eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure: Differential Diagnoses & Workup

Author: Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health
Coauthor(s): 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: Jun 1, 2007

Differential Diagnoses

Abdominal Abscess
Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism
Addison Disease
Luteal Phase Dysfunction
Adnexal Tumors
Luteinizing Hormone Deficiency
Amenorrhea, Primary
Menopause
Anorexia Nervosa
Missed Abortion
Anovulation
Ovarian Cysts
Anxiety Disorders
Ovarian Dysgerminomas
Appendicitis
Ovarian Polycystic Disease
Bulimia
Panic Disorder
C-17 Hydroxylase Deficiency
Pelvic Inflammatory Disease
Chronic Pelvic Pain
Pheochromocytoma
Corpus Luteum Rupture
Pineal Tumors
Depression
Pituitary Macroadenomas
Dysfunctional Uterine Bleeding
Pituitary Microadenomas
Ectopic Pregnancy
Polycystic Ovarian Syndrome
Eosinophilic Granuloma (Histiocytosis X)
Polyglandular Autoimmune Syndrome, Type I
Gonadotropin-Releasing Hormone Deficiency in Adults
Polyglandular Autoimmune Syndrome, Type II
Gynecologic Pain
Postpartum Depression
Hashimoto Thyroiditis
Pregnancy Diagnosis
Hyperprolactinemia
Prolactinoma
Hypopituitarism (Panhypopituitarism)
Tuberculosis
Hypothyroidism
Tuberculosis of the Genitourinary System

Other Problems to Be Considered

Torsion of the ovary
Androgen receptor insensitivity
Chemotherapy
17,20-lyase deficiency
Aromatase enzyme deficiency
Gonadotropin-producing pituitary adenoma
Galactosemia
See Causes

Workup

Laboratory Studies

  • Three groups of tests should be performed when ovarian failure is suspected or has been diagnosed. They include tests that establish the diagnosis of POF/POI, tests that help clarify the etiology, and screening tests for other diseases known to have higher prevalence among women with POF/POI.
  • A pregnancy test (urine or beta human chorionic gonadotropin [bhCG] in the blood) should be the first study performed in every woman of reproductive age who presents with amenorrhea.
  • Studies to establish the diagnosis of POF/POI are as follows:
    • Measuring serum FSH level is the core study to establish the diagnosis of POF/POI after pregnancy has been ruled out. By convention, 2 FSH levels in the menopausal range for the specific assay (>40 µIU/mL by radioimmunoassay), measured at least 1 month apart, are diagnostic of POF/POI.
    • Measurement of serum LH also is important. In most cases of spontaneous POF/POI, FSH is higher than LH. If autoimmune oophoritis is present, FSH may be only mildly elevated, sometimes below the cutoff of 40 µIU/mL, while LH is markedly elevated.
    • A parallel test of serum estradiol is necessary. As a rule, serum estradiol is low in women with POF/POI and is similar to or less than the early follicular phase estradiol of women who cycle normally. The combination of low estradiol and high gonadotropins defines POF/POI.
    • Occasionally, women with POF/POI may have spontaneous follicular activity, and, if hormonal tests are performed during such episodes, levels of FSH, LH, and estradiol could be in the normal range or FSH and LH could be elevated only minimally (below the menopausal range). This may lead to an erroneous rejection of the diagnosis of POF/POI. In these cases, persistent amenorrhea or oligomenorrhea accompanied by menopausal symptoms necessitates a repeat of the above tests in 1-2 months.
  • Studies to clarify the etiology of ovarian failure are as follows:
    • Karyotype: A karyotype should be performed as a part of the routine evaluation after the diagnosis of POF/POI is established. A history of previous pregnancies or age older than 35 years should not discourage the test. X chromosome abnormalities have been described in women who have had normal puberty, have delivered children without abnormalities, and subsequently have developed POF/POI. In addition, unexpected karyotype findings may have important implications for relatives and for future pregnancies. A normal karyotype may be reassuring to the patient, while an abnormal one could provide an explanation of the patient's problem.
    • Refer for genetic counseling and testing for the FMR1 premutation if a family history of premature ovarian failure, mental retardation, or a tremor/ataxia syndrome is present.
    • Ovarian antibodies: Currently, no reliable ovary specific tests exist for the diagnosis of autoimmune ovarian failure. The different ovarian antibody assays that are available commercially are of little diagnostic value because of problems with specificity and sensitivity. Adrenal antibodies are predictive of autoimmune oophoritis based on the presence of steroid cell autoantibodies.
    • The presence of a second autoimmune endocrine or nonendocrine disease traditionally is used as an argument that the ovarian failure of a particular patient is of autoimmune etiology. In most cases, this is not true, the only exception being the combination of Addison disease and POF/POI.
  • Screening tests for other associated diseases/conditions are as follows:
    • Thyroid: The prevalence of hypothyroidism in patients with spontaneous POF/POI is higher than in the general female population of the same age, and screening with a TSH test and thyroid peroxidase antibodies is warranted.
    • Elevated thyroid antibodies should be regarded as a risk factor for hypothyroidism and not as an indicator that the ovaries are affected by an autoimmune process.
    • Adrenal antibodies: Adrenal antibody test (by immunofluorescent assay) or 21-hydroxylase antibody test (by enzyme immunoassay) should be performed as soon as the diagnosis of spontaneous POF/POI has been established. These tests are of value in defining the pathogenesis as autoimmune oophoritis and identifying women who are at risk for autoimmune adrenal insufficiency.
    • Of women who present with POF/POI, 2-5% also have autoimmune adrenal insufficiency. The authors previously have shown that an autoantibody test by immunofluorescence is an efficient means to screen for autoimmune adrenal insufficiency (100% sensitivity and 67% positive predictive value). Therefore, it should be used early in the diagnostic process.
    • Fragile X chromosome premutation screening: Because the prevalence of fragile X chromosome premutation is significantly higher among women with POF/POI compared with women who cycle normally, some authors recommend that a test for fragile X premutation be a part of the initial workup of patients with POF/POI. The finding of fragile X premutation may have implications for the family members and for planned pregnancies.

Imaging Studies

Ovarian ultrasonography has little practical value in the workup of patients with POF/POI.

More on Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure

Overview: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
Differential Diagnoses & Workup: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
Treatment & Medication: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
Follow-up: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
References
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Further Reading

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Keywords

ovaries, reproductive organs, premature ovarian failure, primary ovarian failure, premature menopause, primary ovarian insufficiency, POF, anovulation, endocrine failure

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Contributor Information and Disclosures

Author

Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health
Vaishali Popat, MD, MPH is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, American Medical Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

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, Endocrine Society, Phi Beta Kappa, Society for Gynecologic Investigation, 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; Roche/GSK Spokesperson  Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

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: Galil None Consulting

 
 
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