Primary ovarian insufficiency explained

Primary ovarian insufficiency[1] [2]
Synonyms:Premature ovarian insufficiency,[3] premature menopause,[4] and premature ovarian failure.[5]
Field:Obstetrics and gynecology

Primary ovarian insufficiency (POI), also called premature ovarian insufficiency, premature menopause, and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular (egg producing area) dysfunction or early loss of eggs.[1] [4] POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function.[6] POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40.[7] A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.[5]

Physical and emotional symptoms are similar to those seen during menopause and can include hot flashes, night sweats, dry skin, vaginal dryness, irregular or absent menstruation, anxiety, depression, mental fog, irritability, nervousness, decreased libido, and increased autoimmune disruption. The sense of shock and distress on being informed of the diagnosis can be overwhelming.[1] Hormonal therapy with estrogen and progesterone is the first line treatment and is associated with improvement of symptoms and possibly improvement in other parameters such as bone density, mortality and cardiovascular risk. The general treatment is for symptoms, bone protection, and mental health.[1] [8] Although 5 to 10% of women with POI may ovulate sporadically and become pregnant without treatment,[9] others may use assisted reproductive technology including in vitro fertilization and egg donation[10] or decide to adopt or remain childless.[11]

The causes of POI are heterogeneous and are unknown in 90% of cases.[7] It can be associated with genetic causes, autoimmune disease, enzyme deficiency, infection, environmental factors, radiation, or surgery in 10%.[12] Two to 5% of women with POI and a premutation in FMR1, a genetic abnormality, are at risk of having a child with fragile X syndrome, the most common cause of inherited intellectual disability.[6] [7]

The diagnosis is based on ages less than 40, amenorrhea, and elevated serum follicle-stimulating hormone (FSH) levels.[4] Typical serum FSH levels in POI patients is in the post-menopausal range.[2] Treatment will vary depending on the symptoms. It can include hormone replacement therapy, fertility management, and psychosocial support, as well as annual screenings of thyroid and adrenal function.[13]

Signs and symptoms

The signs and symptoms of POI can be seen as part of a continuum of changes leading to menopause. POI contrasts with age-appropriate menopause in the age of onset, degree of symptoms and sporadic return to normal ovarian function.[6] As some women retain partial ovarian function, symptoms may not be as severe as regular menopause.[6] In others, particularly with coexistent depression, symptoms such as decreased quality of life can be severe.[14]

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. The age of onset can be as early as 11 years.[15] POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function.[6] A contrasting problem can be when a girl never begins menstruation due to a genetic condition causing primary amenorrhea.[12]

Causes

Genetic associations[16]
TypeOMIMGeneLocus
POF1FMR1Xq26-q28
POF2ADIAPH2Xq13.3-q21.1
POF2BPOF1BXq13.3-q21.1
POF3FOXL23q23
POF4BMP15Xp11.2
POF5NOBOX7q35
POF6FIGLA2p12
POF7NR5A19q33
The cause of POI is idiopathic in 39-67% of cases. Some cases of POI are attributed to autoimmune disorders such as autoimmune oophoritis,[17] Hashimoto thyroiditis, Addison disease, type I diabetes mellitus, pernicious anemia, genetic disorders such as Turner syndrome and Fragile X syndrome, metabolic defects, and enzyme defects.[12] One study showed a strong correlation between incidence of POI and certain variants in the inhibin alpha gene.[18] Chemotherapy and radiation treatments (especially radiation to the pelvis) for cancer can sometimes cause POI. The effect of chemotherapy or radiation is variable and in a mouse model, with results consistent with observations in humans, cyclophosphamide can result in an 87% reduction in primordial follicles 72 hours after administration.[12] Women who have had a hysterectomy tend to go through menopause early and have a nearly twofold increased risk of POI.[12] Almost any pelvic surgery has the potential to damage the ovary by affecting its blood supply or causing inflammation in the area resulting in POI, especially surgery to the ovaries themselves (e.g. for treatment of ovarian cysts or endometriosis).[12] Certain environmental toxins such as phthalates, bisphenols, and dioxins are also associated with POI. Certain infectious diseases, such as mumps or HIV may also damage the ovaries, leading to POI.

