Sep 2016 Vol. 2, No.1 ISSN: 2410-1605 JKBMS JOURNAL OF KURDISTAN BOARD OF MEDICAL SPECIALTIES P.O.Box: 0845/32, Ziraa square, KBMS, Erbil, Kurdistan Region, Iraq. Tel: 000964-662646881 Email: journal@kbms.org Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 22-27 Menstrual and Hormonal Changes in Breast Cancer Patients Treated By Adjuvant, Adriamycin and Cyclophosphamide Chemotherapy Jangi Shawkat Muhialdin Salai*, Nermin Jamal Abdulqadr**, Kawa Faeq Dizaye*** JKBMS, 2016 Abstract Background and objectives: The long term effects of adjuvant chemotherapy are very important in patients with breast cancer. Cytotoxic chemotherapy may induce changes in menstrual cycle to variable extents and even may induce amenorrhea. This study was designed to ind out the effect of adjuvant chemotherapy, Doxorubicin and Cyclophosphamide, on ovarian function in patients with early stages breast cancer. Methods: Thirty premenopausal women with newly diagnosed early breast cancer enrolled in this study. In addition to a proper menstruation history, the following parameters FSH, LH, Estrogen, Progesterone, were estimated before and after 4 cycles of chemotherapy with another follow up for menstrual history after 6 months, in each patient. Results: After 4 cycles of adjuvant Doxorubicin and Cyclophosphamide chemotherapy the mean level of FSH and LH was increased and Estrogen level was decreased, signiicantly. While, Progesterone level was decreased non-signiicantly. Menstrual changes detected in most patients after receiving chemotherapy but only %47 of them developed amenorrhea which was persistent after 6 months in %33 of the patients. The induced amenorrhea has found to be related positively with the age of the patient but has no any relation with receptor status, estrogen, progesteron and Her2 (human epidermal growth factor receptor 2), of the tumor and neither with the menstrual phase at which chemotherapy has been given nor with the body mass index. Conclusions: Adjuvant chemotherapy changes ovarian hormonal levels signiicantly and induces transient and permanent amenorrhea in patients with early stages breast cancer. Keywords: Doxorubicin and Cyclophosphamide, Hormonal changes, Amenorrhea. Introduction According to the National Comprehensive Cancer Network (NCCN) guide line, breast cancer can be treated by one or more of the following steps: surgery, radiation therapy, chemotherapy (CT), hormone therapy, and monoclonal antibody therapy. Several large studies have shown, conclusively, that adjuvant CT improves survival, especially in premenopausal women 1-5. One of the beneicial adverse effect of chemotherapy for premenopausal women is the induction of amenorrhea 6-7. Chemotherapy induced amenorrhea (CIA) is the term used to describe the cessation of menses for several months during or soon after the use of chemotherapy due to ovarian atrophy and loss of primordial follicle which leads to ovarian failure, however, these effects is not an “all or nothing phenomenon” 7-8. A review of the literature reveals inconsistencies regarding the deinition of chemotherapy-related amenorrhea, with some authors deining it as a cessation of menses lasting ≥ 3–6 months and others deining it as a cessation lasting 12 months 8 . The impact of various deinitions is illustrated by Padmanabhan et al, 1986, who reported the incidence of amenorrhea from the beginning of CMF (Cyclophosphamide, Methotrexate and 5-Fluorouracil) chemotherapy at 3 months, 6 months, and 12 months later as 50%, 70%, and 80%, respectively 9. It is well known that evaluation of ovarian function can be assessed by different method like menstrual history taking and laboratory measurements. So, history of menstrual bleeding is a convenient method of assessment in determining ovarian function. However, menstrual status cannot thoroughly relect actual ovarian function. The serial measurement of serum ovarian biochemical markers is an acceptable method to relect ovarian function 10-11. Previous studies preferred FSH as a biochemical marker to predict ovarian reserve, but currently Other than FSH, anti-Müllerian *Department of Pharmacology and Biophysics, College of Medicine, Hawler Medical University. Department of Oncology at Rizgary Teaching Hospital ** Department of pharmacy, Rizgary Teaching Hospital *** Department of Pharmacology and Biophysics, College of Medicine, Hawler Medical University 22 Kurdistan Board of Medical Specialties Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 22-27 hormone (AMH) and inhibin B are used as predictive capacity of ovarian function, they appear to be superior to FSH because they are not affected by the administration of tamoxifen. Moreover, AMH and inhibin B relect subtle changes in menstrual transition, which has been compared with FSH. AMH is also strongly recommended for its