About 20%–90% of women experience premenstrual syn-drome (PMS), and 2%–15% of them have severe symptoms [
Group of symptoms according to ACOG diagnostic criteria.
Somatic symptoms | Effective symptoms |
---|---|
(i) Breast tenderness |
(i) Depression |
Criteria for PMS were developed in the 1980s [
Modifying the 7-day hormone-free interval (HFI) has also been investigated and is currently beginning to appear in COCs. A 24/4 day regimen of low-dose COC containing drospirenone (DRSP) regimen which reduces HFI has been investigated and approved by U.S. Food and Drug Administration [
20
So there is suspicion whether the former low-dose COC would be modified in terms of extended 24/4 regimen in order to comparably relieve the premenstrual symptoms [
An open-label randomized controlled trial was performed at the Family Planning Clinic, King Chulalongkorn Memorial Hospital from June 2011 to February 2012.
Child bearing-aged women who were requesting COCs for contraception were recruited from many ways including advertisement, invitation to postpartum and postabortion visits and inviting some who had appointments with the Clinic.
All subjects who met the eligible criteria were considered to participate in the study.
The inclusion criteria consisted of women aged 18–35 years had regular menstrual cycles lasting between 21 and 35 days, did not use injectable or implant hormonal contraceptives within 6 months or oral contraception and IUD within 3 months before the study, and did not wish to use any other form of hormonal treatment, including other hormonal contraception, for the duration of the study protocol. Postabortion and postpartum patients were eligible if they had had three consecutive menstrual cycles before the study.
The exclusion criteria included women who were pregnant or suspected of being pregnant, who were breastfeeding, who were smoking, who were contraindicated for using COCs according to WHO categories 2, 3, and 4, and finally who had PMDD.
The study protocol including participant flow as shown in Figure
Participation flow. DSG group used the preparation of ethinyl estradiol 20
The symptoms had to be relieved within 4 days of menstruation onset without recurrence until at least the cycle day 13th. The symptoms usually present in the absence of the following: pharmacologic therapy, hormone ingestion, drug, alcohol abuse.
Patients suffered from identifiable dysfunction in social or economic performance.
All subjects were required to sign written informed consent forms before being recruited. Randomization numbers were generated in fixed block of four and were allocated in 1 : 1 ratio. The women underwent general physical and pelvic examinations, along with the cervical Pap test—if no previous 1 year examination had been done, and had urinary pregnancy test at the screening and diagnostic period in the initial step of protocol. All subjects were randomly assigned to two groups: group 1 (DSG group) which used the preparation of ethinyl estradiol 20
The subjects were asked to fill the baseline characteristic demographic data in the form and submit it to the nurse coordinator. Vital signs, body weight, body height, and body mass index (BMI) were collected and calculated.
Data were collected at the main visits by assistant nurses and scientists who were blinded from the protocol at the Family Planning Clinic, King Chulalongkorn Memorial Hospital. Arranged data were collected on the visits consistent with the protocol consisted of the following: baseline—before the COCs use, the second visit—after completed 3 cycles use of COCs, the last visit—after completed 6 cycles use of COCs.
Both groups of subjects were evaluated on the premenstrual symptoms at baseline and at the ends of the 3rd and the 6th cycles by using Women’s Health Assessment questionnaire (WHAQ) which was prepared in self-report form. WHAQ was a subset of items selected from the Menstrual Distress Questionnaire. WHAQ was translated from English to Thai and tested for reliability with a Cronbach’s alpha of 80. We were allowed for using this version. Three phases included the following: premenstrual phase: the 4-day period before menstruation, menstrual phase: the first day through the last day of menstruation postmenstrual phase: the reminder of the cycle.
This self-report questionnaire included 6 categories that contained 23 items. The 6 categories were composed of 3 main categories that included impaired concentration, water retention, negative affect.
Another 3 additional categories included increased appetite, feelings of well-being, undesirable hair changes.
The impaired concentration category contained eight items. The water retention category contained four items, and the category of negative effect contained eight items, as shown in Table
Categories (6) and items (23) in each main category of WHAQ scores.
