Treatment of the Infertile Couple

Recognizing that no two couples are exactly alike and that each couple presents is own unique set of problems, nonetheless, some general principles can be stated to at least give you a foundation and a base from which to begin.

Again, as I have mentioned elsewhere, 90% of all infertility problems fall into three main categories – male factor, hormonal problems, and pelvic factors.

Male Factor

The infertile man remains the “black box” of infertility. With occasional (and they are occasional) exceptions, we simply do not know what causes male infertility and without being able to establish a diagnosis, treatment directed at the underlying cause is impossible.

Over the years, a number of therapies have been devised to improve men’s semen quality. Unfortunately, in the vast majority of instances, they simply do not work.

Nonetheless, every man deserves at least a preliminary evaluation to make sure that he is not one of those rare individuals who has a truly diagnosable and treatable problem.

If a man is found to have a hormone problem, it can usually be easily treated.

It is from these rare but treatable hormone problems that we get insight into other conditions. One such rare but very treatable problem is Kallman’s syndrome. Men with Kallman’s syndrome have an inherited deficiency of GnRH – the hormone produced by the hypothalamus that tells the pituitary gland to make FSH and LH which in turn tells the testicles to mature and produce sperm. Curiously, because of where this defect is located within the brain, these men also have no sense of smell.

Because this is a purely hormonal problem, the treatment is purely hormonal and Pergonal or similar drugs are highly effective in allowing these men to progress through puberty, full sexual maturation, and eventually sperm production. When these men ultimately marry, they are highly fertile – their wives usually become pregnant without any difficulty. However, even though these men are very fertile, their sperm counts rarely exceed 3-5 million – but the sperm being produced are all normal and highly motile.

By analyzing such rare conditions, it gives us insight into the more common problems. It clearly illustrates that the actual sperm count is not as important as people think it is – the health of the sperm is far more important and the best gauge of the sperm’s health is their motility – their movement.

When performing a semen analysis, it is much more useful to look at the “total motile count” rather than the actual count. The total motile count is calculated by multiplying the total sperm count times the percent of actively motile sperm (those sperm that are moving forward in a fairly straight line) times the volume of the ejaculate. The resulting number is the total number of apparently “normal” sperm in the entire ejaculate.

A man is considered fertile if his total motile count is greater than 20 million.

He is considered mildly sub-fertile if his total motile count is 10 to 20 million.

He is considered moderate to severely impaired if his total motile count is 0.5 to 10 million.

A man’s whose total motile count is less than 0.5 million is considered to be functional sterile.

For the man whose fertility is mildly impaired, a full evaluation by a Urologist or Andrologist (the male equivalent of a Reproductive Endocrinologist) should be undertaken, looking specifically for a varicocele.

A varicocele is a varicose vein in the scrotum. It has been known for many years that the presence of varicoceles is often associated with male infertility. No one knows with certainty whether there is a cause and effect relationship.

If a man’s semen quality is impaired, if he has a varicocele, and if his wife has no problems that would compromise her fertility, then treatment of the varicocele is indicated. Treatment of the varicocele involves a surgical procedure similar to having a hernia repaired.

For those couples who fit the criteria that I have just mentioned, the pregnancy rates are usually quite good. However, if the wife has any problem that would compromise her fertility, the effectiveness of a varicocele ligation is less certain.

If the semen analysis shows a large number of white blood cells indicating the possible presence of infection, treatment of the man with antibiotics is sometimes effective in improving his fertility.

Hormonal therapy of the infertile man, particularly if his count is low, is occasionally effective. However, it is important to understand that men have a “cycle” the same way women do.

It takes 70 days to make a sperm. Therefore, you will not even begin to see whether your therapy has resulted in any improvement for at least three months and usually six months is required.

A number of drugs have been tried over the years to improve sperm counts in men. These drugs include Clomiphene and Tamoxifen.

Most of the studies that have been properly done evaluating these drugs have failed to show any improvement in sperm counts.

The only drugs that might work are Pergonal and drugs similar to it. However, this involves giving the man an injection three times a week for four to six months. Furthermore, just as in the case of female infertility, many insurance companies will not pay for these drugs and, as most infertile couples are well aware, these drugs are exceedingly expensive.

Unfortunately, the bottom line for most infertile men is that there is simply no effective therapy that is going to improve the quality of the semen they produce. However, there are a number of therapies that will improve the quality of the semen after it has been produced.

