Amenorrhea Workup

Author: Kenneth M Bielak, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG more...
Updated: Jun 5, 2012
Approach Considerations
In most cases, clinical variables alone are not adequate to define the pathophysiologic mechanism disrupting the
menstrual cycle. The clinician must be concerned with an array of potential diseases and disorders involving many
organ systems. However, the history and physical findings help in selecting tests.
Thyroid-stimulating hormone (TSH), prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH)
measurements are always the first line of testing. If hirsutism is predominant upon examination, include androgen
testing: measure testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17-OH
progesterone to determine the organ of cause (eg, adrenal gland vs ovary).
If the history or physical findings suggest a chronic disease process, indicated tests may include of the erythrocyte
sedimentation rate (ESR), liver function tests, blood urea nitrogen (BUN) determination, creatinine determination,
and urinalysis.
If the history and physical findings suggest a delay in puberty, assessing FSH and LH levels and determining bone
age are important in differentiating pubertal delays as a cause.
Testing in secondary amenorrhea
Pregnancy is the most common cause of secondary amenorrhea. A pregnancy test (measurement of serum or
urinary human chorionic gonadotropin) is recommended as a first step in evaluation of a secondary amenorrhea.
After pregnancy testing, all women who present with 3 months of secondary amenorrhea should have a diagnostic
evaluation initiated at that visit. As stated by Speroff et al, "Few problems in gynecologic endocrinology are as
challenging or taxing to the clinician as amenorrhea. The clinician must be concerned with an array of potential
diseases and disorders involving, in many instances, unfamiliar organ systems, some carrying morbid and even
lethal consequences for the patient."
[40]
A complete blood cell count, urinalysis, and serum chemistries should be evaluated to help rule out systemic
disease. Serum prolactin, FSH, estradiol, and thyrotropin levels should also be measured routinely in the initial
evaluation of amenorrhea once pregnancy has been excluded.
Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these
organs. Magnetic resonance imaging can detect hypothalamic/pituitary lesions. Hysterosalpingography and
hysteroscopy are indicated in cases of possible Asherman syndrome.
Hormonal Studies
Hormonal studies may include assays of prolactin, FSH, LH, estradiol, thyroid hormones, or androgens.
Prolactin
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Prolactin levels in excess of 200 ng/mL are not observed except in the case of prolactin-secreting pituitary adenoma
(prolactinoma). In general, the serum prolactin level correlates with the size of the tumor. For more details, see
Hyperprolactinemia.
Psychotropic drugs, hypothyroidism, stress, and meals can also raise prolactin levels. Repeatedly elevated prolactin
levels require further evaluation if the cause is not readily apparent.
FSH, LH, and estradiol
An FSH level of approximately 40 mIU/mL is indicative of ovarian insufficiency. However, this is assay-dependent
and some patients have a lower menopausal level of FSH; check the reference range for the laboratory where the
test is performed. If a repeat value in 1 month confirms this finding and amenorrhea still persists, then the diagnosis
of premature ovarian failure/primary ovarian insufficiency is confirmed.
LH levels are elevated in cases of 17,20 lyase deficiency, 17-hydroxylase deficiency, and premature ovarian failure.
Serum estradiol levels undergo wide fluctuations during the normal menstrual cycle. During the early follicular phase
of the menstrual cycle, levels may be lower than 50 pg/mL. During the preovulatory estradiol surge, levels in the
range of 400 pg/mL are not uncommon. In healthy menopausal women, estradiol levels are routinely lower than 20
pg/mL.
Thyroid hormones
Disorders of the thyroid gland may result in menstrual irregularities; however, for it to present as primary amenorrhea
is uncommon. Measure thyrotropin and free thyroxine (T4)if symptoms of hypothyroidism or hyperthyroidism are
present.
Androgens
Checking levels of testosterone and dehydroepiandrosterone sulfate helps identify hyperandrogenic conditions
resulting in amenorrhea. For more details, see Polycystic Ovarian Syndrome.
Imaging Studies to Consider
Ultrasonography
Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these
organs. However, a report of absence of the uterus on ultrasonography does not always mean that the patient does
not have a uterus. In primary amenorrhea in association with estrogen deficient states, the uterine fundus may be
underdeveloped and may not be readily visible at the time of ultrasonography to less experienced examiners. With
proper estrogen replacement, it may reach the normal size.
Pelvic ultrasonography may be helpful in determining ovarian morphology as well. However, in most cases of
amenorrhea without androgen access, the information obtained with ovarian ultrasonography does not change
clinical management.
