Inflammatory markers and increased carotid intimal thickness in asymptomatic growth hormone naïve patients of Sheehan syndrome.

Inflammatory markers and increased carotid intimal thickness in asymptomatic growth hormone naïve patients of Sheehan syndrome. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Inflammatory markers and increased carotid intimal thickness in asymptomatic growth hormone naïve patients of Sheehan syndrome. shahnaz ahmad mir, asif ahmad naik ahmad naik, bashrat , dar, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3360451/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Objective The dyad of cardio-metabolic risk factors and endothelial dysfunction observed in hypopituitarism untreated for growth hormone deficiency (GHD), a characteristic of Sheehan's syndrome (SS), contributes to the increased cardiovascular mortality and morbidity. The elevated inflammatory markers reported in these patients along with conventional cardiovascular risk factors are considered pivotal contributors to coronary endothelial dysfunction and high risk for cardiovascular events. We aim to investigate the level of conventional cardiovascular risk factors, inflammatory markers and carotid artery Intima-Media Thickness (CIMT) in patients of SS compared to a group of healthy women. Methods A total of 37 SS patients fulfilling the case definition for this study and same number (n = 37) healthy age, BMI and parity matched controls were recruited for the study. The participants underwent detailed clinical, biochemical, hormone analysis and measurement of Tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) levels. CIMT assessment was also done using high-resolution echo-colour Doppler system in both cases and controls. Results Patients with SS had significantly higher mean triglyceride, total cholesterol, low-density lipoprotein cholesterol and lower high-density cholesterol concentrations. The markers of inflammation including TNF-α and IL-6 levels were significantly higher (23.41 ± 10.97 vs. 20.05 ± 2.76pg/ml; p = 0.041) for TNF- α and (37.19 ± 5.38 vs. 32.08 ± 1.18pg/ml; p = 0.004) for IL-6, compared to healthy controls. Furthermore, mean carotid intima medial thickness in patients was significantly increased in comparison to healthy controls (0.71 ± 0.07 vs. 0.59 ± 0.05mm; p = 0.001). Conclusion Our study demonstrated that patients with SS have clustering of cardiovascular risk factors that may contribute to the increased risk for cardiovascular events. Sheehan syndrome endothelial dysfunction CIMT hypopituitarism Take-home massage The take-home message of our research is that postpartum pituitary necrosis (Sheehan syndrome) is one of the common causes of hypopituitarism in our country and because of the high cost of growth hormone they remain deficient throughout life and are at high risk for cardiovascular diseases. So this is kind of the first study that looked at their carotid intimal thickness and endothelial dysfunction in them, So it is important for them to look at their cardiovascular risk and manage them aggressively. INTRODUCTION Sheehan Syndrome (SS) is hypopituitarism resulting from ischemic necrosis of the pituitary gland as a result of extreme hypotension or shock caused by severe hemorrhage during or after parturition 1 . While the incidence of SS is assumed to have declined due to advancements in obstetrical treatment, it continues to remain one of the common causes of hypopituitarism in developing nations 2 . The disorder is rare in western countries but continues to be seen in some developing nations 3,4 . The prevalence of about 3% for SS was reported in women over the age of 20, in an epidemiological survey from the Kashmir valley of the Indian subcontinent with almost two-thirds of them having delivered babies at home 3 . SS is characterized by variable magnitudes of anterior and sometimes posterior pituitary gland dysfunction manifesting either immediately in the postpartum period or after a delay of several years, depending on the amount of tissue destruction 5,6 . Patients with hypopituitarism (particularly women) receiving adequate conventional replacement therapy have higher cardiovascular mortality and morbidity than the general population 7 . The exact mechanism of increased vascular disease in hypopituitarism is still unclear; however, of late, the possible role of GHD in the pathophysiology of increased cardiovascular events has come under scrutiny contrary to earlier belief that GHD confers protection against risk of vascular disease 8 . GHD, a well-known characteristic of SS is associated with clustering of cardiovascular risk factors like abnormalities of lipid and carbohydrate metabolism, insulin resistance, endothelial dysfunction, and increased intimal-medial thickness among others 9–11 . Moreover, the significant prevalence of coronary calcium deposits, in patients with SS unsubstituted for GH predispose them to relatively high risk for coronary heart disease 12 . Endothelial dysfunction, plays an important role in pathogenesis of atherosclerosis and is detected early in people at risk for cardiovascular events 13 . Cytokines, being the mediators of inflammation play a crucial role in the endothelial injury 14 . Several markers of inflammation such as TNF-α and IL-6 predict cardiovascular events in asymptomatic patients at high risk. These peripheral markers of inflammatory activity correlate with the degree of atherosclerosis as detected by CIMT. The present study was designed to investigate whether conventional cardiovascular risk factors, markers of the inflammation and CIMT are elevated in patients with SS unsubstituted for GH compared to healthy controls. MATERIALS AND METHODS This study was a case-control, cross-sectional observational study, conducted in Department of Internal Medicine and Endocrinology, Government Medical College, Srinagar after getting approval from institutional ethical committee. A written informed consent was obtained from all patients and controls and the study was performed according to the Declaration of Helsinki guidelines. Study subjects: Cases (n = 37) Thirty-seven women with Sheehan's syndrome were recruited from Endocrine Clinic after fulfilling the inclusion criteria in this study. Sheehan's syndrome was diagnosed using following "essential criteria" (1) proposed by Diri et al Cases for this study were defined as women meeting the "essential criteria" for SS who were stable on a conventional replacement treatment without Growth hormone replacement for at least 6 months before the study. All cases were growth hormone deficient documented by low IGF 1 levels and growth hormone by ITT when required. Controls (n = 37) Age and BMI matched unrelated healthy controls from same ethnic background. Inclusion criteria: Hemodynamically stable postpartum females of any age group, free of other co-morbidities like diabetes and hypertension, consenting to participate in the study protocol and fulfilling the above stated "case definition” or otherwise healthy for cases and controls respectively. Exclusion criteria : Patients and controls with known atherosclerotic disease or manifest cardiovascular disease in terms of hypertension, peripheral arterial insufficiency, a history of myocardial infarction or stroke and /or diabetes. Special physiological groups viz., pregnant or lactating female Patients extremes of age. Methods All the study participants underwent anthropometric assessments such as measurement of weight, height, waist-hip circumference, blood pressure and detailed systemic examination. BMI was calculated as body weight in kg/height in m 2 . All patients were stable on a conventional replacement treatment for at least 6 months before the study. Growth hormone treatment had not been given to any of the patients previously. Patients attended the Endocrinology