Thursday, September 02, 2004

The Toe Bone is Connected to the Head Bone

It always interests me to learn of some new medical finding that challenges the way we think about human physiology. Yesterday, there was a report in Medscape News about the role of leptin in the regulation of hypothalamic neurohormones. This advances our understanding of basic physiology, and reveals a treatment strategy for some forms of infertility. It also helps explain the infertility often seen in female patients with Anorexia Nervosa. I suspect the same holds true for men with Anorexia, but this was not studied specifically.

In any introductory physiology course, it is taught that there are nine types of endocrine glands in each person:

endocrine glands
Illustration from AMA website

This may lead one to conclude erroneously that the sources of hormones in the body are discrete, well-localized, and understood. That is not the case; it is an oversimplification. Another oversimplified view would be to say that all parts of the body are in constant communication with all other parts. The truth is somewhere in the middle, but the latter view is closer to the truth. This communication often takes place via the release of hormones, although there are many different kinds of chemical messengers.

Today's article illustrates that not all hormones are produced or released in endocrine glands. Leptin, for example, is produced in fat cells. It is released into the bloodstream, where it circulates and interacts with a variety of tissues, signaling them to alter their function in some way. The Medscape article reports on a study that shows how leptin interacts with the hypothalamus, thereby influencing the release of hormones from the anterior pituitary gland. This, in turns, affects reproductive function.

It has been known for a long time that a very low body fat percentage can impair fertility. Indeed, athletic women, and women with Anorexia, often have great difficulty getting pregnant -- although such women are well-advised not to rely on this as a means of contraception. One theory to account for this finding has been to implicate leptin as a factor in hypothalamic function. The study reported in Medscape (free registration required) is a test of that hypothesis:

Leptin Improves Reproductive, Neuroendocrine Function in Hypothalamic Amenorrhea
Yael Waknine
Medscape Medical News 2004. © 2004 Medscape

Sept. 1, 2004 — Leptin replacement therapy in women with hypothalamic amenorrhea improves reproductive, thyroid, and growth hormone axes and markers of bone formation without causing adverse effects, according to the results of a small, prospective, open-label study published in the Sept. 2 issue of the New England Journal of Medicine.

"Functional hypothalamic amenorrhea occurs when a relative energy deficit...disrupts the secretion of hypothalamic gonadotropin-releasing hormone (GnRH) and other neuroendocrine axes," writes Corrine K. Welt, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues, adding that although the precise signal indicating energy availability remains unknown, leptin is a prime candidate.

According to the authors, the adipocyte-secreted hormone leptin regulates homeostasis and circulates at levels corresponding to fat mass and acute nutritional changes. "As compared with controls matched for weight and body composition, women with hypothalamic amenorrhea have low leptin levels and a striking absence of normal diurnal leptin variation," the authors write. [...]

"In women with hypothalamic amenorrhea, the administration of r-met-HuLeptin in an effort to normalize the relative leptin deficiency results in follicular growth and significantly increases levels of LH, estradiol, IGF-1, thyroid hormone, and bone-formation markers, indicating that low leptin levels may be responsible for reproductive and neuroendocrine abnormalities associated with this disorder," the authors point out.

The authors also note that reproductive function improved after a few months, despite the fact that seven of eight women had a history of several years of amenorrhea, and that the improvement was not related to lifestyle modifications, altered exercise patterns, or weight gain.

"Our findings help elucidate the pathophysiology of hypothalamic amenorrhea and may have therapeutic implications," the authors write, adding that further studies are needed to determine the safety and efficacy of recombinant leptin and the optimal dose and duration of treatment required to restore reproductive function without inducing an undesirable amount of weight loss in already lean patients. [...]

The full article at Medscape includes additional information about the physiological effects of leptin, including effects on thyroid function, bone formation, and body weight. It also includes a quote which illustrates that main point of this post:

"Basic science only occasionally reshapes our understanding of major biologic systems as quickly and profoundly as the discovery of leptin has done," comments Rexford S. Ahima, MD, PhD, from the University of Pennsylvania School of Medicine in Philadelphia.

Note that the results of the study are preliminary, from a clinical standpoint. That means that additional study will be needed to determine if administration of leptin would be a safe and effective means of treating hypothalamic amenorrhea.

