Reproductive health of adolescent girls born prematurely: new forecasting opportunities

Cover Page

Cite item


Background. Premature delivery remains one of the most pressing issues in obstetrics.

Aim. To assess the reproductive health of 16-year-old adolescent girls born prematurely to develop an algorithm to optimize its state.

Materials and methods. A total of 180 adolescent girls aged 16 years were evaluated. The study group consisted of 120 adolescents born at a gestational age of 27–36 weeks. Subgroup 1 consisted of 18 girls born at a gestational age of 27–33 weeks, and subgroup 2 consisted of 102 adolescent girls born at 34–36 weeks of gestation. The comparison group consisted of 60 girls born at term. The study material was peripheral venous blood. Hormonal and ultrasonic examination of the internal genital organs were performed.

Results. In the main group vs. comparison group, an increase in serum leptin levels was observed: 9.4 (6.1; 15.5) and 6.9 (4.2; 9.2) ng/ml (p<0.01). The leptin blood concentration in subgroup 2 showed a positive correlation with the body mass index (p=0.001). A more frequent increase in the number of antral follicles (>10 in each ovary) was recorded in adolescents born prematurely. When assessing the results of correlation analysis, a positive direct correlation between the number of antral follicles and serum leptin concentration in adolescent girls born prematurely (p<0.001) was observed. It was found that with a leptin level >15.8 ng/ml, there is an increase in the number of antral follicles, which may be the cause of reproductive disorders.

Conclusion. Premature delivery and its long-term consequences (obesity and metabolic syndrome) contribute to hyperleptinemia, leading to ovarian function suppression in adolescents. Therefore, it is necessary to include leptin level measurement in the algorithm of examining adolescent girls for timely diagnosis and subsequent treatment of possible reproductive disorders.

Full Text

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

ORCID iD: 0000-0002-1145-0563

D. Sci. (Med.), Prof.

Russian Federation, Ivanovo; Ivanovo

Nataliya V. Batrak

Ivanovo State Medical Academy

Author for correspondence.
ORCID iD: 0000-0002-5230-9961

Cand. Sci. (Med.)

Russian Federation, Ivanovo

Maria M. Fomina

Troitsk City Hospital

ORCID iD: 0000-0003-3939-6893

Cand. Sci. (Med.)

