Ovulation Induction Using Gonadotropins

What are gonadotropins?

FSH and LH are hormones produced in the pituitary gland in the brain that control the ovulation cycle. FSH is responsible for growing the follicle (egg sac) and the LH is the trigger for ovulation. These hormones have to be produced in sufficient quantities and secreted in the proper sequence to achieve a normal ovulation. Any imbalance of these hormones can result in lack of ovulation of ineffective ovulation. Ovulatory dysfunctions are the most common causes for female infertility. The success with ovulation therapy in these cases is quite high.

How are they manufactured?

The drugs can either be extracted from the urine of menopausal women or genetically engineered. Some of the formulations contain an equal amount of FSH and LH and others are FSH only preparations. The indications for using one preparation or the other depends on the individual woman’s hormone balance and requirements. The genetically engineered drugs (recombinant DNA technology) are the most pure and potent and are the most commonly used at the present time.

Gonadotropin drugs are used in the following situations

• Women who do not ovulate on their own and who have not responded to clomid
  therapy.
• Women whose pituitary glands do not produce adequate amounts of FSH and LH,
  and as a result these women have decreased estrogen and no menses.
• These drugs are also used to induce development of multiple follicles for fertility treatments, such as IUI and IVF.

How are the drugs given

Gonadotropin treatment involves a series of injections and careful monitoring during each treatment cycle. Use of gonadotropins may involve a certain amount of risk, expense, and inconvenience. With the use of hMG, women who are anovulatory, but have no other fertility problems may expect pregnancy rates approaching those of spontaneously ovulating women of the same age. Most physicians begin gonadotropin treatment on day 2 or 3 of the menstrual cycle.

Injections usually are administered over a period of 7 to 12 days, but may be extended if the ovaries are slow to respond. The follicle size is monitored with ultrasound, and the blood estrogen level may be measured frequently throughout treatment. If tests indicate that the ovaries are not responding to gonadotropins, the dose may be increased. The goal is to achieve one or more mature follicles, and an appropriate estrogen level, so that ovulation can be triggered by an hCG injection.

If too many follicles develop, or if the estrogen level is too high, the physician may decide to withhold the hCG injection rather than risk ovarian hyperstimulation syndrome (OHSS) or a high-order multiple pregnancy.

Risks and Potential Complications

1. Multiple Pregnancy: Despite intensive monitoring, up to 30% of gonadotropin stimulated pregnancies are multiple. Of the multiple pregnancies, most are twins but a small portion are triplets or more. Premature delivery is a known risk for multiple pregnancies. The greater the number of fetuses in the uterus, the greater the risk of premature delivery. Premature delivery can subject the newborn to complications such as severe respiratory distress, intracranial hemorrhage, infection, cerebral palsy, and death. Some patients pregnant with triplets or more choose to undergo a procedure known as multifetal pregnancy reduction in an effort to decrease these risks.
2. Ovarian hyperstimulation syndrome (OHSS): A condition in which the ovaries become swollen and painful. In severe cases, fluid accumulates in the abdominal cavity and chest. In about two percent of gonadotropin cycles, hyperstimulation may be severe enough to require hospitalization. Careful monitoring of ovulation induction cycles with the use of ultrasound and/or measurement of serum estradiol levels, in conjunction with daily adjustment of gonadotropin dosage, will enable the physician to identify risk factors, adjust the dose of the drugs and in most cases prevent severe OHSS. In some cases the cycle is stopped and the ovulation is prevented, thereby preventing severe OHSS.
3. Other less serious side effects of gonadotropin treatment include:
   • Breast tenderness
   • Swelling or rash at the injection site.
   • Abdominal bloating.
   • Mood swings: Some women experience mood swings during gonadotropin therapy, although usually less severe than those that occur with clomiphene. It is difficult to separate the emotional changes due to the dramatic hormone shifts during gonadotropin therapy from the stress associated with this treatment. Regardless of the cause, a change in mood can be expected during gonadotropin therapy.
4. Long Term Risks of Ovulation Drugs:
   • Birth Defects: After years of clinical use, physicians can advise patients confidently that clomiphene citrate and gonadotropins are not associated with an increased risk of birth defects.
   • Ovarian Cancer: It has been suggested that women taking ovulation inducing drugs such as clomiphene and gonadotropin may be at increased risk for ovarian cancer. Recent studies and reanalysis of earlier studies do not support this connection.

