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Dr. Licciardi on TV

I was invited to the MSNBC show “Dr. Nancy”. Here’s what I had to say.

http://www.msnbc.msn.com/id/31388323/#33006217

When is the Right Time for hCG?

The time between the hCG and retrieval
For an FSH injection cycle leading to insemination, it’s ok if the ovulation naturally occurs a little early (via a premature LH surge) because we can just do the insemination early. Rarely it’s too early, before the follicle is big enough, and we cancel the cycle. However, for an IVF cycle we have to cancel the cycle if there is an early natural LH surge, even if it’s only a little early, because the timing of the retrieval is very dependent on when the surge starts. The retrieval needs to be about 34-36 hours past the start of the surge (which would also be the time if the hCG shot).

Because we are not taking blood every hour, if the blood test shows a rise in the LH level, we don’t really know when the rise started so we don’t know the right time for retrieval. Lupron, Antagon and Cetrotide prevent the natural rise of the LH, so the premature surge usually cannot occur. However, these drugs do not interfere with the effects of an hCG injection. So there is no natural surge, but there is an artificial surge which starts the moment the hCG goes in.

Final Maturation
There is a second very important job of the LH Surge/hCG injection:
it causes the egg to mature. As the days of stimulation progress the eggs are slowly maturing, but more is needed for the final maturation. Necessary last minute changes occur inside the egg from the LH/ hCG.

Why is this important? An immature egg will not fertilize. If the retrieval is before about 33 hours after the hCG, the result will be immature eggs. Sometimes they are all immature, or just some.

If the retrieval is 38-39 hours after the hCG, the eggs will be mature but they will already have ovulated. We would retrieve none; they would be floating in the pelvis around the ovaries waiting to get picked up by the tubes. So we need to grab the eggs just after they mature but just before they ovulate, which is at about 34-37 hours after the hCG injection.

What day should you get your hCG?
hCG can only mature eggs that have been growing for enough time for the follicle to become large. The sizes of all of the follicles need to be taken into consideration before giving hCG in IVF cycle.

Not all of the follicles grow at the same rate. For example, if there are 10 follicles, and the biggest is 18mm, they will not all be 18 mm. Some will be mid-sized and some will be much smaller. Each follicle does not need to be 18 mm to produce an egg that is mature. As long as the biggest (the lead follicle) is 17-18mm, the mid-sized (13-16) should also have mature eggs. The small follicles (10-12) may or not be mature. But if the lead follicle is 14 mm, none of the eggs have yet reached maturity. Giving hCG would not be enough to achieve maturity.

How Important are Estrogen Levels?
Not very. When you are monitored for your IVF cycle, the follicle size is much more important that the estrogen (estradiol) levels. We need the estrogen to rise, but if midway through your cycle we see 10 follicles, with the biggest being 13 mm, we don’t really care if the estrogen level is 500 or 900. Estrogen is more important when we are monitoring someone who may be on track for hyperstimulation.

Therefore, we use mostly the size of the follicles, with not much emphasis on the estradiol levels, to determine when to give the hCG. At NYU we feel the best time to get the hCG is when the lead follicle reaches 18 mm. Now because there are many variations from cycle to cycle and from patient to patient, it’s not easy to say that 18 mm is the rule.

For example, let’s say there is one follicle 18 mm, three that are 15 mm and others that are smaller. Here we may worry that some of the small ones may be too immature, so we may wait another day before giving the hCG. Let’s say there are 20 follicles, with the biggest 17mm and an estrogen level of 2900. Here we are aware that the smaller follicles may be immature, but we also are concerned about the estradiol getting much higher because the woman would be increasing her risk of hyperstimulation. So we give the hCG at 17 mm, which may yield some immature eggs, but should give us enough mature eggs to work with.

And there are many more variations. Some women have gotten their hCG a little on the early side and have all mature eggs. Some women in their first cycle get the hCG at 18 mm with lots of good size follicles, and have ½ their eggs be immature. So next cycle we wait till the follicles are 20-22 mm before giving hCG. This sometimes gets more mature eggs but sometimes no matter what we do, that woman’s ovaries make more immature eggs than expected.

So why not wait and give hCG later? Because eggs can get over-mature. This over-maturity can lead to lower embryo quality and lower pregnancy rates.

When we see the records of women who have failed IVF elsewhere, many times we see that he hCG was given with large sized follicles. The first and easiest “fix” we can do is to give the hCG earlier in her next cycle, more inline with our standard procedures.

Why do some doctors wait longer to give the hCG?
Some may feel that the higher the estradiol level the better, so by waiting estrogen levels will go up. This is probably not important. Others may feel that it is necessary to wait so there will be no immature eggs. Well this sounds good, but it may not be worth sacrificing the quality of the eggs form larger follicles, which are probably the best eggs anyway.

And back to the original question.
What if instead of the average 11-12 days it takes to grow the follicles, they are of the right size after only 6 days or 8 days?
If the size is good, but it seems early, we usually go at least one more day that we normally would, maybe 2. If it’s day 9 and the follicles are 19-20 mm, it really sounds ok to give hCG. If it’s day 7 (so 5-6 days of FSH injections), and the follicles are 17-18 mm, more time would probably be a good idea.