sensitivity in predicting ovarian function and stable expression over the menstrual cycle 12-16. The incidence of CIA differs with respect to patient age and chemotherapeutic regimens used 13-14. For this reason the incidence of CIA has varied across studies from 27% to 94% in patients treated with older cyclophosphamide based or doxorubicin-based regimens. The CIA can be regarded as an important clinical sequences of adjuvant chemotherapy because it produces menopausal symptoms like hot lushing, night sweats, sleep disturbance, palpitation, depression, agitation and vaginal atrophy, also might cause cardiovascular morbidity, early bone mineral loss and fertility impairment 12-13,17. The objectives of the study were to evaluate hormonal changes after adjuvant chemotherapy (AC), ind out the incidence of menstrual pattern changes in early stage breast cancer patients treated with AC and evaluate the effect of the molecular characters of the tumor on CIA. Patients and methods This prospective study; was carried at Rizgary Teaching Hospital, from January 2014 to February 2015, after obtaining scientiic committee approval from college of medicine. Thirty newly operated breast cancer women aged (23-50 years old), who had indication for adjuvant chemotherapy, were enrolled in this study after obtaining their consent. All of these patients were planned to receive an adjuvant Cyclo- phosphamide and Doxorubicine (AC) chemotherapy protocol for 4 cycles. The criteria of inclusions were recent breast cancer, pre-menopause, no history of previous chemotherapy, hormonal therapy, oral contraceptive. Postmenopausal women, recurrence breast cancer, patients with gonadotropin-releasing hormone (GnRH) agonist administration or hysterectomy/bilateral oophorectomy histories, and history of chemotherapy for other malignancy were excluded. Before starting irst cycle of adjuvant chemotherapy AC and after inishing four cycles, peripheral venous blood was drawn from each patient, exactly at the day after her menstruation (if she was menstruating). The blood has been centrifuged at 2500 rpm for 10 min, the sera were divided into two aliquot and kept in tubes without anticoagulant. One tube used for hormonal assay including serum: (FSH, LH, Progesterone, Estradiole), and other tube used for biochemical assays including: (liver function test, renal function test and lipid proile). The obtained results were evaluated and comparison was done between pre and post chemotherapy values. Another follow up was carried out after 6 months to evaluate the menstrual pattern of the patients. All results were expressed as mean ± SE. the data were analyzed by using student t test and chi square. Software SPSS program version 20 was used. P values ≤ 0.05 were considered statistically signiicance. Results In this study, giving 4 cycles of adjuvant AC to patients with early stages breast cancer signiicantly increased both FSH and LH levels and decreased the level of estrogen, while did not affect the level of progesterone as shown in Table 1. Table (1): Mean FSH, LH, Estrogen and Progesterone in pre- chemotherapy (basal value) and after administration of four cycles of AC. Parameter Before chemotherapy After chemotherapy (Mean FSH (mIU/ml 2.982 ± 11.295 * (Mean LH (mIU/ml 2.27 ± 12.04 * (Estrogen (pg/ml 11.20 ± 77.37 * (Progesterone (ng/ml 0.557 ± 1.978 0.852 ± 1.136 6.28 ± 42.61 3.93 ± 31.99 9.779 ± 32.56 (Note: * is sign of signiicance, P values < 0.05). Kurdistan Board of Medical Specialties 23 Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 22-27 Among a total of 30 patients enrolled in this study, 14 cases developed CIA and 16 cases were menstruating normally, after inishing four cycles AC. However, six months later we found that 4 patients (28.57%) among CIA resumed their menstruation (temporary CIA) and only 10 patients (71.42%) stayed with deinite CIA. While between 16 patients with no CIA, 7 patients (43.75%) stayed with normal menstruation and 9 patients (56.25%) were suffering from oligomenorrhea Table 2. Table (2): Number and percent of patients with different pattern of menstruation. Number and percent of patients with different pattern of menstruation. CIA 14 patients No CIA 16 patients Deinite CIA Temporary CIA Normal menstruation Oligomenorrhea 10 (71.42%) 4 (28.57%) 7 (43.75%) 9 (56.25%) 33.3% 13.33% 23.33% 30% The mean FSH, LH and progesteron levels in 14 pa- the mean Estrogen level in patients with CIA was sigtients with CIA were signiicantly greater than the niicantly less than the mean Estrogen level of menmean FSH and LH of 16 patients without CIA. While struating patients, as shown in Table 3. Table (3): Mean FSH, LH, Estrogen and Progesterone level in (CIA) patients and patients with no (CIA) after administration of four cycles of adjuvant AC chemotherapy. Parameters CIA