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Premature Ovarian Failure

Hypergonadotropic Hypogonadism Syndrome female

Premature ovarian insufficiency or failure describes an inability of the ovary to perform its endocrine and reproductive functions adequately in women who are below 40 years. It could be due to intrinsic ovarian disorders or secondary to dysfunctional hypothalamus-pituitary axis.


Presentation

History

Amenorrhea, abnormal menstruation and infertility are the commonest symptoms of POF, although amenorrhea could be the sole presentation in some women. Primary and secondary amenorrhea are possible in POF.

The history should consist of patient's menstrual cycle, the periodicity and flow characteristics and a history of the possible etiology of POF including previous or recent radiation or chemotherapy, gynecological surgery, workplace environmental pollution and viral infections. A family history of early menstrual cessation [7] [8], autoimmune diseases such as diabetes mellitus, autoimmune thyroiditis, or intellectual abnormalities, indicating fragile X syndrome should be established.

Symptoms of hypoestrogenemia should be inquired about. These symptoms include mood changes, vaginal dryness and hot flushes. Symptoms of the endocrinopathies associated with POF should also be inquired about. These include asking about abdominal pain, progressive weakness, anorexia and weight loss which suggest adrenal insufficiency or about constipation, low energy levels, dry skin/hair or cold intolerance to exclude hypothyroidism.

Physical examination

Pelvic exam findings may include vaginal atrophy. Ovaries are usually not palpaple in POF, unless in autoimmune causes of ovarian failure.

The patient should be examined for the presence of physical signs of the genetic disorders associated with POF such as Turner syndrome. These include short stature, high arched palate, webbed neck, and poor pubertal breast development.

Physical examination is not complete, however, without assessing for signs of the associated endocrinopathies including orthostatic hypotension, hyperpigmentation or vitiligo, and decreased axillary and pubic hair in adrenal insufficiency, and goiter, dry skin and the thyroid eye signs in thyroid dysfunction. Presence of bilateral hemianopia and signs of hyperprolactinemia such as galactorrhea is suggestive of a prolactinoma.

