Biological role of nitric oxide donors in pregravid preparation of women with luteal phase deficiency

Background. At the menstrual cycle beginning there is a proliferation of endometrial cells under the influence of oestrogen, and in the second half, after ovulation there is a differentiation and hypertrophy of cells under the influence of corpus luteum progesterone. Lutein phase deficiency (LPD) can be divided into 3 types: lack of progesterone production (corpus luteum is absent), low progesterone level (corpus luteum hypofunction), and reduction of progesterone production period (short period of corpus luteum existence, luteal phase duration <11 days). Objective. To describe the role of nitric oxide (NO) donors in women with LPD. Materials and methods. Analysis of literature data on this issue. Results and discussion. The main adverse outcome of LPD is the absence or defective transformation and reception of the endometrium required for successful fertilization of the egg. In case of progesterone deficiency, the depth of trophoblast invasion decreases, resulting in abnormal placental development and inadequate uteroplacental blood flow. The latter can further lead to antenatal foetal death and miscarriage, preeclampsia and eclampsia, placental dysfunction. LPD should be suspected in patients with infertility, abnormal uterine bleeding, severe premenstrual syndrome, endometrial hyperplasia, and habitual miscarriage. Ultrasound signs of LPD include the absence of a dominant follicle, absence of ovulation in the presence of a mature follicle (persistence), absence of corpus luteum in the 2nd phase of the cycle, endometrial thickness in the secretion phase <9 mm, increased echogenicity only in the peripheral parts of the endometrium or three-layered endometrium. Functional tests for the detection of LPD include the basal temperature measurement and examination of smears (hypolutein type of smear, preservation of the symptom of cervical mucus crystallization in the 2nd phase of the cycle). A key element of pregravid preparation for women with LPD is the progesterone donation (in oil solution, in etiloleate or micronized). The therapeutic efficacy of different commercial progesterone drugs is the same. Progesterone helps to prepare the endometrium for trophoblast invasion and promotes uterine hypotension. Incomplete secretory transformation of the endometrium during the treatment with progesterone drugs occurs in case of inadequate blood supply to the endometrium due to low density of functional vessels or insufficient content of NO in the endometrium. Back in the late 90’s of last century, it was shown that NO acts as a powerful uterine relaxant, and reduction of its concentration leads to miscarriage. In humans, NO is produced from L-arginine, however, obtaining the required dose of the latter with food is not always possible. When L-arginine (Tivortin aspartate, “Yuria-Pharm”) is used as a NO donor, peripheral vascular dilatation and neoangiogenesis occur, which improves blood supply and endometrial trophic processes; stimulation of gene transcription and cell cycle, which increases the cell population and physiological thickness of the endometrium; regulation of sex hormone synthesis and expression of their receptors, which increases the receptivity of the endometrium. The regimen of Tivortin aspartate administration is the following: 5 ml (1 g) 6 times per day during the menstrual cycle. According to the results of our own study, L-arginine increases the biological effect of progesterone on the endometrium, promotes a more successful restoration of its physiological structure and thickness in women with LPD. The inclusion of L-arginine in the pregravid preparation of women with LPD showed a 1.9-fold decrease in the infertility incidence, a 3.3-fold increase in the number of pregnancies and births, and a 3.4-fold decrease in the number of miscarriages. Conclusions. 1. The main adverse outcome of LPD is the absence or defective transformation and reception of the endometrium required for successful fertilization of the egg. 2. Usage of L-arginine (Tivortin aspartate) as a donor of NO promotes dilatation of peripheral vessels and neoangiogenesis, stimulation of the cell cycle, regulation of the synthesis of sex hormones. 3. Inclusion of L-arginine in the pregravid preparation of women with LPD leads to the decrease in infertility, to the increase in the number of pregnancies and births and to the decrease in the number of miscarriages.