Endocrine causes of miscarriage

Even 20 years ago, we believed that the most frequent reason for miscarriage is endocrine disruption in the mother's body, and the most common cause was called ovarian hypofunction. Moreover, they pointed out in very numerous works that this is a special hypofunction, an erased form of hormonal disorders, which was detected only with stress tests and in connection with increased hormonal loads during pregnancy.

These findings of many researchers were based mainly on functional diagnostic tests, which in most women with a habitual pregnancy loss showed that they had ovarian hypofunction, which was characterized by an inferior luteal phase (NLF) and alternating ovulatory cycles with anovulatory ones.

It was believed that a deficiency of progesterone leads to an inferior secretory transformation of the endometrium, resulting in inadequate implantation and, in the end, termination of pregnancy. Insufficiency of the luteal phase - this term is used in the morphological evaluation of the endometrium in the postovulatory period, most often at the end of the cycle on day 26 of the 28-day cycle. The found data on the discrepancy of morphological changes to the day of the cycle make it possible to put this diagnosis. Extremely interesting data on this problem were obtained by some groups of researchers. It is shown that an error of 1.81 days from the time of ovulation leads to an incorrect diagnosis. Precisely to establish morphologically NLF it is possible only on 3 and more days after exact are given ovulation.

A biopsy of the endometrium, read by five different pathologists, showed five different interpretations, which leads to a different interpretation of these results by the clinician and the proper purpose of the various therapies. Moreover, the repeated evaluation by the "blind method" of the same pathologist of their previous data gave only 25% of the same interpretations.

It was also found that in women with an undisturbed reproductive function, without a miscarriage in the history, serially produced endometrial biopsy showed 51.4% NLF in one cycle and 26.7% in the following.

The lack of a yellow body does not play a big role in the interruption of pregnancy. Numerous experiments and clinical observations have shown that removal of the yellow body does not always lead to the termination of pregnancy. This is due to the fact that during pregnancy, the yellow body is not the only source of progesterone. The latter is also produced in the adrenal gland, in chorion and in the future - in the placenta.

In addition, a series of studies to determine the level of progesterone in women with miscarriage showed that the diagnosis of NLP by the level of progesterone is not better than in the morphological evaluation of the endometrium.

Nevertheless, even if the mechanism of formation of NLF is not related to the level of progesterone in this category of patients, the mechanism of abortion is associated with those changes that occur in the endometrium as a result of disruption of the processes of secretory transformation caused by insufficiency of production or inadequate response of the target organ to progesterone. In the endometrium, underdevelopment of glands, stroma, vessels, insufficient accumulation of glycogen, proteins, growth factors, excessive amounts of pro-inflammatory cytokines is observed, which leads to inadequate development of the fetal egg and, as a result, miscarriage occurs.

In most women with habitual miscarriages, the level of progesterone in the 2nd phase of the cycle was within the normal range, and in the functional diagnostic tests there was a pronounced NLF.

The development of NLF involves several ways or factors involved. In the pathological process - a decrease in gonadotropin-releasing hormone, a decrease in follicle-stimulating hormone, an inadequate level of luteinizing hormone, inadequate steroidogenesis or impairment of the endometrial receptor apparatus. It is difficult to imagine that a woman with a regular cycle and easily coming pregnancy, with a normal (in most observations) content of progesterone had such severe disorders in the system of regulation of the menstrual cycle. Most likely, the case is in the endometrium, in the defeat of its receptor apparatus. If the reproductive link of the target organ is impaired, the body's response to the normal level of the hormone is insufficient and clinically (according to the functional diagnostic tests), one can note manifestations of hypofunction.

Our studies in patients with clinical manifestations of hypofunction and with uterine hypoplasia showed that in a number of women in the blood in the dynamics of the menstrual cycle, the level of steroid hormones was within the norm. This allowed us to establish the presence of a two-phase menstrual cycle. The content of estradiol in plasma was also normal. However, there was a discrepancy between the level of estradiol and the values of the karyopicnotic index, which led to the hypothesis of an inadequate reaction to the action of the hormone. Progesterone production also corresponded to normal values, i.e. The content of progesterone in the second phase of the cycle indicated a complete steroidogenic activity of the yellow body - 31.8-79.5 nmol / l. When studying the functional state of endometrium in these patients, it was found that the content of total estradiol in the cytosol and in the cell nuclei was significantly reduced at its normal plasma content, and the number of cytoplasmic and nuclear receptors was reliably reduced. When examining women with a habitual miscarriage of late pregnancy, it is established that in the proliferative phase of the cycle the changes in the reception of sex hormones are insignificant in comparison with that in practically healthy women.

The changes consist in a 2-fold increase in the content of the nuclear estrogen receptors (p <0.05) and in the nuclear receptors of progesterone 3 times (p <0.05). However, in the secretory phase of the cycle, there were significant differences in the sexual hormone receptors between healthy women and women with habitual miscarriages of late terms. The level of cytoplasmic, nuclear and total estrogen receptors increased. At the same time, the content of nuclear receptors increased significantly more than cytoplasmic (p <0.05). The greatest changes in the secretory phase of the cycle in women with miscarriages were noted in the content of the nuclear receptors of progesterone, which increased 3-fold. The levels of cytoplasmic and common receptors of progesterone increased slightly. Changes in the content of the receptors of both sex hormones were accompanied by an increase in the ratio of R3 / RP receptors in favor of estrogen receptors in comparison with these data in the control group. In this regard, clinically determined NLF.

Thus, in a number of patients with miscarriages with sufficient production of sex hormones, morphological backwardness and inferiority of one of the most important links of the reproductive system - the endometrium of the uterus - can be preserved. For the biological action of hormones on the tissue, not only the level of steroids in the body is important, but also the preservation of all possible ways of realizing the hormonal effect.

The incomplete luteal phase in many women with miscarriage is associated with other causes, rather than with inferior steroidogenesis: frequent abortions with scraping of the uterine mucosa, chronic endometritis, malformations of the uterus and infantilism, intrauterine synechia. The treatment of such patients by prescribing progesterone, as a rule, does not give an effect. Therefore, the diagnosis of NLF should be a differentiated approach to the restoration of reproductive function. It is also believed that disorders in the receptor link may be the result of impaired expression of the progesterone receptor gene. Specific molecules for treatment can be obtained by cloning.

At present, there are works in which it is emphasized that the decrease in the level of hormones during pregnancy is due not to the fact that the mother has disorders, and that an inadequate fetal egg does not stimulate the mother to the proper production of hormones. The formation of a defective fetal egg can be caused by hypersecretion of LH and hypoxecretion of FSH in the I phase of the cycle. Hypoestrogeny at the stage of selection of the dominant follicle leads to a decrease in the ovulatory peak of LH and a decrease in the level of estradiol, a slowdown in the development of the preovulatory follicle, premature induction of meiosis, intrafocalic overregulation and degeneration of the oocyte. Decreased production of estradiol leads to inferior progesterone production and the lack of proper secretory transformation of the endometrium. Under these conditions, stimulation of folliculogenesis will give a better effect than the postovulatory administration of progesterone.

Thus, the progress of molecular biology and endocrinology allows us to state that NLF is not a frequent cause of miscarriage, as it was believed 10 years ago. NLF can be caused by other disorders that can not be eliminated only by prescribing progesterone preparations during pregnancy. Numerous multicentre studies have shown ineffectiveness of this approach to miscarriage therapy.

Treatment can be prescribed only after a clear diagnosis and understanding of the mechanisms of abortion.

[1], [2], [3], [4], [5], [6]