Ovarian Failure
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).

Ovarian failure due to inappropriate regulatory signals (hypothalamic or pituitary pathology) is known as secondary ovarian failure. Ovarian failure due to a pathological process directly affecting the ovaries (eg, chemotherapy, irradiation, autoimmunity, chromosomal abnormalities) is known as primary ovarian failure (POF). A simple means of distinguishing between the 2 conditions is to measure serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels (elevated in POF and low or normal in secondary ovarian failure).

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, 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 is not equivalent to menopause. Most women with POF retain intermittent ovarian function for many years, and, unlike women who are menopausal, pregnancies may occur.

The focus of this article is premature ovarian failure, a term that will be used as an equivalent to ovarian failure.

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Pathophysiology: Premature ovarian failure can be subdivided into 2 major pathogenetic categories—induced (iatrogenic) POF and spontaneous POF.

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Induced (iatrogenic) ovarian failure

Women exposed to various forms of cancer therapy (high-dose chemotherapy and/or gonadal irradiation) have increased risk of developing ovarian failure. The risk is higher if the treatment occurs after the onset of puberty (relative risk [RR] 2.32), in survivors of Hodgkin lymphoma (RR 3.25), and in patients treated with combined chemotherapy and radiation therapy below the diaphragm (RR 8.56-9.6). After bone marrow transplant and therapy with busulfan, almost 100% of women develop ovarian failure.

The mechanism of iatrogenic ovarian failure includes damage to the proliferating ovarian granulosa cells and/or to the oocytes. Subsequently, follicular depletion and premature ovarian failure develop. It can be temporary in some cases, and ovarian function may return spontaneously. Some women continue to have regular menstrual cycles despite elevated serum FSH levels and reduced fertility (ovarian insufficiency).

Professional exposure to solvents (2-bromopropane) also can result in oocyte destruction, low follicular number, and premature ovarian failure.

Finally, bilateral oophorectomy can be regarded as a form of induced POF.

Spontaneous premature ovarian failure

The pathogenesis of spontaneous premature ovarian failure in most cases is unknown. Two mechanisms are presumed to play a role—follicle depletion and follicle dysfunction.

Pathogenetic classification of premature ovarian failure

Follicle depletion

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

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 FSH and 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 ultrasound.

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

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  • Low initial number

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    • 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.

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    • 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.

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    • 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.

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  • Accelerated follicle atresia: Accelerated follicle atresia or destruction can result from one of the following:

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    • X chromosome monosomy/aneuploidy or mosaicism (as observed in Turner syndrome or some cases with 47,XXX karyotype)

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    • 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)

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    • Galactosemia
    • Cytotoxic therapy
    • Irradiation
    • Inflammation
  • Genes and chromosome regions implicated in the development of POF

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    • 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.

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      • 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.

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        • 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.

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        • 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.

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      • 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.

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        • 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.

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        • 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).

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        • FMR1 gene (fragile mental retardation gene): It is located on Xq27.3. The product is a protein of unknown function. Mutations in that gene represent extreme expansions of CGG repeat in the first exon of the FMR1 gene and are associated with mental retardation. Women who carry a modest expansion of these repeats (60-200, designated as a premutation) demonstrate an increased incidence of POF and are not affected by mental retardation. Why women with the full mutation have no ovarian failure and only those with premutation do is unclear.

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    • Autosomal abnormalities

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      • 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.

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      • Balanced autosomal translocations have been found in otherwise healthy women with POF.

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      • 46,XX gonadal dysgenesis

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        • 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 could be due to a mutant somatic gene for XX gonadal dysgenesis.

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        • 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.

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      • Autosomal recessive disorders associated with POF 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 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.

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    • Specific gene defects

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      • 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 usually is inherited as autosomal dominant. In addition, POF develops. The ovaries initially contain many follicles that do not grow (resistant ovaries), and, later, ovarian depletion develops.

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      • FSH receptor gene abnormalities: Point mutations of this gene, located on chromosome arm 2p, have been described in Finnish women with POF.

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      • 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.

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    • Enzyme deficiencies: The following enzyme deficiencies have been associated with ovarian failure:

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      • 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.

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      • 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.

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      • 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.

