Bioidentical Hormone Pellets

The Hidden Truth about an Efficient and Effective Treatment

The Saga of Hormone Pellets

“The truth may be stretched thin, but it never breaks, and it always surfaces above lies, as oil floats on water. ” Miguel de Cervantes Saavedra — Don Quixote

Every individual, male or female, has been submitted or exposed during his (or her) life to ladies’ mood fluctuations. I remember reading a medical article about the feared pre-menstrual syndrome (PMS). The authors had interviewed thousands of incarcerated young women and found out that most crimes had been committed during the few days preceding menses. There is also an old joke with the following question: “What is the difference between a Pitbull and a woman with PMS?” And the answer is: “Lipstick!” PMS can occur at any time during the reproductive period of a woman’s life; but after menopause, when the ovaries stop functioning, the dire situation can tum into a permanent state. The affected woman feels bad and she can make everybody around her, at work or in the fan-lily, feel miserable. In my practice, we treat a lot of women who experience PMS or who are menopausal. Before talking to them we ask them fill out a questionnaire that we call “the Misery List.” Most of the time, they check the boxes facing symptoms of mood swings, anxiety, depression, lack of energy and libido, insomnia and they can add some poignant and heart touching stories.

In my previous book, “Taking a Stand in Dixieland,” I wrote a chapter entitled “Estrogen, the New Reality Show” where I address the dilemma that all women have to face during the second half of their life. With the evolution of science and the increase in human longevity, unlike the male gender, women are facing a major problem: the lack of production of sex-hormones. No medication other than estrogen can provide any relief from the alarming symptoms or a better protection against bone loss. Many women, by an exaggerated fear of complications —or of the unknown— elect to suffer in silence or make everyone surrounding them share and endure their agony. Their family or friends can grow more and more despairing or simply escape from the torment by leaving, cutting ties or sometimes divorcing. About 70% of menopausal women seek, at some point, relief of their symptoms but only half of them will pursue a long-term treatment.

The prescribed hormones can be given in different forms: oral tablets or capsules, creams, ointments, patches, injections or subcutaneous insertion of pellets. The choice of treatment will generally depend on the personal preference of the physician or the patient. However, many other factors can be entered into consideration such as: cost, efficiency, safety, tolerance, convenience and compliance. In my practice, I have over the years recommended all of the above types of treatments —depending on the situation— obviously insisting on the natural —or bio-identical— hormone and not the one extracted from mare or another animal urine. I’m not joking. Up until the beginning of the 21st century the most commonly prescribed estrogen in America —I have never understood why— was manufactured after concentration and filtration of pregnant mare urine. The brand name was “Premarin” and it’s still available in pharmacy and prescribed by many of my colleagues.

All forms of treatments —including Premarin— can work in some capacity but the most successful one, convenient and better tolerated is the hormone pellet or subcutaneous implant that is injected in the adipose or fat tissue. It’s not everyone’s opinion. There are still some physicians who are vehemently “opposed to pellets.” It’s more often by ignorance of the product because it has been kept out of the traditional academic teaching and textbooks. Also, its utilization requires specific equipment, office organization and proper sterilization. My preference for this type of treatment was forged early in my professional career and nothing during my fifty-year experience on the subject has modified my first and partial opinion about it. All the senior medical students and potential nurse practitioners who rotate through my office can observe every day examples of their positive effects and results. I like for the patients to tell the students their stories. Some of them are so touching or heart warming that I’ve been asked many times why I was not publishing them. This idea had crossed my mind earlier in my career and I’ve asked patients to write their pre and post hormone treatment odysseys in the form of letters.

Most of them could write but only a few could produce an attractive prose that would satisfy an avid reader. The ideal solution would be to have a good student with journalistic talents interview the ladies and unveil all the moving and impressive stories. It can still be done, but here I will, instead, talk about the pellet saga; how the product was discovered, compounded and applied in human therapeutic, with all the hurdles that we had to be overcome and the stratagems that had to be used to convince government agencies of its medical legitimacy. And most of all, how we had to deal with adversity from insurance and/or pharmaceutical lobbies.

There is a significant difference in hormone production between men and women. Although testosterone loss is common as men age, the testicles are producing “male hormone” for an entire lifetime. It has been observed that in the general male population —in a wide range of ages– testosterone has steadily declined over the last few decades. One out of four men over 30 have low testosterone levels, but only one out of every twenty have clinical symptoms linked to such deficiency. They are more likely to experience fatigue, lack of sex drive, depressed mood and sleep disturbance. Sedentary factors such as obesity have been associated with poor sperm quality and low testosterone production. Endocrine disruptors such as bisphenol A (BPA) —a chemical that behaves as estrogen– leaching from plastic containers into water and food has also been blamed. Intra-muscular injections of long-acting testosterone are the most popular and commonly prescribed type of treatment by primary care physicians. It’s regrettable because their long-acting effect due to the cypionate or enanthate radicals is far from being satisfactory. They provide a roller-coaster effect causing difficulty in dosage control and monitoring. On the contrary, the pure and natural testosterone can be administered in the form of gel, patches and pellets. But here again, the pellets provide better results.

Discovery of a New Treatment

My first steps in Endocrinology (1967-1969) took place in a very conservative environment and the philosophy of my French professors was: “Let nature take its course.” When the ovaries stop working at the end of the reproductive life—between the ages of 38 and 50—causing a few miseries, there is no reason to intervene. Do not interfere with Mother Nature unless it’s absolutely necessary.  Estrogens can correct hot flashes and cold sweats, but they should only be used for a short period of time. “Women need to adapt to their miseries by increasing their activities and all the associated complaints should be treated symptomatically.”

When I arrived in Augusta, I was exposed to Dr. Greenblatt’s philosophy:

“All women will potentially be menopaused and if they complain of symptoms or miseries that can be attributed to a lack or decrease in estrogens, don’t hesitate; treat them with the available hormone as long as you deem it necessary or as long as the patient wishes it.”

Many patients were seeing Dr. Greenblatt for treatment consisting of hormone pellets and

returning every four to six months for treatment renewal and continuity of care.  A lot of them were from Augusta

or the Central Savannah River Area, but also many were travelling four to ten hours to be seen and receive the

salutary treatment.  They were coming from states like Florida, Louisiana, Mississippi, North Carolina or Tennessee.

Some were flying from New York, California or Arizona.  It was amazing and the results were astounding.  The women could be in their fifties, sixties or even seventies.  They looked good, were alert, lively and grateful.  They all had a story describing how the hormone treatment had saved them or transformed their lives.  We would have to be blind or stubborn to refuse to acknowledge the obvious satisfactory results.  It did not take long for me to be convinced.

Hormone pellets were first manufactured in 1938.  They had been extensively used in veterinary medicine

and sporadically for humans.  At first, they were most commonly inserted in the subcutaneous tissue immediately

following surgical removal of gonads in order to minimize the detrimental effects of castration (testosterone for

men and estrogens for women).  However, it’s in the early 1950’s that physicians started to use them on humans for long term treatments.  Dr. Greenblatt was one of the first, maybe the first one, to use them extensively in his practice.  They were supplied in bulk in individual small sterile glass containers.  Specially built stainless steel trocars were used for the injections of estradiol or testosterone pellets.  This was done under sterile conditions after infiltrating the skin with lidocaine, a local anesthetic.  They were implanted to a depth of about two inches (5 cm) in the adipose tissue of the lower abdomen or the buttocks, dissolving and steadily releasing the biological hormone over a period of four to six months.  The dispensed amount depended on the patient’s symptoms and weight.  The hormone pellets available on the market were provided by a pharmaceutical company called “Shering USA. ”

When I went into solo practice in 1978, my patients followed me and I ended up having an atypical gynecological practice like the one I had just left.  There was a large contingent of menopausal patients who preferred the pellets for their hormone replacement and they were so satisfied that they were all referring their friends.  It was like a snowball effect.  Then, I understood why Dr. Greenblatt called the pellets his “manna,” a bread-like edible substance which God provided for the Israelites during their travels in the desert during the 40-year period following the Exodus.  Indeed, with a well-organized program it was an easy treatment to administer and monitor.  The competition was practically nonexistent.  Some of our colleagues were knowledgeable about the treatment, but if they were administering it, they would do it only occasionally or often using a poor technique. For example, instead of using a specially built stainless-steel trocar that would ensure an ideal two-inches (5 cm) placement in the adipose tissue —giving the best guarantee to avoid a rejection— they would make an incision with a scalpel and insert the pellets using small forceps.  The placement was so shallow that the pellets would be inefficient and/or rejected half of the time.  In Augusta, Georgia we were realistically the only practices providing the treatment in the Southeastern United States, maybe in the whole country. It was giving us the assurance of a steady income.

