Evidence of a Chemopreventive Effect of Progestin Unrelated to Ovulation on Reproductive Tract Cancers in the Egg-laying Hen

Abstract

Epidemiologic, laboratory, and animal evidence suggests that progestins and vitamin D may be potent ovarian cancer preventives. Our objectives were to evaluate progestins as reproductive tract cancer chemopreventives in the chicken, determine whether restricted ovulation affected the incidence of reproductive tract tumors, and assess whether vitamin D would confer cancer protection either alone or in addition to progestin. A total of 2,400 two-year-old Single Comb White Leghorns were randomized into six groups (400 each) with hormonal and dietary manipulation for 2 years as follows: (i) no intervention, regular feed/caloric intake, (ii) control, (iii) vitamin D, (iv) the progestin levonorgestrel, (v) vitamin D plus levonorgestrel, and (vi) the progestin Provera (medroxyprogesterone acetate). Groups 2 to 6 were caloric restricted to inhibit ovulation. Our results indicated that caloric restriction decreased egg production by more than 60%, and was associated with a greater than 70% decrease in reproductive tract cancers. Ovulatory events did not differ among the caloric-restricted groups (groups 2-6), except for the group receiving levonorgestrel, which had fewer ovulatory events than controls (P ¼ 0.046). After correcting for egg production, birds receiving progestins had significantly fewer reproductive tract cancers [OR, 0.61; confidence interval (CI), 0.39-0.95; P ¼ 0.03], with similar proportionate reductions in tumors arising in either the ovary or oviduct. Vitamin D did not significantly affect cancer incidence overall, or add to the cancer preventive effect of progestins. This study suggests a protective effect of progestins against ovarian and oviductal cancers. These data support the concept that progestins provide a chemopreventive effect unrelated to ovulation. Cancer Prev Res; 6(12); 1283-92. Ó2013 AACR.

Preterm delivery is associated with an increased risk of epithelial ovarian cancer among parous women

“…Furthermore, a study of sheep ovarian cancer cells indicated that progesterone is involved in the restoration or apoptosis of ovarian surface epithelial cells containing damaged DNA after ovulation . Synthetic progestin induces apoptosis in ovarian cancer cell lines, and treatment with progestin induces apoptosis in the ovarian epithelium of macaques and chickens . Furthermore, oral contraceptives with high‐progestin potency seem to provide greater protection against ovarian cancer than low‐progestin formulations .…”

The role of reproductive hormones in epithelial ovarian carcinogenesis

“…In both, progestins were found to have a chemopreventive effect against ovarian (and oviductal) cancer (Rodriguez et al 1998, Barnes et al 2002, Trevino et al 2012. The effect was independent of ovulation (Rodriguez et al 2013) and likely due to the differential expression of TGFB in the ovarian epithelium, with a decreased expression of TGFB1 but an increased expression of TGFB2/3 isoforms. Because this expression pattern is associated with the induction of apoptosis in the OSE (Rodriguez et al 2002), it could enhance the clearance of genetically damaged ovarian epithelial cells (Rodriguez et al 2012).…”

The role of menopausal hormone therapy in women with or at risk of ovarian and breast cancers: Misconceptions and current directions

“…A potential protective effect of progestins in ovarian cancer prevention has been supported by studies of progestin‐only OCPs and limited observations that a higher dose of progestins in OCPs have a greater reduction of risk than lower‐dose pills . This observational evidence is supported by experiments in egg‐laying hens in which progestin treatment led to significantly fewer cancers of the reproductive tract . The role of hormonal therapy in the development of ovarian cancer remains unclear.…”