Possible complications of hormone therapy

For more than a century, doctors have known that hormones play a role in prostate health. But they didn’t understand the link between the two until 1941, when Dr. Charles Huggins demonstrated the healthy prostate’s dependence on the male sex hormones testosterone and dihydrotestosterone for growth. He also proved that shutting off the production of these hormones — either with surgical castration or with the drug diethylstilbestrol (DES) — would tamp down the growth of prostate tumors. Since then, hormone therapy has been the mainstay of treatment for men with advanced prostate cancer.

Although surgical removal of the testicles, or orchiectomy, is a relatively simple operation, most men wanted to avoid the procedure — and the psychological impact that can accompany castration. Instead, they opted for DES, a form of estrogen. Trials launched by the Veterans Administration Cooperative Urological Research Group (VACURG) in the 1960s supported its use: there was no statistically significant difference in survival rates between patients taking the drug and those undergoing orchiectomy.

But DES gradually fell out of favor. Later VACURG data showed that men taking a 5-milligram daily dose of DES had a much greater risk of cardiovascular death than orchiectomy patients. Smaller, 3-milligram doses proved problematic, too.

Aiming to control androgen production (and thus cancer growth) as effectively as DES without the cardiovascular side effects, researchers developed another class of drugs in the mid-1980s. Called LHRH agonists, the drugs work on the brain, preventing the secretion of luteinizing hormone–releasing hormone (LHRH). LHRH secretion is the body’s signal to start testosterone production.*

A review of 24 trials involving more than 6,600 prostate cancer patients found that the men who took LHRH agonists did just as well as those who underwent orchiectomy. Because patients more readily accept LHRH agonists than surgical castration, the drugs have become standard therapy for men with metastatic prostate cancer.

LHRH agonists cause a temporary surge in testosterone, which lasts for about 10 to 20 days, before levels plummet. To prevent cancer from worsening during that time, doctors usually prescribe an anti-androgen to counter the surge. Another, newer class of drugs is the LHRH antagonists; they do not cause the initial jump in testosterone levels and can be used in place of LHRH agonists to rapidly reduce hormone production.

Unfortunately, LHRH agonists come with potentially serious side effects of their own — including cardiovascular problems. Soon after starting hormone therapy medications, most patients experience hot flashes, decreased libido, trouble getting an erection, and fatigue. Several weeks later, metabolic changes lead to weight gain, and the risk of diabetes, heart attack, and sudden death increases. Bone loss sets in, too, upping the risk of fractures.

Here, three physicians from hospitals affiliated with Harvard Medical School to share their expertise on cardiovascular and skeletal complications associated with hormone therapy:

• Harold Rosen, M.D., an endocrinologist and director of the Osteoporosis Prevention and Treatment Center at Beth Israel Deaconess Medical Center.
• Harvey B. Simon, M.D., an internist at Massachusetts General Hospital and editor of Harvard Men’s Health Watch. Simon is particularly interested in the cardiovascular, metabolic, and psychological aspects of hormone therapy. He also serves on Perspectives’ editorial board.
• Matthew R. Smith, M.D., Ph.D., the director of Genitourinary Medical Oncology at Massachusetts General Hospital and a specialist in treating prostate cancer. He has extensively studied hormone therapy and its effects on bone, body composition, metabolism, and the risk of fractures, diabetes, and cardiovascular disease.

Cardiovascular health

How does the history of DES affect where we are today with hormone therapy?

SIMON: Researchers have asked whether the cardiovascular complications associated with DES were due to the absence of testosterone or the presence of estrogen. It’s likely that the presence of estrogen played a large role, since higher doses were much more toxic. The 5-milligram dose caused more cardiovascular complications than the 1-milligram dose. Several years ago, the Women’s Health Initiative showed that estrogen increased cardiovascular risk in postmenopausal women over age 60. So while the DES story was about estrogen being toxic, we’re now dealing with the possibility that the withdrawal of testosterone, due to LHRH agonists, also has adverse metabolic and cardiovascular effects.

How does hormone therapy affect lipid metabolism?

SMITH: We’ve done several studies over the past 10 years to try to answer that question. We showed that LHRH agonists significantly increased HDL and LDL cholesterol, with an even more marked effect on triglycerides. [For more information on cholesterol and triglycerides, see “Lipids explained,” below.] The effect can be observed quickly — in as little as four to 12 weeks.

