Infertility

Authors: Drs Craig Niederberger (University of Illinois) and Brad Van Voorhis (University of Iowa) 2010-04-20

Infertility Male and Female 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.

Introduction

Infertility is a common condition affecting approximately 10%-15% of couples.[1] 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 conceiving a pregnancy when it seems to happen so easily for others. Fortunately, specialists can now pinpoint specific causes through diagnostic tests. In addition, successful treatments are now available to help many couples in their goal to have a family.

What is the definition of infertility?

Infertility is commonly defined as the lack of pregnancy following 12 months of unprotected intercourse. [1] 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. Because approximately 90% of young couples will conceive a pregnancy by one year, if a pregnancy has not happened by one year, an evaluation for possible reasons is warranted. Sometimes the evaluation should begin even sooner than one year.

Conditions that warrant early evaluation:

• 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.

Causes of infertility

To conceive a pregnancy naturally, there are several requirements. First, motile sperm must be deposited near the cervix through intercourse. Next, the sperm must be able to ascend through the cervix, uterus and fallopian tubes, arriving at the same time that a woman has released an egg (ovulated). 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. Finally, the embryo must be able to implant into endometrium, the tissue that lines the uterus.

Infertility can result from a disruption in any of these normal events. Therefore, infertility can be due to problems with sperm production, transportation through the male reproductive tract and delivery into the female reproductive tract. On the female side, infertility may be caused by a lack of ovulation (anovulation), blocked fallopian tubes, or inability of an embryo to implant and establish a pregnancy in the uterus. Infertility often results from combinations of several problems on both the male and female sides.

Male Infertility

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.[2]

To visualize the inside of the testis, imagine tiny spaghetti noodles pressed closely together. Within the noodles, sperm are made. Between the noodles lie the “Leydig” cells that make the male hormone testosterone. While many chemicals produced in the testis are necessary for sperm production, adequate levels of testosterone are absolutely essential for the proper development of sperm. The testosterone producing Leydig cells are hardier than the developing sperm cells. Medical problems that damage sperm cells often spare the Leydig cells, and men who have problems conceiving children frequently have enough testosterone to have masculine features such as beard growth, sex drive and muscle mass. However, men who have both low testosterone levels and infertility are treated with medication to increase testosterone production by the testis.[3]

Within the interior of the tiny tubes where sperm are made, the sperm develop within “Sertoli” cells that surround the sperm cells, protect these distinctive half cells from the body's immune system, and bathe them with chemicals that direct the complex assembly line production of sperm. The hypothalamus and pituitary, both located in the brain, direct the production of sperm and testosterone in the testis. The hypothalamus produces gonadotropin-releasing hormone (GnRH), which instructs the pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), the same hormones as in women. Luteinizing hormone stimulates the Leydig cells in the testis to synthesize testosterone, and testosterone in turn decreases release of pituitary LH. This pituitary “negative feedback” control of testosterone production in the testis is much like a thermostat controlling the temperature in a room, with the thermostat turning down the heater as the room gets hotter, and turning up the heater when it senses the room is cold.[3]

Among other chemicals, Sertoli cells make sex hormone binding globulin (SHBG), which binds to testosterone and effectively inactivates it by removing its active form from the circulation, inhibin which decreases pituitary release of FSH, and activin which increases FSH. When Sertoli cells sense problems with sperm assembly, they release less inhibin. As blood inhibin levels fall, the pituitary makes more FSH, and FSH levels rise. Therefore, a common test of the health of sperm production is FSH, with higher levels revealing a problem. A doctor may also measure inhibin to investigate how well the testis is making sperm.[3]

While the testis produces all of the sperm that ultimately is ejaculated, it only makes about 0.5 milliliters of the two to five milliliters in the typical amount of ejaculated semen. After release from the testis, sperm mature in the epididymis, a small organ attached to the testis. The epididymis contains a long, very thin coiled tube through which sperm pass. As they move through the epididymis, sperm gain the ability to swim and to become active within the female reproductive organs. After the epididymis, sperm travel through the vas deferens, the tube cut during vasectomy to render a man sterile. The vas empties sperm into the ejaculatory ducts located within the prostate, where the sperm mixes with fluid from the prostate and the seminal vesicles. Ejaculated semen initially forms a clot that liquefies with help from an enzyme provided by the prostate. The seminal vesicles, rabbit-ear shaped organs, contribute a thick syrup rich in fructose, a sugar that gives sperm energy to swim.[3]

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.[4]

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.[4]

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.[4]

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:[4]

Semen analysis part	Reference value
Volume	Greater than 2.0 ml
pH	Greater than 7.2
Sperm concentration	Greater than 20 million sperm per ml
Total sperm number	Greater than 40 million sperm per ejaculate
Motility	Greater than 50% with progressive motility
Vitality	Greater than 75% live
White blood cells	Fewer 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.[4] 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.

Antisperm antibodies

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).[4]

Pyospermia stain

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.[4]

DNA testing

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.[5]

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.[6]

What causes problems with sperm, and how can they be treated?

Genetics

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):[7]

• 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-α-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

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:[8]

• 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.

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.

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.[9]

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.[10]

Hormones

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.[11]

Varicocele

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.[12] 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.[13] 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.

Childhood conditions

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.[3] 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:[3]

• 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.

The immune system

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.[14] 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.

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:[3]

• Heat, such as a whirlpool bath
• Radiation
• Excessive alcohol consumption
• Anabolic steroids
• Marijuana
• Medications such as cimetidine, sulfasalazine, and nitrofurantoin
• Nicotine
• 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.

