American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 27 | P a g e “FREQUENCY OF ENDOGENOUS HYPERCORTISOLISM IN WOMEN WITH POLYCYSTIC OVARY SYNDROME ACCORDING TO REFERRAL DATA Urmanova Yu. M. Abulaiuly Zhangentkhan, Bolshakova S. V. Nasyrova Kh. K. Kazakh National Medical University named after S. D. Asfandiyarova, Department of Endocrinology, The Republic of Kazakhstan, Almaty st. Tolebi, No. 94 Tashkent Pediatric Medical Institute, Department of Endocrinology with Pediatric Endocrinology, The Republic of Uzbekistan, 100125, g. Tashkent, st. Bogishamol 223 Abstract The main investigation-to study the frequency of subclinic Cushingoid at women with polycystic ovaries syndrome (PCOS) Material and methods of investigation.120 patients of fertile age were examined with polycystic ovary syndrome (PCOS).. Middle age of patients - 25.5 ± 4. 3 years. . The remoteness of disease doubted within limits from 7 months to 9 years. 20 healthy women of corresponding age made a control group. The complex of researches, including clinical (global analysis of blood and urine), biochemical (glucose of blood, test of tolerance to glucose) hormonal (LH, FSH, prolactin, estradiol, progesteron, free orchidic hormone, dehydroepiandrostendion (DHEA), 17 – oxyprogesterone, antimuller hormone (AMH), insulin on 14 day of cycle), was executed all patients, ULTRASONIC of uterus and ovaries (transabdominal and transvaginal) on 14 day of cycle with follikulometriya in a dynamics, and also MRI of pituitary. Results.Patients were divided into three groups: 1 group. are patients with primary PCOS- 23 cases (19%), 2 gr. are patients with secondary PCOS at obesity are 89 cases (74%), 3 gr. are patients with secondary PCOS and subclinical Cushingoid are 8 cases (7%). A control group is 20 women of similar age. In our research prevailed on the whole 2 degree of obesity in 2 and 3 groups of patients - 53 cases from 120 (44.1%). In the 1 group of patients the reliable decline of both pituitary and ovarian hormones registered on a background of hyperandrogenemia. So, as compared to the group of control on the 14th day of cycle were for LH, FSH, IGF-1 and also estradiol, progesterone, while free testosterone, DGEA - were enhanceable as compared to control data. Further in the second group of patients the reliable decline of pituitary hormones was also educated on a background hyperandrogenemia, while an ovarian function was within the limits of norm. So, as compared to the group of control on the 14 day of cycle American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 28 | P a g e In the third group of patients, the reliable decline of pituitary hormones was also educated on a background hyperandrogenemia, while an ovarian function was within the limits of norm. So, as compared to the group of control on the 14th day of cycle were for LH, FSH, IGF-1, here free testosterone, DHEA, 17 OKS, insulin, - were for certain enhanceable as compared to control data. Conclusions.1) Frequency of met subclinical Cushing among women with PCOS 6.6% is equal. ; 2) In all groups on 14 day of cycle the reliable decline of basale values of for LH, FSH, IGF-1 was marked, progesterone, estradiol on a background hyperandrogenemia (enhanceable level of free testosterone.). Thus in 2 and 3 groups a hyperinsulinemia was marked. Only for patients 3 groups were marked for certain enhanceable values of DHEA, 17 OKS and cortisol of blood. Mean values of prolactin, AMG were in a norm. 3) a further supervision is Needed in a dynamic after probability of renewal of fertile function in all groups of patients with PCOS Keywords: Androgen excess; polycystic ovary syndrome; prevalence Cushing syndrome. Introduction Today, KS is still associated with an increased incidence of subclinical disease [1], but excess mortality has also been reported in patients with Cushing's disease [2–5] and in patients with subclinical Cushingoid [6]. In contrast, the mortality rate was not as high in patients with Cushing's disease who recovered after initial surgery [7,8]. This is obviously reassuring that treatment reduces mortality, but the data also highlight the