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By David M. Odom, MD

Testosterone for Men

We know that a woman faces menopause as her ovaries quit producing eggs at about age 51. Her ovarian hormones decline as typically do adrenal and thyroid function. Women are acutely aware of these changes due to the monthly fluctuations of hormones that have accompanied them for about 4 decades of life.
But, how about men? Men don’t have monthly fluctuations of hormones and so are generally not aware of slow changes caused by an age-related reduction of hormones. But finally, usually at about the same age as the woman, he or his spouse begins to note “diminished libido and sense of vitality, erectile dysfunction, reduced muscle mass and bone density, depression, and anemia.” [1] This complex of signs and symptoms is reflected in a reduction of blood levels of Testosterone.

Testosterone Provides Health Benefit

But, there are other very important reasons to reverse age-related Testosterone decline. At ENDO 2008: the Endocrine Society’s 90th Annual Meeting, June 2008 it was announced that, “low levels of testosterone were found to promote the development of diabetes, “Metabolic Syndrome”, and heart disease in middle-aged & older males. A link has been demonstrated between low levels of testosterone and increased risk for mortality from all causes in adult men of all ages. Middle-aged males with low levels of Testosterone have double the rate of mortality from all causes [20].

Testosterone supplementation reverses these problems, and has thus become very popular over the last 20 years.

How do we diagnose and document low Testosterone? By measuring blood levels. Such measurements are corroborated with analysis of a detailed report of signs and symptoms from the patient.

“Although no consensus exists for defining low hormone levels in aging men, a substantial number of US men may have low sex steroid hormone levels, possibly putting them at risk for adverse health consequences and pre-mature death.” [38]

So, even if a patient’s hormone levels are within the “reference range” of the laboratory, he may still suffer from deficiency symptoms. Importantly, such deficiency symptoms can only be corrected by Testosterone replacement [28]. Raising hormone levels to optimal, youthful levels allows patients to once again feel normal [28].

Natural Testosterone Products

Products used include injectable Testosterone Cypionate, Testosterone Creams or Gels, and subcutaneous Testosterone pellets.

Although dosing schedules vary, injecting a 0.1 ml of Testosterone Cypionate once daily into subcutaneous tissues at the anterior thigh via an insulin syringe using a tiny 31 gauge needle results in very stable blood levels, like a table top, after about 4 days. The art of extracting the oily solution into an insulin syringe through the tiniest needle is rapidly learned. Why oily? No one has successfully produced a stable aqueous solution of Testosterone.

Don’t believe the idea that the oily product results in steady blood levels if injected a week or two apart. The plasma half-life is 8 days [5]. (The "plasma half-life" is the amount of time required for the concentration in blood plasma of a drug to fall to half its maximal value [6].) Variable blood levels provide variable benefit.

“The physician must document and assure adequate blood levels, otherwise hormone replacement is worthless.” [28] All of the health benefits of Testosterone replacement described in the second paragraph, and elsewhere in this article, are achieved via consistent supplementation over time.

Testosterone creams and gels are very convenient. They are best applied twice daily to provide stable blood levels. They are typically widely applied to inner thighs.

The downside to dosing Testosterone this way is that product can get onto family members. A man’s spouse can easily obtain his same blood level through skin-to-skin contact. A youthful male serum Total Testosterone level may be 1000 ng/dl, whereas a normal youthful female level is around 40 ng/dl. So, raising her level to 1000 ng/dl via skin-to-skin contact will cause “hormone imbalance” including the possibility of extreme irritability, not to mention acne. Do you want that?

Dried Testosterone product flaking from the skin may inhabit the bed sheets as an invisible powder, which may then may get onto small children who climb into bed with mommy & daddy on Sunday morning. Getting Testosterone gel onto a child may cause bizarre behavior which can ultimately result in court mandated visits from the social worker. So, the convenience of application of Testosterone creams & gels must be matched by careful cleanliness and vigilance. As to old guys living by themselves.... no problem.

Pellets are inserted subcutaneously, usually at the lateral upper thigh. Re-insertion is required every 3 to 6 months, as individually determined via blood levels [4].

Testosterone Supplementation Does NOT Cause Prostate Cancer

Controversy regarding uncertainty has been raised over this same 20 year time period over two issues: prostate cancer and cardiac risk.

