Premature Ovarian Failure

Premature Ovarian Failure

The loss of ovarian function before the age of 40 is known as “premature ovarian failure” (POF). The phrase refers to a situation in which the ovaries have lost their germinative and hormonal functions due to ovarian follicle exhaustion before the customary age for physiological menopause.

POF is most likely to occur when the number of ovarian follicles is depleted in conjunction with autoimmune ovarian injury and is linked to a hereditary susceptibility.

Approximately 1% of women acquire Premature ovarian failure. POF affects one in every 100 women under the age of 40 and one in every 1000 women under the age of 30.

Premature ovarian failure: First case reports

In 1967, De Moraes-Ruehsen and Jones classified premature ovarian failure as non-physiological amenorrhoea before the age of 40 but beyond puberty. The term “hypergonadotropic hypoestrogenism” was coined in 1939 to explain the hormone profile of women with POF. Atria studied the clinical characteristics of POF in depth in 1950. The author described 20 young women under the age of 35 who had secondary loss of menses, hot flushes, infertility, and endometrial shrinkage.

Premature Ovarian Failure

Premature ovarian failure:Diagnosis

When examining a young female patient who is trying to conceive or has secondary amenorrhoea, the physician may come upon this condition. It may be helpful to discover if there are any menopausal symptoms in order to make a diagnosis in the case of a young girl. Patients with POF typically have a normal age of menarche and regular menstrual cycles, which are followed by oligomenorrhoea or sudden amenorrhoea. After quitting contraceptive medications, secondary loss of menses is sometimes diagnosed. Hot flushes, excessive sweating, hair loss, and skin and mucous membrane dryness are the most common complaints among women.

Premature ovarian failure: Tests reveal a hypergonadotropic-hypogonadic hormone profile.

A hypergonadotropic-hypogonadic hormone profile (also known as primary hypogonadism) includes low oestradiol (E2) levels (20 pg/ml), elevated gonadotropin levels (follicle-stimulating hormone [FSH] > 20 IU/l), low anti-Müllerian hormone (AMH) levels – 0.5 ng/ml (1.0 ng/ml), and low inhibin B levels.

Early ovarian failure is defined as FSH levels greater than 40 IU/l measured at least twice over a 4-6 week period.A single FSH test should not be used to make a diagnosis because this puts young women under a lot of mental stress. The patient should also be informed that ovarian function may resume temporarily (intermittent ovarian failure). Although it is uncommon, several occurrences of pregnancy in women with POF have been reported.

Low E2 levels are caused by ovarian diseases in which the pituitary gland is stimulated to secrete gonadotropic hormone by a feedback mechanism (high FSH levels). The higher the FSH levels, the worse the ovarian failure.

AMH is a glycoprotein generated by the preantral and tiny antral follicles’ granulosa cells. AMH is a member of the peptide growth and growth differentiation factors family. The day of the cycle has no bearing on AMH levels. Its concentrations diminish with age, making it an excellent predictor of reproductive loss, especially early ovarian failure. AMH levels are exceedingly low or nonexistent in people with POF. The levels of AMH are much higher in women with polycystic ovary syndrome (PCOS), which is characterized by an excess number of ovarian follicles (however, there is no folliculogenesis).

Premature Ovarian Failure

Inhibin B can also be used to determine ovarian reserve. However, because it is produced mostly in the follicular phase of the menstrual cycle by the granulosa cells of the early antral follicles, its measurement is dependent on the phase of the cycle. Inhibin B levels in the early follicular phase reflect the quantity and quality of ovarian follicles. As a result, POF patients have lower levels of inhibin B.

Premature ovarian failure: What affects the ovarian follicular maturation?

The process of ovarian follicular development, or folliculogenesis, in human females is a highly organized and complex one. Folliculogenesis is the process of small primordial follicles maturing into giant ovulatory follicles over time. The gamete, or oocyte, is surrounded by supportive somatic cells, the granulosa, and thecal cells, all of which are necessary for the follicle’s growth and development. The oocytes are discharged from the surface of the ovary, gathered by the uterine tube, and either fertilized and deposited in the uterus or lost when the follicles mature.

Follicular maturation is a continuous process that can take up to a year from the start of growth of a primordial follicle to the emergence of an ovulatory follicle. Human females have a set number of primordial follicles when they are born, but only a few hundred of them fully develop, and the oocyte is released during ovulation. The granulosa and thecal somatic cells produce and secrete a variety of hormones and growth factors, including inhibin, FOXL2, IGF-1, melatonin, steroid hormones, and other growth and differentiation factors (such as bone morphogenetic protein 15 [BMP15] and growth differentiation factor 9 [GDF9]), which are regulated by gonadotrophins, FSH, and luteinizing hormone (LH). Ovulation or follicular atresia are the two outcomes of folliculogenesis.

