Premature ovarian failure

Premature ovarian failure
Synonyms Premature menopause, hypergonadotropic hypogonadism, gonadal dysgenesis[1] premature ovarian insufficiency (POI), primary ovarian insufficiency
Classification and external resources
Specialty endocrinology
ICD-10 E28.3
ICD-9-CM 256.31
OMIM 311360
DiseasesDB 9441
eMedicine med/1700
MeSH D016649

Premature ovarian failure (POF) is the loss of function of the ovaries before age 40.[2] A commonly cited triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism. If it has a genetic cause, it may be called gonadal dysgenesis.[3]

The term "primary ovarian insufficiency" was first used in 1942 by Fuller Albright who first described the condition.[1] About 5 to 10% of women with primary ovarian insufficiency conceive subsequent to the diagnosis without medical intervention.[4]

Signs and symptoms

On average, the ovaries supply a woman with eggs until age 51, the average age of natural menopause.[5]

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 normal 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, or can even exist from birth, 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. Premature ovarian failure has components to it that distinguish it from normal menopause.

By the age of 40, approximately one percent of women have POF.[6] Women suffering from POF usually experience menopausal symptoms that are more severe than the symptoms found in older menopausal women.

Emotional health

The most common words women use to describe how they felt in the 2 hours after being given the diagnosis of primary ovarian insufficiency are "devastated, "shocked," and "confused."[7] These are words that describe emotional trauma. The diagnosis is more than infertility and affects a woman’s physical and emotional well-being.[1] Patients face the acute shock of the diagnosis, associated stigma of infertility, grief from the death of dreams, anxiety and depression from the disruption of life plans, confusion around the cause, symptoms of estrogen deficiency, worry over the associated potential medical sequelae such as reduced bone density and cardiovascular risk, and the uncertain future that all of these factors create. There is a need for an evidence-based integrative medicine program to assist women with primary ovarian insufficiency.[8] Presently such a program does not exist in the community, but a community of practice has formed to address this deficiency.[8] Women with primary ovarian insufficiency perceive lower social support than control women, so building a trusted community of practice for them would be expected to improve their well being.[9][10][11][12] It is important to connect women with primary ovarian insufficiency to an appropriate collaborative care team because the condition has been clearly associated with suicide related to the stigma of infertility.[11] Suicide rates are known to be increased in women who experience infertility.[13]

Causes

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.[14] 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 a hysterectomy 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.[15] Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinylestradiol (EE) or with a GnRH-a the receptor sites are free and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur.[16][17] (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.[18])

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

Notes

Mutations in FOXL2 cause Blepharophimosis Ptosis Epicanthus inversus Syndrome (BPES). Premature ovarian failure is part of the BPES Type I variant of the syndrome but not of the BPES Type II variant.[19]

DNA repair deficiency

BRCA1 protein plays an essential role in the repair of DNA double-strand breaks by homologous recombination. Women with a germline BRCA1 mutation tend to have premature menopause as evidenced by the final menorrhea appearing at a younger age.[20] BRCA1 mutations are associated with occult primary ovarian insufficiency.[21] Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.[22]

In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks.[23] In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.[24] MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability.[25][26] The MCM8-MCM9 complex is likely required for the homologous recombinational repair of DNA double-strand breaks that are present during the pachytene stage of meiosis I. In women homozygous for MCM8 or MCM9 mutations, failure to repair breaks apparently leads to oocyte death and small or absent ovaries.[24][25]

Diagnosis

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).

Treatment

Fertility

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 are popular as a means of achieving parenthood 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 hormone called dehydroepiandrosterone (DHEA) in women with POF to increase spontaneous pregnancy rates.[27] 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.[28]

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, some succeeded in getting pregnant through IVF, IUI, IUTPI or natural conception. Many babies have been born after treatment with DHEA.[29]

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.[30]

Hormonal replacement

Most people develop symptoms of estrogen deficiency, including vasomotor flushes and vaginal dryness, both of which respond to hormone replacement therapy. There are several contraindications of estrogen supplement, including smokers over 35 years of age, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of thromboemboli events.

