Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. There is an unmet need for new medical treatment options for endometriosis. Pelvic peritoneal mesothelial cells of women with endometriosis exhibit detrimental metabolic reprogramming that creates an environment favouring the formation and survival of endometriosis lesions. We have generated powerful preclinical proof-of-concept data to show that it is possible to correct this metabolic phenotype using dichloroacetate (DCA), a non-hormonal compound previously used to treat rare metabolic disorders in children. We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain.We will recruit 30 women with endometriosis-associated pain over a 6-month period. All participants will receive approximately 6.25 mg/kg oral DCA capsules twice daily for 6 weeks, with a dose increase to approximately 12.5 mg/kg twice daily for a further 6 weeks if their pain has not been adequately controlled on this dose regime and side-effects are acceptable. If pain is adequately controlled with minimal side-effects, the lower dose will be continued for a further 6 weeks. The primary objective is to determine whether it is possible to achieve acceptable recruitment and retention rates within the defined exclusion and inclusion criteria. Secondary objectives are to determine the acceptability of the trial to participants, including the proposed methods of recruitment, treatment, follow-up frequency and number of questionnaires. The recruitment rate will be determined by the proportion of patients recruited from the pool of eligible women. The retention rate will be determined by the proportion of participants who attended the final trial visit.This is a feasibility study to explore effectiveness and acceptability of the proposed field methodology (recruitment, retention, study processes and compliance with treatment). The results will be used to inform the design of a future RCT.ClinicalTrials.gov, NCT04046081 Registered 6 August 2019.
Abstract Endometriosis requires medical management during a woman’s reproductive years. Most treatments aim to create a hypoestrogenic milieu, but for patients wishing to conceive, drugs that allow normal ovarian function are needed. Targeting angiogenesis, a hallmark of the disease, using dopamine agonists (DAs) is a promising strategy for endometriosis treatment. Herein, we review experimental and clinical data that investigate this concept. In experimental models of endometriosis, DAs (bromocriptine, cabergoline, quinagolide) downregulate proangiogenic and upregulate antiangiogenic pathways in inflammatory, endothelial and endometrial cells, blocking cellular proliferation and reducing lesion size. Impaired secretion of vascular endothelial growth factor (VEGF) and inactivation of its receptor type-2 are key events. VEGF inhibition also reduces nerve fiber density in lesions. In humans, quinagolide shows similar effects on lesions, and DAs reduce pain and endometrioma size. Moreover, a 20-fold downregulation of Serpin-1, the gene that encodes for plasminogen activator inhibitor 1 (PAI-1), has been observed after DAs treatment. Pentoxifylline, a PAI-1, increases pregnancy rates in women with endometriosis. Thus, the data support the use of DAs in the medical management of endometriosis to reduce lesion size and pain while maintaining ovulation. A combined approach of DAs and pentoxifylline is perhaps a smart way of targeting the disease from a completely different angle than current medical treatments.
In Brief Objective: To compare bone mineral density (BMD) and bone turnover changes after therapy withdrawal in postmenopausal women treated with alendronate or estrogen-progestin. Design: In this randomized, blinded, multinational, placebo-controlled trial, 1,609 healthy postmenopausal women ages 45 to 59 years were assigned to receive alendronate, placebo, or open-label estrogen-progestin (conjugated equine estrogens plus medroxyprogesterone acetate or a cyclic regimen of 17β-estradiol, norethisterone acetate and estradiol). Of the original women, one third after year 2 and one third after year 4 were switched from alendronate to placebo, while remaining blinded to treatment assignment. The women taking estrogen-progestin in years 1 to 4 were followed off therapy in years 5 and 6. BMD at the lumbar spine and hip and biochemical markers of bone turnover were measured. Results: The treatment groups described in the current report represent 860 women at baseline; 481 women entered year 5, and 430 completed 6 years. BMD steadily decreased in the placebo group during all 6 years. In contrast, spine and hip BMD increased during the first 4 years in the groups receiving daily continuous alendronate 5 mg and estrogen-progestin. During years 5 and 6, BMD decreased at the lumbar spine -2.42% (95% CI = −4.10, −0.74) and total hip −1.09% (−2.60, 0.41) in the group previously treated with alendronate 5 mg for 4 years. In comparison, large BMD decreases were observed at the spine [−7.69% (−8.96, −6.41)] and total hip [−5.16% (−6.30, −4.01)] among women who had received estrogen-progestin for 4 years. Conclusion: Alendronate produces greater residual skeletal effects than estrogen-progestin after therapy discontinuation. Early postmenopausal women (N = 860) were randomized to placebo, alendronate, or estrogen-progestin for 4 years followed by 2 years on placebo, with 430 women completing all 6 years of the trial in these treatment subgroups. Bone density increased during the first 4 years of treatment with alendronate or estrogen-progestin, but decreases in bone density and increases in bone turnover during the subsequent 2 years were much larger after stopping estrogen-progestin than after stopping alendronate.
The estrogen receptor α (ESR1) gene has been implicated in the process of cognitive impairment in elderly women. In a paired case–control study, we tested whether two ESR1 gene polymorphisms (the XbaI and PvuII sites) are risk factors for cognitive impairment as measured by the six-item Orientation-Memory-Concentration test in postmenopausal Danish women. Hormone replacement therapy, age and executive cognitive ability were examined as covariates for ESR1 gene effects on cognitive impairment. The XbaI polymorphism showed a marginal effect on cognitive abilities (P=0.054) when adjusted for executive cognitive ability. Using a dominant genetic model for the X allele, we found an elevated risk (executive cognitive ability adjusted P=0.033) for cognitive impairment. Hormone replacement therapy also had a borderline effect on cognitive ability (P=0.049) and this effect was reflected in executive cognitive ability. These data support that the ESR1 gene variants affect cognitive functioning in postmenopausal women.