The drugs preparations

Human Menopausal Gonadotropins (hMG)

The first commercially available gonadotropin in the United States, hMG, contains approximately equal amounts of FSH and LH. The FSH and LH in hMG are extracted and purified from the urine of postmenopausal women who have high levels of these hormones. hMG is administered by injection into the muscle (IM) or under the skin (SQ).

Follicle Stimulating Hormone

FSH is the active hormone which is responsible in the natural cycle for stimulating the follicle to grow and the egg within it to mature FSH only drugs can be obtained from highly purifying urinary extracts or alternatively by synthetic means (genetically engineered).

Human Chorionic Gonadotropin (hCG)

Produced in pregnant women by the placenta and extracted from the urine, hCG is similar in chemical structure and function to LH. As such, in a manner similar to the natural LH surge, an injection of hCG can cause the dominant follicle to release its egg. The physician may use ultrasound and blood estrogen levels to determine the day on which to administer hCG. Ovulation will usually occur 36 to 48 hours after hCG is administered. hCG is routinely used to trigger ovulation when gonadotropins are used to induce ovulation. hCG may also be used to trigger ovulation when CC is used to induce ovulation, particularly when a mid-cycle LH surge cannot be reliably detected. A pregnancy test (which measures hCG in the urine or blood) may be falsely positive if performed less than 10 days after hCG is administered.

GnRH Analogs (Agonists and Antagonists)

GnRH is a brain hormone manufactured in the hypothalamus. Its function is to regulate the pituitary gland which in turn controls the ovary. Using different formulations of this hormones it is possible to block the production of FSH and LH and thus prevent an untimely LH surge.

During treatment with fertility medications especially during IVF an untimely LH surge may lead to cancellation of the cycle due to premature ovulation.

The GnRH like drugs belong to two groups; the agonists (Lupron) and the antagonists (Ganirelix). They have a similar mechanism of action and the same final result, prevention of an LH surge.

Bromocriptine and Cabergoline

Some women ovulate irregularly because their pituitary glands secrete too much prolactin. Increased blood levels of prolactin inhibit the release of FSH and LH, and therefore stop ovulation. The prolactin level is elevated in some women because the prolactin producing cells in the pituitary are hyperactive or form an adenoma. High prolactin levels (hyperprolactinemia) also can result from the use of certain drugs such as tranquilizers, hallucinogens, painkillers, alcohol, and, in rare cases, oral contraceptives. Disease of the kidney or thyroid may also raise prolactin levels.

Hyperprolactinemia often is treated with the medication bromocriptine or cabergoline, which reduces the amount of prolactin released by the pituitary. Parlodel® is the brand name for bromocriptine and Dostinex® is the brand name for cabergoline. These medications suppress prolactin production, and the blood prolactin level returns to normal in more than 90% of cases. Bromocriptine is taken orally as a tablet or capsule one to four times a day until the prolactin level is normal. It can also be administered vaginally. Cabergoline is taken as one to two tablets twice each week. Of the women treated, approximately 85% will ovulate and can become pregnant if no other causes of infertility are present. Bromocriptine and cabergoline treatment are usually discontinued during pregnancy. Women who fail to ovulate even after their prolactin levels are normal may be given clomiphene or gonadotropins along with bromocriptine and cabergoline.

Possible side effects of bromocriptine and cabergoline include nasal congestion, fatigue, drowsiness, headaches, nausea, vomiting, fainting, dizziness, and decreased blood pressure. For most patients, adjusting the dosage can eliminate these side effects. Some physicians start their patients on a very low dose and increase it gradually in an effort to prevent side effects. The risk of multiple pregnancies is not increased as a result of bromocriptine or cabergoline therapy.

Gonadotropin Releasing Hormone (GnRH)

GnRH is released from the hypothalamus in small amounts about once every 90 minutes. The pulsatile release of GnRH from the hypothalamus into the blood stream stimulates the pituitary gland to secrete LH and FSH. If GnRH is not being released properly, it can be administered in a pulsatile manner by a special drug delivery system that includes a belt holding a lightweight pump. The pump delivers a small volume of fluid every 60 to 90 minutes through a needle placed beneath the skin (usually in the abdomen) or into a blood vessel. The risk and complications of GnRH, such as multiple births and ovarian hyperstimulation syndrome, are quite small.