In addition to a possible role in the treatment of infertility, it is interesting to speculate about a possible role for leptin in the treatment of Anorexia Nervosa. It is possible that leptin could reverse some of the adverse physiological effects of Anorexia, such as osteoporosis. We already have am effective treatment for Anorexia: eating enough food. But with some patients, this is not acceptable. Weight gain is a side effect. The study reported here indicates that patients treated with leptin do not gain weight, at least in the short term.

This raises an interesting ethical question. At what point would it be ethically permissible to administer leptin to a patient with Anorexia who refuses to eat enough food to gain weight? Would it even be ethical to study this, given that such a study would involve giving an experimental treatment to patients, even though we already have a 100% safe and effective treatment? Ordinarily, the answer would be no. You would not administer an unproven drug if there is an existing treatment that is safe and that always works. The thing is, food does not always work, but the reason for treatment failure is the patient's own behavior. Some patients with Anorexia find the treatment unacceptable, because of the side effect of restoration of normal body weight.

It is ethically permissible to investigate new drugs that may have a lower side effect burden than existing treatments. But if the side effect is actually a restoration of a normal body size and function, does that count?

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Tuesday, August 31, 2004

The Effect of Political Vacuum Upon Embryonic Stem Cells

News@nature.com still has free access for another 24 hours. After that, you need a subscription to one of their journals for access. I think they still will offer free access to their special section, Stem Cell Focus.

Meanwhile, I've taken the liberty of adding two of their articles pertaining to stem cells to my Furl archive. The first is a report on a survey of clinics that perform in vitro fertilization (IVF). The clinics were surveyed regarding their practices followed for the storage and/or disposal of the embryos created in the IVF process. The second is an editorial on the issues raised in the first article.

Published online: 27 August 2004; | doi:10.1038/news040823-15
IVF embryos meet contrasting fates
Emma Marris
Confusion reigns over how US fertility clinics deal with their 'waste'.

What happens to the human embryos created during in vitro fertilization that do not get implanted? A study of IVF clinics in the United States has revealed that they meet incredibly varied fates.

The possibility of using stem cells from human embryos has sparked fierce debate over the moral status of these tiny balls of cells. Although the issue is causing problems worldwide, it has become particularly politicized in the United States. President George W. Bush, for example, is strongly opposed to the harvesting of stem cells from embryos created during IVF. [...]

Some countries, including Britain and Canada, have rules about what happens to the spare embryos, and what level of consent is needed from the couple involved. But there is no such regulation in the United States. [...]

The approaches of the 175 clinics that did dispose of extra embryos varied in the extreme. Some handed the tiny ball of cells over to the couple or individual to take home, whereas some incinerated them as biological waste. Of the clinics that incinerated the embryos, four required the presence of the couple while twenty-five clinics forbade it. Seven clinics even said a prayer during disposal in a quasi-funeral, according to Arthur Caplan, a co-author of the study from the Center for Bioethics at the University of Pennsylvania in Philadelphia.

The majority of clinics surveyed donate extra embryos to research institutions, with the permission of the couple or individual involved, although the clinics varied in the level of consent that was required and how this was obtained. Stem-cell lines derived from these embryos are ineligible for federal funding, however, under current US rules. [...]

"Our results highlight the importance of fully disclosing disposal options when couples first consider enrollment," he says. "Little is known about how clinics deliver this information or about the proportion of couples who, in retrospect, feel they were not fully informed." [...]

What this shows is that there is a political vacuum when it comes to the regulation of IVF clinics. This, I believe, exposes a serious weakness in our political system. Any issue regarding embryonic stem cells is so hot, politically, that no one is willing to address them adequately. At this convention time, we will hear a lot from various politicians who claim to be be courageous. They claim to be willing to take on the tough issues. Mr. Bush does deserve some credit for starting to address the issue, but one wonders how serious he was about the subject, when all he did was authorize federal spending for a few cell lines. He had his bioethics council debate the issues and publish some things, but nothing substantive has come of their efforts.

