Nonhormonal management of endometriosis: Role of dopamine D2 receptor agonists in preserving fertility and ovarian function

Rahi Tinni Basu: Writing – review & editing, Writing – original draft, Formal analysis, Data curation. Pradip Kumar Mitra: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Conceptualization.

Phase 3 trials should assess stratified dosing and combinations. Biomarkers such as VEGF-A expression and microvessel density, a well-established angiogenesis marker detected in the endometriotic tissues via immunohistochemistry, may aid in refining patient selection. Furthermore, long-acting agents may be formulated to enhance adherence. Finally, cost-effectiveness models and extended safety monitoring could support real-world implementation.

A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science (2000–May 2026) to identify preclinical and clinical studies of DRD2 agonists in endometriosis. Boolean search strings combined terms related to DRD2, VEGF-A pathways, angiogenesis, endometriosis, treatment, and fertility outcomes. Eligibility was restricted to peer-reviewed, English-language reports evaluating endometriotic lesion dynamics, angiogenic markers, or reproductive outcomes. Studies with overlapping datasets or those not specific to endometriosis pathophysiology were excluded. Basu et al ( 6 ) first established that dopamine attenuates VEGF-A–induced angiogenesis and vascular permeability by activating DRD2 on endothelial cells. Endometriotic lesions demonstrate significantly elevated VEGF-A expression compared with eutopic endometrium, with increased levels detected at both mRNA and protein levels across stromal, epithelial, and endothelial compartments, fueling aberrant neovascularization essential for implant survival and growth ( 7 , 8 ). The VEGF-A–driven vascular permeability and angiogenesis can be inhibited by dopamine through DRD2 activation on endothelial cells ( 6 ). This dopamine action prevents VEGF receptor 2 (VEGFR-2) phosphorylation and blocks downstream mitogen-activated protein kinase and focal adhesion kinase signaling ( 6 ). Immature neo vessels in endometriotic lesions express high VEGFR-2 levels, whereas mature corpus luteum vessels do not ( 1 , 9 ). DRD2 is expressed in both human eutopic and ectopic endometrium, and DRD2 agonists have not been shown to disrupt normal ovarian functions such as ovulation, steroidogenesis, or folliculogenesis. Therefore, these drugs represent a promising nonhormonal, anti-angiogenic strategy that may selectively induce regression of ectopic endometrial implants, while preserving normal ovarian function and reproductive potential ( 10 , 11 , 12 , 13 ).

DRD2 agonists represent a targeted, fertility-preserving therapeutic approach for endometriosis ( 5 , 16 ). Consistent with robust evidence from preclinical models, and QLARITY phase 2 clinical studies, these drugs can substantially regress endometrial lesions and reduce pain in key trials through selective VEGF-A pathway inhibition ( 5 , 16 ). Meanwhile, they can preserve ovulation in most patients, confirming the integrity of the hypothalamic–pituitary–ovarian axis function and preventing hypoestrogenic side effects common to standard therapies ( 5 ). DRD2 agonists have evolved from a preclinical concept established in 2001 into a clinically viable platform for nonhormonal endometriosis therapy ( 5 , 6 , 16 , 23 ). These agents are particularly promising for adolescents and reproductive-age women seeking long-term disease control compatible with fertility ( 16 ). Thus, they are well-positioned to redefine treatment paradigms. Furthermore, these agents exhibit favorable safety profiles, discontinuation rates, preserved bone mineral density, and cost-effectiveness ( 5 , 17 ). Although the dose of DRD2 agonists used in the clinical trial of endometriosis has been shown to be safe with a low incidence of tolerable side effects ( 5 , 16 , 23 ), clinicians should nonetheless monitor for other manageable adverse effects observed in some Parkinson’s disease patients, including nausea, dizziness, orthostatic hypotension, peripheral edema, fatigue, hallucinations, impulse control disorders (e.g., compulsive gambling, buying, and hypersexuality), sudden sleep attacks, and withdrawal syndrome ( 24 ). Taken together, the overall benefit–risk profile supports progression toward regulatory approval and broader clinical adoption. Overall, DRD2 agonists address a critical unmet need by delivering durable, nonhormonal disease control while maintaining reproductive potential for millions affected worldwide.