Flushing
  • Symptoms include amenorrhoea and symptoms of hypo-oestrogenism such as hot flushes, sleep disturbance, irritability, and vaginal dryness.[bestpractice.bmj.com]
  • The ovaries stop producing estrogen and so symptoms including hot flushes, mood changes and vaginal dryness occur. The ovaries also stop producing eggs and so conception is extremely unlikely.[lifestartfertility.com]
  • They include hot flushes, vaginal dryness, irritability, night sweats, or difficulty sleeping. Menstrual periods may be sporadic or stop completely.[gondracenter.com]
  • Affected women will also eventually experience symptoms similar to those of menopause such as: Hot flushes Night sweats Mood swings and irritability Reduced libido Vaginal dryness and pain during sex Poor concentration Diagnosis The diagnosis of premature[news-medical.net]
  • Common symptoms include the cessation of menses, and the development of hot flushes and vaginal dryness. Obviously, complete ovarian failure results in permanent infertility.[txfertility.com]
Neglect
  • However, there is no validated examination to confirm the diagnosis and it is easily neglected in patients with ovarian insufficiency.[ncbi.nlm.nih.gov]
Amenorrhea
  • The breakpoint in Xq24 may be associated with the amenorrhea.[ncbi.nlm.nih.gov]
  • Three women at the age of 25, 30 and 32 years presented with 5, 6 and 10 years secondary amenorrhea, respectively. They used to have regular menses, and two of them gave birth to a healthy baby(ies).[ncbi.nlm.nih.gov]
  • Premature ovarian failure (POF) is a condition causing amenorrhea, hypoestrogenism and elevated gonadotropins before the age of 40 years and affects around 10% of patients seeking evaluation for secondary amenorrhea.[ncbi.nlm.nih.gov]
  • Prolonged amenorrhea due to premature ovarian failure leading to infertility is one of the serious side-effects of cyclophosphamide. Four cases of cyclophosphamide-induced premature ovarian failure are presented.[ncbi.nlm.nih.gov]
  • A 36-year-old infertile woman presenting amenorrhea and elevated FSH levels (65.56 mIU/mL) after using TW.[ncbi.nlm.nih.gov]
Vaginal Dryness
  • There are increased risks for specific conditions in women who are suffering from early menopause or POF which are: osteoporosis cardiovascular disease symptoms of estrogen and testosterone deficiency including hot flashes, loss of libido, vaginal dryness[whitelotusclinic.ca]
  • Symptoms include amenorrhoea and symptoms of hypo-oestrogenism such as hot flushes, sleep disturbance, irritability, and vaginal dryness.[bestpractice.bmj.com]
  • These may include: Hot flashes Night sweats Decreased sexual drive Pain during intercourse Vaginal dryness Irritability Poor concentration Trouble sleeping Infertility Women with POF do not produce enough estrogen.[fertilityauthority.com]
  • Women with POF are at a greater risk of a range of health issues, including osteoporosis, estrogen deficiency (hot flashes, vaginal dryness, etc.) and heart diseases. These POF-related issues can usually be managed well with hormonal replacement.[centerforhumanreprod.com]
Secondary Amenorrhea
  • Three women at the age of 25, 30 and 32 years presented with 5, 6 and 10 years secondary amenorrhea, respectively. They used to have regular menses, and two of them gave birth to a healthy baby(ies).[ncbi.nlm.nih.gov]
  • Premature ovarian failure (POF), also known as primary ovarian insufficiency, is diagnosed in the event when primary or secondary amenorrhea and hypoestrogenism with high levels of gonadotropins occur in women before the age of 40.[ncbi.nlm.nih.gov]
  • Fifty-two consecutive patients with secondary amenorrhea due to premature ovarian failure and no clinical stigmata of Turner's syndrome.[ncbi.nlm.nih.gov]
  • Premature ovarian failure (POF) is a condition causing amenorrhea, hypoestrogenism and elevated gonadotropins before the age of 40 years and affects around 10% of patients seeking evaluation for secondary amenorrhea.[ncbi.nlm.nih.gov]
  • A 15-year-old girl with mental retardation and minor physical anomalies showed secondary amenorrhea, high gonadotropin levels, and osteoporosis.[ncbi.nlm.nih.gov]
Hot Flushes
  • Symptoms include amenorrhoea and symptoms of hypo-oestrogenism such as hot flushes, sleep disturbance, irritability, and vaginal dryness.[bestpractice.bmj.com]
  • The ovaries stop producing estrogen and so symptoms including hot flushes, mood changes and vaginal dryness occur. The ovaries also stop producing eggs and so conception is extremely unlikely.[lifestartfertility.com]
  • They include hot flushes, vaginal dryness, irritability, night sweats, or difficulty sleeping. Menstrual periods may be sporadic or stop completely.[gondracenter.com]
  • Affected women will also eventually experience symptoms similar to those of menopause such as: Hot flushes Night sweats Mood swings and irritability Reduced libido Vaginal dryness and pain during sex Poor concentration Diagnosis The diagnosis of premature[news-medical.net]
  • Common symptoms include the cessation of menses, and the development of hot flushes and vaginal dryness. Obviously, complete ovarian failure results in permanent infertility.[txfertility.com]
Ovarian Disorder
  • disorder defined as the cessation of ovarian function under the age of 40 years.[genecards.org]

Workup

There should be a high index of suspicion in any woman under 40 years who presents with unexplained infertility, symptoms of hypoestrogenemia or menstrual irregularities.

Investigations to be carried out to confirm a diagnosis of POF include serum hormonal assay (FSH, LH, prolactin, estradiol), pregnancy test and supportive investigations such as thyroid function test and fasting blood glucose to probe into the possible etiology. Genetic testing is also equally necessary.

Serum FSH and estradiol levels are to be measured weekly for 4 weeks; if FSH levels are abnormally elevated (> 20 mIU/mL) and the serum levels of estradiol are lower than normal (< 20 pg/mL), it confirms a diagnosis of ovarian insufficiency. Thereafter, investigations are directed at determining the etiology.

