Primary ovarian insufficiency

Primary ovarian insufficiency
Other names: Premature ovarian failure,[1] hypergonadotropic hypogonadism,[1] gonadal dysgenesis (incorrect),[1] premature menopause (incorrect),[1][2] premature ovarian insufficiency
Video explanation
SpecialtyObstetrics and gynecology
SymptomsIrregular periods, hot flashes, night sweats, vaginal dryness, decreased sex drive[2]
ComplicationsTrouble getting pregnant, osteoporosis, heart disease[3][2]
Usual onset35 to 40 years[2]
CausesUsually unknown[2]
Risk factorsGenetic disorders (fragile X syndrome, Turner syndrome), thyroiditis, Addison disease, cancer treatment, cigarette smoke[2]
Diagnostic methodNo periods for at least 4 months and high FSH[1]
Differential diagnosisPremature menopause[2]
TreatmentHormone replacement therapy, in vitro fertilization with egg donation[4][5]
Frequency1 in 1,000 (age 30), 1 in 100 (age 40)[6]

Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), is a loss of function of the ovaries before age 40.[2] The initial symptom is generally irregular periods.[2] This is than followed by symptoms of menopause such as hot flashes, night sweats, vaginal dryness, and decreased sex drive.[2] There is also frequently trouble getting pregnant.[2] Other complications may include osteoporosis and heart disease.[3]

The cause is unknown in 90% of cases.[2] Occasionally it may be linked to genetic disorders such as fragile X syndrome or Turner syndrome, thyroiditis, Addison disease, cancer treatment, or toxins such as cigarette smoke.[2] The underlying mechanism is either no remaining ovarian follicles or ovarian follicle dysfunction.[1] Diagnosis is based on no periods for at least 4 months and a high follicle-stimulating hormone (FSH) level.[1]

Treatment is generally with hormone replacement therapy with estrogen and progesterone.[4] In those who wish to become pregnant options may include in vitro fertilization with egg donation.[5] About 5 to 10% of women become pregnant subsequent to the diagnosis without medical intervention.[1]

Primary ovarian insufficiency, by age 30, affects about 1 in 1,000 and, by age 40, about 1 in 100 women.[6] In those less than 20 it occurs in 1 in 10,000.[3] The term "primary ovarian insufficiency" is preferred and was first used in 1942 by Fuller Albright.[6][1]

Signs and symptoms

The signs and symptoms of POI can be seen as part of a continuum of changes leading to menopause.[7] POI contrasts with age-appropriate menopause in the age of onset, degree of symptoms and sporadic return to normal ovarian function.[8] As some women retain partial ovarian function, symptoms may not be as severe as regular menopause.[8] In others, particularly with coexistent depression, symptoms such as decreased quality of life can be severe.[9] Infertility can be a 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 (decreased bone density) affects almost all women with POI 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 autoimmune disorders.

Hormonally, POI 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 smaller than normal.[10] The age of onset can be as early as 11 years,[11] or can even exist from birth, but varies widely. By the age of 40, approximately one percent of women have POI.[12] 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 POI. 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.

Emotional health

The most common words women use to describe how they felt in the 2 hours after being given the diagnosis of POI are "devastated, "shocked," and "confused."[13][14] These are words that describe emotional trauma. Santoro & Cooper begin ten of twelve scientific chapters with a clinical vignette to point out the emotional impact of a diagnosis of POI. Those vignettes include: "I almost fell out of my chair!" "I could not stop crying…" "I felt like an old woman." "Great! More bad news!" "...just see what happened, and hope." "You push yourself through the fog that is in your head." "I was shocked. Considering I was only 28 years old..." "She is overwhelmed and distraught." "Despite this devastation..." "....some women have more pronounced mood responses to hormonal changes than others." "...could a scientist create more from a skin biopsy?... Surely, this kind of technology should exist somewhere." and "...night sweats, severe sleep disturbance, dry eyes, and memory loss." The first two pages of each chapter are available at the Primary Ovarian Insufficiency: A Clinical Guide to Early Menopause citation link.[13]

The diagnosis is more than infertility and may affect a woman’s physical and emotional well-being.[1] People may have psychological stress of the diagnosis, associated stigma of infertility, grief from the inability to have children, anxiety and depression from the disruption of life plans, confusion around the cause, shame, insecurity and lowered self-esteem, anger in reflection of being letdown by the medical system (women diagnosed with POI in their 20s have disproportionately reported experiencing dismissiveness, bias, and “not being taken seriously” by healthcare professionals),[15] 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 POI.[15] Presently such a program does not exist in the community, but a community of practice has formed to address this deficiency.[7] Women with POI perceive lower social support than control women, so building a trusted community of practice for them would be expected to improve their well being.[15][16][17][18] It is important to connect women with POI to an appropriate collaborative care team because the condition has been clearly associated with suicide related to the stigma of infertility.[17] Suicide rates are known to be increased in women who experience infertility.[19]

Causes

Genetic associations
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

The cause of POI is idiopathic in 90% of cases.[20] Some cases of POI 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 POI and certain variants in the inhibin alpha gene.[21] 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 POI, 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 POI.

