Comparative randomized study on the sexual function and quality of life of women on contraceptive vaginal ring containing ethinylestradiol/etonogestrel 3.47/11.00mg or 2.7/11.7mg

The objective of the study was to evaluate the sexual function and quality of life (QoL) of healthy women on a new contraceptive vaginal ring (CVR) containing ethinylestradiol (EE) 3.47 mg and etonogestrel (ENG) 11.00 mg (study group) manufactured with a new polymer composition compared to EE 2.7 mg/ENG11.7 mg CVR (control group). Fifty-eight women were randomly allocated to the study group and the control group. The Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS) and the Short Form-36, were used to assess sexual function, sexual distress and QoL, respectively. The study included two follow-ups, at 90 days and at 180 days. The control group reported more adverse events, mainly breakthrough bleeding, than the study group. The sexual function scores in the women in the study group improved with respect to those of the control group both at the 1st (FSFI, p =.009; FSDS, p =.001) and at the 2^nd (FSFI, p =.001; FSDS, p =.002) follow-up. QoL of the study group improved at the 1^st follow-up (p <.05) and 2^nd (p <.01) follow-up. The control group improved their QoL at the 2nd follow-up (p <.01). The more gradual EE release of the new polymer composition could justify the behavioral differences of the women of the two groups.

本研究的目的是应用一种含有3.47mg炔雌醇（EE）和11.00 mg依托诺孕酮（ENG）的新型避孕阴道环（CVR）后评估健康女性的性功能和生活质量（QoL）, 与对照组CVR（EE 2.7 mg /Eng11.7mg）的不同之处在于该环由一种新的聚合物成分制成。58名妇女被随机分配到研究组和对照组。应用女性性功能指数（FSFI）、女性性痛苦量表（FSDS）及短表-36分别对女性性功能、性痛苦和生活质量进行评估。研究包括两次随访, 分别是90天和180天。对照组报告的不良事件比研究组多, 主要是突破性出血。研究组女性的性功能评分在第一次（FSFI, p=0.009；FSDS, p=0.001）和第二次（FSFI, p=0.001；FSDS, p=0.002）随访时均较对照组有所改善。研究组女性的生活质量在第一次随访（P<0.05）和第二次随访（P<0.01）均有所改善。对照组女性生活质量在第二次随访时才有所改善（P<0.01）。新的聚合物成分释放的EE可以证明两组女性的行为差异。 The Chinese abstracts are translated by Prof. Dr. Xiangyan Ruan and her team: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.

Keywords: Contraceptive vaginal ring; CVR polymer composition; FSFI; quality of life; sexual activity

In the field of oral contraception new active formulations, new regimens [[1]], and route of administration such as intravaginal monthly applied method [[4]] have been realized. However, as regards vaginal contraception, until recently, there has only been one contraceptive vaginal ring (CVR) (NuvaRing®, Msd, Italy) containing 2.7 mg of ethinylestradiol (EE) and 11.7 mg of etonogestrel (ENG); it has an external membrane of ethylene vinylacetate, containing 9% vinylacetate, through which 15 µg of EE and 120 µg of ENG are released daily [[5]]. After placement, the ring is kept in the vagina, on average, for a 3-week period of use, followed by a 1-week ring-free period, according to a traditional hormonal contraceptive (HC) regimen [[6]]. Withdrawal bleeding is to be expected within 2–3 days of ring removal. Subsequently, a new ring is placed and the cycle is repeated [[7]].

A similar combined contraceptive vaginal ring having an external membrane of ethylene vinylacetate, containing 28% vinylacetate has been recently introduced (Kirkos®, Farmitalia s.r.l., Catania, Italy). Although it contains different dosages of ENG (11.00 mg) and EE (3.47 mg) compared to Nuvaring, the average hormonal release from both rings is the same (15 µg/day of EE and 120 µg/day of ENG) [[8]]. However, because of the different polymer composition of the external membrane, Kirkos is more stable and the release of the hormones is more gradual on the first days of use, in contrast to the burst observed with the Nuvaring [[8]].

