Metformin decreases the incidence of ovarian hyperstimulation syndrome: an experimental study

Abstract

BackgroundIn assisted reproduction cycles, gonadotropins are administered to obtain a greater number of oocytes. A majority of patients do not have an adverse response; however, approximately 3-6% develop ovarian hyperstimulation syndrome (OHSS). Metformin reduces the risk of OHSS but little is known about the possible effects and mechanisms of action involved.ObjectiveTo evaluate whether metformin attenuates some of the ovarian adverse effects caused by OHSS and to study the mechanisms involved.Material and methodsA rat OHSS model was used to investigate the effects of metformin administration. Ovarian histology and follicle counting were performed in ovarian sections stained with Masson trichrome. Vascular permeability was measured by the release of intravenously injected Evans Blue dye (EB). VEGF levels were measured by commercially immunosorbent assay kit. COX-2 protein expression was evaluated by western blot and NOS levels were analyses by immunohistochemistry.ResultsAnimals of the OHSS group showed similar physiopathology characteristics to the human syndrome: increased body weight, elevated progesterone and estradiol levels (P<0.001), increased number of corpora lutea (P<0.001), higher ovarian VEGF levels and vascular permeability (P<0.001 and P<0.01); and treatment with metformin prevented this effect (OHSS+M group; P<0.05). The vasoactive factors: COX-2 and NOS were increased in the ovaries of the OHSS group (P<0.05 and P<0.01) and metformin normalized their expression (P<0.05); suggesting that metformin has a role preventing the increased in vascular permeability caused by the syndrome.ConclusionMetformin has a beneficial effect preventing OHSS by reducing the increase in: body weight, circulating progesterone and estradiol and vascular permeability. These effects of metformin are mediated by inhibiting the increased of the vasoactive molecules: VEGF, COX-2 and partially NOS. Molecules that are increased in OHSS and are responsible for a variety of the symptoms related to OHSS.

Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2

“…In human breast cancer, VEGF stimulation increased the degree of ERK1/2 phosphorylation, indicating the activation of ERK1/2-associated intra cellular pathways (25). A previous study reported that metformin decreased vascular permeability and expression of VEGF, suggesting that metformin normalizes vascular permeability by regulating VEGF levels (26). Additionally, the effects of metformin and DDP on VEGF modulation have been also described in ovarian cancer in vivo and in Lewis lung cancer rats (3,27).…”

Early treatment with metformin induces resistance against tumor growth in adult rats

“…39,40 Combining these previous observations, the "programming" antitumor growth effect of metformin may be based on inhibiting neovascularization in Walker 256 tumor-bearing rats.…”

Protective Effect of Metformin Against Walker 256 Tumor Growth is Not Dependent on Metabolism Improvement

“…One hallmark of neoangiogenesis is the increased vascular endothelial growth factor (VEGF) levels. In an ovarian tumor treated with metformin, the neoangiogenesis was inhibited showing low levels of VEGF [39,40]. …”