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The advancements in HRT required

Summary :

A. clearing up the misconceptions amongst doctors

B. Progesterone, the most neglected hormone?

C. Hormone balancing essential

D. Safe metabolism of estrogen is required

E. Conventional vs. Bioidentical HRT

F. Method of administration of hormones is essential

G. Potential advantages of bioidentical HRT over conventional

H. Estriol

I. Compounding

J. Proof of purity, efficacy and safety of bioidenticals

(A) Clearing up misconceptions regarding compounding and bioidentical hormones

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  • Opinion 1: Compounded hormones are not regulated
  • Fact: compounded hormones are regulated in terms of section 14(4) of the medicines act 101. Furthermore, according to the pharmacy act, compounding is one of the unique activities specially relating to the pharmacist’s profession. Removing compounding from pharmacists would render them mere dispensors.
  • Opinion 2: They are prescribed by non-medical practitioners
  • Fact: compounded hormones have a schedule status, eg estradiol, estriol are schedule 3 ; testosterone is schedule 4. These schedules are observed in pharmacies. You shouldn’t legally be able to get them without a doctors prescription
  • Opinion 3: Compounded hormones are “not well absorbed”
  • Fact: The compounding pharmacy of SA uses the most advanced transdermal delivery known as a pluronic lecithin gel. Retrospective data from doctors proves improvement of symptoms and lab test changes on hormone levels
  • Opinion 4: “purity, potency, efficacy are not monitored”
  • Fact: Indeed the above is monitored. We randomly send products for quantitative analysis to verify label claim. Efficacy and safety is monitored by the patient’s doctors
  • Opinion 5: “bioidentical hormones are not safer than the alternatives” In fact at recent menopause conference it was stated that they are more dangerous!
  • Fact: A better name for these hormones is human hormones, they occur naturally in your body. They are not horse hormones and not progestins. Humans need human hormones. We do not need mega doses of non-human hormones.
  • Opinion 6: “ It is impossible to balance one’s hormones”
  • Opinion 7: Customization and individualisation of an individuals hormones is not possible
  • Fact: Through lab testing including serum, 24 hr urine, saliva and bloodspot testing, as well as symptomatology improvement it is indeed possible to balance and optimize an individual’s hormones. In antiaging medicine we do not adopt a one size fits all approach like with conventional hrt. We individualize doses and this is why compounding of the right dose for an individual is essential and a necessity!!
  • Opinion 8: Saliva testing is a lot of rubbish
  • Fact: NASA use salivary cortisol to assess the stress levels of astronauts.
  • Extensive work has been done on saliva testing to show that it does reflect tissue levels of hormones
  • Many studies are available on saliva testing, contact dr golding for trials if needed
  • Does transdermal progesterone protect the endometrium, with the evidence below

Progesterone

  • Fertility and sterility Vol 70, no 1 , jan 2003 Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium
  • 37 women studied, 98% completed the study, minimal vaginal spotting occurred in 6 women.
  • Endometrial histologic changes confirmed an antiproliferative effect of transdermal progesterone.
  • Doses used were a 1.5% and 4% cream

(B)   Progesterone, the forgotten hormone?

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Most often in conventional HRT, progestins are used, and progesterone neglected!      They are not the same thing!

Even in hysterectomized women, progesterone should be replenished.      Progestins are omitted, and rightly so, since they elevate the risk for breast cancer

Some differences between progesterone and progestins and scientific evidence for progesterone

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Progesterone

  • Fertility and sterility Vol 70, no 1 , jan 2003 Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium
  • 37 women studied, 98% completed the study, minimal vaginal spotting occurred in 6 women.
  • Endometrial histologic changes confirmed an antiproliferative effect of transdermal progesterone.
  • Doses used were a 1.5% and 4% cream

Progesterone effects not seen with Progestins

  • Natural progesterone helps balance estrogen
  • Leaves your body quickly (unlike progestins)
  • Helps you sleep
  • Natural calming effect
  • Lowers high blood pressure
  • Helps your body use and eliminate fats
  • Lowers cholesterol
  • Protects against breast cancer
  • Increases scalp hair
  • Normalises libido
  • Helps balance fluids in the cells
  • Blood vessel dilation
  • Antiproliferative effect
  • Increases metabolic rate
  • Natural diuretic, natural antidepressant

