NIH CLINICAL CENTER GRAND ROUNDS
Episode 2010-11
Time: 1:07:22
Recorded March 24, 2010
Update in Endocrinology 2010
Monica C. Skarulis, MD
Chief, Clinical Endocrine Section, Clinical Endocrinology Branch, NIDDK
Lynnette Nieman, MD
Senior Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, NICHD
ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future - this is NIH Clinical Center Grand Rounds.
(Music establishes, goes under VO)
ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds, recorded March 24, 2010. Today, two speakers from different institutes give us an update in Endocrinology for 2010. First is Dr. Monica Skarulis, chief of the Clinical Endocrine Section in the Clinical Endocrinology Branch at the National Institute of Diabetes and Digestive and Kidney Diseases. She'll be joined by Dr. Lynnette Nieman, senior investigator in the Intramural Research Program on Reproductive and Adult Endocrinology at the National Institute of Child Health and Human Development.
We take you to the Lipsett Ampitheater at the NIH Clinical Center in Bethesda, Maryland for today's presentation.
SKARULIS: All right. Thank you for that introduction. Hopefully we'll have time to cover our material now. I'm particularly delighted to share the podium with Dr. Nieman today and given the time allotted I'm going to apologize in advance because we probably won't cover all of the most interesting aspects of endocrine that has occurred over the last year but hopefully we'll get to a good deal of it.
The overarching goal for the hour at least from my perspective is to outline new research that impacts the health and care of patients with endocrine disorders and diabetes.
From my part of the talk I'll describe current thinking about environmental influences on thyroid function, then we'll turn to assess the current trends in obesity and its treatment, then we'll go on and evaluate some of the newest evidence diabetes treatment and prevention of cardiovascular complication. So approximately a year ago a day-long symposium was held by the endocrine society that was entirely dedicated to chemical disruption of endocrine pathways. And thyroid hormone is an essential hormone necessary for neonatal growth and development, childhood development and is a key regulator of metabolism in adults. Any chemical disruption of this organ of course would have far-reaching public health implications. So I want to recommend to you this particular article written by Elizabeth Pierson, Lou Braverman at Boston university medical center, which nicely outlines the environmental pollutants and the thyroid.
Here we have the mechanisms of thyroid disruption. They include a direct effect on the thyroid. We have some chemicals that interfere with thyroid hormone binding to transport proteins. We have problems with liver degradation of thyroid hormone and the peripheral conversion of the pro-hormone t-4 to the active hormone t-3. In addition, chemicals that will interact directly with the thyroid hormone receptor, thyroid hormone sensitive cells.
We don't have time to talk about all the mechanisms but we'll go through two. So the first and probably one of most important steps in thyroid synthesis is the uptake by active transport of iodide into the site through the sodium iodide importer. This brings the iodide in, brought through to the lumin, that undergoes oxidation and organfication and incorporation into thyroid globulin and ultimately into thyroid hormone. We study or we can assess clinically the activity of the sodium iodine importer or NIS, looking at radio iodine uptake, a nuclear medicine study.
We have certain anions that can hijack the sodium ioine symporter. These are listed in order of decreasing potency. Perchlorate, thiocyanate which is a by-product found in cigarette smoke and the least potent of them, nitrate, which is found in the environment as well as in food sources like cured meats. It's important to know they all act as competitive antagonists with iodine at the NIS. Perchlorate found attention in the media in part due to findings of high levels of perchlorate in water sources in California. And we know that it is used extensively as a stabilizer in solid propellants, rockets, missiles, it became an important topic of discussion in Washington D.C. when they found munitions dumps in upper Northwest D.C. and in other things that we interact with. Perchlorate is found in drinking water in 35 states and it has also been found in beverages, sodas, food, even prenatal vitamins. And in the nhanescohort 2001 to 2002 they were able to measure perchlorate in the urine and found to about 3 parts per billion.
I'll show you some studies that suggest who maybe at risk for perchlorate and it effect on thyroid function, they are women and unborn children, infants and those that are iodine insufficient or frankly deficient.
Here we have four different studies and we have the nhanescohort. What we found was an inversion relationship with the thyroid function and perchlorate levels in urine. That was modified if one had sufficient iodine in the diet. So they only found thyroid dysfunction in subjects that had urinary iodine concentrations less than 100. In intervention studies to try to address specifically how the administration of perchlorate affects thyroid function giving large doses to several volunteers over two weeks, only the highest dose ten milligrams per day over 14 days resulted in a significant decrease, 50% decrease in the activity of thyroid taking up radioactive iodine.