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      • Aromatase enzyme deficiency: Several families with this defect have been described. The female siblings in these kindreds demonstrated lack of pubertal development, high serum gonadotropin levels, and multiple ovarian cysts. Molecular analysis of the aromatase gene reveals a point mutation.

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    • Signal defects

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      • This is related to FSH and LH receptor abnormalities as described above.

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      • Pseudohypoparathyroidism: Ovarian resistance has been demonstrated in patients with pseudohypoparathyroidism due to a defect in the Gsa subunit of the G protein, which prevents normal cyclic adenosine monophosphate (cAMP) generation.

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    • Autoimmunity: The immune system may play a role in some of the cases of premature ovarian failure. The real prevalence of autoimmune premature ovarian failure is unknown. According to one estimate, the rate is approximately 30%.

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      • POF associated with adrenal autoimmunity

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        • 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.

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        • 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).

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        • Such patients have high prevalence of Addison disease, which may be evident at the time of diagnosis of POF or may develop later.

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        • Whether an isolated form of autoimmune oophoritis (without adrenal involvement) exists is unclear. The authors have observed one woman with spontaneous POF, 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.

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        • Autoimmune oophoritis is a relatively rare condition, and it affects less than 5% of women who present with POF.

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        • Spontaneous POF has been described as part of polyglandular autoimmune syndromes type 1 and 2. In type 1 syndrome, POF is associated with mucocutaneous candidiasis, ectodermal dystrophy, hypoparathyroidism, celiac disease, chronic hepatitis, and Addison disease. This is a very 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.

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        • Spontaneous POF 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. Other associated diseases are type 1 diabetes, vitiligo, lupus, Sjögren syndrome, and rheumatoid arthritis. Whether POF in these cases is autoimmune in nature is unclear.

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        • The mere presence of other autoimmune disease should not lead by default to the conclusion that POF is of autoimmune origin. Ovarian biopsies of women with POF and other autoimmune diseases but without adrenal/steroid cell antibodies or Addison diseases repeatedly have failed to show any features of autoimmune inflammation.

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      • Autoimmune POF without adrenal autoimmunity

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        • Other forms of autoimmune POF that do not have the typical histologic picture of autoimmune oophoritis and markers of adrenal/steroid-producing cell autoimmunity are possible.

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        • 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. 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.

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        • Recently, an antibody targeting a protein that is expressed exclusively in the oocyte has been described in a mouse model of autoimmune ovarian failure. In some cases, human ovarian failure possibly is due to specific antibodies targeting a similar oocyte antigen.

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        • The presence of ovarian antibodies often is regarded as proof of the autoimmune nature of POF. 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 very 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.

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    • Infection

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      • In a retrospective study, Rebar and Connolly reported that 3.5% of patients with POF had a previous infection (eg, varicella, shigellosis, malaria).
      • Others have observed a 3-7% incidence of oophoritis in patients who contracted mumps during an epidemic.
      • Cytomegalovirus oophoritis has been described in various women who are immunocompromised.
      • Nevertheless, a true cause-and-effect relationship between POF and infection has not been established.

    Frequency:
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    • In the US: Premature ovarian failure occurs in approximately 1% of women. The estimated incidence in the United States is 10 cases per 100,000 person-years at ages 15-29 years and 76 cases per 100,000 person-years at ages 30-39 years. Approximately 10-28% of women with primary amenorrhea and 4-18% with secondary amenorrhea have premature ovarian failure.

    Mortality/Morbidity: Long-term follow-up studies to evaluate the impact of POF 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]). Several points concerning morbidity and mortality of patients with POF 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.

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    • Women with POF may be at higher risk for cardiovascular diseases, again due to low estrogen levels.

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    • Patients with POF 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 and presumed but unconfirmed ovarian autoimmunity.
    • POF can coexist with other endocrine and nonendocrine diseases (eg, hypothyroidism, Addison disease, type 1 diabetes, pernicious anemia, lupus).
    • The diagnosis of POF 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.

    Age: By definition, premature ovarian failure is a condition of women younger than 40 years.

    CLINICAL ¡@

    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 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.

    Physical: For more information, see Ovarian Insufficiency.

