[questions to Dr Rosensweet from the. NAAEM Committee:]
- “Formulations:In your email, you mention that the customization for topical hormones musttake into consideration the ratios of E3 to E2. Could you please submit data that outlines the most commonly formulated ratios of E3 to E2 and E2 to E1 in cBHRT preparations? Could you also please send supportive clinical data that reviews the efficacy and effectiveness of these commonly formulated cBHRT preparations?”
- “Bioavailability testing:In your email, you mention that there is variable absorption of hormones inwomen. It would be helpful if you can share bioavailability data (expressed as area under the curve) of E2, E3, and other hormones commonly formulated in cBHRT.”
[Dr R responds:] “I’d like to combine your excellent questions re Formulations (of estrogens) and Bio-availability testing and begin with important background information:
- Formulations: Women’s ovaries produce three physiologically active estrogens: Estradiol (E2), Estriol (E3) and Estrone (E1).cBHRT essentially began in the 1980’s, and with a formulation named “Tri-Est” as it contained E2 + E3 + E1. Hormone testing soon revealed that E1 was not needed as it readily appeared on testing, interconverting from E2.“Bi-Est’ has been and is the most popular of cBHRT prescribed topical estrogens.
- The originator of this formulation, an M.D. in Seattle WA, proposed the addition of Estriol to Estradiol formulations from the research of Henry Lemon M.D., an oncologist at the University of Nebraska, who published several studies in the 1960’s conducted on the importance of estriol. Dr Lemon’s studies demonstrated that the 24-hour urine hormone tests of women who had breast cancer (BCa) were significantly different than those of healthy women:
- Healthy women had a predominance of E3, as expressed in the mathematical formula known as the “Estrogen Quotient (EQ)” or “Estrogen Ratio:”
- E3/(E2 + E1)
- EQ of healthy women averaged 1.3
- Women with BCa had significantly lower EQ, averaging 0.5§(In 2015 I was commissioned to do a study of healthy youngwomen between the ages of 19 & 29: their average EQ was1.1)
- This discovery about estriol occurred decades prior to the discovery of ERβ,which is the estrogen receptor site that governs the de-proliferative phase of breast glandular tissue in the second half of a non-fertilizzedmenstrual cycle. And ERβis preferentiallystimulated by Estriol.
- When treating with Bi-Est, various ratios of E3 to E2 are utilized. The ultimate treatment goal is to arrive at a formulation that results in a tested hormone profile that resembles the healthy EQ.
- A most commonly prescribedstartingformulation consists of 80% E3 + 20% E2.
- Here is an example of an initial prescription:
- Rx: Bi-Est 30 mg/ml 80:20 in organic oils base,oDTD: 8.5 ml
- Sig: 1 –3 drops b.i.d. as directed
- (1 drop contains an estrogen potency equivalent to 0.44 mg of E2, designated as “0.44 mgeeq”)
- (E3 is 1/8thas potent as E2, I am happy to review the math of how mgeeq [“mg of estradiol equivalence”] a unit of estrogen potency, is determined).
- Another example, commonly used in creams and gels:
- Bi-Est 2.5 mg/ml in gel or cream base, 80:20,dispensed in a pump or topi-click, with one pump or click delivering 1⁄2 ml thus 0.75 mgeeq
- (for context: average applied dose of Bi-Est in one day for a woman with good symptom relief is a range between 0.8 mgeeq to 2.4 mgeeq per day, with an average of 1.7 mgeeq/d.)
- Variation possibilities in the ratio of E3 to E2 are multiple.
- Examples are 70:30, 60:40, 50:50,etc
- Variations in prescription of ratios different than 80:20, inmy view, should only be made when based upon the hormone testing of a woman being treated. The goal is a hormone test that results in an EQ ≥1.3, while ≤ 4.0
- Examples will follow
- I have singled out topical administration of estrogens as best medical practice—based on the goal of minimizing risks and maximizing benefits—our medical literature describes that estrogens delivered p.o. have increased risks for alteration of coagulation profiles10, increased breast density11, excessive dosages leading to excessive metabolites12, and inflammatory markers13, among other adversities. Anyone familiar with taking medical histories on women in menopause will on occasion encounter a past medical history of deep venous thrombosis(DVT) and pulmonary embolus (PE) in a small but certain number of women suffering from same when they took oral contraceptives14.
- Traditional and current manufactured and FDA topical estrogen products provide only E2. (Egs: patch and gels)
- And, I would like the Committee to know that I am very aware that there are a multitude of ways to treat with hormones besides cBHRT. Each method has its pros and cons, which are multiple. I am in no way advocating for the change in prescribing preferencesfor any good doctor. My only intention is to support the cessation of further restrictions on cBHRT. I am well aware that millions of women have benefited and been rendered safer by PremPro even, and am grateful that this has occurred over a half century of usage
- Healthy women had a predominance of E3, as expressed in the mathematical formula known as the “Estrogen Quotient (EQ)” or “Estrogen Ratio:”
- Bio-availability data:
- NAMS15has recommended and continues to recommend that hormone testingNOTbe done on women being treated with hormones. It mentions by name “salivary” testing and “blood” testing. I absolutely agree with regards to these two particular methods.
- My experience, and that of my most respected colleagues treating women in menopause with hormones shows that salivary testing can be erratic and too often not give data that correlates well enough with the clinical picture. (Users of this method will dispute this.)
- Blood testing has a pharmacokinetic issue.