In occupational exposures, men who have very significant exposures and fair amount of perchlorate in the urine, when they were studied after three days off from the job, their thyroid uptake increased significantly.
So taken together, these data suggest that perchlorate has an affect on thyroid function, it is potentially modified by the dietary iodine intake. And also it may actually be modified by the pre-existing thyroid pathology or lack thereof. So I would just point out that the EPA to the state while they have been thinking about regulating perchlorate levels in drinking water across the country, they have not done so as yet. Less is known about the human affects of chemicals that are structurally similar to thyroxin. This class interacts directly with the thyroid hormone receptor.
PCBS, polychlorinated biphenols are lipophylic chemicals found ubiquitously, they were used in electrical transformers and coolants and things like that. They have been banned worldwide. However it's thought there's about 1.5 million metric tons of these existing in our environment.
I'll show you a couple of studies related to PCBS. These polybrominated diphenol ethers are similar to them. This phenol which is found and we hear in the media all the time in plastics and exposed to in plastic drinking vessels has been found in animal studies to be a specific antagonist of the thyroid hormone receptor beta, that's very important potentially to human health.
Triclosin, which is you may see it on listed as an ingredient in personal hygiene products including toothpaste, it exists everywhere and it looks very much like thyroid hormone as well. In one of the nhanescohorts they study that. In the urine they found the rates of triclosan in urine directly relates to your economic wealth and household income. But really frighteningly it's been found that high levels inhibits thyroid function in rats and then it also modifies thyroid hormone gene expression in frogs. So this is an important group of chemicals.
In regards to the studies on PCBS, those are really the only chemicals that have not been extensively studied, the findings on thyroid hormone affect are really rather inconsistent but point to an inverse relationship so the higher the PCBS the lower the thyroid hormone function. I want to point out in pregnancy in several different cohorts, PCBS did inversely correlate with thyroid function and the chemicals were always found in breast milk.
So to wrap this up the endocrine disruption of the thyroid. Perchlorate hijacks the sodium iodine symporter and may result in disturbance especially in states of iodine deficiency in chemicals structurally similar to PCBS and triglysin are ubiquitous and can interact with the hormone receptor. Their affects mare more subtle than thyroid function testing can detect at this time.
So lets switch gears and talk about obesity treatment. Some hopeful news came from N. Haynes data published in Jama in January that suggests that obesity rates in adults are changing course particularly in women. This representative graph is the distribution of BMI in men and in women. And you can see that the dashed line represents the years 1999 to 2000 and the solid lines 2007 to 2008. This shows the median BMI in men is still slipping slightly forward, increasing slightly, but in women it looks like it's pretty static. Similar positive results in trends are being seen in children as well. But despite this encouraging news we have to ask ourselves what advances have we made in the treatment of obesity to reverse these trends? And I would say there's been precious little.
Let's start with the good news. The good news is that in this study published by O'Brien in Jama just in February of this year, they looked at the affects of laproscopic gastric banding in severely obese adolescents.
This study was conducted in Australia, where they took 50 adolescents between 14 and 18 years of age with a BMI of 35-kilograms per meter square. If you're not familiar with that metric, 35 is considered to be severely obese, obese class 2. They were randomized to gastric banding versus individualized diet plans and exercise with a good deal of support. And the primary outcome of this study was the number in each group that was age to achieve 50% excess weight loss in two years. This is a method used frequently in bariatric surgical studies. Secondary outcomes include health and quality of life.
This graph basically shows the display of the weight of each participant in the study with the laparoscopic patients in black and the lifestyle modification in blue. What we can see is that not only did most of the weight occur in the banding patients but the heaviest banding patients lost the most weight. And in terms of reaching the primary outcome, 84% of the banned patients lost 50% of their excess weight while only 12% of lifestyle. But I contend that 12% is significant and almost amazing. In terms of the health improvements and adverse events, the gastric banding by losing about 10 times the amount of weight the lifestyle group lost, had resolution of the metabolic syndrome in each case. They had improvement in their insulin sensitivity parameters. And but in both groups there was significant improvements in their blood pressure. In regards to adverse events, the revision of gastric banding was required in 28% of the banding patients and required a lot of interactions with physicians and hospitals. The majority of the revisions occurred because of what we call proximal pouch delation which caused significant symptoms of heartburn reflex or vomiting. But we can conclude that while this study was very small gastric banding is effective for severely obese adolescents.
The more conservative among us may not be ready to submit our patients to bariatric procedures just yet. But on the diet front we have had a very large study which provides comparisons of weight loss, diets of different compositions of fat, protein and carbohydrate. This follows in the wake of a number of studies that were done that demonstrated an advantage to the low carbohydrate diet. We'll review those for a second.