Women who have a family history of premature ovarian failure, those with physical signs of the genetic disorders in POF and all women under 35 years with POF should undergo genetic testing and counselling. Symptomatology of estrogen deficiency should necessitate bone density measurement, since hypoestrogenemia has a potential risk of osteoporosis.

Ultrasound finding of enlarged ovaries and the presence of adrenal or thyroid antibodies [9], all suggest autoimmune ovarian failure, a diagnosis of which is made by these examination findings and presence of other autoimmune diseases.

Treatment

The health care provider should be tactical in informing the patient about a diagnosis of POI/POF. The essentials of the disease should be well explained to the patient and care must be taken to ensure the patient does not mistake the diagnosis for menopause.

The patient should also be reassured of the chances of achieving spontaneous pregnancy while educating them about effective artificial methods to resolve infertility such as embryo or ovum donation and adoption.

The key aspects of medical care include hormone replacement therapy with estrogens and progestins, and androgen therapy.

Hormonal therapy with is recommended for all women with POF to reduce the complications of hypoestrogenemia and alleviate menopausal symptoms.

Although there are no standard dosage recommendations of estrogens for women with POF, doses twice the recommended dose for hormone therapy in postmenopausal women are both safe and effective. These include estradiol (transdermal) 100-150 mcg, 1.25mg daily dose of conjugated equine estrogens (CEE) and estradiol 2-4 mg PO daily. Estrogen prescriptions could be on a cyclical or continuous basis. The choice of therapy, however, should be both patient-based and based on the physician's clinical discretion because all methods are equally effective.

Contrary to common knowledge, estrogen therapy (ET) does not prevent ovulation and pregnancy in these patients. It may increase the chances of achieving pregnancy by reducing the serum LH level to the normal range [8]. All women with POF on estrogen therapy are, therefore, advised to take a pregnancy test as soon as possible if withdrawal menstrual bleeding is not present when expected. Furthermore, oral contraceptives are not recommended in POF as they lead to a higher concentration of estrogens and progestins than is necessary for replacement. Oral contraceptives in POF are also ineffective at preventing conception and pregnancy in women with POF due to the high levels of the gonadotropins.

Cyclical progestins should be administered for a duration of 10-14 days every month. This is to prevent the endometrial effects of unopposed estrogen. In the absence of an expected withdrawal bleeding, just as in estrogen therapy, a pregnancy should be tested for without delay. The recommended regimens of progestin therapy include cyclical prescription of medroxyprogesterone 10 mg PO daily for a duration of 10-12 days monthly or micronized progesterone 200 mg PO daily for 10-12 days monthly.

Although women with ovarian failure have lower serum free testosterone levels than women of the same age without ovulatory dysfunctions, only less than 15% of women with POF have levels below the normal range [10]. Therefore, androgen replacement may not be necessary but should be considered cautiously for women who have low libido, persistent fatigue, or in women in whom depression has been excluded. This should, however, be prescribed for short periods only. Currently available androgen regimen include methyltestosterone 1.25-2.5 mg PO daily, subcuraneous testosterone pellet implants 50mg every 3-6 months and IM testosterone esters 50 mg every 6 weeks.

Management of infertility is a secondary aspect of treatment and basically involves the artificial options noted earlier. No intervention exists, currently, to restore fertility in these patients. Any such unproven treatment is used at the patient's risk as it could lead to permanent inability to spontaneously conceive.

Adjunct treatment such as adotropin therapy is not recommended as it could worsen autoimmune POF. Routine use of prednisolone or dexamethasone in the treatment of autoimmune ovarian insufficiency is also not indicated. 

Prognosis

Women with POF can acheive spontaneous pregnancies without medical intervention. This is because of the occurrence of a spontaneous remission of POI, within which period, the ovaries temporarily regain normal function and fertility is restored [1]. Consequently, patients with POI/POF should be reassured of the chances of spontaneous pregnancy. Artificial methods of conception such as ovum donation are, however, opted for when necessary.