Female Infertility

Anovulation (an absence of ovulation)

What is a normal ovulatory cycle like?

Each month, a pool of eggs is selected to enter the final growth phase of development while growing in individual fluid-filled cysts called “follicles”. The number in this pool varies but, out of this pool, one follicle is selected to become dominant and ovulate at mid-cycle whereas the others degenerate. Commonly, ovulation occurs around day 14 of the reproductive cycle (day one is the first day of menstrual bleeding) but the length of this phase can be somewhat variable, normally between 10 and 20 days. Once the follicle is mature and ready for ovulation, luteinizing hormone (LH) is released from the pituitary gland in the brain. LH triggers the egg to be released from the ovarian follicle on the surface of the ovary. LH can be detected in the urine and is the basis behind the ovulation predictor kits. Following ovulation, the ovary begins to produce progesterone, a hormone that prepares the endometrial lining of the uterus for implantation of the fertilized egg. Progesterone is only produced following ovulation and therefore can be measured in the blood stream as a means of detecting ovulation. If a pregnancy is not established in a given month, progesterone levels drop and a new menstrual cycle begins. Typically, the progesterone that is made following ovulation will cause symptoms in the woman including breast tenderness and bloating. Therefore, an ovulatory woman will typically not only have regular menstrual periods, but will also experience symptoms of breast tenderness, bloating and sometimes mood changes accompanying the production of progesterone.

How to detect ovulation

History

Women who have regular menstrual cycles and seldom miss a period are likely to be ovulatory, particularly if they have symptoms of bloating and breast tenderness prior to menstrual bleeding. Most infertility experts will go beyond this simple history to confirm ovulation by other means.

Basal body temperature graph (BBT)

For this test, a woman is asked to take her temperature the first thing upon waking throughout the month. A woman’s basal temperature is typically .5 to 1˚F higher following ovulation (see graph). The most fertile time of the month is just prior to the rise in the temperature, which unfortunately can only be determined retrospectively. Many infertility experts have abandoned use of the BBT since they can be difficult to interpret and because they are emotionally difficult to keep, as they are a daily reminder to the patient of her difficulties.

Urine LH-detection kits. 

These kits are commercially available and require testing daily urine samples for the presence of the hormone LH-, which is the trigger to ovulation. If a surge in LH is detected, ovulation is about to occur and timing for intercourse or inseminations is optimal for that day and the next day. These tests have been shown to be quite accurate in detecting ovulation, although about 7% of the time an LH surge is detected but no ovulation occurs.[15] 

Serum progesterone levels. 

Because progesterone is only made in high quantities following ovulation, high serum progesterone levels indicate ovulation has occurred. This test is typically obtained about seven days after ovulation (day 21 in a typical 28 day cycle) with levels greater than 3 ng/mL indicating ovulation. Many infertility experts like to see progesterone levels greater than 10 ng/mL, particularly after ovulation-inducing medication use, to indicate optimal progesterone production and fertility.

The collapse of an ovarian follicle also can be documented by a series of ultrasound examinations; certain findings seen by endometrial biopsy can also indicate that ovulation has occurred. However, these tests are not commonly utilized because of expense and discomfort.

What are common causes of anovulation?

Polycystic ovarian syndrome

The most common cause of anovulation among infertile women is polycystic ovarian syndrome (PCOS). This is a syndrome characterized by irregular menstrual cycles, some evidence of increased “male hormone” or androgen production, and multiple small ovarian follicles that can be detected by ultrasound. The exact cause of PCOS is not yet known. The most common complaint with PCOS is irregular menstrual periods due to anovulation. Increased hair growth (“hirsutism”) and/or acne are also common with PCOS, due to the effects of androgen hormones. Most women with PCOS are overweight, but there is a “thin variant” of PCOS as well. Insulin resistance is common with PCOS and this is more pronounced in obese women. Long-term health consequences of PCOS include an increased risk of diabetes, hypertension, and perhaps cardiovascular disease.[16][17] PCOS also has been linked to an increased risk of depression and endometrial cancer.

Treatments for infertility due to PCOS

If a woman is overweight, the first step in managing PCOS is weight loss through diet and exercise. No one particular diet has been shown to be beneficial over another, rather, the important point is to restrict calories to lose weight. In general, 30 minutes or more of exercise daily in addition to regular activities is recommended. Several studies have demonstrated that even a 10% reduction in body weight is very beneficial in establishing more regular ovulatory cycles and improving fertility.[18] Therefore, the goal of weight loss does not need to be a return to ideal weight. Unfortunately, many women with PCOS report great difficulty in losing weight despite restricting calories and exercising faithfully.

If weight loss is difficult or fails to establish ovulatory cycles, several ovulation-inducing medications can be used to treat infertility (see section below on ovulation-induction).

Elevated prolactin level

Elevations in the hormone prolactin can lead to anovulation. Prolactin is a pituitary hormone that can interfere with the regular ovulatory cycle. Prolactin is important for lactation and therefore some, but not all women will note breast milk secretion when prolactin is elevated. Causes of elevated prolactin include small pituitary tumors (prolactinomas), hypothyroidism (abnormally low activity of the thyroid gland), and use of some anti-depressant and anti-hypertensive medications, among others. Because hypothyroidism can cause irregular cycles and elevated prolactin levels, both thyroid stimulating hormone (TSH) and prolactin are commonly measured in women with anovulation.