Our political system is such that it is possible for politicians to avoid dealing with certain topics. Our news media are again failing to call them to action. Of course, the American people also are failing to pay much attention. The issues are raised in medical journals, which the media seem to read from time to time; but apart from that, there seems to be a silent, collective agreement to just ignore the whole thing.

The second article clarifies these issues:

Published online: 27 August 2004; | doi:10.1038/news040823-17
muse@nature.com: A moral minefield
Helen Pilcher
Couples going through IVF should be allowed to choose what happens to their unwanted embryos, says Helen Pilcher.

Who should decide what happens when an embryo created in a fertility clinic goes unused? You might hope, as the potential parent, that the decision would be yours. But you could be disappointed, and so could the researchers who hope to benefit from material that would otherwise go to waste.

Every year, hundreds of thousands of couples undergo expensive, emotionally difficult fertility treatments in the hope of becoming parents. Many opt for in vitro fertilization (IVF), where eggs are fertilized in the lab and implanted back into the mother. But clinics often prepare more embryos than are needed, because they only transfer the best and most couples need more than one treatment cycle. So the question is: what should be done with the 'spare' embryos?

In the United States, there are no laws governing this area. Each of the 400 or so fertility clinics registered with the Society for Assisted Reproductive Technology stands alone, creating and enforcing their own policies. But, according to a recent study 1 , their policies differ... a lot. [...]

But whatever your ethical view, should the offer of donating embryos to medical research really be left to the individual fertility clinics? In Britain, for example, clinics are obliged, if possible, to give couples this option.

If this option is not offered and a couple does not want to store their embryos indefinitely or donate them to other couples with fertility problems, there is only one other choice: to destroy them.

If that happens, we all miss out. Infertile couples have one less option. Researchers miss out on a vital and precious pieces of tissue that could further our understanding of embryology and fertility. Scientific progress is stymied, and medical progress is slowed.

This rare commodity should not be thrown away, at least, not without careful, considered thought. Couples need to give informed consent for any decision made. How is this possible in clinics where only part of the picture is presented?
  1. Gurmankin A. D., Sisti D. & Caplan A. L. Politics and the Life Sciences, 22:2. 2 - 6 (2004).

Dr. Pilcher points out that, in the absence of federal regulation, not only are clinics free to set their own policies, they do not even have to inform couples of the policy the clinic has set. Personally, it is the latter point that disturbs me the most. I am confident that the clinics are careful about the informed consent for the IVF procedure itself. But it appears that they do not have any obligation to get informed consent for the disposition of any unused embryos that may result from the procedure. As far as I can tell from the articles, it appears that they do not even have to inform the couples that there is an issue to be decided at all. The current system of medical ethics appears to be silent on this topic as well, although I have not yet researched that aspect fully.

Clearly, there is work to be done. Politicians, the news media, and the medical profession all need to figure out how to handle these issues.

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Monday, August 30, 2004

Another Look at Economic Data

Courtesy of the Queen of Some Evil, who got it from She Who Usually Will be Obeyed, I noticed an editorial that was published in the Detroit News.  (The link is to theDonald L. Luskin Furled version, in case the DetNews pulls the article.  The link to the original is here.)  It actually wasn't written by anyone at the (conservative) Detroit News.  It was written by Donald Luskin.  He is identified as the chief investment officer of Trend Macrolytics LLC, an independent economics and investment-research firm in Menlo Park, Calif.  I suppose that makes him qualified to comment on matters economic, although I wonder how impartial he can be. 

The gist of the editorial is that the <air quotes>Bush tax cuts</air quotes> are fair, in the opinion of an investment banker.  (The <air quote> tag, for those who haven't read the latest HTML standards, direct the reader to hold up both hands, with palms inclined at a 70% angle to the floor, and gesture up and down with the index and middle fingers together.)  The air quotes are used in this context because, as every high school graduate should know, a tax cut that occurs at the same time as a deficit increase is not really a tax cut.  It is a tax shift, moving taxes from today's taxpayer to the taxpayer of tomorrow. 

Anyway, Mr. Luskin tries to argue that the Democrats have made a false portrayal of the impact of the tax changes:

A report from the nonpartisan Congressional Budget Office has Democratic presidential candidate John Kerry claiming it proves that “Over the last four years, the burden of taxes has shifted from the wealthy to the middle class.”