clinic of Internal Medicine between 8:30 and 9:00 am after an overnight fast of 10–12 hours, without taking the usual morning replacement therapy. The investigation was carried out on an outpatient basis. The venous blood samples were collected for measurements of triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, fasting blood glucose and the routine hematological investigations. Liver and renal function tests were also performed. The biochemical analysis like glucose, total cholesterol, and triglyceride concentrations were performed with a Technicon DAX-72 auto analyzer (Technicon, Bayer Corporation, Tarrytown, New York) in the Central Biochemistry Laboratory, Government Medical College, Srinagar. HDL cholesterol concentrations were measured using RAXT auto analyzer after phosphotungstic acid and magnesium chloride precipitation. LDL cholesterol was calculated by Friedwald formula 15 . Hormonal assays were done by electrochemiluminescence method on Abbot ARCHITECT i 2000SR immunoassay analyzer and following the manufacturer’s protocol. IGFI was measured by CLIA (chemiluminescent immunometric assay). The measurement of carotid intima-medial thickness was performed by a high-resolution echo-colour Doppler system (LOGIQ S8; GE Healthcare, Chalfont St Giles, United Kingdom) as per the standard protocol 16 . Scanning of the extra cranial carotid arteries in the neck was performed bilaterally in three different longitudinal projections: anterior-oblique, lateral and posterior-oblique as well as the transverse projection. Three determinations of intima plus medial thickness were conducted at the site of the greatest thickness and two points, 1 cm upstream and 1 cm downstream from the site of the greatest thickness. These three values were averaged. The greatest value among the six averaged intima plus medial thickness (three from the left and three from the right) was used as the representative IMT value for each individual. The coefficients of variation of the measurements were less than 3%. All scans were read by an independent physician, blinded as to the clinical status of the subjects. The serum TNF-α and IL-6 concentrations were measured in all patients using the commercially available Enzyme-linked immunosorbent assay (ELISA) kits for cytokine detection (eBioscience ELISA Kits, San Diego, CA, USA) with an intra-assay coefficient of variation of 5.3–8.3%. Statistical analysis SPSS Version 20.0 (SPSS Inc., Chicago, Illinois, USA) was used to analyse the recorded data. Continuous variables were expressed as Mean ± SD and categorical variables were summarized as frequencies and percentages. Shapiro–Wilk test and normal probability plot were used to test for normality of data. Normally distributed continuous variables were compared using the student’s independent t-test, and non-normally distributed variables were analyzed using Mann-Whitney U test. A p-value of less than 0.05 was considered statistically significant. All p-values were two-tailed. RESULTS Baseline characters 74 women comprising of 37 patients with Sheehan syndrome and 37 age, BMI and parity matched healthy women were included in this study. Cases and controls were chosen so they had a similar age and BMI distribution similar was with basal heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) distributions. The detail of the biochemical profile and inflammatory markers is given in Table 1 . Table 1 Comparison of description of anthropometric, clinical, biochemical characteristics and inflammatory markers among patients of SS and controls. Variable Cases Mean ± SD Controls Mean ± SD P Value Age in years(Range) 50.1 ± 14.71 (30–80) 47.8 ± 13.54 (29–69) 0.472 Parity(Range) 3.4 + 1.47 (1–7) 2.9 + 1.28(1–6) 0.123 HR (beats/min)(Range) 73.81 + 9.76 (51–98) 76.71 ± 14.20(64–100) 0.231 SBP (mmHg)(Range) 112.6 + 8.74 (90–130) 108.9 ± 12.12(98–126) 0.332 DBP (mmHg)(Range) 74.6 + 7.93 (64–84) 70.9 ± 10.34(70–84) 0.223 BMI (kg/m 2 ) 22.08 ± 2.47 21.43 ± 2.04 0.221 Waist Hip Ratio (Range) 0.89 ± 0.10(0.83–0.99) 0.87 + 0.09 (0.83–0.98) 0.314 Serum Cholesterol (mg/dL) 188.26 ± 45.17 147.53 ± 39.63 < 0.001* Serum TG (mg/dL) 216.29 ± 51.94 154.42 ± 42.17 < 0.001* Serum LDL (mg/dL) 112.38 ± 43.82 74.62 ± 28.85 < 0.001* Serum HDL mg/dL) 46.21 ± 10.69 61.35 ± 8.72 < 0.001* Serum TNF-α (pg/ml) (95% CI) 23.41 ± 10.97(19.8–27.1) 20.05 ± 2.76(19.1–20.9) 0.041* Serum IL-6 (pg/ml)(95% CI) 37.19 ± 5.38(35.4–38.9) 32.08 ± 1.18(32.4–33.2) 0.004* CIMT (mm) (95% CI) 0.71 ± 0.07(0.69–0.74) 0.59 ± 0.05(0.58–0.61) < 0.001* HR ; Heart rate, SBP ; Systolic blood pressure, DBP; Diastolic blood pressure, BMI ; Body mass index, TG ; Triglycerides, LDL; Low-density lipoproteins, HDL ; High-density lipoproteins, CIMT; carotid intimal medial thickness, TNF-α; Tumor necrosis factor alpha, IL- 6; Interleukin 6. * P < 0.05 is considered significant. Data are expressed in mean (± SD) or median (q25–q75), as appropriate. Biochemical parameters and markers of inflammation The patients with SS had significantly higher mean triglyceride (216.29 ± 51.94 in cases vs. 154.42 ± 42.17 mg/dl in controls; p < 0.001), total cholesterol (188.26 ± 45.17 in cases vs. 147.53 ± 39.63 mg/dl in controls; p < 0.001), and LDL cholesterol (112.38 ± 43.82 in cases vs. 74.62 ± 28.85 mg/dl in controls; p < 0.001) and lower HDL cholesterol concentrations (46.21 ± 10.69 in cases vs. 61.35 ± 8.72 mg/dl in controls; p < 0.001). The details of the hormone profile at the time first evaluation in SS patients are given in Table 2 . At least one hormone deficiency was present in all of the patients and more than one hormone deficiency was seen in 90% patients. Table 2 Baseline characteristics and hormone details of patients with Sheehan syndrome Hormone Mean ± SD Normal Values Deficient patients (%) fT3 (pg/dL) 1.41 ± 0.472 1.7–3.71 45.9 fT4 (ng/dL) 0.77 ± 0.741 0.59–1.76 51.4 TSH (mIU/L) 1.62 ± 2.178 0.5–6.5 51.1 LH (mIU/mL) 0.89 ± 1.463 3–12 67.6 FSH (mIU/mL) 3.14 ± 1.036 2-6.6 43.2 GH (ng/mL)* 0.17 ± 0.241 > 3 100.0 Prolactin (ng/mL)* 4.53 ± 2.193 > 2 73.0 Cortisol (mcg/dL)* 3.19 ± 1.356 > 20 86.5 IGF1(ng/ml) 18.55 ± 6.12 105–190 100 T3, tri‑iodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone; GH, growth hormone. *Peak values after insulin tolerance test. Hormone assays performed with specific radioim.munoassay. Data are expressed in frequency, mean (± SD) or median (q25–q75), as appropriate. A statistically significant difference in mean TNF-α level was observed in patients with SS compared to healthy controls (23.41 ± 10.97 in cases vs. 20.05 ± 2.76pg/ml in controls; p = 0.041). Similarly, the mean IL-6 was significantly higher in patients of SS compared to controls (37.19 ± 5.38 in cases vs. 32.08 ± 1.18 pg/ml in controls; p = 0.004). Patients exhibited significantly increased CIMT compared to healthy controls with mean CIMT in cases being 0.71 ± 0.07mm as against 0.59 ± 0.05mm in controls with a p -value of < 0.001(Table 1 ) . DISCUSSION Cardiovascular disease (CVD) is the leading cause of death in both developed and underdeveloped countries and is not rare in patients with hypopituitarism. It is reported that CVD is considerably higher among patients with hypopituitarism alongside abnormal cardiac structure and poor cardiac output 17,18 . It has been documented that females with hypopituitarism have a more than 2-fold rise in cardiovascular mortality as compared to the general population 19 . Patients with SS have varying degree of pituitary insufficiency ranging from partial to complete hormone insufficiency with GHD seen in all 5,6 . Severe GH deficiency is an established feature of SS and is associated with high incidence of cardiovascular morbidity and mortality on account of adverse cardiovascular risk profile including abnormal body composition, altered lipid profile being clustered with reduced quality of life, and osteoporosis 