Overview of Fertility Drugs
Gonadotropin Releasing Hormone Agonists (GnRHa)
(Lupron, Buserelin, Nafarelin, Synarel)
How does the GnRHa work? A GnRHa is a medication with a very similar in structure to the hormone called gonadotropin releasing hormone (GnRH). As such, its initial effect, for approximately 4-6 days, is to stimulate the pituitary gland to produce both LH and FSH . However, like a poorly made key that gets stuck in a lock after opening it, GnRHa ultimately blocks this site from further activity and inhibits the action of this hormone in the brain. This is referred to as “pituitary down-regulation” and the effect continues for as long as GnRHa therapy is maintained uninterrupted. Thus, the blood levels of LH and FSH which are initially raised with the initiation of GnRHa therapy are sustained well above normal for 4-6 days at which time the pituitary gland becomes depleted of FSH and LH stores leading to a profound fall in blood concentrations of these hormones. This is sustained as long as the administration of GnRHa is continued. The progressive decline in blood estrogen levels that accompanies the “down-regulatory process” precipitates the onset of menstruation within 2-4 days (i.e., 6 to 10 days following the commencement of GnRHa therapy).
The reason GnRHa is administered to women who receive gonadotropin therapy is to produce a sustained reduction in the release of biologically active luteinizing hormone by the pituitary and so prevent LH levels from rising insidiously during stimulation with gonadotropins (Gonal-F, Puregon, Follistim, Bravelle, Menopur, Repronex).
GnRHa is overlapped with the BCP for a few days: So, GnRHa is administered in conjunction with the BCP for an additional 4-6 days, whereupon the BCP is discontinued while daily GnRHa injections are sustained. This approach reduces the incidence of cycle cancellation due to ovarian cyst formation. Menstruation will usually occur 6-10 days after stopping the BCP, whereupon daily gonadotropin injections are added to the GnRHa regime.
Recipients of embryos derived from a third party (e.g., egg donation and gestational surrogacy) and thawed embryos (i.e., previously frozen) undergo a similar regime of BCP/GnRHa preparation, but instead of getting gonadotropins, they receive Estrogen therapy. In such cases, the GnRHa is discontinued 5-7 days prior to Embryo Transfer (ET).
The introduction of GnRHa therapy for the purpose of preventing a “premature LH surge” requires that the woman receive GnRHa for a period of three to four (3-4) weeks, whereupon oocyte (egg) retrieval is scheduled. The woman is closely monitored and provided with printed instructions, so as to ensure that she receives the proper medications and tests at the proper time.
There is little need to be alarmed at what at first might seem to be a complex treatment regimen. Extensive studies on non-human primates, as well as limited human evaluations, indicate that GnRHa is relatively harmless to the mother and baby. The drug is rapidly (within hours) eliminated from the system upon discontinuing its administration. We discontinue GnRHa therapy at least 5-7 days prior to transferring embryos/blastocysts to the woman’s uterus. By that time, GnRHa has disappeared from the system. This fact aside, GnRHa is very close in structure to the natural hormone GnRH and is accordingly very unlikely to endanger the developing fetus.
The administration of subcutaneous GnRHa is rarely associated with significant side effects. Some women experience temporary fluctuations in mood, hot flashes, nausea. Women that are prone to symptoms of PMS may find this medication more troubling. However, symptoms are self-limiting and can be treated if bothersome. No serious long-lasting side-effects have been reported.
The injection of GnRHa given subcutaneously is relatively painless. Unfortunately, the drug will incur a modest additional financial burden. Moreover, as mentioned above, the administration of GnRHa will almost always require that gonadotropins be administered for slightly longer than would otherwise be required had GnRHa not been administered. GnRHa administration spares many women the inconvenience and frustration of repeated cancelled treatment cycles with gonadotropins. Indeed, when taking this into consideration, the administration of GnRHa in reality reduces the overall cost of ovulation induction.
GnRH Antagonists (Ganirelix, Cetrotide, Cetrorelix, Orgalutron)
(Ganirelix, Cetrotide, Cetrorelix, Orgalutron)
While initially it was asserted that the introduction of gonadotropin-releasing hormone antagonists i.e., Ganirelix and Cetrotide would have many advantages over GnRH agonists, this promise has not been fulfilled. For example, it was originally theorized that women with ovarian resistance to gonadotropins would become more responsive to COH and have better egg/embryo quality when GnRH antagonist was used than with GnRH agonists. This has not been borne out.
How do the GnRH antagonists work? Unlike GnRH agonists, which lower blood levels of gonadotropins by depleting stored pituitary FSH and LH, antagonists elicit lower blood levels of endogenous gonadotropins by rapidly blocking the release of FSH and LH by the pituitary gland. Furthermore, while the agonist takes 4-10 days to achieve an adequate blood gonadotropin lowering effect, recipients of the antagonist will respond within 1-2 days of initiating treatment.
What is the advantage of using GnRH antagonists? Since the administration of Ganirelix rapidly suppresses pituitary gonadotropin release, and menstruation occurs within two to five days, it can be administered starting in the middle of the cycle and still effectively prevent the dreaded pre-ovulatory rise in blood LH levels that could doom the cycle of treatment to failure. The manufacturers recommend that treatment with the GnRH antagonist be initiated on cycle day 6 following the onset of spontaneous or induced menstruation. Thus, unlike GnRH agonists that require a week or more to initiate adequate pituitary “down-regulation”, administration of antagonists allows for the initiation of ovarian stimulation to begin on short notice.
What are the possible disadvantages of using GnRH antagonists? First, the recommended use of antagonists by the manufacturer calls for the drug to be administered starting on day 6 of a natural or induced cycle. Since the use of hormone therapy such as progesterone or the birth control pill to regulate the onset of menstruation can lead to a diminished response to antagonist/gonadotropin therapy, the treatment schedule must be timed based on the start of spontaneous menstruation. This often renders the process both inconvenient and prohibitively expensive for patients and their IVF centers. Second, currently GnRH antagonists are significantly more expensive than the agonists.
How are GnRH antagonists administered? The use of GnRH antagonists as commonly prescribed (the administration of 250mcg daily from the 6-7th day of stimulation with gonadotropins) is problematic. The initiation of pituitary suppression with GnRH antagonist so late in the cycle of stimulation fails to suppress high tonic pituitary LH in the most formative (early) stage of folliculogenesis-a common problem for many women with fertility problems.
To overcome this hormonal imbalance, we typically prescribe 125mg daily (i.e. half the usual dosage) starting on the day that FSH-dominant gonadotropin (Follistim or Gonal-F) stimulation is initiated. The intent is to purposefully allow only a very small amount of the woman’s own pituitary LH to enter her blood; preventing an LH surge.
Clomiphene Citrate (CLOMID)
A synthetic hormone that is used alone or in combination with other fertility drugs to induce the ovulation of more than one egg. When marketed in the United States, Clomiphene citrate is also known as Clomid or Serophene.