Based on our preliminary data on sexual function and the quality of life (QoL) of women on CVR [[9]], the objective of this investigation was to evaluate the quality of sexual life of healthy women on Kirkos (study group) compared to those using Nuvaring (control group), by a randomized study design.

Seventy-eight women aged 18–37 years, seeking an HC for fertility control at the Family Planning Center of the Research Group for Sexology, Department of General Surgery and Medical Surgical Specialties, School of Medicine, University of Catania, Italy, were invited to participate in this study. The women were not using any kind of HC, and showed no contraindications to HC use. Women who were sexually active and without sexual dysfunction received a proper counseling on the benefits and risks of using a CVR. The study conformed to the ethical guidelines of the 1975 Helsinki Declaration. The study was authorized by the ethics committee of the department. Informed written consent was obtained from each woman before entering the study, and they did not receive payment of any kind.

According to a computer-generated list to randomize participants 1:1, each woman was allocated to the study or the control group.

Clinical characteristics, such as Body Mass Index, age at menarche, menstrual frequency and duration, pain symptoms, parity and vital parameters were evaluated and compared between the groups. Moreover, demographic characteristics such as educational levels and professional situation of both the groups were considered.

Each subject received a diary to record daily sexual events as well as adverse events (AEs) during CVR usage. In addition, any events that were considered directly related to CVR use, such as vaginal discomfort and breakthrough bleeding, were recorded. Subjects who withdrew from the study were asked to classify their reason for withdrawal.

To measure the level of sexual behavior the self-administered Female Sexual Function Index (FSFI) validated in the Italian gynecological population was used [[10]]. The FSFI is composed of 19 questions grouped in six domains: desire (items 1 and 2), arousal (items 3–6), lubrication (items 7–10), orgasm (items 11–13), satisfaction (items 14–16) and pain (items 17–19). Each question has a Likert scale score varying from 0 to 5. The total FSFI score is the sum of all scores obtained in each domain. Scores range from a minimum of 0 (corresponding to the lack of sexual activity) to a maximum of 6 (corresponding to full sexual function). Total score goes from 0 to 36; a cutoff of ≤26.55 is usually accepted for diagnosis of sexual dysfunction. Moreover, for diagnosis of sexual dysfunction, an essential element is that the condition causes significant personal distress for the woman. Therefore, the Female Sexual Distress Scale (FSDS) was used [[11]]. The FSDS consists of 12 items. The maximum score is 48. An FSDS score of ≥11 corresponds to clinically significant distress. We considered women with an FSFI score of less than 26.55 to be affected by sexual dysfunction if they also had an FSDS score of 11 or greater.

The Short Form-36 (SF-36) validate questionnaire was used to assess QoL [[12]]. It contains 36 questions grouped into eight categories: physical functioning (10 items), physical role functioning (4 items), bodily pain (2 items), general health (6 items), vitality (4 items), social functioning (2 items), emotional role functioning (3 items) and emotional well-being (5 items). Women were instructed to place a mark on a 0–100 Likert scale for each item that best represented their feelings symbolized on the scale, from the lowest to the highest score of a given category of QoL. Thereafter, the sum of all items of each category was used to asses QoL and mean values were calculated on the basis of individual items within a given category. Eight scale scores were obtained: higher scores indicated a better functioning.

Finally, the Visual Analogic Scale (VAS) [[13]] was used to define premenstrual syndrome and dysmenorrheal symptoms. Women were instructed to place a mark on a 0 to 100 scale, 0 representing absence of pain and 100 indicating unbearable pain.

All the participants were instructed to insert the first vaginal ring during the first 5 days of the cycle, and to use it for a standard 28-day cycle, each cycle having 3 weeks of ring use followed by one ring-free week. After the ring-free week interval, a new ring had to be inserted. The 1st and the 2nd follow-ups were performed after the 3rd (on 90 days) and 6th (on 180 days) vaginal ring usage, respectively.

All questionnaires were administered at baseline, and at the 1st and the 2nd follow-up visits.