7 . Replacement with recombinant GH results in amelioration of majority of these altered parameters 20 . There is limited data available on the effects of GH deficiency in these patients 21 . Our study demonstrated that the GH naïve patients of SS have clustering of risk factors that plays a role in increasing the cardiovascular risk and in turn contribute to increased morbidity and mortality 22 . The presence of increased markers of inflammation, atherogenic lipid profile and increased CIMT undermine the importance of taking preventive measures to reduce the burden of cardiovascular risk in patients with SS. Present study demonstrated atherogenic lipid abnormalities in the form of higher concentrations of triglyceride, total cholesterol, LDL cholesterol and lower HDL cholesterol in patients with SS on conventional replacement therapy compared to healthy controls. These observations are in agreement with some earlier studies 23–25 . Bulow B et al. reported that in untreated GH-deficient adults, levels of total cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B were increased, and HDL-cholesterol levels reduced compared with those in healthy adults 26 . Kelestimur et al. have documented the favourable impact of growth hormone replacement on the adverse cardiovascular risk profile particularly on atherogenic lipid profile in addition to beneficial effects on quality of life, lean and fat body mass in the patients with Sheehan syndrome 21 . Hormone levels were assessed in all patients and it was observed at least one hormone deficiency was present in all of the patients and more than one hormone deficiency was seen in 90% patients. The earlier reported percentages of hormone deficiencies following ischemic infarction of pituitary includes GH deficiency at 88%, Gonadotropin deficiency at 58–76% and corticotropin deficiency 66%. In few earlier studies involving patients of partial SS, GH deficiency was the universal feature in all these women 5,6 . The location of somatrotrophs in the lower and lateral regions of the pituitary gland makes them vulnerable to the damage caused by ischemic necrosis of the pituitary resulting invariably in GH deficiency, a common feature in SS 27,28 . These hormonal deficiencies and inappropriate and inadequate hormonal replacement predispose these patients to higher risk for metabolic, inflammatory and cardiovascular risk. In addition the inadequate and/or inappropriate hormonal replacement in these patients increases the burden of therapy and makes patients unduly complacent when there is no room for complacency. The hypopituitary adults untreated for GHD have been found to have an increased CIMT, and is accepted as a non-invasive indicator for the atherosclerotic process in the coronary arteries as well as a predictor for cardiovascular events 29–31 . However, there are conflicting results from studies concerning IMT in hypopituitary patients with untreated GHD. While some studies demonstrated increased carotid IMT in GHD patients compared to controls 32,33 others failed to confirm the association 19,34 . In the present study, the mean carotid intima medial thickness was found to be significantly higher in SS patients compared to age, BMI and parity matched controls. Leonsson M et al. observed that patients with GHD had significantly higher CIMT compared to non-obese controls. Moreover, in women several cardiovascular risk factors independent of degree of adiposity were demonstrated 35 . They further observed that the higher WHR, serum triglyceride levels, total and LDL cholesterol combined with lower HDL-cholesterol in the patients seems to be an effect of GHD. Thus, the presence of adverse risk profile as documented in our study may confer further predisposition to adverse cardiovascular events seen in patients with hypopituitarism (SS). Growth hormone replacement in adult patients with hypopituitarism, resulted in a significant decrease in CIMT advocating a direct parietal effect of GH replacement on the arterial wall and may be indicative of a beneficial effect of GH treatment on the vascular system 36 . Our data demonstrate that patients with SS have elevated markers of inflammation including IL-6 and TNF- α compared to healthy controls. Increased inflammation may contribute to the poor cardiovascular risk profile in this population. The possible reasons for higher levels of IL-6 and TNF-α in women with SS include the presence of both hormonal deficiencies coupled with the hormonal replacement regimens. It is known that GH exerts important effects on inflammatory cells to promote production of cytokines. In addition to direct effects of GH on the production of inflammatory markers, there may be important indirect effects of GH through changes in body composition Increased production of IL-6 and TNF- α from monocytes and increased peripheral serum concentrations have been found in patients with GHD as subsequent GH replacement therapy has been associated with the decrease in levels of these cytokines indicating that GH may play a role in the regulation of the vascular wall inflammation. Increased production of IL-6 and TNF- α from monocytes and increased peripheral serum concentrations have been found in patients with GHD and Subsequent GH replacement therapy has been associated with the decrease in levels of these cytokines indicating that GH may play a role in the regulation of the vascular wall inflammation. We thus postulate that GH deficiency might be a contributory factor and might therefore be involved in the regulation of cytokine production in SS patients as demonstrated by our study. The increased adipose tissue mass in patients with GHD might be another possible reason for synthesis of TNF- α and contribute to higher levels of inflammatory markers in these patients. Our study stresses the importance and need for further investigation of role of GHD and treatment thereof in SS patients. CONCLUSION Our study demonstrated that patients with SS on conventional hormone replacement therapy sans GH replacement have clustering of adverse cardiovascular risk factors including atherogenic lipid profile, raised inflammatory markers like TNF alpha and IL6 and increased carotid intima medial thickness compared to healthy controls. SS being one of the commonest causes of adult growth hormone deficiency in our part of the world might be etiologically related to adverse cardiovascular risk profile in these patients. Further studies are needed to investigate the pathophysiological basis and consequences of these observations. This paper was presented in 202 at san diego USA at 32nd annual American college of clinical endocrionology meeting oral presentation Abstact#1184265. Declarations Author contributions .SAM conceptualized idea ,involved in patient management and drafting the manuscript. AAN was involved in patient follow-up, data compilation of manuscript. BD and UA HS was involved in patient management. NAK was the expert radiologist who performed the carotid Doppler .BAL edited the manuscript. All authors have readand approved the final version of the manuscript. Funding .No funding was received for conducting this study. 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Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency. J Clin Endocrinol Metab. 2001; 86(9):4223–32. Leonsson M, Hulthe J, Oscarsson J, Johannsson G, Wendelhag I, Wikstrand J, et al. Intima-media thickness in cardiovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors. Clin Endocrinol (Oxf). 2002; 57(6):751–9. Borson-Chazot F, Serusclat A, Kalfallah Y, Ducottet X, Sassolas G, Bernard S, et al. Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab. 1999; 84(4):1329–33. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Reject 20 Nov, 2023 Reviewers agreed at journal 25 Sep, 2023 Reviewers invited by journal 25 Sep, 2023 Editor assigned by journal 21 Sep, 2023 First submitted to journal 19 Sep, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3360451","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":235760115,"identity":"0ea36252-0d85-4182-8e82-195dd02173b2","order_by":0,"name":"shahnaz ahmad mir","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYDACZgYGCQaGA0AGM5BgkJAhRQtbAkgLD1EWQbQw8BiAOIS16LbzPrxd8eeOvDk7z+dXN2oseBjYDx/dgE+L2WF2Y8uzbc8MdzbzbrPOOQZ0GE9a2g38WtjYJBsbDjNuOMy7zTiHDahFgseMsJaGP4ftNxzmeWac849oLWyHE4FamB/nthGnhdmyse1w8obDbGbMuX0SPGwE/XL+GONNoMNsN5w//Phzzrc6OX72w8fwakEGbBJgkljlIMD8gRTVo2AUjIJRMHIAAJM2RpCGloNGAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7979-889X","institution":"Government Medical College Srinagar","correspondingAuthor":true,"prefix":"","firstName":"shahnaz","middleName":"ahmad","lastName":"mir","suffix":""},{"id":235760116,"identity":"bcbe2f33-1b4d-4d12-b4b5-8956db17b3c7","order_by":1,"name":"asif ahmad naik ahmad naik","email":"","orcid":"","institution":"Government Medical College Srinagar","correspondingAuthor":false,"prefix":"","firstName":"asif","middleName":"ahmad naik ahmad","lastName":"naik","suffix":""},{"id":235760117,"identity":"c5565291-0493-4a17-a6cc-7f45b4f0d22b","order_by":2,"name":"bashrat , dar","email":"","orcid":"","institution":"Government Medical College Srinagar","correspondingAuthor":false,"prefix":"","firstName":"dar","middleName":"","lastName":"bashrat","suffix":""},{"id":235760118,"identity":"fba2727d-93bd-480d-bd9a-e037166d626c","order_by":3,"name":"uzma arshed","email":"","orcid":"","institution":"University of Kashmir","correspondingAuthor":false,"prefix":"","firstName":"uzma","middleName":"","lastName":"arshed","suffix":""},{"id":235760119,"identity":"46ec3652-6351-4e78-b710-eb5b751d2b4f","order_by":4,"name":"naseer ahmad khan","email":"","orcid":"","institution":"Government Medical College Srinagar","correspondingAuthor":false,"prefix":"","firstName":"naseer","middleName":"ahmad","lastName":"khan","suffix":""},{"id":235760120,"identity":"18e14757-3b56-4fed-ad51-7334c1e3c09b","order_by":5,"name":"hardeep singh","email":"","orcid":"","institution":"Government Medical College Srinagar","correspondingAuthor":false,"prefix":"","firstName":"hardeep","middleName":"","lastName":"singh","suffix":""},{"id":235760121,"identity":"bd9c2267-2cf9-4856-9386-fcd25c3a1754","order_by":6,"name":"Bashir ahmad laway","email":"","orcid":"","institution":"Sher-i-Kashmir Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Bashir","middleName":"ahmad","lastName":"laway","suffix":""}],"badges":[],"createdAt":"2023-09-16 05:58:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3360451/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3360451/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43878530,"identity":"582aa469-332c-44cf-a38e-8e8bc3f232b8","added_by":"auto","created_at":"2023-09-29 12:23:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":283563,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3360451/v1/6ca2b20e-0c60-472d-9dbb-d2139f85985b.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eInflammatory markers and increased carotid intimal thickness in asymptomatic growth hormone naïve patients of Sheehan syndrome.\u003c/p\u003e","fulltext":[{"header":"Take-home massage","content":"\u003cp\u003e The take-home message of our research is that postpartum pituitary necrosis (Sheehan syndrome) is one of the common causes of hypopituitarism in our country and because of the high cost of growth hormone they remain deficient throughout life and are at high risk for cardiovascular diseases. So this is kind of the first study that looked at their carotid intimal thickness and endothelial dysfunction in them, So it is important for them to look at their cardiovascular risk and manage them aggressively.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eSheehan Syndrome (SS) is hypopituitarism resulting from ischemic necrosis of the pituitary gland as a result of extreme hypotension or shock caused by severe hemorrhage during or after parturition\u003csup\u003e1\u003c/sup\u003e. While the incidence of SS is assumed to have declined due to advancements in obstetrical treatment, it continues to remain one of the common causes of hypopituitarism in developing nations\u003csup\u003e2\u003c/sup\u003e. The disorder is rare in western countries but continues to be seen in some developing nations\u003csup\u003e3,4\u003c/sup\u003e. The prevalence of about 3% for SS was reported in women over the age of 20, in an epidemiological survey from the Kashmir valley of the Indian subcontinent with almost two-thirds of them having delivered babies at home\u003csup\u003e3\u003c/sup\u003e. SS is characterized by variable magnitudes of anterior and sometimes posterior pituitary gland dysfunction manifesting either immediately in the postpartum period or after a delay of several years, depending on the amount of tissue destruction\u003csup\u003e5,6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePatients with hypopituitarism (particularly women) receiving adequate conventional replacement therapy have higher cardiovascular mortality and morbidity than the general population\u003csup\u003e7\u003c/sup\u003e. The exact mechanism of increased vascular disease in hypopituitarism is still unclear; however, of late, the possible role of GHD in the pathophysiology of increased cardiovascular events has come under scrutiny contrary to earlier belief that GHD confers protection against risk of vascular disease\u003csup\u003e8\u003c/sup\u003e. GHD, a well-known characteristic of SS is associated with clustering of cardiovascular risk factors like abnormalities of lipid and carbohydrate metabolism, insulin resistance, endothelial dysfunction, and increased intimal-medial thickness among others\u003csup\u003e9\u0026ndash;11\u003c/sup\u003e. Moreover, the significant prevalence of coronary calcium deposits, in patients with SS unsubstituted for GH predispose them to relatively high risk for coronary heart disease\u003csup\u003e12\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEndothelial dysfunction, plays an important role in pathogenesis of atherosclerosis and is detected early in people at risk for cardiovascular events\u003csup\u003e13\u003c/sup\u003e. Cytokines, being the mediators of inflammation play a crucial role in the endothelial injury\u003csup\u003e14\u003c/sup\u003e. Several markers of inflammation such as TNF-α and IL-6 predict cardiovascular events in asymptomatic patients at high risk. These peripheral markers of inflammatory activity correlate with the degree of atherosclerosis as detected by CIMT.\u003c/p\u003e \u003cp\u003eThe present study was designed to investigate whether conventional cardiovascular risk factors, markers of the inflammation and CIMT are elevated in patients with SS unsubstituted for GH compared to healthy controls.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e This study was a case-control, cross-sectional observational study, conducted in Department of Internal Medicine and Endocrinology, Government Medical College, Srinagar after getting approval from institutional ethical committee. A written informed consent was obtained from all patients and controls and the study was performed according to the Declaration of Helsinki guidelines.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy subjects:\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eCases (n\u0026thinsp;=\u0026thinsp;37)\u003c/strong\u003e \u003cp\u003eThirty-seven women with Sheehan's syndrome were recruited from Endocrine Clinic after fulfilling the inclusion criteria in this study. Sheehan's syndrome was diagnosed using following \"essential criteria\" (1) proposed by Diri et al Cases for this study were defined as women meeting the \"essential criteria\" for SS who were stable on a conventional replacement treatment without Growth hormone replacement for at least 6 months before the study. All cases were growth hormone deficient documented by low IGF 1 levels and growth hormone by ITT when required.