First of all, it needs to be stated that there is no evidence whatsoever that TRT (Testosterone Replacement Therapy) causes prostate cancer. The following quote is from an important 2004 paper by Harvard urology professors:

“.... it is generally accepted that TRT does not induce the development of prostate cancer. Furthermore, a recent report demonstrated no increased risk of prostate cancer in men with prostatic intraepithelial neoplasia, a precursor of prostate cancer, on TRT.” [2]

The 2014 review article by Osterberg, et al re-emphasizes that point [3]. So, how did this idea come about that Testosterone supplementation is a problem regarding prostate cancer?

It has to do with treatments for far advanced metastatic prostate cancer which responded temporarily to castration [7]. That explanation comes from a paper published in 1941, and re-emphasized in a 1982 article describing worsening outcomes for patients with metastatic adenocarcinoma of the prostate given testosterone along with chemotherapy [8].

But the response of patients with far advanced prostate cancer is not the same issue as cause of prostate cancer.

Osterberg goes on to say: “Many longitudinal studies investigating the relationship of endogenous testosterone levels and subsequent risk of prostate cancer failed to find any association. As such, prostate cancer incidence in men on testosterone therapy is similar to men not on testosterone therapy. Similarly, in a 3 year prospective trial, the incidence of prostate cancer was similar among men receiving TRT and controls.” [3]

So, the bottom line is that TRT does not cause prostate cancer. Young men with naturally high Testosterone levels do not get prostate cancer. Old guys with low Testosterone levels get prostate cancer. “In fact, older men with the highest risk of prostate cancer have the lowest serum testosterone levels.” [13] At the same time, it is currently understood that TRT does not prevent prostate cancer.

There is an even more recent point of view that TRT can be done in selected patients with early prostate cancer. “Current evidence indicates that maximal androgen-stimulated prostate cancer growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with prostate cancer and symptomatic hypogonadism.” [15]

But, I’m not there yet.

If it is determined that a patient wishing to begin TRT has prostate cancer, I will not prescribe TRT. If serial PSA levels done on patients taking TRT show an untoward rise, I will send the patient to a urologist for evaluation.

If early prostate cancer is diagnosed, and such cancerous tissue is found to be entirely within the capsule of the prostate gland, I will want the patient to avail himself of high tech magnetic resonance (MRI) guided laser ablation therapy [9, 10, 11]. I want the patient to be aggressive in ridding himself of the cancer.

What is a PSA test? And what is the relationship of the PSA test to TRT? The Prostate Specific Antigen is an enzyme produced in the prostate gland naturally, but rises in the presence of inflammation, including prostate cancer. It does not directly measure prostate cancer [12]. I repeat, it is important to note that the PSA is not a specific test of prostate cancer, but of inflammation within the prostate gland. A man may have an elevated PSA due to Benign Prostatic Hypertrophy (BPH), a history of prostatitis from old infection, or chronic irritation as seen in bicyclists. Of course, men with reasons other than prostate cancer for an elevated PSA can also get prostate cancer. So, an elevated PSA needs to be evaluated to rule out prostate cancer.

Also note that untreated “hypogonadal men have depressed PSA levels compared to normal age-matched men.” [2] (Frankly, I detest that word, “hypogonadal”. I like “andropausal”.) We know that after TRT has begun in such men, PSA can rise a little, thus necessitating vigilance [2].

Urologists Gore & Rajfer state their belief that the “PSA should then be monitored semi-annually as long as the patient remains on TRT, in addition to having an annual digital rectal examination. A PSA velocity greater than 0.75 ng/mL/y, regardless of the baseline PSA, or a nodule on digital rectal examination while on TRT should prompt further investigation with a prostate biopsy.” [2]

But that was in 2004, and I don’t know of prostate biopsies being done unless suspicion is high.

Osterberg in 2014 says: “Men on TRT should have frequent PSA monitoring; any major change in PSA (>1 ng/mL) within the first 3-6 months may reflect the presence of a pre-existing cancer and warrants cessation of therapy. Current guidelines on the frequency of PSA monitoring and role of pre-treatment transrectal ultrasound guided prostate biopsy are lacking. Taken together, there has been consistent rejection that TRT causes development of prostate cancer in men, however administration of TRT for hypogonadal men previously treated for high-risk prostate cancer should be taken with caution.” [3]

There we go, caution. I like that!

Here’s the summary: Testosterone does not cause prostate cancer. Patients on TRT should have a PSA done every 6 months to rule out prostate cancer. If prostate cancer is found in its very early stage, entirely within the capsule of the prostate grand, it should be extirpated with Magnetic Resonance (MR) Guided Laser Focal Ablation. Testosterone rev’s up advanced, metastatic prostate cancer, making it worse, according to old studies. Testosterone may rev-up a beginning prostate cancer that is already within the prostate gland prior to starting TRT, but even that understanding is being criticized. Most B-HRT doctors, including me, are not willing to take the chance of worsening prostate cancer by prescribing Testosterone.

