The Ovulation Induction Prodedure
Clomiphene Citrate
Clomiphene citrate, a synthetic hormone commonly used to induce or regulate ovulation, is the most often prescribed fertility pill. Brand names for clomiphene citrate include Clomid and Serophene.
Clomiphene works indirectly to stimulate ovulation. In the presence of clomiphene, the brain sends signals to the pituitary gland to release hormones including follicle stimulating hormones (FSH). FSH circulates to the ovary where it stimulates the development of follicles — cystic structures that include an egg and surrounding estrogen-producing cells. Once follicle growth is initiated by clomiphene, the process of ovulation will usually proceed spontaneously.
The dose of clomiphene is tailored to each patient. Typically, a patient will begin clomiphene sometime between the 3rd and 7th day of her menstrual cycle. (We define cycle day 1 as the first day of heavy menstrual flow.) The medication is usually taken for 3, 4, or 5 consecutive days. Often the dose of medication will be higher during the first days of treatment.
Ovulation usually occurs between 9 and 12 days after the first clomiphene citrate pill is taken. A woman desiring to conceive should try to have relations on a regular basis during that time period. Alternatively, the ovulation may be monitored using urine kits, ultrasound or blood testing. The results of these tests can be used either to direct the couple when to have intercourse or to plan procedures such as artificial insemination.
Clomiphene has been used successfully by tens of thousands of women over the past 30 years. The drug has been shown to be reasonably safe and effective. However, certain potential adverse reactions or complications may occur.
What is the Chance of Getting Pregnant?
Not every patient who receives clomiphene will conceive. We expect that 85% of women who do not ovulate will ovulate as a result of taking clomiphene .Of these women, at least 50% will become pregnant. If a woman is already ovulating without the use of fertility drugs the chance of conceiving while taking clomiphene is about 10% per month. Careful attention to a patient’s response to clomiphene as well as other factors affecting her fertility (cervical mucus, fallopian tubes, sperm quality, etc.) will ensure the highest possible pregnancy rate. Most patients who conceive using clomiphene do so within the first four or five months of treatment.
Multiple Gestation
Clomiphene increases the incidence of multiple gestation. The incidence of twins is said to be approximately 10% for clomiphene pregnancies. The risk of triplets is about 1%. The risk of quadruplets, quintuplets, etc. is less than 1%. The number of eggs that a patient will ovulate can be to some degree predicted by counting the number of ripe follicles seen on ultrasound just before ovulation.
Risk of Miscarriage
The 20-25% risk of miscarriage associated with clomiphene is higher than the normal rate of miscarriage (15%). We attribute some increase in the rate of miscarriage to factors preexisting in women who require clomiphene that prevent fertilized eggs from developing normally. However, it is possible that clomiphene might increase the rate of miscarriage by changing the receptivity of the lining of the uterus. The condition (thickness) of the lining of the uterus can be evaluated with ultrasound just prior to ovulation.
No Increase in Birth Defects
Although an occasional medical journal report has described birth defects attributed to clomiphene, the majority of physicians utilizing this medication properly have failed to demonstrate any increase in the 3-5% rate of congenital abnormalities normally seen in our population. Clomiphene must not be taken by women who are already pregnant. Even if some menstrual-like bleeding has occurred, a woman should not take clomiphene if she suspects that she might be pregnant.
Is There a Risk of Future Cancer?
Preliminary data has raised concerns that the use of fertility drugs increases the chance that a woman will develop ovarian cancer later in her life. Some authors suggest that this risk might be higher for a woman who never becomes pregnant. Other authors suspect that the risk of future ovarian cancer might be greater in women who take many (for example, more than 12) cycles of treatment. Women with a family history of ovarian cancer may already be at greater risk for developing this disease. At the current time, scientific evidence neither proves nor disproves a relationship between clomiphene and ovarian cancer.
Side Effects
The most common side effect of clomiphene is hot flashes . Another common side effect is anxiety/irritability. This feeling of nervous tension may persist throughout the clomiphene cycle. Clomiphene may cause headaches, especially in women who experience migraine at the time of their period. Nausea and abdominal pain will rarely occur on the days that clomiphene is taken. If the clomiphene succeeds in stimulating a strong ovulation, the woman will likely experience some pain at the time of her ovulation, bloating through the second half of her cycle, and/or increased cramping at the time of her period (if she has not become pregnant).
Since clomiphene indirectly stimulates a woman’s ovaries, cysts may temporarily appear in her ovary. Rarely, these cysts may rupture or twist. Usually, they resolve spontaneously within a month. We try to examine the ovaries prior to each new clomiphene cycle.
Letrozole and Other Drugs
Letrozole
The latest class of fertility pills are aromatase inhibitors, drugs which temporarily prevent the body from making estrogen. In a fashion not too different from clomiphene, aromatase inhibitors initiate the release of FSH which stimulates the growth of follicles. At Pennsylvania Reproductive Specialists we use the aromatase inhibitor named letrozole (Femara).
Letrozole appears to be slightly less reliable than clomiphene for inducing ovulation. On the other hand, its advantages include less drying -up of cervical mucus, thicker development of the lining of the uterus, and a far lower chance of multiple gestation. As is the case with tamoxifen, metformin and rosiglitazone, letrozole is not certified for use as a fertility drug by the FDA (government). Doctors are free to use these drugs for off-label indications at their discretion.
Tamoxifen
Occasionally, we employ a drug called tamoxifen as an alternative to clomiphene. This medication works through the same mechanisms as clomiphene. It is not FDA approved for use as a fertility drug, but may be used for this “off-label” indication at the discretion of the physician.