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

Dr. Licciardi

References:

  • Silverberg KM, Olive DL, Burns WN, Johnson JV, Groff TR, Schenken RS. Follicular size at the time of human chorionic gonadotropin administration predicts ovulation outcome in human menopausal gonadotropin-stimulated cycles. Fertil Steril. 1991 Aug;56(2):296-300.
  • Kyrou D, Kolibianakis EM, Fatemi HM, Tarlatzis BC, Tournaye H, Devroey P. Is earlier administration of human chorionic gonadotropin (hCG) associated with the probability of pregnancy in cycles stimulated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone (GnRH) antagonists? A prospective randomized trial. Fertil Steril. 2011 Nov;96(5):1112-5.
  • Palatnik A, Strawn E, Szabo A, Robb P. What is the optimal follicular size before triggering ovulation in intrauterine insemination cycles with clomiphene citrate or letrozole? An analysis of 988 cycles. Fertil Steril. 2012;97(5):1089.
  • O’Herlihy C, Pepperell RJ, Robinson HP. Ultrasound timing of human chorionic gonadotropin administration in clomiphene-stimulated cycle. Obstet Gynecol 1982; 59:40.
  • Rahman SM, Karmakar D, Malhotra N, Kumar S. Timing of intrauterine insemination: an attempt to unravel the enigma. Arch Gynecol Obstet. 2011 Oct;284(4):1023-7.

The Natural LH Surge vs. the HCG Injection

We are still working towards the timing of the hCG shot, but we first need a little more background. We need to go over difference between the natural LH surge and the hCG injection.

After LH leaves the pituitary during the surge, it causes the ovulation by landing on specialized spots on the ovarian cells, the LH receptors. All hormones act by landing on (binding to) their specific receptor, and usually one hormone does nothing if it lands on the receptor of a different hormone. There has to be a match.

This is usually dictated by shape. It’s like a lock that recognizes the shape of the key. FSH and LH are similar hormones, but their shapes are a little different. So if LH comes across a FSH receptor, it would not bind.

There is a notable exception. Because hCG and LH are chemically very similar, with very similar shapes, hCG can bind to the LH receptor, and can do it well. Since hCG can land on the LH receptor, hCG can do the same job as LH.

This is actually very important to pregnancy. Pregnancy needs progesterone, which comes from ovarian cells with LH receptors. So LH causes the ovary to make progesterone after ovulation. Good: the progesterone allows the embryo to implant. Then the embryo makes hCG. Better: this causes the ovary to make even more and more progesterone which keeps the implantation going strong. Both occur via the LH receptor.

That hCG can behave like LH is good for treating fertility patients because we can cause ovulation with an injection of hCG instead of an injection of LH. This is good because hCG is easier to get than LH.

So why not just give LH? Up until very recently, LH was not available. Years ago the only way to get FSH for our fertility drugs was to extract it from the urine of menopausal women.

(This is a whole story by itself. Initially, starting in the 1970’s, the urine was obtained from menopausal Italian nuns who would leave jugs of pee for the drug company Serono to pick up in the mornings. Menopausal women have really high amounts of FSH in their blood, and most of it comes out in the urine. The pee would be taken to a factory with a swimming pool-sized pee vat, and they would somehow get the FSH from the pee. Serono went on to be the most profitable company in the world. The Catholic Church was rewarded for its cooperation. Even today, pee swimming pools exist for companies who make fertility drugs from urine.)

Because FSH and LH are similar molecules, the methods used to pull out the FSH grabbed LH too. Once we got the FSH/LH mix, we didn’t have the science to separate the two. So we could not get enough pure LH to cause ovulation. Today we can get pure LH made in a lab, but still in small amounts, not enough to get a good ovulation going.

How do we get the hCG? That is piece of cake, we get it from placentas. There are tons hCG in placentas and it’s easy to extract. Today hCG is also made in a lab, that’s the Ovidrel. It’s pure stuff, and that’s why it can be given in the skin. The placental hCG is given IM because it’s contaminated. hCG is also a protein, and the system for extracting the hCG protein from placentas is pretty crude, so tons of other placental proteins get caught in the net too. These extra proteins can cause a local allergic reaction when given in the skin, but not when given in the muscle.

When we used to get fertility drugs from urine, same thing, they had protein contaminants and needed to be given into the muscle. Recent exceptions are Menopur and Bravelle. These are from urine but using new systems that are better at cleaning out most of the unwanted contaminating proteins. Gonal-F and Follistim are both made in the lab and do not have the contaminants. They are given into the skin.

Today there are 2 products, placental hCG given in the muscle, and the lab-made hCG given in the skin. The placental is still cheaper and words great.

In a cycle stimulated with injected FSH (for IUI or IVF), most of the time the natural LH surge does not occur at all, so we need to give the hCG. In some cases the LH surge does occur, but it happens too soon, before the eggs are mature. This is probably due to the fact that estrogen levels are higher earlier in a medicated cycle, so the LH rises earlier. We don’t know why a premature LH surge only happens in about 20% of cases.

The bottom line is that we cannot count on the natural surge to occur at all, or at the right time, when we are using FSH injections. We need to use the hCG injection for proper timing of ovulation and proper timing of the egg retrieval.

That’s it for now. Next time we finish up by talking about the right time to give the hCG shot.

Thanks for reading,

Dr. Licciardi

References:

  • Cantineau AE, Janssen MJ, Cohlen BJ. Synchronised approach for intrauterine insemination in subfertile couples. Cochrane Database Syst Rev. 2010.
  • Deaton JL, Clark RR, Pittaway DE, Herbst P, Bauguess P. Clomiphene citrate ovulation induction in combination with a timed intrauterine insemination: the value of urinary luteinizing hormone versus human chorionic gonadotropin timing. Fertil Steril. 1997; 68(1):43.
  • Zreik TG, García-Velasco JA, Habboosh MS, Olive DL, Arici A. Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin-timed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles. Fertil Steril. 1999; 71(6):1070.
  • Kosmas IP, Tatsioni A, Fatemi HM, Kolibianakis EM, Tournaye H, Devroey P. Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis. Fertil Steril. 2007; 87(3):607.

A Little More About Normal Ovulation

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.