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Infertility

Evaluation of the infertile couple. Infertility, is the failure to conceive after one year of regular coitus without contraception. The monthly conception rate of normal couples actively attempting is about 20% to 25%. If you look at conception rates on a monthly basis, after three months a normal couple would have about a 57% chance of conception, after six months 72%, after a year 85%. So even after a year of trying, 15% of normal couples will not have conceived. But then the definition is a year of trying without success, that is considered infertile. After two years that goes up to 93%. But the guidelines by the American Society of Reproductive Medicine is to initiate a workup after one year. If you look at another way of looking at conception, if you look at it based on frequency of coitus, less than one time per week - this is conception over six months - 17%, one to two infertility, infertile, infertle, infertilty

This kind of just goes along with the last definition of infertility. Just a different definition. When you are thinking about infertility, think about primary and secondary infertility. Primary infertility refers to couples who have never established a pregnancy, and

The causes for infertility and how it relates to percentage of becoming pregnant includes many factors. Relating from things like endometriosis, male factor, anovulation, tubal factor, and this is just a study showing the numbers that had this, and then their

Some more basic information. Incidence, approximately 10% of couples are infertile. They make the criteria of not being able to conceive within one year. Approximately 15% of infertile couples have no identifiable cause of infertility. Another way of looking at that is there are about four or five million couples every year who have difficulty conceiving. Or another way of looking at it is, one out of every seven. And that number seems to be slowly increasing. Some of the causes of that: probably one of the

Prevalence in the United States, approximately 10% to 20% of couples are infertile. Popular explanations why there is a declining in the United States: changing roles and aspirations for women, postponement of marriage, delayed age of bearing. These three things all go together along with increased infertility. People are waiting longer to have kids and when you wait longer to have kids - it’s mainly based on the woman’s side of the view - the quality of her eggs diminish and the enhancement of her fertility diminishes. Liberalized abortion, concern over environment, unfavorable economic conditions. But really it

When you are thinking about the workup, first think about the physiology of becoming pregnant and then where those … and in any one of those steps there can be a problem and you just basically look at that. I’m not going to go over the physiology of

Okay, in thinking about how to work up the couple, there are four basic areas you want to think about . number one, male factor, and then number two, female factor. Male factor, real easy. You do a semen analysis. We’ll talk in a little greater detail of that. So by simply doing a semen analysis you can get a real good feel for whether or not the guy is the cause of the problem. Again, very often he is forgotten. When you are thinking, or if a couple comes to talk to you about infertility it is a couples thing. It’s not the woman’s problem. I still have a lot of patients who come to me and the woman shows up but the guy’s not there. So you are losing half of your exam right there. Or half of your history by not having the guy there. I will have women that get a million dollar workup and they’ll come to me because they still can’t get pregnant, and I’ll say - might not have the records with me - I’ll say, "What’s your husband’s sperm count?" and they say, "They never did a sperm count." When you are looking at causes for infertility, 40% of the time it is the woman, the other 40% of the time it’s the guy, 20% is just kind of a combo. Do not forget the guy. It’s real easy to find out whether the guy’s got a problem or not by semen analysis. If he’s got a problem, though, it’s real hard to correct. Women on the other hand are a little more complicated, obviously. It’s a little more difficult to find the

So overall then for the evaluation of infertility obviously take a history and physical. If you can, on both the woman and the man. Then you start out with a semen analysis, which is what we will go over first, then assessment of ovulation. If the woman is not ovulating she can’t get pregnant. Assessment of cervical factor and assessment of tubal factor. So that’s how you approach it, those three or four ways: semen analysis, ovulatory mechanisms, cervical factors - which is kind of a combination of male/female - an then tubal factor. We will go into each one of those in greater detail with the next couple of