Preclinical studies using human endometrial transplantation models have demonstrated DRD2 expression in endometriotic lesions, confirmed via polymerase chain reaction (mRNA) and immunohistochemistry (protein) ( 10 ). In these models, ovariectomized nude mice were implanted subcutaneously in the neck with sterile capsules containing 18 mg of 17β-estradiol (60-day release). Four days later, fresh eutopic human endometrial fragments, obtained from women with normal menstrual cycles and no history of endometriosis, were implanted into the peritoneal cavity ( 14 , 15 ). After three weeks, mice received oral treatment with the DRD2 agonists cabergoline (50 μg/kg/day) or quinagolide (50–200 μg/kg/day) for 14 days. These treatments significantly suppressed angiogenesis and promoted regression of endometriotic lesions compared with vehicle-treated controls. The reductions were statistically validated using nonparametric Mann–Whitney and Dunn’s multiple comparisons tests ( P <.05) (R8). Mechanistically, these effects were associated with inhibition of VEGFR-2 phosphorylation, with no evidence of toxicity at therapeutic doses ( 14 , 15 ). A randomized, double-blind, placebo-controlled pilot study involving the administration of cabergoline (orally 0.5 mg, twice weekly) + (placebo daily for 6 months) (n = 4) demonstrated a decrease in their worst pain severity by 86% vs 43% in the NETA (5 mg/day) + placebo (n = 3) twice weekly group. Similarly, average pain decreased by 83% in the cabergoline group and 57% in the NETA group ( 16 ) ( Table 1 ). Table 1 Clinical studies Study component DiVasta et al ( 16 ), 2021 (Cabergoline vs NETA) Pellicer et al ( 5 ), 2025 (QLARITY Trial) Study type Randomized, double-blind, placebo-controlled pilot trial Randomized, double-blind, placebo-controlled, phase 2 trial Sample size 9 patients randomly assigned; seven completed 6 mo (Cabergoline: n = 4; Norethindrone acetate (NETA): n = 3) 67 patients (Quinagolide: n = 35; Placebo: n = 32) Comparison groups Cabergoline 0.5 mg orally twice weekly + daily placebo vs NETA 5 mg orally daily + placebo twice weekly Quinagolide vaginal ring (1080 μg) vs placebo vaginal ring Intervention and duration Cabergoline 0.5 mg tablets twice weekly for 6 mo vs NETA 5 mg tablets once daily for 6 mo, each with a matching placebo; inperson assessments at baseline, 3 and 6 mo with interim telehealth follow-up Quinagolide vaginal ring or placebo for 4 menstrual cycles, with MRI at baseline and end of treatment Primary outcome Change in endometriosis-associated pelvic pain, with Brief Pain Inventory interference scale specified as primary pain outcome over 6 months Reduction in total lesion size (endometrioma, deep infiltrating endometriosis, and adenomyosis) assessed by high-resolution MRI Secondary outcomes Pain intensity (visual analogue scale [VAS]: current, worst, least, average pain), percentage pain relief, depressive symptoms (Beck Depression Inventory-II), functional disability, patient global impression of change, non-narcotic analgesic use, safety laboratories and adverse events Pain reduction, changes in serum prolactin levels, menstrual cycle changes, bleeding patterns, safety/adverse events, MRI-derived perfusion and diffusion-weighted imaging biomarkers Key statistical results Descriptive pilot findings only (no powered between-group hypothesis testing). Mean 6-mo decrease in worst pain in last 24 h: 86% with cabergoline vs 43% with NETA; mean decrease in average pain: 83% vs 57%, respectively. No significant differences between quinagolide and placebo for the primary endpoint (lesion size reduction), menstrual bleeding patterns, or adverse events. However, post hoc analysis of lesion regression showed 61.3% of lesions (n = 19/31) in the quinagolide (1080 μg) vaginal ring group regressed, compared with 35.5% (n = 11/31) in the placebo group (chi-square test; P = .04). Exploratory MRI analyses further suggested greater increase in vascular permeability and worsening lesion structure in the placebo group compared with quinagolide. Clinical studies Despite missing its primary endpoint of reduction in total lesion size, a post hoc analysis of