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 a link to a company that maintains a Web site which 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!

Bicornuate or septate uterus? (part 2)

OK, here's how to tell the difference between a bicornuate uterus and a septate uterus using transvaginal ultraound. Most of the photos below are taken in the sagittal plane, which the plane running from front to rear dividing the body into right and left halves. (Actually, some of the photos are parasagittal views, which are in planes parallel to the sagittal plane, but to the right or left of the midline. See here for an explanation of these planes: http://en.wikipedia.org/wiki/Sagittal_plane). Both these patients had HSGs that showed a duplicated uterine cavity (see previous post for more about how HSGs look in these patients).

Patient #1 (septate uterus): To the left of the midline, a normal uterus is seen. Arrows mark the endometrium. The cervix is off the screen in the upper left. The top of the uterus is in the lower right.










This is a midline (sagittal) view. The uterus is visible, but no endometrium is seen, because we are in the plane of the uterine septum. A cursor in the lower right of the photo marks the top of the uterus.









Moving the probe to view the right side of the uterus, the endometrium reappears.












Rotating the transvaginal probe 90 degrees to give a coronal view of the top of the uterus, we see two endometria contained within a single myometrium, confirming that this is a septate uterus.










Patient #2 (bicornuate uterus). View left of the midline. Normal uterus with endometrial stripe seen. Top of uterus on the right of the screen.











Sagittal (midline) view. No uterus seen. This is a bicornuate uterus.











Right parasagittal view. The uterus reappears (and there is a gestational sac in this side of the uterus).

Bicornuate or septate uterus? (part 1)

This question frequently comes up, and physicians (ob/gyns, radiologists, even fertility specialists) often get tripped up by it. I saw two patients this week who came in with the wrong diagnosis, even though it's pretty straightforward to distinguish the two conditions, and it doesn't require any fancy imaging. One of the patients had been told to give up and use a surrogate! (She now has two healthy children that she carried herself.) What follows is the conversation that I have with patients who present with this question.

The fallopian tubes, uterus, cervix, and upper vagina begin development as two parallel tubular structures - these are the mullerian ducts. During embryonic development, the lower part of these structures grow together - this process is called fusion. Then the parts that are fused together disappear to form a single (larger) tubular structure - this process is called resorption. The fused (and partially resorbed) part of the mullerian ducts becomes the uterus, cervix, and upper vagina. The (unfused) upper part becomes the fallopian tubes. The diagram at left shows a cross-section of a normal uterus.



When this embryonic process goes awry, a number of different genital birth defects can occur. If there is no fusion, two separate uteri result (this is called uterus didelphys). The will be two separate cervices, and sometimes two vaginas. If fusion occurs only at the very bottom of the ducts, you get a bicornuate ("two horned") uterus. The diagram at left is a cross-section of a bicornuate uterus. Note that the upper part of the uterus consists of two distinct structures separated by a cleft. Women with a bicornuate uterus are at an increased of (late) miscarriage, preterm birth, and abnormal fetal lie (usually breech). Although there is a surgical procedure described to fix a bicornuate uterus, it is no longer recommended by experts in the field, because: (1) the pregnancy outcomes are quite good if you just stitch up the cervix in the next pregnancy, and (2) it's a fairly drastic operation, involving cutting the uterus open and sewing it back together.

If fusion occurs but resorption is incomplete, you get a septate uterus. Here is the diagram of a septate uterus. In the middle of the uterine cavity is a fibrous, avascular partition (the septum). Note that from the outside, the top of the uterus appears normal. (It's generally a bit wider than normal, but the top has no cleft just like a normal uterus.) Women with a uterine septum have twice the risk of miscarriage as other women, and they are more likely to have problems with preterm delivery and breech birth, too. The treatment for a uterine septum is to just cut the septum with scissors, and this can be done as an outpatient.

Generally, a woman finds out she has a bicornuate or septate uterus when she gets a hysterosalpingogram for infertility or recurrent miscarriages.


