Circulating Sex Steroids during Pregnancy and Maternal Risk of Non-epithelial Ovarian Cancer

Abstract

Background Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiological data are available. Methods A case-control study was nested within the Finnish Maternity Cohort, the world’s largest bio-repository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex-cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n=171). Odds ratios (OR) and 95% confidence intervals (CI) associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol and sex hormone binding globulin (SHBG) were estimated through conditional logistic regression. Results For SCST, doubling of testosterone, androstenedione and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25–3.74), 2.16 (1.20–3.87), and 2.62 (1.27–5.38), respectively]. These associations remained largely unchanged after excluding women within 2, 4 or 6 years lag-time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT. Conclusions This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Impact Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC.

Insulin-like growth factor-I and C-reactive protein during pregnancy and maternal risk of non-epithelial ovarian cancer: a nested case–control study

“…Although the number of cases was small and statistical power was insufficient to detect moderate or weak associations, reporting of such initial data is still of interest. For example, we observed consistent associations of SCST with androgens with the limited number of cases [2]. Study samples had been stored at relatively high temperature (-25°C), but there were only weak correlations of hormone concentrations with time in storage (0.15 for IGF-1 and -0.17 for CRP) and case and control samples were matched for storage duration.…”

“…An additional link of IGF-I with SCST specifically may be through increasing the expression of enzymes involved in the metabolism of androgens in the ovarian stromal tissue [5,14,15]. Recently, we reported androgens to be directly associated with the risk of NEOC in this same cohort [2]. The observed indication for a possible positive association of IGF-I with GCT, which tended to decrease with approaching diagnosis, is also of interest, particularly given the parallel increase in the incidence of GCT and IGF-I concentrations during puberty.…”

“…As NEOC are very rare, little is known about their risk factors. In a recent study, we observed that first-trimester pregnancy maternal androgens and 17-hydroxyprogesterone concentrations were positively associated with risk of SCST, but not with risk of GCT [2].…”

Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition

“…41 There are no previous data on androgens and EOC by tumor histology, grade or type I/II status. However, prospective data suggest a positive association between serum androgen concentrations in pregnant women and risk of non-epithelial sex cord stromal tumors (SCST); these tumors are of intra-ovarian origin with the majority of SCST diagnosed between ages 30 and 50 42 similarly to low grade/type I tumors in our study (diagnosed between the ages of 37 and 76 in our study population). Recently, the role of androgenic stimulation has been hypothesized for Brenner tumors, also type I tumors, based on the epithelial and stromal expression of AR together with expression of markers of steroidogenesis (calretinin, inhibin, and steroidogenic factor 1) in stromal cells surrounding the epithelial nests.…”

Steroid Hormones and Ovarian Cancer

“…Increased levels of circulating androstenedione in premenopausal patients did increase overall risk, but the low number of subjects in that subgroup precluded a definitive association. In nonepithelial ovarian cancer (NEOC), circulating levels of steroid hormones may provide information about risk of NEOC development (Chen et al, 2010). In a case-control study within the Finnish Maternity Cohort, serum specimens were obtained from women with a singleton pregnancy that preceded their diagnosis of NEOC: 41 women had sex cord stromal tumors (SCST), and 21 had germ cell tumors (GCT).…”