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From the book
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.
What medicines are used for treating infertility ?
How is bromocriptine used for treating infertility ?
How is danazol used for treating infertility ?
How are steroids used for treating infertility ?
How is clomiphene (clomid) used for treating infertility ?
How are gonadotropin injections used for treating infertility ?
What are HMG injections and how are they used in infertility treatment ?
How is HMG therapy monitored
How are FSH injections used for treating infertility ?
How are HCG injections used for treating infertility ?
How is GnRH used for treating infertility ?
How are GnRH analogs used for treating infertility ?
How is metformin used for treating infertility ?
What medicines are useful for treating male infertility ?">
Why is medical treatment of low sperm counts ineffective ?
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:
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.
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.
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.
Some women cannot tolerate bromocroptine. For these women, an alternative option is cabergoline, which is as effective in reducing high prolactin levels, and has fewer side effects.
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.
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.
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. While danazol is useful for suppressing the lesions of endometriosis, it is not useful for treating endometriosis in infertile women. While taking the danazol, ovulation is suppressed, and because all it achieves is temporary suppression of the lesions, once you stop the danazol, the endometriosis recurs. This is why it is usually not advised for treating infertile women with endometriosis anymore, because it has not been shown to be helpful in improving pregnancy rates.
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. Some IVF clinics also use steroids after embryo transfer, because they believe this helps to improve pregnancy rates by inducing immune suppression and enhancing embryo implantation rates.
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 : 1. the cervical mucus making it thicker than usual; and 2. the endometrium (uterine lining), causing it to become thin. It is therefore important to check on sperm/mucus survival with a post coital or post insemination test; as well as check the endometrial thickness on ultrasound scans. If the cervical mucus is poor or the endometrial lining is thin, a change of medication may be advised. Alternatively, low-dose estrogens may be added to your treatment.
An alternative option for clomiphene is the newer anti-estrogen, letrozole. This drug is also used for treating women with breast cancer, and is as effective is clomiphene in inducing ovulation, with the advantage that it does not cause the endometrial lining to become thin.
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 4 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 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.
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. Brand names include Menogon, Repronex and Menopur. 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 . Brand names include: Follistim and Gonal-F. 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.
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 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 treatment where it is used to stimulate several eggs to grow (superovulation).
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 injection. Ovulation occurs 36 hours after the HCG trigger shot. Recently, HCG has also been manufactured using recombinant DNA technology, and this is available under the brand name, Ovidrel.
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. Brand names include Buserelin, Lupron and Lucrin.
GnRH analogs are most commonly used today as adjunctive therapy in order to enhance induction of ovulation with HMG, especially for IVF (in vitro fertilization) treatment. Your own gonadotropins (FSH and LH) produced by your pituitary 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. Brand names include Anatgon and Cetroride. Thus, treatment with the antagonist can be limited to only those 2-3 days when high oestradiol levels may induce an LH surge. However, clinical experience with GnRH antagonists in IVF treatment thus far has shown mixed results, with no evidence that they are any better than the traditional GnRH analogues.
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.
The drug of first choice for women with PCOD today is metformin (this medicine is also used for treating patients with diabetes. ) Doctors have now learned that many patients with PCOD also have insulin resistance - a condition similar to that found in diabetics, in that they have raised levels of insulin in their blood (hyperinsulinemia), and their response to insulin is blunted. This is why some patients with PCOD who do not respond to clomiphene are treated with antidiabetic drugs, such as metformin and troglitazone. Studies have shown that these drugs improve their fertility by reversing their endocrine abnormality and improving their ovulatory response.
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.
As in the female, this is used to lower unusually elevated levels of prolactin.
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.
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, Proxeed, 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!