Diagnostic testing for Premature Ovarian Insufficiency (POI) is important in order to determine the fertility of a woman.

A woman’s age is the basic predictor of the degree of ovarian aging. However, ovarian aging can develop prematurely, and specific diagnostic methods are needed to detect this condition. There are two types of ovarian aging manifestations with respect to the ovarian ability to produce oocytes: 

1)a quantitative test combination of antral follicle count (AFC), determined by vaginal ultrasound scan at the beginning of the menstrual cycle, and the determination of serum anti-Mullerian hormone (AMH) concentration, which can be performed at any time during the menstrual cycle, is used.

 

2)By contrast, oocyte quality is not necessarily related to AFC and serum AMH. Premature decay of oocyte quality is mainly related to a low-for-age production of growth hormone (GH). Due to the pulsatile pattern of GH secretion, insulin-like growth factor-1 (IGF-1), which does reflect the GH secretion pattern, but with a less pronounced pulsatility, was suggested to identify young patients with a premature decay of oocyte quality who could benefit from treatment with GH during ovarian stimulation. The data presented show that the ‘GH/IGF-1’ age can be more than 20 years higher than the chronological age in some young women, and it was this group of patients who appeared to be more likely to benefit from GH administration during ovarian stimulation, although the authors suggested that larger prospective studies were needed to confirm this assumption. There are only a few clues to detect premature ovarian aging in addition to the above criteria, and further research is warranted to detect more molecular markers that could guide the clinician to propose the best treatment regimen.   

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Treatment

 

 

In view of the fact that oxidative stress is the main factor involved in ovarian aging, it can be assumed that agents reducing oxidative damage represent the first-line choice. These agents can be direct antioxidants or molecules affecting cell-signaling pathways involved in the antioxidant defense of ovarian cells. Some molecules combine both of the above activities.    

 

Agents that can be used to treat the consequences of physiological or premature ovarian aging are:

 

1) GH Subcutaneous Activation of cell-signaling pathways acting  against oxidative stress Possible activation of DNA damage repair

 

 

 

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2)Melatonin Oral Direct antioxidant

Acts as an Indirect antioxidant (signaling pathway modulator) Anti-inflammatory agent Immunomodulator

 

 

 

 

3)Coenzyme Q10 Oral Direct antioxidant

 

 

 

 

4)Vitamin C Oral Direct antioxidant 

 

 

 

 

5)Vitamin E Oral Direct antioxidant

 

 

 

 

6)Folic acid Oral Direct antioxidant 

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GH administration during ovarian stimulation was the first treatment shown to be beneficial in older women. A randomized controlled trial, conducted in a group of 100 women of >40 years undergoing assisted reproduction treatment and randomized between a GH treatment group and a placebo group, showed significantly higher delivery and live birth rates in the GH arm as compared to the placebo arm. Subsequent studies confirmed these findings and extended the use of GH treatment also to younger women with POI. This effect of GH is at least partly due to the alleviation of oxidative stress in the ovary, an effect previously described in some other organs. Though it is not a direct antioxidant, GH intervenes in the cell-signaling pathways involved in cellular defense against oxidative stress, and adult GH deficiency causes an inadequate reactivity of cells against radical production. This can explain why age-related or premature GH deficiency contributes to ovarian decay, even in cases where it is primarily due to other causes. Hence, GH can be used as an adjuvant treatment during ovarian stimulation in women with both age-related ovarian decay and POI.   

 

Melatonin is an example par excellence of a molecule acting as a direct antioxidant and a modulator of systems protecting cells against oxidative stress. First introduced into reproductive medicine to treat infertility caused by endometriosis and adenomyosis, it has proven its usefulness in many more indications, including the protection against the contraction of COVID-19. Since then, new data have emerged showing the possibilities of melatonin in preventing ovarian aging. Even though the mechanism underlying the anti-aging effect of melatonin in the human ovary still needs to be fully explained, the administration of melatonin, lacking serious side-effects and providing additional benefits to patients treated with it, is possibly indicated in women with age-related ovarian decay or POI.

 

Other Antioxidants:

Since ovarian aging is mainly due to oxidative stress, superimposed on the existing genetic makeup, any antioxidant agent can be supposed to improve IVF results in older women and in young women suffering from POI.