Those among us who believe a kilo calorie is a kilo calorie no matter the composition, we're surprised when we got the results of the a to z weight loss study published in Jama in 2007. Whereby they compared the affects of an ultra low fat diet, the Ornish diet, the low carbohydrate diet, the Atkins in green and two balanced diet, lifestyle modifications. The patients in the Atkin's diet were the so called biggest losers with a weigh loss of approximately five kilograms in comparison to the other group. The criticism of this study was that it was only a year long.
That was followed by a report in the New England journal, of an Israeli study that consisted mostly of men conducted in the workplace comparing a low fat diet a Mediterranean diet and a low carbohydrate diet. We see this advantage of a low carb diet with about at the end of the day about five kilograms of weight loss.
This new study done by many centers with a lot of heavy hitters running the show, included 811 subjects of which 645 completed. 40% were male and the patients were randomly assigned to diets, they all had a caloric deficit of 750-kilocalories, but the diets were different in that some were high fat, low fat and they looked at high protein or normal amounts of protein. And variable amounts of carbohydrate from 35% through 65%. Each of the patients had group and individualized sessions to improve their compliance. And physical activity was increased to 90 minutes of moderate exercise per week. So how did they do? I would say pretty miserably. What we find is that there were no differences in weight loss among the diets of various compositions, low fat versus high fat. Low carbohydrate versus high carbohydrate, moderate protein versus high protein. The average weight loss was about 3-kilograms over two years of study. In the best of hands with the greatest support.
So the conclusion is that a kilo calorie is a kilocalorie. One could argue that they did not use the same dietary restriction of carbohydrate in the low carbohydrate diet but it's very sobering and it makes one take pause and say maybe bariatric surgery is the right option for patients with diabetes and other co-morbidities.
Now, in the final section of my presentation I would like to review some recent studies on glycemia control and diabetes.
So this study which is the intensive versus conventional glucose control in critically ill patients came after conflicting reports that started with the Vandenberg studies that found advantage when tight control was achieved in patients that were critically ill in ICUS. And the nice sugar study investigators asked the question does intensive glucose control with a target of 81 to 108-milligrams per decaliter result in decreased deaths from any cause within 90 days of ICU admission compared to conventional control which is getting the blood sugar down to 180. So nice sugar is normal glycemia, and intensive care evaluation survival using glucose algorithm regulation. That's a mouthful.
It was an international study including Canada, New Zealand and Australia, large study with 6,000 patients randomized to intensive or conventional arms. The randomization scheme was effective, that the indications and severity of the diseases that led to the ICU admission were equally distributed. The only difference between the two groups turned out the intensive group received more corticosteroids, that was usually for the indication of sepsis. How did they do? When you look at conventional glucose control arm up there in red versus the blue, the first thing we can note is that the intensive glucose control arm did not meet their target blood glucose levels. It was close and it was better but it wasn't a target.
When they looked at the risks associated with even achieving this level of glycemia control you can see they suffered from severe hypoglycemia, the odds of having hypoglycemia increased 15 fold. When one looks at the Kaplan Meier survival curve for these patients with conventional in red intensive in blue, we can see that there was a survival advantage to the conventional glucose control arm rather than the intensive control arm. So the odds of having of dying was increased in the intensive group. So intensive therapy increased the absolute risk of death by 2.6% which represents a number needed to harm of 38 which is really quite low. And the cardiovascular deaths were predominant in that group. So I conclude that less than 180-milligrams per decaliter is the nice sugar to have in the ICU.
So in the last few weeks the accord trilogy was completed. I refer to it as that the first study that we had, that's the action to control cardiovascular risk in diabetes study group, was published first in 2008 and this is a heart, lung and blood study, 10,000 patients randomized to intensive glucose lowering with a target hemoglobin a 1c of six or less versus conventional which was between 7 and 7.9. The goal was to get it there no matter how, use every agent you can in the book. And there was a 2 by 2 factorial design patients were also randomized into a lipid study as well as a blood pressure study. The intensive glucose lowering portion of the study was terminated early due to excess cardiovascular deaths in the intensive arm with a hazards ratio of 1.22. So when those patients were then released from their tight control and allowed to be a more liberal hemoglobin a 1c these two other studies went on. What do we find?
