{"paper_id":"1d12f175-4774-46ed-b448-1a45a0106cb1","body_text":"1 Department of Neuroscience, Obstetrics and Gynecology Unit, Rehabilitation, Ophthalmology, Genetics and Maternal and Paediatric Sciences, University of Genova, 16136 Genova, Italy\n2 Department of Medical Area, Obstetrics and Gynecology Unit, Ospedale S. Maria della Misericordia, Azienda Friuli Centrale, 33100 Udine, Italy\n3 Department of Obstetrics Gynecology and Pediatrics, Obstetrics and Gynecology Unit, Azienda Sanitaria Universitaria Policlinico di Modena, 41121 Modena, Italy\nAbstract\nBackground: In young women, combined hormonal contraceptives can\nameliorate menstrual pain and reduce menstrual loss, but their efficacy in\nadenomyosis has not been proven. The aim of this study was to investigate whether\nultrasound features of adenomyosis are modified by a combined hormonal\ncontraceptive containing dienogest. Methods: Fifty-eight out of 173\npremenopausal women consecutively attending our university hospital outpatient\nservice for contraception were enrolled in this observational study. Women with\nmenstrual pain or heavy menstrual bleeding underwent ultrasonography. An expert\nsonographer diagnosed or excluded adenomyosis and fibroids via morphological\nuterus sonographic assessment (MUSA). The intensity of menstrual pain was\nquantified by each patient on a visual analogue scale (VAS). A total of 38 women\nwith and 20 without ultrasound features of adenomyosis received dienogest-based\nhormonal contraceptive and had a follow-up ultrasound after 6 months of\ntreatment. Results: During treatment, uterine volume decreased\nby –13.1\nKeywords\n- Dienogest\n- Hormonal contraception\n- Ultrasonography\n- Adenomyosis\n- Chronic pelvic pain\n- Heavy menstrual bleeding\nAdenomyosis is a common, debilitating, yet poorly understood gynaecological disease, characterized by ectopic endometrial glands invading the myometrium [1]. It can be either diffuse (adenomyosis), focal or cystic, and localized in any part of the uterus. Risk factors are age, endometriosis, multiple births, uterine surgery, and spontaneous miscarriage [2]. Histological [3] and ultrasound [4] data indicate that the prevalence of adenomyosis ranges from 20% to 45% in asymptomatic and symptomatic women, respectively. Signs and symptoms of the disease are non-specific, and include uterine tenderness and enlargement, abnormal uterine bleeding, menstrual pain and infertility [5, 6].\nRecent data indicate that diagnosis of adenomyosis by 2D trans-vaginal ultrasound has sensitivity and specificity comparable to that of histology or MRI [7, 8, 9, 10, 11]. Diagnosis by sensitive imaging techniques has favoured the tentative search for an effective medical therapy.\nHowever, thus far there is no specific therapy for adenomyosis. Symptom improvement has been achieved by hormone withdrawal at adenomyotic tissue via the administration of GnRH analogues alone [12, 13, 14], or in association with aromatase inhibitors [15], and with an intrauterine system continually releasing levonorgestrel [16, 17, 18] or danazol [19]. Several reports also indicate that the continuous administration of the progestin dienogest reduces symptoms associated with adenomyosis [20, 21, 22, 23, 24].\nHowever, the effect of dienogest on such lesions has scarcely been investigated. In one study, dienogest reduced, to some extent, adenomyotic lesions after 53 weeks of administration [25], while in another it failed to completely block adenomyosis re-growth after suspension of a GnRH-analogue [26]. In young women, combined hormonal contraceptives can ameliorate menstrual pain and reduce menstrual loss, but their efficacy in adenomyosis has not been proven [27, 28, 29]. In this study we therefore set out to investigate whether a medical approach to adenomyosis via the use of hormonal contraceptives containing dienogest actually changes the ultrasound features of the uterus in women with ultrasound signs of adenomyosis, as compared to those without.\nThis is retrospective observational study on premenopausal women, 18 to 50 years of age, attending university hospital outpatient contraception services, each of whom received dienogest-based hormonal contraceptives for at least 6 months. All patients in our clinic routinely sign informed consent to the anonymous use of their clinical data in scientific publications. Data refer to patient management (diagnostic procedures and treatments), performed in accordance with good clinical practice. Diagnostic procedures and treatments are paid partially or completely by the Italian national health system. No incentive is given to the patient. Data are recorded in an electronic database, from where they can be retrieved for retrospective analyses as necessary. Publication of results is approved, as in this case, by the hospital’s internal review board.