Women found to have an elevated prolactin level will need further testing to establish the cause of the elevation. Prolactin levels can then be lowered by medications, usually resulting in regular ovulatory cycles and restored fertility.

Decreased ovarian reserve

Decreased ovarian reserve is known to be more common in older reproductive age women and it can be difficult to diagnose precisely. This is because as menopause approaches the ovaries work sporadically and unpredictably, going through periods of time when ovulation occurs and other times when it doesn’t. In addition, many women with decreased ovarian reserve still have regular periods and still ovulate; it’s just that the number of eggs and the quality of the eggs is reduced.

Physiology

Women are born with a set number of eggs that does not increase over time. This is in contrast to sperm, which are made throughout a man’s lifetime. The number of eggs in the ovary diminishes at different rates in different women. Most women will have regular menstrual cycles early in their life with an egg being released each month at mid-cycle. As menopause approaches, women enter the menopause transition. The menopause transition is characterized by increasing irregularity of the menstrual cycle.[19] Some women will note shorter intervals between menstrual periods, whereas others will have a lengthening out of their cycles. Studies have shown that at least 20% of cycles in the menopause transition are anovulatory. This is a time when the ovaries are functioning sporadically and unpredictably resulting in decreased fertility.

On average, women enter the menopause transition at age 45, but there is great variation. Therefore, entering the menopause transition early can be a cause of infertility. Factors that lower this age include cigarette smoking, ovarian surgery, and genetic factors that can sometimes be suggested by an early age of menopause in a woman’s mother or sisters. In general, levels of the hormone FSH are increased in the menopause transition but this hormone level can fluctuate greatly. With actual menopause, FSH levels remain consistently high and no further menses occurs. However, menopause can only be diagnosed retrospectively since some women who have missed a few periods and have high FSH levels will again ovulate and potentially be fertile.

With increasing age, not only is egg number diminishing, but egg quality is also reduced. Because the eggs are present from birth and not being “renewed,” factors that are not completely understood gradually reduce egg quality. This is evidenced by the increasing percentage of eggs that have chromosomal problems, which lead to reduced fertility, increased risk of miscarriage, and increased risk of having a child with chromosomal problems.

Diagnosis of decreased ovarian reserve

Day 3 FSH and estradiol

The most common test for decreased ovarian reserve is a day 3 FSH and estradiol level.[20] If the FSH is elevated above 12 mIU/mL, this indicates reduced ovarian reserve and suggests that the number of eggs present in the ovary is diminished. Estradiol levels should be less than 80 pg/mL. If estradiol levels are above this level, FSH levels can be falsely lowered leading to inaccuracy.

Clomiphene citrate challenge test (CCCT)

With this test, FSH is measured on cycle day 3, 100 mg of clomiphene citrate is given days 5-9, and FSH is again measured on cycle day 10. As with the day 3 FSH, elevated levels of FSH on either day 3 or day 10 indicate decreased ovarian reserve.

Ultrasound measures

Women with decreased ovarian reserve have small ovaries with decreased ovarian volume (less than 3 cc) and decreased numbers of ovarian follicles. This number is called the antral follicle count and totals less than 10 (combination of both ovaries) suggest decreased ovarian reserve.

Limitations of testing

We truly do not yet have ideal tests for decreased ovarian reserve. All the available tests are better at estimating egg number rather than egg quality, which ultimately may be more important for fertility. Therefore, the tests are better at predicting who has a higher risk of having an IVF cycle cancelled for inadequate egg numbers than in predicting who will or will not get pregnant from a cycle. In addition, all tests have less than ideal sensitivity and specificity leading to false reassurance in some cases and false alarm in others. The problem of false diagnosis of decreased ovarian reserve is worse among younger patients. Therefore, at this time, these tests should only be used as indicators of a possible problem and should seldom be used to exclude patients from trying an infertility treatment.

Treatment

Most infertility experts will advise women who are suspected of having decreased ovarian reserve to move forward with more “aggressive” infertility treatments. These include use of ovulation induction with gonadotropin injections or IVF (see below). Ultimately, if decreased ovarian reserve is confirmed by a lack of ovarian responsiveness to medications, sometimes use of donor eggs is required for good pregnancy rates to occur. Even so, some of these women will still conceive naturally even after this diagnosis is made.

Ovarian failure and premature menopause

Some women have infertility because they are menopausal. This means that the ovaries have ceased ovulating because of a virtual absence of eggs. Estrogen production is also low leading to some of the common symptoms of menopause including complete absence of periods, hot flashes, and vaginal dryness. The average age of menopause is 51, but some women undergo premature menopause, which is defined as menopause prior to the age of 40.

Causes

Premature menopause can be caused by chromosomal problems, genetic disorders, prior ovarian surgery, prior chemotherapy or radiation therapy for cancer, and auto-immune conditions. Despite a complete evaluation, many times the cause of the early ovarian failure is unknown.

Diagnosis

The diagnosis is made by clinical findings combined with a greatly elevated FSH hormone level.

Treatment

The only treatment that is highly effective at this time is the use of donor eggs and IVF.

Stress-induced amenorrhea

Some women will not ovulate or menstruate due to physical or psychological stress. This type of anovulation is also called “hypothalamic amenorrhea” because stress inhibits the secretion of GnRH in the hypothalamus, which in turn causes essentially a “shut-down” of the reproductive cycle and anovulation. The most common source of stress is excessive exercise combined with weight loss or low body weight. (See table) Women with anorexia nervosa fall into this category of anovulation.

Assessment

This is diagnosed by clinical findings of low weight as well as low FSH levels.