Here are some normal uterine cavities on HSG:





























Note that the uterus in the lower photo has a bit of a curve in the top of the cavity. This is a normal variant.

Now take a look at these HSGs:


































There is an obvious cleft in the uterine cavity. This HSGs are commonly read as "bicornuate uterus" by some physicians, but in reality it could be a septate uterus or a bicornuate uterus. Let me state this again: YOU CANNOT DISTINGUISH A SEPTATE UTERUS FROM A BICORNUATE UTERUS WITH A HYSTEROSALPINGOGRAM. Yes, I know there was a paper published years ago which said you could distinguish them by measuring the angle between the cavities, but it just ain't so. The two tests which can best distinguish a septate from a bicornuate uterus are a transvaginal ultrasound and a pelvic MRI.

Now, the sad thing is that one of my recent patients actually had an MRI, and the diagnosis was still missed. It turns out that not all radiologists understand the difference between a septate and a bicornuate uterus. They often just put "uterine duplication" in the MRI report, and that's what probably happened with my patient.

The next post will show how to distinguish a septate uterus from a bicornuate uterus using transvaginal sonography.

Unexplained infertility

Another reader asks: "1. What would be your recommendation for a couple with unexplained infertility? On paper the couple is perfect but even with IUI cycles and injectibles cannot seem to conceive. Especially if Insurance says no to any procedures for infertility treatment, ie IVF or the IUI's. 2. Is there a point when a couple with unexplained infertility and no disposable income for IVF procedures should just give up on having a baby?"

Answer:

Depending on how you define unexplained infertility, the prevalence of this diagnosis in a fertility clinic varies from zero to 20% of the patient population. How can there be such a range? A famous professor/fertility expert once said "a cause for infertility can be found in all couples if enough tests are obtained." I am afraid this reveals a rather unsophisticated understanding of medical testing, as if you do enough tests on normal healthy couples, something will eventually turn up positive. The trick in medicine is to do the right tests on the right patients (this maximizes the "predictive value" of the test). But what are the right tests? One way to approach this would be to do fertility tests on fertile and infertile couples. If the test under study is abnormal more frequently in the infertile group, the test probably has some value in a fertility evaluation. This approach has been performed in a meaningful way for only a few fertility tests: semen analysis (some value) and endometrial biopsy (worthless). I was involved in both these studies, and believe me, they were challenging to do, involving millions of your tax dollars. A friend and mentor once tried to do all the standard fertility tests on both fertile and infertile couples and couldn't collect enough data to make meaningful conclusions. It's an interesting report to read though, as he often found fertile couples with abnormal fertility test results (see here to read it: http://humrep.oxfordjournals.org/content/9/12/2306.full.pdf).

Here is what I recommend for a basic infertility evaluation: semen analysis, hysterosalpingrogram, post-coital test (PCT), and midluteal progesterone level. Yes, I know the PCT is controversial and many fertility clinics don't bother with it, but I still think it's a meaningful (and fairly inexpensive) test. And the progesterone level is an easy way to confirm that ovulation is occurring. If all these tests are normal, I encourage infertile women to have a laparoscopy, unless your insurance won't cover it. In my view, you can't give a diagnosis of "unexplained infertility" without a laparoscopy to confirm it.

So what if all these tests are normal? If the woman is young (less than 30), and the duration of infertility is brief (less than 2 years), I encourage a few months of watchful waiting to see if pregnancy occurs spontaneously. If these criteria are not met, than the next step is to take clomiphene and do intrauterine inseminations. I usually recommend 3 cycles of this. If the woman is older (over 35) or if she has already taken clomiphene, I encourage women to go straight to gonadotropins and IUI. What about doing IVF? Great idea, but it's more expensive than the other two options. It does have a lower risk of triplets or higher, though, as long as you don't get carried away by putting in too many embryos. I occasionally have patients who don't get pregnant with clomiphene/IUI go straight to IVF for this reason. One fertility clinic recently tried to determine whether it was more cost-effective to do the gonadotropin/IUI first or go straight to IVF; the results didn't particularly favor either approach.

