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]
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.
Signs and symptoms
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.
See Presentation for more detail.
Diagnosis
Laboratory studies
The following tests should be performed when ovarian failure is suspected or has been diagnosed:
A pregnancy test (urine or beta human chorionic gonadotropin [bhCG] in the blood)
Measurement of serum follicle-stimulating hormone (FSH) level
Measurement of serum luteinizing hormone (LH) level
Measurement of serum estradiol level
A karyotype should be performed as a part of the routine evaluation after the diagnosis of primary ovarian insufficiency is established.
Imaging studies
Ovarian ultrasonography can be useful in the workup of patients with primary ovarian insufficiency, as it will identify those women with multifollicular ovaries and suggest the diagnosis of either autoimmune oophoritis or 17-20 desmolase deficiency.
A magnetic resonance imaging (MRI) scan of the pituitary and hypothalamus is indicated in the evaluation of secondary ovarian insufficiency in the following circumstances:
Hyperprolactinemia
Associated headache or visual-field cuts
Profound estrogen deficiency with otherwise unexplained amenorrhea
See Workup for more detail.
Management
Medical treatment of patients with primary ovarian insufficiency should address the following aspects:
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.
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
View Table
See Table
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.
Ovarian insufficiency can develop as a result of an ovarian disorder. In this case, the clinical situation is termed primary ovarian insufficiency. Ovarian insufficiency also can develop due to inadequate ovarian stimulation coming from the hypothalamus and pituitary. In this case, the clinical situation is termed secondary ovarian insufficiency. Central ovarian insufficiency is a synonym for this condition (referring to the CNS origin of the disorder).
Causes of primary ovarian insufficiency include the following:
Iatrogenic
Abnormal karyotype
Isolated autoimmune ovarian failure
Premutation in the FMR1 gene
Autoimmune ovarian failure in association with other syndromes, such as autoimmune polyglandular failure, organ-specific autoimmunity, or immunoglobulin A deficiency
Rare genetic causes, such as enzyme deficiencies (galactosemia, 17-alpha hydroxylase, 17-20 desmolase, cholesterol desmolase), Perrault syndrome, and FSH receptor defect
Rare thymic disorders, such as DiGeorge syndrome, ataxia telangiectasia, or tumor
Pure gonadal dysgenesis
Idiopathic (39-67% of patients with POI)[2]
Pseudo POI may be observed in patients with hypothyroidism, antibodies to gonadotropins, isolated gonadotropin deficiency, and gonadotropin-producing pituitary adenoma
Causes of secondary ovarian insufficiency include the following:
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.[3]
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 intellectual disability, while women with premutation demonstrate a 20-30 times increased incidence of POI/POF and are not affected by intellectual disability. 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.[4, 5]
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:
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%.[6] 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.
A Finnish study showed that women with POI have a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis compared with healthy controls. The prevalence of specific autoimmune diseases such as polyglandular autoimmune diseases and Addison disease was significantly higher in women with POI; however, no significant difference was found in the prevalence of type 1 diabetes mellitus or ankylosing spondylitis.[7]
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).[8] 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.
POI/POF occurs in approximately 1% of women.[9] 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.
Race-, sex-, and age-related demographics
The incidence of spontaneous POF/POI appears to be similar among ethnic groups; however, one study showed that it may be more common in Hispanic and African American women and less common in Chinese and Japanese women compared with White women.[10]
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.[11]
Ovarian insufficiency occurs only in women. By definition, POI/POF is a condition of women younger than 40 years.
Women with spontaneous POI/POF have a low but real chance of spontaneous pregnancy. Approximately 5-10% become pregnant subsequent to the diagnosis of POI/POF. HT 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 POI/POF. Therefore, patients with POI/POF 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 POI/POF 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.
The prognosis for women with secondary ovarian insufficiency depends on the etiology of the disorder (see Amenorrhea).
Morbidity/mortality
Long-term follow-up studies to evaluate the impact of POI/POF on the mortality rate at an older age have 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]).[12]
In a 30-year follow-up study conducted in Chile, women with POI had a significantly higher overall mortality rate (34.7% vs 19.3%) and increased cardiovascular mortality (12.0% vs 5.1%) compared with women without POI. After adjusting for other factors, POI remained a significant predictor of mortality (hazard ratio, 1.60; 95% CI, 1.03-2.47), ranking third after diabetes and hypertension.[13]
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.
A systematic review, which included 10 studies, showed that women with POI have reduced sexual function.[14]
Complications
Loss of menstrual regularity, even without the development of amenorrhea, has been associated with an increased risk of wrist and hip fractures related to reduced bone density. A later menarche and menstrual-cycle intervals greater than 32 days both have been associated with increased fracture rates in later years. Young women with ovarian insufficiency that is unresponsive to therapy require HT to maintain bone density.
Generally, women with spontaneous POI/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, POI/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:
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 POI/POF, male intellectual disability (suggest Fragile X syndrome), 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
Patients with early-stage ovarian insufficiency alone have no physical findings. In overt POI and profound secondary ovarian insufficiency, physical examination may demonstrate atrophic vaginitis resulting from an estrogen deficiency. Ovarian insufficiency comprises a continuum along a decline in ovarian function. Patients with ovarian insufficiency frequently produce estrogen intermittently and may not demonstrate physical findings of estrogen deficiency. Thus, the finding of cervical mucus upon pelvic examination does not rule out a diagnosis of ovarian insufficiency.