- Topical administration of an ovarian hormone has variation in:
- Rate of absorption in skin
- Evanescence in blood levels with greater longevity in tissue levels
- Thus, actual elapsedtimeof blood collection following previous dosage administration is:
- Critical as to reported blood level
- Varies considerably from woman to woman based on theabsorptive ability of her skin. This absorption ability varies with health of the skin, thus younger women tend to have considerably better absorption than older women
- All issues related to pharmacokinetics disappear by doing 24-hour urine hormone testing to evaluate hormone levels in women who are being treated with hormones!
- Correlation with the clinical symptoms of women is excellent
- Data re parent hormones and metabolites is extensive, and relates torisks
- Because I could never solve for the pharmacokinetic challenges of bloodtesting, and because I began utilizing 24-hour urine hormone testing over 20 years ago, and have thousands of test results, I cannot comment on your rightfully asked question re “bioavailability data (expressed as area under the curve).” Once a health care professional discovers 24-hour urine hormone testing, masters the required learning curve, testing issues are resolved. This is crucial: you cannot for an example, I assert, treat with the powerful hormone Insulin without proper and precise testing. Ovarian and testicular hormones are also powerful, and treatment with them should always include excellent hormone level testing.
- Accurate testing also permits us to define optimal treatment levels as extrapolated from studies in our medical literature which clearly define what constitutes:
- Too little estrogens: thus, leaving a woman vulnerable, for example, to bone loss and vaginal atrophy
- Excessive estrogens: thus, vulnerability to breast glandular cell proliferation and increased breast density–a known risk factor for breast cancer.
- Optimal testing range:
Total Potent Estrogens (E2 + E1) = 8 –14 mcg/24 hours (I have detailed in our training program the methods and references I drew from in the medical literature to determine these optimal test parameters: I’m happy to provide that process and those references upon request) - Cost is as low as $285
- NAMS does not comment on this method of hormone testing.
- Note: I am not referring to “5-point urine hormone collections” which I do not advocate)
- Ultimate significance of Formulations and Bioavailability:
- Re Bi-Est: because of the remarkable individual differences, woman to woman, a wide range in dosages and formulations are required. Women vary as to individual:
- Sensitivity to any hormone you treat them with
- Absorption and metabolization
- Hormone level need
- Re Bi-Est: because of the remarkable individual differences, woman to woman, a wide range in dosages and formulations are required. Women vary as to individual:
- NAMS15has recommended and continues to recommend that hormone testingNOTbe done on women being treated with hormones. It mentions by name “salivary” testing and “blood” testing. I absolutely agree with regards to these two particular methods.
Comments:
- Note test of 8/2008: pt was on 0.1 Vivelle dot… it produced in her a TPE (E2 + E1) of 10.2…in a healthy range of 8 –14 mcg/24h. However, the EQ was 0.4, as there is no E3 in the patch.
- Select testing dates of 2013 & 2015: low dose being used because of mammographic increased breast density along with family history of BCa. By 2016 we had gradually increased the mgeeq enough to produce a TPE of 10. This was her limit: adding one more drop per day would bring on breast tenderness—i.e., overstimulation of breast glandular tissue in this very sensitive woman.
- 2019 test: we dropped the mgeeq dose a small amount and the TPE’s dropped significantly…a sign of “dermal fatigue” (reduced absorption at a specific site from saturation over time). Note that many symptoms came on with these low TPE’s of 2.9. Also note that the EQ had risen above 4 to 4.9. This prompted a change in dosage and ratio, to increase the E2, the TPE’s, and reduce the EQ. Note in the 2019 test she was thus on 30 mg/ml 70:30. The TPE’s did respond to the increase in the mgeeq to 2.8, but only to 3.2. The EQ dropped into the optimal range: 1.3 –4.0. Patient was having milder symptoms.
- In response to the still too low TPE’s (we like it between 8 –14 for bone and vaginal health),we increased the Bi-Est mg/ml from 30 to 40 while keeping the ratio the same.
Thus, calculation of mgeeq and even ratio changes is very easy for the trained medical professional.
Fulfilling the wide variety of mg/ml and ratios is very routine for compounding pharmacies, with their technical equipment of analytic scales and computers for calculations.
Comments:
- Re 6/2016: (this is many years into her treatment: 15 50:50 was arrived at years ago).
Low dosage had led to low TPE’s. She too was nulliparous with a history of increased breast density, so year upon year we were cautious. Because TPE’s of 5.7 are below threshold for risk for osteoporosis and vaginal atrophy, she titrated up her dose.
- By 10/2017 she had developed mild insufficiency symptoms: increased dosage resulted in an increase in TPE’s. Because of symptoms, we increased dose again, carefully following her mammograms. We also increased the ratio and the mg/ml over time, as symptoms increased. This woman also entered menopause with an elevated SHBG, secondary to early life BCP use (relatively common) which adds complexity to her treatment regimen.
If all of this seems a bit complex:
- Medical care for any specialty you can name has a complex information base that takes years of training and experience to practice Standard of Care let alone to master. Treating women in menopause is also this complex (even though so many are practicing using a minimum of knowledge, experience, testing, etc. Our goal to the absolute best that is possible, bring to women the promise of lowest risk with maximum efficacy and elegance. Menopause Medicine needs to be a Boarded Specialty, and this is our major professional mission!
- These variations in prescription design, customized to each and every individual patient, is one of the many reasons to not further restrict access of women to compounding pharmacists and cBHRT.
- Please invite me back to D.C. to present live to the Committee. I promise that in two hours I can assist you so much in gaining significant deeper insight into how women in menopause are actually being treated with cBHRT. I guarantee it will bring much needed basic depth to your understanding, thus enhance your ability to make informed and wise decisions that will affect millions of American women.