Galactosemia

Women who have inherited classic galactosemia (galactose intolerance) may develop primary ovarian insufficiency.[19]

Mechanism

The pathogenic mechanisms of POI are highly heterogeneous and can be divided into four major categories: follicular migration defect early in embryogenesis; an early decrease in the primordial follicles; increased follicular death; and altered maturation or recruitment of primordial follicles.[12] These result in a decrease of the ovaries' general supply of eggs that normally lasts until an average age of 51 for age of age-appropriate menopause.[20]

Genetic causes such as Turner syndrome have initial ovarian development but then ovaries degenerate rapidly during prenatal life, often leading to gonadal dysgenesis with streak ovaries. In those cases where POI is associated with adrenal autoimmunity, histological examination almost always confirms the presence of an autoimmune oophoritis in which follicles are infiltrated by lymphocytes, plasma cells, and macrophages that attack mainly steroid-producing cells and eventually result in follicular depletion.[12]

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.[21] [22] (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.[23]

Genetic associations include genetic disorders,[6] autoimmune diseases,[3] enzyme defects,[12] and resistant ovaries.[6]

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.[24]

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 amenorrhea appearing at a younger age.[25] BRCA1 mutations are associated with occult POI.[26] Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.[27]

In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks.[28] In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.[29] MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability.[30] [31] 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.

Diagnosis

The diagnosis is based on age less than forty, amenorrhea, and two elevated serum follicle-stimulating hormone (FSH) and decreased estrogen measurements at one-month intervals. 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).[2] The evaluation of amenorrhea for other common causes includes checking a blood pregnancy test, checking the prolactin level, as prolactinomas or certain medications can increase prolactin levels and lead to amenorrhea, and checking the thyrotropin (thyroid hormone) level, as hypothyroidism can cause amenorrhea. A karyotype (to evaluate for Turner's Syndrome) and a Fragile-X premutation carrier analysis is also recommended, with additional genetic testing possibly being warranted based on family history of amenorrhea or early menopause or signs and symptoms of a genetic disorder.

Treatment

Fertility

Between 5 and 10 percent of women with POI may become pregnant with no treatment.[9] As of 2016 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.[10] Some women with POI choose to live child-free.[11]

Researchers have investigated the use of a hormone called dehydroepiandrosterone (DHEA) in women with POI to increase spontaneous pregnancy rates.[32] [33] 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.[34] This includes women referred for donor eggs or surrogacy in 2009.[35] In 2018, there was no significant improvement in ovarian function by 12-month on DHEA supplementation in women with POI.[33] 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.[36]

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.[37]

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 phosphatidylinositol-3 kinase activators to enhance the AKT pathway followed by autografting. They successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered.[38] [39] A 2020 review covered variations including phosphatidylinositol-3 kinase activators to enhance the AKT pathway, fragmentation of ovarian cortex, combining those two into in-vitro activation (IVA), and drug-free IVA. Two laparoscopies are needed in conventional IVA and one with drug-free IVA.[38]

Hormonal replacement

Women with POI can develop symptoms of estrogen deficiency, including vasomotor flushes and vaginal dryness that respond to physiologic replacement of hormones.[14] [4] 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.[4] [40] The transdermal estradiol patch also provides the replacement by steady infusion rather than by bolus when taking daily pills.[40]

Concerns of estrogen supplement are addressed in The US Medical Eligibility Criteria for Contraceptive Use, 2010 provides guidance for safety of contraceptive methods and include guidance for conditions associated with increased risk of thrombosis such as postpartum, history of thrombosis, thrombogenic mutations, systemic lupus erythematosus, diabetes, and hypertension.[41] There is also an increased risk with valvular heart disease and cardiomyopathy.[42]

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. 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.[4]

In observational studies, hormone replacement therapy in women with primary ovarian insufficiency and other causes of early menopause was associated with a lower risk of cardiovascular disease, increased bone density, and a reduced mortality.

Prognosis

Primary ovarian insufficiency is associated with co-morbidities associated with menopause including osteoporosis (decreased bone density), which affects almost all women with POI due to an insufficiency of estrogen. There is also an increased risk of heart disease,[6] hypothyroidism such as Hashimoto's thyroiditis, Addison's disease, and other autoimmune disorders.[43]

Emotional health

The most common words women use to describe how they felt in the two hours after being given the diagnosis of POI are "devastated", "shocked," and "confused."[1] [44] The diagnosis is more than infertility and affects a woman's physical and emotional well-being.[4] 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, shame, insecurity and lowered self-esteem, anger in reflection of being letdown by the medical system, 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.[1] [4] [7] Women diagnosed with POI in their 20s have disproportionately reported experiencing dismissiveness, bias, and "not being taken seriously" by healthcare professionals.[45]