Negative effect |
Water retention |
Impaired concentration |
Additional categories |
---|---|---|---|
(i) Loneliness |
(i) Weight gain |
(i) Insomnia |
(i) Increased appetite |
In addition, adverse events that occurred were reported and managed as soon as possible. The packages of COCs were checked for potential medication damage or medication expiration and also were checked for compliance. All subjects were informed about their right to discontinue the participation in the project.
Adverse drug reactions (ADRs) were evaluated at the end of the 3rd cycle and at the end of the 6th cycle. The subjects were able to report ADRs as they were faced as soon as possible by telephone.
Data were analyzed from intent-to-treat analysis in which randomized subjects included who took at least 1 cycle of COC. Per-protocol analysis would be determined in comparing the outcomes in cases of discontinuation were found.
Repeated analysis of variance (repeated ANOVA) was used to determine the mean WHAQ scores changes within each of the treatment groups.
Analysis of covariance (ANCOVA) was used to determine the difference between the two treatment groups. ANCOVA contained the term of baseline WHAQ score as a covariate.
Baseline characteristic demographic data were determined using descriptive statistics and were compared between the two groups using independent
Level of significance was considered at 95 percent confidence interval and
There were a total of 90 subjects allocated to either group in 1 : 1 ratio. All of them had completed the protocol, although 5 of them had temporary losses but did not affect the protocol. The reason of the losses was resulting from devastating flood crisis in the middle part of Thailand including, but not all, part of Bangkok. There was no statistically significant differences in baseline characteristic demographic data between both groups as shown in Table
Baseline characteristic demographic data.
Characteristics | Treatment group | |
---|---|---|
DSG group |
DRSP group |
|
Age (year ± SD) | 26.6 (±3.9) | 27.9 (±3.4) |
BW (kg ± SD) | 55.6 (±7.9) | 56.5 (±8.4) |
Height (cm ± SD) | 157.1 (±5.2) | 158.9 (±6.1) |
BMI (kg/m2 ± SD) | 22.5 (±2.9) | 22.4 (±3.0) |
Parity (median ± range) | 1 (0–4) | 1 (0–4) |
Education level | ||
primary | 7 | 2 |
secondary | 24 | 24 |
graduated | 13 | 8 |
postgraduated | 1 | 1 |
According to Table
The results of group and subgroup analyses according to the comparison of mean WHAQ scores changes between groups.
Between groups | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
ANCOVA model | ||||||||||
Premenstrual | Menstrual | Postmenstrual | ||||||||
Mean WHAQ scores | DSG | DRSP | Sig | DSG | DRSP | Sig | DSG | DRSP | Sig | |
Baseline | 19.49 ± 6.76 | 21.33 ± 8.53 | 0.259 | 17.13 ± 5.88 | 17.42 ± 6.41 | 0.824 | 5.84 ± 1.98 | 6.16 ± 2.88 | 0.552 | |
Total | 3rd cycle | 19.07 ± 6.27 | 14.78 ± 6.28 | 0.000 | 17.82 ± 6.11 | 12.98 ± 4.27 | 0.000 | 5.96 ± 2.04 | 4.80 ± 1.50 | 0.000 |
