menopause

Why orcas go through menopause

dr. dolittle — Fri, 13 Jan 2017 17:58:30 +0000

Why orcas go through menopause

Image of an orca and her calf from Wikimedia Commons

Orcas are one of only three species of mammals that go through menopause, including humans of course. A new study published in Current Biology may have discovered why this happens in killer whales.

Examination of 43 years worth of data collected by the Center for Whale Research and Fisheries and Oceans Canada, revealed a remarkable finding about the costs of reproduction in orcas. Older mothers tend to spend more time taking care of the family, so to speak, by making sure her offspring know where or when to find food. While this cooperative foraging behavior helps improve survival of the mother's family, further offspring from the mother are 1.7 times more likely to die than her daughter's offspring. This reproductive competition (or conflict) is thought to be a reason why the whales (and perhaps humans) evolved to go through menopause.

Source:

DP Croft, RA Johnston, S Ellis, S Nattrass, DW Franks, LJN Brent, S Mazzi, KC Balcomb, JKB Ford, MA Cant. Reproductive Conflict and the Evolution of Menopause in Killer. Current Biology. 27: 1-7, 2017. DOI: 10.1016/j.cub.2016.12.015

dr. dolittle Fri, 01/13/2017 - 12:58

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Yet again, acupuncture does not work for menopausal hot flashes

oracknows — Mon, 25 Apr 2016 01:30:29 +0000

Yet again, acupuncture does not work for menopausal hot flashes

Arguably, one of the most popular forms of so-called "complementary and alternative medicine" (CAM) being "integrated" with real medicine by those who label their specialty "integrative medicine" is acupuncture. It's particularly popular in academic medical centers as a subject of what I like to refer to as "quackademic medicine"; that is, the study of pseudoscience and quackery as though it were real medicine. Consider this. It's very difficult to find academic medical centers that will proclaim that they offer, for example, The One Quackery To Rule Them All (homeopathy). True, a lot of integrative medicine programs at academic medical centers do offer homeopathy. They just don't do it directly or mention it on their websites. Instead, they offer naturopathy, and, as I've discussed several times, homeopathy is an integral—nay, required—part of naturopathy. (After graduation from naturopathy school, freshly minted naturopaths are even tested on homeopathy when they take the NPLEX, the naturopathic licensing examination.) Personally, I find this unwillingness of academic medical centers that offer naturopathy to admit to offering homeopathy somewhat promising, as it tells me that even at quackademic medical centers there are still CAM modalities too quacky for them to want to be openly associated with. That optimism rapidly fades when I contemplate what a hodge-podge of quackery naturopathy is and how many academic integrative medicine programs offer it.

If you believe acupuncturists, acupuncture can be used to treat almost anything. Anyone with a reasonable grasp of critical thinking should recognize that a claim that an intervention, whatever it is, can treat many unrelated disorders is a huge red flag that that intervention is almost certainly not science-based and is probably quackery. So it is with acupuncture; yet, that hasn't stopped the doyens of integrative medicine at the most respected medical schools from being seduced by the mysticism of acupuncture and studying it. I can't entirely blame them. I must admit, there was a time when even I thought that there might be something to acupuncture. After all, unlike so many other CAM interventions, acupuncture involved doing something physical, inserting actual needles into the body. However, as I critically examined more and more acupuncture studies, I eventually came to agree with David Colquhoun and Steve Novella that acupuncture is nothing more than a "theatrical placebo."

As I've said before, if you look at the evidence for acupuncture critically and in its totality, acupuncture has no specific effects and no effects distinguishable from placebo. Indeed, it doesn't matter where the needles are inserted, in "real" or "sham" acupuncture points, or even if the needles are actually inserted in the skin (a point that will become important later in this post). It's all the same. Basically, acupuncture is the gateway drug of "complementary and alternative medicine" (CAM) that is often a harbinger of the harder stuff, like naturopathy and homeopathy. But, if you believe its adherents, acupuncture can work for practically any symptom caused by pretty much any condition.

Acupuncture and menopause

One of the most popular uses for acupuncture is to treat menopausal symptoms. I'm familiar with this literature because the anti-estrogen drugs used to treat hormone-responsive breast cancer nearly always produce menopausal symptoms, and it is these symptoms that all too often hurt patient compliance with treatment and sometimes even lead patients to discontinue the drugs. Indeed, among practitioners of "integrative medicine" (the art of integrating quackery with real medicine), there's a great deal of enthusiasm for acupuncture for menopausal symptoms, particularly hot flashes, which can be very troublesome for both women undergoing natural menopause and even more so for women experiencing medication-induced menopause as part of their breast cancer treatment. Worse, in the case of cancer treatment, oncologists can't use supplemental estrogen to treat them, hence the search for other treatments. Never mind that clinical studies have been consistently unimpressive. None of this, however, prevents acupuncture advocates from continuing to do clinical trials. In fact, in just the first quarter of 2016, there have already been published two major studies examining acupuncture as an intervention to relieve menopausal symptoms. They are studies that support what I have been saying all along: The more rigorous the study, the more likely it is to find no specific effect greater than that of placebo.

Not long ago, I discussed a rigorous clinical trial. Like pretty much all rigorous clinical trials, it was a negative clinical trial. It failed to find an effect greater than placebo due to acupuncture in relieving menopausal hot flashes. Same as it ever was.

More recently, I saw another study. This one turns the normal rationale for using a good "sham" or placebo intervention in a clinical trial on its head in a way that would be funny if so many academic medical centers weren’t doing studies just like it..

There's already sufficient evidence out there (e.g., studies like this one) to show that acupuncture doesn't work for menopausal symptoms in breast cancer patients undergoing treatment with anti-estrogen drugs and/or chemotherapy (which can also induce menopausal symptoms); that is, other than studies that don't bother to blind anybody. This has not prevented, for example, the Society for Integrative Oncology from including acupuncture in its clinical guidelines for breast cancer patients. Nor did it stop what is considered to be one of the top journals for oncology, The Journal of Clinical Oncology (or, as we affectionately call it, JCO), from publishing a study like this one conducted in Italy, "Acupuncture As an Integrative Approach for the Treatment of Hot Flashes in Women With Breast Cancer: A Prospective Multicenter Randomized Controlled Trial (AcCliMaT)," by Lesi et al from the Unit of Medical Oncology Civil Hospital. The study was published as an Epub Ahead of Print late last month and even featured a a couple of weeks ago in the ASCO Connection, which is the news outlet of the American Society of Clinical Oncology, one of the largest oncology professional societies in the world.

AcCliMaT is what we in the biz like to call a "pragmatic" trial. Those who have been regular readers of SBM know what "pragmatic" means in this context. Basically, pragmatic trials are clinical trials designed to test how well an intervention that has already been validated in rigorous randomized controlled trials (RCTs) works in "real world" situations. The key assumptions behind a pragmatic study design are that we already know that a treatment works and that we are examining how well it works outside the tightly controlled environment of a clinical trial. Why do pragmatic trials? Simple. It's because often in the real world treatments don't work as well as they do in RCTs due to many reasons, including, for example, application of the treatment to patients who wouldn't have met the inclusion criteria of the RCT, less rigorous adherence to the treatment protocol, and patient noncompliance.

Of course, doing a pragmatic trial is putting the cart before the horse for treatments that have not been shown to work through rigorous RCTs, but that's exactly what AcCliMaT does. In fact, the rationale for AcCliMaT almost made me spew the iced tea I was drinking as I wrote this all over my MacBook Pro's screen. Check out the interview with one of the study's co-authors, Giorgia Razzini, in ASCO Connection:

According to study coauthor Giorgia Razzini, PhD, the strength of the study published in JCO is its rigorous and pragmatic design. Previous studies have compared acupuncture for hot flashes to "sham" or non-optimal acupuncture, with the goal of controlling for the therapeutic response that might arise from patients receiving increased attention and a laying on of hands (i.e., the placebo effect). However, this study compared acupuncture to the treatment women with breast cancer would actually receive in clinic, that is, self-care. To further strengthen the study's design, the acupuncturists paid great attention to minimizing behaviors that could potentially contribute to a placebo effect.

"The acupuncturists worked with a multidisciplinary team of oncologists and clinical trial managers to share their expertise and their knowledge and made an effort to standardize the acupuncture as much as possible to reduce the placebo factors present in many complementary medicines. In fact, acupuncturists delivered the intervention without talking to the patient, or at least keeping the talking to a minimum. The study was conducted with extreme attention to trying to minimize the placebo effect," said Dr. Razzini.

There's so much wrong here and only so much verbiage even I can devote to it. The key misconception at the root of this study is simple. Razzini seems to assume that placebo effects derive only from patient interaction, the "laying on of hands," and the like. No doubt these are important contributors to placebo effects, but it's nonsense to think that placebo effects can be minimized so much by not having the practitioners talk to the patients that a comparison of an intervention + self-care to self-care alone wouldn't still yield a positive result. It will, and, not surprisingly at all, in this study it did. Basically, this study had no good control group and failed to control for placebo effects, given that everyone involved was unblinded and knew which group each subject was in. It's also unclear what, exactly, was done to minimize interaction. All it says in the paper is this: "Conversation between acupuncturists and patients was kept to a minimum to limit nonspecific treatment effects."

So basically, this study was a randomized controlled trial of two interventions. The first is "enhanced self-care":

To standardize usual care recommendations, we enhanced self-care by providing all patients with a detailed information booklet about climacteric syndrome management. The booklet (Appendix, online only) was developed by the research team after a consensus process and included details about hot flashes and cancer and recommendations on diet, physical exercise, and eventual psychological support. The content of the booklet was explained to all patients before random assignment, and booklets were then distributed. Patients were asked to follow self-care recommendations for at least 12 weeks from random assignment.

So basically, the control group was given a booklet and told to follow its recommendations. I wonder how well that usually works out. (Hint: Not very.)

The experimental group received enhanced self-care plus acupuncture:

Within 2 weeks of random assignment, in addition to self-care recommendations, the acupuncture group was offered 10 traditional Chinese medicine (TCM) acupuncture sessions once per week for 12 weeks. The treatment protocol identifies six TCM menopausal syndromes according to Maciocia's recommendations (Table 1).²² At the beginning of each acupuncture session, a TCM evaluation of the tongue and radial pulses was performed to identify the prevailing syndrome and consequently choose appropriate acupoints in addition to three common acupoints (ie, SP 6, LI 11, CV 4). Patients received 20-minute acupuncture treatments based on the diagnosed TCM syndrome; moxibustion was provided as per TCM diagnosis. In some cases, supplementary points were punctured, but no more than 11 acupoints were used for each session. Sterile disposable 0.30 × 0.40 mm Huan Qiu needles (Suzhou Huanqiu Acupuncture Medical Appliance, Suzhou, People's Republic of China) were inserted bilaterally to a depth of 0.5 to 1 cm in most areas, except the hip, where the depth was 1 to 2 cm. They were manually manipulated to elicit the de qi sensation. No flicking or rotation of the needle took place once inserted. Participants with lymphoedema were not treated in the affected arm. No other complementary therapy was recommended during the course of acupuncture.

Here's a hint. In any study of nothing (in essence) versus nothing plus an intervention, the nothing plus intervention group will almost always come out on top, because it's not just the patient-practitioner interaction that is responsible for placebo effects. It's the intervention itself, the more invasive, the more powerful the placebo effects. It's not as though this isn't known and hasn't been studied, including how more costly sugar pills induce stronger placebo effects. It's even known that sham surgery is the most powerful placebo of all. This study was, whether intentional or inadvertently, designed to produce a positive response to acupuncture. It could hardly do otherwise.

And that's what happened.

A total of 190 women with breast cancer were randomly assigned. Inclusion criteria included, but were not limited to: diagnosis of breast cancer, age 18 to 65 years, intention to continue hormonal treatment at least through the length of the study, mean number of six or more hot flashes and/or daily mean score of 15 or greater on the Greene Climacteric Scale (GCS) during the week before enrollment, and vasomotor syndromes for at least 6 weeks. Some exclusion criteria included: treatment of climacteric syndromes such as systemic phytoestrogens, tibolone or analog, veralipride, or specific homoeopathic drugs and use of hormone replacement therapy and/or antidepressant drugs in the previous month and no intention to discontinue. The primary outcome measure was the hot flash score at week 12 (end of treatment), which was calculated as the frequency multiplied by the average severity of hot flashes. Secondary outcomes measured included climacteric symptoms and quality of life, measured by the Greene Climacteric and Menopause Quality of Life scales. Outcomes were measured for up to 6 months after treatment.

The results, which are utterly unsurprising given the trial design, are summarized in this graph:

The authors also found that women in the acupuncture plus enhanced self-care group reported a higher quality of life in terms of vasomotor, physical, and psychological symptoms, with most scores on the various measures being around 25%-30% improved compared to the control group.

Based on these utterly unsurprising results, the authors concluded:

In conclusion, AcCliMaT—a multicenter pragmatic trial with a standardized TCM acupuncture protocol—confirmed that acupuncture is an effective and safe intervention for severe menopausal symptoms in women with breast cancer. Further research could help to identify which variables predict treatment response and the optimal duration of acupuncture. Because these findings seem both statistically and clinically meaningful, we hope the practice of treating vasomotor symptoms in women with breast cancer will change.

No, what this trial found is that the acupuncture group did better than the control, but we have no way of knowing if this result was due to placebo effects or not because there was no sham acupuncture control. Of course, the authors know that their results don't show that acupuncture works better than sham acupuncture. They even admit it:

We acknowledge that this design does not allow estimation of the size of the effect resulting from needling itself or from other placebo-related factors, such as patient−provider interaction. Attempts were made to balance and control the potential impact of the latter by providing both groups with a booklet about climacteric syndrome management options and ensuring that therapists in the acupuncture group limited the communication and time spent with patients to the minimum needed for quality treatment. Notably, study participants did not differ in acupuncture response expectancy.

