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Overview Infertility is the inability to conceive after at least one year of unprotected intercourse. Since most people are able to conceive within this time, physicians recommend that couples unable to do so be assessed for fertility problems. In men, hormone disorders, illness, reproductive anatomy trauma and obstruction, and sexual dysfunction can temporarily or permanently affect sperm and prevent conception. Some disorders become more difficult to treat the longer they persist without treatment. Sperm development (spermatogenesis) takes place in the ducts (seminiferous tubules) of the testes. Cell division produces mature sperm cells (spermatozoa) that contain one-half of a man's genetic code. Each spermatogenesis cycle consists of six stages and takes about 16 days to complete. Approximately five cycles are needed to produce one mature sperm. Energy-generating organelles (mitochondria) inside each sperm power its tail (flagellum) so that it can swim to the female egg once inside the vagina. Sperm development is ultimately controlled by the endocrine (hormonal) system that comprises the hypothalamic-pituitary-gonadal axis. Because sperm development takes over 2 months, illness that was present during the first cycle may affect mature sperm, regardless of a man's health at the time of examination. Incidence and Prevalence According to the National Institutes of Health, male infertility is involved in approximately 40% of the more than 2 million infertile married couples in the United States. One-half of these men experience irreversible infertility and cannot father children, and a small number of these cases are caused by a treatable medical condition. Causes and Risk Factors Common causes for male infertility are impaired sperm production, impaired sperm delivery, and testosterone deficiency (hypogonadism). Infertility can result from a condition that is present at birth (congenital) or can develop later (acquired). Causes for infertility include the following: • • • • • • •

Chemotherapy Defect or obstruction in the reproductive system (e.g., cryptorchidism, anorchism) Disease (e.g., cystic fibrosis, sickle cell anemia, sexually transmitted disease [STD]) Hormone dysfunction (caused by disorder in the hypothalamic-pituitary-gonadal axis) Infection (e.g., prostatitis, epididymitis, orchitis) Injury (e.g., testicular trauma) Medications (e.g., to treat high blood pressure, arthritis)

• • • • •

Metabolic disorders such as hemochromatosis (affects how the body uses and stores iron) Retrograde ejaculation (i.e., condition in which semen flows backwards into the bladder during ejaculation) Systemic disease (e.g., high fever, infection, kidney disease) Testicular cancer Varicocele

Retrograde ejaculation occurs when impairment of the muscles or nerves of the bladder neck prohibit it from closing during ejaculation. It may result from bladder surgery, a congenital defect in the urethra or bladder, or disease that affects the nervous system. Diminished or "dry" ejaculation and cloudy urine after ejaculation may be signs of this condition. Testosterone Deficiency Hypogonadism may be present at birth (congenital) or may develop later (acquired). Causes of the condition are classified according to their location along the hypothalamicpituitary-gonadal axis: • • •

Primary, disruption in the testicles Secondary, disruption in the pituitary gland Tertiary, disruption in the hypothalamus

The most common congenital cause is Klinefelter syndrome. This condition, which is caused by an extra X chromosome, results in infertility, sparse facial and body hair, abnormal breast enlargement (gynecomastia), and smaller than normal testes. Congenital hormonal disorders such as leutenizing hormone-releasing hormone (LHRH) deficiency and gonadotropin-releasing hormone (GnRH) deficiency (e.g., Kallmann syndrome) also may cause testosterone deficiency. Other congenital causes include absence of the testes (anorchism; may also be acquired) and failure of testicles to descend into scrotum (cryptorchidism). Acquired causes for testosterone deficiency include the following: • • • • • • • • •

Chemotherapy Damage to the pituitary gland, hypothalamus, or testes Glandular malformation Head trauma affecting the hypothalamus Infection (e.g., meningitis, syphilis, mumps) Isolated LH deficiency (e.g., fertile eunuch syndrome) Radiation Testicular trauma Tumors of the pituitary gland, hypothalamus, or testicles

Diagnosis The search for the cause of infertility usually begins with the male, because male examination and testing is less complicated. A thorough examination and a review of the man's medical and surgical history are necessary, because chronic disease, pelvic injury, childhood illness, abdominal or reproductive organ surgery, recreational drug use, and medications can affect fertility. Physical examination may detect testicular irregularities (e.g., varicocele, absence of vas deferens, tumor), evidence of hormonal disorders (e.g., underdeveloped reproductive organs, enlarged breast tissue), or evidence of testosterone deficiency. Assessing reproductive-fertility history is important; specialists typically inquire about the following: • • • • • •

Early puberty (may result from hormonal disorder) Late puberty (may result from Kallmann's syndrome) Previous pregnancy Sexual intercourse timing (understanding ovulation) STDs (can cause scarring, obstruction) Use of lubricants (may kill sperm)

