Reproductive health of adolescent girls born prematurely: new forecasting opportunities

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TPremature birth is one of the most pressing problems in obstetrics. It is well known that children born prematurely have an increased risk of developing somatic and reproductive disorders in the future. It has been proven that their subsequent risk of developing type 2 diabetes mellitus, obesity, hypertension and metabolic syndrome increases [1]. During intrauterine development, the foundation of reproductive health is laid [2]. Premature birth makes changes in the development of the reproductive system in the postnatal period. Numerous studies have shown that organometric parameters and histological structure of the organs of the reproductive system change during early delivery, while the manifestation of pathology has a delayed character - the puberty period and the period of reproduction [3].The aim of the work is to study the state of reproductive health of adolescent girls 16 years old, born prematurely, to develop an algorithm to optimize its condition. Materials and methods.On the basis of the clinic of the Ivanovo Research Institute of Motherhood and Childhood named after V.N. Gorodkova" of the Ministry of Health of the Russian Federation examined 180 16-year-old girls after receiving informed consent. The main group is represented by 120 teenage girls born prematurely (at 27-36 weeks of pregnancy). 1 subgroup is represented by 18 teenage girls born at 27-33 weeks of pregnancy, 2 subgroup - 102 teenage girls born at 34-36 weeks of pregnancy. The comparison group consisted of 60 teenage girls born at term [4].The material for the study was peripheral venous blood. All the girls were examined according to the order of the Ministry of Health of the Russian Federation No. 572n "On approval of the procedure for providing medical care in the field of obstetrics and gynecology" in 2014-2016. Additionally, ultrasound examination of the internal genitalia was performed to determine the volume of the ovaries, the number of antral follicles, evaluation of the serum content of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, testosterone by immunochemiluminescent method, serum content of antimuller hormone and leptin by enzyme immunoassay [4]. Statistical data processing was carried out using the program "Statistica for Windows 10.0". Results.According to the study, an increase in the body mass index of adolescent girls born prematurely, compared with adolescents born at term (21.0 (19.0-23.0) and 20.0 (21.5-22.0) kg/m2, p<0.05) [4]. In the main group of girls, girls with overweight (17.5 and 6.7%, p<0.05) [4] and with a body weight deficit (15.0 and 5.0%, p<0.05) were more often observed relative to the comparison group [4]. In the main group of girls, there were such changes in physical development as growth deficit (5.8 and 0%, p<0.01), overweight at normal body length values (14.2 and 0%, p<0.001), body weight deficit at normal body length values (5.0 and 0%, p<0.02) [4]. In the main group of girls, there was an increase in the frequency of brachymorphic (14.2 and 5%, p<0.05) and pachymorphic (12.5 and 3.3%, p<0.02) somatotypes [4]. When assessing the menstrual cycle, it was revealed that the girls of the main group were more likely to have oligomenorrhea (24.2 and 8.3%, p<0.01) and secondary amenorrhea (6.7 and 0%, p<0.01). The average menarche age of adolescent girls in the studied groups did not differ significantly, but was higher in the first subgroup of girls (13.1±1.2 and 12.8±1.2 years, p<0.01) compared with the second subgroup. Intermenstrual bleeding was significantly more frequent in the 1st subgroup of girls compared with the 2nd subgroup (27.8 and 4.9%, p<0.05). During ultrasound examination of the internal genitalia among the girls of the main group, smaller sizes of the uterus body relative to the age norm were more often observed compared with teenage girls from the comparison group (15.8% and 3.3%, p<0.01). The thickness of the endometrium of girls born prematurely was less than that of girls born on time (5.0 (3.0-6.0) and 5.0 (4.0-6.0) mm, p<0.05) [4].The Ferriman-Gollway index in the examined main group was higher than in the comparison group (7.0 (5.0-10.0) and 6.0 (5.0-7.0), p<0.001). Testosterone levels in girls born prematurely were higher than in girls born on time (0.9 (0.5-1.3) and 0.7 (0.5-1.1) ng/ml, p<0.05). An increase in the level of anti-muller hormone was revealed in the main group of girls relative to the same indicator in the comparison group (2.4 (1.5 – 3.7) and 1.9 (1.5 – 2.4) ng/ml, p<0.01). In the main group of girls, there was an increase in the level of leptin compared with the girls of the comparison group (9.4 (6.1; 15.5) and 6.9 (4.2; 9.2) ng/ml, p<0.01). In addition, girls from the 2nd subgroup showed a positive correlation between the level of leptin and body mass index (p=0.001).In our study, it was found that an increase in the number of antral follicles of more than ten in each ovary was noted more often in girls of the main group. Correlation analysis showed a direct relationship between the number of antral follicles and the level of leptin in adolescent girls born prematurely (p<0.001).To establish the possibility of using the leptin level indicator to estimate the number of antral follicles, a ROC analysis was performed. It was noted that the leptin content of more than 15.8 ng/ml indicates an increase in the number of antral follicles, which may be the cause of reproductive health disorders. The sensitivity of the method was 95.2%, specificity - 79.3%, accuracy - 86% [4].Based