Metabolism of estrogens in breast cancer.

This extensive literature compilation reviews major studies on estrogen metabolism in cancer, studies which have led to proposed possible etiological roles of estrogens in human breast cancer. Urinary and plasma estrogen excretion patterns and profiles in women with breast cancer are the topics of part 1. Studies of estrogen profiles in women who are at high-risk for breast cancer are critiqued. The estriol hypothesis is presented and criticised in a chapter. The effects of endocrine ablation on urinary estrogen profiles in breast cancer patients are compiled. Production and metabolism of estrogens in women with breast cancer are rendered, including in vivo biotransformation rates and in vitro transformation data. And the search for estrogen metabolites in women with breast cancer is reviewed. In conclusion it is obvious that the question of whether breast cancer patients have an abnormal metabolism of estrogen has not been answered, but further investigations of estrogen metabolism in breast cancer should be continued because: 1) the possibility that estrogens are carcinogenic has not been ruled out; 2) receptors have been discovered which do correlate with hormone dependency of tumors; 3) present evidence suggests that neoplasm may induce abnormal estrogen metabolism; 4) directional changes of estrogen metabolism that occur in pregnancy may also occur in women with target tissue neoplasia; 5) hepatic tissue's relationship to breast cancer has not received attention; and 6) the role of peripheral aromatization in the pathogenesis of mammary cancer is not yet understood.     

Intratumoral levels of estrogens in breast cancer

Breast cancer tissue is an endocrine organ and particularly the estrogen biosynthetic properties of this tissue have been well studied. The concentration of estradiol in breast cancer tissue from postmenopausal patients is considerably higher than that in the circulation and appears to depend largely on local production. Androgenic precursor steroids are abundantly present, but estrogen storage pools like fatty acid derivatives appear to be less important than initially thought. New, potent and highly specific aromatase inhibitors effectively inhibit peripheral conversion of androgens to estrogens (Cancer Res. 53: 4563, 1993) as well as intratumour aromatase, median aromatase activity being 89% lower in the tissue from patients pretreated with aromatase inhibitor 7 days prior to surgery (P<0.001). Also the intratissue concentrations of estrogens were decreased (64% and 80% reduction, respectively for estrone and estradiol; P=0.001 and <0.05; Cancer Res. 57: 2109, 1997). These results illustrate that intratissue estrogen biosynthesis is effectively inhibited by the new generation of aromatase inhibitors. The pathophysiological consequences of this finding are currently under study.     

Plasma estrogens and androgens in male breast cancer

Androstenedione, estrone, estradiol-17β, estriol and testosterone concentrations have been measured by radioimmunoassay in plasma of 17 human males affected by breast cancer. The mean values of estrone, estradiol-17β, and estriol in male breast cancer were significantly higher than in normal controls of comparable age. Androstendione and testosterone were in normal range.Orchidectomy. performed in 3 subjects, decreased the levels of estradiol-17β, but to a lesser extent those of estrone and estriol.     

Recent data on intratumor estrogens in breast cancer

The contribution of local synthesis versus circulatory delivery of normal breast as well as breast cancer tissue estrogens has remained a controversial area for decades. Novel data on tissue estrogen levels confirm a positive normal breast tissue to plasma concentration gradient for estrone, and to a smaller extent estradiol. Remarkably, this gradient is similar for pre- and post-menopausal women. Together with pharmacokinetic data on estrogen disposition, these findings suggest plasma and breast tissue estrogens to rapidly equilibrate, with circulating estrogens being a major contributor to breast tissue estrone levels. A likely explanation to the concentration gradient could be the fact that non-polar estrogens easily dissolve into tissue fat compartments as compared to plasma. While intratumor estrone levels are low as compared to benign tissue concentrations, intratumor estradiol is elevated in ER+ tumors. The correlation between intratumor estradiol levels and expression levels of dehydrogenases reducing estrone into estradiol but also intratumor ER concentrations are consistent with intratumor estrogen activation but also a scavenger effect of the ER.     

