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Introduction

Cervical Mucous

A Woman's Eggs

Ovulation

Sperm

Egg Pickup

Embryo Transport

Immunology


Home : Contents : The Science of Infertility

The Science of Infertility

To survive all species must reproduce. On a scientific basis this process is incredibly beautiful and complex. As thinking beings, difficulty in participating in this life process may be one of the most emotionally painful aspects of our lives.

Many seek medical help for their reproductive problem and technologies are available to help the vast majority of such patients achieve pregnancy and have a baby. However, the process of helping such patients achieve pregnancy is different from treating many medical problems.

Understanding the science of reproduction has enabled us to learn that there are an extraordinarily number of events which must occur for a pregnancy to have a high probability of taking place. People's biologies differ and these events may have difficulty occurring or occasionally may not occur at all. Most of the time this leads to subfertility which may be defined as taking longer than normal to achieve pregnancy. In such a setting, the person does not know when pregnancy will occur or if it will ever occur. Much of contemporary therapy is oriented towards increasing the probability of pregnancy occurring in a timing manner.

If is helpful to understand what is normal in terms of timely reproduction. Approximately 50% of 25-year-old couples will achieve pregnancy in less then 6 months. After one year approximately 80% of 25-year-old couples will be pregnant. Fertility (the quickness to achieve pregnancy) decreases with age. We can see this effect as early as age 23. However, the impact of age is not very significant until about age 35. Because of this, above age 34 patients should seek more aggressive therapy than younger patients to ensure their success in ever getting pregnant. Statistically, there is a major drop in fertility even using high levels of technologies that occurs about age 38. It is very difficult to achieve pregnancy in women (using their own eggs) after age 43.

In this article we will review some of the science behind our growing understanding of reproduction. We hope to share this information with you to provide a basis for understanding our approach to evaluation and treatment for the problem of infertility.

Cervical Mucous

Cervical mucous plays an important role in enabling pregnancy to take place by allowing intercourse to occur at a time distant from fertilization. A woman's cervical mucous is different throughout her menstrual cycle. During most of the cycle it forms a thick plug that prevents sperm from entering the uterus. Preceding the time of ovulation the mucous increases in volume, becomes thinner and more stretchy.

In the middle of a woman's cycle cervical mucous provides a reservoir for sperm. Sperm are able to survive for a number of days within crypts of the cervix. The egg is fertilizable for only about twelve hours. However, sperm that have colonized the cervical mucous are free to leave the cervix at any time and travel up into the uterus and through the tubes to find an egg. For most women cervical mucous functions in this way for at least two days prior to ovulation. In some women cervical mucous enables intercourse to occur up to a week before ovulation and pregnancy to still be able to take place.

The vagina is a very hostile place for sperm. The acidity in the vagina rapidly immobilizes sperm. For a short period of time after ejaculation, sperm are protected by the coagulum formed from a man's semen. During this time, sperm are transferred to the cervical mucous which also protects the sperm from the acidity of the vagina. Sperm that have not entered the cervical mucous in this relatively short period of time become non functional. Although, women often worry about semen falling out of their vagina after intercourse, all useful sperm are likely taken up in the cervical mucous within a short period of time after intercourse.

The cervical mucous also acts as a barrier to abnormal sperm. For example, abnormally shaped sperm is much less likely to get into the cervical mucous than normally shaped sperm.

The natural process that takes place in the vagina is one explanation of why a high sperm count is desirable in pregnancy occurring quickly. A normal man may ejaculate up to one half billion sperm in the vagina. Of these only about 1 million will get into the cervix. When the sperm count is significantly lower it is much more difficult for such a large number of sperm to enter the cervix. The cervix is part of a series of barriers that sperm have to overcome in order to find and fertilize the egg. Relatively few sperm ever make it into the fallopian tubes. And the likelihood of a particular sperm finding an egg is on the order of winning the state lottery.

