eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Ovarian Insufficiency

Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Reproductive Biology and Medicine Branch, National Institutes of Health
Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health

Updated: Jan 15, 2008

Introduction

Background

The ovary functions as an endocrine organ and as a reproductive organ.

As an endocrine organ, the ovary maintains health in young women by secreting steroid hormones such as estrogens, androgens, and progesterone. The ovary also secretes glycoprotein hormones such as inhibin, activin, and follistatin. Regular and predictable menstrual cycles occur if these hormones are secreted in an orderly fashion in response to stimulation provided by the hypothalamus and pituitary.

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.

As a reproductive organ, the ovary maintains a store of oocytes. Ovulation, the release of a mature oocyte from the ovary, is dependent on the growth of ovarian follicles in response to stimulation provided by the hypothalamus and pituitary.

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

Pathophysiology

A graafian follicle is a fluid-filled cystic structure in the ovary that contains an oocyte and granulosa cells. Normal ovarian function in young women is dependent on the growth and development of graafian follicles. Graafian follicles arise and grow from a pool of microscopic structures known as primordial follicles. A store of primordial follicles is required to support normal endocrine and reproductive function of the ovary. The growing graafian follicle is the major source of estradiol production, and a mature graafian follicle must develop to permit normal ovulation. In a sense, primordial follicles can be viewed as inactive endocrine and reproductive units that are stored in the ovary for future use.

Primordial follicles are composed of an oocyte surrounded by a single layer of granulosa cells. The number of primordial follicles in the human ovary peaks at approximately 7 million during the fifth gestational month. After this initial finite pool is in place, no additional primordial follicles are formed. If the expenditure of these primordial follicles is regulated properly, this initial endowment functions throughout a woman's normal reproductive life span. Menopause is defined as the permanent cessation of menses. Normal menopause takes place when the supply of functional primordial follicles is exhausted. On average, natural menopause occurs at age 50 years.

Importantly, normal cyclic sex steroid production in women is linked to gamete production. When primordial follicles are depleted or fail to function, normal cyclic production of estrogen and progesterone ceases and menstruation stops. In most cases, the mechanism leading to primary ovarian insufficiency remains a mystery, even after a thorough evaluation in a clinical research setting.

Primary ovarian insufficiency occurs in some patients because of ovarian follicle depletion. Premature ovarian follicle depletion can occur by 2 mechanisms, (1) due to deficiency in the number of primordial follicles present in the initial in utero endowment or (2) due to an accelerated rate of follicle atresia. For example, fetuses with a single X chromosome, as in those with Turner syndrome, develop normal ovaries with a normal complement of primordial follicles, but accelerated follicle atresia leads to ovarian insufficiency at an early age. Once the responsible genes are identified, the mechanisms of follicle depletion that lead to ovarian insufficiency will be clearer.

Primary ovarian insufficiency also can occur because of follicle dysfunction. Follicle dysfunction means that primordial follicles remain in the ovary, but for some reason, they fail to function normally. Some patients with primary ovarian insufficiency have follicles remaining in the ovary that appear healthy but fail to function despite high gonadotropin levels. Ovarian autoimmunity is a well-established cause of ovarian follicle dysfunction and ovarian insufficiency.

Autoimmune lymphocytic oophoritis, initially described in association with Addison disease, is characterized by intense lymphocytic infiltration found primarily in the theca interna of developing graafian follicles. In patients with this condition, primordial follicles are spared the lymphocytic attack.

In rare cases, enzyme deficiencies, such as 17-20 desmolase deficiency, also can be a cause of follicle dysfunction and ovarian insufficiency. Once the genes involved in primordial follicle activation and function are identified, the mechanisms of follicle dysfunction that lead to ovarian insufficiency will be clearer.

Primary ovarian insufficiency, in its fully developed form, is also known as premature ovarian failure. The term failure is problematic because some patients with this condition get pregnant subsequent to the diagnosis. Thus, the ovary has not truly failed but is more likely functioning in an intermittent and unpredictable manner. Primary ovarian insufficiency is a more accurate term. 

Primary ovarian insufficiency (also known as premature menopause and premature ovarian failure) is associated with amenorrhea and markedly elevated serum gonadotropin levels. However, primary ovarian insufficiency 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.

