Statins: Is it New Weaponry against Endometriosis?

This prospective comparative study was done in the Department of Reproductive Endocrinology and Infertility, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh. Women with symptomatic endometrioma were enrolled in the study and were divided into the treatment arm of ATV plus DNZ and the control arm of DNZ alone. To examine the association between Group A (DNZ plus Statin) and Group B (DNZ) regarding the statistical model, a multilevel mixed-effects regression analysis was conducted to evaluate the relationship between the primary exposures, additional independent factors and outcomes such as endometrioma size and pain level.

Participants of Group A experienced infertility for more than 3 years than Group B, which was found statistically significant (P < 0.001). Again, a mixed-level regression analysis was conducted to assess the association between the primary exposure showed that post-intervention, endometrioma size decreased by 0.81 units (95% confidence interval [CI]: −1.10, −0.52, P < 0.001) and pain levels decreased by 3.81 units (95% CI: −4.31, −3.30, P < 0.001). Interestingly, pain levels were 1.64 units higher in the obese group (95% CI: 0.36, 2.92, P = 0.012). Amongst the participants reporting menstrual problems, endometrioma size was reduced by 0.92 units (95% CI: −1.32, −0.52, P < 0.001).

The findings revealed that both treatment regimens efficiently lowered the size of endometriomas and relieved discomfort in the study subjects.