Common effects of Progesterone and Progestins

  • Builds bone
  • Helps thyroid hormone function
  • Protects against fibrocystic breast disease
  • Protects against endometrial cancer
  • Normalises zinc and copper levels

Progesterone

  • Cancer research 62,881-886,feb 1,2002 Progesterone inhibits human endometrial cancer cell growth and invasiveness: down regulation of cellular adhesion molecules through progesterone B receptors
  • Progesterone controls cell proliferation and differentiation in the female reproductive tract. Acts on progesterone A and B receptors
  • Loss of PRB has recently been linked to poorly differentiated endometrial cancer
  • Cancer research 62,881-886,feb1 2002
  • Progesterone caused time-dependant inhibition of cell cycle
  • Progesterone inhibited endometrial cancer cell division
  • Progesterone induced a secretory phenotype through PRB
  • Progesterone induced replicative senescence through PRA
  • Progesterone and growth factor deprivation induced apoptosis
  • Progesterone inhibited the cell cycle by upregulating cdk inhibitors p21 and p27
  • Progesterone downregulated the expression of cellular adhesion molecules
  • Menopause: The journal of the north american menopause society vol 12 no 2 p 232-237 Percutaneous administration of progesterone :blood levels and endometrial protection.
  • Antiproliferative effects on the endometrium are seen with progesterone creams even at low circulationg blood levels.
  • Despite the low serum levels, saliva testing confirms high levels reflecting high tissue levels.
  • Progesterone gels are watersoluble and enters the microcirculation more rapidly elevating serum progesterone levels .

Progesterone creams and Endometrium

  • Serum progesterone levels greater than 5ng/ml to inhibit endometrial mitosis and to induce a secretory change.
  • Although serum progesterone levels<3.5ng/ml are generally considered too low to cause a secretory endometrium, 2 reports contradict this generality.
  • Leonetti et al fertil steril 2003;79:221-222 reported decreased endometrial proliferative effects despite low serum levels and varying values between people
  • Supported by landes et al obstet gynecol 2003;101(suppl 1) :S6
  • In general the most significant effects are found after 4 to 6 weeks usage.
  • It seems length of treatment rather than dose is what is important
  • Base decisions on endometrial biopsies rather than blood levels
  • Remember %progesterone cream can be increased if needed (for example a 5 or 10% even if required)

Progesterone

  • American Journal of obstetrics and gynecology volume 180,issue 6 june 1999 percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen
  • An appropriate increase in progesterone concentration occurred after 4 weeks
  • After 2 weeks of percutaneous dosing progesterone concentrations were sustained for at least 8 hours and were consistent within a given person
  • Significant elevation of serum progesterone occurred in all women studied
  • The percutaneous application of progesterone cream appears to be a safe and effective route of administration
  • Oral micronized progesterone at a dose of 100mg given 25 days of the month protected the endometrium from proliferation and induced amenorrhea in >90% of women (gillet jy, maturitas 1994;19:103-15.
  • Journal of the american college of cardiology vol 36,no7 2000 Natural progesterone, but NOT medroxyprogesterone, enhances the beneficial effect of estrogen on exercise induced myocardial ischemia in postmenopausal women.
  • Progestins cause coronary vasospasm, unlike progesterone.

Progestins

  • Side effects of progestins not seen with natural progesterone include: increase in appetite, weight gain, fluid retention, irritability, depression, headache, decrease in energy, bloating, breast tenderness, decreases sexual interest, rash,acne, hair loss, nausea, insomnia, breakthrough bleeding,spotting, interferes with the body’s own production of progesterone,does not help balance estrogen, remains longer in your body, coronary artery spasm, stops the protective effects estrogen has on the heart, attaches to other receptors in your body as well, cannot help make estrogen and testosterone,increases ldl,decreases hdl,protects only the uterus from cancer, counteracts the positive effects of estrogen on serotonin.

Progesterone

  • European Journal of neuroscience, vol 23,p43-54,2006 Anti-apoptotic effects of allopregnanolone on P19 neurons.
  • Progesterone and its metabolites are potent modulators of GABA A receptor function contributing to receptor plasticity and modulating the expression of its subunits.
  • Neurosteroids like progesterone can act as survival factors by interfering with the mitochondrial apoptotic pathway

(C) hormone balancing is essential, a woman is more than estrogen!