Male factor. It just says that the male gamete can be examined in the seminal fluid as well as in the cervix, the cervical fluid. So that’s the two ways you want to evaluate it. First from a basic semen analysis and then what’s called a post-coital test. Lots of causes for infertility in men. There has been a lot of talk in the literature, particularly in Time. A year ago they were talking about men’s sperm dropping worldwide. Is this real? Is this not real? NIH came out within the last several months saying that it is real. We don’t really know why it is real but it appears to be real. In this country, sperm counts in men are dropping about 1% to 1.5% a year. In Europe it’s a little bit higher. They are dropping about 2% to 3% - the counts are dropping. So we feel that it is a real thing. Male counts are dropping but we really don’t know why. Everyone is fast to jump on environmental factors, farming, pesticides, that type of stuff. But the real thing is, we don’t know. But it does appear that it is dropping. Anecdotally, the 

This is page one of some of the things that we look at when we do a sperm count and this is not unlike many fertility centers. Here you just look up at the gross characteristics of the sperm count and then one of our techs does another gross microscopic, and these are the World Health Organization type of guidelines that are in parenthesis. This is just looking a the specimen itself. Are there white cells and all that in there. Is there an infective process going on. Here’s the guidelines just counting on a hemocytometer. Then what we do is we wash the sperm as if we were to do an insemination. Because from a fertility standpoint, sometimes these characteristics - before you wash the sperm - can be normal but once you wash the sperm and get rid of a lot of the debris and dead sperm, they don’t process well. They clump up and they have antibodies that causes them to clump so they don’t process well. So processing the sperm in anticipation of treatment, artificial insemination, gives me information about how the sperm are functioning and are they functioning normally. We also go on and we do a quantitative morphology on the sperm, where we do a histologic stain and really get a good feel for normals versus abnormals. To back, when we did a morphology here, this is just looking at the sperm on a hemocytometer, which is how most labs look at it. When we do it, as

We also can look at acrocine, which is one of the components, one of the enzymes that plays a role in the fertilization process, looking at well that functions. We look at how the sperm live over 18 hours. If the sperm die within several hours after ejaculation that’s not a good thing also. I just wanted to give you guys a fell for some of the things that we look for when we do a

The other thing that you want to look at is you want to look at the sperm-cervical interaction. That’s the post-coital test. And in those circumstances, you ask the couple to have intercourse mid-cycle - and to refresh your memory, the first day of menstrual flow is called day one and that’s when you tell a woman to start timing her cycles. And an idealized cycle, is 28 days, however only about 60% of women have a 28-day cycle. So in the middle of that 28-day cycle you tell them to have intercourse on day 13 or 14 and then you’d like to see them within eight hours of having the intercourse. She comes in, you take a small syringe without the needle on the end, pull out some of the cervical mucus and then look at it under the microscope. What you want to look at is just you want to see, are there sperm? Or no sperm? Are the majority of the sperm moving or nonmotile? What does the mucus itself look like? Is it thick or does it have …is it thin and snotty looking? Called spinnbarkeit. I’ll show you some slides

This is a schematic of the cervix and some sperm trying to get up in there and what you want to do is just take a little syringe and pull some of this mucus out and see if you can find some of these sperm in there. This is what’s called ferning. That’s just salt. If you are looking to see if they are ruptured in labor, trying to see if they have rupture or not, you look for the ferning and the same thing when you are doing a post-coital test. If there is an estrogenic effect. These are just some white blood cells. I show a little bit more about the spinnbarkeit in another slide.