In the accord lipid trial which the investigators asked as does a statin used to reduce LDL and a phenol fibrate to lower hdl and triglycerides, does it lower card cardiovascular events as compared with statin alone. We look at the curve here and in terms of the primary outcome, which is all major cardio cardiovascular events there's no advantage to the addition of the phenol fibrate. In a subgroup analysis in women, women faired a little bit worse in that situation. That's despite the fact that triglyceride levels were significantly lower and HDL was higher.
What about blood pressure? So the investigators also wanted to see if they could get the systolic blood pressure to less than 120-millimeters of mercury, was that better in preventing cardiovascular disease than the standard 140. So again, looking at the primary outcome of cardiovascular events we can see that the intensive versus the standard blood pressure approach is no different. However, when you look at the components of cardiovascular risk there seems to be a slight decrease in non-fatal stroke in the patients that had greater blood pressure control. Certainly when we look how the study was conducted the blood pressures certainly were different intensive level was down lower, about 120. But this was done with the use of many more blood pressure medications, close to four compared to about one or two in the standard group. Of course, there were all the side effects associated with that extra anti-hypertensive use.
So the conclusions. Cardiovascular risk factor reduction is critical in diabetes patients, no doubt about that. Intensive glycemia control to get a hemoglobin a 1c below 6 is associated with grave risk. The routine use of phenol fibrate does not reduce cardiovascular events and should be used with caution in women and doesn't seem to decrease major cardiovascular events but might result in a slow small decrease in stroke. But one has to be advised that there are adverse affects of that therapy.
Now, I can't help but touch on a controversial subject, I just need to, in part because of if anybody reads New York Times the Washington Post, you're reading about the rosiglidazone approved for use in type 2 diabetes in 1999.
Here we have in June of 2009 the results of the record study, rosiglitazone evaluation for cardio vascular for type two diabetes. This was to assess non-inferiority in combination with two commonly used agents compared to the dual therapy of those drugs. What they wanted to see is if they could impact on cardiovascular outcomes, cardiovascular hospitalization or death.
Now, in June of 2007 an interim report on this very trial was published in the New England journal and the week before a meta analysis that caused a good deal of furor about what we should do about rosiglidazone causing more myocardial infarctions. The company went on and continued this trial and these are the results they found.
When you look at the primary end point of cardiovascular death or hospitalization in rosiglidazone therapy in red and active control in blue, there appears to be no difference. One looks at the components of cardiovascular risk factor or cardiovascular events, what was already known about rosiglidazone, it worsens heart failure, it indeed in this trial to increase the risk of fatal and non-fatal heart failure by twofold.
So what do we learn now from record? So rosiglidazone added to metforman seems to have a similar rate of cardiovascular event as well as control. Fatal and non-fatal heart failure twice as common with rosiglidazone. Glycemia control was actually better in the rosiglidazone group and weight gain is common with all of them and distal fracture risk which is a class effect with these agents was noted as well.
As I was preparing for this talk I ran across this article, it was published on Saturday, it looks at the association between industry affiliation and cardiovascular risk with rosiglidazone. The authors from mayo analyzed articles that commented on rosiglidazone risk for a possible link between author's position and their financial conflicts of interest.
202 articles were identified, 53% had conflict of interest statement which is a surprise there aren't more conflict of interest statements and 45% had financial conflicts of interest. And what they found was that the author's position whether favorable neutral or unfavorable on the risk of myocardial infarction rosiglidazone was truly associated with whether or not they had financial interests in rosiglidazone manufacturers. In fact, the favorable position was associated with a four fold increase in the rate of financial interest.
So the authors say hey we were unable to clarify the conflict of interest because the majority of the authors who had financial conflicts of interest with piaglitazone also had financial conflicts with the maker of rosiglitazone so nobody is clean. However, the senate has gotten involved.
This is what makes us all very interested in January of this year this staff report on glaxosmithkline in the diabetes drug Avandia was prepared for the committee on finance in the senate. They challenged the FDA to comment. The FDA wisely has a very hard job to do now. They are going to take their time, review the data and we can expect their decision on this drug come July. I think I have to turn the podium over to Dr. Nieman at this point and so I thank you for your attention.
[APPLAUSE]
NIEMAN: Thanks, Monica, that was great. Thank you, John, for the very nice introduction.
So I don't have any financial conflicts, you might think I have a conflict because I'm a member of the subspecialty board of endocrine metabolism that writes the question. So I want you to all understand this is not intended as a board review for internal medicine or endocrinology and it wasn't constructed to reflect any of the questions that I know of on the exam.
So couple of objectives here that you can read.