    Generally, women with spontaneous POF 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 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:

      • Pregnancy test
      • FSH, LH, estradiol
      • Standard blood chemistry - Fasting glucose, electrolytes, and creatinine
      • Karyotype
      • Test for fragile X chromosome
      • 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 premature ovarian failure. For more information, see Ovarian Insufficiency. The differential diagnosis of premature ovarian failure includes the following:

    WORKUP ¡@

    Lab Studies:
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    • 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, tests that help clarify the etiology, and screening tests for other diseases known to have higher prevalence among women with POF.
    • 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.

    Imaging Studies:
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    TREATMENT Section 6 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

    Medical Care: Medical treatment of patients with POF should address the following aspects: ovarian hormone replacement, restoration of fertility, and psychological well being of the patient. For women with secondary ovarian failure, the treatment required to restore ovarian function depends on the specific etiology.

    • Management of premature ovarian failure
      • Inform
        • Discuss the test results on a special visit (not by phone).
        • The diagnosis of POF 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. DEXA bone scan every 2 years may be needed.
        • POF is not menopause. Spontaneous ovarian activity and pregnancies are possible.
        • Allow the patient enough time to accept the diagnosis. Discuss fertility plans later, after the patient has come to terms with her condition.
        • No proven therapies exist to restore fertility, and an experimental treatment should be performed only under a review board–approved research protocol.
        • Currently available options to resolve infertility include change of plans, adoption, and ovum donation.
      • Replace deficient hormones
        • Cyclic/continuous oral/transdermal estrogen and cyclic oral progestin are needed.
        • Full replacement dose is needed to alleviate symptoms and maintain age-appropriate bone density.
      • Follow-up
        • Adequacy of hormone replacement therapy (HRT) should be followed yearly.
        • TSH and adrenal antibodies (expert opinion) should be followed yearly.
        • ACTH stimulation test should be performed yearly if the adrenal antibodies are positive.
        • DEXA bone density scan should be performed as needed.
    • Hormone replacement therapy: All women with premature ovarian failure should receive HRT with estrogens and progestins to relieve the symptoms of estrogen deficiency, to maintain bone density, and to reduce the risk of cardiovascular diseases. Some 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 (conjugated equine estrogens [CEE] 1.25 mg instead of 0.65 mg daily, oral estradiol 2-4 mg instead of 1 mg daily, and transdermal estradiol 100-150 mcg instead of 50 mcg daily). Such doses usually achieve adequate estrogenization of the vaginal epithelium in young women with POF and probably help to 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, and they should be informed that they must obtain a prompt pregnancy test if menstrual bleeding fails to appear when expected.
        • Estrogen also can be provided in the form of combination contraceptive formulations, including oral contraceptives and combination injectable methods (eg, Lunelle). Even though such estrogen doses may be more than is needed for symptom abatement and maintenance of appropriate secondary sexual development, the use of such methods may provide considerable psychological benefits to those reproductive-aged women who may feel stigmatized by taking menopausal hormonal preparations.
      • Progestins
        • Progestins should be administered cyclically, 10-14 days each month, to prevent endometrial hyperplasia that unopposed estrogen may cause. Young women with POF 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.
        • The use of combination contraceptives provides appropriate doses of progestins.
      • Androgens
        • Women with ovarian failure have lower levels of free testosterone compared to normally ovulating age-matched controls, but only a small percentage have levels below the lower limit of normal.
        • Clinical trials are underway to determine whether testosterone replacement should be a part of the standard therapy for young women with ovarian failure. Additional information can be obtained by calling the Section on Women's Health Research at the US National Institute of Child Health and Human Development, Bethesda, Maryland at (877) 206-0911.
        • Until results from these trials are available, androgen replacement could be 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. A testosterone transdermal patch, designed to deliver 150 mcg per day, currently is undergoing a clinical trial.
    • Restoration of fertility: No intervention has been proven to increase the ovulation rate or restore fertility in patients with POF.
      • 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 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 adoption or change of life plans.
      • For women with secondary ovarian failure, the treatment required to restore fertility depends on the specific etiology.

    Surgical Care: Ovarian biopsy is not clinically indicated in women with ovarian failure, but surgical procedures should be performed in women with secondary ovarian failure as indicated when hypothalamic or pituitary lesions are identified.

