Maybe it's my age, but it seems testosterone treatment, whether for men or women seems to be a growing trend. Without a doubt though, this is somewhat controversial. The evidence was somewhat skim when I first become aware of men increasingly seeking #testosterone testing and treatment, but more recently I was working within a holistic clinic who had a plethora of men prescribed testosterone and interestingly, the vast majority of them had exceedingly low cholesterol levels. One must have sufficient fat to create the necessary hormone, testosterone. Additionally, sexual dysfunction can result from underlying trends towards diabetes, so as always, my preference is to ask what our underlying cause is, as even in life's transitions, one should not suffer significant burden if they are truly in an optimal state of health.
Testosterone is prescribed primarily for sexual dysfunction, but is often also offered to boost energy. Many insurance companies won't even pay for the testing however, which can be exceedingly expensive. This makes identification and certainly management of this treatment essentially impossible. Women are offered testosterone for hot flashes, improved #libido, increased bone mass, and an overall increased sense of well-being. More recently I've become aware of practitioners prescribing testosterone for women, for weight loss.
What Do We Know?
Approximately 43 percent of women and 31 percent of men report sexual dysfunction, so it isn't surprising that testosterone is being prescribed more often, a 500 percent increase in sales between 1993 and the turn of the century. Testosterone levels decline in men at an average rate of one to two percent per year. This is thought to be the normal physiologic response to #aging, although can reflect testicular dysfunction, or hypothalamic pituitary dysfunction. By 80 years of age, more than half of men will have low testosterone levels, but keep in mind, half are still normal.
Low testosterone can present differently among men. While some do suffer sexual dysfunction, low libido, potentially even erectile dysfunction or difficulty reaching orgasm, others have foggy minds, increased #fatigue, or start to lose muscle tone. Some have diminished bone density, more depressed mood, even anemia. More often I am told by men that they have less energy, a sense of lost vitality or well-being.
The safety and even efficacy is still in question, which is cause enough for third party payers to deny coverage for testing and practitioners to steer clients away from treatment. The Institute of Medicine has offered us some guidance however.
What Should You Know?
If you want to better understand your testosterone levels, understand that your practitioner can test for total testosterone, free testosterone, and steroid hormone-binding globulin. Luteinizing hormone can also be tested and follicle stimulating hormone, which help discern the difference between primary and secondary hypogonadism. All of these may be included in a hormone panel which can be ordered by your practitioner. Some practitioners will also recommend estradiol, prolactin (may indicate pituitary tumor), complete metabolic panel, prostate evaluation, and a complete blood count.
Approximately 98 percent of the circulating testosterone is bound to steroid hormone-binding globulin or albumin. The amount of testosterone which is bioavailable is what is tested for when ordering free testosterone. Total testosterone is more commonly the level evaluated, which is typically between 300 and 1,000ng/dL. Some practitioners will only initiate treatment after evidence of androgen deficiency is identified in the morning, between 8 and 10am, on three separate occasions. Ideally these samples should be drawn fasting.
Changes in steroid hormone-binding globulin can affect the bioavailability of testosterone, but there really aren't standards yet for evaluating what is bioavailable so this isn't commonly ordered by clinicians. There really aren't even consistent guidelines for the level of total testosterone that defines #hypogonadism; however, the American Association of Clinical Endocrinologists (AACE) are the sort of go-to experts for defining this parameter and their recommendation is lower than 200ng/dL.
Primary causes of hypogonadism in men include decreased testosterone, increased luteinizing hormone and follicle-stimulating hormone. Hypogonadism is simply a decrease in either of the two functions of the testes, either sperm production or testosterone production. This may be related to Klinefelter syndrome, estrogen receptor defects, 5-alpha reductase deficiency, myotonic dystrophy, cryptorchidism, hemochromatosis, mumps orchitis, aging, HIV, AIDS, and other chronic diseases.
Secondary causes are related to the pituitary or hypothalamus and include decreased testosterone, normal or decreased luteinizing hormone and follicle-stimulating hormone. These causes are typically either Kallmann syndrome, fertile eunuch syndrome, pituitary disorders, HIV, AIDS, or other chronic diseases.
Benefits of therapy, while controversial, are thought to be increased libido, increased lean muscle mass, improved cognition, improved mood, increased sense of well-being, less erectile dysfunction, increased bone density, and increased muscle strength. One study found that the administration of 100mg of testosterone enanthate once a week for ten weeks to hypogonadal men increased their strength as measured by the bench press by 22 percent and their squat strength by 45 percent, with fat-free mass also increasing by 5 percent.
