The impact of vaginal bromocriptine on reducing pain and menstrual bleeding in women with adenomyosis: a randomized controlled trial

Bromocriptine, a dopamine receptor agonist that suppresses prolactin secretion from the pituitary gland, is an inexpensive and widely accessible medication with few adverse effects. The study aim was to assesse the efficacy of vaginal bromocriptine in reducing pelvic pain, menstrual bleeding, and cycle irregularities among patients with adenomyosis. In this randomized controled trial, 64 women diagnosed with adenomyosis were randomly assigned to either an intervention group receiving vaginal bromocriptine or a routine- treatment group. The intervention consisted of 5 mg bromocriptine administered vaginally once daily for three months. The control group received standard treatment comprising oral contraceptive pills (OCPs) and mefenamic acid. Primary outcome measures were menstrual bleeding volume, pain intensity, and menstrual cycle regularity. Linear regression models were used to evaluate changes in menstrual bleeding after adjusting for potential confounders. All 64 participants (32 per group) completed the study and were ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS included in the analysis. Baseline demographic, obstetric, and ultrasonographic characteristics were comparable between groups (P > 0.05). After treatment, the mean pain score was significantly lower in the intervention group than in the control group (2.01 vs. 5.10; P = 0.011). Mean menstrual bleeding volume also decreased significantly with vaginal bromocriptine (280.8 mL vs. 525.9 mL; P = 0.001). Final analysis indicated that bromocriptine significantly reduced menstruation bleeding after adjusting for potential confounders (Beta= -1.157, P= 0.001). Vaginal bromocriptine appears to be an effective and well-tolerated therapeutic option for alleviating symptoms of adenomyosis, particularly pelvic pain, excessive menstrual bleeding, and irregular cycles. The beneficial effects may result from reduced prolactin levels, inhibition of angiogenesis, and modulation of the hypothalamic–pituitary–ovarian axis. IRCT registration number: IRCT20240806062668N3 Registration date: 2025-03-19 Patient recruitment date: 2025-04-13

One of the most accepted pathogenetic hypotheses involves disruption or absence of the endometrial–myometrial junctional zone, allowing endometrial mucosa to invaginate into the underlying myometrium [6,7]. Although the pathogenesis is multifactorial, experimental studies have highlighted a potential role for prolactin: elevated serum prolactin may promote endometrial gland growth and activity [8], and in the presence of ovarian steroids, it can induce myometrial cell injury, facilitating endometrial invasion [9]. The burden of adenomyosis extends beyond individual symptoms, imposing substantial long-term healthcare costs comparable to chronic conditions such as diabetes and rheumatoid arthritis [10]. Consequently, it represents both a clinical and economic challenge in gynecology [11]. Medical therapy remains ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS the cornerstone of symptom management and disease modulation [12]; however, no standardized treatment guideline has been established. Current medical options—including gonadotropin-releasing hormone (GnRH) agonists, oral contraceptives, and progestins—often yield modest efficacy, limited tolerability, and considerable expense [1]. For many women, these shortcomings culminate in hysterectomy; in the United States, approximately 82% of patients with adenomyosis undergo hysterectomy for symptom relief, resulting in permanent loss of fertility [13]. Given the substantial impact on quality of life and the therapeutic limitations of existing modalities, the search for new, effective, and well-tolerated interventions remains imperative [2]. Prolactin synthesis occurs not only in the pituitary gland but also in endometrial and myometrial tissues, where it acts as a mitogenic factor for smooth muscle cells under experimental conditions [14]. Evidence suggests a strong correlation between serum prolactin levels and the progression of adenomyosis [15], implying that prolactin-lowering agents may represent a rational therapeutic approach. Bromocriptine—an ergot-derived, sympatholytic dopamine D₂-receptor agonist with potent biological activity— has been used for over three decades to treat hyperprolactinemia, prolactinomas, Parkinson’s disease, acromegaly, and other hormone-dependent pituitary adenomas, as well as certain metabolic disorders such as diabetes mellitus. Prolonged bromocriptine therapy is generally safe, with minimal hepatic, renal, cardiac, or hematologic toxicity [16]. The drug is inexpensive, widely accessible, and well tolerated, with a favorable side-effect profile [16,17]. Vaginal administration further improves tolerability by reducing gastrointestinal reactions and has been shown to effectively lower serum prolactin levels in women with hyperprolactinemia [18]. Recent clinical findings report significant improvements in menstrual bleeding, pain intensity, and overall quality of life following vaginal bromocriptine therapy [15]. ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS Therefore, this trial was designed to evaluate the impact of vaginal bromocriptine on menstrual bleeding and pain among patients diagnosed with adenomyosis.

