.g., brain, pituitary, ovary)Family history of early or delayed menarche Constitutional delay of pubertyGalactorrhea Pituitary tumor

Hirsutism, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH,Cushing syndrome

Illicit or prescription drug use Multiple; consider effect on prolactinMenarche and menstrual history Primary versus secondary amenorrhea; new diseaseSexual activity PregnancySignicant headaches or vision changes Central nervous system tumor, empty sella syndromeTemperature intolerance, palpitations, diarrhea, constipation,

tremor, depression, skin changesThyroid disease

Vasomotor symptoms Primary ovarian insufciency, natural menopauseWeight loss, excessive exercise, poor nutrition, psychosocial

stress, dietsFunctional hypothalamic amenorrhea

Physical examination

Abnormal thyroid examination Thyroid disorderAnthropomorphic measurements; growth charts Multiple; Turner syndrome, constitut ional delay of pubertyBody mass index High: PCOS

Low: Functional hypothalamic amenorrheaDysmorphic features (webbed neck, short stature, low hairline) Turner syndromeMale pattern baldness, increased facial hair, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH,

Cushing syndromePelvic examination

Absence or abnormalities of cervix or uterus Rare congenital causesClitoromegaly Androgen-secreting tumor, CAHPresence of transverse vaginal septum or imperforate hymen Outow tract obstructionReddened or thin vaginal mucosa Decreased endogenous estrogen

Striae, buffalo hump, central obesit y, hyper tension Cushing syndromeTanner staging abnormal Turner syndrome, constitutional delay of puberty, rare causes

Laboratory testing (refer to local reference values)Complete blood count and metabolic panel abnormalities Chronic diseaseEstradiol Low: Poor endogenous estrogen production (suggestive of poor

ovarian function)Follicle-stimulating hormone and luteinizing hormone High: Primary ovarian insufciency, Turner syndrome

Low: Functional hypothalamic amenorrheaNormal: PCOS, Asherman syndrome, multiple others

Free and total testosterone; dehydroepiandrosterone sulfate High: Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH,Cushing syndrome

Karyotype Abnormal: Turner syndrome, rare chromosomal disordersPregnancy test Positive: Pregnancy, ectopic pregnancyProlactin High: Pituitary adenoma, medications, hypothyroidism, other neoplasmThyroid-stimulating hormone High: Hypothyroidism

Low: Hyperthyroidism

Diagnostic imagingMagnetic resonance imaging of head or sella Tumor (e.g., microadenoma)Pelvic ultrasonography Morphology of pelvic organs

CAH = congenital adrenal hyperplasia; PCOS = polycystic ovary syndrome.

Adapted with permission from Maste r-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73(8):1376, with addi-tional information from references 1, 2, 6, and 7.


4/8

Amenorrhea


as well as ultrasonography or MRI, is key to diagnosis,and surgical correction is usually warranted. 18

Rare causes of amenorrhea include complete andro-gen insensitivity syndrome, which is characterized bynormal breast development, sparse or absent pubic andaxillary hair, and a blind vaginal pouch; and 5-alphareductase deciency, which is characterized by partiallyvirilized genitalia. 1 In these conditions, serum testoster-one levels will be in the same range as those found inmales of the same age. 19 The karyotype will be 46,XY,and testicular tissue should be removed to avoid malig-nant transformation. 20

A structural cause of secondary amenorrhea is Asher-man syndrome: intrauterine synechiae caused by uter-ine instrumentation during gynecologic or obstetricprocedures, which can be evaluated and treated withhysteroscopy. 2,21

PRIMARY OVARIAN INSUFFICIENCY

Primary ovarian insufciency, a condition character-ized by follicle depletion or dysfunction leading to acontinuum of impaired ovarian function, is suggestedby a concentration of follicle-stimulating hormone inthe menopausal range (per reference laboratory), con-rmed on two occasions separated by one month, and

diagnosed in patients younger than 40 years with amen-orrhea or oligomenorrhea. 6 Other terms, including pre-mature ovarian failure, are used synonymously withprimary ovarian insufciency. 6,9 Up to 1% of womenmay experience primary ovarian insufciency. This con-dition differs from menopause, in which the average ageis 50 years, because of age and less long-term predict-ability in ovarian function. 6,22,23 More than 90% of casesunrelated to a syndrome are idiopathic, but they can beattributed to radiation, chemotherapeutic agents, infec-tion, tumor, empty sella syndrome, or an autoimmuneor inltrative process. 6

