Ovulation Induction In Infertility: Clomiphene Citrate (Clomid®) or Letrozole, Is There A Clear Advantage?
Recently there has been an increased interest in the use of a medication used for ovulation stimulation called letrozole (Femara ®). The standard medication used of this purpose is clomiphene citrate (CC) (Clomid®). Is one medication better than the other? Recently published research is beginning to answer some of the questions concerning the use of ovulation- enhancing medications such as CC or letrozole.
How does it all work?
The medications used to manipulate ovulation are based upon the physiology of reproduction. Women produce oocytes (eggs) prior to birth and then they never make more oocytes. During their life, women recruit large numbers of oocytes from the resting pool each month and then develop the oocytes so that they can do their job. The job an oocyte has is to mix the genetic material from both a man and a woman and then divide it equally during the first cell division which produces an embryo. The egg must develop structures that allow it to produce embryos that have the correct number of chromosomes. If the egg does not have the proper machinery to do this, then the embryo has the wrong number of chromosome and the embryo does not survive. The ovary takes up to five and a half months to develop the egg and of the large number recruited each month, only one survives and is then released. The release of the oocyte is call ovulation. Ovulation is important, but even more significant to obtaining a normal pregnancy is that the oocyte released must be able to create a normal embryo. Thus egg quality is the critical requirement for reproduction.
When a young woman has a menses, there are approximately 20-30 eggs units (follicles) still developing. At this point, the follicle must be exposed to the hormone FSH in order to continue to develop. For the last two weeks of the development of the oocyte, FSH is critical for the egg to finish its development. During this time the ovary destroys all but one follicle but this mechanism can be overridden by adding FSH. Thus, all clinical manipulations of oocyte development are based upon the hormone FSH.
FSH is made and released from the pituitary gland. The pituitary gland is a small gland that sits at the base of the brain. At one time, the pituitary was called the master gland because so many endocrine functions are controlled by hormones produced by the pituitary gland. It is now known that the pituitary is under control of higher centers in the brain which derive information from the body, compare it to desired norms, and then instruct the pituitary gland as to how much hormone to release. This system is called a negative feedback system and is like the control of room temperature using a thermometer, a thermostat, and a furnace or air conditioner. For example, suppose it is winter and a person wants to keep the room temperature above 70F. There is thermostat which has a thermometer in it. The thermometer measures the room temperature and informs the thermostat about the room temperature. The thermostat compares the setting done by the person which is 70F to the actual temperature and if the actual temperature goes below 70F signals the furnace to go one until the temperature rises above 70F. For ovulation, the brain is the thermostat comparing signals from the body about the hormonal status of the follicle to the desired levels. The pituitary receives signals from the brain to release both FSH and LH based upon what the brain wants done. These hormones go to the follicle and the follicle that has been chosen by the ovary to survive continues to develop. The follicle makes estrogen which then circulates to the brain and tells the brain what the follicle is doing. So the brain then adjusts the FSH level based upon the development of the follicle. When enough estrogen has been produced for a long enough period of time, the brain perceives that the egg is developed and consequently, releases a large amount of the hormone LH. LH causes the follicle to rupture and release the developed oocytes.
Follicles become sensitive to FSH about the time a woman starts her menses. Prior to that, they are not influenced by FSH. However, if follicles are exposed to increased amounts of FSH when they first become sensitive to FSH, then more follicles will continue to develop and fewer will be destroyed by the ovary. Since many younger women have up to 30 follicles that are sensitive to FSH when they start their menses, it is possible to rescue up to 30 follicles. However, as women age they have fewer oocytes in their resting pool and thus fewer oocytes on the day their menses benign. At that point, adding more FSH will not be successful because there simply are not more follicles available. On the other hand, for women with polycystic ovarian syndrome, there can be more follicles that are FSH sensitive at any time in the ovary. Using FSH can then result in too many follicles developing.
Oral ovulation – manipulating medications:
All ovulation manipulating medications work through FSH. There are two broad categories of medications: 1. Oral; 2. Injectable, but for the purpose of this article, we will focus solely on the oral medications; clomiphene citrate and letrozole.