    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 usually have a grief response after hearing the diagnosis. They benefit from a baseline psychological evaluation and appropriate counseling.
    • Genetic counseling may be needed in some cases.

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

    MEDICATION ¡@

    Drug Category: Estrogens -- Used to achieve adequate estrogenization of vaginal epithelium in young women and to maintain bone density.

    Drug Name
    ¡@    		 Estradiol transdermal system (Alora) -- Increases synthesis of DNA, RNA, and many proteins in target tissues.
    Adult Dose Apply 0.05, 0.075, or 0.1 mg/d TD patch twice weekly
    Pediatric Dose Not established
    Contraindications Documented hypersensitivity; thrombophlebitis; undiagnosed vaginal bleeding; pregnancy; breast cancer; estrogen-dependent neoplasia; chronic liver disease; neurophthalmologic vascular disease
    Interactions May decrease effect of tricyclic antidepressants and cause worsening of previously well-controlled depression, which seems to be dose-dependent and is reversible with decrease or discontinuation of therapy
    Effects may decrease during concomitant therapy with carbamazepine and/or phenytoin, and dose increase may be necessary; estrogens may increase seizures in patients with previously well-controlled epilepsy
    Thyroid replacement or suppressive therapy (eg, levothyroxine, triiodothyronine) may need adjustment while taking estrogens because the latter increases SHBG, especially when administered orally, thus leaving less free T4
    Tobacco smoking can have antiestrogenic effect by increasing C-2 hydroxylation of estradiol molecule
    Estrogens may reduce hypoprothrombinemic effects of anticoagulants
    Estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethynylestradiol
    Pregnancy X - Contraindicated in pregnancy
    Precautions Reported endometrial cancer risk among users of unopposed estrogen is approximately 2- to 12-fold greater than in nonusers and appears dependent on duration of treatment and dose; greatest risk appears to be associated with prolonged use (increased risks of 15- to 24-fold for 5-10 y or longer); concurrent progestin therapy may offset risk, but overall health impact in women who are premenopausal is not known
    Some studies suggest possible increased incidence of breast cancer with higher doses or use for prolonged periods; studies focused on women who are postmenopausal, and conclusions may not be applicable to young women with ovarian failure; good counseling should help young women deficient in estrogen feel comfortable taking estrogens
    Therapy during pregnancy is associated with increased risk of fetal congenital reproductive tract disorders and, possibly, other birth defects
    Two studies report 2- to 4-fold increase in risk of gallbladder disease requiring surgery in women receiving oral estrogen replacement therapy, similar to 2-fold increase previously noted in users of oral contraceptives; risk from TD estrogens not established
    Occasional BP increases attributed to idiosyncratic reactions; other studies show slightly lower BP among estrogen users compared to nonusers; postmenopausal estrogen use does not increase risk of stroke, but BP should be monitored regularly; recent studies indicate that medroxyprogesterone acetate may cause adverse changes in lipoprotein metabolism compared to natural progesteronal
    Ongoing debate over long-term cardioprotective effect of estrogens, especially in presence of established cardiovascular disease; complete medical and family histories should be taken before initiating therapy; should be prescribed for no longer than 1 y without physical examination
    Studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity; effect appears dose-dependent and duration-dependent and is less pronounced than with oral contraceptive use; information on hypercoagulability in women who have had previous thromboembolic disease is insufficient
    Estrogen use may be associated with massive elevations of plasma triglycerides, leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism
    May cause fluid retention, careful observation is required when conditions that might be influenced by this factor are present (eg, asthma, epilepsy, migraine, cardiac, renal dysfunction)
    Certain patients may develop the following undesirable manifestations of estrogenic stimulation: abnormal uterine bleeding, mastodynia, and mood changes
    Drug/lab test interactions include accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity; increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay; free T4 and free T3 concentrations are unaltered; other binding proteins may be elevated in serum (ie, corticosteroid-binding globulin [CBG], sex hormone-binding globulin [SHBG]) leading to increased circulating corticosteroids and sex steroids, respectively; free or biologically active
    hormone concentrations are unchanged
    Other plasma proteins may be increased (eg, angiotensinogen/renin substrate, alpha1-antitrypsin, ceruloplasmin)
    Drug Name
    ¡@    		 Conjugated equine estrogens (Premarin) -- 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
