Dienogest mediates midkine suppression in endometriosis

Abstract

Study question: What are the effects of dienogest (DNG) on midkine (MK) production in women with endometriosis?

Summary answer: DNG-mediated down-regulation of MK in vivo and in vitro.

What is known already: DNG is an oral progestin that alleviates painful symptoms of women with endometriosis with a favourable tolerability and safety profile. Its effects on MK, a growth factor that plays an important role in endometriosis, have not yet been investigated.

Study design, size, duration: Prospective in vivo study on 283 patients subjected to laparoscopy for benign pathologies in a University hospital and in vitro cultures of primary endometrial stromal cells (ESC) from 6 of these women with histologically confirmed endometriosis.

Participants/materials, setting, methods: MK concentrations in the peritoneal fluid (PF) of women were measured by ELISA and compared based on endometriosis status and the use of DNG. A subsequent in vitro analysis with ESC was used to confirm the direct influence of DNG and other progestins including, norethisterone acetate (NETA) and medroxyprogesterone acetate (MPA) on MK mRNA production.

Main results and the role of chance: The final study population consisted of 253 women. Of these, 165 suffered from endometriosis, with 62 of them taking DNG (DNG group) and 103 taking no hormone treatment (non-DNG group) during at least 3 months before surgery. Another 88 women were endometriosis free (non-endometriosis group). The concentration of MK was highest in the PF of women in the non-DNG group (median 5.26 ng/ml, IQR 2.74-8.46). Significantly lower concentrations were found in the non-endometriosis group (median 3.51 ng/ml, IQR: 1.90-7.53, P = 0.028). The lowest concentrations were found in the DNG group (median 2.44 ng/ml, IQR: 1.12-4.70, P < 0.0001 versus non-DNG group, P = 0.048 versus non-endometriosis group). The treatment of primary cultured ESC with DNG (10(-5) M) suppressed MK mRNA production (P = 0.016), whereas MPA (P = 0.109) and NETA (P = 0.422) at same concentrations did not show a similar effect.

Limitations, reasons for caution: The non-randomized design of the study.

Wider implications of the findings: These findings could indicate a direct effect of DNG on endometriotic cells that could contribute to its effectiveness in the treatment of this disease.

Study funding/competing interests: Funding was received from Swiss National Science Foundation (Grant No. 320030_140774). M.D.M. has received fees for speaking at scientific meetings from Bayer. The other authors have no conflicts of interest to declare.The authors state that the manufacturer of dienogest has in no way influenced the performance or outcomes of this study.

Keywords: cytokines; dienogest; endometriosis; growth factors; medroxyprogesterone acetate; midkine; norethindrone acetate; norethisterone acetate.