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The following hormonal imbalances lead to overstimulation of the estrogen receptor and thus increase one’s risk for breast cancer:

1. Stress elevates cortisol, depletes dhea and results in a change in the immune system from a TH1 (normal bacterial and viral and cancer cell killing immune system) to a TH2 immune response (autoimmune type of response, and increased cancer risk type of immune response.

2. Underactive thyroid and elevated insulin like in type 2 diabetes or the metabolic syndrome decreases SHBG (sex hormone binding globulin) and this increases the amount of free estrogen and causes overstimulation of the estrogen receptor.

3. Xenoestrogens (ex ddt, exhaust fumes, estrogen farmfed chickens, plastics) we are all exposed to, and these increase our risk as well if we do not metabolize them properly and detoxify through the liver.

4. Low progesterone. Progesterone deficiency occurs before estrogen deficiency in the perimenopause, and the risk for breast cancer goes up as the progesterone level goes down. Progesterone has antiproliferative effects on the breast and uterus. In antiaging medicine we never replenish estrogen without replenishing progesterone. Progesterone is protective against breast cancer, unlike progestins which potentially increase your risk for breast cancer. It is also recommended by antiaging physician’s to supplement progesterone even in hysterectomized women.

5. Low melatonin ; high prolactin.

6. Testosterone replenishment has been shown in trials to lower risk for breast cancer.

7.  pregnenelone, dhea and testosterone hormone replenishment is most often neglected in conventional hormone replenishment therapies.     These hormones have huge health  benefits for woman and men and have been studied in many clinical trials

However too much testosterone like in polycystic ovarial syndrome can increase one’s estrogen level due to aromatization of the testosterone into estradiol with overstimulation of the estrogen receptor.

(D) estrogen should be metabolized to safe metabolites, lowering the risk of breast and hormone related cancers

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So let us take a closer look at the metabolism of estrogen in the liver.

Estrogen is metabolised through two pathways in the liver. The first phase detoxification in the liver is hydroxylation of the estrogen molecule, either to 2,4 or 16 hydroxyestrone. These molecules are fat soluble and in order to eliminate them you need to make these molecules water soluble, through phase 2 detoxification which is either through methylation, sulfation or glucoronidation.

2OH estrone is harmless, whereas 4OH and 16OH estrone are carcinogenic.

To increase the phase 1 production of 2OH estrone rather than 4 or 16OH estrone is a nice way to lower one’s risk for dangerous metabolites:

a) Cruciferous vegetables, I3C (Indole-3-carbinol, D-Indolemethane/ DIM).
b) Moderate exercise.
c) Whey protein.
d) Soy.
e) Omega 3 fish oil.
f) Flax.
g) Vit b6, b12, folic acid (in fact these simple vitamins protect form the dangers of alcohol use in increasing one’s risk for breast cancer).

However taking I3C on its own is not sufficient since phase two detoxification needs to be supported as well. This phase two elimination is essential to excrete toxins and estrogen metabolites as well as for drug metabolism. Methylation can be enhanced by methyl donors for example vit b6, vit b12, sam-e, TMG.

Sulfation can be enhanced by increasing glutathione (the body’s most potent antioxidant).

The following nutrients increase glutathione:

a) NAC (N-acetylcysteine).
b) L-glutamine, glycine, mg,methionine, SAMe.
c) Minimize depletion of glutathione with alpha lipoic acid, silymarin (milk thistle), gincko, whey protein.
d) Brassica based diets (diets high in cruciferous vegetables.
e) Allium diet (leak/onion family…. these increase GST (glutathione sulphur transferase function).

New lab tests are becoming available through Ampath Laboratories.
The following tests will be particularly helpful in our fight to prevent breast cancer:

1. Estrogen quotient (E3/(E2+E1) >1.
2. 2:16 OH estrone ratio in the urine >2, <9. More than 9 would increase one’s risk for osteoporosis since 16OH estrone is a potent estrogen whereas 2Oh estrone is a weak estrogen at the receptor site. 2OH estrone is also an antioxidant and a blood vessel protector.

(E) Conventional HRT vs. Bio-Identical HRT (BHRT)

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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:
  • BHRT has the identical chemical structure to the hormones that exist naturally in the human body, and
  • BHRT is used to replenish levels to physiologically normal concentrations, never exceeding physiological levels, and
  • 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 estrogenincrease 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:

  • In vitro, when given with estradiol, estriol accelerates the removal of estradiol bound to protein receptors.
  • 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.
  • In animal studies estriol has been found to prevent carcinogen-induced mammary tumours; and
  • 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).

