eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Ovarian Insufficiency: Differential Diagnoses & Workup

Author: Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Reproductive Biology and Medicine Branch, National Institutes of Health
Coauthor(s): Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health
Contributor Information and Disclosures

Updated: Jan 15, 2008

Differential Diagnoses

Abdominal Abscess
Gonadotropin-Releasing Hormone Deficiency in Adults
Androgen Excess
Luteinizing Hormone Deficiency
Anorexia Nervosa
Ovarian Failure
Anovulation
Ovarian Polycystic Disease
Anxiety Disorders
Polyglandular Autoimmune Syndrome, Type I
C-17 Hydroxylase Deficiency
Polyglandular Autoimmune Syndrome, Type II
Depression
Polyglandular Autoimmune Syndrome, Type III
Dysfunctional Uterine Bleeding
Prolactinoma
Follicle-Stimulating Hormone Abnormalities

Other Problems to Be Considered

Stein-Leventhal syndrome
Excessive exercise
Mild eating disorder
Emotional stress

Workup

Laboratory Studies

  • Required laboratory studies vary depending on the clinical presentation and should be directed by a focused history and physical examination. Drug therapy, systemic chronic disease, an eating disorder, excessive exercise, depression, or anxiety disorders all should be considered as factors in the loss of menstrual regularity.
  • Insufficiency of ovarian endocrine function generally presents with loss of menstrual regularity.
    • In women who present with a loss of menstrual regularity, obtain a pregnancy test and measure serum prolactin, FSH, luteinizing hormone (LH), and estradiol.
    • Additional studies to be obtained if evidence of androgen excess (acne, hirsutism, male-pattern balding, clitoromegaly) or hypertension is present include measuring serum testosterone and dehydroepiandrosterone (DHEAS) levels. Consider further evaluation for Cushing syndrome or congenital adrenal hyperplasia.
    • In the presence of amenorrhea, and if the patient's serum FSH level is in the menopausal range for the assay system, confirmed with repeat testing, a diagnosis of overt primary ovarian insufficiency is established (also known previously as premature ovarian failure or premature menopause). In this circumstance, a karyotype and testing for the fragile X premutation should be performed.
  • Occult or biochemical primary ovarian insufficiency generally presents as unexplained infertility in women who have regular menses.
    • To evaluate ovarian insufficiency in women presenting with infertility and regular menstrual cycles, measure serum FSH, LH, and estradiol on day 3 of a menstrual cycle.
    • Measure serum progesterone during the midluteal phase to confirm ovulation.

Imaging Studies

  • Overt primary ovarian insufficiency
    • The information obtained by ovarian ultrasound imaging does not change clinical management.
    • Ovarian imaging by ultrasound should be reserved for investigational use in cases of overt primary ovarian insufficiency.
  • Secondary ovarian insufficiency: An MRI of the pituitary and hypothalamus is indicated in the evaluation of secondary ovarian insufficiency in the following circumstances:
    • Hyperprolactinemia
    • Associated headache or visual-field cuts
    • Profound estrogen deficiency with otherwise unexplained amenorrhea

Other Tests

  • Overt primary ovarian insufficiency

    • Obtain serum free T4 and thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies, and fasting blood sugar measurements.
    • Measure adrenal antibodies.
    • Perform bone density scan (DEXA) to evaluate bone mineral density
    • Perform an adrenocorticotropic hormone (ACTH) stimulation test if the adrenal antibody test is positive.
    • Perform other antibody tests such as antinuclear antigens (ANA) and rheumatoid factor tests only as clinically indicated.
  • Secondary ovarian insufficiency
    • Consider the need for an ACTH stimulation test to evaluate secondary adrenal insufficiency as an additional finding.
    • Consider the need for diurnal TSH measurements to evaluate for the presence of central hypothyroidism as an additional finding.

Procedures

  • Overt primary ovarian insufficiency: Clinically, ovarian biopsy is not indicated. The procedure should be performed only as part of an investigation that is approved by an institutional review board.
  • Secondary ovarian insufficiency: Surgical procedures should be performed as indicated when hypothalamic or pituitary lesions are identified.

More on Ovarian Insufficiency

Overview: Ovarian Insufficiency
Differential Diagnoses & Workup: Ovarian Insufficiency
Treatment & Medication: Ovarian Insufficiency
Follow-up: Ovarian Insufficiency
References
Further Reading
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References

  1. Adashi EY, Hennebold JD. Single-gene mutations resulting in reproductive dysfunction in women. N Engl J Med. Mar 4 1999;340(9):709-18. [Medline].

  2. Anasti JN, Kalantaridou SN, Kimzey LM. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol. Jan 1998;91(1):12-5. [Medline].

  3. Cameron IT, O'Shea FC, Rolland JM, Hughes EG, de Kretser DM, Healy DL. Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations. J Clin Endocrinol Metab. Dec 1988;67(6):1190-4. [Medline].

  4. Fanchin R, de Ziegler D, Olivennes F, Taieb J, Dzik A, Frydman R. Exogenous follicle stimulating hormone ovarian reserve test (EFORT): a simple and reliable screening test for detecting 'poor responders' in in-vitro fertilization. Hum Reprod. Sep 1994;9(9):1607-11. [Medline].

