A Comparative Study between Norethisterone Progestogens and Dydrogesterone in the Treatment of Dysfunctional Uterine Bleeding

Problem statement: To compare the effects of both Norethisterone Prog estongens and Dydrogesterone in the treatment of Dysfunctional Ut erine bleeding Design: A prospective study. Setting: Tikrit Teaching Hospital, Iraq. Approach: About 200 patients presented with abnormal uterine bleeding and diagnosed as dysfunctional ute rine bleeding were included in this study. Group A (study group): Include 100 patients were treated wi th norethisterone progestogens. Group B (control group): Include 100 patients were treated with dydr ogesterone the response of the patients were assessed by regularity of menstrual cycle. Results: About 75 patients had regular cycle while 25 patients still had irregular bleeding regarding fir st group. 46 patients had regular cycle while25 pat ients still had irregular bleeding regarding second group , decrease in severity of bleeding and resumption o f regular cycle were more apparent with Norethiserone drug. Conclusion/Recommendations: Both norethisterone progestogens and dydrogesterone can be used in the treatment of dysfunctional uterine bleeding. Norethisterone progertogens showed higher rates of regular resumption of menses than Dydrogesterone and I recommended to use Norethisert one in the treatment of other problems like regulate ovulation in infertile woman. Key words: Norethisterone progestogens, dydogestrone dysfuncti on uterine bleeding, menorrhagia, anovulatory cycle, menstruation

Dysfunctional Uterine Bleeding (DUB): Is best define as abnormal bleeding from the uterus in the absence of organic disease of the genital tract and applies to any abnormal uterine bleeding, including disturbances o f the menstrual cycle, regular and irregular uterine bleeding and alterations in the amount or duration of menstrual loss, but most commonly implies excessive regular menstrual bleeding or essential menorrhagia (Van, 1995a). DUB is a group of disorders characterized by dysfunction of uterus, ovary, pituitary, hypothalam us or other part of the reproductive system, which result s in abnormal or excessive uterine bleeding and the diagnosis is usually made by exclusion of organic disease of the genital tract (Davey, 1995). Abnormal uterine bleeding in general due to organic and non organic causes, the organic causes due to sub mucous fibroid, Adenomyosis, endometrial and end cervical polyp, pelvic inflammatory disease and malignanet disease (Stuartc, 2000). Classification of DUB: Primary: Due to primary dysfunction in the uterus, ovary, pituitary, hypothalamus or higher centers. Secondary: To either: • Intrauterine contraceptive device or administration of sex hormones for contraception or other purposes • Organic disease outside the reproductive system (Jacobs, 1995) Twelve percent of all gynecological problems are due to menorrhagia and the commonest cause for hysterectomy (Charles, 1999). The duration of menstrual blood loss varies normally in different women from 2-7 days with a mean of 5 days, but any menstruation lasting 8 days or longer should be regarded as excessive (Van, 1995b) . The best measure of the amount of menstruation is the total Menstrual Blood Loss (MBL), which is estimated from the total hemoglobin extracted from all tampons, towels and other material used during menstruation and measured objectively by alkaline haematin or other standard method (Hallberg, 1995). DUB can occur at any age; though it’s an etiology and management vary greatly in different age groups so an understanding of the effect of age and parity on management and on the risk of missed uterine pathology is important (Van, 1995b). Am. Med. J. 1 (1): 23-26, 2010 24 The years immediately following the menarche are characterized by irregular menstrual cycles and lon g cycles due to immaturity of the hypothalamus and pituitary and menstrual cycles may be a novulatory, the middle years of reproductive life in normal women a re characterized by regular menstrual cycles and regul ar ovulation, in premenopausal years menstrual cycles often become irregular again due to the decreased number of ovarian follicles and their increased resistance to gonadotrophin stimulation, this resul ts in a progressive increase in corpus lustrum insufficienc y or anovulatory cycles and eventually in cessation of menstruation (Suther Land, 1995). History and examination are important in the diagnosis of DUB, a full blood count is an essentia l investigation in a patient with abnormal bleeding, thyroid function tests to exclude thyroid diseases, mid- luteal progesterone level test is performed when pa tient has a regular cycle only, a level greater than 30 nmol L −1 is indicative of ovulation, prolactin level because increase level result in an ovulation that cause ab normal uterine bleeding, coagulation screen is important i f a bleeding disorder is suspected, serum androgens may be elevated in patients with polycystic ovarian syndro me (Geeta, 2000). Transvaginal ultrasound is an excellent tool for evaluating pelvic structures and pathology, new developments with Doppler ultrasound will provide information on pelvic vascularity while 3-D ultraso und will aid the diagnosis of congenital uterine abnormalities. Hysteroscopy is the gold standard procedure as it provides visualization of entire uterine cavity, is ideally performed during the proliferative phase of the menstrual cycle when the endometrium is at its thin nest (Jane, 2000). In acute situation the main priorities of treatmen t involve, correction of anemia and arresting ongoing bleeding. Progestogens are mainly indicated in patients with anovulatory bleeding, to reverse the effects of est rogen- mediated endometrial proliferation and induce endometrial maturation. Others Drugs can be used in DUB like combined oral contraceptives, danzol, gonadotrophin releasin g hormone analogues like buserelin and goserelin and levenorgestral-releasing intra-uterine contraceptiv e device (mirena). Other agents like antifibrinolytics like tranexami c acid and non-steroidal anti-inflammation agents lik e mefenamic acid can also arrest bleeding (Jane, 2000 ). Dilatation and curettage can reduce bleeding in 75 - 80% of cases in acute situation, endometrial resect ion and ablation by diathermy and laser can reduce bleeding in 40% and finally hysterectomy as option for patients who have not responded to medical therapy or to more conservative surgical options. Both laparoscopic myolysis and embolization techniques have been reported to be successful mode s of treatment (Farn, 2000). Primolut N can be used in dysfunctional bleeding, primary and secondary amenorrhea, premenstrual syndrone, mastopathy and endometriosis. In rare cases nausea may occur, it’s contraindicat ed in pregnancy, sever disturbances of liver function, dubin-johuson syndrome, previous or existing liver tumors. A history of jaundice or severe pruritus during pregnancy, a history of herpes of pregnancy and thrombo-embolic processes. If migrainous headaches or unusual severe headaches, sudden disturbances of vision or hearing , unusual pains or swelling of the legs, stabbing pai ns on breathing, significant rise in blood pressure, onse t of jaundice or itching or hepatitis there is should be discontinuation of the drug. Recent investigations have confirmed that norethisterone is partly metabolized to ethinylestr adiol it’s c-19 derivative that cause more androgenic sid e- effects such as acne and greasy skin than C21 derivatives (Aladin and Yousif, 1990). Dydrogesterone (duphaston): Is C21 derivatives cause less androgenic side-effects but more psychological distress such as anxiety, appear to h ave less effect than C19 derivatives on lipoprotein (Whitehead, 1999).