Women younger than 40 year with primary ovarian insufficiency benefit from physiologic replacement of hormones.[1] Most authorities recommend that this hormone replacement continue until age 50 years, the normal age of menopause. The leading hormone replacement regimen recommended involves the administration of estradiol daily by either skin patch or vaginal ring. This approach reduces the risk of pulmonary embolism and deep venous thrombosis by avoiding the first pass effect on the liver that is induced by oral estrogen therapy.[1] To avoid the development of endometrial cancer young women taking estradiol replacement need also to take a progestin in a regular cyclic fashion. The most evidence supports the use of medroxyprogesterone acetate per day for days one through 12 of each calendar month.[1] This will induce regular and predictable menstrual cycles. It is important that women taking this regimen keep a menstrual calendar. If the next expected menses is late it is important to get a pregnancy test. It this is positive, the woman should stop taking the hormone replacement. Approximately 5 to 10% of women with confirmed primary ovarian insufficiency conceive a pregnancy after the diagnosis without medical intervention.[1]

The transdermal estradiol patch is commonly recommended due to 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.[31]

Epidemiology

It has been estimated that POF affects 1% of the female population.[32]

History

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 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.[33] 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: 'not yet old, menstrual water cut-off').[34]

References

  1. 1 2 3 4 5 6 7 Nelson, Lawrence M. (2009). "Primary Ovarian Insufficiency". New England Journal of Medicine. 360 (6): 606–14. PMC 2762081 Freely accessible. PMID 19196677. doi:10.1056/NEJMcp0808697.
  2. ↑ "Medical Terminology Glossary". Retrieved 2008-01-27.
  3. ↑ Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (July 2009). Andrology: Male Reproductive Health and Dysfunction. Springer. pp. 221–. ISBN 978-3-540-78354-1. Retrieved 10 November 2010.
  4. ↑ Van Kasteren, Y.; Schoemaker, J (1999). "Premature ovarian failure: A systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy". Human Reproduction Update. 5 (5): 483–92. PMID 10582785. doi:10.1093/humupd/5.5.483.
  5. ↑ de Bruin JP, Bovenhuis H, van Noord PA, et al. (September 2001). "The role of genetic factors in age at natural menopause". Hum. Reprod. 16 (9): 2014–8. PMID 11527915. doi:10.1093/humrep/16.9.2014.
  6. ↑ Beck-Peccoz P, Persani L (2006). "Premature ovarian failure". Orphanet J Rare Dis. 1: 9. PMC 1502130 Freely accessible. PMID 16722528. doi:10.1186/1750-1172-1-9.
  7. ↑ Groff, Allison A.; Covington, Sharon N.; Halverson, Lynn R.; Fitzgerald, O. Ray; Vanderhoof, Vien; Calis, Karim; Nelson, Lawrence M. (2005). "Assessing the emotional needs of women with spontaneous premature ovarian failure". Fertility and Sterility. 83 (6): 1734–41. PMID 15950644. doi:10.1016/j.fertnstert.2004.11.067.
  8. 1 2 Cooper, Amber R.; Baker, Valerie L.; Sterling, Evelina W.; Ryan, Mary E.; Woodruff, Teresa K.; Nelson, Lawrence M. (2011). "The time is now for a new approach to primary ovarian insufficiency". Fertility and Sterility. 95 (6): 1890–7. PMC 2991394 Freely accessible. PMID 20188353. doi:10.1016/j.fertnstert.2010.01.016.
  9. ↑ Orshan, Susan A.; Ventura, June L.; Covington, Sharon N.; Vanderhoof, Vien H.; Troendle, James F.; Nelson, Lawrence M. (2009). "Women with spontaneous 46,XX primary ovarian insufficiency (hypergonadotropic hypogonadism) have lower perceived social support than control women". Fertility and Sterility. 92 (2): 688–93. PMC 2734403 Freely accessible. PMID 18829005. doi:10.1016/j.fertnstert.2008.07.1718.
  10. ↑ Nelson, Lawrence M.; Captain, U.S. Public Health Service (2011). "Synchronizing the world of women's health: Young Turks and transformational leaders report for duty". Fertility and Sterility. 95 (6): 1902–. PMC 3153063 Freely accessible. PMID 21841843. doi:10.1016/j.fertnstert.2011.03.009.
  11. 1 2 Nelson, Lawrence M. (2011). "One world, one woman". Menopause. 18 (5): 480–487. PMC 3115754 Freely accessible. PMID 21686065. doi:10.1097/GME.0b013e318213f250.
