Changes in premenstrual symptoms in women starting or discontinuing use of oral contraceptives

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Ekenros, L., Bäckström, T., Hirschberg, A L., Fridén, C. (2019)

Changes in premenstrual symptoms in women starting or discontinuing use of oral contraceptives

Gynecological Endocrinology, 35(5): 422-426 https://doi.org/10.1080/09513590.2018.1534097

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Changes in premenstrual symptoms in

women starting or discontinuing use of oral contraceptives

Linda Ekenros, Torbjörn Bäckström, Angelica Lindén Hirschberg & Cecilia Fridén

To cite this article: Linda Ekenros, Torbjörn Bäckström, Angelica Lindén Hirschberg

& Cecilia Fridén (2019) Changes in premenstrual symptoms in women starting or

discontinuing use of oral contraceptives, Gynecological Endocrinology, 35:5, 422-426, DOI:

10.1080/09513590.2018.1534097

To link to this article: https://doi.org/10.1080/09513590.2018.1534097

© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Published online: 22 Jan 2019.

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PREMENSTRUAL SYMPTOMS AND ORAL CONTRACEPTIVES

Changes in premenstrual symptoms in women starting or discontinuing use of oral contraceptives

Linda Ekenros ^a , Torbj€orn B€ackstr€om ^b , Angelica Linden Hirschberg ^c,d and Cecilia Friden ^a

a Department of Neurobiology, Care Science and Society, Division of Physiotherapy, Karolinska Institutet, Huddinge, Sweden; ^b Department of Clinical Science, Obstetrics and Gynecology, Umeå University, Umeå, Sweden; ^c Department of Women ’s and Children’s Health, Karolinska Institutet, Huddinge, Sweden; ^d Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden

ABSTRACT

It is not clear whether oral contraceptive (OC) treatment affects premenstrual symptoms in women. The aim of the present study was to evaluate changes in premenstrual symptoms (PMS) in women starting to use or discontinuing the use of OCs. Twenty-four healthy women with no previous diagnosis of premen- strual dysphoric disorder were included in this study with a prospective crossover design. Nineteen women completed daily ratings of somatic and mood symptoms during two hormonally different cycles, during a normal menstrual cycle and while using OCs. The menstrual cycle phases were hormonally veri- fied and the low-dose, monophasic OCs were used in a 21/7 regimen. The onset of OC use significantly decreased premenstrual somatic symptoms, but it did not affect mood symptoms. In the women who dis- continued OC use, no significant changes in neither somatic nor mood symptoms appeared in the pre- menstrual phase.

ARTICLE HISTORY Received 4 June 2018 Revised 9 August 2018 Accepted 6 October 2018 Published online 22 January 2019

KEYWORDS

Cross-over design; female sex hormones; menstrual cycle; estrogens; hormonal contraception

Introduction

Menstrual cycle-related symptoms are experienced by 70–80%

women of fertile age [1]. Up to 50% reported mild to moderate pre- menstrual symptoms (PMS) and 2 –8% of those are diagnosed with the more severe premenstrual dysphoric disorder (PMDD) [1,2].

The etiology of PMS/PMDD is still not fully known. However, symptoms are provoked by sex steroids produced by the corpus luteum and are diminished by suppressing ovarian activity [2].

Hence, OC treatment has been a common method to treat PMS [3], although randomized and placebo-controlled studies have shown inconclusive results [4 –6 ]. In placebo-controlled trials, OCs containing drospirenone have demonstrated beneficial effects on somatic, as well as mood symptoms in women with PMS [7–9].

Observational studies have failed to detect differences in cyclic symptoms between non-OC users and OC users [1,10]. To the best of our knowledge, no research has been performed on changes in luteal phase-related mood and somatic symptoms in the same woman when switching from using to not using OCs, or vice versa.

The aim of the study was to prospectively evaluate PMS in healthy women when switching from not using to using low- dose monophasic OCs or after switching from the use of an OC to a normal menstrual cycle in a crossover design.

Methods Study population

Twenty-four female students volunteered to participate. The sub- jects were healthy, nonsmokers and none of the subjects had

been diagnosed earlier with PMDD. All women gave their writ- ten informed consent to participate. The study was approved by the local Ethical Committee (D.nr 01 –311).

