eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Amenorrhea, Primary: Differential Diagnoses & Workup

Author: 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
Coauthor(s): Tamara Prodanov, MD, Research Assistant, National Institute of Health/National Institute of Child Health and Human Development; Karim Anton Calis, PharmD, MPH, FASHP, FCCP, Professor, Medical College of Virginia, Virginia Commonwealth University, Clinical Professor, University of Maryland; Clinical Specialist, Endocrinology and Women's Health, Director, Drug Information Service, Mark O Hatfield Clinical Research Center, National Institutes of Health; Somya Verma, MD, Fellow in Pediatric Endocrinology, National Institutes of Child Health and Human Development; Officer of United States Public Health Service Commissioned Corps; 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; Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Contributor Information and Disclosures

Updated: Aug 14, 2008

Differential Diagnoses

Adnexal Tumors
Imperforate Hymen
Adnexal Tumors
Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism
Adrenal Adenoma
Leydig Cell Tumors
Adrenal Carcinoma
Luteinizing Hormone Deficiency
Androgen Excess
Menopause
Anorexia Nervosa
Ovarian Failure
Anovulation
Ovarian Insufficiency
Anxiety Disorders
Ovarian Polycystic Disease
Benign Lesions of the Ovaries
Pituitary Macroadenomas
C-17 Hydroxylase Deficiency
Pituitary Microadenomas
Cushing Syndrome
Polyglandular Autoimmune Syndrome, Type I
Depression
Polyglandular Autoimmune Syndrome, Type II
Follicle-Stimulating Hormone Abnormalities
Polyglandular Autoimmune Syndrome, Type III
Germ Cell Tumors
Pregnancy Diagnosis
Gonadotropin-Releasing Hormone Deficiency in Adults
Prolactinoma
Hydatidiform Mole
Pseudo-Cushing Syndrome
Hyperthyroidism
Hypopituitarism (Panhypopituitarism)

Workup

Laboratory Studies

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.

Once pregnancy is excluded, a thorough history, review of symptoms, and physical examination are important. If the history and physical examination findings do not reveal the cause of the amenorrhea, 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.

  • Prolactin
    • 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.
  • Follicle-stimulating hormone: 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.
  • Luteinizing hormone: Luteinizing hormone is elevated in cases of 17-20 lyase deficiency, 17-hydroxylase deficiency, and premature ovarian failure.
  • Estradiol: 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.
  • Thyrotropin and free thyroxine (T4): Disorders of the thyroid gland may result in menstrual irregularities; however, for it to present as primary amenorrhea is uncommon. Check for thyroid hormones if symptoms of hypothyroidism or hyperthyroidism are present.
  • Testosterone and dehydroepiandrosterone sulphate: Checking the androgen levels helps identify hyperandrogenic conditions resulting in amenorrhea. For more details, see Polycystic Ovarian Syndrome.

Imaging Studies

  • Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs. However, a report of absence of 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. 
  • 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

Other Tests

Several validated tools are available to measure dietary intake, mood disorder, and eating disorders. These tools include the Minnesota Nutrition Data Systems evaluation to assess dietary intake, Beck Depression Inventory to assess the mood, Modifiable Activity Questionnaire, Paffenbarger Questionnaire to assess the patient's level of physical activity, Multidimensional Eating Disorder Inventory for anorexia and bulimia15 , and the Bulimia Test-Revised (BULIT-R).16

More on Amenorrhea, Primary

Overview: Amenorrhea, Primary
Differential Diagnoses & Workup: Amenorrhea, Primary
Treatment & Medication: Amenorrhea, Primary
Follow-up: Amenorrhea, Primary
Multimedia: Amenorrhea, Primary
References
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References

  1. Greenspan FSFS1GDG. Basic & clinical endocrinology. 7th ed. McGraw-Hill; 2001.

  2. Santoro N, Filicori M, Crowley WF Jr. Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev. Feb 1986;7(1):11-23. [Medline].

  3. Miller KK, Grinspoon SK, Ciampa J, et al. Medical findings in outpatients with anorexia nervosa. Arch Intern Med. Mar 14 2005;165(5):561-6. [Medline].

  4. Kawano Y, Kamihigashi S, Nakamura S, et al. Delayed puberty associated with hyperprolactinemia caused by pituitary microadenoma. Arch Gynecol Obstet. Sep 2000;264(2):90-2. [Medline].