How about the Digital Rectal Exam (DRE)? How important is it for diagnosing prostate cancer? My opinion: doctors, like other professionals are good at what they do every day. Urologists do DRE’s every day. Ask your family practitioner when was the last time he (she) did a DRE. Answer: “Uhh, let’s see.... last week?” I think you get the picture. Somebody is going to stick his finger up your butt, and you won’t really get any important information out of it. This is why we have urologists.

Experts have “expertise”, right? Why is it that doctors tell patients that bio-identical hormones cause cancer, when there is no evidence that they do? Just because a doctor is an expert in one area does not mean that he is an expert in others.

How About Benign Prostatic Hypertrophy (BPH)

Let’s not forget Benign Prostatic Hypertrophy (BPH) in older men. BPH causes urinary retention, difficulty initiating a urine stream, frequency, urgency, dribbling, and nocturia (interruption of sleep to urinate).

Osterberg says: “While older men on testosterone therapy do have an increase in overall prostate size, this increase in size does not differ from the increase in prostatic hypertrophy seen in elderly men not on testosterone therapy. Taken together, TRT does not appear to grossly worsen lower urinary tract symptoms and is not contraindicated in men diagnosed with BPH.” [3] (Observational Study)

In a 2002 study by Pechersky, 207 men, aged 40-83 years, presenting with clinical features of age-related androgen deficiency were given Testosterone supplementation for 6 months. He states: “These findings suggest that exogenous testosterone in middle-aged and older men with some clinical features of age-related androgen deficiency can retard or reverse prostate growth...” [27] (Interventional Study)

Testosterone Supplementation Does NOT Cause Heart Attacks, Stroke, or Blood Clots!

So, now on to cardiac risk, the probability of heart attacks while taking Testosterone.

Many men have not availed themselves of the benefits of Testosterone supplementation due to questions raised by two poorly conceived retrospective examinations of data done at the VA hospital system, one coming to print in November of 2013 and the other in January of 2014 [16, 17].

Harvard urology professor and world-renown researcher, Abraham Morgentaler, MD stated in his January, 2015 paper that: “methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in Testosterone treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors including nearly 10% contamination of the data-set by women.” He noted other serious errors, as well [18].

Dr. Morgentaler goes on to say: “a substantial literature accumulated over several decades fails to provide any credible evidence that Testosterone therapy is associated with increased cardio-vascular mortality or major adverse cardiovascular events.” [18]

But the damage had been done due to the one-sided, wide media reporting of the two VA studies.

On August 6, 2015, a third VA study was published [19], this time looking at the results provided by 83,010 men. The subjects, all with low Testosterone, were divided into three groups: those supplementing Testosterone and achieving normal Testosterone levels; those supplementing Testosterone and not achieving normal levels; and those not supplementing Testosterone at all.

The “Conclusion: In this large observational cohort with extended follow-up, normalization of Total Testosterone levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.” [19] However, only 63% of patients in this study achieved normal testosterone levels after TRT use. (Thus indicating typical non-compliance by many patients directed to take a medicine.) And, that 63 % group was found to have had significantly fewer deaths and cardiovascular events than those whose testosterone levels were not normalized.

This was a very well done study looking at the largest cohort of patients and the longest follow-up for TRT to date, from 1999 to 2014. The data from this study was well collected and well analyzed.

Summary: Testosterone supplementation decreases mortality from all causes, including heart disease [21]. In order to obtain these benefits, the patient needs to supplement consistently, according to directions. Compliance is determined from serial blood level measurements. Patients prescribed Testosterone who do not achieve youthful blood levels are wasting their time [28].

New patients should be evaluated for advanced atherosclerotic disease prior to initiation of Testosterone therapy, so as to avoid the possibility of plaque rupture during the early part of establishing Testosterone supplementation. We all know of instances of sudden chest pain from blocked coronary arteries in men who had no idea that they had atherosclerotic disease. So, I am not telling you that Testosterone causes heart attacks in men with advanced arterial disease, just that I don’t want to see some tragic event occur during initiation of Testosterone therapy.

Association does not prove causation. But, we don’t want to have to deal with unhappy associated events, either.