Endometriosis is a persistent estrogen-reliant gynaecological inflammatory condition portrayed by the expansion and manifestation of histological components such as endometrial glands and stroma in anatomical situations and organs independent of the uterus, leading to reactive fibrosis.[1–3] Around 10%–15% of women have endometriosis in their reproductive age, and nearly 30%–50% have chronic pelvic pain and infertility. It has been reported that endometriosis also occurs amongst teenage girls and after menopause.[4,5] Statins have been demonstrated in recent in vitro experiments to inhibit angiogenesis and reduce the growth of the stroma of the endometrium.[6] The most typical site for endometriosis in the pelvis is ovarian cysts or endometriomas.[7] Losing endometrial glands and stroma triggers a critical persistent inflammatory reaction through cytokines, resulting in prostaglandin synthesis and eventually, fibrosis.[8] It can considerably affect the quality of life for afflicted women and causes symptoms such as discomfort, inflammation, endometrioma development and subfertility.[9] Endometrioma is a progressive cyst that tends to recur in 17%–44% of women with endometriosis. This gynaecological condition is characterised by the persistent retrograde migration and continued existence of shed endometrial cells in the lower abdomen, especially in the cavitas pelvis, containing the ovaries, the uterosacral ligament and the pouch of Douglas [Figure 1].[10] Endometriosis and its effect.Notes: This figure was drawn using the premium version of BioRender.[11] https://BioRender.com/l80r072, accessed on January 17th, 2025, with the agreement license number FW27STE7G3.Image credit: Pratiksha Patel. The precise cause and process of endometriosis progression are still unclear. Individuals suffering from endometriosis exhibit compromised immunological function, elevated cytokine and proinflammatory mediators manufacture, raised in general angiogenic activity, progesterone resistance and overproduction of estrogen.[12] Since ectopic endometriotic implants release more intercellular adhesion molecule-1 and have lower levels of metalloproteinase and CD36 expression than healthy women, they resist phagocytosis and programmed cell death.[13] In this instance, the stimulated macrophage secures proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), tumour necrosis factor-α, ß, integrins and angiogenic factors in increasing quantities [Figure 1].[14,15] Degradation of the extracellular matrix occurs throughout the progressive phase of endometriotic cell attachments; changed expression of matrix metalloproteinases (MMPs) in both eutopic and aberrant endometrial tissues is probably involved in the formation of endometriosis.[16] Excessive reactive oxygen species and inflammatory responses are two significant characteristics of endometriosis. Infertility, dyspareunia, dysmenorrhoea and pelvic pain during the periods of mensuration are common symptoms experienced by women with this health condition.[17,18] Presently available surgical and pharmaceutical therapies for endometriosis management are frequently linked to serious adverse effects and poor long-term outcomes.[19] Endometrioma management involves drug therapy and surgical intervention, with attention given to ovarian reserve, lesion aspects, manifestations and a willingness to carry babies.[10,20] Laparoscopic removal of ovarian endometrioma is the most recommended surgical technique.[21] However, there is a chance that it will cause vascular injury and unintentional removal of healthy ovarian tissue next to the cyst wall, which could harm ovarian reserve.[22,23] Furthermore, endometriosis frequently returns after a conservative procedure, and only approximately 50% of patients get a complete recovery from chronic pain following surgeries.[24] The total volume of endometriomas being reduced and pain relief achieved with drug therapy has turned into an increasingly popular therapeutic option, even if operative engagement for managing endometriomas is becoming debated.[25] The progression of endometriosis depends on both angiogenesis and neuroangiogenesis. Anti-angiogenic substances may suppress endometrial lesions in their early stages or following surgery. Anti-angiogenic chemicals include growth factor inhibitors, endogenous angiogenesis inhibitors, phytochemical compounds, Cyclooxygenase-2 (COX-2) inhibitors, immunomodulators, dopamine agonists, peroxisome, proliferator-activated receptor agonists, progestins, angiogenesis inhibitors, gonadotropin-releasing hormone agonists (GnRHa) and statins.[26] Endometriosis is typically treated with non-steroidal anti-inflammatory drugs (NSAIDs) low-dose estrogen–progestin [oral contraceptive pills (OCPs)] tablets, dienogest (DNZ), GnRHa, danazol or levonorgestrel intrauterine device.[27] All mentioned medications are pharmacologically effective in minimizing endometriosis; nevertheless, their adverse outcomes and high cost are considerable drawback. Since they do not interfere with the ovarian cycle and possess a more focussed effect, non-hormonal medications have gained popularity.[27] DNZ is a progestin that combines the qualities of 19-nortosterone derivatives and progesterone derivatives. This fourth-generation progestin has intense oral pregestational action without any androgenic effects on the body.