IVF DRUGS (GONADOTROPINS)
Gonadotropins are hormones produced by the pituitary gland to stimulate sperm and egg development and release reproductive hormones such as estrogen, progesterone, androgens and testosterone. They are also indirectly involved in the stimulation of secondary sexual characteristics such as hair growth and breast development. There are two types of gonadotropins and include follicle stimulating hormone (FSH) and luteinizing hormone (LH).
Two different types of gonadotropins are available in the market, which include human menopausal gonadotropins (hMG – Repronex, Menopur and Bravelle) derived from menopausal women; and recombinant FSH (rFSH – Gonal-F or Follistim) and recombinant LH (rLH – Luveris), which are genetically engineered. Gonadotropins cannot be absorbed through the stomach or the skin. Therefore, they must be administered by injection rather than as a pill or a patch.
1. Human Menopausal Gonadotropins (HMG) – Repronex and Menopur
HMG includes equal amounts of FSH and LH in its preparations (75 units of FSH and 75 units of LH). In the menopausal years, excessive FSH and LH hormones are released from the pituitary gland due to lack of suppression by ovarian hormones (estrogen, AMH, and Inhibin B). The excess FSH and LH are concentrated, filtered, and purified for medical use. These drugs constitute the older version of gonadotropic drugs that have been available since 1970s under different names such as Puregon, Pergonal and Fertinex that are no longer available in the market.
Repronex and Menopur are manufactured by the same company and have equal efficacy, but Menopur is the newest form of these drugs that has been purified further to minimize side effects and can also be injected under the skin (subcutaneous) or into the muscle (intramuscular). HMG comes in the form of a powder inside a sterile vial that must be mixed with water prior to injection.
LH hormone, which is a component of HMG, directly stimulates the tissue surrounding the ovarian follicles (ovarian stroma), which releases male hormones (androgens – testosterone). Whereas some level of androgens is necessary for egg maturation, development and estrogen production, excessive androgens may adversely affect egg quality and growth. It is also possible that some of the androgens could inhibit the proper development of the endometrial lining. Therefore, excessive ovarian androgen production induced by untimely exposure to LH could have a deleterious effect on egg and embryo quality as well as on the potential for healthy implantation into the endometrium.
2. Recombinant FSH (rFSH) – Gonal-F and Follistim
Recombinant DNA technology has allowed the production of gonadotropins separately in the laboratory, known as recombinant FSH (rFSH) and LH (rLH). They have been reported to be purer than HMG products and the injected volume is much less making it more user friendly with possible less side effects. Gonal F and Follistim are manufactured by separate companies, but have the same efficacy and result in the similar outcomes.
They are available in the form of an injectible pen that can be carried around easily and don’t require mixing with water which is the case with HMG type products. FSH preparation is stored either inside the pen (Gonal F) or come in the form of a cartridge that has to be loaded into the pen (Follistim). They both come in the form of individual vials that can be mixed (similar to HMG products), but this is generally not the preferred way to use them. Gonal F also comes in the form of a multi-dose vial, which allows the desired dose to be used from the same vial each day and perceived to be more convenient by some patients. Once again the efficacy of these two brands is the same.
3. Purified HMG derived FSH – Bravelle
Bravelle is similar to Repronex that has been processed further to extract almost all LH to the point that there is virtually no LH (<2%) remaining. It has equivalent efficacy to the recombinant FSH (rFSH). It is manufactured by the same company that also makes Repronex and Menopur. It requires mixing the powder with the water prior to injection similar to other HMG products.
4. Recombinant LH (rLH) – Luveris
This drug is approved by the FDA for use in hypothalamic amenorrhea cases, where there is insufficient release of FSH and LH hormones that result in lack of ovulation. It is commonly used in ovarian stimulation protocols (especially IVF) to supplement the LH component along with recombinant FSH medications (instead of using HMG that contains both).
GnRH AGONISTS AND ANTAGONISTS
GnRH is released from the hypothalamus and stimulates production of FSH and LH from the pituitary gland, and GnRH agonist/antagonist drugs oppose the action of GnRH. In natural cycles, FSH induces egg development and LH is involved in ovulation. When these hormones are not released, injectible gonadotropins can be administered to grow and mature multiple eggs at once. GnRH agonist/antagonist drugs not only allow multiple eggs to develop with gonadotropin use, but also prevent premature or spontaneous ovulation, thus allowing timely egg recovery and fertilization in the laboratory for IVF treatment.