"Attempts were made…" Sure, utterly inadequate attempts. I could have saved the authors a whole lot of money and effort and predicted the results just by reading the study protocol. Sadly, no one asked me. I will say right now, though: Anyone thinking of designing a similar study, drop me an email or call. I'll predict the results. And JCO editors: The next time you get a manuscript describing a trial like this, consider me (or Steve Novella) as a reviewer. Your peer reviewers dropped the ball big time on this one, as did your publicity department for writing up a glowing article about this study.

It's not as though we didn't already know that acupuncture doesn't work for menopausal symptoms, either. For instance, a systematic review published in JCO in 2013 found no benefit for acupuncture for any cancer-related symptom other than chemotherapy-induced nausea and vomiting (CINV), all due to high risk of bias (ROB) in the studies included and evaluated. (Personally, I find the evidence that acupuncture helps with CINV unpersuasive, because it relied almost entirely on one trial with a low ROB and mixed electroacupuncture and acupuncture studies, but that's a topic for another post.) Similarly, a Cochrane review from 2013 (noted above in the discussion of the first paper) also found no benefit over placebo. Yet none of this stops acupuncture advocates from believing that acupuncture works to alleviate menopausal hot flashes, be they natural or breast cancer treatment-induced, or from doing more studies like the two I just discussed.

I’ve discussed on multiple occasions the ways that advocates try to make ineffective treatments seem effective and how they spin negative results as being positive, particularly how CAM advocates substitute low quality evidence for high quality evidence because high quality evidence shows that their interventions don't work. In these two studies, we have a perfect representation of this. The Italian study, whose design was decent for a pragmatic study but assumed what lawyers would call facts not in evidence (i.e., that acupuncture works for hot flashes), produced a seemingly "positive result." However, it did not adequately control for placebo effects. (An understatement!) When investigators do control for placebo effects adequately, as the Australian investigators did, the results show that acupuncture has no detectable specific effects greater than placebo. This is often much to the disappointment and consternation of the investigators, as the contortions the Australian group went through in its Discussion section illustrate rather amusingly.

Overall, there is no convincing evidence that acupuncture is anything but elaborate, theatrical placebo. The Australian study is quite consistent with this conclusion, and the Italian study provides no evidence to refute it. The Australian investigators, their attempts to explain their negative results notwithstanding, do deserve at least some praise for having followed the results of their study where they led. In contrast, the editors at JCO and ASCO itself should be ashamed for having published and promoted this study.

oracknows Sun, 04/24/2016 - 21:30

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I had accupuncture some years back to treat psoriatic arthitis. I was a skeptic. Yes i felt relieved afterwards. But that euphoria didnt last. My opinion was that the endorphins were kicking in and giving a natural painkiller effect. Now crippled by it. So yes quackey. All i can say is that it made me sleepy when the dr treated me. It did not heal me.

Another failing is that with acupuncture, the extra strength placebo effect is absent. After all, there are a fixed number of inches of skin to place the wires, oh excuse me, "needles" for any sham or "real" acupuncture.
At least, one can give an extra sugar pill with other placebo treatments.
Leaving acupuncture "needles" with a singular, if expensive real world applications as use as microwave antennae, for which they'd be actually effective at - once cut to wavelength and attached to an appropriate receiver circuit.
A chunk of plain wire being the more common, cheaper and effective antenna.

So, can anyone find another valid real world use for those needles? They're too light for doorstops and too easily compressed to hold a window open.

As someone who has found menopause very difficult, I am horrified that resources are being wasted on this. Why not study chocolate? Your treatment group would be just as happy.

Hot flashes are a nuisance, but they are by no means the only or the worst symptom of menopause. I can't imagine how hard it would be to go through chemically induced menopause without any helpful treatment options.

....and I am losing hope that it ever ends.

@REG

Totally agree about the chocolate! I bet it would test out better than the needles, too. Sadly, years of chocolate “treatment” made me fat (finally lost it, though).

I had surgical menopause 15 years ago and still have hot flashes --they never, ever go away for a small group according to my docs. I do HRT (it’s safer than often assumed, especially for those w/o a uterus). I take the smallest dose and have used a very low dose patch as well. Talk to your gyn.
----------------

So when is something going to be done about study reviewers who don’t? Trying to refute these things after the damage done by their glowing release is a giant task.

The absolute worst side effect of chemo (for stage II ER+, HER2+ breast cancer) for me was the hot flashes. I had 2 or 3 an hour around the clock. It was brutal. I have since gone through "natural" menopause. (Not really natural as it occurred years earlier than it would have without chemo.)
In general, I have found doctors to be quite dismissive of hot flashes as a serious problem. (Thanks, I can figure out how to wear layers on my own, without a patronizing suggestion to do so. Wearing layers does not prevent hot flashes, which is what I want.) Consequently, I have never taken Tamoxifen and never will. It is counter-intuitive to take pills that make me feel horrible. It's easy to advise patients to do things that are not causing you personally any discomfort.
I am happy to see that you do take the issue seriously, and that you are aware of the association between hot flashes and Tamoxifen non-compliance. Ordinarily, I see articles about Tamoxifen non-compliance which quote physicians expressing utter bewilderment at the fact that women don't take it at all or stop taking it long before the recommended 5 year period. Generally they are quoted saying that women have to understand how important it is to take it for 5 years, as if none of us know this. Actually, it's physicians who have to understand that unless there is a way of preventing intolerable side effects, patients will simply fail to comply with the drug regimen. It isn't patents who just "don't understand", it's doctors.
So thank you for treating this as a serious issue, rather than women's trivial, childish, refusal to do what we are told.
Yep. Acupuncture is quackery. It infuriates me that hospitals waste research money on it, instead of finding the biological causes and ways of treating them that are safe, even for breast cancer patients.

In conclusion, AcCliMaT—a multicenter pragmatic trial with a standardized TCM acupuncture protocol—confirmed that acupuncture is an effective and safe intervention for severe menopausal symptoms in women with breast cancer.

It's easy to prove anything if you assume your conclusion. I wish the authors had spent even half as much time on logic as they did in coming up with that acronym.

[JCO's] peer reviewers dropped the ball big time on this one

I agree. Even before I got to this part of Orac's post, I was wondering, "How the #$!* did this get past the referees?" The authors even admit that they are making an unsubstantiated claim, for crying out loud!

In fact, acupuncturists delivered the intervention without talking to the patient

Weird bloke in white labcoat walks in, stick me with plenty of tiny needles, and walks out without a word.
Yeah, no way that's going to distract me.

Talking of chocolate and placebos, may I offer my favorite silly paper "showing" improvements of mood in people eating chocolate "enhanced" by various blessings (including a ritual performed by a Mongolian shaman). Published by Elsevier.
http://www.ncbi.nlm.nih.gov/pubmed/17905358

Believe it or not, 'Someone I Know' offered to take me to an acupuncturist because I re-injured a hip flexor ( not the first time). "Why?" I interrupted, " I have plenty of toothpicks I can use by myself". I thought about it.

At any rate, you can't argue with a believer. I thought he had converted but no dice. Since it seems to not be very serious, I am treating it with physiotherapy- based exercises, OTC meds and ice with slowly improving results.

I especially like that an exclusion criterion was use of homeopathic drugs and no intention to discontinue!!!!

Can't I even have a Jolly Rancher?

Previous studies which have controlled for the placebo effect have shown that acupuncture is equivalent to placebo for the treatment of hot flashes.

Razzini boasts that her study does no such thing. Her study finds that self-care plus placebo-equivalent acupuncture does better than self-care alone. Of course it does.

You can't strip the placebo out of acupuncture unless you strip out the acupuncture. Self-care plus placebo means benefit of self-care plus "benefit" of placebo. Self-care will do a pretty good job of minimising the placebo effect. Adding a proven placebo on top guarantees the production of a non-minimal placebo effect.

Obvious innit?

In fact, acupuncturists delivered the intervention without talking to the patient, or at least keeping the talking to a minimum.

[emphasis mine]

They couldn't even standardize the piss poor controls they did put in place. Who knew that studies designed to produce positive results produce positive results?

Funny thought, alties who are quick to hype these kinds of studies tend to complain that Pharma rigs studies of its drugs to be positive. The doublethink runs deeper than just "peer review is broken. Look at these peer reviewed studies that support my beliefs."

If I perform a study whereby I compare a control group to a placebo and miraculously observe a placebo effect from the placebo, can I, too, be published in a prestigious academic journal?

My conclusion will be, "Eureka, the placebo effect is a thing that exists!"

R E G @#3. I volunteered at a local Senior Center not terribly long ago. I was busily fanning myself while chatting with a woman in her 80s. I asked her, I *thought* jokingly, "Does this ever end?" She said, quite seriously, that for her it got less frequent, but never really ended. Sigh.

Talking of chocolate and placebos, may I offer my favorite silly paper “showing” improvements of mood in people eating chocolate “enhanced” by various blessings (including a ritual performed by a Mongolian shaman). Published by Elsevier.

It may be relevant that the first author, Dean Radin -- frequently published in "Explore" -- is also the editor of "Explore". Indeed, it might be more accurate to describe this fine example of Elsevier standards as "The Journal of Radin Publications".

To be fair, Radin has sometimes published his promotions of Distance Healing in Frontiers journals, perhaps for the sake of variety.

And, yet, ten years later, there will still be acupuncture, and still be these sort of studies. Why is it that people insist women don't fall for woo more than men do, and yet, menopause treatment, pregnancy , childbirth and parenting are all filled to the brim with woo? Although, to be honest, all the "official' treatments seem worse than the problem.

Yeesh, I'll probably spend my late forties and fifties lying through my teeth when I'm not gritting them.

I note that he did the "Lies of Brian Deer and Rupert Murdoch" number.

Maybe Rupert's people at Fox didn't realize that their proprietor twirled his moustache behind the scenes, when it was the only network I know of to interview the charlatan Wakefield recently.

Previously, of course, Wakefield has railed against the lies of Brian Deer and the British Medical Journal. And before that it was the lies of Brian Deer and Channel 4 TV.

And I guess all of it includes the lies of my editors, lawyers, peer-reviewers and fact-checkers. As well as the liars on the 5 member GMC panel, of three doctors and two lay members. As well as the lying of Mr Justice Mitting who ruled that Wakefield's claim of ethical approval was false. And the wanton lying of the entire medical and scientific community who've egregiously failed to come forward and dispute the documentary proof of his misconduct.

Oh, and I forgot, the parents of children enrolled in his research who have come forward and denounced it as "fraud"

[The above entry got posted into the wrong thread - sorry - I've added it there too]

Gloves! Gah, that picture!
If anyone is poking holes in you for *any* reason, they must wear new gloves.
Just, gah.

Justatech: When I did acupuncture (at my mom's suggestion) the 'doctor' never wore gloves.

I recently did a class project on HepC in the VA population so I've developed a bit of a thing about gloves and needles.
Gloves protect both people: the stick-er and the stick-ee.
Absence of gloves leads me to ask - what else are they not doing? Have those needles been autoclaved?
When I go to the nail salon they ladies who work there always make a point of opening the autoclave bag in front of you, so you know the tools are clean.
If a 'health practitioner' who wants to use the title of 'doctor' can't be bothered to take as much care as my local $20 nail salon, well, something's wrong.

How far Acupuncture work in late age cerebral atrophy's

Justatech: Probably not autoclaved either. I suspect they just boil the everloving hell out of the needles- or throw them away.

I still wonder though- why is it that anything to do with the reproductive system or with breast cancer gets drenched in woo?

Once again, acupuncture doesn't work for menopausal hot flashes

oracknows — Wed, 13 Apr 2016 04:00:39 +0000

Once again, acupuncture doesn't work for menopausal hot flashes

Of all the forms of quackery that have been “integrated” into medicine of late, arguably one of the most popular is acupuncture. It’s offered in fertility clinics. It’s offered in hospitals and medical clinics all over the place. The vast majority of academic medical centers that have embraced quackademic medicine offer acupuncture. (Quackademic medicine, for those not familiar with the term we reserve for the study of alternative medicine in academic medical centers that really should recognize it as quackery.) Hell, quite a few that haven’t embraced quackademic medicine offer acupuncture. Basically, acupuncture is the gateway drug of “complementary and alternative medicine” (CAM) that is often a harbinger of the harder stuff, like naturopathy and homeopathy. Basically, if you believe its adherents, acupuncture can work for practically any symptom caused by pretty much any condition.

It’s also pure placebo medicine, or, as David Colquhoun and Steve Novella put it, acupuncture is a “theatrical placebo.” As I’ve asked time and time again, Can we finally just say that acupuncture is nothing more than an elaborate placebo? Can We? As I’ve said before, if you look at the evidence for acupuncture critically and in its totality, acupuncture has no specific effects and no effects distinguishable from placebo. Indeed, it doesn’t matter where the needles are inserted, in “real” or “sham” acupuncture points, or even if the needles are actually inserted in the skin. It’s all the same.

One of the most popular uses for acupuncture is to treat menopausal symptoms. I’m familiar with this literature because the anti-estrogen drugs used to treat hormone-responsive breast cancer often produce menopausal symptoms. Indeed, among practitioners of “integrative medicine” (the art of integrating quackery with real medicine), there’s a great deal of enthusiasm for acupuncture for menopausal symptoms. Never mind that clinical studies have been consistently unimpressive. None of this, however, prevents acupuncture advocates from continuing to do clinical trials.

Here comes another one from a couple of months ago that I heard about over the weekend. It’s hot off the presses in Annals of Internal Medicine by Carolyn Ee et al from Australia and Canada, specifically, Melbourne Medical School, University of Melbourne; Royal Melbourne Institute of Technology University; Southern Cross University, Queen’s University in Ontario, and Monash Health in Clayton, Victoria, Australia. It is a randomized clinical trial of acupuncture for hot flashes. What’s different about it is that it’s a clinical trial for regular menopausal hot flashes, not for hot flashes caused by breast cancer treatment, as most of the clinical trials of acupuncture for hot flashes that I read are. Let’s take a look.

