Dr. Crisler operates the website, allthingsmale.com, and offers in-clinic and online consultations. The frontpage of his site argues strongly that he is in the business of anti-aging therapies as shown lecturing to the American Academy of Anti-Aging Medicine and offering subscriptions to Life Extension Magazine. Further exploration of his website reveals that he specializes further in assessment of low testosterone levels, or hypogonadism.
Testosterone cypionate, hGH, hCG, Arimidex (anastrozole) and finasteride (sold previously as Propecia or Proscar, but now available generically). OK, that’s starting to make sense. Testosterone and human growth hormone (hGH) are anabolic agents. That is, they enhance the development of lean, skeletal muscle mass. But you might have some questions at first glance.
(For pharmacology students and professors, dissecting the endocrine pharmacology of this combination would make a great comprehensive qualifying examination question for graduate candidacy.)
Arimidex/anastrozole? Isn’t that used to treat estrogen-dependent breast cancer?
Finasteride? Isn’t that used to treat prostate cancer?
Let’s take a closer look at some of these drugs.
Testosterone cypionate is known as a “depot” form of testosterone that has a half-life of 5-8 days, sold as DEPO®-Testosterone in the US. Testosterone, the steroid hormone primarily responsible for secondary sex characteristics in men, is not active when taken orally because it is rapidly metabolized by the liver. Therefore, if one wishes to boost testosterone, it is commonly formulated into a gel or patch that slowly releases the hormone across the skin. But it is more effectively delivered by injection, usually into muscle. When combined with a fat-soluble compound like cypionic acid, the testosterone is slowly released from the injection site. According to a PowerPoint presentation available at Dr. Crisler’s website (here, 4.5MB), his regimen employs weekly injections of 100 mg testosterone cypionate, about double the manufacturer’s recommendation for treating clinical hypogonadism.
When I was interviewed by Dan Harris for ABC World News Sunday last weekend, we discussed in footage that did not appear whether testosterone qualified as an “anabolic steroid.” The public normally thinks of ultrapotent, clandestine compounds as being the anabolic steroids used by athletes. But in purely pharmacological terms, testosterone is a steroid based on its chemical structure and it has anabolic, or tissue-building, activity. However, testosterone is an anabolic steroid that we make naturally, men and women.
Hence, testosterone is an endogenous anabolic steroid. When injected as testosterone cypionate, this would be called the exogenous supplementation of an endogenous steroid. But true bodybuilders wouldn’t bother with something like testosterone when more potent and effective synthetic anabolic steroids are available on the clandestine market.
Arimidex (anastrozole) is classified as an “aromatase inhibitor.” You may not know that testosterone is the starting material for estradiol, the steroid hormone primarily responsible for secondary sex characteristics in women. Testosterone, which we all make from cholesterol as the starting material, is converted to estrogen by aromatase or CYP19, an enzyme that is highly abundant in the ovaries. When a woman is diagnosed with a form of breast cancer that required estrogen to grow, aromatase inhibitors are given to prevent the ovaries from making more estrogen from testosterone (Older drugs such as tamoxifen can also be given as they directly block the effects of estrogen on breast cancer cells themselves.)
We do not know if Mr. Ray was among the approximately 1% of breast cancers that occur in men. Former drummer of the rock band KISS, Peter Criss, is the most recently public of male breast cancer patients in the US.
However, it does not appear that Dr. Crisler is a board-certified oncologist, so there must be some other reason that he prescribed Arimidex to Mr. Ray. Men have some testosterone that gets converted to estrogen but usually it’s not enough to cause estrogenic side effects such as gynecomastia and testicular shrinkage. But when taking supplemental, supraphysiological doses of testosterone, the small amount of aromatase that men have will convert enough of it to estradiol such that they may experience some feminizing effects.
Interestingly, Dr. Crisler notes on slide #66 of his aforementioned PowerPoint presentation that anastrozole’s #1 use worldwide is in testosterone replacement therapy regimens. Unfortunately, a citation is not available to support that statement.
Finasteride prevents conversion by 5-alpha-reductase of testosterone to dihydrotestosterone or DHT, a form of the hormone that can cause benign prostatic hypertrophy, can promote prostate cancer, and is also partly responsible for hair loss. Hence, finasteride combats several side effects of testosterone supplementation. So, these testosterone injections can be combined with anastrozole and finasteride to maximize testosterone’s anabolic effect while minimizing “unsightly” side effects.
Human growth hormone (hGH) is a peptide normally produced in the pituitary gland that is also anabolic on its own and augments the muscle-building effects of testosterone. [Tom Perls: If there is augmentation, it is not significant according to studies cited elsewhere on hghwatch.com]
Human chorionic gonadotropin or hCG is normally the hormone produced by the placenta during pregnancy and is the hormone detected in the urine by home and clinical pregnancy tests. Yes, men taking this hormone would give a positive pregnancy test.
