The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer

The principal product of ovarian granulosa cells during the follicular phase of the menstrual cycle is estradiol. In adipose tissue a weaker estrogen, estrone, is produced from androstenedione of adrenal origin in relatively large quantities. At least half of this estrone is eventually converted to estradiol in extra-ovarian tissues (26). The sexually dimorphic nucleus of the POA (sexually dimorphic nucleus SDN-POA) in the hypothalamus is important for male copulatory behavior, and it is several-fold larger in male rats than in female rats 105. Testosterone treatment of females during a perinatal period produced larger SDN-POA, similar to the one seen in males, and the application of aromatase inhibitor during this critical period reduced the size of SDN-POA and changed male copulatory behavior 105, 106.

The pentahydroxylated flavone, quercetin (37), present in numerous plant species but reported in the aromatase literature as being isolated from Epilobium capense 130 and Morinda citrifolia L. (noni) 131, was found to be moderately active in two microsomal studies 120, 122 but only weakly active in another microsomal study 130. Quercetin (37) was not active in granulose-luteal cells 129, JEG-3 cells 125, H295R adrenocortical carcinoma cells 127, human preadipocyte cells 126, or using trout ovarian aromatase 128.

Binding to the active site

Zinc deficiency is also well-known to adversely affect male fertility, likely by altering the ratio of testosterone to estrogen. Middle-aged sterile men that supplemented with 220 mg zinc (sulfate) daily for two had an average 250% increase in sperm count and 54% increase in total testosterone levels(the zinc supplement effectively restored fertility) 6. However, more clinical data is needed to confirm the impact of zinc supplements on estrogen levels in men. Some people may start treatment with an aromatase inhibitor or take tamoxifen for a few years and then start aromatase inhibitor therapy.

Moreover, because it is easy to use and widespread, a technology that enables a quick response could be helpful for clinicians in ameliorating symptoms and obtaining fast answers. For https://vagatop.com/understanding-furosemide-uses-benefits-and-risks-2/ vasomotor symptoms, non-hormonal methods such as selective serotonin reuptake inhibitors (SSRIs), gabapentin or clonidine should be tried first (63). In doses commonly needed for relief of hot flushes (75 mg venlafaxine, 20 mg fluoxetine and 300–900 mg gabapentin), side effects for these medications include drowsiness, dry mouth and dyspepsia.

The activity of compounds from this group is probably determined by the ability of nitrogen-based heterocyclic systems to form interactions with heme located in the aromatase binding pocket. Based on extensive molecular docking studies, it was found that azole rings have the ability to bind to iron in the center of the heme moiety 77. Both cytotoxic and cytostatic properties of azole derivatives have been confirmed on various cell lines, with particular emphasis on the hormone-dependent breast cancer cell line MCF-7. A paper on the synthesis and assessment of the biological activity of a series of heterocyclic diaryl-methanes was published by Ana et al. An in vitro study on the MCF-7 breast cancer cell line showed that the 1,2,4-triazole derivative 38 (Figure 10) had the highest activity among the synthesized series. The IC50 value for hit compound 38 of 52 nM was compared with the reference drug Combretastatin A4—3.9 nM 36.

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A series of compounds containing the 1,2,3-triazole moiety were synthesized by McNulty et al. Some of the obtained compounds showed high potency in inhibiting human aromatase (CYP A1). The most potent aromatase inhibitors in the series were compounds containing halogen-aryl moieties in positions that mimic the carbonyl substituents of natural enzymatic substrates. The Ki values for the most active compounds 43 and 44 (Figure 10) were 20 nM and 30 nM, respectively 41. New derivatives of the anticancer drug formestane were developed by Wahab et al. (compounds 7–9, Figure 4). These compounds were synthesized through biocatalyzed structural modifications carried out by C.

Worldwide breast cancer estimates included over one million incident cases and almost 400,000 deaths in the year 2000 1, 2. In the United States, over 178,000 women were expected to be diagnosed with breast cancer in 2007 with over 40,000 deaths occurring from the disease 3. In developed countries, mortality from breast cancer has recently begun to decline, primarily due to earlier detection and improved treatments 4, 5. Breast cancer is thought to be a result of inherited genetic predisposition (e.g., mutations in genes such as BRCA-1, BRCA-2, p53, PTEN/MMAC1, and/or ATM) and/or environmental factors (e.g., radiation exposure, dietary factors, alcohol consumption, hormonal exposure) 2, 6, 7.

The structure also suggests a membrane integration model indicative of the passage of steroids through the lipid bilayer. The expression of aromatase in the ovary plays an important role in the regulation of the reproductive cycle in females. Aromatase is also expressed in the male gonad; however, in contrast to its key role as an endocrine coordinator in females, in males, the paracrine effects of aromatase products are essential for normal spermatogenesis. In both sexes, aromatase is found in a number of extragonadal sites, including bone, breast, adipose tissue and brain. This tissue-specific expression of aromatase maintains tight local control over the synthesis and action of oestrogens.

Additional studies investigating pregnancy rates and pregnancy outcomes following treatment for endometriosis using an AI are needed. This paper will review the role of aromatase in the pathogenesis of endometriosis, discuss the pharmacology of aromatase inhibitors, and examine clinical applications of aromatase inhibitors for the treatment of endometriosis. In contrast, it was demonstrated that atrial natriuretic peptide (ANP) decreases the secretion of 19-OH AD 134. Cytokines produced by either immune cells within the gland or by adrenal cells can also affect adrenal steroidogenesis. For example, IL-6 activates the HPA axis and stimulates a release of ACTH, and also stimulates a release of aldosterone, cortisol, and DHEA 139, 140. Detailed analysis of aromatase reaction steps demonstrated that aromatase allows a free dissociation of 19-hydroxy steroids, which has been attributed to its distributive-dissociative nature 10, 25.

• The most active compound 9 showed significant inhibitory potential with an IC50 of 0.386 μM, comparable to the parent drug for which the IC50 value was 0.335 μM 16.
• From the literature, six isoflavones were tested for aromatase inhibition (Table 8, Fig. 9).
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• Thus, exclusively in primates, a joint venture is formed between the foetal adrenal gland and the placenta to produce extremely high levels of oestrogens.
• Because of the integral role of aromatase and estrogens in endometriosis, Aromatase inhibitors (AIs) have been investigated as a potential treatment option for women afflicted with endometriosis (17, 20–23).

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As such, natural product AIs may be important for the translation of AIs from their current clinical uses as chemotherapeutic agents to future clinical uses in breast cancer chemoprevention. New natural product AIs may be clinically useful for treating postmenopausal breast cancer and may also act as chemopreventive agents for preventing secondary recurrence of breast cancer. Several strategies were employed to investigate the benefit of AIs as an adjuvant treatment for hormone receptor-positive breast cancer in postmenopausal women.