Diseases information. Disorders. Treatment.

Ovulation induction is pretty much the standard way of treating people with ovulatory disorders. The classic treatment would be clomiphene. The thing you should know about clomiphene is that it is NOT a steroid; it is very similar to tamoxifen. The reason, by the way, that tamoxifen was chosen for the treatment of breast cancer, since it was discovered in the 1950’s, the exact same time as Clomid, is that Clomid is much more potent and you can’t give it to somebody every day for five to ten years, whereas you can with tamoxifen. But they have the same mechanism of action, they are partial agonists and antagonists, and what you are doing is essentially fooling the pituitary and hypothalamus into thinking that the estrogen level in the periphery is low, so gonadotropins go up; specifically, their FSH goes up and you are provoking ovulation.

Another tool that we can use for the infertile patient is laparoscopy. At one time, in the 1980’s, this was quite popular. Nowadays, it is pretty much reserved for people who have either unexplained infertility or infertility that you know is from something like a previous history of pelvic inflammatory disease or documented by hysterosalpingogram, blocked tubes that you want to try to open. There is usually some sort of therapeutic maneuver involved. It is quite rare to be used purely for diagnosis nowadays, because it is expensive and you can probably better spend those dollars elsewhere. If the person has some other issue, like pain, that might guide your therapy towards doing this. Examples of things that you might see would include endometriosis, thick and thin pelvic adhesions, which of course you could lyse while you are there.
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Hysterosalpingogram is the final test that you are going to do on pretty much everybody to assess their tubes. Anybody who comes in with infertility and you have no idea what is going on, should probably have some assessment of their tubes. If you have a normal semen analysis and no history to suggest that something should be wrong with a person’s tubes and she has a clear picture, it is perfectly reasonable to treat that person with Clomid empirically. Although some people would argue with me, I would say that it is reasonable not to put her through the expanse and the pain of HSG, but it is clearly part of the basic workup.
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There are different sorts of adhesions - thick, thin, vascular, avascular, that will lead to tenting of the structures. And remember that the tube is much more than just a conduit - it has to be able to move. So just because it is open on HSG does not make it a useful tube.

There is a very interesting study from Canada in which they randomized people going for laparoscopy for whatever purpose - usually pain - and who wanted to get pregnant, to either get treatment or just have a diagnostic laparoscopy and then pull out, unless they saw something very severe. If they had minimal or mild endometriosis, and those people who were randomized to treatment - had a significantly higher rate of pregnancy beyond 20 weeks than the group that was the control, that just had diagnosis. So the removal of endometriosis is definitely a useful tool in the treatment of infertility. This was published in the New England Journal of Medicine. Likewise, you can show that laparoscopy is superior to things like Danazol. Basically, the point here is that endometriosis is a surgical disease; if you have it and can see it and it is minimal or mild, you should remove it. That person will then clearly have an increased chance of getting pregnant.

Finally, a review of fibroids and all sorts of uterine defects. Clearly, if you have a fibroid that invades the tube and blocks it, that is a problem. If you have a submucous fibroid that impedes implantation, that is also a big problem. You can have all sorts of different kinds of fibroids and you can have other sorts of defects in the cavity as well, anything from Asherman’s syndrome to a septate uterus versus a bicornuate uterus. As a general rule, bicornuate uterus does not seem to lead to decreased fecundity.
New Treatments for Infertility

The more high-tech way of dealing with male infertility now is intracytoplasmic sperm injection (ICSI). The setup that we actually have boils down to a way of taking a single sperm and injecting it into an egg that is aspirated after ovulation induction. That sperm, interestingly, can be obtained from the ejaculate the old fashioned way, or it can be obtained from a needle in the vas, or it can be obtained from testicular biopsy, which means that you are taking an immature, immotile sperm and we can now mature those sperm in vitro to the point where they are motile, to be able to select which ones you want to inject. We use a bead of oil to slow them down. We use a little pipelle to pick up each single sperm. You push on the membrane of the leg. Then wee have a holding pipette to hold the egg still. First you catch the sperm and then you have to align the pipelle holding the sperm. Usually we put it so that the polar body is at 12 o’clock or 6 o’clock; that is important because you don’t want to destroy the spindle for it to complete myosis. Remember, with a single polar body you are now in myosis 2 - metaphase. The reason that this is important is that if you don’t see that polar body, she didn’t technically ovulate, even though you extracted the egg, so this is not an egg you want to fertilize. So we look for metaphase 2 cells that have a single polar body to inject. We inject it and the membrane of the egg is very strong. Finally, you remove the needle and this gets placed into the incubator.

The second big area that we need to talk about is ovulation. Ovulatory defects in women make up about forty percent of their cause of infertility. The classic example is polycystic ovarian disease. You need to come to a diagnosis as to what is causing them to be an- or oligoovulatory. There are a lot of other reasons for anovulation, including hyperprolactinemia as a cause, any sort of stress and issues around nutrition that will make a patient oligo- or anovulatory, hypothyroidism is clearly the classic example, but hyperthyroidism as well will lead to oligo- or anovulation and then ovarian failure.

