The clinical effect of dienogest on urinary and sexual symptoms in endometriosis patients

Endometriosis is a female reproductive system disorder in which the organs and space outside the uterus such as the peritoneal cavity, ovaries etc, become implanted by endometrium-like tissue, 1 while affecting almost 10% of women of childbearing age. 2 The implanted tissue resembling the endometrium leads to a chronic inflammation condition affecting structures such as the recto-vaginal septum, uterosacral ligament, and bladder, causing dysmenorrhea, dyspareunia, chronic pelvic pain, infertility, and lower urinary symptoms. 3 Accordingly, studies have investigated the association between endometriosis and pelvic symptoms such as sexual dysfunction or lower urinary tract symptoms (LUTs). An increasing body of literature has depicted that women with endometriosis have lower sexual quality of life including sexual functioning and satisfaction, as well as deep dyspareunia. 4 In clinical settings, radical laparoscopic excision of endometriosis is used as an option to provide some improvement in dyspareunia and quality of sexual life. 5 , 6 Additionally, Buggio et al 7 have discussed the importance of integrating psychological interventions and sexual therapy in the treatment of endometriosis. Furthermore, urinary tract symptoms have also been investigated in endometriosis patients. Gabriel et al, 8 2020 demonstrated that women with surgically confirmed endometriosis are more likely to report several LUTs than those without, with urinary problems such as overactive bladder (OAB) syndromes or urinary incontinence occurring. Miller and Fraser 9 showed that the change in pelvic sensation is the main cause of endometriosis patients the higher prevalence of LUTs. Both disorders lead to alterations in local innervation. Prior studies have shown that pelvic innervation is altered in endometriosis-affected women with a higher density of autonomic, sensory C, and A delta nerve fibers detected within endometriotic lesions. 9 Interestingly, few studies have investigated whether the improvement of endometriosis could help with urinary concerns, 8 and none have focused on urinary symptoms and sexual function together; consequently, we intended to use dienogest (DNG), a progestin medication used in birth control pills and for the treatment of endometriosis, to ameliorate sexual dysfunction and urinary incontinence. The aim of this study was to assess endometriosis-related pelvic pain, lower urinary symptoms, and sexual function after a 6-month treatment with DNG in women with endometriosis, with the hope that treatment of endometriosis-related irritative urinary symptoms using DNG might improve dyspareunia or sexual dysfunction in these patients.

The longitudinal study was performed from January 2017 to January 2019 at Kaohsiung Medical University Chung-Ho Memorial Hospital. The study population (22 women) affected by chronic pelvic pain with a clinical diagnosis of endometriosis (dysmenorrhea, deep dyspareunia, and dyschezia) accompanied with irritative urinary symptoms including frequency and urgency were enrolled. We made a nonsurgical diagnosis of endometriosis based on ESHRE guidelines (Table 1 ) as below. In brief, the diagnosis of endometriosis mainly focused on vaginal examination and the transvaginal ultrasound was conducted in each patient. Diagnosis procedure of enrolled patients criteria They had undergone transvaginal ultrasound (US) to identify endometriosis, deep endometriosis, ovarian endometrioma, or adenomyosis. The exclusion criteria were as follows:women who had: (1) undergone a therapeutic surgical procedure in the past 6 months; (2) received GnRH analog treatment; (3) had undiagnosed abnormal menstrual bleeding; (4) a history of nonorganic sexual dysfunction; (5) urinary tract infection; (6) chronic diseases (cancer, hepatitis, cirrhosis, coronary artery disease, congenital heart disease); (7) kidney diseases; (8) diabetes mellitus; (9) arterial hypertension (defined as systolic blood pressure >140 mmHg and diastolic blood pressure >95 mmHg); (10) renal or metabolic diseases; and (11) were pregnant. The participating patients took a daily dose of 2 mg DNG for 6 months without discontinuation and underwent outpatient visits at the beginning, 1, 2, 3, and 6 months following treatment. The study was approved by the Research Ethics Committee of the Kaohsiung Medical University Hospital. The patients were required to complete validated Chinese versions of questionnaires, including the Visual Analog Scale (VAS) scored from 0 to 10 to assess endometriosis-associated pain, specifically chronic pelvic pain, dysmenorrhea, and dyspareunia, with VAS scores evaluated after 1, 2, 3, and 6 months of treatment; the Overactive Bladder Symptom Score (OABSS) 11 , the Urogenital Distress Inventory (UDI-6) 12 , and the Incontinence Impact Questionnaire (IIQ-7). 