Both clomiphene citrate and letrozole work by increasing the amount of FSH a woman releases but they do it in different ways. The basis for how these work relies upon the fact the estrogen reduces the release of FSH from the pituitary. Since the brain measures estrogen and it perceives an increase in estrogen that the follicle is growing, a decrease in estrogen makes the brain think it is not working hard enough by not producing enough FSH. So anything that lowers the perceived estrogen will make the brain release more FSH. Clomiphene is a medication that attaches very tightly to estrogen receptors. Estrogen receptors are proteins within cells that tell the genetic material to make the proteins that eventually regulate the release of FSH. With normal physiology, estrogen is produced by the follicle, goes to the brain and stimulates the production of proteins by cells that then signal the pituitary to release less FSH. But clomiphene attaches tighter to these receptors and blocks the effect of estrogen so that the receptors do not work and the cell does not make the proteins that would ordinarily reduce the release of FSH. It is in effect a trick that is played on the brain to make the brain think there is no estrogen and the brain thinks it is not working hard enough so it releases more FSH, which should prompt the maturity of the maximum amount of egg follicles available. This situation is the same as what occurs when women are menopausal with one key difference; in a menopausal woman, there are no remaining follicles to make estrogen and a woman’s actual estrogen is reduced. In the case of using these medication to induce ovulation, the brain is tricked into thinking it is menopausal, and thus some of the side effects of clomiphene are as if a person were going through menopause: night sweats, hot flashes, and moodiness.
Letrozole works by blocking the production of estrogen. Estrogen is made from male hormone by a protein called an aromatase. Letrozole blocks the action of the aromatase protein and estrogen production is reduced. Thus both medications taken by mouth work by tricking the brain into thinking the person is menopausal and thus the brain increases the release of FSH.
Who needs it?
Ovulation manipulation is used for women with polycystic ovarian syndrome to make the ovary mature an oocyte. Ovarian manipulation can also be used to treat unexplained infertility or for couples with mild to moderate male factor infertility when intrauterine inseminations are required. These medications are not used if the problem is tubal disease, severe male factor, or other less common forms of ovulation dysfunction.
Brand Preference or Clear Advantage?
Clomiphene was developed first and has been the main form of oral ovulation manipulation since the 1960s. Letrozole is more recent (2001) and thus there is less experience with this medication. Letrozole was originally (and currently) used to reduce the recurrence of Breast cancer and/or minimize the risk in high risk individuals.
The most common use of Clomiphene or Letrozole in the area of Infertility is to treat women with polycystic ovarian disease where the person does not ovulate regularly or does not ovulate at all. The next most common use is for unexplained where the idea is to get more than one follicle to develop and thus release more than one oocyte. Coupled with intrauterine inseminations, the idea is to mature more eggs through ovulation inducing medication, deposit more sperm near the eggs through Intrauterine Insemination (IUI) and ideally this should work.
So which is better? There are numerous reports studying which is better. The results vary widely that drawing a conclusion for any one study is difficult and may be erroneous. A study published in 2011 (Reprod Biomed Online; 23: 91) looked at numerous studies and applied a statistical approach that tries to make sense out of numerous articles when the results conflict. This is known as a meta-analysis. The conclusions for this study were that the two medications were equivalent. The recommendations still suggest the use of clomiphene first for ovulation induction in women with PCOS.
If at first you don’t succeed…
Clomiphene helps many people conceive. But between 50 and 70% of the people using clomiphene will not conceive. The options at this point include switching to letrozole, moving to FSH or IVF. Moving to FSH and IVF is a major increase in intensity of treatment. IVF has very high success rate and many of the risks of treatment with FSH can be managed successfully with IVF. However, it is much easier and cheaper to use letrozole so that the question becomes: what is the success rate of using letrozole compared to the success rate for using IVF when clomiphene fails? One study which addressed this issue compared using letrozole to using FSH-IUI. [2008 Fertil. Steril.; 90:678] The pregnancy rates for letrozole were 8.9% per try with a cumulative take home baby rate of 20% (the sum after 3 cycles of letrozole). The pregnancy rate was 14% per cycle for FSH-IUI and a cumulative take home baby rate of 28%. However, the present success rates for IVF in women with either unexplained (female age < 38 yo) or PCOS approaches 50% per retrieval.
Clomiphene remains the first line of approach for ovulation manipulation when oral medications are indicated. Letrozole is a possible form of treat if clomiphene does not work within 3-4 cycles. IVF still remains the most successful single- cycle form of treatment.