patients Patients with no CIA (Mean FSH(mIU/ml 63.01±9.96 *24.75±4.71 (Mean LH(mIU/ml 42.73±6.32 *22.6±3.62 (Mean Estrogen(pg/ml 10.81±4.83 *51.6±16.65 (Mean progesterone(ng/ml 2.07±1.82 *0.31±0.48 (Note: * is sign of signiicance, P values < 0.05). In this study, the relation between age and CIA has been studied and statistical analysis showed that the age was affecting the induction of amenorrhea signiicantly (p value 0.04). Among a total of 14 patients with CIA only 2 (14.3%) patients were younger than 35 years old, while 12 (85.7%) patients were older than 35 years. In contrast, among 16 patients with no CIA 11 (68.7%) patients were younger than 35 and only 5 (31.3%) of the cases were more than 35 years old, Figure (1). A B Figure (1): Percent of patients with (A) and without (B) CIA within each age group after four cycles of chemotherapy In CIA patients, chemotherapy has been given during the follicular phase of the menstruation in eight (57.1%) patients and during luteal phase in six (42.9%) of them. However, in those 16 patients who maintained their menstruation, AC has been adminis- 24 Kurdistan Board of Medical Specialties Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 22-27 tered during follicular face in six (37.5%) and during association was found between CIA and menstrual luteal phase in ten (62.5%), patients. No signiicant phase at which chemotherapy been given, Table 4. Table (4): Number and percent of patients developed (CIA) related to the phases of menstruation at which chemotherapy has been administered. Menstrual state Follicular phase Luteal phase CIA (57.1%) 8 (42.9%) 6 No CIA (37.5%) 6 (62.5%) 10 In this study we assessed the association between CIA and hormonal receptors and Her2 receptor status. The statistical analysis showed that there is no signiicant association between amenorrhea induced by chemotherapy and receptor status (data not shown-negative results) Other factor which has been studied in this work was the effect of BMI of the patient with the possibility of developing CIA. Our indings show that BMI has no statistically signiicant effect on CIA. We have found that in 14 patients with CIA the mean BMI was (30.13 ± 1.83), 4 patients (28.6%) were within normal range BMI and 10 patients (71.4%) had abnormal BMI (over normal range). Almost the same results have been found in other 16 patients with no CIA, the mean BMI was (30.07 ± 1.49), 3 (18.8%) of them were within normal range (BMI) and 13 (81.3%) had high BMI (data not shown-negative results). Discussion Of more than 230,000 new diagnoses breast carcinoma in the US each year, 25% occur before menopause, and 15% of women are diagnosed in the reproductive age group (age 45 yrs. or younger)18. It has been found that adjuvant chemotherapy prolongs disease-free and overall survival for patients with breast carcinoma 3-4 but also can induce long-term side effects, such as suppression of ovarian function with subsequent premature menopause. This results in loss of childbearing potential and prolonged exposure to the risks of menopause and psychological distress 19-21. It is well known that chemotherapy decreases ovarian reserve rapidly and dramatically, although, ovarian function may recover to some extent and menses may return after the completion of chemotherapy treatment 7. In this study, we assessed ovarian function deterioration in response to adjuvant AC by taking menstrual history and measuring serum biomarkers of ovarian function like FSH, LH Estrogen and Progesterone levels, before and after completion of che- motherapy. We have found that adjuvant AC causes CIA in a good percentage of the patients particularly those above 35 years old. In accordance to Peterek J et al, 2006, the diagnosis of CIA was applied to those patients who developed cessation of menstruation for 3 consequent months after receiving chemotherapy AC 13. As well as, we found that AC signiicantly increased the levels of FSH and LH, while Estrogen level decreased signiicantly, the mean level of above hormones except progesterone reached to menopausal range after giving four cycles of AC. These results are in agreement with other studies, showing that adjuvant chemotherapy induces CIA 22-26. Furthermore, as in Park et al 15, in current study other follow up done to know if there was recovery from CIA and resumption of menstruation, therefore the history of menstruation without estimation of hormones has been used after 12 months of starting chemotherapy. We have found that between the 14 CIA patients 4 of them resumed their menstruation and the remained 10 were still in amenorrhea, while regarding patients with no CIA 7 patients were still has normal menses and 9 patients have developed oligomenorrhea during follow up time. Many studies used menstrual calendar to evaluate ovarian function 5, 