The ZRT Laboratory Blog

A Practical Guide to New Developments in Dispensing of Topical and Vaginal Hormone Preparations

Fri, 07 Feb 2020 11:31:57 -0800

The Compounding Pharmacy industry has certainly taken huge strides in providing devices that allow for easy and accurate delivery of creams, gels and ointments. This has been especially appreciated in the field of hormone replacement, where accurate dosing is critical. Over the years we have gone from jars and measuring spoons to syringes for hormone cream dispensing. Fortunately, now there are much better choices. Let’s take a look at some of the options out there and the benefits of each.

Volume of Hormone Cream – What is Appropriate?

When using topical or vaginal application of hormones, several factors concerning the volume of hormone cream need to be considered.

Early studies with Androgel® showed that the larger the surface of application of the gel, the longer the serum level remained elevated. While serum testing does not reflect the amount of hormone in the tissues, this does demonstrate that the deposit effects in lipophilic tissues like adipose and skin cement (the lipophilic tissue between skin cells) are greater if a hormone is applied to a larger surface area. This factor would support using a large volume of cream, maybe 1 mL or greater.

However, the more a hormone cream is rubbed into the skin, the less chance of transference of the hormone to someone else that comes in contact with the site of application. My instructions to patients for rubbing a cream or gel in “well” require rubbing for at least 1 minute after the gel or cream disappears. It will take too much time and effort on the patient’s part to ensure good compliance if the volume of cream is too large. This requirement would support use of a smaller volume, maybe 0.1 mL or less.

I like to compromise and use 0.25 mL as my standard for hormone topical application. This small volume is not too difficult to rub in well. The dose can be increased to 0.5 mL without the immediate need for a new prescription and is still a reasonable amount for the patient to be able to rub in well.

Accuracy and Ease of Dosing for Topical Hormones

Precision of dosing is important with topical hormone preparations. For years the best method we had available was the use of an oral syringe. Years as a compounding pharmacist taught me that many patients often have difficulties obtaining accurate doses with syringes. Fortunately, there are now alternatives that allow the patient to easily obtain accurate dosing.

One such device is the Topi-CLICK® dispenser. The two types of regular Topi-CLICK® dispensers look similar to a deodorant applicator bottle, but with a twist. The base of the dispenser is turned untilthere is an audible click. The volume dispensed in the center of the dome with each “click” is either 0.25 mL or 0.5 mL depending on the choice of dispensers. The domed top of the dispenser allows for direct application to the skin. I routinely use the dispenser that provides 0.25 mL per click for most topical hormone creams.

Recently the Topi-CLICK Micro® dispenser became available. With this dispenser, one click provides 0.05 mL of cream. This dispenser can be used for the smaller volumes required for vaginal application. I often use estriol or testosterone, or the combination of both, applied to the inner labia for vaginal dryness. I’ve always suggested using 0.1 mL of cream as this was the smallest amount that I felt a patient could measure accurately using a small oral syringe. Now I can use the Topi-CLICK Micro® and know that patients are getting an accurate dose.

Since testosterone applied topically to the same area of skin can cause local hair growth, it may be easier to dose topical testosterone in a very small volume, so it is easier for the patient to rotate application sites and not overlap. This would be another scenario where the Topi-CLICK Micro® dispenser would be appropriate.

Vaginal Administration of Creams

Lastly, if you wish to use a hormone cream intravaginally, the Topi-CLICK Perl® vaginal kit is a great way to go. The hormone cream is contained in a dispenser with a special port to which a vaginal applicator can be attached. The patient turns the base of the dispenser until it clicks, and the applicator is filled with the desired dose (0.25 mL per click). The applicator is reusable and dishwasher safe. This system allows accurate dosing and saves the patient the expense of pre-loaded individual vaginal syringes.

Knowing the correct amount of hormone to apply to the skin or vaginally is only half the battle. It’s also necessary to know which vehicle is appropriate to apply hormones to the site or application. Accuracy of dose is the other factor that determines consistent results with topical/vaginal hormone application. Compounding pharmacists with their training and knowledge of available bases and the devices available to deliver the product can be a great benefit to anyone who is recommending or prescribing hormones.