Inadvertent Loss of a Grandfather Clause

The Shering hormone pellets had been on the market for so long that their composition and utilization had been described for many years in the United States Pharmacopeia National Formulary (USP-NF) and in the Physicians’ Desk Reference (PDR), a compilation of manufacturers’ prescribing information. It was published yearly and could be seen on every American physician’s desk. The Shering pellets were recognized and approved by the FDA with a “grandfather clause” exempting them from the requirements of a piece of legislation affecting their previous use and commercialization. Unfortunately, the pellets were so cheap that Shering, not making enough profit, abandoned its production in 1979. The same phenomenon occurred seven years earlier in France. One of the best-known French drug companies —Roussel— discontinued the manufacture of hormone pellets for the same reason: “not enough prescriptions and no profitability.” The product being removed from the market, as I was inaugurating in Augusta my solo practice, we had to find a substitution. It was provided by “Bartor Pharmacal,” a company based in New York and owned by Frank Bardini, a gentleman who came to visit us in Augusta. At that time, he was one of the few pharmacists in this country who was still compounding drugs, a talent that had slowly disappeared after World War Il. I remember hearing, in the 1970’s, physicians calling jokingly pharmacists, “pill counters” and it was a fairly well-deserved epithet because they had lost —or were not interested in— the art of compounding. Frank Bardini was an exception and he knew how to press and fuse steroid crystals into small compact cylinder shape pellets. He had the experience and possessed the proper equipment to do the job.

We began to use the “Bartor pellets” which were very good and conveniently presented into small breakable glass ampules. We were using them without any problems or questions asked, when in 1980, Mr. Bardini planned to have the product officially approved by the FDA; but by doing so, he did not realize that he was waking up a bureaucratic monster. The “grandfather clause” obtained by Shering was out of date and lost. Compounding was legal but in order to obtain the FDA stamp of approval, it was another story. Mr. Bardini was told at the FDA that he had to start a “New Drug Application “(NDA) that would Involve tons of legal documents and investigational studies. It could cost a fortune; probably too much for a small drug company like Bartor Pharmacal. We already knew in the 1970’s that the acquisition of an FDA license for a new drug was a task that only big pharmaceutical companies could afford; but they were not interested in our project. In summary, we were supportive of Mr. Bardini’s efforts but were afraid that he was undertaking a cumbersome and elusive mission. All new drugs have, and already had, to be submitted to the necessary “Washington, D.C. red tape,” a complicated application process, inevitably painful and expensive. He realized that he had made a mistake and that he should have continued to compound quietly the legal and old-fashioned way without worrying about the “FDA blessing,” but it was too late to back-pedal. He became a center of interest for the dreadful federal administration. The FDA gave him an Investigational New Drug (IND) permit to produce and sell his pellets in uncontrolled studies, but it was only an interim measure before marketing approval. The drug company had to provide a large number of irrefutable studies showing that the product was effective, predictable and safe within a “reasonable period of time,” a vague statement. It was like a “Sword of Damocles,” a potential imminent peril if the conditions were not met. Nobody knew how long was a reasonable period of time. The empirical deadline was to be determined by the FDA and the FDA only.

And nobody knew who was in charge of determining the deadline.

Looking back at the situation in 1979, it would have retrospectively been very smart to make a deal with Shering USA and buy their license. They would have been happy to relinquish it for a symbolic dollar or transmit for a small fee their Grandfather Clause. Anyway, we can still wonder why Frank Bardini wanted so much to obtain an official FDA approval when we know that, at that time, there were no federal or state rules or laws regulating the art of pharmaceutical compounding. To be done in a legal fashion, it only needed to be prescribed by a medical doctor. What was in the back of Frank’s mind? Knowing that he was the only manufacturer on the market, he was hoping that by having his product “FDA approved” he could have a sort of market monopoly for the manufacture and sale of hormone pellets.

In the Crosshairs of the FDA

At first, Frank Bardini thought that he could bypass the aggravating licensing process by using Dr.
Greenblatt’s notoriety and he naturally asked him to be his advocate. Indeed, by then, my former mentor
—74 years old— was nationally and internationally known. He had a long experience in hormonal therapy with many publications written by him or his former Fellows –me included– regarding the beneficial effects of hormone treatments and some regarding specifically the subcutaneous implants or pellets. He went to the FDA headquarters in Rockville, Maryland. This is where he met Dr. Solomon Sobel, director of the FDA’s division of metabolism and endocrine drug products. Dr. Sobel was a fairly unknown entity in the scientific environment but he was very powerful. He had the power and the privilege of his Federal administrative position and he liked to impress and express it to his interlocutors. Dr. Greenblatt was far from being impressed and he always liked to dominate the conversation. Unfortunately, the first encounter ended up with a clash between two superegos. From then on, Dr. Sobel did everything he could to undermine “Frank Bardini’s project.” Dr. Greenblatt’s requests and all petitions coming from the Augusta area —mine included— were totally ignored. Dr. Sobel did not have any trouble to find other “Scientists” who would disparage the hormone pellets. As I said earlier some of our colleagues, mainly in Academia, were vehemently opposed to the use of pellets, often by ignorance, sometimes by jealousy, maybe by conflict of interest. At that time, there were already on the market many hormonal products in direct competition with the pellets and most of the physicians who specialized in hormonal therapy were working with or for a well-established pharmaceutical company. I’m not making any accusation but it’s very probable that some members of the scientific board were connected with existing competing drug manufacturers.

Dr. Sobel and his committee decided that this particular drug —estrogen or testosterone pellet– which had benefited from a Grandfather Clause for nearly 50 years needed to go through a New Drug Application (NDA) process, “as required by law,” like every new drug. None of the previous publications were satisfying the new investigative rules which required “bona fide efforts involving double-blind placebo-controlled trials.” It was added that “investigators who wish to pursue bona fide studies should contact the Division of Metabolism and Endocrine Drug Products for assistance in the protocol design and analysis of data so that the studies will provide the appropriate data. It was hoped that such studies could “yield the kind of data upon which drug approval could be based.”

Period of Reprieve

Optimistic as always and eager to be able to legally sell his product, Frank Bardini signed up for an “Investigational New Drug” (IND) application. It permitted for the use of pellets in uncontrolled studies as an interim measure. Another pharmaceutical firm —I don’t remember its name— signed the application and a contract of collaboration with Bartor Pharmacal. Again, it was anticipated that the two firms that manufactured the product would be able to obtain marketing approval within a non-specified, period of time. The two firms counted on us to come up with some protocols that would satisfy the FDA’s “scientific committee.”

I did my part of the labor. In order to satisfy the conditions for a randomized or “double-blind” study, we had to find a placebo. It was easy. We had to make a pellet that would look like the estrogen or testosterone pellets without having any therapeutic or detrimental effects on the patients. We decided to use pellets of cholesterol that were easy to manufacture and could look and feel like the real thing.

However, the real difficulty started when we had to find volunteers. It was out of question to give the placebo, or ‘the dud” as some would call it, to patients who had taken the treatment for several years. It would not make any sense because shortly following the injection, they would know that they were not obtaining the expected effects. Anyway, they all refused.

We thought that maybe some new patients would be interested by a free treatment provided that they would take the chance of falling into the placebo cohort. But none of the new patients who were complaining of the traditional miseries wanted to take a chance and sign up for “the study.” We had to find menopausal volunteers who, actually, had no complaints and had their ovaries surgically removed at the time of a hysterectomy. The first blood tests from the selected candidates were obtained after surgery in order to confirm the absence of ovarian hormones. The study was designed with the collaboration of Dr. Jim Bryner, a former Medical College of Georgia (MCG) Endocrinology Fellow who was practicing in Salt Lake City, Utah. Sixty women were randomly assigned to one of three treatment groups receiving: (l) two 25 mg. implants of estradiol (2) one 25 mg. implant of estradiol and one 25 mg. implant of cholesterol (3) two 25 mg. implants of cholesterol. Serum samples were obtained at monthly intervals for six months to measure different types of estrogens –estradiol, estrone and estriol– and FSH –a pituitary hormone that is elevated in absence of estrogens–. The different types of lipids and cholesterol were also checked. Here, I will not go into all the details of the randomized study but the results showed that the pellets were safe, effective, well tolerated delivering a steady and predictable amount of hormone corresponding to the injected dose. This study was published in 1982 under the title of “Effects of subcutaneous estradiol implants after oophorectomy.” It’s available in my office in the form of a booklet. The authors were myself, as senior author, Dr. Jim Bryner and Dr. Jan Scholer who owned the lab performing the hormone assays. Some other studies came out at about the same time. One was from Dr. Greenblatt and his new partners Dr. Don Gambrell and Dr. Raja Natrajan. Others were done by private clinics from different states of the Union and some from England and Australia. For all studies, the goal was to verify and demonstrate the effectiveness and safety of testosterone pellets for men and estradiol pellets for women. As expected, they were all giving positive and reproducible results. We all thought that it was ridiculous to perform so many studies to have such an old proven and reliable medication take the test of approval from the FDA.

However, as we will see, there were two major problems: (l) My publication was the only one with a randomized study. (2) Although Dr. Greenblatt was still chairman of the department of Endocrinology at MCG, none of the other works were directly coming from academic institutions. Somehow, official agencies like FDA or NIH would rather see a stamp from a medical school on a scientific paper than the names of private specialists. Personally, I think they are wrong because private specialists publish only when they have an important message to convey, when many academic publications are performed to satisfy research grants. As they say in academia, “publish or perish.” But I must admit that it’s in the school environment that we find the true publishing professionals. They know better than we do how to maximize the good effects from text content and form to satisfy peer reviews. The job has become an art and the best publishing talents are found in academia but hired professionals could be expensive. We, in the private sector, were volunteering our services for a good cause. Indeed, we could not be accused of doing the work for financial rewards because knowing that the two compounding pharmaceutical firms were not prosperous, all authors were benevolent and did not receive any compensations except for the pellets to perform the investigation. The patients were not charged for the service and they did not receive any compensation. Retrospectively, I still think that investing into an academic representation — other than Dr. Greenblatt— would have been a smart move for our compounding friends.

