If you have read my earlier posts, you know I believe that using Ethiodol (oil-based contrast medium) for a hysterosalpingogram increases the post-procedure pregnancy rate. Unfortunately, the only US source for Ethiodol announced in March of 2010 that they were shutting down production "for marketing reasons". Since then, limited supplies of a similar product (Lipiodol Ultra-Fluide) have been made available in the US by FDA-approved importation from a French manufacturer; the current distributor is Guerbet USA. I called up Guerbet today to see if I could buy some Lipiodol Ultra-Fluide, but alas, it is only being made available for use in "life-saving medical procedures", and even if they would sell it to me, one 10 mL ampoule would cost $590 (ouch!).
The company rep said they hope to have Ethiodol back on the market within a year.
mps
Tuesday, July 24, 2012
Monday, July 23, 2012
Insulin sensitizers and polycystic ovary syndrome
I've recently received some requests to address the role of insulin sensitizers for the treatment of polycystic ovary syndrome, in particular D-chiro-inositol. Here are my thoughts as of 7-23-2012.
Many women with PCOS have insulin resistance, and there are a variety of drugs which improve insulin sensitivity. These drugs include metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol, and myo-inositol. Their actions on insulin release and action are rather complex, but it is useful to just consider them all as acting to improve the effect of insulin in the body.
Now, I think there is fairly good evidence that treatment with an insulin sensitizer improves ovarian function in women with PCOS. (Yes, I did participate in one of the largest trials of metformin for PCOS ever performed, which showed no benefit of metformin, but please hear me out.) Metformin is by far the most commonly used insulin sensitizer in PCOS patients. My take on the medical literature is that metformin is most beneficial in PCOS patients who are obese. (The study I participated in wasn't sufficiently powered to show this, but in that study the ovulation rate in PCOS patients with BMI over 34 who were on clomiphene was improved by adding metformin) . It does promote weight loss in these women, which probably ameliorates the syndrome a bit, but it also has some action independent of weight loss. In particular, metformin may improve the response to clomiphene in obese PCOS patients (and that is the patient for whom I most commonly prescribe metformin). However, clomiphene is much more likely to induce ovulation and pregnancy in PCOS patients than metformin. I often start obese PCOS patients on metformin for a couple of months and then add clomiphene if they are not ovulating on the metformin alone.
There is much less known about the effects of the other insulin sensitizers on PCOS, but they probably have some benefit, too. I don't use them, though. The published data on the inositol derivatives is limited and contradictory. There is even one paper that claims D-chiro-inositol worsens egg quality in infertile women. More worrisome is that some insulin sensitizers have been shown to have serious side effects, and this information didn't come to light until the drugs were widely prescribed. Troglitazone (Rezulin) is a good example. Years ago, it was held up as the "next generation metformin", with better efficacy and fewer side effects. It did work some on PCOS, but it was also found to cause liver failure and was pulled from the market. Pioglitazone (Actos) can cause heart failure.
For now, the only insulin sensitizer I use is metformin, and I don't use it all that often.
mps
Many women with PCOS have insulin resistance, and there are a variety of drugs which improve insulin sensitivity. These drugs include metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol, and myo-inositol. Their actions on insulin release and action are rather complex, but it is useful to just consider them all as acting to improve the effect of insulin in the body.
Now, I think there is fairly good evidence that treatment with an insulin sensitizer improves ovarian function in women with PCOS. (Yes, I did participate in one of the largest trials of metformin for PCOS ever performed, which showed no benefit of metformin, but please hear me out.) Metformin is by far the most commonly used insulin sensitizer in PCOS patients. My take on the medical literature is that metformin is most beneficial in PCOS patients who are obese. (The study I participated in wasn't sufficiently powered to show this, but in that study the ovulation rate in PCOS patients with BMI over 34 who were on clomiphene was improved by adding metformin) . It does promote weight loss in these women, which probably ameliorates the syndrome a bit, but it also has some action independent of weight loss. In particular, metformin may improve the response to clomiphene in obese PCOS patients (and that is the patient for whom I most commonly prescribe metformin). However, clomiphene is much more likely to induce ovulation and pregnancy in PCOS patients than metformin. I often start obese PCOS patients on metformin for a couple of months and then add clomiphene if they are not ovulating on the metformin alone.
