Making the Diagnosis of PCOS

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Dr. Mark Perloe:  “Hi, this is Dr. Mark Perloe, and I’m here at the Annual PCOS Support International Meeting in San Diego, California with Samuel Thatcher who is Director of the Center for Applied Reproductive Science in Johnson City, Tennessee, and he also has an office in Asheville, North Carolina.  Your presentation today was quite interesting but a bit controversial.  We heard a number of oohs and aahs with some of the comments.  Traditionally, one of the seemingly important parts of the infertility evaluation was looking for a luteal phase defect.  What are your thoughts about that?”

Dr. Samuel Thatcher:  “Not everyone in the world and especially the people outside the United States believe that luteal phase defect exists.  In a quick summary, the luteal phase defect is a consequence of a follicular phase defect so that if there’s a low progesterone level which many people seem to associate low progesterone with progesterone that needs to be added back, most of the time that either means that the person did not ovulate or the ovulation came out of a follicle that was not a competent follicle to produce adequate amounts of progesterone.  If progesterone is added, I think it might help; it helps in the next cycle and not in the present cycle.  I believe progesterone levels can be valuable, although some people disagree with that, because they do tell us something about ovulation.  Georgianna Jones described the classic luteal phase defect 1949 based on endometrial biopsies, and these biopsies were done prior to the time when hormonal assays were easily available.  She was working at Johns Hopkins Institute, and they had a readily accessible pathology lab so it was very common to take a piece of a tissue and look at it under the microscope.  A lot of our theory about how the reproductive system works pathologically came out of these studies but that was carried through and has been carried through that the endometrial biopsy is the gold standard of diagnosis of ovulation in the luteal phase defect.  It’s just not because endometrial biopsies are incredibly painful, they can be incredibly expensive depending upon the pathology department and the charge by the physician, and if they at best give equivocal information, that does not change the way the treatment will go.”

 Dr. Mark Perloe:  “One of the other concerns in Dr. Jones paper said that in order to make the diagnosis by biopsy, you might need more than one biopsy.  But you were saying that it doesn’t change what you do so can you explain it a bit more, you’re saying if the biopsy was abnormal you would do an ovulation induction but what if the biopsy is normal?”

Dr. Samuel Thatcher:  “It still doesn’t matter.  First of all, what was said in the original papers is if the biopsy came back abnormal, it should be repeated.  If the biopsy is still abnormal, the person should either be given progesterone and people who failed on progesterone should be given clomiphene, and then the endometrial biopsy repeated for the third time to see if it’s been normalized.  That just seems to be a lot of waste.  Now in first line therapy, clomiphene is a relatively safe, cheap, and easy drug to administer.  If at the final analysis you’re going to give clomiphene, just give clomiphene before three biopsies because you’re going to end up at the same place.”

Dr. Mark Perloe:  “Let me go back to that and that is that we’re talking about a patient where we’re going to be treating with ovulation induction who’s trying to get pregnant.  Is there still a role for the endometrial biopsy to diagnose this inadequate follicular phase in patients who have recurrent pregnancy loss?”

Dr. Samuel Thatcher:  “Again, going back to the original paper, an inadequate luteal phase existed in only about 1% of infertile patients, and it’s possible, and I really firmly believe that recurrent pregnancy loss is due to the quality of the egg and not the quality of the endometrium that the embryo is implanting into.  Now when new markers become available that will allow us to measure some particular factor in the endometrium in which we need a piece of that tissue to do it, then that really becomes important.  A little bit of this was heading in that direction with the integrin assay which had some idea that it might give us a little better handle on what causes implantation.  But to take a piece of tissue and let a first year pathology resident look at it in the pathology department, I think there’s no role for it in any circumstances.  Ultrasound and hormonal testing will do the same things.”

Dr. Mark Perloe:  “So in terms of the recurrent loss patient, you will perform that evaluation with progesterones and a mid-cycle ultrasound, perhaps, to look for endometrial thickness.  One of the other areas that I think is controversial is the issue of cervical mucous.  We have heard people worried about checking their mucous to see when and if they ovulate, or there’s not enough mucous, or their concerns about it or doing a post-coital test to determine hostile mucous.  What are your thoughts on that?”