Etiology

Most cases of POF/POI have unknown causes. However, follicle depletion or dysfunction is responsible for many of the cases with known causes. Follicle depletion is often caused by conditions such as chromosomal abnormalities which cause rapid turnover and early depletion of ovarian follicles [3] [4], or from iatrogenic destruction of the follicles from cancer chemotherapy and radiation therapy.

The chromosomal abnormalities associated with follicle depletion include Turner syndrome and premutation in the fragile X mental retardation 1 (FMR1) gene in fragile X syndrome.

Other causes of POF include:

  • Endocrine disorders including hypoparathyroidism , hypothyroidism, hypopituitarism and adrenal insufficiency.
  • Pelvic surgeries such as hysterectomy which may result in impairment of ovarian function if there is an intra-operative impairment of the ovarian blood supply.
  • Autoimmune processes as adrenal or ovarian antibodies have been found in about 4% of women with POF/POI [5]. In this case, the antibodies attack the follicular receptors making them resistant or unresponsive to gonadotropic stimulation. There is usually no abnormality in the number of the follicles.
  • Infiltrative diseases and infections are less common causes of POF.

Epidemiology

Generally, the incidence of POF is approximately 1% in the US in women who are under 40 years [4], with an incidence of 0.4% at age 35 [6].

Sex distribution
Age distribution

Pathophysiology

The decline and cessation of ovarian function in POF leads to hypoestrogenemia, on which all other symptoms of POF are hinged. The decline in hormonal secretion by the ovaries reduces the negative feedback directed to the hypothalamus and pituitary gland causing an uninhibited increase in the serum levels of the gonadotropins (FSH and LH). Low serum estrogen and elevated serum gonadotropin levels are , therefore, classic findings in all patients with POF/POI.

Prevention

POF from non-modifiable risk factors like genetic abnormalities cannot be prevented. However, avoiding modifiable risk factors such as smoking, major pelvic surgeries and interventional procedures such as uterine artery embolization, may lower the risk of developing POF [11]. Up to 100% risk reduction can be achieved in patients requiring radiation for treatment of cancer by shielding of the ovaries or by surgical ovarian transposition away from the field of radiation. Use of gonadotropin-releasing hormone agonist in reducing ovarian follicle damage in patients on cancer chemotherapy is inconclusive. There have been diverse contradictory studies on this issue [12].

Summary

Premature ovarian failure (POF) is characterized by a loss of the endocrine and reproductive functions of the ovaries before the age of 40 years. The condition is not to be confused with menopause, in which case, unlike in POF, the ovaries are completely shut down and in which menstruation and conception are impossible [1].

The reproductive and endocrine functions of the ovary are maintained by coordinated interplay between the hypothalamus, pituitary gland and ovaries. A dysfunction in this axis and depletion of ovarian follicles results in ovarian insufficiency.

The features of ovarian insufficiency are similar to those characteristically seen in menopausal women. These features include; depletion of ovarian follicles, hypoestrogenemia, anovulation, irregular menstruation and infertility or subfertility. All these changes progressively culminate into an irreversible cessation of menstruation defined as menopause [2]. This progressive reduction in ovarian function termed perimenopause or menopausal transition is physiologic in women who are at least 40 years old, hence such changes in women who are younger than 40 is described as premature.

Ovarian insufficiency can be categorized into primary and secondary on the basis of the etiology. Ovarian insufficiency is said to be primary if the ovaries are unresponsive to normal hormonal signals and stimulation by the pituitary gland and hypothalamus as a result of certain ovarian dysfunctions in the face of a normally functioning hypothalamus-pituitary axis. In secondary ovarian insufficiency, the ovaries do not receive appropriate stimulation from the hypothalamus and pituitary gland due to some dysfunctions in the hypothalamus-pituitary. The ovaries are usually normal in this case. Secondary ovarian insufficiency is caused by diseases of the hypothalamus and pituitary gland.

Primary ovarian insufficiency (POI) is also called premature ovarian failure (POF) and is the theme of this article.

