You are currently browsing the archives for the Ovaries category.

AMH (Anti-Mullerian Hormone)

 

award winning fertility doctor new york city

 

Hello to all.

In this blog I will review the usefulness of Anti-Mullerian Hormone, otherwise referred to as AMH. AMH is one of the hormones, along with estrogen and a few others, produced by the ovary.

Like estrogen, AMH is produced by the granulosa cells. The granulosa cells are the small cells that surround each egg.  These small cells are tightly attached to egg surface whereby they help to vitalize and, when the time is right, mature the egg.   This egg-granulosa cell unit is called the follicle.

No one yet knows what the function of ovarian AMH in females.  AMH is present in males, and we know that it has a very important role in the development of normal male sexual anatomy.  What we do know about AMH in females is that the more healthy follicles one has, the higher the AMH levels.

Measurement of AMH levels can help us predict a woman’s fertility, in a very general way.  We already said that estrogen is also produced by the granulosa cells, so why wouldn’t we just need to measure estrogen levels to find out about ovarian health?  Because estrogen only comes from follicle at a time; the one that is in the process of ovulation. A woman may have 100,000 follicles, but on most cases only one per month gets involved in ovulation and becomes an estrogen producer.   Follicles may make different amount of estrogen each month, so judging fertility based on an estrogen test is not helpful.

Many follicles at one time, however, are producing AMH. Now it’s not every follicle, but it is a large number.  It works like this. The ovary contains different follicles in different stages of maturity.  Here is a microscopic view of the ovary.

 

Some follicles are very immature and have few granulosa cells; just one layer surrounding the egg.   Some follicles are more mature and their granulosa cells have multiplied into more cells in multiple layers.  These are the ones producing the most AMH.  In general, if you have a lot of eggs, you have plenty of follicles in all of the stages of development, giving you higher AMH levels.  Lower AMH levels mean fewer follicles of all types.

Follicles are always making AMH therefore levels can be measured any day in the cycle. In fact, it does not matter if a woman is on oral contraceptives, AMH is still produced and can be measured.

AMH may turn out to be and excellent way to measure a woman’s fertility potential, but we are not quite there yet. We do know that a high AMH is good and a low AMH is bad. What’s a good high level? We are still not sure. We know a little.  Any level over 2 is really not bad at all. Certainly, higher than 2 is better still. We know that undetectable levels, less than 0.16, are bad.  But, we have had women with these low levels become pregnant.  The odds of pregnancy are much worse for women with low levels, but people frequently get pregnant with low odds.  Some women have asked me if the level can be too high.  High levels may indicate the presence of polycystic ovaries (ovaries with an above average number of follicles).  While it is true that some women with polycystic ovaries have trouble conceiving, a high AMH level is not the issue.

Recent studies (one was in the headlines a few weeks ago) have used AMH levels to predict IVF outcome.  But again, really high levels were shown to be good and really low levels bad, but overall, not predictive enough to tell someone they can or can not get pregnant.

What we typically do is to put all of the information we have together to estimate ovarian health.  If we use age, FSH levels, AMH, antral follicle counts, the prognosis becomes a bit more clear, but the system is still not perfect.

AMH testing will become more useful sometime soon. More and more women need to have the test done do we can compare levels to outcomes on a large scale. In addition the laboratories need to get better at the testing.  But once we get better with AMH levels, we may be able to do some very important things.

For instance, some studies have been done comparing AMH levels to the time of menopause. Again, not ready for prime time, but the concept may be very important.  What if we could measure AMH in a young woman and determine at what age she will start losing her fertility? Or at what age will she lose half her fertility? What if we could measure AMH levels in a woman destined for chemotherapy and determine if she should freeze her eggs first?

These would all be wonderful uses of this test and it may be that in the future we could reach these goals.

It’s more likely that newer tests will be developed to improve ability to predict.  As alluded to before, combination tests may be more accurate. For example labs are starting to market “fertility profiles” based on AMH, FSH, inhibin and other hormones.

But in the end, like in all of medicine, the genetic tests will dominate.  Scientists are looking for a gene or groups of genes that control the fertile lifespan of women.  As genetic testing becomes less expensive and as we increase our ability to look at more and more genes at one time, the goal of accurately determining a woman’s ovarian age and potential will be reached.

 

Thanks for reading and please don’t forget to read the disclaimer from 5.17.06

 

Dr. Licciardi

 

Preventing Ovarian Hyperstimulation: The Lupron Trigger

award winning fertility doctor new york city

 

Hello everyone, this is another important article on Ovarian Hyperstimulation. The response from readers on this subject has been very positive, thanks for your support.

Saving the best for last, an excellent way to prevent OHSS is to use Lurpon. This requires some explanation.

As many of you have experienced, Lupron is a drug that can be used during an IVF cycle. It is typically started about 1 week before the IVF cycle starts (day 21) or it can be started on day 2. The dose varies, but the usual options are regular lupron, low dose lupron or microdose lupron. None of these have anything to do with reducing OHSS, but I will get to that.

Lupron works by suppressing the pituitary’s ability to produce LH. This is good because in all of the Lupron protocols I just mentioned, one important job of Lupron is to prevent the premature surge of LH. The surge of LH causes ovulation, which is bad for an IVF cycle. If LH surges before the hCG injection, we cancel the cycle for premature ovulation.

