The effects of vaginal bromocriptine and dienogest on women with adenomyosis: a clinical study

Objective Adenomyosis occurs when endometrial glands and stroma develop in the myometrium, leading to symp- toms such as pelvic pain and heavy menstrual bleeding.

This randomized, double-blinded, controlled trial study was conducted on patients with adenomyosis referred to the Rasul-e-Akram Hospital. Group A received vaginal bromocriptine, and group B received dienogest. Transvaginal ultrasonography (TVS), visual analog scale (VAS), and pictorial blood loss assessment chart (PBLAC) evalu- ation were performed at the beginning and after 3, 6, and 9 months of the study.

The mean blood visual chart 3 and 6 months after intervention in the bromocriptine group was significantly lower than the dienogest group (P < 0.001). The mean intensity of menstrual pain 3 months after intervention was sig- nificantly lower in the dienogest group compared to the bromocriptine group (P < 0.001). There was a significant improvement in TVS appearance in both groups at the 6-month follow-up.

Dienogest and bromocriptine both effectively reduced pain intensity, menstrual bleeding, and sono- graphic characteristics in patients with adenomyosis.

Adenomyosis, Dienogest, Bromocriptine, Menstrual bleeding, Pain

Adenomyosis is a benign gynecologic disease in which stroma and endometrial glands are found in the myo - metrium. Symptoms in women with adenomyosis are heavy menstrual bleeding and pelvic pain [3, 7]. The precise etiology of this disease is obscure, but two pri - mary hypotheses have been considered, invagination of the endometrial basalis due to the activation of the tis - sue injury and repair (TIAR) and metaplasia of displaced embryonic multipotent Mullerian remnants or differen - tiation of adult stem cells [6]. Diagnosis of adenomyo - sis is based on surgery and histopathology, but recently, diagnosis and treatment can be achieved through diag - nostic methods such as TVS and magnetic resonance imaging (MRI) [2–4, 6, 7, 17, 18]. Prolactin (PRL), being a mitogen of uterine muscle cells, is considered a risk fac - tor for adenomyosis [2]. Bromocriptine, an ergot alkaloid that suppresses pituitary prolactin synthesis [19], can alleviate adenomyosis symptoms. Vaginal bromocrip - tine can be as effective as the oral form without gastro - intestinal and other side effects [5], and reduces pain and severe menstrual bleeding in women with adenomyosis [3]. Bromocriptine might have antiproliferative activity *Correspondence: Samaneh Rokhgireh [email protected] 1 Department of Obstetrics and Gynecology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran 2 Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran 3 Department of Artificial Intelligence, Smart University of Medical Sciences, Tehran, Iran Page 2 of 8Bahoorzahi et al. Middle East Fertility Society Journal (2024) 29:55 by inhibiting gene expression due to activating several miRNA expressions [10]. Dienogest is a highly selective progesterone with anti - proliferative effects, and there is evidence that it is highly effective in alleviating adenomyosis pain. However, it can cause menorrhagia, and in rare cases of menometrorrha - gia, it may cause severe anemia in patients with adeno - myosis, necessitating drug discontinuation [16]. Given the significance of adenomyosis in women’s health and the limited research comparing the effects of bromocriptine and vaginal dienogest, this study was designed and conducted. The main focus of the study was to compare the therapeutic efficacy of vaginal bro - mocriptine and dienogest in reducing menstrual bleeding and pain associated with adenomyosis and to describe related TVS characteristics in patients referred to Rasul- e-Akram Hospital.

