What is the pathophysiology of aromatase in adult women, particularly those with a history of breast cancer or at high risk of developing the disease?

Pathophysiology of Aromatase in Adult Women

Core Mechanism of Aromatase

Aromatase (CYP19A1) is the cytochrome P450 enzyme complex that catalyzes the conversion of androgens to estrogens through a three-step oxidative demethylation process, removing carbon-19 from androgens to produce phenolic 18-carbon estrogens. 1, 2, 3

Biochemical Process

• Each of the three oxidative steps requires 1 mol of O₂, 1 mol of NADPH, and coupling with cytochrome P450 reductase to complete the conversion 3
• The enzyme converts androstenedione to estrone, testosterone to 17β-estradiol, and 16α-hydroxytestosterone to 17β,16α-estriol 3
• The first two steps involve C19-methyl hydroxylation, while the third step involves aromatization of the steroid A-ring, a reaction unique to aromatase 3
• Aromatase acts as a "suicide substrate" mechanism when inhibited by drugs like exemestane, where the inhibitor binds irreversibly to the active site, causing permanent enzyme inactivation 1

Tissue-Specific Estrogen Production

Postmenopausal Women

In postmenopausal women, the principal source of circulating estrogens is peripheral conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase enzyme in peripheral tissues, not ovarian production. 1, 2

• Aromatase is present in adipose tissue, muscle, liver, and breast tissue itself, making peripheral aromatization the dominant source of estrogen after menopause 4, 5
• Intratumoral aromatase in breast cancer tissues serves as the source of local estrogen production, driving hormone-dependent tumor growth 4

Premenopausal Women

In premenopausal women, the ovary remains the main source of estrogen (primarily estradiol), and aromatization of adrenal androgens is not a significant contributor to circulating estradiol levels. 2

• This fundamental difference explains why aromatase inhibitors are ineffective in premenopausal women without concurrent ovarian suppression or ablation 6, 7

Clinical Relevance in Breast Cancer

Hormone-Dependent Tumor Growth

The growth of many breast cancers is stimulated or maintained by estrogens, making aromatase the critical enzyme enabling tumor progression in hormone receptor-positive disease. 2, 4

• Suppression of estrogen biosynthesis in both peripheral tissues and cancer tissue itself can be achieved by specifically inhibiting aromatase 2
• Aromatase inhibitors markedly suppress endogenous estrogens without directly interacting with estrogen receptors, providing a different mechanism of action compared to tamoxifen 8

Enzyme Selectivity and Specificity

Unlike most P450 enzymes that lack substrate selectivity, aromatase demonstrates hallmark androgenic specificity with an androgen-specific cleft that binds steroid molecules snugly. 3

• The active site contains hydrophobic and polar residues that exquisitely complement the steroid backbone 3
• Aromatase has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone, demonstrating remarkable selectivity 1, 2
• The enzyme does not affect cortisol or aldosterone secretion at baseline or in response to ACTH, eliminating the need for glucocorticoid or mineralocorticoid replacement therapy during aromatase inhibitor treatment 1, 2

Pharmacologic Inhibition Effects

Estrogen Suppression

Aromatase inhibitors at therapeutic doses (25 mg exemestane or 1 mg anastrozole) achieve 85-95% suppression of plasma estrogens (estradiol, estrone, and estrone sulfate) in postmenopausal women. 1

• Exemestane 25 mg daily reduces whole body aromatization by 98% in postmenopausal women with breast cancer 1
• Anastrozole 1 mg reduces estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing 2
• Maximal suppression of circulating estrogens with exemestane occurs 2-3 days after dosing and persists for 4-5 days 1

Androgen Effects

Aromatase inhibition blocks conversion of androgens to estrogens, potentially causing relative increases in androgen levels while estrogen levels decline. 9, 1

• Daily doses of exemestane up to 25 mg have no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, but are associated with small decreases in circulating testosterone 1
• At higher doses (≥200 mg), increases in testosterone and androstenedione levels have been observed 1
• The 17-dihydrometabolite of exemestane has 100 times greater binding affinity for the androgen receptor compared to the parent compound 1

Critical Clinical Caveats

Menopausal Status Verification

Aromatase inhibitors are absolutely contraindicated in premenopausal women with functioning ovaries, as the enzyme cannot adequately suppress ovarian estrogen synthesis. 9, 7

• For women who become amenorrheic with chemotherapy, serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status before initiating aromatase inhibitor therapy 10
• In premenopausal women requiring aromatase inhibitor therapy, concurrent ovarian suppression with LHRH agonists (goserelin, leuprolide) or surgical/radiotherapeutic oophorectomy is required 6

Treatment Selection in Postmenopausal Women

For postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitors demonstrate superior disease-free survival and reduced recurrence rates compared to tamoxifen monotherapy. 10

• Nonsteroidal aromatase inhibitors (anastrozole, letrozole) and steroidal inhibitors (exemestane) are both effective, with no compelling evidence of meaningful differences in efficacy or toxicity among the three agents 6, 10
• Sequential endocrine therapy at disease progression is appropriate for women whose breast cancers respond to initial endocrine therapy with tumor shrinkage or long-term disease stabilization 6