We can’t get the eggs when we want them if they have ovulated prior to the retrieval. Lupron prevents this. Before Lupron was invented, we needed to cancel about 15% of IVF cycle for early ovulation.

Some of you are wondering why we trigger ovulation if we want to get eggs from the ovary. LH, hCG and Lupron cause the eggs to mature and then ovulate. For an IVF cycle, we need those medications to get the eggs to mature while still in the ovary, but we grab them before they are released.

Over the past decade we have been using other drugs, like Cetrotide and Ganarelix, to prevent the premature LH surge. These are easier to use than the Lupron because they are only given 2-4 days prior to the hCG. Some doctors still prefer to use Lupron.

Now on to OHSS and Lupron. In a natural ovulation cycle using no drugs, the follicle develops over about 2 weeks, and then a strong surge in LH causes ovulation. While Lupron causes the pituitary to cease LH secretion, in the first 1-2 days of Lupron use, there is a strong release of LH. That’s why we normally give it early in the cycle, before follicles have developed. Premature ovulation does not occur when we give it early because there are no follicles to ovulate.

It is this strong release of LH that makes Lupron great as a hCG substitute for the trigger shot. The quick surge results in a very short blast of LH, which could take place over 1-2 hours. This is very similar to the body’s LH surge that takes place in a natural cycle. After that, the LH has left the system, ovulation occurs 36 hours later, and ovarian stimulation stops. hCG, on the other hand, stays in the body for days, even up to 2 weeks. All of this time, hCG stimulates and stimulates the ovaries, which is too much for ovaries that have released many eggs.

Why give an hCG instead of a LH injection? For iui and IVF we use hCG as opposed to LH because hCG is easier to make and cheaper than LH, and hCG works just as well. The molecules of hcg and LH are very similar and act in similar ways. Plus, the drug companies have not yet figured out how to get the necessary large amounts of LH cheaply into one little vial.

The bottom line is that Lupron, because it causes just a short burst of LH, works very well in preventing OHSS. We are using it more and more and are very pleased with the results. We commonly use it for our egg donors.

One down side to lupron is that, in very small percentage of cases, it may not cause ovulation. This is a rare occurrence and is more likely to happen in women who are hypothalamic, i.e. they do not get regular ovulation due to exercise, dieting or some other factor. In these cases, there is no LH in the pituitary for Lupron to trigger.

In cases where the threat of OHSS is evident, it’s worth taking a chance with the Lupron. We measure LH levels the day after the Lupron injection. If they are very low, the lupron did not work, and there is no LH surge. Therefore we can give hCG the next day, unless the fear of OHSS causes us to cancel the cycle.

Another detail of Lupron use is that for luteal support, we add estrogen. The ovaries just shut down after Lupron use, and therefore estrogen and progesterone are produced in very low quantities. Typically we prescribe progesterone post IVF, but with Lupron we also give estrogen. Not much of a big deal, as estrogen can be given in the form of a pill three times per day. Estrogen patches can also be used.

Lupron cannot be used for triggering if Lupron has been used in the same cycle. So you are taking Lupron starting on day 21, day 2 or using microflare lupron, a Lupron trigger will not work at all. Here hCG would be the only option.

Many other physicians have been increasing their use of Lupron for ovulation triggering. You should ask your doctor if Lupron is used in his practice to prevent ovarian hyperstimulation.

That’s it for today, thanks for reading, and please read disclaimer 5/17/06.
Dr. Licciardi

References:

  • Engmann L, Benadiva C. Ovarian hyperstimulation syndrome prevention strategies: Luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger. Semin Reprod Med. 2010 Nov;28(6):506-12.
  • Kol S, Itskovitz-Eldor J. Gonadotropin-releasing hormone agonist trigger: the way to eliminate ovarian hyperstimulation syndrome–a 20-year experience. Semin Reprod Med. 2010 Nov;28(6):500-5.

Ovarian Hyperstimulation

award winning fertility doctor new york city

 

Hello Again to Everyone,

Today I am bringing to you the topic of Ovarian Hyperstimulation Syndrome (OHSS). Here you will read about the definition of OHSS, the causes and risks. You will see why OHS is what every good doctor strives to avoid, and of course, what every patient would like to avoid as well.

I would like to start by saying that you will read some things that may be frightening, because the most severe forms of OHSS can lead to significant medical problems. However, OHSS does not occur with great frequency and the severe forms are very rare. The next blog will review ways to lower the risks. In many cases it is preventable, although even when your doctor is very careful, OHSS can still occur.

OHSS occurs as a result of taking fertility drugs. These cause the ovaries to become larger than normal and to leak fluid. The more eggs that are produced in the cycle, the higher the risk of OHSS. The leaking fluid can cause significant abdominal swelling, and some of the fluid could make its way to the lungs. We will get back to these and other problems with OHSS in a bit.

OHSS, except for some very rare instances, can only be caused by fertility drugs. When we use infertility drugs, clomid or the injectables, we are hyperstimulating the ovaries. The goal of fertility treatment is to get the ovaries to make more eggs per month than usual. Sometimes we use the drugs to try to just make one egg, but usually we are going for more. In fact,therapy with any of these drugs is called Controlled Ovarian Hyperstimulation. Controlled is the key word. Therefore we expect all women receiving fertility drugs to have enlarged ovaries with the possibility of a small amount of fluid leaving the ovaries, and some cramping. When Controlled Ovarian Hyperstimulation becomes less controlled, OHSS can result.