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 thus, 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.

Congenital reproductive tract anomalies or Asherman syndrome can cause amenorrhea on a structural basis, but these disorders can be readily distinguished from ovarian insufficiency.

Clinical Situations of Primary Ovarian Insufficiency and Premature Ovarian Failure

Frequency

United States

Overt primary ovarian insufficiency affects 1 in 100 women by age 40 years. It affects 1 in 1000 women by age 30 years and 1 in 10,000 women by age 20 years. The incidence of lesser-stage primary ovarian insufficiency is not available.

International

No clear relationship between incidence and national origin has been demonstrated.

Mortality/Morbidity

Delay in diagnosis of ovarian insufficiency may have potentially serious adverse health effects, such as the development of osteopenia or osteoporosis. In addition, 2 studies have demonstrated that women who develop primary ovarian insufficiency before age 40 years have a higher risk of all-cause mortality compared to women who undergo natural menopause. One study showed a relative risk of 1.56, with a 95% confidence interval (1.07-2.27). The other study showed a relative risk of 1.95, with a 95% confidence interval (1.24-3.07).

Race

No clear relationship has been demonstrated between incidence and race.

Sex

Ovarian insufficiency obviously occurs only in women.

Age

Primary ovarian insufficiency, by definition, occurs before age 40 years.

Clinical

History

Primary ovarian insufficiency may develop insidiously. In a few cases, the earliest sign of primary ovarian insufficiency may be the development of vasomotor symptoms, or hot flashes, even while patients still are menstruating regularly. Usually, the earliest sign of overt endocrine insufficiency of the ovary is the development of shortened or irregular cycles. Occult and biochemical primary ovarian insufficiency generally present as unexplained infertility in a woman with regular menses.

Secondary ovarian insufficiency may be caused by a variety of diverse disorders that have abnormal function of the GnRH pulse generator as a final common pathway. Chronic systemic disease, drug therapy, an eating disorder, excessive exercise, depression, or an anxiety disorder all should be considered as factors in the loss of menstrual regularity. Headache and loss of peripheral vision could be symptoms of a pituitary tumor. Galactorrhea might herald a pituitary prolactinoma.

Symptoms of androgen excess, such as acne, hirsutism, or male-pattern balding, could herald polycystic ovary syndrome or stromal hyperthecosis, late-onset congenital adrenal hyperplasia, Cushing syndrome, or an androgen-secreting tumor.

