Presenter: Philip Zeitler, MD, PhD, Professor of Pediatrics-Endocrinology, Medical Director, Children's Hospital of Colorado Clinical and Translational Research Center.
33 minute presentation
Summary:
Endocrine problems are common in children who have had a bone marrow, stem cell or cord blood transplant. Learn who’s at risk, when to start monitoring for endocrine problems and how they are treated
Highlights:
• The endocrine system regulates growth, metabolism, blood pressure, heart rate, muscle tone, bones, brain development, puberty, sexual function, menstruation, reproduction, pregnancy, sleep, and response to physical and emotional stress
• Growth problems, low thyroid hormone levels, and reproductive problems are the most common endocrine issues seen in children after a bone marrow transplant
• These problems can be treated. The trick is making sure that they're identified before they cause lasting problems
Key Points:
00:38 Overview of the endocrine system: the pituitary, hypothalamus, thyroid and adrenal glands
03:29 What body processes does the endocrine system regulate?
07:24 Low thyroid hormone levels (hypothyroidism) are common after a pediatric BMT
10:21 Growth problems occur in 30% to 60% of pediatric patients after a bone marrow transplant
12:56 Partial growth hormone deficiency after a pediatric bone marrow transplant may not be noticed until puberty, when the child does not experience a normal growth spurt.
13:35 Early onset of puberty may occur in children after a bone marrow transplant and can affect a child’s final height.
16:17: Growth hormone deficiency after a pediatric bone marrow transplant can cause problems in adulthood
20:15 Sex hormone deficiency occurs in nearly all children who undergo a bone marrow transplant after puberty
23:46 Problems with reproduction in children after a bone marrow transplant are less common than growth hormone deficiency and abnormal thyroid function.
27:34 Low levels of cortisol can occur after a pediatric bone marrow transplant, and may be more common than once realized
29:28 It is important to carefully monitor your child’s endocrine system after a bone marrow, stem cell or cord blood transplant
Transcript of Presentation:
00:00 Overview of talk: We're going to talk about our hormonal problems that occur in patients who've had bone marrow transplants, and we'll start with a little bit of an overview about the endocrine system. And then introduce pituitary hormones, where much of the problems arise, and then we'll specifically focus on thyroid problems, problems that occur with growth, and problems with puberty. And then we'll talk a bit about evaluation and treatment of these problems and what you should expect to have in terms of evaluation.
00:38 The role of the pituitary and hypothalamus glands: So how many folks are comfortable with the endocrine system? Good, all right, so we've got some fair amount of background here. So the relevant glands really are the hypothalamus. People often talk about the pituitary gland as being the master gland. If you guys heard that expression before, it's actually not true. I think of the pituitary gland being the Amazon warehouse of hormones. It stores a lot of hormones that are regulating the rest of the endocrine system. But in fact, the hypothalamus is what's really controlling things. So if you have to think about something as being the master gland, it's really the hypothalamus. The pituitary is mostly just making and shipping.
01:25 The role of the thyroid gland: The thyroid gland sits here in the neck. It's a little hard to explain what thyroid hormone does, but mostly it's related to metabolism. The way I like to think about it, thyroid is involved in the expression of almost all genes. But the way I think about its major effects: if you have too much thyroid hormone, it's a bit like being over-caffeinated. Everything is sped up. Heart rate goes up, you lose weight, you get hungry, you know, you get diarrhea, everything is just sped up. If you have too little thyroid hormone, everything just slows down. You get constipated, you actually — if it's really severe — people start to think slowly, speak slowly, etc.
Thymus really shouldn't be on here, it's not an endocrine gland.
02:15 Role of the pancreas: Pancreas makes insulin, we're not really going to talk about it.
02:19 The role of the adrenal glands: The adrenal glands sit above the kidney. They're responsible for the stress hormone, cortisol, and cortisol is a critical for almost all gene expression, but it's most important actions are under the stress situation - say surger. Yyou have severe trauma, you get sepsis, cortisol is made, and what it really does is actually keep the body's response to those things from getting out of control. So, when you get septic, the body releases all sorts of factors that drop the blood pressure, make the blood vessels floppy. Cortisol is responsible for preventing all of that from running off the rails and it controls those things. So if you don't have cortisol under the stressful situation, blood pressure drops, blood sugar drops, everything just collapses.