The development of OHSS through the use of clomid is quite rare, but it has been known to occur. However,the injectables (examples are Follistim, Gonal-F, Menopur, Bravelle) pose much more of a threat. Clomid is a very different drug than the injectables. Clomid nudges along the normal ovulation process by getting the brain (actually the pituitary gland) to put out a little extra FSH. Because there is only so much FSH stored in the pituitary, usually 1-3 eggs will ovulate, as opposed to the one egg that ovulates when no drugs are used. For almost all women, this is not enough stimulation to cause OHSS. The injectables, on the other hand, are more powerful. They are FSH (sometimes with a bit of LH), and more FSH is delivered to the ovaries than in a natural cycle or with Clomid. The injections directly stimulate the ovaries to develop a larger number of eggs for ovulation. Because more eggs are produced, the injectables carry a higher risk of OHSS.

Who is at risk for OHSS? Women who are most likely to make a high number of eggs. The first and obvious group is younger women. For better or for worse, young women have more eggs, and develop more eggs for ovulation when given the injectables. Women with polycystic ovaries (PCO) are at higher risk for OHSS. This is because women with PCO have a very large number of eggs. These eggs are in follicles that have reached the stage just prior to entering the ovulation process. The fertility drugs can get many of these “almost ready” eggs to come up at once. And there are the exceptions, women who do not have risk factors, yet hyperstimulate when exposed to drug.

The severity of OHSS varies widely. Most textbooks divide the various degrees into mild, moderate and severe. Mild does not cause medical problems but may cause a woman to take notice of the changes in her body. In the mild form, the ovaries produce a few eggs and as a result have enlarged slightly. The ovaries have released some fluid, which the patient perceives as bloating. Cramping is mild. Many women have mild hyperstimulation, however they are not at all bothered by the symptoms and they go about business feeling no need to contact a physician for evaluation. The majority of women who take the injectable medications fall into this category. Some women with the same degree of mild hyperstimulation, are more bothered and concerned and may let us know that they do not feel well. Like many things in medicine, we can’t explain why 2 women with the same number of eggs and the same amount of fluid around the ovaries feel differently.

The two worse forms of OHSS are moderate and severe. In these cases, the problems are more complex than just large ovaries and a bit of fluid in the pelvis. In these cases, the OHSS can affect other areas of the body. Dehydration comes into play, and can be very problematic. This occurs as the ovaries leak larger amounts of fluid. The abdomen becomes noticeably distended. Women gain weight as the tummy accumulates more and more fluid. This probably doesn’t sound like dehydration to you, but it is. What’s happening is the leaking fluid comes from the blood which is circulating through the ovaries. As more fluid leaks out, less is fluid is in the blood and the blood becomes thicker, thus the dehydration. Not only does the blood lose water, but with the water flows sodium, so in the blood, sodium levels are low. Proper levels of sodium are necessary for normal function of the brain.

As the blood becomes more concentrated, levels of clotting factors increase. Clotting factors are proteins that are necessary for us to prevent excessive bleeding when injured; they make the blood clot. If the levels of these proteins get too high, the blood will be more likely to clot without any injury. For instance, clots can occur spontaneously in the legs, arms,neck and lungs. The worse the OHSS, the greater the risk if blood clotting.

OHSS can have a big effect on the kidneys. As the dehydration progresses, the overall volume of the blood decreases. Good blood volume is necessary for the normal kidney function of cleaning the blood. Decreased blood volume means that less blood is getting to the kidneys, and therefore the kidneys have trouble doing their job. The blood cannot be cleared of its waste, which is bad for the body.

OHSS has an effect on the lungs. The sheer volume of fluid in the abdomen can make breathing a problem for a couple of reasons. The first has to do with the pressure that builds in the chest as the abdomen fills. We’ve all heard that we breathe with our diaphragm, which is true statement. The abdominal fluid pushes up putting pressure on the diaphragm, making it harder to freely breathe in and out. The second problem has to do with fluid getting into the lungs. When the abdomen gets packed with fluid, it can squeeze through the diaphragm, into the spaces around the lungs. A small amount of fluid around the lungs is tolerable, but larger amounts make it harder to breathe and can cause chest pain.

If you have never taken these drugs, I do not want this blog to discourage you from taking the medicine you may need. If you have any concerns, talk to your doctor about the possible side effects and complications of these medications.
Next time we will discuss ways to prevent and treat OHSS.

Thanks for reading and don’t forget disclaimer 5.17.06.

Dr. Licciardi

References:

  • Ovarian hyperstimulation syndrome. Practice Committee of American Society for Reproductive Medicine. Fertil Steril. 2008 Nov;90(5 Suppl):S188-93.
  • Grossman LC, Michalakis KG, Browne H, Payson MD, Segars JH. The pathophysiology of ovarian hyperstimulation syndrome: an unrecognized compartment syndrome. Fertil Steril. 2010 Sep;94(4):1392-8.
  • Mullin CM, Fino ME, Reh A, Grifo JA, Licciardi F. Symptomatic isolated pleural effusion as an atypical presentation of ovarian hyperstimulation syndrome. Case Rep Obstet Gynecol. 2011; 2011:967849.