This study was conducted on women attending gynecological unit in Tikrit teaching hospital over a period of one year from October 2008 to October 200 9, it is a prospective study. The total number of women included in this study were 225, 25 women withdrew from the study due to intolerance of the side effects of the drugs, 200 w omen were the total patients included in this study, 100 were controls and 100 were the study group. None of those patients were treated with ant bleeding agents in the previous 3 weeks. A full history was obtained from each woman and a full physical examination was performed, the pati ents were divided into 2 groups: • Group A (Study group): Include 100 patients were treated with norethisterone progestogens Am. Med. J. 1 (1): 23-26, 2010 25 • Group B (control group): Include 100 patients were treated with dydrogesterone The patients in both groups were diagnosed as dysfunctional uterine bleeding after exclude the or ganic pathology by careful history taken from the patient s about the attach of bleeding, severity, duration an d associated symptoms, any associated gynecological problems including dysmenorrheal, infertility, menopausal symptoms, any symptoms suggestive of bleeding disorder or myxoedema. History of administration of sex hormones, intrauterine contraceptive device, history of hepar in or wayfaring using, pelvic inflammatory disease and organic pathology outside the reproductive system l ike hemorrhoid, anal fissure that causing bleeding per rectum or haematuria due to renal stone for example and miss diagnosed as vaginal bleeding. General, pelvic and abdominal examination are essential, general examination for stigma of system ic diseases like hirsutisum, strait, thyroid enlargement,skin pigment changes for echymosis, petechi, examination of lymph nodes, liver and spleen. Inspection of vulva for bleeding, infection and speculum examination of vagina and cervix were essential for exclude any pathology. Ultrasound examination was performed for both groups to exclude pelvic mass or possible pregnancy complications, fibroids, ovarian cyst, endometrial polyp and measurement of endometrial thickness. Also Baseline Hemoglobin (Hb) was done for both groups as a part of assessment of the severity of t he bleeding. All patients were in reproductive age group betwee n 20-45 years old and all were married, from the ethi cal point of view all patients were asked if they would like to participate in the study and a full explanation abo ut the nature and side effects of the drugs, if the patien t presented with sever uterine bleeding can be arrest ed by large doses of progestogens, norethisterone acetate (primolut N) 20-30 mg daily is given until bleeding stops (within 24-48 h) and for not more than 3 days, then the progestogens may continued at lower dose for 21 days, if not sever bleeding, norethisterone acetate 5 mg dai ly from the 5th-25th day of cycle and continued for a minimum of 3 cycles, this protocol for the first gr oup (Group A). The protocol for the second group (Group B),the bleeding can be arrested by given 10 mg dydrogesterone (duphaston) one Tablet daily 3 times over 10 days, then continued at lower dose for 21 d ays, if not sever bleeding dydrogesterone 10 mg daily fr om 5th-25th day of cycle and continued for a minimum o f 3 cycles. Table 1: Character of patient Groups Study group Control group Number of patients 100 100 Age (mean ± SD) 28±3.5 27.5±3.8 Table 2: Response of patient according to type of drugs Effects R/(primolut N) R/(duphaston) Total Stop bleeding with 75 46 121 regular cycle Not stop bleeding 25 54 79 Total 100 100 200 For both groups we gave one Tablet primolut N or dydrogesterone 2 times daily from the 19th-26th day of cycle as prophylactic dose after we control the ble eding to prevent recurrence of dysfunctional bleeding for at least 3 cycles.