Patients with primary ovarian insufciency should becounseled about possible infertility, because up to 10%of such patients may achieve temporary and unpredict-able remission. 24 Hormone therapy (e.g., 100 mcg ofdaily transdermal estradiol or 0.625 mg of daily conju-gated equine estrogen [Premarin] on days 1 through 26of the menstrual cycle, and 10 mg of cyclic medroxypro-gesterone acetate for 12 days [e.g., days 14 through 26]of the menstrual cycle) 6 until the average age of natu-ral menopause is usually recommended to decrease thelikelihood of osteoporosis, ischemic heart disease, andvasomotor symptoms. 9 Combined oral contraceptives(OCs) deliver higher concentrations of estrogen and

Diagnosis of Primary Amenorrhea

Figure 1. A diagnostic approach to primary amenorrhea. (FSH = follicle-stimulating hormone; LH = luteinizinghormone; TSH = thyroid-stimulating hormone.)Information from references 1, 2, 5 through 8, 10, and 11.

Perform history and physicalexamination (Table 2)

Pregnancy test; serum LH, FSH, TSH, andprolactin levels; pelvic ultrasonography orother laboratory testing if clinically indicated

Uterus present?

Pregancy test positive pregnant(exclude ectopic pregnancy if indicated)

Abnormal TSH level order thyroidfunction tests and treat thyroid disease

Abnormal prolactin level magneticresonance imaging of the pituitary toexclude adenoma; consider medications

No

Yes Karyotype; free and totaltestosterone levels

Low FSH and LH levels Normal FSH and LH levels Elevated FSH and LH levels

Functional amenorrhea(if energy decit),constitutional delay ofpuberty; rarely, primarygonadotropin-releasinghormone deciency

Consider outowtract obstruction; alsoconsider all other causesof amenorrhea withnormal gonadotropinlevels (Figure 2)

Primary ovarian insufciency

46,XX 46,XY

Order karyotype to evaluatefor Turner syndrome orpresence of Y chromatin

Mllerian agenesis,expect female-rangeserum testosteronelevel

Androgen insensitivitysyndrome, expect male-range serum testosteronelevel


5/8

Amenorrhea


progesterone than necessary for hormone therapy, mayconfer thromboembolic risk, and may theoretically beineffective at suppressingfollicle-stimulating hormonefor contraceptive purposes in this population; thus, a

barrier method or intrauterine device is appropriate insexually active patients. 6,13,25,26 For optimal bone health,patients with primary ovarian insufciency should beadvised to perform weightbearing exercises and supple-ment calcium (e.g., 1,200 mg daily) and vitamin D 3 (e.g.,800 IU daily) intake. 6,27

There is evidence of genetic predisposition to primaryovarian insufciency, and patients without evidence of asyndrome should be tested for FMR1 gene premutation(confers risk of fragile X syndrome in their offspring)and thyroid and adrenal autoantibodies. 6,28-30

Turner syndrome, a condition characterized by achromosomal pattern of 45,X or a variant, can present

with a classic phenotype including a webbed neck, a lowhairline, cardiac defects, and lymphedema. 13,15 Somepatients who have Turner syndrome have only shortstature and variable defects in ovarian function (even

with possible fertility).6,13,15

Thus, all patients with shortstature and amenorrhea should have a karyotype analy-sis.15 Because patients require screening for a number ofsystemic problems, including coarctation of the aorta,other cardiac lesions, renal abnormalities, hearingproblems, and hypothyroidism, and because they mayrequire human growth hormone treatment and hormonereplacement therapy, physicians inexperienced withTurner syndrome should consult an endocrinologist. 13,15

HYPOTHALAMIC AND PITUITARY CAUSES

The ovaries require physiologic stimulation by pituitarygonadotropins for appropriate follicular development

Diagnosis of Secondary Amenorrhea

Figure 2. A diagnostic approach to secondary amenorrhea. (DHEA-S = dehydroepiandrosterone sulfate; FSH =follicle-stimulating hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; TSH = thyroid-stimulatinghormone.)Information from references 1, 2, 4, 6 through 8, 10, and 11.