PCO and other Fertility Related Topics

award winning fertility doctor new york city

 

PCOS (Polycystic Ovaries) and Ovarian Drilling.

Some sort of ovarian surgery has been used to treat PCOs for the last 50 years.The surface of the ovary, also called the cortex, is where the eggs are. This is a relatively thin layer covering the ovary. Beneath this layer, in the mid portion of the ovary, is the tissue that makes the androgens. PCO women have higher levels of androgens than women without, and it is possible that these increased levels are what interfere with normal ovulation. Androgens, by the way, are the hormones that get changed into estrogens, so androgens are absolutely necessary for normal repoduction, but in PCO the androgens are in excess. Opening this layer and removing or destroying the inner tissue, either by wedging out a piece of the ovary, or putting in multiple holes using an electrical probe or a laser, changes the hormonal balance of the ovary. It lowers the androgens and and somehow allows for more frequent ovulation. These procedures are not frequently performed because they do not always work, can cause scar tissue, and there are other alternatives.

There are other ways to stimulate ovulation, including clomid and FSH injections. Clomid works to cause ovulation in women with PCO in most but not all cases. FSH works in almost all cases. With FSH injuctions there is a high risk of ovarian hyperstimulation, unless the starting dose is very low. Certainly IVF is also an option.

Now some may ask why get involved with fertility drugs and the cost of monitoring when a simple surgical procedure will do the trick. In the case where the patient cannot afford complex fertility treatments, but can get surgery, the later does make sense. In addition some women just do not want to take any form of fertility medication, so the surgery may be the best thing for them. There can be complications from the laparoscopic surgery including the usual bleeding, infection and injury to internal organs. These are increased as the size of the patient increases, and more severely PCO patient may be more obese. But more specifically, the ovarian wedging or drilling can cause scar tissue and adhesions around the ovary, decreasing the chance of conception even if ovulation normalizes. This is is more common with wedge resection (taking out a wedge) vs. ovarian drilling.

So before surgery is considered, other methods of assisting ovulation need to be employed, such as weight loss, along with medical interventions such as those listed above, with the possible addition of prednisone and or metformin.

What if there is anovulation from PCO and you are having a laparoscopy for another reason such as pelvic pain, lysis of adhesions, endometriosis, or fibroids. Should you have drilling or wedging when the doctor is in there anyway? If the other methods of inducing ovulation are available to you, I would not cut into the ovaries because of the possible scar formation. Plus, wedging or drilling removes or destroys a large number of follicles. Reducing egg number is just something I like to avoid. If, however, you decide the drilling is best for you, the ovarian surgery is an accepted method and may lead to pregnancy rather quickly.

Other PCO Topics

Cysts from Clomid. Clomid makes follicles, which are the fluid filled cysts that contain the eggs. These follicles usually dissolve away 2 weeks ovulation but sometimes, especially when there are more than one, it takes longer than 2 weeks for them to go away. It is really rare that they are there after 4 more weeks. I have not had a patient have a cyst that lasts for months as a result of taking clomid. I have heard of such things, but they must be quite rare. It’s common to use the birth control pill to help make the cysts go away. Clomid causes the follicles to grow by upping the FSH produced by the pituitary. Birth control pills lower FSH levels so the theory kind of makes sense, but no one has really shown going on the pill makes any of these cysts go away any faster.

When should you come off metfomin, at the first pregnancy test or later in the pregnancy? Every doctor has a different idea. There is a prevailing thinking that PCO increases miscarriage rates. But there is at least one good study showing there is no miscarriage difference between women with PCO and women who normally ovulate. Plus there are other OK studies calling into question an association between miscarriage and PCO. However, there are a few studies in literature from outside the US showing metfomin reduces miscarriage rates in women with PCO, plus it reduces some pregnancy complications, including diabetes. This being said, the continuation of metformin during pregnancy is not standard among REs in the US.

Will provera increase your pregnancy rate if you have irregular periods? If you have PCO and have very infrequent periods, strongly consider taking to your doctor about clomid or FSH injections. Provera, except in rare cases, will do nothing to get you to ovulate. Even if you bleed after provera, you probably did not ovulate, you just bled.

Egg quality clomid vs FSH? Probably similar.

Is a clomid cycle that makes 6 follicles any different than an FSH cycle that makes 6follicles? Probably not, providing the clomid has not thinned out the lining of the uterus.

Sperm Topics:

Sperm quality 15 years after a vasectomy? Can really vary. In most cases the sperm is fine. Now if the sperm will be extracted via a needle, even if we consider the sperm quality excellent, we can only extract enough for IVF. But in some cases the sperm quality is lower than expected, but it’s rare that you can’t get a good IVF cycle out of what you find. If there are any changes for the worse, they may be unrelated to the vasectomy.

Can a CT Scan effect sperm? There is more and more discussion about CT radiation exposure every day. However, at this point, there is no evidence that a CT scan effects sperm counts, motility, or functionality in any way.

Should you have icsi with a sperm count of 12 million with 40% motility? This depends on how many sperm are recovered from the sample after rinsing and spinning (I know, sounds like there is a washing machine joke in here somewhere). Sometimes you can recover more than 5 million motile, sometimes only 2 million. Every lab has it’s threshold and will make a decision based on the number of motile sperm recovered. In our lab, 12 million and 40% motility usually means no icsi, but I would need to reserve judgment until we process the sample.