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A Woman's Eggs

A girl child is born with approximately two million eggs in her ovaries. During the course of her lifetime only three to four hundred eggs will ovulate. These eggs reside in the ovary in a protected inactive state. Each individual woman has an intrinsic "biological clock" which causes some of these eggs to leave this protected state. This occurs throughout a woman's life including during her childhood, during pregnancies, and while on birth control pills. If an egg that has left this protected state receives appropriate stimulation, it will develop as part of a follicle and go on to ovulate. If it does not receive appropriate stimulation it will undergo atrophy and will be lost to that woman forever. For most women there appears to be a rapid acceleration of egg loss from the ovary that starts around age thirty-five. There will be follicular development and ovulation in women until they become menopausal. Menopause occurs when there are no eggs in the ovaries which are capable of leaving this arrested state and being stimulated.

Eggs contained in this arrested state in a woman's ovaries contain four times too many chromosomes. Prior to contributing this egg to becoming a baby, the egg must get rid of three-quarters of these chromosomes. In response to a particular hormonal signal around the time of ovulation, microtubules divide the chromosomes in half and dispose of half of them. In response to fertilization, microtubules again divide the chromosomes in an egg in half and dispose of another half of them. Current theory is that these microtubules do not age very well and as women get older there is greater difficulty in disposing of excess chromosomes. This is one explanation of why women above age thirty-five have children with Down's Syndrome, or an extra chromosome twenty-one, more frequently than younger women. However, this process of retaining excess chromosomes occurs for chromosomes other than chromosome twenty-one.

Such abnormal eggs can still be fertilized, but when the excess chromosome is a large one there is limited development and the patient may lose the pregnancy prior to a missed period. An egg that has left its protected state secretes a protein shell referred to as the zona pellucida. This shell is a major barrier to sperm and has to be overcome by the sperm. However, once the egg has been penetrated by a sperm and fertilization has occurred, the embryo divides inside this shell. The embryo must break out of this shell in order to establish itself as a pregnancy in the mother. As women get older they produce more abnormal shells and their embryos have a greater difficulty in getting out of them. This is thought to be one of the major reasons why women in their forties have a markedly decrease pregnancy rate compared to younger women. There are advanced therapies which can compensate for this problem.

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Ovulation

The primary hormone that stimulates an egg to ovulate is follicle stimulating hormone, or FSH. FSH is produced in a women's pituitary gland. It is very tightly regulated in order to cause women to ovulate only a single egg in a spontaneous cycle. In other species the time interval during which FSH is elevated is longer than in humans so that they will be multiple ovulators and give birth to litters as opposed to a single offspring. FSH stimulates susceptible eggs within the ovaries. The cells around these eggs proliferate and produce estrogen. The estrogen tells a women's pituitary that eggs are growing and she decreases the amount of FSH that is produced.

There are many conditions that lead to a relative FSH deficit. FSH is regulated in a complex manner by a number of hormones. Stress may impair FSH production at times. In my practice we see the effect of stress causing ovulatory dysfunction in some women around the time of Christmas and Hannukah. This may be reflected by intermittent months in which a woman will not ovulate.

As an egg responds to FSH, it creates a follicle or cyst which enables the egg to surround itself by an environment that is different from all the other eggs in the ovary. There are women who have problems with both systemic secretion of FSH and forming the appropriate intraovarian follicular environment. There are a number of tools available to help women overcome these problems. The primary limiting issue in overcoming ovulatory problems is the number of eggs remaining in a woman's ovaries.

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Sperm

Getting pregnant quickly depends upon both the quality and quantity of the available sperm. As noted earlier, the female reproductive tract prevents most sperm from entering it. Once sperm have been given the chance to enter the female reproductive system, the quality of the sperm plays a major role. Many men produce as much as a half billion sperm in a single ejaculate. One might ask why nature created a system that appears to be so inefficient since only a single sperm is needed to fertilize an egg. One part of the answer to this question is that it is simply hard for a man's body to make a good functional sperm.

