THE ROLE OF INHIBIN A, ACTIVIN, AND HCG IN PREDICTING PREGNANCY LOSS IN HYPOTHYROIDISM DURING THE FIRST TRIMESTER

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 176 THE ROLE OF INHIBIN A, ACTIVIN, AND HCG IN PREDICTING PREGNANCY LOSS IN HYPOTHYROIDISM DURING THE FIRST TRIMESTER D. Mukhammedaminova1, S. Sadrieva2, J. Jabakova3, U. Mirzaeva4, D. Maksudova5 Tashkent State Medical University Department of Endocrinology with Pediatric Endocrinology1,2,3,4,5 https://doi.org/10.5281/zenodo.17844388 Abstract. This study is devoted to assessing the prognostic significance of various clinical and laboratory predictors of pregnancy loss in women diagnosed with hypothyroidism during the first trimester. The aim of the research was to identify the most informative risk factors that can predict the threat of miscarriage at early stages of pregnancy. The study included patients diagnosed with hypothyroidism in the first trimester of gestation. Statistical analysis methods were used to evaluate the relationships between hormonal indicators, anamnesis data, and pregnancy outcomes. The results obtained allow for more accurate risk stratification of pregnancy loss and the development of personalized approaches to managing pregnant women with endocrine disorders. Keywords: hypothyroidism, pregnancy loss, first trimester, prognostic factors, pregnancy. Introduction Pregnancy miscarriage remains one of the pressing issues in modern obstetrics and gynecology, significantly impacting women's reproductive health. According to various studies, the risk of spontaneous pregnancy termination is especially high in the first trimester, which is due to the complex processes of implantation and early embryonic development [1,6]. Among the numerous factors contributing to miscarriage, endocrine disorders, particularly hypothyroidism, occupy a leading position. Hypothyroidism is one of the most common endocrine disorders in women of reproductive age, characterized by a deficiency of thyroid hormones, which play a key role in the regulation of metabolism, as well as in the normal course of pregnancy [2, 3]. Thyroid functional disorders in the early stages of gestation can negatively affect both fetal egg implantation and subsequent embryogenesis, increasing the risk of miscarriage [4,5,7]. In this regard, identifying reliable clinical and laboratory predictors that allow for early prediction of the threat of pregnancy termination in women with hypothyroidism is of particular importance. Timely diagnosis and individualized management of such patients can significantly reduce the frequency of complications and improve pregnancy outcomes. This study is aimed at studying the prognostic value of individual clinical and laboratory parameters in pregnant women with hypothyroidism in the first trimester in order to form more accurate algorithms for early diagnosis of the risk of miscarriage. The purpose of the study was to study the levels of fertility predictors as prognostic criteria for the development of habitual miscarriage in the first trimester of hypothyroidism. Materials and methods. During the period from 2022 to 2024, 150 women aged 17 to 37 (average age - 29.63 ± 5.14 years) suffering from the problem of miscarriage in the first trimester with endocrine diseases such as hypothyroidism were examined at the RIACEPMC named after Academician Ya.Kh. Turakulov (director - Professor, MD Alimov A.A.), as well as at the RIACEPMC and "Ayol Care" clinic. All participants underwent a full clinical-hormonal and SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 177 visualization examination. As a result, 71 (47.3%) patients with habitual miscarriage in the first trimester against a background of hypothyroidism were selected from the total number for detailed examination and prognostic assessment. The control group included 20 healthy women of the same age. Inclusion criteria are: women's age from 17 to 37 years, habitual miscarriage in the first trimester against a background of hypothyroidism, history of underdeveloped pregnancy in the anamnesis, provided other