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Is repeated high-dose medroxyprogesterone acetate (MPA) therapy permissible for patients with early stage endometrial cancer or atypical endometrial hyperplasia who desire preserving fertility?

ABSTRACT: OBJECTIVE:Reports on the repeated administration of medroxyprogesterone acetate (MPA) for intrauterine recurrence after fertility-preserving therapy for atypical endometrial hyperplasia (AEH) and early grade 1 endometrioid carcinoma (G1) are lacking. We aimed to clarify the outcomes of repeated MPA therapy in cases of intrauterine recurrence after fertility-preserving therapy with MPA against AEH/early G1. METHODS:Patients with AEH or stage IA well-differentiated endometrioid carcinoma without myometrial invasion who underwent first-line MPA therapy for primary lesions or intrauterine recurrence were divided into initial treatment and repeated treatment groups (162 and 82 patients, respectively). Oral MPA administration (400-600 mg/day) was continued until pathological tumor disappearance. Data regarding clinicopathological factors, adverse events, and outcomes following the initial and repeated hormonal treatments were extracted from medical records and analyzed. RESULTS:Complete response rates in the initial and repeated treatment groups were 98.5% and 96.4%, respectively, among patients with AEH, and were 90.7% and 98.1%, respectively, among patients with G1. In the initial treatment group, 5-year recurrence-free survival (RFS) rates were 53.7% and 33.2% among patients with AEH and G1, respectively. In the repeated treatment group, RFS rates were 14.0% and 11.2% among patients with AEH and G1, respectively. Among patients with AEH, the pregnancy rate tended to be lower in the repeated treatment group than in the initial treatment group (11.1% vs. 29.2%; p=0.107), while no significant group difference was observed among patients with G1 (20.8% vs. 22.7%). CONCLUSION:Repeated treatment is sufficiently effective for intrauterine recurrence after hormonal therapy for AEH/early G1.

SUBMITTER: Yamagami W

PROVIDER: S-EPMC5823982 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProgestin is used for fertility-sparing treatment in cases of endometrial cancer (EC). Progestin can induce hyperprolactinemia by increasing pituitary secretion and endometrial decidualization. However, progestin induces prolactin (PRL) secretion, which stimulates cell proliferation and deleteriously affects treatment. To date, the detrimental effect of PRL, the secretion of which is induced by medroxyprogesterone acetate (MPA) during fertility-sparing treatment, has not yet been fully elucidated. Therefore, we aimed to assess the effects of PRL on EC cells during combined treatment with progestin and metformin.MethodsIn total, 71 patients with EC/endometrial atypical hyperplasia who underwent fertility-sparing treatment at our institution from 2009-2019 were enrolled. Serum PRL levels were determined using enzyme immunoassays; mRNA levels in endometrial tissues were determined using quantitative reverse-transcription PCR. To evaluate MPA-induced decidualization, cancer-associated stromal cells were enzymatically released from surgically removed specimens of six patients with EC. To examine PRL-induced cell proliferation, the EC cell lines Ishikawa, HEC1B, and HEC265 were used. In vitro cell proliferation was evaluated using the WST assay; protein levels of signaling molecules were determined using western blotting.ResultsMPA administration significantly increased serum PRL levels at 3 and 6 months and upregulated IGFBP-1 and PRL mRNA expression in tissues at 3 months of fertility-sparing treatment. Metformin significantly reduced MPA-induced IGFBP-1 and PRL mRNA expression during fertility-sparing treatment and significantly inhibited the upregulation of IGFBP-1 and PRL mRNA and PRL levels due to decidualization induced by MPA and cAMP treatment in primary cultured EC stromal cells. In vitro, PRL increased cell proliferation and ERK1/2 phosphorylation levels, whereas metformin attenuated these increases.ConclusionsMPA upregulated PRL levels in serum and endometrial tissues during fertility-sparing treatment. Metformin co-administration reduced PRL production and attenuated PRL-induced cell-proliferation activity. This study may provide valuable insights on the application of metformin to improve the outcomes of fertility-sparing treatment.

Project description:Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and affects predominantly postmenopausal women. It is estimated, however, that 15%-25% of women will be diagnosed before menopause. As more women choose to defer childbearing until later in life, the feasibility and safety of fertility-sparing EC management have been increasingly studied. Definitive treatment of total hysterectomy and bilateral salpingo-oophorectomy precludes future fertility and may thus be undesirable by women who wish to maintain their reproductive potential. However, the consideration of conservative management carries the oncologic risks of unstaged EC and the risk of missing a synchronous ovarian cancer. It is further complicated by the lack of consensus regarding the initial assessment, treatment, and surveillance. Conservative treatment with progestins has been shown to be a feasible and safe fertility-sparing approach for women with low grade, early stage EC with no myometrial invasion. The two most commonly adopted regimens are medroxyprogesterone acetate at 500-600 mg daily and megestrol acetate at 160 mg daily for a minimum of 6-9 months, with initial response rates commonly reported between 60% and 80% and recurrence rates between 25% and 40%. Photodynamic therapy and hysteroscopic EC excision have recently been reported as alternative approaches to progestin therapy alone. However, limited efficacy and safety data exist. Live birth rates after progestin therapy have typically been reported around 30%; however, when focusing only on those who do pursue fertility after successful treatment, the live birth rates were found to be higher than 60%. Assisted reproductive technology has been associated with a higher live birth rate compared with spontaneous conception, most likely reflecting the presence of infertility at baseline. Close follow-up is of paramount importance, and definitive treatment after completion of childbearing is advised.

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Is repeated high-dose medroxyprogesterone acetate (MPA) therapy permissible for patients with early stage endometrial cancer or atypical endometrial hyperplasia who desire preserving fertility?

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