need to start treatment as early as possible and to pay special attention to patients with Cushing's disease who have not recovered from initial surgery. A reliable therapeutic approach remains open to debate, but the opinion regarding staged bilateral adrenalectomy should not be forgotten. In conclusion, KS remains a diagnostic and therapeutic challenge. Available data show that early and effective treatment improves survival, but later relapses after initial successful surgery occur even in the best centers. [9]. All of the above determines a possibly high frequency of cases of KS due to undiagnosed cases of subclinical variants of the disease. Widespread coverage, active detection of latent forms through screening studies in individuals with phenotypic Cushingoid, contributes to early detection, timely treatment and improvement of irreversible and severe outcomes and prognoses of this disease. The relevance of this problem is due to the fact that timely diagnosis will allow us to identify this category of patients and refer them for further examination and treatment to specialized endocrinological centers. The real impact of these studies will be an increase in the duration and quality of life of patients with KS and the creation of an objective system for their monitoring.[10]. The results of a mass examination of patients for KS in target population groups show a prevailing number of undiagnosed and subclinical cases [11, 12], and there is accumulated American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 29 | P a g e experience to suggest subclinical Cushing's syndrome (CCS) in most cases as an incidental adrenal gland. In general, there are few works in the literature devoted to this topic, which was the reason for carrying out our study. Purpose of the study study frequency of occurrence and characteristics of subclinical Cushingoid in women with PCOS. Material and research methods Under our supervision, the Republican Scientific Research and Medical Center of Endocrinology M3 of the Republic of Uzbekistan named after Acad. Y.H. Turakulov, 120 patients of fertile age with PCOS (primary and secondary) were examined on an outpatient basis for primary or secondary infertility in the period from September 2022 to December 2023. The average age of the patients was 25.5 ± 4.3 years. The duration of the disease ranged from 7 months to 9 years. 20 healthy women of the appropriate age formed the control group. All patients underwent a complex of studies, including general clinical (general blood and urine analysis), biochemical (blood glucose, glucose tolerance test), hormonal (LH, FSH, prolactin, estradiol, progesterone, free testosterone, dehydroepiandrostenedione (DHEA), 17-hydroxyprogesterone (17 ACS), anti-Mullerian hormone (AMH), insulin on the 14th day of the cycle), ultrasound of the uterus and ovaries (transabdominal and transvaginal) on the 14th day of the cycle with dynamic folliculometry, as well as magnetic resonance imaging (MRI) of the sella turcica (clinic “ Diermedic Center, Tashkent) and questioning of patients. If necessary, a glucose tolerance test and determination of cortisol in the blood and free cortisol in 24-hour urine were performed. Anthropometric study-was carried out immediately during the initial examination, in dynamics and included determination of height, BW, determination of body mass index (BMI) (Quetelet index), calculated by the formula: BMI (kg/m2) = (BW, kg) / (height, m)2 . The degree of obesity was determined in accordance with the BMI values recommended by WHO (1997). The patients were prescribed non-drug and etiopathogenetic therapy to reduce body weight. Non-drug therapy included general recommendations for measuring weight every day before and after exercise therapy, counting daily calories, and avoiding easily digestible carbohydrates. Etiopathogenetic therapy included 3 treatment regimens in 3 groups of patients for 6 months: Group 1 was prescribed a combination of siofor 1000 mg per day + iodomarine 100 mg in the morning + levothyroxine 50 mg in the morning + antiandrogens (Yarina, Jess, dexamethasone, etc.). Group 2 was