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Premature ovarian failure: Histopathological diagnosis

POF has been classified into two histological categories. The ovarian follicles are completely depleted in type 1 (afollicular). This type is found in people with POF, which is linked to gonadal dysgenesis, chromosomal abnormalities, and sex development issues. The germinal cells either do not mature or do not exist, resulting in the absence of ovarian follicles. Because the follicular structures in the ovary are retained in type 2 (follicular), ovarian function can be induced or spontaneously restored.

Premature Ovarian Failure

Type 2 POF can take one of three shapes: 1) ovarian follicular inflammation; 2) ovaries with a small number of follicles; or 3) ovaries with a large number of primordial follicles (resistant ovary syndrome-ROS). An afollicular form can develop from a follicular form (in galactosaemia or in an animal model of autoimmune oophoritis).

The occurrence of reactive oxygen species (ROS) appears to have a distinct etiology. Jones and de Moraes-Ruehsen were the first to report three female patients with ROS in 1969; they dubbed it “Savage syndrome” after the first patient’s surname. Other authors have observed a similar set of symptoms, including multiple primordial follicles in the ovary, hypergonadotropic hypoestrogenism, and lower sensitivity to even high-dose gonadotropin, which is used to promote ovulation in patients with both primary and secondary lack of menses.

POF symptoms have been observed in people with ROS. Some studies in ROS patients have revealed the absence of gonadotropin receptors or the presence of antibodies to these receptors that block their activity, whereas others have revealed that the gonadotropin molecule may be abnormally structured (FSH and LH are biologically inactive) or that the thymus may have pathological lesions.

Premature ovarian failure: Causes

Genetic

Turner syndrome, fragile X syndrome (FMR1 gene), and pseudohypoparathyroidism type 1a are examples of hereditary causes of premature ovarian failure (GNAS1 gene). POF has been linked to a variety of non-endocrine and endocrine disorders. Polyendocrinopathies are caused by mutations in the AIRE gene (APS I-III). Based on its putative candidate gene for POF, Inhibin is a putative candidate gene for FSH secretion by the pituitary and gametogenesis in the gonads.

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Table 1

Premature ovarian failure caused by a genetic mutation

TypeOMIMGenLocus
POF1311360FMR1Xq26-q28
POF2A300511DIAPH2Xq13.3-q21.1
POF2B300604POF1BXq13.3-q21.1 POF3608996FOXL23q23POF4300510BMP15Xp11
    
   .2
POF5611548NOBOX7q35
POF6612310FIGLA2p12
POF7612964NR5A19q33

A mutation in the FMR1 gene is one of the causes of POF (called a premutation). FMR1 testing can reveal a propensity for POF, which can lead to decreased fertility or possibly infertility. The test result is critical for women who are debating whether or not to have children. Fragile X syndrome, which is the second most prevalent cause of intellectual disability (mental retardation) after Down’s syndrome, affects men who inherit a deficiency in the FMR1 gene.

It is now sometimes suggested that gene testing for POF be considered before beginning hormonal contraception. Advocates argue that if a woman is aware of a higher chance of getting POF as a result of the mutation, she may decide not to use contraception and have a child earlier in life. Indeed, it is frequently the case that when a woman quits taking long-acting contraceptives, her ovarian function is no longer sufficient to conceive.

Premature ovarian failure: Autoimmune

An autoimmune process involving the generation of anti-ovarian antibodies could also be the reason. Patients with POF can develop symptoms of autoimmune diseases such as autoimmune thyroiditis (Hashimoto’s disease), autoimmune adrenal insufficiency (Addison’s disease), diabetes type 1, coeliac disease, albinism, rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis. They can all occur in patients with POF.

Premature Ovarian Failure

POF is sometimes associated with autoimmune polyglandular syndrome (APS). As a result, in order to identify the former, it’s vital to see if the patient has any other autoimmune endocrine problems, because POF develops 8–14 years before Addison’s illness.

The development of autoimmune disease is a multi-stage process. Genetic and environmental influences must both be present in this scenario. In animal models of insulitis and thyroiditis, the pathogenic mechanisms have been thoroughly explored. To begin with, abnormally large numbers of dendritic cells build up in the endocrine tissue. Then, in an unregulated manner, autoreactive CD4+ and CD8+ cells, which are a source of IgG autoantibodies, are generated. The gland tissue is damaged by autoreactive T cells. Higher macrophage cells and NK cells with MHC class II molecules (histocompatibility complex class II) in the thyroid gland, as well as increased IgG levels in the blood, have been found in patients with autoimmune thyroid illnesses (Graves’ disease and Hashimoto’s disease).