8, 22-24. Reproductive aging in women is a natural progression through 3 stages: reproduction, the menopausal transition and post menopause. The early stage of menopausal transition begins on around age 42 and late stage which begins on average around age 46 and ends on average at age 51 with the inal menstrual period 25-26. In sight of the above physiology of menstruation pattern and age of women, in this study association of age and CIA has been studied. In agreement with other studies 22, 27-30, we have found that the age of the patient at the time of diagnosis was signiicantly associated with the occurrence of CIA. The signiicant increase in incidence of amenorrhea seen in older women more than 35 yrs. treated with chemotherapy, this may be due to the relatively lowKurdistan Board of Medical Specialties 25 Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 22-27 er number of existing oocytes. Approximately 2 million oocytes are present at birth; they have decreased to 200,000 by puberty and to 400 at menopause 25-26, following treatment with chemotherapy, the ovaries have a decreased number of oocytes available for follicular recruitment, along with evidence of ibrosis, these changes are similar to those observed in natural postmenopausal ovaries 10, 31. In accordance with our study, other researchers have found that different types of chemotherapy are associated with different rate of menopausal incidence. Bines et al (1996) reported that 40% of women younger than age 40 years and 76% of women older than age 40 years become menopausal during adjuvant chemotherapy with cyclophosphamide plus methotrexate and 5-luorouracil.Other authors reported a lower risk with anthracycline-containing regimes, such as doxorubicin and cyclophosphamide (AC) or 5-lurouracil, epirubicin, and cyclophosphamide combinations 31. This difference in the incidence rate of CIA may be related to that, in addition to the age of the patient, cumulative dose and type of the cytotoxic agents are the most important factors that determine the likelihood of gonadal failure 28, 32. It is not clear if the duration and dose intensity of chemotherapy independently affect the risk for gonadal failure. Alkylating agents, such as cyclophosphamide, are extremely gonadotoxic because they are not cell cycle-speciic and can damage resting primordial follicles, whereas cycle-speciic agents such as methotrexate and 5-luorouracil do not have any effect on ovarian reserve. In a mouse study, cyclophosphamide induced follicular damage in a dose-dependent manner through a dose range of 20–100 mg/kg, whereas destruction of primordial follicles occurred even at the lowest cyclophosphamide dose 10. With each additional dose of cyclophosphamide administration, an incremental number of primordial follicles are lost and the incidence of ovarian failure increases. Patients who receive cyclophosphamide have a 4- to 9.3-fold greater risk for the development of premature ovarian failure than healthy controls 10, 31-33. In this study, AC typically consists of 4 cycles delivered over 12 weeks with a lower cumulative dose of cyclophosphamide compared with CMF and less anthracycline exposure than many other typical combination regimens. The relation of CIA and phases of menstruation during which chemotherapy has been given was studied by Di Cosimo et al, 2004, they have found that the incidence of CIA higher between the patients received irst cycle CT during follicular phase of menstrual 26 Kurdistan Board of Medical Specialties cycle, because chemotherapy administered within the follicular phase could be responsible for the follicular maturation impairment, primordial follicle depletion and ampliication of physiological apoptotic mechanisms occurring in this phase 34. However, in the current study, we did not ind any signiicant association between incidence of CIA and phase of menstruation at which irst cycle of chemotherapy has been administered. This opposite result might be due to small sample size of the current study and or might be due to patient’s uncertainty of their menstrual cycle dates. Although, the effect of molecular characters of the tumor on the CIA has not been studied widely, in this work we tried to ind out relation between hormonal status (ER and PR) and Her2 with CIA. However, we did not ind any positive effect of these molecular features of the tumor on the incidence of CIA. These results are in agreement with those found by Perez-Fidalgo et al, 2010, 35. Furthermore, in this study, the association between number of cycles of CT at which patients developed amenorrhea and persistence of amenorrhea, although it has been noted that the majority of the patients with permanent amenorrhea developed cessation of menstruation during irst two cycles of chemotherapy but the result was not statistically