Estradiol-like activity

Most oral contraceptive pills used by women today contain a combination of two synthetic hormones. One, most commonly ethynyl estradiol, has estrogen-like activity in regulating the menstrual cycle. The other, most commonly norethindrone, has progesterone-like activity and establishes a state of false pregnancy that prevents ovulation. In a theme that is common in drug development, successful contraceptives are very similar in molecular structure to those natural molecules with similar activity. (Compare the following structures with those in Section 15.3.)... 

Fig. 4 Estrogenic and dioxin-like activities in fractions of sediment extract from Kierikzee harbour fraction 2 showed characteristic ions of 17a- and 17 8-estradiol and estrone, and fraction 4 showed characteristic ions of various polycyclic aromatic hydrocarbons. Reproduced from [95]...

The brain, like the seminal vesicles, is able to reduce testosterone to 5a-dihydrotestosterone (DHT) and, like the placenta, the brain aromatizes testosterone to estradiol (Fig. 52-4). Neither conversion occurs equally in all brain regions. The aromatization reaction is discussed below. Regional distribution of 5a-reductase activity toward testosterone in rat brain reveals that the highest activity is found in the midbrain and brainstem, intermediate activity is found in the hypothalamus and thalamus, and the lowest activity is found in the cerebral cortex [1]. The pituitary has higher 5a-reductase activity than any region of the brain, and its activity is subject to changes as... 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

The relevance attributed to oxidized lipids, and particularly oxidized LDL, in atherogenesis has precipitated interest in the ability of SERMs to this regard. Ex vivo experiments have confirmed that both tamoxifen and raloxifene exert some protection against the oxidation of LDL particles (Arteaga et al. 2003 Zuckerman and Bryan 1996) and that, interestingly, raloxifene is a more powerful antioxidant than tamoxifen or estradiol. It seems that this antioxidant effect is not mediated by the activation of the ER since pure antiestrogens like ICI 182780 and other SERMs like EM 652 have proven to have similar protective effects on LDL (Hermenegildo et al. 2002) (Fig. 9.4). 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

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