Treatment

Women with stress-induced amenorrhea are encouraged to reduce exercise and gain weight. If successful, regular ovulatory cycles usually resume. Sometimes weight gain is difficult and then ovulation- inducing medications can be prescribed. Available oral medications are less successful in women with this type of anovulation and often injectable gonadotropin therapy, including both LH and FSH, are required to stimulate ovulation.

Obesity-related anovulation

Sometimes overweight patients will not meet the criteria for PCOS yet will have anovulation. These women will be aided by weight loss (See table) or use of ovulation induction medications.

Tubal disease/pelvic adhesive disease

Another cause of infertility is damaged fallopian tubes or pelvic adhesions surrounding the fallopian tube and ovary.

Normal physiology

After release of an egg (ovulation), the fallopian tube is thought to move across the surface of the ovary and pick up the egg. The figure below depicts the normal female anatomy.  If the fallopian tube is open, sperm can ascend the female reproductive tract and fertilize the egg at the end of the tube. The fertilized egg (early embryo) then moves down the fallopian tube and enters the uterine cavity five days later where it can implant into the endometrial lining and establish a pregnancy. A normal fallopian tube must be open and free of adhesive disease (scar tissue) in order to serve these functions. Pelvic adhesions may interfere with the ability of the fallopian tube to capture the released egg. If the fallopian tube is completely or partially blocked, sperm may not reach the egg or, the embryo may be stopped as it moves toward the uterine cavity. This may result in infertility or an ectopic (outside the uterus) or tubal (fallopian tube) pregnancy.

What can lead to damaged fallopian tubes or pelvic adhesions?

Sexually transmitted infections

The most common cause of damaged fallopian tubes would be prior sexually transmitted infection including gonorrhea and chlamydia. These organisms are known to ascend the female reproductive tract and infect the fallopian tubes leading first to pelvic pain and fever and then to tubal damage and adhesions. Sometimes a history of an infection is known and in other cases no such history is recalled. Chlamydia, in particular, can cause few symptoms though tubal damage can be severe.

Other infections

It is also possible for other bacteria to ascend the reproductive tract and cause pelvic adhesions. In addition, appendicitis, particularly if the appendix ruptures, can damage fallopian tubes.

Prior pelvic surgery.

Surgeries on the fallopian tubes (ectopic pregnancy, tubal ligation), ovaries (ovarian cysts), or uterus (myomectomy – the removal of uterine fibroids) can lead to scarring in the pelvis. Significant bowel surgery can sometimes cause scarring and tubal damage.

Endometriosis (see below)

How are the fallopian tubes tested?

Hysterosalpingogram (HSG)

The most commonly used test to determine tubal patency (the state of being freely open) is the hysterosalpingogram. This is a radiological (x-ray) test where contrast is injected through the cervix into the uterus and fallopian tubes. By x-ray, the contrast can be seen to spill from the end of the fallopian tube into the peritoneal cavity. If the tubes are blocked, they can either not fill at all or they may fill but then the contrast may not exit the end of the fallopian tube. A tube that is greatly dilated and filled with fluid is called a hydrosalpinx.  A normal HSG is shown in the top figure, and an HSG with obstruction and dilated fallopian tubes is shown in the bottom figure:

How is an HSG performed?

This test is best obtained shortly after menses has stopped but before ovulation has occurred (cycle days five through 13 in most women). Since this test can cause cramping pain, women should take a pain reliever such as ibuprofen (Motrin) one hour prior to the test. The HSG is usually quite good for detecting tubal patency but it is less sensitive for picking up some pelvic adhesions that may restrict movement and proper access of the fallopian tube to the surface of the ovary. Sometimes, muscular spasm of the fallopian tube will lead to the false impression that the tube is permanently blocked.

Ultrasound determination of tubal patency

Some experts can determine tubal patency by injecting saline though the cervix and observing flow of saline through the tubes by ultrasound. The fluid can then be seen exiting the fallopian tubes giving a “yes” or “no” answer to whether the tubes are open. This test can be performed in the office and has the advantage of avoiding radiation exposure but it is not as good as HSG for viewing fine details about the tubal anatomy.

Laparoscopy

Occasionally, a laparoscopy (surgical procedure to view the pelvic organs) is warranted to evaluate tubal patency. This test is being used with less and less frequency due to its high cost and invasive nature. However, in some women laparoscopy is done to evaluate and treat pelvic adhesive disease at the same time. During laparoscopy, dye can be instilled through the cervix and tubal patency can be confirmed by seeing dye exiting the end of the tube.

How can fallopian tube damage be treated?

If the fallopian tubes are badly damaged, the best modern treatment is IVF, which has the advantage of “bypassing” the fallopian tubes entirely. In fact, if hydrosalpinges (dilated and blocked fallopian tubes) are present, studies have shown that removing the tubes entirely leads to improved pregnancy rates with IVF so this may be recommended to you.[21]

If the scarring is less severe, then surgical removal of adhesions by laparoscopy is a reasonable option that will likely improve fertility. However, there is still great risk that adhesions that are removed surgically will reform in the future.

There is one instance where tubal surgery may be particularly helpful. If a couple desires a pregnancy following a tubal ligation, tubal ligation reversal can be considered. Some types of tubal ligations can’t be successfully reversed and the presence of other infertility factors must be assessed. However, if a couple is a good candidate for surgery, tubal ligation reversal is associated with about a 90% tubal patency rate and a 50-60% chance of conceiving a baby in one year. These benefits must be weighed against the risks of having a surgical procedure and a 5-10% chance of having an ectopic (tubal) pregnancy following the reversal. An attractive alternative treatment to consider is IVF.