There is much less known about the effects of the other insulin sensitizers on PCOS, but they probably have some benefit, too. I don't use them, though. The published data on the inositol derivatives is limited and contradictory. There is even one paper that claims D-chiro-inositol worsens egg quality in infertile women. More worrisome is that some insulin sensitizers have been shown to have serious side effects, and this information didn't come to light until the drugs were widely prescribed. Troglitazone (Rezulin) is a good example. Years ago, it was held up as the "next generation metformin", with better efficacy and fewer side effects. It did work some on PCOS, but it was also found to cause liver failure and was pulled from the market. Pioglitazone (Actos) can cause heart failure.
For now, the only insulin sensitizer I use is metformin, and I don't use it all that often.
mps
Wednesday, March 7, 2012
Thyroid problems
Thyroid disease has been linked to menstrual irregularity, infertility, and miscarriage (as well as many other medical problems). I think that anyone with difficulty conceiving, irregular menses, or a history of miscarriage or preterm delivery should have TSH, free T4, and thyroid peroxidase antibody levels checked. Be careful if your doctor or nurse says your TSH level is OK, because even levels in the high-normal range (greater than 2.5) probably need to be treated.
Iodine is necessary for normal thyroid function, and more than one third of reproductive-age women in the US don't get enough iodine. In my opinion, all women attempting pregnancy should take a prenatal vitamin that contains at least 150 mcg of iodine (and 220 mcg may be better). The iodine in the vitamin should be not be derived from kelp, as the levels of iodine in kelp vary dramatically. I recently made a trip to the CVS pharmacy, and I was disappointed to see that fewer than half of the prenatal vitamins contained iodine, and some of ones that did listed kelp as the iodine source. The only over-the-counter prenatal vitamin I found at CVS that had 220 mcg of iodine was Centrum Specialist Prenatal. (I have no financial ties to the company that makes this vitamin.) By the way, prescription prenatal vitamins are no more likely to have iodine than over-the-counter brands.
Monday, February 20, 2012
Creepy Internet flattery?
Someone recently pointed out that one of the other fertility treatment providers in the area had set up a Web site with a name very similar to ours, that had "... Alabama fertility specialists..." embedded in the home page of the site. I contacted my son-in-law, who does Internet search engine optimization for a living. He said, "They're certainly targeting your branded traffic." I checked to see if they were doing the same trick with another fertility clinic in town - nope, just us.
My son-in-law said to just ignore it, but my colleagues at work were upset (especially my nurse practitioner, who pointed out that they had posted some patient instructions she had written years ago). I think it's a compliment, in a creepy sort of way, but I'm mostly sad about the matter. The reputation of the infertility treatment business is already bad enough, what with the octomom and the physician who secretly used his own sperm for inseminations (for the record, that wasn't a board-certified reproductive endocrinologist, but rather someone who just proclaimed himself as "specializing in infertility treatment". But I digress.) I think fertility specialists really need to be operating at the highest level of professionalism, both in real life and on the Internet.
I'm not going to post the link to the site, but you can find it by typing our name into a search engine and looking down the page. If the site has "principal investigator" misspelled, you're there. If you find it's spelled correctly, it means they probably read this blog.
But I hope you won't find it at all.
Monday, December 5, 2011
Testosterone treatment and male infertility revisited
Here is a nice story a local TV station did about testosterone and infertility. Many thanks to Mr. and Mrs. Ayotte for graciously agreeing to be interviewed for this story.
http://www.abc3340.com/story/16158175/doctor-warns-men-about-common-side-effect-of-testosterone-treatments
http://www.abc3340.com/story/16158175/doctor-warns-men-about-common-side-effect-of-testosterone-treatments
Wednesday, August 10, 2011
Aspirin and IVF
There was a study published about 13 years ago in which women undergoing IVF were randomly assigned to either low-dose aspirin or placebo during ovarian stimulation. The women receiving aspirin (it was 100 mg/day in the original study) had a better ovarian response (with almost twice as many eggs obtained in the treatment group) and significantly higher implantation and pregnancy rates.