This randomized, double-blinded, controlled trial study was performed on 60 women with adenomyosis referred to Rasul-e-Akram Hospital of Iran University of Medical Sciences from 2021 to 2023. The study was explained to the participants, and informed consent was obtained by a gynecology resident, indicating their voluntary agree - ment to participate. The regional Ethics Committee of the Iran University of Medical Sciences approved the study with the Ethical Code IR.IUMS.FMD.REC.1400.361 and IRCT20230407057838N1. The patients’ personal infor - mation remained confidential and was identified with a code; only the gynecologist had the patients’ informa - tion. In case of side effects in the patients after taking dienogest or vaginal bromocriptine, the intervention was stopped, and alternative treatments were initiated. The expected sample size (n = (Z1 − α/2 + Z1 − β)2 / (δ12 − δ22) / (µ1 − µ2)) was 60 women. Considering the probability of a 10% sample loss, the sample size was cal - culated as 30 people in each group. Both groups were equivalent in terms of demographic characteristics and clinical attributes. The patients were divided into two groups: group A received vaginal bromocriptine, and group B received dienogest. The allocation to each group was done based on computer-generated admission numbers. For blind - ing, the drugs (vaginal bromocriptine and dienogest) were packed in separate but similar packages with A and B labels attached to them. Gynecology resident who filled out the questionnaires and analyst were blinded (Fig. 1). Inclusion criteria included premenopausal women aged between 35 and 50 years who exhibited symptoms of adenomyosis (menorrhagia with or without pelvic pain), confirmed by a PBAC score (pictorial blood loss assess - ment score) of > 100 and transvaginal ultrasound (TVS); they needed to have regular menstrual cycle, normal serum prolactin (PRL) levels, and used non-hormonal contraceptive methods. The exclusion criteria included the following: women who were less than 6 months postpartum, currently breastfeeding, had a uterus larger than 20 cm, had con - traindications for bromocriptine or ergot alkaloids, were currently being treated with gonadotropin-releasing hormone agonists or antagonists, or were using contra - ceptive steroids, intrauterine contraceptive devices, anti - depressants, or opioid pain relievers. Women were also excluded if they had MRI or transvaginal ultrasound (TVS) findings indicating endometriosis or fibroids (myomas), a medical history of prolactinoma, a high- grade squamous intraepithelial lesion on a Pap test, or were suspected of or diagnosed with malignant diseases of the uterus, ovary, or cervix. At the beginning of the study, a transvaginal ultrasound (TVS) was performed, and adenomyosis was diagnosed based on the Morphological Uterus Sonographic Assess - ment (MUSA) features [8]. The checklist contained questions about the demo - graphic variables including age and marriage. The VAS score questionnaire was used to assess pain, and the pic - torial blood loss assessment (PBAC) score questionnaire was used to evaluate the amount of menstrual bleeding. PBAC is a subjective assessment of the amount of blood loss in menstruation. This method records the number of pads and tampons used and the amount of blood on each pad or tampon; a score of more than 100 indicates the volume of menstrual bleeding is more than 80 cc. PBAC sensitivity and specificity are 86% and 88%, respectively [9, 11, 24]. The asymmetrical myometrial thickness of the anteroposterior wall and irregularity of the endometrial- myometrial junction were measured before and after the study. The participants were provided with identi - cal disposable pads for nine menstrual cycles. Group A received vaginal bromocriptine 5 mg daily, administered deep in the vagina. Group B was administered continu - ous oral dienogest 2 mg once daily. The duration of the intervention was 6 months. Both groups were evaluated for pain and menstrual bleeding in the third, sixth, and ninth month, and TVS changes included irregularity of myometrial-endometrial junction and the asymmetry of myometrial thickness of the anteroposterior wall [23] at the sixth and ninth month. This study utilized various descriptive statistics, including frequency, percentage, mean, and standard deviation (SD). The research com - mittee of the Department of Obstetrics and Gynecology of Iran University of Medical Sciences monitored and validated the data. We used the chi-square test to compare the frequency of variables between the two groups. Repeated measures Page 3 of 8 Bahoorzahi et al. Middle East Fertility Society Journal (2024) 29:55 analysis assessed sonographic findings, pain intensity, and bleeding rates at different time points. An independ - ent t-test was conducted to compare the two groups. Data analysis was performed using SPSS version 23, with a significance level set at P < 0.05, which was considered for all analyses.