Is frozen sperm for iui less active than fresh? It depends on 2 things. One is the numbers and motility pre thaw. The more you have to start with the more you will have in the end. The second thing is how the sperm survives the freezing. Some really good samples just can’t handle the freezing and thawing. We do not know why this is; there are just differences between men that lead to different freezability. So the talk about frozen sperm is not as good for iui as fresh would only be accurate if post thaw counts or motility are low. Donor sperm has been put to the test. Anytime we freeze sperm we do a post thaw of a very small amount. If the post thaw is bad; bad donor. A good thawed sample is good; the good living sperm have not been weakened. Maybe some dies off, but the survivors are usually good survivors.

Most fertility doctors do not believe in the sperm penetration tests, especially when doing icsi anyway.

Miscarriage

What if you have had miscarriages, then surgery for a septum, and now can’t get pregnant? Start with repeating the HSG and getting a semen analysis. You never know, the septum may still be there, or maybe you developed blocked tubes or even a male factor. Also get the day 3 bloods.

Repeat biochemical pregnancies (yes I still hate that term) require the same workup as for miscarriages.

Frozen Embryos

Re-freezing embryos. There are a few papers showing that embryos can survive being frozen, thawed and then frozen again. Logic dictates that this should not be a first option, but there are cases where it seems like the right thing to do. If you thaw more embryos than you want to transfer, which is commonly done to select the best embryos, and surprisingly all the embryos look great, then refreezing the extras may be a good option.

What if you had a baby from a frozen cycle where 10 embryos were transferred, and you want to get pregnant again but only have 5 left? Even with your 1/10 success rate, 5 is plenty. In fact 5 may be too many.

General Topics

Is an endometrium of 14-16 mm too thick? Providing there is no hidden fibroid, polyp or hyperplasia, that thickness is probably OK. And what about an estrogen level that may be too high? There has always been talk about a too high estrogen level and this goes back to studies in mice. However, I have not see women whose problems are that their estrogen levels are too high. Some women with thin linings are put on estrogen injections or vaginal pills, and it is not uncommon to see levels over 2,000 in a frozen or donor egg cycle. Some women undergoing IVF have estradiol levels 5-10,000 (not a good idea for other reasons), and they have no trouble implanting.

Do I endorse Egg Freezing? I don’t really endorse anything. I am a fan of educating to the best of my ability, and allowing my patients to make informed decisions. Egg freezing is very promising, and some early studies show that is more successful that we thought it would be. But, it is still relatively new and expensive.

Both husband and wife diagnosed with hypothyroidism. It’s possible, but get a second opinion just to be sure. Some doctors over diagnose thyroid problems in everyone.

What if you had some questions about your luteal phase, so you were placed on progesterone but are still not pregnant? Don’t wait long. Talk to your doctor about starting clomid because it too is a treatment for luteal phase defect, and it may up your odds of getting pregnant as well.

How long do you need to be on OCP’s prior to an IVF cycle? In reality, you don’t need to be on them at all. One exception is the OCP microdose (also called microflare) IVF protocol. Here the recipe calls for ocps. But for all others, ocps are not necessary. Many programs use them to time the cycle. This means the program wants you to start on a certain day to time the retrieval/transfer. Or they want you to start in a certain week because they may have lab personal coming from the outside for a specified number of days. If you are relatively young and a good responder, the length of time on the pill probably does not matter. However if you are a marginal or poor responder, pill use, especially prolonged, could lower your egg production further.

Thanks for reading and don’t forget the discalimer posted 5/17/06.

Dr. Licciardi

A Little More About Normal Ovulation

 

award winning fertility doctor new york city

 

Here is a question someone asked about the timing of hCG. It’s a good starting point for this blog.

“I am 40 and just had a failed first IVF cycle that resulted in all immature eggs (7 retrieved) after only 5 days of stims (follistim/menopur + ganirelix days 4 & 5) before the hCG shot.
The doctors were very surprised that by day 5 I had 7 follies 12 – 19 (more

I have never heard of anyone only stimming for 5 days. I am curious what your experience has been with people who are fast responders and what you recommend in terms of changing protocols? Do you believe that follicle size alone determines egg maturity or can a short follicular phase be a problem even with larger follicles?”
Figuring out the right time is not that difficult, but there are a few important factors that must be taken into consideration. We need to first start with a brief review of what happens in the natural menstrual cycle, then it will be easier to understand how the IVF cycle works. There are 3 important elements: the growing follicle’s schedule, estrogen levels, and the size of the follicle at ovulation.

Just a reminder: the follicle is the fluid-filled cyst that houses the egg. Each follicle has one egg. We can’t see the egg on ultrasound because it’s microscopic. But we can see the follicle.

The Growing Follicle’s Schedule: By the 2-3rd day of bleeding, the previous month’s follicle has disappeared and the new one, which has already been chosen, has not started to grow much. On ultrasound you may see it, but you may also see other small ones that look the same. It’s the FSH coming from the pituitary gland (the pituitary will be a blog to come) which causes the little follicle to start and continue to grow.