signiicant (data not shown). Unfortunately there is no enough study about this relation in the literature and this issue needs more study with a larger sample size to be clariied. Conclusions Through this study, it has been found that adjuvant chemotherapy, adriamycin and cyclophosphamide, in early breast cancer induces menstrual changes and even permanent amenorrhea in some patients associated with the ovarian hormonal changes. However, these chemotherapies did not cause any signiicant biochemical changes. This study delights the way for further investigation, with a bigger sample size and for a longer period of follow up, to ind out the prognostic effects of CIA on the overall survival and progression free survival. References: 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA cancer j clin. 2014; 64: 9–29. 2. Reyna C, Lee MC. Breast cancer in young women: special considerations in multidisciplinary care. Journal of Multidisciplinary Healthcare. 2014; 7: 419–429. 3. Berry DA, Cronin KA, Plevrotos SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005; Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 22-27 353: 1784-1789. 4. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet. 1998; 352: 930–942. 5. Sukumvanich P, Case LD, Zee KV, et al. Incidence and Time Course of Bleeding After Long-Term Amenorrhea After Breast Cancer Treatment, Cancer. 2010; 116: 3102–11. 6. Bianco AR, Del Mastro L, Gallo C, et al. Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer. 1991; 63: 799–803. 7. Park IH, Han HS, Lee H, et al. Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer. Annals of Oncology. 2012; 23 (1): 2283–89. 8. Walshe JM, Denduluri N, Swain SM. Amenorrhea in Premenopausal Women After Adjuvant Chemotherapy for Breast Cancer. JCO. 2006; 24 (36): 5769-5779. 9. Padmanabhan N, Howell A, Rubens RD. Mechanism of action of adjuvant chemotherapy in early breast cancer. Lancet. 1986; 2: 411–414. 10. Goldhirsch, A, Gelber RD, Castigliore M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. Ann Oncol. 1990; 1: 183–188. 11. Meirow D, Lewis H, Nugent D. et al. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod. 1999; 14: 1903–07. 12. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996; 14: 1718–1729. 13. Petrek JA, Naughton MJ, Case LD, et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol. 2006; 24:1045-51. 14. Lutchman SK, Davies M, Chatterjee R. Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing. Hum Reprod Update. 2005; 11: 69–89. 15. Meng K, Tian W, Zhou M, et al. Impact of chemotherapy-induced amenorrhea in breast cancer patients: the evaluation of ovarian function by menstrual history and hormonal levels. World Journal of Surgical Oncology. 2013; 11: 101-105. 16. Su HI, Sammel MD, Green J, et al. Anti-mullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer. 2010; 116: 592-599. 17. Minton SE, Munster PN. Chemotherapy-induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control. 2012; 9: 466-472. 18. Rebecca LS, Kimberly DM, Jemal A. Cancer statistics. Ca. A Cancer Journal for Clinicians. 2014; 64 (2): 9-29. 19. Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol. 2004; 22: 4174-4183. 20. Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med. 2001; 344(26): 1997–2008. 21. Knobf MT. The inluence of endocrine effects of adjuvant therapy on quality of life outcomes in younger breast cancer survivors. Oncologist. 2006; 11(2): 96–110. 22. Fornier MN, Modi S, Panageas KS, et al. Incidence of chemotherapy- induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer. 2005; 104(8): 1575- 79. 23. Oktay K, Libertella B, Oktem O, et al. The impact of paclitaxel on menstrual function. Breast Cancer Res Treat. 2005; 94: S271. 24. Tham YL, Sexton K, Weiss H, et al. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol. 2007; 30: 126-132. 25. Tortora G, Derrickson B. Principles of Anatomy and Physiology (13th ed.). Canada: John Wiley and Sons, 2010. 26. Steiner AZ. Predicting age at menopause: Hormonal, familial, and menstrual cycle factors to consider. Menopausal Medicine. 2011; 19(2): 1-8. 27. Gradishar WJ, Schilsky RL. Ovarian function following radiation and chemotherapy for cancer. Semin Oncol. 1989; 16: 425-436. 28. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996; 14: 1718-1729. 29. Minton ES, Munster NP. Chemotherapy-induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control. 2002; 9(6): 466-472. 30. Lower EE, Blau R, Gazder P, et al. The Risk of premature menopause induced by chemotherapy for early breast cancer. Journal of Women’s Health & Gender-Based Medicine. 2009; 8(7): 949-954. 31. Goodwin PJ, Ennis M, Pritchard KI, et al. Risk of menopause during the irst year after breast cancer diagnosis. J Clin Oncol. 1999; 17:2365–2370 32. Byrne J, Fears TR, Gail MH, et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol. 1992; 166:788–793. 