 

Unfortunately, there are only a few clinical studies that can conclusively support this reasoning. Coenzyme Q10 (CoQ10) is the antioxidant that accumulates the most evidence in favor of its use in the treatment of women with diminished ovarian reserves, a conclusion corroborated by a recent randomized control trial. However, though potentially less efficient, any antioxidant agent, such as vitamins C and E and folic acid, can be of help.

 

Mitochondrial Therapy

 

The issue of mitochondrial health has been widely debated with respect to the oocyte. Nevertheless, data obtained from a study in an animal model (mouse) indicate that the granulosa cell mitochondria are no less important for the correct oocyte maturation than those of the oocyte itself. Antioxidant agents, such as melatonin, coenzyme Q10, or vitamins C and E (see above) can improve this condition. This can explain why antioxidant pretreatment (coenzyme Q10) improves the ovarian response to gonadotropin stimulation and embryo quality in low-prognosis young women. On the other hand, the accumulation of mitochondrial DNA mutations/deletions in the oocyte, in addition to jeopardizing oocyte developmental potential, can also compromise the health of the offspring. Optimal mitochondrial function is required for oocyte maturation, fertilization, and embryonic development. Improvement of the mitochondrial function, either through the use of small molecules or procedures involving mitochondrial transfers, could lead to better fertility outcomes. Moreover, mitochondrial replacement procedures could open a new page in the treatment of mitochondrial diseases. Mitochondrial transfer from a healthy donor oocyte to the patient’s oocyte is a possible solution, practiced from the late 1990s  but thereafter banned in most countries. This technique can be performed in two different ways: first, by injection of a small amount of donor oocyte cytoplasm into the patient’s oocytes ; second, by transferring the metaphase chromosomes, associated with the meiotic spindle, from the patient’s oocytes to previously enucleated donor oocytes . Curiously, even though the latter technique results in a much higher proportion of “healthy” mitochondria in the reconstructed oocytes as compared to the former one, the efficiency of both techniques appeared similar; more than 40% of live births in young women with previous implantation failures, and several tens of births were obtained with both of them . It has to be stressed, however, that the original indication of both of these techniques was focused on the recurrent failure of embryo development and implantation in young women, rather than on the  avoidance of mitochondrial disease transmission. In addition to mitochondria, ooplasm also contains other developmentally important molecules that can be deficient in patients’ oocytes. One of them is stored maternal mRNA which is crucial for guiding human embryo development until the 4-to 8-cell stage, when the first signs of embryonic genome expression can be detected. However, stored maternal mRNA is also involved in the control of relatively late stages of human preimplantation development, after the activation of embryonic gene expression, when the two mRNA sources act together to regulate the differentiation of the first two embryonic tissues, the inner cell mass, and the trophectoderm . While still banned in the United States, the technique of mitochondrial replacement therapy, using a spindle-chromosome complex transfer from the patient’s oocytes to enucleated donor oocytes, was used with success by a team in a US clinic in Mexico, where there is no legal restriction with regard to this technique, to avoid the mother-to-offspring transmission of a heritable mitochondrial disease, the Leigh syndrome . The authors chose the previously described technique of nuclear transfer, with slight modifications, rather than ooplasmic injection. This technique is currently used, in countries in which it is legally possible, for its initial indication: the repeated failure of embryonic development in young couples with male partners having normal spermatozoa, without strict limitations to previously detected mitochondrial DNA abnormalities.

 

AVOIDING TOXINS:

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In a Cross-sectional analysis from the baseline clinical visit and data collection of the Study of Environment, Lifestyle and Fibroids performed by the National Institute of Environmental Health Sciences. A total of 1,654 volunteers, aged 23–34 years, recruited from the Detroit, Michigan community completed questionnaires on alcohol intake and cigarette smoking and provided serum for anti-Müllerian hormone measurement

Found that Women who reported binge drinking twice weekly or more had 26% lower anti-Müllerian hormone levels compared to current drinkers who never binged (CI: −44, −2, P<0.04). 

This finding suggest alcohol negatively affects ovarian reserve.

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