Our reader with unexplained inferility asks what to do if IVF is not an option, but gonadotropin/IUI hasn't worked. Well, in general you have reached the end of your fertility treatment. The only thing beyond IVF is IVF with donor eggs, which is even more expensive. When to quit? Other than when your money or insurance coverage runs out, or the fertility treatment is driving you crazy, I would recommend quitting when you get to the point of taking gonadotropins and you only make a couple of mature follicles, despite high doses of medicine (300 units or above). This is an ominous sign that you are running out of eggs faster than other women your age, and the success of IVF under these circumstances is low. For those women, egg donor IVF is the best approach.I think women with such diminished ovarian reserve as their only fertility problem are just as likely to conceive on their own as with IVF, and occasionally former patients will call me to confirm that very event (they like to rub it in a bit, but I am happy for them nonetheless).

Acupuncture and Infertility

A reader asks, "What are your thoughts on acupuncture and infertility treatment?"

Short answer: Go get a massage instead.

Long answer: Let's start at Wikipedia (one of my favorite Web sites): "Acupuncture is a practice in which needles are inserted into various traditionally determined points of the body ("acupuncture points") and then manipulated ... Acupuncture is based on tradition and authority, not on the scientific method, and is not based in, and does not relate to, other interrelated fields of science such as human anatomy, human physiology, cellular biology, neuroscience, biochemistry, or physics."

Here is my basic philosophy of treating patients: I don't recommend treatments that are not based on a scientific rationale and supported by at least some reasonable medical/scientific evidence. If you abandon this philosophy and say "let's try treatment X; after all, it can't hurt", you enter the Neverland of medicine, with no rules, boundaries, or logic. And as to the concept "it can't hurt", sometimes it does hurt. Ephedra, an herbal preparation used in traditional Chinese medicine for thousands of years, was pulled off the US market in 2004 after about 100 people died from taking it. And this problem isn't restricted to herbal medicines; there are many cases where well-meaning physicians tried a treatment based on very limited data that turned out to hurt, not help (DES is a classic example).

The problem with my philosophy is that medical evidence is not absolute, it can ebb and flow, and what is "some reasonable evidence" to one person may be insufficient to another. You can find one study in the medical literature that proves just about anything (my favorite example is a paper that claimed preeclampsia was caused by worms. It was published in a fairly respectable obstetric journal!). And although I am pretty conservative about what treatments to recommend, there are physicians more conservative than me on some things.

OK, back to acupuncture. There were a few small studies published that claimed acupuncture improved IVF success. Most of these studies compared acupuncture to nothing. More recently, larger studies which compared Chinese acupuncture to "sham" acupuncture, in which a needle was poked into the patient randomly, showed no influence on IVF outcomes. One study (So EW et al., Hum Reprod. 2009 Feb;24(2):341-8; the study was done in Hong Kong, where they should know something about acupuncture) showed the sham acupuncture group to have a slightly higher success rate (it was just a fluke, but the authors claimed sham acupuncture might have some benefit - arrgh!). Several other large, well-designed clinical trials also have shown no benefit to IVF patients getting acupuncture. Here is what the authors of a recent compilation of acupuncture studies concluded: "New emerging evidence from clinical trials demonstrates that acupuncture performed at the time of embryo transfer does not improve the pregnancy or live birth outcome after treatment. This evidence raises questions regarding the futility of conducting further research in this area and the quality of evidence needed before any specific intervention is incorporated into routine clinical practice, particularly when a scientific rationale is lacking." (El-Toukhy T, Khalaf Y. Reprod Biomed Online. 2010 Sep;21(3):278-9)).

I hope you enjoy your massage.