The all patients involve in this study were marrie d and in reproductive age group (20-45), so both grou ps were matched for the age and it was founded that th ere is no significant difference between mean age of bo th group. Group A (study group): Mean age ± SD = 28±3.5 (SD (Standard deviation) Group B (control group): 27.5±3.8 when applying t- test: T = 1.86, so p<0.05 No significant difference between both groups regarding the age as in Table 1. In the study group which is on primolut N there is 75 patients had regular cycle with arrest bleeding within a period of treatment, while 25 patients still had irregular cycle with no control bleeding. In the control group which is on duphaston there i s 46 patients had regular cycle with arrest bleeding, while 54 patients still had irregular cycle with no contr ol bleeding as in Table 2: Chi-Square (X 2) = 18.4 df = Degree of freedom p>0.05 (probability) = Level of significant There is a very significant difference between bot h groups according to the type of treatment.

The most common cause of abnormal uterine bleeding in premenopausal woman is estrogenized an ovulation (Steve, 2003). Menorrhagia affects approximately 15-20% of women presenting with abnormal uterine bleeding and Am. Med. J. 1 (1): 23-26, 2010 26 cause significant social inconvenience as well as t he potential for significant anemia (James, 2003). Unfortunately, there is no simple clinical way to quantities the amount of blood lost during a menstr ual period, counting the number of sanitary protective’ s used in a menstrual cycle has proven to be inaccura te based on differences in personal hygiene and cultur al back grounds, when accurately quantities, blood loo se during an entire normal adulatory menstrual cycle i s approximately 60-80 mL −1, this amount of blood loose will not cause a decrease in hemoglobin in women consuming normal balanced diet (Beth, 2003). As described by Arthur (2003), dysfunctional uterine bleeding unrelated to mechanical factors, iatrogenic causes, infectious agents, cancer or pregnancy. They’re no one particular pattern of bleeding that unequivocally defines dysfunctional uterine bleedin g (Arthur, 2003). All women in our study were in the reproductive age group and there is no significant difference be tween study and control groups regarding age as in Table 1. About 75 patients were putted on primolut N Tablet had regular cycle and stop their bleeding wh ile 25 patients still had irregular bleeding, which is consistent with the findings of Davey (1995). About 46 patients were putted on duphastone Tablet had regular cycle and stop their bleeding wh ile 54 patients still had irregular bleeding, which is consistent with findings of Charles (1999). So there is a significant difference between both groups according to the type of treatment which is consistent with findings of Matthew (2003).