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Premature ovarian failure: Vaccination

A few years ago, cases of POS following anti-HPV immunization were reported. Following HPV vaccines, the patients developed secondary amenorrhea, which did not respond to hormone replacement therapy. Serological tests revealed low E2 levels and elevated FSH and LH, as well as specific auto-antibodies (antiovarian and antithyroid), implying that the HPV vaccine provoked an autoimmune response.

Evidence of the HPV vaccine’s ability to cause a life-threatening autoimmune disease has been documented. A prominent component of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is post-vaccination autoimmune symptoms, and various vaccines, including HPV, have been identified as possible causes.

Premature ovarian failure: Enzymatic

POF can also be caused by a variety of hereditary enzyme defects, such as galactosaemia.

Premature Ovarian Failure

Premature ovarian failure: Oncologic treatment

POF can also occur as a result of ovary surgery or oncologic treatment (radiotherapy or chemotherapy). Ovarian failure occurs at dosages greater than 0.06 Gy, and permanent and irreversible damage to the ovaries occurs at doses greater than 8 G.

Table 2

Chemotherapy drugs and the risk of fertility impairment

Cyclophosphamide has a high risk of impairing fertility. 
 , Melphalan, Dacarbazine, Busulfan, Chlormethine (e.g., MOPP protocol)
Middlecisplatin, carboplatin, doxorubicin, BEP, ABVD
Lowvincristine, methotrexate, bleomycin, mercaptopurine, vinblastine

Premature ovarian failure: Environmental

POF is almost certainly caused by viral infections (mumps virus, cytomegalovirus, varicella-zoster virus). Tuberculosis, malaria, and shigelella infection are all probable causes.

Premature menopause is caused by a variety of conditions, including smoking. The occurrence of this particular cause, however, is determined by the woman herself.

Premature ovarian failure: Unknown

The cause of the majority of isolated problems is still unknown. Although several potential genes have been discovered, causal mutations have only been discovered in a small percentage of cases. The incidence of various genetic abnormalities is still unknown (e.g., BMP15 mutations). Although auto-antibodies against FSHR were found in a group of women with POF in one study, auto-antigens and specific auto-antibodies for the identification of autoimmune variants of isolated POF are yet unknown.

RAFS (reproductive autoimmune failure syndrome) is a word that is becoming more popular. Hence, measuring them is not suggested. Antiovarian antibodies have no relationship with the presence or severity of oophoritis. Measuring CD8 density on T cells could be a good sign of the immune system’s participation in POF.

Premature Ovarian Failure

Premature ovarian failure: Premature ovarian failure symptoms and effects

Hot flushes, increased sweating, anxiety, reduced libido, weakness, and skin and mucous membrane dryness are the early signs of oestrogen insufficiency.

Premature oestrogen shortage also causes a decrease in bone mineral density (osteopaenia, osteoporosis). Densitometry testing is required in these circumstances since even young women with POF are likely to have a significant decrease in bone mineral density. Women who have developed osteoporosis for reasons other than POF have been proven to have a higher risk of fractures than women who have developed osteoporosis for other reasons (such as hyperthyroidism, steroid treatment, or hyperparathyroidism).

Vitamin 25OHD3 levels should also be evaluated in these patients. A probable deficit might be rectified, and bone mass loss could be avoided.

In addition, low oestrogen levels are linked to metabolic abnormalities that can lead to cardiovascular diseases including atherosclerosis and hypercholesterolemia, as well as urogenital atrophy, which includes vaginal dryness and infections.

Lower fertility, if not infertility, is the most concerning POF-related issue for any young woman.

Because autoimmune hypothyroidism is the most common cause of POF, blood tests for TSH, free T4, anti-thyroid-peroxidase, and anti-thyroglobulin antibodies are indicated. Coeliac disease is the most frequent condition linked to POF.

In 2–10% of POF patients, autoimmunity against the adrenal gland has been discovered.

Premature Ovarian Failure

Premature ovarian failure: Ovarian reserve

On cycle day 3, AMH, FSH, antral follicle count (AFC), inhibin B, and E2 tests are used to determine ovarian reserve. POF patients had increased FSH and E2 levels (cycle day 3), significantly reduced AMH and inhibin B levels, and low AFC levels.

The granulosa cells of the preantral follicles produce AMH. AMH is now thought to be the most effective marker for assessing ovarian reserve. FSH levels can fluctuate from one period to the next.

