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Australian and New Zealand Journal of Obstetrics and Gynaecology 2009; 49: 685688

DOI: 10.1111/j.1479-828X.2009.01093.x

Original Article

Efcacy of micronised vaginal progesterone versus oral dydrogestrone in the treatment of irregular dysfunctional uterine bleeding: A pilot randomised controlled trial
Savas KARAKUS,1 Gurkan KIRAN2 and Harun CIRALIK3
1

Sivas State Hospital Obstetrics and Gynecology Clinic, Sivas, 2Department of Obstetrics and Gynecology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, and 3Department of Pathology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey

Background: The vaginal route is more effective than the other drug delivery routes for some specic indications. Aim: To compare the efcacy of a vaginal progesterone preparation with that of oral dydrogesterone. Methods: A total of 69 women with irregular dysfunctional uterine bleeding were randomly assigned into one of two groups: oral dydrogesterone group (n = 35) and vaginal progesterone group (n = 34). At the end of a three-month treatment period, the women were re-evaluated. The endometrial histology ndings and menstrual cycle characteristics were used as primary outcome measures. Pearson chi-square and Fishers exact test were used for data analysis. Results: Findings from 54 eligible women were evaluated. There was no statistically signicant difference in both menstrual recordings and endometrial histology results between the groups. Conclusions: Vaginal micronised progesterone could be an alternative to oral preparations in the treatment of dysfunctional uterine bleeding. This needs to be further evaluated in adequately controlled randomised trials against other effective treatments. Key words: irregular dysfunctional uterine bleeding, oral dydrogesterone, vaginal progesterone.

Introduction
Dysfunctional uterine bleeding (DUB) is an abnormal bleeding of uterine origin which does not occur because of pregnancy or recognisable pelvic or systemic disease. In general, progestogens, and oestrogens and progestogens in combination are already widely used in the management of irregular or excessive bleeding because of DUB, but the regime, dose and type of progestogen used vary widely. There is no consensus on optimum treatment approach for this clinical situation.1 Dydrogesterone is a retroprogesterone with a molecular structure similar to natural progesterone. As a C-21 steroid, it has a high afnity for progesterone receptors, a low antigonadotropic activity and antioestrogenic activity, but no oestrogenic or androgenic activity. The effect of 10 mg of dydrogesterone is comparable with that of 10 mg of medroxyprogesterone acetate.2

The vaginal route is somewhat novel for systemic drug administration. It has some advantages because it avoids the hepatic rst-pass effect. Currently, there are various drugs which are administered vaginally, including misoprostol, sildenal, bromocriptine, indomethacin, oral contraceptive pills and the drugs used for hormone therapy.3,4 Micronised progesterone preparation (8% gel, Crinone; Merck Serono, Bedfordshire, UK) has been designed for vaginal use. It has bioadhesive characteristics, with its polycarbophil-based gel that conveys controlled and sustained-release properties. As a result of a local direct vagina-to-uterus transport, it produces endometrial changes similar to those seen in the luteal phase, despite subphysiological plasma progesterone levels.5 The aim of this pilot randomised controlled trial was to compare the efcacy of oral short-course dydrogesterone versus vaginal micronised progesterone for the treatment of women with irregular DUB.

Methods
Correspondence: Gurkan Kiran, Kahramanmaras Sutcu Imam Universitesi Tip Fakultesi, Kadin Hastaliklari ve Dogum Anabilim Dali, Yuruk Selim Mah, Hastane Cad. No: 32, 46050, Kahramanmaras, Turkey. Email: gurkankiran@yahoo.com Received 20 January 2009; accepted 12 September 2009.

The study was conducted at our outpatient clinic between August 2004 and April 2005. A power calculation was not performed prior to commencement of the study, as this was a pilot study. Of the 75 women who were assessed for eligibility, three were excluded because of abnormal saline infusion sonohysterography ndings and three did not consent. The remaining 69 eligible women were randomly assigned 685