Understanding why hCG might be given in this cocktail requires that we revisit the hypothalamic-pituitary-gonadal axis (HPGA). Gonadotropin-releasing hormone, or GnRH, is produced in the hypothalamus of the brain and signals that pituitary gland to synthesize and release several peptide hormones that each share a common subunit: LH, FSH, TSH, and hCG. LH, or luteinizing hormone, when released from the pituitary gland and causes the testes to create mature spermatozoa and release testosterone. However, when too much testosterone is produced, or too much is available from external injection, a negative feedback loop suppresses LH secretion. Suppression of LH over time will cause testicular atrophy. It is thought that providing hCG will provide more of the subunit shared with LH, restoring LH levels. I am not convinced that this actually occurs. Restoring LH also is purported to increase the conversion of cholesterol to pregnenolone, a precursor or building block of testosterone. Believe it or not, this is an oversimplification of the pathway but I hope that gives you an idea of the rationale behind hCG use.
There were also some other drugs found in Ray’s room at the lodge prescribed by other physicians that included Diovan (valsartan), an antihypertensive of that competitively binds receptors for an endogenous vasocontrictor, angiotensin II, and an injectable relative of vitamin B12 called methylcobalamin. Although we don’t know for certain if Ray was taking the drugs prescribed by Dr. Crisler, investigators did at least find anastrozole and Genotropin brand of hGH, Propecia brand of finasteride, together with pregnenolone, the testosterone precursor. Also found were bags, suitcases, and pill boxes of energy supplements and amino acids. The complete litany of objects confiscated from his possession are detailed at the Prescott News website.
As mentioned at the outset, one of the biggest reasons investigators were interested in any drugs that might have been in Ray’s possession was that there may have been psychoactive substances that could have impaired his judgment or that of followers/clients in the sweat lodge at the retreat. Ray was reported by several eyewitnesses as being aggressive and aloof, and even unhelpful when medics arrived at the sweat lodge. Dan Harris at ABC News asked me if I thought that Ray’s pharmacopeia might have contributed to his state of mind.
This is very difficult to do for a plethora of reasons, not the least of which because I am not a physician nor am I privy to what drugs he was actually taking or his basal personality characteristics. However, I am a pharmacologist and did train in endocrinology during my postdoctoral fellowship and can make some general comments.
A person taking an anabolic steroid regimen (recall that testosterone is a natural anabolic steroid) is prone to mood swings, anxiety, and aggressive behavior. In “TRT: A Recipe For Success,” a Word document available at All Things Male, Dr. Crisler apparently makes note that the intent is not to create an anabolic steroid cycle but rather testosterone replacement therapy, where testosterone levels are targeted to the upper-level of a normal range. Unfortunately, we cannot be sure if Mr. Ray was taking the drugs as directed or at doses greater than those recommended.
A physician colleague also reminded me that some of the drugs on the search warrant could alone cause electrolyte disturbances that could be exacerbated by being in an enclosed area with hot stones where other people were vomiting and begging to get out after fasting for 36 hours. Specifically, testosterone can cause sodium retention and Diovan/valsartan can cause potassium retention. These ionic imbalances can certainly influence one’s state of mind and one can speculate that these imbalances would be made worse by fasting and dehydration.
Off-label drug prescribing
This case also raises some questions as to how these drugs were prescribed in the first place. Sources close to Ray told ABC News that the “practical mystic” was being treated for a hormonal imbalance.
It is peculiar why a man of Ray’s means living in Carlsbad, CA, would be prescribed drugs by a physician in Michigan rather than seeing a board-certified endocrinologist or urologist at one of the outstanding medical centers in southern California.
Nevertheless, there are no laws that would have prevented Dr. Crisler from prescribing this regimen to Mr. Ray. To the contrary, physicians in the United States, whether they are MDs or DOs, are granted the latitude to prescribe any FDA-approved medicine for any indication they see fit. While it is illegal for drug companies themselves to promote “off-label” uses of drugs (i.e., indications for which the company has not received explicit FDA approval), a physician can legally prescribe a breast cancer drug to a man wishing to build lean muscle mass. I will leave it to my physician colleagues to comment on whether this falls under the standards of medical practice. In fact, the ethics of off-label prescribing would be an excellent separate issue to discuss in another post. [Tom Perls: Actually I disagree here. Most states do not allow the prescribing of anabolic steroids for muscle building and federal law cleaerly allows discribution of HGH only for uses allowed by the Secretary of HHS (FDA).]
But let us not forget that this is a very sad case where three people lost their lives and nearly two dozen people were hospitalized. Press accounts of the sweat lodge incident and subsequent investigation suggest that blame and potential criminal penalties will fall where they may. The Camp Verde Journal noted in its 2009 roundup that:
Lawsuits have been filed by survivors, victims’ families and the Black Hills Sioux Nation, alleging Ray “committed fraud by impersonating an Indian,” thus violating the 1868 Treaty of Fort Laramie.
What we have offered here is a perspective on the pharmacology and toxicology of prescription hormone products and considerations of issues raised in publicly available documents and questions posed of us by the press. It is likely that several factors conspired to end up with this loss of life. As always, tragic events are what drive changes in laws and regulations.