Like Monica I had a question what to choose to present to you. So I chose the orphans, Monica presented the really important things but most people don't think adrenal, pituitary, we would disagree that reproduction is extremely important so I'm going to talk mostly about those orphan glands. I went back to January of 2009. I wanted to choose things that had clinical relevance since not all of you are endocrinologists so I tried to hit on topics of general internal medicine interest or overlap with some subspecialties. These are things I'm going to talk about, we'll start with constructive sleep apnea and metabolism.
As you're aware obstructive sleep apnea is common, occurs in up to 7% of men and 5% of women and recently there was a proposal to use an easy four question query to figure out whether people have this, you ask if they know they have snoring or tiredness during the daytime, observed apnea or high blood pressure.
I'm going to cite papers helpful to you, if you want to look them up in greater detail and this is a nice review on this subject talking about all the things we don't know about it.
What we do know is a number of associations whether causal or not, we don't really know but OSA is associated with cardiovascular disease, glucose intolerance and metabolic syndrome so to people like me who study people like this who have hypercortisolism, we know these patients have these associated morbidities. So this brought up the question of whether hypercortisolism underlies some of these associations and unfortunately they're inconsistent reports of hypercortisolism, mostly limited by small numbers of patients who were studied and a small number of samples obtained. The way we can all be on the same page in terms of why we measure how we measure cortisol and think about its production, this begins in the hypothalamus with release of tropin releasing hormone which causes the corticatroph to release and make acth. That affects the adrenal gland the amount of cortisol. Later in the talk I'll refer to important actions of cortisol or cortisol-like agents on the hypothalamic pituitary components to suppress production of acth and make it a feedback fashion.
So this group decided to sample more appropriately for cortisol in this condition and they did this by obtaining blood every ten minutes to measure both ACTH and cortisol, and this was done over a one full day. It was done before and at the end of three months of compliance with continuous positive airway pressure treatment or CPAP. They also performed a single breath 35% co-2 stress test that causes most cortisol to go up but thought to be a reflection of how strongly one responds to hypoxia of OSA. Don't get too wound up about these graphs. I will go through it with you. There are ACTH values on the left, the cortisol on the right. For each panel there's a before, CPAP and after CPAP, these show the levels during the day but I want you to focus on the secretion pattern obtained through deconvolution analysis. You can see for the panels on the left, as compared to ones on the right there's less secretion on the right than the left and they conclude from all their patients that ACTH and cortisol levels improved with CPAP. They looked at other parameters associated with obstructive sleep apnea and they reported weight was unchanged.
This was of course a three month study, patients weren't counseled to lose weight but it would have been extremely exciting if improvement of hypoxia would have changed weight but on the other hand the systolic blood pressure improved.
So I'm going to now turn to the question of hyponatremia and fracturesch. This is a story going on since mid 2005 or thereabouts. It largely started with this study, reporting that mild chronic hyponatremia was associated with falls, unsteadiness and attention deficit. I'll mention the attention deficits they recorded in these patients examined before treatment with various methods to increase sodium, and when they had normal sodium levels the attention deficit and hyponatremia was equivalent to that of taking a couple of alcoholic drinks so you can put that in context. What I'm showing you here is a total traveled weight plot.
This is the before and these are three patients with low sodium levels, 130 to 134, 126 to 130, sorry. And these plots are showing you the path a patient takes starting this side and going to this side of a platform that senses pressure so they can actually plot out the way the patient was walking. You can see these people are jig jagged all over the place. And here when they had normal sodium levels they're not entirely great but this one is pretty good. They improved. So this then set out a lot of alarm bells I think in people's minds so people wanted to pursue this in this next study in 2008. They went the next step and said if there are falls are there fractures associated with hyponatremia. They went back and looked at 513 people who presented to the emergency room after an incidental fall and they were all ambulatory and they were all older people, more than 65 years of age, though I think that's a very young age at this point in my life but they called them old. So controls they compared were agent sex matched randomly selected patients without history of fracturech. There was no determination of bone mineral density in these folks. The prevalence of hyponatremia in patients with bone fracture and in the controls were 13 and 4% respectively. This was statistically significantly different. And they found that hyponatremia alone was associated with bone fracture with an adjusted odds ratio of 4.16. Of the patients who had fractures hyponatremia was an association in 9.2%.
So this makes us wonder what's going on, these people just falling on their own and that's enough to cause a fracture in somebody who is older or what else is in the etiology?
So Joe Forbales, one the faculty in the endocrine training program who worked at Georgetown has a rat model of hyponatremia, using DDAVP. What they did was look at the bone quality in these rats made hyponatremic for three months and it's well shown that in the rats who had solid food don't become hyponatremic, they have a better bone density than those who become hyponatremic. He found there was a 30% reduction in bone mineral density. So we have another piece of the equation that not only does hyponatremia make people fall but makes rats have a lower bone mineral density. They said what about people?
