Hormone Puzzles

There's a really nice piece of research in Neuropsychopharmacology (2010) 35, 2179–2192 that demonstrates that estradiol, the primary estrogen made in the ovaries after puberty and before menopause, is an anti-psychotic substance. 

Estradiol had anti-psychotic effects for normal male rats and female rats without ovaries, but had less of an effect in female rats with ovaries.

The most likely explanation of the difference is that rat females with ovaries have progesterone in their bodies, produced by their ovaries. Since progesterone competes with estradiol in the brain, the estradiol isn't able to work as strongly in the rats with ovaries.

How do you make a rat psychotic? Good question. Feed them amphetamines, evidently. The estradiol helps protect the brain from the damage from the amphetamines, and therefore acts as an anti-psychotic.

According to a study in the Archives of Internal Medicine, in a study of about a 1,000 people, those of us who eat chocolate regularly tend to be thinner than people who don't.

Who says news websites don't carry happy news? And just in time for Easter!

The article is paywalled, but the BBC summarizes it here:

http://www.bbc.co.uk/news/health-17511011

If anyone dares to tell you that you complain too much about your hot flashes, give them this piece of research: According to research performed at Indiana University, School of Nursing, women in studies who report their hot flashes in diaries are missing more than 50% of their hot flashes. Women who were awake recorded their hot flashes between 36%-50% of the time, and when asleep, they recorded their hot flashes only 22%-40% of the time. More than 50% of the hot flashes are not being reported!

How do the researchers know that women won't reporting anywhere near all of their hot flashes? In addition to keeping a written diary, the study members wore a device that measured the temperature of their skin. A Biolog ambulatory sternal skin conductance monitor, to be exact. The machine measures the temperature of the skin, and a sudden rise in skin temperature has been shown to be highly correlated to a rise in internal body temperature-the classic hot flash. The machine memory was then checked by the researchers and matched against the reported hot flashes in the diaries. 

What does this mean, beyond the old news that women are good at ignoring discomfort? It means that just about any study about hot flashes that relies on the use of written diaries is going to be far less accurate than it could be. The use of this machine, which produces something called an objective measure, is incredibly useful in sorting out which treatments work and which do not. This is particularly important in the treatment of hot flashes since almost any treatment is prone to a placebo effect-it works because we think it will.

You can think of the Biolog machine as a way for the body to talk directly to the researchers, without interference from what the brain thinks "should" happen. 

Three cheers for Dr. Adolf Schindler*, who today said something that needs to be said at every meeting that has anything to do with hormones: medroxyprogesterone acetate, known as MPA, brand name Provera, is not the same thing as progesterone, and any academic research paper that has the word progesterone in the title, but refers only to MPA in the paper, should be tossed out for sloppiness. 

MPA has more differences with progesterone than you can shake a stick at, including the nasty fact that MPA has been found to be toxic to brain cells in a couple of studies, while progesterone is protective of brain cells. Just the fact that MPA is a different molecular compound is enough to make mixing it it up with progesterone a prime example of bad science. 

For the tiny minority of you that care, here's the way the classification should be done: the overall category is progestagens-that's any compound that has a progesterone-like effect on cells in the uteruses of rabbits and other lab animals. This includes progesterone, the compound made by the corpus luteum of the ovaries of mammals after ovulation occurs. Progesterone can also be made in a lab. Progestins are also included as progestagens, and these compounds are made in a lab, are never found in nature, and have their own characteristics depending on their chemical structure. MPA is a progestin, and so are drospirenone and norethindrone, and many others.

So now you know better than the authors of one study examining the impact of progestins on the hearing organs. The authors used the word progestins, but never bothered to identify which progestin they were talking about. This just drives me nuts. This is like saying that diesel and gas are the same thing. They may both fuel cars, but put the wrong one in the tank, and the engine is ruined. The differences are crucial.

So please, give your progestagen its rightful name. Don't use the term progestin unless it's clear what compound you are discussing. 

At the biannual meeting for the International Society for Gynecological Endocrinology in sunny Florence, Italy (which is a change, usually it rains heavily when I'm here) I have heard some truly impressive science lectures. However, there has been one extremely cringeworthy moment. In the process of explaining the vast differences in breast impact between two types of hormone therapy, Gunnar Soderqvist told us about his research method. 71 women volunteered to have mammograms and a core biopsy of the left breast done at before starting treatment, and then had another mammogram and breast biopsy done after two months of treatment. 