• Both norethisterone progestogens and dydrogesterone can be used in the treatment of dysfunctional uterine bleeding • Norethisterone progestogens were more effective in the treatment of dysfunctional uterine bleeding than dydrogesterone

Aladin, A.S. and Z. Yousif, 1990. Iraqi Drug Guide . 1st Edn., John Wiley and Sons, pp: 168-170. Arthur, F., 2003. Hormones and Abnormal Uterine Bleeding. Danforth’s Obstetrics and Gynecology. 9th Edn., Lippincott Williams and Wilkins, ISBN: 0-3452-5430-1, pp: 645-646. Beth, Y., 2003. Abnormal Uterine Bleeding . Danforth’s Obstetrics and Gynecology. 9th Edn., Lippincott Williams and Wilkins, ISBN: 0-7817-3730-3, pp: 643-644. Charles, R., 1999. Dysfunctional Uterine Bleeding. Dewhursts Text Book of Obstetrics and Gynecology for Post Graduates. 6th Edn., John Wiley and Sons, ISBN: 0766526511, pp: 409-411. Davey, D.A., 1995. Dysfunctional Uterine Bleeding. Dewhursts Text Book of Obstetrics and Gynecology for Post Graduates. 5th Edn., John Wiley and Sons, USA., pp: 590-593. Farn, R., 2000. Abnormal Uterine Bleeding. Gynecology by 10 Teachers. 17th Edn., Oxford University Press, Oxford, pp: 54-55. Geeta, N., 2000. Abnormal Uterine Bleeding. Gynecology by 10 Teachers. 17th Edn., Oxford University Press, Oxford, ISBN: 13: 978-0-340- 81664-2, pp: 48-51. Hallberg, L., 1995. Normal and Abnormal Menstruation . Dewhursts Text book of Obstetrics and Gynecology for post Graduates. 5th Edn., John Wiley and Sons, ISBN: 085542652, pp: 590-595. Jacobs, A.J., 1995. Incidence of Missed Organic Disease. Dewhursts Text Book of Obstetrics and Gynecology for Post Graduates. 5th Edn., John Wiley and Sons, ISBN: 085542652, pp: 590-592. Jane, E., 2000. Abnormal Uterine Bleeding. Gynecology by 10 Teachers. 17th Edn., Oxford University Press, ISBN: 13: 978-0-340-81564-2, pp: 51-54. James, R., 2003. Abnormal Uterine Bleeding. Danforth’s Obstetrics and Gynecology. 9th Edn., Lippincott Williams and Wilkins, ISBN: 0-5643- 3830-2, pp: 649-650. Matthew, C., 2003. Endocrine Disorders. Berek and Novak’s Gynecology. 14th Edn., Lippincott Williams and Wilkins, pp: 1076-1080. Suther Land, M., 1995. Incidence and Effects of Age and Parity. Dewhursts Text book of Obstetrics and Gynecology for post Graduates. 5th Edn., John Wiley and Sons, ISBN: 085542652, pp: 592-594. Stuartc, C., 2000. Disorders of the Menstrual Cycle . Gynecology by 10 Teachers. 17th Edn., John Wiley and Sons, ISBN: 0665426511, pp: 48-50. Steve, N., 2003. Abnormal Uterine Bleeding. Danforth’s Obstetrics and Gynecology. 9th Edn., Lippincott Williams and Wilkins, pp: 48-50. Van, E., 1995a. Blood Loss. Dewhursts Text Book of Obstetrics and Gynecology for post Graduates. 5th Edn., John Wiley and Sons, pp: 591-594. Van, E., 1995b. Definition and Classification of Dysfunctional Uterine Bleeding: Dewhursts Text Book of Obstetrics and Gynecology for Post Graduates. 5th Edn., John Wiley and Sons, USA., ISBN: 085542652, pp: 590-591. Whitehead, M.I., 1999. Menopanse. Dewhurst’s Text book of Obstetrics and Gynecology for post Graduates. 6th Edn., John Wiley and Sons, USA., ISBN: 0765426511, pp: 453-454.