This just gives you different problems that may occur with sperm. Cervical mucus interactions. There’s lots of causes that can give you hostile mucus and these are some female-related causes and these are some male-related causes. Typically one of the big things that you hear about when you do a post-coital test you are looking for this hostile mucus. The hostile mucus can be … if it’s going to be hostile mucus it is usually simply due because the woman is not ovulating so she doesn’t have that estrogenized mucus which is that ferning that you would see. That’s usually why you will get a hostile mucus. Some red herrings that people will talk about are antibodies, sperm antibodies. Antisperm antibodies. They will kill the sperm. Those antibodies reside within

Male factor: there are some more involved tests that you can get other than just the sperm count that we talked about. We don’t do those, but they look at sperm functioning, their capability of the sperm to actually fertilize an egg. The only thing that we do is we look at the acrosin and we have found that to be helpful. You can do what’s called a zona-free hamster ovum penetration test. This is where they would take small hamsters, superovulate them, take out their ovaries, take out their eggs and then fertilize them with the sperm that you want and then analyze. And then a good sperm and see how they fertilize that hamster egg. If they

Therapy, again the statement I made back in the very beginning is very very true with men. It’s real easy, or fairly easy to find the problem but once you’ve found the problem there really isn’t much you can do about it medically. If the count is low but not too low, sometimes you can give them Clomid and Clomid is the medication, as you guys know, that is used in the treatment of women. It’s an antiestrogen. What it does is it causes endogenous rise of follicle stimulating hormone and that’s how it gets more follicles to develop in women. While in men, if they have a low count or more importantly low motility, that’s due to their FSH

Some other antiestrogens that have also been used is tamoxifen and a similar type mechanism causes a mild rise in endogenous FSH. Some other researchers in some other fertility centers have even gone as far as giving men - injected them - with injectable gonadotrophins. The Pergonal, Metrodin. That gets very very expensive and again it’s questionable how much improvement you get. But I will treat men occasionally with Clomid or tamoxifen. I’ve done both if their motility is low. Let’s say their motility is in

Surgical; obviously, if they’ve had a vasectomy, they reverse that. The big thing now from a surgical standpoint, is instead of doing a vasectomy, they do an epididymal aspiration. The urologist goes in, it can be done in an outpatient type setting. Can almost be done in an office setting. They take a small needle locally. They can do it locally with some sedation, going with the needle into the epididymis because the epididymis usually has swelled, particularly in individuals who have had a vasectomy. It’s

Okay, we’ll talk about women here. First, ovarian factor. The ovarian factor refers to the ability of the ovaries to release an ova on a cyclic pattern. Obviously if a woman isn’t ovulating on a regular basis it’s going to be more difficult for her to get pregnant. Ovarian functions. We know they produce hormones and produce eggs. So how do you document ovulation? Direct means: you can observe by ultrasound or laparoscopy. That’s a bit involved. We do ultrasounds. When patients come to us we put them on

The simplest and easiest indirect means of determining whether a woman ovulates is with the ovulation predictor kits. They cost anywhere from $15 to $20 for one month. I think it’s money well spent. It really is.

There’s lot’s of reasons why you can have ovulatory defects. Abnormalities in the hypothalamic, pituitary insufficiency, thyroid disease, adrenal disorders, emotional disturbances, metabolic and nutritional disorders. So another thing that you can look at is ovarian dysfunction during the luteal phase, formation of the corpus luteum. Getting into what I talked about a couple of minutes ago, progesterone, adequate progesterone. You get into what’s called luteal phase defect. Do you have a short luteal phase? That’s what this is. A short luteal phase. The reduced progesterone production may cause infertility. It may also be a cause for

This is just showing you that if you were to do an endometrial biopsy, changes that occur in the endometrium throughout the cycle. It’s Noyes criteria for dating endometrial samples and these are just some of the things you look for, just to remind you guys. But again, we don’t do endometrial biopsies as a standard workup for infertility, to look at ovulatory function. In all

This is getting into this luteal phase defect and if you think someone has a luteal phase defect, progesterone supplementation or clomiphene citrate and if that doesn’t work you can go to the injectable gonadotropin. Like I said, this whole idea of a luteal phase defect is a big gray area and since it is a gray area we just supplement all patients with progesterone. The way we supplement them with it is after they ovulate - in other words, after the predictor kit turns blue, if you are doing the predictor kit -