We’ve also done studies to look at the effect on insulin sensitivity in nondiabetic men undergoing treatment with an LHRH agonist, and we showed that there was a marked decrease in insulin sensitivity after 12 weeks. [See “What’s insulin sensitivity?” below.]

What’s even more striking with these medications is the effect on body composition. Men gain fat and lose muscle, which is apparent after as little as 12 weeks. And it’s more than a cosmetic issue. These men experience corresponding metabolic changes that may increase their risk for diabetes and cardiovascular disease. [For details on these and other studies, see “Key cardiovascular and metabolic findings,” below.]

How should physicians counsel patients when prescribing hormone therapy?

SMITH: I think more frequent screening for diabetes is certainly warranted, as is careful consideration of cardiovascular disease risk factors. We should make sure that patients understand what the side effects are and what steps they can take to reduce their risk. In the past, I don’t think men were fully made aware of these things. For example, I’ve met countless patients over the years who became obese on hormone therapy. No one told them that their treatment contributed, at least in part, to changes in their body composition.

SIMON: Physicians need to emphasize the importance of exercise, especially resistance exercises, to try to maintain muscle mass.

It’s also important that the patient is getting enough vitamin D in the diet or is taking supplements. It’s important that there’s a moderate amount of calcium and enough protein in the diet, and that the amount of calories, saturated fat, and trans fats is restricted.

If tests show abnormal lipid or blood sugar levels before hormone therapy, or if these develop during therapy, I think it’s a good idea to treat those aggressively with lipid- or glucose-modifying drugs. How well that will work, though, is a bit unclear. Given the limited state of our knowledge, we need to do clinical trials to find out.

ROSEN: I agree that exercise is critically important for these patients. But we need to keep straight in our minds why we’re recommending it. As a potential insulin sensitizer, I think it makes sense. There are some data to support the fact that exercise will help maintain muscle mass and reduce insulin resistance in men with very low testosterone levels. But I don’t want patients to get the idea that if they exercise, then their bones will be okay. For the most part, exercise doesn’t improve bone density. Rather, it improves muscle strength. If your muscles are strong, you don’t fall; and if you don’t fall, you don’t break bones.

So exercise is not a fool’s errand?

ROSEN: No, absolutely not. But I don’t think I’ve ever seen a study of men taking hormone therapy medications for prostate cancer who are randomly assigned to exercise or not exercise, which would prove that exercise improves muscle strength.

SIMON: There was one very small noncontrolled study from Australia. Ten men on androgen deprivation therapy followed a progressive resistance training program for 20 weeks. They showed significant improvement in muscle strength, muscle endurance, and balance at the end of the program. They were also able to preserve lean body mass with no change in fat mass. It was a small study with no control group, but it showed that it is possible for a man with very low testosterone to positively affect muscle strength.

I think exercise also has a great psychological benefit. If you can get someone to a gym, get him to a trainer, it makes him feel like he’s doing something positive for himself. There are huge psychological costs associated with androgen deprivation therapy and prostate cancer. Exercise can really help with that.

What is hemoglobin A1c? Why is it important in monitoring blood sugar?

ROSEN: It’s a powerful measure for glucose, or blood sugar. [See “Hemoglobin + glucose,” below.] Unlike blood sugar, which fluctuates depending on when and what you ate last, hemoglobin A1c gives a rough indication of glucose control over the last month or two. It’s linked to vascular complications in some diabetes studies.

What does hormone therapy do to glucose metabolism?

SMITH: In the short-term trial that we did, we saw a decrease in insulin sensitivity in nondiabetic men. That fits with others’ observations and supports the finding that hormone therapy increases fasting insulin, which is a measure of insulin sensitivity. We also saw very small but statistically significant increases in hemoglobin A1c. Measuring A1c is a convenient way of seeing if a patient develops clinically meaningful diabetes.

Should patients who have or are at risk for diabetes have additional testing or monitoring if they start hormone therapy? Do patients with diabetes have more diabetic complications on long-term hormone therapy?

SIMON: I don’t think we know the answer to that. A lot of the complications of diabetes take a long time to develop, and there are men who go many, many years on androgen deprivation therapy without complications. But I don’t know of any hard data as to whether diabetic complications are accelerated.

