Clomiphene citrate (Siphene and Fertyl) is an oral medication that is commonly administered
to induce ovulation in women who do not ovulate regularly.
Mechanism of Action
Clomiphene acts within the brain to promote the production of the hormone, GnRH.
As a result, the pituitary gland makes more FSH and LH, the hormones that stimulate
ovarian function.
Dosage and Monitoring
For minimal stimulation, the usual dosage of clomiphene is 100 mg daily for five
days, beginning on day two of the menstrual period. Follicle development in response
to clomiphene is most accurately determined by ultrasonography.
Adverse Effects
Severe adverse effects are uncommon with clomiphene citrate. First, as multiple
follicles can sometimes develop, multiple pregnancies may occur. Another complication
is ovarian cyst formation. While these cysts usually resolve spontaneously, they
may cause bloating and abdominal discomfort. Approximately 10% of women who take
clomiphene citrate experience hot flashes, which may disrupt sleep. A small percentage
of patients (less than 5%) report some visual changes during clomiphene citrate
therapy. Some patients describe blurred vision, while other patients describe seeing
spots or flashes of light or after images.
There does not appear to be any increased risk of birth defects in offspring of
women likewise, the risk of miscarriage in women taking clomiphene does not appear
to be increased over that noted in the general population.
There has been recent concern about an association of the use of clomiphene with
the subsequent development of ovarian cancer. At this time, information about this
subject is very limited. The increased risk of ovarian cancer in patients taking
clomiphene seems to occur only in women who have taken clomiphene for greater than
one year (12 cycles). The risk has not been observed in women who have a successful
pregnancy from clomiphene therapy.
To increase likelihood of pregnancy through ART, multiple oocytes must be produced.
This is accomplished through the administration of gonadotropins-hormonal medications
that stimulate the ovaries. Stimulation can be achieved with a variety of drug regimens.
Gonadotropin medications come in several forms, Nugon, Ovugraf and Menopur are combinations
of FSH and LH. They replace a woman's own LH and FSH which are normally produced
by the pituitary gland. Ovufol, Puregon, Gonal-F and Recagon are preparations that
contain only FSH. Gonal-F and Recagon are recombinant products which are made by
genetically engineered cells. This process ensures uniform purity and potency.
Because the dose of hormones we use in ART is greater than what the body normally
produces, the ovaries typically develop more than one oocyte as occurs in a natural
cycle.
Dosage and Monitoring
Gonadotropins are packaged in vials containing 37.5, 75 or 150 International Units
(IU). This dosage may vary depending on the patient's history, age and whether it's
an IUI or an IVF programme. The dose of gonadotropins is then determined by the
result of the ultrasonography and estradiol tests. Most women require between seven
to ten days of gonadotropin therapy. Most of the injections are given Intra Muscular
though Gonal F and Recagon can also be given via painless Pen needles.
Adverse Effects
Gonadotropin preparations are strong medications. Although rare, a potentially serious
adverse effect of gonadotropins is ovarian hyperstimulation.
There does not appear to be any increased risk of birth defects in offspring of
women who take gonadotropins compared to conceptions in the general population.
However, there is a greater risk of early miscarriage in patients taking gonadotropins.
Multiple pregnancies are another adverse effect of gonadotropin therapy. Approximately
25% of IVF-ET pregnancies are multiple. The risk of more than twins is about 5%.
Although not truly an "adverse effect," the cost of gonadotropins must be taken
seriously.
Human chorionic gonadotropin (hCG) is an injectable medication that is administered
to complete oocyte maturation. The brand names for hCG are Ovutrig or Pregnyl. These
medications come in 5,000 and 10,000 unit ampoules.
Mechanism of Action
Human chorionic gonadotropin is structurally similar to the LH that is produced
by a woman's pituitary gland. It acts on the ovary in a manner similar to a woman's
own LH. Human chorionic gonadotropin, like LH, stimulates the final maturation of
the oocytes in the follicle. It also stimulates progesterone production from the
ovary after egg retrieval. This progesterone is important to prepare the uterus
for implantation of the embryo.
Dosage and Administration
Human chorionic gonadotrophin is commonly administer a single injection of 10,000
units. Once hCG is administered, ovulation usually occurs in approximately 36 to
40 hours. IUI and IVF are scheduled as per this timing. If your response to stimulation
is particularly exuberant, we may recommend decreasing the dose of hCG to 5000 units
in an attempt to reduce the risk of ovarian hyperstimulation syndrome. It typically
takes 8-10 days for single injection of 10,000 units of hCG to be cleared from the
blood stream. As hCG is the same hormone that is produced by a developing pregnancy,
patients should not have a blood or urine pregnancy test sooner than ten days following
the hCG injection.
Adverse Effects
When given by itself, there are few, if any adverse effects to hCG. However, when
given in conjunction with gonadotropins, ovarian hyperstimulation can occur. In
fact, hyperstimulation is extremely rare if hCG is not administered.
Gonadotropin releasing hormone (GnRH) is a hormone produced in the brain that indirectly
stimulates ovarian function. Analogs of GnRH are synthetic forms of this hormone
which do not directly induce follicle development or ovulation but which have become
very important in ART therapy. When given daily, it ultimately suppresses the patient's
own hormones. There are several advantages to using GnRH analogs.
They make ovarian stimulation easier to regulate, since the patient's own hormone
production is suppressed.
Patients who are treated with GnRH analogs tend to produce a greater proportion
of mature oocytes than patients who do not receive them.
GnRH analogs markedly decrease the risk of cycle cancellation for most patients.
Prior to their use, 20-50% of IVF-ET cycles were cancelled because patients would
have a premature LH surge with spontaneous ovulation. Using GnRH analogs, the risk
of cycle cancellation is less than 5%.
Ovarian function can be suspended with GnRH analogs for variable periods of time
if necessary, which allows for flexibility in cycle scheduling.
The major disadvantage of GnRH analogs is that most patients require more medication
for ovarian stimulation. This increases the cost of an ART cycle. For most patients,
this disadvantage is far outweighed by the advantages. Sometimes GnRH analogues
are used in IUI as well especially in patients with PCOS or Endometriosis as this
significantly improves the pregnancy rates.
Dosage and Monitoring
The GnRH analogs we use most commonly are GnRH agonists like leuprolide acetate
(Lupride) or GnRH antagonists like Ganirelix (Orgalutran). Both need to be injected
just under the skin, in a manner similar to insulin injections for diabetes therapy.
The usual dosage of Lupride is 0.5mg twice daily from Day 21 of the cycle. Menstruation
usually occurs four to ten days later. During the time of actual ovarian stimulation,
the dosage of Lupride is halved (e.g., 0.5 mg once daily). Lupron is usually administered
until the day of hCG administration. In the IUI programme a lower dose of Lupride
(usually 0.25mg daily) is used from the 2nd Day of the cycle. Orgalutran is usually
administered from either Day 6 or 7 of stimulation or when the follicle reached
10 - 11 mm size. Its usual dose is 0.25mg once daily.
Adverse Effects
Adverse effects from GnRH analogs are uncommon. Occasionally, ovarian cysts may
form during therapy. These usually resolve spontaneously. Other adverse effects
of GnRH analogs include headaches, mood changes, and altered sleep. Hot flashes
may occur during prolonged therapy. Allergic reactions are rare.