Injectable Fertility Medications

How fertility drugs are used in an IVF cycle.

Super Ovulation With Injectable Fertility Medications

Gonadotropins (hMG) are hormones that function by stimulating the ovaries to produce follicles, each of which contains an egg. The name gonadotropin stems from the term “gonad,” which is the name for an ovary or testicle, and “tropin” meaning to stimulate. Gonadotropins are synthesized and released by the pituitary gland, a small gland located at the base of the brain. The pituitary produces two different types of gonadotropins: luteinizing hormone (LH) and follicle stimulating hormone (FSH). Both of these hormones act on the ovaries in a coordinated fashion to recruit and develop ovarian follicles.

Today, gonadotropins are obtained either as a highly-purified product from human (urinary) sources (hMG), or are the products of genetic engineering and biotechnology (recombinant FSH). Bravelle, Repronex, and Menopur are examples of hMG and contain FSH, with variations in the amount of LH. Gonal-F and Follistim (rFSH) are types of genetically engineered gonadotropins and contain FSH only. Production of these proteins involves incorporating the human FSH gene into a controlled cell-line, which then produces pure FSH identical to that produced by the human pituitary gland.

These medications are given by injection to stimulate the development of follicles if ovulation is not occurring naturally, if many eggs are needed for IVF, or if no success has been met with lesser therapies. FSH should be administered by a trained fertility specialist to minimize potential side effects.

Gonadotropin Treatment Cycle

A gonadotropin treatment cycle refers to the entire process of ovulation induction or superovulation with fertility drugs, cycle monitoring, ovulation triggering, and the determination of pregnancy with a blood test. Two common types of cycles used in conjunction with gonadotropin administration are intrauterine insemination (IUI) and in vitro fertilization (IVF).

Intrauterine Insemination Cycle (IUI) – (This is a general discussion and does not replace the physician’s and nurse’s patient-specific instructions. The following text is for information only.) With the onset of menses, a baseline sonogram and blood tests maybe scheduled. These are usually performed on cycle days 2, 3, or 4, where the first day of full menstrual flow is considered cycle day 1. If the baseline tests are normal, ovarian stimulation with gonadotropins begins.

The stimulation phase of the treatment cycle typically lasts seven to 14 days. During stimulation, patients must come to our office about every two or three days for additional sonograms and/or estradiol blood tests. These tests allow the physician to evaluate the effects of gonadotropin stimulation on the ovaries.

Different women respond to gonadotropins at different rates, and even the same woman may respond differently in multiple cycles. Therefore, the gonadotropin dosage may be increased or decreased during the cycle. It is essential that treatment is monitored closely to ensure proper dosing, and to time the triggering of ovulation with human chorionic gonadotropin (hCG). This medication is given to mimic the LH surge and stimulate ovulation, which occurs approximately 36-40 hours later, at which time insemination(s) or intercourse can be scheduled. Additional medications, such as Lupron or birth control pills, may be employed prior to the stimulation phase.

Gonal-F and Follistim are injected subcutaneously into the abdomen or thigh and are usually self-administered. Both products can be conveniently administered using a pen injection system supplied by the manufacturers. Repronex, Menopur, and Bravelle can also be safely administered subcutaneously, although the original hMG preparations were typically given intramuscularly. We encourage employing the subcutaneous route to ease administration.

Gonadotropin injections should be given at about the same time every day, usually between 7:00 and 9:00 p.m. Most patients are able to administer their own injections but some patients have their spouse or a friend perform the injections for them. All patients meet with our nurses for medication injection training prior to initiating a cycle.

Pregnancy rates using IUI vary from couple-to-couple depending upon many factors, such as age and sperm quality. Typical pregnancy rates with IUI range from 15 to 20 percent per cycle and the incidence of multiple births is approximately 15 percent. High order (equal to or more than three) multiple births are more common with IUI than IVF. This is because the number of embryos placed into the uterus is controlled in IVF, whereas the number of eggs ovulated, fertilized and implanted cannot be exactly determined during IUI cycles.

Risks and Side Effects of Fertility Medications

Gonadotropins are associated with several side effects including:

ovarian hyperstimulation syndrome (1 to 5 percent)
multiple gestation (15 percent)
ovarian torsion (less than 1 percent)
possibly an increased risk of ovarian cancer (this potential side effect is controversial)

Also since these medications are injectable, there is a risk of infection at the injection site, called cellulitis. Ovarian hyperstimulation syndrome (OHSS) is a condition in which there is an excessive ovarian response to fertility medication, usually associated with elevated levels of estradiol. OHSS is comprised of ovarian enlargement (multicystic) and changes in vascular permeability leading to ascites, the abnormal presence of fluid in the abdominal cavity. Other consequences include electrolyte disturbances, and rarely, blood clots. Severe OHSS usually occurs only after hCG is given.

You should call our office if you have any medication problems during the cycle, particularly if you experience dizziness, decreased urination, or weight gain of more than five pounds. These cysts usually recede after four to seven days, but on rare occasions can cause serious problems if fluid accumulates in the abdomen. This usually requires hospitalization or drainage of the fluid in the office. If pregnancy occurs, this condition may persist for two or three weeks, as the pregnancy hormone (hCG) exacerbates hyperstimulation. In rare circumstances, these cysts may rupture or the ovary may twist, possibly requiring surgery and loss of the involved ovary. Other side effects of gonadotropins are breast tenderness, mood swings, and fatigue.