SMITH: We’re doing a prospective study to examine some of these questions. We aren’t looking at who develops diabetes, because that would be a very large study. We’re looking only at changes in insulin sensitivity and in lipid profiles over time in men with low testosterone.

Given these risks, it sounds like physicians need to prescribe it judiciously.

SIMON: Yes. We need to alert the oncology community not to use androgen deprivation therapy when it isn’t clearly indicated. I’m not talking about withholding it from patients with symptomatic metastatic disease. Therapy is clearly important in those cases. But when it’s a borderline call, when we’re dealing with a relatively gradual or modest rise in PSA without metastases, I think physicians need to be a little more judicious about starting therapy.

SMITH: Showing the previously unrecognized harms of hormone therapy has really helped inform decision making. I think it reinforces the point that hormone therapy is a fine thing to avoid if you don’t need it. But if your disease requires it, then I think your physician should be proactive about screening for these side effects and monitoring you during therapy.

You said that the side effects tend to occur relatively quickly. And are the risks cumulative with time? What happens with long-term administration?

SMITH: The metabolic effects on body composition appear to happen fairly rapidly. For example, most of the fat accumulation and nearly all the changes in lipids occur within the first three months. The effects probably don’t accumulate much after that, but this issue is relevant for all men considering hormone therapy, even men going on short-term treatment.

In contrast, the data about thinning bone show that there’s steady loss over the course of treatment and that men appear to lose bone at roughly similar rates with short-term and long-term treatment. So the longer someone is on hormone therapy, the greater the risk of fracture.

Patients commonly gain five to 10 pounds after a few months of hormone therapy. What causes that?

SIMON: I don’t think we really know. It could be that the patient grows depressed about having metastatic cancer, becomes sedentary, and eats more.

SMITH: I agree. Many factors may contribute, including alterations in mood and metabolism. But the effects are striking. It happens quickly, and it happens in nearly all men. And because the effects are similar in most men, research suggests it’s caused primarily by the low testosterone levels, a condition called hypogonadism.

Patients say they’re not eating more, yet they all gain weight. Any advice?

SMITH: I tell my patients this: “If you continue your current level of activity and diet, you will likely gain weight on this treatment, and you’ll find this early on. Even if you don’t gain weight, your body composition will shift. You will lose muscle and gain fat. So if you want to stay where you are, you will need to change your current lifestyle. That means fewer calories and more exercise.”

Any other advice?

ROSEN: Eating more protein and complex carbohydrates that are harder to digest might be of some help. Stone-ground whole wheat, steel-cut oats…

SIMON: I agree entirely. These foods keep you feeling full longer because you have to break down the husk to get the carbohydrate out. They take longer to digest and help minimize spikes in blood sugar.

Do all of these metabolic changes constitute what’s called metabolic syndrome?

SMITH: The classic metabolic syndrome [see “Metabolic syndrome explained,” below] is a combination of disorders that increases the risk of cardiovascular disease and diabetes. The metabolic changes associated with hormone therapy also increase the risk of cardiovascular disease and diabetes, but they do so in a different way. LHRH agonists primarily increase subcutaneous fat; with metabolic syndrome, the fat is thought to be mostly visceral, accumulating around the abdominal organs. You also raise your HDL cholesterol with hormone therapy; with metabolic syndrome, you lower HDL cholesterol. Patients also see a fairly marked rise in adiponectin levels with LHRH agonists, whereas low adiponectin levels are said to be a feature of metabolic syndrome.  (Adiponectin is a hormone secreted into the bloodstream by fat cells. It increases insulin sensitivity in some tissues.) For those reasons, the metabolic changes caused by LHRH agonists seem distinctly different than the classic metabolic syndrome.

Bones

Let’s move on and talk about the impact of hormones on bone density. What is a bone mineral density test? How is it done? What does it measure?

ROSEN: It’s a very easy test with a very low dose of radiation [see Figure 1 below]. The patient lies down on a table, gets properly positioned, and an x-ray is taken of the spine and hip. Based on how much of the x-ray is absorbed by the bone, the machine calculates the bone density and what’s called a T-score. That allows you to compare a particular patient’s bone density to the average bone density for a young, healthy adult. In general, T-scores of −2.5 and lower are thought to reflect osteoporosis [see Figures 2 and 3 below]. By and large, that cutoff seems to identify people who have a significantly increased risk of fracture and who are likely to benefit from drug treatment.