Perform history and physicalexamination (Table 2)

Review medications includingcontraceptives and illicit drugs

Pregnancy test; serum LH, FSH, TSH, andprolactin levels; pelvic ultrasonography orother laboratory testing if clinically indicated

Elevated FSHand LH levels

Normal or low FSH and LH levels

Pregnancy test positive pregnant (excludeectopic pregnancy if indicated)

Abnormal TSH level order thyroid functiontests and treat thyroid disease

Abnormal prolactin level MRI of thepituitary to exclude adenoma; considermedications

Repeat in onemonth; considerserum estradiol

Primary ovarianinsufciency, naturalmenopause; orderkaryotype, especiallyif patient is of shortstature, to rule outTurner syndrome orvariant

Evidence of disorderedeating, excessiveexercise, or poornutritional status

Evidence of high intracranialpressure (e.g., headache,vomiting, vision changes)

Evidence ofhyperandrogenism

History of obstetricor gynecologicprocedures; considerinduction of

withdrawal bleedor hysteroscopyto evaluate forAsherman syndrome

Most likely functionalamenorrhea, butconsider chronic illness

Consider MRI of head toevaluate for neoplasm

Order serum testosterone, DHEA-S,17-hydroxyprogesterone testing

Elevated 17-hydroxyprogesteronelevel

Meets criteriafor polycysticovary syndrome

Rapid onset ofsymptoms or very highserum androgen levels;consider adrenal andovarian imaging toevaluate for tumorConsider late-onset

congenital adrenalhyperplasia

Screen formetabolicsyndrome; treat

accordingly


6/8

Amenorrhea


and estrogen production. Functional hypo-thalamic amenorrhea occurs when thehypothalamic-pituitary-ovarian axis is sup-

pressed due to an energy decit stemmingfrom stress, weight loss (independent of origi-nal weight), excessive exercise, or disorderedeating.1,7 It is characterized by a low estrogenstate without other organic or structural dis-ease. Laboratory tests usually reveal low orlow-normal levels of serum follicle-stimu-lating hormone, luteinizing hormone, andestradiol; however, these levels can uctuate,and the clinical context is the discriminatingfactor. 1,7 Patients with functional amenorrheamay demonstrate the features of the female

athlete triad, which consists of insufcientcaloric intake with or without an eating dis-order, amenorrhea, and low bone densityor osteoporosis. 31 These patients should bescreened for eating disorders, diets, and mal-absorption syndromes (e.g., celiac disease). 1

Treatment of functional hypothalamicamenorrhea involves nutritional rehabilita-tion as well as reductions in stress and exercise levels. 7 Menses typically return after correction of the underly-ing nutritional decit. 32 Bone loss is best treated by rever-sal of the underlying process, and the patient shouldundergo bone density evaluation and take calcium andvitamin D supplements. 7 Although the bone loss is partlysecondary to estrogen deciency, estrogen replacementwithout nutritional rehabilitation does not reverse thebone loss. Combined OCs will restore menses, but willnot correct bone density. 7,31,33-36 Leptin administrationhas been reported to restore pulsatility of gonadotropin-releasing hormone and ovulation in these patients, butits effect on bone health is unknown. 7,37,38 The effectof bisphosphonates on long-term bone health in pre-menopausal women is unclear, as is their teratogenic

potential.7,39

ELEVATIONS IN SERUM PROLACTIN

Prolactin levels can be elevated because of medications(Table 2 1,2,6,7,11), pituitary adenoma, hypothyroidism, ormass lesion compromising normal hypothalamic inhi-bition. 8 Elevated prolactin levels, whatever the cause,inhibit the secretion and effect of gonadotropins, andwarrant MRI of the pituitary. 8 Exceptions may occur incases with a clear pharmacologic trigger and relativelylow levels of serum prolact in (i.e., < 100 ng per mL [< 100mcg per L]). 8 Treatment of prolactinomas may involvedopamine agonists or surgical resection. 8