Most sperm produced by most men are unlikely to ever be able to fertilize an egg. The sperm production process is a hard one. It takes sixty to eighty days for the man to fashion the spermatocyte, which looks like a round cell similar to other cells in the human body, into the specialized entity that is the sperm. It requires the expression of gene products for more than one hundred genes that may have little role elsewhere in the body. The enzymes produced to refashion this sperm need to be produced in a coordinated manner at a specific time. This is likely hard to do.

At the time of ejaculation the sperm do not have the ability to be able to fertilize an egg. Among other things, the sperm membrane has to undergo certain membrane changes which enable it to fasten onto the egg and to undergo the processes required for fertilization. After finding the egg, the sperm must first be able to get through the layer of sticky cells that surround it. This penetration requires a good quality motility of the sperm and usually takes the sperm about two hours to achieve.

The next barrier for the sperm is to get through a protein shell secreted by the egg some weeks prior to ovulation called the zona pellucida. This is a major barrier for the sperm. It is approximately four times as thick as the length of a sperm head. In order to get through this barrier the sperm must firmly attach to the shell of the egg. It then changes its swimming pattern so that it can generate more force and penetrate the egg. If the sperm cannot attach to the egg it would likely bounce off. Once a sperm has fertilized the egg, changes occur in the shell of the egg which make it impossible for additional sperm to attach. Sperm that even have mildly abnormal shapes have been shown to not have the appropriate receptors for this attachment to take place. This is a key reason why subtle and strict analysis of sperm shape is an important of subspecialty lab sperm evaluation.

These receptors which attach to the egg are contained on a structure called the acrosome. Not all sperm have acrosomes. As the sperm penetrates the shell of the egg the acrosome begins to dissolve and it releases digestive enzymes which enable the sperm to be successful in penetrating the egg. Once the sperm has penetrated the egg it has to bind to the egg membrane. In order for it to bind it must have exposed surfaces on the sperm that are normally covered by the acrosome. In particular, if one injects a sperm that has not lost its acrosome underneath the shell of the egg, it will not be capable of fertilizing that egg. With binding to the egg membrane the sperm is then incorporated into the egg and its centriole then plays an important role in directing egg division.

Subspecialty laboratory evaluation of sperm attempts to determine how large the functional subpopulation of an ejaculate is. This is often quite different than the sperm count, and most traditional laboratories do not have the ability to provide this kind of information for the physician.

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Egg Pickup

As a follicle develops within the ovary the cells around the egg begin to produce estrogen. In the normal cycle this estrogen level rises for approximately two weeks. As a consequence of this rising level of estrogen, lutenizing hormone (LH) is produced and stored in the pituitary gland in the brain. After a period of time, this LH is discharged into the bloodstream. It then enables the follicle to undergo a number of maturity steps which lead to ovulation. One of the important results of this LH discharge or LH surge is that the egg will undergo its first division of chromosomes. The egg contains four times too much chromosomes for a normal pregnancy to take place. In response to the LH surge the chromosomes are divided in half, one half stays with almost all of the cytoplasm of one egg and the other half is excluded as a small fragment called the first polar body. LH also induces enzymes which cause the egg to become free floating within the follicle that is developing. These enzymes also eventually lead to the creation of a hole in the follicle wall. The fluid and free floating egg leaves through this hole. The enzymes which cause the digestion of the wall involve a series of biochemical processes which can be interfered with by use of strong non steroidal anti inflammatory drugs such as aspirin. A patient taking a lot of aspirin at the wrong time in her cycle will appear to ovulate, but the egg will not get out.

The egg with its surrounding cells is sticky and so it usually stays on the ovarian surface near where ovulation occurred. However, it does have the ability to potentially go anywhere in the pelvis. The female pelvis is a fairly large place and holds approximately a half gallon of water. The egg and the cells around it are microscopic. Some animal species ovulate into their tubes. Humans are not so fortunate. The tube must pick up the egg and move it inside for fertilization to take place. There are specialized cells on the ends of the tube which do an excellent job of performing this function.

