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New Fertility Treatments, Induction and Ovulation

Forty percent of infertile women suffer from ovulatory dysfunction or ovulatory failure. When you consider the etiology of anovulation, it is good to be systematic and ask where the problem lies - in the hypothalamus, in the pituitary, or in the ovaries. The more symptomatic you are in your assessment, the better chance you have of reaching the correct diagnosis. Treatment options for patients who suffer from anovulation, based on induction of ovulation.

How does clomiphene citrate work? Clomiphene citrate binds to estrogen receptors in the hypothalamus. The perception is that if there is not enough estrogen in the periphery, and if you think there is not enough estrogen in the periphery, they are going to respond by increasing GnRH, obviously in a pulsatile fashion, which will cause increments of pituitary secretion.

How to monitor your patient on clomiphene citrate. We have the low-tech monitoring for people who don't have $15,000 per cycle. This is with the use of a body temperature chart. If you want to be more high-tech, in addition to measuring basal body temperature, you can do multiple vaginal ultrasounds.

What if you don't want to use laparoscopic induction of ovulation? You can go to something more potent, such as gonadotropins. There are various gonadotropins now available. You need to recall that when you treat patients with gonadotropins, FSH is not enough. You need FSH and LH. FSH is needed for recruitment and selection and LH is needed for stimulation of the theca cells so they will produce androgens and then the androgens will be moved to the granulosa cells to produce estrogens.

What about monitoring of patients on gonadotropins? What you need to do is to decide what is the dose that will be effective in evoking an ovarian response. Some patients with need one of Pergonal, some will need two, so you need to find out what the effective dose is going to be. Secondly, you need to decide on a length of time that will be required for follicular maturation. Finally, you need to decide when to give the HCG injection. We did a study with Pergonal with individually adjusted dosages, starting with two amps per day. The estrogen level did not respond. We increased the dose to three amps and again, nothing happened. So the effective dose had not been attained yet. We increased it to four amps and then began to see nice increments of estrogen with the ovaries responding and several days later, estrogen levels were significant and ultrasound demonstrated three nice follicles. We gave HCG and the patient ovulated. The patient conceived in this treatment.

This is the summary in the literature about the result of treatment with human menopausal gonadotropin with Pergonal. If you are dealing with patients who are lacking in endogenous gonadotropins - those people coming to you with amenorrhea.

LH and FSH to be very low - if you give them gonadotropins, it is amazing to see what a great response you will have and the cumulative pregnancy rate will not be too far from the normal population. You will have an almost eighty percent cumulative pregnancy rate for patients who are lacking in endogenous gonadotropins. If on the other hand you are treating patients who did not respond to clomiphene citrate or any other indications, the success rate is not as significant - a success rate of cumulative pregnancy of about twenty to thirty percent.

Complications of gonadotropin therapy include ovarian hyperstimulation and multiple pregnancies. The etiology of ovarian hyperstimulation is unknown, but we know there to be some association with estradiol levels. If you have high estradiol levels around the assumed time of ovulation, you increase the chance that your patient will develop hyperstimulation. Many people feel that if the levels are above 1500 picograms per milliliter, maybe you need to stop the cycle.

What do you see in hyperstimulation? Initially, normally seven to nine days after giving HCG, the patient can come to you with mild abdominal pain and if you examine her, you will see enlarged cystic ovaries. The ovaries will be slightly enlarged. Very quickly thereafter, you will see an increase in capillary permeability. What happens is that you lose a lot of fluids from the intravascular compartment into the third space, meaning that we are going to see ascites and hydrothorax. Obviously, those patients are hypovolemic and they may develop thromboembolic phenomenon. This complication is serious and you need to be aware of this possibility. Unfortunately, every year you hear about fatalities following ovarian hyperstimulation.

How can we prevent ovarian hyperstimulation? Firstly, you need to recognize the patient at risk. You need to do appropriate monitoring and think about alternatives.

Who are the patients at risk to develop hyperstimulation? The patient who gives you a history that previously they had hyperstimulation; these patients are very, very high risk. We have seen again and again that those who had hyperstimulation in the past have a greater chance at having it again. Patients with polycystic ovarian disease are also prone to develop hyperstimulation. Finally, the young patient and especially the lean young patient, is also at risk for developing hyperstimulation.

As we said, you need to monitor your patients. Remember that in the normal menstrual cycle, estrogens are going up and remember that the FSH is going down. Here, you need to be the feedback for this patient. If the ovaries are secreting tons of estrogen and you are not sensitive to this, if you continue giving FSH, don't be surprised if your patient gives birth to sextuplets due to significant hyperstimulation. You need to be the feedback. You need to look at a sharp increase in estrogen level or if you have very high levels around the assumed time of ovulation, those patients are more prone to develop hyperstimulation. Nowadays, we do ultrasound on most patients who get treatment with Pergonal and we are looking at the number of follicles around the assumed time of ovulation.

If you look at the literature in the last several years, some people felt we should not go above 800 picograms per milliliter; other people feel that you can go up to 2000 and some people who are more bold have no problems going up to 3000. Obviously, if you are going to be very strict, your pregnancy rate will be decreased and you need to tailor it individually. Just remember the association between high levels of estrogen and the occurrence of hyperstimulation.