And then obviously we know what the ovaries and testes do, and we'll talk about most of these.
03:29 What body processes does the endocrine system regulate? The endocrine system actually regulates many body processes. We like to think that, really, all the other organs are really just designed to spread hormones around the body. The hormones regulate almost everything: growth, metabolism, blood pressure, heart rate, muscle tone, bones, brain development, puberty and sexual function, menstruation, reproduction, pregnancy, sleep, and as we just said, response to physical and emotional stress. So an important system, but to some extent a relatively fragile one, and it will respond to insult often by becoming abnormal, and in a way, that makes sense, right? Some of these things, if your body is stressed, reproducing is not going to be the most important thing that you're going to be wanting to worry about. Um, so there, it's a relatively fragile system.
04:33 Endocrine system problems in children after a bone marrow transplant (BMT): In BMT specifically, you can see slow or stunted growth. You can get abnormal thyroid function, you can get abnormal function of the ovaries and testes. Oddly, conversely, you can get early onset of puberty and we'll talk about that. You can get adrenal insufficiency, which is low levels of the stress hormone, cortisol. BMT has been associated with obesity, osteoporosis, and diabetes, and we'll talk about some of these. And again, mostly these depend on exactly what therapy you were exposed to.
05:13 Risk factors for developing endocrine problems in children after a bone marrow transplant (BMT): So the risk factors for endocrine effects are the type and amount of chemotherapy drugs used in the conditioning regimen. A good example of that is cytoxan, which increases your risk for failure of the ovaries and testes. Each of the agents that are used, radiation, et cetera, have their own specific risks associated with them. The frequency and amount of radiation that the patient received is very critical. Exposure to glucocorticoids, prednisone, dexamethasone, and, as we'll see, the age of the patient at the time of treatment, is really quite critical.
05:55 The pituitary gland makes hormones that regulate breast development, growth, muscle development, metabolism, cortisol and reproduction: Okay, so the pituitary gland, I said, is the Amazon warehouse of hormones, responsible for synthesizing and shipping. The pituitary gland mostly has two parts: there's a front and the back. The the back part is involved in regulation of water balance, how much you pee, etc. It tends not to get affected in BMT, so we really won't talk about that.
The anterior pituitary gland makes six hormones: prolactin, which is important in breast development and milk production; growth hormone, which does exactly what its name says, but it also is important in muscle development and body composition, distribution of fat, etc; TSH or thyroid stimulating hormone, which regulates the thyroid gland, which is responsible for metabolism; this is a really long name, we just call it ACTH, is responsible for the regulation of cortisol; and then we have these two hormones which we collectively call gonadotropins, LH and FSH — also long names we don't use. They regulate the gonads to both make sex steroids, and to produce sperm and eggs.
07:24 A pediatric bone marrow transplant (BMT) can cause low thyroid hormone levels (hypothyroidism): The thyroid gland regulates heart rate, a ton of the nervous system, body weight, muscle strength, growth and development, is important in regulation of menstrual cycles, mood, energy, cholesterol — really it's involved in almost every function of the body.
After BMT, low thyroid hormone levels are relatively common. There have been a variety of studies. They give a range of effects anywhere from 14 to 50 percent of bone marrow transplant survivors, depending on the study that you look at. The risk factors are radiation therapy for lymphoma; head and neck tumors or medulloblastoma. This is very radiation dose-sensitive at radiation doses greater than 10 gray [and] more severe if the radiation doses [are] greater than 20 gray. Interesting thing about thyroid is the risk for this takes forever to go away. It peaks about two to four years after exposure to radiation, but it can occur up to 25 years later. So this is one of the most long lasting risks.
08:42 Symptoms of low thyroid hormone levels (hypothyroidism): Symptoms of hypothyroidism are fatigue, decreased metabolism, weight gain, excessive sleepiness, difficulty concentrating, dry skin and hair, cold intolerance, pulse slows down —these are pretty severe— deep hoarse voice, and a depressed mood that goes along with the fatigue.
09:10 How often should children who have had a bone marrow transplant BMT be screened for low thyroid levels (hypothyroidism): So, who's at risk? Really, pretty much everyone. This system is relatively fragile. Screening should be done about every three to six months for two years in patients who've had cervical irradiation, irradiation of the neck — because the thyroid is right here in the field —or total body irradiation, like you might see in a bone marrow transplant.