Some have advocated formation of a patient registry as well as a community-based research consortium with integrative care to better understand the etiology and treatment of the condition, including treatment of its psychological effects.[46] 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. Also, when having that social support, it often helps with reducing stress and having better coping skills.[47] [48] [49] 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. Suicide rates are known to be increased in women who experience infertility.[50]

Epidemiology

The prevalence increases with age and is approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and one percent by age of 40.[7] [51] It occurs in 3.7% of women worldwide and 1% of women in the United States. In the United States, the incidence is 1% in White women, 1.4% in Black and Hispanic women, with lower rates seen in Chinese and Japanese women, at 0.5% and 0.1% respectively.[52]

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.[53] [54] POI has been described as a more accurate and less stigmatizing term than premature ovarian failure[4] or premature menopause.[4] [8]

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.'[55]

External links

Notes and References

  1. Book: Santoro NF, Cooper AR . Nanette F . Santoro . Amber R . Cooper . Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016 . i–207 . 10.1007/978-3-319-22491-6 . 978-3-319-22490-9 . 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 from a skin biopsy?... Surely, this kind of technology should exist somewhere." and 12. "...night sweats, severe sleep disturbance, dry eyes, and memory loss.".
  2. Pastore LM, Christianson MS, Stelling J, Kearnsa WG, Segars JH . 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 . January 2018 . 28971280 . 5758472 . 10.1007/s10815-017-1058-4 .
  3. Kirshenbaum M, Orvieto R . Premature ovarian insufficiency (POI) and autoimmunity-an update appraisal . Journal of Assisted Reproduction and Genetics . 36 . 11 . 2207–2215 . November 2019 . 31440958 . 10.1007/s10815-019-01572-0 . 6885484 .
  4. Nelson LM . Clinical practice. Primary ovarian insufficiency . The New England Journal of Medicine . 360 . 6 . 606–14 . February 2009 . 19196677 . 2762081 . 10.1056/NEJMcp0808697 .
  5. Zhang C . The roles of different stem cells on premature ovarian failure . Current Stem Cell Research & Therapy . March 2019 . 15 . 6 . 473–481 . 30868961 . 10.2174/1574888X14666190314123006 . 76665931 .
  6. Book: Eckhardt S, Wellons, M. Chapter 1 Defining Menopause: What Is Early, What Is Late?. Santoro NF, Cooper AR. Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016 . 1–17 . 10.1007/978-3-319-22491-6. 978-3-319-22490-9.
  7. Martin LA, Porter AG, Pelligrini VA, Schnatz PF, Jiang X, Kleinstreuer N, Hall JE, Verbiest S, Olmstead J, Fair R, Falorni A, Persani L, Rajkovic A, Mehta K, Nelson LM . 6 . A design thinking approach to primary ovarian insufficiency . Panminerva Medica . 59 . 1 . 15–32 . March 2017 . 27827529 . 10.23736/S0031-0808.16.03259-6 .
  8. Welt CK . Primary ovarian insufficiency: a more accurate term for premature ovarian failure . Clinical Endocrinology . 68 . 4 . 499–509 . April 2008 . 17970776 . 10.1111/j.1365-2265.2007.03073.x . 21359408 .
  9. van Kasteren YM, Schoemaker J . Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy . Human Reproduction Update . 5 . 5 . 483–92 . 1999 . 10582785 . 10.1093/humupd/5.5.483 . free .
  10. Book: Ikhena DE, Robins JC . Chapter 8 IVF and Egg Donation: Special Considerations . Santoro NF, Cooper AR. Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016. 125–136 . 10.1007/978-3-319-22491-6 . 978-3-319-22490-9.
  11. Book: Bevilacqua B . Chapter 10 Primary Ovarian Insufficiency (POI) and Mood Disorders . Santoro NF, Cooper AR. Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016. 145–138 . 10.1007/978-3-319-22491-6 . 978-3-319-22490-9.
  12. Book: Foyouzi N, Green LJ, Camper SA . Chapter 2. Etiologies of Primary Ovarian Insufficiency . Santoro NF, Cooper AR. Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016. 19–35 . 10.1007/978-3-319-22491-6 . 978-3-319-22490-9.
