Understanding Your Medicines
from the book How to Have a Baby:
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
table of contents
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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:
(a) Bromocriptine (Proctinal, B-crip,Parlodel)
(b) Clomiphene (Clomid, Fertyl, Ovofar, Serophene)
(c) Danazol (Ladogal, Danazol)
(d) H.M.G. (Humegon, Pergonal, Nugon,)
(e) F.S.H. (Metrodin, Puregon, Gonal-F, Recagon)
(f) H.C.G. (Pregnyl, Profasi, Life)
(g) GnRH analogues (Buserelin, Lucrin)
(h) GnRH antagonists ( Cetrorelix)
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.
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 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 effect 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
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.
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
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
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
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 are responding to HMG
and when the dose needs to be adjusted. In addition, monitoring estrogen levels
helps to prevent hyperstimulation. Ultrasound, allows doctors to actually see
the ovaries and determine the number of follicles which are developing and their
size. Ultrasound is also used to determine when and if the ovulatory HCG
injection should be given. If there are too many follicles developing, 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
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 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
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.
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.
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.
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
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
As in the female, this is used to lower unusually elevated levels of
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.
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.
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.
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!
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
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