After the first couple years, it's recommended to continue to follow [the patient] every year for five years. It's very simple. It just requires a blood test for two hormones. We look at both the TSH, which is the stimulating hormone, as well as the final product, the T4, which is the hormone made by the thyroid. We look at both of these because you can see both abnormalities in the pituitary depending on the radiation field, and in the thyroid hormone production itself. Treatment, simple. It's a pill, levothyroxine replacement therapy, very easy to do.
10:21 Growth problems occur in 30% to 60% of pediatric patients after a bone marrow transplant (BMT): Now, growth problems after BMT. Probably the second most common thing we see, occurs in anywhere from 30 to 60 percent of studies in of childhood BMT survivors, and it's really 100 percent of survivors who've had prior cranial radiation therapy. Again, it depends on the dose, but if you're getting doses anywhere above 36 gray, or so, the risk for growth hormone deficiency is extremely high.
The risk factors: radiation to the brain. It turns out that the system regulating growth hormone is very sensitive to radiation. Again, [it] makes sense, right? If your body is under attack in some way, the least important thing [to do] is to get bigger, right?, To grow. So, this system shuts down pretty easily.
Spinal. In addition to the growth hormone effects of radiation to the brain, you can get direct effects of spinal radiation. So, if you have spinal radiation at doses greater than 25 gray, [you] can actually reduce the ability of the spine to grow. Newer kinds of chemotherapy, the nibs, these are kinase inhibitors, and [it] turns out that kinases are important in the pathway, the action of growth hormone. So these have been associated with both growth hormone deficiency and poor growth. And glucocorticoids are, at moderate to high doses, very growth suppressive.
When should you start thinking about this? Well, growth hormone deficiency, this is actually not quite right. It's actually less than this. It can occur right after the treatment and certainly by five years, patients who've experienced much in the way of radiation exposure are at substantial risk for growth hormone deficiency. Both the timing and the time of onset, and the percentage of the population that will be affected, is dose dependent. So, if you'd like to think if you're 30 gray, you [have] about a 50 percent chance of having growth hormone deficiency; greater than 50 gray, it's a 100 percent chance. And the higher the dose, the faster that this occurs.
12:56 Partial growth hormone deficiency after a pediatric bone marrow transplant (BMT) may not be noticed until puberty, when the child does not experience a normal growth spurt: Growth problems can be done by many different things. You can get obviously growth hormone deficiency directly, but another thing that happens is you can get partial growth hormone deficiency and this requires very careful attention, because these patients will grow fine until puberty, but then they don't get a growth spurt. And since the growth spurt in a typical kid accounts for about 13 centimeters of height, that can be a substantial impact on the final height if that growth spurt doesn't occur, and this seems to be related to a partial growth hormone deficiency.
13:35 Early onset of puberty in children after a bone marrow transplant (BMT): You can get premature and precocious puberty in patients, and this really occurs in patients who've had any insult to the central nervous system. So, radiation, brain tumors, seizure disorders or anything like this that disrupts the central nervous system in some way actually increases the risk for early onset of puberty.
Why does that occur? We don't really know except that the system, believe it or not, is actually active when kids are born. And little boys, for example, are making testosterone levels about equivalent to that of adult males, at the lower end of adult male range, and then that system gets shut down over the first few weeks to months of life. And, so, there's some active suppression that goes on that shuts down puberty. And, so, the idea is that if you disrupt the central nervous system, you're disrupting that suppression, and therefore the system turns back on again, but it's really not known very well.
14:39 Early onset of puberty can affect a child’s final height: There are a couple of problems with this, in that if you start your puberty at a lower prepubertal height, you're not going to get the final height you would otherwise [get]. So if you start puberty at six instead of 12, that's an extra six years of growth that you're not getting. So that can have a serious impact on height. And for reasons that are not entirely clear, early puberty doesn't tend to have the same degree of growth spurt. So if you start early, you also don't get as much growth during that spurt. And in addition, it appears, although there's some controversy about this, that the time of puberty is also shortened. So instead of being three and a half to four years, it may occur over two years. So again, you get less time to grow. So that can have a substantial effect. And then you add on [to] this [the] potential for restricted spinal growth, if there has been spinal radiation.
