eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure

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

Introduction

Background

The human ovary functions as both a reproductive organ and an endocrine organ. These functions are tightly coupled.

Predictable cyclicity is the hallmark of healthy ovarian function during the reproductive years. Each month, highly coordinated hormonal and ovarian morphological changes develop and release a mature oocyte that is ready for fertilization. A disruption of this process results in reproductive failure (anovulation) or endocrine failure (low serum levels of ovarian steroid hormones and inhibins).

Aging is associated with a decline in the number of ovarian follicles, menstrual irregularities, ovarian hormonal deficiency, anovulation, decreased fertility, and, finally, a complete and irreversible cessation of menses known as menopause, usually occurring at a mean age of 51 years.

POF, also known as premature ovarian failure, primary ovarian insufficiency, premature menopause, or early menopause, is a condition characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin levels in women younger than 40 years. Although often used as synonyms, POF and menopause are not equivalent. Most women with POF retain intermittent ovarian function for many years, and, unlike women who are menopausal, pregnancies may occur.

However, the term premature ovarian failure is problematic because it implies the permanent cessation of ovarian function. In fact, many women with this condition experience intermittent ovarian function that may last for decades after the diagnosis. Pregnancy may even occur in some women years after the diagnosis. The preferred term for this condition is primary ovarian insufficiency (POI), as first introduced by Fuller Albright in 1942.

Pathophysiology

Premature ovarian failure, or primary ovarian insufficiency, can be subdivided into 2 major pathogenetic categories—induced (iatrogenic) POF/POI and spontaneous POF/POI. The focus of this article is on spontaneous POF/POI, a term that will be used as an equivalent to ovarian failure.

Spontaneous premature ovarian failure

The pathogenesis of spontaneous POF/POI in most cases is unknown. Two mechanisms are presumed to play a role—follicle depletion and follicle dysfunction.

Pathogenetic classification of POF/POI

  • Ovarian follicle depletion
    • Low initial follicle number
      • Pure gonadal dysgenesis
      • Thymic aplasia/hypoplasia
      • Idiopathic
    • Accelerated follicle atresia
      • X chromosome related (Turner syndrome, X chromosome deletions and translocations)
      • Galactosemia
      • Fragile mental retardation 1 (FMR1) gene premutation
      • Viral oophoritis (theoretical possibility that has not been proven)
      • Autoimmunity (theoretical possibility that has not been proven)
      • Environmental toxins
      • Iatrogenic
      • Idiopathic
  • Ovarian follicle dysfunction
    • Steroidogenic enzyme defects
      • 17-alpha-hydroxylase deficiency
      • 17-20-desmolase deficiency
      • Aromatase enzyme deficiency
    • Autoimmunity
      • Lymphocytic oophoritis with positive adrenal antibodies/Addison disease (steroid hormone–producing cell autoimmunity)
      • Gonadotropin receptor antibodies
    • Signal defects
      • Abnormal gonadotropin receptor
      • Abnormality in the G-protein signaling pathway  
    • Specific genetic defects (blepharophimosis-epicanthus-ptosis syndrome)
    • Idiopathic (resistant ovary syndrome)
Follicle depletion

Follicle depletion is a major pathogenetic mechanism for development of POF/POI. 

The presence of normal numbers of follicles in the ovaries (approximately 300,000-400,000 at the beginning of puberty) is crucial for normal periodic ovulation. Full maturation of one dominant follicle is dependent on the simultaneous development of a support cohort of nondominant follicles. These, although destined to undergo atresia, play an important role in the fine-tuning of the hypothalamic-pituitary-ovarian axis by secreting regulatory hormones such as estradiol, inhibins, activins, and androgens.

Pathological conditions that cause depletion or a reduction of the follicle number may lead to a disruption of the highly coordinated process of follicular growth and ovulation. The lack of developing follicles leads to reduced circulating estradiol and inhibin levels and elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Occasionally, a "lonely" follicle may develop, stimulated by the high levels of FSH; however, instead of progressing to a normal ovulation, it is inappropriately luteinized (by the high LH levels) and may persist as a cystic structure visible on ultrasonography.