Basically, this trial enrolled women older than 40 in the late menopausal transition or postmenopause with at least 7 moderate hot flashes daily. Hilariously (I have to laugh so that I don’t cry, thinking of the resources wasted on this therapy and the unethical nature of it all, given that acupuncture is mystical pseudoscience) the authors further note that these women thus met the criteria for traditional Chinese medicine diagnosis of kidney yin deficiency. Curious just what the heck “kidney yin deficiency” is, I looked it up. Here’s a description. First of all, kidney yin is:

When The theory of yin and yang is used to explain the organic structure of the human body; the physical form pertains to yin, while activities or functions pertain to yang. The physical forms are the material basis for functions, while functions are the motivating power for physical forms. They are mutually complementary. TCM views the kidneys as the center of the body's yin and yang, the "congenital foundation," or the origin of life. In other words, the kidneys store the primordial yin and primordial yang (also called kidney yin and yang), which is the place where nutrients are stored and physiological functions take place.

Kidney yin, also called primordial yin, true yin or true water, is the foundation of the yin fluid of the whole body; it moistens and nourishes the organs and tissues.

TCM kidneys Kidney yang, also called primordial yang, true yang or true fire, is the foundation of the yang qi of the whole body; it warms and promotes the functions of the organs and tissues.

This is, of course, utterly unscientific, based as it is on concepts not at all unlike the concepts behind “traditional Western medicine,” namely the idea that “imbalances” in something are the cause of all disease. In the case of traditional Western medicine, it’s an imbalance in the four humors. In traditional Chinese medicine, it’s an imbalance in the five elements. In any case, what are the symptoms of kidney yin deficiency? Not surprisingly, some of them resemble menopause:

Presentations of kidney yin deficiency include: soreness and weakness of the lumbar regions and knees, dizziness, ringing in the ears, hearing problems, a dry mouth and throat, a hot sensation in the palms, soles and chest, spontaneous sweating, constipation, and seminal emission. The pulse is weak or fine and rapid; the tongue is red and covered with a light coating of fur. Kidney yin deficiency syndrome always produces signs of yin vacuity internal heat.

According to Ee et al:

Women were included if they were postmenopausal (>12 months since their final menstrual period) or in the late menopausal transition (follicular-stimulating hormone level ≥25 IU, amenorrhea ≥60 days, and VMSs), had a mean HF score of at least 14 (equal to 7 moderate VMSs daily) (16), or had kidney yin deficiency diagnosed using a structured Chinese medicine history as well as a tongue and pulse examination performed by experienced acupuncturists (Appendix Figures 1 and 2). Kidney yin deficiency, of which night sweats is a cardinal symptom, is a Chinese medicine clinical syndrome diagnosed in 76% to 81% of symptomatic postmenopausal women (17, 18).

They were even kind enough to provide a questionnaire to diagnose kidney yin deficiency (click to embiggen)

Yes, this questionnaire was really used.

As you can see, this questionnaire is so vague as to be pointless. Certainly, it’s not enough to diagnose menopause. After all, there are no questions about frequency of menstrual periods or when the subject’s last menstrual period was, and the questionnaire includes information about Chinese pulse diagnosis, which is not reproducible, and Chinese tongue diagnosis, which is basically reflexology on the tongue.

So far, not so good.

Basically, 327 women were randomly assigned to acupuncture (n = 163) or sham acupuncture (n = 164). The study was blinded, but not completely. Study design was a stratified, blind (participants, outcome assessors, and investigators, but not treating acupuncturists), parallel, randomized, sham-controlled trial with equal allocation. Overall, it wasn’t a bad design as far as acupuncture studies go. True, it lacked blinding of the treating acupuncturist, which would have been required for a true double-blind study design, but it did use a pretty good acupuncture sham, the fake retractable needles that don’t break the skin also inserted in the “wrong” places. Participants received 20 minute acupuncture sessions (or sham acupuncture sessions) twice weekly for two weeks and then weekly thereafter.

So what were the results? Do you even have to ask? Basically, this was a completely negative trial, which is why I wasn’t as concerned about whether or not the acupuncturists were blinded or not. (This would have been a much bigger issue if there had been a positive result.) At the end of the eight week treatment period, Mean hot flash scores at the end of treatment were 15.36 in the acupuncture group and 15.04 in the sham group (P = 0.77). Hot flash scores declined about 40% in both groups and persisted for six months. The investigators couldn’t find evidence of an advantage of acupuncture over sham acupuncture on quality of life, anxiety, or depression. That’s about as negative as it gets. I do have to give the investigators credit. They didn’t try too hard to torture the data to provide the result they wanted with post hoc analyses, as many investigators carrying out clinical trials are tempted to do.

They did, however, try to make excuses. Indeed, the shorter version of the whole discussion section seems to be: How can it possibly be that we didn’t find acupuncture to be superior to sham for menopausal hot flashes? They noted:

Our findings are consistent with those from a recent Cochrane review (10), which reported that acupuncture was more effective than no treatment and had a moderate effect size but was not efficacious when compared with sham. Although another recent meta-analysis reported moderate standardized effect sizes of acupuncture of −0.35 and −0.44 for HF frequency and severity (13), this analysis pooled data from sham-controlled trials and trials comparing acupuncture with no treatment. In addition, the shortcomings of the included studies (small sample sizes, high attrition rates, and failure to use intention-to-treat analyses) may have inflated the treatment effects.

Which, of course, leaves the question of why bother to do this study in the first place, given that there’s enough evidence out there to do a Cochrane review and that review found no evidence that acupuncture was more efficacious in menopausal hot flashes than sham acupuncture, and there was enough evidence to do a meta-analysis whose results were probably due to the inclusion of low quality evidence. There was (and is) no strong clinical or scientific rationale to do randomized studies of acupuncture for menopausal hot flashes.

This next paragraph made me chuckle out loud as I read it:

The first limitation of our trial and acupuncture clinical research more broadly is the lack of an inert sham comparison treatment. Although the Park sham device was the best available sham acupuncture method at the time of study design, its validity as an effective control treatment needs further determination. It creates a needle-prick sensation, essential for the patient to believe that a needle has been inserted; however, this sensation produces minor physiologic effects (26). The interpretation of sham-controlled acupuncture trials must occur within this context. However, what we have successfully examined is the effect of needling compared with pressure from a blunt needle. Second, despite our broad recruitment strategy, our findings can only be generalized to Caucasian Australian women with kidney yin deficiency. Nonetheless, 87% of otherwise eligible women met criteria for symptoms of kidney yin deficiency, consistent with previous studies (17, 18). Third, our method of Chinese medicine diagnosis was a simplified version of usual practice and failed to define secondary diagnoses. In addition, our acupuncturists could not be blinded, but we provided comprehensive training and performed quality assurance visits to minimize bias. Finally, our findings cannot be generalized to women with bilateral salpingo-oophorectomy or worsening of VMSs after breast cancer; we excluded these women because they have more severe VMSs (47, 48). Future research should examine the role of acupuncture in breast cancer.

Yes, let’s count the excuses. The sham needles weren’t an adequate control. Our findings can’t be generalized to all women with menopause but only to Caucasian Australian women who also—by the way—have kidney yin deficiency. Our method of traditional Chinese medicine diagnosis was too simplified. Our acupuncturists couldn’t be blinded. We can’t generalize our findings to women with menopause doe to surgery or to breast cancer treatment. So let’s study the role of acupuncture in alleviating menopausal symptoms in breast cancer patients.

Oh wait. There’s already sufficient evidence out there (e.g., studies like this one) to show that acupuncture doesn’t work for menopausal symptoms in breast cancer patients; that is, other than studies that don’t bother to blind anybody.

So once again, we have yet another study that shows that acupuncture doesn’t work, and once again we have investigators who refuse to believe their own results and have to be dragged, kicking and screaming, by the data to the conclusion that their hypothesis was false. Even then, they can’t help making lots of excuses and planning their next study even though this one was totally negative.

Same as it ever was.

oracknows Wed, 04/13/2016 - 00:00

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Did they correlate their results with their midi-chlorian count

I take it "kidney yin deficiency" is supposed to be contrasted with conditions like "heart yin deficiency", "brain yin deficiency", "gonad yin deficiency", etc. Or, for that matter, "kidney yang deficiency" (which would be equivalent to "kidney yin excess"). And I suppose that in principle a patient could have "kidney yin deficiency" and "heart yang deficiency" simultaneously.

The standard words we use to describe this kind of solution to the complex problem of medicine: Simple, elegant, and wrong.

"Presentations of kidney yin deficiency include...seminal emission."

Did they control for that finding in the postmenopausal women?

It almost seems that Orac writes about *nothing but* quackery and alternative medicine.

Maybe if real medicine was more effective,
and real doctors did a better job of educating the ailing,
Orac wouldn’t be railing,
for 2,000 words every day.

I see your ability to use the search function on this site is about as good as your ability to hold a rational argument....

“Presentations of kidney yin deficiency include…seminal emission.”

Ohh jeez, the NSFW things I could say related to that. WTF the annals of internal medicine journal were thinking.

Alain

Am I doing something wrong? That link "hot off the presses in Annals of Internal Medicine" is taking me to a library log-in. And I see that the article is behind a paywall.

Oh well time to wander down to the university. Exams are almost over so grabbing a library terminal for a minute to download the article should be easy enough.

It's a bit embarrassing to see a Queen's name there, speaking as an alumnus, but at least the author is not from the Faculty of Medicine. Turns out that he is in the School of Rehabilitation Therapy. "Simon French,B.App.Sc.(Chiropractic), M.P.H., Ph.D., is an Assistant Professor in the Rehabilitation Science program and holder of the Canadian Chiropractic Research Foundation Professorship."

I know a couple of other faculty from the School and much of what they do seems pretty good. Hopefully French just was a bit off when he agreed to get involved. However those "Chiropractic" terms are not reassuring and the School's web-site is about as uninformative re faculty as any I have seen.

I really enjoyed how they selected subjects:
they use either SB measures or one based in TCM diagnosis.

AS if those measures were somehow related to each other.
What if some people with yin deficiency didn't experience menopause at all- especially those with 'seminal emissions'?

The sham needles weren't of the right type?

I need a drink.

Am I doing something wrong? That link “hot off the presses in Annals of Internal Medicine” is taking me to a library log-in. And I see that the article is behind a paywall.

I'm not surprised that a just-published article is behind a paywall. I would guess that Orac copied and pasted the link by which he accessed the article. Even without that detail, I'd probably still be unable to read the article: even though I work at a university, said university does not have a medical school.

Speaking of links, I suspect Orac intended the word "QUESTIONNAIRE" to be a link to the questionnaire he discusses, but as of this writing there is no link.

soreness and weakness of the lumbar regions and knees, dizziness, ringing in the ears, hearing problems, a dry mouth and throat, a hot sensation in the palms, soles and chest, spontaneous sweating, constipation, and seminal emission. The pulse is weak or fine and rapid; the tongue is red and covered with a light coating of fur.

That's me after an evening in the pub, that is.

Apart from the seminal emission, you understand.

The questionnaire is there. For some reason WordPress published a version back from the latest, which didn't yet have any images.

See Noevo says (#4),

It almost seems that Orac writes about *nothing but* quackery and alternative medicine.

MJD says,

I'd like Orac to write about why quackery and alternative medicine continue to use some harmful products in their pseudoscience marketplace.

For example,

http://acuwarehouse.com/products/exam-latex-glove-light-powdered

Tthe FDA is proposing a ban on such products:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491466.htm

Statistically, one out of 20 trials involving acupuncture or homeopathy should reach p = 0.05 significancy. No reason to lose our time studying them.

It's actually higher than that, as John Ioannidis showed. Due to bias, issues in carrying out clinical trials, etc., we expect considerably more than 5/100 trials of homeopathy to be "positive." That 1 in 20 number is the lowest it can be when we set our p-value to 0.05. It's an "ideal world" number. The real number will always be higher.

I agree with you, but how to disprove them except by considering that there is a general institutional problem in confusing procedures and science.

The questionnaire is there.

And it is every bit as vague and useless as you claim. Not to mention innumerate: it claims that the maximum symptom score is 36, but the actual highest possible is 30 (ten boxes that can be between 0 and 3). With two possible "bonus" points for tongue and pulse (and no description of the criteria by which a patient would earn those "bonus" points).

Statistically, one out of 20 trials involving acupuncture or homeopathy should reach p = 0.05 significancy.

That's only true if all of your errors are random errors. Systematic errors will usually make this false positive rate higher, and those errors are frequently not accounted for in statistical analysis. Bias, as Orac says, is a major source of systematic error in medical trials. That includes most study design issues, since the purpose of well-designed controls is to minimize observer and experimenter bias.

In principle, overestimating systematic errors can result in inflated p-values, such that fewer than 1 in 20 studies would see a positive result by chance. In practice, that almost never happens. It is far more common for systematic errors to be underestimated (if not outright ignored) than to be overestimated.

@ Eric
Again, I agree. The point I wanted to make is that there will be many trials showing positive results for acupuncture and homeopathy, and we cannot deal with that if we consider science only from a procedural point of view.

Once again, acupuncture doesn’t work for menopausal hot flashesanything.

FTFY.

I went into an art gallery today, they wouldn't sell me the vegetables I needed for tonight's dinner.

The car shop who were doing some work on my car also didn't stock the newspaper and magazine I wanted to buy.

Your point is?

Dogmatic man drones
More rigid than Curia
Winter approaches

I think I've found a scientifically valid usage for accupuncture needles, one that would be totally reliable and evidence based in their approach and usage.
Microwave antennae for a phased array in the centimeter and shorter wavelength.
Note the lack of a medical usage for the damned things. Still, they're stainless steel (usually), hence corrosion resistant, the appropriate length (and can be adjusted in the connector for precision length) and in that, useful for more than landfill fill.
For medical uses, I don't know, perhaps as a door stop or to keep a window propped open, assuming at least a case quantity?