(F) Method of administration: Oral vs. Transdermal

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Transdermal delivery of estrogen is much safer than oral estrogen due to :

a)      no elevation of blood clotting factors as seen with oral estrogen

b)      no elevation of blood pressure as seen with oral estrogen

c)       no elevation of highly sensitive crp and triglycerides as seen with oral estrogen

d)      no elevation in incidence of gallstones as seen with oral estrogen

e)      no lowering of IgF1 as seen with oral estrogen

f)       no interference with trptophan metabolism as seen with oral etsrogen

1.        http ://en.wikipedia.org/wiki/Charles _Darwin

Charles Darwin , theory of natural selection

2.        http:// www.johnleemd.com/store/premenstrual syndrome.html excerpted from : WHAT YOUR DOCTOR MAY NOT TELL YOU ABOUT BREAST CANCER

3.        http://www.fda.gov/bbs/transcripts/transcript010908.pdf

Transcript of FDA Press conference on FDA Actions on Bio-identical hormones FTS HHS FDA Susan Cruzan January 9,2008-10-20

4.        http://www.ncbi.nlm.nih.gov/pubmed/12626212

Climacteric.2002 Dec;5(4):332-40.     Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. De Lignieres B et al. French cohort study.

5.   http://www.womentowomen.com/breasthealth/estrogenbreastcancer.aspx Causes of breast cancer – the Estrogen controversy, Dixie Mills MD

6.   http://www.johnleemd.com/store/cancer_progest.html

Breast cancer Book Intro. What your doctor may not tell you about  breast cancer by John R.Lee, M.D., David Zava PhD

7.        http://content.nejm.org/cgi/content/short/356/25/2591

Estrogen therapy and coronary-artery calcification.     NEJM Volume 356: 2591-2602 June 21,2007 Number 25. JoAnn E. Manson, M.D.,et al

8.        http://www.jpands.org/vol13no2/hotze.pdf

Point/Counterpoint : The Case for Bio-identical Hormones Steven F Hotze Journal of American Physicians and Surgeons Volume 13 Number 2 Summer 2008-10-20

9.        http://www.townsendletter.com/June2007/painfree0607.htm

The safety of bio-identical hormones –the data vs. the hype by Jacob Teitelbaum,MD

10.     http://www.drerika.com/pg/jsp/bhi/bio-identical_vs_synthetic.pdf

Bio-identical vs. Synthetic HRt, A review of the literature

11. http://www.bio-identicalhormoneinitiative.org/ Bio-identical hormone  initiative, Erika Schwartz MD, David Brownstein MD, Ken Holtorf MD

  • 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 – [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).

(G) 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 – ).

  • 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 – ).

  • 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 – ).

  • 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 – ).

  • 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).

  • 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 – ).

  • 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 – [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.

(H) Estriol, another neglected hormone in conventional HRT

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Functions of Estriol

  • Estriol improves menopausal symptoms including hot flashes,insomnia and vaginal dryness
  • Helps your gut maintain good bacteria (lactobacilli) and helps reduce pathogenic bacteria
  • Estriol benefits the vaginal lining
  • Increases hdl,decreases ldl cholesterol
  • Restores the proper ph of the vagina and helps prevent urinary tract infections
  • Has been used to treat breast cancer
  • Blocks estrone by occupying the estrogen receptor site on breast cells

Estriol

  • Hum Reprod 2000 May; 15(5):1028-36 Safety and efficacy of estriol for symptoms of natural or surgically induced menopause.
  • Estriol proven to be safe and effective in symptom relief. Endometrial biopsy and breast evaluation were normal after 12 months, blood pressure dropped, estriol had no significant effect on lipids except for triglycerides
  • Maturitas 2002 Jun 25;42(2):149-156 The effects of estriol on the endometrium in postmenopausal women.
  • No statistically significant differences were found on endometrial thickness and histology
  • Maturitas 1981 Dec;3(3-4):321-7 Endocrinological and clinical investigations in post-menopausal women following administration of vaginal cream containing estriol. Clinical effect was excellent and no untoward effects were reported
  • Maturitas 2000 oct 31;36(3):217-22 Comparison of the long term effects of oral estriol with the effects of conjugated estrogen on serum lipid profile in early menopausal women.
  • estriol did not induce hypertriglyceridaemia and prevents a postmenopausal rise in total cholesterol.
  • estriol may be a safe alternative for women with high triglycerides, and in women who are reluctant to continue conventional hrt because of uterine bleeding
  • Arch Gynecol Obstet 1992;251(3):115-120 effects of protracted administration of estriol on the lower genitourinary tract in postmenopausal women. The risk of estriol treatment was insignificant
  • Arch Gynecol obstet 1993;253(2):71-74 When applied to facial skin, does estrogen ointment have systemic effects? Serum hormone levels and the appearance of vaginal smears showed no significant change during treatment
  • J gerontol A biol Sci Med sci 2000 Apr;55(4): B 183-90;discussion B191-3 Estriol replacement improves endothelial function and bone mineral density (by inhibiting bone resorption) in very elderly women
  • E3 may be useful for use in hrt in elderly women
  • Orv Hetil 1995 Feb 12;136(7):343-345 Treatment of climacteric urogenital disorders with an estriol-containing ointment
  • Vaginal burning,dryness,urinary dysfunctions,dyspareunia,itching all ceased.
  • E3 is suitable for treatment of chronic vaginitis and cystitis
  • Acta Endocrinol Suppl (copenh) 1980;223:17-27 Pathophysiologic considerations in the treatment of menopausal patients with estrogens;the role of estriol in the prevention of mammary carcinoma.
  • The protective effects was specific for mammary carcinomas.
  • Clinical experience thus far with estriol therapy has indicated little hazard of cancer development
  • J Steroid Biochem 1984Apr;20(4B):959-62 Estriol production and metabolism in normal women
  • Estriol circulates at low but relatively steady levels in the blood. In some women estriol appears to be secreted by the ovary, especially in the luteal phase
  • BJOG 2000 Aug;107(8):1029-34 Estradiol-releasing vaginal ring versus vaginal pessaries in the treatment of bothersome lower urinary tract symptoms.
  • Low dose vaginally administered estradiol and estriol are equally efficacious in alleviating lower urinary tract symptoms.
  • The form of administration of the vaginal ring, seems to be more acceptable than estriol pessaries
  • Mol Endocrinol 1997 Nov;11(12):1868-78 Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol.
  • Estriol is a weak estrogen, resulting from impaired hER (human estrogen receptor)-ERE (ligand response element)
  • Anti-estrogenic activity occurs in a dose dependant fashion, where it reduces estradiol dependant transcription. Estradiol binding to receptor is also decreased
  • Estriol is hypothesized then to oppose carcinogenic effects of estradiol
  • Ann Chir Gynaecol Suppl 1987;202:39-41 Local estriol treatment improves the structure of elastic fibers in the skin of postmenopausal women
  • The elastic fibers in the papillary dermis were thickened, better orientated and increased in number in half of these patients
  • JAMA 1978 Apr 21;239(16):1638-41 Estriol in the management of menopoause
  • Clinical effectiveness was related to dose (2-8mg/d po)
  • Estriol 8mg failed to induce endometrial proliferation
  • Improves vasomotor instability and improves vaginal maturation
  • Maturitas 2001 Sep28;39(3):253-7 Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women
  • Estriol is highly effective for the treatment of atrophic vaginitis

(I)  compounding summary

Correcting misconceptions about compounding bioidentical hormones

  • Prescriptions are prepared by compounding pharmacies
  • Provides individualized and customized therapy that does not meet the definition of manufacturing as described by state boards of pharmacy, FDA and the supreme court
  • Compounding is a profession of pharmacy that HAS ALWAYS been REGULATED by individual state boards of pharmacy
  • Compounded hormones must be prescribed by a physician. The decision to prescribe is a professional judgement made in the interest of the patient
  • One of the foremost references on BHRT is the textbook The clinical Gynecologic Endocrinology and Infertility by speroff and fritz. Failure of commercial products to provide the benefits of endogenous estradiol for example should not be confused with the literature that supports exogenous use of low dose bioidentical estrogen
  • Progesterone has clear advantages over progestins (already discussed)
  • Essential to understand that progesterone protects against breast cancer, progestins increase the risk for breast cancer.

