Primary ovarian insufficiency

Primary ovarian insufficiency (POI), also called premature ovarian insufficiency, premature menopause, and premature ovarian failure, is the partial or total loss of

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.^[16]

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.^[17] 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.^[15]

Causes

The cause of POI is

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.[15] 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.^[22]

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.^[15]

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]

Genetic associations include genetic disorders,^[8] autoimmune diseases,^[3] enzyme defects,^[15] 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.^[26]

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.^[27] BRCA1 mutations are associated with occult POI.^[28] Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.^[29]

In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks.^[30] In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.^[31] MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability.^[32][33] 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.^[31][32]

Diagnosis

The diagnosis is based on age less than forty, amenorrhea, and two elevated serum

Researchers have investigated the use of a hormone called dehydroepiandrosterone (DHEA) in women with POI to increase spontaneous pregnancy rates.^[34][35] 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.^[36] This includes women referred for donor eggs or surrogacy in 2009.^[37] In 2018, there was no significant improvement in ovarian function by 12-month on DHEA supplementation in women with POI.^[35] 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.^[38]

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.^[39]

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.^[40][41] 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.^[40]

Hormonal replacement

Women with POI can develop symptoms of estrogen deficiency, including

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.^[10]

Prognosis

Primary ovarian insufficiency is associated with co-morbidities associated with menopause including

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.[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. Also, when having that social support, it often helps with reducing stress and having better coping skills.^{[47][48][49][50]} 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.^[49] Suicide rates are known to be increased in women who experience infertility.^[51]

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][52] 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.^[10]

History

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]

References