Magnetic resonance imaging
MRI of the pituitary and hypothalamus is often indicated in the evaluation of amenorrhea. Request imaging of the
hypothalamic/pituitary area specifically, rather than a study of the entire brain. This achieves higher resolution. MRI
is indicated in the following circumstances:
Associated headaches or visual-field cuts
Profound estrogen deficiency with otherwise unexplained amenorrhea
Hyperprolactinemia
Elevated gonadotropins in the setting of markedly elevated serum estradiol level
Questionnaires
Several validated tools are available to measure dietary intake, mood disorder, and eating disorders. These tools
include the following:
Minnesota Nutrition Data Systems evaluation - to assess dietary intake
Beck Depression Inventory - to assess mood
Modifiable Activity Questionnaire - to assess the patient's level of physical activity
Paffenbarger Physical Activity Questionnaire
Multidimensional Eating Disorder Inventory - for anorexia and bulimia
[41]
Bulimia Test-Revised (BULIT-R)
[42]
Progesterone Withdrawal Test
Prior to the development of readily available assays to measure serum levels of estradiol, the progesterone
challenge test was used as a bioassay with which to demonstrate estrogen effect at the level of the endometrium.
Progesterone has been shown to predictably induce a withdrawal bleed if the circulating serum estradiol level is at
least 50 pg/mL. However, the progesterone withdrawal test can provide inappropriately reassuring information that
may delay the etiology of ovarian insufficiency.
The progesterone withdrawal test is no substitute for evaluating ovarian health. Demonstrating the presence of
normally functioning ovaries requires the concurrent measurement of serum estradiol and FSH.
Algorithms for Evaluation of Amenorrhea
Amenorrhea with delayed puberty
Obtain studies of thyroid function (thyroid-stimulating hormone [TSH] and thyroxine [T4]) and bone age. If TSH levels
are elevated and T4 levels are low, the cause is hypothyroidism. If the bone age is delayed, the cause is
constitutional delay.
If the bone age is normal, obtain LH, FSH, and prolactin levels. If LH and FSH levels are elevated, obtain a
karyotype.
If the karyotype is 45,X, the cause is gonadal dysgenesis (ie, Turner syndrome). Amenorrhea can also occur when 1
of the 2 X chromosomes is abnormal, such as a ring chromosome, or if a partial loss of the p or q arm of the X
chromosome occurs. If the karyotype is 46,XX, the primary cause is ovarian failure from pure gonadal dysgenesis.
Perform an autoimmune workup. Consider an etiology of autoimmune oophoritis, effects of radiation therapy or
chemotherapy, 17-alpha-hydroxylase deficiency, or resistant ovary syndrome. Check for neurosensory loss.
If the karyotype is 46,XY, the cause is Swyer syndrome. The patient has streak gonads and neither testosterone nor
Mllerian inhibitory factor (MIS) is produced; thus, the patient has a female phenotype and does not enter puberty.
These gonads have an increased incidence of malignant transformation and should be removed.
If LH and FSH levels are low or within the reference range and bone age is normal, obtain a head MRI. If head MRI
findings are abnormal, the cause is pituitary tumor, pituitary destruction, or hypothalamic disease
If prolactin levels are elevated, obtain a head MRI. If head MRI findings are abnormal, the cause is pituitary tumor or
a brain lesion disrupting the pituitary stalk. If the MRI finding is normal, the cause may be marijuana use or
psychiatric medicine, specifically dopamine antagonist medications, which lead to a decrease in prolactin inhibiting
factor and a subsequent increase in serum prolactin levels.
If head MRI findings are normal with normal history and physical examination findings, the etiology may be drug use,
an eating disorder, athleticism, or psychosocial stress.
If head MRI findings are normal but clinical evaluation and screening study findings are abnormal, chronic disease
can be excluded.
Amenorrhea with normal puberty with uterus present
Obtain a pregnancy test. If the pregnancy test result is positive, refer the patient to the appropriate specialist. If the
pregnancy test result is negative, obtain TSH, prolactin, FSH, and LH levels.
If the TSH level is elevated, the diagnosis is hypothyroidism. If the prolactin level is elevated, the diagnosis is
hyperprolactinemia. Causes include prolactinoma, CNS tumors, and medications. MRI is indicated.
If the FSH level is low, obtain head MRI. If MRI findings are abnormal, consider hypothalamic disease, pituitary
disease, or pituitary tumor. If MRI findings are normal, proceed with clinical evaluation to exclude chronic disease,
anorexia nervosa, marijuana or cocaine use, and social or psychological stresses.
