Infertility

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Infertility

Infertility is the inability of a man and woman to carry a pregnancy to full term and to conceive a child after attempting to do so for at least one full year. Primary infertility refers to a situation in which pregnancy has never been achieved. Secondary infertility refers to a situation in which one or both members of the couple have previously conceived a child, but are unable to conceive again after a full year of trying.

Currently in the United States, according to the American Society for Reproductive Medicine (ASRM), about 15 to 20% of couples struggle with infertility at any given time, which, as of 2005, involves about 6.1 million people in the United States that are in the reproductive age population. Infertility has increased as a problem, as demonstrated by an early study conducted between the years of 1965 and 1982, which compared fertility rates in married women ages 20 to 24 years of age. In that time period, infertility increased 177%. Some scientific studies in the 2000s attribute this continued increase in infertility on primarily social phenomena, including the tendency for marriage to occur at a later age, and the associated tendency for attempts at first pregnancy to occur at a later age. Fertility in women decreases with increasing age, as illustrated by the following statistics:

infertility in married women ages 16 to 20 years: 4.5%
infertility in married women ages 35 to 40 years: 31.8%
infertility in married women over age 40 years: 70%.

Since the 1960s, there has also been greater social acceptance of sexual intercourse outside of marriage, and individuals often have multiple sexual partners before they marry and attempt conception. This has led to an increase in sexually transmitted infections. Scarring from these infections, especially from pelvic inflammatory disease (PID)—a serious infection of the female reproductive organs—seems to be partly responsible for the increase. Furthermore, use of the contraceptive device called the intrauterine device (IUD) also has contributed to an increased rate of PID, with subsequent scarring.

To understand issues of infertility, it is first necessary to understand the basics of human reproduction. Fertilization occurs when a male sperm merges with a female ovum (egg), creating a zygote, which contains genetic material (DNA, deoxyribonucleic acid) from both the father and the mother. If pregnancy is then established, the zygote will develop into an embryo, then a fetus, and ultimately a baby will be born.

Sperm are small cells that carry the father’s genetic material. This genetic material is contained within the oval head of the sperm. Sperm are produced within the testicles, and proceed through a number of developmental stages in order to mature. This whole process of sperm production is called spermatogenesis. The sperm are mixed into a fluid called semen, which is discharged from the penis during a process called ejaculation. The whiplike tail of the sperm allows the sperm motility; that is, permits the sperm to essentially swim up the female reproductive tract, in search of the egg it will attempt to fertilize.

The ovum (or egg) is the cell that carries the mother’s genetic material. These ova develop within the ovaries. Once a month, a single mature ovum is produced and leaves the ovary in a process called ovulation. This ovum enters the fallopian tube (a tube extending from the ovary to the uterus) where fertilization occurs.

If fertilization occurs, a zygote containing genetic material from both the mother and father results. This single cell will divide into multiple cells within the fallopian tube, and the resulting cluster of cells (called a blastocyst) will then move into the uterus. The uterine lining (endometrium) has been preparing itself to receive a pregnancy by growing thicker. If the blastocyst successfully reaches the inside of the uterus and attaches itself to the wall of the uterus, then implantation and pregnancy have been achieved.

Unlike most medical problems, infertility is an issue requiring the careful evaluation of two separate individuals, as well as an evaluation of their interactions with each other. In about 3 to 4% of couples, no cause for their infertility will be discovered. The main factors involved in causing infertility, listing from the most to the least common, include: (1) Male factors; (2) Peritoneal factors; (3) Uterine/tubal factors; (4) Ovulatory factors; and (5) Cervical factors.

Male factor infertility

Male factor infertility can be caused by a number of different characteristics of the sperm. To check for these characteristics, a semen analysis is carried out, during which a sample of semen is obtained and examined under the microscope. The four most basic characteristics evaluated are: (1) Sperm count or the number of sperm present in a semen sample. The normal number of sperm present in just one milliliter (ml) of semen is over 20 million. A man with only 5 to 20 million sperm per ml of semen is considered subfertile, a man with fewer than five million sperm per ml of semen is considered infertile. (2) Sperm motility. Better swimmers indicate a higher degree of fertility, as does longer duration of survival. Sperm are usually capable of fertilization for up to 48 hours after ejaculation. (3) Sperm morphology or the structure of the sperm. Not all sperm within a specimen of semen will be perfectly normal. Some may be developmentally immature forms of sperm, some may have abnormalities of the head or tail. A normal semen sample will contain no more than 25% abnormal forms of sperm. (4) Volume of a representative semen sample. The semen is made up of a number of different substances, and a decreased quantity of one of these substances could affect the ability of the sperm to successfully fertilize an ovum.

The semen sample may also be analyzed chemically to determine that components of semen other than sperm are present in the correct proportions. If all of the above factors do not seem to be the cause for male infertility, then another test is performed to evaluate the ability of the sperm to penetrate the outer coat of the ovum. This is done by observing whether sperm in a semen sample can penetrate the outer coat of a guinea pig ovum; fertilization cannot, of course, occur, but this test is useful in predicting the ability of the patient’s sperm to penetrate a human ovum.

Any number of issues can affect male fertility as evidenced by the semen analysis. Individuals can be born with testicles that have not descended properly from the abdominal cavity (where testicles develop originally) into the scrotal sac, or they can be born with only one testicle, instead of the normal two. Testicle size can be smaller than normal. Past infection (including mumps) can affect testicular function, as can a past injury. The presence of abnormally large veins (varicocele) in the testicles can increase testicular temperature, which decreases sperm count. A history of exposure to various toxins, drug use, excessive alcohol use, use of anabolic steroids, certain medications, diabetes, thyroid problems, or other endocrine disturbances can have direct effects on spermatogenesis. Problems with the male anatomy can cause sperm to be ejaculated not out of the penis, but into the bladder, and scarring from past infections can interfere with ejaculation.

Treatment of male factor infertility includes addressing known reversible factors first, for example discontinuing any medication known to have an effect on spermatogenesis or ejaculation, as well as decreasing alcohol intake and treating thyroid or other endocrine disease. Varicoceles can be treated surgically. Testosterone in low doses can improve sperm motility.

Some recent advances have greatly improved the chances for infertile men to conceive. Azoospermia (lack of sperm in the semen) may be overcome by mechanically removing sperm from the testicles either by surgical biopsy or needle aspiration (using a needle and syringe). The isolated sperm can then be used for in vitro fertilization. Another advance involves using a fine needle to inject a single sperm into the ovum. This procedure, called intracytoplasmic sperm injection (ICSI) is useful when sperm have difficulty fertilizing the ovum and when sperm have been obtained through mechanical means.

Other treatments of male factor infertility include collecting semen samples from multiple ejaculations, after which the semen is put through a process that allows the most motile sperm to be sorted out. These motile sperm are pooled together to create a concentrate that can be mechanically deposited directly into the female partner’s uterus at a time that will coincide with ovulation. In cases where the male partner’s sperm is proven to be unable to cause pregnancy in the female partner, and with the consent of both partners, donor sperm may be used for this process. These procedures (depositing the male partner’s sperm or donor sperm by mechanical means into the female partner) are both forms of artificial insemination.

In January 2005, the Fertility and Sterility journal, which is associated with the ASRM, published an article concerning infertility. The results showed that one in ten American couples are infertile, approximately 100,000 pregnancies are attempted each year using in vitro fertilization, and more than 177,000 babies have been born in the United States through in vitro fertilization.

Female factor infertility

Peritoneal factors refer to any factors (other than those involving specifically the ovaries, fallopian tubes, or uterus) within the abdomen of the female partner that may be interfering with her fertility. Two such problems include pelvic adhesions and endometriosis.

Pelvic adhesions are thick, fibrous scars. These scars can be the result of past infections, particularly sexually transmitted diseases such as PID, or infections following abortions or prior births. Previous surgeries can also leave behind scarring. Complications from appendicitis and certain intestinal diseases can also result in adhesions in the pelvic area.

Endometriosis also results in pelvic adhesions. Endometriosis is the abnormal location of uterine tissue outside of the uterus. When uterine tissue is planted elsewhere in the pelvis, it still bleeds on a monthly basis with the start of the normal menstrual period. This leads to irritation within the pelvis around the site of this abnormal tissue and bleeding, and ultimately causes scarring.

Pelvic adhesions contribute to infertility primarily by obstructing the fallopian tubes. The ovum may be prevented from traveling down the fallopian tube from the ovary, and the sperm prevented from traveling up the fallopian tube from the uterus; or the blas-tocyst may be prevented from entering into the uterus where it needs to implant. Scarring can be diagnosed by examining the pelvic area with a scope, which can be inserted into the abdomen through a tiny incision made near the naval. This scoping technique is called laparoscopy.

Obstruction of the fallopian tubes can also be diagnosed by observing through an x-ray examination whether dye material can travel through the patient’s fallopian tubes. Interestingly enough, this procedure has some actual treatment benefits for the patient, as a significant number of patients become pregnant following this exam. It is thought that the dye material in some way helps clean out the tubes, decreasing any existing obstruction.

Pelvic adhesions can be treated using the same laparoscopy technique utilized in the diagnosis of the problem. For treatment, use of the laparoscope to visualize adhesions is combined with use of a laser to disintegrate those adhesions. Endometriosis can be treated with certain medications, but may also require surgery to repair any obstruction caused by adhesions.

Uterine factors contributing to infertility include tumors or abnormal growths within the uterus, chronic infection and inflammation of the uterus, abnormal structure of the uterus, and a variety of endocrine problems (problems with the secretion of certain hormones), which prevent the uterus from developing the thick lining necessary for implantation by a blastocyst.

Tubal factors are often the result of previous infections that have left scar tissue. This scar tissue blocks the tubes, preventing the ovum from being fertilized by the sperm. Scar tissue may also be present within the fallopian tubes due to the improper implantation of a previous pregnancy within the tube, instead of within the uterus. This is called an ectopic pregnancy. Ectopic pregnancies cause rupture of the tube, which is a medical emergency requiring surgery, and results in scarring within the affected tube.

X-ray studies utilizing dyes can help outline the structure of the uterus, revealing certain abnormalities. Ultrasound examination and hysteroscopy (in which a thin, wand-like camera is inserted through the cervix into the uterus) can further reveal abnormalities within the uterus. Biopsy (removing a tissue sample for microscopic examination) of the lining of the uterus (the endometrium) can help in the evaluation of endocrine problems affecting fertility.

Treatment of these uterine factors involves antibiotic treatment of any infectious cause, surgical removal of certain growths within the uterus, surgical reconstruction of the abnormally formed uterus, and medical treatment of any endocrine disorders discovered. Progesterone, for example, can be taken to improve the hospitality of the endometrium toward the arriving blastocyst. Very severe scarring of the fallopian tubes may require surgical reconstruction of all or part of the scarred tube.

Ovulatory factors are those factors that prevent the maturation and release of the ovum from the ovary with the usual monthly regularity. Ovulatory factors include a host of endocrine abnormalities, in which appropriate levels of the various hormones that influence ovulation are not produced. Numerous hormones produced by multiple organ systems interact to bring about normal ovulation. Therefore, ovulation difficulties can stem from problems with the ovaries, the adrenal glands, the pituitary gland, the hypothalamus, or the thyroid.

The first step in diagnosing ovulatory factors is to verify whether or not an ovum is being produced. Although the only certain proof of ovulation (short of an achieved pregnancy) is actual visualization of an ovum, certain procedures suggest that ovulation is or is not taking place.

The basal body temperature is the body temperature that occurs after a normal night’s sleep and before any activity (including rising from bed) has been initiated. This temperature has normal variations over the course of the monthly ovulatory cycle, and when a woman carefully measures and records these temperatures, a chart can be drawn that suggests whether or not ovulation has occurred.

Another method for predicting ovulation involves measurement of a particular chemical that should appear in the urine just prior to ovulation. Endometrial biopsy will reveal different characteristics depending on the ovulatory status of the patient, as will examination of the mucus found in the cervix (the opening to the uterus). Also, pelvic ultrasound can visualize developing follicles (clusters of cells that encase a developing ovum) within the ovaries.

Treatment of ovulatory factors involves treatment of the specific organ system responsible for ovulatory failure (for example, thyroid medication must be given in the case of an underactive thyroid, a pituitary tumor may need removal, or the woman may need to cease excessive exercise, which can result in improper activity of the hypothalamus). If ovulation is still not occurring after these types of measures have been taken, certain drugs exist that can induce ovulation. These include Clomid®, Pergonal®, Metrodin®, Fertinex®, Follistim®, and Gonal®, F. These drugs, however, may cause the ovulation of more than one ovum per cycle, which is responsible for the increase in multiple births (twins, triplets, etc.) noted since these drugs became available to treat infertility.

KEY TERMS

Assisted hatching —The process in which a small opening is made in the outer shell of the pre-embryo or blastocyst to increase the implantation rate.

Blastocyst —A cluster of cells representing multiple cell divisions after successful fertilization of an ovum by a sperm. This is the developmental form that must implant itself in the uterus to achieve pregnancy.

Cervix —The front portion, or neck, of the uterus.

Ejaculation —A spasmodic muscular contraction expelling semen from the penis.

Endometrium —The blood-rich interior lining of the uterus.

Fallopian tubes —In a woman’s reproductive system, a pair of narrow tubes that carry the egg from the ovary to the uterus.

Ovary —The female organ in which eggs (ova) are stored and mature.

Ovum (plural=ova) —The reproductive cell of the female which contains genetic information and participates in fertilization. Also popularly called the egg.

Semen —The fluid which contains sperm which is ejaculated by the male.