6th cycle | 16.24 ± 6.48 | 7.62 ± 2.46 | 0.000 | 15.40 ± 5.42 | 7.49 ± 2.87 | 0.000 | 5.38 ± 1.54 | 4.29 ± 0.82 | 0.000 | |
Baseline | 7.76 ± 3.21 | 7.38 ± 3.77 | 0.610 | 7.16 ± 3.02 | 5.93 ± 3.20 | 0.066 | 1.51 ± 1.36 | 1.38 ± 1.48 | 0.657 | |
Negative effect | 3rd cycle | 7.33 ± 2.95 | 5.07 ± 3.13 | 0.000 | 7.11 ± 2.99 | 4.36 ± 2.68 | 0.000 | 1.47 ± 1.38 | 0.80 ± 1.14 | 0.006 |
6th cycle | 5.60 ± 3.10 | 1.56 ± 1.52 | 0.000 | 5.67 ± 2.99 | 1.58 ± 1.34 | 0.000 | 1.13 ± 1.27 | 0.07 ± 0.33 | 0.000 | |
Baseline | 4.71 ± 3.08 | 5.51 ± 3.61 | 0.261 | 2.87 ± 2.74 | 3.62 ± 2.90 | 0.208 | 0.36 ± 0.80 | 0.69 ± 1.18 | 0.121 | |
Water retention | 3rd cycle | 4.51 ± 2.98 | 3.64 ± 2.39 | 0.000 | 3.51 ± 2.67 | 2.42 ± 1.83 | 0.000 | 0.56 ± 0.94 | 0.29 ± 0.66 | 0.005 |
6th cycle | 3.87 ± 2.37 | 1.98 ± 1.82 | 0.000 | 3.22 ± 2.32 | 1.33 ± 1.43 | 0.000 | 0.38 ± 0.61 | 0.16 ± 0.56 | 0.043 | |
Baseline | 4.49 ± 3.29 | 5.84 ± 4.31 | 0.097 | 4.56 ± 3.17 | 5.27 ± 3.60 | 0.322 | 0.73 ± 0.96 | 0.87 ± 1.12 | 0.546 | |
Impaired concentration | 3rd cycle | 4.11 ± 3.41 | 3.27 ± 3.11 | 0.000 | 3.96 ± 2.90 | 3.02 ± 2.34 | 0.000 | 0.62 ± 0.94 | 0.36 ± 0.68 | 0.063 |
6th cycle | 3.27 ± 3.14 | 0.93 ± 1.10 | 0.000 | 3.20 ± 2.70 | 1.11 ± 1.49 | 0.000 | 0.38 ± 0.86 | 0.04 ± 0.30 | 0.013 | |
Baseline | 1.84 ± 1.63 | 2.09 ± 1.47 | 0.457 | 1.53 ± 1.34 | 1.80 ± 1.29 | 0.339 | 0.18 ± 0.54 | 0.27 ± 0.58 | 0.452 | |
Increased appetite | 3rd cycle | 1.96 ± 1.36 | 1.33 ± 1.07 | 0.000 | 1.58 ± 1.20 | 1.11 ± 0.96 | 0.000 | 0.36 ± 0.57 | 0.11 ± 0.32 | 0.007 |
6th cycle | 2.04 ± 1.28 | 1.07 ± 1.03 | 0.000 | 1.38 ± 1.15 | 0.62 ± 0.86 | 0.000 | 0.24 ± 0.48 | 0.11 ± 0.38 | 0.167 | |
Baseline | 0.64 ± 0.83 | 0.51 ± 0.63 | 0.392 | 1.04 ± 0.85 | 0.80 ± 0.79 | 0.161 | 3.02 ± 0.66 | 2.96 ± 0.64 | 0.626 | |
Feeling of well being | 3rd cycle | 1.11 ± 0.91 | 1.47 ± 0.73 | 0.008 | 1.62 ± 0.75 | 2.07 ± 1.01 | 0.002 | 2.91 ± 0.76 | 3.24 ± 0.86 | 0.042 |
6th cycle | 1.42 ± 0.81 | 2.09 ± 0.67 | 0.000 | 1.89 ± 0.83 | 2.78 ± 0.67 | 0.000 | 3.20 ± 0.76 | 3.91 ± 0.29 | 0.000 | |
Baseline | 0.04 ± 0.30 | 0.00 ± 0.00 | 0.320 | 0.04 ± 0.30 | 0.00 ± 0.00 | 0.320 | 0.04 ± 0.30 | 0.00 ± 0.00 | 0.320 | |
Undesirable hair changes | 3rd cycle | 0.04 ± 0.30 | 0.00 ± 0.00 | 1.000 | 0.04 ± 0.30 | 0.00 ± 0.00 | 1.000 | 0.04 ± 0.30 | 0.00 ± 0.00 | 1.000 |
6th cycle | 0.04 ± 0.30 | 0.00 ± 0.00 | 1.000 | 0.04 ± 0.30 | 0.00 ± 0.00 | 1.000 | 0.04 ± 0.30 | 0.00 ± 0.00 | 1.000 |
DSG: desogestrel and DRSP: drospirenone.
At the end of the 3rd menstrual cycle, mean WHAQ scores in the DRSP group were significantly lower than those DSG group in all the 3 phases of menstrual cycle; even the baseline WHAQ score in DRSP group was a little nonsignificantly higher. Predominately, at the end of the 6th menstrual cycle, mean WHAQ scores in DRSP group were continuing to decrease significantly much more than those the DSG group.
