A Prospective Cohort Study of Metformin as an Adjuvant Therapy for Infertile Women With Endometrial Complex Hyperplasia/Complex Atypical Hyperplasia and Their Subsequent Assisted Reproductive Technology Outcomes

Abstract

ObjectiveTo investigate the adjuvant efficacy of metformin treatment to achieve pathological complete response (CR) in patients with endometrial complex hyperplasia (CH) and complex atypical hyperplasia (CAH), and secondarily, to evaluate their pregnancy outcomes after following assisted reproductive technology (ART).Study DesignThis prospective cohort study analyzed 219 patients diagnosed with infertility and CH/CAH from January 2016 to December 2020. Among these patients, 138 were assigned to the control group (progesterone alone) and 81 were assigned to the study group (progesterone+metformin). After 8/12 weeks of therapy, the treatment responses were assessed by histological examination of curettage specimens obtained by hysteroscopy. Once the pathological results indicated CR, the patients were able to receive ART. The ART treatment and follow-up data of these patients were collected and analyzed.Results116 patients in the control group achieved CR, compared with 76 patients in the study group. The CR rate in the control group was significantly lower than that in the study group (P=0.034). We then divided the patients into subgroups to compare the treatment responses. In the subgroup analyses, patients with body mass index (BMI) ≥25 kg/m2 and patients with polycystic ovarian syndrome (PCOS) had higher CR rates in the metformin group compared with the control group (P=0.015, P=0.028 respectively). Subsequently, 68 patients in the control group and 47 patients in the study group received an ART cycle. We examined the pregnancy indications and found no significant differences in the clinical pregnancy rate and live birth rate between the two groups (P>0.05).ConclusionRegression of CH/CAH may be improved by progesterone+metformin compared with progesterone alone. The effect was particularly pronounced in patients with BMI ≥25 kg/m2 and patients with PCOS. Metformin had no obvious effect on subsequent ART outcomes. The trial is registered on the publicly accessible website:Clinical Trial Registrationhttp://www.chictr.org.cn/showproj.aspx?proj=15372, identifier ChiCTR-ONR-16009078.

Progestin plus metformin improves outcomes in patients with endometrial hyperplasia and early endometrial cancer more than progestin alone: a meta-analysis

“…Among the 13 studies, 1 study was presented as a conference in 2020 ( 19 ), and finally as an article in 2023 ( 20 ), and 5 studies enrolled both patients with EH and patients with EEC ( 19 – 24 ), and 5 studies focused only on patients with EH ( 8 , 11 , 12 , 25 , 26 ), and 2 studies enrolled only patients with EEC ( 9 , 10 ). Six studies were prospective trials ( 9 , 11 , 12 , 23 , 26 , 27 ), while seven were retrospective trials ( 8 , 10 , 19 – 22 , 24 , 25 ). The study published by Matsuo et al.…”

“…There are two routes of progestin therapy, with systemic administration including oral medroxyprogesterone acetate, megestrol acetate, norethindrone, depo-medroxyprogesterone acetate, and local administration via a levonorgestrel-releasing intrauterine device. The route of progestin therapy were systemic administration in eight studies ( 8 , 12 , 19 , 20 , 22 – 24 , 26 ), and local administration alone in two studies ( 11 , 27 ), and systemic administration combined with local administration in one studies ( 10 ), and systemic or local administration in two studies ( 21 , 25 ). The dose of metformin was administered in a range from 500 mg/d ( 21 ) to 2,500 mg/d ( 20 , 25 ), with the commonly administered dose of 1,000 mg/d and 1,500 mg/d.…”

“…For patients with PCOS, two studies have shown that PCOS status is not a risk factor for disease prognosis ( 10 , 21 ), and another study found that PCOS patients had a significantly higher CR rate in the Prog-Met group compared to the Prog group (p=0.028) ( 8 ). Metformin may reverse endometrial dysfunction in PCOS women, and improve pregnancy outcomes in obese and/or insulin resistant patients ( 4 ).…”

Metformin and the Liver: Unlocking the Full Therapeutic Potential

“…Metformin, in addition to its role as an antidiabetic agent, has garnered attention for its potential anticancer properties in several neoplasia [152][153][154][155][156], although the mechanisms underlying its anticancer effects are not fully understood [26]. Preclinical studies using in vitro and in vivo models have provided valuable insights: metformin might inhibit cell proliferation [157] by inducing cell cycle arrest [158], and promoting apoptosis [159] through the AMP-activated protein kinase (AMPK) pathway [160], the mammalian target of rapamycin (mTOR) pathway [157], and the insulin-like growth factor (IGF) signalling pathway [161].…”

Metformin: A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation

“…All this clinical evidence indicated that Met had a certain ability to regulate sex steroid hormone profiles. In addition, clinical trials have also proven that Met can improve endometrial hyperplasia (EH), endometrial cancer (EC), bladder cancer, prostate cancer (PCa), and so on [ [13] , [14] , [15] ]. Related preclinical studies have shown that Met inhibits cellular proliferation and blocks the cell cycle in the G0/G1 stage of atypical EH and endometrioid EC and PCa cell lines, resulting in its antiproliferative effect [ 16 ].…”