13 The OABSS included four items: daytime frequency (0-2), nocturia (0-3), urinary urgency (0-5), and urinary incontinence (0-5). The UDI-6 questionnaire was used to screen for stress, irritative, and obstructive symptoms and included six items: (1) urinating frequently (0-3), (2) leakage related to a sense of urgency (0-3), (3) leakage related to activity (0-3), (4) coughing or sneezing causing small amounts of leakage (0-3), (5) difficulty emptying the bladder (0-3), and (6) pain or discomfort in the lower abdomen or genital area (0-3). Higher UDI-6 scores represent higher levels of disability. Finally, the IIQ-7 questionnaire examined how these symptoms affected patients’ quality of life (QoL) in terms of physical activity, travel, social relations, and emotional health. Assessment of sexual function was performed using the Female Sexual Function Index (FSFI) questionnaire, which has been validated in Chinese gynecological populations. 14 , 15 This instrument consists of six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain, each scored from 0 (no sexual activity) to 5 (always/very high). A score is calculated for each domain, and the total score is obtained by summing all items. A cutoff of <26.55 is commonly accepted for the diagnosis of sexual dysfunction. 10 The OABSS, UDI-6, IIQ-7, and FSFI questionnaires were collected at the beginning and 6 months after treatment. Serum estradiol levels were also evaluated before and after 6 months of treatment. The data were reported as means ± SD. IBM SPSS Statistics 20 and the paired sample t-test were used for comparison between the two groups, with differences considered statistically significant at p < 0.05.

Table 2 shows the baseline demographic characteristics of the study groups. The 22 women diagnosed with endometriosis had a mean age of 39.6 years, a mean body mass index (BMI) of 22.5 kg/m², and a mean parity of 1.5. Two patients had diabetes mellitus, and four had hypertension (Table 2 ). Demographic data of enrolled patients BMI = body mass index. We first evaluated pelvic pain using VAS score (Fig. 1 ). Our data showed that the VAS score changed from 6.57 to 2.27 in the first month after treatment, while the VAS scores of the second, third, and sixth months after treatment were 1.7, 1.02, and 1.06, respectively, indicating significant improvement in the VAS score from the first month till the sixth month ( p < 0.001). Changes of VAS scores at baseline, 1, 2, 3, and 6 mo posttreatment of dienogest. VAS = Visual Analogue Scale. The line chart showed the change in VAS score treating dienogest 2mg/day for 1, 2, 3, and 6 months. Data are presented as mean. * p < 0.001, significantly different from baseline in VAS. Urinary symptoms were also evaluated in our study. Our data showed that the OABSS, UDI-6, and IIQ-7 scores decreased from 3.3 ± 2.3 to 2.4 ± 1.5 (p = 0.035), from 2.7 ± 2.5 to 2.0 ± 1.9 (p = 0.028), and from 2.7 ± 3.6 to 1.2 ± 1.7 (p = 0.038), respectively. The data showed a statistically significant improvement after 6 months of treatment with 2 mg DNG. In addition, serum estradiol levels significantly decreased from 84.6 ± 5.6 to 32.3 ± 5.8 pg/mL after 6 months of 2 mg DNG treatment (Table 3 ). Urinary-related questionnaire results at baseline and 6 mo posttreatment of Dienogest Values are expressed as mean ± SD or numbers. IIQ-7 = Incontinence Impact Questionnaire; OABSS = Overactive Bladder Symptom Score; UDI-6 = Urinary Distress Index. Statistical significance; paired t test. The effect of DNG on sexual function in endometriosis is shown in the FSFI scores obtained at baseline and after 6 months of DNG treatment. At baseline, the mean total FSFI score was 23.9 ± 6.2, which indicated sexual dysfunction (FSFI <26.55), with desire being the lowest domain (mean score of 2.5 ± 1.0). After 6 months of DNG treatment, no significant differences were observed in any FSFI domains or the total FSFI score (Table 4 ). Changes of FSFI scores at baseline and 6 mo posttreatment of dienogest Values are expressed as mean ± SD or numbers. FSFI = Female Sexual Function Index. Statistical significance; paired t test. Some adverse effects were also recorded after the treatment of DNG, as the following charts indicate effect of DNG on menstruation (Fig. 2 ). The effect of dienogest on menstruation at baseline, 1, 2, 3, and 6 mo posttreatment. The bar chart shows the number change of menstruation situation with treatment of dienogest 2 mg/die for 1, 2, 3, and 6 months. Data are presented as number of patients. Our data showed that some patients with heavy menstruation revealed improvement; however, some patients with regular period missed or dropped a period after treatment of DNG, while other adverse effects are also shown (Fig. 3 ). The adverse effects of dienogest at baseline, 1, 2, 3, and 6 mo posttreatment. Some adverse effects included headache, nausea, depression, swollen breast, weight gain, acne vulgaris, gastritis, bloat, abdominal pain, pharyngitis, and vaginal spotting all recorded at different times following treatment. Data are presented as number of patients.