[28] After extended use, DNZ causes endometrial atrophy because it has a strong progestogenic impact in the endometrium and functions as an agonist at the progesterone receptor with a weak affinity, like progesterone.[29] On endometrial tissue, it stimulates anti-proliferative, anti-immunologic and anti-angiogenic actions. In addition to this, DNZ differs from other progestins in its class due to its anti-proliferative and anti-angiogenic characteristics [Figure 2].[30,31] Mechanism of action of Dienogest. Notes: This figure was drawn using the premium version of BioRender.[11] https://BioRender.com/, accessed on January 17th, 2025, with the agreement license number QQ27STR3MJ.Image credit: Pratiksha Patel. A broad spectrum of antioxidants has been shown to suppress endometrial stroma growth, whereas moderate oxidative stress stimulates this process. Statins suppress the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and have innate antioxidant characteristics.[32] Isoprenyl and other downstream products of the mevalonate pathway are depleted when HMG-CoA reductase is hindered.[33] When isoprenyl is depleted, small GTPases such as Ras and Rho become less active, reducing the signalling of crucial growth-regulating mechanisms. Mevalonate is a precursor of cholesterol and MCP-1, a monocyte chemoattractant protein that plays a significant role in peritoneal inflammation and promotes endometrial adhesion, proliferation and neovascularization.[34] Again, statins effectively suppress cell growth and vascular development in clinical studies for the proliferation of endometriosis-like tissue.[35] Statins, frequently called 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors, have anti-proliferative, anti-oxidant, anti-angiogenic and anti-inflammatory qualities. They may also hinder the function of MMP, making them an intriguing medication for the medical management of endometriosis [Figure 3].[6,36,37] Mechanism of action of statin.Notes: This figure was drawn using the premium version of BioRender.[11] https://BioRender.com/y77l502, accessed on January 17th, 2025, with the agreement license number KK27SUFBFR.Image credit: Pratiksha Patel. Research has shown that simvastatin inhibits the growth of human endometrial stromal (HES) cells in a way that varies with concentration, as indicated by a decline in DNA synthesis and cell viability.[26,38,39] Investigators also discovered that the mevalonate pathway was inhibited by simvastatin and this action did not depend on the availability of cholesterol.[38] In addition, it has been demonstrated that statins prevent the growth of stromal cells originating from human endometriotic deposits in the ovaries (endometriomas).[40] Statins have been shown to significantly suppress tumor angiogenesis in human colorectal and breast cancers through lowering vascular endothelial growth factor and hypoxia-inducible factor-1.[41] Thus, statins can be used to treat endometriosis-related pain and pain associated with relapses. Four categories can be used to characterise the multiple beneficial properties of statins: anti-angiogenic, anti-proliferative, anti-invasive and anti-inflammatory.[6,42] The enhancing amount of information suggests that these medications can help with endometriosis, polycystic ovary syndrome, adhesion prevention, ovarian cancer, pre-eclampsia and anti-phospholipid syndrome.[43,44] Simvastatin and GnRHa did not significantly differ in their efficacy[45,46] between the two patient groups, according to a previous study; triptorelin and simvastatin did not suggestively diverge in their ability to prevent pain occurrences following endometriosis surgery;[47] atorvastatin (ATV) is the suggested drug from the statin group in this study because simvastatin is not currently available in our country. Simvastatin causes a wave of apoptosis and significant phenotypic alterations, including the shrinking of cells and cytoskeleton disruption, which can be repaired in the presence of geranylgeranyl pyrophosphate.[48] The same responses were seen in the presence and absence of estradiol. One of the main mechanisms influencing the development of endometrial tissues is probably the control of endometrial stromal cells’ programmed cell death.[49] Although the exact mechanism of endometriosis is unidentified, accumulating proof suggests that inflammation is essential to the disease’s aetiology.[50] The ATV dosage ought to be modified based on the patient’s reaction. ATV can be taken at any time of day, with or without meals.[51] It could be necessary to reduce dosages in people who have hepatic insufficiency. Patients experiencing an unexplainable chronic increase in serum transaminases or those with active hepatic illness should not use the medication.[52] Thus, statin monotherapy has a low frequency of adverse reactions and is well tolerated.[53] Combining ATV with cyclosporin, nicotinic acid, erythromycin, fibric acid derivatives or azole anti-fungals raises the risk of adverse effects (such as myopathy or rhabdomyolysis). Thus, it is best to avoid doing so.[54] Statins, in conjunction with established hormonal therapies for the control of symptomatic endometrioma, and researchers have stated that statin possibly becomes an additional or supplementary approach for treating symptomatic endometrioma.[46,55,56] In this context, the present study intends to assess the additive effect of ATV in managing symptomatic endometrioma, thereby introducing a noble non-hormonal medication.