1. Leuprolide – Lupron
Lupron is a GnRH agonist type drug which results in down-regulation of the GnRH receptors (binds to the receptor and decreases the number of receptors), thus preventing the actual GnRH hormone to exert its effects on the pituitary gland. The initial effect of Lupron is to release some FSH and LH from the pituitary gland (Lupron flare) and subsequently lower their levels. The initial FSH release may stimulate the ovaries and result in follicle development that can turn into a cyst prior to starting ovarian stimulation. LH can stimulate testosterone production, which may adversely affect egg quality. Birth control pills can be used in conjunction with Lupron to prevent the flare effect or Lupron can be started following ovulation and before the period starts (luteal phase start). Its common side effects include headaches, hot flashes, insomnia and mood changes. Once the drug is discontinued, side effects frequently subside within a few days.
2. Cetrotide and Ganirelix
These two drugs are GnRH antagonists which bind to the GnRH receptor and immediately block the action of the hormone. They do not result in the flare effect or cause cyst formation, which can be observed in some patients who take Lupron. Both drugs are routinely used in IVF cycles to prevent premature ovulation. They are manufactured by different companies, but have the same efficacy and the side effects (similar to Lupron).
Side Effects of Gonadotropins
Close monitoring of patients taking gonadotropins is necessary in order to minimize the side effects. Some women taking gonadotropins report breast tenderness and engorgement, headaches, insomnia, mood changes, bloating, and increased vaginal discharge.
In the general population, multiple pregnancy rate without taking any fertility medications is 1-2%. Conversely, approximately 20-40% of pregnancies resulting from gonadotropin therapy are multiple pregnancies. While most of these pregnancies are twins, 3-5% are high order multiples (triples or more). In Dr. Bayrak’s IVF practice, the risk of triplet pregnancy is less than %1 due to limiting of the number of embryos being transferred. Multiple pregnancies are associated with an increased rate of complications such as pregnancy loss, preterm/premature delivery, severe mental and physical disability due to prematurity, bleeding, abnormal placenta formation, high blood pressure, diabetes and other maternal and fetal problems.
In spontaneous conceptions, the risk of ectopic pregnancy is 1-2% compared to 3-4% in cycles using gonadotropins. Although most patients taking gonadotropins are followed closely with blood tests and pelvic ultrasounds after becoming pregnant and ectopic pregnancies diagnosed early, pregnancy in the fallopian tube can rupture and cause internal bleeding. It can be treated medically with an injection (Methotrexate) or surgically. Rarely, an intrauterine pregnancy can occur with ectopic pregnancy at the same time due to two implantations in two separate places. This type of pregnancy, called a hererotopic pregnancy, may be difficult to diagnose. In such cases, surgery is required to remove the ectopic gestation in order to allow the intrauterine pregnancy to continue.
Gonadotropins and Cancer:
Based on large scale studies, it has been reported that gonadotropin use does not increase the risk of ovarian or breast cancer.
The risk of birth defects or pregnancy complications appears to be higher in the infertile population who also use gonadotropins for IVF treatment. It is believed that the patient’s baseline risk increases the odds of complications, rather than the medications used or IVF treatment.
Ovarian Hyperstimulation Syndrome (OHSS):
OHSS is characterized by enlarged ovaries, pelvic pressure/fullness sensation and fluid accumulation in the abdomen following gonadotropin treatment. While most cases are mild (10-20% of gonadotropin cycles), severe cases can occur as well (1% of cycles). In the mild form, some discomfort is felt by the patients, which resolves on its own without any complications. In the severe form, marked enlargement of ovaries and fluid accumulation in the abdomen can result in difficulty in breathing, intolerable abdominal pain, kidney dysfunction, blood clot formation, ovarian torsion (twisting of the ovary) and even death, although extremely rarely. In severe cases, hospitalization may be required for close monitoring and drainage of fluid from the abdomen by a procedure called paracentesis, which may be necessary to improve symptoms.
OHSS is self-limiting with supportive therapy and usually resolves in 1-3 weeks. When a pregnancy forms in the presence of OHSS the syndrome is more severe and lasts longer compared to a cycle that does not result in a pregnancy. Patients at risk should be identified early and monitored closely to avoid the severe form. Some of the prevention and treatment modalities include delaying the administration of HCG injection until estradiol levels fall to a certain threshold (coasting), freezing all embryos and transferring them in a subsequent cycle and administration of albumin and intravenous fluids. At Dr. Bayrak’s practice, moderate or severe OHSS is extremely rare due to specific protocol design for each individual case and close monitoring of response to gonadotropin treatment.