Gonadotropin Injection Therapy – Superovulation

Is gonadotropin therapy for me?

You are a candidate for gonadotropin therapy if:

• You have normal or low day 3 Follicle Stimulating Hormone (FSH) and normal day 3 Estradiol levels.  If you have no spontaneous menses (amenorrhea) or you fail to menstruate after treatment with Provera – it is unlikely that you will respond to Clomiphene  therapy and you will need treatment with gonadotropins to stimulate ovulation.
• You fail to ovulate with Clomiphene Citrate  (Clomid; Serophene) – Clomiphene resistance
• You ovulate but fail to conceive with Clomiphene
• You have a thin uterine lining while undergoing Clomiphene treatment.
• Your husband is diagnosed with male factor  infertility with mild decrease in sperm count; in such cases gonadotropin therapy is coupled with intrauterine insemination (IUI).
• You have been told that you have unexplained infertility.
• You are undergoing In Vitro Fertilization  (IVF).

Why is the FSH level so important?

If you have high menstrual day 3 FSH levels or if you are menopausal, gonadotropin therapy or IVF  is unhelpful and you should consider donor egg IVF, adoption or surrogacy  (your partner’s sperm is used to inseminate another woman who will be carrying the pregnancy).

What is the appropriate type and amount of medication for me?

Generally speaking, when the problem is lack of ovulation, ovarian stimulation resulting in the development of a single follicle is ideal. The more eggs that develop, the higher is the risk of multiple pregnancies.

In cases of unexplained infertility or when utilized in conjunction with intrauterine insemination for male factor, 2-4 follicles may be optimal.

Most commonly, a dose of 75 international units (IU) of gonadotropin (FSH, HMG) is given daily and is incrementally increased every 5-6 days until the desired response is achieved; the treatment results in a cumulative pregnancy rate of 60 - 80% after 6 cycles, but also carries a risk for multiple pregnancy.

A gentler stimulation has been advocated in patients with PCOS  utilizing lower gonadotropin dosage, and slower rate of increase in the medication dose. This treatment is more likely to result in the development of a single follicle (egg), lowering the risk of multiple pregnancy or severe complications such as Ovarian Hyperstimulation Syndrome (OHSS).

Women diagnosed with a hypothalamic cause for their abnormal ovulation, usually have low levels of FSH and LH and may benefit from treatment with gonadotropin preparations containing both FSH and LH (i.e. Pergonal, Humegon, Menopur or Repronex).

Obese patients may respond poorly to this treatment (poor responders) and require high dose of gonadotropins. If they are found to have high insulin level, an “insulin blocker” such as Metformin may be added to improve the likelihood of successful ovulation.

Some patients undergoing gonadotropin treatment may ovulate spontaneously and prematurely before the eggs are completely ready for ovulation; for such cases, medication such as GNRH agonists or antagonists (pituitary suppression) can be given to block premature ovulation.

How is gonadotropin therapy monitored?

The treatment is expensive and labor intensive, requiring frequent monitoring by blood estrogen levels and ultrasounds to measure the number and size of the follicles (which contain the eggs) and to measure the thickness of the lining of the uterus.

• You will be scheduled for an ultrasound and estrogen level on day 2 or day 3 of your menstrual cycle before you are cleared to start treatment. Sometimes an ovarian cyst can be present which may result in postponement of the stimulation cycle.
• Your doctor will determine the type and dose of the gonadotropins to be utilized and you will undergo daily injections of the hormone for about 8-10 days.
• An estrogen blood level is measured after 3 days of injections. The medication is sometimes increased if the estrogen level is low or decreased if the estrogen level is too high. In the course of treatment you will have several ultrasounds and estrogen level measurements to help your doctor determine when you are ready for ovulation.
• HCG "trigger" is given when ultrasound shows that the largest (dominant) follicle is 16-20 mm in size and the uterine lining is at least 8 mm thick. 
• Ovulation occurs about 36-40 hours after the HCG injection.
• Intrauterine inseminations (IUI) are performed 24-36 hours after the HCG shot to coincide with ovulation. After ovulation your doctor may decide to treat you with progesterone suppositories or pills to improve the likelihood of successful implantation.
• A progesterone level is measured 7 days after ovulation. A progesterone level greater than 15ng/ml is indicative of good ovulation. A pregnancy test is performed 14 days after ovulation, and if pregnant, progesterone therapy is typically continued for an additional 6-8 weeks.