FDA Verdict

Everything went well for the next seven years. Bartor Pharmacal could fabricate and sell their pellets in complete tranquility using the IND but despite the fact that a good number of studies were showing excellent results the NDA was not satisfied. It takes much more than an abundance of medical testimonies to complete the NDA requirements. Officially, the goals of the IND are to provide enough information to permit FDA reviewers to reach the following key decisions: (l) Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks. (2) Whether the proposed drug labeling (package insert) is appropriate, and what it should contain. (3) Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.

But it’s a little more complicated than that. The red tape is generally fairly extensive. There is a lot of cumbersome paperwork to fill and sign and you need a good but costly legal counsel. Some say that it’s the reason medications are so expensive in this country by comparison with Mexico, Canada and Europe. Unfortunately, our pharmacist friend had –according to the FDA— “not done his homework.” The committee estimated that they had not received enough randomized studies with reliable enough results. My publication was the only one showing a “double blind” protocol which was considered essential, according to the FDA, to evaluate drug effectiveness. As I explained earlier, most authors expressed their frustration about their difficulty to find volunteers for the reception of a substance without therapeutic effect. In my opinion, the FDA should have been more lenient in consideration of the fact that we were dealing with a drug that had been used for many years. Instead of insisting on the necessity of studies using placebo they should have paid more attention to reproducibility and international experience. They didn’t take into consideration the previous works done in Australia and Europe, where hormone implants were used abundantly and legally. Professor John Studd and his team from King’s College school of medicine in London had also done extensive studies on the subject. Dr. Studd was known as being Margaret Thatcher’s private Doctor. Yes! The famous “Iron Lady,” Prime Minister of the United Kingdom (1974-1990).

Actually, many scientists feel that it’s wrong to base a medication approval solely on randomized studies. We’ve witnessed how certain statistical work related to science can be skewed or biased. A typical example occurred recently when the powerful drug company Gilead fought tooth and nail to make “Remdesivir,” an expensive antiviral medicine, recognized as efficient in the treatment of COVID-19. It was competing against very cheap drugs like “Ivermectin” or “Plaquenil or Hydroxychloroquine.” Some biased studies from Boston and New York renowned academicians came out trying to demolish the cheap drugs. Two famous medical journals, The Lancet and the New England Journal of Medicine, had to shamefully apologize and retract an article because they “could no longer vouch for the veracity of the primary data sources.” “Garbage in, garbage out” as they say in computer science. With at least 30 years of experience, the treatment with estradiol pellets had already successfully gone through the stages of trial and error followed by correction. The only missing stage was reproduction. Instead of insisting on randomized studies, the FDA should have been satisfied with all the indisputable proofs of reproducibility which we definitely provided.

Dr. Greenblatt, Frank Bardini’s main spokesperson, passed away in 1986 and in 1988 Bartor and the other firm were told by the FDA that they had exhausted their IND and were forbidden to manufacture or commercialize estradiol pellets. For some reason, the decision was not affecting the testosterone pellets. I’ve never known why. Maybe the studies for males done with testosterone pellets were satisfying the “scientific committee,” but some accused the “all male FDA panel” of having more compassion for the male gender. The news surprised and disappointed us. We thought the NDA was a done deal. Until then, Bartor had been our only supplier and we were dumfounded when we realized that we could not treat our patients with their drug of choice. The menopausal ladies who depended on the treatment were downhearted and furious. We had to come up with Plan B.

Menopausal Women’s Rebellion

The first option was to discontinue the use of pellets and switch to other types of treatment: oral tablets, injections, patches or creams. The results were not satisfying the disappointed patients who by then, were convinced and firmly believed that the pellets provided better relief of their symptoms and miseries than any other type of treatment. There was an atmosphere of anger and rebellion. The ladies demanded an explanation and wanted to know if they could in any way intervene and pressure the FDA. Among my patients there were judges, lawyers, doctors, bankers, business owners, wives of army officers or politically well-connected gentlemen. I decided to compose a letter that I handed or mailed to all my patients whose lifestyle and well-being were affected by the FDA decision.

My letter to the patients

February 20. 1988

To my patients who have been treated with estradiol pellets:

The drug company that manufactures estradiol pellets and many physicians have worked for the last eight years to obtain an FDA approval for release in the market.  All these years, we have been able to administer the pellets because of a “compassionate IND (Investigation of New Drug) permit” that was granted by the FDA.

Many testimonies and studies have demonstrated the safety and effectiveness of the estradiol pellets.  One of the studies in which I participated in 1982 showed well-controlled and predictable serum hormone levels in patients who had received the drug.

I have a 20-year experience with estradiol pellets. The side-effects are scarce, minor and can easily be controlled.  The benefits far outweigh the possible drawbacks.  Many menopausal patients have been saved from mental disorders, crippling osteoporosis, arthritic pain and incapacitating headaches or hot flashes.  Many marriages have been rescued.  Many women who would have been disabled otherwise are able to maintain a productive life because of the hormonal treatment.  These patients have tried to no avail —or could not take-— the other types of estrogens presently approved by the FDA (oral. injectable, cream and patches).

It is now our opinion that the estradiol pellet is not receiving a fair trial.  The committee that decides on its fate is composed of individuals who have little experience with the drug or with the treatment of menopausal women.  The FDA has notified the manufacturer that it must cease to produce estradiol pellets and is now threatening to forbid physicians to use them despite professional testimonies and scientific evidence of their effectiveness.  The genuine endeavor to place this legitimate drug in the market has turned into a political battle.

Therefore, if you wish to continue to receive your treatment, I encourage you to write to your senator, your congressman and Commissioner Young, who heads the FDA, a letter expressing your feelings and your experiences.

I will remain, as long as I have your support, constant in my determination to keep this useful medication from being eliminated.

Sincerely yours,

Edouard J. Servy M.D.

P.S. Commissioner Young ‘s address: Health, Education & Welfare. Food and Drug Administration. 5600 Fisher Lane. Rockville, MD 20857

The ladies were prompt to react and write letters. Commissioner Young was bombarded with hundreds of letters from patients and in many occasions from the husbands.  His mailbox was filled with letters requesting, demanding or begging for a favorable intervention.  Each letter described the torment caused by the FDA decision to the ladies’ health and lifestyles.  The senators and congressmen from Georgia, South Carolina, North Carolina, Florida, Virginia —and states as far as New York and Arizona– received also many letters of unhappy constituents.  I have in my files their responses with their promises to intervene. They all asked for explanations and justifications from the FDA.  Among them are letters from members of Congress like Butler Derrick, Floyd Spence from South Carolina; Bill Grant from Florida; Doug Barnard, Lindsay Thomas, J. Roy Rowland and Richard Ray from Georgia.  There are also letters from Senators Sam Nunn and Wyche Fowler Jr. from Georgia; Strom Thurmond and Fritz Hollings from South Carolina; Senators Bob Grantham and George Kirkpatrick from Florida.

According to Augusta Representative Doug Barnard that I saw later, on many social occasions, Southern Congressmen and Senators were quite surprised and disturbed by the outcry from east to west of irate women who were complaining of being hormonally deprived by the FDA.  He said that talking privately to each other and to the health commissioner, they were asking: “What in the hell is going on?”

At that time there was no internet or social media but the ladies were calling each other, venting their frustration and threatening to charter buses, go to Washington, D.C. or Rockville, Maryland and picket in front of the US Congress or the FDA headquarters.  Copies of the letters were mailed to my office. They were all interesting but I will only quote some extracts of two out among hundreds of other letters.  They are wonderful. testimonies.  I received permission from the patients to use their name.

Letters from the patients

In her letter of August 15, 1988 to Commissioner Young, Helen Cook said:

“Without the access to the pellets I can almost be assured of lapsing into a crippling arthritis, physical exhaustion and severely debilitating depression. suffered these and many other symptoms for which I was unsuccessfully treated until 1976.  Estradiol pellets changed the course of my entire life! After hysterectomy in 1963, I experienced annual episodes of hospitalization, although regularly taking estrogen in all available forms to prevent incapacitating depression all to no avail… I can remember feeling so tired that I wished I might carry my head in a basket.  It was too heavy to bear.  When I was referred to Dr. Servy in 1976 I had been absent from work for one month and incapable of returning.   Because I was a widow with a large family (six children) to support and due to my past work record, I was not fired…  I was treated with this procedure on a regular basis and did not become ill again for more than a day or two during the next nine years of work, except one time when I stopped treatment.  I rose in rank to become a Vice-President of Candler General Hospital in 1979.

In 1981, I tried to stay in Savannah rather than travel all the way to Augusta, I was treated by a local Endocrinologist who prescribed oral estrogen.  I became ill again and decided to return to Augusta to resume the treatment with pellets.