• Often, the development of menstrual irregularity is not taken seriously, either by the patient or by her health care provider.
  • Approximately 5% of young women experience 3 months without a menses each year, and only 40% of these women seek medical evaluation.
  • Even when women with menstrual-cycle irregularity do seek medical evaluation, they are often prescribed an oral contraceptive to regulate the cycle, with minimal attempts to determine the etiology of the disordered cycles. Sometimes, this leads to the unfortunate circumstance of a young woman, who presents with early-stage primary ovarian insufficiency, taking the oral contraceptive for years, only to find that she has overt primary ovarian insufficiency upon stopping oral contraceptive many years later when she desires pregnancy.
• No characteristic menstrual history precedes the development of overt primary ovarian insufficiency.
  • Patients may experience a prodrome of polymenorrhea, dysfunctional uterine bleeding, or oligomenorrhea.
  • In some cases, amenorrhea develops acutely, with no warning.
  • Sometimes the disorder becomes acutely apparent when menstruation fails to return after a pregnancy or after discontinuing oral contraceptives.
  • Once patients develop amenorrhea and profound estrogen deficiency, symptoms of vaginal dryness and dyspareunia develop.
• Most patients who develop overt primary ovarian insufficiency do so after undergoing normal puberty and establishing regular menses. A few patients experience menarche, never establish regular menses, and then progress to overt primary ovarian insufficiency many years later.
• Between 10% and 15% of women with overt primary ovarian insufficiency present with primary amenorrhea. A chromosomal abnormality can be detected in nearly 40% of patients who present with primary amenorrhea in association with pubertal delay (see Turner Syndrome).
• Past history of ovarian surgery, chemotherapy, and radiation therapy should be elicited. At present, the role of viral or other infections in the development of premature ovarian failure is unclear.
  • Mumps oophoritis occurs in 5% of women with mumps and is suspected when lower abdominal pain and ovarian tenderness are present in a patient with mumps parotitis. Nearly all patients with mumps oophoritis can be reassured that normal ovarian function can be expected to return after recovery, although in rare cases, mumps oophoritis has been implicated as a cause of overt primary ovarian insufficiency.
  • Ovarian failure has been reported to follow other acute infections such as Shigella infection, malaria, and varicella, although cause-and-effect relationships have not been established.
• Risk factors associated with osteoporosis, such as family history of osteoporosis, nontraumatic fracture, smoking, and current exercise status, should be discussed.
• A thorough review of systems should be conducted to uncover autoimmune disorders that may be found in association with autoimmune primary ovarian insufficiency.
  • Addison disease can be subtle, and particular attention should be paid to symptoms such as weight loss, anorexia, easy fatigability, weakness, vague abdominal pain, salt craving, or increased skin pigmentation.
  • Other autoimmune disorders that may be found in association with primary ovarian insufficiency include hypothyroidism, Graves disease, Sjögren syndrome, rheumatoid arthritis, and vitiligo.
• A family history of overt primary ovarian insufficiency can be elicited in 10-20% of cases. In patients with Perrault syndrome, familial autosomal recessive primary ovarian insufficiency may occur in association with deafness. Approximately 12% of women with familial primary ovarian insufficiency are found to have this based on a premutation in the fragile X–associated mental retardation 1 gene (FMR1) gene. This gene, in the fully mutated state, is the cause of fragile X syndrome, the most common heritable cause of mental retardation. Premutations in the FMR1 gene have also been associated with a tremor/ataxia syndrome in older men and some older women (FXTAS).

Physical

Patients with early-stage ovarian insufficiency alone have no physical findings. In overt primary ovarian insufficiency 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 primary ovarian insufficiency have 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.

Causes

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
  • Pseudo primary ovarian insufficiency 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:
  • Eating disorders, exercise, psychiatric disorders, chronic debilitating disease
  • Drugs
  • Pituitary tumors, such as prolactinomas, or other tumors that secrete pituitary hormone, such as with Cushing syndrome or acromegaly
  • Pituitary necrosis (Sheehan syndrome)
  • Hypothalamic tumor
  • Craniopharyngioma
  • Kallmann syndrome
  • Infiltrative hypothalamic process, such as sarcoidosis

Differential Diagnoses

Other Problems to Be Considered

Stein-Leventhal syndrome
Excessive exercise
Mild eating disorder
Emotional stress

Workup

Laboratory Studies

• Required laboratory studies vary depending on the clinical presentation and should be directed by a focused history and physical examination. Drug therapy, systemic chronic disease, an eating disorder, excessive exercise, depression, or anxiety disorders all should be considered as factors in the loss of menstrual regularity.
• Insufficiency of ovarian endocrine function generally presents with loss of menstrual regularity.
  • In women who present with a loss of menstrual regularity, obtain a pregnancy test and measure serum prolactin, FSH, luteinizing hormone (LH), and estradiol.
  • Additional studies to be obtained if evidence of androgen excess (acne, hirsutism, male-pattern balding, clitoromegaly) or hypertension is present include measuring serum testosterone and dehydroepiandrosterone (DHEAS) levels. Consider further evaluation for Cushing syndrome or congenital adrenal hyperplasia.
  • In the presence of amenorrhea, and if the patient's serum FSH level is in the menopausal range for the assay system, confirmed with repeat testing, a diagnosis of overt primary ovarian insufficiency is established (also known previously as premature ovarian failure or premature menopause). In this circumstance, a karyotype and testing for the fragile X premutation should be performed.
• Occult or biochemical primary ovarian insufficiency generally presents as unexplained infertility in women who have regular menses.
  • To evaluate ovarian insufficiency in women presenting with infertility and regular menstrual cycles, measure serum FSH, LH, and estradiol on day 3 of a menstrual cycle.
  • Measure serum progesterone during the midluteal phase to confirm ovulation.

