Conventional HRT vs

Conventional HRT vs. Bio-Identical HRT (BHRT)

Brent Murphy – B.Pharm (Rhodes), MPS

Introduction:

"Bioidentical" hormone replacement therapy (BHRT) is a modification of conventional hormone replacement therapy that involves use of supplemental doses of hormones, with 3 important criteria:
1. BHRT has the identical chemical structure to the hormones that exist naturally in the human body, and
2. BHRT is used to replenish levels to physiologically normal concentrations, never exceeding physiological levels, and
3. BHRT is administered via a mode/route of administration that most mimics the body’s natural production (eg given transdermally to avoid metabolic byproducts produced by first pass metabolism to the liver, which occurs only with oral dosage routes, which for example increases the risk of blood clotting (REFERENCE: Scarabin PY, Oger E, Plu-Bureau G; EStrogen and ThromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003 Aug 9;362(9382):428-32). The term "bioidentical" is used because the administered hormones although chemically synthesised, are identical to the endogenous hormones of the human body. Estradiol, progesterone, estriol (another natural estrogen) and testosterone are the most common.
In contrast, conventional hormone replacement therapy often involves the use of non-bio-identical hormones which have been modified so that their chemical structure is not the same as endogenous human hormones (hormones the body naturally makes), or are extracted from animal which have non-human estrgoens (eg equilin from horses’ urine does not occur in humans naturally). Another example is where a molecule is added to progesterone to make medroxyprogesterone acetate, which makes this form of synthetic progesterone more bioavailable via oral routes, and patentable -but also increases the risk of cancer (REFERENCE: Campagnoli C.; Pregnancy, progesterone and progestins in relation to breast cancer risk.; J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50).

Cancer issues: Estriol, Progesterone and Progestins:

All non bio-identical progesterone and non-bio-identical estrogen increase the risk of breast and endometrial cancer (REFERENCES: (1) International Agency for Research on Cancer (IARC) - Summaries & Evaluations -PROGESTINS (Group 2B) Supplement 7: (1987) (p. 289) – [http://www.inchem.org/documents/iarc/suppl7/progestins.html]; (2) J. E. Rossouw et al "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial" in Journal of the American Medical Association (2002) Volume 288, pages 321-333. (3) G. L. Anderson et al "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial" in Journal of the American Medical Association (2004) Volume 291, pages 1701-1712. (4) C. Straczec, et al "Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration" in Circulation (2005) Volume 112, pages 3495-500). This is in contrast to bio-identical progesterone and bio-identical estriol estrogen which are considered protective against breast cancer:
A) Bio-identical progesterone protects against breast cancer, whereas progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) increase risk. (REFERENCE: Campagnoli C.; Pregnancy, progesterone and progestins in relation to breast cancer risk.; J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50).
B) Estriol binds to the second estrogen receptor ERBeta, which is a tumor suppressing receptor (REFERENCE: Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P.; Loss of ERbeta expression as a common step in estrogen-dependent tumor progression.; Endocr Relat Cancer. 2004 Sep;11(3):537-51).
Additionally, one of the leading researchers on estriol, Henry Lemon, MD, of the University of Nebraska postulated that estriol is probably a safer from of estrogen in regard to breast cancer for the following reasons: 1) In vitro, when given with estradiol, estriol accelerates the removal of estradiol bound to protein receptors.
2) Investigators have been able to initiate very little carcinogenesis in animal studies unless large doses (200-500mcg/kg/day) were used on a continuous basis.
3) In animal studies estriol has been found to prevent carcinogen-induced mammary tumours; and
4) Unlike estrone and estradiol, estriol metabolism does not result in the formation of large numbers of carcinogenic substances.
(REFERENCE: Lemon HM; Pathophysiologic consideration in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma.; Acta Endocrinol (Copenh); 1980; 223: S17-S27) However, whilst Estriol appears to be safer than estrone and estradiol and, in some situations provides some protection against carcingenesis, other research reports that estriol’s use in breast cancer patients with active disease or in patients with at high risk of breast cancer should be approached with caution. Estriol’s breast cancer benefits seem to occur when intermittent (ie once daily doses) are used in preference continuous dosages (2-3 times daily). More research is needed in this regard, but thus far looks promising (REFERENCE: Head K.Estriol: Safety and Efficacy; Alt Med Rev; 1998; 3(2): 101-113).