FSH levels greater than 15 IU/l are considered abnormal, while FSH levels greater than 20 IU/l make getting pregnant extremely unlikely. According to some evidence, even at FSH levels of more than 10 IU/l, the ovarian reserve is thought to be decreased. FSH values are frequently normal in women with poor ovarian reserve. As a result, both FSH and AMH levels should be evaluated in order to estimate ovarian reserve.

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Premature ovarian failure: Treatment

If at all possible, casual therapy should be used. Following the introduction of a gluten-free diet, some patients with coeliac disease have reported a return of ovarian function. Hormone replacement therapy has also been used as a substitute treatment.

Aside from that, beneficial benefits have been documented following POF treatment with immunomodulation therapy (to stimulate ovulation), such as high-dose corticosteroids and intravenous immunoglobulin. In addition, patients who underwent thymectomy for myasthenia gravis have reported a recovery of ovarian function. Monoclonal antibodies (e.g., etanercept) have also been tried to treat POF induced by autoimmune ovarian injury.

Melatonin supplementation has recently been proposed as a therapy option for perimenopause. It has been shown to improve thyroid function while also raising gonadotropin levels. According to some studies, melatonin may also help to restore fertility and menstruation, as well as prevent menopause-related depression.

Premature Ovarian Failure

Melatonin is primarily generated by the pineal gland, although it is also produced by other human tissues such as the retina, digestive tract, skin, bone marrow, and lymphocytes. Although its paracrine activity is widely acknowledged, its precise involvement is as yet unknown. Because light interferes with the synthesis of melatonin, it is synthesized in the dark.

The presence of LH, FSH, androgens, and oestrogen receptors in the pineal gland has been proven. Furthermore, during ovulation, melatonin has been found in the follicular fluid. Its concentrations are three times higher than in blood serum, and its levels are higher in the mornings and during the seasons of the year when there is less sunshine. Melatonin, which can be found in the follicular fluid, comes from the blood, and mature follicles are most likely able to store it because the ovaries cannot make it. Melatonin appears to help with ovulation.

According to research, melatonin levels are lower throughout perimenopause and following menopause. Lower LH levels were seen in women 43–49 years of age (perimenopause), but not in those following menopause, after taking 3 mg of melatonin daily for six months (aged 50–62 years). FSH levels were observed to be lower in women who had low melatonin levels at the start. Melatonin treatment resulted in greater thyroid hormone concentrations in all cases. Because it regulates the release of pituitary gonadotropins, melatonin is frequently referred to as a time-keeping hormone.

Melatonin also helps to control the immune system. It increases non-specific humoral and cell-mediated immunity as well as antibody-mediated immunity, both in vitro and in vivo. As a result, some people have tried to employ melatonin to cure cancer. According to epidemiological studies, shift employment has been linked to the development of breast cancer and colorectal cancer in women.

The question is whether melatonin supplementation can protect the body from harmful processes like cancerogenesis and improve circadian rhythms and fertility. The effect of melatonin on the control of ovarian function is still unknown.

Dehydroepiandrosterone (DHEA) supplementation has also been shown to have beneficial effects on women experiencing premature menopause. Infertile women with POF who qualify for donor-egg in vitro fertilization (IVF) therapy have had spontaneous pregnancies. Low DHEA levels in these patients were addressed with DHEA supplementation, resulting in a long-awaited pregnancy prior to IVF therapy. It has been proven that giving DHEA to patients with premature ovarian failure improves their chances of getting pregnant, lowers their risk of miscarriage, and improves the outcome of IVF treatment. According to the most recent recommendations from October 2014, DHEA supplementation should not be utilized in patients with POF who have normal adrenal function.

In women who have POF as a result of chemotherapy, stem cell transplantation has been tried to restore the ovary’s germinative function. Oogenesis has been effectively reestablished in the ovaries in certain experiments, but the ovarian follicles have not matured or generated egg cells, indicating that more study is needed.

Premature Ovarian Failure

Conclusion

Menopause before the age of 40 is known as “premature ovarian failure,” and it affects roughly 1% of women. Infertility (lack of ovulation) and hypoestrogenism are the main issues. Genetic predisposition, autoimmune and enzymatic problems, infections, and iatrogenic causes are all possible causes of POF.

For reproductive-aged women, POF is a devastating diagnosis. The diagnosis is straightforward. It does, however, have substantial health implications, including psychological discomfort, infertility, osteoporosis, autoimmune disorders, ischemic heart disease, and increased mortality risk. To avoid long-term repercussions, management should begin right now. The mainstay of treatment is oestrogen therapy. Studies of postmenopausal oestrogen therapy should not be utilized to assess treatment risks in these young women.

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