prescribed a combination of siofor 1000 mg per day + veroshpiron 75 mg twice a week + iodomarine 100 mg in the morning + levothyroxine 50 mg in the morning + reduxin 15 mg in the morning after meals. American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 30 | P a g e Group 3 was prescribed a combination of siofor 1000 mg per day + veroshpiron 75 mg twice a week + iodomarine 100 mg in the morning + levothyroxine 50 mg in the morning + steroidogenesis blockers (ketoconazole 200 mg twice a day) + cabergoline 5 mg per week. The second stage included stimulation of ovulation, antiandrogens (dexamethasone - tab.), progestins, etc. in order to achieve fertility. The obtained data were processed using Microsoft Excel and STATISTICA_6 computer programs. The significance of differences in quantitative indicators (n>12) was determined using the Wilcoxon method for unrelated ranges; to determine the significance of small samples (n<12), the nonparametric Fisher component randomization test was used for independent samples; for qualitative values, the Fisher-Irvine exact test was used. Differences between groups were considered statistically significant at P 0.05. Mean values (M) and standard deviations of means (m) were calculated. Research Results The patients were divided into three groups: 1 gr. – patients with primary PCOS – 23 cases (19%), 2 gr. – patients with secondary PCOS with obesity – 89 cases (74%), 3 gr. – patients with secondary PCOS and subclinical Cushingoid - 8 cases (7%). Table 1 shows the distribution of patients by age. Table 1. Distribution of patients by age (WHO). Age, years 1 group 2nd group 3 group 18 – 29 21 86 5 30-44 2 3 3 45-59 - - - 60-74 - - - 75 and > - - - Total 23 89 8 Table 2 givesaveragesBMI by group before treatment.As can be seen from Table 2, in our study, degree 2 obesity prevailed - 53 cases out of 120 (44.1%) Table 2. AveragesBMI by group before treatment. No. GROUP 30.0-34.9 kg/m2 35.0-39.9 kg/m2 40 kg/m2 1 1 group n= 9 32, 6± 3.2 n= 7 37.5± 3.8 n= 7 41.6±4.2 2 2nd group n= 33 33, 4±4.2 n= 44 37.9±4.2 n= 12 42.7±3.9 3 3 group n= 2 35, 7±4.3 n= 2 38.8±3.9 n= 4 42.8± 3.5 Total 44 (36.6%) 53 (44.1%) 23 (19.1%) For a more in-depth analysis, we performed statistical studies of the average values of basal levels of blood plasma hormones (on the 14th day of the cycle), which is presented in table 3, in all 3 groups. American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 31 | P a g e As can be seen from Table 3, As can be seen from Table 2, in group 1 of patients there was a significant decrease in both pituitary and ovarian hormones against the background of hyperandrogenemia. Thus, compared to the control group, on the 14th day of the cycle, LH, FSH, IGF-1, as well as estradiol, progesterone were significantly reduced, while free testosterone and DHEA were increased compared to control data. Further, in the second group of patients, a significant decrease in pituitary hormones was also revealed against the background of hyperandrogenemia, while ovarian function was within normal limits. Thus, compared to the control group, on the 14th day of the cycle, LH, FSH, IGF-1 were significantly reduced, while free testosterone and DHEA were increased compared to control data. In the third group of patients, a significant decrease in pituitary hormones was also revealed against the background of hyperandrogenemia, while ovarian function was within normal limits. Thus, compared to the control group, on the 14th day of the cycle, LH, FSH, IGF-1 were significantly reduced, while free testosterone, DHEA, 17 OCS, insulin, plasma cortisol were significantly increased compared to control data. So, in all groups, on the 14th day of the cycle, there was a significant decrease in the basal values of LH, FSH, IGF-1, progesterone, estradiol against the background of hyperandrogenemia (increased levels of free testosterone). At the same time, hyperinsulinemia was observed in groups 2 and 3. Only patients in group 3 showed significantly increased values of DHEA, 17 OCS and blood cortisol. The average values of prolactin and AMH were normal. Table 3. Average values of