on the data obtained, the algorithm of the survey of teenage girls was expanded. When determining the leptin level of more than 15.8 ng/ml, an obstetrician-gynecologist at the place of residence in the risk group [4] was monitored for the formation of polycystic ovary syndrome, as well as an endocrinologist's consultation. When determining the level of leptin equal to or less than 15.8 ng/ml, observation by an obstetrician-gynecologist was recommended in accordance with the order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020.Discussion.Leptin is a protein of 167 amino acids, which is produced in white adipose tissue directly into the vascular bed, and can also cross the blood-brain barrier. Leptin is also produced by brown adipose tissue, in the mammary gland, skeletal muscles, stomach and pituitary gland, as well as in the placenta, but the relative contribution of these organs and tissues to the overall level of circulating leptin is low. In the population, the level of leptin usually correlates with the total amount of adipose tissue in the body, with the exception of the fasting period [5]. Leptin has a variety of effects on various tissues. Leptin can significantly reduce hyperinsulinemia through the central nervous system [5, 7], stimulates the sympathetic and parasympathetic nervous system. Experimental models have shown that intravenous or intracerebroventricular injection of leptin stimulated sympathetic innervation in brown adipose tissue, muscles, liver, kidneys and adrenal glands and parasympathetic in the liver [6]. The effect of leptin on carbohydrate and fat metabolism is known. In addition to lowering blood glucose levels, it can inhibit the production and secretion of insulin by beta cells. In turn, insulin can affect adipose tissue, stimulating the production and secretion of leptin. This interaction is called the adipoinsular axis, a double loop of hormonal feedback involving insulin and leptin that can function to maintain nutrient balance. [6, 7, 8, 9]. Leptin does not have a noticeable effect on insulin levels in plasma or pancreas [10] and the state of beta cells [11], but it can increase insulin sensitivity [12], so leptin can have a direct effect on insulin sensitivity, glucose uptake and utilization, as well as on glycogen synthesis in muscles [15].In the presence of insulin, leptin increases lipolysis; however, with a decrease in insulin levels, leptin suppresses lipolysis. This decrease in lipolysis reduces the release of glycerol and fatty acids, which contributes to the suppression of gluconeogenesis [13, 14]. Leptin receptors have been found in isolated hepatocytes and the liver of rodents, suggesting that leptin may have a direct effect on the liver. In the liver, there is a cross-connection between leptin and insulin signaling pathways. Thus, in vivo data suggest that under conditions of hyperinsulinemia, the direct effect of leptin on hepatocytes reduces insulin sensitivity [6]. Leptin increases glucose uptake by brown adipose tissue [16]. Incubation of adipocytes of white adipose tissue with leptin disrupted stimulated glucose uptake by insulin and glycogen synthesis, phosphorylation of insulin receptors and binding of insulin to insulin receptors, which confirms that leptin directly and indirectly inhibits glucose uptake in white adipose tissue [6].Experimental models have shown that the administration of leptin can reduce the levels of adrenocorticotropic hormone and corticosterone [13, 14]. Interestingly, leptin suppressed the release of glucocorticoids stimulated by adrenocorticotropic hormone by the adrenal cortex [6]. It is known that leptin is a key regulator of ovarian functioning. Leptin in high concentrations is in the follicular fluid, which is comparable to its concentration in the blood. In low concentrations, leptin stimulates folliculogenesis. In high concentrations, leptin inhibits ovarian function, leading to anovulation [18]. Conclusions. Given the close relationship between the endocrine and reproductive systems, changes in leptin levels affect the functional activity of the ovaries, which can lead to the formation of polycystic ovary syndrome, manifested by a violation of menstrual and reproductive function [19, 20, 21]. Thus, it can be reasonably concluded that miscarriage and its long-term consequences in the form of obesity and metabolic syndrome in adolescence contribute to hyperleptinemia, leading to suppression of ovarian function. Therefore, when examining adolescent girls, it is necessary to include in the algorithm the determination of the level of leptin for timely diagnosis and subsequent treatment of possible reproductive disorders.

About the authors

Anna I. Malyshkina

Ivanovo State Medical Academy; Gorodkov Ivanovo Scientific-Research Institute of Maternity and Childhood

Email: ivniimid@inbox.ru
ORCID iD: 0000-0002-1145-0563

D. Sci. (Med.), Prof.

Russian Federation, Ivanovo; Ivanovo

Nataliya V. Batrak

Ivanovo State Medical Academy

Author for correspondence.
Email: batrakn@inbox.ru
ORCID iD: 0000-0002-5230-9961

Cand. Sci. (Med.)

Russian Federation, Ivanovo

Maria M. Fomina

Troitsk City Hospital

Email: fominadoc@yandex.ru
ORCID iD: 0000-0003-3939-6893

Cand. Sci. (Med.)

Russian Federation, Troitsk

Olga Yu. Kiseleva

Ivanovo State Medical Academy

Email: avekiseleva@gmail.com
ORCID iD: 0000-0003-1727-7316

Cand. Sci. (Med.), Assoc. Prof.

Russian Federation, Ivanovo

Dmitrij V. Shepelev

Ivanovo State Medical Academy

Email: dcrigere@gmail.com
ORCID iD: 0000-0002-7604-4427

Student

Russian Federation, Ivanovo

References

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