The importance of FSH and LH in IVF

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Hugo Verhoeven, MD: “My name is Hugo Verhoeven from the Centre for Reproductive Medicine in Düsseldorf in Germany. I am on the Editorial Board of OBGYN.net and I’m reporting from the fourth COGI meeting, Controversies in Obstetrics and Gynaecology, here in Berlin, Germany.

It’s an exceptional honour for me having the chance to speak with Dr Westergaard from Copenhagen. He is the medical director of the Fertility Clinic, Trianglen, in Copenhagen. We have known each other for quite a long time, and the topic of our interview today will be the role of FSH and LH in ovulation induction, of course, in IVF. So for our listeners: what is the role of FSH and LH in the regulation of ovulation? Could you give a brief overview of that?”

Lars Westergaard, MD: “FSH is, as its name indicates, follicular stimulating hormone, and FSH is a gonadotrophin which stimulates the growth of small follicles. LH stands for luteinizing hormone which matures the eggs in the end, but also has a role in the early steps of follicle growth.”

Hugo Verhoeven, MD: “In the early days of ovulation induction, I think it was Bruno Lunenfeld, who started working with extract of the pituitary gland, they were giving the patient what I think was a combination of FSH and LH?”

Lars Westergaard, MD: “It was not the pituitary gland, that was Gemzel in Sweden. It was urine-derived, from menopausal urine, and that’s why that preparation was called Human Menopausal Gonadotrophins [hMGs] and these were used for the next 40 years with great success. The characteristic of that preparation is that it contains FSH as well as LH in equal amounts.”

Hugo Verhoeven, MD: “And it is derived from the urine of menopausal women?.”

Lars Westergaard, MD: “Yes, because when you enter the menopause, there will be a huge increase in the secretion of gonadotrophins from these women, which is not there in younger ages.”

Hugo Verhoeven, MD: “So those products are just concentrations of urine so there must be a big variability in the dosage of the different hormones in the different batches of hMG, is that correct?”

Lars Westergaard, MD: “Well, of course in the production process they are standardised, so according to WHO standards, one ampoule should contain 75 units of FSH and 75 units of LH.”

Hugo Verhoeven, MD: “So that hMG was used for many, many years. Thousands of babies have been born after hMG stimulation. Why was there then a tendency to go to gene technological medication? What could be the reason for that?”

Lars Westergaard, MD: “The reason was that there was, as you just mentioned, some batch-to-batch variation between these so for one thing, there was an urge to separate the two gonadotropins so that you could treat with one at a time, either FSH or LH, and using hMG you were forced to use the same ratio between FSH and LH. That might have some importance because in the normal cycle, at the start of the cycle, FSH is twice as high as LH and then at protein ovulation, this ratio reverses, so FSH is lower than LH just before ovulation. It was conceived that that might have some importance for the maturation of the eggs.

Then another argument for switching to recombinant products was that there was at some time a shortage of urine in the world; it’s difficult to collect and also to check the production process, and when you produce recombinant products, you use cell lines, which are injected with the genes for human FSH, and you can produce it eternally in how many amounts you want to, so you can be free of being dependent on the urine products. That was the main drive, I think. Then it was also thought that in the usual advanced stimulation for IVF, there was no need for LH and, indeed, some people thought that LH was harmful for the cells and there was another push towards using pure FSH products.”

Hugo Verhoeven, MD: “Why could LH be harmful?”

Lars Westergaard, MD: “The arguments were that women with polycystic ovarian syndrome have an increase LH level and they are difficult to stimulate and they have an increased risk of early pregnancy loss, spontaneous abortions, and that was the thinking behind the harmfulness of LH.”

Hugo Verhoeven, MD: “Okay. We have now on the market hMG, we have highly purified hMG.”

Lars Westergaard, MD: “Urine.”

Hugo Verhoeven, MD: “Yes. We have recombinant FSH, we have recombinant LH.”

Lars Westergaard, MD: “That’s right.”