A semen analysis, usually performed by a fertility specialist, is used to examine the entire ejaculate, because seminal fluid can affect sperm function and movement. Generally, three semen samples are taken at different times to account for variables such as temperature and error. Most specialists prefer three samples that differ no more than 20% from one another before proceeding with diagnosis. Six sperm factors are analyzed in semen analysis: • • • • • •

Concentration (sperm/milliliter; cc) Morphology (sperm shape; normal structure associated with sperm health) Motility (or mobility; % sperm movement) Standard semen fluid test (thickness, color) Total motile count (total number of moving sperm) Volume (total volume of ejaculate)

Azoospermia is the absence of sperm in the semen. Men with normal reproductive tracts and hormone systems can have azoospermia due to a lack of sperm-producing tissue in the testes or an obstruction. Obstructions can be viewed with x-ray. The World Health Organization has established criteria for normal sperm concentration, morphology, and motility. Total motile sperm count, which should be about 40 million, is calculated by multiplying volume by concentration by motility. The semen fluid test looks at factors that may impede sperm performance. Abnormally thick semen may cause sperm to swim more slowly through cervical mucus, obstructing fertilization. Abnormal sperm shape (i.e., disfigured or multiple heads or tails) usually

indicates poor sperm health. Infertility is likely if 60% or more of sperm in semen is abnormally shaped. Other tests are concerned specifically with sperm's ability to swim through cervical mucus and bind to and penetrate an egg. The postcoital Sims-Huhmer, or sperm-mucus interaction test, examines whether the sperm are able to swim through the female reproductive tract. This ability is referred to as forward progression. In the middle of the menstrual cycle, the cervical mucus becomes watery. Intercourse is recommended during this time, followed, the next day, with an inspection of the mucus to determine if • • •

enough semen was delivered to the cervix; sperm are healthy and do not show large numbers of clumped, motionless, or dead cells; and sperm are swimming energetically through the cervical mucus.

The sperm penetration assay (SPA), or sperm-oocyte interaction test, examines the ability of sperm to penetrate the egg by combining it with a hamster egg. The immunobead test looks at semen for the presence of antibodies that damage sperm. Post-ejaculation urinalysis may identify diseases that affect fertility, such as kidney disease, diabetes, and repeated urinary tract infection (UTI). Blood tests identify disorders that impair testosterone and sperm production. Treatment At least one-half of male fertility problems can be treated so that conception is possible. There are three categories of treatment for male infertility: • • •

Assisted reproduction Drug therapy Surgery

Assisted reproduction therapy includes methods to improve erectile dysfunction, induce ejaculation, obtain sperm, and inseminate an egg: o o o o o

Electroejaculation Sperm retrieval and washing In vitro fertilization (IVF) Intracytoplasmic sperm injection (ICSI) Gamete intrafallopian transfer (GIFT)

Electroejaculation This procedure can be used to produce ejaculation when neurological dysfunction prevents it. An electrical rectal probe generates a current that stimulates nerves and induces ejaculation; semen dribbles out through the urethra and is collected. Retrograde ejaculation is associated with the procedure and sodium bicarbonate is usually taken the day before to make the urine alkaline (nonacidic) and

nondetrimental to sperm. Candidates for electroejaculation include men who have undergone testis removal (orchiectomy), retroperitoneal lymph node dissection (RPLND), and those with spinal cord injuries. Sperm retrieval This technique is used to obtain sperm from the testes or epididymis when obstruction, congenital absence of the vas deferens, failed vasectomy reversal, or inadequate sperm production causes azoospermia. Using a technique called micro epididymal sperm aspiration (MESA), a surgeon makes an incision in the scrotum and gathers sperm from the epididymis, the elongated, coiled duct that provides for the maturation, storage, and passage of sperm from the testes. Percutaneous epididymal sperm aspiration (PESA, or fine needle aspiration) is similar to MESA but does not involve microsurgery. A physician uses a needle to penetrate the scrotum and epididymis and draws sperm into a syringe. Testicular sperm extraction (TESE), the removal of a small amount of testicular tissue, is used to retrieve sperm from men with impaired sperm production, or when MESA fails. (see also Testis Biopsy) These procedures are done under local anesthesia, usually take about 30 minutes, and may cause pain and swelling. Sperm washing This procedure isolates and prepares the healthiest sperm for insemination. Sperm and washing medium are combined and spun rigorously (centrifuged) and the process is repeated if necessary. The process separates sperm from white blood cells and fatty acids (prostaglandins) in the semen that may hinder sperm motility. It also concentrates sperm, which increases the chance for conception. Sperm retrieved by MESA, PESA, or TESE may be used in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). IVF involves combining eggs with sperm in a laboratory, providing proper fertilization conditions, and transferring the resulting embryos to the uterus. To retrieve an egg, a specialist uses ultrasound to guide a fine needle through the vaginal wall and into the ovary or makes an incision in the abdomen to get to the ovary (laparoscopy). Once the eggs are retrieved, they are combined with prepared sperm in a sterile dish for 2 to 4 days. After fertilization, the embryos are transferred to the uterus. IVF is used most commonly for infertility caused by female reproductive abnormalities. Intracytoplasmic sperm injection (ICSI) may be used with immotile sperm during in vitro fertilization. Using a tiny glass needle, one sperm is injected directly into a retrieved mature egg. The egg is incubated and transferred to the uterus. Fertilization occurs in 50% to 80% of cases and approximately 30% result in a live birth. The egg may fail to divide or the embryo may arrest at an early stage of development. Younger patients achieve more favorable results and poor egg quality and advanced maternal age result in lower success rates.