Dr. Samuel Thatcher:  “The post-coital test has the same utility of an endometrial biopsy; it’s much easier to perform, and we’re looking at tests now that have been outmoded by our present therapy and diagnostic tools.  There’s nothing wrong with a post-coital test if we want to see if there is any sperm; it’s a good way of saying, yes, there’s sperm in the vagina.  The man doesn’t have to go and produce the semen sample; it’s much less formal.  The problem is that two different independent studies have shown that the post-coital test has no relationship to fertility.  In these sort of circumstances many times on an ultrasound scan, and I don’t believe ultrasound should be overused but it also should not be underused, but a single well timed ultrasound scan at mid-cycle is going to show the endometrial thickness.  You can actually see the cervical mucous on the ultrasound scan, and it’s an excellent bioassay.  Many times we’ll do an insemination at the same cycle, and if you look at that and the mucous will stretch out the door, you say - gee, it’s a great post-coital test if you looked at a semen sample in which you know the exact numbers and you put it up through that mucous, you’ve already bypassed the problem many times you’re trying to diagnose so you can treat.”

Dr. Mark Perloe:  “So it sounds like the most cost effective approach to infertility management, if you’ve got sperm and you’ve got good anatomy on the woman’s side, is some form of ovulation induction and insemination before anything else?”

Dr. Samuel Thatcher:  “There are three things that a person needs to be fertile.  One is an egg, the second is a sperm, and the third is a way for them to get together.  There’s getting to be some degree of controversy about laparoscopy, and I’m pretty pro-laparoscopy.  In fact, in one of the other issues I’m kind of negative in is a hysterosalpingogram because in our population of patients, endometriosis is much more common than tubal disease and at laparoscopy not only can you treat the endometriosis, but you can diagnose the quality of the uterus by hysteroscopy and evaluate the entire pelvis.  So I believe there are really three therapies and almost diagnostic testing is very limited; one is clomiphene induction or possibly one of the insulin altering agents, the second is laparoscopy, and the third is assisted reproduction and particularly in vitro fertilization.  That really is the long and short if it doesn’t diagnose it, it will cure the problem directly.”

Dr. Mark Perloe:  “We’re left with a bit of a quandary about the laparoscopy.  We have the ENDOCAN study, which shows that there is an improvement in fertility after treating mild or minimal but there’s concerns in the low pregnancy rates in the control group and treatment of adhesions.  But in all the other studies that have looked at mild and minimal endometriosis with adequate controls there really hasn’t been any benefit going to surgery to make that diagnosis.  So to go to laparoscopy we have to be looking for a more significant structural abnormality than a few powder burns.”

Dr. Samuel Thatcher:  “For the diagnosis of endometriosis or the diagnosis of infertility in general, the problem is that the pain pattern of endometriosis is really non-specific for the degree of endometriosis.  I think it’s true when everyone sees these little powder burn sites, they will take care of them and many times the patient feels better and sometimes they get pregnant.  So whether or not it actually helps or harms is really not the issue but how do you know the person doesn’t have severe endometriosis until you look?  Some of the worst cases of endometriosis are in patients that have no symptoms whatsoever so it’s not necessarily for the diagnosis of endometriosis, it’s the diagnosis of the entire pelvic status.  Then if the pelvis is okay, you can move to more aggressive ovulation induction.  If it’s abnormal, you may want to move directly to assisted reproduction.”

Dr. Mark Perloe:  “Okay, so I’m a patient coming to you, and I have about four or five periods a year.  I’m a bit overweight, and I have some hair growth in places that I don’t want it but my real interest is getting pregnant.  I’ve read a lot about this metformin stuff but my other doctors have said I probably ought to be on clomiphene.  What are your thoughts, and how would you decide what to do?”

Dr. Samuel Thatcher:  “There’s a lot of hype and metformin has almost reached cult status if anyone looks at the Internet about polycystic ovarian syndrome.  Clomiphene is still a particularly good drug, and it will give a one-cycle fix.  So usually the way I approach it, especially if the patient hasn’t received any sort of therapy before, is I’ll give a cycle of clomiphene almost as a diagnostic trial because I’d like to see where we’re starting from.  Since we know that most pregnancies and clomiphene are going to be achieved in the first three or at most four cycles, and many, many people use too many cycles of clomiphene, if we start out with one and probably still starting at the lowest dose and then there’s no response at all with the clomiphene, we know we have a more serious problem.  Then we can move to either a different drug or a more aggressive diagnostic capacity.  On the other hand, if someone has been on multiple cycles of clomiphene, it may be better to go straight to an insulin-altering drug.  But we use clomiphene as a diagnostic test, and a diagnostic test that gets people pregnant is a pretty good diagnostic test.”

