AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

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 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.

• 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

• 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.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

For more information, see Ovarian Insufficiency.

The history of a patient with ovarian failure could be quite variable, depending on the pathogenesis. In cases of spontaneous ovarian failure, the typical scenario is a sudden onset of amenorrhea, usually after discontinuation of oral contraceptives, or after a pregnancy. In as many as 50% of cases, a long history of oligomenorrhea and polymenorrhea, with or without menopausal symptoms, is present. In 10% of the affected women, POF/POI presents as primary amenorrhea. Occasionally, menopausal symptoms appear before the menses have stopped. In these cases, the physicians could miss the diagnosis easily because of the young age of the patients and the low index of suspicion. The presenting symptoms may vary according to the presence of other associated endocrine and nonendocrine autoimmune diseases.

• Symptoms
  • The most commonly encountered symptoms are a result of prolonged hypoestrogenism and include hot flashes, sweats, irritability, dry skin, dry eyes, vaginal dryness, discomfort and pain during sexual intercourse, decreased libido, and decreased energy.
    
  
  
  • Symptoms may be due to the presence of other endocrine disorders. Patients with coexisting hypothyroidism may have cold intolerance, dry skin, constipation, and bradycardia. Of patients with spontaneous POF/POI, 2-6% may develop Addison disease and may present with hypotension, hyperpigmentation, orthostatic blood pressure drop, salt craving, loss of appetite, and abdominal pain.
    
  
  
  • Sometimes, patients with autoimmune oophoritis may present with unexplained episodes of lower abdominal pain or acute pain that may prompt emergency laparotomies. 
    
  
  
  • Compared with controls, women with spontaneous POF/POI have been shown to have a higher prevalence of clinical findings consistent with dry eye syndrome.
     
• Medical history
  • Patients should be asked about previous exposure to radiation, chemotherapy, or toxic environmental agents. History of past or current autoimmune and endocrine disorders also should be obtained.
  
  
  • Time of menarche, the previous menstrual pattern, and growth history may provide clues for the diagnosis of chromosomal or genetic syndromes.
  
  
  • Surgical procedures involving the pelvic organs, especially the ovaries, sometimes may result in damage to the ovarian blood supply and, eventually, decreased ovarian reserve and ovarian insufficiency.


• Family history
  • Evidence of a familial component exists in some cases of POF/POI, including the finding of an autosomal dominant pattern of inheritance across 4 generations.
  
  
  • Patients who are carriers of fragile X premutation may have a family history of male mental retardation, learning disability, or psychiatric diseases.
  
  
  • Patients with POF/POI may have family history of other autoimmune diseases, including autoimmune endocrine diseases. Whether the presence of autoimmune disease in first-degree relatives increases the likelihood of autoimmune ovarian failure is unclear, and studies addressing this question currently are underway.

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical treatment of patients with POF/POI should address the following aspects: ovarian hormone replacement, restoration of fertility, and psychological well being of the patient.

• Management of premature ovarian failure
  
  
  • Inform
    
    
    • Discuss the test results on a special visit (not by phone).
    
    
    • The diagnosis of POF/POI can be particularly traumatic for young women.
    
    
    • Use of appropriate terminology is important (use of premature ovarian failure or insufficiency is preferred instead of premature menopause or early menopause).
    
    
    • Explain the nature of the disease and advise the patient of sources of information and support.
  
  
  • Counsel
    
    
    • The ovary is not only a reproductive organ but also is a source of important hormones that help maintain strong bones. Adequate replacement of these missing hormones, a healthy lifestyle, and a diet rich in calcium are essential.
    
    
    • POF/POI is not menopause. Spontaneous ovarian activity and pregnancies are possible.
    
    
    • Allow the patient enough time to accept the diagnosis. Family planning decisions are best made after the patient has had some time to come to terms with her condition.
    
    
    • No proven therapies exist to restore fertility; experimental treatment should be performed only under a review board–approved research protocol.
    
