Fertility drugs are
extensively used in treating infertility. They are usually
the first line of therapy in treating female infertility.
You must be aware of what medicines you are taking and
why. It's easy for doctors to prescribe medicines -
but it's your responsibility to be well-informed about
your medicines, so you know what to expect.
Medicines used in infertility treatments include:
Bromocriptine
This is a drug which is used specifically to treat women
with hyperprolactinemia - a condition in women fail
to ovulate because the pituitary is producing too much
of the hormone called prolactin. Hyperprolactinemia
is the cause of menstrual disturbance in about 10% of
anovulatory women. Bromocriptine lowers prolactin levels
to normal (the normal range in most laboratories being
less than 20 ng/ml) and allows the ovary to get back
to normal.
Side effects: The drug often causes
nausea and dizziness during the first few days of treatment
but the chances of these symptoms occurring can be reduced
by starting the drug at a very low dose and gradually
building up to a maintenance dose of 2 or 3 tablets
daily.
Dose: A 2.5 mg tablet is available
; and the starting dose is usually 2.5 mg to 5 mg daily
- taken at bedtime. After starting bromocriptine, prolactin
levels can be tested (after at least one week of medication)
to confirm that they have been brought down to normal.
If the levels are still elevated, the dose will need
to be increased. Once normal prolactin levels have been
achieved (and some women need as much as 4 to 6 tablets
a day to achieve this) this is then the maintenance
dose. Once your prolactin blood level is within the
normal range, your periods should become more regular
and you should start ovulating normally again. Remember
that bromocriptine only suppresses an elevated prolactin
level while you are taking it – it does not "cure"
the problem. This is why the tablets must be taken daily
until a pregnancy occurs, after which they should be
stopped. This is expensive medication - and some pharmaceutical
companies may provide it at reduced rates if your doctor
requests them to do so on your behalf.
Danazol
This is a synthetic hormone, prescribed as one type
of treatment for endometriosis. It acts by suppressing
the brain's production of follicle stimulating hormones
and hence suppresses ovarian function. This is similar
to an artificial menopause and results in the shrinking
of not only the endometrium in the uterus (and hence
no periods); but also hopefully the misplaced patches
of endometrium outside the uterus found in patients
with endometriosis, causing them to disappear.
Side Effects: Hot flushes, weight
gain, acne, hirsutism (hairiness). These side effects
are quite troublesome, and some women have to discontinue
the drug because of these. Usually, while taking the
danazol, your periods will stop completely - pseudomenopause.
Dose: The standard dose used to be
800 mg daily (4 tablets of 200 mg each). However, the
side-effects at this dose are considerable, and many
doctors have reported good results with doses as low
as 200 mg daily. The usual course of treatment is 6-9
months and the extent of the improvement in endometriosis
is then reviewed. Danazol is expensive medication, and
is usually not advised for women with endometriosis
who are trying to get pregnant.
Steroids - Dexamethasone, is often
use as an adjunct to ovulation induction treatment,
especially in patients with hirsutism who have high
levels of androgens. It helps by suppressing the production
of androgens by the adrenal glands. The dose is usually
a 0.5 mg tablet, taken daily at bedtime. Side-effects
at such a low dose are unusual.
Clomiphene
Clomiphene is the drug of first choice for inducing
ovulation - growing eggs. It is cheap, effective, easily
available and well tolerated. It is also used for superovulating
normal women to help them grow more eggs. Clomiphene
is an antiestrogen and it acts by "fooling "
the pituitary into believing that estrogen levels in
the body are low as a result of which the pituitary
starts producing more FSH and LH - the gonadotropin
hormones which in turn leads to stimulation of the ovaries.
Only women who produce estrogen will respond to clomiphene;
and some doctors will test for this by seeing if they
bleed in response to progestins - a progestin challenge
test.
The starting dose is one tablet (50 mg.) a day for
five consecutive days. The first tablet can be taken
on day 2, 3, 4 or 5 of the cycle - this is usually decided
by your doctor and depends on the length of your menstrual
cycle. It is not enough to just take clomiphene - it
is equally important to monitor the response as well.