For in reality, the headline is:
Extra! Extra! Read all about it! Accupuncture study complains of a lack of proper sham therapy, fails to note irony in the study complaint.

@Daniel: One thing to keep in mind is that there is nothing magical about a p-value of 0.05. Many fields, including medicine, have traditionally adopted this significance threshold as a compromise between the ability to generate enough data (which in this context means enrolling enough participants) to get a significant result and the need to have a sufficiently stringent threshold to weed out spurious results. Other fields such as particle physics, where the experiment can be repeated thousands or even millions of times, can and do insist on a stricter threshold: particle physics, for instance insists on a 5σ threshold, which is about p<3*10^-7 (for comparison, p<0.05 is about 2σ). The reason the threshold is so strict for particle physics is because they have been burned too many times by 3σ significances that turned out to be spurious.

Given the routine occurrence of spurious p<0.05 results in medicine, one can argue that a stricter threshold is needed. The difficulty is that, as you change the number of participants, the p value of a non-spurious result decreases as the square root of that number, so that, e.g., you would need 25 times as many participants to get a significance of p<0.01 as to get p<0.05. Which for studies involving human subjects is prohibitively expensive when it is even possible.

For medical uses, I don’t know

For non-medical use, there's always lace knitting.

http://www.craftsy.com/blog/2014/07/tips-for-knitting-lace-yarn/

@ Eric
It is not a question of threshold. A threshold at p<0.01 would allow a certain number of homeopathic trials to show significance while preventing serious projects to be carried out. The issue is hypothesis driven research versus ad hoc (interest driven) analysis of data. The whole process of hypothesis driven research means defining precisely what is the hypothesis, and which experiment would disprove it. Working for disproving a hypothesis is not what is encouraged in the current way of assessing scientific activity by publications. In addition, understanding some hypotheses may mean a certain level of knowledge and/or intelligence. There cannot be any hypothesis on homeopathy.
In addition, a problem in biomedical sciences is that physics requires a minimum of intelligence, which may be lacking in biochemistry.
What is needed in biomedical sciences is a process of cooptation based on knowledge and intelligence, and not on "productivity" (USA) or "services rendered" to the boss (France).

Hi there. Was wondering what your view was on the fact that nobody today is getting the 90 nutrients that the human body requires everyday to function, and why doctors aren't mentioning this. Thanks!

Was wondering what your view was on the fact that nobody today is getting the 90 nutrients that the human body requires everyday to function

My vindaloo recipes don't require nearly so many ingredients, and these don't really serve as nutrients by the end of the cooking, I suspect. Is vinegar a nutrient?

I'd wager it is because it doesn't need mentioning? Unless you have literally the worst diet in the world, you'll get everything you need through your fo-

*assassinated by Big Supplement*

Arnold Vindaloo -
My view is that the doctors don't metion it because most of the people they see aren't suffering from missing nutrients. In fact, a lot of people they see are suffering from too many nutrients.

Most people today are living much longer than the average of a few decades ago, suggesting there's no big problem with missing nutrients.
Perhaps you can tell us how you came up with such a wierd statement. You get extra marks if you can keep it within 50 words.

After googling "90 nutrients", I found that this claim was mostly made by one Dr Joel Wallach. Do you know what studies he based this claim on, and if some other scientists replicated this ?

the fact that nobody today is getting the 90 nutrients that the human body requires everyday to function,

If we need them to function, but we're not getting them, then we're dead. This is contrary to experience.
I have learned not to trust any theory that predicts my own non-existence.

Rebecca Fisher:
the tongue is red and covered with a light coating of fur.

Your own, or someone else's?

the tongue is red and covered with a light coating of fur.

The furry tongue sock is a welcome addition to your cold weather ensemble, much like the nose mitten.

I think I prefer the nose mitten.

@31 Dr Joel Wallach the veterinarian with the huge product line?

@ Arnold
Was wondering what your view was on the fact that nobody today is getting the 90 nutrients that the human body requires everyday to function, and why doctors aren’t mentioning this".
I am a doctor and the only explanation I can find is that we are all dead. This might limit my ability of mentioning this or anything.

My vindaloo recipes

Dinner at Narad's!

Dinner at Narad’s!

I can recommend it.

It'll be dinner at mom's house for me tomorrow; just have to hang in there for one more day/night, then a longish flight tomorrow. Looking forward to it.

I do worry that some of these people apparently have advanced degrees from the top Instuitions in my home City.
At first I thought it was a student prank.
Let me see if I follow.
They did a study which proved that Sham accupuncture worked as well as "real" accupunture. Eg it didnt.
The reason is that the Sham accupuncture is to "real"

BTW I am enjoying the posts in here.

There's a lot of talk in this thread about seminal emission, but the more import thing is the seminal omission (intellectual integrity) producing an excess of yin leaving the argument weak as water.

How embarrassment.

How embarrassment.

I think that was Effie you are channeling.

Kylie was more a "so excellent" type of person.

Once again the paper ends with "more research is needed " or a variation thereof. One day we might see a paper end with "no further research is needed as enough evidence shows there is nothing here to see" - this would be a paper worth reading.

Was wondering what your view was on the fact that nobody today is getting the 90 nutrients that the human body requires everyday to function, and why doctors aren’t mentioning this.

It's not "fact", it's hogwash. That's why.

http://www.quackwatch.com/01QuackeryRelatedTopics/DSH/colloidalminerals…

Hot flashes can be awful. The sweats are just as bad if not worse. Fortunately, I know that "this, too, shall pass". And NO ONE is coming near me with a freaking acupuncture needle.

What's with all the heavy metals in the 90 nutrients pill? I thought nutritionists were generally anti-heavy-metals!

Hi there. Dr.Joel Wallach conducted proper experiments in the lab using monkeys and other animals. He was also given an award for his findings, albeit the MDs did not like it because he proved that all diseases link back to nutritional deficiencies. Also; most trace minerals play a part in healthy optimised brain function. Even if it sounds like "nonsense", this should be looked into more. Has a proper experiment conducted disproving Dr. Wallach? Thanks.
I am not here to spread hate. I am just an inquiring mind.

Dr.Joel Wallach conducted proper experiments in the lab using monkeys and other animals. He was also given an award for his findings

Can you give the references of these "proper experiments" or this award ?
I am also pretty wary of anyone who extrapolate something on humans from animal data, without checking with proper clinical trials after the preliminary research.

Is that Dr. Joel D. Wallach, DVM, ND?

Doing a quick pubmed search he MAY have been the author of "Hypoglycemic shock in captive alligators." and "Frostbite and its sequelae in captive exotic birds", though it's difficult to know for sure.

It's not obvious to me that there are any pubmed indexed papers by him regarding nutritional deficiencies being the cause of all diseases.

Dr. Joel Wallach won a G.O.D award from the UN.

Acupuncture bait and switch: Electrified hot flash edition

oracknows — Wed, 26 Aug 2015 07:45:25 +0000

Acupuncture bait and switch: Electrified hot flash edition

It's always disappointing to see a good journal fall for bad medicine, particularly when it's in your field. For example, the Journal of Clinical Oncology (affectionately referred to by its abbreviation JCO) is the official journal of the American Society of Clinical Oncology (ASCO) and probably the most read clinical journal by those involved in the clinical care of cancer patients. Just as most oncologists, surgeons, and radiation oncologists who specialize in the care of cancer patients belong to ASCO, most of them also at least peruse JCO on a regular basis because major results of large cooperative group trials are often published there. Basically, everyone wants to publish his oncology clinical trial in JCO. Getting into Clinical Cancer Research is good, but getting in JCO is great.

So when I see a study that some of you have been e-mailing and Tweeting at me in JCO, I can't help but wonder what the hell happened to peer review at the journal. I also realize that, being in the biz myself, by criticizing the peer review at JCO I might endanger my own chances of ever publishing in there given that my meatspace identity isn't exactly a particularly well-kept secret (nor is it meant to be anymore). Oh, well. It needs to be said. Earlier this week there appeared in the Early Release Articles a study by Jun J. Mao and colleagues at the University of Pennsylvania entitled Electroacupuncture Versus Gabapentin for Hot Flashes Among Breast Cancer Survivors: A Randomized Placebo-Controlled Trial. Sounds neat, right? Sounds like a head-to-head battle between every acupuncturist's version of transcutaneous electrical nerve stimulation (TENS), electroacupuncture (EA), versus gabapentin (a.k.a. Neurontin) in a battle royale to see which can alleviate hot flashes the best.

And make no mistake, hot flashes are an incredibly important problem in oncology, particularly for breast cancer patients. Patients who have breast cancer that is estrogen receptor positive, which means that the cells are responsive to estrogen, are frequently treated with drugs that block estrogen action. If a woman is postmenopausal, the usual drug used is a member of a class of drugs called aromatase inhibitors. If the woman is premenopausal, the usual drug used is Tamoxifen. In either situation, the most common—and frequently the most troubling—side effect of the drug is menopausal symptoms, mainly hot flashes. What a lot of people who aren't cancer doctors or patients don't understand is that these hot flashes can be horrible. Believe it or not, I learned this lesson with the very first patient I treated as an attending surgeon, lo these many years ago. This woman had such horrendous hot flashes from her Tamoxifen, as well as psychological symptoms, that she and her oncologist, after attempts at dose reductions and other strategies to ameliorate her symptoms, jointly decided that she couldn't take it any more. Unfortunately, for patients with hormone-responsive breast cancers, the most bang for the buck in terms of preventing recurrence comes from the hormonal therapy, at least equal to that of any chemotherapy. So the degradation of quality of life and sometimes even symptoms necessitating cessation of hormonal therapy are a major problem in oncology. Unfortunately, our existing treatments are not the greatest, which opens the door to woo such as acupuncture. Where there's woo, there's quackademic medicine to study the woo, and that's just what this study is.

Basically, this study is a bait-and-switch. I realize that I just discussed another bait-and-switch acupuncture study less than a week ago, but sometimes a doc's gotta do what a doc's gotta do.

So where's the bait and switch? In this case, it's on more levels than you think. In fact, before I dive into the story itself, let's look at the spin being put on the results. I like to call this how not to report on an acupuncture study:

Needles beat pills for treating hot flashes in breast cancer survivors, according to a new trial that compared acupuncture, "sham" acupuncture, the medication gabapentin and a placebo pill.

Interestingly, sham acupuncture came in second place for effectiveness, the researchers said.

Furthermore, the effects of acupuncture were "significant and enduring for hot flashes while gabapentin's effect only happened when a patient was taking the medication," said study first author Dr. Jun Mao, an associate professor of family medicine and community health at the University of Pennsylvania in Philadelphia.

The study was published Aug. 24 in the Journal of Clinical Oncology.

As usual, the reporting that "acupuncture beat pills for hot flashes" is a completely inaccurate assessment of what the study actually showed. The study showed nothing of the sort. Barring an incredibly strong effect, it couldn't possibly have (more on that later). Sadly, dissecting the BS attached to acupuncture studies is a rather specialized skill set; so perhaps I'm being too harsh. There were others who fell for this. When this study was presented as an abstract at the San Antonio Breast Cancer Symposium in December, similar stories were written about it. Of course, given the depth and breadth of science presented at the SABCS, it never ceases to amaze me how the press always seems to zero in on studies like this one, which tell us very little but give the appearance that acupuncture works.

Acupuncture is, of course, a theatrical placebo. Its effects are nonspecific, which is why it is such an adaptable placebo. As I joked sarcastically last time, if you believe its practitioners and adherents, acupuncture can treat almost any disease or health problem to which human beings are prone, which is why last week I could be blogging about a bait and switch study of acupuncture to treat hypertension and this week I can be writing about a bait and switch study of acupuncture to treat hot flashes caused by hormonal treatment in breast cancer patients. That's why several years ago I was writing about worthless acupuncture studies examining acupuncture for hot flashes.

This study, in fact, shares a major flaw with the one I blogged about in 2008. Specifically, it has no control group that received no treatment at all. For a study that goes on and on about placebo effects and how acupuncture provides more of a placebo effect than pills, that's a rather glaring omission. So let's look at the study design. Basically it's a four arm study, two arms of which look at electroacupuncture (EA) versus acupuncture and the other two at gabapentin versus a placebo. Interestingly in this study compared to most electroacupuncture studies, the EA is considered the "real" acupuncture and the standard acupuncture (SA) is described as the "sham," which, I have to admit, is not inappropriate, given that acupuncture is a sham and electroacupuncture is basically transcutaneous electrical nerve stimulation rebranded as the sham that is acupuncture. (We all know that those ancient Chinese must have had access to electricity, right?) It is funny, though, because the SA group did use retractable needles and really were sham acupuncture. Consequently, the investigators weren't really comparing EA versus the same acupuncture without the current but rather EA to at true sham.

So basically, the groups were as follows: electroacupuncture (EA); standard acupuncture (SA), gabapentin (GP), and placebo pill (PP). There were 120 patients with stage I to III breast cancer treated for cure at the Abramson Cancer Center of the Hospital of the University of Pennsylvania in Philadelphia and with no evaluable disease (i.e., no detectable disease left after treatment) and at least two hot flashes per day for at least a month. They excluded patients with stage IV disease, active breast cancer treatment, initiation or change in hormonal adjuvant therapy within the past 4 weeks, plans to initiate or change hormonal treatment in the coming 14 weeks, pregnancy or breast feeding, bleeding disorders or use of warfarin/heparin, an allergy to or previous use of GP for hot flashes, current use of an anticonvulsant, or documented renal failure in the past 12 months. They were then randomly assigned to one of the four groups according to this schema (click to embiggen):

In any case, the EA and SA groups received their "acupuncture" treatment for 30 minute sessions, twice a week for two weeks, then once a week for six more weeks. Meanwhile, in the GP versus PP groups, the GP group received 900 mg per day of gabapentin or placebo for eight weeks. Outcomes were measured once a week using the average hot flash composite score (HFCS) as measured by the Daily Hot Flash Diary, a commonly used instrument to measure hot flash severity and frequency. Adverse events were also monitored. Patient outcomes were followed for 24 weeks.