The most common technique is a sperm wash with Intra-Uterine Insemination (IUI). Quite simply, the man produces a specimen, it is brought to the office, and the semen is put through a special separation process which removes both the dead or poorly motile sperm and also the various other hormones and chemical substances in the semen.

Following this, the washed sperm are placed directly inside the uterus.

The effectiveness of IUI has still not been fully resolved. There are good studies which definitely show improved pregnancy rates – other studies do not. Nonetheless, the preponderance of evidence does indicate that pregnancy rates are better with IUI.

It is also important to understand that IUI by itself if not a very effective remedy. It should be combined with superovulation , preferably using Pergonal or a similar drug. Again, you quickly run into the problem that many insurances will not pay for the Pergonal. For that matter, many insurances won’t pay for intrauterine insemination either.

If your insurance company has these restrictions, the use of Clomiphene with the IUI is an alternative but it must always be kept in mind that there are anti-fertility effects to the Clomiphene. Nonetheless, for those couples where the wife has either no fertility problem or perhaps early endometriosis, and the husband’s semen quality is somewhat impaired, ovarian stimulation combined with IUI is often an effective remedy and should be tried prior to more advanced (and more expensive) therapies.

For those couples who have tried intrauterine insemination without success or for those couples where the husband’s semen quality is so poor that IUI is not a reasonable option, the next step would be one of the Assisted Reproductive Technologies (ART) such as In Vitro Fertilization (IVF).

In IVF, the sperm are put through a wash identical to that for IUI. However, instead of simply placing the sperm inside the uterus and leaving it up to mother nature, the woman goes through ovarian stimulation with Pergonal or similar drugs, her eggs are retrieved from her ovaries, placed in a dish, and the husband’s sperm are added. You only need about 50,000 sperm per egg so for those men whose semen quality is very poor, IVF offers a reasonable hope of pregnancy.

For those men whose sperm will not fertilize the egg, or for those men whose semen quality is so poor that even IVF is not an option, or for those men who must have sperm extracted from the vas, the epididymis, or the testicle itself, direct injection of the sperm head into the egg offers an option for pregnancy when no other treatment is successful.

This direct injection of the sperm head into the egg is called Intra-Cytoplasmic Sperm Injection (ICSI). It has allowed men who were functionally sterile to father their own children.

Because of ICSI, it can be truly said that there is almost no such thing as male infertility anymore – except for the cost involved. IVF usually costs about $8,000 to $10,000. If ICSI is necessary, there will be an extra charge of $1,000 to $1,500.

When ICSI was first introduced, it was heralded as a great leap forward and indeed it is. However, more recent data indicates that some babies conceived by ICSI have chromosomal abnormalities. Couples must be aware of this and it is recommended that babies conceived by ICSI be evaluated by chorionic villus sampling (CVS) at about ten weeks gestation.

Hormone Problems

Hormone problems are the easiest problems to treat.

All infertile women should be tested for thyroid disease, although today, thyroid disease is a rare cause of infertility. However, there are some thyroid problems that predispose a woman to recurrent miscarriage and this must be evaluated.

Many women have elevations in the hormone called prolactin which is produced by the pituitary gland. In some instances, the elevated prolactin is the result of a small tumor. For this reason, an MRI is recommended when an elevated prolactin is found. Even though medication will control the tumors and surgery is rarely necessary, it is important to know whether those tumors are present.

If a woman has an elevated prolactin, treatment with medication is highly effective and often results in a pregnancy.

For women with irregular periods who are either ovulating irregularly or not ovulating at all, there are a number of drugs. Clomiphene is the initial therapy of choice. About 90% of women who are given Clomiphene will ovulate but only 40% will get pregnant. It is now well-known that there are many anti-fertility effects to Clomiphene and these must be evaluated to make sure the drug is working as it is intended.

If the Clomiphene does not work, there are a variety of other techniques that can be used to enhance its effectiveness depending upon other types of hormone problems that woman might have.

If the Clomiphene still doesn’t work, the next treatment would be gonadotropin therapy with Pergonal and related types of drugs. Unfortunately, there are a number of insurance companies (particularly the HMO’s) that will not pay for Pergonal. The drug itself costs anywhere from $1000 to $2500 per cycle depending upon how the woman responds to it.
Because of the extensive experience that I and other Reproductive Endocrinologists have had with these types of drugs, if failure to ovulate is that woman’s only problem and her husband’s semen quality is reasonably normal, pregnancy rates in excess of 90% can be expected.

