Premature ovarian failure

Premature ovarian failure
Premature ovarian failure
Classification and external resources
ICD-10 E28.3
ICD-9 256.31
OMIM 311360
DiseasesDB 9441
eMedicine med/1700
MeSH D016649

Premature Ovarian Failure (POF), also known as premature ovarian insufficiency, primary ovarian insufficiency (this is the most accurate term as some women may still conceive), premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40.[1] A commonly cited triad for the diagnosis is amenorrhea, hypergonadotropinism, and hypoestrogenism. If it has a genetic cause, it may be called gonadal dysgenesis[2]



Fuller Albright et al. in 1942 first reported a syndrome in young women characterized by menopausal levels of follicle stimulating hormone (FSH), low estrogen levels and amenorrhea. They named the condition "primary ovarian insufficiency" to distinguish the condition from secondary ovarian insufficiency, which is the failure of the pituitary to secrete FSH.[3] Chapter 28 of the early Qing dynasty work Fù Qīngzhǔ Nǚkē (《傅青主女科》Fù Qīngzhǔ's Gynecology) describes the cause and appropriate treatment for premature menopause (年未老经水断 niánwèilǎo jīngshuǐduàn, glosses as: 'age not-yet old menstrual water cut-off').[4]


It has been estimated that POF affects 1% of the population.[5]


On average, the ovaries supply a woman with eggs until age 51, the average age of natural menopause.[6]

POF is not the same as a natural menopause, in that the dysfunction of the ovaries, loss of eggs, or removal of the ovaries at a young age is not a natural physiological occurrence.

Infertility is the result of this condition, and is the most discussed problem resulting from it, but there are additional health implications of the problem, and studies are ongoing. For example, osteoporosis or decreased bone density affects almost all women with POF due to an insufficiency of estrogen. There is also an increased risk of heart disease, hypothyroidism in the form of Hashimoto's thyroiditis, Addison's disease, and other auto-immune disorders.

Hormonally, POF is defined by abnormally low levels of estrogen and high levels of FSH, which demonstrate that the ovaries are no longer responding to circulating FSH by producing estrogen and developing fertile eggs. The ovaries will likely appear shriveled.

The age of onset can be as early as the teenage years, but varies widely. If a girl never begins menstruation, it is called primary ovarian failure. The age of 40 was chosen as the cut-off point for a diagnosis of POF. This age was chosen somewhat arbitrarily, as all women's ovaries decline in function over time, however an age needed to be chosen to distinguish usual menopause from the abnormal state of premature menopause.[citation needed] Premature ovarian failure however often has components to it that distinguish it from normal menopause.

By the age of 40, approximately one percent of women have POF.[7] Women suffering from POF usually experience menopausal symptoms that are more severe than the symptoms found in older menopausal women.


The cause of POF is usually idiopathic. Some cases of POF are attributed to autoimmune disorders, others to genetic disorders such as Turner syndrome and Fragile X syndrome. An Indian study showed a strong correlation between incidence of POF and certain variants in the inhibin alpha gene.[8] In many cases, the cause cannot be determined. Chemotherapy and radiation treatments for cancer can sometimes cause ovarian failure. In natural menopause, the ovaries usually continue to produce low levels of hormones, but in chemotherapy or radiation-induced POF, the ovaries will often cease all functioning and hormone levels will be similar to those of a woman whose ovaries have been removed. Women who have had their tubes tied, or who have had hysterectomies, tend to go through menopause several years earlier than average, likely due to decreased blood flow to the ovaries. Family history and ovarian or other pelvic surgery earlier in life are also implicated as risk factors for POF.

There are two basic kinds of premature ovarian failure. Case 1) where there are few to no remaining follicles and case 2) where there are an abundant number of follicles. In the first situation the causes include genetic disorders, autoimmune damage, chemotherapy, radiation to the pelvic region, surgery, endometriosis and infection. In most cases the cause is unknown. In the second case one frequent cause is autoimmune ovarian disease which damages maturing follicles, but leaves the primordial follicles intact.[9] Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinyl estradiol (EE) or with a GnRH-a the receptor sites are freed and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur.[10][11] (Since the serum anti-müllerin hormone (AMH) level is correlated with the number of remaining primordial follicles some researchers believe the above two phenotypes can be distinguished by measuring serum AMH levels.[12])

The POF Fact Sheet lists potential causes of POF in various languages:

  • Genetic disorders
  • Autoimmune diseases
  • Tuberculosis of the genital tract
  • Smoking
  • Radiation and/or chemotherapy
  • Ovarian failure following hysterectomy
  • Prolonged gnrh therapy
  • Enzyme defects
  • Resistant ovary
  • Induction of multiple ovulation in infertility

Genetic associations include:

Type OMIM Gene Locus
POF1 311360 FMR1 Xq26-q28
POF2A 300511 DIAPH2 Xq13.3-q21.1
POF2B 300604 POF1B Xq13.3-q21.1
POF3 608996 FOXL2 3q23
POF4 300510 BMP15 Xp11.2
POF5 611548 NOBOX 7q35
POF6 612310 FIGLA 2p12
POF7 612964 NR5A1 9q33


Serum follicle-stimulating hormone (FSH) measurement alone can be used to diagnose the disease. Two FSH measurements with one-month interval have been a common practice. The anterior pituitary secretes FSH and LH at high levels due to the dysfunction of the ovaries and consequent low estrogen levels. Typical FSH in POF patients is over 40 mlU/ml (post-menopausal range).