Now, let’s talk about the real side effects of Testosterone supplementation.

Irritability In Some People At Higher Doses

Wives and others who have known you for years may notice some various behavior changes as you supplement Testosterone. They might find you more energetic. Perhaps, more optimistic and playful. Increased sexuality is likely.

But, a return to youthful behavior may include a rise of irritability.

Here are two ways to handle irritability that actually work (Anger management courses, not included): One, is to lower the dose. Do that in consultation with your doctor, with the goal of obtaining beneficial blood levels, without getting snippy with the missus. Remember that low blood levels mean lack of health benefit.

The second technique is to daily rub a dab of over-the-counter 1.5% Progesterone cream onto your abdomen. Unfortunately, it is illegal in California to sell OTC Progesterone cream, for whatever mysterious reason. So, your doctor will have to prescribe it to be obtained from the compounding pharmacy.

Increase of Red Blood Cells

“The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit”. [22]

In my opinion, the most problematic side effect of Testosterone supplementation that I have to deal with is the increase of red blood cells, called erythrocytosis. Sometimes, the hematocrit, or packed red blood cell volume, rises way above the normal of 45 %, to levels greater than 65%. Such levels may occur after many months of Testosterone therapy, and alarm other physicians caring for the patient. Although higher hematocrits are almost universal with Testosterone therapy, levels greater than 65% are not common [23].

The problem is not the increase of red blood cells, it’s the perception of it. Patients become concerned because other doctors are concerned. Many scientific and lay articles about Testosterone have stated that taking Testosterone causes Polycythemia Vera (PV). PV is a disease of progenitor cells in the bone marrow that produce all the cellular elements in the blood, not just the red blood cells [23]. So, there are also increases of white blood cells and platelets. PV may progress to leukemia. PV is accompanied by inflammation.

It is the rise of platelets with PV that causes blood clot formation in arteries and veins. Untreated PV causes heart attacks when the excess platelets initiate the clotting process.

Testosterone supplementation causes only a rise of red blood cells, and there is no coincident inflammation. Studies do not show an increase of thrombosis with erythrocytosis [24].

The increase of red blood cells seen after Testosterone therapy is the same response as seen in people living at high altitude. The kidneys produce more of the hormone, erythropoietin, that stimulates production of red blood cells [24].

Although heart attacks are a great risk in someone with Polycythemia [23], people living at high altitudes have very high levels of red blood cells, but no rise in the rate of myocardial infarction.

So, what is the source of doctors, including researchers, referring to “erythrocytosis” as “polycythemia”? [24] After all, words have consequences, especially in this case.

Doctors have gotten into the habit of calling ANY increase of red blood cells as “polycythemia”. This is a mistaken use of terms [24].

Many patients on Testosterone supplementation have been unnecessarily sent off to the blood bank to have a unit of blood drawn, sometimes several weeks in a row, simply to reduce the concentration of red blood cells to match a hematocrit of 45%. Some of these individuals end up with iron deficiency and fatigue after frequent phlebotomy [24].

I have heard the explanation that red blood cells are the main determinant of viscosity of blood [25], thus, increasing risk for patients with narrowed arteries from coronary arteriosclerotic disease.

I cannot deny that this is a theoretical problem with patients supplementing Testosterone. But, the current scientific medical literature does not support such a finding [24].

Here is the way that I like to handle this issue:

Prior to initiation of Testosterone therapy, screen at risk patients for arteriosclerosis with a CT of the heart (Calcium Scoring) and carotid ultrasound. Of course, determine platelet count and hematocrit prior to initiation of Testosterone. Do not use excessive doses of Testosterone. If injecting Testosterone cypionate, use small daily doses to create stable, physiologic blood levels, thus avoiding large fluctuations. Great variation of blood levels are thought to create more side effects. Determine hematocrit levels several times after initial evaluation.

If phlebotomy is considered to be beneficial, it’s better to become a regular blood donor at the local blood bank, following their guidelines for intervals between donations. Measure iron levels to avoid deficiency of iron. (In general, it’s a good idea to measure iron levels to avoid excess iron, as well.)

Health Benefit Results From Consistent Supplementation

At the same time, since we know that Testosterone benefits cardiovascular disease, don’t under treat, causing ineffective blood levels, and losing that benefit.

It is thought that many instances of under treatment are caused by lack of patient compliance with daily testosterone supplementation schedules. Lack of patient compliance is a major issue in all areas of medicine, not just natural hormone replacement therapy. Management failures with diabetes and high blood pressure are two common examples. Age management doctors offices need to provide follow-up and monitoring of patients to bolster consistency. Communication is key. All of this follow-up communication requires organization and costs money.