lesion regression in the QLARITY phase 2 trial demonstrated that 61.3% of lesions (n = 19/31) in the quinagolide (1080 μg) vaginal ring group regressed, compared with 35.5% (n = 11/31) in the placebo group (chi-square test; P = 0.04) ( 5 ) ( Table 1 ). A nuanced interpretation of the phase 2 QLARITY trial is essential to understand the emerging clinical profile of DRD2 agonists. The phase 2 QLARITY trial requires cautious interpretation. The primary endpoint—change in total lesion volume from baseline to cycle 4—did not differ significantly between quinagolide and placebo, indicating no clear short-term volumetric benefit at the patient level. However, a post hoc lesion-level analysis showed a higher proportion of regressing individual lesions with quinagolide than with placebo (61.3% vs 35.5%, P = .04, unadjusted for multiplicity), suggesting a biologically plausible effect that may be masked when heterogeneous lesions are pooled into a single global volume measure. Although these findings are exploratory and limited by sample size, they support the prospective incorporation of lesion-level endpoints in future trials ( 5 ). Furthermore, mechanistic and biomarker data are consistent with this signal. Exploratory analyses indicated more pronounced therapeutic effects in superficial and VEGF-A–high lesions, consistent with an angiostatic mechanism mediated via VEGFR-2 inhibition, whereas deep infiltrating endometriosis, characterized by a fibrotic, VEGF-A–independent vasculature, was inherently less susceptible to rapid volumetric reduction and likely contributed to the neutral primary outcome. Preservation of ovulatory cycles in 93% of participants demonstrates that DRD2 agonists can exert localized angiostatin activity without disrupting hypothalamic–pituitary–ovarian axis function, providing proof-of-concept for a nonhormonal strategy preserving reproductive potential ( 5 ). In summary, DRD2 agonists from different pharmacologic classes demonstrate a consistent biological and clinical signal in endometriosis ( 5 , 16 ). Lesion regression rates exceeding 60%, a significant decrease in pain severity coupled with high ovulation preservation, reinforce the usefulness of DRD2 agonists in targeting the VEGF-A/VEGFR-2 axis in endometriosis ( 5 , 16 ). Although current studies remain modest in size, the reproducible pattern of disease modification without hormonal suppression supports the expansion of this investigation to larger, phase 3 validation trials. Unlike hypoestrogenic agents that suppress ovulation broadly, DRD2 agonists target angiogenesis locally ( 16 ). Consequently, they can preserve fertility and bone health, making them suitable for adolescents and women planning pregnancy ( 5 , 17 ). They are also more cost-effective than GnRH agonists. Given its advantage of preserving fertility, DRD2 agonists yield superior quality-adjusted life years compared with standard therapies ( Table 2 ). Table 2 DRD2 vs. hormonal therapies Parameter DRD2 agonists GnRH/progestins Mechanism VEGF-A/VEGFR-2 inhibition ( 14 , 18 ) Estrogen suppression ( 5 , 19 ) Ovulation Preserved ( 20 ) Suppressed ( 21 ) Bone density Stable ( 17 ) Declined ( 19 ) Cost Low High Fertility Maintained ( 5 , 22 ) Impaired ( 5 ) DRD2 = Dopamine D2 receptor; GnRH = gonadotropin-releasing hormone; VEGF-A = vascular endothelial growth factor A. DRD2 vs. hormonal therapies DRD2 = Dopamine D2 receptor; GnRH = gonadotropin-releasing hormone; VEGF-A = vascular endothelial growth factor A. Trials also reported that DRD2 agonist therapy led to low discontinuation rates (∼3%) and transient side effects, including headache or nausea ( 5 ). No serious adverse or hypoestrogenic effects were reported, making these drugs well tolerated ( 5 ). Additionally, no patient experienced bone loss, thromboembolism, hypertension, or fertility risks ( 5 ). Cohorts have also exhibited excellent tolerability and pain relief ( 16 , 23 ). However, further comparative trials are required to fully quantify the long-term efficacy and pain outcomes of DRD2 agonists relative to established hormonal treatments.

R.T.B. has nothing to disclose. P.K.M. has nothing to disclose.