So you look at the hip and spine. What about the forearm?

ROSEN: I’d stay away from the forearm. Forearm bone density tends to fall less with age than bone density in the hip and the spine, so the forearm results might make your bones look healthier than they really are.

At what point are hormone therapy patients referred to you for a bone mineral density test?

ROSEN: The International Society for Clinical Densitometry recommends that all men ages 70 or older should have a bone density test, as well as younger men who have risk factors for fracture, such as hypogonadism. So I think any man who is on androgen deprivation therapy should have a bone mineral density test. The results can help physicians decide if the patient should take medication to prevent further bone loss.

Should the test happen before the patient starts hormone therapy or after?

ROSEN: You certainly can get a baseline score beforehand and then another score when the patient is undergoing treatment. It’s always helpful to see if there’s ongoing bone loss. However, if somebody has osteoporosis or is near to osteoporosis, a condition called osteopenia, and is going on androgen deprivation therapy, which we know to be associated with acute bone loss, I don’t think we have to wait to witness more bone loss before treating that patient. So I would treat men with osteoporosis or osteopenia who are undergoing androgen deprivation therapy if they had a T-score of −2 or lower.

Dr. Smith, tell us about the work you’ve done on the evaluation of bone health in patients on hormone therapy.

SMITH: There are two kinds of osteoporosis studies. One type uses bone mineral density as a surrogate for fracture risk. You can do those studies in fairly small trials over one to two years. The second category includes practice-changing trials, large trials that demonstrate fracture prevention. To date, we only have results from the former kind, but that will change later this year when the results of two pivotal trials are reported. There have been a number of small randomized controlled trials looking at strategies to prevent bone loss during androgen deprivation therapy. They’ve concluded that drugs classified as intravenous bisphosphonates, oral bisphosphonates, and SERMs appear effective at increasing bone mineral density. [For details on these and other studies on bone health, see “Hormone therapy and bone loss,” below.]

What are bisphosphonates and SERMs? How do they work?

ROSEN: Bisphosphonates, including Actonel (risedronate), Boniva (ibandronate), and Fosamax (alendronate), are very similar. They interfere with the ability of cells called osteoclasts to break down and chew up bone. The osteoclast is central to the accelerated bone loss that one sees with male or female hypogonadism. Bone loss associated with menopause, hypogonadism, and steroid use seems to be lessened by bisphosphonate treatment. All of the bisphosphonates seem to work in these situations. Fosamax probably has the best track record, and it has been approved by the FDA for use in men.

SERM stands for selective estrogen receptor modulator. A SERM like Evista (raloxifene) mimics the effect of estrogen at the bone and counteracts the effect of estrogen at the breast. That makes it a helpful drug in women, and it certainly has the potential to get the effect we’re looking for in hypogonadal men. However, it slightly increases the risk of deep-vein thrombosis, which is the formation of blood clots, usually in the legs.

Some people switched to SERMs because they experienced gastrointestinal problems or had a worsening of underlying gastrointestinal disease on Fosamax, which is taken orally. But now that intravenous bisphosphonates can be given instead of Fosamax, there aren’t many scenarios in which I would recommend a SERM in a man.

Do bisphosphonates merely inhibit the osteoclasts? Or do they boost the activity of bone-forming cells, too?

ROSEN: The sad, likely truth is that these drugs probably just decrease bone resorption and breakdown by the osteoclasts. Over time, bone formation probably decreases, too. Now, can I find a study that says something different? Yes. A recent study showed that zoledronic acid (Zometa), an intravenous bisphosphonate, increases the rate at which layers of minerals are deposited, which is a measurement of bone formation. But this might be some sort of artifact that makes it seem like bone is forming. Probably bisphosphonates just reduce bone resorption and therefore reduce bone loss. They probably are not bone-building drugs in any way, shape, or form.

What role, if any, does estrogen play? Isn’t estrogen a mediator for bone loss?

SMITH: In men with prostate cancer, researchers have published some data from short-term trials showing that the addition of estrogen has favorable effects on biochemical markers of bone turnover. For example, using the drug bicalutamide without an LHRH agonist blocks testosterone’s action in the prostate but raises testosterone and estrogen levels in the blood. It completely spares bone.