Study design and setting This pilot parallel randomized controlled clinical trial was conducted to assess the impact of vaginal bromocriptine on reducing pain and menstrual bleeding in patients with adenomyosis. Participants were recruited from Al-Zahra Hospital, affiliated with Tabriz University of Medical Sciences, and the infertility center of Jahrom University of Medical Sciences. The trial was conducted between 2024 and 2025, adhering to predefined inclusion and exclusion criteria. Inclusion Criteria Eligible participants were premenopausal women aged 25 years or older presenting with heavy menstrual bleeding, defined as a Pictorial Blood Loss Assessment Chart (PBAC) score exceeding 100. Diagnosis of adenomyosis was based on transvaginal ultrasound criteria, including an irregular endometrial– myometrial junction, asymmetric myometrial wall thickness, presence of myometrial cysts, and fan-shaped acoustic shadowing in the myometrium. Additional inclusion criteria included normal baseline serum prolactin levels, use of adequate contraception (ranging from contraceptive devices and sterilization to sexual abstinence), and the ability and willingness to read and understand study information. Exclusion Criteria Exclusion criteria encompassed women actively trying to conceive, those in the postpartum period for less than 6 months, breastfeeding individuals, and women with a uterine size greater than the level of the umbilicus (equivalent to >20 weeks gestation). Furthermore, women with acute pelvic infection, ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS those using an intrauterine device (IUD), or with contraindications to bromocriptine or ergot alkaloids were excluded. Participants exhibiting intolerance or adverse reactions to bromocriptine during the evaluation phase, recent use of gonadotropin-releasing hormone (GnRH) agonists or antagonists, steroidal oral contraceptives, intrauterine hormonal devices, antidepressants, or opioid analgesics were also deemed ineligible. Individuals with transvaginal ultrasound or MRI findings suggestive of endometriosis, a history of hyperprolactinemia, high-grade cervical intraepithelial lesions, or suspected uterine or ovarian malignancy were excluded. Other contraindicating factors included a history of peptic ulcer disease, syncope, seizures, uncontrolled hypertension, cardiovascular or cerebrovascular disease, valvular heart disease, diabetes, Parkinson’s disease, psychosis, pleural or pericardial effusion, pulmonary fibrosis, Raynaud phenomenon, lactose intolerance, and current use of opioid medications. Sample Size Based on a previous study [15], mean blood loss scores (m) and standard deviations (sd) were assumed for the intervention (m₁=349, sd₁=155) and control (m₂=233, sd₂=175) groups. With a minimum power of 80% to detect a significant difference in menstrual blood loss between groups and a maximum type I error rate of less than 5%, the required sample size was calculated to be 32 participants per group, totaling 64 patients. Randomization and Blinding Participants were assigned to the intervention and control groups using a balanced block randomization method. This process involved random allocation within predetermined blocks to ensure complete randomness. A total of 16 blocks were used, each containing 4 participants. The sequence within each block determined individual group placement, thereby maintaining a balanced distribution of participants across groups regarding potential confounding variables. Participants in the control group received oral ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS contraceptive pills (OCPs) and mefenamic acid (for pain management). Randomization was performed by an independent individual who concealed the allocation sequence. Participants were unaware of their group assignments (Figure 1). To mitigate assessment bias, research nurses collecting data on pain and bleeding scores were blinded to treatment allocation. Interventions Treatment commenced with one 2.5 mg vaginal tablet inserted once daily for the first week. Subsequently, the dose was increased to twice daily, achieving a total daily dose of 5 mg (one 2.5 mg vaginal tablet every 12 hours). Day 1 of the study was defined as the first day the participant successfully received the full 5 mg daily dose. The medication was continued for a total duration of three months. Follow-up Follow-up visits were scheduled during the proliferative phase of the menstrual cycle in the third month of treatment. The final evaluation occurred at the end of a 4-month follow-up period, one month after discontinuation of the study medication. According to the study protocol, any participant experiencing adverse effects or intolerance to bromocriptine would lead to treatment discontinuation and potential withdrawal from the study. No such events were observed. Outcomes and Measurements The primary outcomes were: (i) the change in Visual Analogue Scale (VAS) pain score and (ii) the change in Pictorial Blood Loss Assessment Chart (PBAC) score from baseline to Day 30. Menstrual blood loss was assessed using the standardized PBAC, which estimates menstrual volume by recording the number of sanitary pads and/or tampons used daily and assigning scores based on saturation levels. This tool is validated for distinguishing between ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS normal and heavy menstrual bleeding and is suitable for diverse populations, including