  12. ↑ Sterling, Evelina; Nelson, Lawrence (2011). "From Victim to Survivor to Thriver: Helping Women with Primary Ovarian Insufficiency Integrate Recovery, Self-Management, and Wellness". Seminars in Reproductive Medicine. 29 (4): 353–61. PMC 4350677 Freely accessible. PMID 21969269. doi:10.1055/s-0031-1280920.
  13. ↑ Kjaer, T. K.; Jensen, A.; Dalton, S. O.; Johansen, C.; Schmiedel, S.; Kjaer, S. K. (2011). "Suicide in Danish women evaluated for fertility problems". Human Reproduction. 26 (9): 2401–7. PMID 21672927. doi:10.1093/humrep/der188.
  14. ↑ 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): 90–8. PMID 19324345. doi:10.1016/j.fertnstert.2009.02.014.
  15. ↑ Check JH (1991). "Letter to the Editor". Fertil. Steril. 55 (2): 447–8.
  16. ↑ 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.
  17. ↑ Blumenfeld Z (September 2007). "Pregnancies in patients with POF gonadotropin stimulation and pretreatment with ethinyl estradiol". Fertil. Steril. 88 (3): 763; author reply 763. PMID 17681336. doi:10.1016/j.fertnstert.2007.07.001.
  18. ↑ 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. PMID 16954410. doi:10.1093/humrep/del346.
  19. ↑ http://ghr.nlm.nih.gov/condition/blepharophimosis-ptosis-and-epicanthus-inversus-syndrome
  20. ↑ Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A (2006). "Premature menopause in patients with BRCA1 gene mutation". Breast Cancer Res. Treat. 100 (1): 59–63. PMID 16773440. doi:10.1007/s10549-006-9220-1.
  21. ↑ Oktay K, Kim JY, Barad D, Babayev SN (2010). "Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks". J. Clin. Oncol. 28 (2): 240–4. PMC 3040011 Freely accessible. PMID 19996028. doi:10.1200/JCO.2009.24.2057.
  22. ↑ Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K (2013). "Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans". Sci Transl Med. 5 (172): 172ra21. PMC 5130338 Freely accessible. PMID 23408054. doi:10.1126/scitranslmed.3004925.
  23. ↑ Lee KY, Im JS, Shibata E, Park J, Handa N, Kowalczykowski SC, Dutta A (2015). "MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex". Nat Commun. 6: 7744. PMC 4525285 Freely accessible. PMID 26215093. doi:10.1038/ncomms8744.
  24. 1 2 AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U, Ketterer DM, Afzal S, Ramzan K, Faiyaz-Ul Haque M, Jiang H, Trakselis MA, Rajkovic A (2015). "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability". J. Clin. Invest. 125 (1): 258–62. PMC 4382257 Freely accessible. PMID 25437880. doi:10.1172/JCI78473.
  25. 1 2 Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, Ketterer DM, Matic J, Chipkin J, Jiang H, Trakselis MA, Topaloglu AK, Rajkovic A (2014). "MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability". Am. J. Hum. Genet. 95 (6): 754–62. PMC 4259971 Freely accessible. PMID 25480036. doi:10.1016/j.ajhg.2014.11.002.
  26. ↑ Fauchereau F, Shalev S, Chervinsky E, Beck-Fruchter R, Legois B, Fellous M, Caburet S, Veitia RA (2016). "A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency". Clin. Genet. 89 (5): 603–7. PMID 26771056. doi:10.1111/cge.12736.
  27. ↑ "Clinical Trial: Study of Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)"
  28. ↑ Gleicher N, Weghofer A, Barad DH (2010). "Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS)". Reprod. Biol. Endocrinol. 8: 140. PMC 2992540 Freely accessible. PMID 21067609. doi:10.1186/1477-7827-8-140.
  29. ↑ Mamas L, Mamas E (February 2009). "Premature ovarian failure and dehydroepiandrosterone". Fertil. Steril. 91 (2): 644–6. PMID 18321501. doi:10.1016/j.fertnstert.2007.11.055.
  30. ↑ 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): 617–30. PMID 20462941. doi:10.1093/humupd/dmq010.
  31. ↑ Kalantaridou SN, Nelson LM (2000). "Premature ovarian failure is not premature menopause". Ann. N. Y. Acad. Sci. 900: 393–402. PMID 10818427. doi:10.1111/j.1749-6632.2000.tb06251.x.
  32. ↑ 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. PMID 18028747. doi:10.1016/S1472-6483(10)60388-4.
  33. ↑ 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. PMC 2888894 Freely accessible. PMID 19939372. doi:10.1016/j.fertnstert.2009.10.023.
  34. ↑ Fu Qing-zhu's Gynecology. Fu Qing-zhu, Yang Shou-zhong, Liu Da-wei (trans.). Boulder CO: Blue Poppy Press. 1992. ISBN 0-936185-35-X.
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