Endocrine causes of non-pregnancy

Even 20 years ago we believed that the most common cause of miscarriage was endocrine disorders in the mother's body, and the most common cause was ovarian hypofunction. Moreover, it was indicated in many works that this was a special hypofunction, a latent form of hormonal disorders, which was revealed only during stress tests and in connection with increased hormonal loads during pregnancy.

These conclusions of many researchers were based mainly on functional diagnostic tests, which showed that most women with habitual pregnancy loss had ovarian hypofunction, which was characterized by an incomplete luteal phase (ILP) and alternating ovulatory and anovulatory cycles.

It was believed that progesterone deficiency leads to incomplete secretory transformation of the endometrium, which will result in incomplete implantation and, ultimately, termination of pregnancy. Luteal phase insufficiency is a term used in the morphological assessment of the endometrium in the postovulatory period, most often at the end of the cycle on the 26th day of a 28-day cycle. The data found on the discrepancy between morphological changes and the day of the cycle allow this diagnosis to be made. Extremely interesting data on this problem were obtained by some groups of researchers. It was shown that an error of 1.81 days from the time of ovulation leads to an incorrect diagnosis. It is possible to accurately establish morphologically LPI only on the 3rd or more day after the exact date of ovulation.

An endometrial biopsy “read” by five different pathologists yielded five different interpretations, leading to different interpretations of these results by the clinician and, in fact, different treatments. Moreover, a “blind” re-evaluation by the same pathologist of his previous data yielded only 25% of the same interpretations.

It was also found that in women with intact reproductive function, without a history of miscarriage, serial endometrial biopsy showed 51.4% NLF in one cycle and 26.7% in the next.

Insufficiency of the corpus luteum does not play a major role in the termination of pregnancy. Numerous experiments and clinical observations have proven that removal of the corpus luteum does not always lead to termination of pregnancy. This is due to the fact that during pregnancy the corpus luteum is not the only source of progesterone. The latter is also produced in the adrenal glands, in the chorion and later in the placenta.

In addition, a series of studies on determining progesterone levels in women with miscarriage have shown that the diagnosis of NLF by progesterone levels is no better than by morphological assessment of the endometrium.

However, even if the mechanism of formation of NLF is not associated with the level of progesterone in this category of patients, the mechanism of termination of pregnancy is associated with the changes that occur in the endometrium as a result of the disruption of secretory transformation processes caused by insufficient production or inadequate response of the target organ to progesterone. In the endometrium, there is underdevelopment of glands, stroma, vessels, insufficient accumulation of glycogen, proteins, growth factors, an excessive amount of proinflammatory cytokines, which leads to inadequate development of the ovum and, as a result, a miscarriage occurs.

In most women with habitual miscarriage, the progesterone level in the second phase of the cycle was within the normal range, and according to functional diagnostic tests, there was pronounced NLF.

The development of NLF suggests several pathways or factors involved in the pathological process - a decrease in gonadotropin-releasing hormone, a decrease in follicle-stimulating hormone, inadequate levels of luteinizing hormone, inadequate steroidogenesis or disorders of the receptor apparatus of the endometrium. It is difficult to imagine that a woman with a regular cycle and easy pregnancy, with normal (in most cases) progesterone levels, had such severe disorders in the system of regulation of the menstrual cycle. Most likely, the matter is in the endometrium, in the damage of its receptor apparatus. In case of a disorder of the reproductive link of the target organ, the body's response to the normal level of the hormone is insufficient and clinically (according to functional diagnostic tests) manifestations of hypofunction can be noted.

Our studies of patients with clinical manifestations of uterine hypofunction and hypoplasia showed that in a number of women the level of steroid hormones in the blood during the menstrual cycle dynamics was within the normal range. This allowed us to establish the presence of a two-phase menstrual cycle. The content of estradiol in the plasma was also normal. However, a discrepancy was noted between the level of estradiol and the values of the karyopyknotic index, which led to an assumption about an inadequate response 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 full steroidogenic activity of the corpus luteum - 31.8-79.5 nmol/l. When studying the functional state of the endometrium in these patients, it was found that the content of total estradiol in the cytosol and in the cell nuclei was significantly reduced with its normal content in the plasma, and the number of cytoplasmic and nuclear receptors was reliably reduced. When examining women with habitual miscarriage in late pregnancy, it was found that in the proliferative phase of the cycle, changes in the reception of sex hormones are insignificant compared to those in practically healthy women.

The changes consist of a 2-fold increase in the content of nuclear estrogen receptors (p<0.05) and a 3-fold increase in nuclear progesterone receptors (p<0.05). However, significant differences in the reception of sex hormones between healthy women and women with habitual late-term miscarriage were revealed in the secretory phase of the cycle. The level of cytoplasmic, nuclear, and total estrogen receptors increased. The content of nuclear receptors increased to a significantly greater extent than that of cytoplasmic receptors (p<0.05). The greatest changes in the secretory phase of the cycle in women with miscarriage were noted in the content of nuclear progesterone receptors, which increased 3-fold. The levels of cytoplasmic and total progesterone receptors increased insignificantly. Changes in the content of receptors of both sex hormones were accompanied by an increase in the ratio of receptors of the ER/RP in favor of estrogen receptors compared with these data in the control group. In this regard, NLF was clinically determined.

Thus, in a number of patients with miscarriage, with sufficient production of sex hormones, morphological retardation and inferiority of one of the most important links of the reproductive system - the uterine endometrium - may persist. For the biological effect of hormones on tissues, not only the level of steroids in the body is important, but also the preservation of all possible ways of realizing the hormonal effect.

In many women with miscarriage, the defective luteal phase is associated with other causes, not with defective steroidogenesis: frequent abortions with curettage of the uterine mucosa, chronic endometritis, uterine malformations and infantilism, intrauterine adhesions. Treatment of such patients with progesterone, as a rule, does not produce an effect. Therefore, when diagnosing NLF, there should be a differentiated approach to restoring reproductive function. It is also believed that disorders in the receptor link can be the result of impaired expression of the progesterone receptor gene. Specific molecules for treatment can be obtained by cloning.

Currently, there are studies that emphasize that the decrease in hormone levels during pregnancy is due not to the fact that the mother has disorders, but that an inadequate fertilized egg does not stimulate the mother to produce hormones properly. The formation of an inferior fertilized egg can be due to hypersecretion of LH and hyposecretion of FSH in the first phase of the cycle. Hypoestrogenism 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 rate of development of the preovulatory follicle, premature induction of meiosis, intrafollicular overripening and degeneration of the oocyte. A decrease in estradiol production leads to inadequate production of progesterone and the absence of proper secretory transformation of the endometrium. Under these conditions, stimulation of folliculogenesis will give a better effect than 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 was believed 10 years ago. NLF can be caused by other disorders that cannot be eliminated only by prescribing progesterone preparations during pregnancy. Numerous multicenter studies have shown the ineffectiveness of such an approach to the treatment of miscarriage.

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

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