33. Gorman JR, Usita P, Madlensky L, Pierce JP. Young breast cancer survivors: Their perspectives on treatment decisions and fertility Concerns. Cancer Nursing 2011; 34(1): 32–40. 34. Di Cosimo S., Alimonti A., Ferretti et al. Incidence of chemotherapy-induced amenorrhea depending on the timing of treatment by menstrual cycle phase in women with early breast cancer. Annals of Oncology. 2004; 15: 1065–1071. 35. Perez-Fidalgo JA, Rosello S, Garcia-Garre E, et al. Incidence of chemotherapy induced amenorrhea in hormone sensitive breast cancer patients: the impact of addition of taxanes to anthracycline-based regimens. Breast Cancer Res Treat. 2010; 120(1): 245-251. Kurdistan Board of Medical Specialties 27 Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 28-31 Effect of Body Mass Index on Gastroesophageal Relux Disease Sabah Jalal Shareef * JKMBS, 2016 Abstract Background and objectives: The gastroesophageal relux disease is a diagnostic and therapeutic challenge in surgery because of its complicated etiology and pathophysiology. Its incidence is increasing parallel with obesity throughout the world. This study tried to ind a relation between body mass index and gastroesophageal relux disease. Methods: This study done on one hundred gastroesophageal relux disease patients in Rizgary teaching hospital, Erbil city Kurdistan region of Iraq from Jan 2014 to June 2014, the study attempted to access the relation between body mass index and symptom severity of gastroesophageal relux disease through relux episodes known by number of episodes per week, and also impact of body mass index on endoscopic changes. Results: This study was carried out on 100 patients (%45 male) and (%55 female), the mean age ± SD of participants was 12.5 ± 37.13 from 75-17 years, the body mass index (BMI) classiied to normal <25, overweight between (30-25), obese patients >30.The symptoms severity increased with increase body mass index , but its relation with endoscopic indings were not signiicant. Conclusions: The effect of increased body mass index on gastroesophageal relux disease is an increase in relux episodes, but its relation to endoscopic inding was not signiicant. Keywords: Gastroesophageal relux disease symptoms, body mass index, endoscopic indings. Introduction The Gastroesophageal relux disease (GERD) was not recognized as a signiicant clinical problem until the mid-1930s and was not identiied as a precipitating cause for esophagitis until after World War II. In the early twenty-irst century, it has grown to be a very common problem and now accounts for a majority of esophageal pathology. It is recognized as a chronic disease, and when medical therapy is required, it is often lifelong treatment 1. The etiology of GERD is complicated. One of the important factors is abnormal competence of lower esophageal sphincter (LES). Normal LES is required preventing the relux. This is inluenced by both its physiological function and its anatomical location relative to the diaphragm and the esophageal hiatus 2. The competence of the LES and its ability to establish a barrier to relux depends on several factors. For example: adequate pressure and length, radial symmetry, and motility of the esophagus and stomach. Competent sphincter should be at least 2 cm length and carries a pressure tone between 6 and 26 mm Hg 3. Gastroesophageal relux disease (GERD) means the presence of symptoms or mucosal damage from gastroesophageal relux, it is a common, morbid, and costly medical condition 4. The relation between the increase in body mass index and symptom severity of GERD which is identiied by a number of heartburn attacks per week was one of the long-standing debates 5. The increase in body * Department Of Surgery, College Of Medicine, Hawler Medical University 28 Kurdistan Board of Medical Specialties mass index is associated with an increase of esophageal acid exposure 6. The parallel rise in GERD and obesity suggests a link between the two. A recent meta-analysis of 20 studies reported a positive association between increasing body mass index (BMI) and the presence of GERD within the USA6. Elevated BMI and greater waist circumference are associated with increased intragastric pressure and lower esophageal pressure, the greater likelihood for a hiatal hernia, impaired lower esophageal sphincter function and more frequent, more prolonged and more proximal episodes of esophageal acid exposure7-12. Patients and methods the current study was done in Rzgary teaching hospital on one hundred GERD patient from January 2014 to 30th June 2014 on different age groups from (1775) years, 45% were male and 55% were female patients whom they agreed on the study the study was approved by research ethics committee at college of medicine, Hawler medical university. Diagnosis