If you are using hormone replacement therapy, it is important to test your hormone levels with reliable and convenient testing to ensure that you are obtaining physiologic levels. Order ZRT’s saliva test kit or blood spot test kit to measure your hormones to ensure you are properly monitoring topical dosing.

Related Resouces

How to Convert Patients to BHRT from Conventional Therapies

Thu, 23 Mar 2017 13:58:00 -0700

Practice Takeaway:

I always try to taper the estrogen dose down over a period of 2-6 months depending on the individual’s difficulty with withdrawal symptoms. Once I have the patient on a lower dose (Premarin 0.3 mg or Estrace 0.25 mg every other day at the most), I will switch over to a bi-est consisting of 50% estradiol and 50% estriol.

The reason for this is, if you stop the estrogen abruptly or decrease the dose too quickly, the patient can experience severe withdrawal symptoms of estrogen deficiency.

About Conventional Therapies

Conventional therapies and dosages provide too much hormone, even if the manufactured product being used contains bioidentical hormones rather than a synthetic agent. Determining dosages and managing symptoms in patients who want to covert from conventional therapies to bioidentical therapy can be one of the most difficult challenges facing the BHRT practitioner.

Conventional oral estrogen therapies, such as Premarin® and Estrace®, create a supraphysiologic overall estrogen status. While Premarin® 0.625mg and Estrace® 0.5 mg produce an estradiol level equivalent to that seen in normal premenopausal women, because of the high conversion of oral estradiol to estrone in the first pass effect, estrone levels in women taking these doses are usually 3 to 7 times higher than the normal level of a premenopausal woman.

In the case of Premarin®, the product consists of more estrone (50%) than estradiol (5-19%), and therefore patients are consuming a product with a high amount of estrone as well as highly converting the estradiol in the product to estrone. Estrone levels in women taking Premarin are most often 5-10 times higher than normal premenopausal levels when normal premenopausal estradiol levels are achieved.

What about Simply Reducing the Dose to Physiologic Levels?

Bringing the estrogen levels in these patients back to normal premenopausal women is not as simple as reducing the dose to a physiologic dose, or switching to a physiologic dose of bioidentical estrogens that would produce normal levels in most women. In these patients, changes in the estrogen receptors and the brain take place, and have to be considered when converting them over to physiologic doses of bioidentical estrogens.

Taking a supraphysiologic dose for a long period creates a higher threshold for estrogen in the brain. This is similar to the mechanism of narcotic tolerance or addiction. Giving a patient who has no pain, and therefore no need for morphine, a sufficient dose of morphine for several months raises the threshold for the narcotic, and removing the narcotic will create withdrawal symptoms. The same can be seen with supraphysiologic doses of estrogen used in convention therapies. If you stop the estrogen abruptly or decrease the dose too quickly, the patient can experience severe withdrawal symptoms of estrogen deficiency. For this reason, I always try to taper the estrogen dose down over a period of 2-6 months depending on the individual’s difficulty with withdrawal symptoms. Once I have the patient on a lower dose (Premarin 0.3 mg or Estrace 0.25 mg every other day at the most), I will switch over to a bi-est consisting of 50% estradiol and 50% estriol.

Because women vary significantly in their individual withdrawal symptomology, tapering the dose should be scheduled in a manner that allows for flexibility to an individual’s response. In my opinion, it is sometimes physically and psychologically difficult for a woman to skip her estrogen dose entirely for even a day. Typically, I will ask the patient to reduce to half of her usual dose, and take this half dose every third day for a period of 9 to 12 days, while maintaining her present dose on the other days. If she tolerates this decrease, then I ask her to take the half dose 2 out of 3 days for 9 to 12 days. (Note: some patients need to reduce the dose for much longer periods of time in order to tolerate withdrawal symptoms well enough to reduce it again).

Because women vary significantly in their individual withdrawal symptomology, tapering the dose should be scheduled in a manner that allows for flexibility to an individual’s response.

