WHAT IS INFERTILITY?
Infertility is a common condition affecting approximately 10%-15% of couples. One unusual aspect of this field of medicine is that it involves two patients who each need to be evaluated; in many cases, both also need to be treated. Some couples have difficulty in conceiving their first pregnancy (primary infertility) whereas other couples experience problems after conceiving pregnancies in the past (secondary infertility). In either case, stress and grief are common when couples have difficulty.
Infertility is commonly defined as the lack of pregnancy following 12 months of unprotected intercourse. Couples with no infertility problems have a monthly pregnancy rate of 20-25% following properly timed intercourse. As a result, it is not uncommon for couples to take several months to conceive a pregnancy. Since approximately 90% of young couples will conceive a pregnancy within one year, if a pregnancy has not happened within a year , an evaluation for possible reasons is warranted. Sometimes the evaluation should begin even sooner than one year.
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CONDITIONS THAT WARRANT AN INFERTILITY EVALUATION IF A PREGNANCY HAS NOT BEEN ACHIEVED WITHIN 6 MONTHS
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- Woman’s age greater than 35
- Very irregular menstrual cycles.
- A woman with a past history of pelvic inflammatory disease, extensive pelvic surgery or known severe endometriosis (when tissue similar to the lining of the uterus is found outside the uterus).
IS INFERTILITY INCREASING IN THE UNITED STATES?
We do not know for sure if the prevalence of infertility is increasing but certainly the use of treatments for infertility is increasing, probably due to several societal trends. In most developed countries, there is a trend toward later age of marriage and first pregnancy in women, often for educational and career purposes. Because a female’s fertility declines with age, this naturally leads to an increasing time to conception and problems with infertility. In addition, couples today are more aware of infertility treatment options, in part through media coverage of infertile couples and infertility treatments. This may also increase demand for the services.
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CAUSES OF INFERTILITY
For pregnancy to occur
Infertility can result from a disruption in any of these normal events, including:
- motile sperm must be deposited near the cervix through intercourse
- the sperm must be able to ascend through the cervix, uterus and fallopian tubes, arriving at the same time that a woman has ovulated (released an egg)
- Fertilization usually occurs near the end of the fallopian tube and the fertilized egg (embryo) is then transported over several days into the uterine cavity.
- The embryo must be able to implant into endometrium, the tissue that lines the uterus.
Infertility often results from combinations of several problems on both the male and female sides.
- Male related problems with sperm production and/or sperm transport through the male reproductive tract and delivery into the female reproductive tract
- On the female side, infertility may be caused by anovulation (a lack of ovulation), blocked fallopian tubes, or inability of an embryo to implant and establish a pregnancy in the uterus.
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HOW ARE SPERM MADE?
The making of sperm is a complex affair, a process referred to as “spermatogenesis”. At the beginning, round, nondescript cells in the testes duplicate themselves, and these copies then divide twice to form cells with half of the man's chromosomes. A sperm half cell will ultimately join with the half cell that is the egg to make an embryo. But first, a sperm must change in shape dramatically to become the elegant submarine that swims upstream in the female reproductive organs to penetrate the egg. The complicated manufacturing of a single sperm requires two to three months to complete, yet the testis produces hundreds of millions to billions of sperm each day. A result of the months long production of sperm is that should a man require treatment to improve spermatogenesis, he must wait two to three months before therapy's effects are seen.
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HOW ARE SPERM TESTED?
Basic semen analysis
The basic test of a man's ability to conceive children is the semen analysis. Optimally, the man produces semen by masturbation in a private room in the semen analysis laboratory, but if that is not possible, a man may bring semen collected at home in to the laboratory. Because men with low numbers of sperm may deplete their sperm reserve by ejaculating too frequently, it is best for a man to wait two to three days after his last ejaculation before he performs a semen analysis.
While the semen analysis is the most commonly used initial test for male fertility, it is not very accurate. Many men with a “normal” semen analysis by the numbers have problems conceiving children and, not infrequently, men with an abnormal semen analysis successfully impregnate their partners. The semen analysis measures average aspects of sperm, whereas male fertility is characterized not by the average, but the most exceptional sperm. The most exceptional sperm travels through the entire female reproductive tract, penetrates and fertilizes the egg, and no test currently exists that can characterize this extraordinary sperm. As the exceptional sperm is more likely found in a larger number of good sperm, the better the results of the semen analysis, the better a man's chances, and the shorter time it should take to impregnate his partner. Because a better initial screening test for male fertility is not yet available, doctors currently use the semen analysis to assess the chance a man is likely contributing to a couple's difficulty conceiving children.