ICSI does not increase the incidence of multiple pregnancies. Long-term information about the health and fertility of children conceived through this procedure is not available because it was first performed in 1992. While excess sperm from MESA or PESA can usually be frozen for future use, most TESE-derived sperm are not of sufficient quality or quantity for frozen storage (cryopreservation). Multiple MESA or PESA procedures are not recommended, since repetition can lead to scarring. Gamete intrafallopian transfer (GIFT) This procedure is recommended for couples with unexplained fertility problems and normal reproductive anatomy. Mature eggs and prepared sperm are combined in a syringe and injected into the fallopian tube using laparascopy. Embryos that result from this procedure naturally descend into the uterus for implantation. Average conception rate for these procedures is about 30%. Drug therapy for male infertility includes medications to improve sperm production, treat hormonal dysfunction, cure infections that compromise sperm, and fight sperm antibodies. The administration of testosterone is similar to that used to treat testosterone deficiency. Tamoxifen (Nolvadex®), an antiestrogen agent, may be used to stimulate gonadotropin (a male hormone) release, which leads to testosterone production. Antibiotics, like levofloxacin (Levaquin®) and doxycycline (Periostat®), are used to treat fertility-impairing infections of the urinary tract, testes, and prostate, and STDs. Surgery for male infertility is performed to treat reproductive tract obstruction and varicocele. Vasoepididymostomy is a microsurgical procedure that corrects obstruction in the coiled tube that connects the testes with the vas deferens (epididymis). Obstructions commonly result from STDs and also include cysts and tubal closure (atresia), which is usually genetic. Vericocelectomy, the removal of a varicocele from the testes, often results in increased sperm count. Naturopathic Treatment Naturopathic treatment for male infertility focuses on improving sperm quantity, sperm quality, and overall male reproductive health. Researchers reported that sperm counts have fallen almost 50% since the 1930s. Although some dispute these findings, it is generally accepted that sperm counts are declining. The cause may be environmental and dietary and lifestyle changes may interfere with men's sperm production. If this is so, improving diet and making healthy lifestyle choices should positively impact male reproductive health. Nutrition The importance of a healthy diet cannot be overstated. To function properly, the reproductive system requires the proper vitamins and minerals. Nutritional deficiencies

can impair hormone function, inhibit sperm production, and contribute to the production of abnormal sperm. • • • • •

Eat a natural foods diet that focuses on fresh vegetables, fruits, whole grains, fish, poultry, legumes, nuts, and seeds. Drink 50% of body weight in ounces of water daily (e.g., a 150 lb man would drink 75 oz of water). Eliminate processed and refined foods (e.g., white flour), junk food, sugars, alcohol, and caffeine. Avoid saturated fats and hydrogenated oils (e.g., margarine); use olive oil. Pumpkin seeds are naturally high in zinc and essential fatty acids which are vital to healthy functioning of the male reproductive system. Eat pumpkin seeds to help maintain a healthy reproductive system.

Supplements The following supplements may increase sperm count and/or motility. Allow 3-4 months for the supplements to work. • • • • • • •

• • •

Arginine - Take 4 gr daily. Needed to produce sperm. If the sperm count is below 10 million per ml, arginine probably will not provide any benefit. Coenzyme Q10 - Take 10 mg daily. Increases sperm count and motility. Flaxseed oil - Take 1 tbsp daily. Is a source of essential fatty acids. L-carnitine - Take 3-4 grams daily. Required for normal sperm function. Multivitamin-mineral - Buy a high-quality product and take one serving size (differs from brand to brand). Selenium - Take 200 mcg daily. Improves sperm motility. Vitamin B-12 - Take 1000 mcg daily. A B-12 deficiency reduces sperm motility and sperm count. Even if no deficiency exists, B-12 supplementation may help men with a sperm count of less than 20 million per milliliter or a motility rate of less than 50% Vitamin C - Take 500 mg 2 times daily. Is an antioxidant. Vitamin E - Take 400 IUs 2 times daily. Is an antioxidant and improves sperms' ability to impregnate. Zinc - Take 30 mg 2 times daily. Required for a healthy male reproductive system and sperm production.