The ovarian follicle reserve can be depleted prematurely because of a low initial number or an accelerated rate of follicle atresia.

Low initial number

  • A disruption in any step of germ cell formation, migration, oogonia proliferation, and meiosis will result in a deficient initial follicle number. The final outcome could be a formation of streak gonads and primary amenorrhea, as in familial 46,XX gonadal dysgenesis, an autosomal-dominant disease with sex-linked inheritance.
  • In milder cases, the initial follicle number is sufficient to support pubertal development, initiation of menstrual cycles, and even fertility, but ovarian failure due to follicle depletion develops early in the reproductive life.
  • In primates, the fetal thymus plays an important role in establishing the normal endowment of primordial follicles. Not surprisingly, human conditions with thymic hypoplasia/aplasia have been associated with POF/POI.
Accelerated follicle atresia: Accelerated follicle atresia or destruction can result from one of the following:
  • X chromosome monosomy/aneuploidy or mosaicism (as observed in Turner syndrome or some cases with 47,XXX karyotype)
  • X chromosome abnormalities (X chromosome rearrangement, X isochromosome and ring chromosome, translocations of X chromosome material to an autosome [t(X;A)], fragile X premutation)
  • Galactosemia
  • Cytotoxic therapy
  • Irradiation
  • Inflammation
Genes and chromosome regions implicated in the development of POF/POI
  • X chromosome genes: Multiple X chromosome genes are involved in regulating female fertility and reproductive lifespan and may be involved in the pathogenesis of ovarian failure.
    • Xp (short arm) genes: Deletions or disruptions of critical regions of the short arm of the X chromosome (Xp11, Xp22.1-21.3) have been described in association with gonadal dysgenesis and primary or secondary amenorrhea. The importance of the genes located on the short arm of the X chromosome for normal ovarian development and survival is evident from the fact that half of the patients with partial deletions of the short arm of the X chromosome have amenorrhea.
      • Zfx (X-linked zinc finger protein): Located on Xp22.1-21.3, this gene encodes a widely expressed protein of unknown function. Zfx "knockout" mice are small, less fertile, and have a diminished germ cell number in the ovaries and testes.
      • USP9X gene (ubiquitin-specific protease 9 gene): It is located on Xp11.4, and its product is widely expressed in many tissues. In Drosophila, USP9X is required for eye development and oogenesis, but its role in human gonadal development is unclear.  
    • Xq (long arm) genes: Analysis of terminal deletions and autosomal translocations yielded information on the importance of several areas located on the long arm of the X chromosome. These include Xq13-21, Xq22-25, and Xq26-28.
      • FMR1 gene: This gene is located on Xq27.3. Mutations in this gene represent expansions of CGG repeat in the promoter region of the FMR1 gene. 1-40 CGG repeats are considered normal, 40-60 repeats are considered a gray area, 60-200 repeats are considered premutation, and more than 200 CGG repeats represent full mutation. Full mutation is associated with mental retardation, while women with premutation demonstrate a 20-30 times increased incidence of POF/POI and are not affected by mental retardation. Why women with the full mutation have no ovarian failure and only those with premutation have ovarian failure is unclear. This may be related to unusual increases in mRNA levels in premutation carriers.1
      • XIST locus (X inactivation site): Located on Xq13, this locus is required for the reactivation of the silenced X chromosome during oocyte maturation. Two X chromosomes with 2 intact XIST loci are necessary for normal meiosis to occur in oocytes. Thus, impairment of the XIST locus results in meiotic arrest and oocyte depletion due to apoptosis.
      • DIA gene (diaphanous gene): This gene, located on Xq21, is homologous to the diaphanous gene in Drosophila. DIA protein is abundantly expressed in the ovaries and other tissues and is important for establishing cell polarity and morphogenesis. DIA mutations in Drosophila lead to sterility in both sexes. The Xq21 region contains at least 7 other genes involved in ovarian development. This region is pseudoautosomal (present on both X and Y chromosomes).     
  • Autosomal abnormalities
    • Trisomies 13 and 18, but not trisomy 21, are associated with ovarian dysgenesis and failure. Therefore, a possibility exists that ovarian genes are located on chromosomes 13 and 18.
    • Balanced autosomal translocations have been found in otherwise healthy women with POF/POI.
    • 46,XX gonadal dysgenesis/agenesis
      • Approximately two thirds of cases with gonadal dysgenesis in individuals who are 46,XX are genetic. The inheritance is autosomal recessive, and the penetrance is variable. Therefore, a possibility exists that some of the sporadic cases of karyotypically normal POF/POI could be due to a mutant somatic gene for XX gonadal dysgenesis.
      • 46,XX gonadal dysgenesis sometimes is a part of a genetic syndrome, such as gonadal dysgenesis and neurosensory deafness (Perrault syndrome); gonadal dysgenesis and cerebellar ataxia; gonadal dysgenesis, arachnodactyly, and microcephaly; and gonadal dysgenesis, short stature, and metabolic acidosis. 
    • Autosomal recessive disorders associated with POF/POI include the following:
      • Cockayne syndrome
      • Nijmegen breakage syndrome
      • Werner syndrome
      • Bloom syndrome    
    • ATM gene (ataxia-telangiectasia mental retardation gene)
      • ATM is a protein kinase involved in DNA metabolism and cell cycle control.
      • Mutations in this gene, located on chromosome 11q22-23, are associated with ovarian atrophy and amenorrhea despite normal female sexual differentiation.
Follicle dysfunction