Imaging Studies

• Overt primary ovarian insufficiency
  • The information obtained by ovarian ultrasound imaging does not change clinical management.
  • Ovarian imaging by ultrasound should be reserved for investigational use in cases of overt primary ovarian insufficiency.
• Secondary ovarian insufficiency: An MRI 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

Other Tests

• Overt primary ovarian insufficiency
  
  
  • Obtain serum free T₄ and thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies, and fasting blood sugar measurements.
  • Measure adrenal antibodies.
  • Perform bone density scan (DEXA) to evaluate bone mineral density
  • Perform an adrenocorticotropic hormone (ACTH) stimulation test if the adrenal antibody test is positive.
  • Perform other antibody tests such as antinuclear antigens (ANA) and rheumatoid factor tests only as clinically indicated.
• Secondary ovarian insufficiency
  • Consider the need for an ACTH stimulation test to evaluate secondary adrenal insufficiency as an additional finding.
  • Consider the need for diurnal TSH measurements to evaluate for the presence of central hypothyroidism as an additional finding.

Procedures

• Overt primary ovarian insufficiency: 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.

Treatment

Medical Care

No proven treatments restore normal ovarian function for women who have overt primary ovarian insufficiency. The goals are to inform them about their condition, counsel them regarding solutions for family planning, and provide ovarian hormone replacement therapy as clinically indicated.

For women with secondary ovarian insufficiency, the treatment required to restore ovarian function depends on the specific etiology.

• Primary ovarian insufficiency
  
  
  • Patients should be informed that spontaneous remission could occur. Even women with overt primary ovarian insufficiency have a 5-10% chance of becoming pregnant with no treatment. Sometimes, these spontaneous pregnancies occur many years after diagnosis. Unproven treatments to restore fertility should be avoided because they have the potential of interfering with the development of a spontaneous pregnancy.
  • Gonadotropin therapy carries a theoretical risk of exacerbating autoimmune primary ovarian insufficiency.
  • The use of prednisone or dexamethasone in an attempt to restore ovarian function in suspected autoimmune oophoritis is not clinically indicated. Use of these agents carries a risk of osteonecrosis. Their use in patients with primary ovarian insufficiency should be confined to studies approved by an institutional review board.
  • Counseling patients who are infertile that waiting a period of time to permit a spontaneous remission to occur may be in order. A change in life plans or adoption may then be the best solution for some couples. After an appropriate amount of time has passed for the couple to develop the needed emotional reserve after learning of the diagnosis, ovum donation is another option for them to consider.
  • Patients with overt primary ovarian insufficiency require ovarian hormone replacement (see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure).

Surgical Care

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

Consultations

• Consultations regarding associated endocrine disorders, such as hypothyroidism or adrenal insufficiency, may be required.
• Patients with infertility due to primary ovarian insufficiency normally have a grief response after hearing the diagnosis. They benefit from a baseline psychological evaluation and appropriate counseling.

Diet

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

Activity

• To maintain bone and cardiovascular health, patients should perform 20-30 minutes of weight-bearing exercise each day.

Medication

Patients with overt primary ovarian insufficiency require ovarian hormone replacement (see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure).

The required medical therapy for secondary ovarian insufficiency depends on the etiology of the condition.

Estrogens can be administered transdermally or orally. The appropriate dose for young women with ovarian failure has not been established in control studies. The authors recommend full replacement doses for young women. These generally are approximately twice as high as those normally recommended for hormone replacement therapy for postmenopausal women.

The authors prefer to administer estradiol by skin patch. This avoids the first-pass effect of oral estrogen on the liver. Generally, for young women who are estrogen deficient, the authors begin with the 100-mcg patch. However, some women do not tolerate the patch. In these women, the authors use oral micronized estradiol at 2 mg/d.

Progestins

Should be given cyclically 12 days each month to prevent the endometrial hyperplasia that unopposed estrogen may cause. In young women, regular withdrawal bleedings are preferable because even young women with primary ovarian failure have a 5-10% chance of spontaneous pregnancy (unlike postmenopausal women). If expected withdrawal bleeding is missing, a pregnancy test should be performed and a timely diagnosis of pregnancy would not be missed. Other causes of amenorrhea also may remit spontaneously and result in an unexpected pregnancy.

Medroxyprogesterone acetate (Provera)

Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until maturity of positive feedback system is achieved.
Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal; typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal. Provera tabs are 2.5 mg, 5 mg, and 10 mg.

Dosing

Adult

10 mg/d PO 12 d each mo, usually days 1-12 of calendar month

Pediatric

Not applicable

Interactions

Most interactions (eg, decreased efficiency when coadministered with aminoglutethimide, slight decreases in clearance of digoxin, increases in liver enzymes when coadministered with tamoxifen, increases in half-life of warfarin [71%]) described are at relatively high doses, which are not used for HRT

Contraindications

Documented hypersensitivity; thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or patients with past history of these conditions; liver dysfunction or disease; known or suspected malignancy of breast or genital organs; undiagnosed vaginal bleeding; missed abortion; as a diagnostic test for pregnancy; known or suspected pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Be alert to the earliest manifestations of thrombotic disorders (eg, thrombophlebitis, cerebrovascular disorders, pulmonary embolism, retinal thrombosis); should these occur or be suspected, discontinue immediately
Discontinue pending examination if sudden partial or complete loss of vision occurs or with sudden onset of proptosis, diplopia, or migraine; if examination reveals papilledema or retinal vascular lesions, withdraw medication
Perform pretreatment physical examination, including special reference to breast and pelvic organs and Papanicolaou smear
Because progestogens may cause some degree of fluid retention, carefully observe conditions that can be influenced (eg, epilepsy, migraine, asthma, cardiac or renal dysfunction)
In case of breakthrough bleeding, consider nonfunctional causes; in cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated
Carefully observe patients with history of psychic depression, and discontinue therapy if depression recurs to a serious degree
Carefully observe in diabetes
Advise pathologist of progestin therapy when relevant specimens are submitted
Because of occurrence of thrombotic disorders (eg, thrombophlebitis, pulmonary embolism, retinal thrombosis, cerebrovascular disorders) in patients taking estrogen-progestin combinations and because mechanism is obscure, be alert to earliest manifestations of these disorders
Only administer to women who are breastfeeding when clearly necessary because many drugs are excreted in human milk; detectable amounts of progestin have been identified in milk; effects on infant are not known

Estrogens

Estrogens can be given continuously or cyclically (21 d on, 7 d off). Because no controlled studies are available to compare the efficacy and safety of one method over another, the choice of therapy should be determined after considering patient preference and physician experience. Some patients cannot tolerate estradiol patches. CEEs can be used to achieve adequate estrogenization of vaginal epithelium in young women and to maintain bone density.

Ethinyl estradiol (Estinyl)

Reduces the secretion of LH and FSH from the pituitary by decreasing amount of gonadotropin-releasing hormones.
Use 30-35 mg ethinyl estradiol combined with any form of progesterone.
Restoration of regular menstrual cycles prevents endometrial hyperplasia associated with anovulation. Improvements of hyperandrogenic effects are seen in 60-100% of women but usually require a minimum of 6-12 mo of use. A pregnancy test should be performed before initiating therapy. If the woman has had no menstrual period for 3 mo, withdrawal bleeding should be induced by administration of 5-10 mg of medroxyprogesterone acetate (Provera) daily for 10 d; then, therapy is begun with OCPs.

Dosing

Adult

2 mg PO qd

Pediatric

Not established

Interactions

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 ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and reduce contraceptive efficacy; increase in fluid retention caused by estrogen intake may reduce seizure control; antibiotics may alter GI flora and cause a reduction in absorption of oral contraceptives, which may reduce efficacy

Contraindications

Documented hypersensitivity; thrombophlebitis, undiagnosed vaginal bleeding; cardiovascular disease, cerebrovascular disease, migraine with focal aura, known or suspected carcinoma of the breast, known or suspected estrogen dependent neoplasia, cholestatic jaundice of pregnancy or jaundice with prior pill use, acute or chronic hepatocellular disease with abnormal liver function; known or suspected pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Exercise caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease

Transdermal estradiol (Alora, Climara, Esclim, Vivelle-dot)

Used to provide adequate estrogen for the vaginal epithelium in young women and probably maintain bone density adequately.