Estrogen Receptor Downregulation

When a woman is exposed to high levels of strong estrogens (estradiol and/or estrone) for a sufficient period of time, the estrogen receptors are usually lower in number and responsiveness. Over time, the decrease in sensitivity may become permanent—at least to some degree—so the patient may never respond to estrogens in the same manner as a typical patient given estrogen replacement. Therefore, these patients often require a higher dose of a preparation such as biest. Although in almost every other type of patient, I always start at the low end of suggested estrogen dosing guidelines, with the patients who have been on supraphysiologic amounts of estrogen for years I start at the midpoint of the suggested range. And I do not hesitate to increase the dose if the patient suffers significantly from estrogen withdrawal symptoms. The same excessive hormone burden is seen with the use of manufactured transdermal creams, lotions, gels and patches. These products produce supraphysiologic levels of the hormones they contain.

Testosterone Receptor Downregulation

Men who are administering conventional doses of topical testosterone have 5 to 10 times the amount of testosterone in their tissues than when they are 18 years of age. After several months on a high dose, the effectiveness of the testosterone wears off as receptors are down regulated. Usually the dose of testosterone is increased, until eventually the testosterone becomes ineffective at symptom management at even super high doses. Men who have to withdraw from these supraphysiologic doses can suffer the symptoms of apathy, muscle weakness, decrease in stamina, depression and even suicidal thoughts.

Due to the wide variance in degree of testosterone withdrawal symptoms in men, I have not yet determined a tapering program. I have tried, or seen tried, up to a 50% weekly reduction in the amount of testosterone administered. With the use of a cream or gel, I usually ask the patient to not use the product for a few days to a week. If they feel poorly, they go back to using the product at 75% to 90% of the former dose for the same amount of time that they went without any supplementation; then repeat this schedule until physiologic levels are reached.

Change Synthetic Progestin to Bioidentical Progesterone

Changing a synthetic progestin to bioidentical progesterone, or just adding progesterone, is much easier. Immediately stop the progestin and start progesterone. Progesterone has effects on estrogen synthesis and metabolism, as well as increasing sensitivity of the estrogen receptors. These effects may not be fully appreciated for several weeks. Also, synthetic progestins can take several weeks to clear completely form the body. So it is best to make the switch as soon as possible. Withdrawal should not be an issue because of the slow clearance of the progestins, and because the progestins outside of the uterus do not produce the same effect on the receptors as progesterone. In essence, you are replacing a progesterone antagonist with progesterone.

In Summary, Comfort is Key

When converting patients from conventional to bioidentical therapies, practitioners need to keep the patient’s comfort in mind. It can be a difficult time for patients of either sex, and the practitioner should show flexibility and patience in obtaining the long term goal of establishing physiologic levels.

Learn More

Jim Paoletti, BS Pharmacy, FAARFM, FIACP, is Director of Education for Power2Practice, the first EMR and complete software solution for Integrative and Functional Medicine. Jim has over 30 years of experience creating and using bio-identical hormone therapies in both retail pharmacy and clinical practice and is the author of A Practitioner's Guide to Physiologic Bioidentical Hormone Balance.

Testosterone Replacement Therapy: Ensuring an Accurate Dose!

Thu, 07 Jul 2016 11:44:00 -0700

Testosterone replacement therapy has the potential to drastically improve quality of life of those who need it. However, many men who begin topical testosterone are given too much of the hormone.

Explanations for this erroneous tendency are rooted in incorrect dosing principles that have been established on false assumptions, misconceptions, invalid conclusions and aggressive marketing instead of physiology and science.

Why are testosterone replacement standards and prescribing processes so frequently misguided?