possible reasons are excluded. All participants underwent dynamic observation and treatment for 0, 3, 6, and 12 months, as well as during the first trimester of pregnancy. The course of pregnancy, childbirth, early postpartum period, and the main parameters of fetoplacental system functioning were studied. The following methods were used in the study: General clinical and biochemical studies: general blood and urine analysis, blood biochemistry: total cholesterol, ALT, AST, electrolytes (potassium, sodium, urea, creatinine, calcium), vitamin D3, blood glucose on an empty stomach; Hormonal studies: Prolactin, LH, FSH, estradiol, progesterone (7.21 DMC), TSH, free thyroxine, antibodies to TPO, inhibin A, activin, AMH, HCG - all these indicators were measured in all patients, as well as repeatedly after 3, 6 and 12 months and in the first trimester of pregnancy; Study of somatic status: Anthropometry: measurement of height, weight and calculation of body mass index (BMI), assessment of the state of internal organs and systems; Gynecological research methods: One of the key indicators of reproductive function is the analysis of the menstrual cycle (MS). The International Federation of ObstetriciansGynecologists (FIGO) proposed a classification of MS disorders (MSD) in 2011. Deviations such as absence of menstruation (amenorrhea), disruption of the duration and intensity of bleeding are included. Based on the above, we assessed the gynecological condition and monitored ovulation using comprehensive basal temperature data and ultrasound of the ovaries and uterus. Additional diagnostic methods: ECG, ultrasound of internal and genital organs, and if necessary, MRI and CT of the chest organs. The examination program for pregnant women, women in labor, and their newborns included regular observation and filling in the database. All pregnant women participating in the study were observed from the early stages of pregnancy. Dispensary examination of women who underwent pregnancy preparation was conducted at the RSNPMC A&G polyclinic in Tashkent under the supervision of the author and gynecologist of this center (s.m.n. Navrözova R.S.). Other women were observed in women's consultations at their place of residence. Upon admission to the pathology or maternity ward, patients underwent general and specialized obstetric examinations. All pregnant women who waited for their due date gave birth at the RSNPMC of Obstetrics and Gynecology, the 6th maternity hospital in Tashkent, the TashPMI Perinatal Center, or at their place of residence. Research results. In this study, a comparative analysis of anthropometric and biochemical indicators in women with hypothyroidism and the control group was conducted. Comparative analysis of anthropometric and biochemical indicators in women with hypothyroidism and in the control group Parameter Group 1 (Hypothyroidism) n=71 Group 3 (Control) n=20 P Age (years) 29.63 ± 5.14 28.2 ± 4.07 0.497 SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 178 BMI (kg/m2) 25.29 ± 3.77 21.7 ± 1.52 <0.001 SBP (mm Hg) 107.11 ± 9.77. 106 ± 11.42 0.925 DAD (mm Hg) 68.87 ± 6.82 65.5 ± 5.10 0.120 Menarche age (years) 13.20 ± 1.12 12.6 ± 1.27 0.136 Glucose (μmol/l) 4.95±0.43 5.13±0.37 0.169. Vitamin D (ng/ml) 27.88±7.74 33.05±7.87 0.037 The results of the analysis revealed statistically significant differences between the studied groups in several key parameters. The most pronounced difference was noted in the body mass index (BMI): in women with hypothyroidism, BMI was 25.29 ± 3.77 kg/m2, while in the control group, this indicator was significantly lower - 21.7 ± 1.52 kg/m2 (p < 0.001). These data confirm the existing notion that hypothyroidism, especially in its subcompensated or decompensated forms, is accompanied by a decrease in basic metabolism, fluid retention in the body, and a tendency towards weight gain. Excess body weight, in turn, is considered an independent risk factor for reproductive disorders, including habitual miscarriage. Also, a significant decrease in the level of vitamin D in women with hypothyroidism was