This is best done by serial daily vaginal ultrasound
scans. The ovulation induced by clomiphene occurs about
5 to 7 days after the course of tablets is completed
- that is, day 12-16 of your cycle. If ovulation fails
to occur, the dose can be increased for subsequent cycles,
till upto 200 mg per day. Often human chorionic gonadotrophin
(HCG) is given to trigger ovulation to mimic the woman's
natural LH surge. Ultrasound and blood oestrogen levels
may be used to determine the best day to administer
HCG. If ovulation does not occur - the patient becomes
a candidate for HMG or FSH (see below).Usually blood
testing of progesterone levels (done 7 days after ovulation)
accompanies clomiphene treatment to help identify the
correct dosage needed. Clomiphene induces ovulation
in approximately 70% of appropriately selected patients
and has a 30-40% pregnancy rate.
Clomiphene increases a woman's risk of twin pregnancy
by approximately 10%. However, the risk of having more
than two babies is 1 %. Occasionally ovarian cysts occur
following clomiphene administration. These usually disappear
when the drug is stopped.
Side effects can include hot flushes and mood swings
early in the cycle,; and depression, nausea and breast
tenderness later in the cycle. Severe headaches or visual
problems, though rare, are indications to stop the medication.
As clomiphene works as an "antioestrogen"
it can have an adverse effect on cervical mucus making
it thicker than usual. It is therefore important to
check on sperm/mucus survival with a post coital or
post insemination test. If this is consistently negative
due to poor mucus, a change of medication may be advised.
Alternatively, low-dose estrogens may be added to your
treatment.
Long term effects: As the drug is only given for 5
days early in the cycle it does not have any long term
effect on future ovulations or on hormone levels; or
on pregnancy. Some doctors were worried that the prolonged
use of clomiphene would increase the risk of the patient
developing ovarian cancer. However, extensive research
has shown that this worry is unfounded.
Misuse of clomiphene: Clomiphene is an easy drug to
misuse because it is cheap and easy to prescribe. It
is common to find patients who have been taking clomiphene
for months on end, with no result. Clomiphene should
not be taken, unless adequate monitoring is also performed
simultaneously. It should also not be prescribed for
more than 6 months. If it hasn’t worked by then,
you should move on to the next stage of treatment. Clomiphene
is also commonly misused as "empiric " treatment
- as a treatment to "enhance fertility" when
the doctor cannot offer anything else.
Gonadotropins
Gonadotropin treatment is "big-gun " therapy,
and is usually reserved for difficult anovulatory problems.
The two gonadotropin hormones, Follicle Stimulating
Hormone (FSH) and Luteinizing Hormone (LH) are produced
in the pituitary and their secretion is controlled by
a third hormone, Gonadotropin Releasing Hormone (GnRH),
released by the hypothalamus. At the start of a new
cycle, the hypothalamus begins to release GnRH. GnRH
then acts on the pituitary gland to release FSH and
LH. These two hormones stimulate the ovary, causing
follicles to develop (as the name suggests, this is
the primary action of the FSH - to stimulate follicular
growth). When it is time for ovulation, a sudden burst
of LH is released from the pituitary (the LH surge)
which causes the egg to be released from the mature
follicle in the ovary.
This is a very finely tuned system, designed by Nature
to ensure the release of a single mature egg every month.
This involves orchestrating a symphony of messages from
the ovary, the pituitary and hypothalamus. The messages
are transmitted by hormones - which are chemical messengers
in the blood stream. When the egg is ripe, the mature
follicle releases an ever increasing amount of estrogen,
which is produced by the granulosa cells which line
the follicle. This estrogen produced by the dominant
follicle progressively increases in quantity as the
egg matures, until a surge of estrogen is released into
the blood (the estrogen surge). This high level of estrogen
stimulates the pituitary to release a large amount of
LH hormone - the LH surge. This LH in turn acts on the
mature follicle, causing it to rupture to release the
mature egg. Thus it is the mature egg which signals
the brain that it is ready for release, and triggers
off its own ovulation!
How does Nature ensure that only one egg is released
every cycle? About 30-40 follicles will start growing
in response to the FSH produced by the pituitary. However,
of these follicles, only one is destined to grow (become
dominant) and rupture to release its mature egg. The
others will die - a process called atresia. The dominant
follicle releases increasing amounts of estrogen as
it grows bigger. This estrogen in turn decreases the
production of FSH by the pituitary (in a negative feedback
control loop), so that without high levels of FSH, the
smaller follicles no longer have a stimulus to grow;
and they gradually die. The dominant follicle by now
has become so big, that it can grow by itself, and doesn't
need the additional FSH stimulation.
HMG ( Human Menopausal Gonadotropins, Menotropins)
When the pituitary doesn't release FSH and LH or releases
them in an improper balance, HMG ( Human Menopausal
Gonadotropin) substitutes for them and acts directly
on the ovaries to stimulate the development of the follicle.