    
    • Currently available options to resolve infertility include change of family building plans, such as adoption, ovum donation, or embryo donation.
  
  
  • Hormone replacement therapy (HRT)
    
    
    • All women with POF/POI should receive cyclical HRT with estrogens and progestins to relieve the symptoms of estrogen deficiency and to maintain bone density.
    
    
    • A few women may need HRT even before amenorrhea develops to alleviate menopausal symptoms.
  
  

  • Estrogens

    • Estrogens can be administered orally or transdermally. The appropriate dose for young women with ovarian failure has not been established in control studies. According to the authors’ clinical judgment, administer doses twice as high as the recommended dose for HRT for women who are postmenopausal (transdermal estradiol 100-150 mcg instead of 50 mcg daily, conjugated equine estrogens [CEE] 1.25 mg instead of 0.625 mg daily or oral estradiol 2-4 mg instead of 1 mg daily). Such doses usually achieve adequate estrogenization of the vaginal epithelium in young women with POF/POI and help maintain age-appropriate bone density.
    
    
    • The estrogens can be administered continuously or cyclically (21 d on, 7 d off). Because no controlled studies compare the efficacy and safety of one method over another, the choice of therapy should come after consideration of the patient's preference and physician's experience.
    
    
    • Estrogen replacement therapy does not prevent ovulation and conception in these patients; in fact, it may improve the chance of pregnancy by theoretically lowering the LH level to normal range and preventing premature luteinization of the remaining follicles.⁵ Patients should be informed that they must obtain a prompt pregnancy test if menstrual bleeding fails to appear when expected.
    
    
    • Oral contraceptives provide more sex steroid than is required for replacement, and the authors advise against this approach. Furthermore, owing to the elevated gonadotropin levels, oral contraceptives may not be effective in preventing pregnancy in women with premature ovarian failure.
  
  
  • Progestins
    
    
    • Progestins should be administered cyclically, 10-14 days each month, to prevent endometrial hyperplasia that unopposed estrogen may cause. Young women with POF/POI have a 5-10% chance of spontaneous pregnancy (unlike women who are postmenopausal). If an expected withdrawal bleeding is missing, a pregnancy test should be performed and a diagnosis of pregnancy should not be delayed.
    
    
    • The recommended regimens include medroxyprogesterone 10 mg daily for 10-12 days each month or micronized progesterone 200 mg daily for 10-12 days each month.
  
  
  • Androgens
    
    
    • Women with ovarian failure have lower levels of free testosterone compared with normally ovulating age-matched controls, but only 13% have levels below the lower limit of normal.⁶
    
    
    • Androgen replacement could be carefully considered for women who have persistent fatigue, low libido, and poor well being despite adequate estrogen replacement and when depression has been ruled out or adequately treated. This should be performed with great caution and for relatively short periods until more data are available.
    
    
    • Available medications include oral methyl testosterone 1.25-2.5 mg/d, injectable testosterone esters 50 mg every 6 weeks intramuscularly, and subcutaneous testosterone pellet implants 50 mg every 3-6 months.
  
  
  • Restoration of fertility: No intervention has been proven to increase the ovulation rate or restore fertility in patients with POF/POI.
  
  
  • Gonadotropin therapy carries a theoretical risk of exacerbating autoimmune premature ovarian failure.
  
  
  • The use of prednisone or dexamethasone in an attempt to restore ovarian function in suspected autoimmune ovarian failure is not indicated clinically.
    Use of these agents carries a risk of osteonecrosis. Their use in patients with premature ovarian failure should be confined to studies approved by an institutional review board.
  
  
  • Unproven treatments to restore fertility should be avoided because they have the potential of interfering with the development of a spontaneous pregnancy.
  
  
  • Patients with POF/POI can have successful pregnancy with a donor egg. A decision to proceed with such a procedure should be made after a fair discussion of different options. The age of the patient is of less importance than the age of the egg donor.
  