Endometriosis

Endometriosis is a disease in which endometrial glands are growing in the peritoneal cavity. During a normal menstrual period, the endometrium, or the lining of the uterus, is sloughed and exits the cervix and vagina with menstrual bleeding. However, some of the blood and sloughed endometrium also refluxes through the fallopian tubes allowing it to attach and grow in the pelvic cavity causing endometriosis. Common sites for endometriosis are the area just behind the uterus called the cul-de-sac as well as around the fallopian tubes and ovaries. Endometriosis causes infertility and pelvic pain. The pain commonly worsens around the time of the menstrual period.

Endometriosis can vary both in amount of disease and severity of symptoms. Mild endometriosis is characterized by small implants of tissue causing essentially no distortion of pelvic anatomy. The way that this degree of disease impairs fertility is not clear. Severe endometriosis can essentially invade the entire pelvis leading to blood-filled ovarian cysts (endometriomas) and great amounts of scarring that can disrupt the fallopian tubes. In this case, infertility may be caused by distortion of the normal anatomy.

How can endometriosis be detected?

For many cases of endometriosis, the presence of the disease can be suggested by pain symptoms and/or findings on pelvic or ultrasound exam. However, the only way to diagnose endometriosis with certainty is by laparoscopy.

Should I have a laparoscopy to evaluate for endometriosis?

As recently as ten years ago, experts were suggesting that a laparoscopy should always be done as part of the infertility evaluation when no other causes had been found. Experts now feel that laparoscopy should only be done in selected patients. When extensive endometriosis is suggested by severe pain symptoms or findings on exam, laparoscopy is often warranted both to diagnose and treat the disease as it will likely improve both the pain and fertility. In the absence of pain symptoms or abnormal findings on exam, laparoscopy is likely not necessary. The reason is that at least half the women in this circumstance will have no endometriosis and therefore no benefit from surgery. The other half of women may have some endometriosis present but treatment of mild endometriosis improves fertility only slightly. In other words, in the case of mild endometriosis making the diagnosis or treating the disease has little impact on ultimately achieving a pregnancy. In this circumstance, saving the expense of surgery and applying it to an IVF cycle, for example, is likely a more cost-effective approach.[22]

Uterine factor infertility

Occasionally, abnormalities of the uterus are thought to contribute to infertility. These lesions are most often diagnosed by ultrasound examination of the pelvis.

Fibroids

Fibroids (myomas, leiomyomas) are very common smooth muscle tumors of the uterus. Because fibroids are so common, it is difficult to know if the fibroids are actually causing the infertility or if they are merely present but having no impact on fertility. Most infertility experts will consider fibroids to be the cause of infertility only if all other factors have been ruled out. Fibroids that are located next to the endometrial lining of the uterus have the biggest impact on fertility. When appropriate, fibroids can be surgically removed leading to improved fertility.[23]

Endometrial polyps

Endometrial polyps are small growths of the endometrium that are usually benign in premenopausal women. Larger polyps tend to persist and there is some evidence that removing these by surgery improves fertility.  Endometrial polyp is shown before and after removal:

 Uterine scarring (Asherman’s syndrome)

Intra-uterine scars can be present from a past uterine surgery – most commonly a Dilation and Curettage, a procedure to scrape and collect the tissue from inside the uterus – and these can cause infertility.

Inadequate endometrial development or “luteal phase defect”

Progesterone is critical for implantation and pregnancy. Some have theorized that inadequate progesterone production or endometrial response to progesterone is a cause of infertility. For many years, infertility experts recommended that an endometrial biopsy be done to diagnose luteal phase defect. However, a recent large study found that luteal phase defect was present just as often in fertile women as in infertile women raising questions as to whether this is truly a cause of infertility.[24] In addition, it is known that interpretation of the endometrial biopsy is quite difficult and varies significantly from one pathologist to another. These findings suggest that endometrial biopsy should seldom, if ever, be performed solely for the evaluation of infertility.

Cervical factor infertility

It is possible for the cervical mucus to be thickened, impairing the normal transport of sperm from the vagina into the reproductive tract. However, this is a rare cause of infertility and testing for this is seldom done.

Throughout most of the cycle, cervical mucus is thick and slows sperm from ascending the female reproductive tract. Around mid-cycle when ovulation occurs, cervical mucus both increases in amount and thins out allowing sperm to more readily ascend the female reproductive tract. Abnormal cervical mucus may contribute to infertility if it is too thick, most commonly as a side effect of the ovulation-inducing medication clomiphene citrate (see below). Although clomiphene citrate has beneficial effects on ovulation, it can have negative effects on cervical mucus production and thickness.

How Can You Test for Cervical Mucus Problems?

The test for abnormal cervical mucus is called the post-coital test, which is performed by obtaining a cervical mucus sample at mid- cycle several hours following intercourse to look for the presence of motile (mobile) sperm by microscopic examination. This test has fallen out of favor because of a lack of standardization of the test and because the common treatment for an abnormal test, intrauterine insemination, is often used even when the test is normal. In other words, the results do not often change the management.

Summary of the Infertility Evaluation

Commonly, infertility specialists will investigate all common causes of infertility by the following tests:

• Day 21 progesterone level, which detects ovulation
• Seminal fluid analysis.
• HSG
• Pelvic ultrasound and ovarian reserve testing in some women

Unexplained Infertility

Despite a thorough workup, at least 25 to 30% of couples will have no obvious explanation for their infertility. This is called unexplained infertility, a diagnosis that can be quite frustrating to couples. However, it is reassuring to note that pregnancy rates with treatments in couples with this disorder are as good or better than in couples who have a known cause.