Patient Information

Premature ovarian failure (POF), also called primary ovarian insufficiency, describes the inability of the ovaries to carry out normal functions in women under the age of 40. The ovaries function normally to produce the female sex hormones and release a mature egg once during every menstrual cycle. Therefore infertility, irregular menstruation and menopausal symptoms are resultant features in POF.

Premature ovarian failure is often erroneously referred to as early or premature menopause, however, both conditions aren't the same, because patients with POF may still have intermittent periods and have chances of becoming pregnant which is impossible in women in their menopausal years.

Essentials to treatment include replacement of the hormones (estrogens and progestins) and treatment of infertility. Normalizing blood eestrogen levels in women with premature ovarian failure prevents some complications of POF such as osteoporosis.

Causes

Most cases of POF have unknown causes. However, some identifiable causes include autoimmune disorders, genetic abnormalities, under active thyroid or adrenal glands, viral infections and damaged by chemotherapy and radiation therapy used in treating cancer patients.

Symptoms

Women with premature ovarian failure show signs and symptoms which are similar to those experienced by women on menopause and are all caused by estrogen deficiency. They include absent or irregular periods, hot flashes, reduced libido , vaginal dryness and mood changes.

Diagnosis

The steps in making a diagnosis of POF involve answering a series of questions asked by your doctor, undergoing examination of parts of your body and carrying out certain tests. The doctor may ask about your menstrual cycle, and a history of cancer chemotherapy or radiation therapy, and questions regarding any symptom you might be experiencing at that moment. The physical examination would seek to elicit the features of premature ovarian failure.

The following tests may be recommended by your doctor: pregnancy tests, hormone assay, to measure blood levels of female sex hormones and tests to check for your genetic or chromosomal arrangement composition. Other tests would be ordered to identify the cause of the ovarian failure.

Treatment

Treatment of POF is with cyclical estrogen and progestin therapy, unless these hormones are not recommended by the doctor; this therapy helps to reduce the symptoms of estrogen deficiency.

In vitro fertilization of donated oocytes with concomotant use of estrogen and a progestin is one management method used if pregnancy is desired. This technique is very sucessful, however, noteworthy is that some women with diagnosed POF may become pregnant without any medical intervention as noted earlier.

No treatment has been proven to reverse infertility in women with premature ovarian failure.

Some women, after genetic testing, may be found to posses a Y chromosome. These women shall require surgery for the removal of both ovaries (bilateral oophorectomy) because of the risk of developing ovarian germ cell cancer.

References

Article

  1. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606.
  2. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas. 1992;14:103–115.
  3. Reynaud K, Cortvrindt R, Verlinde F, et al. Number of ovarian follicles in human fetuses with the 45,X karyotype. Fertil Steril. 2004;81:1112-1119.
  4. Hreinsson JG, Otala M, Fridstrom M, et al. Follicles are found in the ovaries of adolescent girls with Turner's syndrome. J Clin Endocrinol Metab. 2002;87:3618-3623.
  5. Rafique S, Sterling EW, Nelson LM. A new approach to primary ovarian insufficiency . Obstet Gnecol Coin North Am 2012;39:567-86.
  6. Coulam CB, Adamson SC, Annergers JF. Incidence f premature ovarian failure. Obstet Gynecol. 1986;67:604-606.
  7. Tosh D, Rao KL, Rani HS, et al. Association between fragile X premutation and premature ovarian failure: a case-control study and meta-analysis. Arch Gynecol Obstet. 2014;289:1255-1262.
  8. Perry JR, Corre T, Esko T, et al. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet. 2013;22:1465-1472.
  9. Kalu E, Panay N. Spontaneous premature ovarian failure: management challenges. Gynecol Endocrinol. 2008;24:273-279.
  10. Kalantaridou SN, Calis KA, Vanderhoof VH, et al. Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure. Fertil Steril. 2006 Nov. 86(5):1475-82.
  11. McKinlay SM. The normal menopause transition: an overview. Maturitas. 1996;23:137-145.
  12. Kim SS, Lee JR, Jee BC, et al. Use of hormonal protection for chemotherapy-induced gonadotoxicity. Clin Obstet Gynecol. 2010;53:740-752.

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Last updated: 2018-06-21 22:04