  
  • Other possibilities include embryo adoption, adoption, or change of life plans.

Surgical Care

Ovarian biopsy is not clinically indicated in women with ovarian failure.

Consultations

• Consultation with an endocrinologist may be indicated in some cases because of concerns of hypothyroidism or adrenal insufficiency.


• Patients with infertility due to POF/POI usually have a grief response after hearing the diagnosis. They may benefit from a baseline psychological evaluation and appropriate counseling.


• Genetic counseling may be needed in some cases.


• Referral for eye care is indicted in women with symptoms of dry eye.

Diet

Patients with ovarian failure should consume 1200-1500 mg of elemental calcium per day in their diet. If this is not feasible, calcium supplementation is appropriate. An adequate intake of vitamin D also is important.

Activity

Women with POF/POI should be encouraged to engage in weight-bearing exercises for 30 minutes per day, at least 3 days per week, to improve muscle strength and maintain bone mass. Participation in outdoor sports is strongly recommended.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Estrogens

Used to achieve adequate estrogenization of vaginal epithelium in young women and to maintain bone density.

Drug Name	Conjugated equine estrogens (Premarin)
Description	Contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. Mixture of sodium estrone sulfate and sodium equilin sulfate. Contains as concomitant components, sodium sulfate conjugates, 17-alpha-dihydroequilenin, 17-alpha-estradiol, and 17-beta-dihydroequilenin. Available in 0.3-mg, 0.625-mg, 0.9-mg, 1.25-mg, and 2.5-mg PO tablets.
Adult Dose	1.25 mg/d PO
Pediatric Dose	<12 years: Not established 12-13 years: 0.3 mg PO qod for as long as 6 mo, increase to adult dose at 6-mo intervals >13 years: Administer as in adults
Contraindications	Documented hypersensitivity; known or suspected pregnancy; breast cancer; undiagnosed abnormal genital bleeding; active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast malignancy or prostatic malignancy in men)
Interactions	May reduce hypoprothrombinemic effect of anticoagulants Coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels Pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme Loss of seizure control has been noted when administered concurrently with hydantoins
Pregnancy	X - Contraindicated in pregnancy
Precautions	Certain patients may develop undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding or mastodynia) Estrogens may cause some degree of fluid retention (caution) Prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia

Drug Category: Progestins

When administered orally in the recommended doses to women adequately exposed to exogenous or endogenous estrogen, they transform the proliferative endometrium into a secretory one.

Drug Name	Progesterone (Prometrium)
Description	Used to prevent endometrial hyperplasia in women with a uterus who are receiving estrogen replacement therapy.
Adult Dose	200 mg PO hs for 12 d sequentially each 28-d cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction; known or suspected malignancy of breast or genital organs; missed abortion; use as a diagnostic test for pregnancy
Interactions	Ketoconazole may increase bioavailability (clinical relevance of in vitro findings is unknown)
Pregnancy	X - Contraindicated in pregnancy
Precautions	Capsules contain peanut oil and should never be used by patients allergic to peanuts May cause fluid retention, and conditions that might be influenced by this (eg, epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation Patients who have a history of depression should be observed carefully Transient dizziness may occur, use caution when driving a motor vehicle or operating machinery (small percentage of women may experience extreme dizziness and/or drowsiness during initial therapy)

Drug Category: Androgens

Responsible for normal growth and the development and maintenance of secondary sex characteristics in males. In addition, androgens have exhibited metabolic activity and may cause retention of nitrogen, sodium, potassium, and phosphorus and decrease urinary excretion of calcium. In the presence of sufficient caloric and protein intake, they will improve nitrogen balance. Androgens also have been reported to stimulate production of RBCs through the enhancement of erythropoietin production. Also increase muscle mass, improve muscle strength, and increase libido.