Another age management specialist states: “My practice is made up primarily of pro-active patients who exercise, eat well, and have very few comorbidities. In other words, I have very few patients with heart disease, and the ones who do have heart disease are quite meticulous about their diet, exercise regimen, and follow-up.” [26] All of us bio-identical HRT doctors would LOVE to have this kind of patient population! However, I deal with the real world.

Testosterone Supplementation Increases Estrogen (=Estradiol) Levels, A Good Thing!

Next, let’s discuss the issue of estrogen levels in males.

First of all, I want to say that “estrogen” is a generic term encompassing many different specific substances. Further, it is generally agreed that Estradiol is the most important estrogen in males as well as in females. So, both genders make Estradiol.

Estradiol is an important hormone to protect bone, cognition, and the heart, whether in women or men. It has been determined that neither Testosterone nor Estradiol promote prostate cancer.

Giving Testosterone to men increases Estradiol via the activity of the Aromatase enzyme. That is, this enzyme converts Testosterone into Estradiol. As well, Aromatase becomes more active with age.

A common opinion among anti-aging physicians and age management advocacy organizations is that higher levels of Estradiol in males should be blocked. However, there are health benefits of Estradiol for men as well as women.

In men, as well as women, Estradiol is protective of the heart, prevents bone loss, diabetes, lipid derangements, memory loss, and loss of libido [28].

In men, raising Estradiol through the administration of Testosterone prevents these problems.

Still, it has been common practice among many doctors prescribing Testosterone to prevent a rise in Estradiol by prescribing so-called Aromatase inhibitors, like Arimidex® (=Anastrozole).

I follow the point of view of Neal Rouzier, MD of Palm Springs, who is the leading teacher of natural hormone replacement therapy in the US. He states: “Testosterone supplementation always increases serum estrogen (estradiol) levels. If indeed this increase in estrogen in men were harmful, it would have been revealed by now, based on hundreds of studies throughout the last 50 years.” [28] “.... (In the) hundreds of studies evaluating testosterone, never once have increased estrogen levels in men been shown to be harmful.” [28] “Optimal estrogen levels (in men as well as in women) are necessary for adequate bone growth, prevention of osteoporosis, dementia, Alzheimer’s and heart disease.” [28]

Like Dr. Rouzier, I do not recommend that any man taking Testosterone attempt to lower Estradiol. The important factor is the ratio of Testosterone to Estradiol. Optimization of both produces health benefit.

Normally, and without the benefit of Testosterone supplementation, the levels of this vital hormone of youth slowly declines over the decades. We refer to the term, “andropause”, as the time in a man’s life when he has reached a situation of hormonal decline similar to that of a woman at menopause.

But, in a woman, the loss of Estradiol is sudden and very dramatic, resulting in hot flashes, but also, over time, decline of brain and heart function as well as bone loss.

In men, the slow decline of Testosterone is balanced by the increased activity of Aromatase. It is not until he is in his seventies that his Testosterone level is so low that his production of Estradiol via conversion of Testosterone is not enough to protect his brain and bones. So, as the age-matched woman is losing bone in her fifties, the man does not have osteoporosis until his seventies. Early Alzheimers occurs in women in their 50's who are dramatically sensitive to loss of Estradiol, but occurs more commonly in men in their mid-seventies.

Remember that it is the conversion of testosterone into estrogen that is responsible for most bone growth [29]. Blocking testosterone in men causes bone loss, but giving Estradiol alone reverses the bone loss [30,31,32] “Estrogen is more important than testosterone in the determination of age-related bone mineral density men and women” [34] “This is another perfect example of estrogen’s positive effect in males and proof we should never lower estrogen in men.” [28]

In the same way, Brain protection is the hormone province of Estradiol: "... men with high levels of total estradiol demonstrated better ... verbal memory performance ... compared to men with lower levels of total estradiol. We did not detect an association between testosterone and cognitive performance. These findings indicate that high levels of total estradiol in older men are associated with better performance on a cue-based, controlled learning test of verbal memory that is a sensitive predictor of dementia." [33]

Estradiol increases the “good cholesterol”, HDL. [33] “HDL and estrogen stimulate the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, anti-adhesion, and anti-inflammatory effects,” thus preventing heart attacks and strokes [36].

Bottom line: Do not block Estradiol in men undergoing Testosterone supplementation.

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