Herbal Medicine Herbal remedies usually do not have side effects when used appropriately and at suggested doses. Occasionally, an herb at the prescribed dose causes stomach upset or headache. This may reflect the purity of the preparation or added ingredients, such as synthetic binders or fillers. For this reason, it is recommended that only high-quality products be used. As with all medications, more is not better and overdosing can lead to serious illness and death.

The following herbs may be used to treat male infertility: •

• • •

Ginseng (Panax ginseng) - Known as a male tonic (an agent that improves general health) and used to increase testosterone levels and sperm count. Siberian ginseng (Eleutherococcus senticosus) may also be used. Astragalus (Astragalus membranaceus) - Increases sperm motility. Sarsaparilla (>Smilax spp.) - Known as a male (and female) tonic. Saw palmetto (Serenoa repens) - Used for overall male reproductive health.

Other Recommendations • • • •

Avoid alcohol. Alcohol consumption is associated with an increased number of defective sperm. Consider acupuncture. Do not smoke, or quit smoking. There is an association between smoking and low sperm count, poor sperm motility, and abnormal sperm. Proxeed - is a new nutritional supplement that may improve sperm health and fertility rates. The ingredients include L-carnitine and acetylcarnitine, two vitamin-like substances synthesized naturally by the body. These chemicals are involved in cellular metabolism and are found in semen at a rate that is proportionate to the amount of healthy sperm. Proxeed improves sperm count, concentration, and motility when taken orally for about 2 months. Approximately 30% of couples using it experience pregnancy. It is available without a prescription, although couples considering it should consult their physician.

Semen Analysis Semen analysis is used to evaluate male fertility—a man's ability to reproduce. This test, which also is called a sperm count, is used to measure the amount and quality of seminal fluid or ejaculate. Seminal fluid contains male reproductive cells (semen or sperm) and normally is expelled through the penis during ejaculation (sexual climax; orgasm). Semen analysis also can be used to help diagnose Klinefelter's syndrome, which is the most common congenital (inherited) cause for testosterone deficiency. This condition, which is caused by an extra X chromosome, results in male infertility (inability to conceive after one year of unprotected intercourse), sparse facial and body hair, abnormal breast enlargement (gynecomastia), and small testes. In most cases, at least two sperm counts are performed following vasectomy to look for sperm in the semen. Semen analysis usually is performed by a fertility specialist. Seminal fluid can affect factors such as sperm shape, function, and movement, so the entire ejaculate is examined. Prior to semen analysis, ejaculation should be avoided for 2–3 days. The semen sample can be collected in a sterile glass container through masturbation (i.e., sexual stimulation) or through sexual intercourse using a special type of condom provided by the physician.

The sample must be analyzed within 1–2 hours to provide accurate results. Many specialists require three different semen samples to account for factors that can affect results, such as variations in temperature and laboratory errors. It often is recommended that the results of the tests do not vary by more than 20%. Semen analysis includes the following factors: • • • • • •

Volume (total volume of ejaculate) Standard semen fluid test (e.g., thickness, color, acidity) Concentration (sperm count; sperm/mL) Morphology (sperm shape and structure; associated with sperm health) Motility (% of sperm that show forward movement; mobility) Total motile count (total number of moving sperm)

Normally, seminal fluid is clear to milky white in color, thick and sticky (viscous) in consistency, has a pH (acidity) level between 7.8 and 8.0, and contains few or no white blood cells (leukocytes). The World Health Organization (WHO) has developed the following values for normal semen analysis: • • • • • •

Total volume—greater than 2 mL Concentration—at least 20 million sperm per mL Morphology—at least 15% normal sperm Motility—greater than 50% sperm with forward movement, or 25% with rapid movement within 1 hour of ejaculation White blood cells—fewer than 1 million per mL Further analysis (sperm mixed antiglobulin reaction [MAR] test) shows adherent particles in less than 10% of sperm