  5. Farhi J, Homburg R, Ferber A, Orvieto R, Ben Rafael Z. Non-response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre-empting the rise in basal follicle stimulating hormone levels. Hum Reprod. Feb 1997;12(2):241-3. [Medline].

  6. Hagerman RJ, Hagerman PJ. The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev. Jun 2002;12(3):278-83. [Medline].

  7. Johnson J, Canning J, Kaneko T, et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. Mar 11 2004;428(6979):145-50. [Medline].

  8. Munster K, Helm P, Schmidt L. Secondary amenorrhoea: prevalence and medical contact--a cross- sectional study from a Danish county. Br J Obstet Gynaecol. May 1992;99(5):430-3. [Medline].

  9. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of female fecundity. Lancet. Sep 19 1987;2(8560):645-7. [Medline].

  10. Nelson LM, Anasti JN, Flack MR. Premature ovarian failure. In: Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive Endocrinology, Surgery, and Technology. 2. Philadelphia, Pa: Lippincott Williams & Wilkins; 1995:1393-410.

  11. Prior JC, Vigna YM, Schechter MT. Spinal bone loss and ovulatory disturbances. N Engl J Med. Nov 1 1990;323(18):1221-7. [Medline].

  12. Thomas MA, Rebar RW. Delayed puberty in girls and primary amenorrhea. Curr Ther Endocrinol Metab. 1997;6:223-6. [Medline].

  13. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW. The FMR1 premutation and reproduction. Fertil Steril. Mar 2007;87(3):456-65. [Medline].

  14. Nelson LM, Covington SN, Rebar RW. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril. May 2005;83(5):1327-32. [Medline].

  15. McConkie-Rosell A, Abrams L, Finucane B, Cronister A, Gane LW, Coffey SM. Recommendations from Multi-disciplinary Focus Groups on Cascade Testing and Genetic Counseling for Fragile X-associated Disorders. J Genet Couns. May 12 2007;[Medline].

  16. Armstrong AY, Calis KA, Nelson LM. Do survivors of childhood cancer have an increased incidence of primary ovarian insufficiency?. Nat Clin Pract Endocrinol Metab. Apr 2007;3(4):326-7. [Medline].

  17. Ventura JL, Fitzgerald OR, Koziol DE, Covington SN, Vanderhoof VH, Calis KA. Functional well-being is positively correlated with spiritual well-being in women who have spontaneous premature ovarian failure. Fertil Steril. Mar 2007;87(3):584-90. [Medline].

  18. Kalantaridou SN, Calis KA, Vanderhoof VH, Bakalov VK, Corrigan EC, Troendle JF. Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure. Fertil Steril. Nov 2006;86(5):1475-82. [Medline].

  19. Corrigan EC, Raygada MJ, Vanderhoof VH, Nelson LM. A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome. Fertil Steril. Nov 2005;84(5):1508. [Medline].

  20. Bakalov VK, Anasti JN, Calis KA, Vanderhoof VH, Premkumar A, Chen S. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril. Oct 2005;84(4):958-65. [Medline].

  21. Smith JA, Vitale S, Reed GF, Grieshaber SA, Goodman LA, Vanderhoof VH. Dry eye signs and symptoms in women with premature ovarian failure. Arch Ophthalmol. Feb 2004;122(2):151-6. [Medline].

  22. Nelson LM, Bakalov VK. Mechanisms of follicular dysfunction in 46,XX spontaneous premature ovarian failure. Endocrinol Metab Clin North Am. Sep 2003;32(3):613-37. [Medline].

  23. Gordon CM, Nelson LM. Amenorrhea and bone health in adolescents and young women. Curr Opin Obstet Gynecol. Oct 2003;15(5):377-84. [Medline].

  24. 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].

  25. Novosad JA, Kalantaridou SN, Tong ZB, Nelson LM. Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation. BMC Womens Health. Mar 17 2003;3(1):2. [Medline].

  26. 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].

  27. Alzubaidi NH, Chapin HL, Vanderhoof VH, Calis KA, Nelson LM. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol. May 2002;99(5 Pt 1):720-5. [Medline].

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Further Reading

For further reading, see Medscape's Ob/Gyn and Women's Health.

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Keywords

premature ovarian failure, premature menopause, autoimmune ovarian failure, autoimmune oophoritis, reduced ovarian reserve, hypergonadotropic amenorrhea, menopause, perimenopause, Turner syndrome, gonadal dysgenesis, hyperprolactinemia, hypothalamic amenorrhea, polycystic ovary syndrome, Stein-Leventhal syndrome, primary amenorrhea, secondary amenorrhea, oligomenorrhea, metrorrhagia, polymenorrhea, amenorrhea

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Contributor Information and Disclosures

Author

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

Coauthor(s)

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.

Medical Editor

Robert K Zurawin, MD, Associate Professor, Director of Fellowship Programs, Minimally Invasive Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine; Chief of Gynecology, Texas Children's Hospital
Robert K Zurawin, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Harris County Medical Society, North American Society for Pediatric and Adolescent Gynecology, and Texas Medical Association
Disclosure: Johnson and Johnson Honoraria Speaking and teaching; Conceptus Honoraria Speaking and teaching

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, Assumption Community Hospital
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: Nothing to disclose.

 
 
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