established compared to the control group: 27.88 ± 7.74 ng/ml versus 33.05 ± 7.87 ng/ml, respectively (p = 0.037). Considering the participation of vitamin D in the regulation of immune, endocrine, and reproductive functions, its deficiency can be considered as one of the pathogenetic links in the disruption of the gestational process in hypothyroidism. Blood pressure indicators in both groups did not differ statistically significantly: the average values of systolic (SAB) and diastolic (DAB) blood pressure were within normal limits, indicating the absence of pronounced hypotensive or hypertensive states in the studied population. Blood glucose levels also did not show significant differences between the groups (p = 0.169), which may indicate the absence of pronounced carbohydrate metabolism disorders in women with hypothyroidism within this sample. The age of menarche onset was somewhat higher in women with hypothyroidism (13.20 ± 1.12 years) compared to the control group (12.6 ± 1.27 years), however, this difference did not reach the level of statistical significance (p = 0.136). Symptomatology in women with hypothyroidism compared to the control group in the first trimester of pregnancy Group 1 (hypothyroidism) n=71 3rd group (control) n=20 OSH [95% CI] sleep disturbance 28 (39.44%) 10 (50.00%) * 0.651 [0.240, 1.764] early toxicosis 30 (42.25%) 12 (60.00%) ** 0.469 [0.187, 1.171] irritability 29 (40.85%) 8 (40.00%) 0.846 [0.394, 1.810] memory deterioration 28 (39.44%) 0 (0.00%) 0.710 [0.304, 1.683] skin dryness 38 (53.52%) 10 (50.00%) 1.163 [0.531, 2.546] headaches 48 (67.61%) 6 (30.00%) *** 5.227 [2.440, 11.194] general weakness 44 (61.97%) 13 (65.00%) 1.150 [0.530, 2.499] constipation 34 (47.89%) 6 (30.00%) * 2.539 [1.197, 5.374] Note: significance level: *** - p<0.001; ** - p<0.01** - p<0.05 SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 179 Sleep disturbances were recorded in 39.44% of women with hypothyroidism and in 50.00% of women in the control group (OSH = 0.651; 95% CI: 0.240-1.764), which does not indicate the presence of a statistically significant difference. The frequency of early toxicosis was 42.25% in the main group and 60.00% in the control group (OSH = 0.469; 95% CI: 0.187-1,171), the difference is statistically insignificant, however, there is a tendency towards less frequent occurrence of toxicosis in women with hypothyroidism. Irritability was comparable in both groups - 40.85% and 40.00%, respectively (OSH = 0.846; 95% CI: 0.394-1.810). Memory deterioration was observed in 39.44% of patients with hypothyroidism and was not recorded in the control group (OSH = 0.710; 95% CI: 0.304-1.683), however, there is also no statistical significance. Skin dryness was noted in 53.52% of women with hypothyroidism and in 50.00% of women in the control group (OSH = 1.163; 95% CI: 0.531-2.546) differences are statistically insignificant. Headaches were detected in 67.61% of patients with hypothyroidism and only in 30.00% of patients in the control group. ES was 5.227 (95% CI: 2.440-11.194), which indicates a high statistical significance of differences and a possible link between this symptom and the presence of hypothyroidism. General weakness occurred with approximately the same frequency in both groups - 61.97% versus 65.00% (OSH = 1.150; 95% CI: 0.530-2.499), no statistically significant differences were found. Constipation was registered in 47.89% of women with hypothyroidism and in 30.00% of women in the control group (OSH = 2.539; 95% CI: 1.197-5.374), which indicates a significantly higher probability of their occurrence in women with impaired thyroid function. Thus, the most pronounced and statistically significant differences between the groups were noted in the frequency of headaches and constipation, which may indicate specific clinical manifestations of hypothyroidism in the first trimester of pregnancy. For a more detailed analysis of these patients' condition, we can examine the frequency of menstrual disorders presented in the table, which reflects the frequency of various disorders. Frequency