According to the National Institutes of Health (NIH), approximately 1 couple in 6 has difficulty conceiving. It is estimated that male infertility is a factor in about 30–40% of these cases. The most common cause for infertility in men is an enlarged mass of veins in the spermatic cord within the scrotum (called varicocele). The spermatic cord is made up of veins, arteries, lymphatic vessels, nerves, and the duct that carries sperm from the testes to the seminal vesicles (vas deferens). Overall, varicocele contributes to approximately 40% of male infertility cases. In men who have fathered a child but are no longer able to do so (a condition called secondary infertility), varicocele is the cause in as many as 80% of cases. Surgery to correct varicocele (called varicocele repair or varicocelectomy) can improve the shape and structure (morphology) of sperm. Following varicocele repair, approximately 50% of men are able to father a child within the first year. Although semen analysis often can suggest male infertility, the results may not identify the cause for the condition. Additionally, some men with low sperm counts are able to

reproduce (i.e., are fertile). In many cases, abnormal semen analysis results require additional testing. LOW SPERM COUNT Low sperm count is typically identified by a semen analysis. It is calculated by multiplying the volume (cc) of the semen by the concentration (million sperm/cc) by the motility (% moving). Normal sperm count is more than 40 million motile sperm in the ejaculate. Fewer than 40 million may cause conception difficulties. There are a number of things that can cause low sperm count and a number of things that can help increase sperm count. Causes Varicoceles Varicoceles are dilated veins in the scrotum (just as an individual may have varicose veins in their legs). These veins are dilated because the blood does not drain properly from them. These dilated veins allow extra blood to pool in the scrotum, which has a negative effect on the sperm production. This condition is the most common reversible cause of male factor infertility and may be corrected by minor outpatient surgery. Most experts do this microscopically to preserve the arterial supply and lymphatics. A sub-inguinal incision (about 1 inch above the penis and 1 inch from the midline) is usually used, as this avoids incising the abdominal muscles and creates less postoperative pain. Abnormalities in the seminal fluid If the seminal fluid is very thick, it may be difficult for the sperm to move through it and into the woman's reproductive tract. Often, the semen can be processed to separate the moving sperm from the surrounding debris, dead sperm, and seminal fluid. The processed sperm is usually placed directly inside the uterus with a small tube (catheter). This is called intrauterine insemination (IUI). Problems with the ductal system A patient may have bilateral (both sides) congenital (from birth) absence of the vas deferens. He may have obstructions either at the level of the epididymis (the delicate tubular structure draining the testes) or higher up in the more muscular vas deferens. He may have become mechanically blocked during hernia or hydrocele repairs. He may have become blocked by scar tissue as a response to an infection. Sperm are stored in sacs called the seminal vesicles and are then deposited in the urethra, which is the tube through which men urinate and ejaculate. The sperm must pass through the ejaculatory ducts to get from the seminal vesicles to the urethra. If these are blocked on both sides, no sperm will come through. In some situations, the ducts may be repaired or unblocked to allow sperm to flow through the man's reproductive tract. If this is not possible, the sperm may be harvested to allow them to flow through the man's reproductive tract. Because they are obtained in

lower numbers, they must be used in conjunction with advanced reproductive techniques to attempt a pregnancy. Immunologic Infertility Men can develop an immunologic response (antibodies) to their own sperm. The causes for this may include testicular trauma, testicular infection, large varicoceles or testicular surgery. Sometimes, there are unexplained reasons why this occurs. These antibodies have a negative effect on fertility, although the exact reason why this is the case is unclear. Most likely, these antibodies act negatively at several points along the pathway to fertilization. They make it more difficult for the sperm to penetrate the partner's cervical mucous and make its way into the uterus. They make it more difficult for the sperm to bind with the zonapellucida (the external membrane or shell of the egg). Also, the antibodies make it more difficult for the sperm to fuse with the membrane of the oocytes (eggs) themselves. The treatment for anti-sperm antibodies is somewhat controversial. Men may be treated with corticosteroids. However, this can lead to significant morbidity in the man. The most significant is aseptic necrosis of the hip (noninfectious destruction of the joint), requiring hip replacement. Most of the time, the first level of intervention includes intra-uterine inseminations. If the couple is planning in-vitro fertilization (IVF) the presence of anti-sperm antibodies is usually an indication to inject the sperm directly into the egg (ICSI) instead of conventional IVF. Testicular Failure This generally refers to the inability of the sperm-producing part of the testicle (the seminiferous epithelium) to make adequate numbers of mature sperm. This failure may occur at any stage in sperm production for a number of reasons. The testicle may completely lack the cells that divide to become sperm (“Sertoli Cell-Only syndrome”). There may be an inability of the sperm to complete their development ("maturation arrest"). Sperm may be made in such low numbers that few, if any, successfully travel through the ducts and into the ejaculated fluid (hypospermatogeneses). This situation may be caused by genetic abnormalities, hormonal factors, or varicoceles. Even in the case where the testes are only producing low numbers of sperm, the sperm may be harvested and used in conjunction with advanced reproductive techniques to attempt a pregnancy. Drugs There are a number of fairly common drugs, which may have a negative effect on sperm production and/or function. They include: • •

