cycle on estrogen synthesis in human ovarian ..
G-protein-coupled estrogen receptor functions as a G coupled plasma membrane-associated receptor and works independent of nuclear ERs. It binds various estrogens including E2, E1 and E3, ER antagonists, phytoestrogens, and xenoestrogens (). GPER, which mediates rapid estrogen signaling via stimulation of adenylyl cyclase, is expressed in normal ovary, where it regulates physiological processes such as follicle maturation. The receptor is expressed in many EOC samples. However, the prognostic impact of GPER expression in EOC is controversial. In an earlier study, GPER was seen to be preferentially expressed in “high risk” tumors with a worse prognosis (). Later, no relation between GPER expression and survival rates of EOC patients was found (). Recently, GPER expression was shown to correlate with gonadotropin (LH and FSH) receptors. Only in EOCs, which are negative for gonadotropin receptors, a higher GPER expression was associated with a more favorable outcome for the patients. These findings suggest that GPER may reduce ovarian cancer cell proliferation in the absence of gonadotropin signaling only (). Therefore, synthetic agonists and antagonists for GPER, which are now available, might be tested in gonadotropin receptor-negative tumors of EOC patients ().
and the ovarian estrogen synthesis
Epidemiological and experimental studies showed that higher endogenous estrogen exposure through early menarche (years), late menopause (>55years), nulliparity, obesity (postmenopausal), use of postmenopausal HRT, and increased plasma E2 levels lead to an increased risk of breast cancer. Of particular importance is the circulating inactive plasma estrogen precursor E1-S, which has been reported to serve as the predominant source for tumor E2 in postmenopausal patients with breast cancer. E1-S is derived from peripheral tissues, including the adrenal gland, adipocytes, liver, muscle, skin, and bone (). Following its cellular uptake by transporters of the OATPs family (), E1-S is desulfonated to E1 by STS and E1 is further converted to E2 by 17β-HSDs. This intracellular production of E2 stimulates the proliferation of estrogen-dependent tumor cells (). As compared to the other sources of unconjugated estrogens (which act as precursors for the aromatase pathway), E1-S (precursor for the sulfatase pathway) has about 5–10 times higher plasma circulating levels than other estrogens (). Moreover, sulfatase activity is 130–200 times higher than aromatase activity () and the concentration of sulfatase is three times higher in breast cancer tissues than normal tissues (). Two-thirds of all breast cancers have a positive ER status and as consequence, they are sensitive to estrogens. These tumors respond well to hormone therapy (). Also in endometrial cancer, biosynthesis of active estrogen is achieved from E1-S, which is transported into endometrial cells, where it is converted to E2 by STS and 17β-HSDs ().
While in premenopausal women, the main part of active estrogens derives from the synthesis in the ovary, after the menopause, estrogens are formed locally in various tissues such as in liver, brain, and adipose tissue. There, E2 is produced from circulating androgen and estrogen precursors. These precursors are bound to sex-steroid binding globulins in the blood. They are transported to the ovary, where they are taken up into ovarian epithelial cells by transporters, e.g., from the family of organic anion transporting peptides (OATPs) (). The importance of the visceral adipose tissue of postmenopausal women for E2 production is reflected by the high concentrations of estrone-sulfate (E1-S), 5-androstendione, and dehydroepiandrosterone-sulfate (DHEA-S) in these cells. The local concentrations are up to 60× higher than in serum, while E2 and testosterone levels are increased by sevenfold only (, ).
local estrogen synthesis from circulating steroid hormone precur-
Ovarian cancer is still the deadliest of all gynecologic malignancies in women worldwide. This is attributed to two main features of these tumors, namely, (i) a diagnosis at an advanced tumor stage, and, (ii) the rapid onset of resistance to standard chemotherapy after an initial successful therapy with platin- and taxol-derivatives. Therefore, novel targets for an early diagnosis and better treatment options for these tumors are urgently needed. Epidemiological data show that induction and biology of ovarian cancer is related to life-time estrogen exposure. Also experimental data reveal that ovarian cancer cells share a number of estrogen regulated pathways with other hormone-dependent cancers, e.g., breast and endometrial cancer. However, ovarian cancer is a heterogeneous disease and the subtypes are quite different with respect to mutations, origins, behaviors, markers, and prognosis and respond differently to standard chemotherapy. Therefore, a characterization of ovarian cancer subtypes may lead to better treatment options for the various subtypes and in particular for the most frequently observed high-grade serous ovarian carcinoma. For this intention, further studies on estrogen-related pathways and estrogen formation in ovarian cancer cells are warranted. The review gives an overview on ovarian cancer subtypes and explains the role of estrogen in ovarian cancer. Furthermore, enzymes active to synthesize and metabolize estrogens are described and strategies to target these pathways are discussed.
Felicitas Mungenast and Theresia Thalhammer* ..
AB - As in many mammalian and avian species, testicular androgens or their metabolites activate courtship and copulatory behaviors in adult male zebra finches. However, studies of sexual differentiation of these behaviors and related anatomical structures provide conflicting results. For example, posthatching estradiol can both masculinize courtship and the neural structures involved in song in females and inhibit the development of masculine copulation in males. These and other results have led to the hypotheses that (1) testicular androgens are converted to estradiol in the brain of developing males, and estradiol serves to masculinize the song system, whereas (2) estradiol secretion by the female ovary allows feminine rather than masculine copulatory behavior to develop. Treating embryonic zebra finches with the estrogen synthesis inhibitor fadrozole causes functional testicular tissue to develop in genetic females. The present study investigated the effects of such treatment on the development of singing and copulatory behavior as well as song system anatomy in males and females. While exogenous testosterone facilitated the display of sexual behaviors in adult males, the testicular tissue in females had no masculinizing effect on the production of audible courtship song or copulation. Their song control nuclei were also not masculinized, even in individuals lacking ovarian tissue. In contrast, embryonic inhibition of estrogen synthesis in males significantly stimulated song production. These results suggest that while manipulations of steroid hormone exposure can influence the display of sexual behaviors, gonadal secretions may not be required for normal sexual differentiation of the song system in zebra finches.