Between 5 and 10 percent of women with POF may spontaneously become pregnant. Currently no fertility treatment has officially been found to effectively increase fertility in women with POF, and the use of donor eggs with In-Vitro Fertilization (IVF) and adoption have become more popular as a means of becoming parents for women with POF. Some women with POF choose to live child-free. (See Impaired Ovarian Reserve for a summary of recent randomized clinical trials and treatment methods.)

Currently New York fertility researchers are investigating the use of a mild male hormone called dehydroepiandrosterone (DHEA) in women with POF to increase spontaneous pregnancy rates.[13] Published results from studies conducted on DHEA have indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POF.[14] [15]

Additionally, over the last five years a Greek research team has successfully implemented the use of dehydroepiandrosterone (DHEA) for the fertility treatment of women suffering with POF.The majority of the patients were referred for donor eggs or surrogacy, however after a few months of DHEA administration they succeeded in getting pregnant through IVF, IUI, IUTPI or natural conception. Until now a great number of babies have been born after treatment with DHEA.[16]

Ovarian tissue cryopreservation can be performed on prepubertal girls at risk for premature ovarian failure, and this procedure is as feasible and safe as comparable operative procedures in children.[17]

Hormonal replacement

It is important to initiate the hormonal replacement therapy after the diagnosis of POF, as untreated patients are at a great risk of bone loss due to increased osteoclast activities, resulting in osteopenia as well as osteoporosis.[18] Furthermore, most of the patients develop symptoms of estrogen deficiency, including vasomotor flushes and vaginal dryness, both of which respond to estrogen therapy effectively. There are several contraindications of estrogen supplement, including smokers over 35 years of age, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of thromboemboli events. If the patient has strong family history of thromboemboli events, care must be taken to proceed with the hormonal replacement therapy. As the minimum, testing for Factor V Leiden, Protein C, and Protein S should be performed to ensure the low risk of developing thromboemboli events while on the estrogen replacement. The transdermal estradiol patch (typically 100 mcg) is commonly recommended because of several advantages. It provides the replacement by steady infusion rather than by bolus when taking daily pills. It also avoids the first-pass effect in the liver.[19]

Related Conditions

In popular culture

In the fourth season of the British television show Skins, the character Katie Fitch is diagnosed with this after going in for a pregnancy test (since she missed several periods). This greatly upsets her because of her wish to have a family one day, and informs her character development.


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  2. ^ Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (July 2009). Andrology: Male Reproductive Health and Dysfunction. Springer. pp. 221–. ISBN 9783540783541. Retrieved 10 November 2010. 
  3. ^ Hubayter ZR, Popat V, Vanderhoof VH, et al. (October 2010). "A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency". Fertil. Steril. 94 (5): 1769–74. doi:10.1016/j.fertnstert.2009.10.023. PMID 19939372. 
  4. ^ Fu Qing-zhu's Gynecology. Boulder CO: Blue Poppy Press. 1992. ISBN 0-936185-35-X. 
  5. ^ Chatterjee S, Modi D, Maitra A, et al. (2007). "Screening for FOXL2 gene mutations in women with premature ovarian failure: an Indian experience". Reprod. Biomed. Online 15 (5): 554–60. doi:10.1016/S1472-6483(10)60388-4. PMID 18028747. 
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  8. ^ Prakash, G. J.; Ravi Kanth, V. V.; Shelling, A. N.; Rozati, R.; Sujatha, M. (2010). "Mutational analysis of inhibin alpha gene revealed three novel variations in Indian women with premature ovarian failure". Fertility and Sterility 94 (1): 90. doi:10.1016/j.fertnstert.2009.02.014. PMID 19324345.  edit
  9. ^ Check JH (1991). "Letter to the Editor". Fertil. Steril. 55 (2): 447–8. 
  10. ^ Blumenfeld Z, Halachmi S, Peretz BA, et al. (April 1993). "Premature ovarian failure—the prognostic application of autoimmunity on conception after ovulation induction". Fertil. Steril. 59 (4): 750–5. PMID 8458491. 
  11. ^ Blumenfeld Z (September 2007). "Pregnancies in patients with POF gonadotropin stimulation and pretreatment with ethinyl estradiol". Fertil. Steril. 88 (3): 763; author reply 763. doi:10.1016/j.fertnstert.2007.07.001. PMID 17681336. 
  12. ^ Méduri G, Massin N, Guibourdenche J, et al. (January 2007). "Serum anti-Müllerian hormone expression in women with premature ovarian failure". Hum. Reprod. 22 (1): 117–23. doi:10.1093/humrep/del346. PMID 16954410. 
  13. ^ “Clinical Trial: Study of Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)”
  14. ^ Gleicher N, Weghofer A, Barad DH (2010). "Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS)". Reprod. Biol. Endocrinol. 8: 140. doi:10.1186/1477-7827-8-140. PMC 2992540. PMID 21067609. 
  15. ^ “DHEA: Treatment for Women with POA and POF”
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  17. ^ Jadoul, P.; Dolmans, M. -M.; Donnez, J. (2010). "Fertility preservation in girls during childhood: is it feasible, efficient and safe and to whom should it be proposed?". Human Reproduction Update 16 (6): 617. doi:10.1093/humupd/dmq010. PMID 20462941.  edit
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