eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Ovarian Insufficiency

Author: Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Coauthor(s): Vaishali Popat, MD, MPH, Clinical Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Contributor Information and Disclosures

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

Open table in new window

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

• Search for CME/CE on This Topic »

• Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure (Obstetrics and Gynecology)
• Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia) (Pediatrics: Genetics and Metabolic Disease)

• Female Sexual Problems Causes
• Female Sexual Problems Treatment
• Amenorrhea Overview
• Female Sexual Problems Overview
• Menopause Overview

• Recent Advances in Adrenal Autoimmunity
• Fertility Preservation for Breast Cancer Patients
• Fresh Ovarian Tissue and Whole Ovary Transplantation