https://orcid.org/0000-0002-9551-2847
ABSTRACT
Introduction
Dysmenorrhea and mastodynia are the most common gynecologic pain causes in women of all ages and races during their reproductive life. The following study aimed to show the influence of two POP´s in the development of dysmenorrhea and mastodynia after nine months of use.
Material and methods
A total of 858 women with 6691 drospirenone (DRSP) cycles and 332 women with 2487 desogestrel (DSG) cycles were analyzed. Women included in this study were all child-bearing potentials, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study medication treatment, aged 18 to 45.
Results
At screening, 168 (19.6%) of the 858 patients using DRSP and 64 (19,3%) of the DSG patients reported that they had suffered from dysmenorrhea within six cycles prior to the first visit before starting with the medication. 20,2% of the DRSP and 10,9% of the DSG group had a sever dysmenorrhea. After 9 cycles this was reduced to 0,6% and 3,1% respectively. In total, 96 women (11.2%) in the DRSP and 49 (14,8%) experienced mastodynia within six cycles before the screening. Of these 91.6% in the DRSP group and 91,8% in the DSG group had no or mild mastodynoa at follow-up.
Discussion
The progestins 4 mg and desogestrel 0,075 mg showed a marked effect in the non-contraceptive aspects of dysmenorrhea and mastodynia so that new possibilities are opened for these two benign gynecological diseases. Future studies must reaffirm these first data.
摘要
介绍
痛经和乳腺疼痛是各年龄各种族女性在育龄期最常见的女性疼痛原因。接下来的研究旨在显示两种单孕激素片剂在使用9个月后对痛经和乳腺疼痛的改变。
材料和方法
共分析了858名女性的6691个屈螺酮（DRSP）周期和332名女性的2487个去氧孕烯（DSG）周期。本研究纳入的女性均有生育能力、有妊娠可能、同意在药物研究治疗期间仅使用研究药物避孕的女性, 年龄为18至45岁。
结果
在开始用药前的筛查中, 858例DRSP患者中有168例（19.6%）, DSG患者中有64例（19.3%）报告她们在第一次就诊前的6个周期内存在痛经。DRSP组的20.2%和DSG组的10.9%有严重痛经。治疗9周期后, 这一比例分别降至0.6%和3.1%。DRSP组96名女性（11.2%）和DSG组49名女性（14.8%）在筛查前的6个周期内经历过乳腺疼痛。这些人中的91.6%（GRSP组）和91.8%（DSG组）随访时没有或仅有轻度乳腺疼痛。
讨论
屈螺酮4 mg和去氧孕烯0.075 mg对痛经和乳腺疼痛患者的非避孕效果显著, 为这两种女性良性疾病的治疗开辟了新的可能。未来的研究可以参考这些初步的数据。
Introduction
Dysmenorrhea, defined as painful cramps that occur with menstruation, is the most common gynecologic problem in women of all ages and races and one of the most common causes of pelvic pain [Citation1, Citation2]. Estimates of the prevalence of dysmenorrhea vary widely between 16.8% to 81% [Citation3], and rates as high as 90% have been recorded [Citation4]. Symptoms typically begin in adolescence and may lead to school and work absenteeism, as well as limitations on social, academic, and sports activities [Citation5].
Dysmenorrhea is considered primary in the absence of underlying pathology. Onset is typically six to 12 months after menarche, with peak prevalence occurring in the late teens or early twenties. Secondary dysmenorrhea results from specific pelvic pathology. It should be suspected in older women with no history of dysmenorrhea until proven otherwise [Citation6]. Symptoms include menorrhagia, intermenstrual bleeding, dyspareunia, post-coital bleeding, and infertility.
Endometriosis is the most common cause of secondary dysmenorrhea [Citation7]. The incidence is highest among women 25 to 29 years of age and lowest among women older than 44 years. Black women have a 40% lower endometriosis incidence than white women [Citation8].
Protective factors against dysmenorrhea include regular exercise, oral contraceptive use, and early childbirth [Citation6].
Characteristic symptoms of primary dysmenorrhea include lower abdominal or pelvic pain with or without radiation to the back or legs, with initial onset six to 12 months after menarche [Citation9]. Pain typically lasts eight to 72 h and usually occurs at the start of menstrual flow. Other associated symptoms may include low back pain, headache, diarrhea, fatigue, nausea, or vomiting [Citation1]. Family history may help differentiate primary from secondary dysmenorrhea; patients with a family history of endometriosis in first-degree relatives are more likely to have secondary dysmenorrhea [Citation1].
About 10% of young adults and adolescents with dysmenorrhea have secondary dysmenorrhea; the most common cause is endometriosis [Citation10]. Changes in timing and intensity of the pain or dyspareunia may suggest endometriosis, and menstrual flow abnormalities may be associated with adenomyosis or leiomyomata. A history of sexually transmitted infection or vaginal discharge related to dyspareunia raises suspicion for pelvic inflammatory disease (PID). Asking about a history of sexual trauma is also recommended [Citation11].