basal levels of blood plasma hormones (on the 14th day of the cycle) in group 1 in all groups Hormones 1 group 2nd group 3group Control Norm LH 6.7 ± 0.4* 7.8 ± 0.3 * 7.4 ± 0.2* 29.3 ± 2.1 From 15 to 90 mIU/ml FSH 2.3 ± 0.2 * 2.6 ± 0.4* 2.1 ± 0.3* 15.2 ± 4.3 From 5 to 16 mIU/ml Prolactin 223.5 ±11.3 201.2 ±12.3 243.9 ±12.3 154.3 ± 9.5 120-900 mIU/l Free testosterone 3.3 ± 0.3* 3.4 ± 0.2* 4.3 ± 0.6* 0.2 ± 0.05 0.2-1.0 ng/ml Progesterone 2.3 ± 0.5* 4.7 ± 0.8* 3.5 ± 0.4 * 44.3±9.3 11-80 nmol/l Estradiol 0.18 ±0.04* 0.23 ±0.02* 0.21 ±0.05* 1.7±0.1 0.34 – 1.8 nmol/l DHEA 6.7 ± 0.2* 6.3 ± 0.6* 8.9 ± 0.4* 3.1±0.4 0.29-7.81 mcg/ml for ages 18 to 30 years 17-OX 2.6±0.1 3.5±0.4 8.6±0.5* 2.9±0.6 1.54 – 6.1 mg/day AMG (on day 5) 5.3± 0.3 3.2±0.6 4.8±0.5 3.9±0.6 From 1.0 to 10.6 ng/ml IGF-1 21.4 ± 3.5* 19.2 ± 2.3* 18.3 ± 2.2* 251.4 ± 13.5 233-344 nmol/ml Insulin 5.4 ± 0.5 11.4 ± 1.7* 13.5 ± 2.2* 5.9±0.8 Up to 10 pg/ml Cortisol 277.5 ± 22.6 287.9 ± 24.7 797.3 ± 25.9* 294.4 ± 23.8 250-720 nmol/ml American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 32 | P a g e Note: *– significance of differences compared to control, DHEA – dehydroepiandrostenedione, 17 OCS – oxyprogesterone, AMH – anti-Mullerian hormone Table 4 shows the characteristics of MRI data of the pituitary gland. Table 4. Characteristics of pituitary MRI datapatients with PCOS MRI data 1 group, n = 23 2 group, n = 89 3 group, n=8 Total Pituitary adenomatosis 14 (60.8%) 35 (39.2%) 6 (75%) 55 (45.8%) Pituitary microadenoma 2 (6.6%) 14 (15.7%) 2 (25%) 18 (15%) Empty sella syndrome 3 (13.0%) 23 (25.8%) - 26 (21.7%) Variant of the norm 4 (17.0%) 17 (19.1%) - 21 (17.5%) Neuroimaging of the pituitary gland in patients with PCOS revealed in many cases hyperplasia (adenomatosis) of the pituitary gland - 55 out of 120 cases (45.8%), which can be explained by ovarian failure in these patients. In second place in frequency was SPTS (empty sella syndrome) - 26 cases (21.7%), and in third place was pituitary microadenoma - 18 cases (15%). Next, we studied the clinical characteristics in 3 groups (Table 5). Table 5 Features of clinical characteristics in 3 groups. Peculiarities 1 group, n = 23 2 group, n = 89 3 group, n=8 Total Obesity - 89 (100%) 8 (100%) 97 (80.8%) Hirsutism 20 (86.9%) 34 (38.2%) 8 (100%) 62 (69.6%) Acne 19 (82.3%) 47 (52.8%) 8 (100%) 74 (83.1%) Acanthosis 9 (39.1%) 58 (42.6%) 8 (100%) 73 (60.8%) Striae - - 8 (100%) 8 (6.6%) Amenorrhea secondary 8 (34.7%) 32 (35.9%) 8 (100%) 48 (53.9%) Primary amenorrhea 3 (13.0%) 5 (5.6%) - 6 (6.7%) Infertility primary 17 (73.9%) 74 (83.1%) 8 (100%) 99 (82.5%) Infertility Secondary 5 (21.7%) 15 (16.8%) - 20 (16.6%) Hyperpolymenorrhea 14 (60.8%) 22 (24.7%) - 36 (30%) Opsomenorrhea 7 (30.4%) 16 (17.9%) - 23 (19.2%) Oligomenorrhea 5 (21.7%) 15 (16.8%) - 20 (16.6%) Hyperandrogenemia 21 (91.3%) 87 (97.7%) - 108 (90%) Anovulation 19 (82.3%) 78 (87.6%) 8 (100%) 103 (85.8%) Hypoovulatory syndrome 3 (13.0%) 11 (12.3%) - 14 (11.6%) Arterial hypertension - 5 (5.6%) 6 (75%) 11 (9.1%) American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 33 | P a g e As can be seen from Table 5, the most pronounced neuroendocrine disorders occurred in group 3 of patients - obesity, hirsutism, acne, acanthosis, secondary amenorrhea, primary infertility, stretch marks, arterial hypertension, anovulation - in 100% of cases. In groups 1 and 2 the above complaints were also encountered, but less frequently and in an erased form. The discussion of the results So, in women suffering from PCOS of primary, secondary origin and PCOS with KS, serious reproductive abnormalities from dysmenorrhea up to infertility were detected; disturbances in the gonadotropic function of the pituitary gland were identified in the form of insufficient secretion of LH and FSH in the middle of the cycle. Almost 50% of patients from group 3 had a BMI above 40 kg/m2. Thus, the most pronounced disorders of the pituitary-ovarian function system were found in the third group of patients with PCOS with subclinical Cushingoid, who had a significant decrease in the functional state of the pituitary-gonad, namely a decrease in LH, FSH, estradiol and progesterone in the blood plasma on the 14th day of menstruation cycle against the background of hyperandrogenemia and hypercortisolemia, which was confirmed by ultrasound of the uterus and ovaries by depletion of the ovarian follicular apparatus and anovulation. Conclusions: 1) The incidence of subclinical Cushingoid among women with PCOS is 6.6%. 