of the study The objectives of this study were to assess whether the DNZ + ATV combination is more effective than DNZ alone in women with symptomatic endometrioma.

This prospective comparative study was conducted over 1 year at the Department of Reproductive Endocrinology and Infertility, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka, Bangladesh, following Institutional Review Board (IRB) approval. The study population consisted of women aged 18–38 years with symptomatic endometrioma diagnosed through a transvaginal ultrasound (TVS) and experiencing pain, particularly dysmenorrhoea. Participants were divided into two groups: a treatment arm receiving ATV plus DNZ and a control arm receiving DNZ alone. Sample size determination The sample size was determined to be 19 participants to achieve 80.415% power to detect a difference of 0.1800 using a two-sided Z-test with a significance level of 0.0500 and a null hypothesis population proportion of 0.0500. Finally, the targeted sample size is 19. Up to 10% of patients may drop out. Hence, we took 21 patients in each group. Eligibility criteria Exclusion criteria included endometrioma with a mean diameter ≥6 cm, desire for immediate fertility treatment, contraindications to statins or DNZ, psychiatric disturbances interfering with pain perception, sonographic features of other ovarian cysts, recent use of hormonal suppression or surgery for endometriosis, active renal or hepatic disease, history of myopathic disease and medications interacting with statins (e.g., erythromycin, gemfibrozil, anti-fungals, anti-retrovirals or other cholesterol-lowering drugs). Study procedure Participants were enrolled after clinical diagnosis of endometriosis based on sonographic findings of chocolate cyst with dysmenorrhoea and fulfilling inclusion and exclusion criteria. The volunteers received a thorough explanation of the study’s goals, justification and possible advantages. Informed written permission was obtained after women were counselled about the medications and any unanticipated adverse effects. Participants were split into one of the two treatment arms using an odd-even technique. Interviews, physical exams and laboratory studies were used to gather data. A comprehensive evaluation that considered the patient’s age, occupation, body mass index (BMI), socioeconomic status, infertility, endometrioma size and kind, type of pelvic pain and prior medical and surgical treatment was conducted. Transvaginal ultrasonography was used to measure endometrioma diameters both before and after treatment. Tablet DNZ (2 mg) and tablet ATV (40 mg), 1 tablet daily at night, were given in Group A for 3 months. Tablet DNZ (2 mg), 1 tablet each daily, was given to the women of Group B for the same duration. The last visit was scheduled at the end of 3 months. At the last follow-up visit, a transvaginal sonogram was performed to measure the chocolate cyst, and the pain score was assessed alone by repeating the laboratory tests. Patients were given the investigator’s phone number if any complications arose. Any adverse events were noted. All the participants were advised to use the barrier method for contraception. All the variables of interest were enrolled in the datasheet for this study [Figure 4]. A flow chart illustrating the methodology of the study.Notes: This figure was drawn using the premium version of BioRender[8] https://BioRender.com/, accessed on January 18th, 2025, with the agreement license number TC27T12CWT.Image credit: Pratiksha Patel. Statistical analysis plan The baseline characteristics between Group A (DNZ + ATV) and Group B (DNZ) were assessed. Continuous variables were presented as mean ± standard deviation (SD), whereas qualitative data were presented as numbers with percentages. To examine the association between Group A and Group B regarding baseline characteristics, an independent sample t-test was used for continuous data, and the Chi-square test was applied for qualitative data to estimate the P value. A paired sample t-test was conducted to evaluate within-group changes in endometrioma size between pre- and post-intervention in both groups. A multiple mixed-level regression analysis was also performed to assess the association between the primary exposures, other independent factors and outcomes such as endometrioma size and pain level. Estimates were generated using multiple linear regression models, controlling for variables such as time (pre- and post-intervention), treatment group (Group A and B), age, locality, occupation, type and duration of infertility, income, BMI and socioeconomic status. The change in pain was calculated as post-intervention minus pre-intervention levels. All statistical analyses were conducted using STATA-15 and graphs were generated with GraphPad Prism 8.3.2 [Dotmatics (Life Sciences, Cheminformatics, Bioinformatics, Boston, Massachusetts, USA)]. A p<0.05 was considered statistically significant. Ethical approval Ethical approval was taken from the IRB of BSMMU, Shahbag, Dhaka, Bangladesh, Reference no. BSMMU/2022/5649, dated 06 June 2022. The study participants were explained in detail in an easily understandable local language about this research. Then, voluntary informed written consent was obtained from the patient before any intervention and data collection. This research strictly follows the declaration of Helsinki by the World Medical Association.