Please help me and many like me to maintain the healthy productive lives which we now enjoy. Insist that estradiol pellets be approved for use on the market, or otherwise, please be kind enough to furnish me with good reason why you do not.”

Copies of the letter went to Senator Sam Nunn and Wyche Fowler and to Congressmen Lindsay Thomas and Roy Rowland.

Here is another letter written to the Health Commissioner by Carolyn Matthews from Fort Lee VA, on August 22, 1988:

“Please read this letter with an open mind.  When I was 44 (seven years ago), I began to have numerous problems, to include uncontrolled weeping for no specific reason, hot flashes, shaking, vaginal dryness, loss of any interest in sex, bad breath and waking up in the middle of the night in a puddle of perspiration.  Then after changing my sheets, not being able to sleep. At that time, I was head of a department for one of the larger banks in Virginia (Central Fidelity).  I went to a doctor in Richmond who checked my hormone levels and pronounced me officially entering the “change.”  Now I am a fairly intelligent lady, very well-read, and I knew I needed estrogens.  Both my mother and grandmother suffered from severe osteoporosis, and watching them die with their lungs caved in led me to study the cause of that as well.  The physician prescribed first Menest.   In three weeks, I had gained 30 pounds and had enormous headaches.  So back I went and he switched me to Premarin.  This time the headaches were so bad I lived on extra-strength pain medication and was beginning to feel like a junkie.  Once again, he tried Estratest.  This time I broke in the worst case of acne I’ve ever seen.   I then went to a dermatologist who prescribed Tetracycline and informed me I would have the problem as long as I took the Estratest I then got a yeast infection from the antibiotics…  I felt like killing myself.  I was so depressed, so bitchy that I hated myself and feared for my marriage and my sanity.

Fortunately, I talked to a friend from Georgia who suggested I consult a particular physician from Augusta. The 850 miles round trip didn’t phase me at all after what I had been through.   At that point this physician treated me with estradiol pellets.   It was time-consuming but worth all the time and money.   For the first time in months, I began, after about a week, to feel like a human being again.   My marriage is now happier than it has ever been, I’m head of a department at Fort Lee, Virginia, and feel like I can handle all my problems without falling apart.  My only request to you is PLEASE don ‘t take this lifesaving product off the market.  You will be sentencing me to a certain divorce, loss of job. Maybe loss of life.   I was glad you were there many times when we in America were protected from controversial drugs, but after more than twenty years on the market (seven with me), I feel in my heart that I am safe…  Thank you for reading this letter, it is so important to me and others.”  

Copies of this letter went also to Representative Thomas Bliley Jr. and Senator Paul Tribble Jr. from Virginia.

All the letters tell the same type of story.  In our practice, when we see new patients, pellets are rarely the first line of treatment.  There are a lot of women who prefer or are satisfied with patches, creams or oral treatments. But if the first options don’t provide proper relief of the symptoms, we don’t hesitate to recommend the pellets and I must admit that 90% of the patients who try the pellets want to continue the treatment for many years.  Now there are also many patients who come to see us because they have tried all other options elsewhere and want specifically to receive the pellets that were not available in the other practices.  As claimed by some of the ladies –using an old expression— “we feel like it’s the Cadillac of all types of hormonal treatments.”  The pellets are slowly dissolving and the hormone is steadily released in the blood stream like the natural sex-hormones produced by the ovaries or the testes.   The serial blood tests checked in multiple studies —including ours– have proved it.

Response from the FDA

The Commissioner Young or his assistants, the Consumer Safety Officers Diane Walker or Hugh Cannon answered the patients, the Senators or the Congressmen with the same generic type of letters.  There was very little variation between the different texts.  Amazingly, Dr. Solomon Sobel the director of the FDA’s division of metabolism and endocrine drug products who had picked a fight with Dr. Greenblatt remained silent. They didn’t want to expose to the patients and elected officials the obvious atmosphere of animosity.  Here is a summary of their response:

“As you may be aware, estradiol pellets were on the market some years ago but were not the subject of approved new drug applications (NDA ‘s), as required by law.  Because of findings on the potential carcinogenicity of estrogens, particularly as a consequence of long-term use, the firms marketing these products were notified that they must either obtain approved NDA ‘s for their product or cease marketing them.

Investigational new drug applications (IND ‘s) were permitted for the use of pellets in uncontrolled studies as an interim measure because it was anticipated that the two firms that manufacture the product would be able to obtain marketing approval within a reasonable period of time.  After approximately 8 years, neither of the firms has been able to demonstrate safety and efficacy adequately to support approval of an NDA.  Because of this, and because of the Federal Food, Drug, and Cosmetic Act and regulations issue, it does not provide for open use of an unapproved drug product as has occurred with the estradiol pellet, there is no legal basis for permitting the estradiol IND ‘s to continue.

Further, the FDA presented the issue of the use of this product in uncontrolled studies for which inadequate data existed for approval before the Fertility and Maternal Health Drugs Advisory Committee.   The Committee Recommendation was that uncontrolled studies should cease.  FDA has concurred with that recommendation.

Studies which are bonafide investigative efforts involving double-blind, placebo-controlled trials, however, are allowed.  Investigators who wish to pursue bonafide studies should contact our Division of Metabolism and Endocrine Drug Products, at the letterhead address, for assistance in the protocol design and analysis of data so that the studies will provide the appropriate data.  It is hoped that such studies can yield the kind of data upon which drug approval could be based.”

Carolyn Matthews was not satisfied with Ms. Walker’s answer and she responded with another letter.

“You seem to overlook that these implants have been used for about 30 years, not 8 years as you stated, with great safety.  The late Dr. Greenblatt has saved many of us from a fate worse than death.  The issue is not safety of estrogen.  I fit were, millions of young women would not be safe as they are popping birth control pills like candies.  Further, millions of menopausal women are taking oral or injectable estrogens approved by the FDA. The issue here is rather the method of introduction of estrogen to the body.  As I explained in my first letter, I exhausted all other possibilities first.  Do you think I like going 500 miles one way twice a year for treatment?

On the other hand, if you are in the program, you have a yearly exam and mammogram and a biopsy every three years if you have a uterus.  I can only hope you will reconsider your stand until you really know all the facts… I have no idea of your own particular health, age or status.  Someday you, yourself may need this life-saving mode of treatment.  And that is what it is.  It saved my life.  If you do need it, I pray it will be available for you too.  I would not wish anyone my own personal hell, I had to put up with, before treatment.”

We were not happy either with their answer.  Here I’m going to quote Dr. Don Garnbrell ‘s response.  He was working in the Greenblatt Clinic. In his letter he summarized our feelings: “(l) The pellet has been a time-proven effective product to many thousands of women, particularly consistent when other dosage forms have a ‘roller coaster effect.’  (2) Careful screening of patients decreases to minimum or negates any potential apprehension for cancer, based on 40 years of experience.  This is much to the contrary of what an ill-advised public and some skeptical professionals think.  (3) It appears that there is a lack of knowledge, experience and unreasonable attitude of an idealistic FDA.  It will never allow the passage of this medication.  The regulations are an ‘over-kill’ to good judgment.  Otherwise, this drug would have been approved with less resistance.  (4) For these reasons this drug must go through an “orphaned drug” channel.  (5) Those of us who have banded to confront the FDA would first welcome a meeting with Commissioner Dr. Frank Young, Dr. Solomon Sobel and whatever ‘qualified practicing gynecological experts’ they have.  To further enlighten their knowledge of this product, the practicality, the safety and effectiveness that would put things in perspective.  (6) Reviewing the present FDA demands, we doubt adequate estrogen levels have been satisfactorily determined with other types of estrogen treatments.  Can we request approved data for these products through the Freedom of Information Act?”

The possibility of an “orphan drug” was evoked.  An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance.  The Orphan Drug Act was enacted in the United States in 1983.  There was a major problem, menopause was not a rare disease.

Note: In the U.S. and the E.U., it is easier to gain marketing approval for an orphan drug. There may be other financial incentives, such as an extended period of exclusivity, during which the producer has sole rights to market the drug.  All are intended to encourage development of drugs which would otherwise lack sufficient profit motive to attract corporate research budgets and personnel.

Improvisation or Do-it-yourself Option

François Rabelais (1494 — 1553), an eminent French writer, physician and humanist from the Renaissance, said: “Science without conscience is the soul’s perdition…. Gestures, in love, are incomparably more attractive, effective and valuable than words.”

After doing more research we found out that the “notification of interdiction to manufacture and commercialize estrogen pellets” was specifically addressed to the two firms that had applied for an IND. The mode of fabrication of steroid (estradiol and testosterone) pellets was described in the Annual US Pharmacopeia book.  In the late 1980’s, there were no rules or regulations that could keep a pharmacist from compounding steroids in any form — tablet, suppository, cream, ointment or pellets— and sell them, as long as they were prescribed by a licensed medical doctor.

We knew that in the winter of 1988 a decision regarding the pellets’ survival had to be made.

Knowing, first hand, about the stubbornness of the antagonistic parties I predicted the probability of a fatal verdict.  We didn’t know any other firm capable of fabricating or compounding steroid pellets.  I could not find any knowledgeable compounding pharmacist in Augusta or in the Southeast United States.