Compounding

  • Conjugated estrogens entered the market in 1943.
  • Due to massive promotional campaigns over the years,non human and non-bioidentical hormones assumed a major share of the market place
  • BHRT did not compete with the highly marketed,patented, nonhuman hormones
  • During the 1980s compounding began making its way back into mainstream healthcare.
  • Insulin was once extracted from pigs and cows
  • Thyroid supplements were originally obtained from pigs.
  • However when human insulin,thyroid hormones became available these were preferred.
  • There is still a pharmaceutical industry driven support for legislation that would control and minimize pharmacy compounding. As an important part of today’s health care, compounding supplies IV admixtures, parenteral nutrition,pediatric preparations, pain management medications.
  • THERE SHOULD BE NO PLACE FOR NON-BIOIDENTICAL HORMONES!!

(J) concerns regarding efficacy, quality, purity and safety of bioidenticals

As regards quality and purity:

While there have been a few occasions that American bio-identical hormones have not always contained the amount of hormone that their label claims, this is not the situation in South Africa. The Compounding Pharmacy of South Africa uses hormones that are independently assayed twice (once abroad and again locally) to identify active substances (e.g. Estradiol) and quality (levels of bacteria, yeasts, moulds etc), as well as purity. Further, the products are tested after manufacture by an independent facility to verify that the amount of hormones contained in the creams match the label claim. These documents are available on file from the Compounding Pharmacy of South Africa.

As regards safety:

Bio-identical hormones (e.g. estradiol, estriol, progesterone) have a lower risk of cancer1-4, unlike non-bio-identical hormones (eg conjugated estrogens, progestins, medroxyprogesterone)1-2, 5-7 Further, a requirement of bio-identical hormone replacement is to mimic the way hormones are produced and released in the body.  For this reason bio-identical hormones are applied transdermally, not orally, which studies have shown to be significantly safer than the oral route8-9.

1.    Campagnoli C.; Pregnancy, progesterone and progestins in relation to breast cancer risk; J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50.

2.    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.

3.    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).

4.    Lemon HM; Pathophysiologic consideration in the treatment of menopausal patients with estrogens; the role of estriol in the prevention of mammary carcinoma.; Acta Endocrinol (Copenh); 1980; 223: S17-S27.

5.      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]

6.    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; Journal of the American Medical Association [JAMA] (2002) Volume 288, pages 321-333.

7.    G. L. Anderson et al; Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.; Journal of the American Medical Association [JAMA] (2004) Volume 291, pages 1701-1712.

8.    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

9.    Marianne Canonico et al., Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women -Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study; Circulation Feb 2007;115;840-845).

As regards effectiveness:

Numerous studies show that the bio-identical hormones: estradiol, progesterone, DHEA and testosterone, not only help in the management of menopausal symptoms, PCOS, bone density, fibroids and sexual function, but are also antiaging because they reduce the morbidity and mortality scores of age-related chronic diseases eg. dementia, heart and blood vessel disease, cancers, diabetes, metabolic syndrome, and auto-immune and inflammatory diseases. Please see the studies from respected journals provided below:

1.    Buford TW, Willoughby DS.; Impact of DHEA(S) and cortisol on immune function in aging: a brief review.; Appl Physiol Nutr Metab. 2008 Jun;33(3):429-33.

2.    Pluchino N et al.; One-year therapy with 10mg/day DHEA alone or in combination with HRT in postmenopausal women: Effects on hormonal milieu.; Maturitas. 2008 Apr 2

3.    Akishita M et al.; Association of plasma dehydroepiandrosterone-sulfate levels with endothelial function in postmenopausal women with coronary risk factors.; Hypertens Res. 2008 Jan;31(1):69-74.

4.    Kedziora-Kornatowska K et al.; The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states.; Adv Med Sci. 2007;52 Suppl 1:126-30.

5.    Rodriguez A etal.; Aging, androgens, and the metabolic syndrome in a longitudinal study of aging.; J Clin Endocrinol Metab. 2007 Sep;92(9):3568-72. Epub 2007 Jun 26.

6.    Genazzani AD et al.; Might DHEA be considered a beneficial replacement therapy in the elderly? ;Drugs Aging. 2007;24(3):173-85.

7.    Genazzani AR et al.; Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women.; Gynecol Endocrinol. 2006 Nov;22(11):627-35.

8.    Aoki, K., et al.  Prevention of diabetes, hepatic injury, and colon cancer with dehydroepiandrosterone.  J Steroid Biochem Mol Biol.  85(2-5):469-472, 2003.