Some patients with spontaneous POF/POI have numerous ovarian follicles with seemingly normal oocytes that fail to grow and ovulate in the presence of elevated gonadotropins. Most of these patients have idiopathic disease, but, in some cases, a specific cause can be found.

  • Specific gene defects
    • FOXL2 gene (forkhead transcription factor gene): It is located on chromosome 3q22-23. Abnormalities of this gene cause blepharophimosis-epicanthus-ptosis syndrome, a rare congenital dysplasia of the eyelids, which is usually inherited as autosomal dominant. The ovaries initially contain many follicles that do not grow (resistant ovaries), and, later, ovarian follicle depletion develops.
    • FSH receptor gene abnormalities: Point mutations of this gene, located on chromosome arm 2p, have been described in Finnish women with POF/POI.
    • LH receptor gene defects: Inactivation mutations of the LH receptor gene (on chromosome arm 2p) have been described in women with primary amenorrhea, normal breast development, high LH and FSH levels, and low estradiol levels.  
  • Enzyme deficiencies: The following enzyme deficiencies have been associated with ovarian failure:
    • Cholesterol desmolase deficiency: Patients with this enzyme deficiency can barely produce any steroid hormone. They have enlarged lipid-filled adrenals, lack of ovarian function, and rarely survive to adulthood.
    • 17-alpha-hydroxylase deficiency: This is a form of congenital adrenal hyperplasia. Patients have impaired adrenal and ovarian steroid hormone synthesis. They develop hypertension, hypokalemia, and ovarian failure.
    • 17-20-desmolase deficiency: Although this enzyme is a part of the 17-alpha-hydroxylase cytochrome P450 complex, an isolated deficiency is possible. In this case, only ovarian failure develops. Patients with 17-alpha-hydroxylase/17-20-desmolase deficiency have low serum estrogens, high gonadotropins, enlarged ovaries with multiple cysts, and amenorrhea. 
  • Signal defects
    • This is related to FSH and LH receptor abnormalities as described above.
    • Pseudohypoparathyroidism: Ovarian resistance has been demonstrated in patients with pseudohypoparathyroidism due to a defect in the Gsα subunit of the G protein, which prevents normal cyclic adenosine monophosphate (cAMP) generation.   
  • Autoimmunity: The immune system may play a role in some of the cases of POF/POI. The real prevalence of autoimmune POF/POI is unknown. According to one estimate, the rate is approximately 30-40%.2 The presence of other autoimmune disease in a patient with POF/POI should not by default lead to the conclusion that POF/POI is of autoimmune origin. Ovarian biopsies of women with POF/POI and other autoimmune diseases but without adrenal/steroid cell antibodies or Addison disease have repeatedly failed to show any features of autoimmune inflammation.
    • POF/POI associated with adrenal autoimmunity
      • Numerous case reports exist of histological findings consistent with autoimmune oophoritis. The ovaries are of normal size or are enlarged. Many follicles at different stages of development are present. Most or all follicles beyond antral stage are affected by lymphomonocytic infiltration of the theca interna that rarely involves the granulosa. Primordial follicles and follicles below the secondary stage of development are not affected.
      • The patients with histologic findings of autoimmune oophoritis have circulating antiadrenal and/or steroid cell antibodies with unclear functional significance. They may be regarded as markers of autoimmune attack against steroid hormone–producing cells (both in the ovaries and the adrenal gland).