Study design

A crossover design was used in which the subjects were divided into Non-OC Starters and OC Starters, depending on whether they started the study using OCs or not (Figure 1). The Non-OC Starters (n ¼ 12) had not been using OCs for at least 3 months prior to entering the study, whereas the OC Starters (n ¼ 12) had been using OCs for at least 3 months up to 9 years. The OCs used in the study were all low-dose, monophasic pills with the amount of ethinyl estradiol ranging between 25 and 30 mg, com- bined with different progestagens. The administrative scheduling of OCs was 21 days of active hormones and 7 days of withdrawal (pill-free phase). All subjects performed daily ratings of PMS during the entire study period using Cyclicity Diagnoser (CDs);

see description below.

The Non-OC Starters entered the study on day 1 in the men- strual cycle and an ovulatory cycle was confirmed by detection of elevated progesterone after the surge of luteinizing hormone (LH) (Figure 1). After the ovulatory cycle, the Non-OC Starters were prescribed oral contraceptives for 1 month before assess- ment. During the second pill chart, which started on the first pill-free day, ratings of symptoms using the CD scales were performed.

The OC Starters entered the study on the first pill-free day of the OC treatment cycle (Figure 1). After the first pill chart was

CONTACT Linda Ekenros linda.ekenros@ki.se Department of Neurobiology Care Science and Society, Division of Physiotherapy, Karolinska Institutet, Alfred Nobels Alle 23, Huddinge, Stockholm 171 77, Sweden

ß 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

GYNECOLOGICAL ENDOCRINOLOGY 2019, VOL. 35, NO. 5, 422 –426

https://doi.org/10.1080/09513590.2018.1534097

completed, the same women discontinued the OC treatment for a washout period and awaited ovulation. If ovulation did not occur after 3 months, the subject was excluded from the study.

The remaining subjects detected ovulation and rated their PMS.

Cyclicity diagnosis

A prospective rating of PMS was performed daily during the two assessment cycles in the respective group. A previously validated cyclicity diagnosis of PMS, Cyclicity Diagnoser (CD) [11,12], was used. The CD scale consists of somatic symptoms (swelling and breast tenderness); negative mood parameters (depression, fatigue, irritability, tension, mood swings); positive mood param- eters (cheerfulness, energy); symptoms measuring control (diffi- culty in concentrating, out of control); sleep problems; and less interest in daily activities. In addition, the CD scale contains parameters for measuring menstrual bleeding; and the compre- hensive symptom general impairment aimed at measuring inter- ference with family life, usual social activities, and work or school efficiency. The CD scale is a Likert scale ranging from 0 to 8.

Related symptoms were grouped together and the mean scores of the symptoms were summarized. The somatic symp- toms were summarized with a maximum score of 16 and the negative mood symptoms were summarized with a maximum score of 40. The comprehensive symptom of general impairment

was treated separately. To determine cyclicity in individual women, the symptoms were compared between the menstrual and the premenstrual phases. Subjects were considered cyclic if they showed a significant increase in at least one negative mood symptom and/or at least one somatic symptom in the premen- strual phase, compared to the menstrual phase.

To procure comparable cycles, the cycles were idealized to 28 days. Day 1 was set to the first day of menstrual flow (scores

3 on the CD scale) [13]. The follicular phase (menstrual phase) was defined as day 3 up to and including day 9 in the menstrual cycle. In the OC cycle, the menstrual phase was defined as day 3 to day 7 in the pill-free phase, and including day 1 and day 2 on the pill chart. The premenstrual phase was in the menstrual cycle defined as day 24 to day 28 of an ovulatory cycle and the first 2 days in the consecutive cycle [14]. The definition of the premenstrual phase in the OC cycle was set to day 17 to day 21 on the pill chart and the first two pill-free days in the consecu- tive cycle.

Blood sampling and hormone assays

Hormone levels were determined to verify ovulatory cycles as well as verification of compliance with OC treatment. After cen- trifugation, serum was separated and stored at 20 ^ C until ana- lyzed. Follicular stimulating hormone (FSH), LH, estradiol (E2), progesterone (P-4), and sex hormone-binding globulin (SHBG)

Figure 1. Flowchart of study design.

GYNECOLOGICAL ENDOCRINOLOGY 423

were analyzed in serum using chemiluminescent enzyme immu- nometric assays (IMMULITE Automated Analyzer, DPC).

Ovulation was determined by Ovustrix ^V

(Clearplan, Unipath Limited, Bedford, England) by detecting the LH surge in urine.