A comparison of demographic and clinical variables between the two groups was conducted. The mean age of participants in the bromocriptine and dienogest groups was 39.05 ± 4.99 and 38.08 ± 5.68, respectively (P = 0.41). Table 1 displays the demographic and clinical variables of the two groups. The results indicated no significant dif - ferences between the variables in the bromocriptine and dienogest groups (P > 0.05). Fig. 1 Consort flow diagram Table 1 Comparison of the demographic and clinical variables between the two groups * P value was calculated using an independent t-test at 95% CI Variables Group (mean ± SD) P value* Bromocriptine Dienogest Age 39.05 ± 4.99 38.08 ± 5.68 0.41 BMI 25.74 ± 0.51 25.79 ± 0.48 0.71 Number of births 2.47 ± 1.51 2.55 ± 1.48 0.824 Number of abortions 0.15 ± 0.36 0.10 ± 0.30 0.505 Time of last birth 5.4 ± 3.42 5.4 ± 3.52 0.998 Menarche age 13.57 ± 0.81 13.5 ± 0.81 0.682 Page 4 of 8Bahoorzahi et al. Middle East Fertility Society Journal (2024) 29:55 The comparison of clinical variables related to men - struation between the bromocriptine and dienogest groups is presented in Table  2. There were no signifi - cant differences regarding the variables, such as the time of starting menstrual pain and the time of relief in each cycle (P > 0.05). Before the intervention, myometrial-endometrial junc - tion was irregular in all patients. However, it became reg- ular at 6 and 9 months after the intervention (Table  3). The myometrial thickness of the anteroposterior wall was asymmetric in all patients before the intervention. In 6 and 9 months after the intervention, 46.8% (n = 29) of patients in the bromocriptine group and 53.2% (n = 33) in the dienogest group showed symmetric anterior–poste - rior wall thickness (Table 4). The chi-square test demonstrated that in both bro - mocriptine and dienogest groups, 9 months after the intervention, the state of asymmetry of the myome - trial thickness of the anteroposterior wall, the irregu - lar appearance of the myometrial-endometrial junction improved compared to before the intervention. There was no significant difference between the two groups in terms of asymmetry of myometrial thickness of the anteroposterior wall and irregular appearance of myo - metrial-endometrial junction in 6 and 9 months after the intervention. Three months after the intervention, the mean visual blood chart score in the bromocriptine group was sig - nificantly lower than in the dienogest group. Still, it was lower in the dienogest group after 6 months (P < 0.001). In the ninth month of the study, however, the difference between the two groups was not statistically significant (Table 5). Table 2 Comparison of clinical variables related to menstruation frequency between two groups * P value was calculated using the chi-2 statistic test at 95% CI Variables Group (%) P value* Bromocriptine Dienogest Menstrual pain No 2 (66.7) 1 (33.3) 0.9 Yes 38 (49.4) 39 (50.6) Menstrual pain onset time 1 or 2 days before menstruation 4 (57.1) 3 (42.9) 0.924 1 or more hours before menstruation 31 (42.2) 32 (50.8) After starting menstruation 5 (50.0) 5 (50.0) Menstrual pain relief time 1st menstrual day 1 (50.0) 1 (50.0) 0.731 3rd menstrual day 8 (42.1) 11 (57.9) 4th menstrual day and later 31 (52.5) 28 (47.5) Table 3 Comparison of irregularity of myometrial-endometrial junction between two groups of bromocriptine and dienogest * P value was calculated using the chi-2 statistic test at 95% CI Time Group P value* Bromocriptine Dienogest Before Regular 0 (0%) 0 (0%) 1 Irregular 40 (50%) 40 (50%) After 6 months Regular 31 (47%) 35 (53%) 0.95 Irregular 0 (0%) 0 (0%) After 9 months Regular 31 (47%) 35 (53%) 0.95 Irregular 0 (0%) 0 (0%) Table 4 Comparison of the anterior–posterior myometrial thickness between bromocriptine and dienogest groups * P value was calculated using the chi-2 statistic test at 95% CI Time Group P value* Bromocriptine Dienogest Before Symmetric 0 (0%) 0 (0%) 1 Asymmetric 40 (50%) 40 (50%) After 6 months Symmetric 29 (46.8%) 33 (53.2%) 0.90 Asymmetric 2 (50%) 2 (50%) After 9 months Symmetric 29 (46.8%) 33 (53.2%) 0.90 Asymmetric 2 (50%) 2 (50%) Page 5 of 8 Bahoorzahi et al. Middle East Fertility Society Journal (2024) 29:55 Further investigation using Tukey’s test indicated that in both groups, the visual blood chart score consistently decreased over time (P < 0.001) (Fig. 2). Moreover, the mean intensity of menstrual pain in the dienogest group was significantly lower than in the bro - mocriptine group at 3 months and 6 months after the intervention (P < 0.001). There was no significant differ - ence between both groups regarding pain intensity at the beginning of the study and 9 months after the interven - tion (Table  6). Tukey’s test showed that in both groups, the mean intensity of menstrual pain progressively decreased over time (P < 0.001) (Fig. 3). Regarding drug side effects, three patients in the bro - mocriptine group (n = 31) experienced nausea, one patient had headache and constipation, and four patients had spotting in the dienogest group (n = 35).