OTHER CENTRAL NERVOUS SYSTEM ETIOLOGIES

Amenorrhea can be caused by previous central nervoussystem infection, trauma, or autoimmune destructionof the pituitary. 1 A notable consideration in primaryamenorrhea is constitutional delay of puberty, a diag-nosis of exclusion that is difcult to distinguish fromfunctional amenorrhea without history of an energydecit. Although rare, primary gonadotropin-releasinghormone deciency, such as occurs with Kallmann syn-drome (including anosmia), must be considered. 40

Other Causes of AmenorrheaPOLYCYSTIC OVARY SYNDROME

PCOS is a multifactorial endocrine disorder, usuallyinvolving peripheral insulin resistance. It is character-

ized by hyperandrogenism found on clinical or labo-ratory examination, polycystic ovaries as suggested byultrasonography, and ovulatory dysfunction. The Rot-terdam Consensus Criteria published in 2003 requirethe presence of two of the three above conditions fordiagnosis, whereas the Androgen Excess Societys 2006guidelines require hyperandrogenism and either of theremaining two conditions. 41,42 In PCOS, serum androgenlevels are typically no greater than twice the upper limitof normal. Thus, higher levels suggest other causes ofhyperandrogenism 1,14,43 (Figure 21,2,4,6-8,10,11).

With insulin resistance contributing to the underly-ing pathology of PCOS, patients should be screened for

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidencerating References

Pregnancy should be excluded in all patientspresenting with amenorrhea.

C 1, 2, 6, 7, 11

In the evaluation of amenorrhea, hormone-induced withdrawal bleeding has poor

sensitivity and specicity for ovarian function.

C 1, 6, 13, 16,17

In patients with functional hypothalamicamenorrhea (especially with the femaleathlete triad), the primary treatment isweight restoration through nutritionalrehabilitation and decreased exercise.

C 7, 31, 32

In patients with functional hypothalamicamenorrhea, combined oral contraceptivesdo not improve bone density and should notbe used solely for this purpose.

C 7, 31-36

Patients with polycystic ovary syndrome whoare overweight should be evaluated forglucose intolerance, dyslipidemia, and overallcardiovascular risk.

C 1, 44

Metformin (Glucophage) may improveabnormal menstruation in patients withpolycystic ovary syndrome.

A 44, 48-53

A = consistent, good-qualit y 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 evidencerating system, go to http://www.aafp.org/afpsort.xml.


7/8

Amenorrhea


dyslipidemia and overall cardiovascular risk. Glucoseintolerance should be assessed with a fasting glucoseand two-hour glucose tolerance test, because patients

may have insulin resistance and beta-cell dysfunc-tion. 1,44 In patients with PCOS who are overweight,weight loss combined with exercise is the rst-line treat-ment. 44 Chronic anovulation with resultant unopposedestrogen secretion is a risk factor for endometrial can-cer, and low-dose combined OCs are more frequentlyprescribed to reduce this risk than higher-dose pills orprogestin-only methods. 44-46 Many combined OCs sup-press the secretion of ovarian androgen and may beuseful in decreasing hirsutism and acne, although dataare limited. 10,44,47 Metformin (Glucophage) can increaseinsulin sensitivity, thereby improving glucose tolerance.

It may also improve ovulation rate, reduce the incidenceof menstrual abnormalities, and improve serum andro-gen concentrations. 44,48-53

PREGNANCY AND CONTRACEPTION

All evaluations for amenorrhea should begin with apregnancy test. If abdominal pain is present, ectopicpregnancy should be considered. Patients should bequestioned about contraceptive use, because extended-cycle combined OCs, injectable medroxyprogesteroneacetate (Depo-Provera), implantable etonogestrel (Impl-anon), and levonorgestrel-releasing intrauterine devices(Mirena) may cause amenorrhea. 10

THYROID AND ADRENAL DISEASE

Severe hyperthyroidism is more likely to cause amenor-rhea than mild hyperthyroidism or hypothyroidism, andthe serum thyroid-stimulating hormone level should bemeasured in the evaluation of amenorrhea. 1,54

