Testosterone for Men and Women

BY MARK SCHOLZ, MD

Testosterone is really cool. It improves concentration, energy, strength, and libido. Both men and women experience enhanced performance with higher testosterone levels.  The problem is that testosterone tends to decline with age.  Also, testosterone-blocking therapy to treat prostate cancer can have lingering effects, even after the treatment is stopped.  For women, testosterone levels often decline sharply after menopause.

Low testosterone causes many undesirable effects including muscle atrophy, weight gain, tiredness, osteoporosis, low libido and impotence.  Absent testosterone in women* is usually a secondary effect of menopause, so it usually occurs in conjunction with low estrogen. In women the loss of estrogen and testosterone causes weight gain, tiredness, osteoporosis vaginal atrophy and low libido.

Judicious administration of testosterone in men and a combination of estrogen and testosterone in women, can dramatically improve quality of life. Bioidentical hormone therapy is the term often used by the doctors who specialize in this area.  The idea is to restore hormone levels back to normal.

Risks of Testosterone Therapy
As might be expected, like any powerful tool, misuse of testosterone can be dangerous. Administering testosterone in men with prostate cancer is controversial (see below).  However, there are also risks even in men without prostate cancer.  One reason is that when testosterone is administered to men estrogen levels also rise.  Higher estrogen in men may increase the risk of heart attacks and strokes. Therefore, estrogen levels should be monitored and compensatory treatment with Femara®, an estrogen blocking pill, may be necessary in some cases.

In men, testosterone may also cause an excessive increase in the red blood cell count (RBC). Overly high RBC levels have also been linked to higher risks of heart attack or stroke. The RBC count, therefore, needs to be monitored by measuring the hematocrit, a component of the complete blood count (CBC). If the hematocrit rises above 50% men should consider lowering their testosterone dosage or undergoing a phlebotomy (donating a unit of blood).  In women, excessive amounts of testosterone can cause masculinization.  Estrogen replacement also slightly increases the risk of breast and uterine cancer.  Obviously a full discussion of all the risks and benefits is essential before starting treatment.

Administering bioidentical hormones is as much an art as a science. The hormones themselves are delivered in the form of creams, pills or shots. Studies show that the measurement of hormone levels in the blood stream or in saliva is moderately helpful for guiding the selection of an appropriate dosage. A better indication of proper dosage, however, is the subjective sense of well-being reported by the person receiving the treatment. Therefore, starting hormone therapy should proceed slowly with an incremental escalation of dose while closely observing for the appearance of side effects.

Giving Testosterone to Men with Prostate Cancer
Denying every man with a history of prostate cancer from receiving testosterone is ridiculous. Studies clearly show that about half the men in their 50s and almost all men in their 80s harbor minor forms of prostate cancer; most is low-grade and harmless.  Almost all of these men have substantial testosterone coursing through their blood (from their testicles).  They seem to do just fine. As long as men are regularly screened to ensure the absence of clinically significant prostate cancer, the risks of restoring low levels of testosterone back to normal should be quite low.

Living Longer and Living Better
Just in our lifetimes we are observing a dramatic enhancement of human longevity.  When I was in oncology training at USC just twenty-five years ago, the attitude toward a patient’s death while in his in early 70s would have been, “He lived a full life.”  That attitude is no longer accepted.  Now men and women are not only living longer, they are retaining substantial youthfulness into their 80s. As part of an overall health program that includes diet, exercise and appropriate healthcare, restoring sex hormone levels back to normal can be transformational.  Since giving small amounts of testosterone to females is a foreign idea to many people, in my next blog I will elaborate on this concept further.

* Premenopausal women normally have testosterone in their blood, albeit at much lower levels than men.

The ROYAL Shade of Blue

BY MARK SCHOLZ, MD

Men in the ROYAL shade have metastatic prostate cancer that has spread to bone, or, to lymph nodes outside the pelvis, or, they have a PSA over 100, or, they have a rising PSA with a low testosterone level. Metastases are typically detected by doing a body scan or a bone scan.

