Ovulation Induction

Follicle Stimulating Hormone (FSH)

During the menstrual cycle, the ovaries produce an egg in response to two hormones, follicle stimulating hormone (FSH) and Luteinizing hormone (LH).  In the follicular phase (first one-half) of the menstrual cycle, these hormones stimulate the ovary and cause a follicle containing an egg to grow.  In regularly cycling women, ovulation occurs as this developing follicle ruptures and the egg is released.  The ovulated egg enters the fallopian tube and within several hours is ready for fertilization.  In most normal cycles only one egg is released from the ovary.

When FSH and LH are produced in improper amounts, abnormalities in ovulation may occur.  A medication called FSH may be given to try to correct this problem with ovulation.  Gonal-F, Follistim, Bravelle, Repronex, Pergonal and Humegon all contain FSH and function by stimulating the ovary to develop eggs.  FSH stimulation is of great benefit in patients who lack usual pituitary function and thus require assistance to achieve ovulation.  FSH has also been used to treat normally ovulating women who have not become pregnant by conventional means as an "empiric" therapy along with intrauterine insemination (IUI).  In this circumstance, FSH stimulation is combined with IUI in an attempt to increase the number of eggs ovulated and, as a result, increase the likelihood of pregnancy.

Success Rates

The success rate with FSH will depend upon the reason for using it.  If FSH is used strictly for patients who are not ovulating, but have no other infertility factors, then success rates approach 60-70% after 3-6 cycles.

If FSH is used in patients as empirical therapy to increase the likelihood of pregnancy, then success rates are approximately 30% after 3-4 cycles.  That is, one in three women completing 3-4 cycles of "empiric" FSH therapy will achieve pregnancy.

Administration and Monitoring

FSH is a medication that must be given by intramuscular (Pergonal, Humegon) or subcutaneous injection (Bravelle, Follistim, Gonal-F, Repronex).  It cannot be taken orally because it is a protein and would be digested in the stomach.  At your FSH consultation, your husband, or the person who will give your injections, will be taught how to mix the FSH and how to administer the injection.

Because FSH is such a potent stimulator of the ovary, close monitoring will be required during your FSH stimulation.  Monitoring will be done in the morning so that laboratory results can be ready by the same afternoon.  Monitoring will consist of two tests to assess how the FSH stimulation is progressing.  These two tests are a vaginal ultrasound and a blood test to measure the serum estradiol level.  Since FSH works to cause follicles to develop in the ovaries, a vaginal ultrasound will be used to follow follicular growth.  Follicles of 17-20 mm size are optimal.  Also, since mature follicles produce estradiol, blood samples for estradiol will be performed to assess the follicular growth. 

You will be expected at the office between 8:00 and 10:30 a.m. on the days of monitoring, and you will have an ultrasound and estradiol on each monitoring day.  Laboratory results do not usually return until 2:00 p.m.  After laboratory results are ready, they will be reviewed by Drs. Hill, Whitworth, Weitzman, or Eblen to determine how much FSH you will need to take and when monitoring is needed again.  You will be given a voice mailbox in our office and instructed on its use.  You will need to check this mailbox between 2:00 p.m. and 3:30 p.m. to find out your results and treatment plan.  We ask that you check this voice mail by 3:30 p.m. as our office closes at 4:30 and it is important that any questions be resolved prior to closing. Any calls to the physicians after regular office hours which are not emergencies will result in an additional $ 25.00 charge per phone call.  Patients having monitoring out-of-our office will be charged a cycle management fee of $325.00.

The Stimulation 

You will need to begin your FSH injections within 3-5 days following your menstrual period; therefore, call the day of your menstrual period to notify our office that you are ready to start FSH.  If your  menstrual period starts on Saturday or Sunday, call first thing Monday morning after 8:30.  The day that you will start FSH, and the dosage that is required will be decided by your doctor.  Never take more or less FSH than is prescribed.  Usually, you will take FSH injections for 3-4 days before you will be monitored for the first time.  No specific preparation is necessary prior to presenting for monitoring.  You may eat normally, and you do not need a full bladder.  On the day you report for monitoring, you will not know the dose of FSH until 2:30 p.m. when your laboratory values are known and have been discussed.  You will then phone in to find out how much FSH to take and when your next monitoring is scheduled.  When monitoring reveals that sufficient follicular growth has been achieved, human chorionic gonadotropin (hCG) will be administered to cause ovulation.  hCG, like FSH, must be given by injection, and is not active orally.  You will receive the supply of hCG, and instructions for use on your first day of monitoring.  24-48 hours after hCG, you will have IUI performed.  IUI will need to be scheduled by you for a time convenient for you and your husband.  IUI is described in greater detail on a separate sheet.  After your IUI, you will receive two supplemental hCG injections.  These injections are given because they help to support the luteal phase (last one-half) of your cycle, which is very important in early pregnancy.  The dates of these injections will be given to you when you come in for your IUI.