Those are politically motivated lies that distort the findings of the report. Here’s the truth.

The report proves that what President Bush said about his tax cuts is true: “Tax relief is for everyone who pays income taxes.”

I note that Luskin uses real quotation marks, without providing the sources of the quotations.  I would not go that far, on either count, whatever the sources.  Luskin states that Mr. Kerry claims the report proves "the burden of taxes has shifted;" while Bush states “Tax relief is for everyone who pays income taxes.”  I argue that both statements are true. 

The facts are not in dispute.  The dispute arises over how one defines "middle class," "burden," and, ultimately, how one defines fairness.   

Luskin backs up his argument with this graphic:

Notice that the percentages in the "Income Group" column do not add up to 100%.  They add up to 116%.  That is because part of the top 20% are stratified in the last three rows in each section.  He takes the top 20%, then breaks that down into the 90th percentile, 95th percentile and 99th percentile.Keep that in mind when looking at the graphs, because it changes the perception one gleans from the visual representation of the data.  To be clear, I am not implying that the data are presented in a misleading way; it's just that it could be confusing at first. 

In his editorial, Luskin points out that the wealthiest 20% of American taxpayers are paying a larger percentage of the total income tax.  Of course, there are many kinds of tax.  Recall that payroll taxes are increased in proportion to income, up to about $68,000.  Then the payroll tax levels off.  Indeed, there are many ways the government extracts money from people, so many that it is difficult for anyone to figure out what is really going on with taxes.  Payroll taxes are regressive.

That is a game played on both sides of the aisle.  Taxes may go down, but fees of various sorts go up.  Fees are just regressive taxes.  There has been a shift in the way that government collects money from people, away from progressive taxes, and toward regressive taxes. 

Look at the numbers, and think about both absolute number, as well as percentages.  The bottom 20% of income tax payers get a 1.1% cut.  That gets them one extra loaf of bread per year.  The middle 20% get enough to buy a wide-screen TV.  The top 1% get enough to buy a new BMW.  Is that fair?  Clearly, fairness is a matter of opinion.  

Now, think about the statement attributed to Democrats, that the tax "burden" has been shifted.  What constitutes a burden?  If you make $125,000 a year, $10,000 is a burden.  If you make $1,000,000, it is pocket change.  According to the graph, the greatest increase in the percentage of total taxes paid falls on those in the 80th to 85th percentiles.  Are those people "middle class?"  It depends on who you ask.  To the bottom 20%, those in the 80-85% range are rich.  To those in the 80-85% range, they consider themselves upper-middle class. 

Is it fair to increase the percentage of tax paid by about 4% for those in the 80-85% range, but by only 0.6% for those in the top 1%?  It is a matter of opinion, but my opinion is that it is not fair. 

What about the 0.6% increase in the share of income tax paid by the top 1%?  Is that a "burden?"  Probably not.  But the increased share paid by the 80-85% may well be a burden. 

My main objection to Luskin's editorial is that the analysis is not so simple as he makes it out to be.  He ignores the shift in taxation methodology from progressive to regressive methods, then praises Bush because the analysis of the progressive taxes looks......progressive.   A surprising finding? ... Not. 

After roundly criticizing the Democrats for distorted portrayals of the data, Luskin adds the comment:

...the 2002 tax cuts allowed for greater deductibility of capital expenses for corporations — a deliberate (and successful) attempt to stimulate corporate capital investment after the terrorist attacks of Sept. 11, 2001. The CBO attributes those corporate tax cuts to individuals, based on the extent to which individuals receive dividends and capital gains.

Naturally, the highest-income earning taxpayers will get the bulk of this — even though all taxpayers enjoy the many benefits of a stronger economy as a result of greater capital investment by corporations.

He states that "all taxpayers enjoy the benefits of a stronger economy."  That is a damn lie.  Almost everyone who buys anything is a taxpayer.  Remember that most states have a sales tax.  Also, remember that the percentage of persons living below the poverty line has increased every year for the past three years -- with the greatest increase  occurring among children.  This simple fact demonstrates the falsity of Luskin's statement.  Not  all taxpayers are enjoying the benefit of a stronger economy.  In fact, an increasing number of taxpayers are impoverished. 

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