More important that luteal phase defects is age. Age is probably the most important thing when you have to think about treatment of the infertile couple. You have to think of the age of the woman. It is so important. Because I have patients coming to me that are older, from a fertility standpoint, with the idea that I can do something to reverse old man time and make their eggs

This looks at pregnancy rates based on age, doing IVF and these data are older. They are a little bit better now, but just looking at age, pregnancy rates - if you do the most involved stuff that we can offer patients, the IVF stuff - less than 25 you can tell them they have a 35% chance of pregnancy per transfer: 25-29, 23%, 30-34, 21%, 35-39, 19%, 40, 12%. Actually that’s

A few things speed the process up. Obviously chemotherapeutic agents, radiation, smoking. Smoking is bad. It’s an antiestrogen. It will make a woman’s ovaries function unlike her chronologic age. Kind of a new term that is coming out is we are looking at how ovaries function chronologically. You know, chronologic age versus non-chronologic age. So smoking makes a woman’s ovaries function older than they really are. And endometriosis will age ovaries, will age eggs. And it’s just simply the

There is some new data that guys, when they get into their 50’s and they were to fertilize a young woman, say in her 20’s or 30’s, sperm from guys in their 50’s also start to have some chromosomal abnormalities. Some recent work where they looked at some of these kings in Europe that had younger wives and the children that were born from this type of situation were more

This is a paper that I put out trying to look at predictors of what will give you good outcome versus bad outcome. One of the things you look at is age - is very important - and number two is you measure an LH, FSH and in particular, FSH - follicle stimulating hormone - early in the cycle, day three, day four. If it’s elevated, and elevated would mean that it’s greater than 10 that would suggest that that ovary is functioning older than it should. This is probably due because inhibin is another compound that regulates FSH release and the inhibin 

Therapy for correction of ovulatory factor problems, basically that focuses around, if she isn’t ovulating every month, how to get her to ovulate. There’s only two sets of medications you can use so it’s not hard to remember that. One is Clomid or Serophene. They are antiestrogens. Like I had discussed when talking about men, they act at the level of the CNS to increase endogenous … to inhibit the negative feedback effect of low levels of estrogen and by doing that they increase endogenous FSH. This medication has been around for many many years. It’s very good in stimulating ovulation in patients that have an ovulatory problem, particularly women that have polycystic ovarian disease. The starting dose is 50 mg a day. You can either do it for five days starting days three through seven or five through nine. I’ve done it both ways. I don’t think any one way is better than doing it … doing it three through seven is any better or worse than doing it five through nine. You can go up to 250 mg a day. We rarely do that. If you look at the literature, if a woman is going to respond to Clomid 50% will respond to the 50 mg dose. If the 50 mg dose doesn’t get her to ovulate, you can go up to 100 mg a day. You’ll pick up another 25%. So if a woman is going to respond to Clomid, 75% of them will respond either to the 50 mg or 100 mg dose. We will go up as high as 150 mg. You pick up another 5% or so, but we won’t go up to the 200 or 250 because it is an antiestrogen. Because it is an antiestrogen, even though it has good effects on the brain, it has bad effects on other estrogen-sensitive tissues. Cervical mucus. It will make it thick. So even though she is ovulating, if her mucus is thick, you’ve got a plug there. She isn’t going to get pregnant. It can also affect the lining of the uterus, the endometrium. It will make it thinner. So even though she is ovulating implantation may not occur. So we don’t go up to the higher doses. If it doesn’t work at 150 then we move on to the next class of medications, the injectable gonadotrophins. Pergonal, Metrodin; now the new medications that are on the market are the recombinants, Follistim and Gonal-F. The first class of medications, the Pergonal, Metrodin, Humegon, those type of things, those medications contain LH and FSH, primarily FSH and this is highly purified FSH from urine. Urine collected from post menopausal women. It’s run over columns and collected out. So they even call it Ultra Purinal, the Metrodin, but it is hormone that has simply been extracted from urine.

