Fertility Injections

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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 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 and may be fertilized, giving rise to multiple gestation (twins, triplets, quadruplets, etc.). Second, hyperstimulated ovaries may 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. Alternatively, the medication is dispensed in premixed "pens" which allow for more convenient administration. Sometimes, a spouse, relative or friend will be recruited to administer the medication. The "pens" allow women to give themselves injections with little hastle.

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) .Two types of hCG are avaiable-- one obtained from pregnant women, the other the product of recombinant technology. hCG functions similarly to luteinizing hormone (LH).( LH is available as a recombinant product at such a high price as to preclude its use to trigger ovulation) hCG 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.

Because there is a tendency for the next menstrual period to begin too soon,hormones 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 which are dispensed in convenient "pens"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 Menopur or Bravelle to our patients who do not have a prescription plan that covers injectables.

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)

• ectopic pregnancy and miscarriage (slightly increased over normal rates)

• rupture, bleeding or twisting of ovarian cysts

• severe hyperstimulation

Human chorionic gonadotropin (hCG)
Human chorionic gonadotropin (hCG) is a protein produced during pregnancy.The original form of hCG is recovered from the urine of pregnant women, purified (which eliminate the risk of infection) and marketed in the form of a powder. Another form of hCG (Ovidrel) is now manufactured by recominant techniques, that is, by cell cultures that have been genetically programmed to make this protein. Most of our patients receive hCG rather than Ovidrel since the hCG preparation is cheaper and, perhaps, slightly more effective.

The biological action of hCG is identical to the action of another hormone-luteinizing hormone (LH). Luteinizing hormone is currently available as a medication in quantities too small and expensive to be used for triggering ovulation.. As a substitute for luteinizing hormone, hCG is used to trigger ovulation and maintain hormone production from the ovaries after ovulation. 

The dose of hCG, which we will use to trigger ovulation, varies according to the individual and the clinical situation. Below are instructions for reconstituting hCG in the most commonly prescribed dosages. Usually, Hcg is sold in a glass vial, which has a rubber diaphragm at its top through which a needle may be inserted to inject and withdraw liquid. The liquid used to dissolve the hCG (the diluent) is supplied in a similar vial. Usually, 10 cc of water are supplied in the diluent. Be careful to keep track of which vial contains the hCG powder and which vial contains only the diluent water. Once you have dissolved the hCG powder with water, the liquid in both bottles will appear identical.

GnRH Like Drugs
Gonadotropin releasing hormone (GnRH) is a small molecule synthesized in the brain which circulates to the pituitary gland where it releases the hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH in turn circulates to the ovary where it stimulates the growth of the ovarian follicle (the cyst which contains the egg which will be released at the time of ovulation) and the production of the hormone estrogen.

LH is produced in a midcycle surge which triggers the release of the egg from its follicle. LH also stimulates the production of the hormone progesterone during the second half of the menstrual cycle.

Gonadotropin releasing-like hormones are available as medication. Some of these drugs are called agonists. Agonists are substances which have an action similar to the hormone they resemble. Other GnRH congeners are called antagonists. Antagonists directly counteract the action of the hormone they resemble.

It is a curious property of GnRH agonists that when they are administered in a continuous fashion for more than 7-10 days, they assume an antagonistic action on the pituitary. This means that GnRH agonists will stimulate the production of FSH and LH for about one week, after which time the production of FSH and LH is suppressed. In treating endometriosis and fibroids, we utilize the suppressive effects of GnRH agonist drugs to treat diseases. For fertility treatment we may use both actions.

Fertility Treatment
GnRH agonists are frequently used in combination with fertility drugs. Both the agonist and antagonist property of these medications can be utilized when ovulation is stimulated. In the recipes referred to as "flare up", we administered GnRH agonists simultaneously with fertility drugs to amplify the stimulation of the ovary. Remember, for the first 7-10 days that these drugs are used, a woman's own FSH and LH are elevated. The woman's FSH and LH will add to the stimulation provided by the FSH and LH found in injectable gonadotropins. A flare up recipe is most often used in woman who have a sluggish response to the gonadotropins.

Another recipe involves the use of GnRH agonists or antagonists prior to the initiation of ovulation. These recipes are called "suppression" regimens. In a long suppression regimen, GnRH agonist is begun in the month prior to ovulation stimulation. Once menses has begun, we start gonadotropins. This regimen is utilized to synchronize a woman's ovaries so that no one follicle will have achieved a head start before gonadotropins are begun. For short suppression GnRH antagonist is given once gonadotropin injections have begun for the purpose of preventing premature ovulation.

In both the flare up and suppression regimens of GnRH agonists/antagonists, a woman's own LH surge is inhibited. Therefore, there is no chance that a woman will spontaneously ovulate prior to the administration of hCG. This phenomenon is useful in in vitro fertilization when we do not want a woman to have released her eggs prior to the time we go to harvest them.