Testosterone Overdose Begins With Incorrect Dosing Principles

For topical application, a physiologic daily dose of any sex steroid (in either sex) is approximately the same as our daily production during our prime—if the person no longer makes any of a hormone endogenously.
50 or 100 mg of topical hormone is a commonly administered dosage, which is 5 to 10 times the amount of testosterone he made at 18 years old! BHRT should be a restoration therapy in the sense that we are dosing enough hormone to restore the level by adding to what the patient is still producing.
The physiological production of testosterone in a young adult male is approximately 6 mg per day.
A physiologic dose of topical testosterone for a male is 1 to 10 mg daily. Administration of too much hormone will suppress endogenous production and eventually lead to receptor downregulation.

Why Such High Doses

The culprit lies in testing methods. No studies have ever validated the use of serum testing for topically applied hormone, and no correlation has been shown between venous serum levels and bioavailability (available at site of physiologic activity) or long-term efficacy.

In contrast, Dr. Frank Stanczyk has shown that venous serum testing cannot be used to judge the effect of topically applied progesterone in uterine tissue. Applying the principles of evidence based medicine and using the strongest scientific evidence (instead of a manufacturer’s marketing piece), one would avoid using venous serum testing for any topically applied hormone.

Drug manufacturers have led us down the wrong road by relying on irrelevant serum testing methods.

They used venous serum levels to determine how much hormone is "delivered," "absorbed" or is "bioavailable" in their topical products. These three terms have been bastardized by the pharmaceutical industry, which defines them only by the amount of hormone seen in the serum.

In true medical terms:

Bioavailability is defined as "the degree and rate at which a substance (a drug) is absorbed into a living system or is made available at the site of physiological activity."
Absorb means "to take up especially by capillary, osmotic, solvent or chemical action."
Both definitions have to do with the amount of hormone that goes into the system, not the amount left over in venous serum.
"Delivered" is a label initiated by the drug manufactures so as to avoid the term "dose" in the context of topical manufactured products.

There is a Better Way

As a result of relying on serum testing for topically applied hormones, doctors and patients are confused as serum levels often go down initially, even if only 5 or 10 mg daily is prescribed. Since most males are still producing at least a fair amount of the original 6 mg daily, even 5 to 10 mg can bring their total level to higher than physiologically normal. This scenario results in decreased endogenous production and downregulation of testosterone receptors, resulting in reduced symptom management.

Venous serum testing only reflects the endogenous hormone level and not the topically applied hormone, so the suppression of production causes a reduction in the serum level. As result, the prescribing practitioner may increase the dose even higher due to the decreased venous serum level. This is blatantly incorrect! We give a patient testosterone and because a level goes down, we give him more? Before increasing the dose further, should one not first be able to explain why the level would go down?

When an educator, such as myself, suggests a topical testosterone dose reduction, resistance is the most common reaction. Similarly, lowering estrogen dosages in women over the past 20 years to 1/10th to 1/20th or what was initially used, also met this type of resistance.

Common reasons for resisting a lower dose include:

Lack of knowledge as to any other approach to sufficiently addressing the symptomology.
The amount of knowledge, education and time it requires to properly balance all hormones, nutrition and lifestyle factors, in opposition to simply increasing the dose of testosterone.
Some prescribers simply state that they do not understand saliva testing and/or that topical testosterone doesn’t work in men. These same practitioners fail to explain why venous serum doesn’t show a linear relationship to topical testosterone dosing, or why testosterone is the only hormone in either sex that doesn’t work topically.

This resistance results from the fact that it is much easier to follow suit and not have to learn and think about how to correct the real problem.

A vital solution to the issue of overprescribing and overdosing testosterone is accurate and indicative hormone level testing and monitoring. Saliva testing and capillary dried blood spot testing present such an answer.

Discerning between free and protein bound hormones is especially important when monitoring topical or transdermal hormone therapy. Studies show that the transdermal method of delivery results in increased tissue hormone levels, thus measurable in saliva, but no parallel increase in serum levels.

With the use of dried blood spot testing, like saliva, hormones are present in the "capillary" blood from the finger and are representative of the hormones delivered to other tissues. When hormones are delivered through the skin as supplements, the capillary dried blood spot hormone level rises in concert with the increase in salivary hormone levels, because hormone delivery to all tissues is well represented.