Dosing

Adult

Alora: 0.05, 0.075, and 0.1 mg/d applied twice weekly
Climara: 0.025, 0.05, 0.075, and 0.1 mg/d applied once weekly
Esclim: 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d applied twice weekly
Vivelle-dot: 0.037, 0.05, 0.075, 0.1 mg/d applied twice weekly

Pediatric

Not applicable

Interactions

May decrease effect of tricyclic antidepressants and cause worsening of previously well-controlled depression, which seems to be dose-dependent and reversible with decrease or discontinuation of therapy
Effects may decrease during concomitant therapy with carbamazepine and/or phenytoin, dose increase may be necessary, but estrogens may increase seizures in previously well-controlled patients with epilepsy
Thyroid replacement or suppressive therapy (eg, levothyroxine, triiodothyronine) may need adjustments while patient is taking estrogens because the latter increases the sex hormone-binding globulin (SHBG), especially when administered orally, thus leaving less free T₄ (active hormone) available
Tobacco smoking can have antiestrogenic effect by increasing C-2 hydroxylation of estradiol molecule

Contraindications

Pregnancy; undiagnosed abnormal genital bleeding; breast cancer; estrogen-dependent neoplasia; active thromboembolic disorder; chronic liver disease; neuroophthalmologic vascular disease

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Reported endometrial cancer risk among unopposed estrogen users is approximately 2- to 12-fold greater than in nonusers and appears dependent on duration of treatment and dose; greatest risk appears 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 premenopausal women is not known
Some studies suggest possible increased incidence of breast cancer in women taking estrogen therapy at higher doses or for prolonged periods; studies focused on postmenopausal women, 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
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 transdermal estrogens not established
Occasional blood pressure increases attributed to idiosyncratic reactions; other studies show slightly lower blood pressure among estrogen users compared to nonusers; postmenopausal estrogen use does not increase risk of stroke, but blood pressure should be monitored at regular intervals
Administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases; if hypercalcemia occurs, discontinue use and take appropriate measures to reduce serum calcium level
Addition of a progestin to estrogens may cause adverse effects (eg, adverse effects on lipoprotein metabolism [lowering HDL and raising LDL]) that could diminish cardioprotective effect
May cause adverse changes in lipoprotein metabolism compared to natural progesterone; careful assessment of each patient's cardiovascular risk factors, combined with a lipid profile, is recommended before initiating long-term hormone replacement therapy
Impaired glucose tolerance seen
Possible enhancement of mitotic activity in breast epithelial tissue, but epidemiological data are lacking
Complete medical and family histories should be taken before initiating therapy; should be prescribed for no longer than 1 year without another physical examination being performed
Studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity; effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use; information on hypercoagulability in women who have had previous thromboembolic disease is insufficient
Estrogen therapy may be associated with massive elevations of plasma triglycerides, leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism
Careful observation is required when conditions that might be influenced by fluid retention, resulting from estrogen use, are present (eg, asthma, epilepsy, migraine, cardiac or renal dysfunction)
Certain patients may develop undesirable manifestations of estrogenic stimulation (eg, abnormal uterine bleeding, mastodynia)
May be poorly metabolized in patients with impaired liver function, administer with caution
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), 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)
Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels
Reduced response to metapyrone test may be seen; reduced serum folate concentration
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases frequency of carcinomas of breast, uterus, cervix, vagina, testis, and liver
Administration of any drug to women who are breastfeeding should occur only when clearly necessary because many drugs are excreted in human milk; additionally, shown to decrease quantity and quality of milk

Follow-up

Further Outpatient Care

• Patients with overt primary ovarian insufficiency should be seen annually to monitor their ovarian hormone replacement and to detect the development of associated conditions such as hypothyroidism or adrenal insufficiency.
• Annual measurement of fasting blood sugar, free thyroxine, TSH, and adrenal antibodies is in order.
• The follow-up care for patients with secondary ovarian insufficiency depends on the mechanism of the disorder.

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 hormone replacement to maintain bone density.

Prognosis

• Patients with primary ovarian insufficiency should be informed that spontaneous remission could occur.  Women with overt primary ovarian insufficiency have a 5-10% chance of becoming pregnant with no treatment. Sometimes these spontaneous pregnancies occur many years after diagnosis.
• The prognosis for women with secondary ovarian insufficiency depends on the etiology of the disorder (see Amenorrhea).

