Primary Ovarian Insufficiency

Menopause is a physiological change that happens in women between the ages of 45 and 55. When menopause happens before the age of 40, it is referred to as premature menopause. For many years, this disorder was known by various names, but it is now known as Primary ovarian insufficiency (POI), and idiopathic POI is estimated to affect 1% of females under the age of 40. If not treated properly, POI can lead to a variety of long-term health problems. POI has been linked to a higher risk of cardiovascular morbidity and mortality, as well as a higher risk of morbidity and death related to osteoporotic fractures.

For the long-term health of individuals with POI, it is commonly acknowledged that estrogen replacement up to the usual age of physiological menopause is essential. This will be administered to most women as menopausal hormone therapy (MHT), although it may also be taken as part of the combined oral contraceptive pill. POI is a leading cause of infertility in women, causing severe psychological and emotional distress for women and their families. Because women are unable to produce new eggs once their ovarian reserve has been depleted, oocyte or embryo donation are frequently the sole possibilities for pregnancy.

 

Primary Ovarian Insufficiency Causes

The actual cause of POI will not be discovered in the majority of cases. POI can be caused by a lower ovarian reserve at birth, accelerated follicular atresia that causes ovarian reserve to be depleted sooner, or rare diseases affecting growth hormones and their receptors that prevent follicles from being recruited into the menstrual cycle. Iatrogenic factors are the most common among patients with a clear cause.

 

Iatrogenic Causes

Many young women have survived their tumors thanks to advancements in the treatment of malignant diseases of childhood and adolescence, but at the expense of their ovarian reserves. Not all chemotherapeutic drugs are hazardous to the ovaries, and the alkylating compounds provide the greatest danger because their action is independent of cell cycles. The amount of pelvic radiotherapy required to elicit POI is low, and it is proportional to the ovarian reserve. A woman with a good ovarian reserve will be able to survive some damage from chemotherapy treatment, while a woman with a poor ovarian reserve will have a considerably higher risk of POI as a consequence of the same treatment. The use of GnRH agonists to decrease ovarian activity before chemotherapy may lower the risk of POI afterward. Transposing the ovaries out of the radiation area can also help to reduce the risk of POI from therapy.

 

Surgical Causes

Surgical oophorectomy, which is most usually used to treat pelvic cancer or as a preventative measure to avoid hormone-related malignancies, is another iatrogenic cause of POI. Surgical menopause is frequently linked to a rapid drop in hormone levels, resulting in a dramatic onset of vasomotor symptoms that can be difficult to manage. Unilateral oophorectomy has been demonstrated to cause menopause to occur sooner. Pelvic surgery for benign illnesses has also been demonstrated to impair ovarian reserve, presumably due to a reduction in ovarian blood flow in the case of hysterectomy and salpingectomy. Surgical procedures on the ovary can damage primordial follicles and ovarian reserve declines after ovarian cystectomy. Post-operatively, bilateral endometrioma surgery is linked to a 2 percent probability of POI.

 

Genetic Causes

The most common cause of POI has been linked to genetic factors. In the vast majority of instances, the genetic cause is unknown, and there are numerous candidate genes. The most prevalent recognized genetic cause of POI is X chromosomal defects, which can be found in up to 16% of cases. The X chromosome contains genes that regulate proper ovarian function, and structural anomalies such as the absence or partial deletion of the X chromosome I (Turner Syndrome), X-related mutations, and translocations can cause aberrant gene expression and ovarian insufficiency.

 

Turner Syndrome

1 in every 2500 live births is affected by Turner Syndrome. Turner Syndrome is characterized by small stature, a webbed neck, and a wide carrying angle. Women with Turner Syndrome mosaicism (45XO/ 46XX) are more prone to undergo spontaneous puberty, but will almost certainly experience POI. The option of ovarian stimulation for oocyte retrieval and cryopreservation is available to these young women if they are identified early. The specific karyotype and structure of the mother X chromosome determine the risk of Turner Syndrome inheritance to kids. Women with Turner Syndrome, on the other hand, are more likely to suffer thyroid dysfunction, deafness, skeletal problems, renal or cardiovascular problems, and an increased risk of aortic root dissection-related morbidity and mortality during pregnancy. For some women, these risks are going to be too high during which case surrogacy should be considered. In women with Turner Syndrome who undergo POI prior to puberty, puberty should be induced. It is generally accepted that estrogen is started at a minimal dose, and slowly increased to mimic the natural rise in estrogen over a couple of years. Once breast development has begun, cyclical progestogens are then introduced.

 

Fragile X Mental Retardation 1 (FMR1)

The FMR 1 gene is a CGG trinucleotide repeat-containing unstable region on the X chromosome. These repeats expand in children in an unpredictable manner, and individuals with 50–200 repeats are considered permutation carriers.

