Fertility Drugs II: Injectable Gonadotropins

(Pergonal®, Humegon®, Repronex®, Fertinex®, Gonal-F®, Follistim®)

What are injectable gonadotropins?

Injectable gonadotropins are medical preparations of naturally occurring hormones that the brain produces to stimulate the ovaries to produce hormones and to prepare eggs for release. The two hormones are follicle stimulating hormone, or FSH, and luteinizing hormone, or LH.

What do these two hormones do?

Human eggs wait in the ovary in a partially matured state. Early in each menstrual cycle, the brain sends FSH to the ovary, which in turn selects a group of eggs to begin the maturation process. The FSH stimulates the maturation of the eggs, and stimulates the release of increasing amounts of estrogen. LH is released along with the FSH, and stimulates the ovary to release additional hormones that also play a role in egg development. Typically, only one of the recruited eggs becomes fully mature. When this single, dominant egg is ready for release, a great, one-time release of LH, known as the LH surge, tells the ovary to release the one mature egg

When we use HMG (Human Menopausal Gonadotropin) or FSH as a medication, we bypass the body’s normal process of egg development and release. In this way, we can induce ovulation in women who do not ovulate on their own, produce more than one mature egg each cycle and fix faulty egg developing systems. These medications are either used by themselves, in conjunction with intrauterine insemination procedures, or for in vitro fertilization.

What are Pergonal, Humegon, Fertinex and Repronex?

Pergonal, Repronex, Humegon and Fertinex are the commercial names for the naturally derived HMG and FSH preparations available in the United States. They are all manufactured by purifying the secreted hormones from human urine. Pergonal is 50% LH and 50% FSH. It is given by injection only, using a 1½-inch needle injected deep into the muscle, usually in the backside. Humegon is virtually identical to Pergonal, but is manufactured by a different company. Repronex can be injected subcutaneously with a smaller needle (approximately ¼”). Fertinex is a newer form of FSH. Its advantage is a better purification process, making it also injectable using a smaller needle.

What are Gonal-F and Follistim?

These are recombinant forms of purified FSH, manufactured by a biosynthetic method. Due to increased purity, both products can be given subcutaneoulsy with a small needle similar to Fertinex and Repronex.

Is one preparation superior to another?

In theory, FSH is more important than LH in the development of mature eggs. However, purified FSH and HMG seem to work equally well in terms of pregnancy rates. Some centers use a combination of the two preparations in patients’ cycles. The E2 may rise more slowly or to a lower peak level in the very beginning of the cycle with the recombinants. This does not appear to affect the outcome.

How is HMG given?

HMG is given by intramuscular (IM) injection either once or twice daily. Repronex, Fertinex and the recombinants require a smaller needle injected just below the skin surface.

How is the cycle monitored?

Cycles typically start on the third day of the menstrual cycle, although day four or five starts are not uncommon. The development of the eggs is monitored by blood tests for estradiol and transvaginal ultrasound examinations for follicle size and endometrial thickness.

Please define estradiol, progesterone, follicle size and endometrial thickness.

Estradiol is the most important hormone in the estrogen family of sex steroid hormones. It does many things to prepare the reproductive system for pregnancy. It rises in a predictable way in a natural cycle, and provides important information about egg development in a gonadotropin cycle. Progesterone provides support for the second half of the menstrual cycle, after ovulation, supporting and stabilizing the uterine lining. Prior to ovulation, progesterone slowly rises, providing information that the more mature eggs are approaching readiness for release. Follicle size refers to the appearance of the eggcontaining areas of the ovaries in the days leading up to ovulation. The eggs themselves are too small to see on an ultrasound, but the small, fluid-filled follicles that contain the eggs are easy to see and measure. Typically, follicles start at less than 10 millimeters and increase to at least 18 millimeters just prior to the LH surge. Endometrial thickness refers to the ultrasound appearance of the uterine lining. The lining thickens from 3-4 millimeters at the start of the cycle to greater than approximately 8 millimeters prior to the LH surge. In addition, the appearance of the lining may change from a homogeneous white line to a characteristic three-lined (also known as a Type I or trilaminar appearance) prior to ovulation. The subsequent release of progesterone further changes the appearance of the lining.

Does the LH trigger come naturally during gonadotropin cycles?

Since the normal communication between the brain and the ovary is affected by the use of HMG or FSH, we trigger the LH surge ourselves. Since pure LH is difficult to prepare and rapidly loses its effectiveness after injection, we use human chorionic gonadotropin, a naturally occurring hormone that looks and acts very much like LH in this situation. Other names for human chorionic gonadotropin are HCG (generic name), Profasi®, Pregnyl®, Novarel® and Ovidrel® (commercial names).

What are the risks of injectable gonadotropins?

The principal risks are multiple pregnancy and ovarian hyperstimulation syndrome.
Gonadotropins constitute the family of medications most associated with multiple pregnancy. News reports of high-order multiple pregnancy - quadruplets, quintuplets or even higher - are almost always related to the use of injectable gonadotropins. Since gonadotropins bypass the body’s usual mechanism for limiting the number of mature eggs available in any given cycle, the possibility of multiple pregnancy is always a foremost consideration in managing a gonadotropin cycle.

Ovarian hyperstimulation syndrome (OHSS) refers to a combination of symptoms created after ovulation by the very stimulated ovaries. The principal problem is a release of large amounts of fluid by the ovaries coupled with a leaking of fluid from the blood vessels into the abdomen. Symptoms include bloating, decreased output of urine, nausea and vomiting. Serious cases can include fluid around the lungs and imbalances in electrolytes (principally sodium and potassium). The most serious cases can require intensive care and be life-threatening.

Are these risks preventable?

They can be minimized, but not completely prevented. Thankfully, a small number of eggs will fertilize and develop in any gonadtropin cycle, usually one or two. The risk of a higher level multiple can be decreased by adjusting the medication dose to provide fewer eggs, withholding the HCG and abstaining from intercourse to prevent pregnancy completely in a cycle with too many mature eggs, or performing an in vitro fertilization procedure, removing the eggs and limiting the number of resulting embryos returned. As a last resort, high level multiple pregnancies can be reduced after the pregnancy has been established.

Do these medications increase the risk of ovarian cancer?

The honest answer is we do not know yet. Because these medications bypass the body’s normal mechanism for controlling egg development, one can theorize that they may stimulate abnormal as well as normal development. No study has definitively implicated injectable gonadotropins in higher rates of ovarian cancer, but research has not disproved a potential link either. For this reason we try to limit HMG use to a reasonable number of cycles.

Is there an increase in birth defects or pregnancy complications?

None other than those associated with the higher multiple pregnancy rate.

Edited by:
David Sable, M.D.
The Institute for Reproductive Medicine and Science of Saint Barnabas Livingston, NJ

Owen Davis, M.D.
The Center for Reproductive Medicine and Infertility, The Cornell Institute for Reproductive Medicine, New York, NY

This fact sheet was funded by an unrestricted educational grant from Kings Pharmacy
Tel: 1 800 795-4647 http://www.kingsrx.com