How does Letrozole work?

Letrozole is a type of medication known as a non-steroidal aromatase inhibitor. This means that it blocks an enzyme in the body which converts male hormones to female hormones. Letrozole use will result in a decrease in the levels of estrogen. This decrease in estrogen tells a part of the brain (called the pituitary gland) to make more of a hormone called Follicle Stimulating Hormone (FSH). When this hormone increases, it stimulates the ovary to produce eggs and follicles.

In a simpler description: it increases the production of FSH and FSH is the hormone that induces the ovary to produce follicles and eggs.

This is the same mechanism of action of clomiphene (Clomid/Serophene), the first-line fertility medications that have been used for over forty years.

What are the side effects of Letrozole?

There are virtually no side effects with letrozole.

Ovarian cysts may form with letrozole but these will typically resolve on their own.

What are the Advantages of Letrozole over Clomid?

1. Side effects: Letrozole is essentially side-effect free. Clomiphene is associated with significant side effects, including hot flashes, vaginal dryness, headaches, and mood swings. 
   
   
2. Clomid use for many cycles can cause thickening of cervical mucus, which makes it harder for sperm to enter the uterus and find an egg. It can also thin the lining of the uterus which makes it harder for a fertilized embryo to implant into the uterus.
   
   
3. Letrozole is less likely to result in a multiple pregnancy.
   
   Letrozole: Twins approximately 5%%, Very rare to have triplets.
   Clomid: Twins approximately 10%, approximately 1% triplets.
   
   
4. Newer studies suggest a higher rate of ovulation and pregnancy with letrozole.
   
   Letrozole: ovulation 62%, pregnancy 27%
   Clomid: ovulation 48%, pregnancy 19%

What are the Advantages of Clomid over Letrozole?

Clomid is the only oral FDA-approved medication for ovulation induction. Letrozole is approved by the FDA exclusively for the treatment of postmenopausal women with breast cancer. Use of letrozole for ovulation induction is an off-label use. Many medications are used for off-label indications.

The use of letrozole for this indication came under fire based on a small Canadian study published by Biljan. This study was poorly controlled and involved very small numbers of patients and birth defects. However, it suggested that the use of letrozole was associated with an increased risk of birth defects. Therefore Novartis Pharmaceutical, the company that makes letrozole has issued a letter advising that letrozole not be used for ovulation induction.

Many studies have since been done and have not shown an increased risk of birth defects with the use of letrozole. Letrozole has a half-life of forty hours. When used for ovulation induction, it is completely cleared from your blood by the time of conception. This makes it very difficult to explain how the use of letrozole could result in congenital malformations. There is no question that this medication should not be used during pregnancy, but it is used for ovulation induction only following the onset of normal menses and a negative pregnancy test.

What is the Dosage?

The usual starting dose of Letrozole is 2.5 or 5 mg a day for five days starting either on day three or five of your cycle. We may need to increase your dose to cause ovulation. Either a dose works, or it doesn’t. If taking 2.5mg a day does not result in normalization of ovulation (and therefore your cycle) one month, there is no point in trying that dose again. The dose needs to be increased the next month. More is worse, not better. Once the dose normalizes the cycle and results in good ovulation, there is no point in increasing the dose further.

Most conceptions with letrozole occur in the first three of four treatment cycles. If you do not become pregnant after six cycles, it is recommended to pursue alternative treatments (Clomid, injectable hormones, insemination).