Drug Name	Testosterone enanthate (Andro LA 200, Delatestryl, Durathate-200)
Description	Derivative of the primary endogenous androgen testosterone. For IM administration. In active form, androgens have a 17-beta-hydroxy group. Esterification of 17-beta-hydroxy group increases duration of action. Hydrolysis to free testosterone occurs in vivo. Each mL of sterile colorless-to-pale yellow solution provides 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol (chloral derivative) as preservative.
Adult Dose	50 mg IM q6wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe cardiac or renal disease; undiagnosed genital bleeding
Interactions	May increase effects of anticoagulants Anabolic effects may enhance hypoglycemia Elevated serum levels of oxyphenbutazone may result with coadministration May decrease levels of TBG, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4 (free thyroid hormone levels remain unchanged, however, and no clinical evidence of thyroid dysfunction) Caution when coadministering with ACTH or corticosteroids, especially in patients with hepatic or cardiac disease (enhances tendency toward edema)
Pregnancy	X - Contraindicated in pregnancy
Precautions	Observe women for signs of virilization (eg, deepening of the voice, hirsutism, acne, clitoromegaly, menstrual irregularities); discontinuation of therapy at time of evidence of mild virilism is necessary to prevent irreversible virilization (such virilization is usual following androgen use at high doses and is not prevented by concomitant use of estrogens) Because androgens may alter serum cholesterol concentration, caution should be used when administering these drugs to patients with a history of MI or coronary artery disease; serial determinations of serum cholesterol should be made and therapy adjusted accordingly

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• See Treatment.


• Patients with ovarian failure should be seen annually to monitor their HRT.


• Symptoms and signs of thyroid disease and adrenal insufficiency should be sought during the annual follow-up visits.


• TSH levels should be checked every 3-5 years (every year if antiperoxidase antibody test is positive).


• If a woman with POF/POI has positive adrenal antibodies on her initial evaluation, even if all adrenal function tests are normal, she is at high risk of developing adrenal insufficiency and should have an annual ACTH stimulation test. Whether women with initially negative adrenal antibody tests continue to carry higher than normal risk for adrenal insufficiency and whether any follow-up tests are justified is less clear. Until enough evidence is acquired, the authors suggest that an adrenal antibody test should be performed every 3-5 years.


• Patients with secondary ovarian failure should be monitored for manifestations of the underlying hypothalamic/pituitary pathology (progression of space-occupying lesions and development/progression of hypopituitarism).

Prognosis

• Women with spontaneous POF/POI have a low but real chance of spontaneous pregnancy. Approximately 5-10% become pregnant subsequent to the diagnosis of POF/POI. HRT does not prevent such pregnancies. Paradoxically, even oral contraceptives, which are designed for pregnancy protection of women without ovarian abnormalities, may not suppress the rare spontaneous ovulations of women with POF/POI. Therefore, patients with POF/POI should be well instructed about their reproductive situation so that they can make informed decisions regarding fertility.

• Ovum donation remains the best current option to resolve the infertility, but patients with POF/POI should not be encouraged hastily because spontaneous pregnancy is a real possibility and ovum donation is as successful in older women as it is in younger women.

Patient Education

• Women with POF/POI should be educated on the nature of their disease and the current research efforts. The mere understanding of the problem helps patients cope better.


• Support Web sites are available (International Premature Ovarian Failure Association).


• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education articles Amenorrhea and Menopause.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Women with POF/POI who desire fertility occasionally opt for unproven treatments. Of particular concern is the tendency to regard POF/POI as an autoimmune disease that can be treated successfully with corticosteroids. Currently, no scientific proof exists that this is true. The anecdotal reports of restored ovulation or fertility after treatment with prednisone could represent reporting bias or random phenomena.

• Corticosteroid treatment could lead to severe complications (the authors have observed 2 cases of osteonecrosis in women with presumed autoimmune POF/POI) and should be performed only as a part of review board–approved research protocols. Other unnecessary and expensive treatments or tests also should be discouraged.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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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].
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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,