9.    Casson, P. R., et al.  Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women.  Am J Obstet Gynecol.  169(6):1536, 1993.

10.  Chang, D. M., et al.  Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: A multicenter randomized, double-blind, placebo-controlled trial.  Arthritis Rheum.  46(11):2924-2927, 2002.

11.  Christeff, N. et al.  Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy.  Ann N Y Acad Sci.  917:962-970, 2000.

12.  Maes, M., et al.  Decreased dehydroepiandrosterone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS.  Neuro Endocrinol Lett.  26(5), 2005.

13.  Teitelbaum, J.  Effective treatment of chronic fatigue syndrome.  Integrative Medicine.  4(4):23-29, 2005.

14.  Takayanagi, R., et al.  Dehydroepiandrosterone (DHEA) as a possible source for estrogen formation in bone cells: correlation between bone mineral density and serum DHEA-sulfate concentration in postmenopausal women, and the presence of aromatase to be enhanced by 1,25-dihydroxyvitamin D3 in human osteoblasts.  Mech Ageing Dev.  123(8):1107-1114, 2002.

15.  Schmidt, P. J., et al.  Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression.  Arch Gen Psychiatry.  62(2):154-162, 2005.

16.  Morales, A. J., et al.  Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.  Journal of Clinical Endocrinology and Metabolism.  78(6):1360-1367, 1994.

17.  Genazzani, A. D., et al.  Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women.  Fertil Steril.  76(2):241-248, 2001.

18.  Genazzani, A. D., et al.  Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids.  Fertil Steril.  80(6):1495-1501, 2003.

19.  Hackbert, L., et al.  Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women.; Journal of Women’s Health and Gender-Based Medicine.  11(2):155-162, 2002.

20.  Amaducci, L. A., et al.  Risk factors for clinically diagnosed Alzheimer’s disease:  a case control study of an Italian population.  Neurology.  36:992-931, 1986.

21.  Behl, C., et al.  Neuroprotection against oxidative stress by estrogens:  structure -activity relationship.  Mol Pharmacol.  51(4):535-541, 1997.

22.  Dubal, D. B., et al.  Estradiol:  a protective and trophic factor in the brain.  Alzheimer’s Disease Review.  4:1-9, 1999.

23.  Fillit, H., et al.  Observations in a preliminary open trial of estradiol therapy for senile dementia - Alzheimer's type.  Psychoneuroendocrinology.  11:337­345, 1986.

24.  Green, P. S., et al.  Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells.  Neuroscience Letters.  218(3):165-168, 1996.

25.  Paganini-Hill, A., et al.  Estrogen deficiency and risk of Alzheimer’s disease in women.  American Journal of Epidemiology.  140:256-261, 1994.

26.  Stone, D. J., et al.  Increased synaptic sprouting in response to estrogen via an apoliporotein E-dependent mechanism:  implications for Alzheimer’s disease.  J Neurosci.  18(9):3180-3185, 1998.

27.  Wen-Sen Lee, et al.  Progesterone inhibits arterial smooth muscle cell proliferation.  Nature Medicine.  3(9):1005-1008, 1997.

28.  Formby, B., et al.  Progesterone inhibits growth and induces apoptosis in breast cancer cells:  Inverse effects on Bcl-2 and p53.  Ann Clin Lab Sci.  28(6):360-369, 1998.

29.  Foidart, J. M., et al.  Estradiol and progesterone regulate the proliferation of human breast epithelial cells.  Fertility and Sterility.  69(5):963-969, 1998.

30.  Fitzpatrick, L. A., et al.  Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women:  a cross-sectional survey.  J Women's Health Gen Med.  9(4):381-387, 2000.

31.  Kanda, N., et al.  Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.  Arthritis Rheum.  40(9):1703-1711, 1997.

32.  Bates, K. A., et al.  Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease.  Cell Mol Life Sci.  62(3):281-292, 2005.

33.  Luo, X. H., et al.  Effects of estriol on the proliferation and differentiation of human osteoblastic MG-63 cells.  Endocr Res.  29(3):343-351, 2003.

34.  Hayashi, T., et al.  Estriol (E3) replacement improves endothelial function and bone mineral density in very elderly women.  J Gerontol A Biol Sci Med Sci.  55(4):B183-B190, 2000

Last Updated (Wednesday, 29 June 2011 14:05)

 
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