of menstrual disorders in groups with hypothyroidism and in the control group. Group 1 (hypothyroidism) n=71 2nd group (control) n=20 OSH [95% CI] Algomenorrhea 5 (7.04%) 6 (30.00%) Hypothesis: OSH = 0.2 [0.05, 0.4] Amenorrhea 12 (16.90%) 0 (0.00%) Hypermenorrhea 12 (16.90%) 2 (10.00%) Hypothesis: OSH = 1.0 [0.23, 3.5] Dysmenorrhea 14 (19.72%) 2 (10.00%) Hypothesis: OSH = 2.58 [0.5, 4.7] Oligomenorrhea 12 (16.90%) 3 (15.00%) Hypothesis: OSH = 1.13 [0.2, 3.2] Opsomenorrhea 16 (22.54%) 2 (10.00%) Hypothesis: OSH = 3.72 [0.8, 6.7] The greatest differences are observed in algomenorrhea and amenorrhea, where hypothyroidism and hyperprolactinemia are associated with a lower chance of developing these disorders compared to the control group. While other conditions, such as hypermenorrhea and dysmenorrhea, have higher risks compared to the control group. These differences in menstrual function may be related to hormonal disorders, which also affect women's overall health. The study SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 180 examined the changes in hormone levels in women at different stages of pregnancy: initially, in the first, second, and third trimester. Indicator Originally 1 trimester 2 trimester 3rd trimester Activine 5.61 ± 3.34 14.1 ± 3.65 3.53 ± 2.27 2.57 ± 1.45 Ingibine A 8.53 ± 5.23* 106 ± 52.9 323 ± 117 352 ± 100 IGC 639 ± 231*. 19277 ± 27660 39788 ± 16389* 66760 ± 10199* Prolactin 45.4 ± 23.2*. 3276 ± 1186*. 9906 ± 2012 19629 ± 2119* TTG 12.1 ± 5.55* 9.01 ± 5.31* 2.80 ± 1.27* 2.98 ± 1.49* FSG 10.1 ± 7.11* 14.5 ± 4.18. 0.103 ± 0.0791 0.0686 ± 0.0680 Progesterone 3.56 ± 3.22 10.3 ± 6.33* 57.4 ± 13.7 261 ± 90.9 Analysis showed that the initial levels of a number of hormones in patients with hypothyroidism differed significantly from the normative values, reflecting the endocrine characteristics of this pathology: Activin showed maximum concentrations in the 1st trimester (14.1±3.65), while the initial level was significantly lower (5.61±3.34), with a subsequent decrease by the 3rd trimester (2.57±1.45). Inhibin A was characterized by a pronounced increase during pregnancy: from 8.53 ± 5.23 in the initial state to 352 ± 100 in the 3rd trimester (p < 0.05 at the initial level). Human chorionic gonadotropin (CHG) increased sharply from 639 ± 231 in the initial stage to maximal values in the 3rd trimester (66,760 ± 10,199), while the values in the 2nd and 3rd trimesters were also statistically significantly higher than the initial values (p < 0.05). Prolactin levels also increased during pregnancy from the initial 45.4±23.2 to 19,629±2,119 in the 3rd trimester, which is a statistically significant change (p<0.05). The concentration of thyroid-stimulating hormone (TSH) decreased from a high initial level (12.1 ± 5.55) to more normal values by the 2nd and 3rd trimesters (2.80 ± 1.27 and 2.98 ± 1.49, respectively), reflecting compensatory therapy or the body's adaptation. Follicle-stimulating hormone (FSH) showed a tendency to decrease after the first trimester. Progesterone levels increased significantly from the initial 3.56 ± 3.22 to 261 ± 90.9 in the 3rd trimester, which corresponds to the physiological changes of pregnancy. Linear regression for predictors of pregnancy outcomes for women with hypothyroidism Predictor Assessmen t SE Confidence interval (95%) t. p. Standards called estimate Intercept 0.80954 0.11321 [0.58425, 1.03484] 7.1509. <0.001 - Age 0.00196 0.00223 [-0.00248, 0.00639] 0.8784 0.382 0.02325 BMI 0.00105 0.00364 [-0.00618, 0.00829] 0.2901 0.773 0.00939 Obesity 0.00653 0.04618 [-0.08537, 0.09842] 0.1414 0.888 0.01568 Early toxicosis -0.03289. 