Of course, in any acupuncture study, blinding is of critical importance; so whenever you see an acupuncture study, look at the blinding. In this case, monitors blinded to treatment group tallied adverse events (AEs). That's good. The patients were blinded to treatment group between EA and SA and between GP and PP, but were not blinded to whether they fell into one of the acupuncture groups or the medication groups. So was the principal investigators, study investigators, study staff, and the statistician. The acupuncturists, however, were not blinded to whether the patients received EA or SA, which is another huge flaw, almost as bad as the lack of a no treatment control group. In fact, it's bad that they didn't even blind patients between the acupuncture and pill groups. All that would have required would have been to give all the patients in the two acupuncture groups a placebo pill and all the patients receiving pills sham acupuncture and then blind the acupuncturists to experimental group by using a needle that retracts in such a way that the acupuncturist can't tell if it really went into the skin or not (such needles do exist) and then having every patient hooked up to the current generator, which could be set to light up and have its gauge show that it's producing current whether it actually is or not. That way, everyone can be blinded. Then add a wait list/no treatment control. But that's not what they did. I realize my way would be more difficult and expensive, but it is the only way likely to generate anything resembling useful data.

Here's another aspect:

Because placebo response to a pill has been previously reported to be approximately 20%,20 assuming baseline HFCS had a mean of 16 with a standard deviation of 4, we needed 26 participants in each placebo group to detect a 20% difference (3.2 HFCS/day) with 80% power using a two-sided significance level of .05. Assuming a 15% dropout rate, we needed to recruit 30 subjects per arm, for a total of 120 subjects. Our trial was not designed to evaluate the efficacy of EA or GP because sample size requirements would be much larger on the basis of previous literature. Evaluations of the short- and long-term effects between EA and other groups were secondary aims.

In other words, this study shows nothing about whether EA is actually efficacious, because it wasn't designed to. It's too small. So right away, any results must be interpreted in light of this knowledge, which is why all the discussion of placebo effects. First, however, here is the singularly unimpressive result of the study in the form of a single graph:

First, notice that all groups appeared to be improving right up until the end of the eight week treatment phase and are bunched up. How the authors interpret this result is rather interesting:

By week 8 (end of the intervention), acupuncture produced a significantly greater placebo effect than did pills, with the SA group having a significantly lower HFCS than the PP group (−2.39; 95% CI, −4.60 to −0.17; P = .035). Compared with PP, EA also had improvement in hot flashes (−4.1; 95% CI, −7.0 to −1.3; P = .005), whereas GP showed nonsignificant improvement (−1.8; 95% CI, −3.9 to 0.2; P = .085). We observed differences among treatment groups in the HFCS score (P < .001 for time and treatment interaction), with −7.4 for EA, −5.9 for SA, −5.2 for GP, and −3.4 for PP (Table 2 and Fig 2). Participants in the active treatment groups (EA and GP) experienced 47.8% and 39.4% improvement in hot flashes, respectively, compared with baseline. Placebo participants in the SA and PP groups experienced 45.0% and 22.3% improvement, respectively.

So, in other words, everyone improved (which is usually what happens on clinical trials of symptoms with a large subjective component), and somehow the authors see this as evidence that "sham acupuncture" produces a stronger placebo effect than the placebo pills. They also state that the SA group had less nocebo effect (equated with AEs, which I don't consider appropriate given that some of the AEs included bruising In actuality, this might be true, but we really don't know if that's true. For one thing, there is no control group receiving no treatment. How do we know that a no treatment group wouldn't also show a roughly 20% decline in HFCS composite scores just due to the subjects being on a clinical trial? We don't. In fairness, the authors acknowledge this limitation. They also acknowledge that their study wasn't powered to detect efficacy, which puzzled me to no end. Why bother to do the study if it can't demonstrate efficacy? And why say things like this at the end:

In conclusion, acupuncture is associated with enhanced placebo effects and lower nocebo effects when compared with taking pills for hot flashes among survivors of breast cancer. Eight weeks of EA produced promising short- and long-term treatment outcomes for hot flashes compared with other comparators and had fewer adverse effects than GP. These preliminary findings need to be confirmed in larger studies with long-term follow-up. For survivors of breast cancer experiencing hot flashes, acupuncture could be preferable to GP because of sustained benefit after treatment and fewer adverse effects, whereas patients who dislike needles or do not have the time required for acupuncture treatments may prefer GP.

Here's why:

The results with the sham acupuncture, which bested gabapentin, suggest that "there is more than a placebo effect with the sham acupuncture," said Dr. Gary Deng, interim chief of the integrative medicine service at Memorial Sloan Kettering Cancer Center in New York City. "There is a component of behavior of doing a sham procedure, so it psychologically may trigger a different kind of reaction from patients versus taking the placebo pill."

Deng pointed out that clinicians have come to realize that the placebo effect is very important in treatment. "In fact, in clinical practice, every doctor uses it all of the time," he said. "The so-called bedside manner or communication with patients -- all of these enhance the effect of the patients feeling they're getting something."

No one is quite sure why placebos work for some people and not for others, said Deng. "It's like psychotherapy," he added. "Why does it work for some people and not others?" He suggested that differences in anatomy and genetics might be possible explanations, but said "there is a fertile field for further research."

Because the most rigorous studies of acupuncture (and other "complementary and alternative medicine" or "integrative medicine" therapies) are almost always negative and the totality of the literature on acupuncture is consistent with its being a "theatrical placebo," acupuncture advocates, like CAM advocates in general, are now selling it as the "power of placebo." Of course, we know that more invasive interventions produce a stronger placebo effect. For instance, injections tend to produce stronger placebo effects than pills and surgical interventions produce the strongest placebo effects of all. So it would not be surprising if as theatrical a procedure as acupuncture produced a stronger placebo effect than a pill. If you accept that what was measured were placebo effects (and I do not without a no treatment control), then all this study basically showed was that SA is a better placebo than a pill, a result we could already have surmised from the literature, meaning that there was really no need to do this study.

In any event, I've never argued that placebo effects can't be important. However, there is an inherent problem with using them, and that's that you have to lie to the patient, attempts to demonstrate the existence of "placebo effects without deception" that show nothing of the sort notwithstanding. Worse, when a fantasy treatment based on a prescientific understanding of human physiology and disease retconned by Chairman Mao into a seemingly effective therapy is used as the placebo, the message is not so much that we could get the same effects using ethical means of increasing placebo effects, such as good bedside manner, encouraging words, and the like. It's that magic works through placebo effects, which is exactly how this study will be sold.

In the end there are two bait and switches in this study: electroacupuncture sold as acupuncture and acupuncture sold as a powerful placebo that has clinical utility. Same as it ever was.

oracknows Wed, 08/26/2015 - 03:45

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To my mind, major journals are complicit in this infiltration of quackery into medicine. To cite a recent set of examples, I am beginning to think that there is an effort at PLOS One to pass off acupuncture studies with minimal and inadequate reviews. Otherwise, I cannot find a reason why these studies, with so many glaring lacunae in methodology and interpretations, would find their way into a journal, such as PLOS One:

1. http://www.scilogs.com/in_scientio_veritas/authors-of-plos-one-study-on…

2. http://www.scilogs.com/in_scientio_veritas/cam-peer-review-plos-problem/

3. http://www.scilogs.com/in_scientio_veritas/plos-one-acupuncture-lacks-c…

I did complain rather loudly on Twitter, but I am yet to hear from the PLOS One folks.

Of additional potential concern is the underdosing of gabapentin in this study.
In someone with normal kidney function, the target dose for gabapentin for this indication should be at least 900 mg three times daily. This study used one-third of that dose. If the patient were not having dose-limiting side effects or modified dosing requirements due to decreased kidney function, then that dosing scheme is inadequate.

This is a bit of a side point. But it is a problem that also occurs in pharmaceutical trials as well. (Comparison of one drug to an inadequate dosing of the standard treatment.)

My own practice is to prefer venlafaxine rather than gabapentin as the first choice pharmacologic treatment, all else being equal, due to some (limited) evidence that patient tolerability is higher. http://jco.ascopubs.org/content/28/35/5147.full

I am ashamed that such a great place, where I did two years of fellowship, is promoting such nonsense. At least they had the sense not to offer it to me when I was a patient there. They would have gotten an earful.

In the end there are two bait and switches in this study: electroacupuncture sold as acupuncture and acupuncture sold as a powerful placebo that has clinical utility. Same as it ever was.

Amen.

...are now selling it as the “power of placebo.”

When the health industry starts selling placebo treatments to me is when I start paying them in placebo money.

Yeah, I hope that 1 million dollar check I am going to write them makes them feel wonderful before it ceases to do anything for their bank account.

@Kausik Datta
haha. funny i was just going to link your comment on SBM.

Oh, is that live now? *toddles off to check*

But seriously, for me, both Orac's and Dr. Novella's analyses have separate values. I love Orac's attention to the scientific details.

@ Kausik Datta
"Otherwise, I cannot find a reason why these studies, with so many glaring lacunae in methodology and interpretations, would find their way into a journal, such as PLOS One"
These papers are reviewed by acupuncture experts. Peer review does not make science.
But "hot" papers make high impact.

@Daniel,
"These papers are reviewed by acupuncture experts. Peer review does not make science."

True. To me, that points to a failure of the peer review system, because these reviewers seem to be reviewing acupuncture, and not the science.

This hearkens to what Dr. Novella wrote in the SBM piece: [I quote] "It seems almost that these types of studies are designed not to ask if acupuncture works, but to show that it works..." [End quote]

I suppose the bottom line here is that gabapentin is a pretty crappy drug for treating hot flashes.

Does the paper show the absolute values of HFCS (average, median or range) for each subgroup at time 0? Since a subjective measure like this cannot be linear, especially near the top and bottom boundaries, the subsequent deltas may not be comparable between subgroups.

As a perimenopausal woman, I can vouch that hot flashes can be miserable. Mine have dropped off with time, (and HRT treatment), but for a while I was having 1 ever 1-2 hours. I can't imagine knowing I couldn't treat them - I went flying to the doctor for HRT after the first week of that frequency. I would have tried gabapentin if I'd known that was an option, as I had used it for restless leg syndrome, to see if it worked. But not acupuncture.

These papers are reviewed by acupuncture experts.

This failure mode of peer review is not limited to acupuncture studies, or even medicine in general. It's a particular problem in medicine because medicine is such a large field that it's particularly easy to game the review system.

Here's how it works. The authors will suggest potential reviewers, and the editor will (or should) draw other potential reviewers from (a) his knowledge of who's who in the field and (b) whose papers are cited in the manuscript. The bigger the field, the greater reliance the editor has to put in the latter option. It's too easy for an editor to fail to notice that the literature review in the manuscript is unbalanced (or worse, not care because he agrees with the authors' views), and select reviewers who are sympathetic to that view. Of course the authors' suggested reviewers are likely to be sympathetic as well, which is why only the most foolish or desperate editors will pick more than one reviewer from the list the authors provide.

Also, reviewers can't be expert in everything. So maybe you get a reviewer who is expert on one specific aspect of the paper, and makes the authors improve that part, but overlook some other mistake that would be obvious to an expert in that aspect, but not to the reviewer. This happens routinely in my field, which is a good deal smaller than biomedical fields. I've read several papers in my field which left me thinking, "How the #$&% did that get past the referees?"

Maybe I've forgotten too much of what I was taught about statistics over the last 30 years, but the graph labelled Fig.2 raises hackles. The error bars overlap in all measurements up to 12 weeks, but can then be read as fantastically singular at 24 weeks. What am I missing?

@ Eric Lund
The problem is not related to the field. If one defines "excellence" in science by the number of peer reviewed papers with high short term impact (and two years is very short in science), one should not be surprised to see all this bullshit.
Before giving positions in scientific institutions, it would be better to evaluate individuals on their basic knowledge in the domain and, if possible, their creativity.

And Lo! I have invented a new treatment: Kitten-puncture.

We know from studies like this one that acupuncture is a theatrical placebo, where someone listens to you, and cares about you, and then pokes you a little bit, and you feel better.

Come to my (imaginary) clinic where you'll get a nice cold glass of tea, a big fluffy robe, and then you lie down on a nice soft table with soothing music, and I plop a pile of kittens on your back. It's a pleasant environment, you get stabbed slightly (kitten paws and claws are cleaned between patients) and then you go home.

Now I just need a cat-allergy alternative.

kitten paws and claws are cleaned between patients

I'd pay money to see how that's done.

Kittens are self-cleansing.

MO'B: Oh, that's easy! First you have them walk across a sticky pad, then dip their little feet in hand sanitizer. The trick is to keep them from licking the sanitizer.

First you have them walk across a sticky pad, then dip their little feet in hand sanitizer.

JustaTech - I admit to fairly limited kitting (kitten sounds ungrammatical - see "Elderly Man River") experience. However, the kittings I've known would not willingly walk across a sticky pad nor dip their paws into the entirely inappropriate hand sanitizer (shouldn't it be paw sanitizer? And if so, would that be for male cats only?).

The advocates of CAM love to have it both ways: when criticized that their treatments are no better than placebo, they elevate the placebo to a sort of venerated status, as if it is equivalent to actual effective medical treatments. As has been said often, there is a placebo effect, but the placebo itself has no affect.