Mechanism

There are two basic kinds of POI. 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.[22] 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.[23][24] (Since the serum Anti-Müllerian 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.[25])

The first case contrasts with age-appropriate menopause with an onset at less than 40 years of age.[8] The ovaries generally supply a woman with eggs until age 51, the average age of age-appropriate menopause.[26]

Genetic associations include:

  • Genetic disorders
  • Autoimmune diseases
  • Enzyme defects
  • Resistant ovaries

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.[27]

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.[28] BRCA1 mutations are associated with occult POI.[29] Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.[30]

In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks.[31] In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.[32] MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability.[33][34] 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.[32][33]

Diagnosis

The diagnosis is based on ages less than 40, amenorrhea for 4 months or more, and two elevated serum follicle-stimulating hormone (FSH) measurements at one-month intervals.[35] The anterior pituitary secretes FSH and LH at high levels to try to increase the low estrogen levels that are due to the dysfunction of the ovaries. Typical FSH in POI patients is over 40 mlU/ml (post-menopausal range).[36]

Treatment

Fertility

Between 5 and 10 percent of women with POI may become pregnant with no treatment.[37] Currently no fertility treatment has been found to effectively increase fertility in women with POI, and the use of donor eggs with in-vitro fertilization (IVF) and adoption are a means of achieving parenthood for women with POI.[38] Some women with POI choose to live child-free.[39] See impaired ovarian reserve for a summary of recent randomized clinical trials and treatment methods.

Researchers have investigated the use of a hormone called dehydroepiandrosterone (DHEA) in women with POI to increase spontaneous pregnancy rates.[40][41] Results from studies on DHEA in 2010 indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POI.[42] This includes women referred for donor eggs or surrogacy in 2009.[43] In 2018, there was no significant improvement in ovarian function by 12-month on DHEA supplementation in women with POI.[41] Given the inconclusiveness of potential benefits and risks of testosterone and DHEA supplementation, longer-term, randomized studies are warranted for women and girls with POI.[44]

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.[45]

In 2013, Kawamura in Japan and his collaborators at Stanford University published treatment of infertility of POI patients by fragmenting ovaries followed by in vitro treatment of ovarian fragments with Akt stimulators and autografting. They successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered.[46] An IVA (in vitro activation) approach has been successfully adopted by a group in Zhengzhou University, China.[47] Up to summer of 2018, there were more than one dozen successful cases in Japan, China, Spain, Poland, and Denmark.

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 POI benefit from physiologic replacement of hormones.[35] 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.[35] 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.[35] 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 POI conceive a pregnancy after the diagnosis without medical intervention.[35]

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.[48]

Epidemiology

It is estimated that POF affects 1% of the female population.[49]

History

Fuller Albright et al. in 1942 reported a syndrome with amenorrhea, estrogen deficiency, menopausal FSH levels, and short stature. They used the term “primary ovarian insufficiency” to distinguished POI from ovarian insufficiency secondary to a primary failure of pituitary FSH and other hormonal secretion.[50][51] POI has been described as a more accurate and less stigmatizing term than premature ovarian failure[35] or premature menopause.[35][52]

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.'[53]