Ketoconazole (an anti-fungal) Sulfasalazine (for inflammatory bowel disease)

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Spironolactone (an anti-hypertensive) Calcium Channel Blockers (anti- hypertensives) Allopurinol, Colchicine (for gout) Antibiotics: Nitrofuran, Erythromycin, Gentamicin Methotrexate (cancer, psoriasis, arthritis) Cimetidine (for ulcers or reflux)

Hormonal Abnormalities The testicles need pituitary hormones to be stimulated to make sperm. If these are absent or severely decreased, the testes will not maximally produce sperm. Importantly, men who take androgens (steroids) for body building, either by mouth or injection, shut down the production of hormones for sperm production. A hormonal profile must be performed on all men with male factor infertility. This will help rule out serious medical conditions, give more information on the sperm-producing ability of the testes, and may reveal situations where hormonal treatment is indicated. Infections Men may have infections of their reproductive tract. These may include infections of the prostate (prostatitis), of the epididymis (epididymitis), or of the testis (orchitis). Post-pubertal viral infections of the testes may cause significant damage (atrophy) of the testes and may cause absolute and irreversible infertility. Bacterial infections or sexually transmitted diseases may cause blockages at the sperm ducts. The patient may have normal production of sperm, but the ducts carrying it are obstructed. Active bacterial or viral infections may have a negative effect on sperm production or sperm function. White blood cells, which are the body's response to infection, may also have a negative effect on sperm membranes, making them less hearty. If excessive white blood cells or bacteria (more than 1 million/cc) are seen in a semen specimen, cultures should be done. This usually includes cultures for commonly asymptomatic, sexually-transmitted diseases including mycoplasma, ureaplasma and chlamydia. Also, a general genital culture is usually taken. If the infection and the white blood cells are persistent, then antibiotics may be considered. It is important to note that, in most men, the ejaculate is not sterile. In controlled studies, the average man will culture positive for approximately two organisms. It is therefore very important to be judicious in the treatment of non-sexually-transmitted organisms found on cultures. Genetic Abnormalities When these conditions are treated, a man will often see a significant improvement in his semen analysis. Lifestyle Factors

Cigarette smoking has been shown to significantly affect semen quality. Regular smoking causes a 23% decrease in sperm density (concentration) and a 13% decrease in motility (when averages are taken from nine separate studies). To a lesser extent, smoking causes an increased number of sperm with abnormal morphology (shape). Smoking causes toxicity to the seminal plasma (the fluid ejaculated with the sperm). Sperm from non-smokers were adversely affected (had significantly decreased viability) when placed in the seminal plasma (hormonal) of smokers. Smoking effects the hypothalamic-pituitary-gonadtropin axis, most commonly affecting levels of estradiol and estrone (estrogens, which are hormones found in higher concentrations in women). The Leydig Cells, which are in the testes and produce testosterone, may have secretory dysfunction. Most worrisome is that there is evidence that suggests that paternal smoking may also be associated with congenital abnormalities and childhood cancer, though the relative risk in most studies is less than two. Recreational Drugs Marijuana Marijuana often causes a decreased average sperm count, motility, and normal morphology. It affects the hormonal axis (HPG), causing decreased plasma testosterone. It may also have a direct negative effect on the Leydig Cells. Cocaine Even infrequent cocaine use causes decreased sperm counts, motility and normal morphology. These effects can be found in men who have used cocaine in the two years preceding their initial semen analysis. Cocaine also decreases the ability of sperm to penetrate cervical mucous, making it difficult for them to enter the uterus. Anabolic Steroids (male hormones) •

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The use of anabolic androgenic steroids has reached almost epidemic proportions. Nearly 7% of 12th grade males use or have used them to build muscle mass and improve athletic performance. These male hormones suppress the testes ability to make testosterone. This decreases the intratesticular testosterone level. Anabolic steroids depress testicular production of testosterone and thus, levels of testosterone inside the testes itself. This may cause severely diminished spermatogenesis or complete absence of sperm (azoospermia). When taken, these steroids cause a persistent depression of the hypothalamus and pituitary, which may be irreversible even when the steroids are stopped.

Alcohol Moderate alcohol use does not affect male fertility. Excessive alcohol use affects the hormonal axis and is a direct gonadotoxin. It may cause associated liver dysfunction and nutritional deficiencies, which are also detrimental for sperm production.