It is important to understand that, despite the scare stories you may have read in the magazines or heard on the 11 o’clock news, there is no valid scientific evidence that taking these drugs increases your risk of developing ovarian cancer. It is important to understand that infertility is a major risk factor for ovarian cancer. Women who have never had children have a risk of developing ovarian cancer that is two to three times higher than women who have had children. Each child lowers your risk of ovarian cancer by about 20%.

Pelvic Factors

Pelvic disease is the most common cause of infertility accounting for 50% of all infertility problems. The principal pelvic diseases responsible for infertility are endometriosis, damage from a previous infection, and damage from previous surgery.

There are many clues that I look for to alert me to the presence of pelvic disease. Such clues include significant pain with periods, significant pain in between periods, deep pain with intercourse, a history of a previous pelvic infection, a history of previous pelvic surgery, a history of a tubal pregnancy (even if treated with medication) or, by process of elimination, if a woman is infertile, her husband is normal, and she has regular ovulatory menstrual cycles.

The way that many women are evaluated for possible pelvic disease is an X-ray of the uterus and tubes – a hysterosalpingogram. I rarely do these types of X-rays because I have found that they are rarely necessary. It is also well-known that these types of X-rays are notoriously inaccurate with error rates as high as 50%.

All you can really tell from the X-ray is whether the tubes are open and even then there may be errors. Since endometriosis does not block fallopian tubes, the X-ray is of no value in evaluating a woman with possible endometriosis.

Even women who have severe pelvic adhesions but whose tubes are not blocked will have a normal X-ray.

The best way to evaluate a woman for pelvic disease is with a hysteroscopy and laparoscopy. This is the only way that you can really determine if there is a problem. This is the only way you can determine how bad that problem is.

If a woman has endometriosis, it is treated based upon the severity of her disease – not the symptoms it is producing. This is discussed at greater length in my pamphlet on endometriosis.

If a woman has pelvic damage from either previous surgery or a previous infection, it is critically important to assess the severity of the damage because recommendations for further therapy will depend upon it.
For milder degrees of pelvic damage, corrective surgery is indicated as pregnancy rates higher than those achievable by IVF can be expected. However, if the damage is very severe, then IVF offers a better chance of pregnancy.

Unfortunately, with most insurances refusing to pay for IVF, many couples are forced to choose a less effective therapy (surgical correction) for purely financial reasons. Hopefully, this will be corrected in the future but I would not hold my breath waiting for it to occur.

Recent advances in IVF are yielding pregnancy rates on the order of 50%. Given this better success rate, many insurance companies may rethink their position – not because they really care but because it is cheaper to pay for IVF than the surgery necessary to correct severe pelvic disease.

Whenever possible, pelvic disease should be treated laparoscopically, reserving full open surgery for only the most severe cases.

The reason for this is quite simple – open surgery creates significant adhesions, particularly if the surgery is being done for adhesions and tubal disease in the first place.

This is not to say that laparoscopic surgery cannot create adhesions – it does. However, laparoscopic surgery creates less severe adhesions than does open surgery.

If a woman has severe adhesions, severe pelvic damage, or severe endometriosis, that woman should undergo a “second look laparoscopy”. A second look laparoscopy is a laparoscopy done about six to eight weeks after the initial surgery. The purpose is to get rid of the adhesions that we know are going to reform. Adhesions as they initially form tend to be rather thin and relatively easy to get rid of.

However, as adhesions mature, with the passage of time they become thicker and more dense. If you go after them aggressively and get rid of the early adhesions as they are forming, the likelihood that they will recur in the future is substantially reduced.

Please understand that a second look laparoscopy is recommended only for those women with significant pelvic damage. Milder adhesions do not require a second look laparoscopy.

Any woman who undergoes an open surgical procedure should also have a second look laparoscopy because the likelihood of adhesion formation is very high. This is particularly true for women undergoing myomectomy – a surgical procedure to remove fibroid tumors from the uterus while conserving the uterus for future childbearing. It has been my experience that the incidence of adhesions following myomectomy is very very high – approaching 100%. I have had many patients in my practice over the years where I know that there ability to become pregnant was definitely the result of the second look laparoscopy. I have also had numerous patients in my practice who have had myomectomies done by other Gynecologists where a second look was not done. When these women came to me, the laparoscopy that I did revealed severe adhesions which were significantly compromising their ability to become pregnant.

Fibroid Tumors

I have made the section dealing with fibroid tumors separate from the other pelvic factors because I believe it deserves its own discussion.