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eControls (n\u0026thinsp;=\u0026thinsp;37)\u003c/strong\u003e \u003cp\u003eAge and BMI matched unrelated healthy controls from same ethnic background.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion criteria:\u003c/h2\u003e \u003cp\u003eHemodynamically stable postpartum females of any age group, free of other co-morbidities like diabetes and hypertension, consenting to participate in the study protocol and fulfilling the above stated \"case definition\u0026rdquo; or otherwise healthy for cases and controls respectively.\u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion criteria\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients and controls with known atherosclerotic disease or manifest cardiovascular disease in terms of hypertension, peripheral arterial insufficiency, a history of myocardial infarction or stroke and /or diabetes.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSpecial physiological groups viz., pregnant or lactating female Patients extremes of age.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAll the study participants underwent anthropometric assessments such as measurement of weight, height, waist-hip circumference, blood pressure and detailed systemic examination. BMI was calculated as body weight in kg/height in m\u003csup\u003e2\u003c/sup\u003e. All patients were stable on a conventional replacement treatment for at least 6 months before the study. Growth hormone treatment had not been given to any of the patients previously. Patients attended the Endocrinology clinic of Internal Medicine between 8:30 and 9:00 am after an overnight fast of 10\u0026ndash;12 hours, without taking the usual morning replacement therapy. The investigation was carried out on an outpatient basis. The venous blood samples were collected for measurements of triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, fasting blood glucose and the routine hematological investigations. Liver and renal function tests were also performed. The biochemical analysis like glucose, total cholesterol, and triglyceride concentrations were performed with a Technicon DAX-72 auto analyzer (Technicon, Bayer Corporation, Tarrytown, New York) in the Central Biochemistry Laboratory, Government Medical College, Srinagar. HDL cholesterol concentrations were measured using RAXT auto analyzer after phosphotungstic acid and magnesium chloride precipitation. LDL cholesterol was calculated by Friedwald formula\u003csup\u003e15\u003c/sup\u003e. Hormonal assays were done by electrochemiluminescence method on Abbot ARCHITECT \u003cem\u003ei\u003c/em\u003e2000SR immunoassay analyzer and following the manufacturer\u0026rsquo;s protocol. IGFI was measured by CLIA (chemiluminescent immunometric assay).\u003c/p\u003e \u003cp\u003eThe measurement of carotid intima-medial thickness was performed by a high-resolution echo-colour Doppler system (LOGIQ S8; GE Healthcare, Chalfont St Giles, United Kingdom) as per the standard protocol\u003csup\u003e16\u003c/sup\u003e. Scanning of the extra cranial carotid arteries in the neck was performed bilaterally in three different longitudinal projections: anterior-oblique, lateral and posterior-oblique as well as the transverse projection. Three determinations of intima plus medial thickness were conducted at the site of the greatest thickness and two points, 1 cm upstream and 1 cm downstream from the site of the greatest thickness. These three values were averaged. The greatest value among the six averaged intima plus medial thickness (three from the left and three from the right) was used as the representative IMT value for each individual. The coefficients of variation of the measurements were less than 3%. All scans were read by an independent physician, blinded as to the clinical status of the subjects.\u003c/p\u003e \u003cp\u003eThe serum TNF-α and IL-6 concentrations were measured in all patients using the commercially available Enzyme-linked immunosorbent assay (ELISA) kits for cytokine detection (eBioscience ELISA Kits, San Diego, CA, USA) with an intra-assay coefficient of variation of 5.3\u0026ndash;8.3%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSPSS Version 20.0 (SPSS Inc., Chicago, Illinois, USA) was used to analyse the recorded data. Continuous variables were expressed as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and categorical variables were summarized as frequencies and percentages. Shapiro\u0026ndash;Wilk test and normal probability plot were used to test for normality of data. Normally distributed continuous variables were compared using the student\u0026rsquo;s independent t-test, and non-normally distributed variables were analyzed using Mann-Whitney U test. A p-value of less than 0.05 was considered statistically significant. All p-values were two-tailed.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characters\u003c/h2\u003e \u003cp\u003e74 women comprising of 37 patients with Sheehan syndrome and 37 age, BMI and parity matched healthy women were included in this study. Cases and controls were chosen so they had a similar age and BMI distribution similar was with basal heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) distributions. The detail of the biochemical profile and inflammatory markers is given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of description of anthropometric, clinical, biochemical characteristics and inflammatory markers among patients of SS and controls.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in years(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.71 (30\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.8\u0026thinsp;\u0026plusmn;\u0026thinsp;13.54 (29\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.472\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.4\u0026thinsp;+\u0026thinsp;1.47 (1\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.9\u0026thinsp;+\u0026thinsp;1.28(1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR (beats/min)(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.81\u0026thinsp;+\u0026thinsp;9.76 (51\u0026ndash;98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.71\u0026thinsp;\u0026plusmn;\u0026thinsp;14.20(64\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSBP (mmHg)(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112.6\u0026thinsp;+\u0026thinsp;8.74 (90\u0026ndash;130)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.12(98\u0026ndash;126)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.332\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBP (mmHg)(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.6\u0026thinsp;+\u0026thinsp;7.93 (64\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.34(70\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.08\u0026thinsp;\u0026plusmn;\u0026thinsp;2.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.221\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWaist Hip Ratio (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10(0.83\u0026ndash;0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.87\u0026thinsp;+\u0026thinsp;0.09 (0.83\u0026ndash;0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.314\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum Cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e188.26\u0026thinsp;\u0026plusmn;\u0026thinsp;45.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147.53\u0026thinsp;\u0026plusmn;\u0026thinsp;39.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum TG (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e216.29\u0026thinsp;\u0026plusmn;\u0026thinsp;51.