The newer stuff is recombinant. They’ve taken the gene sequences for formation of LH and FSH, injected it into a cell, eukaryotic cell. That eukaryotic cell now produces FSH and LH. It’s a very pure type of medication. It is very good and we have had some very good success with it. And they just came on the market last year. One is called Follistim, one of the trade marks and the other one is Gonal-F. The problem with these medications are, they are very very expensive. They are dispensed in what are called amps. And they are either 75 IU in one amp or 150. Typically you work with just the 75. But one amp will run you - and there is a lot of variation from pharmacy to pharmacy - but will run between $40 to $80 an amp. If Clomid fails, that’s the only thing you have to go to. To do injectable gonadotrophins with say intercourse or insemination, you are going to run an average of 10 to 20 amps. So that’s $500 to $1000 in medications alone. If you are going to be IVF, you are going to double that dose. The standard amount of medication used for test tube baby type stuff is 40 amps. Very very expensive stuff and that’s why this fertility treatment starts to get so expensive. Because these medications are so expensive. But there’s only two types of truly hormonal, fertility medicines. The Clomid, the antiestrogens and then the injectable gonadotrophins.

Luteal phase defect supplementing with progesterone and giving the injectable gonadotrophins. Well what about cervical factor? We kind of talked about that. With the men, you have them do intercourse mid-cycle just looking to see what … this is the spinnbarkeit. In other words, mid-cycle you put their specimen on a slide and then you take the cover slip and pull the two apart and it should be 7 or 8 centimeters. This means it is very favorable mucus. And that’s a good spinnbarkeit. Then this is the ferning that you are looking at again. Correction of cervical factor; some people give estrogen. That hasn’t been found … we haven’t found that to be of much benefit. Antibiotics if they have a lot of white blood cells. What we do, if there’s any hint of cervical factor, either because of thick mucus or because they’ve had surgery to their cervix, we do artificial insemination.

Coital factor: I’m not going to get much into that. Uterine factor. What about uterine factor? Uterine and tubal factor. Plumbing problem. That’s another major area of pathology in patients that have an infertility problem, is tubes. Plumbing. If they’ve had some kind of infection in the past, gonorrhea, Chlamydia, something like that and obviously the plumbing is messed up. They can’t get pregnant. So you need to check that out. A simple and easy way to check that out is having a hysterosalpingogram performed. It’s an old test. It’s been around for many many years and it’s done down in radiology. They take a catheter, have the patient get in the dorsal lithotomy position, take a cone cannula, place it in the cervix and inject some radiopaque dye under fluoroscopy. As the radiopaque dye goes up through the cervix into the uterus, the pressure then forces the dye out into the tubes. Good test. Tells you … gives you a lot of information and it not only is diagnostic but it’s therapeutic. Pregnancy rates increase the first couple of months after you do this test. Why is that? Couple of reasons. This radiopaque dye sometimes, if there are some white blood cells within the tubes themselves that are in there, residing in there killing sperm, it kills those white blood cells which may be affecting the sperm. If the tubes are closed a little bit, it reopens the tubes. So pregnancy rates do increase. I see that in my own practice and I can show you half a dozen articles over the several years that I’ve looked at that, that will confirm that as well. But I have patients come in. Part of my basic workup is an HSG and I’ll say, "Don’t do the HSG until you are really serious about getting pregnant" and voila, the next month they will call me and say after their HSG they are pregnant. Happens two or three times a year.

Correction of uterine factor: really the only way you can correct uterine or tubal factors is to go in and surgically remove the abnormality. Do a hysteroscopy to look inside the uterus itself, if you see an abnormality to correct it surgically. If she’s got a lot of myomas and they are both submucosal and intramural, that requires a laparotomy. If she’s got blocked tubes you can go in and do a fimbrioplasty or fimbrioplasty can be done. Unfortunately, bad tubes are always bad even though you open them up. If they do stay open after surgery they are at risk for an ectopic pregnancy. So if a patient is advised to do a fimbrioplasty they