HMG is a natural product containing both human FSH and
LH, 75 or 150 international units of each per ampule.
This material is extracted from the urine of post menopausal
women, carefully purified and then freeze dried in sterile
glass ampules where it is sealed until use.
Recently, biotechnology (using recombinant DNA) has
been used to produce synthetic FSH. Chinese Hamster
ovary cells have been genetically engineered , so that
they are capable of quickly producing, or "expressing",
commercial quantities of FSH in bioreactors .This is
an exciting advance, and means that companies can now
manufacture large quantities of pure hormone, without
risk of contamination. However, these products have
been priced exorbitantly, which makes them unaffordable
for many patients. While they are as good as the conventional
urinary gonadotropins, they are no better – and
may actually be less cost-effective, because they are
so expensive. Hopefully, increasing competition may
mean that these hormones will be inexpensively available
in the future. However, this is likely to take a few
years more.
Dose: Most women need to take daily
injections of HMG over a period of several days each
month. The exact number of days will be determined by
your physician through monitoring your response to the
injections. HMG therapy usually begins on day 3 to day
5 of the menstrual cycle. If you are not menstruating,
the injections may be started at any time. Every patient
is different in her response to HMG and even the same
patient may not respond in the same way from cycle to
cycle. Therefore, the dosage of HMG required to produce
maturation of the follicle must be individualized for
each patient. This is the key to success with these
injections. It is recommended that the lowest possible
dose consistent with good results be used. HMG cannot
be taken orally because it is a protein and would be
digested in the stomach. It is given by intramuscular
injections into the buttocks, or the thighs.
Side effects: Many women worry that
if they take HMG, this will cause them to "run
out of eggs" because the HMG stimulates the maturation
of a large number of eggs. However, remember that every
month, 30-40 eggs start to mature. In the natural cycle,
only one matures, while the rest die. HMG helps to rescue
the eggs which would otherwise have died, so it does
not cause you to lose or waste your precious eggs !
Along with its intended benefits, HMG is a potent drug
with the potential to cause side effects. The most common
side effect with HMG relate to overstimulation of the
ovary and every effort is made to avoid this by monitoring
the response to HMG carefully. Mild to moderate uncomplicated
ovarian enlargement, sometimes accompanied by abdominal
distension and/or abdominal pain occurs in about 20%
of those treated with HMG and HCG. This generally is
reversed without treatment within 2 to 3 weeks.
A potentially serious side-effect of HMG is the ovarian
hyperstimulation syndrome ( OHSS) which is characterized
by enlargement of the ovary and an accumulation of fluid
in the abdomen. This fluid can also accumulate around
the lungs and may cause breathing difficulties. If the
ovary ruptures, blood can accumulate in the abdominal
cavity, as well. The fluid imbalance can also affect
blood clotting and, in rare cases could be life threatening.
Fortunately, the hyperstimulation syndrome is not common,
occurring in about 1 - 3% of patients. Treatment consists
of bed rest and careful monitoring of fluid levels.
Another risk with HMG therapy is when it is too successful
at producing eggs - thus resulting in mutiple pregnancies,
with the risks associated with these. Of the pregnancies
following therapy with HMG most (80%) will be single
births. The multiple gestation rate is approximately
20%, the majority of which have been twins. About 5%
of the total pregnancies result in three or more conceptuses.
Despite careful monitoring, multiple gestations can
not be altogether avoided.
Other adverse reactions that have been reported with
HMG therapy are mild and include allergic sensitivity,
pain, rash, swelling at the injection site. Many women
are worried that the HMG will cause them to put on weight.
However, remember that the HMG is a "natural"
hormone. It does not affect your caloric balance, and
does not cause you to become fat ! However, many women
do restrict their physical activity when taking infertility
treatment. This restriction causes them to burn fewer
calories, and this may lead to weight gain which they
then attribute mistakenly to the HMG injections. HMG
may cause fluid retention, but this is temporary, and
HMG injections have no long-term side-effects.
Monitoring HMG therapy
Monitoring of patients receiving HMG therapy is essential
for dosage adjustment and prevention of side effects.
Each woman's response is different and the dose given
needs to be adjusted carefully. The two most commonly
used techniques are serum estrogen levels and ultrasound.
Estrogen levels in the blood help the doctor to determine
how well the ovaries there is a greater chance of multiple
births and the decision may be made to avoid the ovulatory
injection of HCG.