Infertility Treatments

The recommended treatments will, of course, vary depending on the cause. In certain instances (tubal damage, severe endometriosis, fibroids and polyps) surgery will be recommended. With many other causes of infertility, the basic concept is to increase the number of eggs and sperm at the site of fertilization to improve the chances of conceiving a pregnancy. These treatments fall under the categories of ovulation induction and insemination used either alone or in combination. In vitro fertilization (IVF) is being used with increasing frequency for all types of infertility as success rates continue to improve with this treatment. IVF has the highest pregnancy rate per cycle of any treatment available today.

What can I do to improve my chances for conceiving with or without treatments?[25]

• Stop smoking. Cigarette smoking reduces the monthly chance for natural conception.
• Women should try to adjust diet and exercise to maintain a body mass index of between 20 kg/m2 and 27 kg/m2 (see table below), for optimal fertility.
• Both partners should limit alcohol intake to no more than four drinks per week. Once pregnant, all alcohol consumption by the woman should stop.
• Women should limit caffeine intake to no more than 250 mg/day (approximately 2 cups of coffee a day). Caffeine intake higher than this has been associated with increased time to conceive.
• Exercise by the female for more than 60 minutes per day is associated with increased chance of anovulation. Therefore, it is probably wise to use this as a limit while trying to conceive.
• Try methods to alleviate stress. Although stress is seldom the cause of infertility, infertility treatments are extremely stressful. There is a high drop-out rate from infertility treatments, usually due to stress. Since infertility treatments often take persistence couples need to be emotionally ready for a “long race.” In addition, some studies report a beneficial effect of stress reduction on fertility. Options to consider for stress management include counseling, exercise, yoga, meditation, massage, and acupuncture among several others.

The desirable weight range for optimal fertility- these weights correspond to a body mass index (BMI) between 20and 27 kg/m2.

	Desired Weight (pounds)
Height	Lower weight limit	Upper weight limit
4’10”	95	129
4’11”	99	134
5’0”	102	138
5’1”	106	143
5’2”	109	147
5’3”	112	152
5’4”	116	157
5’5”	120	162
5’6”	124	167
5’7”	127	172
5’8”	131	176
5’9”	135	183
5’10”	139	188
5’11”	143	193
6’0”	147	199
6’1”	151	204

Ovulation Induction Medications

Oral medications

Clomiphene citrate (Clomid) is commonly used to enhance ovulation in women who are either anovulatory or women who are already ovulating but not getting pregnant. The medication is very effective in women who are not ovulating and there are only small beneficial effects in women who are already ovulating.

How is the medication given?

A starting dose is chosen (typically 50 or 100 mg) and given for five days starting on cycle day 3-5 (day 1 is the first day of menstrual bleeding). To detect ovulation, women can use a urine LH-detection kit, but this should not start before day 11 of the cycle as the drug can cause a false-positive reading. Often a day 21 progesterone level is also measured. Sometimes the dose needs to be adjusted up if ovulation doesn’t occur with initial doses.

Common side effects include:

• hot flashes
• mood swings
• pelvic discomfort
• twins- 8-10% chance, less than 1% chance of triplets or more

Let your doctor know about severe pelvic pain or visual changes including difficulty with night vision or seeing flashing lights.

How long should I take clomiphene citrate?

It is usually very reasonable to take this medication for four to six months as long as it is stimulating ovulation. Most of the pregnancies achieved with clomiphene citrate are seen in this time period.

Other oral medications for ovulation induction:

Tamoxifen: a drug similar to clomiphene citrate in its actions.

Letrozole (Femara): a drug that acts by a different mechanism than clomiphene citrate (it inhibits estrogen formation temporarily) and can work to induce ovulation. This drug is not FDA-approved for this purpose.

Metformin: This drug can lower insulin levels in women with PCOS and, when used alone, has only modest effect in increasing ovulation. Recent studies of a large population of women with PCOS have shown that the combination of metformin and clomiphene citrate was no more effective than clomiphene citrate alone. [26]Nevertheless, there may be some women who are not ovulating on clomiphene citrate alone who will ovulate in response to the combination of these drugs.

Injectable drugs for ovulation induction

Gonadotropin injections

Another option for inducing ovulation in women is the use of gonadotropin (LH and FSH hormone) injections. These medications are given by daily injections and they act by directly stimulating ovarian follicular development and ovulation. These medications are expensive and require careful monitoring by ultrasound due to the significantly increased risk of ovarian hyperstimulation and multiple gestations as compared to oral medications.

Combination protocols of oral and injectable drugs

Sometimes oral medications are given first, followed by injectable gonadotropins. This combination can reduce the number of injections needed and also reduces the total amount of gonadotropin drugs used and therefore the cost of treatment. Pregnancy rates are similar to gonadotropins alone.[27]

Intrauterine insemination

Intrauterine insemination (IUI) is a commonly used treatment for infertility. The basic concept is that with natural intercourse many sperm never ascend the female reproductive tract because they are lost out of the vagina or never make it past the cervical mucus. With IUI, a semen sample is brought to the laboratory when the female partner is ovulating. This sample is then processed so the motile sperm are isolated and concentrated from the ejaculate. The concentrated sperm are then placed past the cervix into the uterus through a small catheter.

