Premature ovarian insufficiency (POI) is a clinical syndrome, defined by a loss of ovarian activity up to 40 years, characterized by amenorrhea more than 4 months with increased FSH and low estradiol, traditionally defined as hypergonadotropic hypogonadism. Prevalence of premature ovarian insufficiency is 1%. Since about 50% of women with primary ovarian insufficiency have intermittent ovarian function resulting in intermittent and unpredictable menstruation rather than full amenorrhea, a more practical definition is 4 months or more of “disordered” menstruation (amenorrhea, oligomenorrhoea, polymenorrhea, or metrorrhagia) in combination with menopausal levels of FSH.
A triad of symptoms determines premature ovarian insufficiency:
Amenorrhea or disordered menstruations for at least 4 months,
Reduction of serum estradiol concentration,
Elevated concentrations of serum FSH (more than 40 IU/L, in at least two samples, separated by 1 month).
Premature ovarian insufficiency usually results in premature exhaustion of the follicular pool; this can occur before the menarche or at any time up to 40 years. Although menstrual cycles stop in these patients, some of them still contain residual small ovarian follicles that do not produce enough circulating estrogens and progesterone to modulate the functions of the uterus.
The association between reduced natural fertility and a decrease in the success rate of ART with an increase in FSH concentration and an increase in age confirms the presumption of ovarian insufficiency.
In 90% of cases of primary ovarian insufficiency, the cause remains a mystery. Evidence of a number of genetic factors is growing rapidly.
The development of primary ovarian insufficiency can be explained:
Reduced ovarian reserve at birth,
Accelerated intake of the primary follicle,
Increased follicular atresia (exhaustion) or follicular dysfunction.
Follicular dysfunction indicates that the follicles remain in the ovary, but the pathological process prevents their normal function (e.g., due to mutation of the FSH receptor).
Follicle depletion indicates that the original follicles did not remain in the ovary. This may be because the uterus did not have a sufficient initial pool of primary follicles, accelerated follicular consumption or autoimmune or toxic destruction of follicles. Follicular depletion is the cause in almost all cases (depletion of the primary follicle pool is the cause of primary ovarian insufficiency in most women).
Management of Disease
First attention should be focused on excluding those causes of primary ovarian insufficiency, which have important potential health consequences for the patient or other members of her family. Those with chromosomal translocations or deletions or fragile X pre-mutations should receive appropriate genetic counseling, and those with an autoimmune disease will require careful monitoring over time to ensure rapid recognition and treatment of emerging and potentially serious health problems.
It is important to emphasize that effective management of primary ovarian insufficiency requires careful counseling and emotional support, as well as specific evaluation and treatment. Young women with primary ovarian insufficiency are not ready for diagnosis. Affected women need and deserve enough time for careful education and planning for their long-term management
Long-term consequences of premature ovarian insufficiency:
Psychological problems and depression,
Reduction of sexual and general well-being,
Ischemic heart disease,
Increased risk for mortality.
The ovarian function includes both fertility and endocrine benefits of ovarian steroids. Loss of ovarian function can adversely affect bone health, cardiovascular system and sexual function.
Influence on Fertility
When the concentration of FSH exceeds 12-15 mIU / mL in women who are less than the usual age of 40, the ovaries are unlikely to respond to stimulanting agents such as human menopausal gonadotropins and recombinant FSH. The poor ovarian response is associated with advanced age of the woman and low ovarian reserve, all of which lead to a decrease in pregnancy rates in ART. It is important to distinguish the deficient ovarian reserve (DOR) from premature ovarian insufficiency and poor ovarian responders (POR).
Options for determining DOR include (i) a woman with any of the risk factors for POR and / or (ii) an abnormal test of the ovarian reserve (i.e., the antral follicular count (AFC) <5-7 follicles or AMH <0.5-1.1 ng / mL). DOR is characterized by poor fertility even when ART is used and represents a serious problem in reproductive medicine.
The level of AMH correlates with the pool of primary follicles and the number of antral follicles; both AMH and AFC are considered the most reliable and accurate markers of the ovarian reserve. In the ESHRE consensus, POR, AMH and AFC are more likely to be considered as a post-hoc test for confirming DOR after the first stimulation of the ovaries, which leads to poor results.
Consensus in Bologna ESHRE 2011 defines women as “poor ovarian respondents” when at least two of the following three characteristics are present:
Advanced maternal age (≥40 years) or any of the risk factors for POR,
Previous poor ovarian response (≤3 oocytes with conventional stimulation protocol),
An abnormal test for the stock of the ovaries (i.e. antral follicular count (AFC) <5-7 follicles or AMH <0.5-1.1 ng / mL).
According to these criteria, the AFC of 5-7 follicles, or an AMH level of 0.5-1.1 ng / mL determines a low ovarian reserve. Recently, it has been proposed to adjust the cut-off levels of AMH to 0.7-1.3 ng / mL.
