Drugs used for ovarian stimulation Clomiphene citrate, aromatase inhibitors, metformin, gonadotropins, gonadotropinreleasing hormone analogs, and recombinant gonadotropins
David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham in Textbook of Assisted Reproductive Techniques, 2017
Aromatase, a cytochrome P450-dependent enzyme, acts as the ultimate step in the synthesis of estrogen, catalyzing the conversion of androgens to estrogens (33). The conversion of androgens to estrogens also occurs at peripheral sites, such as in muscle, fat, and the liver (34). Recently, a group of new, highly selective aromatase inhibitors has been approved to suppress estrogen production in postmenopausal women with breast cancer. Aromatase inhibitor is a competitive inhibitor of the aromatase enzyme system, and inhibits the conversion of androgens to estrogens. It inhibits the aromatase enzyme by competitively binding to the heme of the aromatase–cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues where it is present (Figure 39.2). Treatment significantly lowers serum estrone, estradiol, and estrone sulfate, and has not been shown significantly to affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones. Maximum suppression is achieved within 48–78 hours. The first aromatase inhibitor to be developed was aminoglutethimide, but its usage was stopped owing to side eff cts, one of which was adrenal insufficiency (35). However, this development stimulated the formulation of numerous other aromatase inhibitors that were described as first-, second-, and third-generation inhibitors according to chronologic development. They were further classified as type I (steroid analogs of androstenedione) and type II (nonsteroidal) (Table 39.1).
Endocrine Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Many breast cancers are stimulated to grow by estrogen and progesterone. The aromatase inhibitors are a family of agents that reduce the amount of estrogen in the body by blocking the cytochrome P450 aromatase enzyme (P450AROM), which is key for the synthesis of estrogen in certain parts of the body. However, as they do not inhibit ovarian estrogen synthesis (the main source of estrogen in premenopausal women), they can only be used in postmenopausal women, or those in whom the ovaries have stopped working or have been removed. In postmenopausal women most of the estrogen is produced via conversion of the androgens androstenedione and testosterone to estrone and estradiol, respectively, by P450AROM (a process known as aromatization) as the final step in the steroidogenesis pathway from cholesterol (see Figure 8.1). This occurs in peripheral tissues such as the fatty tissues (i.e., adipose tissue) of the breast, muscle, and skin, and in some sites in the brain. Estrogen produced in this way acts locally in these peripheral tissues where it was synthesized. For example, breast tissue can contain up to a twentyfold higher concentration of estrogen than other tissues, and any circulating estrogen in postmenopausal women (as well as in men) is the result of locally produced estrogen escaping local metabolism and entering the circulatory system. Selective inhibition of P450AROM leads to reduced estrogen levels in the body, and this can lead to a reduction in tumor growth without affecting other hormones produced by the steroidogenesis pathway.
Hormonal therapy of breast cancer
A. R. Genazzani in Hormone Replacement Therapy and Cancer, 2020
The aromatase inhibitors prevent the production of estrogen from testosterone. Three agents are registered by the US FDA for therapy of metastatic breast cancer: the non-steroidal agents anastrozole and letrozole, and the steroidal agent exemestane. All are extremely potent and specific inhibitors, suppressing aromatization by 97%29, 99%30 and 98%31, respectively. These agents do not cause the estrogenic side-effects seen with tamoxifen (endometrial proliferation, thromboembolism), but are associated with its antiestrogenic side-effects (vaginal dryness, hot flushes, nausea)32, and these agents probably also lack the favorable estrogenic effects of the SERMs (bone mineralization, lipid metabolism), although this is still being studied.
Medical management of non-obstructive azoospermia: A systematic review
Published in Arab Journal of Urology, 2021
Mohammad H. Alkandari, Armand Zini
Common ways of increasing intra-testicular testosterone levels in men with NOA and hypergonadotrophic hypogonadism are by use of aromatase inhibitors (steroidal and non-steroidal) and anti-oestrogens. Aromatase inhibitors block aromatase enzyme, which converts testosterone to oestrogen in peripheral tissues. A comparative study on 140 infertile men with an abnormal testosterone:oestrogen ratio showed that both groups of aromatase inhibitors significantly improved that ratio but were never successful in producing sperm in the ejaculate [14]. The same study group also reached the conclusion that patients might benefit from this treatment if they are undergoing a sperm retrieval surgery. Another study showed similar results when men with low testosterone and either a low testosterone:oestrogen ratio or failed clomiphene were prescribed daily anastrozole (non-steroidal aromatase inhibitor) [15]. Although, none of these men had sperm in the ejaculate after treatment, 73% underwent successful micro-TESE after anastrozole.
Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity studies
Published in Xenobiotica, 2019
Senem Ozcan-Sezer, Elif Ince, Atilla Akdemir, Özlem Öztürk Ceylan, Sibel Suzen, Hande Gurer-Orhan
Aromatase is a cytochrome P450 (CYP) enzyme complex which catalyses the conversion of androgens into estrogens and it catalyses the rate limiting step of endogen estrogen biosynthesis (Ahmad, 2015; Di Nardo & Gilardi, 2013; Furr, 2006; Ghosh et al., 2016; Santen et al., 2009). Aromatase is a source of local estrogen production in breast cancer tissue and increased aromatase expression is reported in postmenopausal women with ER + breast cancer (Brueggemeier et al., 2005). Therefore, inhibition of aromatase is a promising target for hormone-dependent breast cancer therapy (Briest & Davidson, 2007; Ghosh et al., 2009). Aromatase inhibitors can be classified into two major groups as steroidal and non-steroidal derivatives. Among the non-steroidal inhibitors, the most studied compounds were indoles. (Brueggemeier et al., 2005; Furr, 2006). Furthermore, many indole-based compounds have been shown to inhibit aromatase activity in several studies (Kang et al., 2018; Pingaew et al., 2018; Wang et al., 2013).
Single nucleotide polymorphisms in treatment of polycystic ovary syndrome: a systematic review
Published in Drug Metabolism Reviews, 2019
Ritu Deswal, Smiti Nanda, Amita Suneja Dang
PCOS appear to underlie menstrual dysfunction in approximately 80% of patients. Abnormal menses manifests as oligomenorrhoea and primary/secondary amenorrhea resulting from oligo or anovulation. About 80–90% of women with PCOS have oligomenorrhoea and 10–20% have amenorrhea (Teede et al. 2010). Classes of drugs used to treat menstrual irregularities are (i) oral contraceptive pills (OCPs), (ii) insulin-sensitizing drugs, (iii) aromatase inhibitors, (iv) glucocorticoids, (v) gonadotropins, and (vi) sSelective estrogen receptor modulators (SERMs) (Williams and Creighton 2012). Most of the differences in treatment regimens among individuals were just because of genetic polymorphisms (Khrunin et al. 2010). The important genetic predictors related to MI have been discussed in Table 1. The drug of choice for treating MI in PCOS is clomiphene citrate, metformin, and oral contraceptives.
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