As the next week goes by, the chosen (or dominant) follicle gets bigger and bigger, until it ovulates somewhere usually between days 11 and 20, most often close to day 14. It’s pretty rare to ovulate before day 11, but not so rare to ovulate later. The day of ovulation is related when the follicle starts to grow, and the cycle length gives us a hint as to when this was. It takes about 2 weeks for the follicle to grow from tiny to big. That means for a 28 day cycle, the follicle grows till ovulation, usually day 14.

What if the cycles are, say, 35 days? Well it still takes the 2 weeks to grow, it just starts later. So for a 35 day cycle the early follicle sleeps for about a week, then wakes up and starts growing day 7 and ovulates day 21. We don’t know what causes these differences.

What if the cycle is 24 days? In this case the follicle probably takes less than 2 weeks to grow, so 2 weeks is not mandatory. Again, the reason for these differences are unknown.

Estrogen Levels: As the follicle grows, it makes more and more estrogen, so the blood levels of estrogen rise each day. The estrogen is not coming from the egg, it comes from the tons of little ovarian cells (the granulosa cells) that surround the egg. The estrogen is probably not important for the egg, but one of estrogen’s very important jobs is to thicken up the lining of the uterus.

Estrogen’s second job is to cause the ovulation. The pituitary gland is constantly monitoring the estrogen levels, and when they get high enough, the pituitary dumps out LH (this is what your home ovulation kit reads) and this is what causes the egg to pop out.

There is not an exact estrogen level that causes the ovulation. Most of the time it’s anywhere from 150 to 350. Why there is a difference we do not know, it may be that there are other unknown hormones that work with the estrogen to get the job done.

Follicle Size: The size of the follicle is important too. Most ovulations occur with a follicle that is 20-25 mm(about one inch), but 16 mm is close to the bare minimum and 30 mm is close to the top size.

Next time we will talk about the timing of ovulation in an IVF cycle.

Thanks for reading,

Dr. Licciardi

References:

  • Miller PB, Soules MR. The usefulness of a urinary LH kit for ovulation prediction during menstrual cycles of normal women. Obstet Gynecol. 1996; 87(1):13.
  • Berga S, Naftolin F. Neuroendocrine control of ovulation. Gynecol Endocrinol. 2012 Mar; 28 Suppl 1:9-13.
  • Fritz MA, Speroff L. The endocrinology of the menstrual cycle: the interaction of folliculogenesis and neuroendocrine mechanisms. Fertil Steril. 1982 Nov; 38(5):509-29.

Just Before Blastocyst: The Morlula

 

 

award winning fertility doctor new york city

 

So what happens after day 3? Two days later we would like it to be a blastocyst. The day before it becomes a blastocyst, it should be a morula. A morula forms when the 8 cell embryo divides further, and at the same time the cells become very close to each other. Here it’s difficult to see the borders of the cells, so the morula looks like one big blob. It ‘s solid in the middle. It’s still inside the shell. There are about 12-30 cells in a morula.
Here are some pictures:

Here is a nice looking morula.

 

Here are a few others . The top right looks nice, the others look OK, the bottom right looks the worst.

 
 
 

 
 
 
Most morulas (some write the pleural morulae, but most write it morulas) look about the same, so we don’t give them a number or a grade. We may say “nice” for a good one, but that’s about it.
Is it ok to transfer a morula? If your doctor wants to transfer your embryos on day 4, you will probably have morulas, but it will be hard for you to get a handle on quality. Most programs transfer day 3 or day 5. Day 4 transfer is ok, but most of us would say if you are waiting till day 4, just wait till day 5 so that the embryos have more time to grow, and quality can be better assessed.
 
What if on day 5 you are told the best embryos are morulas, not blastocysts? Not so good. I have had patients get back 2 morulas and become pregnant with twins. However the chances of pregnancy are much higher if you have blastocysts.
 
 
If there are morulas on day 5, isn’t it better to wait another day until they are blastocysts? No, because even if they become blasts on day 6 they are still a day behind. Rarely, we transfer on day 6. This may happen if , for example, there are 4 morulas and we want to give them, one more day to see which ones, if any, develop a little more.
 
Can we do anything to make the embryos grow faster? The same answer as last time. We try to change things up a bit next cycle, but there is no special drug protocol for slow embryos. Its just a matter of trying again and hoping for a better outcome.
 
Thanks again,
 
Dr. Licciardi
 
References:
  • Prados F, Debrock S, Lemmen J, Agerholm I. The cleavage stage embryo. Human Reproduction, Vol.27, No.S1 pp. i50–i71, 2012.
  • Blake DA, Farquhar CM, Johnson N, Proctor M. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst Rev. 2007 Oct 17 ;(4):CD002118.
  • Puissant F, Van Rysselberge M, Barlow P, Deweze J, Leroy F. Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod 1987; 2(8):705-8.
  • Racowsky C. Combelles CM. Nureddin A. Pan Y. Finn A. Miles L. Gale S. O’Leary T. Jackson KV. Day 3 and day 5 morphological predictors of embryo viability. Reprod Biomed Online 2003; 6(3):323-31.