So the same group looked at a cohort of nhanespatients, all adults selected for age greater than 50 years and without any calcium abnormalities judged by the presence of other diagnoses such as hyperpara thyroidism, the mean sodium level was 133 so not severe hyponatremia. They found a positive linear association between sodium and bone mineral density in the hyponatremic patient bus not the normal. Among those hyponatremic looking at total hip BMD, this followed in other areas but for time I'm going to show you total hip, the sodium explained 14 points of a percent of variation. BMD decreased a reasonable amount for everyone millimolar decrease in serum up, and the adjusted odds of osteoporosis in this group was 2.85. This is I think a very exciting series of developments because hyponatremia is common in the elderly but sometimes related to ADH.
This brings me to another new recent study that just came out, the salt water study, I spared you the whole title that ends up being salt water but at any rate this is a group of investigators looking at a vasopressant antagonist that causes a water diaresis, not sodium and this agent has been studied in relatively short term trials up until now.
In this study there were over 111 hyponatremic patient whose received the agent for mean follow up of 171 days so there was a large number of patient days to look at exposure. In the group mean serum sodium increased from 130.8 to 135. This was an intended outcome with dosing. And this continued during everyone's observation period. The drug was very well tolerated. The common side effect was people complained of having a lot of urine. So that was sort of an expected adverse effect. Only 5.4% of patients discontinued the drug because of one side effect or another.
So this study per se hasn't been linked to anything related to hyponatremia and bone but I would guess since we have hyponatremia leading to falls and contributing to fracture, my guess is we're going see trials of these patients and with the hypothesis of establishing new natremia reduce the risk of falls. So that's an exciting potential approach to really reducing fractures which are tremendously costly to our society and to the patients themselves.
So I'm going the touch on traumatic brain injury and its effect on the pituitary gland. This story goes back to about 2006, 2007. This is a Turkish group. They looked at 22 amateur kick boxers who boxed in national international championships to let us know they did this often and they were good at what they did. They were age 27 years and compared them to 22 healthy controls. They measure ad variety of hormones and they did testing particularly for growth hormone insufficiency and they found five people with growth hormone deficiency and two with ACTH deficiency.
IGF-1, a correlate of growth hormone deficiency was negatively correlated with their age, the duration of supports, and number of boughts so this suggest it is more you do this and getting trauma the more likely you are to have growth hormone deficiency. So the conclusion from this is that martial arts and other sports with head trauma including soccer and diving not only maybe related to IQ issues but might increase the hypopituitarism, a think parents got wound up, endocrinology parents more than others were wound up about this. But this group decided to pursue this and then around the same time came out with this study looking at what happens with people who are not voluntarily being traumatized in terms of their brain but who were admitted after a serious injury either motor vehicle accident or falls. I have the endocrine parameters not that anybody needs to remember them except the endocrinology fellow also get a test after that. They did a number of tests to look at whether or not there was hypopituitarism and they found is shown here on the left with initial in black and 12 month follow up in white, they found a lot of gonetyl reproductive hormone deficiency initially which ameliorated significantly, but they looked like they were seeing more growth hormone deficiency over time though this didn't turn out to be statistically significant. This suggests that what you should do is not only screen for pituitary deficiency initially but also to look at everyone at 12 months. You can imagine with the amount of neurologic injury we see, how costly that would be.
So the Dutch decided they didn't like this idea very much and they decided they were going to do their own study. I should say that these patients, let me point out, these all are patients admitted to the neurosurgery intensive care unit so they had relatively severe TBI. Here is the Dutch study, they looked at 107 people drawn from consecutive patients who presented to their emergency room who required neurologic, neurosurgical evaluation. They considered those to have TBI. 77 had only mild TBI, this is already a difference from the previous study. The study these patients not initially but at about a year after their trauma. They did a variety of endocrine tests, they had a little bit different set of criteria for diagnosing hypopituitarism, they did a pretty straight forward easy screen initially and if anything looked weird they confirmed with additional testing but that was done to show you could be cost effective with this analysis. So overall they found only one patient of the entire group with partial adrenal insufficiency caused by low ACTH levels. And so they concluded that it was not cost effective to screen unless there were clinical features of hypopituitarism.