  5. Crosignani PG. Current treatment issues in female hyperprolactinaemia. Eur J Obstet Gynecol Reprod Biol. Apr 1 2006;125(2):152-64. [Medline].

  6. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. Apr 1986;67(4):604-6. [Medline].

  7. Sherman SL. Premature ovarian failure among fragile X premutation carriers: parent-of-origin effect?. Am J Hum Genet. Jul 2000;67(1):11-3. [Medline].

  8. Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. Aug 2002;17(8):2096-100. [Medline].

  9. Morcel K, Camborieux L, , Guerrier D. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Orphanet J Rare Dis. 2007;2:13. [Medline].

  10. Huhtaniemi I, Alevizaki M. Gonadotrophin resistance. Best Pract Res Clin Endocrinol Metab. Dec 2006;20(4):561-76. [Medline].

  11. Jones ME, Boon WC, McInnes K, Maffei L, Carani C, Simpson ER. Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab. May 2007;3(5):414-21. [Medline].

  12. Current evaluation of amenorrhea. Fertil Steril. Sep 2004;82 Suppl 1:S33-9. [Medline].

  13. Professional Guide to Diseases (Professional Guide Series). 8th ed. Lippincott Williams & Wilkins; 2005.

  14. Diaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics. Nov 2006;118(5):2245-50. [Medline].

  15. Garner DM, Olmsted MP, Polivy J. Development and validation of a multidimensional eating disorder inventory for anorexia nervosa and bulimia. Int J Eating Disorders. 1983;2:15-34.

  16. Thelen MH, Farmer J, Wonderlich S, Smith M. A revision of the bulimia test: the BULIT-R. Psychol Assess. 1991;3:119-24.

  17. Davis SR. Premature ovarian failure. Maturitas. Feb 1996;23(1):1-8. [Medline].

  18. DiPiro JT TRYG. Hormone therapy in women. Pharmacotherapy. In: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:1493-513.

  19. Davis SR. The therapeutic use of androgens in women. J Steroid Biochem Mol Biol. Apr-Jun 1999;69(1-6):177-84. [Medline].

  20. Adams Hillard PJ, Nelson LM. Adolescent girls, the menstrual cycle, and bone health. J Pediatr Endocrinol Metab. May 2003;16 Suppl 3:673-81. [Medline].

  21. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. Feb 7 1996;275(5):370-5. [Medline].

  22. Reindollar RH, Tho SPT, McDonough PG. Delayed Puberty: an updated study of 326 patients. Transactions of the Gynecological and Obstetrical Society. 1989;8:146-62.

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Further Reading

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Keywords

amenorrhea, primary amenorrhea, secondary amenorrhea, hypothalamic amenorrhea, pituitary amenorrhea, menstruation, absence of menstruation, gonadotropin-releasing hormone, GnRH, follicle-stimulating hormone, FSH, luteinizing hormone, LH, hypothalamus-pituitary-ovarian axis, HPO, gonadal dysgenesis, Turn syndrome, spontaneous primary ovarian insufficiency, POI, premature ovarian failure, POF, premature menopause, Swyer syndrome, 46,XY gonadal dysgenesis, 46,XX gonadal dysgenesis, polycystic ovarian syndrome, vaginal agenesis, mullerian dysgenesis, Mayer-Rokitansky-Kuster-Hauser syndrome, MRKH

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Contributor Information and Disclosures

Author

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 Association of Clinical Endocrinologists, American College of Physicians, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Tamara Prodanov, MD, Research Assistant, National Institute of Health/National Institute of Child Health and Human Development
Disclosure: Nothing to disclose.

Karim Anton Calis, PharmD, MPH, FASHP, FCCP, Professor, Medical College of Virginia, Virginia Commonwealth University, Clinical Professor, University of Maryland; Clinical Specialist, Endocrinology and Women's Health, Director, Drug Information Service, Mark O Hatfield Clinical Research Center, National Institutes of Health
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.

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.

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.

Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, 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.

Medical Editor

Thomas Michael Price, MD, Associate Professor of Reproductive Endocrinology, Director of Reproductive Fellowship Training 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 Society for Reproductive Medicine, Phi Beta Kappa, and Society for Gynecologic Investigation
Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee Consulting; Gerson Lehrman Group Advisor  Consulting fee Consulting; Roche/GSK Spokesperson  Consulting fee Consulting; Abbott Pharmaceuticals Grant/research funds PI; Adiana Grant/research funds PI

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center
Bryan D Cowan, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons
Disclosure: Wyeth None Speaking and teaching

 
 
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