Asian women [19]. Average pain intensity was measured using the VAS at three intervals following menstruation: within the first 3 days, between days 3 and 7, and more than 7 days after menstruation. VAS scores ranged from 0 (no pain) to 10 (most severe pain imaginable). Pain scores were meticulously recorded according to the study protocol. Statistical Analysis All data were analyzed using SPSS version 24 (Chicago, IL, USA). Descriptive statistics, including mean and standard deviation, were used for normally distributed quantitative data, while frequencies and percentages were used for qualitative or categorical variables. To compare menstrual blood loss and pain scores between the two groups, the Independent Samples t-test was used for normally distributed variables, and the Mann–Whitney U test was used for non-normally distributed variables. Within-group comparisons (before and after treatment) were conducted using the paired t-test. Menstrual bleeding (ml) was considered the primary outcome variable. Linear regression analysis was performed for additional adjusted analyses, controlling for baseline treatment differences and employing change-from- baseline comparisons. This approach aimed to estimate the Standardized Coefficients (Beta) for menstrual bleeding after accounting for potential confounders. The study groups and baseline variables were entered as independent variables into the model. The control group (treatment as usual) served as the reference group, allowing for the estimation of the impact of bromocriptine (intervention group) in reducing menstrual bleeding compared to the control group. A significance level of less than 5% was considered statistically significant for all analyses.

Obstetric and clinical characteristic of the participants at baseline ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS A total of 64 patients diagnosed with adenomyosis, with 32 patients randomized to each group, were included in the final analysis. All participants completed the 3-month treatment period and underwent a subsequent 1- month follow-up. No participants were lost to follow-up throughout the study duration. The demographic and baseline characteristics of the study participants are detailed in Table 1. The mean age was 32.5 years in the intervention group and 33.8 years in the control group, with no statistically significant difference observed between the groups (P > 0.05). Similarly, mean body weight and body mass index (BMI) did not differ significantly between the groups (P = 0.561). Other demographic factors, including occupation and educational level, also exhibited no significant variations (P > 0.05). Concerning obstetric history, the mean number of cesarean deliveries (1.24 vs. 1.42) and mean parity (1.15 vs. 1.24) were comparable at baseline, with no statistically significant differences (P > 0.05). Table 2 presents the transvaginal ultrasound findings at the time of study entry, along with selected clinical parameters prior to the intervention. Ultrasound assessments indicated that both groups were comparable in terms of uterine volume, endometrial thickness, and the number of myometrial cysts, showing no statistically significant differences at baseline (P > 0.05). Furthermore, posterior uterine wall thickening and the presence of an asymmetric, heterogeneous myometrium did not differ significantly between the groups (P > 0.05). Pre-intervention measurements of pain intensity and menstrual bleeding volume also revealed no significant differences between the two treatment arms. The menstrual cycle length was likewise comparable (P > 0.05). Clinical outcomes post-intervention The primary clinical outcomes following the intervention period are summarized in Table 3. Mean pain scores demonstrated a statistically ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS significant reduction in the intervention group (2.01) compared to the control group (5.1) (P = 0.011). A significant difference was also observed in menstrual bleeding volume post-treatment, with the intervention group averaging 280.8 mL versus 525.9 mL in the control group (P = 0.001). Menstrual duration, categorized into three intervals (7 days), was significantly shorter in the intervention group compared to the control group (P = 0.001). Regarding menstrual regularity post-treatment, 75% (24 patients) in the intervention group reported regular cycles, compared to 25% (8 patients) in the control group, a statistically significant difference (P = 0.001). Table 4 presents the results of the linear regression analysis, which aimed to estimate the impact of bromocriptine and to perform change-from-baseline comparisons for menstruation bleeding, adjusted for potential confounders. The final analysis indicated that bromocriptine treatment significantly reduced menstrual bleeding compared to the control group (Beta = -1.157; P = 0.001). Conversely, the presence of myometrial cysts (Beta = 0.626; P = 0.027) and endometrial thickness (Beta = 0.635; P = 0.048) were positively associated with higher menstrual bleeding volumes. Specifically, for each unit increase in myometrial cysts and endometrial thickness, menstrual bleeding increased by approximately 0.626 and 0.635 times, respectively. Other variables, including age, weight, history of cesarean delivery, uterine volume, posterior uterine wall thickening, and heterogeneous myometrium, showed no significant association with increased menstrual bleeding (P > 0.05).