So here we have two studies on slightly different populations using slightly different criteria to make a diagnosis but I think one might take this together and say we screen if there were severe TBI initially or subsequent symptoms meaning screening later on, how often you have to keep evaluating for development of hypopituitarism. So risk factors for adrenal sufficiency, some are new, for example, opiates are now recognized to inhibit ACTH through mechanism not very clear but certainly a lot of us are treating our patients with pain medications that are opiates and these people may have at least biochemical abnormalities. And we also know the glucocorticoids feedback on the axis and suppress the ACTH release. These patients can have secondary adrenal insufficiency because of this. This just to remind you all this can come from any root of administration so rectal, encephlation, vagal nerve injections, oral medication, and dermatologic preparations. And there may also be drug interactions from drugs that you give someone.
This later paper examines drug interactions and in patients who had inhaled steroids looking at two of the most potent ones likely to suppress the axis. These are all both metabolized by the sip 3a-4 system, and these 15 patients who they reported also were taking inhibitors primarily protease inhibitors, but also the verapamil and dilitazem. The thought here is that these kinds of interactions also occur with every other root of administration so if you have a patient on a steroid as well as one of these other drugs one has to think about these development of these complications.
I put this up here mostly so that you can see the url, not to remember all these various drugs but just to remind us that here these lessons are listed again. And this kind of a website I think is very useful but even for us here at the NIH the more useful thing is to talk with our pharmacist, these people have been extremely helpful looking at drug interactions when we have had questions. We know that children who are abused grow up to be adults not well adjusted. We don't understand the mechanism of this, there's quite a few studies in rats that suggest it may have to do with the glucocorticoid receptor amount and ratio in the brain. Certainly in rats it's clear that licking and grooming of the infant by the dam leads to demethylation of the promoter for hippocampal glucocorticoid receptor, associated with increased adult expression, a low hypothalamic pituitary adrenal response to stress and high levels of grooming in these pups as they become adults.
So the question is there a similar mechanism in people? And I think this is a fantastic example, a translational science taking observation in a non-human species and looking at people. And what they did was obtain the hippocampi from human suicide victims who did or did not have childhood abuse. What they found out was those with childhood abuse had increased methylation and decreased glucocorticoid receptor. This is the name of the receptor and the hippocampus. And so this parallels the rat study and I think carries potential implications for how we might want to approach these patients.
Just a note on this, we know that prolactin is needed for proliferation of breast tissue in utero and at the time of pregnancy and so since it's needed for proliferation there's a thread of thought running through the lay press and medical literature as to whether or not prolactin underlie it is development of breast cancer.
That was studied in another Dutch study here. What they did was look at their country's database of prescriptions to identify people who received a dopamine agonist, that those are used to treat hyperprolactinemia to use as a surrogate marker. They had a reasonably large study but it would have been better to be larger. A relatively young age and they found a calculated odds for breast cancer to be not significant. So this is I think somewhat helpful and reassuring certainly a larger study might have been more helpful.
Just a word on the child health institute and part of our mission is to be sure that every child is planned, wanted and that relates to contraceptives. So there are some issues in contraception. One is that in 2001, about 50% of pregnancies in the United States were unintended. But half of these occurred despite contraceptive use. And the pearl index for actual use, the number of unintended pregnancies per 100 women years of exposure, combined oral contraception is as high as 8%. So it's important to identify reasons for decreased efficacy. And the study I'm going to talk about really targeted in on combined oral contraceptives. As you may or may not know, these contraceptives contained estrogen and progestins and they suppress lH and FSH.
Just to run through a little bit here, we have the pituitary and the hypothalamus making their hormones which act on the ovary to influence follicular growth and development, subsequently to trigger ovulation and endometrial development which makes endometrium susceptible to a blastocyst. We know that the primary level of action for these agents is here, to reduce lH and FSH.
So these investigators asked whether oral contraceptives work as well in obese women as non-obese women. They gave a pill with a common combination of estrogen and progestin. They look at tubes of women, one obese and one not. And they found that of this small group of ten per group, six of the obese women and three of the normal weigh women had at least two elevated estradiol levels, estradiol went up in the previous graph when follicular genesis suggesting they were not suppressed. And they looked at also progesterone levels and found that two of the six women who are obese and one of three normal weight subjects had at least two consecutive progesterone levels greater than three, obviously small sample size here because of problems with getting blood. This is consistent with ovulation. So basically if we think about how do these things work, if you can grow up a follicle, as a larger percent could, and then if you could ovulate that follicle, you have an egg possibly available for fertilization.
This didn't look at whether endometrium is affected but raises questions about whether or not the formulations of oral contraceptives work as well in obese women. Clearly even a non-inferiority study would require thousands of women, and a superiority or inferiority study would require a huge number of women to test this question.