Even More about Polycystic Ovaries

Should every PCO patient be on a drug like Metformin? This is up to you and your doctor. If you are diabetic or borderline diabetic, Metformin may be just what you need. What if you are a little overweight and have high cholesterol? This is more debatable.
What if you are trying to get pregnant? Say you are normal weight or above weight, no diabetes, don’t ovulate and were told you have PCO. Here, the early studies said yes; as very high rates of ovulation and pregnancy were reported. In fact, some studies showed pregnancy rates from Metformin were higher than Clomid. Many doctors went with this information and gave their patients Metformin rather than Clomid feeling that lowering the insulin levels was the key to natural ovulation.
And then as more studies were published, the results looked less favorable. Metformin did not allow for normal ovulation as often as advertised. I realize there are some of you who took Metformin, ovulated, got pregnant and swear by that system. I am very happy for you, but most people did not have your experience. Most ovulated rarely or never. I noticed this in my practice and found I was just extending the infertile time for my patients.
The New England Journal of Medicine recently published an excellent paper on PCO, written by members of the Cooperative Multicenter Reproductive Medicine Network. The title is “Clomiphine, Metformin or Both for Infertility in the Polycystic Ovary Syndrome”, published February 8, 2007. I hate to get too scientific, but I want to say a few words about this because the findings surprised even some of the authors. Most studies that are published are not of high enough quality to make doctors change they way they practice medicine. There are many reasons for the low quality including a low number patients studied, non-randomization, flaws in the statistics, and the list goes on and on. This paper is of very high quality. In summary, while 24.9% of the patients taking Clomid never ovulated; the rate was 44.7% in women taking Metformin. There was a 22.5% live birth rate in women taking Clomid, a 7.2% live birth rate in the Metformin group. Rates with Clomid were not increased by adding Metformin. So Clomid was clearly better for becoming pregnant than Meformin.
Now this is just one study and treatment needs to be individualized. I just wanted to present the case that as of 2/08/07, Metformin is being questioned as a reliable primary method of conceiving. I’ll finish up with PCO next time, and remember speak to your doctor and read the disclaimer 5/17/06.

References:

  • Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-7 (also Fertil Steril 2004;81:19-25)
  • Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356(6):551-66.
  • Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008;23:462-77 (also in Fertil Steril 2008;89:505-22.)
  • Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91:456-88.
  • Goldzieher JW, Axelrod LR. Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963; 14:631-53.

Polycystic Ovaries and Insulin Resistance

Thanks for all the comments. I would like to address the very important comment about insulin resistance and PCO. I need to start by saying that, as with many things in medicine, we though we had this figured out but in the end, we may be a little off the mark.
What is the definition of PCO? 2/3 of the following:
1) no or infrequent ovulation
2) physical signs of excess androgens, or high levels of androgens in the blood.
3) polycystic ovaries on ultrasound (12 or more little follicles on each ovary)

The physical signs of PCO vary considerably. Some women are thin and just don’t ovulate, and have polycystic ovaries on ultrasound. The opposite is women who are heavy, abnormally hairy, have high levels of androgens; testosterone and the other male hormones. Even normal women have these hormones, but not in excess.
So your PCO may be completely different that your friend’s PCO. And the treatment of your PCO may also be different.
Now let’s get to PCO and insulin resistance.
Insulin is the hormone made by the pancreas that allows us to use sugar. Sugar (glucose) needs to get from our food, into the circulation and then into our cells. Cells can not function without glucose. It’s the insulin that allows us to properly use the glucose. No insulin, no proper glucose utilization, no life.
Diabetes is a condition where there is a problem with insulin. Without insulin, blood levels of glucose rise to dangerous levels. Type 1 diabetics don’t have insulin, and need to take insulin by injection.
Type II diabetics make some insulin. Some Type II diabetics make a small amount and need a little help with medications to improve the action of insulin. However, most Type II diabetics make more that enough insulin, but for some reason the insulin doesn’t work well and glucose levels rise. So they have high levels of insulin and glucose. These patients are “insulin resistant”. They also take medications to improve the actions of insulin.
Some women with Type II diabetes have PCO, some women with PCO have Type II diabetes. A number of decades ago, researchers noticed this relationship and started asking if PCO was related to diabetes and some progress was made in the area of insulin resistance. That is to say, it was determined that some women with PCO also have insulin resistance.
When all this came about, researchers were quick to say that all women with PCO have some degree of insulin resistance. They may not be diabetic, but their insulin levels are high. By the way, insulin resistance is not in the definition of PCO.
Here comes the most important point of this blog. Because insulin also acts a growth hormone, it can make people bigger and fatter. People who are insulin resistant, have higher levels of insulin and may be bigger. (Now I know that some of you are type II diabetics and have normal weight, but most type IIs are at least a bit overweight.) The idea was if we lower the insulin (with medications that help insulin work more efficiently) patients will lose weight, and ovulation will occur normally. And it’s not just about the weight, there may be other benefits of lowering the insulin levels that help women with PCO. Lowering insulin levels also may lower the androgen levels. Metformin, aka Glucophage, is the most commonly used drug for this purpose. We will get into this next time.

References:

  • Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-7 (also Fertil Steril 2004;81:19-25)
  • Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356(6):551-66.
  • Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008;23:462-77 (also in Fertil Steril 2008;89:505-22.)
  • Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91:456-88.
  • Goldzieher JW, Axelrod LR. Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963; 14:631-53.