2) In all groups, on the 14th day of the cycle, there was a significant decrease in basal values of LH, FSH, IGF-1, progesterone, estradiol against the background of hyperandrogenemia (increased levels of free testosterone.). At the same time, hyperinsulinemia was observed in groups 2 and 3. Only patients in group 3 showed significantly increased values of DHEA, 17 OCS and blood cortisol. The average values of prolactin and AMH were normal. 3) It is necessary to further monitor the dynamics of the likelihood of restoration of fertile function in all groups of patients with PCOS. Information about authors: 1) Urmanova Yulduz Makhkamovna – DSc Doctor of Medicine. Sciences, Professor of the Department of Endocrinology, Pediatric Endocrinology of the Tashkent Pediatric Medical Institute, and leading researcher of the Department of Neuroendocrinology of the Republican Specialized Scientific and Practical Medical Center of Endocrinology of the Republic of Uzbekistan. Service address: Ruz, Tashkent, 100125, st. Mirzo-Ulugbek 56, tel/fax: +099871-2621509. Mobile Tel. +99890-904-01-65 2) Abulaiuly Zhangentkhan; DSc, Dr. med. sciences, professor, head of the department endocrinology, Kazakh National Medical University named after SD Asfandiyarova, The Republic of Kazakhstan, Almaty st. Tolebi, No. 94 American Journal of Interdisciplinary Research and Development ISSN Online: 2771-8948 Website: www.ajird.journalspark.org Volume 28, May - 2024 34 | P a g e 3) Bolshakova Svetlana Viktorovna – PhD, candidate of medical sciences, associate professor, head of the department endocrinology, Kazakh National Medical University named after SD Asfandiyarova, The Republic of Kazakhstan, Almaty st. Tolebi, No. 94 4) Nasyrova Khurshida Kudratullayevna – DSc, Doctor of Medical Sciences, Associate Professor, Head of the Department of Endocrinology with Pediatric Endocrinology, Tashkent Pediatric Medical Institute Service address: Ruz, Tashkent, 100125, st. Mirzo-Ulugbek 56, tel/fax: +099871-2621509. The contact person: Urmanova Yulduz Makhkamovna – Doctor of Medicine. Sciences, Professor of the Department of Endocrinology with Pediatric Endocrinology of the Tashkent Pediatric Medical Institute, Service address: Ruz, Tashkent, 100125, st. Mirzo-Ulugbek 56, Mobile Tel. +99890-9040165 emailyulduz.urmanova@mail.ru References 1. Abraham S.B.1,Abel B.S.,Rubino D. A direct comparison of quality of life in obese and Cushing's syndrome patients. //Eur J Endocrinol.2013 Apr 15;168(5):787-93. doi: 10.1530/EJE-12-1078. Print 2013 May. 2. Grossman AB /Clinical Endocrinology//Chapter7. Cushing Syndrome. UK. 2011, 950 pg. 3. Hammer G et al. Transsphenoidal microsurgery for Cushing, s disease: Initial outcome and long-term results. J Clin Endocrinol Metab 2004; 89:6348–6357. 4. Kirk LF, Hash RB, Katner HP, Jones T. Cushing's disease: clinical manifestations and diagnostic evaluation. //Am. Fam. Physician 2000 - Vol. 62 -P. 1119-27 5. 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Santos A1, Crespo I, Aulinas A, Resmini E. /Quality of life in Cushing's syndrome.//Pituitary. 2015 Apr;18(2):195-200. doi: 10.1007/s11102-015-0640-y. 11. Yasuda K. Cyclic Cushing's disease: pitfalls m the diagnosis and problems with the pathogenesis. //Intern. Med. 1996 - Vol. 35, N. 3 - P. 169-70 12. Valassi E,Biller BM,Swearingen B./Delayed remission after transsphenoidal surgery in patients with Cushing's disease//.J Clin Endocrinol Metab.2010 Feb;95(2):601-10. http://www.ncbi.nlm.nih.gov/pubmed?term=Valassi%20E%5BAuthor%5D&cauthor=true&cauthor_uid=20080848 http://www.ncbi.nlm.nih.gov/pubmed?term=Biller%20BM%5BAuthor%5D&cauthor=true&cauthor_uid=20080848 http://www.ncbi.nlm.nih.gov/pubmed?term=Swearingen%20B%5BAuthor%5D&cauthor=true&cauthor_uid=20080848 http://www.ncbi.nlm.nih.gov/pubmed/20080848