Hugo Verhoeven, MD: “In your opinion, what is the indication for each of those medical products?”

Lars Westergaard, MD: “Oh, that’s a bit difficult because nearly all IVF cycles or the vast majority of them, are treated with a so-called long protocol in which you use GnRH, gonadotrophin releasing hormone agonist, which is started one week before expected menstruation and then for 14 days. The pituitary secretion of FSH and LH would decrease.

Then you start stimulation, and then you can start with recombinant FSH and it was shown, when you use the long down regulation protocol, that you have much improved results by the IVF, more eggs, more fertilized eggs, more babies. That is well documented.

But then, at the same time recombinant FSH came in to the market and then it was combined and we, in Odense [Denmark], found out in the mid-90s that there was a sub-group of women who were too heavily down-regulated who required more than FSH, who required some additional LH in order to improve the outcome, and we demonstrated that women who were treated with gonadotrophin releasing hormone, down regulation combined with recombinant FSH, a sub-group of these, about one-third of them, acquired such low LH levels during stimulation that the production of oestrogen from the ovaries decreased and that had an impact on the reproductive outcome.

They had a five to eight times increased risk of spontaneous abortion when they became pregnant. That was the first sign that there were some women, who needed additional LH support during ovarian stimulation.”

Hugo Verhoeven, MD: “So you have a huge amount of patients coming to see you. How do you decide whether you are going to use the long protocol, a short protocol, whether you are going to use FSH alone, or a combination of FSH and LH? When are you starting the LH? A lot of questions at once.”

Lars Westergaard, MD: “The long protocol, as I mentioned, has shown itself to be very efficient. It’s clearly more efficient in the IVF clinics, so it’s very hard for us to leave that. But when you then use the long protocol, you have to take care of the levels of LH during advanced stimulation and that has been very difficult to sort out; what is the lower threshold of LH, which requires some LH addition? Our studies have shown that if you are below in the mid-follicular phase, which is after seven days of FSH stimulation, if LH is below .5 units per litre you must have some LH. Then you could argue why measure LH? You could just give them all hMG.

But there are some new very recent studies showing that you can over-do LH. If LH will be too high, then it can have a reverse effect on reproductive outcome. So, as of today, our opinion is that there is a band of LH levels, which is optimal for the ovarian stimulation and for oocyte fertilization, embryo development, and pregnancy chance. The challenge is to clearly define that band and what we have done recently is that we have resolved if, after a long down regulation at the start of stimulation, LH levels are below 1.2 units per litre, which is similar to those found in women with severe hypergonadatrophic hypergonadism, they need some LH stimulation and that can be with hMG or it could be with recombinant LH.”

Hugo Verhoeven, MD: “Recombinant LH. Okay, that means that pure FSH will normally do its job and it’s only a small amount of patients where we need an addition of LH?”

Lars Westergaard, MD: “The proportion of patients, that’s really controversial and that’s what we are finding out about here. Some are of the opinion that it’s very low, below 5% of normal women, but in my view, it’s much more, up to 30% to 35%.”

Hugo Verhoeven, MD: “So we have now on the market not only the GnRH analogues, the agonists, but we have also the antagonists, so if we are using antagonists for the prevention of premature ovulation, wouldn’t that be another and easier possibility to avoid that down regulation of LH at the much too lower level?”

Lars Westergaard, MD: “That’s fine at the start of the cycle, but in the antagonist protocols, you usually administer the antagonist after five or six days of stimulation, but when you administer the antagonist, there will be a very steep decline of LH. It will be very low after that and, as of now, nobody really knows if these women at that point must have some LH support.”

Hugo Verhoeven, MD: “Are you doing it?”

Lars Westergaard, MD: “Yes, I am doing it, but as of now, no scientific data supports that it is right to do it. We are looking at it.”

Hugo Verhoeven, MD: “Well, I think we got a lot of quite interesting information. Thank you very much for the interview and all the best.”

Lars Westergaard, MD: “Thank you very much.”