More on Polycystic Ovaries

Please start off by going back to the archived blogs from 7/06/06 and 7/22/06. These will update you with the basics of cysts and polycystic ovaries.
So let’s say you were told you have PCO, or Polycystic Ovaries, and you want to get pregnant. What are your next steps?
The first steps have to do with further diagnostics. You don’t ovulate and getting you to ovulate is probably all you need to get pregnant. Clomid may be all you need. Do you need to do any other tests before you start the Clomid? Probably not but you may. It is common for women to have more than one fertility problem. Some women with PCO also have blocked tubes (totally unrelated to having PCO) or a low sperm count. And some have other hormonal issues.
The basic things to check are your prolactin, thyroid and 17 hydroxyprogesterone. The last is a test for congenital adrenal hyperplasia, a rare disorder that can create a picture like PCO. If the blood tests are all ok, then you can consider the hysterogram and semen analysis. It is OK to start Clomid without these 2 tests, may patients do. Just understand that these tests need to be performed eventually. It’s really bad if you get a Clomid prescription for 6-12 months. A few months are fine and if you’re not pregnant, then check the tubes and sperm.
How do you know if the Clomid is working? If the time in between cycle is greater than 35 days and Clomid gives you cycle that are around 28 days, it’s working. If you still rarely get a period, it is not working. There are more accurate ways to check. If you take your temperature (temperature charting is too much work, but I know some of you are regular temperature takers) there is usually no clear rise mid cycle, but there is when Clomid is working. Progesterone causes the rise and progesterone is only present after ovulation. No ovulation, no progesterone, no temperature rise. The ovulation predictor kits are another option. These are hard for women who get cycles far apart because it’s difficult to know when to start testing, and testing can go on for weeks if ovulation is not happening. But if you were getting 50 day cycles and now they are 29 days, you are ovulating. It becomes easier to use the kits and time intercourse if your cycles become more regular. The best way to prove that you have ovulated is a blood test for progesterone. The problem with this is people get hung up about the level. This is not important. If your level is 6, 9 or 21 it does not matter. Progesterone levels vary throughout the day anyway. As long as it is elevated above baseline (2-3 depending on the lab) you are OK. More next time and please read the disclaimer 5/17/96.
Dr. Licciardi

References:

  • Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356(6):551-66.
  • Misso ML, Costello MF, Garrubba M, Wong J, Hart R, Rombauts L, Melder AM, Norman RJ, Teede HJ. Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2012 Sep 6. [Epub ahead of print].
  • Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2009 Oct 7 ;(4):CD003053.

What About Tubes that are Blocked at the Other End, Near the Ovary?

This we call “distal occlusion” and it can take a few forms. The most obvious and severe is what’s called a hydrosaplinx (or hydro for short), or bilateral hydrosalpinges when both are affected. This type of tube is completely closed near the ovary (the distal end). Such a tube could be closed due to scar from a pelvic infection. The infection could be due to Chlamydia (most common), Gonorrhea or a post surgical infection. Sometimes scarring can occur after surgery without infection. Even when the surgery was on the uterus, myomectomy is a common culprit, the general healing of the pelvis could cause tubal scarring to occur. Occasionally these tubes are filled with fluid and are visible on ultrasound, but usually they are not. The diagnosis here is very straightforward. Either by HSG or at laparoscopy, the tubes are seen to be large, swollen and obvious. Hydros are quite a problem for patients because they can mean surgery, IVF or both. Surgery can work, but the odds of pregnancy after surgery have been reported to be about 20% lifetime (there are a few other studies with higher rates, but 20% seems to be the most commonly quoted number). The reason surgery does not succeed is that in many cases the scar tissue quickly returns and the tubes re-block. Even if the tubes remain open, the interior lining of the tubes, necessary to the transport of egg and sperm, has been permanently damaged.
IVF has a much higher pregnancy rate, so most patients head that way. There are some studies showing a hydro will lower the IVF rate by about 1/3, the predominant theory being fluid inside the tube backs up into the uterus and interferes with implantation, either by flooding the embryo away or poisoning the embryo with toxic substances. Therefore some patients elect to have their hyro tubes removed before IVF to maximize their odds. No one should be forced to have their tubes removed. The pregnancy rate may be lower, but there are tons of pregnancies in women who kept their tubes.
Distal blockage can be not as severe. In these cases there may be tubal enlargement, but they are open on HSG. There can be minor scar tissue around the ends of the tubes that is very treatable. Just cutting away the scar tissue can render the tubes open and very functional.

References:

  • Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev 2004.
  • Kodaman PH, Arici A, Seli E. Evidenced-based diagnosis and management of tubal factor infertility. Curr Opin Obstet Gynecol 2004; 16(3):221-9.
  • ASRM Practice Committee. The role of tubal reconstructive surgery in the era of assisted reproductive technologies. Fertil Steril 2008; 90(5 Suppl):S250-3.
  • Johnson NP, Mak W, Sowter MC. Laparoscopic salpingectomy for women with hydrosalpinges enhances the success of IVF: a Cochrane review. Hum Reprod 2002; 17(3):543-7.
  • Kontoravdis A, Makrakis E, Pantos K, Botsis D, Deligeoroglou E, Creatsas G. Proximal tubal occlusion versus salpingectomy result in similar improvement in in-vitro fertilization outcome in patients with hydrosalpinx. Fertil Steril 2006; 86(6):1642-9.