15:39 Growth hormone regulates more than growth: Growth hormone is made throughout life. Most hormones are named for what they were first noticed to do, right? That doesn't mean —God didn't give it that name, right? — we gave it that name, and so lots of hormones actually do more than it seems like they should.
So, growth hormone probably should be better called anabolic hormone because it, in fact, does a lot of stuff. It makes you grow, but it also supports your bones and supports your muscles. It makes you stronger, it makes your heart pump harder, it regulates fat distribution and, so, you make it your entire life.
16:17: Growth hormone deficiency after a pediatric bone marrow transplant can cause problems in adulthood: So patients who are growth hormone deficient may be still growth hormone deficient as adults, and that can be associated with decreased muscle mass, increased adipose tissue, heart complications and, interestingly, low tolerance for exercise. So, patients who are grown adults with growth hormone deficiency are actually — even just in their daily activities — may be functioning close to their maximum exercise, so that they feel very fatigued. Even just walking upstairs may feel like an aerobic event for them. You can get diabetes, decreased bone density, and abnormalities in your cholesterol. So, some people who were exposed to bone marrow transplant or other risks as kids may still be growth hormone deficient as adults. The one thing is, you don't need as much growth hormone as an adult as you do as a kid. So sometimes you have enough when you're an adult, even if you didn't have enough as a kid. Does that make sense? Okay.
17:24 Who’s at risk for growth hormone deficiency after a bone marrow transplant? So, who's at risk for growth hormone deficiency? Any patient who had radiation therapy dose greater than 18 gray —that's when you first start to see problems — or any patient who had surgery to the hypothalamic area. They should be screened if they're experiencing poor growth following completion of therapy. Lots of people don't grow well while they're in therapy. We don't worry too much about that. I t's logical, right? It's not the most important thing at the time.
17:53 When should you screen your child for growth hormone deficiency after a bone marrow transplant? All patients should be screened for growth problems at the first sign of puberty if they've not already been evaluated. And that's because of the things I told you about. Puberty may be occurring early. They may have a terrible growth spurt during puberty if they're partially deficient. So rather than talking yourself into thinking everything's fine, we believe that you really should be evaluated at puberty to be sure that everything is fine, and that the pubertal growth spurt is going to go well.
And we would recommend any kid at risk — a girl greater than 10 or a boy greater than 12 —even if they've not gone into puberty [be evaluated for growth hormone levels], to establish close monitoring [and] to make sure that that growth really is happening well.
One of the things that we see, unfortunately, is that sometimes kids go into early puberty — so they're in puberty at say five or six — [and] they get a growth spurt, which makes their growth look okay. No one notices that they're actually in puberty and that they're having a growth spurt. So, in fact, their growth is not great. And then all of a sudden they’ve finished puberty and they stopped growing and they're really short. So, this is why we think it's really important that at least this be considered, if not a formal endocrine evaluation at this time. Treatment for growth hormone deficiency is growth hormone replacement therapy.
19:22 Spinal radiation can affect spine growth and cause disproportion between spine and long bones: Effect of spinal radiation on the skeleton. Radiation has greater effect on spine than the long bones. You start to see problems at doses greater than 25 gray. And the younger you are — it makes sense — the younger you're exposed, the greater the reduction in spine height.
So, if you are radiated at a year, the average loss is about three to 3.5 inches; at five years, 2.7 inches; at 10 years, two inches. Now, one thing is that the effect of this radiation on the spine may become more apparent at puberty, because that's when the spine grows. And, so, if the spine is unable to grow, you get growth of the long bones, the legs, but not the spine, and you get disproportion. We don't see that as much as we used to because the radiation therapists are getting much better at focusing their therapy.
20:15 Sex hormone deficiency occurs in nearly all children who have a bone marrow transplant (BMT) after puberty: Okay. Turning to sex hormones. Deficient sex hormones —so, estrodial, estrogen and testosterone — have been reported in 31 percent of patients (these are local data) who had a BMT prior to puberty, but in nearly all patients who had a BMT during or after puberty. So, during this period when everything is shut down, there seems to be less damage that occurs from therapy, but in patients where puberty is actually ongoing or has already occurred, and the gonads are active, there's a greater hit. The risk factors are total body irradiation, abdominal radiation, obviously, and chemotherapy with some agents, particularly the alkylating agents like cyclophosphamide or cytoxan.