Blood taken by conventional venipuncture rises very little, not at all, or even decreases in some cases with skin delivery of hormones. This might seem odd, but blood being delivered back to the heart through the veins has already delivered its bioavailable hormone load, and hormones remaining in the bloodstream are tightly bound to serum proteins such as SHBG and albumin.

An easy way to conceptualize capillary blood (teeming with bioavailable hormones) versus venous blood (depleted of bioavailable hormones) is to think of the oxygen content of red blood cells in the capillary beds versus the venous blood returning to the heart. Blood being delivered to the tissues through the arteries, arterioles, and finally through the capillary beds of tissues is charged with oxygen that is released into the tissues. Blood traveling back to the heart is depleted of oxygen. In a similar way, hormones delivered through the skin are picked up by red blood cells, and the hormone-laden red blood cells are then transported within seconds throughout the body to capillary beds of all tissues. There the hormones are released. This is why we see high capillary blood levels of hormones in blood spot testing and much less hormone in venipuncture serum.

Learn More:

Related Resources:

Determining the Functional Causes of Hypothyroid Symptoms

Tue, 08 Dec 2015 09:30:00 -0800

Hypothyroidism is defined as “lack of thyroid hormone production from the thyroid gland.”

However, many patients who produce sufficient hormone from the gland still suffer from low thyroid symptoms.

When thyroid levels are not within normal ranges, many conventional treatment protocols rush into thyroid replacement therapy.

Two problems exist with this approach:

If the patient has normal levels of T4 and T3—but a slightly elevated TSH—they are classified as “Subclinical Hypothyroid” and continue to suffer from symptoms.
If the patient has low levels of T4 and/or T3, they are given thyroid replacement therapy—even though they may produce enough thyroid hormone from their thyroid gland endogenously.

A note about Optimal Ranges vs. Normal Ranges of T4 and T3

Patients with thyroid hormone levels in the lower or higher 25% of the normal range often exhibit signs of hypothyroidism or hyperthyroidism.
Optimal levels are determined by subtracting the lower and higher 25% from the normal range.

The Functional Approach to Hypothyroid Symptoms

A functional approach to assessing and treating the symptoms of hypothyroidism—or more appropriately termed, “hypometabolism”—would be to look at the physiology of production, binding, metabolism, absorption and transport of the thyroid hormones as well as thyroid receptor function. In doing so, one can determine where the issues are in the process that are causing the symptoms.

The number one cause of all thyroid issues in the United States is an autoimmune thyroid reaction.

Thyroid Peroxidase Antibody (TPOab) will often reveal a thyroid autoimmune issue.
If autoimmune issues are suspected, Thyroglobulin Antibody (TgAb) should also be tested.

The thyroid gland mainly produces T4 thyroid hormone with a small amount of T3, so T4 testing is critical.

The best test to determine T4 production is Total T4 (TT4).
Free T4 (fT4) should be measured. If the result is in optimal range, it can be assumed that endogenous TT4 is optimal.
However, if the fT4 result is less than optimal, then we must explore whether the lower-than-optimal level is due to less-than-optimal production (low TT4) or excessive binding—or a combination of both.

The importance of Thyroid Binding Globulin (TBG).

More than 99% of circulating thyroid hormones are bound to serum proteins, primarily Thyroid Binding Globulin (TBG).
T4 is bound more extensively than T3, with only 0.04% of the total amount of T4 circulating as free and 0.4% of the total amount of T3 circulating as unbound.
Therefore, a small difference in the amount of TBG can have a significant effect on the amount of free thyroid hormone in circulation.

Comparing fT4 to TT4 can determine whether the thyroid hormones are excessively bound and unavailable to receptors. If fT4 is significantly lower (within its range) than TT4 (within its range), excessive binding is indicated.

The importance of fT4 to Free T3 (fT3) conversion and cortisol.