Medical treatment for adenomyosis requires a drug that has low side effects and effectively reduces pain and the intensity of menstrual bleeding. Bromocriptine, which is currently used for managing type 2 diabetes [22], is also effective in the treatment of hyperprol - actinemia [12], acromegaly [1 ], and Parkinson’s disease [21]. Research on the mechanism of pain and bleed - ing of adenomyosis and potential treatment options remains sparse, but animal research has suggested that increased uterine prolactin concentration might be a risk factor since prolactin is a smooth muscle cell mitogen. If prolactin contributes to the pathogenesis of adenomyosis, lowering uterine prolactin may serve as a beneficial medical treatment. Therefore, bromocrip - tine, as a prolactin inhibitor, may be effective in alle - viating menstrual bleeding and pain in women with adenomyosis [2 ]. However, further studies are needed to investigate the role and mechanism of bromocriptine in alleviating related symptoms. In this study, bromocriptine was administered vagi - nally to achieve higher drug concentrations in the uterus, thereby maximizing efficacy while minimizing blood lev - els to reduce adverse drug effects. Previous studies have shown that vaginal bromocriptine has fewer gastrointes - tinal side effects in comparison with the oral form of the drug [1]. In the present study, three patients in the bro - mocriptine group experienced nausea after receiving the prescribed dose. The side effects noted in this study were temporary, and patients did not report any long-term side effects throughout the study. Table 5 Comparison of mean blood visual chart between two groups before, 3, 6, and 9 months after the intervention * P value was calculated using an independent t-test at 95% CI Time Group (mean ± SD) P value* Bromocriptine Dienogest Before 302.32 ± 18.43 302.42 ± 18.05 0.920 After 3 months 140.22 ± 14.06 176.0 ± 14.22 < 0.001 After 6 months 85.93 ± 5.17 79.62 ± 3.69 < 0.001 After 9 months 66.96 ± 8.62 66.14 ± 4.35 0.620 P value* < 0.001 < 0.001 Fig. 2 Blood visual chart trend in bromocriptine (a) and dienogest (b) group Table 6 Comparison of intensity of menstrual pain between two groups before, 3, 6, and 9 months after the intervention * P value was calculated using an independent t-test at 95% CI Time Group (mean ± SD) P value* Bromocriptine Dienogest Before 6.75 ± 0.75 6.72 ± 0.5 0.833 After 3 months 4.2 ± 0.69 3.02 ± 0.71 < 0.001 After 6 months 1.19 ± 0.6 2.04 ± 0.86 < 0.001 After 9 months 0.48 ± 0.35 0.48 ± 0.28 0.958 P value* < 0.001 < 0.001 Page 6 of 8Bahoorzahi et al. Middle East Fertility Society Journal (2024) 29:55 The findings from limited studies in this area sup - port our results and highlight the effectiveness of bro - mocriptine. Andersson et  al. [2] reported that vaginal bromocriptine significantly reduced heavy menstrual bleeding and pain intensity in women with diffuse adeno- myosis. Andersson et  al. [1] demonstrated a significant reduction in both the myometrial-endometrial junction and asymmetric myometrial wall thickness as observed through transvaginal sonography (TVS), indicating the radiologically proven effectiveness of vaginal bromocrip - tine on adenomyosis. Our research showed a significant impact of dien - ogest and bromocriptine on the sonographic features of adenomyosis. The most significant improvement in the endometrial-myometrial junction and anterior–posterior myometrial thickening asymmetry was observed in the sixth month, with no further sonographic changes noted after the drug was discontinued. In another study, Andersson et al. [2] found significant improvements in menstrual bleeding, pain, and quality of life following vaginal administration of bromocriptine, which is consistent with our study’s results. It is note - worthy, however, that the quality of life was not explic - itly investigated in our study. A recent study by Tang et al. [21] indicated that bromocriptine had an antiproliferative effect on the endometrium of women with adenomyosis in both in vivo and laboratory conditions. Bromocriptine appears to inhibit the proliferation of endometrial tissue in adenomyosis by regulating irregular microRNAs and proliferation-related signaling pathways. Dienogest has been acknowledged in numerous sources for its effectiveness in treating adenomyosis [10]. Some studies have compared dienogest with other drugs, but none has compared it with bromocriptine. In the pre- sent study, dienogest