    ¡@    		 Medroxyprogesterone (Provera) -- Derivative of progesterone. Androgenic and anabolic effects have been noted, but apparently is devoid of significant estrogenic activity. Parenterally administered dosage form inhibits gonadotropin production, which, in turn, prevents follicular maturation and ovulation. Available data indicate that this does not occur when the usually recommended PO dose is administered qd.
    Adult Dose 10 mg PO qd for 10-12 d monthly
    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 May decrease effects of aminoglutethimide
    May cause increased sulfobromophthalein retention and other hepatic function tests
    May cause increase in PT factors VII, VIII, IX, and X
    Coadministration with food results in approximate doubling of medroxyprogesterone maximum concentration and increases area under the concentration-time curve (AUC) by 20-30% (clinical significance unknown)
    May interfere with pregnanediol determination
    Pregnancy X - Contraindicated in pregnancy
    Precautions Caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, and asthma
    In case of breakthrough bleeding; as in all cases of irregular vaginal bleeding, nonfunctional causes (eg, malignancy) should be borne in mind and adequate diagnostic measures are indicated
    Patients who have a history of psychic depression should be carefully observed and drug discontinued if depression recurs to serious degree
    Patients with diabetes should be observed carefully
    Because of occurrence of thrombotic disorders (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations and because the mechanism is obscure, physician should be alert to earliest manifestations of these disorders; discontinue medication pending examination if sudden partial or complete loss of vision occurs or if sudden onset of proptosis, diplopia, or migraine occurs; if examination reveals papilledema or retinal vascular lesions, withdraw medication
    Drug Name
    ¡@    		 Progesterone (Prometrium) -- 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
    ¡@    		 Methyltestosterone (Android) -- Synthetic testosterone derivative with significant androgen activity. Tablets are available in 5-mg, 10-mg, and 25-mg strengths.
    Adult Dose 1.2-5 mg PO qd
    Pediatric Dose Not established
    Contraindications Documented hypersensitivity; severe cardiac or renal disease; benign prostatic hypertrophy with obstruction in men; undiagnosed genital bleeding
    Interactions May increase effects of anticoagulants
    Concurrent administration of oxyphenbutazone may result in elevated serum levels of oxyphenbutazone
    In patients with diabetes, metabolic effects of androgens may decrease blood glucose and insulin requirements
    Pregnancy X - Contraindicated in pregnancy
    Precautions When administered to pregnant woman, may cause virilization of external genitalia of female fetus (virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotallike structure); degree of masculinization related to amount of drug administered and age of fetus (most likely to occur when drugs are administered in first trimester); if patient becomes pregnant, she should be apprised of potential hazard to the fetus
    Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities), discontinuation at time of evidence of mild virilism is necessary to prevent irreversible virilization (such virilization is usual following androgen use at high doses); instruct patients to report any adverse effects (eg, hoarseness, acne, changes in menstrual periods, more hair on the face, nausea, vomiting, changes in skin color, ankle swelling)
    Because of hepatotoxicity associated with use of 17-alpha-alkylated androgens, LFTs should be obtained periodically; has been associated with development of peliosis hepatis and hepatic neoplasms, including hepatocellular carcinoma (peliosis hepatis can be life-threatening or fatal); cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose (if cholestatic hepatitis with jaundice appears or if LFTs become abnormal, discontinue therapy and determine etiology); drug-induced jaundice is reversible when medication is discontinued
    Drug Name
    ¡@    		 Testosterone enanthate (Andro LA 200, Delatestryl, Durathate-200) -- Derivative of the primary endogenous androgen testosterone. For IM administration. In active form, androgens have a 17-beta-hydroxy group. Esterification of 17-beta-hyroxy 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 ¡@

    Further Outpatient Care:
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    Prognosis:
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    Patient Education:
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    MISCELLANEOUS ¡@

    Special Concerns:
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    • Women with POF who desire fertility occasionally opt for unproven treatments. Of particular concern is the tendency to regard POF 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) 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.
    BIBLIOGRAPHY ¡@

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