      • These patients have high prevalence of Addison disease, which may be evident at the time of diagnosis of POF/POI or may develop later.
      • Whether an isolated form of autoimmune oophoritis (without adrenal involvement) exists is unclear. The authors have observed one woman with spontaneous POF/POI, histologically proven oophoritis, and positive adrenal antibodies. The findings of her adrenal function tests have remained completely normal over 3 years, and she has no clinical or laboratory manifestation of other autoimmune diseases.
      • Autoimmune oophoritis is a relatively rare condition, and it affects less than 5% of women who present with spontaneous POF/POI.
      • Spontaneous POF/POI has been described as part of polyglandular autoimmune syndromes type 1 and 2. In type 1 syndrome, POF/POI is associated with mucocutaneous candidiasis, ectodermal dystrophy, hypoparathyroidism, celiac disease, chronic hepatitis, and Addison disease. This is a rare autosomal recessive disorder that presents in childhood, mainly in people of Finnish, Sardinian, and Iranian Jewish descent. This disorder is caused by mutations in a gene located on chromosome arm 21q22. The product of that gene is a protein with unknown function, termed AIRE (autoimmune regulator). Autoimmune polyglandular syndrome type 2 consists of autoimmune thyroid diseases, type 1 diabetes, Addison disease, and, in some cases, POF. This syndrome is less well defined than type 1 and is associated with specific human leukocyte antigen (HLA) subtypes.
      • Spontaneous POF/POI can be associated with autoimmune endocrine and nonendocrine diseases outside of the polyglandular autoimmune syndromes. By far the most common is Hashimoto thyroiditis with or without hypothyroidism. It is found in 15-25% of women with spontaneous POF/POI. Other associated diseases are type 1 diabetes, vitiligo, lupus, Sjögren syndrome, and rheumatoid arthritis. Whether POF/POI in these cases is autoimmune in nature is unclear.  
    • Autoimmune POF/POI without adrenal autoimmunity
        • Other forms of autoimmune POF/POI that do not have the typical histologic picture of autoimmune oophoritis and markers of adrenal/steroid-producing cell autoimmunity are possible.
        • Controversy exists regarding the presence of FSH receptor–blocking antibodies. Chiauzzi et al reported FSH receptor–blocking antibodies in 2 patients with myasthenia and POF/POI. Others have failed to find such antibodies. Several researchers have reported the presence of a nonimmunoglobulin serum inhibitor that effectively blocks the interaction of FSH with its receptor.
        • The presence of ovarian antibodies often is regarded as proof of the autoimmune nature of POF/POI. Several assays have been developed. These include indirect immunofluorescence on monkey ovary slides or enzyme immunoassays using different ovarian extracts containing numerous unspecified antigens. These ovarian antibody assays have shown little specificity. As many as one third of women who cycle normally have positive tests. On the other hand, a negative result with one assay does not rule out the possibility of a positive result with a different assay. Until assays with specific ovarian antigens are developed, ovarian antibody tests have little value in determining the etiology of POF/POI.  
    • Infection: A true cause and effect relationship between POF/POI and infection has not been established. In a retrospective study, Rebar and Connolly reported that 3.5% of patients with POF/POI had a previous infection (eg, varicella, shigellosis, malaria).3 Others have observed a 3-7% incidence of oophoritis in patients who contracted mumps during an epidemic. Cytomegalovirus oophoritis has also been described in various women who are immunocompromised.