Treatment with testosterone gel, patch, or even intramuscular injection is indicated for men with low total testosterone levels who have these symptoms. Regardless of the route of administration, studies do support testosterone #supplementation for libido and sexual function in hypogonadal men. When men have normal testosterone levels though, the evidence is mixed with whether supplementation can be advantageous.
The optimal delivery method really hasn't been determined either, yet oral dosing is not recommended because it is metabolized so quickly by the liver that it is virtually impossible to maintain a normal serum testosterone concentration. Many clinicians (as well as Up-to-Date) recommend gels (AndroGel, Testim, and Fortesta) because they typically result in normal and relatively stable serum testosterone concentrations, and most patients prefer them to other preparations. Insurance coverage may dictate regimen however. Gels typically do cost the most, with solutions (Axiron), pellets (Testopel), patches (scrotal patch is no longer available) and pellets more middle line, and injectables the least expensive. Pellets do require surgical insertion.
Axiron is an interesting approach. It is a solution and comes in a metered-dose pump with applicator. Each depression yields 30mg of testosterone. The package insert suggests a starting dose of 30mg applied to each axilla (total of 60mg) once a day and adjustment of the dose down to 30mg or up towards 120mg once a day, depending on serum testosterone concentrations. Generic versions are now available, and studies have demonstrated this effective.
Injections last 10 to 14 days and do require frequent visits to the doctor or training in self-injection. These are fatty or oil-based delivery systems which gradually release testosterone prolonging their presence. Testosterone cypionate 150mg-200mg every other week is a popular regimen, although sometimes this is initiated at 75mg-100mg weekly.
When 100mg of testosterone enanthate (available in short supply in the United States) is utilized once a week, the mean serum testosterone concentration increased to slightly higher than the upper limit of normal one to two days after the injection and gradually decreased to the mid-normal range by the time of the next injection. When the dose was increased to 200mg in an attempt to prolong the dosing interval to every two weeks, the peak serum testosterone concentration increased further, and the nadir, just before the next injection, decreased to the low-normal range. Less information is available for testosterone cypionate, but those studies available do demonstrate outcomes to be similar.
Pellets and transbuccal troches are the newest methods of delivery but have not been well studied. Individuals do tend to notice improvement within just a few days no matter the preparation they choose, and gels reach normal range typically within a month and remain steady throughout the entire day and night. Occasional skin irritation does occur.
When bone density is of interest for men, it is more often the bioavailability of testosterone and estrogen levels that are of interest to clinicians. Total testosterone is less helpful. No studies have demonstrated a decrease in fractures when men supplement with testosterone for this purpose, but bone loss does seem to cease and bone density is improved. Testosterone treatment also demonstrates consistently that lean body mass increases, but muscle strength isn't necessarily improved.
While sexual dysfunction may be the initial motivator for testosterone testing and supplementation, in my own experience as a practitioner, it is the cognitive and psychological improvements that cause them to continue treatment. Men frequently share that they just feel better, and many of them share they demanding jobs that require clarity for which testosterone offers significant improvement. Neuropsychological testing has revealed improvements in spatial cognition and spatial and verbal memory with testosterone replacement. Mood and depression is less supported in the literature, but quality of life does seem to be improved.
What About Safety?
Most studies of testosterone therapy in hypogonadal men have been on men younger than 65 years of age, but the Institute of Medicine has evaluated the safety and effectiveness on older men and found no compelling adverse effects. The controversy lies in not having well-done, long-term studies and in treating older men, or younger men without evidence of suboptimal morning androgen levels. The Institute of Medicine reports that testosterone replacement therapy should only be offered for those reasons approved by the FDA and that outside of these reasons, prescribing is inappropriate. Specifically, offering testosterone for reasons limited to enhancing strength or mood in otherwise healthy older men may not be worth the risk.
The rise in testosterone prescriptions in healthy, middle-aged men is likely due, at least in part, to direct-to-consumer advertising encouraging use of testosterone products for nonspecific symptoms, such as decreased energy and sexual interest.
What are those risks? Potentially, an enlarged prostate may result. Yes, I've seen this a few times in practice now. It has been considered benign, so not a cause of cancer, but still unwelcome. If the PSA is elevated above 4ng/ml, there is an abnormal or indurated prostatic nodule on digital exam, hematuria, or there is an increase to 3ng/mL in clients at high risk for prostate cancer, then referral to urology is warranted.
Testosterone treatment does not seem to impact lipids, cRP, or insulin sensitivity. It also doesn't seem to impact the liver negatively when prescribed at recommended doses, but oral dosing is not recommended for this reason. Some do experience acne, alopecia, and hirsutism.