Risks

FSH is associated  with the following risks:

1.       Multiple gestation -  Multiple gestations are possible in any patient taking FSH.  Twins may occur in up to 25% of patients, with 6% of patients having triplet (or more) gestations. High order multiple gestation pregnancy is associated with increased risk of pregnancy loss, premature delivery, infant abnormalities, handicaps due to the consequences of very premature delivery, pregnancy induced hypertension, hemorrhage and other significant maternal complications. Careful monitoring can reduce the risk of multiple gestation, but this risk cannot be completely eliminated.  If an excessive number of follicles are produced during your FSH stimulation, your physician may decide to cancel the cycle to decrease your risk of multiple gestation.

2.       Ovarian Hyperstimulation (OHSS) - All patients given FSH develop some ovarian stimulation.  In rare patients the stimulation can be abnormally marked or severe.  This situation is known as OHSS. OHSS occurs in only 1-5% of FSH stimulations and is more likely to occur in women with polycystic ovarian syndrome or in conception cycles. OHSS may require hospitalization and can be life-threatening.  Early symptoms of hyperstimulation are excessive low back or ovarian pain, nausea and vomiting, weight gain, bloating, abdominal distention, and infrequent urination.  These symptoms will most likely occur one to two weeks after hCG.  If you suspect hyperstimulation, contact our office at 321-4740.  If the risk of hyperstimulation is too high, your doctor may be forced to cancel the FSH stimulation.  If this happens follow instructions carefully to achieve the best outcome.  Remember, there is a great deal of individual variation in response to FSH.                                                                     

3.       Ectopic (Tubal) Pregnancies - Ectopic pregnancies occur in approximately 1-2 percent of pregnancies.  With FSH stimulation this rate is increased to 1-3%.  These can be treated with medicine or surgery.  Rarely combined uterine and tubal pregnancies occur and would need to be treated with surgery.

4.       Birth Defects - The rate of birth defects after FSH cycles is not increased over that of the general population, at 3-5 percent.  These children are also developmentally no different than their peers.

5.       Ovarian twisting - Less than 1% of the time, the stimulated ovary can twist on itself, cutting off its own blood supply.  Surgery is required to untwist or even remove it.

6.       Ovarian Cancer - The risk of ovarian cancer seems in part related to the number of times a woman ovulates.  Infertility increases this risk; birth control pill use decreases it.  Controversial data exists that associate ovulation stimulation drugs like FSH to the risk of future ovarian cancer.  While research is underway to help clarify this issue, the careful use of gonadotropins is still reasonable, especially considering that pregnancy and breast feeding reduce cancer risk (American Society for Reproductive Medicine, Fact Sheet on the Side Effects of Gonadotropins).

Miscellaneous

When on FSH your ovarian follicular growth is accelerated.  Because of this, the follicular (time to ovulation) period of the cycle is also shortened.  As a result, your cycle length on FSH will be shorter than usual.  Do not be alarmed if your FSH cycles are only 23-24 days in length.  Different women respond differently to FSH - some quickly, some slowly.  Since there is much variation, you are urged to keep two days supply of FSH on hand so that at 5:00 p.m. you do not begin a frantic search for more FSH.  Because it is an injection, many pharmacies do not keep FSH on hand.  Many local pharmacies can order FSH and are happy to fill an order.  Clearly, at 5:00 p.m. it can be very frustrating to find you need more FSH and have none on hand!  It is impossible to correctly predict how much FSH you will require - even after the stimulation is underway.  Save yourself the anxiety and keep two days supply ahead of your needs.  This will keep for months in the refrigerator and will only be "unused" if you become pregnant.  Remember weekends and be certain you have sufficient supply to last until the next weekday.

Patients who choose to do a second or third cycle of FSH in consecutive months will need to have an ultrasound to check for ovarian cysts sometime within the first three days of the menstrual period.  Large ovarian cysts are not uncommon following an FSH stimulation and may affect prognosis for pregnancy.  Thus if large cysts are present we recommend waiting one month prior to beginning another FSH cycle. 

In conclusion, FSH is a hormone capable of powerful ovarian stimulation.  If used as instructed, it can safely cause ovulation and result in increased pregnancy rates in selected cases.  Close monitoring is essential for the safe use of FSH.  If any problems or questions arise during your FSH stimulation, do not hesitate to contact your doctor. 

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Clomiphene Citrate

Purpose: Clomiphene citrate is a medication used to stimulate ovulation in women who have infrequent periods and/or long cycles. It may also be used to stimulate ovulation of multiple eggs in patients with regular cycles and unexplained infertility Clomiphene works by blocking the estrogen receptors in the hypothalamus, causing it to “think” there is an estrogen deficiency in the bloodstream.  As a result, the hypothalamus orders the pituitary gland to secrete more FSH and LH into the bloodstream.  The high level of FSH induces the development of a follicle and its egg.  As the follicle grows it secretes estrogen into the bloodstream.  About a week after the last Clomiphene tablet is taken, the hypothalamus senses the now high estrogen level and tells the pituitary to release a surge of LH.  As a result, the egg is released from the mature follicle.

Administration: Clomiphene citrate can be purchased under the brand name Clomid or Serophene.  Clomiphene is a pill and is taken by mouth.  Treatment is started on either cycle day three, four, or five with an initial dose of 50 mg/day or five days.  If ovulation occurs, this dose is continued in subsequent cycles.  If the patient does not ovulate, 100 mg/day for five days is prescribed.  If ovulation still does not occur, the daily dosage may be increased by 50 mg/day to a maximum dose of 250 mg/day for five days.