71 women agreed to two mammograms in the space of two months, and two core biopsies of their healthy breast in two months. What did they offer them? A new car?

Dr. Soderqvist showed us a picture of the needle. I haven't felt so faint since I saw the amniocentesis needle. Then he showed us a picture of a woman in the mammogram machine, with the breast all squished out the side. It looked so painful-they didn't show her face, though.

Thanks to a man by the name of John Lee, millions of women seem to think that progesterone cream will treat their menopause symptoms. Nope. Not even close. There have been a number of studies to see if progesterone will help with hot flashes, or if it will increase bone mass or protect the heart and they all end up conclusively proving that progesterone simply does not play that role in the human female body. So don't take progesterone expecting it to have the same benefits as estradiol because that is not its function.

If using progesterone cream makes your hot flashes go away, then you are experiencing the placebo effect. The placebo effect occurs when your symptoms respond to a treatment, and the effects are the result of a psychological expectation, rather than an actual chemical effect. This is not to say the placebo effect is a bad thing, but it has limits as a medical treatment.

Here's the research: Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women

and more: Double-blind placebo-controlled study to evaluate the effect of pro-juven progesterone cream on atherosclerosis and bone density

Thanks to a man by the name of John Lee, millions of women seem to think that progesterone cream will treat their menopause symptoms. Nope. Not even close. There have been a number of studies to see if progesterone will help with hot flashes, or if it will increase bone mass or protect the heart and they all end up conclusively proving that progesterone simply does not play that role in the human female body. So don't take progesterone expecting it to have the same benefits as estradiol because that is not its function.

If using progesterone cream makes your hot flashes go away, then you are experiencing the placebo effect. The placebo effect occurs when your symptoms respond to a treatment, and the effects are the result of a psychological expectation, rather than an actual chemical effect. This is not to say the placebo effect is a bad thing, but it has limits as a medical treatment.

Here's the research: Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women

and more: Double-blind placebo-controlled study to evaluate the effect of pro-juven progesterone cream on atherosclerosis and bone density

From the file of unintended consequences: a lady in her late forties visited a "hormone therapist " of dubious science and was given a combination of estrogens, and progesterone, all identical to the hormones made by the adult female body. This lady was not post-menopausal, but perimenopausal, meaning she had not yet stopped having periods.

Unfortunately, the "hormone doc" forgot to tell her that this can boost fertility, and despite the odds, it IS possible to get pregnant in your late forties. OOPS. Her periods stopped, and she thought it was menopause-it was an unplanned pregnancy instead.

Moral of the story-you need birth control right up until you stop having periods, and are confirmed as being in menopause. A birth control method like Nuvaring, which uses progestins and a synthetic estrogen will often be a better choice because the progestin in it can reduce heavy bleeding, decrease ovarian cysts and prevent uterine fibroids-all problems commonly experienced by women in their forties.

The bioidentical hormones aren't strong enough to suppress ovulation and prevent pregnancy. A pregnancy in the late forties presents a number of serious risks to the mother, risks that are much higher than most birth control methods. That's why the synthetic progestins and estrogens will often be the best choice for a perimenopausal women who needs extra estrogen for her body and brain, but doesn't want to have more children.

A nice blog piece that covers this comes from Dr. Elizabeth Vliet at:

Women got to hear yet again last week that hormone use might increase their risk of breast cancer from a report by the Million Women Study. Sadly, although this study has  more than a million participants, it was so poorly designed that it is not capable of giving the world terribly useful information about almost anything. There's lots to say in criticism of the study, but the internet posts by women begging for solid information about what to do in perimenopause or post-menopause suggest that a clear voice is needed. No problem.

The International Menopause Society has a series of statements that are intended for women and their doctors to place the various studies in context and help clarify the relative risks and benefits of hormone therapy. Look at: http://www.imsociety.org/comments_and_press_statements.php?SESSID=5tk73tg09ccs65bcu32m2q4vh2

For another clear and detailed statement about the evidence for and against hormone therapy look at the Endocrine Society Scientific Statement on Postmenopausal Therapy: http://www.endo-society.org/journals/ScientificStatements/upload/jc-2009-2509v1.pdf

For the most part, you should ignore newspaper and internet headlines because they do not place the evidence in context, they are not capable of evaluating your personal needs, and the study may or may not have serious flaws that require a trained researcher months to discover. 

The word has been trickling out to psychiatrists that they can often boost the effectiveness of psychiatric medication for their female patients if they also prescribe an estradiol patch. Women over 35, women who have problems with their ovaries, post-menopausal women and post-partum women may be particularly vulnerable to mental problems due to lack of estradiol in the body. Estradiol plays a vital role in the performance and maintenance of the female brain, which is probably why mental illnesses are statistically more common in women at the times in life when there has been a "hormone event".

"Hormone event" sounds like a lot more fun than it really is. It means a time when there is a large hormone change, like puberty, menopause, and after giving birth. If a woman already has a mental illness, this kind of "event" can send her off kilter and into a locked ward. It may seem as if the medication no longer works, or that the disease has entered a more severe stage. Often, the psychiatrist will increase the medication, which increases the risk of serious side effects. Little known pharmacology fact-if you give a patient too much psychiatric medication, you can actually induce the symptoms you meant to cure. So if your loved one seems to be getting worse after his or her dose of medication is increased, consider this possibility.

So if you are lucky and see a psychiatrist who recognizes the problem, checks your hormones, and prescribes an estradiol patch to boost the effectiveness of your psychiatric medication, your problems are over, right? Well......

I swear this happened to a friend. She was working in a public school when a mother of one of the children came into her office and began to rant about her psychiatrist and how the patch he gave her didn't do a damn thing. Aware that this woman was schizophrenic, my friend sat quietly and hoped she would talk herself out. Suddenly, the woman pulled down her pants, bared her hip and dramatically pointed to the estradiol patch, screaming, "it doesn't do a damn thing, and it won't stay on!"

My friend looked at the patch, which was held on with band-aids, and asked her if she had peeled off the backing on the patch.

"What backing?"

Problem solved. After explaining that the plastic patch backing had to be peeled off, and then applied to clean, dry skin, and then pressed on with the hand for thirty seconds or so, the woman ripped off the band aids and applied it correctly. 

By the following week the scenes had stopped, and the woman's behavior greatly improved for the rest of the school year.

So I just want to suggest that any psychiatrist who prescribes an estradiol patch should demonstrate application techniques to the patient, or to whomever handles the patient's medication. 

Note on the microwave this morning. 

Her doctor, being a very smart cardiologist indeed, knew that there was a simple, non-invasive treatment that would improve her heart rhythms, relax the veins and arteries to take the pressure off of her heart, and would improve the muscle function of the heart. This medication is the same stuff that her body made when it was younger, so it won't cause any liver or kidney problems, and is relatively inexpensive. I'll even give you a really big clue-it will help improve her bladder control and incontinence problems. Give up?

Estradiol. The primary female hormone made by the ovaries before menopause.

Madame X uses an estradiol patch on her arm twice a week, and has not had cardiac arrhythmia problems since she started using it. At 82 years of age, this is not about hormone replacement therapy, but about finding the best treatment for her personal health problems. During the recent health crisis, the hospital removed her from all medications while it tried to figure out the source of her kidney problems-this is standard protocol with sound science to back it up. However, the loss of her estradiol patch nearly killed her as her blood pressure dropped and she developed heart arrythmias. After intervention from her cardiologist, her estradiol patch was replaced, and within hours her heart rhythm settled back down again. From a humane point of view, this was much less scary for an elderly, confused woman than a bunch of heart machines. From a cost point of view, this was thousands of dollars cheaper. She's feeling a lot better today. They will send her, with her estradiol patches, to a rehab facility in a day or two.

Want to read the research? Here's a list of selected research citations about cardiac arrhythmiasfrom the government research database, PubMed:

http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&IdsFromResult=20004189

Selected research about the effects of estradiol on the urinary tract is here:

http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&IdsFromResu

OK, no one is ever going to buy the third edition of Reproductive Toxicology for its humor value. Not unless they have a serious personality disorder, anyway. But just when you have settled into a dry "serious science" paragraph on page 14 about normal development of the male reproductive system, this sentence suddenly ambushes the reader:

"Although beyond the scope of this chapter owing mainly to its complexity, one cannot divorce development of the brain from reproductive function as sexually dimorphic development of certain brain regions is necessary for regulation of mating as well as other male-specific traits (e.g. refusing to ask for directions when lost).