Insulin Lowering Drugs
Another popular “off-label” drug usage involves medications normally prescribed to non-insulin requiring diabetics. Metformin (Glucophage) and pioglitazone (Actos) are examples of medications that lower a woman’s insulin levels. Lowering insulin levels improves ovulation in some women with the condition known as polycystic ovarian syndrome (PCO).
Common side effects of metformin include gas and intestinal upset. Serious side effects are extremely rare. Pioglitazone has fewer common/minor side effects, but require blood test monitoring to detect liver problems. The incidence of miscarriage and, perhaps, birth defects may be reduced in PCO patients who take insulin lowering drugs.
Injectable Gonadotropins
The pituitary gland which sits at the base of the brain secretes chemical messengers (or hormones) which control the function of other glands, such as the thyroid, adrenal and ovary. Two chemical signals emitted by the pituitary that control the ovaries are follicle stimulating hormone (FSH) and luteinizing hormone (LH). LH and FSH are called gonadotropins.
FSH causes one or more of the eggs resting in the ovary to activate. As eggs mature, fluid collects around them forming what is called a follicle. The cells of the follicle wall produce estrogen. Luteinizing hormone (LH) triggers the follicle to release its ripe egg and produce the hormone progesterone.
Gonadotropins are ideal substances to stimulate the ovaries of women who either have no pituitary gland or lack their own gonadotropins. Also, gonadotropins may be more effective than fertility pills for stimulating the ovaries of individuals whose own FSH and LH are not properly coordinated. Finally and most commonly, gonadotropins are used to purposely hyperstimulate the ovaries of infertile women who ovulate normally. Controlled hyperstimulation is a part of several advanced reproductive technologies, including gamete interfallopian transfer (GIFT) and in vitro fertilization (IVF).
Monitoring
In a natural ovulation cycle, follicles and surrounding cells emit chemical signals which feedback to the pituitary so that only one egg proceeds to ovulation each month. Because they override this innate feedback system, gonadotropins require careful monitoring in order to prevent unwanted hyperstimulation of the ovary.
Hyperstimulation has two undesirable consequences. First, too many eggs release, giving rise to multiple gestation (twins, triplets, quadruplets, etc.). Second, hyperstimulated ovaries become enlarged and cystic. These hyperstimulated ovaries may twist or produce chemical signals that cause fluid to leak out of blood vessels into body cavities, endangering a woman’s health.
We employ ultrasound and blood testing to monitor our patients who take gonadotropins. Ultrasound predicts the number of eggs that will be released. (Remember, not every released egg will be fertilized.) Blood tests help determine the extent of overstimulation and time ovulation properly. If monitoring suggests too much risk of multiple birth or hyperstimulation, the treatment cycle may be cancelled.
Taking the Medication
Since FSH and LH are not absorbed intact into the body from the stomach, the medication is given by injection. Gonadotropins are dispensed as a powder which is dissolved in a sterile water vehicle just before it is injected. The procedure for reconstituting the medication is not difficult to learn. Often a spouse, relative or friend will be recruited to administer the medication.
A typical gonadotropins cycle begins 2 to 7 days after a menstrual flow. Injections are usually given daily until the follicles are ripe. The number of injections required will vary from woman to woman and from cycle to cycle. The usual range is between 5 to 12 shots. Once the process has begun, frequent trips to the doctor’s office for blood tests, exams and ultrasounds will be scheduled.
When the monitoring studies show that the follicles are ripe, ovulation is triggered with another gonadotropin product called human chorionic gonadotropin (hCG) . hCG functions similarly to luteinizing hormone (LH). It initiates the three aspects of ovulation – release of the egg, production of progesterone and maturation of the egg. The eggs are released from their follicles about 40 hours after the hCG injection.
After ovulation hormone levels essential to implantation are supported by either booster shots of hCG or progesterone in pill, suppository or injection form. Pregnancy cannot be detected until two weeks after ovulation.
Preparations
Currently, there are five brands of injectable gonadotropins available for ovulation induction. One of these products – Repronex – is a combination of FSH and LH hormones that is obtained from the urine of postmenopausal women. Although Repronex has recently been approved for subcutaneous injection, we prefer the intramuscular route. Menopur is a purified version of Repronex which patients may inject subcutaneously (with a small needle just beneath the skin).
Bravelle is a highly purified FSH preparation also derived from postmenopausal urine. Because the LH activity and impurities have been removed, Bravelle can be given through a shorter needle under the skin (subcutaneously).
Gonal-F and Follistim are preparations of FSH hormone that are produced in animal cells by bio-recombinant technology (as opposed to obtained from the urine of postmenopausal women). . These preparations can be given subcutaneously.
The most obvious differences between preparations are the route of administration (intramuscular versus subcutaneous) and the cost. Recombinant FSH is more convenient and slightly stronger than gonadotropins from menopausal urine but not enough to outweigh its higher cost. Thus, we usually prescribe Repronex to our patients who do not have a prescription plan that covers injectibles.
An exhaustive list of the side effects and complications of gonadotropins is provided in the product package inserts.
Side Effects Common side effects include:
- pain at the injection site
- fatigue weight gain/water retention
- mood change
- pain at the time of ovulation pain in the week(s) following ovulation (from ovaries enlarged by cysts)
Less common but more serious complications include:
- multiple gestation (30% twins, 6% triplets; multiple gestation increases the risk of pregnancy complications)
- pregnancy and miscarriage (slightly increased over normal rates)
- rupture, bleeding or twisting of ovarian cysts
- severe hyperstimulation
We are concerned that the use of fertility drugs may increase the chance that women will develop ovarian cancer later in life. Current information suggests that some women who are infertile are carry an increased risk of future ovarian cancer which is not further increased by the use of fertility drugs. These concerns underscore the need to use fertility drugs with care and caution.
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