Lubricants Most vaginal lubricants, including K-Y Jelly, Surgilube, and Lubifax, are toxic to sperm. Couples should avoid their use during the fertile time of a woman's cycle. Exercise Moderate amounts of exercise can only be helpful. However, long distance runners (men who run greater than 100 miles per week) and distance cyclers (men who ride greater than 50 miles per week) have decreased spermatogenesis. These activities should be moderated when a sub-fertile man is attempting conception. Treatment More than 50% of men will have a treatable cause of low sperm count. These factors include varicoceles (dilated veins in the scrotum), infections, hormonal abnormalities, abnormalities in the seminal fluid, ductal blockages, and difficulties with erections and ejaculation. When these conditions are treated, either through medication (hormones or antibiotics) or surgery (varicocelectomy, vasal reconstruction, repair of a blocked ejaculatory duct), a man will often see a significant improvement in his semen analysis. Those men with poor semen analyses whose conditions are not treatable may still have the option of using advanced reproductive techniques to achieve a pregnancy. Even those men with no sperm in the ejaculate may be able to have some living sperm procured from them through other methods and achieve a pregnancy using advanced reproductive techniques. Those few men who produce absolutely no sperm at all will have this information so that they can explore other options.

Principles Spermatozoa, after passage through the epididymis, are motile cells. Sperm motility becomes critical at the time of fertilization because it allows or at least facilitates passage of the sperm through the zona pellucida. Without technologic intervention, a non-motile or abnormally-motile sperm is not going to fertilize. Hence, assessing the fraction of a sperm population that is motile is perhaps the most widely-used measure of semen quality. In evaluating motility with most species, sperm are classified as non-motile, progressively motile or non-progressively motile. A progressively motile sperm swims forward in an essentially straight line, whereas a non-progressively motile sperm swims, but with an abnormal path, such as in tight circles. Another term that is sometimes used is "total motility" which refers to the fraction of sperm that display any type of movement. This concept is rarely used for evaluating animal semen, but is the norm for describing human sperm motility. There is considerable variability among species in what is considered normal or acceptable motility. For example, to pass a breeding soundness examination, it is

recommended that bulls have greater than 30% progressively motile sperm, stallions greater than 60% and dogs greater than 70%. Normal humans typically have total sperm motility of greater than 50%. When analyzing motility, it is important to know whether the semen sample has been abused in any way. Exposure to heat, cold, any kind of residue on collection equipment, or the wrong pH or osmolality of an extender can adversely affect motility. Motility is also affected by periods of sexual inactivity - males that have not ejaculated for prolonged periods often have poor motility on the first ejaculate, but much better motility for a second ejaculate collected soon thereafter.

Techniques for Evaluation of Sperm Motility There are several means for evaluating motility. Which technique to use depends on experience of the operator, the desire for precision and repeatability, and availability of equipment. In almost all cases, motility is reported as the percentage of sperm that manifest motility (usually progressive motility). Manual motility estimates (wet mount): This commonly-used technique involves placing a sample of diluted semen on a microscope slide, examining it with a microscope and estimating the fraction of the population that is motile. More specifically, a sample of semen is diluted in warm extender or buffered saline, and about 10 to 20 microliters of this sample is pipetted onto a clean, prewarmed microscope slide. A coverslip is lowered onto the sample, avoiding formation of air bubbles if possible, and the slide is examined using a microscope with a 20X objective. At least ten widely-spaced fields are examined to provide an estimate of the percentage of motile cells. If estimating motility is a commonly required technique, a microscope warm stage may be worth purchasing.

A bright field microscope can be used for evaluating motility if the field diaphragm is closed to enhance contrast and ability to visualize sperm. A much better choice is a phase contrast microscope or a microscope equipped for differential interference contrast (DIC). Examine the images above to appreciate the difference in these three types of microscopy - clearly, unstained sperm are difficult to observe using bright field. Manual motility estimates are easy to perform and require minimal equipment. In the hands of an experienced evaluator, manual estimates generally provide good estimates of motility. The chief limitation of this technique is its subjective nature. Samples with outstanding motility tend to be scored lower than they should be ("it can't be that good ..") and poor samples tend to be scored higher than they should ("it can't be that bad .."). Track motility estimates: A wet mount of diluted semen is prepared as described for a manual estimate, and sperm are photographed using an exposure time long enough for motile sperm to leave tracks across the image (roughly 0.2 seconds). Using this technique, non-motile sperm appear .. well .. non-motile, and sperm with non-progressive motility leave tracks that are circular or otherwise abnormal. If a digital camera is used, the image can be displayed on a computer monitor for convenient tabulation. The images below depict the track motility technique. On the left, three progressively motile sperm (two are marked) are represented by three straight tracks. On the right, a circular track is seen, representing a non-progressively motile sperm. Non-motile sperm are seen in both images.