Patient Education

• Carefully counsel patients who are infertile and have overt primary ovarian insufficiency. Waiting an appropriate amount of time to permit a pregnancy to occur by spontaneous remission may be in order.
• A change in life plans or adoption may be the best solution for some couples.
• In most cases, infertility is a primary concern of women with ovarian insufficiency. Taking the time to explain that physiologic replacement of estrogen and progesterone will not prevent chances for spontaneous pregnancy will help compliance. Also, explaining that the results of the WHI study do not apply directly to the young women helps with compliance in the long run.
• At an appropriate time after the couple has developed the needed emotional reserve through support and appropriate counseling, ovum donation is another option for them to consider.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education articles Female Sexual Problems, and Amenorrhea.

Miscellaneous

Medicolegal Pitfalls

• Infertility resulting from ovarian insufficiency may present the medical legal dilemma of being asked to administer unproven therapies on an empiric basis. Unproven therapies, such as prednisone or dexamethasone treatment, may have significant adverse sequelae. Complications from empiric therapy, such as osteonecrosis after treating overt primary ovarian insufficiency with prednisone, carry substantial risks of medical legal action and large recoveries.

Special Concerns

• Often, a delay in diagnosis of ovarian insufficiency occurs because the loss of menstrual regularity may be viewed as a common occurrence that does not need evaluation. The authors believe that a women who is not experiencing regular menses for 3 months should be evaluated for the possibility of primary or secondary ovarian insufficiency.

References

1. Adashi EY, Hennebold JD. Single-gene mutations resulting in reproductive dysfunction in women. N Engl J Med. Mar 4 1999;340(9):709-18. [Medline].

2. Anasti JN, Kalantaridou SN, Kimzey LM. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol. Jan 1998;91(1):12-5. [Medline].

3. Cameron IT, O'Shea FC, Rolland JM, Hughes EG, de Kretser DM, Healy DL. Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations. J Clin Endocrinol Metab. Dec 1988;67(6):1190-4. [Medline].

4. Fanchin R, de Ziegler D, Olivennes F, Taieb J, Dzik A, Frydman R. Exogenous follicle stimulating hormone ovarian reserve test (EFORT): a simple and reliable screening test for detecting 'poor responders' in in-vitro fertilization. Hum Reprod. Sep 1994;9(9):1607-11. [Medline].

5. Farhi J, Homburg R, Ferber A, Orvieto R, Ben Rafael Z. Non-response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre-empting the rise in basal follicle stimulating hormone levels. Hum Reprod. Feb 1997;12(2):241-3. [Medline].

6. Hagerman RJ, Hagerman PJ. The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev. Jun 2002;12(3):278-83. [Medline].

7. Johnson J, Canning J, Kaneko T, et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. Mar 11 2004;428(6979):145-50. [Medline].

8. Munster K, Helm P, Schmidt L. Secondary amenorrhoea: prevalence and medical contact--a cross- sectional study from a Danish county. Br J Obstet Gynaecol. May 1992;99(5):430-3. [Medline].

9. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of female fecundity. Lancet. Sep 19 1987;2(8560):645-7. [Medline].

10. Nelson LM, Anasti JN, Flack MR. Premature ovarian failure. In: Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive Endocrinology, Surgery, and Technology. 2. Philadelphia, Pa: Lippincott Williams & Wilkins; 1995:1393-410.

11. Prior JC, Vigna YM, Schechter MT. Spinal bone loss and ovulatory disturbances. N Engl J Med. Nov 1 1990;323(18):1221-7. [Medline].

12. Thomas MA, Rebar RW. Delayed puberty in girls and primary amenorrhea. Curr Ther Endocrinol Metab. 1997;6:223-6. [Medline].

13. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW. The FMR1 premutation and reproduction. Fertil Steril. Mar 2007;87(3):456-65. [Medline].

14. Nelson LM, Covington SN, Rebar RW. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril. May 2005;83(5):1327-32. [Medline].