Fibroid tumors are benign tumors of the uterine muscle and are the most common benign tumor of the female pelvis. They tend to become more common as women age. They can be seen in teenage girls but are much more common in women in their thirties and forties. They tend to shrink (but not disappear) after menopause. Estrogen definitely stimulates the growth of fibroids but it is not quite that simple.

Fibroid tumors are not rare in infertile women and sometimes the decision as to whether or not they need to be removed is not an easy one.

If a woman’s problem is recurrent miscarriage and she has one or more fibroid tumors that appear to be compromising the uterine cavity, the decision is easy as the fibroid tumors are most likely playing a role in her pregnancy loss.

For the woman who has never become pregnant, the decision to proceed to removal of the fibroid tumors (myomectomy) is sometimes not that easy.

Before recommending myomectomy, it is necessary to fully evaluate that couple to make sure that no other reason for the woman’s infertility can be found.

Generally speaking, small fibroids within the uterus or large fibroids on the outside of the uterus probably do not play a role in infertility and can usually be left alone.

Fibroids that are near or protruding into the lining of the uterus, particularly if they are larger than 3 to 4 cm. in diameter, are probably playing a role in the infertility of that woman and, if no other obvious reasons for her infertility can be found, myomectomy is warranted.

For your informational purposes, to help you gauge this, a ping pong ball is 4 cm. in diameter.

Unexplained Infertility

THIS SECTION ALSO APPLIES TO COUPLES BEING TREATED WITH CLOMIPHENE OR PERGONAL AS AN ALTERNATIVE TO IVF OR AS PRELIMINARY TREATMENT BEFORE IVF

Unexplained Infertility refers to that group of couples who, after having gone through an infertility evaluation, either have no detectable abnormalities (rare in my practice), or whose problems do not “explain” their infertility. Early stage endometriosis is an example of a problem that fall into the latter category.

What to do with such couples has long been debated. A review of recent data has come up with numbers and statistics that offer a solution. A properly controlled, randomized, prospective study has been published (New England Journal of Medicine – January,1999).

If couples with “Unexplained Infertility” are followed, without treatment, many of them will ultimately achieve a pregnancy, but less often than “normal” couples. Various studies list the success rate as anywhere from 30% to 80%. The differences will depend on the age of the couple, the duration of their infertility, and how extensive their evaluation was before being classified as “Unexplained Infertility”.

I often tell couples that based on these statistics, my therapies may not increase the likelihood of their having a baby – only how quickly they become pregnant.

You have to look at the data in several ways. You must look at the actual effectiveness of the various treatments and you must also consider the “cost per baby”. As you might expect, these two outcomes are inversely related to each other.

You must also not just consider the overall pregnancy rate but the chance of conception in any one given cycle – again a reflection of what I mentioned earlier, namely that therapy will not achieve a greater chance of pregnancy, only allow it to happen more quickly.

A recent study in “Fertility and Sterility”, the journal of the American Society for Reproductive Medicine lists the following data. The abbreviations used are listed at the end of this pamphlet.

Pregnancy rates per cycle:

No treatment-just observation 1.3-4.1%
IUI only 3.8%
CC only 5.6%
CC + IUI 8.3%
hMG only 7.7%
hMG + IUI 17.1%
IVF 20.7%
GIFT 27%

Estimated cost of each pregnancy achieved:

CC + IUI $10,000
hMG + IUI $17,000
IVF $50,000

The success rate for GIFT is somewhat higher than for IVF because couples with more severe problems have to use IVF. Only the most “ideal” couples can take advantage of GIFT. Furthermore, GIFT requires a laparoscopy, thereby increasing the cost and the risk.

One study found no real difference between the two and therefore favored IVF since it avoided the need for laparoscopy.

The New England Journal article quotes the following pregnancy rates (after 4 cycles of treatment unless, of course, a pregnancy occurred sooner):

hMG + IUI 33%
IUI only 18%
hMG + ICI 19%
ICI only 10%

To be included in this study, the woman had to have no significant infertility problem (early stage Endometriosis was allowed) and the man had to have some motile sperm in his semen. Obviously, some of the men had poor enough semen quality to be considered “subfertile”. Pregnancy rates in this group were lower than for those couples in whom the man’s semen quality was “normal”.

Based on this data (which is not new – just better summarized), I have long recommended hMG + IUI for those couples with “Unexplained Infertility”. Unfortunately, what your insurance will or will not cover often mandates the treatment, not what is necessarily best for you.

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