If one defines “excellence” in science by the number of peer reviewed papers with high short term impact

I'm aware that it is standard practice to rate journals that way, and I agree it is foolish to do so. I haven't heard of individuals being rated in this fashion, but that would be even more foolish. There is no reason why a good paper shouldn't continue to get citations 10, 20, or even 50 years after publication. There is, however, a reason not to evaluate potential hires on this basis: early-career scientists will not have been in the field long enough to have any ten-year-old papers to cite. And those are the people who are generally considered for assistant professor positions in the US, or the equivalent in other countries.

The pressure for journals to boost their "impact factor" produces a fair amount of pathology. This article is a mild example. It may not mean what the authors think it means, but at least we have no reason to suspect that the described studies didn't happen more or less as described in the paper. Wakefield et al (1998, Lancet) was fraudulent, and there have been many other prominent cases. Nature and Science, which are derisively called "glamour mags" for a reason, are particularly susceptible because they specialize in "hot research" regardless of field; about two thirds of the papers retracted in the wake of the Jan-Hendrik Schön scandal were published in those two journals.

I wouldn't be so sure that kittehs would always avoid sticky surfaces as one of my own willingly ambled across newly varnished- still wet- wood which necessitated a concerted effort on my part in removing said varnish before she licked it or she stuck to something somewhere.

AND my Very Large Cat is quite adept at inserting his own puncturing implements into skin although he knows nothing about meridians.

I'm 50-ish years old, and take gabapentin for neuropathic pain (an approved use) - and I still get hot flashes. Interestingly, I didn't know the drug is used this way, though off-label. I suspect that since the drug makes a person feel drowsy, that the women who are awoken at night time due to hot flashes, find it easier to sleep through them.
This still doesn't explain why the placebo pills have such a marked effect on patients reporting fewer hot flashes (or less severe ones).

@ Eric Lund
The whole process of evaluating science by productivity is insane. And this is why I like quackademics: it's a very good illustration of this.

To Eric "I’m aware that it is standard practice to rate journals that way, and I agree it is foolish to do so."
A two year impact factor was important for librarians in order to know which journals they had to buy. It makes sense. The H index is frequently used by "scientists" to evaluate others. This is stupid and dangerous.

I have a question aboput the following statement:
"the EA is considered the “real” acupuncture and the standard acupuncture (SA) is described as the “sham,”

I don't have access to the paper, but I had a quick look at the protocol (which was available online), and they mention Streitberger needles. To my extent of knowledge, these are supposed to be fake needles that never pierce the skin, but only create the illusion of doing so by hiding in a sheath. Can anyone with access to the paper clarify what type of needles were actually used?

Thanks!

It doesn't matter how robust the evidence is patients are just people that are affraid of pain, loss, death or debilitating illness they are not rational by any means but they are our core buisness. banging this drum is pointless.

Orac,
Would a concisely couched letter to the editor of JCO not achieve your purpose?

ORAC~
A well placed review of a flawed study.
Ii's unnecessary to refer to Jun J. Mao as "Chairman Mao" if even he is the chariman of a dept. or the supporting institution. Reserve sarcasm for you own acquaintances.

I didn't refer to him as "Chairman Mao." I was referring to the real Chairman Mao, who ruled China for decades. Follow the link on his name. It explains all. In fact, it never even occurred to me that Dr. Mao shared Chairman Mao's name, although now in retrospect it's pretty funny to me and I wish I had thought of riffing on Dr. Mao's name in this post.

As for sarcasm, even though there was no sarcasm about Dr. Mao in my post (again, I was referring to the real Chairman Mao from history), I will be sarcastic when and where I damned well feel like it on this blog. If you don't realize that, you obviously haven't been reading very long. I have no intention of changing that.

Not A Troll @ 4: Ouch!, That almost cost me a new keyboard;-) Someone ought to try it as a defence against passing bad cheques. 'That wasn't a bad cheque, it was an acupuncture cheque! An homeopathic cheque if you will, a very good cheque with prosperous financial energy and a most righteous and honourable history!!'

JustATech@ 15: 'Kitten-puncture:' also has the relaxing benefits of a good massage. To get the little moggies to walk across the sticky pad, just place windup mice on the other side of it. A sanitiser gel made from ethanol wouldn't be quite so acutely toxic as one made from methanol, so you'd have time to intervene if they started licking their paws. Just don't make any claims about 'the healing energy of soft fluffy kitties' and we'll recommend you to our friends.

Seriously though, why didn't the nefarious study in question use a TENS arm as a control against EA? Someone needs to do this one: EA, TENS, and a no treatment arm. Thereby demonstrating that any claimed effect of EA is indistinguishable from that of TENS, and removing the magic from the medicine.

@ Lurker
If you remove the magic, then you lose the impact. This paper has been published because of the magic. This blog is popular because of the magic. Orac has published in a high impact factor journal about magic, could he do this with serious issues?

Riard Fitzgerald:

As distinct, I suppose, from you and your friends and acquaintances, who are not at all afraid of pain, loss, death, or debilitating illness? Brave, brave sir Riard.

Most people are afraid of at least some of these things. Some people who aren't actually afraid of pain know that it interferes with most other things, including clear thinking and ability to get things done, even relatively simple things like laundry. I have a relative who tried acupuncture for pain, in the hope that it would let her focus better and/or reduce her doses of narcotics, acetominophen, and NSAIDs. (The acupuncture significantly increased her pain levels, as well as being a waste of money and her limited time and energy.)

Come to my (imaginary) clinic where you’ll get a nice cold glass of tea, a big fluffy robe, and then you lie down on a nice soft table with soothing music, and I plop a pile of kittens on your back

This would be as effective as acupuncture is. Heck, it would probably work better than acupuncture for a lot of people.

Seriously though, why didn’t the nefarious study in question use a TENS arm as a control against EA? Someone needs to do this one: EA, TENS, and a no treatment arm. Thereby demonstrating that any claimed effect of EA is indistinguishable from that of TENS, and removing the magic from the medicine.

I briefly looked around for just such a thing, and didn't find much.

I rather suspect that the EA fanbois don't want to know what we suspect it will show (that is, no difference between EA and TENS), and everyone else suspects it would be a waste of time and money, with little chance of publication.

In 2015, you will find that Acupuncture is both an art and science.

You all are playing around with incomplete concepts and remedies. PLUS you are behind the science. Unfortunately most are behind the science even the schools of Acupuncture.

The art is --- well profoundly well balanced within that time in history, the culture and the real-life observations.

The science is in the book of C. Chan Gunn, MD and an old study done by Cannon Law of denervation.

Gunn lays out the perfect 1 to 1 cause and effect reality based problem + solution = resolution. Muscle pain + the needle as the remedy = resolution of the pain.

If you want more evidence you can study Gunn works. Then you can blend his work into that of Travell, Simons, Rachlin, Hackett et al for the complete 360 view of what is not very observable in the bits and pieces of RCT research.

The grandmothers effect, paternal or maternal matters (?)

razib — Fri, 30 Oct 2009 05:02:08 +0000

The grandmothers effect, paternal or maternal matters (?)

I've discussed menopause as an adaptation and the grandmother effect before. I was also pleased to see the responses of Larry Moran's readers when he presented his standard anti-adaptationist line of argument. I don't want to retread familiar ground here, I'm not sure if menopause is an adaptation, but let's assume so for the purposes of reviewing a new paper which has come out and offers a slight but fascinating twist on the grandmother hypothesis. Grandma plays favourites: X-chromosome relatedness and sex-specific childhood mortality:

Biologists use genetic relatedness between family members to explain the evolution of many behavioural and developmental traits in humans, including altruism, kin investment and longevity. Women's post-menopausal longevity in particular is linked to genetic relatedness between family members. According to the 'grandmother hypothesis', post-menopausal women can increase their genetic contribution to future generations by increasing the survivorship of their grandchildren. While some demographic studies have found evidence for this, others have found little support for it. Here, we re-model the predictions of the grandmother hypothesis by examining the genetic relatedness between grandmothers and grandchildren. We use this new model to re-evaluate the grandmother effect in seven previously studied human populations. Boys and girls differ in the per cent of genes they share with maternal versus paternal grandmothers because of differences in X-chromosome inheritance. Here, we demonstrate a relationship between X-chromosome inheritance and grandchild mortality in the presence of a grandmother. With this sex-specific and X-chromosome approach to interpreting mortality rates, we provide a new perspective on the prevailing theory for the evolution of human female longevity. This approach yields more consistent support for the grandmother hypothesis, and has implications for the study of human evolution.

This figure illustrates the pedigree in question:

Let's start from the offspring.

For a male child, the Y chromosome comes form the father. So the X must come form the mother. You therefore know that a male child can not logically have inherited an X chromosome from their paternal grandmother. Their X chromosome comes from their mother, who has an X from both parents. Therefore, there is a 25% probability that any given allele on the maternal grandmother's X chromosome will be passed down (50% mother to daughter, and then 50% from daughter to son).

For a female child, there are two X chromosomes. One from the father, and one from the mother. The father is passing on the paternal grandmother's X chromosome. So there is a 50% probability that an allele from the paternal grandmother will pass on down to her grandaughter. There is again a 25% probability that a given allele from the maternal grandmother will be passed down.

The X chromosome is just one among many. 92% of human genes are autosomal, they're not on the sex chromosomes. The coefficient of relatedness of a grandparent to a grandchild is 1/4, so 23% due to autosomal inheritance (92/4). The remainder is taken up by the X (the Y has very few functional genes), and that remainder varies as described above. In theory a paternal grandmother will likely share 27% of her genes with her granddaughter, and only 23% with her grandson (in the case of maternal grandmothers it will be 25%).

Inclusive fitness tells us that this should bias how much time and resources a grandmother will devote to her grandchildren. Another issue in relation to the grandmother effect is that "paternity uncertainty" presumably biases paternal grandmothers against as much investment as maternal grandmothers. The data on this, as noted in the paper, is mixed. Additionally, the effect of this should be proportional to the amount of paternity uncertainty, which seems to vary quite a bit between societies (e.g., from 0.1% to 10%). While the argument about paternity is based on a frequency which varies and which we do not know with a great degree of accuracy, the genetic logic above is clear and distinct. The predictions are clear, a rank order of investment should be:

PGM → granddaughter > MGM → granddaughter & grandson > PGM → grandson

To evaluate their predictions they looked at seven societies, Japan, Germany, England, Ethiopia, The Gambia, Malawi and Canada. The grey bars below are girls, the black are boys. Each letter represents a society. "Odd ratios" are rather self-explanatory, greater than 1 means more than typical likelihood of survival, and less than 1 means less than typical.

Here's a table which summarizes their findings:

And their conclusion:

Genetic relatedness between kin is often used to explain behavioural phenomena associated with altruism and caretaking, as well as biological traits and developmental trends. The grandmother hypothesis is the prevailing theory to explain why human female longevity extends beyond menopause. It suggests that elderly women are able to contribute to their grandchildren's survivorship through nutritional provisioning, which would increase a woman's inclusive fitness because she shares one-quarter of her genes with a grandchild. In seven previously studied populations, separating grandchild survivorship rates by sex reveals that X-chromosome relatedness correlates with grandchild survival in the presences of MGMs and PGMs. In all seven populations, boys survive better in the presence of their MGM than PGM. In all bar one population, the PGM has a more beneficial effect on girls than on boys. Our X-linked grandmother hypothesis demonstrates how the effects of grandmothers could be sex-specific because of the unusual inheritance pattern of the X-chromosome. This provides a more universally applicable model to explain differential survival of grandchildren in the presence of their grandmothers.

Empirical findings in this field are confusing, often contradictory, and not reproducible. This is why Virpii Lummaa has had so much success with Scandinavian records, they go back a long way and they're copious. The underlying mechanisms shouldn't be too hard to conceive of, consider the strangeness of genetic imprinting. Rather, there needs to be more said about the proximal manners in which these sorts of behaviors would work themselves out; the authors are rather sketchy on that, and with the problems with cross-cultural reproducibility one never knows if a theory was generated after noticing a trend in the data which one simply happens to have on hand.

Note: I think one can add more twists & turns by adding variations of mating systems, which would effect paternal and maternal X chromosomes a bit differently. But we've come far as it is.

Citation: Molly Fox, Rebecca Sear, Jan Beise, Gillian Ragsdale, Eckart Voland, and Leslie A. Knapp Grandma plays favourites: X-chromosome relatedness and sex-specific childhood mortality Proc. R. Soc. B published online before print October 28, 2009, doi:10.1098/rspb.2009.1660

razib Fri, 10/30/2009 - 01:02

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Interesting post, but I'm not entirely getting that 31% figure for PGM-granddaughter relatedness. The granddaughter inherited 92/4 = 23% of her genes from the PGM's autosomes. That leaves about 8% of the granddaughter's genes on X chromosomes. But only half of those X-chromosome genes are paternal. So why isn't the total 92/4 + 8/2 = 27% instead of 92/4 + 8 = 31%?

you're right! fixed.

If the paternal grandmother provides 27% of the genes that a granddaughter has and 23% of the genes that a grandson has, does it then follow that the paternal grandfather provides his granddaughter with 23% of the genes and the grandson with 27% of the genes?

Menopause as an adaptation

razib — Tue, 13 Oct 2009 02:17:46 +0000

Menopause as an adaptation

I've talked about menopause before. One question in evolutionary anthropology is whether it is an adaptation, a derived trait in our species which emerged due to the force of natural selection, or simply a physiological byproduct of some other phenomenon. The key point is the peculiar asymmetry in male and female reproductive potentials; males decline gradually over time, while the general suite of female reproductive function simply shuts down at during middle age. Eric Michael Johnson reviews a new paper by the redoubtable Virpi Lummaa, Fitness benefits of prolonged post-reproductive lifespan in women. Eric concludes:

Dr. Lummaa has done just that in her study published in the journal Nature, demonstrating that children are 12% more likely to survive to adulthood when they have a grandmother's support than when they don't. That may not seem like a lot, but consider all of the descendants from that surviving 12%, each carrying the trait for reproductive senescence, and you can see how it wouldn't take long for the trait to become fixed in a population. Furthermore, one of the key innovations of her study was her choice of sample set. By using Finnish records dating from the 18th and 19th centuries she could ensure that any modern health benefits wouldn't influence the results and would therefore accurately pinpoint the grandmother's role.