According to the findings of this study, vaginal administration of bromocriptine resulted in statistically significant and clinically meaningful reductions in pain intensity and menstrual bleeding. These improvements were corroborated by gynecologic assessments and patient-reported satisfaction. Quantitatively, the study reported significant between-group differences in pain scores (2.01 vs. 5.1) and menstrual bleeding volume (280.8 vs. 525.9 mm³). ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS The pathogenesis of pain in adenomyosis is multifactorial, involving the ectopic infiltration of endometrial tissue into the myometrium, heightened prostaglandin production, stimulation of nociceptive nerve endings, and chronic inflammatory processes [11]. Bromocriptine, a dopaminergic agent, exerts its effects by inhibiting pituitary prolactin secretion. This action is associated with the modulation of pro-inflammatory pathways and a reduction in the excessive production of pro-inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1 beta (IL-1β) [12]. Furthermore, prolactin has been implicated in enhancing uterine contractility through increased oxytocin sensitivity [13]. Consequently, bromocriptine-induced prolactin suppression may indirectly alleviate painful uterine contractions during menstruation, thereby contributing to pain relief [14, 20]. A notable secondary finding was the marked reduction in menstrual bleeding volume within the intervention group. This effect is predominantly attributed to the diminished growth and activity of adenomyotic tissue. In adenomyosis, ectopic endometrial tissue within the myometrium promotes angiogenesis, induces uterine hypertrophy, and contributes to the formation of fragile vascular networks, all of which are implicated in heavy menstrual bleeding [14]. Bromocriptine may mitigate the growth of such tissue by downregulating the expression of angiogenic factors, including Vascular Endothelial Growth Factor (VEGF), and by inhibiting cellular proliferation within the endometrium [15]. Additionally, a reduction in prolactin levels can attenuate cyclooxygenase-2 (COX-2) activity in the uterus, thereby decreasing inflammation and subsequent menstrual blood loss [16]. By ameliorating local inflammation, bromocriptine may also enhance vascular stability and function, thus preventing abnormal uterine bleeding [16, 21]. The observed reduction in menstrual duration in the intervention group represents another significant clinical outcome. Prolonged menstruation in adenomyosis is partly attributed to persistent inflammation within the heterotopic endometrial tissue and impaired vascular repair mechanisms [18]. ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS By potentially decreasing vascular permeability and improving endometrial function, bromocriptine may facilitate the restoration of a more physiological menstrual duration. While molecular mechanisms, such as the regulation of the Phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway and mammalian Target of Rapamycin (mTOR) inhibition, might contribute to enhanced endometrial repair post-menstruation, further detailed molecular investigations are warranted [22]. Improvements in menstrual cycle regularity were also substantially observed in the intervention group. This effect may be attributed to bromocriptine’s modulatory influence on the hypothalamic–pituitary–ovarian (HPO) axis. Elevated serum prolactin levels are known to suppress HPO axis function, potentially leading to anovulation and menstrual irregularities [22]. By reducing prolactin concentrations, bromocriptine may help restore the normal pulsatile release of Gonadotropin-Releasing Hormone (GnRH) from the hypothalamus, subsequently normalizing the physiological secretion of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) from the pituitary gland [23]. This normalization of endocrine rhythms is expected to re-establish ovulatory cycles and improve menstrual regularity [24]. Furthermore, bromocriptine may suppress the growth of adenomyotic tissue through the reduction of steroid hormone levels, such as estrogen, which plays a critical role in the development and progression of adenomyosis [25]. Prior animal and human studies have suggested that prolactin can increase the sensitivity of uterine estrogen receptors, thereby promoting the growth and survival of adenomyotic tissue. Consequently, prolactin suppression by bromocriptine might attenuate estrogen-driven proliferative effects within these tissues [26]. An important methodological consideration in this study is the utilization of the vaginal route for bromocriptine administration. This administration pathway bypasses first-pass hepatic metabolism, thereby increasing drug concentrations within the pelvic region and adjacent uterine tissues [27]. ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS Consequently, higher local drug levels can be achieved at the target site, potentially with a reduced incidence of systemic side effects. Previous research has also indicated that vaginal bromocriptine is generally better tolerated than oral formulations, with a lower prevalence of gastrointestinal and neurological adverse events [28]. Comparisons with existing literature further substantiate the beneficial effects of bromocriptine. For instance, Andersson et al. reported that dopamine agonists can inhibit the growth of endometriotic lesions and alleviate chronic pelvic pain [18]. Similarly, Tang et al. demonstrated that bromocriptine reduced the thickness of heterotopic endometrial tissue in mouse models of adenomyosis. Although the majority of current literature pertains to endometriosis, the shared pathophysiological mechanisms between endometriosis and adenomyosis lend support to the applicability of these findings in the context of adenomyosis.

