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0MENSTRUAL IRREGULARITIES IN OBESE GIRLS
1Mirzayeva N.B., 2Erkinova Sh.B.
1Associate professor 2Group-618
1,2Tashkent Pediatric Medical Institute, Department of Obstetrics and Gynecology, pediatric
gynecology https://doi.org/10.5281/zenodo.13926456
Abstract. Currently, obesity is considered one of the main causes of reproductive system dysfunction in women, leading to decreasedfertility, pathological pregnancy and childbirth. One of the earliest studies that showed a link between obesity and reproductive dysfunction was published in the early 20th century by H. Evans and K. Bishop (1922). The authors noted that fertility was restored when excess body weight was reduced. The relationship between reproductive dysfunction and obesity was outlined in 1934 in a classic article by Stein and Leventhal describing polycystic ovary syndrome. In 1952, J. Rogers and G. Mitchell presented the results of observation of women with obesity, anovulatory menstrual cycles, and oligo- or amenorrhea. After consulting dieticians, the menstrual rhythm was restored in most of the patients who lost weight; oligomenorrhea persisted in those who failed to lose weight. Although these observations were relatively random, they laid the foundation for subsequent studies of the relationship between obesity and anovulation. In subsequent years, researchers repeatedly emphasized the high frequency of menstrual irregularities, infertility, and habitual miscarriage in overweight women.
Keywords: obesity, body mass index (BMI), functional hyperandrogenism, corticotropin-releasing hormone (CRH), sex hormone-binding globulin (SHBG), adrenocorticotropic hormone.
Relevance. The pathological impact of obesity on the reproductive system can be traced from the very beginning of its functioning. The frequency of menstrual dysfunction in obese girls is significantly higher than in adolescents with normal and low body weight. Pubertal processes are normally associated with the accumulation of adipose tissue and changes in leptin production. Around 10-11 years of age, healthy girls experience a sharp increase in serum leptin levels, which coincides with the physiological growth spurt. Leptin acts as a signaling system from adipose tissue to the brain, "informing" it that a critical mass of adipose tissue has been reached to initiate puberty and further development of reproductive function. Increased leptin production by adipocytes in prepubertal girls is responsible for increased kisspeptin production in neurons of the arcuate and anteroventral-paraventricular nuclei of the hypothalamus. This initiates pulsatile secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus, followed by cyclical production of gonadotropins and the onset of menarche. Menarche occurs on average at 12.5 years of age, when a certain amount of fat accumulates in the body. After menarche, leptin levels decrease and begin to increase again from puberty until menopause. Decreased tissue sensitivity to insulin is also a physiological phenomenon for puberty. Increased levels of sex hormones, growth hormone, and cortisol, characteristic of puberty, contribute to the development of insulin resistance in adolescents. During this period, lifestyle changes that lead to an imbalance in energy intake and expenditure can trigger weight gain.
The purpose of this study. Obesity is associated with approximately 3 times more frequent anovulatory infertility, and significantly reduces the effectiveness of various types of therapy aimed at restoring fertility. Thus, in a study conducted in European multicenter, it was shown that in women with a BMI >30 kg/m2, the prevalence of infertility is 2.7 times higher than in women with normal body weight. The frequency and severity of reproductive dysfunction, as well as other diseases associated with obesity, increases with the degree of obesity and the amount of adipose tissue, especially in the visceral region. The role of obesity in the pathogenesis of reproductive dysfunction is confirmed by the restoration of the ovulatory menstrual cycle after normalization of body weight.
The problem of obesity is of particular importance during the perimenopause period. Since adipose tissue is the site of conversion of bioactive estrogens from androgen precursors, it would seem that obese women should develop such manifestations of climacteric disorders as vegetative-vascular disorders and osteoporosis less often. However, the results of a number of studies have shown that in obese women, an increase in FSH levels and a decrease in estrogen concentrations occur on average 4 years earlier, therefore, in women aged 40-44 who suffer from obesity, "hot flashes" are observed more often compared to women with normal body weight, and only by the age of 50-55 do these differences disappear.