12% is a very big effect and would lead to rapid evolutionary change (on the order of thousands of years in the most simple population genetic model of a single locus of dominant effect). Seeing as to the fact that there are several models of Pygmy stature arguing that it is a product of life history changes, exploring this group's physiological defaults might be interesting. A friend once told me that anthropologists report that Bantu populations regard Pygmy women as particularly fertile. Finally, one major consideration about menopause for me is that I was once told by a biological anthropologist who collaborated with some doctors in this area is that the process has many "moving parts" and seems to involve proactive shutting down a host of physiological processes. Whatever the fitness implications, the physiological tightness of menopause and the rarity of the phenomenon among animals suggests to me that the spandrel model should be viewed with skepticism.

razib Mon, 10/12/2009 - 22:17

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"males decline gradually over time, while the general suite of female reproductive function simply shuts down at during middle age"

The female reproductive funtion also declines gradually over time starting around 35. The difference between men and women is that there is a common and finite end to a female's reproductive life.

Why we like to compare woman to animals in this sense I don't know. The effort to birth and raise a human child is enormous compared to an animal. Why would anyone wonder why the ability to do so actually ceases when in fact the will to do so also ceases.

Except for the media grabbing few, women don't want to give birth to babies at 60 so why waste time and money working out why we don't?

12% is, indeed, a very large effect but what does it have to do with evolution?

We're looking at a study where every single woman underwent menopause so one of the things we certainly aren't doing is testing to see whether menopause has an effect on the survivability of grandchildren.

Let's think about reasons why some families have grandmothers to help out and some don't. First, there's the relative proximity of living grandmothers. Then there's the question of the relationship between parents and grandparents. Let's not forget possible financial help that has nothing to do with direct caregiving. Finally, there's the issue of whether a family even has a surviving grandmother.

None of theses things are affected in any way by the fertility or non-fertility of the grandmother, right? The 12% difference has nothing to do with menopause.

Now let's think about a time in the past when menopause was presumably evolving. You had two kinds of females in the population, those who underwent menopause and those who didn't. There will still be all kinds of families who experience the help of a grandmother irrespective of whether she can still have kids or not. That's the background that a presumed adaptation has to deal with.

If there are non-menopausal women who live into their fifties, are close to their grandchildren, and whose husband is dead, then they will presumably help raise thier grandchildren. Same thing applies to non-menopausal women who simply don't risk getting pregnant any more even though their spouse is alive. (Just say "no." It's probably more common than you think. Women are not stupid.)

In fact, the adaptationist just-so story only really applies to that small subset of women who have the following characteristics.

1. They live past 50 years old.
2. They have grandchildren who are young and still need care.
3. They don't have too many grandchildren in different families so their caregiving can be effective.
4. They live near their grandchildren and can help out.
5. They have a good relationship with their children and their spouses.
6. Their husbands are still living.
7. They choose to get pregnant.

That's the only group that menopause affects. It eliminates #7 but has no effect on any of the other factors. It certainly doesn't have any effect on whether the grandmother was dead or alive at 50 years old.

Given that there were many families that received no help from grandmothers, whether they had the menopause allele or not, and given that there were many families who received help even if the grandmothers did not have the menopause allele, the question is "what is the adaptive value of menopause under those circumstances."

What does the Lummaa study have to say about that?

Since you are a supporter of this adaptationist explanation can you describe for me the kind of society where you think this allele became fixed in the population? Was it a hunter-gather society of small bands or a large agricultural society of small towns? Or something else?

I'd like to hear more details about how this grandmother hypothesis actually worked in Australopithicus or Homo erectus societies. Please include your estimate of how many grandmothers survived past the age where menopause could make a difference as you estimate the fitness coefficient.

It's an old paper, published in 2004.

@Larry Moran: I have responded to your critique of my and Razib's support for the grandmother hypothesis at The Primate Diaries: http://scienceblogs.com/primatediaries/2009/10/reply_to_moran_the_adapt…

@Razib: You don't allow hotlinks? Dude, what gives?

@Razib: You don't allow hotlinks? Dude, what gives?

if you're talking about the SB site, i don't control access to that. i think tim blocked hotlinking a long time ago. if you're talking gnxp.com, yeah, i blocked it cuz of some malicious types who kept switching websites a few years ago (no need to go into details).

I wonder what the effect is if you control for age of the parents? It strikes me as reasonable to believe that children without "a grandmother's support" are likely to have older parents (possibly because this is a neat account of my immediate family history). As a related measure, what is the effect of parent age at birth on child survival?

The key point is the peculiar asymmetry in male and female reproductive potentials; males decline gradually over time, while the general suite of female reproductive function simply shuts down at during middle age.

This does not seem all that peculiar given the asymmetry in having children.

Though men and women contribute genetic material during sex, only women experience the birthing process. Assuming the birthing process involves additional risks (e.g., birthing complications) relative to sex alone, and these risks increase with maternal age, it would seem evolutionary advantageous for physiological mechanisms (i.e., menopause) to evolve that would stop reproductive capacity at some point (e.g., around middle age). Such a mechanism would seem beneficial to the long-term survival of mother and infant. The best evidence for this that comes to mind at the moment include: the tendency for women who have not had children to reach menopause sooner (suggesting the presence of a biological clock that is sped up when a woman does not have a child after a critical age), and women with the largest time gap between age of pubertal onset and age of having their first child increases risk of birthing complications. The current explanation for the latter finding, is that a larger time gap corresponds with increased exposure to the hormones estrogen and progesterone, which somehow impair uterine contractions during labor. This also seems to explain the finding of more cesarean sections with increased maternal age, and suggests there's also an optimum start time for the biological clock (e.g., the age of pubertal onset) as well.

...children are 12% more likely to survive to adulthood when they have a grandmother's support than when they don't...

Is this finding supposed to explain how the physiological mechanisms associated with menopause evolved? If so, I'm having some difficulty grasping the connection. If it is not meant to explain how menopause itself evolved, then there are relatively more mundane (sociocultural) explanations for post-reproductive lifespan as suggested by Michael Watts' questions.

Approximately 5% of the U.S. and Canadian population are from skipped generation families (i.e., children being raised by grandparents). These families occur among all ethnic groups, but is more frequent among ethnic minorities (e.g., African American, Hispanic, Aboriginals). I suspect part of the reason for the difference stems from higher teenage pregnancy rates, but also, from the more collectivistic mindset of minority groups relative to mainstream culture.

So I suspect the grandmother effect would also be observed when we compare survival into adulthood rates of children in skipped generation families vs. children living with parents, especially if the parents are teenagers and/or had children during their early teens. (On a related side note: research indicates a tendency for puberty to start earlier in children who grow up in high conflict homes, and later for women who grow up in low conflict homes).

Hormone replacement therapy (HRT) is the main treatment for menopausal symptoms. It relieves hot flushes and vaginal dryness, and reduces the chance of urinary infections. It can also help if you feel depressed. Try B-6 it helped with the hot flashes and the night sweats, it will make your urine dark almost orange, but it does help. Also good cardio workouts, they help with the mood swings.

@hotflash "Except for the media grabbing few, women don't want to give birth to babies at 60 so why waste time and money working out why we don't?"

Because it's the job of science to look at how things are and try to figure out how/why.

@hotflash

"Why we like to compare woman to animals in this sense I don't know"

It really isn't a comparison since we are, in fact, animals. Our emotions and other aspects of us are controlled by things we don't yet fully understand. We really don't understand alot about ourselves, including basic instincts, emotions, sexuality and reproductive functions, personality, decision making processes, morality, ect.

The will to have children may be an effect of menopause rather than an independant function, or it may be the result of cultural adaptation rahter than physical adaptaion.

And clearly you have no passion for science whatsoever, asking why we spend money on learning new things that aren't of immediate use is like asking why we went to the moon. And to be fair, we got teflon out of that. The potential for a vast growth in knowledge from any discover far outweighs the money spent on such research.

Genes which affect female development

razib — Mon, 18 May 2009 06:41:35 +0000

Genes which affect female development

There are several papers and letters in Nature Genetics on the relationship between menarche, menopause, etc. and genetics.

Meta-analysis of genome-wide association data identifies two loci influencing age at menarche:

We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 10-9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 10-9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.

Loci at chromosomes 13, 19 and 20 influence age at natural menopause:

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 10-11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 10-11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 10-8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

Genome-wide association studies identify loci associated with age at menarche and age at natural menopause:

Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 10-7-3 10-13) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 10-7-1 10-21) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits.

Genetic variation in LIN28B is associated with the timing of puberty:

The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 10-8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 10-10; combined P = 3.6 10-16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 10-7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.

Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche:

Earlier menarche correlates with shorter adult height1 and higher childhood body fat2. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 10-14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height3, 4. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height...did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI)...and 5 of those associated with earlier AAM.

These work are interesting because if the genetic mechanisms by which menopause occurs are elucidated, perhaps the question of whether it is an adaptation, or not, will be resolved (or greater clarity attained). Below are some figures on the global distribution of some of the larger effect SNPs identified from the HGDP browser.

rs314277 on LIN28B, with "A" variant increasing menarche by 0.0963 years.

rs1172822, -0.4 year per "T" allele for age at menopause.

rs236114; +0.5 year per "A" allele for age at menopause. I think the labels for the HGDP are off here. Pubmed agrees with the paper, so I suspect T = A, and C = G.

rs7333181; +0.5 year per "A" allele for age at menopause.

rs314276, "C" allele, 0.12 years earlier menarche, earlier breast development, earlier voice breaking and more advanced pubic hair development (in boys), faster tempo of height growth in girls and shorter adult height in both sexes.

1) Be careful to compare across populations obviously. Effect sizes (or perhaps direction) might differ for a given variant.

2) The fact that these loci are implicated in lots of traits is not surprising, but intriguing. One of the arguments for the timing of menopause is that is adaptive for older women to aid in the rearing of their daughter's offspring, as opposed to risking further pregnancy. These data suggest a connection between onset of puberty and menopause. All things equal shifting the onset of puberty will have a much bigger direct fitness effect it seems to me than the secondary effects of grandmothers.

razib Mon, 05/18/2009 - 02:41

Tags

Genomewide Association

Menarche

menopause

puberty

I think the labels for the HGDP are off here. Pubmed agrees with the paper, so I suspect T = A, and C = G.

just reporting different strands, I guess...

Did conflict between old and young women drive origin of menopause?

edyong — Tue, 01 Apr 2008 06:30:00 +0000

Did conflict between old and young women drive origin of menopause?

You could argue that life is all about cheating death and having enough sex to pass on your genes to the next generation, as many times as possible. From this dispassionate viewpoint, human reproduction is very perplexing for our reproductive potential has an early expiry date. At an average age of 38, women start becoming rapidly less fertile only to permanently lose the ability to have children some 10 years later during menopause.

From an evolutionary point of view, this decline is bizarre. Other long-lived animals stay fertile until close to the end of their lives, with elephants breeding until their 60s and the great whales doing so in their 90s. In comparison, a human woman is exceptional in losing her child-bearing potential years or decades before losing her life. Even in hunter-gatherer societies that lack our access to modern medicine and technology, women who pass through menopause can expect to live well into their sixties.

Now, a pair of scientists have proposed a new model to explain the origins of menopause. Michael Cant from the University of Exeter and Rufus Johnstone from the University of Cambridge suggest that the loss of fertility helps to lessen reproductive conflicts between successive generations of women.

A few theories have already been put forward to resolve this conundrum. I've previously blogged about one of these, which suggests that the menopause reduces the health risks that repeated childbirth brings to both mother and child. This idea complements the most popular theory, known as the "grandmother hypothesis", which suggests that older, infertile women can still boost their reproductive legacy by feeding, teaching and caring for their existing children and grandchildren.

The basic idea makes sense and while some studies have backed it up, it's clearly not the whole story. Some analyses of hunter-gatherer populations have found that the indirect advantages of helping your family don't outweigh the potential benefits of having more children yourself. Alone, the grandmother hypothesis can explain why women continue to live past the menopause, but not why they go through it in the first place.

A new model

Cant and Johnstone believe that the current picture is incomplete because previous studies have ignored the fact that new children affect not just their mothers, but other members of the community too. The children of all the fertile women within any group draw upon the same pool of food, resources and attention from other adults, which effectively leads to a form of "reproductive competition" between mothers.

Cant and Johnstone suggest that menopause serves to minimise this conflict and cite the timing of menopause as evidence for their theory. In humans, there is remarkably little overlap between the reproductive periods of different generations. In hunter-gatherer societies, mothers tend to stop being fertile at more or less the same time that their daughters become sexually mature.

This degree of separation is truly exceptional among other primates, which, as the graph below shows, mostly become fertile while their mothers are still more than capable of conceiving. For example, the fertile periods of successive generations of Japanese macaques overlap by about 12 years, which is about 70% of their total reproductive lifespan. Based on the trends shown by other primates, human women would be expected to keep on bearing children till the ripe old age of 70, rather than the much earlier cut-off in their 50s.

From birth, a woman is outfitted with a lifetime supply of follicles, shells of cells that contain immature egg cells, and these are used up as she goes through more and more menstrual cycles. The stocks are gradually worn away but the process accelerates dramatically at about the age of 38, in a way that doesn't happen in chimps, monkeys or rodents. If this acceleration never happened, the earlier and slower rate of follicle loss would lead to menopause at around the age of 70, the same age predicted by trends in other primates.

Old vs. new

If older and younger women do indeed experience reproductive conflict, why is it the older generation who cedes ground by becoming infertile, and not the younger one? After all, in most mammals that cooperate to raise young, it's the other way round - the older generation continues to breed and suppresses the fecundity of the younger generation. Cant and Johnstone believe that it all boils down to how the social groups of our ancestors mingled with one another.