\nFor the purposes of this study, retrospective data pertaining to 173 women\nconsulting the outpatient service for contraception in the period December\n2016–October 2018 was retrieved. Among the women in question, 95 had been\nsuffering from menstrual pain or abnormal uterine bleeding and had been referred\nfor an outpatient ultrasonographic evaluation to be performed in the follicular\nphase (days 4 to 9) of the menstrual cycle (Fig. 1). For these women, the\nfollowing information were retrieved from the electronic database: age, number of\nbirths, previous uterine surgery, presence of abnormal uterine bleeding, duration\nof menstrual cycle in days, menstrual pain scored on a 0–10 cm visual analogue\nscale (VAS) [28], ultrasound uterine features, presence of pelvic endometriosis,\nand type of contraceptive prescribed. On the basis of their request and medical\neligibility, each woman received either a combined hormonal contraceptive, a\nlevonorgestrel intrauterine system (IUS), an etonorgestrel implant, or a\nprogestin only pill (desogestrel). Data from a follow-up visit and ultrasound\ninvestigation performed after 6 months of treatment were also retrieved. On the\nbasis of baseline ultrasound investigation, the women were divided into those\nwith ultrasound features of adenomyosis (n = 55) and those without ultrasound\nfeatures of adenomyosis (n = 40). Women already on hormones at baseline were\nexcluded (n = 3 with and n = 2 without adenomyosis). Similarly, women who did not\nhave a follow-up ultrasound at six months were not considered in this analysis (n\n= 4 with and n = 8 without adenomyosis). Among those with follow-up ultrasound,\nthe vast majority of women received combined hormonal contraception containing\ndienogest in association with ethinylestradiol or in a quadriphasic association\nwith 17\nFlow-chart of study design. DNG, dienogest.\nUltrasound investigations were performed in an outpatient service for\ngynaecological ultrasound investigation by one experienced sonographer (A.X.),\nwho was blind to the type of treatment the woman was receiving. In our clinical\npractice, blindness is routine so that ultrasound investigations are as objective\nas possible [30]. Specifically, ultrasound was performed by a trans-vaginal\nultrasound (TVS) probe during the proliferation phase of the menstrual cycle\n(days 5–10), using a GE E6 (GE Medical Systems, Zipf, Austria) ultrasound\nmachine and a wideband 5–9 MHz transducer. Power Doppler was performed using\nfixed, preinstalled settings (frequency, 6–9 MHz; pulse repetition frequency,\n0.6–0.3 kHz) to distinguish myometrial cysts from blood vessels. Uterine volume\nwas measured by means of the ellipsoid formula (uterine longitudinal diameter\nUltrasound diagnosis of pelvic endometriosis was performed, in line with the IDEA consensus opinion, by 2D-TVS [31]. Ultrasound diagnosis of diffuse adenomyosis was defined, according to MUSA criteria [11], as the contemporaneous presence of at least two or more of the following features: (1) heterogeneous myometrium, seen as irregular myometrial echo-texture with decreased or increased echogenicity; (2) hypo-echoic striation in the myometrium (fan-shaped shadowing), seen as a pattern of thin acoustic shadows not arising from echogenic foci and/or leiomyoma (Fig. 1); (3) myometrial anechoic lacunae or cysts, seen as a round anechoic areas within the myometrium, hyper-echogenic islands, and sub-endometrial lines and buds (Fig. 2); (4) asymmetrical myometrial thickening of the uterine wall (Fig. 2); (5) globular uterine configuration; and/or; (6) increased uterine volume; (7) presence of a poorly defined, thickened, irregular, interrupted endo-myometrial junctional zone (JZ) [8] (Fig. 2). Information regarding other additional signs such as uterine tenderness and the question-mark or the ear sign were not available in the records [30]. Asymmetrical thickening of uterine walls was defined as thicker posterior or anterior uterine wall, unrelated to leiomyoma. To this end, the ratio between the anterior and posterior wall thickness was calculated. A ratio around 1 indicates that the myometrial walls are symmetrical, while a ratio well above or below 1 indicates asymmetry [11] (Fig. 2). In the selected sample there was no case of focal adenomyosis. The concomitant presence of fibroids was also assessed [11], and the volume of each fibroid was measured by means of the ellipsoid formula.