Comparison of the roles of estrogens and androgens in breast cancer and prostate cancer

Breast cancer (BC) and prostate cancer (PC) are the second most common malignant tumors in women and men in western countries, respectively. The risks of death are 14% for BC and 9% for PC. Abnormal estrogen and androgen levels are related to carcinogenesis of the breast and prostate. Estradiol stimulates cancer development in BC. The effect of estrogen on PC is concentration-dependent, and estrogen can regulate androgen production, further affecting PC. Estrogen can also increase the risk of androgen-induced PC. Androgen has dual effects on BC via different metabolic pathways, and the role of the androgen receptor (AR) in BC also depends on cell subtype and downstream target genes. Androgen and AR can stimulate both primary PC and castration-resistant PC. Understanding the mechanisms of the effects of estrogen and androgen on BC and PC may help us to improve curative BC and PC treatment strategies.     

Physiological significance of estrogens in men--breakthrough in endocrinology

Estradiol (E2) is traditionally recognised as the female sex hormone. It has been believed for 40 years, that E2 didn't exert any influence or caused impairment of the gonadal function in men. The main source of E2 in men is adipose tissue and the brain. E2 is also produced in adrenals, liver, mammary glands, hair and in male gonad. Daily production and the level of E2 in the blood in men are higher than those in postmenopausal women. At the end of the 80-ties we were first reporting that during sexual maturation E2 can be the important hormonal signal for the initiation of spermatogenesis. The traditional view about unimportant or inhibitory role of E2 in male physiology was finally refuted thanks to discovering estrogen receptors in males. In the 90-ties, transgenic mice with the lack of estrogen receptor (ER) or gene encoding enzyme aromatase, that enable the conversion of testosterone into E2, were also produced. Observations of men with inherited mutations of these genes, considerably extended our knowledge about E2 in men in stroma bones formation, inhibition of their growing, lipids metabolism and sexual maturation, the effects that were attributed to testosterone action until today. New data also points at important role of estrogens and ER in the function of the cardio-vascular system and in counteracting coronary disease in men.     

Intracrinology of estrogens and androgens in breast carcinoma

Intratumoral metabolism and synthesis of biologically active steroids such as estradiol and 5-dihydrotestosterone as a result of interactions of various enzymes are considered to play very important roles in the pathogenesis and development of hormone-dependent breast carcinoma. Among these enzymes involved in estrogen metabolism, intratumoral aromatase play an important role in converting androgens to estrogens in situ from serum and serving as the source of estrogens, especially in postmenopausal patients with breast carcinoma. However, other enzymes such as 17β-hydroxysteroid dehydrogenase (17β-HSD) isozymes, estrogen sulfatase (STS), and estrogen sulfotransferase, which contribute to in situ availability of biologically active estrogens, also play pivotal roles in this intratumoral estrogen production above. Androgen action on human breast carcinoma has not been well-studied but are considered important not only in hormonal regulation but also other biological features of carcinoma cells. Intracrine mechanisms also play important roles in androgen actions on human breast carcinoma cells. Among the enzymes involved in biologically active androgen metabolism and/or synthesis, both 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; conversion from circulating androstenedione to testosterone) and 5-reductase (5Red; reduction of testosterone to DHT (5-dihydrotestosterone) were expressed in breast carcinoma tissues, and in situ production of DHT has been proposed in human breast cancer tissues. However, intracrine mechanisms of androgens as well as their biological or clinical significance in the patients with breast cancer have not been fully elucidated in contrast to those in estrogens.     

Physiological and pharmacological studies on nematodes

Classical transmitters and neuroactive peptides act as transmitters or modulators within the central and peripheral nervous systems of nematodes, for example Ascaris suum and Caenorhabditis elegans. Acetylcholine (ACh) and gamma-aminobutyric acid (GABA) are respectively the excitatory and inhibitory transmitters onto somatic body wall muscle while 5-hydroxytrypamine (5-HT) is the excitatory transmitter onto pharyngeal muscle. 5-HT also reduces ACh-induced contractions of somatic muscle and this action of 5-HT is mediated through activation of adenylate cyclase while that on pharyngeal muscle is mediated through inositol phosphate activation. Glutamate, dopamine and octopamine also have transmitter roles in nematodes. Neuroactive peptides of the RFamide family can excite somatic muscle, for example, AF-1 (KNEFIRFamide), AF-2 (KHEYLRFamide), AF-3 (AVPGVLRFamide) and AF-4 (GDVPGVLRFamide) or inhibit and relax this muscle, for example, PF-1 (SDPNFLRFamide), PF-2 (SADPNFLRFamide) and PF-4 (KPNlRFamide). In addition PF-3 (AF-8) (KSAYMRFamide) has a biphasic action on pharyngeal muscle, excitation followed by inhibition while AF-1 only inhibits this muscle. The peptide effects can be either pre- or postsynaptic or both and are likely to be mediated through second messenger systems. In addition these peptides modulate the action of classical transmitters, particularly ACh.     