0.02090 [-0.07448, 0.00870.] -1.5737 0.119 -0.07899 SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 181 The results of linear regression show that certain variables have a significant influence on the outcome of pregnancy in women with hypothyroidism. Interception (Intercept) proved to be statistically significant, with a score of 0.80954 (p < 0.001), which confirms the presence of the main effect. Among the predictors, the most significant influence on pregnancy outcome is exerted by HCG 1-4 weeks (estimate -7.86e-5, p < 0.001), which indicates a significant influence of this hormone on pregnancy outcome. Also statistically significant are Activin 1st trimester (estimate 0.01462, p < 0.001) and HCG 5-8 weeks (estimate -5.46e-6, p < 0.001), which demonstrated a positive and negative impact on pregnancy outcomes, respectively. Inhibin A in the 1st trimester also showed statistical significance (estimate -2.51e-4, p = 0.002), which indicates its importance in predicting pregnancy outcomes. Variables such as age, BMI, obesity, and early toxicosis did not show statistically significant impacts on pregnancy outcomes, with p-values of 0.382, 0.773, 0.888, and 0.119 respectively. These results confirm that, in this context, these predictors do not significantly affect the outcome of pregnancy in the group of women with hypothyroidism. Coefficients of standardized estimates for significant predictors (e.g., HCG 1-4 weeks and HCG 5-8 weeks) demonstrate their strong influence on the dependent variable. This emphasizes the importance of monitoring these hormones during pregnancy, especially in women with endocrine disorders. Thus, the results of the linear regression model indicate the importance of a number of biochemical markers, such as HCG, Activin, and Ingibin A, as predictors of pregnancy outcomes, while general health indicators such as age and BMI do not have a statistically significant impact on this outcome. ANOVA results for women with hypothyroidism Indicator Sum of squares df Mean square F. p-value Age 0.00662 1. 0.00662 0.7716 0.382 BMI 7.22e−4. 1. 7.22e−4. 0.0841 0.773 Obesity 1.72e−4 1. 1.72e−4 0.0200 0.888 Early toxicosis 0.02126 1. 0.02126 2.4766 0.119 Activine -6.31e−5. 0.00343 [-0.00689, 0.00677] -0.0184. 0.985 -0.00047 Ingibine A -0.00128. 0.00209 [-0.00544, 0.00287] -0.6149. 0.540 -0.01601 IGC 14weeks -7.86e−5. 1.28e−5 [-1.04e−4,- 0.32e−5] -6.1473. <0.001 -0.26911. Activin 1 trimester 0.01462 0.00362 [0.00741, 0.02183] 4.0338 <0.001 0.20580 Ingibine A 1 trimester -2.51e−4. 7.79e−5. [-4.06e−4, - 9.64e−5] -3.2282. 0.002 -0.14890. IHC 5-8 weeks -5.46e−6. 7.66e−7 [-6.98e−6, - 3.93e−6] -7.1225. <0.001 -0.40753. TTG 0.03472 0.0355 [-4.57e-3030.157] -5.1824. 0.014 0.4590 Prolactin -1.51e−4. 4.79e−5. [0.00741, 0.02183] 4.6581 <0.001 0.2860 SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 11 NOVEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 182 Activine (0.07-10) 2.90e−6 1. 2.90e−6 3.38e−4 0.985 Ingibine A 0.00325 1. 0.00325 0.3781 0.540 IGC 1-4 weeks 0.32444 1. 0.32444 37.7899 <0.001 Activin 1 trimester 0.13970 1. 0.13970 16.2718. <0.001 Ingibine A 1 trimester 0.08947 1. 0.08947 10.4213. 0.002 The results of the multifactorial ANOVA test, presented in the table, demonstrate the statistical significance of various factors related to pregnancy outcomes. During the analysis, the following variables were assessed: age, body mass index (BMI), obesity, early toxicosis, as well as hormone levels (activin, inhibin A, and HCG at different gestational ages). From the presented data, it can be seen that variables such as 1-4 weeks of HCG, 1st trimester of activin, 1st trimester of inhibin A, and 5-8 weeks of HCG have statistically significant correlations with the results (p < 0.05). These data confirm the importance of these hormonal markers in predicting pregnancy outcomes. Conversely, variables such as age, BMI, obesity, and early toxicosis did not show a statistically significant relationship with the results (p > 0.05), indicating their lack of prognostic value in the context of this study. Summarizing this study and the available evidence, we can conclude that the study confirmed the significant role of thyroid and reproductive hormones in the pathogenesis of PNB against the background of hypothyroidism. The conducted correlation and regression analysis revealed reliable relationships between TSH, activin A, inhibin A, and HCG, allowing them to be considered as potential predictors of an unfavorable pregnancy. 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