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to receive 90 mg of vaginal micronised progesterone (8% gel) (group 1, n = 34) or 20 mg of oral dydrogesterone (Duphaston; Solvay Pharmaceuticals B.V., Weesp, the Netherlands) (group 2, n = 35). Treatment in group 1 consisted of self-application of vaginal progesterone cream, every other evening from the 17th to the 27th day of the menstrual cycle. The patients in group 2 were treated with dydrogesterone 10 mg orally twice daily for 10 days, starting from the 15th day of the menstrual cycle. Simple randomisation was conducted using computer-generated sequence. Allocation concealment was not performed. Six women discontinued treatment in each group and two women were lost during the follow-up in group 2. Oral oestrogen was added to a patient in the vaginal progesterone group and this patient was excluded from the nal analysis (Fig. 1). Six patients in each group left the study without declaring any reason, leaving 54 patients for nal analysis. An intention-totreat analysis was not performed. The study was approved by the Ethics Committee of our institution and informed consents were obtained from the subjects prior to their enrollment. After exclusion of other vaginal bleeding causes, including genital tract pathologies, iatrogenic causes and systemic conditions, the patients were dened as having DUB. For this purpose, a detailed history was obtained and physical examination was carried out. Menstrual cycle questionnaire for previous 36 months was used to obtain information about bleeding characteristics. An initial transvaginal ultrasound and saline infusion sonohysterography followed by endometrial sampling were performed in all patients. Blood samples were tested for progesterone, follicle-stimulating hormone, luteinising hormone, oestradiol, prolactin, testosterone, dehydroepiandrosterone sulphate and liver enzyme levels, complete blood count, activated partial thromboplastin time and prothrombin time.
Excluded (n = 6) Not meeting inclusion criteria (n = 3) (abnormal SIS* finding) Refused to participate (n = 3)

Patients who had no menopausal symptoms, did not take hormone therapy, were between 35 and 45 years of age, diagnosed with DUB, did not have contraindication for progesterone or progestins and had endometrial thickness > 5 mm by transvaginal ultrasound were included in the study. Patients taking anticoagulants or antiprostaglandins, preferring hormonal contraceptive methods and with known intolerance to progesterone or progestins were excluded. Treatment in group 1 consisted of self-application of vaginal progesterone cream, every other evening from the 17th to the 27th day of the menstrual cycle, for three cycles. Coitus was discouraged for 2 h after drug administration. The patients in group 2 were treated with dydrogesterone 10 mg orally twice daily for 10 days, starting from the 15th day of the menstrual cycle, for three cycles. Menstrual days were recorded by the participants for each cycle. Patient satisfaction was evaluated by an interview in the clinic or by phone during the study period. It was measured with a question, Please assess your overall satisfaction during treatment. Patients were asked to choose one of the two possible answers: not satised or satised. Additionally, endometrial sampling from all participants was repeated at the 22nd day during the third treatment cycle. SPSS 13.0 (SPSS, Chicago, IL, USA) was used for statistical analysis. Pearson chi-square and Fishers exact test were used for data analysis.

Results
There were no signicant differences between the two treatment groups in age, gravidity, parity and body mass index (Table 1). Patients who have had cycle length less than 35 days and no intermenstrual bleeding were accepted as having regular bleeding. A regular bleeding pattern was obtained in 93% (25 27) and 81% (22 27) of the patients at the end of the rst month in the vaginal and oral treatment groups respectively. The patients with regular cycles at the end of the rst month continued to have regular cycles in the next two months at a rate of 92.0% (23 25) in the vaginal and 77.3% (17 22) in the oral preparation groups (Table 2). There were no statistically signicant differences in patient satisfaction between the groups. In total, 85% (23 27) and 78% (21 27) of the patients were satised with their treatment in the vaginal and oral medication groups respectively (P = 0.491).
Table 1 Demographic characteristics of the patients with irregular DUB in each group. Values were expressed as mean SD Vaginal progesterone Oral dydrogesterone group (n = 27) group (n = 27) P* Age Gravidity Parity BMI (kg m2) 39.1 4.4 3.0 29.2 3.6 2.1 1.4 5.4 39.6 4.8 3.6 30.3 3.0 2.3 2.2 3.7 0.539 0.584 0.209 0.371

Assessed for eligibility (n = 75)

The patients were randomly allocated to vaginal or oral preparation (n = 69)

Vaginal micronized progesterone group (n = 34)

Oral dydrogesterone group (n = 35)

Lost to follow up (n = 0) Discontinued medication (n = 6)

Lost to follow up (n = 2) Discontinued medication (n = 6)

Analyzed (n = 27) Excluded from analysis (n = 1) SIS, Saline infusion sonohysterography.

Analyzed (n = 27) Excluded from analysis (n = 0)

Figure 1 Flow diagram of this study SIS, Saline infusion sonohysterography.