Previous literature has demonstrated that endometriosis greatly affects the quality of sexual life. 16 Therefore, a treatment that can improve the symptoms is urgently needed. The daily use of DNG has been approved for the clinical treatment of endometriosis, 17 with its mechanism of action including antiproliferative, immunological, and antiangiogenic effects that contribute to the reduction of endometriosis-associated symptoms. Our study included 22 women suffering from endometriosis-related pelvic pain and irritative urinary symptoms. The treatment of 2 mg DNG daily for 6 months significantly improved urinary incontinence. Ekin et al 18 observed an association between urinary tract dysfunction (UTD) and adenomyosis. They found a higher incidence of irritative symptoms, including urgency and frequency, in patients with adenomyosis, indicating that the causes of UTD tend to be related to cytokine factors. 18 They also demonstrated that the levonorgestrel-releasing intrauterine system used for treating menorrhagia and dysmenorrhea improved urinary incontinence along with irritative and obstructive symptoms in patients with adenomyosis. 19 In our study, we validated that endometriosis sufferers revealed improvement on OAB symptoms following treatment with 2 mg DNG daily for 6 months, further improving urinary symptoms and quality of life. It is unknown whether the presence of urinary symptoms is related to bladder endometriosis. Bladder endometriosis occurs in approximately 2% to 6% of patients with endometriosis, and localized bladder wall thickening represents the main diagnostic criteria. 20 In our study, none of the patients in the adenomyosis group had hematuria or were classified as bladder endometriosis under US examination. Endometriosis on the pelvic peritoneum of the bladder and uterosacral ligaments could be attributed to neurogenic dysfunction leading to lower urinary tract symptoms. 21 Several studies have investigated the effects of DNG in women with endometriosis, with data confirming that DNG ameliorates pelvic pain and improves quality of life. 22 , 23 Some research has also revealed that treatment of DNG on main blood hormone concentrations has had effect on timing for discontinuation of DNG in climacteric patients suffering from endometriosis and adenomyosis. 24 Takagi et al 24 showed that for oral administration of DNG for 2 mg/d for more than 12 months where serum estradiol and follicle-stimulating hormone (FSH) levels were measured after 3 to 6 months revealed FSH levels in three patients increased during DNG administration accompanied with reduction of E2. These data were similar to ours on serum E2 (Table 2 ). A recent study also revealed that a 12-month period of DNG showed improvement on FSFI score 25 ; however, our data did not reveal the same trends as their data and we suggest that the mean ages of this (28 ± 8) and our (40 ± 8) study might be the key point which led to the difference in FSFI result. Some increasing evidence also indicated that urinary concerns might affect sexual function and quality of life. 26 , 27 We had expected progressive reduction of the pain syndrome and lower urinary symptoms might accompany improvement of quality of sexual life. A study with a longer treatment period is required for confirmation. Even though the mean VAS score in the study decreased progressively over all the treatment period, the quality of sexual life did not recover as per our expectation. One possible explanation is that dyspareunia or pelvic pain, a frequent complaint from women with endometriosis, is not the only determinant of sexual function. Sexuality is a complex issue and is influenced by many features and organic dyspareunia is only one factor among several elements in sexual function. Psychological dimensions such as fear and anticipation of pain are powerful contributors to low desire, while lack of communication about sexuality and avoidance of sexual intercourse are other possible causes for problems in the relationship. A recent systematic review also stated that women with endometriosis not only reported significantly lower sexual satisfaction but also showed some impact on partners. It seems certain that endometriosis does affect a couple’s relationship, but no research has investigated any such correlation yet. 28 In our opinion, psychosocial support including sexual and couple therapy might be beneficial. A continuous treatment of DNG created a hyper-progestogenic and moderate hypoestrogenic endocrine status. In our study, circulating estradiol level significantly decreased after a 6-month treatment, which may decrease sexual function. Women’s sexual desire is subject to hormonal influence, and gradual and age-related cessation of ovarian function decreases levels of estradiol accompanied by diminished sexual desire in a significant portion of postmenopausal women 29 , 30 ; similarly, women who undergo bilateral oophorectomy have reported a postoperative decline in sexual desire, 29 , 30 although estrogen-only therapies that produce periovulatory levels of circulating estradiol are found to increase sexual desire. 