Data analyses and statistical methods

All data are presented using descriptive statistics, means (SD/

SEM), and the number of observations. To diagnose cyclical changes in CD scale symptoms in individual women, the Mann –Whitney U-test was used to identify women with cyclicity [12]. To detect changes in the number of women with cyclicity between the normal menstrual cycle and the OC cycle, the Chi- square test was used. To analyze the difference between the men- strual and premenstrual phase, the Wilcoxon rank sum test was used. Group data were further analyzed by using repeated meas- ures ANOVA, comparing the 7 days in the menstrual phase with the 7 days in the premenstrual phase during the menstrual cycle vs. the OC cycle. The Fisher post hoc test for multiple compari- sons was used to assess differences between the menstrual cycle and the OC cycle. All tests were two-sided and the level of sig- nificance was set to  .05.

Results Drop-outs

Out of the 24 women included, five had to be excluded for vari- ous reasons (Figure 1).

Nineteen subjects completed the study. The mean (SD) for age and BMI in the Non-OC Starters ( n ¼ 11) were 27.2 (4.5) years and 23.4 (4.5) kg/m ² , respectively, and for the OC Starters (n ¼ 8) 26.4 (2.5) years and 23.7 (6.9) kg/m ² . There were no sig- nificant differences between the groups.

Hormone levels

Hormone levels in the different phases of the menstrual cycle and on the corresponding days of the OC cycle are shown in Table 1 and it shows a normal variation.

The premenstrual phase of the menstrual cycle and the OC cycle

In all women (n ¼ 19), the summarized somatic symptoms dur- ing the premenstrual phase were significantly higher during the normal menstrual cycle, compared to the corresponding days of the OC cycle (p < .05) (Figure 2A). However, the summarized negative mood symptoms did not differ between the two cycles (Figure 2B). The score on the comprehensive symptom

impairment tended to be higher during the premenstrual phase of the menstrual cycle compared to the OC cycle ( p ¼ .06).

Cyclicity in Non-OC starters and OC starters

Among the Non-OC Starters, 8 out of 11 women showed signifi- cant cyclical changes ( p < .05) in the summarized somatic symp- tom scores during the normal menstrual cycle. After having switched to OC treatment, there was a tendency to fewer subjects (4/11) showing cyclicity in summarized somatic symptom scores ( p ¼ .09). Figure 3 illustrates summarized somatic symptoms in one woman showing cyclicity during the normal menstrual cycle, but not during the following OC cycle. In contrast, for summar- ized negative mood scores, 4 out of 11 women were considered to be cyclic during the normal menstrual cycle, whereas in the OC cycle, there was no significant change in negative mood scores (2/11).

For the OC Starters, 2 out of 8 women showed cyclicity in summarized somatic symptoms during the OC cycle. After wash- out, there was no significant change in the summarized somatic symptoms (2/8) in the normal menstrual cycle. For summarized negative mood scores, the proportion of women showing cyclic- ity in the OC cycle was 2 out of 8. After the washout period, a proportion of 4/8 women showed cyclicity in summarized nega- tive mood scores (ns).

Change in cyclicity in the groups of Non-OC starters and OC starters

The Non-OC Starters ( n ¼ 11), showed a significantly higher increase in summarized somatic symptoms in the premenstrual phase of the normal menstrual cycle compared to the following OC cycle (p < .05). However, there was no significant difference in the cyclicity of summarized negative mood symptoms within the normal menstrual cycle than the OC cycle. For the OC Starters, the cyclicity in summarized somatic symptoms, as well as the cyclicity of summarized negative mood symptoms within the OC cycle, was comparable to that in the following normal menstrual cycle.

Discussion

To the best of our knowledge, this is the first prospective study on cyclical symptoms in healthy women switching from not using OCs to OC treatment or vice versa. In all of the women, it was demonstrated that somatic symptoms were significantly greater during the premenstrual phase of the normal menstrual cycle compared to the corresponding days of the OC cycle. In the Non-OC Starters, the proportion of women showing cyclicity in somatic symptoms during the normal menstrual cycle was sig- nificantly greater compared to the following OC cycle. However,

Table 1. Mean (SD) of hormone levels during the three different phases in the Menstrual cycle and the OC cycle respectively.