Patients with a diagnosis of premature ovarian insufficiency should be informed that there is little chance of a spontaneous pregnancy, but despite this, they should be encouraged to use contraception if they want to avoid pregnancy. Although the probability of achieving pregnancy after diagnosis is only about 5-10%, some women with premature ovarian insufficiency really think about it.
Relatives of women with non-atrogenic premature ovarian insufficiency who are concerned about their risk of developing premature ovarian insufficiency failure should be informed that:
There is currently no proven prognostic test to identify women who will develop premature ovarian insufficiency unless a mutation known as associated with premature ovarian insufficiency is found,
There are no established premature precautions associated with ovarian failure,
Preservation of fertility seems a promising option, although research is not enough,
Their potential risk of early menopause should be considered when planning a family.
Serial blood analysis and transvaginal ultrasonography can demonstrate the development of follicles, but often there are disordered patterns of folliculogenesis, and premature luteinization is common. Evidence suggests that physiological exogenous therapy with estrogens allows, but does not improve follicular development or ovulation. Although attempts to induce ovulation with exogenous gonadotropins have often been made, women with established hypergonadotropic hypogonadism are poor candidates. Attempts to improve ovulation rates achieved with gonadotropin therapy by pre-treatment with estrogen or GnRH agonist have achieved some limited success, but pregnancy and fertility rates remain extremely low. Infertility associated with premature ovarian insufficiency cannot be treated with intracondrial reproductive technologies.
In the case of patients who are cancer survivors, it is important to keep in mind that in order to be autonomously fertile, a woman should have the following:
Receptive uterus that will support embryo implantation and fetal development to term.
The functioning of the neuroendocrine system, which regulates the menstrual cycle and can support pregnancy,
A healthy pool of follicles that grows in response to hormonal signals and produce mature and convenient gametes,
A receptive uterus that will support embryonic implantation and fetal development before the term.
Cancer treatments such as chemotherapy, radiation therapy, bone marrow transplantation or surgery, either alone or in combination, can threaten fertility by endangering these three main components of the reproductive axis, depleting the scent of the woman’s ovary, causing her premature menopause, changing the function of the HPG axis, or by making her uterus unsuitable for embryos.
The preservation, observation and restoration of fertility are becoming an integral part of caring for women who have had cancer, and just as important as advising patients that their fertility can threaten their cancer treatment, it is equally important to tell them that they may in fact never lose their fertility.
Premature ovarian insufficiency patients are infertile because of lack of follicle growth and ovulation; the only successful treatment option is IVF using donor oocytes; there is no evidence that any form of treatment, other than donating eggs and IVF, may increase the likelihood of pregnancy. Pregnancy of oocyte donations is a high risk and should be managed in the appropriate obstetric group. Antenatal aneuploidy screening should be based on the age of the donor.
Following by the increased cancer survival rates due to advances in diagnosing and treating of childhood, adolescents and adults, there is a significantly increased life expectancy of women diagnosed with cancer, and there is growing interest in preventing loss of reproductive fitness due to either cancer or its treatment with gonadotoxic treatments; efforts to preserve fertility received considerable attention. Unfortunately, cancer therapy has contributed to an increase in the population of women with premature ovarian insufficiency. That is why counseling on future childbearing options will be necessary before chemotherapy or radiation therapy begins.
The established methods for maintaining fertility include the cryopreservation of oocytes and embryos, which are derived from conventional reproductive clinical practice and oophoropexy transposition, which can be offered to women who have undergone pelvic irradiation. Ovarian tissue cryopreservation (OTC) is considered experimental, requires additional informed consent and is usually offered to patients for whom established methods could not be applied. The most appropriate strategy for maintaining fertility depends on various parameters, including the type of cancer, the chemotherapeutic strategy, the patient’s age, and the status of the partner. According to the American Society of Reproductive Medicine, the only established method of preserving fertility is the embryo cryopreservation. However, cryopreservation of ovarian tissue becomes a promising alternative to ovarian hyperstimulation, especially in patients with pre-pubertal cancer, in whom ovarian hyperstimulation with subsequent oocyte or cryopreservation of embryos is contraindicated or when the time necessary for ovarian stimulation is impossible. The benefits of using cryopreserved ovarian tissue include the possibility of future transplantation to restore temporarily hormonal function and fertility.
Not all patients are candidates for or want to continue maintaining fertility; thus, patients should also be informed about alternative options for having a family after cancer, such as oocyte donation, adoption, and choosing not to have children.
It is very important to inform women with premature ovarian insufficiency that there are no interventions that have been reliably proven to increase ovarian activity and natural conception, and that, when premature ovarian insufficiency is established, the opportunity for fertility preservation is missed.
The delay in childbearing is associated with an increased risk of infertility. Women with early age-related ovarian reserve may be at particular risk and may therefore be overrepresented among infertile patients.