IUI is indicated for cases of unexplained infertility, cervical factor infertility, and mild male factor infertility. IUI is much less effective when there are severe male factor problems defined by low numbers of motile sperm in the ejaculate (less than 10 million motile sperm) or in the prepared sample to be placed into the uterus (< 1 million motile sperm). IUI is also commonly utilized in conjunction with ovulation induction medications as pregnancy rates are improved as compared to using these treatments separately.[28]

What pregnancy rates can be expected from various treatments?

The pregnancy rates with different treatments will vary depending on the cause of the infertility and the woman’s age. Listed below are rates that might be expected in a 35 year old woman with unexplained infertility.

Outcomes to expect from common infertility treatments

	Delivery rate/cycle	Multiple birth rate/pregnancy
Timed intercourse	2 – 3%	1%
IUI alone	5%	1%
Clomid alone	5%	10%
Clomid & IUI	8%	10%
hMG alone	12% – 15%	15%
hMG & IUI	15% – 18 %	15%
IVF*	29-32 %	30 %

*- based on 2005 national data from SART

Donor sperm

When the male partner has no sperm present and treatment of the male is unsuccessful, donor sperm can be used. Many sperm donor banks are available which collect sperm and test the donors for sexually transmitted disease as well as screening them for common genetic conditions. The samples must be frozen in order to properly test for sexually transmitted diseases to ensure the sample is not itself infected with bacteria or viruses that could be harmful. Following thawing, the sample is then processed and typically is placed into the uterus through an intrauterine insemination at the time that the recipient female is ovulating. Pregnancy rates with donor insemination vary again depending on the female’s age but average approximately 10% per month. Remember that natural intercourse in couples with no problems results in pregnancy rates of 20% per month. Because the sperm sample is frozen, the pregnancy rate is lower than is seen with fresh sperm. However, after the course of six to 12 months of treatment, at least 70% of women should be pregnant using this technique. If pregnancy is not occurring following the initial insemination cycles, further investigation of the female is indicated.

In vitro fertilization

 IVF has the highest pregnancy rates of any infertility treatment.[29] However, it is also the most involved and expensive of the treatments so usually other treatments are attempted first with most causes of infertility.

 

  

Steps in the IVF process: 

1. Ovarian stimulation is done with combinations of injectable drugs for several weeks. The goal is to get many follicles developing so that eggs can be retrieved.  In the figure above, A shows an ultrasound view of an unstimulated ovary.  B is the same ovary after several days of stimulation.  The black ovals are fluid-filled ovarian follicles which contain eggs.

 2. Once the eggs are thought to be mature based on ultrasound measurements of the follicles, egg retrieval is performed under ultrasound guidance (C).  This step is performed with sedatives and pain medications.

3. The retrieved eggs (D) are next fertilized in the laboratory, either by mixing eggs with sperm in a culture dish (E) or by injecting a single sperm into the egg (F) by a process called intracytoplasmic injection (ICSI). 

4. The resulting embryos are then cultured for several days (G is a 3-day old 8-cell embryo, H is a 5-day old blastocyst embryo) before the best embryos are selected to by transferred back to the uterus (I). 

5. Extra embryos of good quality are frozen for later use, if needed.

Outcomes

Outcomes are very dependent on the age of the woman being stimulated. In addition, different centers have different pregnancy rates dependent, in part, on the populations of patients they are treating. Because some centers may treat mainly older patients or patients who have had IVF failures elsewhere (“tougher patients”), it is difficult to directly compare centers. However, age-specific outcomes from various centers are available.

Other treatments available with IVF include:

• Preimplantation genetic diagnosis (PGD) – used to avoid genetic diseases in offspring.
• Preimplantation genetic screening (PGS) - used to screen for chromosomal abnormalities in embryos in hopes of decreasing the pregnancy loss rate and perhaps increasing the pregnancy rate.  In the figure above, a single cell is removed from an 8-cell embryo (A).  The cell is then analyzed for the numbers of chromosomes present using color-coded probes (B).  In this case, the presence of 3 bright red probes indicates  that there is an extra, abnormal chromosome instead of the expected number of 2 chromosomes.
• Donor eggs or embryos- used mainly in couples where the woman does not produce sufficient numbers of good quality eggs herself.   Depending on the age of the donor, high pregnancy rates are seen with this treatment. 
• Cryopreserved embryo transfer- often, extra embryos from the "fresh" IVF cycle are frozen for later use.  These embryos can be thawed and transferred back to the uterus.  Although pregnancy rates are generally somewhat lower than in the fresh cycle, these cycles have the advantage of being less expensive.
• Surrogacy - hiring another woman who will have embryos transferred and carry the pregnancy.
• Egg freezing - a new technique that is currently experimental.  The goal of this treatment is to hopefully preserve a woman's fertility into the future.