The semen analysis varies widely from sample to sample, and throughout the year. Typically, a doctor requests that a man obtain two semen analyses to judge that patient's fertility. The semen analysis itself is a complex test, performed by a specially trained technician. Semen analyses may vary substantially among laboratories.
The World Health Organization (WHO) publishes the criteria most widely used for semen analysis, now in its 4th edition. The values in the WHO criteria are designed to identify infertile men, but many men with infertility have values above these numbers. In other words, being above the reference value does not guarantee fertility, or a medical condition that may be treated to improve fertility. The main parts of the semen analysis include:
|Semen analysis part
||Reference value for WHO Criteria for Infertile Men
||Less than 2.0 ml
||Less than 7.2
||Less than 20 million sperm per ml
|Total sperm number
||Less than 40 million sperm per ejaculate
||Less than 50% with progressive motility
||Less than 75% live
|White blood cells
||More than 1 million per ml
Morphology: the shape of the sperm
In general, sperm vary in shape even in fertile men. According to the fairly loose WHO criteria, the semen analysis is normal if 30% of sperm look normal. In an attempt to make morphology a more precise measurement, “strict criteria” were devised. Although the number may vary, laboratories often use 4% as the cutoff for strict morphology. That means if up to 95% of sperm are oddly shaped by strict criteria, the semen analysis is considered normal. Scientific studies do not agree on the ability of strict morphology to predict sperm function, and even highly trained laboratory personnel may disagree on how many sperm are normal by strict morphology in a single sperm sample. As a result, a strict morphology result may or may not be meaningful in assessing a man's fertility. Two good rules of thumb are:
- If all of the sperm are abnormally shaped in the same way (for example, they all have perfectly round instead of oval heads,) there's a problem.
- If the abnormal shape is associated with an identified condition, such as a varicocele (varicose veins in the scrotum), the condition is likely a problem.
Sperm are typically protected from the body's immune system by specialized bridges between Sertoli cells. If that blood-testis barrier is broken, a man's body may begin to attack his own sperm. Conditions that may break the blood-testis barrier include injury to the testis, the testis twisting on itself, undescended testes in childhood, vasectomy, and infection. Antibodies made by a man to his own sperm, known as “antisperm antibodies”, are measured by the “immunobead” test (IBT).
White blood cells may be drawn to the semen by infection or inflammation, and damage the sperm. This condition is known as “pyospermia”. Tests for pyospermia count the number of white blood cells in the semen. Typically, less than one million cells per milliliter is normal, but more than three million white blood cells per milliliter may affect a man's fertility.
A sperm's basic job is to transport its genetic cargo to the egg. The quality of the DNA contained within the sperm may affect egg fertilization and early embryo development. One commercial test of DNA quality is the “Sperm Chromatin Structure Assay” (SCSA). The SCSA measures DNA melting in acid, called “denaturation.” Studies in the scientific literature disagree over whether DNA denaturation as measured by the SCSA predicts embryo development and pregnancy. Other tests of DNA quality include the Comet and the terminal uridine deoxynucleotidyl transferase nick end labeling (TUNEL) assays, both commonly performed in molecular biology laboratories for scientific studies of cells. In scientific journals, researchers have reported correlation between Comet and TUNEL results and embryo quality and in-vitro fertilization (IVF) outcomes. Although not yet widely available, Comet and TUNEL may be promising tests to measure sperm DNA quality.
DNA is organized in cells in chromosomes. Two currently available ways of testing chromosomes are the karyotype, in which a picture is made of the 23 pairs of human chromosomes and missing or extra areas are identified, and the Y-chromosomal microdeletion assay, where specific regions of the Y chromosome are determined to be missing. These tests screen only a fraction of the many genes that contribute to male fertility. While recommended for men with very low sperm counts or no sperm in the ejaculate, a doctor will balance the costs of these tests and the chance of discovering a genetic condition in an individual man.
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WHAT CAUSES PROBLEMS WITH SPERM, AND HOW CAN THEY BE TREATED?
Perhaps surprisingly, much of male infertility is thought to be due to genetics. With the human DNA sequence completed by the Human Genome Project in April 2003, more conditions of male infertility caused by genetics will be discovered in coming years. Some known genetic causes of problems with male fertility include (among many others):
- Klinefelter syndrome: two sex X chromosomes in addition to the Y (XXY)
- Kallmann syndrome: pituitary production of LH and FSH is low or absent
- Kartagener syndrome, primary ciliary dyskinesia, immotile cilia syndrome: these are structural problems in the microscopic tubes in the sperm tail
- Congenital bilateral absence of the vas deferens (CBAVD): changes in the gene responsible for cystic fibrosis cause the vas deferens on both sides to be absent
- Androgen insensitivity syndrome: the receptor that binds to testosterone is altered
- 5-a-reductase deficiency: the enzyme that converts testosterone to the more active form dihydrotestosterone is altered
- Persistent Müllerian duct syndrome: female organs develop in the male embryo
- Changes in the deleted in azoospermia (DAZ) gene: alterations in a gene on the Y chromosome involved in making sperm
Azoospermia refers to the condition where no sperm are found in the ejaculate. Azoospermia is different than anejaculation, where the man does not ejaculate. Azoospermia with a low ejaculate volume (typically less than one milliliter) may be caused by:
Azoospermia with a normal semen volume may be caused by obstruction of the epididymis or vas deferens ("obstructive azoospermia", OA) or to problems with spermatogenesis ("non-obstructive azoospermia", NOA). A doctor can distinguish between obstructive and non-obstructive azoospermia with approximately 90% accuracy by measuring testis size and FSH. Biopsy of the testis is occasionally necessary to determine whether azoospermia is obstructive or non-obstructive.
- Obstruction of the ejaculatory ducts emptying semen into the urethra. This may be treated by using surgery to open the ejaculatory ducts, or if surgery is not possible or unsuccessful, to extract sperm directly from the testis or epididymis for IVF.
- Retrograde ejaculation of sperm into the bladder. Rather than being propelled forward during ejaculation, sperm goes backwards into the bladder. This may be treated by medicines to strengthen the bladder neck, or retrieving sperm from the bladder for artificial insemination or IVF.
- Conditions like CBAVD which cause problems in development of the prostate and seminal vesicles. These may be treated by extracting sperm directly from the testis or epididymis for IVF.
A man may be born with obstructive azoospermia or he may have had a vasectomy, injury or infection as a cause later in life. The treatment of obstructive azoospermia is to correct the obstruction with microsurgery if possible. If surgical reconstruction is not possible or successful, sperm is extracted from the testis or epididymis. As it is immature, sperm extracted from the testis or epididymis must be used in IVF, typically with intracytoplasmic sperm injection (ICSI).
Like obstructive azoospermia, non-obstructive azoospermia may be present from childhood, or acquired later in life due to injury or infection. A man with non-obstructive azoospermia may be treated with medicine to stimulate spermatogenesis, requiring three months or more of treatment. If sperm is not found in the ejaculate after treatment, or if the couple prefers immediate treatment, sperm is extracted from the testis for IVF.
A surgeon may use many different ways of extracting sperm from the testis, including open surgery, microsurgery, using a needle to aspirate draw out sperm, and retrieving sperm from the testis or epididymis. All choices are possible with obstructive azoospermia, as large numbers of sperm are present in the testis. Non-obstructive azoospermia limits a surgeon's choices. In order to obtain enough sperm, a surgeon may use microsurgery, open surgery, or multiple needle punctures from the testis.
Extracted sperm may be frozen for later use with IVF. Advantages of freezing sperm include that the couple may choose a date for the extraction procedure, the female partner may be present for the extraction, and the couple will know whether sperm was able to be extracted before IVF is done. There is no difference in the success of IVF with frozen sperm or sperm extracted on the day of IVF.
Failure of the pituitary to release LH and FSH causes failure of the testis to produce testosterone and sperm. This condition is diagnosed by low testosterone accompanied by relatively low LH levels. The most extreme example of pituitary failure is Kallmann syndrome, which may be treated with HCG and recombinant FSH, often requiring lengthy treatment periods of a year or more. Milder forms of pituitary problems are common, and may be treated with clomiphene citrate if the pituitary is responsive.
Failure of the Leydig cells in the testis to make testosterone results in low levels of testosterone accompanied by very high levels of LH as the negative feedback of testosterone on the pituitary is decreased. Treatment is surgical extraction of sperm if possible, as the body is already providing its own hormonal stimulation.
Testosterone therapy is not used for male fertility. Although the blood levels of testosterone rise with external application of testosterone, negative feedback on the pituitary and the resulting fall in LH causes the very high levels of testosterone in the testis to fall. For this reason, scientists have studied external testosterone for male contraception.