of patients depends on full history taking and thorough clinical examination with esophagogastro duodenoscopy (OGD). The procedures were explained to the patients and informed verbal consent was taken from each participant, most of these patients had heartburn and acid regurgitation, with variable number of attacks per week, the BMI of patient calculated by measuring the height with meter and Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 28-31 weight with kg. Patient classiied into normal BMI <25 and overweight BMI between 25-30, and obese patients BMI >30. Esophagogastroduodendoscopy had done for all patient with Xylocaine spray to the throat and those who didn’t tolerate OGD with this procedure they had been scoped with midazolam 5 mg slow iv injection, and the result was classiied to erosive esophagitis or non-erosive esophagitis(NERD), (normal looking OGD) a hiatus hernia and lax lower esophageal sphincter. Those patients in whom other indings like duodenal ulcer or gastric ulcer, and 2 cases were carcinoma of stomach were excluded from the study, all patients were sent for H pylori Ag in stool, abdominal ultrasound had done for all patients to exclude Gall bladder disease, serum amylase, and serum lipase were done to all patients to exclude pancreatitis and ECG for those above 40 years old to exclude cardiac problems, 24 hour ph studying and manometer was not done because it was not available Results This study was carried out on 100 patients (45% male) and (55% female), Fig1, the mean age ± SD of participants was 37.13 ± 12.5 ranged from 17-75 years. Figure (1): Gender distribution of study sample. Regarding the relation between frequency of heartburn attacks (relux episodes) and BMI, the current study revealed that the number of heartburn attacks was signiicantly (<0.001) increasing with increasing BMI, in which 20 patient with BMI >30 had 5 attacks per week, while only 5 patients with BMI <25 had 5 attacks per week, Table 1. Table (1): Relation between BMI and number of heartburn attacks BMI group No. and % within BMI group 1.00 2.00 3.00 4.00 5.00 Normal (<25) No. 7 19 7 1 5 39 % 17.9 48.7 17.9 2.6 12.8 100 No. 2 6 9 1 10 28 % 7.1 21.4 32.1 3.6 35.7 100 No. 0 1 6 6 20 33 % 0.0 3.0 18.2 18.2 60.6 100 No. 9 26 22 8 35 100 % 9.0 26.0 22.0 8.0 35.0 100 Overweight (25-29.9) Obese (>30) Total No. of heartburn attacks The relation between Increasing BMI and endoscopic inding was not signiicant (p value=0.749) as 12 patients with normal BMI <25 had hiatus hernia with lax sphincter and esophagitis, comparing to 16 patients with BMI >30 had hiatus hernia with lax sphincter Total and esophagitis, 48% of patients on endoscopy were normal looking indicating non-erosive esophagitis (NERD). And 52% of patients showing esophagitis as shown in Table 2 Kurdistan Board of Medical Specialties 29 Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 28-31 Table (2): Relation between BMI and Endoscopic inding Endoscopic inding Hiatus Lax No. and hersphincter+ BMI group % within nia+ lax erosive BMI group sphincter+ esophagitis esophagitis Normal Overweight Normal looking esophagus +lax sphincter Normal Total No. 5 12 11 11 39 % 12.8 30.8 28.2 28.2 100 No. 5 10 7 6 28 % 17.9 35.7 25.0 21.4 100 No. 4 16 8 5 33 % 12.1 48.5 24.2 15.2 100 No. 14 38 26 22 100 % 14.0 38.0 26.0 22.0 100 P value 0.749 Obese Total Discussion Endoscopic inding was not signiicant as shown in Table 2. And there is 48% normal looking endoscopy might be non-erosive esophagitis (NERD), and 52% were showing Esophagitis of variable grades according to Los Angeles classiication of esophagitis which is of 4 grades (A.B.C.D). Normal looking OGD might be due to non-erosive esophagitis which called (NERD) or due to the Liberal use of Proton pump inhibitor (PPI) by most of Medical and Paramedical Personnel before diagnosing with endoscopy and this will lead to healing of most cases of esophagitis which shows normal Endoscopy. The incidence of NERD in Gastroesophageal Relux disease patients in this study was 48% while in western countries are 50%, and in china, 66.2% showed erosive esophagitis and 38.8% were NERD and in Nigeria 74.4%.as the study was done in Nigeria 17. Other study done in Budapest revealed a strong correlation between BMI and GERD severity. This inding suggests that obesity and increased BMI is not the only necessarily the primary cause of GERD but it could be a risk factor for more serious mucosal lesions in the esophagus 18. This study demonstrates that obese patients (BMI>30) are associated with more severe symptoms of GERD than those of normal BMI <25 demonstrated by increase in frequency of heartburn attacks per week as shown in table 1, this might be due to the fact that obesity has negative association with lower esophageal sphincter tone leading to increasing esophageal