Materials and methods of research. The presence of obesity in adolescent girls affects the process of puberty. This process in adolescents with excess body weight begins earlier than in girls with normal body weight, in particular, menarche occurs earlier. Thus, with excess body weight, menarche begins 1.4±0.2 years earlier than in girls with normal body weight, i.e. the age of menarche decreases to 9-11 years. Moreover, the acceleration of the rate of puberty does not correspond to the rate of development of the genital apparatus. Early age of menarche can be considered as an independent prognostic factor for the increase in body mass index (BMI) and other complications of obesity. According to a number of authors, the timely onset of menarche in women with various forms of obesity and reproductive dysfunction is observed in only 31% of cases. But over time, this trend changes to the opposite, as a result of which obese girls enter the reproductive period later than their healthy peers, and subsequently chronic anovulation develops, the risk of which is directly dependent on the BMI value. Despite numerous reports of reproductive system dysfunction in obese women, the mechanisms of these disorders are still not entirely clear, and their severity does not always correlate with BMI, traditionally used to diagnose obesity. At the same time, it is becoming increasingly clear that adipose tissue, especially of visceral origin, plays an important role in both the metabolism of sex hormones and the synthesis of biologically active substances (leptin, adiponectin, resisting, etc.) that have endocrine and paracrine activity. In contrast to men, in whom weight gain is associated with hypotestosteronemia and a tendency toward decreased gonadotropin secretion, women develop a state of "functional hyperandrogenism". This condition is associated with increased estrogen production, impaired steroid transport by plasma proteins, and altered activity of several enzyme systems involved in steroid metabolism. First of all, obesity causes hyperleptinemia, the most important consequences of which are:
- disruption of the nature of pulsatile secretion of GnRH, and consequently, the nature of gonadotropin formation;
- suppression of steroidogenesis in ovarian cells;
- disruption of feedback mechanisms in the regulation of the menstrual cycle;
- disruption of the processes of embryonic nutrition and an increase in the probability of its death upon the onset of pregnancy.
Hyperleptinemia can have a stimulating effect on some hypothalamic releasing factors, in particular on corticotropin-releasing hormone (CRH). Increased secretion of CRH can lead to disruption of FSH and LH secretion, resulting in suppression of the maturation of the dominant follicle and ovulation.
Leptin receptors are found on the surface of granulosa cells, theca cells, and interstitial cells of the ovaries. Thus, taking into account the data on the presence of leptin receptor mRNA in ovarian tissue, a direct effect of this hormone on steroidogenesis of rat granulosa cells in vitro was demonstrated. In this case, a dose-dependent suppressive effect of leptin on insulin-like growth factor type 1 (IGF-1) was shown, potentiated by an increase in FSH-stimulated estradiol synthesis by granulosa cells. These data support the hypothesis that an increase in leptin levels in obese individuals can counteract the maturation of the dominant follicle and ovulation. It is very interesting, indicating that leptin in increasing concentrations (10-300 ng/ml) inhibits insulin-dependent production of estradiol and progesterone in granulosa cell culture. This effect is due to the presence of specific binding sites for leptin. Thus, leptin suppresses steroidogenesis in granulosa and theca cells [3], exhibiting antagonism towards IGF-1, insulin, LH and transforming growth factor-P (TGF-P). Moreover, regardless of the effect on steroidogenesis mechanisms, high concentrations of leptin suppress dominant follicle development and disrupt ovulation.
In obese women, the level of circulating sex hormone-binding globulin (SHBG) is reduced, which is the liver's response to increased levels of circulating testosterone and insulin. Insulin directly inhibits SHBG synthesis in hepatocytes. Fat distribution also plays an important role in changing SHBG concentrations. In women with central (android) obesity, the level of SHBG in the blood plasma is usually lower than in women of the same age and with comparable body weight with peripheral (gynoid) obesity. In addition, hypoestrogenism is caused by a decrease in the level of SHBG and a change in estrogen metabolism, leading to a relative increase in biologically active fractions. Thus, 3 mechanisms ensure the presence of increased amounts of biologically active estradiol in the blood in obesity:
- increased production of estradiol from estrone in peripheral (extraovarian) tissues, maintaining increased levels of circulating estradiol;
- increased levels of biologically active circulating estradiol due to decreased levels of
SHBG;
- local conversion of estrone to estradiol in target tissues. This local mechanism is physiologically significant in target tissues such as the mammary gland, where tissue proliferation occurs in response to estrogen.