Table 1 presents the baseline characteristics of study participants divided into Group A (DNZ + ATV) and Group B (DNZ). The average age of participants in Group A was 29.8 years, slightly higher than the 27.5 years in Group B, with a P = 0.090, indicating no significant difference. Most participants in both groups resided in urban areas, with no significant difference in residence distribution (P = 0.739). Occupational status and BMI categories were also similar across groups, with no significant differences (P = 0.99 and not provided) However, income distribution showed a trend towards significance, with more participants in Group B earning less than Bangladesh Taka ([BDT] currency) 30,000 (P = 0.121). Regarding infertility type, Group B had a higher proportion of primary infertility cases, although this difference was not statistically significant (P = 0.116). The duration of infertility was significantly different between the groups, with most participants in Group A experiencing infertility for more than 3 years, whereas most in Group B had infertility for <3 years (p<0.001). Baseline characteristics of the study participants Endometrioma size significantly decreased in both groups following the intervention. In Group A (DNZ + ATV), the mean ± SD size of the endometrioma was 4.86 ± 0.77 before the intervention and reduced to 4.77 ± 0.91 after the intervention [Figure 1]. Similarly, in Group B (DNZ), the size decreased from 4.57 ± 0.97 pre-intervention to 3.98 ± 0.97 post-intervention [Figure 5]. Within-group changes of Endometrioma size between pre-and post-intervention in Groups A and B, a paired sample t-test was used to estimate the p value.Illustration credit: Md Ahsanul Haq. Pain levels also decreased significantly in both groups following the intervention. In Group A (DNZ + ATV), the mean ± SD pain level dropped from 6.76 ± 1.26 pre-intervention to 2.81 ± 0.93 post-intervention. Similarly, in Group B (DNZ), pain levels decreased from 6.52 ± 1.60 before the intervention to 2.86 ± 2.23 afterward [Figure 6]. Pain level changes within the group between pre-and post-intervention in Group A and, Group A and B. Paired sample t-test was used to estimate the p value.Illustration credit: Md Ahsanul Haq. We conducted a multiple mixed-level regression analysis to assess the association between the primary exposures, other independent factors and outcomes such as endometrioma size and pain level. The results showed that post-intervention, endometrioma size decreased by 0.81 units (95% confidence interval [CI]: −1.10, −0.52, P < 0.001) and pain levels decreased by 3.81 units (95% CI: −4.31, −3.30, P < 0.001) [Table 2]. No significant associations were found for the treatment group (Group A and B), age, locality or infertility status. However, pain reduction was 1.36 units greater amongst participants with infertility duration of ≥3 years compared to those with ≤3 years duration. Both endometrioma size and pain levels significantly decreased by 0.79 and 1.07 units, respectively, amongst the higher-income group (>30,000 BDT) compared to the lower-income group (<30,000 BDT). Interestingly, pain levels were 1.64 units higher in the obese group (95% CI: 0.36, 2.92, P = 0.012). In addition, participants reporting menstrual problems had a reduction in endometrioma size by 0.92 units (95% CI: −1.32, −0.52, P < 0.001) [Table 2]. The effect of time, treatment intervention, and other potential independent factors on endometrioma size and pain changes