High levels of the female hormone estradiol may impair male fertility; this condition can be treated with medications such as anastrozole (Arimidex). High levels of sex hormone binding globulin may also lower the amount of effective testosterone, referred to as “bioavailable” testosterone. If the total or bioavailable testosterone is too low, clomiphene citrate may be used to increase the production of testosterone in the testes.
Because it is outside of the body, the testis is cooler than other organs, a condition that is important to sperm survival; conversely, heat is toxic to sperm production. The cords transporting blood to and from the testis are arranged in a radiator-like “counter current heat exchange.” A common cause of male fertility is varicose veins in the scrotum that heat the testis and disrupt sperm production. Varicose veins in the scrotum are called a varicocele. Until the 1990s, doctors argued whether varicoceles were important to male fertility, and if treating them helped. It was discovered that treating varicoceles that were neither felt nor visible to the naked eye was not helpful, but that varicoceles that could be felt or were visible damaged sperm production, and that male fertility improved with treatment. Treating a varicocele usually involves an outpatient surgical procedure called a “varicocelectomy,” which may be done with the surgeon using magnifying lenses or the operating microscope to preserve the tiny arteries carrying blood to the testis. A varicocele may also be treated by an experienced interventional radiologist.
Sperm production in the pre-adolescent boy is inactive until he reaches puberty. If the testis does not descend in the scrotum, a condition called cryptorchidism, early sperm cells may be permanently damaged. Early treatment of cryptorchidism by surgery to bring the testis into the scrotum, called orchidopexy, is important to preserve a male's later fertility. Other childhood conditions that may affect future fertility include:
The immune system
- Mumps orchitis: mumps involving the testis. Treatment is prevention of mumps, or if it occurs, treating as best as possible the episode of mumps.
- Testis torsion: the testis twists on itself. Treatment is surgical untwisting of the testis as soon as possible.
- Testis trauma: injury significant enough to disrupt the inside of the testis. If the outer sheath of the testis is ruptured, treatment is surgical repair.
White blood cells in the semen release toxic chemicals that may affect sperm function. Antioxidants and anti-inflammatory medication may help prevent sperm damage by excessive white blood cells in the semen.
If the man's body is producing antibodies to his own sperm, “antisperm antibodies,” steroids may be used to desensitize the immune system. Intrauterine insemination with washed sperm may be used , but IVF with ICSI may be necessary to treat antisperm antibodies.
Problems with erections and ejaculation
Difficulty with erection of the penis becomes increasingly likely as a man ages. Many treatments are available to treat erectile dysfunction. Problems with ejaculation may be due to injury to the nerves controlling ejaculation, such as in spinal cord injury, or disease of the nerves by conditions like diabetes. Anejaculation (a condition where a man cannot ejaculate) may be treated by collection of sperm with vibratory stimulation of the penis or stimulation of the nerves using a procedure called electroejaculation, or by surgical extraction of sperm from the testis or epididymis and IVF.
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WHAT CAN I DO TO IMPROVE MY SPERM?
The sperm are rapidly dividing and growing populations of cells. A well balanced diet with green leafy and brightly colored vegetables provides the chemicals necessary for DNA and sperm function. A chemical found in red meat and dairy foods, l-carnitine, may be important to sperm function as well.
Avoiding substances and conditions known to be toxic to sperm may also improve male fertility. Sperm toxins include:
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- Heat, such as a whirlpool bath
- Excessive alcohol consumption
- Anabolic steroids
- Medications such as cimetidine, sulfasalazine, and nitrofurantoin
- Almost all lubricants (such as KY jelly)
WHO CARES FOR MEN WHO ARE HAVING PROBLEMS WITH FERTILITY?
Specialists in male infertility are often referred to as “andrologists,” but the term often is applied to many different kinds of health care personnel involved in male reproductive medicine, including doctors, scientists, and laboratory technicians. Urologists are surgeons who specialize in the male reproductive and urinary systems, and learn during their training how to diagnose and treat men with infertility. After five or six years of residency after medical school, urologists may choose to spend an additional one to two years of fellowship training to specialize further in male reproductive medicine and surgery. Other kinds of doctors, such as endocrinologists, may choose to specialize in the areas of their fields that involve male fertility.
In a visit to his doctor for a fertility evaluation, a man may expect to have a thorough physical examination with emphasis on the male genitalia, laboratory tests ordered for hormones and semen analyses and, most importantly, a discussion of all of the man and his partner's questions and concerns. A man's partner is strongly encouraged to join him for his fertility evaluation. The doctor will discuss a man's concerns with him privately and with his partner.
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