In obesity, the estrone/estradiol ratio shifts toward estrone, which predisposes to disruption of the normal functioning of the feedback mechanism. Hyperestrogenemia sensitizes pituitary gonadotrophs to GnRH and reduces the threshold level of ovarian estradiol required to initiate the ovulatory surge in LH. Hyperstimulation of immature follicles probably underlies their cystic degeneration. The increase in the frequency of menstrual dysfunction with the progression of obesity is due to changes in the extra glandular formation of estrone from androgens and the inhibition of cyclic secretion of LH. In addition, obesity is associated with a lower formation of inactive estradiol metabolites (2-hydroxyestrogens) and a high production of active metabolites. Against the background of hyperestrogenism and progesterone deficiency, the proliferation time
of the endometrium is extended, which leads to the development of its hyperplasia, manifested by bleeding in 50-60% of obese women. Obesity increases the risk of developing not only hyperplastic processes, but also endometrial cancer and breast cancer. The most important consequences of hyperestrogenemia are the disruption of feedback mechanisms in the regulation of the menstrual cycle, ovulation disorders, increased proliferation of epithelial cells of the milk ducts and endometrial cells, and uterine bleeding. Hyperinsulinemia and insulin resistance play an important role in the mechanisms of reproductive dysfunction in obesity. The increase in the formation and secretion of insulin by pancreatic P-cells in obesity is caused, in particular, by Pendorphin due to increased activity of the opioidergic system of the brain, as well as high concentrations of free fatty acids and glucose. Insulin resistance in android obesity is caused by an increase in the content of free fatty acids in the blood and the suppression of insulin uptake by hepatocytes due to increased androgen production. In addition, increased leptin production by adipocytes stimulates lipolysis in adipose tissue and skeletal muscles and suppresses the action of insulin in peripheral organs and tissues. By the way, under physiological conditions, leptin weakens insulin production in the pancreas, but this does not occur in obesity due to leptin resistance.
The most important consequences of hyperinsulinemia:
- an increase in the amount of P450c17a mRNA;
- an increase in the synthesis of androgens in theca cells of the ovaries, proliferation of theca cells;
- FSH-stimulated synthesis of estrogens;
- an increase in the level of LH secretion;
- activation of the GnRH gene;
- decreased synthesis of SHBG by the liver;
- increased levels of free testosterone;
- increased risk of developing endometrial and/or breast cancer.
In insulin resistance and hyperinsulinemia, insulin penetrates the hypothalamus, which leads to an increased release of CRH, which triggers a series of hormonal changes in the pituitary gland and peripheral endocrine glands. This increases the secretion of adrenocorticotropic hormone (ACTH), prolactin in the pituitary gland, and decreases the secretion of growth hormone and thyroid-stimulating hormone (TSH). Under the influence of increased stimulation of ACTH, the production of cortisol by the adrenal glands increases. Increased secretion of CRH can also lead to a violation of the secretion of FSH and LH. Excess insulin increases the release of LH in response to stimulation of the pituitary gland by gonadotropin-releasing hormone. The role of insulin in ovarian function is reduced to enhancing LH-dependent synthesis of testosterone. Excess insulin suppresses the production of SHBG in the liver, thereby increasing the content of biologically active fractions of testosterone in the blood. Thus, insulin increases free testosterone levels through 2 independent mechanisms: increased ovarian secretion of testosterone precursors (e.g., androstenedione) and suppression of SHBG. However, it is unclear how insulin stimulates androgen production in the ovaries while the body is "resistant" to the action of insulin. Several hypotheses have been proposed to explain this paradoxical situation:
1) insulin acts on the ovary not only through insulin receptors but also through IGF-1 receptors in the ovaries;
2) since insulin has many functions, a selective defect in some of them can be assumed;
3) there may be organ-specificity of insulin sensitivity;
4) insulin may bind to a hybrid insulin receptor (this is unlikely since hybrid insulin receptors have not been identified in human ovaries).