ANOVA was used to compare the demographic and clinical data between the two groups. Paired Student's t test was used to compare the within group values obtained at baseline with those of follow-ups from the FSDS, SF-36 domains and VAS. For comparisons of the intragroup values obtained from the FSFI items between baseline and both the follow-ups, the nonparametric Wilcoxon rank-sum test was used; and to compare the intergroup FSFI scores, the Mann-Whitney U-test was used. Scores are presented as mean ± SD. Intention-to-treat analyses were performed for all efficacy variables with the last observation carried forward for patients who prematurely discontinued treatment. All women who had a baseline evaluation and at least one efficacy assessment after the baseline examination/interview were included in the analysis. The result was statistically significant when p < .05. Statistical analyses were carried out using the Primer of Biostatistics statistical computer package (Glantz SA, New York, USA: McGraw-Hill, Inc.1997).

Seventy-eight women were invited to participate in the study. Among them, 20 (25.6%) refused to use a CRV, choosing to adopt an oral contraceptive or intra uterine device. Consequently, 58 (74.4%) women were randomized to the study group (on Kirkos; n = 29) or the control group (on Nuvaring; n = 29).

Fifty-four women performed the 1st follow-up visit on day 90, 29 of the study group and 25 of the control group. In fact, the study group reported mild adverse events that did not cause discontinuation, namely breakthrough bleeding (n = 2; 6.9%) and breast tenderness (n = 4; 13.8%), arising during the 2nd cycle of CVR use. Women in the control group reported moderate adverse events, namely, breakthrough bleeding (n = 6; 20.6%), nausea (n = 5; 17.2%) and breast tenderness (n = 7; 24.1%), arising during the 1st cycle of CRV use, causing discontinuation in 4 (13.8%) of them. Finally, at the 2nd follow-up visit on day 180, 46 women completed the study, 26 of the study group and 20 of the control group. In fact, 3 (10.3%) and 5 (17.2%) women of study group and control group, respectively, did not show at the end study evaluation. Interestingly, 4 (13.8%) women in the study group referred breast tenderness, and 2 (6.9%) and 3 (10.3%) women in the control group had bleeding and nausea, respectively, that did not cause discontinuation. However, based on intention-to-treat analyses, they were included in the analysis. The intensity of withdrawal bleeding was reported to be mild to moderate by both groups, and no amenorrhea was reported.

Table 1 shows the absence of both clinical and demographic differences between women in both groups (p < .05).

Table 1. Demographic characteristics.

Table 2 shows the intra and intergroup statistical analysis of monthly frequency of sexual activity at baseline and at both the follow-ups.

Table 2. Monthly frequency of sexual activity at baseline and during the first and second follow-ups of use of the contraceptive vaginal ring Kirkos® (study group) and NuvaRing® (control group).

1 Paired Student's t test.

• 2 Non-paired Student's t test.
• 3 Values are means ± SD.

Table 3(A) shows the intergroup statistical comparisons of the FSFI and FSDS scores. The scores of the study group were improved with respect to those of the control group, both at the 1st (FSFI, p = .009; FSDS, p = .001) and at the 2nd (FSFI, p = .001; FSDS, p = .002) follow-up.

Table 3A. Intergroup analysis of the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS) scores at baseline and during the first and second follow-ups of use of the contraceptive vaginal ring Kirkos® (study group) and NuvaRing® (control group).

• 4 p values determined by Mann-Whitney U-test.
• 5 Non-paired Student's t test.
• 6 Values are means ± SD.

Table 3(B) shows the intragroup statistical analysis. At the 1st follow-up lubrication and orgasm of women in the study group improved (p < .05); interestingly, at the 2nd follow-up all items improved (p < .001). On the contrary, no FSFI item of the control group changed at the 1st follow-up (p=NS), while desire (p < .01), orgasm (p < .01), satisfaction (p < .004) and pain (p < .02) improvement was recorded at the 2nd follow-up. Finally, the FSFI total score and FSDS score of both groups improved in both follow-ups (p < .001).

Table 3B. Intragroup analysis of the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS) scores at baseline and during the first and second follow-ups of use of the contraceptive vaginal ring Kirkos® (study group) and NuvaRing® (control group).