So I want to touch on endocrine disrupters, it's one of the most important things happening in endocrinology recently. Here this is also pertinent for us because we're in a place where there's concern about disrupters in the water.
As Monica mentioned BPA is quite in the press now and I want to remind you that the FDA and NIH have made statements on this saying both agencies have some concern about the potential effects, and here the effect is not just on the thyroid but acting as an estrogen at many different sites. The EPA has not decided to put this on the controlled or banned list and it's still under review. I just want to point out for those interested in this, the endocrine society has a scientific statement on all endocrine disrupters, what are their mechanisms, what's known and not known and this also came out in 2009.
So since we have one fisherman in the audience I thought I would talk about intersex and male bass. This group looked at pollutants in water collected at various points in the potomac water. This one here, downstream of bass at all sites regardless of the collection area, intersex is when you see ovarian elements in the testes. There was a lower prevalence at this site here at least in the large mouth bass.
So I'm finishing by reminding you so we can't update you but it's going to come out soon this year and there are three guidelines from NHLBI in March. Supposedly the new guidelines on lipids and hypertension should be coming out soon, and another update on overweight and obesity in December.
We have both talked about a lot of things on your endocrinology update and we thank you very much.
[APPLAUSE]
Maybe a few questions for our speakers or both of them.
QUESTION: First I would like to thank you for such great data. I had a reflex reaction to one of Dr. Nieman's. Some of us grew up before we knew low sodium was so important for hypertension and heart disease and how is that data you which is important going to juxtaposition with that?
NIEMAN: Dietary sodium doesn't really change your plasma sodium level or serum sodium level very much so there doesn't seem to be a relationship with how much people eat and what their level is in terms of their blood.
The hypocalciuma is related to sodium exchange for calcium in the bone. Trying to maintain calcium used to exchange for sodium.
There's no question and there have been recent studies that neither of us had a chance to talk about that have clearly shown again that a low sodium diet is very important in prevention of hypertension, stroke and those things.
Most of the time people are hyponatremic not because of diet, except for beer drinkers who only drink beer, but because of medications and other reasons.
QUESTION: It does raise the question whether the current sort of voguishness of habitual water drinking might be an increased risk for older patients.
NIEMAN: That's a great point. I think that people should be drinking to thirst, the problem is the elderly lose their thirst mechanism and they have been told to drink 8-liters a day of water and that probably contributes to this problem.
QUESTION: A question to the endocrine disrupters and analogs. It's shown in male decreases the number of sperms and what is happening, I can't think of turning this into an egg in a male fish amphibian. Any idea?
NIEMAN: They interact with the estrogen receptor and much of this is thought to be a pure estrogen effect and since estrogen and testosterone antagonize each other that is the waving of hands you'll read. In all endocrine disrupture literature the mechanisms are not well worked out. We know they interact with the receptor. They're agonists of receptor at least BPA for estrogen, antagonist for thyroid and it's thought to work through that but that hasn't been formally tested.
QUESTION: Interesting information, so much confusion, some of the information could be available for the lay people. I know a lot of this is published in the Jama and New England Journal of Medicine.
Dr. Collins start ad new dialogue with Washington Post, it will be interesting to see how it would be presented in a simpler way for the public.
Thank you.
QUESTION: Where do you think would be a good next focus for this issue of child abuse which I thought was fascinating that the trans-generational effect of child abuse might not be a question of nurture, but might be inheritable through epigenetics. What is the next thing to tease out that a little bit?
SKARULIS: So I think where that's going is really to stay in the rodent models and also there's some monkey work going on. I think the real problem is going to be thinking about ways to intervene because you really can't give demethylation agent to people.
Because it would act on a lot of different target areas. I think the real question is going to be can you do something else with the infant rats for example to see if you can modulate that in some way.
[APPLAUSE]
ANNOUNCER: You've been listening to NIH Clinical Center Grand Rounds recorded March 24, 2010. On today's presentation, two speakers from different institutes gave us an update in Endocrinology for 2010. First we heard from Dr. Monica Skarulis, chief of the Clinical Endocrine Section in the Clinical Endocrinology Branch at the National Institute of Diabetes and Digestive and Kidney Diseases. She was joined by Dr. Lynnette Nieman, senior investigator in the Intramural Research Program on Reproductive and Adult Endocrinology at the National Institute of Child Health and Human Development. You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link -- or by clicking the "View Videocast" link on the podcast homepage at www.cc.nih.gov/podcast. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services