The trade was known and had existed in the past but it was considered as useless and practically extinct. Albeit done in a small scale, drug compounding was still practiced in Europe.  The big corporations like CVS, Walgreen, Walmart or Costco did not exist.  Most of the drugstores were privately owned and were well serving their neighborhoods.  I knew several pharmacists in Augusta.  When I suggested to them that they should start compounding hormonal creams like progesterone, estradiol or testosterone they were not receptive.  In their words, “compounding is an old and lost art that is useless, obsolete and a waste of time.”   It’s interesting to see that now —30 years later— compounding pharmacists are everywhere and they are advertising for business.  Nowadays, in Augusta only, there are at least five compounding pharmacists and there are many around the country who advertise about their products and the fact they can ship it overnight.  But in 1988, since my requests remained unanswered, I had to look elsewhere and figure out another solution.

I remembered that I had a French cousin, Pierick Rousseau, who was working in the Paris headquarters of Roussel-UCLAF, one of the major European pharmaceutical companies that had manufactured steroid pellets in the distant past.  I asked Pierick to do some research and I also did my homework.  I learned how we could compress and fuse steroid crystals to fabricate pellets.  I don’t remember the cost of estradiol and testosterone powder, but I found out that it was inexpensive and easy to obtain with a medical license.  Also, Pierick told me where and how I could buy a machine to make pellets.  There was a manufacturing company internationally renowned in the industry by the name of “SVIAC Schindler” located in the Paris suburb of Vitry-Sur-Seine.  It was selling large “Frogerais compressors” that could work electrically or by hand to make pellets.  The company was advertising for its tremendous amounts of experience, having become the high standard for the tablet press industry.  I visited it with my cousin and ordered a hand compressor, a beautiful machine made of polished stainless steel with unbreakable plastic guards in line with international safety standards.

I had promised my “pellet patients” that I would do everything in my power to continue to treat them.

One of my former rugby players, Frank Wadford, was a licensed pharmacist in Georgia and South Carolina.  In my lab we had several laminar flow hoods and there was one that I could devote to the manufacture of pellets and we could sterilize the pellets using our autoclave.  The compressor was shipped from Paris and it arrived in February 1989, on time to allow a continuity of treatment.  The total cost was 42,326 French Francs, the equivalent of about $6,000.  I have kept the bill.  We made a good number of pellets that I started administering to the patients who did not have time to be deprived from their favorite drug.  The pellets were beautiful and effective.  However, a few months after we started manufacturing our own pellets, we found out through mail advertisement that several other compounding pharmacists were making pellets.  There was one in Colorado, “the College Pharmacy” and one in Chattanooga, Tennessee, “Solutions Pharmacy.”  The procedure was taking too much of our team’s time and Frank Wadford had a day job in a local drugstore.  Therefore, we decided to try the commercially available products and ended up using the Tennessee “Solutions Pharmacy” for many years to come.  The owners retired in 2010 and we are now using a firm from Atlanta “The Pavilion Compounding Pharmacy.”  The manufacture of pellets continued without any hindrance for many years, but in 2012 a scandalous event occurred in New England, provoking significant reforms with new strict rules and regulations affecting compounding pharmacies.

New FDA Compounding Regulations

Poor compounding practices can result in serious drug quality problems, such as contamination or a drug that contains too much active ingredient.  This can lead to serious patient injury and death.  In September of 2012 a deplorable event caused a drastic but needed reform in drug compounding.  An outbreak of fungal meningitis occurred among patients receiving contaminated medication for epidural or joint steroid injections that were manufactured by the New England Compounding Center (NECC), a compounding pharmacy based in Framingham, Massachusetts.  It affected nearly 800 people in 20 states.  More than 100 patients died, making it “the largest public health crisis caused by a pharmaceutical drug,” according to US Attorney Andrew Lelling.  The deaths were caused by contaminated vials of preservative-free methylprednisolone acetate, a steroid manufactured by the compounding pharmacy.

Barry Caden, the NECC’s owner and head pharmacist, was sentenced to nine years in prison in 2017 after he was convicted of 57 counts of racketeering, racketeering conspiracy, mail fraud and introduction of misbranded drugs into interstate commerce with the intent to defraud and mislead.  Glenn Chin, the former supervisory pharmacist at the NECC, was sentenced to eight years in 2018 on 77 counts, including racketeering, racketeering conspiracy, mail fraud and introduction of misbranded drugs.  It was not finished.  For the same meningitis outbreak of 2012, two of their former associate pharmacists were sentenced in May 2019.  For Gene Svirskiy, it was 30 months in prison and one year of supervised release and for Christopher Leary, two years of probation and 100 hours of community service, according to court documents.  The first eight months of Leary’s probation to be done in home confinement with electronic monitoring.

After Congress questioned the FDA about failing to prevent the outbreak, the Drug Quality and Security Act (DQSA) was passed by the Senate on November 27, 2013.  This act gave the FDA the authority to monitor the manufacturing of compounded drugs.  FDA Commissioner Scott Gottlieb stated that the agency is working toward a policy aimed at encouraging more compounding pharmacies to register under the DQSA.

Now because of this particular event, compounding pharmacies are submitted to strict federal regulations, specific state licensing and the possibility of unannounced FDA inspections.  It is specified that compounded drugs can serve an important medical need for patients, but they do not have the same safety, quality, and effectiveness assurances as approved drugs.  Under DQSA, compounded drugs do not need to be FDA-approved, but the practice is regulated by State Boards of Pharmacy.

Every licensed pharmacist is legally permitted to compound both non-sterile and sterile medications. However, not all pharmacists are adequately trained to perform these tasks.  The Pharmacy Compounding Accreditation Board (PCAB) was established in 2007. It offers the most comprehensive compliance solution in the industry, with standards based on U.S. Pharmacopeia Convention (USP) guidelines.  PCAB assesses pharmacies that compound medications whether in the retail, hospital, mail order, or closed-door setting. This includes the combining, mixing, or altering of drug ingredients to create a medication pursuant to a prescription order for an individually identified patient. PCAB Accreditation in combination with the pharmacy’s commitment to continuous compliance significantly reduces the risk associated with compounding medications and demonstrates a commitment to meeting the highest industry standards for quality and safety.  Compounding has become increasingly important because of recent manufactured drug shortages where compounding pharmacists have stepped in to fill the gap.  Medications such as antibiotics, chemotherapy, and parenteral nutrition are routinely compounded.

 

For decades we and all physicians have been able to buy pellets in bulk from compounding pharmacies.  We were storing them properly and dispensing them as needed.     This is not possible any more.  The drug has to be prescribed and it will be compounded following the details of the prescription.  It is subsequently packaged and numbered in such a way that we can trace its origin, shelf life of each compounded medicine and its composition with all utilized ingredients.  All pellets must follow strict guidelines related to their manufacture, weight, packaging and storing.  Since early 2014, pellets must be packaged separately by the pharmacist for each patient, as for any other medically prescribed drug.

Third Party Payer

Until 1980 we never heard any complaints from patients or insurance companies.  The drug was produced by Shering USA and FDA officially approved with a “Grandfather Clause” and insurance payment was prompt without discussion.  There was a contract between patient and insurance and we, physicians, were left out of the deal.  Neither patients nor insurance companies were complaining, so we assumed that when the patients were submitting a copy of our bills they were reimbursed without hesitation.  It took a few years for the insurance companies to catch on but when they realized in the early 1990’s that estradiol pellets were dispensed under an IND and were not FDA-approved, they refused to pay.  We pleaded the fact that the pellets, like all compounded drugs, were legally produced and dispensed, specifying that FDA-licensing was not needed; the compounding pharmacies being only subject to “state licensing under strict FDA regulations.”  It didn’t help.  The private insurances kept their position.

We estimate that it was in the early 1990’s that the “golden age” ended for the private practice of medicine in the USA.  There were computers installed in every office and units of the hospitals.  Stickers were used for any items and the costs were steadily added to the patients’ bills by the unit clerk.  For example, items like cotton, gauze or antiseptics that were used by nurses and physicians daily and free of charge became suddenly packaged, labelled and billed at a cost three to four times higher than in a regular pharmacy.  Price gouging was imposed, apparently justified and tolerated.  The nurses who used to spend most of their daily activity in direct patient care were forced to change their habits.  Their function had to be documented and as a result they started spending, as they do now, 80% of their precious time entering data in the hospital’s computers.  Malpractice suits, legitimate or frivolous, became common place.  Lawyers began to advertise and were soliciting work, encouraging complaints and promising easy rewards.  In the meantime, the cost of malpractice protection went sky high, from a few thousand dollars a year to between twenty and sixty thousand, depending on the medical specialty.  Some physicians had to spend three months of their yearly earnings to be legally protected.  For the malpractice victims and lawyers, it was a win-win situation since the physicians did all they could to stay off the newspaper’s front page and waste their time in the courthouse.  Guilty or not, they preferred to admit guilt and settle out of court.  Before the 1990’s, it was considered as unethical, or I believe illegal, for physicians to advertise; but subsequently, our colleagues were allowed to use billboards, newspapers and television to attract more patients.  Also, insurance companies learned to increase their profits by (l) raising all premiums with a tailored increase for high risk factors like smoking, obesity, diabetes…etc…(2) scrutinizing potential surgical procedures that had to be pre-certified, (3) arguing with the medical or surgical decisions, (4) limiting medical or surgical fees, (5) imposing a significant deductible, used as a surgery deterrent, (6) imposing a co-pay for the purchase of prescribed medications, (7) refusing to insure patients with preexisting conditions.