The limitations of this study include a relatively short follow-up period. Additionally, the study lacked long-term imaging and comprehensive biochemical assessments to evaluate the drug’s structural and sustained effects. The reliance on subjective instruments for measuring pain intensity and menstrual regularity could potentially introduce assessment bias. To mitigate these concerns, the study employed blocked randomization and participant blinding, alongside standardized instruments for assessing menstrual blood loss and pain intensity across the study groups. Another methodological consideration is the difference in background therapy: the control group received oral contraceptive pills (OCPs) ± mefenamic acid, whereas the intervention group received bromocriptine monotherapy. While this difference in adjunctive treatment may be minor, it could complicate the precise attribution of observed effects solely to bromocriptine. However, the ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS use of balanced block randomization aimed to mitigate this potential confounding factor. Although the power analysis indicated an 80% power to detect moderate effect sizes (with significant P-values), a larger sample size would be beneficial for enhancing the generalizability of the results.

Based on the findings of this study, vaginal bromocriptine appears to be an effective adjunctive therapy for patients diagnosed with adenomyosis. It demonstrates significant efficacy in reducing pain intensity, menstrual blood loss, and menstrual duration, while concurrently improving menstrual cycle regularity. Considering its favorable tolerability profile, ease of administration, and enhanced local efficacy, vaginal bromocriptine presents a promising, low- risk therapeutic option that may complement conventional treatments for the management of adenomyosis. Declarations Ethics approval and consent to participate The study protocol was approved by the ethics committee of Tabriz University of Medical Sciences to number IR.TBZMED.REC.1403.795. Written informed consent was obtained before the study. The study was conducted in accordance with the Declaration of Helsinki. Consent for publication Not Applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors have no competing interests to declare. ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS Funding This study was funded by Tabriz University of Medical Sciences, Iran Authors’ contributions: HA, PH, EE, and MA contributed to protocol development, data creation and collection, manuscript development, and review. PH supervised the trial. PH and MA treated and followed up on the patients. HA analyzed, interpreted, reviewed, provided the first draft of the manuscript and edited. All authors read, provided comments and approved the final manuscript. Acknowledgments Authors would like to thank statistical supports of “Clinical Research Development Unit of Al-Zahra Educational, Research and Treatment Center”, Tabriz University of Medical Sciences, Tabriz, Iran.

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Sherwal V, Malik S, Bhatia V: Effect of bromocriptine on the severity of ovarian hyperstimulation syndrome and outcome in high responders undergoing assisted reproduction. Journal of human reproductive sciences 2010, 3(2):85-90. 28. Badianyama M, Das PK, Gaddameedi SR, Saukhla S, Nagammagari T, Bandari V, Mohammed L: A Systematic Review of the Utility of Bromocriptine in Acute Peripartum Cardiomyopathy. Cureus 2021, 13(9):e18248. TAU: Treatment as usual included OCP and/or Mefenamic acid Figure 1. Consort flow diagram Table 1. Baseline characteristics of the participants Groups (n= 64) Variables Intervention (n= 32) Mean ± SD Control (n= 32) Mean ± SD P-value Age (year)* 32.5 ± 5.6 33.8 ± 5.6 0.574 Weight (kg)* 71.4 ± 6.0 70.4 ± 7.8 0.561 Cesarean** 1.24 ± .38 1.42 ± 0.25 0.749 Parity** 1.15 ± 0.41 1.24 ± 0.33 0.951 History of infertility (n %)* 9 (28.2) 11 (34.4) 0.148 Single 12 11Marital Status (n) married 21 20 0.611 BMI (Body mass index) 25.5 ± 3.6 25.9 ± 3.3 0.924 Academic 23 22Educational (n) Non- academic 9 10 0.803 Employed 15 15Occupation al (n) Self- employed 10 11 0.851 Enrollment Excluded (n= 72) ￿ Not meeting inclusion criteria (n=72) ￿ Declined to participate (n= 0 ) ￿ Other reasons (n= 0 ) Follow-Up Analysed (n=32) ￿ Excluded from analysis (give reasons) (n= 0) Analysis Analysed (n= 32) ￿ Excluded from analysis (give reasons) (n= 0) Lost to follow-up (give reasons) (n= 0) Discontinued intervention (give reasons) (n=0) Lost to follow-up (give reasons) (n=0) Discontinued intervention (give reasons) (n=0) Allocated to control (TAU) (n= 32) ￿ Received allocated intervention (n= 32 ) ￿ Did not receive allocated intervention (give reasons) (n=0 ) Allocation Allocated to intervention (Vaginal Bromocriptine) (n= 32) ￿ Received allocated intervention (n= 32 ) ￿ Did not receive allocated intervention (give reasons) (n= 0 ) Randomized (n= 64) Assessed for eligibility (n= 156 ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS Unemploy ed 7 6 * T-test ** Mann-Whitney Table 2. Comparison of transvaginal ultrasound results and clinical features between the two study groups at the baseline Groups (n= 64) Variables Intervention (n= 32) Mean ± SD Control (n= 32) Mean ± SD P-value Uterine volume (cubic centimeters) 150.5 ± 32.6 147.8 ± 30.9 0.681 Endometrial thickness (mlm) 10.2 ± 1.3 10.5 ± 1.6 0.432 Myometrial cysts (n) 23 21 0.589 Thickening of the posterior wall of the uterus (n) 18 20 0.615 Heterogeneous myometrium(n) 26 25 0.743 Asymmetrical thickening of the myometrium (n) 20 19 0.798 Pain (before) Mean ± SD 7.1 ± 1.3 7.6 ± 1.4 0.618 Bleeding during menstruation (before) Mean ± SD 616 ± 60.6 601 ± 56.6 0.881 7 5 7 0.485 Table 3. The study outcomes after interventions Groups (n= 64) Variables Intervention (n= 32) Mean ± SD Control (n = 32) Mean ± SD Mean difference P-value ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS Pain 2.01 ± 1.2 5.1 ± 1.7 3.19 ± 1.03 0.011 menstrual bleeding (ml) 280.8 ± 20.6 525.9 ± 45.7 245.1 ± 27.5 0.001 Menstrual regularity (n%) 24 (75%) 8 (25%) - 0.001 7 2 9 - 0.001 Table 4. Results of linear regression analysis* to estimate the impact of bromocriptine and related factors on menstrual bleeding Variables Standardized Coefficient (Beta)** 95% CIs P-value Control Ref. Ref. Ref. Groups Intervention (bromocriptine) - 1.157 -3.19 – -7.61 0.001 Age (year) 0.067 - 0.96 – 8.01 0.137 Weight (kg) 0.12 -0.23 – 1.61 0.194 Cesarean history (n) 0.028 - 2.01 – 3.82 0.543 Parity (n) -0.145 -1.63 – 2.21 0.641 Uterine volume (cubic centimeters) 0.012 - 2.34 – 3.08 0.788 Endometrial thickness (mlm) 0.635 0.031 – 2.15 0.048 Myometrial cysts (n) 0.626 0.14 – 3.32 0.027 Thickening of the posterior wall of the uterus (n) 0.116 -1.05 – 4.96 0.135 Heterogeneous myometrium (n) 0. 374 -0.971 – 2.51 0.269 * menstrual bleeding was considered as outcome variable ** Adjusted R square= 0.654; Durbin-Watson= 2.06 ACCEPTED MANUSCRIPT ARTICLE IN PRESSARTICLE IN PRESS