References

  1. 1 2 3 4 5 6 7 8 9 10 Nelson, Lawrence M. (2009). "Primary Ovarian Insufficiency". New England Journal of Medicine. 360 (6): 606–14. doi:10.1056/NEJMcp0808697. PMC 2762081. PMID 19196677.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Primary Ovarian Insufficiency". medlineplus.gov. Archived from the original on 17 October 2020. Retrieved 24 October 2020.
  3. 1 2 3 Sharara, Fady I. (2013). Ethnic Differences in Fertility and Assisted Reproduction. Springer Science & Business Media. p. 56. ISBN 978-1-4614-7548-4. Archived from the original on 2021-08-29. Retrieved 2021-01-18.
  4. 1 2 Collins, Gretchen; Patel, Bansari; Thakore, Suruchi; Liu, James (March 2017). "Primary Ovarian Insufficiency: Current Concepts". Southern Medical Journal. 110 (3): 147–153. doi:10.14423/SMJ.0000000000000611. PMID 28257537.
  5. 1 2 Choe, J; Archer, JS; Shanks, AL (January 2020). "In Vitro Fertilization". PMID 32965937. {{cite journal}}: Cite journal requires |journal= (help)
  6. 1 2 3 Hillard, Paula J. Adams; Hillard, Paula Adams (2008). The 5-minute Obstetrics and Gynecology Consult. Lippincott Williams & Wilkins. p. 134. ISBN 978-0-7817-6942-6. Archived from the original on 29 August 2021. Retrieved 26 October 2020.
  7. 1 2 Cooper AR, Baker VL, Sterling EW, Ryan ME, Woodruff TK, Nelson LM (May 2011). "The time is now for a new approach to primary ovarian insufficiency". Fertility and Sterility. 95 (6): 1890–7. doi:10.1016/j.fertnstert.2010.01.016. PMC 2991394. PMID 20188353.
  8. 1 2 3 Eckhardt S, Wellons, M (2016). "Chapter 1 Defining Menopause: What Is Early, What Is Late?". In Santoro NF, Cooper AR (eds.). Primary Ovarian Insufficiency A Clinical Guide to Early Menopause. Springer. pp. 1–17. ISBN 978-3-319-22490-9. Archived from the original on 2020-11-11. Retrieved 2020-09-07.
  9. ↑ Allshouse AA, Semple AL (2016). "Chapter 3 Signs and Symptoms of Primary Ovarian Insufficiency". In Santoro NF, Cooper AR (eds.). Primary Ovarian Insufficiency A Clinical Guide to Early Menopause. Springer. pp. 40–49. ISBN 978-3-319-22490-9. Archived from the original on 2020-11-11. Retrieved 2020-09-07.
  10. ↑ "New research shows stem cell therapy may help women with primary ovarian insufficiency". stemcellstransplantinstitute.com. 25 March 2018. Archived from the original on 29 August 2021. Retrieved 6 September 2020.
  11. ↑ Going through the menopause aged 11 Archived 2018-06-29 at the Wayback Machine BBC News 13 April 2018
  12. ↑ Beck-Peccoz P, Persani L (April 2006). "Premature ovarian failure". Orphanet Journal of Rare Diseases. 1: 9. doi:10.1186/1750-1172-1-9. PMC 1502130. PMID 16722528.
  13. 1 2 Santoro NF, Cooper AR (2016). Primary Ovarian Insufficiency A Clinical Guide to Early Menopause. Springer. pp. i-207. ISBN 978-3-319-22490-9. Archived from the original on 2020-11-11. Retrieved 2020-09-07. Each scientific chapter begins with a clinical vignette: 1. "I almost fell out of my chair!" 2. "I could not stop crying..." 3. "I felt like an old woman." 4. "Great! More bad news!" 5. "...just see what happened, and hope." 6. "You push yourself through the fog that is in your head." 7. "I was shocked. Considering I was only 28 years old..." 8. "She is overwhelmed and distraught." 9. "Despite this devastation..." 10. "...some women have more pronounced mood responses to hormonal changes than others." 11. "...could a scientist create more <eggs> from a skin biopsy?... Surely, this kind of technology should exist somewhere." and 12. "...night sweats, severe sleep disturbance, dry eyes, and memory loss." {{cite book}}: Cite has empty unknown parameter: |7= (help)
  14. ↑ Groff AA, Covington SN, Halverson LR, Fitzgerald OR, Vanderhoof V, Calis K, Nelson LM (June 2005). "Assessing the emotional needs of women with spontaneous premature ovarian failure". Fertility and Sterility. 83 (6): 1734–41. doi:10.1016/j.fertnstert.2004.11.067. PMID 15950644. Archived from the original on 2020-11-16. Retrieved 2019-06-29.
  15. 1 2 3 Orshan SA, Ventura JL, Covington SN, Vanderhoof VH, Troendle JF, Nelson LM (August 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. doi:10.1016/j.fertnstert.2008.07.1718. PMC 2734403. PMID 18829005.