Studies show that about 75% of women taking HMG will
ovulate. It is estimated that 20% to 42% of patients
receiving HMG will become pregnant, as long as the fallopian
tubes are open and the sperm count is adequate.
Intercourse is advised daily or every other day beginning
on the day prior to the administration of HCG. Your
doctor may want to advise you further on this point.
Some doctors will perform an intrauterine insemination
on the day of ovulation to increase the chances of a
pregnancy.
HMG has to be imported into India, and is very expensive.
It is therefore best used by infertility specialists
only. The commonest use of HMG today is in IVF and GIFT
programmes where it is used to stimulate several eggs
to grow (superovulation).
FSH
This represents a more recent purified form of HMG which
contains mostly FSH and negligible amounts of LH. The
indications for use, administration and ovarian response
are almost identical to HMG. However, as FSH contains
almost no LH, it has a theoretical advantage for women
with PCO ( polycystic ovarian syndrome) who characteristically
have an elevated LH level. However, it is also more
expensive than HMG.
HCG
HCG is produced by the placenta during pregnancy. Because
it is very similar biologically to LH it is used to
trigger ovulation by mimicking the natural LH surge
at mid cycle. It can be used in combination with Clomid
and also HMG/FSH to induce ovulation. It is isolated
and purified from the urine of pregnant women. It is
available in ampoules as a sterile white powder containing
5000 IU or 10000 IU. This powder is dissolved in a diluent
and administered by IM injection.
Synthetic GnRH
Synthetic GnRH stimulates the pituitary gland to secrete
LH and FSH. It is used to induce ovulation in selected
women with hypothalamic dysfunction. The hormone has
to be given in a manner which mimics the natural secretion
of LHRH, i.e. in "pulses" approximately 90
minutes apart. This is given by means of a small pump
placed under the skin of the arm or abdomen. This treatment
is now given instead of HMG at certain specialist centres.
It has the advantage over HMG that it produces an ovulation
cycle which is similar to the natural cycle and multiple
ovulation is very unusual.
GnRH Analogues
These drugs may be used for the treatment of endometriosis
and fibroids. They work by initially stimulating, then
switching off ( down-regulating) the pituitary gland,
and are administered intranasally or by injection. They
thus induce a "menopausal" state, allowing
the endometriosis and fibroids to shrink, since there
is no further production of estrogens.
GnRH analogs are most commonly used today as adjunctive
therapy in order to enhance induction of ovulation with
HMG, especially for IVF ( in vitro fertilisation) treatment.
Your own gonadotropins (FSH and LH) are turned off by
the GnRH analogues ( this is called pituitary downregulation)
, so that your physician has a clean slate to work with
when administering exogenous gonadotropins to induce
superovulation.
GnRH antagonists
Currently, most in-vitro fertilization (IVF) centres
use pituitary down-regulation with gonadotrophin-releasing
hormone (GnRH) agonists to prevent premature luteinization.
However, this requires at least 7–14 days of GnRH
agonist pretreatment. A more rational approach would
be to use the newer GnRH antagonists, which cause an
immediate blockage of the GnRH receptors on the pituitary
gland. Thus , treatment with the antagonist can be limited
to only those 2-3 days when high oestradiol levels may
induce an LH surge. Clinical experience with GnRH antagonists
in IVF treatment thus far has been encouraging and demonstrates
a high efficacy in preventing the LH surge.
Growth Hormone
Some women will respond very poorly to HMG injections.
They grow few or no follicles, inspite of being given
large doses. In some of these "poor responders"
synthetic growth hormone (HGH, human growth hormone)
has been used to try to enhance the response of the
ovary to the HMG. However, the response to this very
expensive drug has been quite disappointing, and it
is no longer used.
Medicines Used In Male Infertility Treatments
HMG and HCG
These are useful in stimulating sperm production in
men with hypogonadotropic hypogonadism (men with low
FSH and LH levels, because of hypothalamic or pituitary
malfunction), but this is a rare condition.
Treatment often takes many months to restore the sperm
quality to fertile levels. Combination treatment is
required, with HCG stimulating testosterone production;
and FSH stimulating sperm production. Initially, the
man takes HCG injections thrice a week for about 6 months.
This normally causes the size of the testes to increase
and the testosterone to reach normal levels. HMG injections
are then added. These can be mixed with the HCG and
are also given thrice a week. Once sperm production
has been achieved, the HMG can be stopped; and HCG treatment
continued alone. While sperm counts achieved are usually
low (less than 10 million per ml), a successful pregnancy
can be achieved in 50 % of correctly diagnosed patients.
