Primary ovarian insufficiency

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Primary ovarian insufficiency
Other namesPremature 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.[citation needed]

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.[citation needed] 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.[citation needed] 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.[citation needed] Premature ovarian failure has components to it that distinguish it from normal menopause.[citation needed]

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.[citation needed]

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.[citation needed]

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

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