For the last 30 years the private insurances have kept on claiming that estradiol pellets are investigational drugs and are not approved by the FDA.  It’s not a problem because the patients don’t mind paying cash for the beneficial treatment.  However, about five years ago, Medicare realized it could not follow the same theory.  It decided to pay for the medical service and the procedure, but it was so poorly covered that by the time we paid for instrument sterilization and the working personnel, the physician would have to pay in order to inject pellets in a Medicare patient.  In other words, they wanted us to pay to practice medicine.  It was out of question.  So, our office decided in 2015 to refuse signing the yearly Medicare contract.  Now, we can still see our patients who are 65 or older, as long as they were our patients before they became Medicare eligible.  Actually, we have calculated that when the patients pay cash for their pellet treatment every four to six months, they pay about the same price or less than what they would pay with their co-pay for any other type of estrogen prescription (patches, oral tablets, cream or injectables) and the results are much better.

Alternative therapies

Hormone pellets are one form of hormone replacement therapy.  Hormone (estradiol, progesterone or testosterone) pellets exactly match human hormones.  Because of this, they are often described as natural or bio-identical.

  1. For women:

The most commonly used estrogens are the oral tablets.  There are two types: (l) pure estradiol (brand name: Estrace) (2) conjugated or esterified estrogens (brand names: Premarin, Estratab, Menest).  We can find generics for the pure estradiol but not for the conjugated estrogens which are derived from the urine of pregnant mares. There is no generic for Premarin, there may never be.  Although it makes more sense to take the pure estradiol –the natural or bio-identical hormone– conjugated estrogens are still the most advertised and prescribed in this country.  When traveling overseas in Europe, Asia or South America, my gynecologist colleagues like to ask me with a smirk on their face: “Are you still using mare urinary estrogens in the USA?”  I have to humbly admit that “we” do, but I quickly add that I personally don’t.  The two types of oral treatments work to some degree but the human body is better prepared to metabolize (digest) the natural estradiol.  Anyway, hormones produced by human beings are naturally secreted directly into the circulating blood, so the passage through stomach and liver is not natural.

Therefore, these two organs have to do some extra-work to filter the drug.  Consequently, the patients have to take 2 mg a day (300 mg for 5 months) of oral estradiol to obtain the same blood levels as one 50 mg pellet injection every five months.  And I’m not talking about the conjugated types (mare urine extracts) that cannot be monitored with blood tests.  Then there is Estratest, a tablet containing both conjugated estrogen and methyl-testosterone that could be useful when the association of the two hormones is indicated.  Other brands add a natural or synthetic progesterone to estrogen compounds with the goal of minimizing menstrual bleeding.

Then there are the patches that contain estradiol which will have to cross the skin barrier and go directly into the blood stream, bypassing digestion.  They need to be replaced once or twice a week.  It’s an efficient and well tolerated method that is preferred by many patients.  It’s not as convenient as the pellets but, like the pellets, it provides adequate blood levels and can also be easily monitored. Creams and ointments must be applied daily, but are also easily monitored.

As far as the injectables are concerned, it’s another story.  That’s probably the least desirable type of hormonal treatment.  (l) they are advertised as being long-acting when they actually provide a very high level of activity for the first few days, then there is a rapid decrease.  They provide an unwanted roller-coaster phenomenon. (2) Generally, the patients request their injections more and more often, causing an effect of  “tachyphylaxis” — a rapidly diminishing response to successive doses of a drug, rendering it less effective–.  (3) If long-acting testosterone is mixed with estrogen we frequently witness signs of masculinization (hairiness).  (4) I only use the injectables after surgical removal of the ovaries in order to prevent the immediate unpleasant post-operative effects like cold sweats and hot flushes.  Estradiol can also be inserted vaginally and provide some local or general effects, depending on the strength of the dose. For example, a vaginal cream can treat dryness but not have an effect on hot flashes.  The medications can be taken daily (known as continuous use) or on certain days only (cyclic).

After hysterectomy, there is no need to add progesterone to the treatment; but if the uterus is still present, it’s indispensable to prescribe progesterone in a continuous or cyclic fashion in order to prevent excessive cell buildup and eliminate the risk of uterine cancer.   Progesterone can be compounded in the form of oral tablets, suppositories, cream, pellets and injectable oily solutions.  The most commonly used progesterone are oral capsules or tablets.  There are three types available on the market: (l) Pure progesterone (brand name: Prometrium), (2) synthetic Medroxy-progesterone (Provera) and (3) synthetic Norethindrone Acetate (Norlutate or Aygestin). (4) Progesterone pellets can also be manufactured, but we rarely use them in our practice.

The cost can be a determining factor in the long-term treatment decision.  The average retail monthly prices are: oral estradiol ($ 120), Premarin ($ 200), Estratest ($ 280), patches ($ 120), injectable ($ 140), pellets ($ 230 for a period of 4 to 5 month, meaning $ 48 to $58 per month).  The prices may vary depending on insurance, promotions, coupons or co-pay.  It’s interesting to see that although the pellets injection is never reimbursed by third party payers, we generally find that the pellet patient’s final expense is usually lower than the cost of other treatments, even for those covered by insurance.

  1. For men:

Oral treatments of methyl-testosterone can only be taken for a short period of time because of the potential liver toxicity.  Intra-muscular testosterone injections are not advised for the same reason as the estrogen injections; a roller-coaster effect, tachyphylaxis and the inconvenience of monthly costly visits to the physician’s office.  A treatment with patches or creams makes more sense but they must be applied daily or weekly.  The blood stream is directly reached after crossing the skin barrier.  Patches are better tolerated since the digestive enzymes are by-passed.  Testosterone pellets are definitely the best option for the long-term replacement, if such a treatment is recommended.  They are well tolerated, less expensive and only need to be given every five to six months.  In addition, unlike the estradiol pellets previously mentioned, they are often covered by insurance. Once again, we don’t know why. There is definitely a gender bias decision from the insurance companies that is hard to explain.

Generic Drugs

A generic drug is a medication created to be the same as an existing approved brand-name drug in dosage form, safety, strength, route of administration, quality, and performance characteristics.  Generic medicines are supposed to work the same as brand-name medicines.  A major reform in the drug market

was voted in 1984.   The Drug Price Competition and Patent Term Restoration Act is commonly referred to as the Waxman-Hatch Act, after the law’s primary authors, Rep. Henry Waxman (D, Calif) and Sen. Orrin Hatch (R, Utah).  The Waxman-Hatch law is said to have given birth to the modern generic drug industry

in the United States.  Since the law was enacted over 23 years ago, the number of generic manufacturers and number of generic drug products on the market have expanded exponentially.

The new law made major changes to the Federal Food, Drug, and Cosmetic Act (FFDCA) by dramatically changing generic drug approval laws.  The Waxman-Hatch Act allows for approval of a generic copy of a previously approved “pioneer” drug product without the submission of a full New Drug Application (NDA).  As we saw earlier in our dealings with the FDA regarding the hormone pellets, an NDA traditionally requires a manufacturer to submit data on the safety and efficacy of a drug by conducting expensive and time-consuming clinical trials. However, the current generic approval process involves submission of only an Abbreviated New Drug Application (ANDA) that relies on FDA approval of the pioneer drug (or patented brand name drug) to demonstrate safety and effectiveness.  The generic drug does not require proof that it is safe and effective.  A proof that has already been given by the brand name drug manufacturer and through many years of clinical use in the general population.  We could argue that since the estradiol pellet is a generic compound of the old FDA approved “Shering USA product,” it falls also into this category and its legitimacy cannot be denied.

Generic drug versions may be introduced once the patent for the brand-name drug expires.  The patent protection for a brand-name drug is usually 20 years from the date of submission of the patent.  However, it can take several years of development and testing before a drug reaches the market.  This explains why the new brand-name drugs are so expensive and so intensely advertised in order for the pharmaceutical company to make fast and significant profits.  There is another major concern: the new generic manufacturers have been allowed to outsource to other countries, some located in the Far-East where it is difficult to guarantee proper supervision and submit to thorough FDA or USDA inspections.  It’s not uncommon for us to receive complaints from patients who claim that new “cheaper” generic drugs -imposed by their insurance or advocated by the pharmacists— fail to provide the expected effect.

Hormones and cancer

Estrogens have been accused of causing uterine and breast cancer.  Testosterone has also been accused of causing prostate cancer in men.  The information has come out in some medical publications, relayed and magnified by the press.  Unfortunately, journalists or TV announcers like the expression “breaking news” and they have a tendency to amplify the effects of the bad news.  They also minimize or often fail to announce the good news.  They want to sell their papers or attract more audiences.  Therefore, they don’t want to be boring and good news can be dull and monotonous.  Many studies claim hormonal advantages and safety but they don’t attract the alarmist media or a generally thrill seeking public.  It’s important to evaluate the situation with a reasonable mind, common sense and an objective look at all the scientific publications.  Traditional teaching and personal experience are important factors that need to enter into the equation.  Actually, the topic has become redundant and it’s very unusual to discover any new or original ideas in the modem literature.