These problems are rare at doses less than 40 gray, but if you get to doses greater than 50 gray, 20 to 50 percent of patients will have long-term problems. These may look [like] anything from never having menstruation to having menstruation that peters out and stops. Having menstrual irregularities, so abnormal periods. Delayed or no puberty in both boys and girls, and, as I said, you can actually see premature or precocious puberty in girls more than boys. And that's an interesting thing that seems to be related to the fact that suppression — girls tend to escape from that suppression more commonly than boys — we see early puberty in girls much more commonly than boys just in typical kids. And so the suppression system seems to be not as robust in girls, and in boys it seems to be affected more commonly, but you can see it in both and it's important to pay attention to [it], and you need to make sure that you're working with your doctors to be sure that puberty is not intervening.
Why does this happen? As I said, there's something about loss of inhibition from higher centers. In addition, as I mentioned at the beginning, weight gain tends to be common in survivors of BMT. So, some people have wondered about whether attaining a higher body mass earlier, somehow is promoting this. I'm not sure I buy that. You typically see this at radiation doses greater than 18 gray to the head. Girls are affected more than boys, and the impact depends on the age at time of treatment. So, what you find is that the earlier the radiation exposure, the earlier the onset of menses in girls. So like everything else, kids who were treated early tend to have greater impact.
23:20 Premature puberty can affect a child’s height: So premature puberty effect on final height. At diagnosis, patient's height is usually normal. During treatment, the height relative to peers decreases due to the treatment. After treatment height seems to improve, but may be due to early onset of puberty which can make the growth rate look good. And then the early onset of puberty means growth ends early and the child ends up being short, and this is also dose dependent.
23:46 Problems with reproduction in children after a bone marrow transplant (BMT) are less common than growth hormone deficiency and abnormal thyroid function. Reproductive problems are less common than growth hormone deficiency or abnormal thyroid function after BMT. As I said, they're particularly sensitive in children going through puberty and less sensitive if the exposure occurs earlier. Early puberty is a risk and may have very significant consequences on growth and development.
Briefly about fertility. I think you probably have other talks about this. In boys, sterility is present in those who receive greater than nine grams of cytoxan, and girls who've had their ovaries radiated at a dose of 32 gray have increased risk for ovarian failure, and there's some evidence for possible risk of defects in the offspring.
24:32 When should a child be evaluated for reproductive issues after a bone marrow transplant (BMT)? Who needs to be evaluated? Anybody who's had total body irradiation, pelvic irradiation, cranial irradiation or chemotherapy with agents like cyclophosphamide or procarbazine.
When? Anybody, any girl at 10, or any boy at 12, should be seen, or at the first sign of puberty in case it occurs earlier, because somebody needs to really establish close monitoring to be sure that puberty is progressing properly.
Screening is done by physical exam. If puberty is delayed, you can measure LH, FSH, and the sex hormones. Mostly what you're looking for is evidence that the gonads have started to fail. If early puberty, again, measurement of LH and sex hormones can be helpful.
In addition, your doctor will likely recommend a bone age x-ray. What that allows us to do is to see how mature the growth plates are, and to see if they're more mature than they should be at that age. There are stimulation tests that can be done, and there are new emerging markers of gonad function that you may hear about, but their role in all of this is still being figured out.
25:43 Bone age is a better predictor of puberty than chronological age: This is the bone age. This is a way to determine the degree of development. Puberty will generally start at a bone age of 12, irrespective of the child's age. So you may have late bloomers, right? Some boys are really late, they're 14 or 15 before puberty starts, but their bone age will be 12. So, it's a marker of biological development. So bone age of 12 in boys, 10 to 11 in girls. It's a better predictor of puberty than chronological age. It doesn't diagnose anything, but it really just tells us where the child is and how much growth potential is remaining.
26:25 Treatment for early onset of puberty after a bone marrow transplant (BMT): Early puberty. You want to carefully monitor for loss of adult height potential. That includes close tracking of height and bone age. You want to be evaluating for growth hormone deficiency because if you have early puberty, and you miss the growth hormone deficiency, that can have a substantial effect. And again, that early puberty may make it look like the kid is growing okay, but in fact they're not growing very well because they're having a growth spurt at the wrong age.
