Ovarian reserve is a term that is used to determine the capacity of the ovary to provide egg cells that are capable of fertilization resulting in a healthy and successful pregnancy. With advanced maternal age the number of egg cell that can be successfully recruited for a possible pregnancy declines, constituting a major factor in the inverse correlation between age and female fertility.

The primary theory being held to explain the poor ovarian reserve is the depletion of the ovarian pool of non-growing follicles, believed to be at its maximum in-utero and shrinking gradually towards menopause. Several mechanisms have been suggested to explain the decline in oocyte quantity and quality. These include possible differences in germ cell formation during fetal life, changes in the quality of the granulosa cells surrounding the oocyte as well as accumulated damage to the oocytes during childhood and reproductive life. However, the exact mechanism(s) are still mostly obscure. 

Approximately 10% of women deviate from age-specific standards and, before reaching menopause, are assumed to suffer from premature ovarian aging (POA). The size of a woman's initial follicle pool between birth and menarche is of great importance because it reflects the symbolic starting point of follicle depletion. Published ovarian reserve models demonstrate that, due to genetic preprogramming, pools vary greatly in size. 

The most important predictors of the ovarian response to hormonal stimulation are age, biochemical parameters (basal FSH levels in the early follicular phase, serum antimullerian hormone [AMH]), and morphological characteristics (antral follicular count [AFC] and ovarian volume). 

Although ovarian reserve declines with age, it does not represent an optimal predictor of ovarian response. Basal serum FSH (follicle stimulating hormone) concentrations begin to rise on average a decade or more before the menopause. More recently it has been demonstrated that it is a good predictor only at very high threshold levels (>FSH 12 mIU/mL) predicting a very compromised ovarian reserve. 

AMH is produced from preantral follicles and small antral follicles up to 7-8 mm. AMH provides a quantitative evaluation of the amount of follicles that cannot be assessed by AFC. For this reason AMH level has a very low inter- and intracycle variability remaining stable during menstrual cycles but some factors like smoking and current oral contraceptive pills can determine variability. A recent meta-analysis has confirmed AMH an excellent predictor of poor ovarian response to ovarian stimulation although the ideal test is the response of the ovaries to ovarian stimulation itself.

However, the same meta-analysis underlines that AMH and AFC, alone or in combination, did not improve the prediction of ongoing pregnancy rate, with the age of the woman being the most important factor related to live birth rates. 

Poor ovarian reserve can be treated with hormonal stimulation. Predicting ovarian response before starting hormonal stimulation is the only way to administer an efficient and safe treatment. 

Considering modern trends of maternity postponement and the increasing demand for assisted reproduction technologies (ART), the evaluation of functional ovarian reserve has arisen in an attempt to better advise interested couples, helping physicians in the inference of follicular response and success rates, and guiding the elaboration of individualized stimulation protocols, with a reduction of emotional and financial burdens of hard and stressful therapeutic processes. In this context, the identification of women with a lower reproductive potential is a great challenge for reproductive medicine specialists.

Associated diseases 

Premature ovarian failure (POF)

Premature ovarian failure is defined as no menses for six months before the age of forty due to any cause. Often diagnosed by elevated gonadotropin (Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) levels. In some cases (more so in younger women) ovarian function and ovulation can spontaneously resume. With POF up to 50% of women may ovulate once in any given year and 5–10% may become pregnant. POF is often associated with autoimmune diseases.

Premature menopause

Premature menopause is a outdated synonym for premature ovarian failure. The term encompasses premature menopause due to any cause, including surgical removal of the ovaries for any reason. Early menopause and premature ovarian failure are no longer considered to be the same condition.

Complications 

  • infertility

Risk factors 

In poor responders the mechanism of ovarian insufficiency is prematurely determined and not fully understood. Some causes of decrease in ovarian reserve have been identified: ovarian surgery especially in case of endometrioma, genetic defects, chemotherapy, radiotherapy, autoimmune disorders, single ovary, chronic smoking, and unexplained infertility. Moreover, new risk factors of low ovarian response have been proposed: diabetes mellitus Type I, transfusion-dependent B-thalassemia, and uterine artery embolization for the treatment of uterine leiomyoma.