When I first heard the findings presented at a fertility meeting (in Tours, France; ah, those were the days!), I was impressed - here is an inexpensive medicine that almost doubles the IVF pregnancy rate. The study seemed well designed and the results clear (but in reviewing the paper I see that although 298 patients were randomized, Table 1 in the manuscript reports the results on only 74 women). Here is the citation if you want to dig up the article yourself: Rubinstein M, Marazzi A, de Fried EP. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertility and Sterility 1999;71(5):825-829. The authors theorized that aspirin improved the blood flow to the ovaries and uterus, which led to the beneficial effects.
I suspect that within a year of this article being published, more than half the IVF patients in the US were on low-dose aspirin. Since then, at least 12 randomized controlled trials of aspirin treatment during IVF have been performed, and the conclusion is ... aspirin does nothing to improve the success of IVF. Here is a recent meta-analysis of all the studies: http://www2.cochrane.org/reviews/en/ab004832.html
It's too bad, really. It was such a nice story.
When I first heard the findings presented at a fertility meeting (in Tours, France; ah, those were the days!), I was impressed - here is an inexpensive medicine that almost doubles the IVF pregnancy rate. The study seemed well designed and the results clear (but in reviewing the paper I see that although 298 patients were randomized, Table 1 in the manuscript reports the results on only 74 women). Here is the citation if you want to dig up the article yourself: Rubinstein M, Marazzi A, de Fried EP. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertility and Sterility 1999;71(5):825-829. The authors theorized that aspirin improved the blood flow to the ovaries and uterus, which led to the beneficial effects.
I suspect that within a year of this article being published, more than half the IVF patients in the US were on low-dose aspirin. Since then, at least 12 randomized controlled trials of aspirin treatment during IVF have been performed, and the conclusion is ... aspirin does nothing to improve the success of IVF. Here is a recent meta-analysis of all the studies: http://www2.cochrane.org/reviews/en/ab004832.html
It's too bad, really. It was such a nice story.
Thursday, June 30, 2011
Clomiphene - part 1
Fertility clinics (and their patients) often talk about high-tech fertility treatments like in vitro fertilization, but the most successful infertility treatment is an inexpensive pill - clomiphene. For the next few posts, I'm going to go over some points about clomiphene that every infertile woman should know.
Clomiphene (marketed as Clomid or Serophene) was synthesized in the late 1950's by the chemist Frank P. Palopoli, who worked for a Cinncinnati drug firm, the William S. Merrell Company. (This company had gained some notoriety by aggressively pushing for approval to sell a new sleeping pill that was already available in Europe. A woman named Frances Kelsey who reviewed the application for the US FDA stubbornly refused to approve it until the company submitted more information about the drug's safety. The sleeping pill was thalidomide, and it was soon recognized to cause serious birth defects when used in pregnancy. It turns out the Merrell Co. had rather casually given US physicians over 1 million tablets of the new drug to try out on patients before approval. But I digress ...)
It had long before been recognized that compounds consisting of ethylene with three phenyl groups attached had interesting estrogen-like properties. A variety of these compounds were synthesized and tested; some had both estrogenic and anti-estrogenic properties. Clomiphene was one of these. The first clinical trial of clomiphene to induce ovulation was published in 1961, and it came on the market in 1967. It is often said that clomiphene was initially developed to prevent pregnancy, but I am not aware of any such clinical trials involving this drug.
