Ovarian Insufficiency

Updated: Nov 17, 2016
  • Author: Vincent A Pellegrini, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Overview

Background

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

Predictable menstrual cyclicity is a 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 may result in anovulation and ovarian steroid hormone deficiency.

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.

Ovarian insufficiency is a failure of the ovary to function adequately in a woman younger than 40 years, in its role either as an endocrine organ or as a reproductive organ. In women aged 40 years or older, the expected physiologic decline of ovarian function that takes place with aging is termed perimenopause or the menopausal transition. [1]

See Menopause: Changes and Challenges, a Critical Images slideshow, to help identify comorbidities and diseases in the postmenopausal population.

As defined by the World Health Organization, ovarian insufficiency can be caused by a primary disorder in the ovary or it can occur as a result of secondary causes. Ovarian insufficiency is considered primary if the ovary fails to function normally in response to appropriate gonadotropin stimulation provided by the hypothalamus and pituitary. Ovarian insufficiency is considered secondary if the hypothalamus and pituitary fail to provide appropriate gonadotropin stimulation.

Primary ovarian insufficiency (POI) (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, POI and menopause are not equivalent. Most women with POI retain intermittent ovarian function for many years, and, unlike women who are menopausal, pregnancies may occur.

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Pathophysiology

POI is, in reality, a continuum of disorders. Dividing the continuum of ovarian insufficiency into 4 clinical states is the authors' preferred method to facilitate explanation. These states are not permanent. Patients may move from one state to another in an unpredictable manner. In some cases, normal ovarian function may even return for a period of time.

  • Occult primary ovarian insufficiency presents as unexplained infertility in a patient with a normal basal serum follicle-stimulating hormone (FSH) level. These patients have an inexplicable failure to respond adequately to FSH therapy during attempts at superovulation.
  • Next on the continuum, biochemical primary ovarian insufficiency presents as unexplained infertility in patients with an elevated basal serum FSH level. In this clinical situation, patients also fail to respond adequately to FSH therapy during attempts at superovulation.
  • Overt primary ovarian insufficiency is the clinical condition that has previously been referred to as premature ovarian failure or premature menopause. This clinical state is characterized by elevated basal serum FSH levels in association with disordered menstrual cycles as demonstrated by oligomenorrhea, polymenorrhea, or metrorrhagia.
  • Premature ovarian failure is the extreme state of complete primordial follicle depletion. This is an irreversible state characterized by the presence of amenorrhea, permanent infertility, and elevated menopausal gonadotropin levels. At present no proven method can determine that a woman has no primordial follicles remaining in the ovary, so, in effect, this term is merely a construct (ie, a concept that cannot be proven). For this reason, the authors prefer not to use the term premature ovarian failure (POF).

Table. Clinical Situations of Primary Ovarian Insufficiency and Premature Ovarian Failure (Open Table in a new window)

Ovarian Clinical Situation Menses Gonadotropins Fertility
Occult insufficiency Normal Normal Reduced
Biochemical insufficiency Abnormal Elevated Reduced
Overt insufficiency Abnormal Elevated Reduced
Premature ovarian failure Absent Elevated Zero

Secondary ovarian insufficiency, a result of inadequate or inappropriate gonadotropin stimulation of the ovary, can be caused by a variety of disorders that are covered in other articles. Pituitary tumors, such as prolactinomas, are associated with hyperprolactinemia, and this can be a cause of secondary ovarian insufficiency. A pituitary adenoma secreting ACTH and causing Cushing syndrome is an important, but much less common, cause of secondary ovarian insufficiency. Cushing syndrome may present with signs of androgen excess, and the disorder might be confused with polycystic ovary syndrome, late-onset congenital adrenal hyperplasia, or an androgen-producing tumor of the adrenals or ovary.

The physiologic origin of the stimulus from the CNS to release gonadotropins to provide ovarian stimulation comes from the gonadotropin-releasing hormone (GnRH) pulse generator. This structure is located in the arcuate nucleus of the hypothalamus. This pulse generator requires appropriate positive regulatory signals from the CNS to function properly. Inappropriate regulatory signals from the CNS can lead to failure of the GnRH pulse generator to function properly. Failure of the GnRH pulse generator results in inadequate synthesis, storage, and secretion of pituitary gonadotropins.