Many facts are indisputable.  The cellular activity of sexual female tissue and organs like vagina, uterus and breast is stimulated by estrogens.  The lining of the uterine cavity, called endometrium, depends for its growth exclusively from estrogen and progesterone.  If a woman, for one reason or another, does not produce any progesterone, her endometrium will develop excessively, bleed in an erratic fashion, become pre-cancerous and cancerous if not treated.  The transformation can be prevented if the patient is treated with progesterone.  If early cancerous lesions are detected, the disease can be treated easily and efficiently with a hysterectomy.  It’s one of the easiest cancers to treat.  That should be the only reason why estrogens deserve to be qualified as carcinogenic.

As far as the breast is concerned, we have heard, time after time, from journalists, TV anchors, some surgeons and primary care physicians that “estrogens cause breast cancer.”  After many years of personal experience and evaluation of the medical world literature I can emphatically and without hesitation claim that this is a “fake news.”  Yes, estrogens stimulate cellular growth in the breast like in all female sexual organs but it does not cause or create breast cancer.  If we discover an early cancer, we avoid or discontinue estrogens.  When counselling my patients, I always compare the situation with what happens in a fireplace.  If there is no fire (cancer), the breast representing the logs in a cold fireplace and estrogens being an oily combustible, we cannot accuse the oil of causing the fire but once there is fire, we will refrain from throwing oil on the smoldering logs in order to prevent any flare up.  All our patients are asked to have a yearly mammography and we have found over the years that whether menopausal women take estrogens or not the cancer rate is the same (11.5 %) as in the rest of the western world population.   It means that one in eight or nine American women will develop breast cancer in their lifetime and it will happen more likely later in life.  This is the most common cancer in women and it represents 15.2 % of all cancers in the USA.  There are 3.5 million breast cancer survivors in the country.  Breast cancer ratios are not always the same for different populations.  For example, in Asia, the rate is much lower, one out of 16 in China and one out of 38 in Japan.  We have not been able to explain why such a large discrepancy exist, but we know that Japanese women living in the USA have the same ratio as other women living here.  So, we suspect a significant influence of the diet and the environment.

We cannot accuse estrogens of causing breast cancer and we cannot either claim that it’s preventing it. Now, we also know that the earlier cancer is detected, the better the prognosis of cure.  This is why it’s important to have a yearly mammography after age 40.  There are also some studies showing that women who have been on hormonal treatment before breast cancer detection, tolerate better the treatment and have a better prognosis and quality of life.  Now, I will quote two professors who have each one more than 50 years of experience in women ‘s care.  I met them both on two separate occasions when they visited Augusta.

The first one, Dr. Studd, was an English guest lecturer at one of the Medical College of Georgia (MCG) Grand Rounds in the late 1970’s.  He criticizes the well-publicized American Women ‘s Health Initiative (WHI) study that caused a general unfounded cancerphobia related to hormone treatment of menopausal women.  When I was Chief in the Department of Obstetrics & Gynecology at University Hospital in the mid-1980’s, I interviewed the second one, Dr. Creasman, while he was applying for the chairmanship of the Department of Obstetrics & Gynecology at MCG.   I thought he was an excellent candidate and voted for him.  Unfortunately, the job was given to a less deserving candidate pushed by an ill-advised lobby.  Dr. Creasman was instead hired by the Medical University of South Carolina (MUSC) in Charleston SC.  He has for many years promoted the pursuit of hormone replacement in breast cancer survivors.

(l) Dr. John Winston Studd is a British gynecologist and an academic and medical historian.  In 1969 he started the first menopause clinic in Europe. He is past President of the Section of Obstetrics and Gynecology at the Royal Society of Medicine.  He said: “In spite of all the occasional bad news you get about cancer of the breast or strokes or whatever, it really isn’t true and there was this very expensive 2002 study of oral estrogens in America where they chose the wrong drug, the wrong route, the wrong patients, the wrong age, and came to the wrong conclusions and this is a study that cost more than one billion dollars…and the investigators are now going around the world lecturing and apologizing for the mistakes they’ve made and for this big baby-boomer generation in America who have been denied for about ten, twenty years hormone therapy for their symptoms and their long-term health based upon bad data.  So, all the evidence now is that there are not more heart attacks but fewer heart attacks, there are not more strokes but fewer strokes, and the breast cancer story that keeps popping up is not related to estrogens because every study that looked at estrogens alone showed no change or a decrease in breast cancer.”

(2) Dr. William T. Creasman is professor of gynecologic oncology at MUSC in Charleston SC.  Ever since he suggested the use of hormone replacement therapy (HRT) in breast cancer survivors in the early 1980’s, interest in this field has been guarded but present.  Prescribing HRT to breast cancer survivors was initially thought of being outrageous.   Yet even then with experience in HRT spanning a good three decades, doctors in the field had started to question conventional wisdom.  The debate on whether to treat breast cancer survivors with HRT has been revisited from time to time as there has been a powerful demand for a solution for such symptomatic women.

Current guidelines typically consider HRT contraindicated in breast cancer survivors, but findings suggest that in some women symptom relief may outweigh the potential risks of HRT.  Dr. Creasman said in a recent 2019 interview about weighing HRT use after breast cancer: “I think by and large the gynecologic oncologists feel that it could be safely given in women who have had breast cancer.  Now the medical oncologists will disagree with that. However, I think the data would tend to suggest that replacement therapy can be used in these Individuals.”

As far as men are concerned, many studies have shown that there is no relationship between a man’s testosterone level and his risk of developing prostate cancer.  We can also say that testosterone does not cause prostate cancer but can stimulate the growth of an existing prostate cancer.  This is why it’s indispensable to monitor the prostate specific antigen (PSA) —a strong marker of prostate cancer– and make sure that it remains in the normal range when men are treated with testosterone replacement.  Also, there is no increase in recurrence risk following radical prostatectomy or radiation therapy associated with testosterone replacement therapy.  Finally, the ratio of prostate cancer in men is very comparable with breast cancer in women.  One out of eleven men will develop prostate cancer in their lifetime and it’s more likely to happen at an older age.  The official ratio in Asia is much lower than in the USA, as for breast cancer.  Here again we find a lot of similarity —in epidemiology, pathology and treatment– when comparing the effects of estrogens on the breast and the effects of testosterone on the prostate.

Present Status of Hormone Pellet Treatment

We see every year a new hormonal product being launched on the market and the manufacturing drug company never misses sending their sales representatives to our clinic. All drug sales and prescribers are officially registered in the internet pharmaceutical records.  I assume that all pharmaceutical companies have free access to the records because their “sales rep” generally know what we prescribe and how much.  Therefore, it is well known that our clinic is heavily prescribing hormonal medications.   The new products may be tablets, patches, gels or vaginal rings with new packaging, new pricing or new ingredients claiming that the product will be more efficient and easier to absorb or digest.  Interestingly, nothing can improve what has been available to us for the last 30 years. We still have the same options of marketed generic tablets or patches and compounded creams or suppositories.  Above all, there is presently nothing that can surpass the pellets in efficiency, compliance and successful results.

The pellets are still prepared the same exact way they were manufactured 80 years ago: using the same type of mechanical device to compress steroid crystals into the shape of small cylindrical pellets.  A specially built stainless-steel (3.5 or 5 mm) trocar ensures an ideal two-inches (5 cm) deep placement in the adipose tissue.  The diameter varies between 3.5 mm for pellets under 100 mg to 5 mm for pellets over 100 mg.  Depending on the type of treatment, the physician can order pellets weighing 25, 50, 75, 100 or 200 mg.  The trocars are regularly inspected and sterilized using an autoclave.  Disposable plastic trocars are also available but we don’t use them in our clinic in order to lower the cost of the procedure and avoid excessive and unnecessary waste.  Being flexible, the plastic trocars cannot be directly inserted and require an unnecessary scalpel incision and a stitch.  Many physicians prefer avoiding the use of trocars by making an incision and sliding the pellets under the skin using small forceps.  We do not recommend this technique because the placement is so shallow that the pellets are not well absorbed and are often rejected when located too close to the skin.  The use of trocar guarantees a two-inch (5 cm) depth in the adipose tissue.  This is necessary for a proper slow and steady hormone release providing a predictable absorption with a long-acting effect.  A liquid antiseptic: such as alcohol or iodine, is applied to prepare the skin followed by a minimal local anesthesia using ethyl chloride spray and/or a small injection of Lidocaine.

For women: The usual treatment consists of a dose of 50 mg of estradiol for a woman of average stature, but the dosage can vary depending on the need, weight and metabolism. We often add from 25, 50 or 75 mg of testosterone.   It sounds like a lot but it’s actually a very small dose when compared with the amount —about one tenth– of estradiol received.   We can easily monitor the absorption and the release of hormone by measuring it directly in the blood; this is another advantage of using natural hormones. Testosterone is measured in serum in nanograms per ml (ng/ml) and estradiol in picograms per ml (pg/ml).