31 , 32 Estradiol promotes sexual desire by affecting the central nervous system, and these effects are likely moderated by peripheral actions of estradiol, acting directly on genital regions such as the vaginal walls to increase lubrication. 31 In our study, although endometriosis-related pelvic pain and irritative urinary symptoms had both improved 6 months after treatment, the low level of serum estradiol might be one of the contributors to persistent low sexual desire and sexual function, although this is only a 6-month assessment. Caruso et al 33 showed that with long-term use of DNG for 2 years, the FSFI scores did not change at the 3-month follow-up but improved from 6 to 24 months, with FSDS scores also showing a similar trend. Importantly, indexes such as desire in FSFI slightly decreased, which bears resemblance to our study in 6 months of follow-up, although our data slightly decreased in almost every index with no significant change at the 6-month follow-up point. We suggest that the difference between our results could be attributed to the age of the patients and our opinion is that the beneficial effect of DNG on sexual function might show in a longer-term follow-up of 12 months or more. There are some limitations in our study, mainly being that it is not a randomized controlled trial and it lacks a comparison control group; furthermore, the lack of laparoscopy to confirm endometriosis means our diagnoses are based on clinical findings. Endometriosis and interstitial cystitis/painful bladder syndrome share similar symptoms. 34 Even though we performed transvaginal US to identify pelvic endometriosis or adenomyosis, because interstitial cystitis can be difficult to distinguish from endometriosis, there is a possibility of an evil twins syndrome. 35 Additionally, the sample size was small and a 6-month follow-up might be too short to lead to a definitive consequence. Probably a longer period without pelvic pain could lead to a greater awareness of being able to experience sexuality without discomfort. Besides, some studies have also investigated the DNG effect on VAS score and menstrual bleeding. Caruso et al 33 demonstrated that oral administration of 2 mg/d partially improved the quality of life from three months and improved in all categories from 6 to 24 months. Our data also showed a similar trend in VAS score (Fig. 1 ). Jensen et al 36 depicted that treatment of DNG and estradiol valerate could significantly alleviate heavy menstrual bleeding from 120 to 40 mL/cycle. Our data also demonstrated a similar trend where heavy menstruation in endometriosis could be ameliorated by treatment of DNG although some cases in our study missed a period (Fig. 2 ). The results mentioned above suggest that our data still holds possesses valid significance to this field. To summarize our current study, we integrated our own data with previous literature to provide a possible mechanism of DNG on urinary symptoms in endometriosis. Previous studies have shown that endometriosis is a chronic inflammatory disease characterized by increased numbers of immune cells and their downstream cytokines. 37 – 39 The local inflammation caused by endometriosis induces sensory C and A nerve fibers to develop higher density within endometriotic lesions. 8 The upregulation of pelvic sensation creates urinary symptoms or some pelvic disorders. Our data revealed that DNG could ameliorate endometriosis-induced upregulation of OABSS, UDI-6, and IIQ-7 total scores, while also decreasing VAS scores and improving heavy menstrual bleeding caused by endometriosis (Fig. 4 ). We suggest that the therapeutic effect might come from its anti-inflammatory activity. Hypothesis diagram of dienogest on endometriosis-related urinary symptoms and adverse effects. Women with endometriosis showed a hyperinflammatory condition and increased numbers of immune cells, while the production of inflammatory cytokines stimulated the increase of sensory C and A nerve fibers, then the upregulation of these sensory nerve fibers led to urinary symptoms or other pelvic disorders. The daily administration of DNG for 6 mo might ameliorate endometriosis-induced upregulation of OABSS, UDI-6, and IIQ-7 total scores while also decreasing VAS scores and improving heavy menstruation caused by endometriosis. IIQ-7 = Incontinence Impact Questionnaire; OABSS = Overactive Bladder Symptom Score; UDI-6 = Urogenital Distress Inventory; VAS = Visual Analogue Scale. In conclusion, a 6-month short-term treatment for endometriosis with DNG appears to relieve pelvic pain and irritative urinary symptoms, although it has limited impact on sexual function despite improvement in the degree of minimizing sexual pain. Further studies with longer treatment duration and follow-up might elucidate this issue.

This research was funded by Kaohsiung Medical University Chung-Ho Memorial Hospital, grant number KMUH110-0R42 and KMUH111-1R40.