The most prevalent cause of mental disabilities is Fragile X syndrome, which affects more men than women. Carriers of the premutation gene may develop POI, and they should be informed that the FMR1 gene may be transmitted down to their children. Preimplantation screening may be used to determine whether the patient does not produce a kid with Fragile X. This is because it is impossible to determine how the FMR1 gene will evolve in later generations.

 

Other Uncommon Genetic Causes

There are a few more critical gene mutations that can cause POI, but they're all quite uncommon. Ataxia telangiectasia is an autosomal recessive disorder in which mutations in the ATM gene induce a protein kinase deficiency, leading to cell cycle dysregulation and immunological deficiency. Blepharophimosis-ptosis-epicanthus-inversus syndrome is an autosomal dominant disorder caused by mutations in the Forkhead box L2 gene. Galactosemia is caused by mutations in the GALT enzyme, which affects a few people. POI is caused by mutations in the FSH and LH receptors, which are highly rare. BMP 15 is a member of the Transforming Growth Factor Beta family of proteins that might cause dysregulation of the follicular granulosa cells, raising the chances of POI.

 

Autoimmune Causes

Other autoimmune indicators are present in up to a third of women with POI, and women with POI are more likely to have autoimmune thyroiditis, inflammatory bowel disease, Type I diabetes, systemic lupus erythematosus, Sjogren's syndrome, and Addison's disease. Ovarian antibody testing is unreliable and not advised. As a result, attempts to cure autoimmune oophoritis are controversial because irreparable depletion of primordial follicles has already happened by the time women report symptoms of POI.

The etiology of POI has been linked to viral diseases such as mumps, herpes simplex, herpes zoster, and cytomegalovirus. Tuberculosis, shigella, and malaria are among the other infections that have been documented.

 

Primary Ovarian Insufficiency Symptoms

Hot flushes, increased sweating, anxiousness, reduced libido, lethargy, and skin and mucous membrane dryness are the early signs of estrogen insufficiency.

Premature estrogen shortage also causes a decrease in bone mineral density (osteopenia, osteoporosis). Densitometry testing is required in these circumstances since even young women with POI 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, 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 estrogen levels are linked to metabolic abnormalities, which 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 POI-related issue for any young woman.

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

 

Primary Ovarian Insufficiency Diagnosis

Hypergonadotropic amenorrhea in a woman under 40 years of age is one of the diagnostic criteria for POI. 6 weeks apart, two FSH values should be acquired. Disorder, hyperprolactinemia, polycystic ovary syndrome, hypothalamic amenorrhea, and pregnancy are all possible causes of oligomenorrhea. An AMH level can help determine ovarian reserve, whereas a pelvic ultrasound scan can help diagnose autoimmune oophoritis. There may be a familial history of early menopause in 12–15 percent of sufferers, especially in younger women and those with a history of mental illness in male relatives, suggesting the FMR1 premutation.   Other tests should be conducted after a POI diagnosis has been made in order to determine the cause. Although the overall incidence will be idiopathic, karyotype and FMR1 premutation testing should be done in conjunction with autoimmune disease screening tests.

 

Primary Ovarian Insufficiency Treatment

The early presenting symptoms of irregular menstrual cycles and vasomotor symptoms, as well as counseling on bone and cardiovascular health, fertility, and psychological pain, should be addressed. An interdisciplinary team approach is frequently the most successful way of assisting patients and their families through this trying time, and professional counselors are crucial for mental health support. Patients should, in an ideal world, have easy access to support groups and skilled care. Care should be coordinated through the family doctor, who should have access to fertility, reproductive endocrinology, and psychiatric services.

 

Vasomotor and Urogenital Symptoms

Vasomotor symptoms are the most common presenting symptoms in women with POI, and they can be quite distressing, especially in women who have experienced rapid ovarian failure, such as that caused by oophorectomy or chemotherapy. MHT (Menopausal Hormone Therapy) is the most effective treatment for vasomotor symptoms and should be used at least until menopause is reached. The advantages of MHT considerably outweigh the dangers for women with POI, and worries about an increased risk of breast cancer and cardiovascular disease should not be applied to this age group. Due to the avoidance of hepatic first-pass metabolism, any elevated risk of venous thromboembolic disease (VTE) may be decreased by using non-oral treatment. Progestogens should be taken to guard against endometrial hyperplasia while the uterus is intact. 

Urogenital symptoms are a direct result of the hypoestrogenic state, which causes the vaginal epithelium to thin. This causes vaginal dryness and irritation, as well as the possibility of superficial dyspareunia. While many vaginal moisturizers and lubricants may provide some comfort, estrogen replacement is the most beneficial. Systemic estrogens may not be enough to relieve these symptoms in some women, and the use of locally active vaginal estrogens should be considered in these circumstances. Despite the fact that MHT remains the mainstay of POI treatment, some women, particularly survivors of hormone-dependent malignancies, will be unable or unwilling to take it. In this group of women, managing vasomotor symptoms is difficult.