Bimanual examination may reveal ovarian enlargement in patients who have lymphocytic oophoritis or steroidogenic enzyme defects.
Patients with Turner syndrome have characteristic physical stigmata, and a careful search for these should be conducted. However, patients with small interstitial deletions involving the X chromosome as a cause of ovarian insufficiency may not demonstrate these findings.
Autoimmune disorders known to be associated with POI have the following characteristic physical findings that should be elicited:
Changes in pigmentation, such as premature gray hair, may be associated with autoimmune hypothyroidism.
Vitiligo or increased pigmentation of the gums or the skin folds may herald Addison disease. Patients with Addison disease also may experience a loss of axillary and pubic hair because of reduced ovarian and adrenal androgen production.
Thyroid enlargement resulting from concomitant Hashimoto thyroiditis or Graves disease may be present.
Three groups of tests should be performed when ovarian failure is suspected or has been diagnosed. They include tests that establish the diagnosis of POI/POF, tests that help clarify the etiology, and screening tests for other diseases known to have higher prevalence among women with POI/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.
Studies to establish the diagnosis of POI/POF are as follows:
Measuring serum FSH level is the core study to establish the diagnosis of POI/POF 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 POI/POF.
Measurement of serum LH is also important. In most cases of spontaneous POI/POF, 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 POI/POF 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 POI/POF.
Occasionally, women with POI/POF 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 POI/POF. 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 POI/POF 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 POI/POF. 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 POI, intellectual disability, 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 is traditionally 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 POI/POF.
Ovarian ultrasonography can be useful in the workup of patients with POI/POF as it will identify those women with multifollicular ovaries and suggest the diagnosis of either autoimmune oophoritis or 17-20 desmolase deficiency.
Secondary ovarian insufficiency
An MRI scan of the pituitary and hypothalamus is indicated in the evaluation of secondary ovarian insufficiency in the following circumstances:
Hyperprolactinemia
Associated headache or visual-field cuts
Profound estrogen deficiency with otherwise unexplained amenorrhea
Clinically, ovarian biopsy is not indicated. The procedure should be performed only as part of an investigation that is approved by an institutional review board.
Secondary ovarian insufficiency
Surgical procedures should be performed as indicated when hypothalamic or pituitary lesions are identified.
Medical treatment of patients with POI/POF should address the following aspects: ovarian hormone replacement, restoration of fertility, and psychological well-being of the patient. (For management of secondary ovarian insufficiency, refer to articles discussing the specific causes of it, such as anorexia nervosa, hypothalamic amenorrhea, prolactinoma.)
Management of primary ovarian insufficiency
Inform
Discuss the test results on a special visit (not by phone).
The diagnosis of POI/POF can be particularly traumatic for young women.
Use of appropriate terminology is important (use of POI 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 is also 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.
POI/POF 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 therapy (HT)
All women with POI/POF should receive cyclical HT with estrogens and progestins to relieve the symptoms of estrogen deficiency and to maintain bone density.
A few women may need HT 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 HT 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 POI/POF 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 therapy (ET) 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.[15] 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 POI.
Progestins
Progestins should be administered cyclically, 10-14 days each month, to prevent endometrial hyperplasia that unopposed estrogen may cause. Young women with POI/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.
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.[16]
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 methyltestosterone 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 POI/POF.
Gonadotropin therapy carries a theoretical risk of exacerbating autoimmune POI.
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 POI 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.
Autologous intraovarian platelet-rich plasma therapy has shown promise in increasing anti-Mullerian hormone levels and reducing follicle-stimulating hormone levels in women with ovarian insufficiency. However, this therapy remains experimental.[17, 18]
Patients with POI/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 embryo adoption, adoption, or change of life plans.
Surgical care
Ovarian biopsy is not clinically indicated in women with ovarian failure.
Patients with ovarian failure should be seen annually to monitor their HT.
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 POI/POF 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).
Consultation with an endocrinologist may be indicated in some cases because of concerns of hypothyroidism or adrenal insufficiency.
Patients with infertility due to POI/POF 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.
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 is also important.
Activity
Women with POI/POF 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.
Clinical Context:
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.
Clinical Context:
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.
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.
Clinical Context:
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.
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.
Vincent A Pellegrini, MD, Obstetrician/Gynecologist, Reading Hospital and Medical Center; Clinical Director, IVF Program, RHPN Women’s Clinic and IVF-Fertility, Reading Health System; Medical Director, ConoverSystems.org
Disclosure: Nothing to disclose.
Coauthor(s)
Karim Anton Calis, PharmD, MPH, FASHP, FCCP, Clinical Professor, Medical College of Virginia, Virginia Commonwealth University School of Pharmacy; Clinical Professor, University of Maryland School of Pharmacy; Director of Clinical Research and Compliance, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
A David Barnes, MD, MPH, PhD, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, CA), Pioneer Valley Hospital (Salt Lake City, UT), Warren General Hospital (Warren, PA), and Mountain West Hospital (Tooele, UT)
Disclosure: Nothing to disclose.
Chief Editor
Richard Scott Lucidi, MD, FACOG, Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Group, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Disclosure: Nothing to disclose.
Robert K Zurawin, MD, Associate Professor, Chief, Section of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine
Disclosure: Received consulting fee from Ethicon for consulting; Received consulting fee from Bayer for consulting; Received consulting fee from Hologic for consulting.
Vaishali Popat, MD, MPH, Clinical Investigator, Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
