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Primary ovarian insufficiency

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Primary ovarian insufficiency
Obstetrics and gynecology

Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature

hypergonadotropism, and hypoestrogenism.[5]

Physical and emotional symptoms include

adopt or remain childless.[13]

The causes of POI are heterogeneous and are unknown in 90% of cases.

environmental factors, radiation, or surgery in 10%.[14] 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.[8][6]

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.[15]

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]

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.[medical citation needed] The age of onset can be as early as 11 years.[16]. POI can be seen as part of a continuum of changes leading to menopause[7] that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function.[8] A contrasting problem can be when a girl never begins menstruation due to a genetic condition causing primary amenorrhea.[14]

Causes

The cause of POI is

inhibin alpha gene.[medical citation needed] Chemotherapy and radiation treatments 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.[14] Women who have had a hysterectomy tend to go through menopause early and have a nearly twofold increased risk of POI.[14] 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.[14]

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. The etiologies of POI are highly heterogeneous and include genetic, autoimmune, metabolic or enzyme defects. But these account for only 10% of the cases and 90% have an unknown, idiopathic cause.[14] 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.[17]

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.[14]

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.[18][19] (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.[20]

Genetic associations include genetic disorders,[8]autoimmune diseases,[3]enzyme defects,[14] and resistant ovaries.[8]

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.[21]

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.[22] BRCA1 mutations are associated with occult POI.[23] Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.[24]

In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks.[25] In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.[26] MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability.[27][28] 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.[26][27]

Diagnosis

The diagnosis is based on age less than forty, amenorrhea for four months or more, and two elevated serum follicle-stimulating hormone (FSH) measurements at one-month intervals.[4] 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]

Treatment

Fertility

Between 5 and 10 percent of women with POI may become pregnant with no treatment.

in-vitro fertilization (IVF) and adoption are a means of achieving parenthood for women with POI.[12] Some women with POI choose to live child-free.[13] 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.[29][30] 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.[31] This includes women referred for donor eggs or surrogacy in 2009.[32] In 2018, there was no significant improvement in ovarian function by 12-month on DHEA supplementation in women with POI.[30] 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.[33]

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.[34]

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.[35][36] 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.[35]

Hormonal replacement

Women with POI can develop symptoms of estrogen deficiency, including

vasomotor flushes and vaginal dryness that respond to physiologic replacement of hormones.[9][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][37] The transdermal estradiol patch also provides the replacement by steady infusion rather than by bolus when taking daily pills.[37]

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.[38] There is also an increased risk with valvular heart disease and cardiomyopathy.[39]

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]

Prognosis

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,

autoimmune disorders.[40]

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."

cardiovascular risk, and the uncertain future that all of these factors create.[1][4][6] Women diagnosed with POI in their 20s have disproportionately reported experiencing dismissiveness, bias, and “not being taken seriously” by healthcare professionals.[42]

There is a need for an

integrative medicine program to assist women with POI.[42] 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.[42][43][44][45] 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.[44] Suicide rates are known to be increased in women who experience infertility.[46]


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.[6][47]

History

pituitary FSH and other hormonal secretion.[48][49] POI has been described as a more accurate and less stigmatizing term than premature ovarian failure[4] or premature menopause.[4][10]

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.'[50]

References

  1. ^ . 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."
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  16. ^ Going through the menopause aged 11 BBC News 13 April 2018
  17. PMID 11527915
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  21. ^ "Blepharophimosis, ptosis, and epicanthus inversus syndrome". Medline Plus. Retrieved 10 November 2020.
  22. S2CID 19572648
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  31. PMID 21067609.{{cite journal}}: CS1 maint: unflagged free DOI (link
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  47. PMID 16722528.{{cite journal}}: CS1 maint: unflagged free DOI (link
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  49. ^ 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.
  50. .

External links