 

More Information 

 

Web Resources

The American Society for Reproductive Medicine patient site

 

The Society for Assisted Reproductive Technology 

 

The American Urological Association's section on Male Infertility in UrologyHealth.org

 

Blogs

Dr. Niederberger's blog on male health

Books about infertility 

Infertility in the Male, 4th edition

References

1. Niederberger CS, Joyce GF, Wise M, Meacham RB, Male Infertility. In: Litwin MS, Saigal CS, editors. Urologic Diseases in America. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office, 2007; NIH Publication No. 07–5512:461-82.
   UDA chapter on male infertility
2. Niederberger CS, Lamb DJ: Spermatogenesis in the adult, in Lipshultz LI and Howards SS (eds): Infertility in the Male, ed 3. St. Louis, Mosby Year-Book Inc., 1997, chap 5:106-22.
3. Sigman M, Lipshultz LI, Howards SS: Evaluation of the subfertile male, in Lipshultz LI and Howards SS (eds): Infertility in the Male, ed 3. St. Louis, Mosby Year-Book Inc., 1997, chap 9:173-93.
4. Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA (eds): WHO manual for the standardized investigation, diagnosis and management of the infertile male. Cambridge, Cambridge University Press, 2000.
5. Tarozzi N, Bizzaro D, Flamigni C, Borini A. Clinical relevance of sperm DNA damage in assisted reproduction. Reprod Biomed Online. 2007 Jun;14(6):746-57.
   PubMed citation
6. Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod. 2000 Jul;15(7):1431-4.
   PubMed citation
7. Jaffe T, Oates RD: Genetic aspects of infertility, in Lipshultz LI and Howards SS (eds): Infertility in the Male, ed 3. St. Louis, Mosby Year-Book Inc., 1997, chap 15:280-304.
8. The Male Infertility Best Practice Policy Committee of the American Urological Association and the Practice Committee of the American Society for Reproductive Medicine (ASRM). Report on evaluation of the azoospermic male. American Urological Association and American Society for Reproductive Medicine Clinical Practice Guidelines 2001:1-7.
   AUA guidelines for azoospermic male
9. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod. 1999 Jan;14(1):131-5.
   PubMed citation
10. Prins GS, Dolgina R, Studney P, Kaplan B, Ross L, Niederberger C. Quality of cryopreserved testicular sperm in patients with obstructive and nonobstructive azoospermia. J Urol. 1999 May;161(5):1504-8.
    PubMed citation
11. Jarow J: Nonsurgical treatment of male infertility: empiric therapy, in Lipshultz LI and Howards SS (eds): Infertility in the Male, ed 3. St. Louis, Mosby Year-Book Inc., 1997, chap 23:410-22.
12. World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril. 1992 Jun;57(6):1289-93.
    PubMed citation
13. Madgar I, Weissenberg R, Lunenfeld B, Karasik A, Goldwasser B. Fertil Steril. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril. 1995 Jan;63(1):120-4.
    PubMed citation
14. McConnell JD: Abnormalities in sperm motility: techniques of evaluation and treatment, in Lipshultz LI and Howards SS (eds): Infertility in the Male, ed 3. St. Louis, Mosby Year-Book Inc., 1997, chap 13:249-67.
15. McGovern PG, Myers ER, Silva S, Coutifaris C, Carson SA, Legro RS, Schlaff WD, Carr BR, Steinkampf MP, Giudice LC, Leppert PC, Diamond MP; NICHD National Cooperative Reproductive Medicine Network. Absence of secretory endometrium after false-positive home urine luteinizing hormone testing. Fertil Steril. 2004 Nov;82(5):1273-7.
    PubMed citation
16. Legro RS. A 27-year-old woman with a diagnosis of polycystic ovary syndrome. JAMA. 2007 Feb 7;297(5):509-19.
    PubMed citation
17. Shroff R, Syrop CH, Davis W, Van Voorhis BJ, Dokras A. Risk of metabolic complications in the new PCOS phenotypes based on the Rotterdam criteria. Fertil Steril. 2007 Nov;88(5):1389-95.
    PubMed citation
18. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007 Aug 25;370(9588):685-97.
    PubMed citation
19. Santoro N. The menopausal transition. Am J Med. 2005 Dec 19;118 Suppl 12B:8-13.
    PubMed citation
20. Bancsi LFJMM, Broekmans FJM, Mol BWJ, Habbema JDF, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril. 2003 May;79(5):1091-100.
    PubMed citation
21. Strandell A, Lindhard A, Waldenström U, Thorburn J. Hydrosalpinx and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod. 2001 Nov;16(11):2403-10.
    PubMed citation
22. Van Voorhis BJ, Stovall DW, Allen BD, Syrop CH. Cost-effective treatment of the infertile couple. Fertil Steril. 1998 Dec;70(6):995-1005.
    PubMed citation
23. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2008 Mar 11
    PubMed citation
24. Coutifaris C, Myers ER, Guzick DS, Diamond MP, Carson SA, Legro RS, McGovern PG, Schlaff WD, Carr BR, Steinkampf MP, Silva S, Vogel DL, Leppert PC; NICHD National Cooperative Reproductive Medicine Network. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril. 2004 Nov;82(5):1264-72.
    PubMed citation
25. Barbieri RL. The initial fertility consultation: recommendations concerning cigarette smoking, body mass index, and alcohol and caffeine consumption. Am J Obstet Gynecol. 2001 Nov;185(5):1168-73.
    PubMed citation
26. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66.
    PubMed citation
27. Ryan GL, Moss V, Davis WA, Sparks AE, Dokras A, Van Voorhis BJ. Oral ovulation induction agents combined with low-dose gonadotropin injections and intrauterine insemination: cost- and clinical effectiveness. J Reprod Med. 2005 Dec;50(12):943-50.
    PubMed citation
28. Van Voorhis BJ, Barnett M, Sparks AET, Syrop CH, Rosenthal G, Dawson J. Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vit fertilization. Fertil Steril 2001 Apr;75(4):661-8.
    PubMed citation
29. Van Voorhis BJ. Clinical practice. In vitro fertilization. N Engl J Med. 2007 Jan 25;356(4):379-86.
    PubMed citation