Sperm —Substance secreted by the testes during sexual intercourse. Sperm includes spermatozoon, the mature male cell which is propelled by a tail and has the ability to fertilize the female egg.

Spermatogenesis —The process by which sperm develop to become mature sperm.

Zygote —The cell resulting from the fusion of male sperm and the female egg. Normally the zygote has double the chromosome number of either gamete, and gives rise to a new embryo.

The cervix is the opening from the vagina into the uterus through which the sperm must pass. Mucus produced by the cervix helps to transport the sperm into the uterus. Injury to the cervix during a prior birth, surgery on the cervix due to a pre-cancerous or cancerous condition, or scarring of the cervix after infection, can all result in a smaller than normal cervical opening, making it difficult for the sperm to enter. Furthermore, any of the above conditions can also decrease the number of mucus-producing glands in the cervix, leading to a decrease in the quantity of cervical mucus. In other situations, the mucus produced is the wrong consistency (perhaps too thick) to allow sperm to travel through it. Certain infections can also serve to make the cervical mucus environment unfavorable to the transport of sperm, or even directly toxic to the sperm themselves (causing sperm death). Some women produce antibodies (immune cells) that identify sperm as foreign invaders.

The qualities of the cervical mucus can be examined under a microscope to diagnose cervical factors as contributing to infertility. The interaction of a live sperm sample from the male partner and a sample of cervical mucus can also be examined.

Treatment of cervical factors includes antibiotics in the case of an infection, steroids to decrease production of anti-sperm antibodies, and artificial insemination techniques to completely bypass the cervical mucus.

Assisted reproduction comprises those techniques that perhaps receive the most publicity as infertility treatments. These include in vitro fertilization (IVF), gamete intrafallopian tube transfer (GIFT), and zygote intrafallopian tube transfer (ZIFT). All of these are used after other techniques to treat infertility have failed.

IVF involves the use of a drug to induce multiple ovum production, and retrieval of those ova either surgically or by ultrasound-guided needle aspiration through the vaginal wall. Meanwhile, multiple semen samples are obtained from the male partner, and a sperm concentrate is prepared. The ova and sperm are then cultured together in a laboratory, where hopefully several of the ova are fertilized. Cell division is allowed to take place up to either the pre-embryo or blastocyst state. While this takes place, the female may be given medication to prepare her uterus to receive an embryo. When necessary, a small opening is made in the outer shell (zona pellucida) of the pre-embryo or blastocyst by a process known as assisted hatching. Two or more pre-embryos or two blastocysts are transferred into the uterus, and the wait begins to see if any or all of them implant and result in an actual pregnancy.

There has been medical controversy over whether children conceived using IVF are more liable to suffer birth defects. A 2005 metastudy—a study of all existing studies—found a 30–40% increase in birth defects risk for IVF babies versus those conceived naturally. If this effect is real, the cause is not known. Without a doubt, however, because most IVF procedures place more than one embryo into the uterus, the chancefor a multiple birth (twins or more) is greatly increased.

GIFT involves retrieval of both multiple ova and semen, and the mechanical placement of both within the fallopian tubes, where fertilization may occur. ZIFT involves the same retrieval of ova and semen, and fertilization and growth in the laboratory up to the zygote stage, at which point the zygotes are placed in the fallopian tubes. Both GIFT and ZIFT seem to have higher success rates than IVF.

Ova can now be frozen for later use, although greater success is obtained with fresh ova. However, storing ova may provide the opportunity for future pregnancy in women with premature ovarian failure or pelvic disease or those undergoing cancer treatment.

Any of these methods of assisted reproduction can utilize donor sperm and/or ova. There have even been cases in which the female partner’s uterus is unable to support a pregnancy, so the embryo or zygote resulting from fertilization of the female partner’s ovum with the male partner’s sperm is transferred into another woman, where the pregnancy progresses to birth.

Chances at pregnancy can be improved when the pre-embryos are screened for chromosomal abnormalities and only the normal ones are transferred into the uterus. This method is useful for couples who are at an increased risk of producing embryos with chromosomal abnormalities, such as advanced maternal age or when one or both partners carry a fatal genetic disease.

Multiple ethical issues have presented themselves as a result of assisted reproduction. Some of these issues involve the use of donor sperm or ova, and surrogate motherhood. Other issues include what to do with frozen embryos, particularly when the couple has divorced.

A particularly difficult ethical problem has come about by virtue of the technique of transferring multiple embryos or zygotes into the female. When pregnancy occurs in which there are multiple developing fetuses, there is a greatly increased chance for pregnancy complications, preterm delivery, and life-long medical problems. Techniques allowing only one or two of the fetuses to continue developing may be employed.

See also Reproductive system.