also significantly reduced menstrual pain and bleeding. Neither vaginal bromocriptine nor dienogest caused significant adverse effects. Both drugs demonstrated effectiveness in reducing pain intensity and menstrual bleeding. The mean blood visual chart score before the intervention in both groups had no significant difference. Three months after the intervention, the mean blood visual chart score was significantly lower in the bromocriptine group. During the subsequent 6 months, dienogest was slightly more effective, possibly due to the decidualization of the endometrium by the progestogenic activity of dienogest. After 3 months of stopping the intervention in the 9th month, both medications showed similar effects,each intervention reduced bleeding to the same extent. After 6 and 9 months of study, the aver - age blood visual chart score was below 100. Dienogest was more effective at reducing pain intensity by the 3rd month, while bromocriptine showed greater effectiveness by the 6th month. Although bromocriptine’s effect on pain intensity began slightly slower, both bromocriptine and dienogest produced similar results, making them effective options for treating adenomyosis. Miao et al. [13] conducted a study to assess the effec - tiveness and safety of dienogest in women suffering from symptomatic adenomyosis. The results of this study were consistent with the present study’s findings, indicating that dienogest is an effective and well-tolerated long- term treatment for symptomatic adenomyosis. These findings are also consistent with the results of Zhang et al. ’s study [25]. Furthermore, Ono et al. [15] study dem- onstrated that dienogest was highly effective in pain relief in endometriosis and adenomyosis. Similarly, Neriishi et al. ’s study [14] found that 24 weeks of dienogest treat- ment significantly reduced pain in patients with sympto - matic adenomyosis. Studies indicate that patients with endometriosis treated with dienogest may experience irregular uterine bleeding and metrorrhagia. Additionally, women with uterine adenomyosis and fibroids are at a higher risk of experiencing moderate-to-severe bleeding. This heavy Fig. 3 Intensity of menstrual pain trend in bromocriptine (a) and dienogest (b) group Page 7 of 8 Bahoorzahi et al. Middle East Fertility Society Journal (2024) 29:55 bleeding in women with adenomyosis may lead patients to discontinue the treatment, but this adverse effect has not been reported with the use of bromocriptine. No such side effect due to bromocriptine was observed in our study and Andersson et al. ’s study [2 ]. Therefore, in this group of patients with irregular uterine bleeding and metrorrhagia due to dienogest use, bromocriptine could be a suitable substitution [20]. Bromocriptine can be effectively prescribed, especially for patients who have contraindications to hormonal treatment. One of the strengths of the current study was its novel comparison between vaginal bromocriptine and dien - ogest, which are the most commonly prescribed drugs. This comparison was conducted for the first time and demonstrated that both drugs have a favorable effect. Another strength of the study was the follow-up after cession of intervention to evaluate the recurrence of symptoms. However, the study also had some limita - tions, such as the small sample size. In future studies, evaluating the quality of life is rec - ommended, which is a more accurate criterion.

The results of this study show that both vaginal dien - ogest and bromocriptine effectively reduce pain inten - sity and menstrual bleeding and improve sonographic characteristics.

We are most grateful to Iran University of Medical Sciences for conducting this research. Authors’ contributions P .B. contributed to the writing of the original draft and performed the experi- mental technique in the conceptualization of the work. S.R,S.A., N.H., and R.D. performed the collection of data. S.R. contributed to the writing the review, and the editing of the paper and contributed to the conceptualization. Funding NA. Data availability The underlying data supporting the results of our study can be found in the manuscript. Declarations Ethics approval and consent to participate NA. Consent for publication All authors consent to the publication of this study. Competing interests The authors declare no competing interests. Received: 28 August 2024 Accepted: 14 December 2024

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