Primary dysmenorrhea (PD), defined as menstrual pain without an identified organic cause, is estimated to affect between 45% and 95% of menstruating girls and women and is a leading cause of work- and school-related absences [Citation12]. Recent studies have established PD as a potential risk factor for the development of chronic pelvic pain; however, the mechanism through which this process occurs is unknown [Citation13, Citation14].
One proposed mechanism for the transition from cyclical to chronic pelvic pain is central sensitization (CS). CS is characterized by alterations in the central nervous system that increase responsiveness to pain leading to hypersensitivity [Citation15, Citation16]. CS has been shown to play a role in numerous chronic pain conditions, including chronic pelvic pain [Citation17–19]. Specifically, repeated experiences of nociceptive input from the reproductive organs and viscera, as is the case with PD, can result in neuronal hypersensitivity and hyperalgesia and can change how the brain processes pain-related information [Citation15, Citation16, Citation20]. Brain imaging studies have shown altered brain structure and function in women with PD compared to controls, even during non-painful cycle phases [Citation21–23]. And experimental pain paradigms have shown evidence of CS in women with PD as demonstrated by increased pain sensitivity to laboratory stimuli compared to controls. Considering these differences, which appear to be stable across menstrual cycle phases, studying the years between the onset of painful menstruation and the development of chronic pelvic pain could be critical to understanding this transition [Citation24–26]. One previously cited study from Hardi et al. found that the average time between the emergence of dysmenorrhea and consultation with a doctor for dysmenorrhea was 5.1 years. Assessing pain during this time when symptoms are not otherwise recorded or reported may enable the identification of risk factors for the development of chronic pain [Citation13].
The following study aims to show the influence of a 4 mg drospirenone-only pill and 0,075 mg desogestrel used for contraception in the development of dysmenorrhea and mastodynia after nine months of use.
Material and methods
The data are obtained from a phase III study double-blinded, double-dummy randomized controlled trial including 73 primary and secondary gynecological health care centers including university hospitals in Austria, Czech Republic, Germany, Hungary, Poland, Romania, Slovakia, and Spain. The study was performed between August 1, 2012, and January 27, 2014. The protocol was designed and conducted according to existing legal regulations and in accordance with good clinical practice in conducting clinical trials and the declaration of Helsinki, including recommendations made in the European Medicines Agency (EMA) CHMP Guideline on Clinical Investigation of Steroid Contraceptives in Women. Institutional review board approval was obtained for all study sites.
Ethical approval
All participants gave their written informed consent to participate in the clinical trial after obtention of the correspondent ethical committee’s approval.
Ethical approval was obtained for each of the investigational centers. The overall approval for the trial with the leading ethical committee was given the 13.07.2012 by the Landesamt für Gesundheit und Soziales Berlin, Geschaäftstelle der Ethik Kommission des Landes Berlin, number 11/0606 EK.
Study medication
Study medication was DRSP, one tablet of 4 mg non-micronized DRSP per day, via the oral route, with consecutive administration of 24 active pills and four placebo tablets, and no tablet-free interval between 2 successive cycles. The comparator was DSG 0.075 mg in a regimen of 28 active pills. Medication compliance was measured using an electronic diary, providing time and hour for each tablet intake and allowing for calculation of the number of uses of study medication delayed for more than 12 h, i.e. more than 36 h after the last tablet intake.
Study populations
A total of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles were analyzed. Women included in this study were all of the child-bearing potentials, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study medication treatment, aged 18 to 45, with systolic blood pressure (SBP) <140 mmHg, diastolic blood pressure (DBP) <90 mmHg. depicts the clinical data.
Table 1. Demographical data of the study population.
All participants gave their written informed consent to participate in the clinical trial after obtention of the correspondent ethical committee’s approval.
This was a descriptive analysis as both investigated parameters were secondary endpoints of the primary clinical trial. No statistical evaluations were hence performed.
Results
Dysmenorrhea
At screening, 168 (19.6%) of the 858 patients using DRSP and 64 (19,3%) of the DSG patients reported that they had suffered from dysmenorrhea within six cycles prior to the first visit before starting with the medication. At follow-up, only these subjects were asked about the intensity of dysmenorrhea and pain medications used since the first visit. A total of 150, i.e. more than half of these subjects of both groups, reported having no dysmenorrhea anymore.
Mild and moderate intensity of dysmenorrhea prevailed before the study, whereas at follow-up, most patients had dysmenorrhea of mild intensity.
Severe intensity of dysmenorrhea within six cycles prior to study start was documented in a higher percentage in the DRSP group 34 subjects, 20.2%) compared to the DSG group (seven patients, 10.9%). At follow-up severe dysmenorrhea was reported only for one patient in the DRSP group (0.6%) and two (3.1%) patients of the DSG group (see )
Table 2. Development of dysmenorrhea of the evaluated patients.