Clomiphene was designed to induce ovulation in women who didn't release an egg on their own. Before clomiphene became available, the only options for ovulation induction were ovarian wedge resection (major surgery) or injectable gonadotropins. Although how clomiphene works still isn't completely understood, its major action is to block estrogen receptors in the brain, which leads to release of gonadotropin releasing hormone (by the hypothalamus), which in turns causes the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland. It is the FSH and LH which stimulate the ovary to mature an egg, but in effect, clomiphene acts like a mild ovarian stimulant, and the multiple pregnancy rates with clomiphene are lower (@5-10% of the pregnancies) than with FSH injections (@20%). More importantly, the risk of multiples greater than twins with clomiphene is only 1% compared to 5% of pregnancies with FSH injections (when used for ovulation induction; these rates are not applicable to IVF, in which the number of embryos reaching the uterus is controlled). A common misconception is that clomiphene doesn't increase the risk of triplets or higher, but that isn't so - the risk is about 100 times higher than for a spontaneous pregnancy (which is only about 1 in 10,000 births). By the way, clomiphene's multiple pregnancy risk does not seem to be related to the dose at which it is administered. Most of the multiples I've seen with clomiphene occurred with a dose of 50 or 100 mg a day (and the only set of clomiphene quintuplets I ever saw had conceived in her first cycle at 50 mg/day). Whether you get more follicles by increasing the clomiphene dose beyond what is required to achieve ovulation is questionable. I think the answer is "no".
I found this funny/sad/poignant video clip about clomiphene broadcast by the Canadian Broadcasting Company more than 40 years ago. Watch it and tell me what you think:
http://archives.cbc.ca/programs/754-15149/page/2/
MPS
Clomiphene (marketed as Clomid or Serophene) was synthesized in the late 1950's by the chemist Frank P. Palopoli, who worked for a Cinncinnati drug firm, the William S. Merrell Company. (This company had gained some notoriety by aggressively pushing for approval to sell a new sleeping pill that was already available in Europe. A woman named Frances Kelsey who reviewed the application for the US FDA stubbornly refused to approve it until the company submitted more information about the drug's safety. The sleeping pill was thalidomide, and it was soon recognized to cause serious birth defects when used in pregnancy. It turns out the Merrell Co. had rather casually given US physicians over 1 million tablets of the new drug to try out on patients before approval. But I digress ...)
It had long before been recognized that compounds consisting of ethylene with three phenyl groups attached had interesting estrogen-like properties. A variety of these compounds were synthesized and tested; some had both estrogenic and anti-estrogenic properties. Clomiphene was one of these. The first clinical trial of clomiphene to induce ovulation was published in 1961, and it came on the market in 1967. It is often said that clomiphene was initially developed to prevent pregnancy, but I am not aware of any such clinical trials involving this drug.
Clomiphene was designed to induce ovulation in women who didn't release an egg on their own. Before clomiphene became available, the only options for ovulation induction were ovarian wedge resection (major surgery) or injectable gonadotropins. Although how clomiphene works still isn't completely understood, its major action is to block estrogen receptors in the brain, which leads to release of gonadotropin releasing hormone (by the hypothalamus), which in turns causes the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland. It is the FSH and LH which stimulate the ovary to mature an egg, but in effect, clomiphene acts like a mild ovarian stimulant, and the multiple pregnancy rates with clomiphene are lower (@5-10% of the pregnancies) than with FSH injections (@20%). More importantly, the risk of multiples greater than twins with clomiphene is only 1% compared to 5% of pregnancies with FSH injections (when used for ovulation induction; these rates are not applicable to IVF, in which the number of embryos reaching the uterus is controlled). A common misconception is that clomiphene doesn't increase the risk of triplets or higher, but that isn't so - the risk is about 100 times higher than for a spontaneous pregnancy (which is only about 1 in 10,000 births). By the way, clomiphene's multiple pregnancy risk does not seem to be related to the dose at which it is administered. Most of the multiples I've seen with clomiphene occurred with a dose of 50 or 100 mg a day (and the only set of clomiphene quintuplets I ever saw had conceived in her first cycle at 50 mg/day). Whether you get more follicles by increasing the clomiphene dose beyond what is required to achieve ovulation is questionable. I think the answer is "no".
I found this funny/sad/poignant video clip about clomiphene broadcast by the Canadian Broadcasting Company more than 40 years ago. Watch it and tell me what you think:
http://archives.cbc.ca/programs/754-15149/page/2/
MPS
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