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.

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.

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

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.

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

Back in the Top 25/Why we are different

Someone sent me this link the other day: (http://fertilitysuccessrates.com/report/United-States/women-under-35/data.html). The company that maintains this Web site pulls IVF success rates off the SART Web site (which includes the statement “programs should not be compared …”), compares them, and publishes lists of the “top 25 programs” in the country. We’ve shown up on that list twice now. Of course, it’s better to be on the list than not, but the first time we were listed I pretty much ignored it. Small programs like ours are more likely have a high (or a low) success rate than bigger programs in any given year. After all, it’s possible for a good baseball player to hit three home runs in a row, but no one has ever hit 30 in a row. As numbers go up, success rates regress toward a mean. But if you show up twice, maybe there is something to it …

The first time we were listed in the “top 25”, a friend who runs a fertility clinic in another state called me. “Michael, what’s your secret? Blast transfer, 5% oxygen in the incubators, assisted hatching on everyone?” No, we don’t do any of those things routinely. I told him it was due to good staff, good patients, and good luck. I suppose there might be more to it than that, though. Here are some things that make our IVF program different from others:

1. We do IVF cases in series. This isn’t all that uncommon, but we batch our patients more than most other programs. – we only do IVF for one week every quarter. Some IVF programs are afraid they will lose “impatient patients” to other clinics by doing this, and that might be true. However, there is nothing like a short, intense run of IVF cases to focus your mind on the treatment. The lab is spotless, the culture medium is tested and fresh, and the staff can concentrate on one task. We bring in a good embryologist who works hard for one week and isn’t around afterwards to twiddle her thumbs while waiting for more IVF cases to dribble in (you other IVF program directors know what I’m talking about here). Doing IVF in series also forces our patients (and our staff) to rest a bit between cycles, and I think this is a good thing. We’ll do four series this year; next year we might do five.

There are some disadvantages to this approach, though. It puts more responsibility on me to keep up with freezing embryos at the end of a series, maintaining lab accreditation, following up on laboratory upkeep, etc.; but I have some technical staff who are good at that, and I don’t mind opening up the back of our laminar flow hood to see why it isn’t working (the damned thing is made in Denmark, and sometimes you have to call Copenhagen if you have a problem, but it’s a sweet machine – the embryology techs love it). Also, our nurse coordinator has to be able to launch people’s stimulation cycles so that the retrievals fall on the right day; and we basically use one stimulation protocol (OCP/long Lupron/FSH/Menopur) on everyone because we have gotten comfortable programming these cycles. No antagonist cycles here (and every time I look at the antagonist data, I’m convinced the protocol we are using is right for us).

2. We have a good IVF lab. If you see cheap furnishings in our waiting room, it’s because the furnishings in the IVF lab are really expensive. When we set up the lab, we got HVAC design specs from an IVF air quality guru and ordered the best equipment we could get. I originally wanted to stock the IVF lab with equipment made in the USA, but I wound up buying a laminar flow hood made in Denmark (see above), an embryo freezer made in Australia, and microscopes made in Japan (the incubators are US-made, however). I think US IVF programs are generally better than foreign ones, but some of the best IVF equipment is made outside the US. I occasionally visit or inspect other IVF labs, and I’ve never seen one nicer than ours. Our contract embryologist says the same thing. We also pay a lot of attention to getting the pH of our culture media just right; I have found that a surprising number of IVF labs don’t do this.

3. We do have a great staff. Front office, financial, nurses, lab techs, my medical assistant – they are all dedicated and caring. Most days we all eat lunch together in the break room. It may be what matters most, and it can be the hardest thing to fix if it isn’t right.

4. We let the husband be in the room during the egg retrieval. I’ve never seen another IVF program that does this. I doubt that it affects the success of the treatment, but I do think it relaxes the wife a bit to have the husband there, and it gives the husband an appreciation for what is going on. I’ve been allowing husbands to watch the retrievals for over 15 years and have never had a problem with it. Part of the reason why other programs don’t do this is they use deep sedation (basically general anesthesia) for the retrievals, and the anesthetists don’t like having the spouse around. We use lighter sedation (given by a nurse or a doctor). It works for us.

5. We don’t do ICSI (sperm injection) on everyone. If you look at US statistics, about 30% of the IVF cases are done because of a male factor, but over 60% of the cases employ ICSI, and some programs do ICSI on all their IVF cycles. While I don’t think doing ICSI necessarily lowers the success of IVF (it certainly doesn’t in our program), I am uncomfortable doing unneeded procedures. There are two things going on here: One is that some of the male fertility tests (like strict sperm morphology and SCSA) label many semen samples as abnormal when they really aren’t, so ICSI gets recommended. The other issue is that some IVF programs are fearful of having an IVF cycle end up with no fertilization, so they just ICSI all the cases. Around here ICSI adds about a thousand dollars to an IVF cycle, so why do it if it isn’t needed? (Hmm, on second thought, maybe that’s a third reason why ICSI is so popular. After all, that microinjector equipment is quite expensive.)

6. Free parking!

MPS

Please stop giving our patients testosterone!

We have had a rash of new infertility patients whose husbands had been put on testosterone by their primary care providers. The usual story is that the husband complains of fatigue, maybe during a routine visit. The doctor (or in one case the nurse practitioner) gets a testosterone level, which is just below the normal range. The man gets put on testosterone. No one bothers to ask if he is trying to father a child. The couple subsequently shows up in our office with infertility, and the semen analysis shows ... no sperm.

The other story we hear occasionally is that the husband isn't taking any prescription meds, but his friend at the gym is providing him with a "nutritional supplement", which turns out to be a testosterone-like substance. We have learned to ask about this whenever we see an abnormal semen analysis.

Testosterone isn't a great contraceptive - only about 80% of men will develop azoospermia. I wonder if there is some sort of recent drug company campaign that is leading to this recent increase in testosterone prescriptions.

My partner Dr. Malizia recently saw an even more bizarre infertility case. The wife was getting testosterone from one of those "natural hormone replacement" clinics you see advertised on TV.

Please don't take testosterone if you are trying to have a baby!