A question often asked: “Is it useful to take testosterone with estrogens?”  Yes!  It’s useful but not mandatory.  There are three types of androgens or “male hormones”: testosterone, androstenedione and dehydroepiandrosterone (DHEA).   DHEA is produced by the male and female adrenal glands and it is sold over the counter as an anti-aging supplement.  Testosterone is the main male hormone produced by the testicles, but it is also produced, in a much lower quantity, by the ovaries.  The ovaries also produce two androgens testosterone and androstenedione.  Testosterone is the most efficient and useful of the two androgens, so it makes sense to add some testosterone to estrogen in a program of hormone replacement.  Testosterone is useful for energy and sex drive (libido), but more importantly, it completes the beneficial effects of estrogen for prevention of bone loss.

“How long a woman may use hormone replacement therapy for menopause?” It depends on several factors that she and her physician will discuss in depth.  Some may choose a short course of hormone therapy; other women may continue the therapy for a longer course.  We recommend the use of hormone pellets for women who have not experienced relief from menopause symptoms with other forms of hormone replacement therapy.  As long as ongoing monitoring of the woman’s health occurs, hormone replacement therapy can be continued indefinitely.  Over the years, I have been asked many times by my patients: “When should I stop my hormone treatment?”   I learned to answer with another question: “When do you want to start not feeling your best?”  Then I offer them to switch to another similar medication.  Usually, after trying another type of hormonal treatment —pills, creams or patches– for six months to one year, the patients return requesting to resume pellet injections.  They state that not only the pellets alleviate better their menopausal symptoms but they provide a better quality of life.

Hormone pellets are a time-release form of therapy, which means they continuously deliver hormones over the course of several months.  This allows for a more consistent and gradual release of hormones when compared with other hormone replacement therapies.  There is no age limit to those who can use hormone pellets and no identified negative effects for using pellets continuously.  While many Wellness Centers offer hormone pellets, not all are properly medically supervised.  This means they advertise and make claims about the benefits such as “rejuvenation” that are not accurate.  In this type of environment, creation and use of hormone pellets are not always well regulated, so it’s essential to undergo this form of hormone therapy at a medical practice or institution.  The physicians evaluate all patients before placing hormone pellets and recommend routine check-ups to monitor their effects.  Additionally, a number of educational resources are provided to patients interested in this service.

For men: The usual treatment varies between 400 and 800 mg, depending on body size, age, need and metabolism.  It’s given in the same fashion, but using larger 5 mm diameter trocars that allow us to insert 200 mg pellets.  The effects are also directly monitored in the blood allowing us, if necessary, to adjust the dosage.  Also, we check the PSA (Prostate Specific Antigen) to be sure that we are not dealing with an early prostate cancer.

Side Effects

There are very few side-effects or complications.  The pellets can be rejected but it occurs in less than one percent of cases with the proper use of a trocar.  From time to time the site of injection will bleed lightly.  A constant pressure for three minutes will suffice to control the bleeding.  It’s important to know that once the pellets are injected, they cannot be removed.  We have to warn our colleagues who by ignorance –or laziness– try to blame all illnesses or undesirable symptoms on hormones. In my fifty-year experience –using pellets for hormonal treatments–, I’ve had to deal with very few events like when a physician wanted to have the pellets surgically removed.  I will tell two remarkable stories, among many, to prove my point.

Once, a general surgeon called me from an operating room in Charlotte, North Carolina.  He had made, under anesthesia, a two-inches incision in the right buttock of one of my patients and had tried for one hour unsuccessfully to find and retrieve the pellets that I had injected two weeks before.  The patient had consulted a neurologist two days before complaining of a severe migraine headache.  The neurologist, without looking any further, blamed the hormonal treatment and asked the surgeon to remove the pellets.  I told the surgeon that he —or the neurologist or the patient– should have called me before deciding to operate.  I had to explain to him that he undertook an impossible task.  The next day, I called my patient inquiring about her headache.  Amazingly, the pellets were still in her buttocks and the headaches were gone.  I have followed her and kept on treating her with the same hormones for many years evoking often, with humor, that unpleasant event that had left an indelible scar on her right buttock.

One of my former employees who is a friend and a menopausal patient has been treated with pellets for several years.  She had a car accident and suffered legs, pelvis and rib cage trauma with significant bruising.  She was treated at the Augusta University (MCG) Trauma Unit.  After a short hospitalization, she was released and went home.  The next day she received a phone call from the hospital asking her to return urgently to the Emergency Room.  They had to apologize because they had overlooked the results of a CT scan showing small clots in her lungs (pulmonary embolism or PE).  The young physician in charge prescribed wisely blood thinners (anticoagulants), but despite the history of a recent serious trauma — which was sufficient to cause the problem– he had to blame the fact that the patient was taking hormones suggesting to have the pellets surgically removed. This time, I did not have to intervene.   Our friend told the young doctor that his suggestion was ridiculous.  She had enough knowledge and experience to realize that the trauma was the primary reason for the formation of clots.

Hormones, estrogens in particular, have been officially blamed for an increase in coagulability and clotting. Here, I must say that despite the fact that we provide hormonal replacement to many, many patients we don ‘t see in our practice cases of deep vein thrombosis (DVT) where the hormone treatment could be blamed.   Perhaps it’s because we only use natural —or bio-identical—hormones.   The few cases of DVT and/or pulmonary embolism (PE) that I’ve encountered in my long career were either following a trauma or a surgical intervention in the pelvis. It is possible that some synthetic hormones such as the birth control pills or the derivatives of mare urine increase blood coagulability, but I personally doubt that natural hormones have such a detrimental effect.

As far as men are concerned, the hormone treatment must be carefully monitored because too much testosterone can cause undesirable side effects.   The most common one is ‘hemoconcentration” —an excess of red blood cells—that is measured by checking the serum hemoglobin.  Excess testosterone symptoms can include acne or oily skin, prostate swelling, breast enlargement, worsening of sleep-apnea or trouble breathing while sleeping, edema or fluid retention.

Also, we must warn the patients that are treated with any type of testosterone therapy —pellets included—that they will notice a decrease in testicle size and there will be an inevitable drastic decrease in sperm count, something that all males who wish to procreate —in the near or far future — need to know.   Finally, excess use of testosterone or anabolic steroids can cause “roid rage.”  It’s an aggressive behavior with a form of loss of impulse control with anger and overreactions to simple life events.

Conclusion

Margaret Thatcher (1925-2013) said: “Disciplining yourself to do what you know is right and important, although difficult, is the high road to pride, self-esteem, and personal satisfaction.”  Hormone replacement therapy by hormone pellet implantation has been used with great success in the U.S., Europe and Australia for more than half-a-century and found to be superior to other methods of hormone delivery.  It is not experimental.  The hormone pellets are compounded and packaged by specialized pharmacists under sterile conditions.   The manufacturers follow strict U.S. Pharmacopeia and Food and Drug Administration regulations.

Natural or bioidentical hormone pellets mirror the hormones produced by the body.  Hormone pellet implants are compacted crystals of pure hormonal steroid injected deep in the adipose tissue of the buttocks or the abdomen.  They provide consistent physiologic levels with minimal fluctuations.  Their use bypasses the liver metabolism and does not increase the risk of blood clots.  They are safe, efficient, convenient and well tolerated. The complex preparation and organization for hormone pellet implantation have made most physicians reluctant to use this method of treatment.  Another deterrent factor is the unsubstantiated bad press given to the female hormonal therapy that makes gynecologists reluctant to implement efficient and long-term hormonal treatments.

All women will eventually be deprived of sex hormones at the end of their reproductive life.  In our practice, after discussing pros and cons, we almost always start hormonal therapy using the more conventional gels, patches or oral methods.  We offer pellets if the patients are not satisfied or have not experienced relief from their miseries with other forms of treatment.  About 60 percent of patients who embark on long-term hormonal therapy end up requesting hormone pellets after comparing results and benefits.  Studies have found them to be a superior option regarding protection of bone density and cardiovascular health.  The addition of a small dose of testosterone will help to better mimic the lost ovarian function and complete the beneficial effects.  The majority of our patients undergoing long-term hormone therapy find pellets more appealing.

For men, generally speaking, there is not as much dispute or controversy.  There is a normal slow and progressive decrease in testosterone production in aging men, —after the age of sixty– but no complete cessation of function.  However, it’s estimated that about one out of twenty younger men —past the age of forty– may experience hypogonadism or “Low T,” also called andropause.  Testosterone replacement will eventually be required.  Unfortunately, intra-muscular injections are presently the most popular and commonly prescribed type of treatment by primary care physicians despite the roller-coaster effect and the difficulty of dosage control and monitoring.  We definitely prefer gel and/or patches to injectables, but here again, testosterone pellets offer the most convenient, efficient and natural option.

In summary, there is a maxim stating that “the difference between effectiveness and efficiency can be summed up shortly, sweetly and succinctly. Being effective is about doing the right things, while being efficient is about doing things right.”   Hormone pellets are an effective and efficient method of hormone treatment.