Based on Table
The results of group and subgroup analyses according to the comparison of mean WHAQ scores changes within groups.
Within group | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Repeated ANOVA | |||||||||||||
Premenstrual | Menstrual | Postmenstrual | |||||||||||
Mean WHAQ scores* | DSG |
Sig. | DRSP |
Sig. | DSG |
Sig. | DRSP |
Sig. | DSG |
Sig. | DRSP |
Sig. | |
Baseline–3rd cycle | 0.42 ± 0.41 | 0.307 | 6.56 ± 0.79 | 0.000 | −0.69 ± 0.34 | 0.046 | 4.44 ± 0.76 | 0.000 | −0.11 ± 0.26 | 0.672 | 1.36 ± 0.34 | 0.000 | |
Total | Baseline–6th cycle | 3.24 ± 0.77 | 0.000 | 13.71 ± 1.25 | 0.000 | 1.73 ± 0.63 | 0.008 | 9.93 ± 0.96 | 0.000 | 0.47 ± 0.30 | 0.132 | 1.87 ± 0.45 | 0.000 |
3rd cycle–6th cycle | 2.82 ± 0.65 | 0.000 | 7.16 ± 0.91 | 0.000 | 2.42 ± 0.58 | 0.000 | 5.49 ± 0.55 | 0.000 | 0.58 ± 0.27 | 0.041 | 0.51 ± 0.25 | 0.050 | |
Baseline–3rd cycle | 0.42 ± 0.19 | 0.031 | 2.31 ± 0.45 | 0.000 | 0.04 ± 0.17 | 0.800 | 1.58 ± 0.45 | 0.001 | 0.04 ± 0.13 | 0.736 | 0.58 ± 0.21 | 0.008 | |
Negative effect | Baseline–6th cycle | 2.16 ± 0.44 | 0.000 | 5.82 ± 0.58 | 0.000 | 1.49 ± 0.33 | 0.000 | 4.36 ± 0.50 | 0.000 | 0.38 ± 0.18 | 0.039 | 1.31 ± 0.23 | 0.000 |
3rd cycle–6th cycle | 1.73 ± 0.40 | 0.000 | 3.51 ± 0.43 | 0.000 | 1.44 ± 0.30 | 0.000 | 2.78 ± 0.39 | 0.000 | 0.33 ± 0.15 | 0.034 | 0.73 ± 0.18 | 0.000 | |
Baseline–3rd cycle | 0.20 ± 0.13 | 0.130 | 1.87 ± 0.27 | 0.000 | −0.64 ± 0.17 | 0.000 | 1.20 ± 0.31 | 0.000 | −0.20 ± 0.12 | 0.107 | 0.40 ± 0.14 | 0.005 | |
Water retention | Baseline–6th cycle | 0.844 ± 0.32 | 0.012 | 3.53 ± 0.46 | 0.000 | −0.36 ± 0.37 | 0.345 | 2.29 ± 0.39 | 0.000 | −0.02 ± 0.14 | 0.872 | 0.53 ± 0.18 | 0.005 |
3rd cycle–6th cycle | 0.644 ± 0.31 | 0.040 | 1.67 ± 0.32 | 0.000 | 0.29 ± 0.31 | 0.365 | 1.09 ± 0.25 | 0.000 | 0.18 ± 0.12 | 0.132 | 0.13 ± 0.11 | 0.225 | |
Baseline–3rd cycle | 0.38 ± 0.18 | 0.036 | 2.58 ± 0.38 | 0.000 | 0.60 ± 0.21 | 0.007 | 2.24 ± 0.40 | 0.000 | 0.11 ± 0.14 | 0.417 | 0.51 ± 0.18 | 0.006 | |
Impaired concentration | Baseline–6th cycle | 1.22 ± 0.34 | 0.001 | 4.91 ± 0.63 | 0.000 | 1.36 ± 0.29 | 0.000 | 4.16 ± 0.52 | 0.000 | 0.36 ± 0.17 | 0.041 | 0.82 ± 0.18 | 0.000 |
3rd cycle–6th cycle | 0.84 ± 0.28 | 0.005 | 2.33 ± 0.46 | 0.000 | 0.76 ± 0.23 | 0.002 | 1.91 ± 0.29 | 0.000 | 0.24 ± 0.16 | 0.140 | 0.31 ± 0.11 | 0.009 | |
Baseline–3rd cycle | −0.11 ± 0.14 | 0.417 | 0.76 ± 0.12 | 0.000 | −0.04 ± 0.10 | 0.643 | 0.69 ± 0.14 | 0.000 | −0.18 ± 0.11 | 0.103 | 0.16 ± 0.08 | 0.051 | |
Increased appetite | Baseline–6th cycle | −0.20 ± 0.18 | 0.284 | 1.02 ± 0.18 | 0.000 | 0.16 ± 0.18 | 0.399 | 1.18 ± 0.18 | 0.000 | −0.07 ± 0.12 | 0.570 | 0.16 ± 0.10 | 0.128 |
3rd cycle–6th cycle | −0.09 ± 0.13 | 0.486 | 0.27 ± 0.13 | 0.050 | 0.20 ± 0.14 | 0.162 | 0.49 ± 0.14 | 0.001 | 0.11 ± 0.09 | 0.229 | 0.00 ± 0.08 | 1.00 | |
Baseline–3rd cycle | −0.47 ± 0.12 | 0.000 | −0.96 ± 0.12 | 0.000 | −0.58 ± 0.12 | 0.000 | −1.27 ± 0.16 | 0.000 | 0.11 ± 0.12 | 0.375 | −0.29 ± 0.15 | 0.068 | |
Feeling of well being | Baseline–6th cycle | −0.78 ± 0.13 | 0.000 | −1.58 ± 0.13 | 0.000 | −0.84 ± 0.16 | 0.000 | −1.98 ± 0.16 | 0.000 | −0.18 ± 0.15 | 0.242 | −0.96 ± 0.11 | 0.000 |
3rd cycle–6th cycle | −0.31 ± 0.12 | 0.015 | −0.62 ± 0.12 | 0.000 | −0.27 ± 0.13 | 0.038 | −0.71 ± 0.17 | 0.000 | −0.29 ± 0.15 | 0.063 | −0.67 ± 0.14 | 0.000 | |
Baseline–3rd cycle | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | |
Undesirable hair changes | Baseline–6th cycle | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — |
3rd cycle–6th cycle | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — | 0.00 ± 0.00 | — |
DSG: desogestrel and DRSP: drospirenone.
*Mean WHAQ scores were calculated from summed scores of all the subjects divided by the number of subjects.
Adverse effects were identified in Table
The comparison of the prevalence of adverse effects (episodes per 100 samples) between both groups.
Adverse events (AEs) | Prevalence of events (%) |
Between-group |
|
---|---|---|---|
DSG* | DRSP* | ||
Nausea/vomiting | 8 (17.8) | 1 (2.2) | NS |
Dizziness | 1 (2.2) | 4 (8.9) | NS |
Amenorrhea | 3 (6.7) | 1 (2.2) | NS |
Spotting | 2 (4.4) | 2 (4.4) | NS |
Mastalgia | 1 (2.2) | 0 (0) | NS |
*DSG: desogestrel group and DRSP: drospirenone group.
Repeated ANOVA showed significant body-weight reduction at the end of 6th cycle and between the 3rd and the 6th cycles in DRSP group, but there was no significant change in body-weight along the protocol in DSG group. According to Table
The comparison of the body-weight change between both groups.
Body weight (kg) | Comparison |
Between-group |
|
---|---|---|---|
DSG* |
DRSP* |
||
Baseline | 55.6 (±7.9) | 56.5 (±8.4) | 0.446 |
3rd cycle | 55.9 (±8.1) | 56.3 (±8.5) | 0.232 |
6th cycle | 55.9 (±7.9) | 55.5 (±8.7) | 0.003 |
*DSG: desogestrel group and DRSP: drospirenone group.
No serious adverse drug effects and inadvertent pregnancy were reported.