\nThe study was focused on detecting modification of ultrasound parameters of adenomyosis during treatment. A secondary outcome was the clinical response in terms of VAS score for menstrual pain and length of menstrual cycles.\nUltrasund features of adenomyosis. (A) Hypoechoic striation in the myometrium (parallel shadowing), seen as a pattern of thin acoustic shadows. (B) Myometrial anechoic lacunae or cysts, seen as round anechoic areas within the myometrium. (C) Asymmetrical myometrial thickening of the uterine wall. (D) Poorly defined endo-myometrial junctional zone (JZ).\nStatistical analysis was performed using StatView statistical software (version\n5.01.98, SAS Institute Inc., Cary, NC, USA). Descriptive\nanalysis was applied. Comparisons within groups were performed by paired\nt test. The chi-squared test was used to compare changes in prevalence\nover time. As applicable, means or prevalence in the two groups were compared via\nthe Student’s t test or chi-squared test, respectively, as a secondary\nstatistical analysis. A two-tailed p value\nThe study was powered to document a within-group difference in volume between prior to and after 6 months of treatment that was greater than or at least equal to one standard deviation (SD) of the difference. In such a setting, if type I error is 0.05 and type II error is 0.2, 11 cases are sufficient to document an intragroup difference.\nA secondary analysis evaluated other ultrasound features and compared data between women with and without concomitant pelvic endometriosis or with and without adenomyosis.\nAmong the 95 women whose records were retrieved, 55 had ultrasound features\nconsistent with adenomyosis, while 40 women displayed inhomogeneous echo-textured\nmyometrium with no ultrasound features of adenomyosis (Fig. 1). Analysis\nwas performed only on those women with a baseline and 6-month scan who had\nreceived dienogest-based hormonal contraceptives (n = 58) (Fig. 1). Among these\n58, 38 had ultrasound features of adenomyosis and 20 did not. Women received\neither estradiol valerate and dienogest (n = 22 women with adenomyosis and n = 8\nwomen without adenomyosis) or ethinyl estradiol and dienogest (n = 16 with\nadenomyosis, and n = 12 without adenomyosis). The mean age was 36.2\n| Adenomyosis (n = 38) | No adenomyosis (n = 20) | |\n| Age (yrs.) | 36.2 |\n40.3 |\n| Full-term pregnancies (n) | 0.8 |\n1.0 |\n| Women with uterine surgery (n) | 11 (29%) | 0.0 (0%) |\n| Uterine volume (mm |\n84568 |\n80154 |\n| Women with fibroids (n) | 10 (26%) | 4 (20%) |\nUterine volume was 84.509\nModification of Ultrasound Features of Adenomyosis. Ultrasound of the uterus before (A) and after 6 months (B) of therapy.\nDuring the six-month period, in women with adenomyosis uterine volume decreased\nsignificantly by –10.601\n| Before | During treatment | p value | ||\n| Adenomyosis (n = 38) | ||||\n| Ultrasound features | ||||\n| Uterine volume (mm |\n84509 |\n73906 |\n0.001 | |\n| Wall asymmetry (ratio; mm) | 2.8 |\n1.9 |\n0.0001 | |\n| Parallel shadowing (%) | 95 | 0 | 0.0001 | |\n| Myometrial cysts (%) | 8 | 0 | 0.0001 | |\n| Inhomogenous myometrium (%) | 100 | 100 | 0.999 | |\n| Uterus globular configuration (%) | 87 | 87 | 0.999 | |\n| Poorly defined junctional zone (%) | 89% | 89% | 0.999 | |\n| Clinical signs | ||||\n| VAS score for menstrual pain | 7.3 |\n1.9 |\n0.0001 | |\n| Cycle length | 5.3 |\n4.1 |\n0.0001 | |\n| No Adenomyosis (n = 20) | ||||\n| Ultrasound features | ||||\n| Uterine volume (mm |\n80513 |\n104891 |\n0.07 | |\n| Wall asymmetry (ratio; mm) | 1.1 |\n1.2 |\n0.894 | |\n| Parallel shadowing (%) | 0 | 0 | 0.999 | |\n| Myometrial cysts (%) | 0 | 0 | 0.999 | |\n| Inhomogenous myometrium (%) | 75 | 75 | 0.999 | |\n| Uterus globular configuration (%) | 10 | 10 | 0.999 | |\n| Poorly defined junctional zone (%) | 0 | 0 | 0.999 | |\n| Clinical signs | ||||\n| VAS score for menstrual pain | 1.3 |\n0.5 |\n0.0001 | |\n| Duration of menstrual flow (days) | 4.2 |\n3.8 |\n0.0001 | |\nSome sonographic features of adenomyosis were modified by treatment. Hypo-echoic\nstriation of the myometrium (parallel shadowing) was present in 95% of cases and\nmyometrial cysts in 8% at baseline, but both had disappeared completely after 6\nmonths of hormonal contraception (p = 0.0001) (Table 2). The prevalence\nof uterine-wall asymmetry (8/38; 21%) was unchanged after treatment, but mean\nasymmetry decreased from a ratio of 2.8\nThe mean VAS score for menstrual pain was 7.3\nDuring treatment, VAS score for menstrual pain decreased to 1.9\nMenstrual flow duration declined significantly in women both with (from 5.3\nSide effects were few and minor among women who completed the 6 months of therapy. Spotting and breakthrough bleeding occurred in 9.6% of women, with no need for discontinuation. Twelve women on dienogest-based contraceptive did not return at follow-up. Considering the worst-case scenario that all these women had withdrawn due to side effects related to the treatment, continuation rate at 6 months of dienogest-based hormonal contraceptives was 83%.