  13. Tiosano D, Mears JA, Buchner DA . Mitochondrial Dysfunction in Primary Ovarian Insufficiency . Endocrinology . 160 . 10 . 2353–2366 . October 2019 . 31393557 . 6760336 . 10.1210/en.2019-00441 . free .
  14. Book: Allshouse AA, Semple AL . Chapter 3 Signs and Symptoms of Primary Ovarian Insufficiency . Santoro NF, Cooper AR. Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016. 40–49 . 10.1007/978-3-319-22491-6 . 978-3-319-22490-9.
  15. https://www.bbc.com/news/video_and_audio/headlines/43705088/going-through-the-menopause-at-11-years-old Going through the menopause aged 11
  16. Web site: OMIM - Online Mendelian Inheritance in Man. . 3 November 2020. omim.org . Johns Hopkins University. 4 November 2020. An Online Catalog of Human Genes and Genetic Disorders.
  17. 5327623 . 2017 . Komorowska . B. . Autoimmune premature ovarian failure . Przeglad Menopauzalny = Menopause Review . 15 . 4 . 210–214 . 10.5114/pm.2016.65666 . 28250725 .
  18. Marozzi A, Porta C, Vegetti W, Crosignani PG, Tibiletti MG, Dalprà L & Ginelli E 2002 Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Human Reproduction 17 1741–1745.doi:10.1093/humrep/17.7.1741.
  19. Thakur. Mili. Feldman. Gerald. Puscheck. Elizabeth E.. January 2018. Primary ovarian insufficiency in classic galactosemia: current understanding and future research opportunities. Journal of Assisted Reproduction and Genetics. 35. 1. 3–16. 10.1007/s10815-017-1039-7. 1573-7330. 5758462. 28932969.
  20. de Bruin JP, Bovenhuis H, van Noord PA, Pearson PL, van Arendonk JA, te Velde ER, Kuurman WW, Dorland M . 6 . The role of genetic factors in age at natural menopause . Human Reproduction . 16 . 9 . 2014–8 . September 2001 . 11527915 . 10.1093/humrep/16.9.2014 . free .
  21. Blumenfeld Z, Halachmi S, Peretz BA, Shmuel Z, Golan D, Makler A, Brandes JM . Premature ovarian failure—the prognostic application of autoimmunity on conception after ovulation induction . Fertility and Sterility . 59 . 4 . 750–5 . April 1993 . 8458491 . 10.1016/S0015-0282(16)55854-3 .
  22. Blumenfeld Z . Pregnancies in patients with POF gonadotropin stimulation and pretreatment with ethinyl estradiol . Fertility and Sterility . 88 . 3 . 763; author reply 763 . September 2007 . 17681336 . 10.1016/j.fertnstert.2007.07.001 . free .
  23. Méduri G, Massin N, Guibourdenche J, Bachelot A, Fiori O, Kuttenn F, Misrahi M, Touraine P . 6 . Serum anti-Müllerian hormone expression in women with premature ovarian failure . Human Reproduction . 22 . 1 . 117–23 . January 2007 . 16954410 . 10.1093/humrep/del346 . free .
  24. Web site: Blepharophimosis, ptosis, and epicanthus inversus syndrome. Medline Plus . 10 November 2020.
  25. Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A . Premature menopause in patients with BRCA1 gene mutation . Breast Cancer Research and Treatment . 100 . 1 . 59–63 . November 2006 . 16773440 . 10.1007/s10549-006-9220-1 . 19572648 .
  26. Oktay K, Kim JY, Barad D, Babayev SN . 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 . January 2010 . 19996028 . 3040011 . 10.1200/JCO.2009.24.2057 .
  27. Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K . 6 . Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans . Science Translational Medicine . 5 . 172 . 172ra21 . February 2013 . 23408054 . 5130338 . 10.1126/scitranslmed.3004925 .
  28. Lee KY, Im JS, Shibata E, Park J, Handa N, Kowalczykowski SC, Dutta A . MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex . Nature Communications . 6 . 7744 . July 2015 . 26215093 . 4525285 . 10.1038/ncomms8744 . 2015NatCo...6.7744L .
  29. 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 . 6 . Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability . The Journal of Clinical Investigation . 125 . 1 . 258–62 . January 2015 . 25437880 . 4382257 . 10.1172/JCI78473 .
  30. 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 . 6 . MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability . American Journal of Human Genetics . 95 . 6 . 754–62 . December 2014 . 25480036 . 4259971 . 10.1016/j.ajhg.2014.11.002 .
  31. Fauchereau F, Shalev S, Chervinsky E, Beck-Fruchter R, Legois B, Fellous M, Caburet S, Veitia RA . 6 . A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency . Clinical Genetics . 89 . 5 . 603–7 . May 2016 . 26771056 . 10.1111/cge.12736 . 33006407 .