What are some of the types of ovarian dysfunction? Hypothalamic, hyperprolactinemia, hyperthyroidism, hypothyroidism, premature ovarian failure. The workup is essentially the same workup for secondary amenorrhea. All you have to remember, besides measuring beta hCG, because presumably she is not pregnant, is a TSH, prolactin, some assessment of endogenous estrogen - an FSH or progestin challenge - and a pregnancy test if she is just amenorrheic.

What are some of the ways of assessing whether or not somebody is ovulatory? There are a whole host of ways to do it. The classic way of doing it, of course, is to measure a luteal phase progesterone. If you measure P4, it should be elevated in the luteal phase and it is this progesterone that leads to elevation in your basal body temperature curve. This is certainly a very valid way of assessing whether or not somebody ovulates. Progesterone is thermogenic and in general raises the body temperature about one degree Celsius. Ovulation predictor kits are essentially an RIA or ELISA that measures LH in the urine. It usually will predict ovulation 12 to 24 hours in advance of ovulation. It tells you whether or not she ovulated, it is cheap and it helps you therapeutically to guide the couple. Endometrial biopsy is the classic unquestioned way of finding out whether or not someone is ovulating. We all know that immediately after ovulation, you should have subnuclear vacuolization - that is the classic thing - and you can time the endometrial lining by whether or not this person has ovulated, right down to the day. It is a little invasive and obviously expensive. It can produce an endometritis. So as a general rule, we don’t do it very often anymore except in the case of recurrent loss.

There are a lot of other reasons for male factor infertility and they pretty much follow all of the things of female ovulatory disorders. They are hypogonadotropic and hypergonadotropic. If you have low gonadotropins - usually we are talking about FSH - then you think of things that are more central. Anything from hyperprolactinemia, hypothyroidism, all the same things you think about in a woman. If they are hypergonadotropic, then you have to think of testicular failure. That is a situation where you are going to do a karyotype, just like you would in a woman if you were looking for, for example, Turner’s with hypogonadism, failed testicular function.

When I was a resident, we did post coital tests on absolutely everybody; even when I was a Fellow, we did it on almost everybody. The truth is, however, that it doesn’t make a lot of sense. The definition of a normal post coital is at least 10 to 20 normal motile sperm in the little swab that you take from the cervix, usually four to five hours after intercourse, without any white cells and with motility. The problem with this is that the only thing it tells you is that they are having intercourse. If there is a question and they are reticent to discuss it with you, if the issue is impotence or something else between the couple, this will help you determine whether or not there is penetration and an ejaculate in the vagina. Other than that, it doesn’t really tell you very much.
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How do you treat male factor? Primarily, you try to concentrate the number of sperm that you do have and then give it to her in an intrauterine insemination. Why not just put it in the vaginal intracervically? This question was answered recently in a New England Journal of Medicine article from about two years ago. There was a multicenter national trial in which they showed that in people who had ovulation induction, if you gave them intrauterine insemination (IUI) they had a three-fold better chance of getting pregnant with a confidence interval of 2.5 to 3.0. That was much better than if you did intracervical. People were randomized to all of these different groups. It was a very clean study with huge numbers - in the 300 to 400 range. So in general, we recommend doing intrauterine insemination now instead of just ovulation induction with intercourse to try to do the following. Basically, you have a sample and with an IUI, you spin down the sample, re-suspend it in a media that contains little beads usually, allow the sperm to swim up, which is essentially selecting from the best and strongest swimmers and then take the supernatant off, spin it down again and do the exact same thing over again so that you are going through the process twice and then taking those motile sperm, counting them, re-suspending them in 0.5 cc of media and injecting it into her.
Treatments for Infertility

What are some of the other concerns? We all know that over 35, as a general rule, we recommend that people get some sort of counseling so that they know what their options are in terms of amniocentesis, CVS, what have you. Why is that? Not only in spontaneous pregnancies, but obviously in IVF, you can show that the incidence of aneuploidy is astronomically higher independent of anything else, just from age.

So what do we do? Well, the place to start is with the semen analysis. Pretty much anybody who comes into my office as a couple who have six to 12 months of infertility, depending on age, has a semen analysis. We do this regardless of the male’s history, regardless of whether he had a child two years ago with another partner, or whatever. We do a semen analysis because the incidence is pretty high of finding something - somewhere around thirty to thirty-five percent of all couples that just show up at your doorstep, before you know anything about them, will have a male factor. This is something that we can pretty much cure if you take money out of the equation. Close to ninety-nine percent of male factor is curable, even with so-called testicular failure.
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What is a semen analysis? The numbers you need to remember are 20 million motile sperm per cc in the ejaculate and 3 to 5 ml is the normal ejaculate and at least fifty percent normal forms - normal morphology. The reason that the numbers are low - fifty percent - is because in the normal ejaculate you find other things and that is to be expected. So you have to take that into account.