    Frequency

    United States

    Premature ovarian failure/primary ovarian insufficiency occurs in approximately 1% of women. The estimated incidence in the United States is 1 case per 1000 women by age 30, 1 case per 250 women by age 35 and 1 case per 100 women by age 40. Approximately 10-28% of women with primary amenorrhea and 4-18% with secondary amenorrhea have POF/POI.

    Mortality/Morbidity

    Long-term follow-up studies to evaluate the impact of POF/POI on the mortality rate at older age have not been conducted. In a survey of 19,000 women aged 25-100 years, Snowdon et al have shown increased all-cause mortality in women who had ovarian failure before age 40 years (age-adjusted odds ratio of death 2.14 [95% confidence interval, 1.15-3.99]) and stroke mortality (odds ratio 3.07 [95% confidence interval, 1.34-7.03]).4 Several points concerning morbidity and mortality of patients with POF/POI are worth considering, as follows:

    • A long-lasting hypoestrogenic state at a young age may prevent women from achieving and maintaining adequate bone density. This may put them at increased risk for osteoporosis and fractures later in life.
    • Women with POF/POI may be at higher risk for cardiovascular diseases, again due to low estrogen levels.
    • Patients with POF/POI may be more inclined to undertake unproven treatments to restore fertility and, in this way, may be exposed to iatrogenic damage. The authors recently have observed 2 cases of bone necrosis due to prolonged treatment with corticosteroids in women with POF/POI and presumed but unconfirmed ovarian autoimmunity.
    • POF/POI can coexist with other endocrine and nonendocrine diseases (eg, hypothyroidism, Addison disease, type 1 diabetes, pernicious anemia, lupus).
    • The diagnosis of POF/POI may have a deleterious psychological impact and may lead to depression in a young, otherwise healthy woman.

    Race

    No studies exist regarding race differences in the incidence of spontaneous POF/POI.

    Age

    By definition, POF/POI is a condition of women younger than 40 years.

    Clinical

    Physical

    Generally, women with spontaneous POF/POI have unremarkable clinical findings.

    Occasionally, signs of Turner syndrome may be evident (short stature, shieldlike chest, webbed neck, shortened IV and V metacarpal bones, wide carrying angle of elbows, low-set ears and low hairline, and Madelung deformity of the wrists).

    In other patients, POF/POI is a part of familial syndromes and unusual clinical manifestations can be found, such as deafness in Perrault syndrome or blepharophimosis, eyelid dysplasia, and achondroplasia.

    Pay attention to signs of thyroid disease, such as the presence of goiter, exophthalmos, bradycardia or tachycardia, and cold-and-dry or soft-and-warm skin.

    Looking for clinical signs of adrenal insufficiency, such as orthostatic hypotension, hyperpigmentation, and decreased axillary and pubic hair, is important.

    Other findings associated with the presence of autoimmune diseases may include vitiligo (often associated with thyroid and adrenal autoimmunity), premature graying of hair (in thyroid diseases), nail dystrophy and mucocutaneous candidiasis (in autoimmune polyglandular syndrome type 1), and alopecia areata and malar rash (in lupus).

    Pelvic examination usually reveals atrophic vaginitis. However, some women have intermittent follicular function and produce enough estradiol to keep the vaginal mucosa well estrogenized. Usually, the ovaries are small and barely palpable. Enlarged ovaries could be found occasionally, as in some cases of immune oophoritis.