\nThis study shows that treatment with dienogest-based hormonal contraceptive changes ultrasound features of adenomyotic uteri, improving menstrual pain and reducing menstrual flow duration. A certain degree of progesterone resistance in patients with adenomyosis has been reported [32]. Nevertheless, gestodene-containing oral contraceptives are effective in suppressing aromatase expression in the ectopic endometrium of adenomyotic foci, similar to that exerted in the eutopic endometrium [27], and effects of hormone therapy on symptoms related to adenomyosis have been reported in the literature [28, 29].\nRecent data indicate that severity of menstrual pain is associated with ultrasound features of adenomyosis [33]. This is supported by the fact that we detected changes in ultrasound features of adenomyosis and lessened menstrual pain with dienogest-based hormonal contraceptives. Volume reduction of adenomyotic uteri was about –13%. This shrinkage was not the consequence of alterations in any concomitant fibroids, whose volume tended to increase.\nHence, dienogest-based hormonal contraceptives appeared to modify uterus volume by a selective action on adenomyotic tissue. This is supported by the fact that the uterine volume of women without adenomyosis features was not affected. The uterine shrinkage observed was accompanied by the disappearance of the hypo-echoic striation present in 95% of uteri with adenomyosis. Similarly, myometrial cysts, seldom present, completely disappeared, while uterine asymmetry, an indicator of asymmetrical adenomyotic infiltration, was significantly decreased. Concomitantly, endometrial thickness was reduced to below 4 mm.\nAll these findings are consistent with the capability of dienogest treatment to control and reduce the activity of functional endometrium, including that displaced either within the myometrium [32] or outside the uterus [34]. Eighty-three percent of women completed the 6 months of combined treatment, and only 9% reported minor menstrual abnormalities. This contrasts with that recently reported with dienogest alone, where the rate of menstrual abnormalities was considerably higher [35].\nOur findings suggest that dienogest-based hormonal contraceptives can be safely used for long-term treatment of symptomatic adenomyosis, as an alternative to treatments such as GnRH-agonists or aromatase inhibitors, capable of inducing a marked hypo-estrogenic state [12, 13, 14, 15]. A clinical implication of the apparent ability of dienogest-based hormonal contraceptives to alter, though not completely abolish, sonographic landmarks of adenomyosis is that ultrasonographic diagnosis of the disease will be more difficult and less accurate in women taking them. This is information relevant to both clinical and research settings.\nA potential weakness of the study is the lack of histological confirmation of the diagnosis of adenomyosis. However, sensitivity and specificity of ultrasound seems to be comparable to that of histology or MRI [7, 8, 9, 10, 11]. All ultrasound scans were performed using top-of-the-range equipment. In addition, although the study is retrospective, the sonographer was blind to the women’s treatment, as is routine in our clinical practice.\nThe follow-up period was only 6 months, and a longer evaluation period is therefore warranted. The number of cases was limited, although not negligible. Women were treated with two different types of dienogest-based contraceptives, and further research will be necessary to establish whether there are any differences between the two.\nAlthough prospective studies are needed to confirm our data, present findings indicate that dienogest-based hormonal contraceptives improve the ultrasound features of adenomyosis, and reduce menstrual pain and bleeding.\nAX, AC, GG designed the research study. AX, AB performed the research. AC, GG analysed the data. AX wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.\nRetrospective data collection was approved by the internal review board (IRB 7/2019) at our hospital, and each woman signed her consent to the anonymous use of her data in scientific publications.\nThanks to all the peer reviewers for their opinions and suggestions.\nThis study received no external funding.\nThe authors declare no conflict of interest.","source_license":"CC0","license_restricted":false}