Genotoxic effects of estrogens

Estrogens are associated with several cancers in humans and are known to induce tumors in rodents. In this review a mechanism of carcinogenesis by estrogens is discussed which features the following key events: (1) Steroid estrogens are metabolized by estrogen 2- and 4-hydroxylases to catecholestrogens. Target organs of estrogen-induced carcinogenesis, hamster kidney or mouse uterus, contain high levels of estrogen 4-hydroxylase activity. Since the methylation of 4-hydroxyestradiol by catechol-O-methyltransferase is inhibited by 2-hydroxyestradiol, it is proposed that a build up of 4-hydroxyestrogens precedes estrogen-induced cancer. (2) The catecholestrogen or diethylstilbestrol (DES) are oxidized to semiquinones and quinones by the peroxidatic activity of cytochrome P-450. The quinones are proposed to be (the) reactive intermediates of estrogen metabolism. (3) The quinones may be reduced to catecholestrogens and DES and redox cycling may ensue. Redox cycling of estrogens has been shown to generate free radicals which may react to form the organic hydroperoxides needed as cofactors for oxidation to quinones. (4) The quinone metabolites of catechol estrogens and of DES bind covalently to DNA in vitro whereas DNA binding in vivo has only been examined for DES. When DES is administered to hamsters, the resulting DES-DNA adduct profile in liver, kidney, or other organs closely matches that of DES quinone-DNA adducts in vitro. In vitro, DES-DNA adducts are chemically unstable and are generated in incubations with organic hydroperoxide as cofactor. It is proposed that the instability of adducts and the lower sensitivity of previous assay methods contributed to the reported failures to detect adducts. Steroid estrogen-DNA adducts in vivo are currently under investigation. (5) Tumors are postulated to arise in cells rapidly proliferating due to the growth stimulus provided by the estrogenic activity of the primary estrogen or of hormonally potent metabolites such as 4-hydroxyestradiol. The covalent modification of DNA in these cells is temporary because of the chemical instability of adducts and will result in altered genetic messages in daughter cells, whereas in non-proliferating cells there may be no lasting genetic damage. The sequence of events described above is a plausible mechanism for tumor initiation by estrogens and is partially substantiated by experimental evidence obtained in vitro and/or in vivo.     

Endogenous estrogens and breast cancer a possible relationship between body fat distribution and estrogen availability

The growth of hormone-dependent human breast cancer is related to the activity of endogenous estrogens. The evidence for an etiological role of endogenous estrogens is still circumstantial. Life style and in particular dietary factors are held responsible for large geographic differences and time-trends in breast cancer incidence. The measurement of urinary estrogen metabolites and plasma estrogens has given no satisfactory explanation for the latter. The newly developed interest in the bioavailability of plasma sex steroids may offer a better understanding of the biology and epidemiology of breast cancer. Based on our observations on the relationship between plasma free fatty acids and estrogen-protein-binding and recently gained insight in the metabolic consequences of different types of body fat distribution we postulate that Western life style may act on breast cancer incidence through an influence on body fat distribution and resulting changes in sex steroid availability.     

Physiological and pharmacological variations in rabbit prolactin plasma levels

By using a specific homologous double-antibody RIA, physiological and pharmacological variation in prolactin plasma levels were studied in the rabbit. The study of plasma levels during 24 h period demonstrated the presence of a rhythmic secretion of prolactin with higher values between 15.00 and 19.00 h. Prolactin plasma levels were low in neonatal rabbits and increased gradually with the age of the animals. In adult rabbits a significant higher prolactin plasma concentration was found in female animals. Blood levels fluctuate during the first half of pregnancy but the mean levels were higher than those found during the second half of gestation. A remarkable increase of plasma levels was observed 24 h before parturition and during lactation. Plasma prolactin concentrations increased after injection of both chlorpromazine and sulpiride. The hyperprolactinaemic effect of sulpiride was abolished by bromocriptine.