Method of administration: Oral vs Transdermal:

The sex steroid hormones can be administered orally, but when administered in this way most of the hormone is destroyed by the liver soon after entering the body. In the case of progesterone, the resulting metabolic by-products can cause unwanted side-effects. In the case of estrogens, oral administration can alter the production of clotting factors by the liver, increasing the risk of dangerous strokes. For these reasons, topical administration of sex steroid hormones is increasingly popular, since they bypass the liver –mimicking what naturally occurs in the body (this is one of the prerequisites of BHRT). Some hormones have been made available as manufactured transdermal patches, particularly estradiol. Progesterone and estriol are mostly available in the form of topically applied creams made by a trained pharmacist from a compounding pharmacy, preferably incorporated into liposomes to improve bio-availability:
Incorporation of the hormones into liposomal gels is the most effective way of ensuring transdermal systemic absorption (REFERENCES: [1] Kumar R, Katare OP.; Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: a review; AAPS PharmSciTech. 2005 Oct 6;6(2):E298-310 -attached [2] Willimann HL, Luisi PL. Lecithin organogels as matrix for the transdermal transport of drugs. Biochem Biophys Res Commun. 1991 Jun 28; 177(3):897-900).
– see document titled: Pharmacodynamics of Transdermal Delivery for additional information. Dangers of Conventional, non bio-identical HRT:
Bio-identical hormone replacement therapy has received increased attention since the termination of the Women's Health Initiative hormone replacement therapy clinical trials showed increased risks of breast cancer, stroke and heart disease, using non-bioidentical estrogens and progestins (REFERENCES: (1) J. E. Rossouw et al "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial" in Journal of the American Medical Association (2002) Volume 288, pages 321-333. (2) G. L. Anderson et al "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial" in Journal of the American Medical Association (2004) Volume 291, pages 1701-1712. (3) C. Straczec, et al "Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration" in Circulation (2005) Volume 112, pages 3495-500).

SUMMARY: Potential advantages of BHRT over conventional Hormone Replacement Therapy

• Emphasis on topical administration; avoids problems such as blood clotting that are caused by the rapid metabolism of orally administered hormones (Scarabin PY, Oger E, Plu-Bureau G; EStrogen and ThromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003 Aug 9;362(9382):428-32 -attached).
• Bio-identical Progesterone may work differently and more safely in the body than medroxyprogesterone acetate (a progestin) (Simoncini T, Mannella P, Fornari L, Caruso A, Willis MY, Garibaldi S, Baldacci C, Genazzani AR.; Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells.; Endocrinology. 2004 Dec;145(12):5745-56 -attached).
• Progestins, but not bio-identical progesterone, increases risk of breast cancer (Campagnoli C.; Pregnancy, progesterone and progestins in relation to breast cancer risk.; J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50).
• Inclusion of estriol may be protective against hormone-induced cancer. Unlike estradiol, estriol binds preferentially to the second estrogen receptor (ERbeta). ERbeta may function as a tumor suppressor (Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P.; Loss of ERbeta expression as a common step in estrogen-dependent tumor progression.; Endocr Relat Cancer. 2004 Sep;11(3):537-51 - attached).
• Endometrial safety: Estriol is able to restore normal vaginal cytology at a dose 3-5 times lower than the dose of estriol that causes endometrial hyperplasia. This is in contrast to the other estrogens where the therapeutic dose is similar to the dose that causes hyperplasia ([1] Husin J.; Cytological Evaluation of the effect of various estrogens given in post menopause. Acta Cytologica; 1977; 21:225-228. [2] Head K.Estriol: Safety and Efficacy; Alt Med Rev; 1998; 3(2): 101-113 -attached).
• Estradiol alone is not adequate (even though some coverts to estriol). This is because doses above 0.25mg daily can raise estradiol to supra-physiological doses, yet not raise estriol enough to improve the estrogen quotient (ratio of Estriol: Estrone+Estradiol), essential for breast cancer protection. Therefore Estriol must be administered in addition. (Wright, JD.; Bio-Identical Steroid Hormone Replacement Therapy – Selected observations of 23 years of clinical and laboratory practice; 2005: Ann N.Y. Acad. Sci.; 1057: 506-524 -attached).
• Emphasis on individualized doses rather than "one dose fits all" approach of conventional hormone replacement therapy (Romero M.; Bioidentical hormone replacement therapy. Customising care for peri-menopausal and menopausal women.; Adv Nurse Pract. 2002 Nov;10(11):47-8, 51-2).
• Incorporation of the hormones into liposomal gels is the most effective way of ensuring transdermal systemic absorption ([1] Kumar R, Katare OP.; Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: a review; AAPS PharmSciTech. 2005 Oct 6;6(2):E298-310 -attached [2] Willimann HL, Luisi PL. Lecithin organogels as matrix for the transdermal transport of drugs. Biochem Biophys Res Commun. 1991 Jun 28; 177(3):897-900). – see document titled: Pharmacodynamics of Transdermal Delivery for additional information.