Ultrasound monitoring of gonadotropin treatment

• Ultrasound of the ovaries (below, right) demonstrating follicles containing eggs ready for ovulation.
• Ultrasound of the uterus (below, left - outlined in blue); the lining of the uterus or endometrium is outlined in orange. The endometrial thickness is greater than 8mm (outlined in yellow) and is ready for the fertilized egg or embryo to implant.

How successful is gonadotropin therapy?

• 60% cumulative pregnancy rate after 6 cycles of treatment in patients with PCOS. 
• The treatment is most successful in women who fail to ovulate with Clomiphene therapy (Clomiphene resistant).
• At BocaFertility we have experienced a pregnancy rate of 25% per cycle and a delivery rate of 22% per cycle for all patients treated with gonadotropins and IUI.

What about the risks of gonadotropin therapy?

As with any medical treatment, there are some risks specific to fertility medications:

• Multiple pregnancy - (mostly twins) occur in approximately 20% of ovulation induction cycles utilizing gonadotropin injections.  
• Poor response - treatment is discontinued during IVF  when there is no response or when less than 3 eggs develop. When this happens, a different stimulation protocol utilizing higher gonadotropin dose is usually advised.  
• Cycle cancellation – Gonadotropin injections are discontinued and ovulation is prevented when too many eggs develop or when the estrogen level is very high, as this may increase the risk of multiple pregnancies and ovarian hyperstimulation syndrome.
• Ovarian Hyperstimulation Syndrome (OHSS) - is a potentially life threatening complication resulting from overstimulation of the ovaries. The condition is associated with ovarian enlargement, torsion (twisting) of the ovaries, weight gain, accumulation of abdominal fluid, decrease of blood volume and low blood pressure, requiring hospitalization and aggressive treatment. OHSS may occur even with mild stimulation. Fortunately, the severe form of Ovarian Hyperstimulation Syndrome is uncommon, occurring in less than 1% of patients.

Commonly used fertility medications

Clomiphene Citrate tablet brands are taken by mouth usually at a dose of 50 mg daily for 5 days between days 5-9 of your menstrual cycle. In patients with shorter cycles the medication is sometimes started earlier on day 3 of cycle.

Injectable Gonadotropin pens – are given to help a woman produce and release healthy eggs when ovulation is a problem or to stimulate the ovaries to produce multiple eggs during In Vitro Fertilization (IVF). You must be closely monitored by an experienced fertility specialist. throughout the treatment.

Conventional gonadotropin injections - potent hormones injections containing FSH and LH and must be closely supervised by a fertility specialist.

HCG “trigger” – an HCG medication given to "trigger" ovulation when ultrasound shows that the largest (dominant) follicle is between 16-20 mm. The medication is sometimes utilized to maintain adequate progesterone production from the ovary after ovulation.

Progesterone preparations – utilized to maintain optimal progesterone levels after ovulation and through the first 12 weeks of pregnancy. The medications can be given in the form of vaginal tablets, vaginal suppositories or injections.

GnRH medications –

• GnRH agonists are used are given to suppress pituitary function during IVF and in the treatment of endometriosis or uterine fibroids. During IVF it important to prevent your own trigger to ovulation. They can be given beginning a week before your menses (long protocol). They can also be given together with the gonadotropin injections beginning on day 2-3 of cycle (micro-dose or short protocol).
• GnRH antagonists such as Ganirelix or Cetrotide are given daily, beginning on day 6 of gonadotropin injections.