Menstrual cycle OC cycle

MP OP PMP Pill-free Day 7 –8 Day 14 –15

FSH (IU/l) 6.5 (1.9) 7.4 (3.6) 3.6 (2.4) 5.9 (3.0) 4.5 (3.6) 2.3 (1.9)

LH (IU/l) 4.7 (1.4) 10.9 (7.0) 3.7 (1.9) 3.7 (1.8) 5.0 (3.4) 2.2 (2.8)

E

(pmol/L) 114 (31) 268 (171) 403 (220) 100 (44) 109 (24) 289 (27)

P-4 (nmol/L) 1.7 (1.4) 8.3 (7.1) 36.5 (19) 1.2 (0.3) 1.2 (0.3) 1.4 (0.4)

SHBG (nmol/L) 55.0 (18) 53.7 (16) 57.2 (16) 110 (63) 107 (63) 117 (69)

FSH: follicle- stimulating hormone; LH: luteinizing hormone; E

: estradiol; P-4: progesterone; and SHBG: sex hormone-bind- ing globulin.

424 L. EKENROS ET AL.

the proportion of women showing cyclical mood symptoms was not changed. In the group of OC Starters, the proportion of women showing cyclicity in somatic or mood symptoms did not change in the following normal menstrual cycle.

The present study demonstrated that somatic symptoms were more frequently reported during the normal menstrual cycle, compared to during the OC treatment cycle. However, in a study of prospective ratings, about 75% experienced cyclicity in som- atic symptoms, regardless of the use of OCs [1]. Negative mood symptoms are less common in women regardless of OC treat- ment. This was found in the present study and are in agreement with Sveinsd ottir and B€ackstr€om [ 1]. However, Zethraeus et al.

[15] showed that women who used OCs reported significantly lower general well-being compared to women on placebo.

Only a few randomized controlled trials have been published evaluating the effect of OCs on PMS [5,16]. The treatment effect of combined OCs on PMS and PMDD seems to be dependent on the type of progestagen, the dosage of ethinyl estradiol, and the length of the withdrawal phase [2,7–9,17–19]. In the present study, the OC Starters had proportionally fewer symptoms, com- pared to the Non-OC Starters. The reason for this group to have fewer symptoms might be due to good tolerance to the OC treat- ment as they had used OC under a longer period prior to the study. The eventual discontinuation of OC treatment due to side effects usually occurs during the initial months of OC use [20,21]. It can be speculated that this group did not gain any sig- nificant increase in cyclical symptoms scores when terminating

OC use since the washout period of 1 month were too short, despite an ovulatory cycle.

The sample size in the present study was quite small. Twenty- four women were included initially. The dropout rate was, how- ever, relatively high, which is common in this kind of menstrual- cycle-related study. Some of the women entering the study on OCs had to be excluded because they failed to show ovulation within 3 months. It has been reported that it might take up to six cycles to normalize the menstrual cycle [22]. Additionally, the cycle length in these women was not known beforehand, resulting in difficulties in detecting the time of even- tual ovulation.

Some other limitations of this study should also be addressed.

The OC Starters had been on OCs for different periods of time and the women were using different types of progestagens, even though all were low-dose monophasic pills combined with ethinyl estradiol.

More studies with an extended number of subjects, grouped under different types of OC and a more comparable length of treatment, should be conducted for confirmation of our results.

In conclusion, OCs seem to improve somatic premenstrual symptoms in healthy women of fertile age, but they did not seem to have an effect on mood symptoms in this study group.

Acknowledgments

Many thanks to all the women who volunteered to participate in the present study and to the personnel at Women s Health, for collecting blood samples and performing serum analyses.

Disclosure statement

No potential conflict of interest was reported by the authors.

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Figure 2. Illustrates the symptom scoring for summarized somatic symptoms (A) and for summarized negative mood symptoms (B) in the entire study group ( n ¼ 19) during the menstrual cycle and OC cycle, respectively. A significant increase in summarized somatic symptom scores was found during the menstrual cycle, as com- pared to the OC cycle; no significant changes between cycles were found in the negative mood symptoms. The 7 days in the premenstrual phase are set to 24 –28, including days 1 –2.

Figure 3. Illustration of summarized somatic symptoms for one woman (Non-OC Starter) showing cyclicity during the normal menstrual cycle, but not during the OC cycle. Day 1 signifies the first day of bleeding in the normal menstrual cycle and the first pill-free day in the OC cycle.

GYNECOLOGICAL ENDOCRINOLOGY 425

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