Late-onset congenital adrenal hyperplasia, androgen-secreting tumor, and Cushing syndrome must be distin-guished from PCOS in the evaluation of hyperandrogenicamenorrhea. A high serum 17-hydroxyprogesterone

level measured at 7:00 a.m. suggests congenital adrenalhyperplasia, which can be conrmed with an adreno-corticotropin stimulation test. 14 An adrenal or ovar-ian tumor should be considered with rapid onset ofsymptoms or when serum androgens are signicantlyelevated, although cutoff levels are nonspecic. 14,43 Rarely, hypercortisolism from Cushing syndrome mayresult in amenorrhea, and can be evaluated by a dexa-methasone suppression test when stigmata of disease arepresent 4,14,44 (Table 11,2,4-11).Data Sources: A PubMed search was completed using the MeSH func-tion with the key phrases amenorrhea, evaluation, and treatment. Thesearch included meta-analyses, randomized controlled trials, clinical

trials, and reviews. Also searched were the Agency for HealthcareResearch and Quality evidence reports, Essential Evidence Plus, theCochrane Database of Systematic Reviews, the National Guideline Clear-inghouse database, the U.S. Preventive Services Task Force Web site,

Clinical Evidence, and UpToDate. Search date: August 1, 2011.The opinions and assertions contained herein are the private views of theauthors and are not to be construed as ofcial or as reecting the viewsof the U.S. Air Force, the U.S. Army Medical Department, or the U.S.military at large.

The AuthorsDAVID A. KLEIN, MD, MPH, is completing a fellowship in adolescent medi-cine at San Antonio Military Medical Center in San Antonio, Tex. At thetime this article was written, he was the medical director of the FamilyHealth Clinic at Lajes Air Base, Azores, Por tugal.

MERRILY A. POTH, MD, FAAP, is a professor in the Department of Pedi-

atrics at the Uniformed Health Services University of the Health Sciencesin Bethesda, Md., and a staff pediatric endocrinologist at Walter ReedNational Military Medical Center in Bethesda.

Address correspondence to David A. Klein, MD, MPH, Ft. Sam HoustonMedical Clinic, 3100 Schoeld Rd., Ft. Sam Houston, TX 78234 (e-mail:[email protected]). Reprints are not available from the authors.

Author disclosure: No relevant nancial afliations.

REFERENCES

1. Practice Committee of American Society for Reproductive Medicine.Current evaluation of amenorrhea. Fertil Steril . 2008;90(5 suppl):S219-S225.

2. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility.7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2005:401-464.

3. Euling SY, Herman-Giddens ME, Lee PA, et al. Examination of USpuberty-timing data from 1940 to 1994 for secular trends: panel nd-ings. Pediatrics. 2008;121(suppl 3):S172-S191.

4. Reindollar RH, Novak M, Tho SP, McDonough PG. Adult-onset amen-orrhea: a study of 262 patients. Am J Obstet Gynecol . 1986;155(3):531-543.

5. Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development:a study of 252 patients. Am J Obstet Gynecol . 1981;140(4):371-380.

6. Nelson LM. Clinical practice. Primary ovarian insufciency. N Engl J Med .2009;360(6):606-614.

7. Gordon CM. Clinical practice. Functional hypothalamic amenorrhea.N Engl J Med . 2010;363(4):365-371.

8. Pickett CA. Diagnosis and management of pituitary tumors: recentadvances. Prim Care. 2003;30(4):765-789. 9. Welt CK. Primary ovarian insufciency: a more accurate term for prema-

ture ovarian failure. Clin Endocrinol (Oxf). 2008;68(4):499-509. 10. Zieman M, Hatcher RA, Cwiak C, Darney PD, Creinin MD, Stosur HR.

A Pocket Guide to Managing Contraception. New York, NY: ArdentMedia; 2010.

11. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician . 2006;73(8):1374-1382.

12. Diaz A, Laufer MR, Breech LL; American Academy of Pediatrics Com-mittee on Adolescence; American College of Obstetricians and Gyne-cologists Committee on Adolescent Health Care. Menstruation in girlsand adolescents: using the menstrual cycle as a vital sign. Pediatrics.2006;118(5):2245-2250.

13. Rebar RW, Connolly HV. Clinical features of young women with hyper-gonadotropic amenorrhea. Fertil Steril . 1990;53(5):804 -810.