I appreciate and understand Dr. Rosen’s comments, but there are now data on SERMs in men. I am the principal investigator for a two-year, phase III clinical trial of a SERM called toremifene, or Acapodene, that was recently completed. In 1,389 prostate cancer patients on androgen deprivation therapy, those treated with toremifene were half as likely as those taking a placebo to develop vertebral fractures. Participants also had statistically significant increases in bone mineral density in the hip, spine, and thighbone. Compared with patients on a placebo, patients on toremifene also had lower levels of triglycerides and LDL cholesterol — the bad cholesterol — and higher levels of HDL cholesterol.

Should patients have their calcium and vitamin D levels checked before starting bisphosphonate treatment?

ROSEN: Before getting any therapy for osteoporosis, I think patients should have tests to determine their blood levels of calcium and creatinine, which hint at kidney function. Osteoporosis drugs are not indicated in people with high creatinine levels. Rather than check for vitamin D deficiency, I would just treat it. I would recommend 800 international units of vitamin D and 1,200 milligrams of calcium a day. As long as somebody has normal blood calcium and creatinine levels, is on a reasonable calcium and vitamin D regimen, and has no obvious malabsorptive syndrome, I think he’s okay to go on a bisphosphonate.

Dr. Simon, you’ve written a lot about calcium and risk of prostate cancer. Can you review that?

SIMON: A number of studies suggest a high dietary intake of calcium — 1,500 milligrams and up — is associated with an increased risk for advanced or metastatic prostate cancer. That said, there are other studies that disagree, and even in the worrisome studies, we’re talking about associations, not a cause-and-effect relationship. And we’re not talking about men who already have the disease, but about how the long-term intake of calcium may increase the risk of disease. That may be due to suppression of vitamin D. If a man has osteopenia or is at risk of osteoporosis because of androgen deprivation therapy and he takes vitamin D, I think a moderate intake of calcium — 1,200 milligrams or so a day — is a very good idea.

Let’s talk about mouth and jaw care in patients undergoing androgen deprivation therapy. What should patients know if they develop osteopenia or osteoporosis and start taking bisphosphonates?

ROSEN: My own opinion is that osteonecrosis of the jaw, or the failure of the jaw to heal after a procedure, is rare. It’s primarily associated with high-dose intravenous bisphosphonate treatment — a dose that’s about 10 times higher than we use for osteoporosis. The American Association of Oral and Maxillofacial Surgeons (AAOMS) issued a position paper in 2006 that says osteonecrosis of the jaw is a very rare complication of bisphosphonate therapy given in osteoporosis doses.

According to AAOMS guidelines, patients can have dental procedures they need without modification of treatment unless they have been taking oral bisphosphonates for more than three years. In that case, the guidelines recommend stopping the bisphosphonate for three months before a dental procedure involving the jawbone and restarting it after the bone has healed. They do recommend having any necessary invasive dental procedures prior to starting intravenous bisphosphonates. These guidelines may be overly cautious, but I think they’re reasonable and should allow patients to get the oral surgery, implants, and extractions that they need while continuing osteoporosis treatment.

So let’s pull all of this together. How would you treat an older man with a borderline bone mineral density score who’s going on hormone therapy?

ROSEN: I would say that anybody who has already experienced fractures, particularly fractures without trauma, or anybody with a T-score of −2 or lower should be on bisphosphonates. If the T-score is better than that, I think he can be treated with calcium, vitamin D, and exercise.

And your bisphosphonate of choice?

ROSEN: Fosamax. In addition to having FDA approval for men, it went “off patent” in February 2008. It’s likely that this drug will soon be much, much cheaper than other options, depending on how fast generic versions make their way into pharmacies. It used to run about $750 a year.

Any final comments?

SIMON: I hope our discussion hasn’t scared patients, but I think it’s important to tell them about the side effects of hormone therapy. This therapy is helpful for patients with advanced prostate cancer. Not curative, but helpful. For men who need it, hormone therapy does more good than harm.

SMITH: Most men with prostate cancer are more likely to die from other causes than from prostate cancer. With earlier and improved intervention, we have transformed prostate cancer into a chronic disease for many men. That means that we need to pay attention to the other medical issues that our survivors face. We really need to consider their overall health, including the important issues around body composition, obesity, cardiovascular disease, diabetes, and fractures.

Originally published April 1, 2008; last reviewed March 22, 2011.