    The diagnostic approach to patients with ovarian failure is as follows:

    • History
      • Last spontaneous menstrual cycle
      • Prior pelvic surgeries, irradiation, or chemotherapy
      • Symptoms of adrenal insufficiency, including the following:
        • Orthostatic hypotension
        • Skin hyperpigmentation
        • Unexplained weakness
        • Salt craving
        • Abdominal pain
        • Anorexia
      • Symptoms of hypothyroidism
      • Family history of POF/POI, male mental retardation, autoimmune disorders
    • Physical examination
      • Signs of hypoestrogenism
      • Enlarged ovaries versus nonpalpable ovaries
      • Physical stigmata of Turner syndrome or other genetic syndromes, including the following:
        • Short stature
        • Webbed neck
        • Low position of the ears
        • Low posterior hairline
        • Cubitus valgus
        • Shield chest
        • Short IV and V metacarpals
      • Signs of autoimmune diseases, Addison disease, and hypothyroidism
    • Tests
      • Pregnancy test
      • FSH, LH, estradiol
      • Standard blood chemistry - Fasting glucose, electrolytes, and creatinine
      • Karyotype
      • Test for fragile X chromosome (FMR1 premutation)
      • Thyroid-stimulating hormone (TSH)
      • Antithyroid peroxidase antibody
      • Serum adrenal antibodies
      • Bone density by dual-energy x-ray absorptiometry (DEXA) scan

    Causes

    See Pathophysiology.

    See Pathogenetic classification of POF/POI. For more information, see Ovarian Insufficiency. The differential diagnosis of premature ovarian failure includes the following:

    • Pregnancy
    • Secondary ovarian insufficiency/failure due to the following:
      • Eating disorder
      • Extreme physical exercise
      • Prolactinoma and other conditions causing hyperprolactinemia
      • Pituitary and hypothalamic tumors
      • Hypothalamic and pituitary infiltrative and inflammatory processes
      • Pituitary hemorrhage
    • Systemic diseases, including other endocrine disorders
    • Medications
    • Hyperandrogenic conditions due to the following:
      • Polycystic ovarian syndrome
      • Congenital adrenal hyperplasia
      • Ovarian or adrenal androgen-producing tumors
      • Ovarian hyperthecosis
    • Outflow tract abnormalities
    • Pseudo premature ovarian failure due to the following:
      • Gonadotropin-producing pituitary adenoma
      • Antibodies to gonadotropins

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
[ CLOSE WINDOW ]

References

  1. Bardoni B, Mandel JL, Fisch GS. FMR1 gene and fragile X syndrome. Am J Med Genet. 2000;97(2):153-63. [Medline].

  2. Kim TJ, Anasti JN, Flack MR. Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol. May 1997;89(5 Pt 1):777-9. [Medline].

  3. Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steril. May 1990;53(5):804-10. [Medline].

  4. Snowdon DA, Kane RL, Beeson WL, et al. Is early natural menopause a biologic marker of health and aging?. Am J Public Health. Jun 1989;79(6):709-14. [Medline].

  5. Nelson LM, Anasti JN, Kimzey LM, et al. Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure. J Clin Endocrinol Metab. Nov 1994;79(5):1470-5. [Medline].

  6. 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].

  7. Anasti JN. Premature ovarian failure: an update. Fertil Steril. Jul 1998;70(1):1-15. [Medline].

  8. Anasti JN, Adams S, Kimzey LM, et al. Karyotypically normal spontaneous premature ovarian failure: evaluation of association with the class II major histocompatibility complex. J Clin Endocrinol Metab. Mar 1994;78(3):722-3. [Medline].

  9. Bannatyne P, Russell P, Shearman RP. Autoimmune oophoritis: a clinicopathologic assessment of 12 cases. Int J Gynecol Pathol. 1990;9(3):191-207. [Medline].

  10. Belvisi L, Bombelli F, Sironi L, Doldi N. Organ-specific autoimmunity in patients with premature ovarian failure. J Endocrinol Invest. Dec 1993;16(11):889-92. [Medline].

  11. Betterle C, Rossi A, Dalla Pria S, et al. Premature ovarian failure: autoimmunity and natural history. Clin Endocrinol (Oxf). Jul 1993;39(1):35-43. [Medline].