Endometriosis is a chronic gynaecologic disorder that is extremely challenging to treat. The development of endometriomas and discomfort characterises endometriosis.[57] Since medical management avoids the threat of ‘endometrioma surgery’, which reduces ovarian reserve, it has become the cornerstone of treatment for symptomatic endometrioma.[58] The latest suggests that adding DNZ + ATV can improve the effectiveness of treatment.[59] Historically used to decrease cholesterol, statins have also demonstrated anti-inflammatory and anti-proliferative qualities, which may help endometriosis.[60] The study subjects were divided into Group A (DNG + ATV) and Group B (DNG). The present study showed that the mean age in Group A (DNG + ATV) was 29.8 ± 4.03 years, whereas in Group B (DNG), it was 27.8 ± 4.65 years, with no significant difference between the two groups. This finding suggests that the age distribution was similar in both groups. Most patients in both groups resided in urban areas, with 66.7% in Group A (DNG + ATV) and 71.4% in Group B (DNG). There were no significant differences between Group A (DNG + ATV) and Group B (DNG) in terms of age group, residence, occupation and income (P > 0.05). These findings are consistent with the study results from the other researchers.[61,62] Again, the current study showed that before treatment, the mean endometrioma size in Group A (DNG + ATV) was 4.86 ± 0.77 cm, which is more significant compared to Group B (DNG) (4.58 ± 0.97 cm) (P = 0.306). However, there is no significant difference in the post-treatment endometrioma size between the two groups, with both groups having a mean endometrioma size of around 4 cm (Group A [DNG + ATV]: 3.83 ± 0.91 cm, Group B [DNG]: 3.98 ± 0.97 cm) (P = 0.603). There is a significant decrease in endometrioma size within both groups after treatment (P < 0.001). The mean change in endometrioma size was higher in Group A (DNG + ATV) (1.03 ± 0.77 cm) compared to Group B (DNG) (0.60 ± 0.49 cm). The mean percentage reduction in endometrioma size was also higher in Group A (DNG + ATV) (21.2%) compared to Group B (DNG) (13.1%). These results suggest that both treatments effectively reduced endometrioma size, with DNZ + ATV showing a higher percentage reduction than DNZ alone. The study by Harada et al. 2009[63] reported decreased endometriosis size after treatment with DNZ and intranasal buserelin acetate. The mean size of endometriotic lesions was reduced from 13.7 to 10.1 mm in the DNZ group and from 14.5 to 9.7 mm in the intranasal buserelin acetate group after 24 weeks of treatment. The study conducted by Wu et al. 2024[64] investigated the efficacy and safety of DNZ in treating deep infiltrating endometriosis. Although the study did not report on reducing endometriosis size, it is essential to note that a decrease in endometriosis size is not always a reliable indicator of symptom relief. The study’s primary outcome was the reduction in pain associated with endometriosis, and the analysis narrated that DNZ pharmacodynamics more profoundly minimizes pain triggered by endometriosis.[64] In Group A (DNG + ATV), the pre-treatment pain score was 6.76 ± 1.26, whereas in Group B (DNG), it was 6.52 ± 1.60. The variation amongst the two groups was not statistically significant (P = 0.595). Similarly, the post-treatment pain score did not show a considerable difference between the two groups, with Group A (DNG + ATV) having a mean score of 2.81 ± 0.93 and Group B (DNG) having a mean score of 2.86 ± 2.13 (P = 0.926). The mean change in endometrioma size was also similar between the two groups, with Group A (DNG + ATV) having a mean shift of 3.95 ± 1.07 cm and Group B (DNG) having a mean change of 3.67 ± 1.49 cm. The mean percentage reduction in endometrioma size was slightly higher in Group A (DNG + ATV) (58.4%) compared to Group B (DNG) (56.1%). Angioni et al. 2020 revealed that DNZ effectively reduced endometrioma size and pain scores.[65] Another survey by Maiorana et al. 2017 reported that DNZ effectively reduced pain in women with endometriosis over 12 months.[66] El Taha et al. 2021 and Murji et al. compared the efficacy of DNZ. Both group reported that combined oral contraceptives (COCs) to relieve pain associated with endometriosis. Like our findings, they stated that one and the other, DNZ and COCs, led to a scaling down in endometriosis measurement (breadth and width) after therapeutic intervention.[28,67] The principal findings of this research are depicted in Figure 7. Principal findings of this study.Notes: This figure has been drawn by utilizing premium version of BioRender. University, K. (2025) https://BioRender.com/c80i030, accessed on January 17th, 2025, with the agreement license number HG27U93FK7.Image credit: Pratiksha Patel.

of the study The results may not be as extensively acceptable as possible because of the small sample size. Again, the study sample was chosen from one focal point in Dhaka, Bangladesh. This research obtained no financial support to extend our research. Since the VAS is a subjective tool, molecular methods of measuring pain should be used instead. Furthermore, the follow-up period was brief, and neither the therapies’ long-term effects nor their safety was assessed.

This study evaluated the efficacy of DNZ alone to DNZ + ATV in women with symptomatic endometrioma. The findings revealed that both treatment regimens efficiently lowered the size of endometriomas and relieved discomfort in the study subjects. On the other hand, neither post-treatment endometrioma size nor pain reduction differed significantly between the two groups. These results imply that women with symptomatic endometrioma may not benefit substantially more from taking an ATV in addition to DNZ treatment. Future research recommendation Additional well-designed prospective research with larger sample sizes, multicentre and randomisation is needed to establish the most effective strategy for symptomatic endometrioma with these agents. In addition, higher doses and regimens for ATV as a single agent involving laparoscopic evaluation are needed. Longstanding follow-up studies are also required to see the adverse effects of statins in premenopausal women. Consent for publication The author reviewed and approved the final version and has agreed to be accountable for all aspects of the work, including any accuracy or integrity issues. Data availability This is an original paper. Data from the principal author are available only for research purposes. Authorship contribution All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted, and decided to be accountable for all aspects of the work. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

The authors are very grateful to Mr. Md. Ahsanul Haq, icddr, b-Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka 1212, Bangladesh, who helped us do the statistical analysis.

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