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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3) (Figure 8.1). Estradiol is the most prominent estrogen in nonpregnant females who are between the menarche and menopause stages of life. However, during pregnancy estriol becomes the predominant estrogen, and after the menopause there is a change to estrone as the main form of estrogen. There is also a fourth type of estrogen known as estetrol (E4) which has a fourth hydroxy group (at the C15-position) and is produced only during pregnancy. Estradiol is the most potent of the estrogens, with a potency approximately 80 times that of estriol, which has the lowest potency of all the estrogens, perhaps explaining why it is produced in greater abundance than the others. All of these different forms of estrogen are biosynthesized from the androgens androstenedione and testosterone by the aromatase enzyme (Figure 8.1), and all four major families of steroids have their origins in cholesterol at the beginning of the biosynthetic process, which is synthesized itself from acetate residues.
Hydroxylated C18 and C19 Steroids; Their Significance and Factors Related to Their Biosynthesis
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
The binding affinity of rat uterine cytosol and chromatin preparations for 2-hydroxyestradiol is reportedly 25% that of estradiol.40 This binding does not appear to be related to an estrogenic response, since the catechol estrogen exhibits < 1% of the uterotropic activity of estradiol.41 Moreover, 2-hydroxyestrone, with only 0.1% of the uterotropic activity of estrone,42 has been shown40 to possess 20% of the binding affinity of the latter steroid. In contrast to this, certain other steroids showing little or no uterotropic activity, such as 2-methoxy phenolic steroids and estetrol [estra-1,3,5(10)-triene-3, 15α, 16α, 17β-tetrol], are bound scarcely at all to the rat uterine receptors in vitro. It has been suggested40 that these data imply an antiestrogenic role for the 2-hydroxysteroids. It is of interest to note that, in a study reported in 1955,43 2-hydroxyestradiol was demonstrated to possess 1% of the uterotropic activity of estradiol in vivo in the oophorectomized rat and in the mouse. Nevertheless, the same catechol estrogen considerably stimulated formate incorporation into uterine protein in vitro as compared with the effect of estradiol.
Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause
Published in Expert Review of Clinical Pharmacology, 2022
Céline Gérard, Jean-François Arnal, Maud Jost, Jonathan Douxfils, Françoise Lenfant, Coralie Fontaine, René Houtman, David F. Archer, Robert L. Reid, Rogerio A. Lobo, Ulysse Gaspard, Herjan J.T. Coelingh Bennink, Mitchell D. Creinin, Jean-Michel Foidart
Four natural estrogens are found in human species over the course of life (Figure 1A). The names and abbreviations reflect the number of hydroxyl groups present on the 4-ring backbone, as is similar for all hormones. Estrone (E1) is present throughout life and is considered the primary estrogen during the menopausal years in women. Estradiol (E2), produced by the ovaries, is the primary estrogen during the reproductive years. Estriol (E3) is produced naturally by the placenta and is the major estrogen during pregnancy. Lastly, estetrol (E4) is the estrogen of fetal life, produced by the fetal liver, and present only during pregnancy with relatively high levels in the fetus and lower levels in the maternal circulation. Interestingly, whereas E1, E2, and E3 are found in other mammalian species, E4 is primarily only found in humans, present as early as 9 weeks of gestation. Some higher order mammals have limited levels of E4 present but only in the last few weeks of gestation. The unique role of E4 in humans, compared to lower-order mammals, is still not understood.
Managing vasomotor symptoms in women after cancer
Published in Climacteric, 2019
Estetrol is an impeded estrogen which is currently being studied in postmenopausal women as a treatment for VMS64. The hepatic effects of this estrogen differ from those of ethinyl estradiol and estradiol65. Specifically, estetrol does not stimulate synthesis of sex hormone binding globulin or ceruloplasmin, causes only a minor 6.4% increase in triglyceride compared to 61% with estradiol, and exerts only minimal effects of clotting factors. Further studies indicate anti-estrogenic properties on some tissues and potentially less agonistic effects on the breast66. These properties provide scientific plausibility that estetrol might have a benefit/risk ratio superior to that of estradiol65. In women with a uterus, a progestogen will be necessary to protect the uterus. Estetrol may be associated with a decreased risk of breast cancer, due to its inhibitory effects on the breast, as well as a reduction in deep vein thrombosis and pulmonary emboli based on preclinical studies of its specific actions65.
Oral investigational drugs currently in phase I or phase II for the amelioration of menopausal symptoms
Published in Expert Opinion on Investigational Drugs, 2019
Andrea R. Genazzani, Ulysse Gaspard, Jean-Michel Foidart
Estetrol is a natural estrogen, exclusively produced by the human fetal liver [31]. It is coined a Native Estrogen with Selective action in Tissues, exhibiting mixed agonist and antagonist activities [32–34], that differentiate it from Selective Estrogen Receptor Modulators (SERMs). Like classical estrogens, E4 activates the nuclear Estrogen Receptor alpha (ERα) to induce genomic transcription. In contrast to other estrogens, however, E4 blocks the cell surface ERα and inhibits the membrane ERα effects of E2 (Figure 4) [32–34,46]. It is devoid of ERα Membrane Initiated Steroid Signaling (MISS) in the endothelium, and is able to antagonize E2 effects [32]. In addition, in preclinical models, it has been shown that E4, by selectively activating the nuclear ERα, is able to convey the beneficial vascular effects of E2 [32]. The nuclear ERα plays a prominent role in the vasculoprotective action of estrogens, in particular, E4, as this estrogen is a selective ERα agonist [34].