*A level of P < 0.05 was accepted as statistically signicant. BMI, body mass index; DUB, dysfunctional uterine bleeding.

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Transvaginal progesterone in irregular DUB

Table 2 Effects of vaginal versus oral preparations on menstrual cycles Vaginal progesterone group, n (%) First cycle Regular Irregular Second cycle Regular Irregular Third cycle Regular Irregular 25 (92.6) 2 (7.4) 24 (88.9) 3 (11.1) 25 (92.6) 2 (7.4) Oral dydrogesterone group, n (%) 22 (81.5) 5 (18.5) 24 (88.9) 3 (11.1) 23 (85.2) 4 (14.8)

P* 0.42

0.67

*A level of P < 0.05 was accepted as statistically signicant.

Endometrial sampling results were classied as secretory and non-secretory endometrium (including proliferative, early secretory, etc.). These results were similar for both groups (Table 3). At the end of a three-month period, secretory endometrium was obtained in 88.9% and 81.5% of the patients in the vaginal and oral medication groups respectively (P = 0.732). Oral oestrogen was added to a patient in the vaginal progesterone group because of a 45-day menstrual delay, and regularity was obtained after this intervention. This patient was excluded from the nal analysis. There was groin pain after the cessation of menstrual bleeding in one patient and 5-kg weight gain in another patient in this group. There were no side effects in patients receiving oral dydrogesterone. A left ovarian cyst 3 cm in diameter was detected by transvaginal ultrasound in a patient in whom menstrual bleeding started on the 20th day of her cycle at the third month.

Discussion
Dysfunctional uterine bleeding is a common problem in women of childbearing age. It is diagnosed after all other causes of abnormal uterine bleeding, such as pregnancy, iatrogenic causes, systemic conditions and obvious genital tract pathologies, are ruled out.6 A number of treatment alternatives have been proposed for the management of irregular DUB and several of these, including danazol, combined oral contraceptives, cyclical progestogens and GnRH analogues, have been used successfully. Local progesterone therapy is one of the methods used in the treatment of irregular DUB. It can be delivered
Table 3 Endometrial changes before and after treatment

directly to the endometrium using hormonal intrauterine devices.7,8 Although the routes most commonly preferred in drug delivery are oral for systemic effects and topical for local effects, modern technology has yielded vaginal drugdelivery systems that optimised pharmacokinetic proles. There are several drugs which have been approved for vaginal administration and many of them reach serum levels sufcient to have systemic effects.4 Although there are many studies investigating the effects of micronised vaginal progesterone in luteal phase support,925 in the treatment of endometrial hyperplasia,26 secondary amenorrhoea,5 cyclical mastodynia,27 threatened abortion 28 and menopausal symptoms,2931 information on the efcacy of these medications in the treatment of irregular DUB is scanty. In this study, the pathologist was blinded to the method of treatment. However, the patient and the clinician were aware of the groups because of the nature of the study. Nevertheless, the results of histological evaluation were consistent with the clinical outcome in most patients. Hence, we found that both vaginal and oral progesterone preparations had similar effects clinically and histopathologically, with acceptable side effects. Despite its small sample size, our study could enlighten our vision about indications of vaginal progesterone gel formulations. In a study on pharmacokinetics of intramuscular and vaginal progesterone, Miles et al.32 demonstrated that higher endometrial tissue concentrations could be obtained with transvaginal route, and increased serum progesterone concentrations could be obtained by intramuscular route. Conversely, Kimzey et al.33 showed that vaginal micronised progesterone cream caused delayed but reached sustainable serum progesterone concentrations when compared with that by oral route. If we consider its easy administration, avoidance of the hepatic rst-pass effect and large potential area for absorption,26 vaginal micronised progesterone may represent an alternative to oral preparations in the treatment of DUB. This needs to be further evaluated in adequately controlled randomised trials against no treatment and other effective treatments.

Acknowledgements
This work was carried out as registrar (Savas Karakus, MD) completion thesis study. The authors would like to thank to Yakup Gumusalan, MD, and Joshua P . Kesterson, MD, for their linguistic assistance and Hasan Cetin Ekerbicer, MD, for his assistance during statistical analysis.

References
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*A level of P < 0.05 was accepted as statistically signicant. Vaginal progesterone group. Oral dydrogesterone group.

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