In all social mammals, groups exchange members to some extent and in most cases, it's the males that strike out. But for ancestral humans, there's plenty of evidence to suggest that the females were more often the ones who left home and found new groups. Genetic evidence, along with the behaviour of hunter-gatherers and our close relatives, the chimps and bonobos, all support this idea.

This simple fact changes how related different females are to other members of their group and that shifts the balance of conflict in favour of the young newcomers. A young female entering a group is better off raising children of her own, for she is completely unrelated to the group's existing members and gains no indirect benefits from helping to raise their children. On the other hand, an old female can benefit from either having more children herself or helping to raise any grandchildren that her sons father with the young newcomers.

Using a simple model to simulate these interactions, Cant and Johnstone found that these asymmetric benefits skew the results of the competition towards the younger females. The competition resolves itself in a stable way if the older females stop reproducing when the younger ones begin.

The duo freely admit that their hypothesis will need to be tested further and suggest ways of doing so. For a start, they note that if they are correct, scientists should be able to show that young mothers experience drawbacks if they have children alongside older grandmothers who are still doing the same, as is the case in some polygamous societies.

Finally, Cant and Johnstone note that their new hypothesis is not meant to be an alternative to existing ones, but a complement to them. They hope that it will help us to more fully understand the origins of menopause if we view it as a reflection of the "ghost of reproductive competition past".

Images from PNAS and Petercantfail

Reference: doi:10.1073/pnas.0711911105. This paper will be published in PNAS and I will upload a citation when it is.

edyong Tue, 04/01/2008 - 02:30

Tags

reproductive conflict

Reproductive Lifespan

evolution

Human Evolution

I may have missed something but that doesn't really explain why elephants and whales don't have a reproductive competition and why their females continue to reproduce. Don't they have the same competition for resources amongst herd members?

According to the paper, the difference lies in the degree of resource sharing in humans and the extent to which children depend on adult help. It matters that hunted and gathered resources are shared extensively among the rest of the group. Also, human children are born fairly helpless and are heavily dependent on the help of adults to survive. These two factors combine to generate competition for both resources and help from adults. That makes sense to me but I wonder if anyone else has anything to add to this?

Assuming that is indeed the young women who are the newcomers (captives, perhaps), most existing members of the group are more related to the offspring of the older women. So if there's only enough food for some of the kids, I would expect the newbie and her husband to lose out.

Thanks for the follow-up Ed, I did miss something, apparently.

Ford - I think the model assumes that the newbie's husband was the son of one of the group members. The model's more sophisticated than I managed to describe in the post and it's probably worth checking out in full.

There are 3 human characteristics that may add to the evolutionary advantage of menopause: uprightness, brain size and hidden ovulation.
1) I've read that the biological cost of building and operating larger brains requires a trade-off and that we have smaller guts than chimps. Might that also create a drawdown from a woman's reproductive organs?
2) uprightness exacts a toll on bones and joints. After a certain age, maybe the resource cost of supporting a woman and her child are greater than the likely success of raising the child plus the woman's later contribution--due to the added damage to bones & joints from pregnancy and carrying infants. That's the social group's weighing in. For the individual woman, maybe the physical toll causes there to be an advantage to supporting her grandchildren over gambling she can successfully have more of her own.
3) Maybe the biological cost of hidden ovulation takes a toll. Maybe the biological cost of always being available for intercourse takes a toll. Maybe a reproductive system can't survive too many years of constant, "unfruitful" use. (Maybe the Catholics are right--it ain't for entertainment. Our original sin occurred 5 million years ago with hidden ovulation.)

Add to the mix that human males pose one of the greatest threats to female health with their jealous rages, forced obedience, and "kicking the dog--or wife" after unsuccessful status fights. And their attractiveness as targets of this violence is greatest during child-bearing years. Maybe females that had children, survived to raise them, and then became unavailable for mating had a survival advantage over females that continued to be available for mating and beating.
I'm a recovering lawyer, working as a programmer. Should I keep my nose out of a science I have no training in?

"I'm a recovering lawyer, working as a programmer. Should I keep my nose out of a science I have no training in?"

Absolutely not! You have posited three hypotheses for other people to consider and done so in a modest suggestive way. I think that sort of thing is to be encouraged not sniffed at.

I think that probably all three of your points and certainly 2 and 3 are dealt with by the earlier theory I blogged about - i.e. that repeated bouts of childbirth take a physical toll on a woman's body that brings costs to both her health and that of her children. That's supported by some evidence but I'm not sure as to the reasons behind those costs.

One of the things i enjoyed about practicing law was the challenge of quickly gaining enough understanding of a technical area to make my expert look smarter than their expert. So if any reader has thought about law school but wonders if they'd lose the payoff they get from technical studies--go to law school.
Your summary of the article and new hypothesis only seems to identify the differences in individual costs/gains in competing for group resources. In other words, you introduce the group's interest in maximizing resource application, but only discuss the individual costs/gains.
If the inquiry into reasons for menopause advantage focus on individuals, there is no reason to introduce the group's interests. The focus simply remains upon the costs to the individual in continuing to bear vs. advantages in stopping to aid grandchildren. Which is the "grandmother hypothesis" without the new hypothesis.
In summary: does the new hypothesis propose that uniquely-human social structure caused the group's resource allocations to favor young mothers over old? And if yes, the group's evaluation would have to be based on more than the likelihood of successful bearing and maturation of offspring--or it is just a gloss on the grandmother theory.

I think the place to look might be in the uniquely-human monogamy of parents. He wants to know that he's feeding only his children. She wants to know that he's feeding only her children. Of course monogamy is not ubiquitous among humans, but it is the prevalent behavior. Thus, it is not the group's resource allocation decisions as much as it is the 2-parent dynamic that gives an advantage to a couple that shifts focus from their children to their grandchildren.

Women... you'll never figure them out.

From the post: 'In hunter-gatherer societies, mothers tend to stop being fertile at more or less the same time that their daughters become sexually mature.'

Which societies are these? If young women become fertile by 15, the same age as their mothers did, these mothers will be 30. Does menopause start that early? Am I missing something?

If young women become fertile by 15, the same age as their mothers did, these mothers will be 30. Does menopause start that early? Am I missing something?

Puberty generally started later in hunter-gatherer societies, so fertility probably began a bit later than 15. Menopause was also earlier. Our society has early puberty and late menopause for a number of reasons, including better nutrition, but also including artificial hormones and the like.

Statement regarding the use of bisphenol A

neurotopia — Fri, 03 Aug 2007 11:20:35 +0000

Statement regarding the use of bisphenol A

The LA Times has an interesting story about a statement regarding the use of bisphenol A, a compound that has many uses in the plastics industry and also happens to have estrogenic effects.

The scientists -- including four from federal health agencies -- reviewed about 700 studies before concluding that people are exposed to levels of the chemical exceeding those that harm lab animals. Infants and fetuses are most vulnerable, they said.

This is an important point. Organisms in utero can be exquisitely sensitive to growth factors and hormones, sometimes hundreds or even thousands of times more sensitive than their adult counterparts. Our youngin's should be the first place we look for effects of bisphenol A exposure.

The statement, published online by the journal Reproductive Toxicology, was accompanied by a new study by researchers from the National Institutes of Health finding uterine damage in newborn animals exposed to BPA. That damage is a possible predictor of reproductive diseases in women, including fibroids, endometriosis, cystic ovaries and cancers. It is the first time BPA has been linked to female reproductive tract disorders, although earlier studies have found early-stage prostate and breast cancer and decreased sperm counts in animals exposed to low doses.

Note the cautionary nature of the statement, which is appropriate given that we don't have any human studies to back up these statements. It is important to note that....

The scientists' statement and new study -- along with five accompanying scientific reviews that summarize the 700 studies -- intensify a highly contentious debate over whether the plastic compound poses a public threat. So far no governmental agency here or abroad has restricted its use.

...but there is legitimate concern. Humans are likely to be exposed to more bisphenol A than are our rodent test subjects. This stuff is in literally just about every single plastic we use. And bisphenol A isn't the only estrogenic compound in use today, by a long shot. It's possible that bisphenol A might act synergistically with other compounds to mess us up developmentally, or contribute to various forms of cancer, who knows. I think this statement expresses a good balance of skepticism and plausibility.

neurotopia Fri, 08/03/2007 - 07:20

Tags

menopause

Natural Sciences

have access to payday loans? That remains to be seen. Just because Americans see themselves as living in âthe land of the freeâ doesnât mean that interest groups (i.e. banks and credit

Thoughts on Approaching Hormone Therapy Data

neurotopia — Mon, 09 Jul 2007 23:53:43 +0000

Thoughts on Approaching Hormone Therapy Data

I recently posted three "Basics"-style blurbs about menopause and hormone therapy (HT). If you missed it, they are here, here, and here. The field has gone through a lot of upheaval since the WHI studies in 2002, and I would just like to share my thoughts on how to approach where we stand now. These are the sorts of questions and considerations that researchers and health care professionals need to keep in mind when they evaluate HT. After the reference-heavy previous posts this one is going to just be my thoughts, and very off-the-cuff at that.

We, as humans, have a tendency to put things in conceptual boxes. Cholesterol bad. Eggs bad. No wait eggs good. Hormone therapy good. No wait hormone therapy bad. Unfortunately, endocrinology doesn't like boxes. Hormones abhor predictability. In fact endocrinology is a frakkin' nightmare even when you're dealing with one simple feedback loop. So when you hear that "estrogen is bad again" in the news, STOP.

Firstly, in the world of hormone therapy, there is no singular hormone therapy. There are different formulations of estrogen or progesterone. They each have different affinities for the various receptors they target. They each activate their receptors in different ways. They all clear out of the body differently. There is no singular dosage. There is no singular route of administration, which can also dramatically affect bioavailability and clearance. We simply cannot draw conclusions from a study of one singular therapy and then extrapolate them to all forms "hormone therapy". One estrogenic compound is NOT representative of all other estrogenic compounds. Medroxyprogesterone acetate (MPA, or Provera) is DEFINITELY NOT like natural progestin.

Secondly, watch your study population closely. A recent paper suggested that surgically menopausal women may benefit from immediate administration of Premarin, for a duration of 7 years or so, by showing less signs of atherosclerosis. What does this study tell us? That surgically menopausal women's arteries benefit from the administration of Premarin. These results do not necessarily apply to osteoporosis, or breast cancer. These results are not generalizable to women with intact uteri receiving Premarin/Provera, as Provera may very well counteract the beneficial effects of Premarin as in the WHI studies. However, other formulations of progesterone may do nothing or enhance estrogen's effects.

Does your study population look at naturally menopausal women or surgically menopausal women? That will affect the hormone therapy being used. Studies of surgically menopausal women tend to have MUCH younger sample populations, and the sudden loss of circulating estrogen and progesterone is a shock to the system, as opposed to the gradual cessation that takes place over many years in perimenopause. Is your study population highly symptomatic or asymptomatic following menopause? Believe it or not, women who experience fewer hot flashes and the like can respond differently to HT than women who experience many symptoms. Does your study population have a large number of risk factors for various diseases of aging? These risk factors may impact HT negatively, especially if it has been a number of years since menopause.

Second-and-a-halfly, what's your outcome? Estrogen can be beneficial for preventing bone loss, but it also causes breast and uterine cancer when there's no progesterone to oppose it. Don't generalize a beneficial effect of a particular HT to all outcomes; organ systems can and do respond very differently.

Thirdly... WHEN you receive HT matters. It matters A LOT. The WHI trials showed us that when there is a large gap between menopause and treatment initiation, there is an increased incidence of some rather serious health risks (but only when on Prempro, not necessarily applicable other formulations!). Newer studies and also animal studies suggest that if you want to maximize benefit from HT, you need to take it at menopause or shortly thereafter. The "window of opportunity" to benefit from HT does close. The specific therapy and duration of exposure is something to discuss with your physician, as each woman has different needs with regards to cardiovascular, skeletal, and mental health.

When dealing with HT, nothing is as it seems in a headline. New results do not "replace" our old ones, estrogen does not become good and bad and good again. Rather our newer, more refined studies serve to highlight the subtleties of the endocrine system, and we must constantly be aware that under certain conditions a therapy may be very beneficial while under other conditions, which may appear to vary modestly, that same therapy can be useless or even damaging.

And if you're a lay person reading this, please talk to your physician. While I can't dispense medical advice, I can help you find the starting points for an important conversation.

Oh, and one other thing... an increasingly large percentage of the population has been on birth control, which can also have long-term consequences and may interact with later HT. We may very well have to throw out everything we know about HT to accomodate our changing demographics. Ain't hormones a blast?

neurotopia Mon, 07/09/2007 - 19:53

Tags

The thing that is almost impossible to convey to non-menopausal doctors is that for some of us the 'feel good' effects of taking HRT far outweigh the possible risks. I have been told by several doctors that 'you can't expect to keep feeling young forever' and 'you have to accept the changes that come with age.'I see no reason why I should accept joint and muscle pains, mental slowness, poor memory and general fatigue when there is a simple treatment that reverses all of those things. I would rather accept the risk of a shortened life lived to the full than live half a life for the next 30 years.

must talk to you !!!!!!!!!!!!!!!!!!!!!!

I am doing my thesis diss. in social work welfare, policy and practice on mid-life women and menopause, hrt etc. at WSSW Yeshiva Universities school of social work here in ny

love your comments. can we talk.

i can be reached at 718-432-5388
or 917-362- 3933
cannot wait to connect

Human growth hormone has become a unique healing option for adults having GH (Growth Hormone) deficiency. Most recent studies show that a number of metabolic and psychological abnormalities related with HGH deficiency can be inversed with HGH replacement therapy, even at a lesser dose which does not carry any side-effects.