Medication for pain relief was used by 49 (29.2%) patients before screening in the DRSP group and 15 (23.4%) in the DSG group respectively. At follow up this was reduced to eight women (4.8%) in the DRSP group and three (4.7%) in the DSG group.
Mastodynia
In total, 145 patients (11.2% DRSP group and 14.8% DSG group) experienced mastodynia/mastalgia within six cycles prior to the screening. Of these, 81 patients had no mastodynia/mastalgia at follow up. Mastodynia/mastalgia of severe intensity was reported by five patients (three, 3.1% in the DRSP group and two, 4.1% in the DSG group) at screening, whereas none of the patients reported having severe mastodynia/mastalgia at follow-up. Only two (2.1%) DRSP group patients took medication for pain relief at screening and none of the patients took pain medication at follow up (see ).
Table 3. Devolvement of mastodynia of the evaluated patients.
Discussion
Oral contraceptives are widely advocated as standard treatment for women with primary dysmenorrhea, yet a review from Wong et al. [Citation27] found only scant rigorous clinical evidence to support this practice. The evidence to employ OCPs in clinical practice for dysmenorrhea seems to stem from studies designed to test the contraceptive efficacy of different brands of oral contraceptives or epidemiological studies. A longitudinal epidemiological study of over 500 nineteen-year-old Swedish women who compared the occurrence and severity of dysmenorrhea in those taking combined oral contraceptives with non-oral contraceptives or IUD users is only one of the exiting clinical trials [Citation28]. At age twenty-five, these same women were also re-contacted five years later [Citation29]. The original study showed that those taking OCPs had reduced prevalence and severity of dysmenorrhea compared with non-users. The follow-up study also showed that those women who did not use OCPs in the original survey but were now users had significantly reduced pain. Although changes in parity were controlled for, the overall result could be attributed to the passage of time rather than the efficacy of OCPs for dysmenorrhea.
Another issue that needs to be considered is that oral contraceptives as a treatment for dysmenorrhea do not just depend on their efficacy but also the suitability of oral contraceptives for the woman. If a woman wants a pregnancy or has contraindications to the OCP, then the OCP would be an unsuitable treatment option at that time [Citation27].
In contrast, there are only little data on progestin-only formulations showing a real improvement of dysmenorrhea. These data are almost all in association with endometriosis. Caspar described that using NETA, MPA, and Dienogest significantly reduced the endometriosis-associated dysmenorrhea. All these formulations have no regulatory approval for contraception [Citation30].
Regarding mastodynia, the amount of available data is also very low, so the use of drospirenone represents a step forward in this pathology.
From the historical point of view, medical therapy for breast pain using a drug that proved to be effective for mastalgia is limited to danazol and bromocriptine. Danazol is the only drug approved by the Food and Drug Administration for pharmaceutical treatment for mastalgia. Unfortunately, danazol has a high rate of dose-related androgenic side effects such as depression, irregular uterine bleeding, acne, bloating, and voice changes that result in one-sixth of patients discontinuing use and barrier contraception should be used because of danazol’s teratogenic effect in unexpected pregnancies [Citation31]. These reasons ultimately restrict the use of danazol.
A study using bromocriptine for premenstrual mastalgia resulted in a 54% response rate compared with 19% from placebo [Citation31]. Kaleli et al. could also show that lisurid maleat improved the symptoms of mastodynia. Nevertheless, both anti prolöactin drugs never have been used widely and lack contraceptive efficacy [Citation32]
Dydrogesterone and medrogesterone have been used in a controlled trial by Winkler et al. [Citation33]. They could show that under the use of 10 mg/day from day 14 to day 25 for six cycles, 75% of the patients treated with dydrogesterone and 86% of the patients treated with medrogestone were completely pain-free.
The efficacy of both progestins in dysmenorrhea and mastodynia are probably due to its high progestogenic activity. Krattenmacher [Citation34] described the progestational activity of drospirenone by evaluating the endometrial transformation using ovariectomized rabbits. The results from these animal models are consistent with results from receptor-binding assays and demonstrate that drospirenone has progestogenic activity.
Another reason maybe the fact that both formulations create a reliable endometrial transformation as the transformation dose per cycle is 2 mg for etonorgestrel and 50 mg for drospirenone [Citation35].
The progestins 4 mg and desogestrel 0,075 mg showed a marked effect in the non-contraceptive aspects of dysmenorrhea and mastodynia so that new possibilities are opened for these two benign gynecological diseases. Future studies must reaffirm these first data.
Disclosure statement
Pedro-Antonio Regidor and Enrico Colli are employees of Exeltis.
Funding
The author(s) reported there is no funding associated with the work featured in this article.
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