Letrozole - an Aromatase Inhibitor For Ovulation Induction

Letrozole is being used as an infertility treatment. It is the most recent addition to the drugs being used for fertility treatment. Fertility drugs are used often in infertility treatments. There are two situations in which fertility drugs may be useful. First, these drugs can be used to induce an egg to develop and be released in women who are not ovulating on their own. Fertility drugs can also be used to increase the chances of pregnancy in women who are already ovulating.

Aromatase is an enzyme that is responsible for the production of oestrogen in the body. Letrozole is in a class of medications known as aromatase inhibitors. Letrozole works by inhibiting aromatase thereby suppressing estrogen production. Clomiphene citrate, on the other hand, blocks oestrogen receptors. In both cases, the result is that the pituitary gland produces more of the hormones needed to stimulate the ovaries. These hormones, FSH and LH, can cause the development of ovulation in women who are anovulatory or increase the number of eggs developing in the ovaries of women who already ovulate. As a result, several studies have now been published using letrozole as a fertility drug. By reducing oestrogen production the hypothalamus and pituitary increase their hormone production and this increases the stimulation to the ovaries.

Clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining.

Letrozole is a medication that has been widely used in women with breast cancer.

Recently, the manufacturer of Letrozole sent a notice to doctors warning that there are reported cases of birth defects that arose in the children of women who received Letrozole while pregnant. Novartis, the manufacturer of letrozole, reviewed their safety database and found 13 reports of pregnant women receiving the drug worldwide. Of those 13 women, two had children with birth defects. In the United States, the labeling of letrozole already warns that it has been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and is clearly concerned about their liability if given in pregnancy.

There are no reports of letrozole being associated with birth defects when given prior to pregnancy. It is important to make the distinction that when used as a fertility medication, letrozole is given before the establishment of pregnancy. Letrozole is a medication that is metabolized rapidly in the body. It is not thought to have significant levels in the blood or tissues for a prolonged period of time.

At least one major pharmaceutical company, Serono, is conducting studies with a similar medication called anastrozole in the hopes of obtaining FDA approval to market it specifically as a fertility medication.

One of the earliest studies using letrozole as a fertility drug looked at 12 women with inadequate response to clomiphene citrate. Ovulation on letrozole occurred in 9 of 12 cycles and 3 patients conceived. A later study by the same investigators compared the effects of letrozole to those of clomiphene citrate. This time 19 women were studied. Ten women received clomiphene citrate and nine women received letrozole. This study was unable to demonstrate any difference in the number of women who ovulated, the number of eggs that developed in each woman, or the thickness of the uterine lining during treatment. However, a more recent study by a different group of investigators found that compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate.

Nobody has yet identified the optimal dose for letrozole. Three dose regimens have been tested: 2.5 mg, 5 mg and 7.5 mg. Different studies comparing these dose regimens have occasionally found favor with one dose or another but there is no conclusive data that one dose is better than another. The usual length of treatment is for five days.

Some early studies suggested that the pregnancy rates with letrozole far exceeded those with clomiphene citrate and were possibly even higher than gonadotropins. Further data has determined that this is not the case. Pregnancy rates with letrozole are similar to those seen with clomiphene citrate and are lower than the pregnancy rates seen with gonadotropins. Older patients have a lower chance of success than younger patients.

Treatment with letrozole may still be successful even if other treatments have failed. For example, some data shows that in women who did not ovulate with clomiphene citrate, they still may ovulate with letrozole.

Letrozole side effects

Letrozole works based on its ability reduce estrogen levels. Low estrogen levels of any cause can cause a woman to have symptoms. The data on side effects comes from women who have been using letrozole for an extended period of time in order to treat breast cancer. The treatment duration for letrozole is only five days. Side effects are similar to those seen with clomiphene citrate:

  • Hot flushes
  • Headaches
  • Breast tenderness

Studies conducted so far have shown either no increased risk of miscarriage or a decrease in miscarriage risk. Letrozole should not be given to women who are already pregnant. Studies in rats and mice have shown that letrozole increases the risk of fetal death and malformations. Since there are no studies in human beings, it should be assumed that a similar effect is possible.

The aromatase inhibitors such as Letrozole would seem to hold promise for ovulation induction and superovulation. For the moment they should be considered for research in carefully controlled clinical trials.

Ovulation Induction - Summary

With the exception of primary ovarian failure (the menopause), ovulatory disorders can usually be successfully treated. Ovulation induction regimens depend on the underlying cause (infertility cause).

Sometimes appropriate advice may be all that is required. When weight loss is responsible for secondary amenorrhoea (amenorrhoea causes), improved diet leading to correction of your weight may prove to be successful.

The main drugs used to overcome anovulation are clomiphene (clomiphene)(clomiphene citrate), tamoxifen (tamoxifen infertility), bromocriptine (bromocriptene), metformin (12), and gonadotrophins (gonadotrophins).

risks of ovulation induction

There are three concerns associated with drugs used to induce ovulation:

    1. They are associated with a greater chance of multiple pregnancy. The general rate of twins in the population is one in every eighty deliveries but with clomiphene, it is one in twenty or a four-fold increase. Higher order multiple pregnancies (e.g. triplets and quads) can occur with clomiphene but this is rare. Injections of gonadotrophins are more likely than clomiphene to result in multiple pregnancy.
    2. Occasionally ovulation induction can lead to ovarian hypersensitivity syndrome (OHSS).
    3. Finally, there has been concern that ovulation induction treatments may increase the chance of ovarian cancer. A comparison was made of the risk of cancer among women who received clomiphene with the risk among infertile women who did not receive it. There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.41994-01. A confounding factor is that infertility is itself associated with an increased risk. Furthermore, the risk is reduced with secondary infertility and is dependent on the causation of the infertility.2004-01Several infertility units have reported their data. Some seemed to confirm the link between clomiphene and ovarian cancer but the majority have produced reassuring results.1999-02,2004-02 2006-01

Related Medical Abstracts - Click on the paper title:-

Related Medical Abstracts - Click on the paper title:-

Ovulation Induction Monitoring

Monitoring may be required to confirm that ovulation is occurring and to ensure that too many follicles are not developing. Blood tests for progesterone levels around the twenty-first day of the cycle provide an indication of ovulation (Q9.17). Ultrasound monitoring of follicular development is helpful with tablet treatment (clomiphene and tamoxifen) and is really essential with gonadotrophins. When controlled ovarian hyperstimulation is undertaken in IVF protocols, oestradiol levels are used. The need for monitoring hormone levels in IVF protocols has been questioned.1998-01, 2006-01

Related Medical Abstracts - Click on the paper title:-


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