Pretty much the one male factor that everyone talks about is varicocele. It is really quite controversial. Does it even cause infertility? Does it cause oligospermia? Does it cause azoospermia? The truth is that we don’t actually know the answer to that question. We also clearly don’t know the answer as to whether or not varicocelectomy - removing it - makes a bit of difference. I can tell you that there is no randomized trial to answer that question and you can find just as many cohort studies of people who stay that removing it will make a difference as people who say that removing it doesn’t, regardless of their background - urologic or gynecologic. I can tell you that for the same money, if it boils down to that, nowadays, to me it personally doesn’t make a lot of sense if you have some sperm in the ejaculate and you can get around the problem. If there is a urologic reason and you are worried about what this really is - is it veins, is it a tumor or is it something else - that is obviously a different story. But if you are sure that it is a varicocele, which usually you can be with simple palpation, then I would believe that surgery is pretty much secondary. That is pretty much the standard nowadays.

A study came out of California that was updated about five years ago. Patients were categorized based on age; less than 30, 30 to 34, 35 to 39, greater than 40, and day three FSH’s were measured on everybody. They also measured all sorts of other parameters; how high did their estradiol get; how many eggs did they get; how many of those eggs were fertilized; how many of those people had implantation and pregnancy resulting from their IVF. All of these variables were measured and what one can clearly see is that basal FSH, day three, is actually better than just age as an independent variant to measure to predict whether or not this person is going to get pregnant. This is a very useful tool. In fact, it is obviously both the variables of age and FSH that we use, but clearly, it has been shown that FSH independently will improve your ability to counsel a woman on her chances for success.

Clearly, the potential of getting pregnant is therefore reduced by about thirty to fifty percent, depending on who you read. I have outlined in my notes that at what rate decrement is as a person ages in a way that I think makes it a little bit easier and more palatable and understanding. There are of course other issues when you are counseling somebody who wants to get pregnant and who is a little bit older and that is that almost any single obstetric complication you can dream of is increased with age - diabetes, hypertension, pre-eclampsia, eclampsia, preterm delivery, preterm death, abortion - everything. Chromosomal abnormalities also have to be factored in at the time of the counseling session with the couple.

With IVF, independent of any other variable, just age, ongoing pregnancies per embryos transferred, about fifty percent at less than 30 linearly drops down to almost nothing by the time a person is over 40; there are just a handful of pregnancies. So IVF is not the answer for these patients.

Amongst the factors in women that one has to seriously consider are ovulatory dysfunction, the most common problem that we face, along with tubal disease. This varies in studies from forty to fifty percent, depending on who you read, but it is a large number of people. Unexplained infertility is a huge problem that is very difficult to deal with.

Why is this such a big problem now? It is even more of a problem now than it was years ago because of the aging demographics of the female population in the United States. Without a doubt, the number one type of patient that we see and probably most reproductive endocrinologists and general gynecologists see is the patient who has a career, who has delayed having children until the mid to late 30’s and is now faced with this dilemma of not being able to get pregnant or their sense of urgency increases and they just want to know if they can get pregnant.

If you look at the numbers from the Census Bureau, clearly the number of women who are older have increased and will increase as time goes on, by the middle of this century. The number one thing that we can absolutely document is that fecundity - the ability to conceive - decreases with age, independent of absolutely any other factor. The rate of impaired fecundity is pretty well in the young population, but as you get to the 35 to 45 range, it easily reaches thirty percent and in some studies, even higher.

We are beginning to try to talk about the perimenopausal period. Probably the best way to assess this is a day three FSH. On day three of the cycle, it may take 5 miu/ml to get a certain level of estrogen when you are 20 years old. To get that same level of estrogen when you are 40 years old might take 10 to 15 miu/ml of FSH. While phenotypically the person may still be ovulatory and may have no difference in anything other than this biochemical change, it clearly represents incipient ovarian failure as a woman ages. The other more recent test that people are doing is inhibin. What you need to know for the exam is that specifically, you want to measure inhibin B. I don’t know why inhibin B goes up in the follicular phase and inhibin A goes up in the luteal phase, but inhibin B is what you want to measure. Inhibin is a peptide that comes from the ovary. As the ovary fails, the level of inhibin B drops. So you are looking for low inhibin B and FSH when you are trying to document incipient ovarian failure. Clearly, phenotypically the length of the follicular phase is what changes; once the person ovulates, the length of the luteal phase is pretty sacrosanct at 14 days in humans. The big problem is accelerated follicular loss. You are born with a certain number of eggs and you just ovulate them down to zero; there are somewhere around 300 to 400 eggs in a woman’s lifetime. That means that not only do you have less as you get older, but that the quality is clearly going to be different as well.