15. McConkie-Rosell A, Abrams L, Finucane B, Cronister A, Gane LW, Coffey SM. Recommendations from Multi-disciplinary Focus Groups on Cascade Testing and Genetic Counseling for Fragile X-associated Disorders. J Genet Couns. May 12 2007;[Medline].

16. Armstrong AY, Calis KA, Nelson LM. Do survivors of childhood cancer have an increased incidence of primary ovarian insufficiency?. Nat Clin Pract Endocrinol Metab. Apr 2007;3(4):326-7. [Medline].

17. Ventura JL, Fitzgerald OR, Koziol DE, Covington SN, Vanderhoof VH, Calis KA. Functional well-being is positively correlated with spiritual well-being in women who have spontaneous premature ovarian failure. Fertil Steril. Mar 2007;87(3):584-90. [Medline].

18. Kalantaridou SN, Calis KA, Vanderhoof VH, Bakalov VK, Corrigan EC, Troendle JF. Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure. Fertil Steril. Nov 2006;86(5):1475-82. [Medline].

19. Corrigan EC, Raygada MJ, Vanderhoof VH, Nelson LM. A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome. Fertil Steril. Nov 2005;84(5):1508. [Medline].

20. Bakalov VK, Anasti JN, Calis KA, Vanderhoof VH, Premkumar A, Chen S. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril. Oct 2005;84(4):958-65. [Medline].

21. Smith JA, Vitale S, Reed GF, Grieshaber SA, Goodman LA, Vanderhoof VH. Dry eye signs and symptoms in women with premature ovarian failure. Arch Ophthalmol. Feb 2004;122(2):151-6. [Medline].

22. Nelson LM, Bakalov VK. Mechanisms of follicular dysfunction in 46,XX spontaneous premature ovarian failure. Endocrinol Metab Clin North Am. Sep 2003;32(3):613-37. [Medline].

23. Gordon CM, Nelson LM. Amenorrhea and bone health in adolescents and young women. Curr Opin Obstet Gynecol. Oct 2003;15(5):377-84. [Medline].

24. Adams Hillard PJ, Nelson LM. Adolescent girls, the menstrual cycle, and bone health. J Pediatr Endocrinol Metab. May 2003;16 Suppl 3:673-81. [Medline].

25. Novosad JA, Kalantaridou SN, Tong ZB, Nelson LM. Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation. BMC Womens Health. Mar 17 2003;3(1):2. [Medline].

26. Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. Aug 2002;17(8):2096-100. [Medline].

27. Alzubaidi NH, Chapin HL, Vanderhoof VH, Calis KA, Nelson LM. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol. May 2002;99(5 Pt 1):720-5. [Medline].

Keywords

premature ovarian failure, premature menopause, autoimmune ovarian failure, autoimmune oophoritis, reduced ovarian reserve, hypergonadotropic amenorrhea, menopause, perimenopause, Turner syndrome, gonadal dysgenesis, hyperprolactinemia, hypothalamic amenorrhea, polycystic ovary syndrome, Stein-Leventhal syndrome, primary amenorrhea, secondary amenorrhea, oligomenorrhea, metrorrhagia, polymenorrhea, amenorrhea

Contributor Information and Disclosures

Author

Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Reproductive Biology and Medicine Branch, National Institutes of Health
Lawrence M Nelson, MD, MBA is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Endocrine Society, and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health
Vaishali Popat, MD, MPH is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, American Medical Association, and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Robert K Zurawin, MD, Associate Professor, Director of Fellowship Programs, Minimally Invasive Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine; Chief of Gynecology, Texas Children's Hospital
Robert K Zurawin, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Harris County Medical Society, North American Society for Pediatric and Adolescent Gynecology, and Texas Medical Association
Disclosure: Johnson and Johnson Honoraria Speaking and teaching; Conceptus Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

A David Barnes, MD, PhD, MPH, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital, Mammoth Lakes, California, Pioneer Valley Hospital, Salt Lake City, Utah, Warren General Hospital, Warren, Pennsylvania and Mountain West Hospital, Tooele, Utah
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center
Bryan D Cowan, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Vladimir Bakalov, MD and Carmen Pastor, MD, to the development and writing of this article.

For further reading, see Medscape's Ob/Gyn and Women's Health.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)