The conversion of fT4 to Free T3 (fT3) peripherally is an important step in the functional processing of thyroid.

fT4 does not provide the genomic actions of thyroid and must be converted to fT3 to become active.
Comparing the fT3 level (within its range) to the fT4 level (within its range) can help determine if the patient is adequately converting fT4 to the active fT3.
If fT3 is significantly lower (within its range) compared to fT4 (within its range), the patient is not converting fT4 to fT3 well.

There are many causes of less than optimal conversion of fT4 to fT3, but one of the common causes is high cortisol.

Free T3 must be absorbed into the cell, transported to the nucleus and receive proper thyroid receptor response to exhibit optimal function.

Adequate cortisol is required for thyroid receptor function and proper absorption into the cells.
Ferritin is required for intracellular transport and utilization of fT3.
Thyroid receptor function is affected by Vitamin D levels, in addition to both low and high cortisol levels.

Therefore, to obtain the necessary information for a full analysis of thyroid function, the following tests should be initially ordered for the patient:

TPOab
TSH
TT4
fT4
fT3
25-OH Vitamin D
Ferritin

Learn More:

Jim Paoletti, FAARFM, FIACP, is Director of Education for Power2Practice and author of A Practitioner's Guide to Physiologic Bioidentical Hormone Balance. He writes on thyroid imbalance as well as converting patients to bioidential hormone therapy.

Confused About Hormone Therapy Terminology?

Fri, 16 Oct 2015 09:00:00 -0700

When a patient says that she wants “natural” hormone therapy, does the term mean the same thing to you as it does to her?

Let’s explore that question further by dissecting the terminology most commonly used by patients (and even some experts) when discussing hormone restoration therapy: “natural,” “synthetic” and “bio-identical.”

Natural

The term “natural” cannot be used to describe hormones or hormone therapies, because it lacks a unified definition:

For many laypeople, natural means “found in nature.” In other words, the substance was not man-made in a laboratory.
For others, natural means that even if the end substance cannot be found in nature, the source materials used to create it can.
For some scientific types, natural does not refer to the source of a substance, but that it is found naturally in the system to which it is being introduced.

Synthetic

Synthetic is another term with a variable definition, depending on who is asked:

It is often used to represent any therapeutic agent produced by a drug manufacturer that does not contain exclusively bio-identical hormones.
Others have used the term to describe any therapeutic agent that is produced in the lab.
Still others feel that synthetic should apply to any substance that is foreign to the body.

Due to overwhelming confusion over these two terms, it is best to avoid using “natural” and/or “synthetic” when discussing hormone therapies or options.

Bio-Identical

Bio-identical means that the hormone has the exact same chemical structure as the endogenous hormone, and thus, it is indistinguishable from the hormone produced by the body.

Is the therapy bio-identical or non-bio-identical?

When using a substance that is foreign to the body, the therapy is non-bio-identical. Furthermore, substances that are foreign to the human body will increase risk for adverse reactions.

For years, the standard hormone replacement therapy protocol included the use of many agents, which (at least partially) contain substances that are foreign to the human body. More recently, bio-identical hormones have been available in manufactured drug choices; but if you want to achieve optimal patient outcomes, there is much more involved than simply selecting therapy agents.

Evolving Our Best Practices for Optimal Patient Outcomes

Aim to restore hormones to normal pre-menopausal levels in a manner that balances the different, yet highly interactive hormones.
Refer to bio-identical therapy as restoration therapy rather than replacement therapy. Why? We are restoring hormones to normal levels using the same exact hormone rather than replacing a patient’s hormones with substitutes.
Regularly measure and monitor hormone levels along with patient symptoms. Restoration must be facilitated in a responsible manner using highly scientific methods.
Make adjustments on an individual basis. Consider the influences of other endocrine hormones on the outcomes of the sex steroid therapies.

There are no standard doses that can be applied across the board to women in general, so therapy must be individualized for optimal outcomes. Too much bio-identical hormone may have as much overall health risks as lack of the hormone.

Learn More:

Jim Paoletti, FAARFM, FIACP, is Director of Education for Power2Practice and author of A Practitioner's Guide to Physiologic Bioidentical Hormone Balance. View these educational resources to learn more: