Dienogest Versus Luteal Phase Fluoxetine in the Management of Premenstrual Syndrome

Dienogest Versus Luteal Phase Fluoxetine in the Management of Premenstrual Syndrome: A Randomized Double Blind Placebo Controlled Trial

Two hundreds and ten women with premenstrual syndrome will be randomly divided into 3 equal groups using computer generated random numbers. Group 1 will receive oral dienogest (visanne® Bayer, Germany) 2mg for 14 days starting from the 15th day of menstruation, Group 2 will receive fluoxetine (Prozac® Lilly, UK) 20mg and group 3 will receive an oral placebo foe 14 days starting from the 15th day of menstruation.

Study Overview

• Status: Unknown
• Conditions: Premenstrual Syndrome
• Intervention / Treatment: Drug: Dienogest; Drug: Fluoxetine; Drug: Placebo

Detailed Description

Premenstrual syndrome (PMS) manifests with distressing physical, behavioral and psychological symptoms, in the absence of organic or underlying psychiatric disease, which regularly recur during luteal phase of each menstrual cycle and disappear or significantly improve by the end of menstruation. Approximately 85-90 % of women may experience premenstrual emotional and physical changes in their reproductive age and the prevalence of severe PMS ranges from 3% to 8%.

The etiology of PMS is unknown but cyclical ovarian activity and the effect of estradiol and progesterone on serotonin and gamma-amino butyric acid are key factors. Absence of PMS before puberty, in pregnancy and after the menopause supports a role of cyclical ovarian activity in PMS etiology. PMS symptoms include psychological symptoms like mood swings, irritability, depression and feeling out of control; physical symptoms like breast tenderness, bloating and headaches; and behavioral symptoms like reduced visuospatial and cognitive ability. To diagnose PMS, symptoms should be recorded prospectively over two cycles using a symptom diary. Several symptom diaries exist but the Daily Record of Severity of Problems (DRSP) is reliable and simple for patients.

There is increasing evidence that serotonin may be important in the pathogenesis of PMS. A number of selective serotonin reuptake inhibitors have been used to treat PMS. Fluoxetine at was found to significantly reduce symptoms of tension, irritability and dysphoria, as well as physical symptoms compared with placebo, as measured by visual analogue scales. Luteal phase sertraline was found effective in the management of severe PMS.

Historically, treatment with progesterone was based on the hypothesis that in PMS sufferers, the ratio of progesterone and its derivatives to other hormones was lower than is usual in women. This allowed oestrogens to cause water retention, because there was insufficient progesterone to oppose them.

Gama amino butyric acid (GABA) produced by inhibitory neurons calms symptoms of anxiety, irritability and aggression. Part of the receptors, called GABA(A) on the neurone surface, necessary for GABA to have its effect, cannot be made without the break-down products of progesterone. The occurrence of severe symptoms has been correlated with falling levels of progesterone metabolites. Therefore, progesterone could relieve the symptoms of PMS by preventing falling levels of progesterone metabolites and loss of GABA(A) enhancement.

PMS will be diagnosed prospectively using the DRSP. DRSP is a questionnaire comprised of 25 physical and emotional symptoms including impairment of physical and social activities, women will be asked to give a score of 1 to 6 for each symptom 1 = not at all, 2 = minimal, 3 = mild, 4 = moderate, 5 = severe, 6 = extreme. The investigators will add the symptoms scores of the first day of menses and PMS will be excluded if the score was < 50. If the total score is greater than 50, the patients will record two cycles of symptoms. If more than three items have an average score of more than 3 (mild) during the luteal phase, the investigators will add the scores of five-day intervals during the luteal and follicular phases. PMS will be diagnosed when the luteal phase score is 30 percent greater than the follicular phase score in the 2 months. Women with PMS will be asked to take the drugs for 3 months and keep recording their symptoms and symptom scores will compared to those documented before treatment.

Two hundreds and ten women with premenstrual syndrome will be randomly divided into 3 equal groups using computer generated random numbers. Group 1 will receive oral dienogest (visanne® Bayer, Germany) 2mg for 14 days starting from the 15th day of menstruation, Group 2 will receive fluoxetine (Prozac® Lilly, UK) 20mg and group 3 will receive an oral placebo foe 14 days starting from the 15th day of menstruation.

• Study Type: Interventional
• Enrollment (Anticipated): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Recruiting
    • Cairo University Hospitals
    • Contact: AbdelGany Hassan, MRCOG, MD; Phone Number: 002 01017801604; Email: abdelgany2@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• PMS
• Consents to the procedure

Exclusion Criteria:

• Previous medical treatment for PMS
• Body mass index > 35 kg/m2
• Irregular periods
• Medical disorders like diabetes, hypertension, cardiac, liver, kidney or heart disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dienogest; women will receive oral dienogest 2mg for 14 days starting from the 15th day of menstruation	Drug: Dienogest; women will receive oral dienogest 2mg for 14 days starting from the 15th day of menstruation
Active Comparator: Fluoxetine; women will receive oral fluoxetine 20mg for 14 days starting from the 15th day of menstruation	Drug: Fluoxetine; women will receive oral fluoxetine 20mg for 14 days starting from the 15th day of menstruation
Placebo Comparator: Placebo; women will receive oral placebo for 14 days starting from the 15th day of menstruation	Drug: Placebo; women will receive oral placebo for 14 days starting from the 15th day of menstruation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of DRSP score	DRSP scores will be documented in each treatment month, the mean score will be compared with the pretreatment score	Monthly, up to 3 months

Collaborators and Investigators

• Sponsor: Cairo University

Publications and helpful links

General Publications

• Endicott J, Nee J, Harrison W. Daily Record of Severity of Problems (DRSP): reliability and validity. Arch Womens Ment Health. 2006 Jan;9(1):41-9. doi: 10.1007/s00737-005-0103-y. Epub 2005 Sep 20.
• Lustyk MK, Widman L, Paschane A, Ecker E. Stress, quality of life and physical activity in women with varying degrees of premenstrual symptomatology. Women Health. 2004;39(3):35-44. doi: 10.1300/J013v39n03_03.
• Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JM, Li X. GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature. 1998 Apr 30;392(6679):926-30. doi: 10.1038/31948.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: April 20, 2015
• First Submitted That Met QC Criteria: April 27, 2015
• First Posted (Estimate): April 28, 2015

Study Record Updates

• Last Update Posted (Actual): December 1, 2020
• Last Update Submitted That Met QC Criteria: November 30, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Menstruation Disturbances; Syndrome; Premenstrual Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Contraceptive Agents, Male; Fluoxetine; Dienogest
• Other Study ID Numbers: PMS