Lastly, some data underlines the role of body mass index (BMI) in female reproduction: obese poor responders could have a lower pregnancy rate than nonobese poor responders.

One of the fundamental steps to reach the success is still related to the number of eggs obtained after hormonal stimulation by gonadotropins in combination with GnRH analogues. In patients defined “poor responders,” the limited number of obtained eggs remains the main problem in optimizing the live birth rates. In fact, as a result of a lower number of oocytes retrieved, there are fewer embryos to select and transfer and subsequently these patients have lower pregnancy rates per transfer and lower cumulative pregnancy rates per started cycle compared with normal responders.

Maternal diet which eliminates high fat/high sugar during pregnancy influences the later life reproductive potential of female offspring. The reproductive system appears to be exquisitely sensitive to early life influences. Maternal diet during pregnancy affects numerous parameters including follicular reserve.

  • infertility

Chinese medicine

Chinese medicine (CHM) has played a unique advantage to improve egg quality and ovarian response, enable a reduction in the dose of gonadotrophin, increase pregnancy rate, and reduce the incidence of ovarian hyperstimulatin syndrome (OHSS). 

Chinese medicine also helps the patients undergo the in vitro fertilization. The mechanisms of adjuvant therapy with CHM in IVF patients may be as follows: (1) reduced ovarian blood flow resistance and increased ovarian perfusion, thus promoting the follicular development and improving the quality of oocyte, (2) improved the endometrial microcirculation and increased the blood flow of endometrium, promoted endometrial thickened, and improved endometrial receptivity and embryo implantation, leading to higher success rate of embryo implant.

Pharmacotherapy

There are several stimulation protocols, which can improve the outcome in poor responding patients. The final decision is always based on patient’s doctor and patient itself. 

The stimulation is primary done with the gonadotropins. Gonadotropins are hormones, which stimulate the pituitary gland to product follicle stimulating hormone. If there is initial poor response, it often leads to increase the dosage. Some studies have showed that there is a small benefit in this strategy. The number of follicles for growth varies every month and no increasion in dosage will altered this number.

Fortunately, there is possibility to combinate stimulating medication with anti-oestrogens and dehydroepiandrosterone. Anti-oestrogens (e.g. Clomiphene) are combined with FSH injections and this maximase the ovarian response. The purpose is to mask the brain women’s own oestrogen levels, and the pituitary gland will produces more FSH and stimulates the ovary. 

Dehydroepiandrosterone (DHEA) is steroid hormone which is a precursor od testosterone and oestrogen and decreases with age. The benefit is that DHEA can be used as a supplementation of oestrogen which is neccessary for follicle growth. 

Surgical therapy 

There is no surgical therapy for this condition.

Natural or Mini-IVF (minimal stimulation in vitro fertilization protocol), but without the use of hCG to trigger ovulation, instead the GnRH agonist (a synthetic peptide that interacts with the gonadotropin-releasing hormone receptor to elicit its biologic response) in a diluted form is taken as a nasal spray to trigger ovulation. Human chorionic gonadotropin (hCG) has a long half life and may stimulate (luteinize) small follicles prematurely and cause them to become cysts. Whereas nafarelin acetate in a nasal spray induces a short lived luteinizing hormone surge that is high enough to induce ovulation in large follicles, but too short lived to adversely affect small follicles. This increases the likelihood of the small follicles and oocytes therein developing normally for upcoming cycles and also allows the woman to cycle without taking a break and consequently increases the probability of conception in poor ovarian reserve women and advanced reproductive aged women.

Oocyte donation followed by in vitro fertilization is the most successful method for producing pregnancy in perimenopausal women with no ovarian response. After stimulation of donor, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. The fertilized eggs (embryos) are cultivated under very stringent conditions and examined every day by the embryologist to evaluate their progress. The embryos are usually cultured for 3 to 5 days, before the best one(s) are selected to be put (transferred) in to the womb.

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