Russian Federation, Troitsk

Olga Yu. Kiseleva

Ivanovo State Medical Academy

ORCID iD: 0000-0003-1727-7316

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

Russian Federation, Ivanovo

Dmitrij V. Shepelev

Ivanovo State Medical Academy

ORCID iD: 0000-0002-7604-4427


Russian Federation, Ivanovo


  1. Рафикова Ю.С., Подпорина М.А., Саприна Т.В., и др. Отдаленные последствия недоношенности – метаболический синдром у детей и подростков: есть ли риск? Неонатология: новости, мнения, обучение. 2019;7(1):21-30 [Rafikova YuS, Podporina MA, Saprina TV, et al. The long-term consequences of prematurity – metabolic syndrome in children and adolescents: is there a risk? Neonatologiya: novosti, mneniya, obuchenie (Neonatology: News, Opinions, Training). 2019;7(1):21-30 (in Russian)]. doi: 10.24411/2308-2402-2019-11003
  2. Никулина Е.Н., Елгина С.И., Ушакова Г.А. Репродуктивное здоровье девушек-подростков, рожденных недоношенными. Фундаментальная и клиническая медицина. 2017;2(1):50-8 [Nikulina EN, Elgina SI, Ushakova GA. Reproductive health of adolescent girls born prematurely. Fundamental and Clinical Medicine. 2017;2(1):50-8 (in Russian)].
  3. Артымук Н.В., Елгина С.И., Никулина Е.Н. Овариальный резерв недоношенных девочек при рождении и в пубертатный период. Фундаментальная и клиническая медицина. 2017;2(3):6-12 [Artymuk NV, Elgina SI, Nikulina EN. Ovarian reserve of premature girls at birth and during puberty. Fundamental and Clinical Medicine. 2017;2(3):6-12 (in Russian)]. doi: 10.23946/2500-0764-2017-2-3-6-12
  4. Фомина М.М. Состояние репродуктивного здоровья девочек-подростков, рожденных недоношенными: Дис. … канд. мед. наук. Иваново, 2016. Режим доступа: Ссылка активна на 10.05.2022 [Fomina MM. Sostoianie reproduktivnogo zdorov'ia devochek-podrostkov, rozhdennykh nedonoshennymi: Dis. … kand. med. nauk. Ivanovo, 2016. Available at: Accessed: 10.05.2022 (in Russian)].
  5. D'souza AM, Neumann UH, Glavas MM, Kieffer TJ. The glucoregulatory actions of leptin. Mol Metab. 2017;6(9):1052-65. doi: 10.1016/j.molmet.2017.04.011
  6. Tanida M, Yamamoto N, Morgan DA, et al. Leptin receptor signaling in the hypothalamus regulates hepatic autonomic nerve activity via phosphatidylinositol 3-kinase and AMP-activated protein kinase. J Neurosci. 2015;35(2):474-84. doi: 10.1523/JNEUROSCI.1828-14.2015
  7. Lam NT, Covey SD, Lewis JT, et al. Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver. J Mol Endocrinol. 2006;36(1):163-74. doi: 10.1677/jme.1.01937
  8. Тиньков А.А. Экспериментальное исследование влияния солей железа и меди на свободнорадикальное окисление и локальные механизмы регуляции метаболизма жировой ткани: Автореф. дис. ... канд. мед. наук. Челябинск, 2014. Режим доступа: Ссылка активна на 10.05.2022 [Tin'kov AA. Eksperimental'noe issledovanie vliianiia solei zheleza i medi na svobodnoradikal'noe okislenie i lokal'nye mekhanizmy reguliatsii metabolizma zhirovoi tkani: Avtoref. dis. ... kand. med. nauk. Chelyabinsk, 2014. Available at: Accessed: 10.05.2022 (in Russian)].
  9. Park S, Ahn IS, Kim DS. Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sci. 2010;86(23-24):854-62. doi: 10.1016/j.lfs.2010.03.021
  10. Fujikawa T, Chuang JC, Sakata I, et al. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci USA. 2010;107(40):17391-6. doi: 10.1073/pnas.1008025107
  11. Yu X, Park BH, Wang MY, et al. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci USA. 2008;105(37):14070-5. doi: 10.1073/pnas.0806993105
  12. Neumann UH, Denroche HC, Mojibian M, et al. Insulin knockout mice have extended survival but volatile blood glucose levels on leptin therapy. Endocrinology. 2016;157(3):1007-12. doi: 10.1210/en.2015-1890
  13. Bates SH, Gardiner JV, Jones RB, et al. Acute stimulation of glucose uptake by leptin in l6 muscle cells. Horm Metab Res. 2002;34(3):111-5. doi: 10.1055/s-2002-23192
  14. Perry RJ, Zhang XM, Zhang D, et al. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Med. 2014;20(7):759-63. doi: 10.1038/nm.3579
  15. Perry RJ, Peng L, Abulizi A, et al. Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis. J Clin Invest. 2017;127(2):657-69. doi: 10.1172/JCI88477
  16. Denroche HC, Kwon MM, Glavas MM, et al. The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapy. Mol Metab. 2016;5(8):716-24. doi: 10.1016/j.molmet.2016.06.009
  17. Denroche HC, Kwon MM, Quong WL, et al. Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol. Diabetologia. 2015;58(5):1100-8. doi: 10.1007/s00125-015-3529-4
  18. Рыжов Ю.Р., Шпаков А.О., Гзгзян А.М. Роль лептина в регуляции репродуктивной системы и перспективы его использования во вспомогательных репродуктивных технологиях. Проблемы репродукции. 2020;26(2):53-61 [Ryzhov YuR, Shpakov AO, Gzgzyan AM. The role of leptin in the regulation of the reproductive system and the prospects for its use in assisted reproductive technologies. Russian Journal of Human Reproduction. 2020;26(2):53-61 (in Russian)]. doi: 10.17116/repro20202602153
  19. Zheng SH, Du DF, Li XL. Leptin levels in women with polycystic ovary syndrome: A systematic review and a meta-analysis. Reprod Sci. 2017;24(5):656-70. doi: 10.1177/1933719116670265
  20. Seth MK, Gulati S, Gulati S, et al. Association of leptin with polycystic ovary syndrome: a systematic review and meta-analysis. J Obstet Gynaecol India. 2021;71(6):567-76. doi: 10.1007/s13224-021-01510-0
  21. Liang J, Lan J, Li M, Wang F. Associations of leptin receptor and peroxisome proliferator-activated receptor gamma polymorphisms with polycystic ovary syndrome: a meta-analysis. Ann Nutr Metab. 2019;75(1):1-8. doi: 10.1159/000500996

Supplementary files

There are no supplementary files to display.

Copyright (c) 2022 Malyshkina A.I., Batrak N.V., Fomina M.M., Kiseleva O.Y., Shepelev D.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies