Steroid enzymes at work

Aromatase enzyme converts androgens to estrogens

Androgens          ➔          Estrogens

aromatase enzyme

Aromatase function in more detail

Aromatase is responsible for the production of 18-carbon estrogens from 19-carbon androgen steroids:TESTOSTERONE and ANDROSTENEDIONE - the gene CYP19 encodes the aromatase enzyme (a member of the Cytochrome P450 enzyme superfamily).

ANDROSTENEDIONE ➔  ESTRONE (in women)

(In the female, FSH increases aromatase activity, enhancing this conversion)

TESTOSTERONE ➔  ESTRADIOL

Aromatase  production

Different body tissues produce estrogen via aromatase response to different activating promoters,  tissue-specific regulation of CYP19 (aromatase gene) expression is achieved through the use of distinct promoters controlled by hormones and other factors, including:

• Glucocorticoids (E.g. CORTISOL, the drug prednisone),
• Class 1 cytokines:    E.g. IFN-γ, IL-2, IL-6, IL-11, and TNF-α(present in infection);
• Retinoids.    E.g. vitamin A
• FSH

Aromatase can be found in several tissues

• Tissues having beneficial estrogen presence - includes gonads, brain, adipose tissue (E.g. found in the breast), placenta, blood vessels, skin, bone, and endometrium.
• Health conditions where inappropriately high levels of aromatase are present in tissues - endometriosis, uterine fibroids, breast cancer(enhanced aromatase activity found in breast fat)and endometrial cancer.

Aromatase ACTIVITY is inhibited by (examples):

• Nettle root
• PROGESTERONE
• Drugs: MEHP (monoethylhexylphthalate); fenarimol; substituted analogs of ANDROSTENEDIONE, e.g., C-10 substituted (19R-10 β-oxiranyl-), or C-4 substituted (OH-, formestone), or C-7 substituted (7 α-SC6H4-p-NH2-), or 2 β, 19 bridged (2 β, 19-methylene-), fadrazole, letrozole, and arimidex,

Aromatase ACTIVITY is ▲Enhanced by:

• Age;
• Obesity;
• INSULIN;
• Gonadotropin hormones (E.g. FSH, LH, hCG);
• Alcohol.
• Location in certain estrogen-dependent local tissue E.g. next to breast tissue
• Endometrial cancer, endometriosis, and uterine fibroids.

Aromatase ACTIVITY is ▼Reduced by:

• PROLACTIN (stimulates milk production for breast-feeding);
• Smoking;
• Anti-mullerian hormone (AMH).  Produced by reproductive tissues.   Inhibits the development of the Mullerian ducts in the male embryo, which develop into reproductive organs in females.
• Drugs (post-menopausal only) Letrozole (Femara^®), anastrozole (Arimidex^®), and exemestane (Aromasin^®).

Aromatase conversion pathway directly affected by:

• Flavonoids and lignans  (both polyphenols).   Enterolactones are lignan precursors found in E.g.flaxseed;
• Drugs.   Aminoglutethimide, MEHP, Fenarimol, Fadrazole, Letrozole, Anastrozole, Arimidex, Prochloraz, Enconazole/miconazole/ketoconazole, Imizolil, 4-hydroxyANDROSTENEDIONE, 10-propargylestr-4-ene-3,17-dione

Enzyme 5α-Reductase (5AR)

5α-Reductase converts:

 TESTOSTERONE➔  DIHYDROTESTOSTERONE (DHT) (normally in males)

Mainly in peripheral tissue, but also in testes; DHT is significantly more potent than TESTOSTERONE, and thought to be involved in prostate enlargement, prostate cancer and PCOS.

There are two 5AR forms (isoenzymes)

• 5-alpha reductase 1 (SRD5A1) - used to create neurosteroids
• 5-alpha reductase 2 (SRD5A2) - converts TESTOSTERONE ➔ DHT

5AR Inhibited by:

• PROGESTERONE
• Drugs (E.g. Finasteride , Dutasteride) - used against BPH, prostate cancer and male pattern baldness
• Saw Palmetto (Serenoa repens)
• Willow herb - contains oenothein B, with 5AR inhibitor activity
• Astaxanthin - this carotenoid has demonstrated some 5AR inhibitor activity
• Black cohosh (Cimicifuga racemosa) Maturitas. 2006.Department of Clinical and Experimental Endocrinology, University of Goettingen, Robert-Koch-Strasse, Gottingen, Germany
• 5AR Inhibitor (5ARI) drugs (E.g. Finasteride , Dutasteride) have been associated with adverse outcomes, which side-effects may also be experienced with any natural 5AR inhibitor:
• Adverse sexual outcomes - such as lack of libido, erectile dysfunction (ED), and ejaculatory dysfunction (EjD). Since Nitric Oxide (NO) is required to maintain an erection, a suggested theory is that lack of DHT inhibits nitric oxide synthase (NOS) activity.
• Anxiety / Depression - common side effects of 5ARI s believed to be caused, in part, by the prevention of the endogenous production of the neurosteroid allopregnanolone from PROGESTERONE
• Cancer
• Finasteride - inhibits the function of only type 2 form of 5AR (SRD5A2); however, it was found in a study of 18,000 healthy men, that although the finasteride group had a lower incidence of cancer (18.4% vs. 24.4%) there were more cases of aggressive cancer with finasteride than with placebo group (37% vs. 22.2%, P<0.001). Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224 ;
• Dutasteride - inhibits both forms of 5AR (SRD5A2 and SRD5A2);

P450_SCC (Cytochrome P450 cholesterol side-chain cleavage enzyme)

At the inner membrane, a series of enzymatic reactions occurs:

Enzyme P450SCC Converts:

Cholesterol ➔  PREGNENOLONE (in mitochondria)

Production / Activity of P450_SCC regulated by:

• LH

P450_SCC inhibitors include:

• Estrogens
• Drugs: Aminoglutethimide, 3-methoxybenzidine, cyanoketone, azastine, and danazol.
• P450SCC pathway directly affected by:
• Lead;
• Vitamin A deficiency;
•  Drugs: Ketoconazole, Mibolerone, Aminoglutethimide, Taxol, Cis-platinum,

Enzyme 3ß-HSD (3ß-Hydroxysteroid Dehydrogenase)

3ß-HSD converts:

PREGNENOLONE ➔  PROGESTERONE

DHEA  ➔  ANDROSTENEDIONE;

3ß-HSD Production/Activity stimulated by:

• LH
• FSH (in the male) - stimulates release of a Sertoli cell factor that increases LH effect on 3ß-HSDactivity;

3ß-HSD production / activity suppressed by:

• TESTOSTERONE (through inhibitory effects on cAMP-mediated 3ß-HSD mRNA)

3β-HSD pathway by:

• Lead;
• Daidzein /genistein /biochanin A (isoflavones)
• Drugs: Lithium chloride, Mibolerone, Danazol (ethinylTESTOSTERONE), Cyproterone acetate, Ethionine, Cyanoketone, Mitomycin C, Aflatoxin

Enzyme 17ß-HSD (17ß-Hydroxysteroid Dehydrogenase)

17ß-HSD converts:

ANDROSTENEDIONE <=> TESTOSTERONE

ESTRONE (E1) <=> ESTRADIOL (E2)

ESTRADIOL (E2) synthesis occurs principally through oxidation of ESTRONE (E1)  - and is a reversible reaction;

The ESTRADIOL (E2) / ESTRONE (E1) ratio before menopause is > 1 - after menopause ESTRONE 1 is the predominant estrogen.

Both ESTRADIOL (E2) and ESTRONE (E1) can be metabolized to the biologically weaker ESTRIOL (E3), and to a number of other metabolites - via A-ring (Anti-carcinogenic) metabolic pathways, E.g, 2-HYDROXYESTRONE and its methylated form 2-METHOXYESTRONE or D-ring (potentially carcinogenic) metabolism E.g, 16α- HYDROXYESTRONE.

Tissue enzymes (E.g sulfatases and 17ß-HSDs) originating in bowel bacterial flora and the intestinal mucosa, activate strogens locally to ESTRADIOL (E2) and ESTRONE (E1). Stanczyk F. Estrogens used for replacement therapy in postmenopausal women. Gynecol Endocrinol. 2001;15(suppl 4):17-25.

17ß-HSD pathway directly affected by:

• Lignans
• Enterolactones (lignan precursors) found in E.g.flaxseed inhibit
• Drugs: Cotinine, Danazol, Cyclosporin A, Lithium chloride.

 

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