  12. Betterle C, Volpato M. Adrenal and ovarian autoimmunity. Eur J Endocrinol. Jan 1998;138(1):16-25. [Medline].

  13. Biscotti CV, Hart WR, Lucas JG. Cystic ovarian enlargement resulting from autoimmune oophoritis. Obstet Gynecol. Sep 1989;74(3 Pt 2):492-5. [Medline].

  14. Bondy CA, Nelson LM, Kalantaridou SN. The genetic origins of ovarian failure. J Womens Health. Dec 1998;7(10):1225-9. [Medline].

  15. Byrne J. Infertility and premature menopause in childhood cancer survivors. Med Pediatr Oncol. Jul 1999;33(1):24-8. [Medline].

  16. Check JH, Nowroozi K, Chase JS, et al. Ovulation induction and pregnancies in 100 consecutive women with hypergonadotropic amenorrhea. Fertil Steril. May 1990;53(5):811-6. [Medline].

  17. Chen S, Sawicka J, Betterle C, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison''s disease, and premature ovarian failure. J Clin Endocrinol Metab. May 1996;81(5):1871-6. [Medline].

  18. Christin-Maitre S, Vasseur C, Portnoi MF, Bouchard P. Genes and premature ovarian failure. Mol Cell Endocrinol. Oct 25 1998;145(1-2):75-80. [Medline].

  19. Conway GS, Kaltsas G, Patel A, et al. Characterization of idiopathic premature ovarian failure. Fertil Steril. Feb 1996;65(2):337-41. [Medline].

  20. Coope J. Hormonal and non-hormonal interventions for menopausal symptoms. Maturitas. Mar 1996;23(2):159-68. [Medline].

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

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

  23. Fenichel P, Sosset C, Barbarino-Monnier P, et al. Prevalence, specificity and significance of ovarian antibodies during spontaneous premature ovarian failure. Hum Reprod. Dec 1997;12(12):2623-8. [Medline].

  24. Finer N, Fogelman I, Bottazzo G. Pregnancy in a woman with premature ovarian failure. Postgrad Med J. Dec 1985;61(722):1079-80. [Medline].

  25. Fiumara A, Sorge G, Toscano A, et al. Perrault syndrome: evidence for progressive nervous system involvement. Am J Med Genet. Jul 30 2004;128A(3):246-9. [Medline].

  26. Garguillo AR, Hill JA. Autoimmune endocrinopathies in female reproductive dysfunction. In: Volpe R, ed. Contemporary Endocrinology: Autoimmune Endocrinopathies. Totowa, NJ: Humana Press; 1999:365-91.

  27. Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet. May 2004;74(5):1051-6. [Medline].

  28. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev. Feb 1997;18(1):107-34. [Medline].

  29. Kalantaridou SN, Braddock DT, Patronas NJ, Nelson LM. Treatment of autoimmune premature ovarian failure. Hum Reprod. Jul 1999;14(7):1777-82. [Medline].

  30. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure. Endocrinol Metab Clin North Am. Dec 1998;27(4):989-1006. [Medline].

  31. Kalantaridou SN, Naka KK, Papanikolaou E, et al. Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy. J Clin Endocrinol Metab. Aug 2004;89(8):3907-13. [Medline].

  32. Koh JM, Kim CH, Hong SK. Primary ovarian failure caused by a solvent containing 2-bromopropane. Eur J Endocrinol. May 1998;138(5):554-6. [Medline].

  33. LaBarbera AR, Miller MM, Ober C. Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol Microbiol. Mar 1988;16(3):115-22. [Medline].

  34. Lonsdale RN, Roberts PF, Trowell JE. Autoimmune oophoritis associated with polycystic ovaries. Histopathology. Jul 1991;19(1):77-81. [Medline].

  35. Luborsky JL, Visintin I, Boyers S. Ovarian antibodies detected by immobilized antigen immunoassay in patients with premature ovarian failure. J Clin Endocrinol Metab. Jan 1990;70(1):69-75. [Medline].

  36. Meyers CM, Boughman JA, Rivas M. Gonadal (ovarian) dysgenesis in 46,XX individuals: frequency of the autosomal recessive form. Am J Med Genet. Jun 28 1996;63(4):518-24. [Medline].