  32. Mamas L, Mamas E . Dehydroepiandrosterone supplementation in assisted reproduction: rationale and results . Current Opinion in Obstetrics & Gynecology . 21 . 4 . 306–8 . August 2009 . 19610174 . 10.1097/gco.0b013e32832e0785 . 23452697 .
  33. Wong QH, Yeung TW, Yung SS, Ko JK, Li HW, Ng EH . 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 . May 2018 . 29520734 . 5984890 . 10.1007/s10815-018-1152-2 . free .
  34. Gleicher N, Weghofer A, Barad DH . Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS) . Reproductive Biology and Endocrinology . 8 . 140 . November 2010 . 21067609 . 2992540 . 10.1186/1477-7827-8-140 . Norbert Gleicher . free .
  35. Mamas L, Mamas E . Premature ovarian failure and dehydroepiandrosterone . Fertility and Sterility . 91 . 2 . 644–6 . February 2009 . 18321501 . 10.1016/j.fertnstert.2007.11.055 . free .
  36. Book: Joachim CM. Chapter 12 Hormone Replacement Therapy in Women with POI: A Patient's Perspective . Santoro NF, Cooper AR. Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016. 179–199. 10.1007/978-3-319-22491-6 . 978-3-319-22490-9.
  37. Jadoul P, Dolmans MM, Donnez J . 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 . 2010 . 20462941 . 10.1093/humupd/dmq010 .
  38. Ferreri J, Fàbregues F, Calafell JM, Solernou R, Borrás A, Saco A, Manau D, Carmona F . Drug-free in-vitro activation of follicles and fresh tissue autotransplantation as a therapeutic option in patients with primary ovarian insufficiency . Reprod Biomed Online . 40 . 2 . 254–260 . February 2020 . 31956062 . 10.1016/j.rbmo.2019.11.009 . 210830148 .
  39. Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, Ho CH, Kawamura N, Tamura M, Hashimoto S, Sugishita Y, Morimoto Y, Hosoi Y, Yoshioka N, Ishizuka B, Hsueh AJ . 6 . 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 . October 2013 . 24082083 . 3808580 . 10.1073/pnas.1312830110 . 2013PNAS..11017474K . free .
  40. Kalantaridou SN, Nelson LM . Premature ovarian failure is not premature menopause . Annals of the New York Academy of Sciences . 900 . 1 . 393–402 . 2000 . 10818427 . 10.1111/j.1749-6632.2000.tb06251.x . 2000NYASA.900..393K . 37586048 .
  41. Tepper NK, Whiteman MK, Marchbanks PA, James AH, Curtis KM . Progestin-only contraception and thromboembolism: A systematic review . Contraception . 94 . 6 . 678–700 . December 2016 . 27153743 . 10.1016/j.contraception.2016.04.014 . 11034842 .
  42. Gynecologic considerations for adolescents and young women with cardiac conditions: ACOG Committee Opinion, Number 813 . Obstet Gynecol . 136 . 5 . e90–e99 . November 2020 . 33093425 . 10.1097/AOG.0000000000004133 . free . American College of Obstetricians Gynecologists' Committee on Adolescent Health Care .
  43. Book: Santoro NF, Wierman ME, Canty-Woessner C. Chapter 6 Nonreproductive Conditions Associated with Primary Ovarian Insufficiency (POI) . Santoro NF, Cooper AR . Primary Ovarian Insufficiency A Clinical Guide to Early Menopause . Springer . 2016 . 101–114 . 10.1007/978-3-319-22491-6 . 978-3-319-22490-9.
  44. Groff AA, Covington SN, Halverson LR, Fitzgerald OR, Vanderhoof V, Calis K, Nelson LM . Assessing the emotional needs of women with spontaneous premature ovarian failure . Fertility and Sterility . 83 . 6 . 1734–41 . June 2005 . 15950644 . 10.1016/j.fertnstert.2004.11.067 . free .
  45. Orshan SA, Ventura JL, Covington SN, Vanderhoof VH, Troendle JF, Nelson LM . 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 . August 2009 . 18829005 . 2734403 . 10.1016/j.fertnstert.2008.07.1718 .
  46. Cooper AR, Baker VL, Sterling EW, Ryan ME, Woodruff TK, Nelson LM . The time is now for a new approach to primary ovarian insufficiency . Fertility and Sterility . 95 . 6 . 1890–7 . May 2011 . 20188353 . 2991394 . 10.1016/j.fertnstert.2010.01.016 . free .
  47. Nelson LM . Synchronizing the world of women's health: young Turks and transformational leaders report for duty . Fertility and Sterility . 95 . 6 . 1902 . May 2011 . 21841843 . 3153063 . 10.1016/j.fertnstert.2011.03.009 .
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