Many people will try complementary and alternative therapies, although there is little proof that they work. Clonidine, an alpha-adrenergic agonist, and many SSRIs and SNRIs, including venlafaxine, desvenlafaxine, escitalopram, citalopram, and paroxetine, are among the pharmaceutical options. Paroxetine should not be provided to women who are simultaneously on tamoxifen since it disrupts the metabolism of the latter. Gabapentin and pregabalin are also beneficial in the treatment of VMS. Yoga, relaxation therapy, and exercise have minimal evidence of effect, while data on acupuncture is mixed.

 

Cardiovascular Health

Women with POI have a higher risk of dying young, owing to an increased risk of cardiovascular disease, with surgical menopausal women being the most vulnerable. Women with surgical POI had a higher risk of cardiovascular illness if they did not use HRT, however, large cohort research indicated that even if they take HRT, women with POI have a higher risk of cardiovascular diseases than premenopausal women. Women with POI have a higher risk of ischemic cerebral infarctions, which may be reduced by taking MHT. POI was linked to a higher risk of developing or dying from ischemic heart disease and overall cardiovascular disease, according to a recent systematic review and meta-analysis.

 

Bone Health

Women with POI have a 6-fold higher chance of developing osteoporosis. Estrogen shortage causes reduced peak bone density and an increased risk of osteoporotic fractures, both of which are linked to higher morbidity and death. Women with POI should get a baseline BMD test and be tested for vitamin D deficiency, thyroid disease, and celiac disease. Women should be urged to engage in regular weight-bearing activity, consume enough amounts of dietary calcium, consider supplements, and begin MHT to promote bone density. In addition to cardioprotection and the relief of vasomotor and urogenital symptoms, MHT is a very effective technique for boosting bone density and decreasing fracture risk.

 

Fertility Problems

The impact of POI on fertility will make the identification of POI more challenging for many women. Women are born with a finite number of oocytes, and once their ovarian reserve is depleted, they are unable to produce new eggs. Although there is little possibility of spontaneous pregnancy after idiopathic POI, it can still happen due to random spontaneous ovulation even after the confirmation of POI has been obtained. Although the chances of spontaneous conception are minimal, women with POI who want to have a family should start on MHT rather than the pill because MHT does not prevent ovulation.

Embracing the minimal probability of spontaneous pregnancy, accepting their fertility problems, adopting or fostering children, or utilizing assisted reproductive techniques (ART) to conceive with their own oocytes or donated oocytes or embryos are possible alternatives for women with POI. ART can help detect genetic reasons for POI, especially if the woman has a chromosomal defect or carries the FMR1 premutation. It's crucial to keep in mind that the small probability of pregnancy may be unwanted for a number of women, and in these circumstances, a good contraceptive strategy should be discussed.

Options for fertility preservation for women who need chemotherapy or radiotherapy and are at high risk of POI include oocyte/embryo cryopreservation, ovarian cortex cryopreservation, or ovarian transposition out of the scattered radiation. Because current cancer treatments are so effective, long-term survival rates for many cancers are great, and many cancer survivors later discover that POI-related infertility is a serious problem. The only fertility preservation treatments recommended by the American Society of Reproductive Medicine are embryo and mature oocyte cryopreservation, as well as ovarian translocation. Exogenous FSH is used to stimulate the ovaries for 3-4 weeks, after which oocytes are collected transvaginally. A GnRH antagonist regimen with a GnRH agonist trigger for oocyte maturation should be employed to reduce the risk of ovarian hyperstimulation syndrome. Mature oocytes are vitrified, and once these oocytes have effectively thawed, the odds of a successful fertilization increase.

Live birth is equivalent to a fresh oocyte. Fertilized oocytes can be vitrified into embryos as a potential substitute. Laparoscopic ovarian cortex biopsy is an experimental procedure used when a stimulated IVF cycle to collect eggs before gonadotoxic therapy, such as for hematological malignancies, is not possible. Pre-pubertal girls can also have ovarian cortex biopsies, with the tissue containing many primordial follicles being stored for subsequent transplantation back to the patient.

The main problems with this approach are the significant number of follicles that die during the thawing process, as well as the revascularization process after transplantation. As a result, employing this tissue for long-term hormone synthesis is problematic, as the tissue does not operate in vivo for very long after transplantation. There have only been about 30 kids delivered using this treatment internationally, and there is fear that the ovarian tissue may reintroduce malignancy into the patient.

 

Conclusion

Premature ovarian insufficiency is infrequent but not uncommon, affecting about 6% of women under the age of 40. It will result from a variety of factors. Any young woman who has had secondary amenorrhea or oligomenorrhea for more than four months should be evaluated for this diagnosis. Because POI is a chronic disorder with several comorbidities, it should be managed by a multidisciplinary team of support groups and specialists. When not contraindicated, hormone replacement therapy is the mainstay of treatment and should be maintained until the typical age of menopause.