  37. Miller ME, Chatten J. Ovarian changes in ataxia telangiectasia. Acta Paediatr Scand. Sep 1967;56(5):559-61. [Medline].

  38. Namnoum AB, Merriam GR, Moses AM, Levine MA. Reproductive dysfunction in women with Albright''s hereditary osteodystrophy. J Clin Endocrinol Metab. Mar 1998;83(3):824-9. [Medline].

  39. Nelson LM, Anasti JN, Flack MR. Premature ovarian failure. In: Adashi E, ed. Reproductive Endocrinology, Surgery, and Technology. Philadelphia, Pa: Raven Press; 1996:1394-410.

  40. Nelson LM, Anasti JN, Kimzey LM, Defensor RA, Lipetz KJ, White BJ. Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure. J Clin Endocrinol Metab. Nov 1994;79(5):1470-5. [Medline].

  41. 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].

  42. Nelson LM, Kimzey LM, White BJ. Gonadotropin suppression for the treatment of karyotypically normal spontaneous premature ovarian failure: a controlled trial. Fertil Steril. Jan 1992;57(1):50-5. [Medline].

  43. 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].

  44. Prueitt RL, Zinn AR. A fork in the road to fertility. Nat Genet. Feb 2001;27(2):132-4. [Medline].

  45. Rebar RW, Cedars MI. Hypergonadotropic forms of amenorrhea in young women. Endocrinol Metab Clin North Am. Mar 1992;21(1):173-91. [Medline].

  46. Rebar RW, Morandini IC, Erickson GF, Petze JE. The hormonal basis of reproductive defects in athymic mice: diminished gonadotropin concentrations in prepubertal females. Endocrinology. Jan 1981;108(1):120-6. [Medline].

  47. Rosen GF, Stone SC, Yee B. Ovulation induction in women with premature ovarian failure: a prospective, crossover study. Fertil Steril. Feb 1992;57(2):448-9. [Medline].

  48. Schwartz CE, Dean J, Howard-Peebles PN, et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet. Jul 15 1994;51(4):400-2. [Medline].

  49. Sedmak DD, Hart WR, Tubbs RR. Autoimmune oophoritis: a histopathologic study of involved ovaries with immunologic characterization of the mononuclear cell infiltrate. Int J Gynecol Pathol. 1987;6(1):73-81. [Medline].

  50. Sharf M, Israeli I, Graff G. The value of ovarian biopsy in the diagnosis and treatment of amenorrhea-related sterility. Obstet Gynecol. Jan 1972;39(1):89-94. [Medline].

  51. Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet. Dec 29 1999;89(4):186-200. [Medline].

  52. Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. Jul 1999;33(1):2-8. [Medline].

  53. Smith JA, Vitale S, Reed GF, et al. Dry eye signs and symptoms in women with premature ovarian failure. Arch Ophthalmol. Feb 2004;122(2):151-6. [Medline].

  54. Taylor AE, Adams JM, Mulder JE, et al. A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea. J Clin Endocrinol Metab. Oct 1996;81(10):3615-21. [Medline].

  55. Tong ZB, Nelson LM. A mouse gene encoding an oocyte antigen associated with autoimmune premature ovarian failure. Endocrinology. Aug 1999;140(8):3720-6. [Medline].

  56. Tung KS, Lu CY. Immunologic basis of reproductive failure. Monogr Pathol. 1991;(33):308-33. [Medline].

  57. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. Sep-Oct 1999;5(5):483-92. [Medline].

  58. Yan G, Schoenfeld D, Penney C, et al. Identification of premature ovarian failure patients with underlying autoimmunity. J Womens Health Gend Based Med. Apr 2000;9(3):275-87. [Medline].

  59. Zarate A, Karchmer S, Gomez E, Castelazo-Ayala L. Premature menopause. A clinical, histologic, and cytogenetic study. Am J Obstet Gynecol. Jan 1 1970;106(1):110-4. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

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

[ CLOSE WINDOW ]

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

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.