Third Trimester Estrogens and Maternal Breast Cancer: Prospective Evidence.

Context: Full-term pregnancy is associated with a transient increase and life-time decrease in maternal breast cancer risk. Estrone (E1), estradiol (E2), and estriol (E3) are in high concentration during the third trimester. E1 and E2 metabolism produces carcinogenic intermediaries, and E3 metabolism does not. Objective: We tested the hypothesis that higher E3 in pregnancy is protective while higher E1 plus E2 increases risk. Design: Prospective case-cohort study (n = 620; 204 cases) nested in a 38-year follow-up of 15,528 pregnant women in the Child Health and Development Studies. We measured E1, E2, and E3 in archived third trimester serum and estimated associations with breast cancer. Setting: Northern California Kaiser members receiving obstetric care from 1959 to 1967. Main Outcome Measure: Breast cancer diagnosed through 1997. Results: Doubling of E1+E2 was associated with greater risk [hazard ratio (HR), 1.7; 95% confidence interval (CI), 1.2 to 2.4]. In contrast, doubling of E3 or the E3/E1+E2 ratio was associated with protection (HR, 0.7; 95% CI, 0.5 to 1.0; HR, 0.6; 95% CI, 0.4 to 0.8, respectively). Associations were stronger for diagnoses within 15 years after delivery compared with 16 to 38 years (Pinteraction = 0.0002) for gravidas >27 years at delivery vs ≤27 (Pinteraction = 0.01) and for primiparas vs multiparas (Pinteraction = 0.02). Conclusions: Relatively high third trimester E3 levels might protect parous women from breast cancer and E1 and E2 might enhance the risk. If findings are confirmed, third trimester pregnancy estrogens could help explain how parity affects breast cancer.

Phylogenetic comparisons implicate sex hormone-binding globulin in "masculinization" of the female spotted hyena (Crocuta crocuta).

Exposures to sex steroids during fetal development are thought to contribute to the unique urogenital anatomy and social dominance of the female spotted hyena: overt phenotypes not shared by other hyenids (i.e. striped hyena, brown hyena, and aardwolf). Because both androgens and estrogens influence development of genitalia and behavior, and because plasma SHBG regulates their access to tissues, we compared the Shbg gene sequences, structures, and steroid-binding properties in the four extant hyenids. We found the hyenid Shbg genes (>95% identical) and mature protein sequences (98% identical) are highly conserved. As in other mammals, the hyenid SHBG all bind 5α-dihydrotestosterone with high affinity (K(d) = 0.62-1.47 nm), but they also bind estrone and dehydroepiandrosterone with similarly high affinity, and this unusual property was attributed to specific amino acids within their SHBG steroid-binding sites. Phylogenetic comparisons also indicated that the spotted hyena SHBG precursor uniquely lacks two leucine residues and has a L15W substitution within its secretion signal polypeptide, the reduced size and hydrophobicity of which markedly decreases the production of SHBG and may therefore explain why serum SHBG concentrations in male and female spotted hyenas are approximately five times lower than in other hyenids. This is important because low plasma SHBG concentrations in spotted hyenas will increase exposure to biologically active androgens and estrogen as well as to their precursors (dehydroepiandrosterone and estrone), which may contribute to the masculinized external genitalia of female spotted hyenas and to female social dominance over males.

DDT and DDE exposure in mothers and time to pregnancy in daughters.

Reproductive-tract anomalies after administration of the potent oestrogen, diethylstilboestrol, in pregnant women raised concerns about the reproductive effects of exposure to weakly oestrogenic environmental contaminants such as bis[4-chlorophenyl]-1,1,1-trichloroethane (p,p'-DDT) or its metabolites, such as bis[4-chlorophenyl]-1,1-dichloroethene (p,p'-DDE). We measured p,p'-DDT and p,p'-DDE in preserved maternal serum samples drawn 1-3 days after delivery between 1960 and 1963. We recorded time to pregnancy in 289 eldest daughters 28-31 years later. Daughters' probability of pregnancy fell by 32% per 10 microg/L p,p'-DDT in maternal serum (95% CI 11-48). By contrast, the probability of pregnancy increased 16% per 10 microg/L p,p'-DDE (6-27). The decreased fecundability associated with prenatal p,p'-DDT remains unexplained. We speculate that the antiandrogenic activity of p,p'-DDE may mitigate harmful androgen effects on the ovary during gestation or early life.

Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties.

Norelgestromin (NGMN) and levonorgestrel (LNG) are the main active metabolites of norgestimate (NGM), but their relative contributions to the pharmacological effects of NGM are unclear. We have therefore determined the serum distribution of these NGM metabolites and assessed their steady-state concentrations in women following >or=3 cycles of oral contraceptive (OC) use. The administration of 250 microg NGM/35 microg ethinyl estradiol (EE) resulted in significantly higher sex hormone-binding globulin (SHBG) levels (p = 0.002), and 30% lower serum non-protein-bound (NPB) levels of testosterone, when compared to treatment with 150 microg LNG/30 microg EE. We also confirmed that NGMN does not bind to SHBG, and found that 97.2% of this metabolite is bound to albumin while only 2.8% is in the NPB fraction. In contrast, most of the LNG was bound to SHBG (92.5% and 87.2% after NGM/EE and LNG/EE treatment, respectively), and the NPB fraction of LNG (0.7%) during NGM/EE treatment was lower (p < 0.001) than during LNG/EE treatment (1.4%). Combining these serum distributions with the C(max) and AUC(0-24h) data obtained after NGM/EE treatment gave NPB and albumin-bound values of NGMN that were much greater than the corresponding LNG values. Furthermore, the C(max) and AUC(0-24h) values for NPB LNG during NGM/EE treatment were estimated to be lower than during LNG/EE treatment. Since LNG is primarily bound by SHBG, its access to target tissues is restricted. Moreover, because SHBG does not bind NGMN, it appears to be quantitatively the more important NGM metabolite available to target tissues, and probably accounts for a substantial proportion of the progestogenic activity of NGM/EE OCs. However, it is also possible that simultaneous exposure of NGMN and LNG after treatment with NGM/EE may provide clinical benefits not seen with LNG/EE combinations.