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e154.42\u0026thinsp;\u0026plusmn;\u0026thinsp;42.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum LDL (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112.38\u0026thinsp;\u0026plusmn;\u0026thinsp;43.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.62\u0026thinsp;\u0026plusmn;\u0026thinsp;28.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum HDL mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.21\u0026thinsp;\u0026plusmn;\u0026thinsp;10.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.35\u0026thinsp;\u0026plusmn;\u0026thinsp;8.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum TNF-α (pg/ml) (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.41\u0026thinsp;\u0026plusmn;\u0026thinsp;10.97(19.8\u0026ndash;27.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.05\u0026thinsp;\u0026plusmn;\u0026thinsp;2.76(19.1\u0026ndash;20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.041*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum IL-6 (pg/ml)(95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.19\u0026thinsp;\u0026plusmn;\u0026thinsp;5.38(35.4\u0026ndash;38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18(32.4\u0026ndash;33.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIMT (mm) (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07(0.69\u0026ndash;0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05(0.58\u0026ndash;0.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHR ; Heart rate, SBP ; Systolic blood pressure, DBP; Diastolic blood pressure, BMI ; Body mass index, TG ; Triglycerides, LDL; Low-density lipoproteins, HDL ; High-density lipoproteins, CIMT; carotid intimal medial thickness, TNF-α; Tumor necrosis factor alpha, IL- 6; Interleukin 6. * \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered significant. Data are expressed in mean (\u0026plusmn;\u0026thinsp;SD) or median (q25\u0026ndash;q75), as appropriate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical parameters and markers of inflammation\u003c/h2\u003e \u003cp\u003eThe patients with SS had significantly higher mean triglyceride (216.29\u0026thinsp;\u0026plusmn;\u0026thinsp;51.94 in cases vs. 154.42\u0026thinsp;\u0026plusmn;\u0026thinsp;42.17 mg/dl in controls; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), total cholesterol (188.26\u0026thinsp;\u0026plusmn;\u0026thinsp;45.17 in cases vs. 147.53\u0026thinsp;\u0026plusmn;\u0026thinsp;39.63 mg/dl in controls; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and LDL cholesterol (112.38\u0026thinsp;\u0026plusmn;\u0026thinsp;43.82 in cases vs. 74.62\u0026thinsp;\u0026plusmn;\u0026thinsp;28.85 mg/dl in controls; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and lower HDL cholesterol concentrations (46.21\u0026thinsp;\u0026plusmn;\u0026thinsp;10.69 in cases vs. 61.35\u0026thinsp;\u0026plusmn;\u0026thinsp;8.72 mg/dl in controls; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eThe details of the hormone profile at the time first evaluation in SS patients are given in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. At least one hormone deficiency was present in all of the patients and more than one hormone deficiency was seen in 90% patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics and hormone details of patients with Sheehan syndrome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormal Values\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDeficient patients (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efT3 (pg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.7\u0026ndash;3.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efT4 (ng/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.741\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.59\u0026ndash;1.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH (mIU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.62\u0026thinsp;\u0026plusmn;\u0026thinsp;2.178\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u0026ndash;6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH (mIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.89\u0026thinsp;\u0026plusmn;\u0026thinsp;1.463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSH (mIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2-6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGH (ng/mL)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.241\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProlactin (ng/mL)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCortisol (mcg/dL)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIGF1(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e18.55\u0026thinsp;\u0026plusmn;\u0026thinsp;6.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105\u0026ndash;190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eT3, tri‑iodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone; GH, growth hormone. *Peak values after insulin tolerance test. Hormone assays performed with specific radioim.munoassay. Data are expressed in frequency, mean (\u0026plusmn;\u0026thinsp;SD) or median (q25\u0026ndash;q75), as appropriate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA statistically significant difference in mean TNF-α level was observed in patients with SS compared to healthy controls (23.41\u0026thinsp;\u0026plusmn;\u0026thinsp;10.97 in cases vs. 20.05\u0026thinsp;\u0026plusmn;\u0026thinsp;2.76pg/ml in controls; p\u0026thinsp;=\u0026thinsp;0.041). Similarly, the mean IL-6 was significantly higher in patients of SS compared to controls (37.19\u0026thinsp;\u0026plusmn;\u0026thinsp;5.38 in cases vs. 32.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18 pg/ml in controls; p\u0026thinsp;=\u0026thinsp;0.004). Patients exhibited significantly increased CIMT compared to healthy controls with mean CIMT in cases being 0.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07mm as against 0.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05mm in controls with a \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.001(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCardiovascular disease (CVD) is the leading cause of death in both developed and underdeveloped countries and is not rare in patients with hypopituitarism. It is reported that CVD is considerably higher among patients with hypopituitarism alongside abnormal cardiac structure and poor cardiac output\u003csup\u003e17,18\u003c/sup\u003e. It has been documented that females with hypopituitarism have a more than 2-fold rise in cardiovascular mortality as compared to the general population\u003csup\u003e19\u003c/sup\u003e. Patients with SS have varying degree of pituitary insufficiency ranging from partial to complete hormone insufficiency with GHD seen in all\u003csup\u003e5,6\u003c/sup\u003e. Severe GH deficiency is an established feature of SS and is associated with high incidence of cardiovascular morbidity and mortality on account of adverse cardiovascular risk profile including abnormal body composition, altered lipid profile being clustered with reduced quality of life, and osteoporosis\u003csup\u003e7\u003c/sup\u003e. Replacement with recombinant GH results in amelioration of majority of these altered parameters\u003csup\u003e20\u003c/sup\u003e. There is limited data available on the effects of GH deficiency in these patients\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study demonstrated that the GH na\u0026iuml;ve patients of SS have clustering of risk factors that plays a role in increasing the cardiovascular risk and in turn contribute to increased morbidity and mortality\u003csup\u003e22\u003c/sup\u003e. The presence of increased markers of inflammation, atherogenic lipid profile and increased CIMT undermine the importance of taking preventive measures to reduce the burden of cardiovascular risk in patients with