Secondary ovarian insufficiency can result from abnormal function of the GnRH pulse generator, even in the absence of any structural CNS abnormality, such as a tumor. Secondary ovarian insufficiency also can be a result of excessive exercise or eating disorders such as anorexia nervosa or bulimia. Stress, anxiety, and depression, as well as numerous centrally acting drugs, can disrupt normal GnRH pulse-generator function and, thus, also can be causes of secondary ovarian insufficiency.

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

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Spontaneous Primary Ovarian Insufficiency

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

Follicle depletion

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

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

  • X chromosome monosomy/aneuploidy or mosaicism (as observed in Turner syndrome or some cases with 47,XXX karyotype)
  • X chromosome abnormalities (X chromosome rearrangement, X isochromosome and ring chromosome, translocations of X chromosome material to an autosome [t(X;A)], fragile X premutation)
  • Galactosemia
  • Cytotoxic therapy
  • Irradiation
  • Inflammation

The genes and chromosome regions implicated in the development of POI/POF are as follows:

  • 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. [2]
    • 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 POI/POF 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. [3, 4]
      • 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 POI/POF.
    • 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 POI/POF 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 POI/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 POI/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.

  • 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 POI/POF.
    • 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 cases of POI/POF. The real prevalence of autoimmune POI/POF is unknown. According to one estimate, the rate is approximately 30-40%. [5] The presence of other autoimmune disease in a patient with POI/POF should not by default lead to the conclusion that POI/POF is of autoimmune origin. Ovarian biopsies of women with POI/POF and other autoimmune diseases, but without adrenal/steroid cell antibodies or Addison disease, have repeatedly failed to show any features of autoimmune inflammation.
    • POI/POF 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 POI/POF 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 POI/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.
      • Autoimmune oophoritis is a relatively rare condition, and it affects less than 5% of women who present with spontaneous POI/POF.
      • Spontaneous POI/POF has been described as part of polyglandular autoimmune syndromes type 1 and 2. In type 1 syndrome, POI/POF 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 POI/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 POI/POF. Other associated diseases are type 1 diabetes, vitiligo, lupus, Sjögren syndrome, and rheumatoid arthritis. Whether POI/POF in these cases is autoimmune in nature is unclear.
    • Autoimmune POI/POF without adrenal autoimmunity
      • Other forms of autoimmune POI/POF 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 POI/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.
      • The presence of ovarian antibodies is often regarded as proof of the autoimmune nature of POI/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 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 POI/POF.
  • Infection: A true cause and effect relationship between POI/POF and infection has not been established. In a retrospective study, Rebar and Connolly reported that 3.5% of patients with POI/POF had a previous infection (eg, varicella, shigellosis, malaria). [6] 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.
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Epidemiology

Frequency

United States

POI/POF occurs in approximately 1% of women. [7] 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 POI/POF.

Mortality/Morbidity

Long-term follow-up studies to evaluate the impact of POI/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% CI, 1.15-3.99]) and stroke mortality (odds ratio 3.07 [95% CI, 1.34-7.03]). [8] Several points concerning morbidity and mortality of patients with POI/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.
  • Women with POI/POF may be at higher risk for cardiovascular diseases, again due to low estrogen levels.
  • Patients with POI/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 POI/POF and presumed but unconfirmed ovarian autoimmunity.
  • POI/POF can coexist with other endocrine and nonendocrine diseases (eg, hypothyroidism, Addison disease, type 1 diabetes, pernicious anemia, lupus).
  • The diagnosis of POI/POF may have a deleterious psychological impact and may lead to depression in a young, otherwise healthy woman.

Race

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

A difference between races was observed in bone density (one of the complications of estrogen deficiency) of women with POI. In a study of 442 women with POI, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have BMD Z-scores below 2 (P < 0.0001 for both) as compared with Caucasian women. This association of race with low Z-scores was considered to be a consequence of the lower vitamin D levels, low calcium intake, and lower compliance with hormone therapy in women of minority races. Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. Therefore, minority women with POI should pay extra attention to correcting vitamin D deficiency, calcium intake, and hormone replacement. [9]

Sex

Ovarian insufficiency occurs only in women.

Age

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

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