  16. ↑ Nelson LM (May 2011). "Synchronizing the world of women's health: young Turks and transformational leaders report for duty". Fertility and Sterility. 95 (6): 1902. doi:10.1016/j.fertnstert.2011.03.009. PMC 3153063. PMID 21841843.
  17. 1 2 Nelson LM (May 2011). "One world, one woman: a transformational leader's approach to primary ovarian insufficiency". Menopause. 18 (5): 480–487. doi:10.1097/GME.0b013e318213f250. PMC 3115754. PMID 21686065.
  18. ↑ Sterling EW, Nelson LM (July 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. doi:10.1055/s-0031-1280920. PMC 4350677. PMID 21969269.
  19. ↑ Kjaer TK, Jensen A, Dalton SO, Johansen C, Schmiedel S, Kjaer SK (September 2011). "Suicide in Danish women evaluated for fertility problems". Human Reproduction. 26 (9): 2401–7. doi:10.1093/humrep/der188. PMID 21672927.
  20. ↑ Martin LA, Porter AG, Pelligrini VA, Schnatz PF, Jiang X, Kleinstreuer N, et al. (March 2017). "A design thinking approach to primary ovarian insufficiency". Panminerva Medica. 59 (1): 15–32. doi:10.23736/S0031-0808.16.03259-6. PMID 27827529.
  21. ↑ Prakash GJ, Ravi Kanth VV, Shelling AN, Rozati R, Sujatha M (June 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. doi:10.1016/j.fertnstert.2009.02.014. PMID 19324345.
  22. ↑ Check JH (1991). "Letter to the Editor". Fertil. Steril. 55 (2): 447–8.
  23. ↑ Blumenfeld Z, Halachmi S, Peretz BA, Shmuel Z, Golan D, Makler A, Brandes JM (April 1993). "Premature ovarian failure--the prognostic application of autoimmunity on conception after ovulation induction". Fertility and Sterility. 59 (4): 750–5. doi:10.1016/S0015-0282(16)55854-3. PMID 8458491.
  24. ↑ Blumenfeld Z (September 2007). "Pregnancies in patients with POF gonadotropin stimulation and pretreatment with ethinyl estradiol". Fertility and Sterility. 88 (3): 763, author reply 763. doi:10.1016/j.fertnstert.2007.07.001. PMID 17681336.
  25. ↑ Méduri G, Massin N, Guibourdenche J, Bachelot A, Fiori O, Kuttenn F, et al. (January 2007). "Serum anti-Müllerian hormone expression in women with premature ovarian failure". Human Reproduction. 22 (1): 117–23. doi:10.1093/humrep/del346. PMID 16954410. Archived from the original on 2021-08-29. Retrieved 2011-07-23.
  26. ↑ de Bruin JP, Bovenhuis H, van Noord PA, Pearson PL, van Arendonk JA, te Velde ER, et al. (September 2001). "The role of genetic factors in age at natural menopause". Human Reproduction. 16 (9): 2014–8. doi:10.1093/humrep/16.9.2014. PMID 11527915. Archived from the original on 2020-05-16. Retrieved 2011-07-23.
  27. ↑ "BPES". Archived from the original on 2013-07-03. Retrieved 2013-08-31.
  28. ↑ Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A (November 2006). "Premature menopause in patients with BRCA1 gene mutation". Breast Cancer Research and Treatment. 100 (1): 59–63. doi:10.1007/s10549-006-9220-1. PMID 16773440. S2CID 19572648.
  29. ↑ Oktay K, Kim JY, Barad D, Babayev SN (January 2010). "Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks". Journal of Clinical Oncology. 28 (2): 240–4. doi:10.1200/JCO.2009.24.2057. PMC 3040011. PMID 19996028.
  30. ↑ Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, et al. (February 2013). "Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans". Science Translational Medicine. 5 (172): 172ra21. doi:10.1126/scitranslmed.3004925. PMC 5130338. PMID 23408054.
  31. ↑ Lee KY, Im JS, Shibata E, Park J, Handa N, Kowalczykowski SC, Dutta A (July 2015). "MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex". Nature Communications. 6: 7744. Bibcode:2015NatCo...6.7744L. doi:10.1038/ncomms8744. PMC 4525285. PMID 26215093.
  32. 1 2 AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U, et al. (January 2015). "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability". The Journal of Clinical Investigation. 125 (1): 258–62. doi:10.1172/JCI78473. PMC 4382257. PMID 25437880.
  33. 1 2 Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, et al. (December 2014). "MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability". American Journal of Human Genetics. 95 (6): 754–62. doi:10.1016/j.ajhg.2014.11.002. PMC 4259971. PMID 25480036.
  34. ↑ Fauchereau F, Shalev S, Chervinsky E, Beck-Fruchter R, Legois B, Fellous M, et al. (May 2016). "A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency". Clinical Genetics. 89 (5): 603–7. doi:10.1111/cge.12736. PMID 26771056.