SS. Present study demonstrated atherogenic lipid abnormalities in the form of higher concentrations of triglyceride, total cholesterol, LDL cholesterol and lower HDL cholesterol in patients with SS on conventional replacement therapy compared to healthy controls. These observations are in agreement with some earlier studies\u003csup\u003e23\u0026ndash;25\u003c/sup\u003e. Bulow B et al. reported that in untreated GH-deficient adults, levels of total cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B were increased, and HDL-cholesterol levels reduced compared with those in healthy adults\u003csup\u003e26\u003c/sup\u003e. Kelestimur et al. have documented the favourable impact of growth hormone replacement on the adverse cardiovascular risk profile particularly on atherogenic lipid profile in addition to beneficial effects on quality of life, lean and fat body mass in the patients with Sheehan syndrome\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHormone levels were assessed in all patients and it was observed at least one hormone deficiency was present in all of the patients and more than one hormone deficiency was seen in 90% patients. The earlier reported percentages of hormone deficiencies following ischemic infarction of pituitary includes GH deficiency at 88%, Gonadotropin deficiency at 58\u0026ndash;76% and corticotropin deficiency 66%. In few earlier studies involving patients of partial SS, GH deficiency was the universal feature in all these women\u003csup\u003e5,6\u003c/sup\u003e. The location of somatrotrophs in the lower and lateral regions of the pituitary gland makes them vulnerable to the damage caused by ischemic necrosis of the pituitary resulting invariably in GH deficiency, a common feature in SS\u003csup\u003e27,28\u003c/sup\u003e. These hormonal deficiencies and inappropriate and inadequate hormonal replacement predispose these patients to higher risk for metabolic, inflammatory and cardiovascular risk. In addition the inadequate and/or inappropriate hormonal replacement in these patients increases the burden of therapy and makes patients unduly complacent when there is no room for complacency.\u003c/p\u003e \u003cp\u003eThe hypopituitary adults untreated for GHD have been found to have an increased CIMT, and is accepted as a non-invasive indicator for the atherosclerotic process in the coronary arteries as well as a predictor for cardiovascular events\u003csup\u003e29\u0026ndash;31\u003c/sup\u003e. However, there are conflicting results from studies concerning IMT in hypopituitary patients with untreated GHD. While some studies demonstrated increased carotid IMT in GHD patients compared to controls\u003csup\u003e32,33\u003c/sup\u003e others failed to confirm the association\u003csup\u003e19,34\u003c/sup\u003e. In the present study, the mean carotid intima medial thickness was found to be significantly higher in SS patients compared to age, BMI and parity matched controls. Leonsson M et al. observed that patients with GHD had significantly higher CIMT compared to non-obese controls. Moreover, in women several cardiovascular risk factors independent of degree of adiposity were demonstrated\u003csup\u003e35\u003c/sup\u003e. They further observed that the higher WHR, serum triglyceride levels, total and LDL cholesterol combined with lower HDL-cholesterol in the patients seems to be an effect of GHD. Thus, the presence of adverse risk profile as documented in our study may confer further predisposition to adverse cardiovascular events seen in patients with hypopituitarism (SS). Growth hormone replacement in adult patients with hypopituitarism, resulted in a significant decrease in CIMT advocating a direct parietal effect of GH replacement on the arterial wall and may be indicative of a beneficial effect of GH treatment on the vascular system\u003csup\u003e36\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur data demonstrate that patients with SS have elevated markers of inflammation including IL-6 and TNF- α compared to healthy controls. Increased inflammation may contribute to the poor cardiovascular risk profile in this population. The possible reasons for higher levels of IL-6 and TNF-α in women with SS include the presence of both hormonal deficiencies coupled with the hormonal replacement regimens. It is known that GH exerts important effects on inflammatory cells to promote production of cytokines. In addition to direct effects of GH on the production of inflammatory markers, there may be important indirect effects of GH through changes in body composition Increased production of IL-6 and TNF- α from monocytes and increased peripheral serum concentrations have been found in patients with GHD as subsequent GH replacement therapy has been associated with the decrease in levels of these cytokines indicating that GH may play a role in the regulation of the vascular wall inflammation. Increased production of IL-6 and TNF- α from monocytes and increased peripheral serum concentrations have been found in patients with GHD and Subsequent GH replacement therapy has been associated with the decrease in levels of these cytokines indicating that GH may play a role in the regulation of the vascular wall inflammation. We thus postulate that GH deficiency might be a contributory factor and might therefore be involved in the regulation of cytokine production in SS patients as demonstrated by our study. The increased adipose tissue mass in patients with GHD might be another possible reason for synthesis of TNF- α and contribute to higher levels of inflammatory markers in these patients. Our study stresses the importance and need for further investigation of role of GHD and treatment thereof in SS patients.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur study demonstrated that patients with SS on conventional hormone replacement therapy sans GH replacement have clustering of adverse cardiovascular risk factors including atherogenic lipid profile, raised inflammatory markers like TNF alpha and IL6 and increased carotid intima medial thickness compared to healthy controls. SS being one of the commonest causes of adult growth hormone deficiency in our part of the world might be etiologically related to adverse cardiovascular risk profile in these patients. Further studies are needed to investigate the pathophysiological basis and consequences of these observations.\u003c/p\u003e \u003cp\u003e This paper was presented in 202 at san diego USA at 32nd annual American college of clinical endocrionology meeting oral presentation Abstact#1184265.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor contributions .SAM \u0026nbsp;conceptualized idea ,involved in patient management and drafting the manuscript. AAN was involved in patient follow-up, data compilation of\u003c/p\u003e\n\u003cp\u003emanuscript. BD and UA \u0026nbsp;HS was involved in patient management.\u003c/p\u003e\n\u003cp\u003eNAK was the expert radiologist \u0026nbsp;who performed the carotid Doppler .BAL \u0026nbsp; edited \u0026nbsp; the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors have readand approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding .No funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003eDeclarations Conflict of interest ;The authors have no competing interests to declare\u003c/p\u003e\n\u003cp\u003eConsent to participate Informed consent was obtained from all individual\u003c/p\u003e\n\u003cp\u003eparticipants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDiri H, Karaca Z, Tanriverdi F, Unluhizarci K, Kelestimur F. Sheehan\u0026rsquo;s syndrome: new insights into an old disease. Endocrine. 2016; 51(1):22\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eKilicli F, Dokmetas HS, Acibucu F. 