If FSH is elevated, premature ovarian failure is the diagnosis. Obtain a karyotype. If the karyotype is abnormal,
mosaic Turner syndrome may be present. If the karyotype is normal (46,XX), the cause is premature ovarian failure.
An association with fragile X syndrome may be observed.
[43]
If fragile X syndrome is present, family members should
be offered genetic testing.
Consider premature ovarian failure due to the following:
Autoimmune oophoritis
Exposure to radiation or chemotherapy
Resistant ovary syndrome
Multiple endocrine neoplasm (MEN) syndrome
If TSH, prolactin, and FSH levels are within reference range, perform a progestin challenge test. If withdrawal
bleeding occurs, consider anovulation secondary to PCO syndrome. If no withdrawal bleed occurs, proceed with
estradiol (E
2
) priming, followed by a progestin challenge.
If the challenge does not induce menses, consider Asherman syndrome, outlet obstruction, or endometrial thinning
secondary to elevated androgens (PCO syndrome) or hypothalamic amenorrhea with decreased estrogen
production.
If the challenge induces menses, a hypothalamic dysfunction with low circulating E
2
is present. Acquired
hypothalamic causes of amenorrhea after puberty has been achieved is a diagnosis of exclusion. The FSH and LH
levels may be low or may be below the reference range. The causes include eating disorders, caloric restriction,
exercise, stress, and medications.
If hirsutism and/or acne are present, check testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxy
(17-OH) progesterone level. If the testosterone and DHEAS levels are within the reference range or are moderately
elevated, perform a progesterone challenge. If withdrawal bleeding occurs, the diagnosis is PCOS. If the 17-OH
progesterone level is elevated, the diagnosis is adult-onset adrenal hyperplasia.
If the testosterone level or DHEAS is 2 or more times higher than the reference range, consider PCOS,
hyperthecosis, or an androgen-secreting tumor of the ovary or adrenal gland
Amenorrhea with genital tract abnormalities
Obtain a pelvic sonography. If the uterus is absent and the vagina foreshortened, obtain a karyotype. If the karyotype
is 46,XY, obtain testosterone levels.
If testosterone levels are within reference range or are high (male range), the cause is androgen insensitivity or 5-
alpha-reductase deficiency. Surgical gonad removal is recommended in patients with androgen insensitivity. If
testosterone levels are within reference range or are low (female range), the cause is testicular regression or
gonadal enzyme deficiency. Surgical gonad removal is recommended.
If the karyotype is 46,XX, the cause is Mllerian agenesis (ie, Rokitansky-Kuster-Hauser syndrome).
Contributor Information and Disclosures
Author
Kenneth M Bielak, MD Clinic Director of Family Practice Center, Associate Professor, Department of Family
Medicine, University of Tennessee Health Science Center College of Medicine
Kenneth M Bielak, MD is a member of the following medical societies: American Academy of Family Physicians ,
American College of Sports Medicine , American Medical Association , and American Medical Society for Sports
Medicine
Disclosure: Nothing to disclose.
Chief Editor
Richard Scott Lucidi, MD, FACOG Associate Professor of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine
Richard Scott Lucidi, MD, FACOG is a member of the following medical societies: American College of
Obstetricians and Gynecologists and American Society for Reproductive Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Elizabeth Alderman, MD Director of Fellowship Training Program, Director of Adolescent Ambulatory Service,
Professor of Clinical Pediatrics, Department of Pediatrics, Division of Adolescent Medicine, Albert Einstein College
of Medicine and Children's Hospital at Montefiore
Elizabeth Alderman, MD is a member of the following medical societies: American Academy of Pediatrics ,
American Pediatric Society , North American Society for Pediatric and Adolescent Gynecology , and Society for
Adolescent Medicine
Disclosure: Merck Honoraria Speaking and teaching
A David Barnes, MD, PhD, MPH, FACOG Consulting Staff, Department of Obstetrics and Gynecology,
Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General
Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of
Forensic Examiners , American College of Obstetricians and Gynecologists , American Medical Association ,
Association of Military Surgeons of the US , and Utah Medical Association
Disclosure: Nothing to disclose.
Karim Anton Calis, PharmD, MPH, FASHP, FCCP Adjunct Clinical Investigator, Program in Developmental
Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development,
National Institutes of Health; Clinical Professor, Medical College of Virginia, Virginia Commonwealth University
School of Pharmacy; Clinical Professor, University of Maryland School of Pharmacy
Karim Anton Calis, PharmD, MPH, FASHP, FCCP is a member of the following medical societies: American
College of Clinical Pharmacy , American Society of Health-System Pharmacists , and Endocrine Society
Disclosure: Nothing to disclose.