8/8

Amenorrhea


14. dAlva CB, Abiven-Lepage G, Viallon V, et al. Sex steroids in androgen-secreting adrenocortical tumors: clinical and hormonal features incomparison with non-tumoral causes of androgen excess. Eur J Endocri-nol . 2008;159(5):641-647.

15. Sybert VP, McCauley E. Turners syndrome. N Engl J Med . 2004;351(12):1227-1238.

16. Rarick LD, Shangold MM, Ahmed SW. Cervical mucus and serumestradiol as predictors of response to progestin challenge. Fertil Steril .1990;54(2):353-355.

17. Nakamura S, Douchi T, Oki T, Ijuin H, Yamamoto S, Nagata Y. Relation-ship between sonographic endometrial thickness and progestin-inducedwithdrawal bleeding. Obstet Gynecol . 1996;87(5 pt 1):722-725.

18. Folch M, Pigem I, Konje JC. Mllerian agenesis : etiology, diagnosis, andmanagement. Obstet Gynecol Surv . 2000;55(10):644-649.

19. Maimoun L, Philibert P, Bouchard P, et al. Primary amenorrhea in fouradolescents revealed 5 -reductase deciency conrmed by molecularanalysis. Fertil Steril . 2011;95(2) :804.e1-e5.

20. Capito C, Leclair MD, Arnaud A, et al. 46,XY pure gonadal dysgenesis:clinical presentations and management of the tumor risk. J Pediatr Urol .2011;7(1):72-75.

21. Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndromeonecentury later. Fertil Steril . 2008;89(4):759-779.

22. van Noord PA, Dubas JS, Dorland M, Boersma H, te Velde E. Age at natu-ral menopause in a population-based screening cohor t: the role of men-arche, fecundity, and lifestyle factors. Fertil Steril . 1997;68(1):95-102.

23. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarianfailure. Obstet Gynecol . 1986;67(4):604-606.

24. van Kasteren YM, Schoemaker J. Premature ovarian failure: a system-atic review on therapeutic interventions to restore ovarian function andachieve pregnancy. Hum Reprod Update . 1999;5(5):483-492.

25. Trenor CC III, Chung RJ, Michelson AD, et al. Hormonal contraceptionand thrombotic risk: a multidisciplinary approach. Pediatrics. 2011;127(2):347-357.

26. Alper MM, Jolly EE, Garner PR. Pregnancies after premature ovarianfailure. Obstet Gynecol . 1986;67(3 suppl):59S-62S.

27. Management of osteoporosis in postmenopausal women: 2010 posi-tion statement of The North American Menopause Society. Meno-

pause . 2010;17(1):25-54. 28. Caronia LM, Martin C, Welt CK, et al. A genetic basis for functional

hypothalamic amenorrhea. N Engl J Med . 2011;364(3):215-225. 29. Bachelot A, Rouxel A, Massin N, et al.; POF-GIS Study Group. Pheno-

typing and genetic studies of 357 consecutive patients presenting withpremature ovarian failure. Eur J Endocrinol . 2009;161(1):179-187.

30. Wit tenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premuta-tion and reproduction. Fertil Steril . 2007;87(3):456-465.

31. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J,Warren MP; American College of Sports Medicine. American College

of Sports Medicine position stand. The female athlete triad. Med SciSports Exerc . 2007;39(10):1867-1882. 32. Falsetti L, Gambera A, Barbetti L, Specchia C. Long-term follow-up of

functional hypothalamic amenorrhea and prognostic factors. J ClinEndocrinol Metab . 2002;87(2):500-505.

33. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC. The effectsof estrogen administration on trabecular bone loss in young womenwith anorexia nervosa. J Clin Endocrinol Metab . 1995;80(3):898-904.

34. Gordon CM, Grace E, Emans SJ, et al. Effects of oral dehydroepian-drosterone on bone density in young women with anorexia nervosa: arandomized trial. J Clin Endocrinol Metab . 2002;87(11):4935-4941.

35. Strokosch GR, Friedman AJ, Wu SC, Kamin M. Effects of an oral con-traceptive (norgestimate/ethinyl estradiol) on bone mineral density inadolescent females with anorexia nervosa: a double-blind, placebo-controlled study. J Adolesc Health . 2006;39(6):819-827.

