Several protocols are commonly used for ovulation induction and ovulation enhancement with menotropins. The physician in charge of your COH or IVF cycle should be experienced in the use of these medications to optimize your ovarian response and limit your exposure to the risk of complications. Common features of appropriate protocols include:
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(1) Perform an ultrasound exam prior to initiating a cycle.
There should be no large cysts within the ovaries at the onset of a stimulation cycle. Cysts greater than 2 cm (and possibly 1.5 cm) are relative contraindications for starting these medications.
Larger cysts (2 cm) appear to interfere with optimal stimulation either by producing local hormones (that disrupt the surrounding follicular development) or by mechanically interfering with follicular development (due to their size).
I generally advise patients with large ovarian cysts to cancel the cycle and return the following month for an ultrasound. They may start stimulation when the cyst is gone. Most cysts seem to be residual (corpus luteum) cysts from the prior cycle and are spontaneously absorbed (removed) by the body within days to weeks.
Selected patients are allowed to initiate a cycle despite a large ovarian cyst if the circulating estrogen concentration is found to be low (indicating that the cyst is not producing estradiol). If a larger cyst in the ovary persists over several months then further evaluation and probably removal would be recommended. Removal of persistent nonfunctional large cysts of the ovary is primarily to rule out serious pathology (such as cancer).
(2) Menotropins are started during the early part of the cycle
A “standard” protocol for COH is 2 ampules of menotropin per day starting on cycle day 2, 3 or 4. The first day of heavy flow is cycle day 1. Medications are usually given in the evening (at about the same time each day). Monitoring bloodwork for estradiol concentration is initiated after 3-4 days of medication. This estrogen level allows adjustment of the medication dosage and determination of when to return to the office for additional bloodwork (and possibly an ultrasound). Once additional testing with ultrasounds is begun, monitoring is usually more frequent and may even be required each day. On average, a “typical stimulation” may involve 5-10 days of medication and the patient may need to return to the office on 2-5 occasions for monitoring.
(3) Dosing of menotropins may be changed from cycle to cycle
Some patient’s ovaries are difficult to stimulate with menotropins. If 2 ampules per day result in a poor response, then increasing the dosage of medication (from 2 to 4 ampules per day) is considered. Ultimately, a limit for the amount of menotropins used per cycle should be determined. Generally I do not use greater than 8 ampules per day since I have not seen reasonable success in achieving a pregnancy with greater doses.
Other patients may have ovaries that will respond by maturing too many follicles at once. If there is a larger than desired response to 2 ampules per day, then decreasing the amount of medication to 1 ampule or 0.5 ampule is considered.
(4) GnRH agonists may be used for ovarian suppression or “a flare”
GnRH agonists (a type of medication) are often used concurrently with menotropins during stimulated cycles.
The most common indication for use of a GnRH agonist is when more even development of follicles is desired (especially during IVF cycles). If a stimulated cycle resulted in maturation of only 1 or 2 mature eggs despite the presence of multiple other less mature follicles then the addition of a GnRH agonist for the next cycle may be helpful to synchronize follicular development. In these situations, the GnRH agonist is started about a week prior to the expected menses to suppress any early development of follicles (so the follicles are at a common baseline of development when the menotropins are started).
Use of a GnRH agonist also enables the physician to push the developing follicles to larger sizes at the end of the stimulation cycle. This is possible because the patient will not be able to mount an LH surge (trigger her own ovulation) while on a GnRH agonist.
The method of administration of the GnRH agonists varies from injectable medications to an intranasal spray. Many different GnRH agonists have been developed and those clinically available have different half lifes (durations of effectiveness). Medication is taken either once or twice a day (depending on the particular product chosen). In the USA, available GnRH agonists include lupron (injectable) and synarel (nasal spray).
The (time) course of action of the GnRH agonists is biphasic. The GnRH agonist molecule is a biologically active modification of natural GnRH that has very long acting “GnRH like” activity (the modifications to natural GnRH result in very slow degradation of the GnRH agonist). Initially (for the first few days) GnRH agonists result in the release of stored FSH and LH from the pituitary gland (which is a GnRH like activity). The chronic activation of the GnRH receptors on the pituitary gland (by the long acting GnRH agonists) then results in both suppression of production of new FSH and LH molecules and downregulation of the GnRH receptors (suppression of the pituitary gland’s ability to respond to GnRH). Therefore, following the initial few days of stimulation there is longer term suppression of FSH and LH and a consequent suppression of follicle development within the ovary. GnRH agonists also (transiently) disable the woman’s ability to trigger ovulation via the LH surge .
A “flare” protocol exists, for which the GnRH agonist is started at (about) the same time as the menotropins. This flare protocol takes advantage of the initial release of pituitary FSH and LH, which may enhance egg development. With the flare protocol there will be pituitary and ovarian suppression by the time of ovulation so there is an inability to mount the LH surge (signal to ovulate). Flare protocols usually are shorter than other stimulation protocols and (generally) result in the development of fewer mature eggs.
(5) Polycystic ovaries are often difficult to stimulate
Polycystic ovaries are characterized by a large number of follicles that are arrested in early to mid development. When stimulating polycystic ovaries, the goal is to avoid excessive numbers of small follicles with very high circulating estradiol concentrations since this situation can result in severe forms of ovarian hyperstimulation syndrome. Protocols to avoid excessive development of ovarian follicles differ dramatically from one another. Some start with a high dose of menotropins and cut back once a few follicles have begun to develop. Others start with a low dose of menotropins, hoping that only a small number of follicles will respond. Still others administer 1-3 months of birth control pills to suppress follicular development and then use a GnRH agonist to continue to suppress abundant follicular development until menotropins are started. There is usually a considerable learning curve (trial and error period) to customize the menotropin strategy for each individual patient with PCOS (since the ovaries generally respond uniquely and unpredictably). Trying several different menotropin protocols might be required before settling on an ideal protocol for a particular patient’s ovaries.
(6) Giving steroids may suppress excessive androgenic hormone production
Circulating androgenic hormones can interfere with follicular development. Androgenic hormones are associated with male pattern hair growth and occasionally dark irregular discoloration of the skin usually in areas of creases (such as arm pits, neck, under breasts). Blood hormone studies can usually (but not always) confirm high circulating levels of these hormones. If androgen concentrations are elevated or if there are clearcut physical signs of excess androgens then consideration of concurrent low dose glucocorticoid steroid medication (such as dexamethasone or prednisone) is often considered.
(7) GnRH pumps are available
As an alternative to menotropin therapy these pumps will infuse the hypothalamic releasing hormone, GnRH, in preset amounts and time intervals. GnRH will directly stimulate release of FSH and LH from the pituitary gland. In my experience, patients do not like the concept of an indwelling catheter either placed under the skin or into a blood vessel. The catheter stays in place for weeks to months and works by means of a small pump (about the size of a transistor radio) that the patient carries.
At the end of the stimulation process, human chorionic gonadotropin (hCG, such as Profasi) is administered (intramuscular injection) to simulate the LH surge and trigger both the final maturational step in egg development and the release of the mature egg(s).
Human menopausal gonadotropins are expensive. For controlled ovarian hyperstimulation (COH) with intrauterine inseminations (IUIs) two to three (but up to six) ampules per day are taken for about 7 +/- 3 days, for a normal total of 15-25 ampules. For In Vitro Fertilization about twice as much medication may be normal. Since each ampule costs about 30-50 (US) dollars the total for the medication can be one (or more) thousand (US) dollars per attempted cycle. In addition, the professional and other fees for monitoring can be expensive.