Men with advanced prostate cancer tend to live longer than men with other types of cancer. One major reason is because prostate cancer doesn’t usually spread to critical organs like the brain, the liver or lungs.  Another reason is the availability of so many effective treatments. Standard hormonal treatment with Lupron and Casodex, for example, can induce long remissions. And just recently, the FDA approved two new types of hormone therapy—Xtandi and Zytiga. These medications are so powerful they can induce remissions in men who have become resistant to Lupron and Casodex. In addition to Xtandi and Zytiga, two non-hormonal treatments—Provenge and Xofigo—have also been recently approved by the FDA.

Since so many effective treatments are available, wasting time on a treatment that has stopped working is a terrible crime. Therefore, after initiating a new treatment close monitoring of disease status is essential. Monthly blood tests and PET scans with sodium fluoride or carbon 11 acetate help to determine when a specific treatment stops working. Ineffective treatment should be stopped as soon as disease progression occurs so that a more effective therapy can be started in a timely fashion.

Treatment for ROYAL
Men in the ROYAL category who have never had hormone therapy should start testosterone inactivating pharmaceuticals (TIP).  The standard approach is to begin with Lupron and Casodex in combination.

Men who have become resistant to Lupron, but have fewer metastases and a slower PSA doubling time, should take Provenge to boost their immune system. Studies show that Provenge works better when treatment is started earlier. Preliminary research has also suggested that Provenge might be more potent if it is combined with spot radiation directed at a site of metastatic cancer. Studies to evaluate this possibility are ongoing.

With or without Provenge, radiation to cancer metastases has historically been reserved for controlling bone pain, a use for which it is quite effective. However, newer thinking suggests that radiation directed to all known sites of metastases—when the numbers of metastases is relatively small, say less than five—may occasionally lead to longer remissions.

Potent medications to strengthen the bones—Xgeva and Zometa—are routinely recommended when bone metastases are present. These medications have three potential benefits: They inhibit cancer growth in the bones; they reduce bone pain; and they help counteract calcium loss that hormonal therapies commonly cause.

If men in ROYAL have the type of prostate cancer that progress quickly while on Lupron and Casodex, the first step should be to stop Casodex and start one of the following three options:

1.    Second-line TIP such as Zytiga or Xtandi

2.    Chemotherapy with Taxotere or Jevtana

3.     Xofigo, a form of injectable radiation

Three additional treatment options can be considered if these first three options are no longer effective in controlling the disease:

1.       Combination chemotherapy using Carboplatin or Xeloda with a Taxane or the combination of both Revlimid and Avastin added to a Taxane. 

2.       The “off-label” use of Cabozantinib (XL-184), a medication being researched for prostate cancer but already FDA-approved to treat thyroid cancer

3.       Other investigational medications

Investigational trials represent an opportunity for patients to get medications prior to FDA approval.  A patient’s enthusiasm for embarking on a study that uses an investigational medication, however, needs to be tempered by what is actually known about the effectiveness of the specific medication.  Some medications are so new that even the investigators performing the trial don’t know if they are going to work or not.

While on treatment men need to have their blood monitored monthly by checking PSA, PAP, ALP and CTC levels. Medication side effects and cancer-related problems also need to be screened for with monthly blood tests such as CBC, a metabolic panel and a hepatic panel.  A periodic bone scan and body scan should be performed to track the disease status.  Two to three months after starting a new treatment, if the blood markers are not improving, a change in therapy needs to be considered.    

Reducing the Side Effects of Treatment
Fatigue is one of the biggest challenges faced by men in ROYAL. First, both chemotherapy and radiation can cause tiredness. Second, muscle loss is a frequent occurrence from TIP-induced, low testosterone.  Stimulants such as Provigil or Nuvigil may be helpful, but the most important priority is to counteract muscle loss with consistent, diligent exercise. Resistance training with weight lifting is only known effective method for restoring muscle mass.