In Vitro Fertilization Drug Treatment Protocols

Fertility drugs used to superovulate the ovaries by causing the production of numerous follicles may be given in a variety of combinations, which are called protocols. The physician determines the individualized specific treatment protocol for each patient. The following information describes the standard or initial protocol used for the majority of patients. Each patient’s protocol is individualized and may vary from the standard.

Standard IVF Protocol

With the standard IVF protocol, four types of fertility drugs may be given:

Lupron: a gonadotropin-releasing hormone (GnRH) antagonist, which acts on the pituitary gland to inhibit gonadotropin (FSH and LH) secretion and prevent premature ovulation. Ganirelix is a GnRH agonist and may be used instead of Lupron to control ovulation timing.
Progesterone: helps supports endometrial development and maintain early pregnancy.
Gonadotropins: medications consisting of FSH alone or combined FSH/LH. They directly act on the ovaries to stimulate the development and maturation of the eggs

Down-Regulation for IVF With Lupron

In order to optimize the stimulation of the ovaries, a fertility drug called Lupron is given starting one week before the expected period, on cycle day 21 of a 28-day cycle. Alternately, if instructed to initiate oral contraceptive pills (OCPs), then Lupron is administered beginning on day 14. Lupron acts by suppressing two hormones made in the pituitary gland, which normally cause the ovary to develop follicles and release eggs.

By suppressing these two hormones (follicle stimulating hormone (FSH) and luteinizing hormone (LH)), the ovaries should be quiet. They will not recruit eggs or produce the ovarian hormone called estradiol. Down regulation or ovarian suppression with Lupron allows the physician to have greater control over ovarian stimulation, which provides for even growth of ovarian follicles and prevents a condition known as premature luteinization. This is a premature attempt by your body to ovulate.

Lupron is administered subcutaneously, meaning underneath the skin and not into the muscle. This medicine is typically injected into the thigh and is easily self-administered. Lupron is usually given 10 to 14 days before ovarian suppression occurs, but may also be given earlier without affecting the ovarian stimulation. Approximately 10 percent of patients require longer than 10 to 14 days of Lupron to completely suppress the ovaries. The Lupron dose will typically be reduced by half once the stimulation phase of the cycle begins.

Ganirelix Acetate/Cetrotide for IVF

Ganirelix and Cetrotide are both gonadotropin releasing hormone (GnRH) antagonists that suppress the pituitary gland’s LH secretion by binding to the GnRH receptor. These act immediately to suppress pituitary LH secretion to prevent premature ovulation. Depending on the patient, the physician may decide to use one of these medications in place of Lupron.

Ganirelix Acetate or Cetrotide is usually started after ovarian stimulation has begun, typically around stimulation day 6, or when the lead follicles are approaching 12 mm in mean diameter. Ovulation triggering is handled similarly to a Lupron cycle.

Ovarian Stimulation and IVF

A menstrual period should begin within 7 to 14 days from starting the Lupron injections. The clinic should be notified when the period starts so that a baseline ultrasound and blood estradiol test can be scheduled. The purpose of these tests is to confirm that the Lupron has successfully suppressed the ovaries to a baseline state.

Suppression means that the ovaries should contain no follicles that are greater than 15 mm in size, and the blood estradiol level should be less than 50 pg/ml. In approximately 10 to 15 percent of patients, one or both of these conditions are not met. Depending upon the results of these tests, the Lupron medication may be extended for another week and the patient may be asked to return for another sonogram and blood estradiol test. Occasionally an ovarian cyst aspiration may be performed for a persistent ovarian cyst.

After ovarian suppression has been achieved, ovarian stimulation using gonadotropin fertility drugs may commence at a scheduled time, which is referred to as the cycle start. These gonadotropin fertility drugs are continued throughout the stimulation phase of the cycle, that is, until hCG is administered.

The dose of gonadotropins will be based upon age, weight, number of follicles, cycle day 3 FSH and estradiol levels, and the response to previous stimulation cycles. The initial dose of medication will be taken for 2-3 days before returning to the clinic in the morning for an estradiol blood test. The dose of medication may be changed based upon the level of estradiol. Medication will usually be taken for two more days before for another estradiol blood test. Sonograms are conducted starting on day 6 or 7 of the stimulation. In general, return follow-up sonograms and estradiol blood tests occur every one to three days to monitor the growth of the follicles. Patients will be asked to return more frequently toward the end of their ovarian stimulation. Most people require eight to 12 days of ovarian stimulation, thus necessitating four to six sonograms and estradiol blood tests.

Ovulation Triggering (hCG) and IVF

When the follicles have met the criteria that indicate the eggs are mature, patients are instructed to administer hCG (Pregnyl or Ovidrel). In general, at least two follicles with a mean diameter of at least 18 mm and an appropriate estradiol level must be present before hCG is administered. Usually 5,000 to 10,000 units of hCG will be injected 36 hours before the planned oocyte retrieval. For example, Pregnyl or Ovidrel will be injected at 7:00 p.m. Monday evening, so that oocyte retrieval can occur at 7:00 a.m. Wednesday morning. Gonadotropins and Lupron/Ganirelix are discontinued after the hCG injection.

Administration of hCG is commonly called follicle triggering. The purpose of this medicine is to induce the final stages of oocyte maturation and the release of the eggs by the ovary. Timing the administration of this medication is extremely important and the physician/nurses instructions must be followed exactly.