  35. 1 2 3 4 5 6 7 Nelson LM (February 2009). "Clinical practice. Primary ovarian insufficiency". The New England Journal of Medicine. 360 (6): 606–14. doi:10.1056/NEJMcp0808697. PMC 2762081. PMID 19196677.
  36. ↑ Pastore LM, Christianson MS, Stelling J, Kearns WG, Segars JH (January 2018). "Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR, and FOR". Journal of Assisted Reproduction and Genetics. 35 (1): 17–23. doi:10.1007/s10815-017-1058-4. PMC 5758472. PMID 28971280.
  37. ↑ van Kasteren YM, 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. doi:10.1093/humupd/5.5.483. PMID 10582785.
  38. ↑ Ikhena DE, Robins JC (2016). "Chapter 8 IVF and Egg Donation: Special Considerations". In Santoro NF, Cooper AR (eds.). Primary Ovarian Insufficiency A Clinical Guide to Early Menopause. Springer. pp. 125–136. ISBN 978-3-319-22490-9. Archived from the original on 2020-11-11. Retrieved 2020-09-07.
  39. ↑ Bevilacqua B (2016). "Chapter 10 Primary Ovarian Insufficiency (POI) and Mood Disorders". In Santoro NF, Cooper AR (eds.). Primary Ovarian Insufficiency A Clinical Guide to Early Menopause. Springer. pp. 145–138. ISBN 978-3-319-22490-9. Archived from the original on 2020-11-11. Retrieved 2020-09-07.
  40. ↑ Mamas L, Mamas E (August 2009). "Dehydroepiandrosterone supplementation in assisted reproduction: rationale and results". Current Opinion in Obstetrics & Gynecology. 21 (4): 306–8. doi:10.1097/gco.0b013e32832e0785. PMID 19610174.
  41. 1 2 Wong QH, Yeung TW, Yung SS, Ko JK, Li HW, Ng EH (May 2018). "The effect of 12-month dehydroepiandrosterone supplementation on the menstrual pattern, ovarian reserve markers, and safety profile in women with premature ovarian insufficiency". Journal of Assisted Reproduction and Genetics. 35 (5): 857–862. doi:10.1007/s10815-018-1152-2. PMC 5984890. PMID 29520734.
  42. ↑ Gleicher N, Weghofer A, Barad DH (November 2010). "Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS)". Reproductive Biology and Endocrinology. 8: 140. doi:10.1186/1477-7827-8-140. PMC 2992540. PMID 21067609.
  43. ↑ Mamas L, Mamas E (February 2009). "Premature ovarian failure and dehydroepiandrosterone". Fertility and Sterility. 91 (2): 644–6. doi:10.1016/j.fertnstert.2007.11.055. PMID 18321501.
  44. ↑ Joachim CM (2016). "Chapter 12 Hormone Replacement Therapy in Women with POI: A Patient's Perspective". In Santoro NF, Cooper AR (eds.). Primary Ovarian Insufficiency A Clinical Guide to Early Menopause. Springer. pp. 179–199. ISBN 978-3-319-22490-9. Archived from the original on 2020-11-11. Retrieved 2020-09-07.
  45. ↑ Jadoul P, Dolmans MM, 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. doi:10.1093/humupd/dmq010. PMID 20462941.
  46. ↑ Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, et al. (October 2013). "Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment". Proceedings of the National Academy of Sciences of the United States of America. 110 (43): 17474–9. Bibcode:2013PNAS..11017474K. doi:10.1073/pnas.1312830110. PMC 3808580. PMID 24082083.
  47. ↑ Zhai J, Yao G, Dong F, Bu Z, Cheng Y, Sato Y, et al. (November 2016). "In Vitro Activation of Follicles and Fresh Tissue Auto-transplantation in Primary Ovarian Insufficiency Patients". The Journal of Clinical Endocrinology and Metabolism. 101 (11): 4405–4412. doi:10.1210/jc.2016-1589. PMC 5095246. PMID 27571179.
  48. ↑ Kalantaridou SN, Nelson LM (2000). "Premature ovarian failure is not premature menopause". Annals of the New York Academy of Sciences. 900 (1): 393–402. Bibcode:2000NYASA.900..393K. doi:10.1111/j.1749-6632.2000.tb06251.x. PMID 10818427.
  49. ↑ 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.{{cite journal}}: CS1 maint: url-status (link)
  50. ↑ Hubayter ZR, Popat V, Vanderhoof VH, Ndubizu O, Johnson D, Mao E, et al. (October 2010). "A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency". Fertility and Sterility. 94 (5): 1769–74. doi:10.1016/j.fertnstert.2009.10.023. PMC 2888894. PMID 19939372.
  51. ↑ Albright F, Smith PH, Fraser R (1941). "A syndrome characterized by primary ovarian insufficiency and decreased stature: report of 11 cases with a digression on hormonal control of axillary and pubic hair". Am J Med Sci. 204: 625–48.
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