Xgeva and Zometa cause gum recession and infections of the jaw bone, a condition called osteonecrosis.  This phenomenon is much more likely to occur after a tooth extraction so men on this therapy are advised to avoid extractions as much as possible.  Osteonecrosis, when it occurs, generally resolves, albeit slowly, after Xgeva or Zometa are stopped.

A variety of different medications can be useful for reducing side effects from hormone therapy. Low-dose estrogen skin patches can control hot flashes. Excessive mood swings can be stabilized with low doses of antidepressant pills. Breast enlargement can be prevented with Femara. 

Final Thoughts

In this blog I have outlined a traditional, sequential approach to treatment selection.  Strong consideration, however, should be given to using these active new agents in combination and at an early stage.  Men in ROYAL have a potentially life-threatening type of prostate cancer. An aggressive and imaginative treatment plan should be designed that has the specific goal of attaining and maintaining a complete remission, i.e. a PSA less than 0.1. In my opinion, the standard “one treatment at a time” approach that is so popular at academic centers, it is a grave disservice to the men fighting aggressive prostate cancer. 

All Newly Diagnosed Men Should Be From Missouri. But There Are Limits . . .

BY RALPH BLUM

Missouri is known as the “Show Me State,”  a nickname made popular around 1899 by Congressman Willard Duncan Vandiver, who famously declared, "I'm from Missouri and you've got to show me." Appropriately enough, the state animal is a mule. Newly diagnosed men with prostate cancer, take heed. But also, know when to listen to the experts.

The newly diagnosed men I know who’ve had the best treatment results questioned everything related to the pros and cons of various treatment options. You need to develop the “I’m from Missouri” mindset, so that when an authority figure with a big reputation pronounces, “You need surgery. I’ve got space in my operating schedule next Thursday,” your automatic reaction is not “Whatever you say, doc.” It is “Well, I’m from Missouri and I need to know more before I make that decision.”

 Remember: 90% of us have the slow growing type of prostate cancer. Time is on our side. Second or even third opinions make sense. But—and I am here to tell you there’s a big “But…” Once you have chosen a treatment you had better pay attention to your doctor’s advice. I learned the hard way.

Back in 2002, when my PSA bumped up to 18.3, given my aversion to being sliced open, fried by radiation or poisoned by chemotherapy, it was only logical that I decided to pursue the minimally invasive treatment known as hormone blockade. The objective of hormone blockade is to reduce the production of testosterone—the hormone (androgen) in the blood credited with fueling the growth and spread of prostate cancer—as near as possible to castrate level. But there are some basic rules to follow once you opt for hormone blockage, and I soon began to wish I had taken Mark’s advice about how to avoid some of the adverse side effects that occur in the absence of testosterone. The most talked about one, of course, being no libido.

The protective measures are simple enough: You need to exercise in order to prevent weight gain and muscle wasting—even if, like me, exercise has not been part of your routine. Recommended: 45 minutes of weight training twice a week. Hate it, resent it, but do it. Otherwise? Somewhere down the line, chances are you’ll find your ability to lift, squeeze, steer and reach are all seriously compromised. The truth of “Use it or lose it” becomes painfully apparent. And the longer you wait, the greater the deficit, the harder to repair the damage.  

And then there’s my least favorite adverse side effect from injections of Lupron, which is breast enlargement.Official name gynecomastia. My options were: Either low dose radiation prior to the use of Lupron, or  taking the estrogen blocking drug Femara. I wasn’t keen on undergoing radiation unless it was of critical importance. And somehow I just never got around to taking Femara. Next thing I knew, there they were—my very own set of boobs. A souvenir of my trek through the libido-free zone.

So I’m a living example where ignoring instructions was mulish behavior of the wrong kind. If memory serves, this set of honkers is bigger than those of my first girlfriend. But on the bright side, after months of hormone blockade, my PSA had bottomed out at 0.05, only a breath away from the magic goal line marked “undetectable.” And nowadays, I am only from Missouri on carefully selected occasions.