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Lipids, lipoproteins, apolipoproteins, and other cardiovascular risk factors. Tietz Textb Clin Chem. 2006;903\u0026ndash;68. \u003c/li\u003e\n\u003cli\u003eExamination Carotid Ultrasound. The Joint Committee of \u0026ldquo;The Japan Academy of Neurosonology\u0026rdquo; and \u0026ldquo;The Japan Society of Embolus Detection and Treatment\u0026rdquo; on Guideline for Nuerosonology. Neurosonology. 2006;19:49\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eAbdu TA, Elhadd T, Pfeifer M, Clayton RN. Endothelial dysfunction in endocrine disease. Trends Endocrinol Metab TEM. 2001;12(6):257\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eLaway BA, Ramzan M, Allai MS, Wani AI, Misgar RA. Cardiac structural and functional abnormalities in females with untreated hypopituitarism due to sheehan syndrome: response to hormone replacement therapy. Endocr Pract. 2016;22(9):1096\u0026ndash;103. \u003c/li\u003e\n\u003cli\u003eB\u0026uuml;low B, Hagmar L, Eskilsson J, Erfurth EM. 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Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors. J Clin Endocrinol Metab. 2000; 85(2):574\u0026ndash;84. \u003c/li\u003e\n\u003cli\u003eMir SA, Shah T, Singh H, Shabir I, Laway BA. Serum Lipid and Leptin Concentrations in Patients with Sheehan Syndrome. Indian J Endocrinol Metab. 2018;22(4):466\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eBhat MA, Laway BA, Shah ZA, Wani AI, Mubarik I. Insulin resistance, metabolic syndrome and chronic low grade inflammation in Sheehan\u0026rsquo;s syndrome on standard replacement therapy: a case control study. Pituitary. 2015;18(3):312\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eOzbey N, Algun E, Turgut AS, Orhan Y, Sencer E, Molvalilar S. Serum lipid and leptin concentrations in hypopituitary patients with growth hormone deficiency. Int J Obes Relat Metab Disord J Int Assoc Study Obes. 2000;24(5):619\u0026ndash;26. \u003c/li\u003e\n\u003cli\u003eB\u0026uuml;low B, Hagmar L, Mikoczy Z, Nordstr\u0026ouml;m CH, Erfurth EM. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf). 1997;46(1):75\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eZargar AH, Masoodi SR, Laway BA, Shah NA, Salahuddin M, Siddiqi MA, et al. Clinical spectrum of Sheehan\u0026rsquo;s syndrome. Ann Saudi Med. 1996;16(3):338\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eD\u0026ouml;kmetaş HS, Kilicli F, Korkmaz S, Yonem O. Characteristic features of 20 patients with Sheehan\u0026rsquo;s syndrome. Gynecol Endocrinol. 2006 ;22(5):279\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eWofford JL, Kahl FR, Howard GR, McKinney WM, Toole JF, Crouse JR. Relation of extent of extracranial carotid artery atherosclerosis as measured by B-mode ultrasound to the extent of coronary atherosclerosis. Arterioscler Thromb J Vasc Biol. 1991;11(6):1786\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eHulthe J, Wikstrand J, Emanuelsson H, Wiklund O, de Feyter PJ, Wendelhag I. Atherosclerotic changes in the carotid artery bulb as measured by B-mode ultrasound are associated with the extent of coronary atherosclerosis. Stroke. 1997;28(6):1189\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999 ;340(1):14\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003ePfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab. 1999;84(2):453\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eMarkussis V, Beshyah SA, Johnston DG, Fisher C, Nicolaides AN, Sharp P. Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. The Lancet. 1992;340(8829):1188\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eElhadd TA, Abdu TA, Oxtoby J, Kennedy G, McLaren M, Neary R, et al. Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency. J Clin Endocrinol Metab. 2001; 86(9):4223\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eLeonsson M, Hulthe J, Oscarsson J, Johannsson G, Wendelhag I, Wikstrand J, et al. Intima-media thickness in cardiovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors. Clin Endocrinol (Oxf). 2002; 57(6):751\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eBorson-Chazot F, Serusclat A, Kalfallah Y, Ducottet X, Sassolas G, Bernard S, et al. Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab. 1999; 84(4):1329\u0026ndash;33. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Sheehan syndrome, endothelial dysfunction, CIMT, hypopituitarism","lastPublishedDoi":"10.21203/rs.3.rs-3360451/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3360451/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe dyad of cardio-metabolic risk factors and endothelial dysfunction observed in hypopituitarism untreated for growth hormone deficiency (GHD), a characteristic of Sheehan's syndrome (SS), contributes to the increased cardiovascular mortality and morbidity. The elevated inflammatory markers reported in these patients along with conventional cardiovascular risk factors are considered pivotal contributors to coronary endothelial dysfunction and high risk for cardiovascular events. We aim to investigate the level of conventional cardiovascular risk factors, inflammatory markers and carotid artery Intima-Media Thickness (CIMT) in patients of SS compared to a group of healthy women.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 37 SS patients fulfilling the case definition for this study and same number (n\u0026thinsp;=\u0026thinsp;37) healthy age, BMI and parity matched controls were recruited for the study. The participants underwent detailed clinical, biochemical, hormone analysis and measurement of Tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) levels. CIMT assessment was also done using high-resolution echo-colour Doppler system in both cases and controls.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePatients with SS had significantly higher mean triglyceride, total cholesterol, low-density lipoprotein cholesterol and lower high-density cholesterol concentrations. The markers of inflammation including TNF-α and IL-6 levels were significantly higher (23.41\u0026thinsp;\u0026plusmn;\u0026thinsp;10.97 vs. 20.05\u0026thinsp;\u0026plusmn;\u0026thinsp;2.76pg/ml; p\u0026thinsp;=\u0026thinsp;0.041) for TNF- α and (37.19\u0026thinsp;\u0026plusmn;\u0026thinsp;5.38 vs. 32.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18pg/ml; p\u0026thinsp;=\u0026thinsp;0.004) for IL-6, compared to healthy controls. Furthermore, mean carotid intima medial thickness in patients was significantly increased in comparison to healthy controls (0.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 vs. 0.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05mm; p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur study demonstrated that patients with SS have clustering of cardiovascular risk factors that may contribute to the increased risk for cardiovascular events.\u003c/p\u003e","manuscriptTitle":"Inflammatory markers and increased carotid intimal thickness in asymptomatic growth hormone naïve patients of Sheehan syndrome.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-29 12:15:39","doi":"10.21203/rs.3.rs-3360451/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Reject","date":"2023-11-20T05:27:07+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-09-25T08:41:45+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-09-25T07:13:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-09-21T12:11:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2023-09-20T02:37:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"cc62f530-cfb2-4b65-bbbf-814ce087b245","owner":[],"postedDate":"September 29th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2023-09-29T12:15:39+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-29 12:15:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3360451","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3360451","identity":"rs-3360451","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}