Ovarian Insufficiency



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

Predictable menstrual cyclicity is a hallmark of healthy ovarian function during the reproductive years. Each month, highly coordinated hormonal and ovarian morphological changes develop and release a mature oocyte that is ready for fertilization. A disruption of this process may result in anovulation and ovarian steroid hormone deficiency.

Aging is associated with a decline in the number of ovarian follicles, menstrual irregularities, ovarian hormonal deficiency, anovulation, decreased fertility, and, finally, a complete and irreversible cessation of menses known as menopause, usually occurring at a mean age of 51 years.

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

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

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

Primary ovarian insufficiency (POI) (premature ovarian failure, premature menopause, or early menopause) is a condition characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin levels in women younger than 40 years. Although often used as synonyms, POI and menopause are not equivalent. Most women with POI retain intermittent ovarian function for many years, and, unlike women who are menopausal, pregnancies may occur.


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.

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.

Spontaneous Primary Ovarian Insufficiency

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

Follicle depletion

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

The presence of normal numbers of follicles in the ovaries (approximately 300,000-400,000 at the beginning of puberty) is crucial for normal periodic ovulation. Full maturation of one dominant follicle is dependent on the simultaneous development of a support cohort of nondominant follicles. These, although destined to undergo atresia, play an important role in the fine-tuning of the hypothalamic-pituitary-ovarian axis by secreting regulatory hormones such as estradiol, inhibins, activins, and androgens.

Pathological conditions that cause depletion or a reduction of the follicle number may lead to a disruption of the highly coordinated process of follicular growth and ovulation. The lack of developing follicles leads to reduced circulating estradiol and inhibin levels and elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Occasionally, a "lonely" follicle may develop, stimulated by the high levels of FSH; however, instead of progressing to a normal ovulation, it is inappropriately luteinized (by the high LH levels) and may persist as a cystic structure visible on ultrasonography.

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

Low initial number

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

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

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.



United States

POI/POF occurs in approximately 1% of women.[7] The estimated incidence in the United States is 1 case per 1000 women by age 30, 1 case per 250 women by age 35 and 1 case per 100 women by age 40. Approximately 10-28% of women with primary amenorrhea and 4-18% with secondary amenorrhea have POI/POF.


Long-term follow-up studies to evaluate the impact of POI/POF on the mortality rate at older age have not been conducted. In a survey of 19,000 women aged 25-100 years, Snowdon et al have shown increased all-cause mortality in women who had ovarian failure before age 40 years (age-adjusted odds ratio of death 2.14 [95% CI, 1.15-3.99]) and stroke mortality (odds ratio 3.07 [95% CI, 1.34-7.03]).[8] Several points concerning morbidity and mortality of patients with POI/POF are worth considering, as follows:


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 to white women.[9]

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.[10]


Ovarian insufficiency occurs only in women.


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


Generally, women with spontaneous POI/POF have unremarkable clinical findings.

The diagnostic approach to patients with ovarian failure is as follows:


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.


See Pathophysiology.

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).

Laboratory Studies

Three groups of tests should be performed when ovarian failure is suspected or has been diagnosed. They include tests that establish the diagnosis of 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:

Studies to clarify the etiology of ovarian failure are as follows:

Imaging Studies

Primary ovarian insufficiency: 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 of the pituitary and hypothalamus is indicated in the evaluation of secondary ovarian insufficiency in the following circumstances:

Other Tests

Overt primary ovarian insufficiency

Secondary ovarian insufficiency


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.

Medical Care

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

Surgical Care

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


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.


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.

Medication Summary

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

Estradiol transdermal system (Alora)

Clinical Context:  Increases synthesis of DNA, RNA, and many proteins in target tissues.

Conjugated equine estrogens (Premarin)

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.

Class Summary

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

Medroxyprogesterone acetate (Provera)

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.

Progesterone (Prometrium)

Clinical Context:  Used to prevent endometrial hyperplasia in women with a uterus who are receiving estrogen therapy.

Class Summary

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.

Methyltestosterone (Android)

Clinical Context:  Synthetic testosterone derivative with significant androgen activity. Tablets are available in 5-mg, 10-mg, and 25-mg strengths.

Testosterone enanthate or cypionate

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.

Class Summary

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.

Further Outpatient Care

See Treatment.

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).


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.


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).

Patient Education

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

NICHD Primary Ovarian Insufficiency (POI) Website

For patient education resources, see the Women's Health Center. Also, see the patient education articles Female Sexual Problems and Amenorrhea.


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.


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

Disclosure: Nothing to disclose.


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Ovarian Clinical Situation Menses Gonadotropins Fertility
Occult insufficiencyNormalNormalReduced
Biochemical insufficiencyAbnormalElevatedReduced
Overt insufficiencyAbnormalElevatedReduced
Premature ovarian failureAbsentElevatedZero