Dr. Mark Perloe:  “Now when people are using metformin, we’ve seen patients who come in who’ve been on placed on 500 and started clomiphene right away.  They use them in combination; some people will use metformin for a given trial and then add clomiphene on top of that.  What’s your approach?”

Dr. Samuel Thatcher:  “We would start out with a cycle of clomiphene and then we use metformin alone for probably two to three months because one issue is it takes around one hundred days for a follicle to go through its entire development process, so we want to try to change the overall ovarian environment.  After that, we’ll retry the clomiphene, so we repeat our challenge after the patients been on metformin somewhere two to three months, not in the first month and many times not in the second month but come in the third month for metformin.  Many of them will get pregnant on the metformin that have not gotten pregnant on the clomiphene, we drop back to the same issues.”

Dr. Mark Perloe:  “In your experience, and I’m sure it’s similar to most, not everybody is going to respond or tolerate the metformin therapy.  Have you found any factors that help you predict where success will lie and who may not be successful with metformin therapy?”

Dr. Samuel Thatcher:  “It’s true that we have maybe 20%-25% of the patients who believe it’s a medicine from heaven, and about 20%-25% think it’s from hell, and the middle portion of them kind of take it or leave it.  That’s actually the criteria that we use for a continuation of metformin is to try to determine a kind of overall tolerance to the medication.  We do fasting insulin and stimulated insulin after a glucose tolerance test; clearly the patients who are hyperinsulinemic and certainly the ones that are borderline glucose intolerant are going to actually be the very best candidates for metformin.  There looks to be a group of polycystic ovarian patients who do not have insulin resistance, and who probably do not do as well with the metformin.  On the other hand, many times they’ll sneak up and surprise us, and we’ve had patients that we would never believe would get pregnant on metformin that do.”

Dr. Mark Perloe:  “You mentioned hyperinsulinemia as perhaps different from insulin resistance.  Most labs have a cutoff somewhere between 25-30 for insulin.  Do you have a value that you consider too high, and is it consistent with what the labs say is the value to be concerned about?”

Dr. Samuel Thatcher:  “I know you use even lower insulin levels than we do, I think you say 10.  What was interesting is we were sending our insulin levels to two labs, one of them came back with a normal level of 1-14 and the other one came back as a normal level of 1-25.  When we called them, they were using exactly the same tests so it doesn’t make any sense to a variation.  We really don’t have any idea because the problem is when they were looking at the validation of the insulin assay; they added PCO patients and insulin resistant patients in that so the insulin levels have been skewed toward the higher side.  It looks like if they’re above 20, the patient almost always is insulin resistant or has high levels of insulin.  If they’re under 10, they’re almost never, and we kind of are in the gray area between 10 and 20.”

Dr. Mark Perloe:  “We chose 10 as a value to consider because there’s some data looking at subsequent risks of cardiovascular complications, and it appears it’s with values above 10 at least in the assay used in that particular study there may be an increased risk.  On the other hand, in terms of treating patients we’ve looked at oligo-ovulation and hyperandrogenism as factors and many patients with levels as low as 6 or 4 may well resume normal ovulation once placed on it.  So I think that brings up an important factor, do patients have to have abnormal insulin values in your program to get started on metformin?”

Dr. Samuel Thatcher:  “Almost as our previous discussion, I’m not sure that any testing has to be done if you’re going for the end result of a pregnancy.  On the other hand, to actually understand and our center is called the Center for Applied Reproductive Science, we take that to heart and we’re trying to find out.  So each patient actually gives us a bit of information about themselves but also information about other patients, and we’re trying to actually find out which patient will respond best.  So the overall cost of the diagnosis is not terribly high when you consider the benefits that might come out of it.  I don’t think there has to be a lot of testing, on the other hand, if we don’t test and we don’t look and apply those tests to the individual, how will we ever know why we were successful?”

Dr. Mark Perloe:  “Thank you so much, I appreciate you stopping to talk with us.”