acid exposure 13. Much evidence exists to support an association between obesity and GERD symptom severity. The pathophysiology of this association is an increase in the intragastric pressure and decrease in intraesophageal pressure with disruption of lower esophagogastric junction structures and that attributed to the crural diaphragm. This study was consistent with study done Hashem El-Serag 14. Any excess body fat gives excess risk for heartburn; this is true because fat or obesity causes increase in intra-abdominal pressure and increase in intragastric pressure and decrease in intraesophageal pressure with disruption of lower esophageal structure results in relux of acid to esophagus and esophagitis 15. This study is also consistent with a study done in California USA, which they demonstrate positive association between increasing BMI and presence of GERD Conclusions 16 . The obesity and GERD are increasing in the world, Regarding the relation between increasing BMI and 30 Kurdistan Board of Medical Specialties Journal of Kurdistan Board of Medical Specialties (2016) Vol. 2, No.1: 28-31 as the increase in BMI is a high-risk factor for the development of gastroesophageal relux disease with the complication of esophagitis as barrette esophagus and carcinoma of the esophagus, so decreasing weight 14. is strongly advisable for symptomatic improvement 15. of GERD and decreasing the incidence of complications. 16. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Brunicardi F, Andersen D, Billiar T, Dunn D., Hunter J., Matthews J (ed.). An esophagus and diaphragmatic hernia, Schwartz›s Principles of Surgery, 10th edition. New York: Mc Graw-Hill; 2015. P. 966. Williams N, Bulstrade C, Connel RP (editors). The Esophagus. Bailey & loves, Short Practice of Surgery. Taylor and Francis group; 2013,. P. 995. Courtney M. Townsen JR., Beauchamp DR, (editors). Esophagus. Sabiston textbook of surgery. Philadelphia: Elsevier; 2012. P. 1030 Beck IT, Champion MC, Lemire S, Thomson AB, Anvari M, Armstrong D, Bailey RJ, Barkun AN, Boivin M, Bursey RF, et al. The Second Canadian Consensus Conference on the Management of Patients with Gastroesophageal Relux Disease. Can J Gastroenterol. 1997 Sep;11 (Suppl B):7B–20B. [PubMed]. Wajed SA, Streets CG, Bremner CG, Elevated body mass disrupts the barrier to gastroesophageal relux. Arch Surg. 2001; 136:10148. Corley DA, Kubo A Am J Body mass index, and gastroesophageal relux disease: a systematic review and meta-analysis. Gastroenterology. 2006; 101(11):2619-28. Blondeau K, Boecxstaens V, Van Oudenhove L. increasing body weight enhances prevalence and proximal extent of relux in GERD patients ‹on› and ‹off› PPI therapy. Neurogastroenterol Motil. 2011; 23: 724–e327. Fornari F, Callegari-Jacques SM, Dantas RO. Obese patients have stronger peristalsis and increased acid exposure in the esophagus. 2011; 56:1420–6. de Vries DR, Van Herwaarden MA, Smout AJ. Gastroesophageal pressure gradients in gastroesophageal relux disease: relations with a hiatal hernia, body mass index, & esophageal acid exposure.Am JGastroenterol 2008; 103: 1349–54. Ayazi S, Hagen JA, Chan LS, , DeMeester SR, Lin MW, Ayazi A, Leers JM, Oezcelik A, Banki F, Lipham JC, DeMeester TR et al. Obesity and gastroesophageal relux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with relux symptoms. Journal ofGastrointest Surg 2009; 13: 1440–7. Kuper MA, Kramer KM, Kirschniak A, Kischniak A, Zdichavsky M, Schneider JH, Stuker D, et al. Dysfunction of the lower esophageal sphincter and dysmotility of the tubular esophagus in morbidly obese patients. Obes Surg 2009; 19: 1143–9. Schneider JH, Kuper M, Konigsrainer A. Transient lower esophageal sphincter relaxation in morbid obesity. Surgery 2009; 19: 595–600. Anggiansah, Sweis R, Anggiansah A, Wong T, Cooper D, Fox M.et 17. 18. al, the effect of obesity on esophageal function, acid exposure and the symptoms of Gastroesophageal relux Disease. Aliment Pharmacol Ther. 2013;37(5):555-563. Hashem El-Serag. The association between obesity and GERD: A Review of the Epidemiological Evidence Published online 2008. Peura DA, Pilmer B. The Effect increasing body mass index on heartburn severity, frequency and response to treatment with Dexlansoprazole or lansoprazole. 2013;37 (8) Douglas A. Corley and Ai Kubo. Body mass index and Gastroesophageal Relux disease: a systematic review and meta-Analysis. American Journal of Gastroenterology. 2006;101(11):26192628. Nwokediuko S, Ijoma U, Obienu O, Agunyenwa C. Gastroesophageal Relux Disease a Clinical and Endoscopic Study of Nigerian Patients. The Internet Journal of Gastroenterology. 2008; 101(8) pp. 1900-43. Tamas GT, Demeter P. Does Body Mass Index associated with the endoscopic severity of gastroesophageal relux disease. 2004; 12: 49-52 Kurdistan Board of Medical Specialties 31