Clients with a history of prostate or breast cancer (whether "cured" or not) are not appropriate candidates for testosterone therapy. Known ASCVD (including stents, CABG, or history of CHF) should be evaluated first, and recommendation obtained, from cardiology. CHF which is uncontrolled or poorly controlled is a clear contraindication. Any illicit or unprescribed substances found on a drug screen would be a contraindication for therapy. Obstructive sleep apnea which is uncontrolled and severe, is also a contraindication, but if well treated with CPAP, these men are appropriate candidates. Erythrocytosis or a hematocrit over 50 would also rule out a client for testosterone therapy candidacy as erythrocytosis is stimulated, which is why a complete blood count is monitored during therapy as well.
Use of Testosterone in Women
Testosterone is an essential precursor of estrogen in women and made in the ovaries and adrenal glands. There is a steady decline in testosterone levels from the second decade through menopause. No clear lower limit of testosterone has been established in women (although 15ng/dL is commonly used). One study found levels from zero to ten resulted in a significant decrease in libido, as well as markedly decreased orgasms.
These reasons alone have motivated some practitioners to prescribe testosterone for women, but a patch was voted against approval by the FDA in 2004 due to safety concerns. The panel felt there weren't enough women in the studies available at the time, and long-term effects had not been established. However, oral testosterone has been commonly prescribed since the 1970s, in the form of esterified estrogen with methyltestosterone (Estratest) - yet not FDA approved. It is marketed for use for hot flashes, although there is marginal evidence to support its use for sexual dysfunction.
Following concerns related to estrogen and progesterone replacement therapy, more women have been interested in testosterone therapy for their hot flashes and sexual discomforts. The Endocrine Society are developing guidelines currently as many as half of all women report sexual dysfunction post-oophorectomy and post-menopausal. The psychological complaints of menopause have been supported in a limited number of studies, with testosterone treatment, yet all these studies are also supplementing with estrogen.
Interestingly, clinicians have not offered women who are pre-menopausal testosterone treatment for low libido in fear it may cause them masculinization, but if levels are identified as low, it is clear women have lowered sex drive. One 12-week trial did find among 34 women, that a 1% cream of 10mg testosterone per day, applied to the thigh, did improve well-being in women, as well as mood and sexual function without increase in hirsutism, acne, or voice changes.
Testosterone has been used in women with ovarian failure, Turner's syndrome, HIV infection, to improve bone density, and for chronic corticosteroid use. Dementia and depression have also been considered as potential uses for testosterone treatment in women. The risks really are dose dependent and related to duration, and just aren't found to be too common. These effects seem to be reversible. Short term use has not impacted cardiovascular disease or hepatic changes.
Monitoring Treatment
When testosterone treatment is offered, the AACE recommends monitoring by offering men a thorough review of their health history with a physical exam, including digital prostate exam (every six months to a year until stable) and measuring prostate-specific antigen levels. Testosterone levels should also be evaluated in those receiving injections until stable, which may be every three months initially, and with dose changes. Hematocrits, lipid profiles, and liver function tests should be evaluated every three to six months, then annually when stable. When evaluating total and free testosterone, levels should be drawn midway between injections to obtain appropriate clinical data for evaluation.
Serum testosterone levels measured midway between injections in men who are supplemented with testosterone enanthate or cypionate, should ideally be mid-normal, so about 500 to 600ng/dL (17.3 to 20.8nmol/L). If higher, supplementation dose should be reduced. If transdermal preparations are utilized, testing can occur at any time with the recognition that peak values will be six to eight hours after application of the patch. Serum concentrations vary substantially when a gel is used by not in a predictable way; therefore, two serum testosterone measurements are recommended prior to making dose adjustments. Many clinicians do not opt for two evaluations, but one really is necessary. There are practitioners who do not follow-up, monitoring serum concentrations what-so-ever.
Estradiol levels can increase as a consequence of testosterone therapy. Anastrazole can be offered at 0.25mg by mouth on the day of injection and then repeated again on day 3. Estradiol should be evaluated again at one month. Not always is this elevation an issue for clients so anastrazole does not need to be administered exclusively with elevated estradiol, but is an option for individual clients.
Women are also offered a thorough health history and physical, but rather than testing testosterone levels, they are more simply monitored for symptoms. Semiannual clinical breast exams are also recommended for women, and a complete blood count, lipid level, annual mammograms, and endometrial ultrasonography annually.
If you are concerned about the potential you may have low testosterone, would like to be tested, or are interested in treatment, please call the office and schedule an appointment with me.