Grant Number:	5R21CA181923-02 Interpret this number
Primary Investigator:	Pike, Malcolm
Organization:	Sloan-Kettering Inst Can Research
Project Title:	Hormonal Effects on Fallopian Tube and Ovary Inclusion Cysts, and Ovarian Cancer
Fiscal Year:	2015

DESCRIPTION (provided by applicant): It is estimated that there will have been ~22,300 new diagnoses and ~15,500 deaths from ovarian cancer in the US in 2012. Five-year survival is less than 50%; there is currently no effective screening approach. Preventive strategies are of paramount importance. Increasing parity and increasing use of oral contraceptives (OCs) provide significant protection against ovarian cancer, as does an early age at menopause. The protective effects of parity and OC use continue for extended periods of time; epidemiological studies show that the parity effect lasts for at least 40 years, while the OC effect continues for t least 30 years after stopping OC use. The mechanism(s) underlying these effects are not understood. A long-favored hypothesis is that protection from parity and OC use is achieved by blocking ovulation, but recent evidence suggests that it may be by reducing exposure of the relevant tissue to 'unopposed' estrogen, i.e., estrogen that is not 'opposed' by a progestin. Pregnancy is associated with high levels of estrogen but also high levels of progesterone, while the estrogen in OCs is associated in each pill with a progestin and the extent of this is greater than during a normal menstrual cycle. Early menopause is protective as it reduces exposure of the relevant tissue to the relatively high levels of estrogen in the premenopausal period. It has recently become clear that the majority of high-grade serous ovarian cancers (HGSOC), which comprises some 70% of ovarian cancers, are likely to arise in the fallopian tube fimbria (FTF). Some HGSOCs also probably arise in cortical inclusion cysts (CICs) within the ovary. We propose that a major source of the protection from parity and OC use is due to their significantly reducing cell proliferation in FTF and CICs. Proliferating cell populations are more susceptible to carcinogenic effects secondary to increased chances of mutation and progression. There is some evidence that FTF proliferation is much greater in the follicular phase of the menstrual cycle ('unopposed' estrogen) than in the luteal phase ('opposed' estrogen). No information is available concerning proliferation in the postmenopausal period. Whether such changes occur in CICs is not known. We are proposing to determine proliferation rates in the FTF and CICs in the follicular and luteal phase of the menstrual cycle and after menopause in women undergoing a risk-reducing bilateral salpingo-oophorectomy (RR-BSO). The results of this study will provide valuable information for further hormonal chemoprevention efforts.





None