Sharon N Covington, LCSW-C, BCD Clinical Assistant Professor, Department of Obstetrics and Gynecology,
Georgetown University School of Medicine; Associate Investigator, Integrative Reproductive Medicine Unit,
Reproductive Biology and Medicine Branch, National Institutes of Child Health and Human Development, National
Institutes of Health; Private Practice, Covington and Hafkin and Associates; Director of Psychological Support
Services, Shady Grove Fertility Reproductive Science Center
Sharon N Covington, LCSW-C, BCD is a member of the following medical societies: Academy of Certified Social
Workers , American Orthopsychiatric Association , American Society for Reproductive Medicine , National
Association of Social Workers , and Society for Assisted Reproductive Technologies
Disclosure: Nothing to disclose.
Gayla S Harris, MD Associate Professor, Department of Obstetrics and Gynecology, University of Tennessee
Medical Center
Gayla S Harris, MD is a member of the following medical societies: American Society for Reproductive Medicine
Disclosure: Nothing to disclose.
Lawrence M Nelson, MD, MBA Head of Integrative Reproductive Medicine Group, Intramural Research Program
on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National
Institutes of Health
Lawrence M Nelson, MD, MBA is a member of the following medical societies: American College of Obstetricians
and Gynecologists , American Society for Reproductive Medicine , Association of Professors of Gynecology and
Obstetrics , Endocrine Society , and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.
Vaishali Popat, MD, MPH Clinical Investigator, Intramural Research Program on Reproductive and Adult
Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Vaishali Popat, MD, MPH is a member of the following medical societies: American College of Physicians and
Endocrine Society
Disclosure: Nothing to disclose.
Thomas Michael Price, MD Associate Professor, Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, Director of Reproductive Endocrinology and Infertility Fellowship
Program, Duke University Medical Center
Thomas Michael Price, MD is a member of the following medical societies: Alpha Omega Alpha , American
College of Obstetricians and Gynecologists , American Medical Association , American Society for Reproductive
Medicine , Association of Professors of Gynecology and Obstetrics , Endocrine Society , Phi Beta Kappa , Society
for Gynecologic Investigation , Society for Reproductive Endocrinology and Infertility , and South Carolina Medical
Association
Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee Consulting;
Gerson Lehrman Group Advisor Consulting fee Consulting; Adiana Grant/research funds PI
Tamara Prodanov, MD Research Assistant, National Institutes of Child Health and Human Development,
National Institutes of Health
Disclosure: Nothing to disclose.
Shannon D Sullivan, MD, PhD Staff Physician, Department of Endocrinology, Washington Hospital Center
Shannon D Sullivan, MD, PhD is a member of the following medical societies: American Association of Clinical
Endocrinologists , American Thyroid Association , and Endocrine Society
Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of
Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Suzanne R Trupin, MD, FACOG Clinical Professor, Department of Obstetrics and Gynecology, University of
Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women's Health Practice; CEO and Owner,
Hada Cosmetic Medicine and Midwest Surgical Center
Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American Association of
Gynecologic Laparoscopists , American College of Obstetricians and Gynecologists , American Institute of
Ultrasound in Medicine , American Medical Association , Association of Reproductive Health Professionals ,
International Society for Clinical Densitometry , and North American Menopause Society
Disclosure: Nothing to disclose.
Somya Verma, MD, Fellow in Pediatric Endocrinology, National Institutes of Child Health and Human
Development; Officer of United States Public Health Service Commissioned Corps
Disclosure: Nothing to disclose.
Wayne Wolfram, MD, MPH Associate Professor, Department of Emergency Medicine, Mercy St Vincent Medical
Center
Wayne Wolfram, MD, MPH is a member of the following medical societies: American Academy of Emergency
Medicine , American Academy of Pediatrics , and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Andrea L Zuckerman, MD Assistant Professor of Obstetrics/Gynecology and Pediatrics, Tufts University School
of Medicine; Division Director, Pediatric and Adolescent Gynecology, Tufts Medical Center
Andrea L Zuckerman, MD is a member of the following medical societies: American College of Obstetricians and
Gynecologists , Association of Professors of Gynecology and Obstetrics , Massachusetts Medical Society , North
American Society for Pediatric and Adolescent Gynecology , and Society for Adolescent Medicine
Disclosure: Nothing to disclose.
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