Reproductive Toxicology, Third Ed. (2010), Robert W. Kapp, Jr., Rochelle W. Tyl, eds.

A lot of "hormone specialists" or "bioidentical replacement specialists" will tell their patients to spit into a tube at certain times for a period of days, and then send the whole set of tubes to a lab for testing. The theory here is that the free hormones in spit will reflect the levels of free hormone in the blood and presto! Treatment can be made based on these numbers. 

If only that worked. 

Let's start with some obvious clues. Do diabetics use spit to test their insulin levels, or do they use blood?( Correct answer-blood). Do fertility specialists use spit testing, or do they use blood tests? (Correct answer, blood) Do endocrinologists(doctors specializing in the treatment of hormonal problems) ever use spit tests to measure hormone levels in blood for treatment of a patient? (Correct answer, no, not unless they want to lose their license).

If spit testing, which is much cheaper than blood testing, really worked, insurance companies would be demanding that we use it and would stop paying for blood testing. I'd be really happy if I didn't have to go get blood taken from my arm a couple of times a year, personally. But until a better technology has been developed, that's what you have to do to get an accurate measurement of the hormone levels in your blood supply. Blood testing is also essential to get an accurate measurement of the whole hormone picture-bound hormones, weakly bound hormones, and free hormones. We used to think that only the free hormones mattered, but now we know that even weakly bound hormones affect the function of hormone receptors

Why else is spit testing so inaccurate? For starters, if you are using plastic tubes, the spit will cause a breakdown of the plastic and the saliva will get contaminated with the chemicals in the plastic, chemicals which are usually estrogen-like. Reputable blood testing companies ALWAYS use glass for just that reason.

The saliva itself can be affected by lots of common medications like antihistamines, antidepressants, and some cold and sleep remedies, and this will change the results. Not to mention the disruption in the saliva that may occur thanks to your diet, your toothpaste, your glass of wine....you get the picture.

Although saliva testing of the so-called stress hormone, cortisol, is widely used in research studies, it is not properly used for the diagnosis and treatment of hormone problems. Do yourself a favor, and stick with blood tests. Other wise, you may end up with the wrong hormones in the wrong dose-not a pretty picture!

You can read about one doctor who compared saliva tests and blood tests of her patients, and what she discovered here:

Dr. Ignaz Semmelweis discovered in 1847 that if doctors washed their hands before delivering babies, the mothers were much less likely to die of "childbed fever." We now know that childbed fever was simply a bacterial infection, usually developed thanks to the filthy hands of the doctors attending the birth. Ironically, the less prestigious midwives in another ward of the same hospital were much less likely to see their patients die from this problem. Women who gave birth in the street on the way to the hospital were less likely to die from this disease!

Why? Well, in those days, doctors learned about anatomy just like they do today, by dissecting dead bodies. Bodies were not preserved and disinfected like they are now. The doctors and their trainees would commonly go from dissecting a germ-ridden, diseased corpse right to the bedside of a woman in labor without washing their hands or changing their clothes. SInce the germ theory of disease transmission had not been developed, no one thought this was a problem or linked it to maternal deaths. Midwives did not dissect corpses, so they did not bring the infection to their patients.

Dr. Semmelweiss, after a great deal of work, linked the fever to the corpses. He figured out that washing in a solution similar to today's bleach killed the smell of the dead bodies, and he thought that perhaps that removed the source of the poison that was killing the new mothers. He did the right thing-disinfection-without really understanding how it worked. The results were impressive, though.  The mortality rate dropped dramatically, from about 18% to about 1%, and dropped even more when they started disinfecting the instruments, too. 

Sadly, Semmelweis probably did not effectively communicate his findings, and the language barriers and political instability of the era did not help. Other doctors felt that this emphasis on cleanliness was too much trouble, and did not make sense according to the scientific theories of the time. They felt there was no connection, despite clear evidence to the contrary, or they misunderstood the theory. Prominent European obstetricians denounced his theories as ridiculous, while he accused them of being murderers. Semmelweiss finally died in an asylum in 1865.