Insulin receptors and IGF-1 receptors have been identified in granulosa tissue, theca cells, and stromal cells of the ovaries of healthy women and women with polycystic ovary syndrome (PCOS). IGF-1 and IGF-2 are well-known modulators of ovarian function. The above growth factors are capable of influencing the processes of steroidogenesis in the ovaries, which is manifested by stimulation of LH secretion and enhancement of LH-induced synthesis of androgens by theca cells, increase in production of FSH-dependent receptors by granulosa cells, increase in their sensitivity to FSH and estradiol, increase in aromatase activity in granulosa cells, due to which estradiol secretion is stimulated. Activation of receptors leads to a decrease in the peripheral level of IGF-binding protein (IGFBP) as a result of suppression of production of IGFBP types I and II and increase in activity of IGFBP protease. A decrease in the level of IGFBP promotes an increase in the bioavailability of IGF, also increasing the final effect of IGF-1 and IGF-2 at the level of target tissues. The IGF/IGFBP system is regulated by insulin. In particular, insulin enhances its own effect and the effect of IGF by increasing the number of IGF receptors type I. Insulin can also inhibit the production of IGFBP type I, which increases the bioavailability of IGF. Thus, hyperinsulinemia can lead to the formation of a vicious circle, which will result in excessive insulin and IGF action on the ovaries. It has been shown that IGF-1 exerts its effect in physiological concentrations, while insulin in normal concentrations does not exert a similar effect on the body, with the exception of its synergistic effect on LH-induced androgen synthesis by theca cells. Despite the fact that insulin and IGF-1 receptors are products of different genes, due to their structural similarity, insulin can bind to IGF-1 receptors, although with less affinity than to its own receptors. However, in hyperinsulinemia, as well as in a situation where insulin receptors are blocked or there is a deficiency, it can be expected that insulin will bind to IGF-1 receptors to a greater extent and activate enzymatic processes, similar to this factor. Thus, under hyperinsulinemia, the effect of insulin is mediated through IGF-1 receptors, insulin imitates its action, increasing androgen synthesis in the ovaries.
In addition, to explain the sensitivity of ovarian cells to the effects of insulin, it can be assumed that stimulation of ovarian androgen production and glucose transport are carried out by different intracellular signaling systems. Studies on granulosa cells from porcine ovaries and theca cells from women with PCOS suggested that inositol phosphoglycan is a secondary messenger of the intracellular signaling system stimulating steroidogenesis in these tissues. Inositol phosphoglycan is an amplifying signaling system that can remain intact in conditions characterized by insulin resistance under conditions of defective tyrosine kinase system and impaired glucose transport. Therefore, using an alternative intracellular signaling system, the effect of insulin on steroidogenesis will be preserved even in conditions of significant insulin resistance against the background of impaired glucose tolerance.
Researches and discussion. Obesity is also associated with increased estrogen production. As early as 1978, P. Siiteri and P. MacDonald discovered that androgens are aromatized in adipose tissue, producing ^ of circulating estrogens in this way. The relationship between the amount of adipose tissue and estrogen levels has been identified in a number of studies. The degree of aromatization significantly correlates with fat mass. Obesity increases aromatase activity in adipocytes and increases the conversion of androgens to estrogens. In case of pregnancy,
complications such as threat of termination of pregnancy, fetal macrosomia, development of gestosis, up to severe form - eclampsia and death of the fetus are observed. Complications of the gestational process in women with obesity are observed in 45-85% of cases. When pregnancy occurs, the frequency of early gravid losses reaches 40-50%. Women with obesity are more likely to experience such complications of childbirth and the postpartum period as weakness of labor, premature or delayed rupture of membranes. Gestosis, large fetus, abnormalities of labor - all this contributes to an increase in the frequency of surgical interventions in childbirth, asphyxia of the fetus and newborn, birth trauma of the mother and newborn. Certainly, the identified metabolic and hormonal disorders accompanying obesity can lead to reproductive dysfunction. The listed features will be links in the pathogenesis of processes leading to ovulation disorders and its clinical manifestations - menstrual rhythm disorders and infertility.
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