Here is an ultrasound that was done before HCG. There are many follicles in the right ovary and the same in the left ovary. If you have many follicles, the majority of them are not too large, maybe 1 cm, and those patients are also prone to develop hyperstimulation. We know that there is a specific preovulatory follicular configuration which will characterize the patient who later on will develop hyperstimulation. Gonadotropins should be interrupted in the presence of multiple preovulatory follicles, especially if most of them are small and immature. If you have most of your follicles about 1 cm, the chance for conception is very remote and it would be a mistake, especially if you had too many, to go ahead and give HCG for the reason mentioned before.

What are the alternatives? You can try other medications before going to gonadotropins and you can exhaust treatment with Clomid, Clomid and HCG, low-dose FSH and you can also try to rescue cycles prone to hyperstimulation. If you see that your patient's levels of estrogens went up, you can definitely, during the treatment course, decrease the amount of gonadotropins and try to rescue those cycles. If you cannot rescue the cycle, it may be a good idea to abort the cycle. Another way, if you have the money, is to consider converting ovulatory induction cycles to IVF. You can convert it to an IVF cycle and then cycle all the follicles, all the granulosa cells, you will definitely reduce the chances for hyperstimulation and you can freeze embryos and use them later on. However, this is very costly and is an issue that needs to be discussed with each patient.

GnRH is another alternative. Remember that if you want to succeed in treating your patient with GnRH, you need to give GnRH in a pulsatile fashion every 90 minutes to pulse. If you think about the previous complications with GnRH, the multiple pregnancies occur not so often. Moreover, most of the multiple pregnancies will be twins and ovarian hyperstimulation is hardly ever seen with GnRH, so as you can see, there are some advantages to using GnRH. Remember also that with gonadotropins, optimal ovulation and pregnancy rate are achieved when pulsatile GnRH is administered to hypogonadotropic patients. If, on the other hand, you give it to patients like PCOD or patients with normal cycles, your chances for success are reduced significantly.

What about hyperprolactinemia? It is amazing to see that if you increase prolactin levels, you will initially see luteal phase defects, you continue to increase prolactin levels and you will see oligomenorrhea. Cycles will be more than 35 days - there will be 40 to 50 days between cycles. And if you continue to increase prolactin levels investigationally, you are going to get amenorrhea. You can check this; you can give metoclopramide. If you are going to follow patients who are receiving psychiatric medication, you will see that there is a nice correlation in the levels of prolactin on one hand and the clinical appearance. If you have a patient who does not have high levels of prolactin, it does not make sense that she will have amenorrhea.

It is easy to treat with bromocriptine. Remember that before starting this treatment, you need to arrive at the exact diagnosis. If you have a microadenoma as the cause for hyperprolactinemia, remember that you can go ahead and treat with bromocriptine. There is a low likelihood for growth of the prolactinoma. However, if you have a microadenoma, i.e., an adenoma that is

What about unexplained fertility? You will see many times in your clinic patients that will have regular ovulatory cycles, normal progesterone, you will not find any mechanical problems, they will have a normal hysterosalpingogram and a normal semen analysis. If you don't treat them, you will have a three to five percent chance of pregnancy per cycle. Compared to the normal

A study that was recently published in the Lancet looked at the pregnancy rate per cycle following treatment with IVF and intrauterine insemination (IUI). Treatment for unexplained infertility with IVF or IUI gives relatively good percentages; seventy to eighty percent for IVF and twelve or thirteen percent for IUI, which is a significant improvement from no treatment. Note what happens with time and age. At age 35, the numbers of successes decline significantly. We know that around the age of 35 to 40, you see an increase of FSH and a decrease in inhibin. You can already hear from your patient that they have a shortened follicular phase. We

A group of patients who were treated with clomiphene citrate for anovulation under 30 years of age, the clinical pregnancy rate was relatively good - nineteen percent per cycle; however, when they reached the age of 40 and above, the clinical pregnancy rate went to five percent per cycle. Before you go ahead and treat your patients, they need to be aware of their success rate and maybe some of them will decide that with this success rate, they may want to go for ovum

In normal physiology, when the follicle reaches maturity, it will secrete enough estrogens to bring about ovulation. Sometimes a situation occurs in which a follicle has not grown to maturity, but estrogen levels, which are not so high, will cause an early LH surge. If you have an early LH surge, normally what you will see is an untimely elevation of progesterone before it should happen and you will see oocyte maturation. In IVF, it has been shown that there is a significant decrease in the fertilization rate for those cases.

This is a study looking at about 20 patients who had early luteinization. All of them were above the age of 38. The study looked at ways to prevent early luteinization. They were treated with clomiphene citrate, gonadotropins, then with the agonist and gonadotropins. When they were treated with clomiphene citrate, most patients developed early luteinization; the same happened with Pergonal. When treated with the GnRH agonist, a medial hypophysectomy-like was created and then the situation could be controlled much better. They were given

Just a word about ovulation, induction and ovarian cancer. The incidence of ovarian cancer is 1 in 70 and the proposed mechanism is uninterrupted ovulation. We are all aware of protective factors and the protective factors are term pregnancy and combination oral contraceptives. What about ovulation induction? There is uncertainty about the long-term safety of fertility

In summary, ovulatory dysfunction is present in approximately fifteen to twenty-five percent of infertile couples. There are measures available now to induce ovulation in women with responsive ovaries, recognition of the underlying cause will optimize treatment and success and remember that ovulation can be achieved in more than ninety percent of women with at least