Treatment Choice in Primary Dysmenorrhea
Condition: Primary Dysmenorrhea
MeSH terms: Dysmenorrhea
Study type: Interventional
Phase: Phase 4

Summary: 
      Our aim is to evaluate and compare the pain relief of estradiol valerate/dienogest and
      ethinylestradiol/ drospirenone by using doppler indices.

      100 nullipara patients with symptoms of severe primary dysmenorrhea (PD) requesting
      contraception aged from 18 to 35 were included to the study. Visual analog scale (VAS), the
      uterine artery doppler indices including systole/diastole rates ( S/D), pulsatility index
      (PI) and resistance index (RI) values were evaluated and recorded in both uterine vessels
      before treatment. The 66 PD patients who met the inclusion criteria were divided into 2
      groups and 33 healthy controls created Group 1. Group 2 were administered estradiol
      valerate/dienogest while Group 3 were administered 0.03 mg ethinylestradiol and 3 mg
      drospirenone. Both VAS scores and doppler indices were repeated after 3 months treatment. The
      changes in values were recorded.
    

Detailed description: 
      This prospective, randomized, controlled clinical trial was conducted in Kayseri Education
      and Research Hospital, in Turkey between 2015 and 2016. Nullipara patients with symptoms of
      severe primary dysmenorrhea (PD) requesting contraception aged from 18 to 35 were included to
      the study. Afterwards, based on computer generated random numbers the patients were allocated
      to one of the two study arms; Group2 (Qlarista group) and Group3 (yasmin group), equally.

      The PD was diagnosed clinically. The characteristic of pain was periodic (at least following
      3 menstrual cycles), midline, lower abdominal cramps or pelvic colic like pain that starts up
      to one day before menses, lasts for the 3 days of bleeding, gradually diminishes over 12 to
      72 hours and ends after period. The pain starts generally in 2 to 3 years after menarche with
      regular menses (25-31 day). Also absence of pelvic pathology was important in these patients
      for diagnosis.

      Patients with history of pelvic inflammatory diseases, endometriosis, ovarian cysts, chronic
      abdominal pain, fibroids, obstructive endometrial polyps, cervical stenosis, inflammatory
      bowel syndrome, irritable bowel syndrome, major abdominal or pelvic surgery, intrauterine
      device and congenital obstructive müllerian malformations were excluded. Smoking,
      overweighted (body mass index (BMI) ≥ 30) patients that oral contraceptive pills (OCP)
      treatment was contraindicated were also excluded. Additionally, patients enrolled
      simultaneously into other studies that require drug intake or otherwise prevent compliance
      with protocol were out of the study.

      Visual analog scale (VAS) from 0 (no pain) to 10 (maximum pain, 'worst pain I have ever
      felt') was applied to patients on the first day of menstrual cycle. Patients with VAS score
      of between 7 to10 and PD accompanied with vomiting, nausea, dizziness, headache, nervousness,
      diarrhea and fatigue were classified as severe PD. The ages (years), BMI (kg/m2), length of
      menstrual cycle (days) and length of bleeding (days) and demographic data of patients were
      recorded.

      Before treatment during menstruation period all ultrasound examinations were carried out
      trans abdominally with Toshiba Xario machine ( Shimoishigami, Otawara-shi, Tochigi 324-8550,
      Japan) equipped with a 2.8-7 megahertz (MHz) transducer by a single radiologist (Ş.T.) The
      uterine artery blood flows were measured at the lateral level of uterine artery neighbour to
      cervicocorporeal junction in both sides (right and left). Doppler indices including
      systole/diastole rates ( S/D), pulsatility index (PI) and resistance index (RI) values were
      evaluated and recorded in both uterine vessels. Both VAS scores and doppler indices were
      repeated after 3 months treatment. The changes in values were recorded.

      According to previously published studies and after power analyses, when α error and β error
      were considered, respectively, as 0.05 and 0.20, with 80% power number of patients for each
      group were determined as minimum 30. Power Analysis and Sample Size Software (PASS) 11
      software (NCSS, Kaysville, USA) was used to perform these analyses. Regarding dropout rates
      (40 % -50 %) in similar studies over the treatment period we planned to include 100 patients
      with PD and 40 healthy controls. The PD patients who met the inclusion criteria were divided
      into 2 groups. Patients in Group 2 were administered estradiol valerate/dienogest (Qlarista;
      Bayer HealthCare Berlin, Germany). Qlarista consists of 28 tablets (including 2 tablets of
      3mg estradiol valerate, 5 tablets of 2mg estradiol valerate plus 2mg dienogest, 17 tablets of
      2mg estradiol valerate plus 3mg dienogest, 2 tablets of 1mg estradiol valerate and 2 non
      hormonal tablets as placebo, respectively). Patients in Group 3 were administered 0.03 mg
      ethinylestradiol and 3 mg drospirenone (21 tablets) (Yasmin; Bayer HealthCare Berlin,
      Germany). Patients were randomly administered to the 2 treatments in a 1:1 ratio. Instead of
      relieving, patients were not allowed to use rescue medication (NSAI drugs) to prevent
      menstruation related pelvic pain.

      All procedures performed in studies involving human participants were in accordance with the
      ethical standards of the institutional and/or national research committee and with the 1964
      Helsinki declaration and its later amendments or comparable ethical standards. Ethics
      approval for the study was obtained from Erciyes University Hospital (protocol
      number:2014/290). Informed consent was obtained from all patients who included in our study.

      All analyses were performed using the SPSS for Windows 21.0 (SPSS Inc. USA) software package.
      The normality of distribution for variables was assessed using the Shapiro Wilk test. Data
      was presented as means ± standart deviation (SD) for continuous variables. To assess the
      differences in variables between groups, the independent t test was used. As the results did
      not have a normal distribution, Kruskal-Wallis, Mann-Whitney U-test and Bonferroni correction
      was used in the comparisons between the groups. For comparison, the Wilcoxon test was applied
      to the results (VAS scores, Doppler flow parameters) before and after receiving therapy. For
      all comparisons, the P < 0.05 value was determined as statistically significant.
    

Intervention name(s): estradiol valerate/dienogest; ethinylestradiol and drospirenone
Intervention type(s): Drug; Drug
Intervention description(s): oral, 28 tablets including 2 tablets of 3mg estradiol valerate, 5 tablets of 2mg estradiol valerate plus 2mg dienogest, 17 tablets of 2mg estradiol valerate plus 3mg dienogest, 2 tablets of 1mg estradiol valerate and 2 non hormonal tablets as placebo, respectively; oral,0.03 mg ethinylestradiol and 3 mg drospirenone (21 tablets)
Other intervention name(s): Qlarista; Bayer HealthCare Berlin, Germany; Yasmin; Bayer HealthCare Berlin, Germany
Intervention MeSH terms: Dienogest; Drospirenone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Ethinyl Estradiol; Estradiol; Polyestradiol phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: estradiol valerate/dienogest; ethinylestradiol/ drospirenone; pelvic pain; primary dysmenorrhea; uterine artery doppler indices