Menotropins are a powerful group of medications in which the most
active ingredient in terms of ovulation induction or enhancement
is follicle stimulating hormone (FSH). The unit of measurement
for FSH is the International Unit (IU) which is based on an international
reference preparation (IRP). One ampule of lyophilized (freeze
dried) FSH generally has 75 IU of FSH (some have 150 IU of FSH
so you should read the label).
Some menotropins, such as Pergonal and Humegon, also contain 75
IU (or 150 IU if there is 150 IU of FSH) of LH. LH stimulates
the production of estrogen's precursor hormones (androstenedione
and testosterone) in the ovary. Many women secrete adequate LH,
making the addition of LH in these medications unnecessary. If
the anticipated estrogen production is quite large, such as when
heavily pushed to maximally produce mature eggs in IVF cycles,
then many infertility specialists prefer to have additional LH
available. Also, there are some women who do not produce LH in
adequate amounts and these women benefit from the additional LH.
The basic infertility evaluation should be completed prior to
the use of menotropins.
Menotropins are contraindicated in women with no ovarian reserve
(menopause). A woman with early ovarian failure will occasionally
have a spontaneous recovery of ovulation (for unknown reasons)
but attempts at ovulation induction or enhancement in these women
are usually unrewarding. Ovulation induction can be considered
if the FSH concentration is less than the LH concentration and/or
the estradiol concentration is greater than 40 pg/ml (the amount
required for a withdrawal flow).
There should always be documentation of tubal patency and availability
of sperm prior to initiating treatment with menotropins. I often
recommend a laparoscopy to assess and optimize the pelvis prior
to menotropin therapy. An exception is when the only finding on
evaluation is a clear-cut ovulation disorder. The appropriateness
of laparoscopy should be individually discussed with each couple
considering menotropins.
Menotropins can be used for either ovulation induction, ovulation
enhancement in a process referred to as "controlled ovarian
hyperstimulation" (COH) or "assisted reproductive technology"
(ART, including IVF).
Menotropins are injectable medications. Most of these have considerable
contamination with other proteins and are given as intramuscular
injections deep into the upper outer quadrant of the gluteus maximus
muscle (rear end). Fertinex is an exception in that it has been
highly purified through affinity chromatography so that it can
be self administered subcutaneously (under the skin) in the upper
thigh. Recombinant forms of menotropins are also highly purified
and can be administered subcutaneously.
In my experience, the partner of the woman being treated is the
most reliable and caring person to give the intramuscular injections
once taught the proper technique (to prepare and administer the
medication). The shot is given at night (occassionally twice a
day) in a dosage that may change from day to day.
There are several protocols commonly used for ovulation induction
and 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 response and limit complications. Common features
of appropriate protocols include:
(1) perform an ultrasound exam prior to initiating a cycle.
* There should be no large cysts within the ovary at the
onset of a stimulation cycle. Cysts greater than 2 cm (and possibly
1.5 cm) are relative contraindications for starting the medication.
Larger cysts may interfere with optimal stimulation either by
producing hormones locally to disrupt the surrounding follicular
development or by mechanically interfering with follicular development
due to their size. I will generally advise that the patient with
a large ovarian cyst return the following month for an ultrasound
and may start stimulation if the cyst has gone away. Most of these
cysts seem to be residual (corpus luteum) cysts from the prior
cycle and are removed by the body within days to weeks. Selected
patients will be 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 functioning hormonally).
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 in 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 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 take 7-12 days of medication and the patient
will have returned to the office on 3-5 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 results in a poor response,
then increasing the dosage of medication is considered. Increasing
from 2 to 4 ampules per day is common. Generally I do no use greater
than 6 ampules per day since I have not seen reasonable success
in achieving a pregnancy with greater doses. Some patient's ovaries
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 are a type of medication often used with
menotropins in stimulated cycles. Their most common indications
are when more even development of follicles is desired. If a prior
stimulated cycle resulted in maturation of only 1 or 2 mature
eggs despite the presence of multiple other follicles then use
of a GnRH agonist may be helpful. In these situations, the GnRH
agonist is started about a week prior to the expected menses to
suppress any early development of follicles (the follicles are
at a common baseline of development when the menotropins are started).
Also, use of agonists allows for greater control and the ability
to push follicles to larger sizes at the end of the stimulation
cycle.
* the GnRH agonists may be administered in a variety of
ways, including as injectable medications or taken as an intranasal
spray. There are many different GnRH agonists available and each
has a different half life (duration of effectiveness). Thus, these
medications may need to be taken either once or twice a day depending
on the particular product chosen.
* GnRH agonists will initially result in the release of
stored FSH and LH from the pituitary gland. This stimulatory response
to these medicines lasts for the first few days. GnRH agonists
also suppress the production of new FSH and LH so that once the
stored hormones have been released the circulating FSH and LH
is very low. Therefore, following the initial few days of stimulation
there is a suppression of the ovary for the duration of administration
of the medication. Since these medications deplete stored LH the
brain is also incapable of triggering ovulation via an 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 further 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).
(5) menotropins are commonly used during IVF
* higher doses of menotropins along with a relatively strong
GnRH agonist (such as lupron) are generally used for In Vitro
Fertilization (IVF). A standard IVF protocol would consist of
lupron (initiated on idealized cycle day 21 of the prior cycle)
and 4 ampules of menotropins per day (initiated early in the next
cycle). Both GnRH agonist and menotropins are continued until
ovulation is desired, then the LH surge is simulated with hCG
(profasi).
(6) polycystic ovaries are often difficult to stimulate
* Polycystic ovaries are characterized by a large number
of follicles 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 can result in severe forms of ovarian hyperstimulation
syndrome. Protocols to avoid excessive development 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 patients 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.
(7) giving steroids may suppress excessive androgenic hormone
production
* If a woman has abundant circulating androgenic hormones
these 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 the androgens are elevated or if there are
clearcut signs of excess androgens then consideration of concurrent
low dose glucocorticoid steroid medication (such as dexamethasone
or prednisone) is considered.
(8) GnRH pumps are available
* As an alternative to menotropin therapy these pumps will
infuse the 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.
Intensive monitoring is required to maximize appropriate egg development
and minimize exposure to complications. This monitoring includes
transvaginal ultrasounds and bloodwork for hormone (esp. estradiol)
levels. Usually, I will perform a baseline ultrasound exam to
rule out large ovarian cysts and then obtain bloodwork and ultrasounds
every 1-4 days until there is full maturation. A typical cycle
might involve 7-12 days of medication. At the end of the stimulation
process, human chorionic gonadotropin (hCG, such as Profasi) is
given into the intramuscular region 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
10 +/- 3 days, for a normal total of 20-30 ampules. For In Vitro
Fertilization about twice as much medication may be normal. Since
each ampule costs about 50 dollars the total for the medication
is easily 1-2 thousand dollars per attempted cycle. In addition,
the professional and other fees for monitoring can be expensive.
Obtaining menotropin medication can be difficult. Menotropins
are not carried as routine stock in many pharmacies. Therefore,
you should confirm that your pharmacy has actually received a
supply for you prior to attempting to fill your prescription.
If you are unable to identify a pharmacy that will order this
medication for you, a local infertility center (such as my office)
should be able to direct you. Menotropins are stable if stored
at room temperature up until their stated expiration date.
There are few side effects to the human menopausal gonadotropins
(menotropins). Stress associated with a cycle of IVF or COH can
be intense and a free flow of communication between partners can
be very effective at reducing this stress. Organization is important
for working couples since monitoring may take 30-60 minutes in
the morning, exclusive of travel time.
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