WHAQ score could range from 0 to the maximal score of 92. WHAQ was a subset of items selected from the Menstrual Distress Questionnaire [
This study demonstrated the main result in which low-dose COC containing DRSP reduced the premenstrual symptoms as measured by WHAQ, and it provides good contraceptive efficacy consistent with the previous studies [
Although the etiology of the premenstrual disorders has not been understood, the symptoms seem to occur primarily in the setting of ovulatory menstrual cycles and have been hypothesized to result from alterations between gonadal hormones and CNS neurotransmitters including serotonin, GABA, and endorphins, as well as other modulators, in genetically predisposed individuals [
Some authors supposed that rise and fall of sex steroids can precipitate premenstrual symptoms. Even more, the hormone-free interval resulted from the formulation of 21/7 COC would contribute to the aggravating symptoms. So the shortening of the HFI to 3-4 days was proposed in order to maintain sufficient levels of exogenous estrogen and progestin to inhibit follicular development and suppress ovarian steroids synthesis [
The newer OC formulation of DRSP/EE 3 mg/20
Using ANCOVA model which limits the potential errors resulting from uneven baseline parameters between groups, even at the baseline, self-report showed nonsignificant higher mean WHAQ score, and low-dose COC containing DRSP seemed to be more efficient than low-dose COC containing DSG regarding the premenstrual symptoms along the study period of 6 cycles.
DRSP is pharmacologically similar to endogenous progesterone. Progesterone is known to exert direct sedative effect on the central nervous system, as reflected in the slowing of electroencephalogram in humans and the alteration of arousal threshold stimuli in the hypothalamus of various animals. Deficiency of progesterone would increase nervous excitability, irritability, tension, anxiety, and aggression [
Some investigators have demonstrated abnormally elevated plasma testosterone in women with premenstrual symptoms and aggression [
Unlike the other kinds of progestin, DRSP has antimineralocorticoid (aldosterone antagonistic) and anti-androgenic properties [
Also, our study showed that low-dose COC containing DSG in an extended 24/4 regimen has an effect on the premenstrual symptoms regarding the severity of reduction. This result showed one of the noncontraceptive benefits which might be due to lower estrogen (EE) dose, the effect of decreasing HFI and probably the minimal androgenic effect of DSG among gonane subgroups within the 19-nortestosterone group of progestogens.
The other potential strength of the study was the lacking of discontinuation, since the study recruitment reflected in good pills compliance which was shown in the follow-up visits. In the study, beside the premenstrual symptoms reduction effect, either of COCs showed favorable body-weight changes and comparable minimal events of adverse effects. Those might explain the good compliance in both DSG and DRSP groups. The trend towards a slight decrease in body weight in DRSP group was consistent with the previous study using DRSP containing COC [
There are some possible limitations of this study. First, an open-label randomized controlled trial may have influence on self-report regarding the premenstrual symptoms. Second, the main outcome and the average WHAQ scores were rather subjective and based on the recent memory that might be affected by several factors.
The premenstrual symptoms which are partition of PMS have been considered as an individual persistent problem among general childbearing-aged women. These cyclic symptoms have repeatedly affected their physical, emotional, and psychological well being resulting in a negative impact on the quality of life, or even, the surrounding people. Several studies have been performed to accomplish the discovery of medications that can improve these symptoms. Given the positive study results from either DSG or DRSP group, it was the potential benefits of the study included characteristics of noncontraceptive efficacy, especially the effect on PMS, that resulted from COCs in an extended regimen use.
To our knowledge, this study was the first study which compared the efficacy of low-dose COC formulations containing either DRSP or DSG regarding the premenstrual symptoms. Until more data from sufficient studies demonstrate the therapeutic efficacy according to other kinds of modalities or other COCs, either of COCs used in this study may be an alternative choice for the selected women seeking contraception who suffer from some degree of PMS. The future studies may have objectives to investigate the therapeutic effects of other extended COC regimen, in order to minimize or abolish HFI or other potential COCs in the selected population with premenstrual symptoms.
In conclusion, from our study, low-dose COC containing either DSG or DRSP could reduce the premenstrual symptoms. Low-dose COC containing DRSP showed greater efficacy and earlier reduction regarding the premenstrual symptoms than low-dose COC containing DSG according to the interval period of either 3 or 6 cycles.
The authors have no connection to any companies or products mentioned in this paper.
This research received a grant from the Ratchadapisek-Sompoch Research Fund, Faculty of Medicine, Chulalongkorn University. This research has been registered on ClinicalTrial.gov (NCT01482338) on December 2011.