ABSTRACT
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.
ABSTRACT
We have previously shown that in utero nicotine exposure causes impaired fertility, follicle immaturity, and ovarian dysfunction in adult female rat offspring. These characteristics overtly resemble the clinical profile of polycystic ovarian syndrome (PCOS) and recent studies have shown that thiazolidinediones such as rosiglitazone improve fertility in women with PCOS but the mechanism is not well defined. Our goal was to examine whether rosiglitazone would (1) ameliorate the altered ovarian physiology that occurs following fetal and neonatal exposure to nicotine and (2) to examine whether this could be due to normalization of ovarian vascularization. At weaning, offspring of nicotine-exposed dams were given either vehicle (NV) or rosiglitazone (3 mg kg(-1) day(-1); NR). Offspring of saline-exposed dams received vehicle (SV). Tissues were collected when the female offspring reached 26 weeks of age. NV animals had reduced granulosa cell proliferation and increased ovarian cell apoptosis. Treatment with rosiglitazone increased proliferation, and decreased apoptosis, compared NV animals. NV animals had decreased ovarian vascularity relative to controls, whereas NR animals had an intermediate level of ovarian vessel density. Moreover, ovaries from NV animals had decreased levels of the pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF both of which were increased with rosiglitazone treatment. Rosiglitazone reversed some of the nicotine effects in the ovary and increased ovarian vascularization, follicle maturation and improved oocyte competence. Rosiglitazone may be an important treatment option for PCOS and the present study provides a potential mechanism by which rosiglitazone may have beneficial effects on fertility in these patients.
Subject(s)
Fertility/drug effects , Nicotine/adverse effects , Ovary/drug effects , Prenatal Exposure Delayed Effects/physiopathology , Thiazolidinediones/pharmacology , Animals , Animals, Newborn , Blood Vessels/drug effects , Cells, Cultured , Drug Evaluation, Preclinical , Female , Fertility/physiology , Hypoglycemic Agents/pharmacology , Infertility, Female/physiopathology , Maternal Exposure/adverse effects , Ovary/blood supply , Ovary/physiology , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Rats , Rats, Wistar , RosiglitazoneABSTRACT
Women born to mothers who smoked during pregnancy have been shown to have impaired fertility, although the mechanisms underlying this association are unknown. Nicotine administration in adult animals has adverse effects on the ovary and uterus; however, the effects of fetal exposure to nicotine on postnatal ovarian function have not been determined. The goal of this study was to assess the effect of fetal and neonatal exposure to nicotine on ovarian function and fertility of the offspring. Nulliparous female Wistar rats were given 1 mg.kg-1.d-1 nicotine bitartrate, subcutaneously for 14 d prior to mating, during pregnancy and throughout lactation until weaning. Measures of fertility, breeding success, and serum levels of ovarian steroid hormones in offspring were assessed at 4 and 6 mo of age. Fetal and neonatal exposure to nicotine significantly increased the time to pregnancy as the animals aged. Similarly, evidence of altered ovarian steroidogenesis including increased serum progesterone concentrations and a decreased estrogen:progesterone ratio was observed in 6-mo-old animals. We conclude that fetal and neonatal exposure to nicotine results in delayed ovarian dysfunction in adult female offspring.