36. Sim LA, McGovern L, Elamin MB, Swiglo BA, Erwin PJ, Montori VM.Effect on bone health of estrogen preparations in premenopausalwomen with anorexia nervosa: a systematic review and meta-analyses.Int J Eat Disord . 2010;43(3):218-225.

37. Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treat-ment for hypothalamic amenorrhea. Proc Natl Acad Sci USA. 2011;108(16):6585-6590.

38. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in womenwith hypothalamic amenorrhea. N Engl J Med . 2004;351(10):987-997.

39. Briggs GG, Freeman RK, Yaffee SJ. Drugs in Pregnancy and Lac tation:a Reference Guide to Fetal and Neonatal Risk. 8th ed. Philadelphia, Pa.:Lippincott Williams & Wilkins; 2008:49-51.

40. Shaw ND, Seminara SB, Welt CK, et al. Expanding the phenotype andgenotype of female GnRH deciency. J Clin Endocrinol Metab . 2011;96(3):E566-E576.

41. Azziz R, Carmina E, Dewailly D, et al.; Androgen Excess Society. Posi-tions statement: criteria for dening polycystic ovary syndrome as apredominantly hyperandrogenic syndrome: an Androgen Excess Societyguideline. J Clin Endocrinol Metab . 2006;91(11):4237-4245.

42. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus WorkshopGroup. Revised 2003 consensus on diagnostic criteria and long-termhealth risks related to polycystic ovary syndrome (PCOS). Hum Reprod .2004;19(1):41-47.

43. Waggoner W, Boots LR, Azziz R. Total testosterone and DHEAS levelsas predictors of androgen-secreting neoplasms: a populational study.Gynecol Endocrinol . 1999;13(6) :394-400.

44. American College of Obstetricians and Gynecologists. ACOG practicebulletin no. 108: polycystic ovary syndrome. Obstet Gynecol. 2009;114(4):936-949.

45. Navaratnarajah R, Pillay OC, Hardiman P. Polycys tic ovary syndrome andendometrial cancer. Semin Reprod Med . 2008;26(1):62-71.

46. Papaioannou S, Tzafettas J. Anovulation with or without PCO, hyperan-drogenaemia and hyperinsulinaemia as promoters of endometrial andbreast cancer. Best Pract Res Clin Obstet Gynaecol . 2010;24(1):19-27.

47. Banaszewska B, Pawelczyk L, Spaczynski RZ, Dziura J, Duleba AJ.Effects of simvastatin and oral contraceptive agent on polycystic ovarysyndrome: prospective, randomized, crossover trial. J Clin EndocrinolMetab . 2007;92(2):456-461.

48. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitisingdrugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) forwomen with polycystic ovary syndrome, oligo amenorrhoea and sub-fertility. Cochrane Database Syst Rev . 2010;(1):CD003053.

49. Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS. Metformintreatment exerts antiinvasive and antimetastatic effects in human endo-metrial carcinoma cells. J Clin Endocrinol Metab . 2011;96(3):808-816.

50. Bridger T, MacDonald S, Baltzer F, Rodd C. Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syn-drome. Arch Pediatr Adolesc Med . 2006;160(3):241-246.

51. Eisenhardt S, Schwarzmann N, Henschel V, et al. Early effects of metfor-min in women with polycystic ovary syndrome: a prospective random-ized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab .2006;91(3):946-952.

52. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-inducedresumption of normal menses in 39 of 43 (91%) previously amenor-rheic women with the polycystic ovary syndrome. Metabolism . 1999;48(4):511-519.

53. Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical fea-tures, endocrine and metabolic proles, and insulin sensitivity in poly-cystic ovary syndrome: a randomized, double-blind, placebo-controlled6-month trial, followed by open, long-term clinical evaluation. J ClinEndocrinol Metab . 2000;85(1):139-146.

54. Kakuno Y, Amino N, Kanoh M, et al. Menstrual disturbances in variousthyroid diseases. Endocr J . 2010;57(12):1017-1022.

Amenorrhea an Approach to Diagnosis

Documents

Transcript of Amenorrhea an Approach to Diagnosis