When these tubes are damaged, for example by a pelvic infection, it is difficult for surgery to make them adequately functional. Simply having the tubes open is not enough. The tubes must actually be able to pick up the egg.

Egg pickup amazingly occurs as often as it does, because the pelvic organs are able to move freely in a woman's body as she undertakes her normal daily activities. On a theoretical basis, one would hypothesis that moderate activity would be helpful for some patients in achieving pregnancy (as opposed to bed rest). The egg needs to be picked up in about twelve hours. After that it is either difficult to fertilize or is more likely to result in a miscarriage if fertilization occurs.

The body forms intra-abdominal adhesions in response to any injury. Common injuries are infection, endometriosis, or tissue handling or drying from prior surgery. The injured tissue secretes a sticky substance and attaches to more normal tissue. A blood supply is created between the normal and the abnormal tissue which results in healing substances being transferred to the injured tissue. Over time this connection becomes durable. From the viewpoint of good health, the ability of a body to form inner abdominal adhesions is desirable. However, such adhesions can certainly limit fertility. For example, if an adhesion resulted in the midpoint of the tube being tethered, a women might succeed in picking up an egg that ovulated on that side only if the egg ovulated near the end of the tube. However, the egg is as likely to ovulate distant from the tube as it is near to the tube. If the ovary were tethered, any egg ovulating on the underside of the ovary has no chance of being picked up. Pelvic adhesions can be completely asymptomatic. They can only be diagnosed with a surgical procedure such as a laparoscopy. "Minor" adhesions can be repaired during the same surgery and may markedly improve that woman's ability to ge pregnant.

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Embryo Transport

Fertilization always takes place in the distal third of a fallopian tube. The fertilized embryo remains there for approximately three to four days. During this time period, the embryo undergoes several cellular division within the zona pellucida. After three or four days the embryo is then transported into the uterus. If this transport does not occur then either the pregnancy stops growing or it becomes a tubal pregnancy, which usually requires surgical intervention.

Once the embryo has been transported into the uterus, it remains there for three or four days. The embryo continues to divide within the zona pellucida. The more cells that it divides into, the more likely the pregnancy is able to become established. The embryo then has to break out of its own zona pellucida in order to make contact with the maternal uterus. If it is not able to do that this pregnancy will be lost, and it will never have been detectable as a pregnancy. As women age they produce zone pellucidas that are harder for the embryo to get out of. The embryo mass in an aged ovary also has additional problems in getting out of the zona pellucida. This is likely the primary mechanism where by there is markedly decreased fertility in women as they age. Most women at least intermittently ovulate into the fifties, but pregnancies in the last forties are extremely rare.

At the approximate time that the embryo is breaking out of or hatching from its zona pellucida, there are changes in the lining of the uterus which enable the pregnancy to get established. Specialized structures develop in cells within the lining of the uterus, called pinopodes, which define the implantation window. They remove any fluid in the uterine cavity to ensure good contact between the embryo and the maternal uterine surfaces. The lining of the uterus also expresses proteins (for example, integrins) which help the embryos attach.

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Immunology

The maternal immune system has to undergo a number of changes to allow pregnancies to implant and to develop. The trophoblastic tissue, or developing placenta, may be attacked by certain cell populations that are part of a woman's immune system. A woman's immune system has to act in such a way to decrease the activity of these cells. One of the functions of a hormone produced in early pregnancy called progesterone, is to decrease this destructive action of the immune system. Some women produce antibodies to parts of the developing placenta. Such women may have difficulty in getting pregnant, staying pregnant and in the healthy growth of the baby during the pregnancy. As the pregnancy develops there are immunological markers of that pregnancy that are obviously different from the mother. Maternal immune system needs to protect the fetus from normal activation of her immune system.