And treatment is available. There's Lupron, which is an injection, and supprelin, which is an implant, and these are very effective therapies. One thing I want to say, actually, is unlike these guys, everything we find we can fix. So, there are a lot of things you say, oh my god, all these things can happen to people who've had bone marrow transplants’’, but the reality is, if the hard part is identifying them, the easy part is actually treating them, for the most part. They just, they're all treatable. Delayed puberty, we replace estrogen and testosterone.
27:34 Low levels of cortisol can occur after a pediatric bone marrow transplant (BMT), and may be more common than once realized: Low levels of cortisol have historically been thought to be uncommon, and you can imagine that evolutionarily, you'd want this system to be incredibly robust, right? Because it's incredibly important to keep you from collapsing when something happens to you. So, it is generally less affected by things. However, it may be more common than had been previously appreciated, and you can see it with radiation doses greater than 30 gray, but [you see it] down the road, five, seven, 10 years later. In addition, exposure to high doses of prednisone, dexamethasone [is a risk] — because what they are is very, very potent versions of cortisol — so the body sees that and says, oh, you already have tons [of cortisol], you don't need me, and it shuts down. And if the system has been shut down for a long time, it may take time to recover. It will recover, but it may take time.
You can get loss of appetite and weight loss, fatigue, just feeling poorly. Malaise decreased stamina, and you can actually get low levels of sodium in the blood.
Who's at risk? Patients who've had any surgery involving the hypothalamic or pituitary region, and radiation doses greater than 30 gray. If you're accumulating other hormone deficiencies, then you need to start thinking about cortisol deficiency and exposure to these high dose, high potency glucocorticoids. They should be evaluated whenever symptoms develop. You should be evaluated whenever there are beginning to be accumulation of other pituitary hormone deficiencies, and we generally recommend retesting prior to transition to adult care so that you're sure that when you're transitioning this kid to a new doctor, that you know all the problems that are present.
29:28 It is important to monitor your child’s endocrine system after a bone marrow transplant (BMT): So the endocrine system really requires a careful surveillance and evaluation and a partnership. Evaluation and monitoring depends on the risk factors. It's critical that your child's doctor knows the details of your child's therapy. Okay. It's really important that the endocrinologist or whoever else is evaluating, knows what the risk factors exactly are. So that communication between the bone marrow transplant people and the endocrinologist is critical. And we're lucky that we have a very good communication system.
You need to be very suspicious of new signs or symptoms because these can be very mild and partial. And so there has to be a high index of suspicion. I have, too often, I'll admit, talked myself out of thinking that a deficiency was present only to be like, oh, look at that’’. So’, it's very easy to talk yourself out of it because they can be mild, and when you have multiple deficiencies, they can be confusing.
So, we talked about partial growth hormone deficiency in early puberty. If you go into early puberty, it may mask the growth hormone deficiency because the puberty is making you grow faster.
Another example is if you have both TSH deficiency and T4 deficiency in the thyroid. Historically, people look at the TSH rising when the T4 isn't being made, but if you're losing TSH, that won't go up. So now you have this confusing situation. Or if you have gonadal failure, ovarian failure, LH will usually rise. But if you also have lost LH, you won't see that rise. And, so, these multiple deficiencies can be very confusing.
I don't need to tell you this, but I emphasize it. You're your child's best advocate. If you feel like the doctor is not paying attention to something that's happening to your child, you just have to push. I'm sure Brandon agrees that when we're busy, we have a lot of patients, we like to think everything's fine. You have to keep pushing us and if we say something is X and two months later, it doesn't seem like X, you've got to say it wasn't X and make us pay attention. Early intervention will improve outcome and quality in life in these patients.
31:56 Summary of Presentation: So you've already been through a lot. Endocrine diagnoses may come as a surprise to you. You probably were told this but you don't remember because there were a lot of other things going on when your child was first diagnosed. These usually are discussed but people don't remember it.
But remember, all hormone problems identified can be treated. Treatments are relatively easy and have no side effects because we're simply giving back what's supposed to be there. The trick is making sure that they're identified before they cause lasting problems.
And we believe that optimal endocrine care of bone marrow transplant survivors requires coordinated care and communication among the patients' physicians, patients' providers — healthcare providers that are knowledgeable about the risks, endocrine risks, of bone marrow transplant. We would argue for early involvement of an endocrinologist in at-risk cases, not just those who already have endocrine problems, and collaboration works best, we believe, when an endocrinologist is an integral part of the patient's care team, somebody who's just paying attention to that during and after therapy.
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