• 7 p values determined by non-parametric Wilcoxon's rank sum test.
• 8 Paired Student's t test.
• 9 Values are means ± SD.

Figure 1 shows the SF-36 scores. The study group reported QoL improvement at the 1st (p < .05) and at the 2nd (p < .01) follow-ups. The control group had improvement of QoL at the 2nd follow-up (p < .01).

Graph: Figure 1. Intragroup analysis of the quality of Life categories at baseline and during the first and second follow-ups of use of the contraceptive vaginal ring Kirkos® (study group) and NuvaRing® (control group).

Figure 2 shows the percentage of the improvement of the premenstrual syndrome and dysmenorrhea of women of both groups. Even if the women of the study group had a better improvement of premenstrual syndrome and dysmenorrhea (p < .001) than the women of the control group, the intergroup analysis was not statistically significant (p < .05).

Graph: Figure 2. Premenstrual syndrome and dysmenorrhea of women on Kirkos® (Study group) or on Nuvaring® (control group) before and at 90 and 180 day follow-ups. *p < .001.

This randomized and controlled study investigated and compared the sexual health and the quality of life and safety of two groups of women using 21/7 regimen CVR containing EE/ENG 3.47/11.00 mg (Kirkos, study group) or EE/ENG 2.7/11.7 mg of ENG (Nuvaring, control group) for 180 days. The women underwent two follow-ups, at 90 days and 180 days after baseline evaluation, using two different contraceptive vaginal rings for 6 cycles of 21/7 days. The main limit of our study was the small number of the sample in both groups. Another limit was the lack of EE plasma measurement. In fact, these data could have allowed us to make a correlation between sexual activity and fluctuation of the sexual steroid.

Unlike the study group where bleeding was mild, in the control group the breakthrough bleeding rate was moderate and caused discontinuation in 13.8% of women. This discrepancy in breakthrough bleeding rate and frequency between the two groups could depend on the different polymer composition of the two vaginal rings. In fact, by pharmacokinetic bioequivalence studies the steroidal release, particularly for EE, has been shown to be more gradual in women on Kirkos than on Nuvaring, without the burst phenomenon in the first days once the ring is inserted [[8], [14]].

Regarding sexual health, a better improvement was observed in the study group than in the control group. Furthermore, the monthly frequency of sexual activity increased more in the study group than in the control group. It is important to remember that both the groups were constituted by women without sexual dysfunction, who were seeking an HC for fertility control alone. This could be a limit of the study given that the role of HC by means of a vaginal ring on any changes in the sexual function of women who have sexual disorders due to the fear of an unwanted pregnancy was not investigated [[16]].

Assessment of QoL is believed to be a crucial parameter to take into account before concluding on the efficacy of drug intake. In this investigation, the study group had a faster improvement of QoL than the control group. On the contrary, at the 2nd follow-up both groups reached similar psychophysical wellbeing.

It would seem difficult to consider these differences in sexual behavior and in QoL between the two groups as depending on hormonal effects between the two vaginal systems. In fact, even if the two rings contain different dosages of EE and ENG, the average hormonal release from both systems was shown to be the same, 15 µg of EE and 120 µg of ENG daily [[8]].

Plasma estrogen levels of women on HCs usually undergo a reduction, and the sexual effects of the steroid depend on the quantity and quality of estrogen, and on the type of progestin [[17]], and finally on the administration route [[18]]. We showed that OCs containing 15 µg EE, the same dosage contained in the CVR, negatively influenced female sexual behavior, reducing genital arousal and desire and mainly increasing dyspareunia [[1]]. On the contrary, dyspareunia may improve in women on OCs having ≥ 20 µg EE [[19]]. Even if the CVR releases on average 15 µg/day of EE, the improved lubrication could be due to the local activity of EE before it enters the systemic blood flow and is metabolized [[1]].

The CRV that we wanted to investigate is of recent production, thus the above aspects defined as limits may be the objective of future studies.

The authors wish to thank the Scientific Bureau of the University of Catania for language support.

No potential conflict of interest was reported by the authors.