Unfortunately, these expensive injections are often
misused as "empiric" therapy in men with low
sperm counts - with expectedly disappointing results.
Bromocryptine
As in the female, this is used to lower unusually elevated
levels of prolactin.
Testosterone
This is given to suppress sperm production in the hope
that when medication is stopped (usually after 5-6 months),
then the sperm production will "rebound "
to higher levels than originally (testosterone rebound).
This form of treatment is now seldom used as it may
further impair fertility and is hazardous. Testosterone
is also be used for the treatment of impotence or diminished
libido when blood testosterone levels are low. Testosterone
is available as an oily injection and is given intramuscularly,
usually once a week. Oral preparations are also available
now, but these are more expensive and may not be as
effective.
Clomiphene
This is the most commonly prescribed medicine for infertile
men. Its use is largely empirical and very controversial
as the results are not predictable. This is usually
prescribed as a 25 mg tablet, to be taken once a day,
for 25 days per month, for a course of 3 to 6 months.
It acts by increasing the levels of FSH and LH, which
stimulate the testes to produce testosterone and sperm.
The group of men who seem to benefit the most from clomiphene
have low sperm counts, with low or low-normal gonadotropin
levels. However, while clomiphene may increase sperm
counts in selected men, it hasn't been proven effective
in increasing pregnancy rates.
Antibiotics
Just as in the female, antibiotics can resolve a chronic
infection in the reproductive tract in the male. Often
no specific organism is isolated but improvement in
the numbers of normal sperm as well as the reduction
in white cells in semen can be seen in some men following
several weeks of antibiotics.
Vitamins
No supportive evidence that they work but sometimes
they are worth a try.
Ayurvedic treatment and other magic potions
Everyone seems to have a "magic potion" to
cure low sperm counts - the trouble is that no one has
ever proven that anything works! Take all claims with
a liberal pinch of salt.
The problem with the medical treatment of a low sperm
count is that for most people it simply doesn't work.
After all, if the reason for a low sperm count is a
microdeletion on the Y-chromosome, then how can medication
help ? The very fact that there are so many ways of
"treating" a low sperm count itself suggests
that there is no effective method available. This is
the sad state of affairs today and much needs to be
learnt about the causes of poor production of sperm
before we can find effective methods of treating it.
However, patients want treatment, so there is pressure
on the doctor to prescribe, even if he knows the therapy
may not be helpful . When most patients go to a doctor,
they expect that the doctor will prescribe a medicine
and treat their problem. Since most people still believe
there is a "pill for every ill", they expect
that the doctor will give them a medicine ( or an injection)
which will increase their sperm count. No patient ever
wants to hear the truth that there is really no effective
treatment available today for increasing the sperm count.
Since most doctors know this, they are pressurised
into prescribing medicines for these patients, because
they do not want the patient to be unhappy with them.
They are worried that if they do not fulfill the patient’s
expectation of a prescription, the patient will desert
them, and go elsewhere, which is why they often do not
tell the patient the complete truth. The doctor also
remembers the occasional anecdotal successes (who come
back for followup , while the others desert the doctor
and are lost to followup) is why patients with low sperm
counts are put on every treatment imaginable - with
little rational basis - Vitamin E, Vitamin C, high-protein
diets, hoemeopathic pills and ayurvedic churans. However,
the very fact that there are hundreds of medicines itself
proves that there is no medicine which works !
Many doctors justify their prescriptions by saying
- " Anyway it can't hurt - and in any case, what
else can we do? " However, this attitude can be
positively harmful. It wastes time, during which the
wife gets older, and her fertility potential decreases.
Patients are unhappy when there is no improvement in
the sperm count and lose confidence in doctors. It also
stops the patient from exploring effective modes of
alternative therapy - such as IVF and ICSI . Today empiric
therapy should be criticised unless it is used as a
short term therapeutic trial with a defined end-point.
A word of warning. Medical treatment for male infertility
does not have a high success rate and has unpleasant
side effects, so don't take it unless your doctor explains
his rationale. The treatment is best considered "experimental"
and can be tried as a therapeutic trial. Make sure,
however, that semen is examined for improvement after
three months and then decide whether you want to press
on regardless.
It is worth emphasising how small the list for male
infertility treatment is - especially as compared to
female treatment. This simply reflects our ignorance
about male infertility - we know very little about what
causes it, and our knowledge about how to treat it is
even more pitiable!
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