Track motility estimates require more time to perform that manual estimates, but they are objective and repeatable. Additionally, one can save the images for a permanent record. Computer-aided motility analysis : A number of systems have been developed that allow motility to be analyzed with the aid of a computer. These systems acquire an image in essentially the same manner as described for the track motility technique, and image processing software detects and tabulates the tracks and immotile cells. Other information is readily obtained, including sperm velocity and other motion characteristics. Additional information on these tools is provided under Computer-Aided Semen Analysis.

Poor Sperm Quality and Miscarriage For a long time, miscarriage has been presumed to be mostly a woman's issue. While miscarriages due to chromosomal abnormalities are really just like a bad throw of the dice other problems which cause miscarriage like hormonal imbalances, incompetent cervix, fibroids and others all relate directly back to women. Low sperm counts or poor motility have long been implicated in infertility but it's only recently that men's role in miscarriage has been examined. Women are born with all of the eggs they'll ever have. Therefore, if you're thirty-nine years old, your eggs have been around for thirty-nine years too. Men produce sperm all the time, so the idea of a male “biological clock” was never really put forth until recently. Still, there's now evidence that as a man ages, his sperm may be more prone to genetic mutation. If a sperm with a genetic mutation fertilizes an egg, that pregnancy is more likely to end in miscarriage due to chromosomal abnormalities. A study conducted by Carrell et al, published in the June 2003 edition of Obstetrics and Gynecology, examined the relationship between chromosomally abnormal sperm and recurrent pregnancy loss. Couples were chosen for the study who'd had at least three pregnancy losses prior to twenty weeks gestation. The study found that in these couples who had experienced recurrent pregnancy loss, sperm motility was decreased, percentage of “normal” sperm was decreased and the amount of tapered sperm was increased. Wikipedia defines sperm motility as “the ability of sperm to move properly towards an egg.” According to the Mayo Clinic's website “sperm with large, small, tapered or crooked heads or kinky, curled or double tails are less likely to fertilize an egg.” Despite the fact that this study and others show a link between poor sperm quality and miscarriage, it seems to be a more subjective connection for men than for women. While women's fertility decreases obviously and measurably as they near menopause, it seems that some men will have trouble with lowered sperm quality as they age and others will not. Some men, notably celebrities Charlie Chaplin and Tony Randall, have fathered children well into their seventies and beyond with no ill effects. In addition to his age, a man's general health and environmental factors all seem to factor into the quality of sperm. . In addition to miscarriage, advanced paternal age is may sometimes be a factor in Down's Syndrome, Schizophrenia and Autism according to MSNBC.com.

Infertility is the inability to get pregnant after a year of unprotected intercourse. About 10% of couples in the United States are affected by infertility. Both men and women can be infertile. According to the American Society for Reproductive Medicine, 1/3 of the time the diagnosis is due to female infertility, 1/3 of the time it is linked to male infertility and the remaining 1/3 is due to a combination of factors from both partners. For approximately 20% of couples the cause can not be determined.

How Does Age Affect Fertility? The number of infertile couples rises with increasing age. Women are born with a finite number of oocytes (eggs). Thus, as the reproductive years progress, the number and quality of the oocytes diminish. The chances of having a baby decrease by 3-5% per year after the age of 30. This reduction in fertility is noted to a much greater extent after age 40.

What Causes Female Infertility? Female infertility can be caused by a number of factors, including the following: •

•

•

•

Damage to fallopian tubes. Damage to the fallopian tubes (which carry the oocytes from the ovaries to the uterus) can prevent contact between the oocyte and sperm. Repetitive pelvic infections, endometriosis and multiple pelvic surgeries may lead to scar formation and fallopian tube damage. Hormonal causes. Some women have problems with ovulation. Synchronized hormonal changes leading to the release of an oocyte from the ovary and the thickening of the endometrium (lining of the uterus) in preparation for the fertilized egg do not occur. These problems may be detected using basal body temperature charts, ovulation predictor kits, and blood tests to detect hormone levels. Cervical causes.A small group of women may have a cervical condition in which the sperm cannot pass through the cervical canal. Whether due to abnormal mucus production or a prior cervical surgical procedure, this problem may be treated with intrauterine inseminations (see below). Unexplained infertility. The cause of infertility in approximately 20% of couples will not be determined using the currently available methods of investigation.

How Is the Cause of Infertility Determined? If male infertility is suspected a semen analysis is performed. This test will evaluate the number and health of his sperm. A blood test can also be performed to check his level of testosterone and other male hormones.

If female infertility is suspected, your doctor may order several tests, including: • •

A blood test to check hormone levels An endometrial biopsy to check the lining of the uterus

Two diagnostic tests that may be helpful in detecting pelvic adhesions (scar tissue) and tubal obstruction are hysterosalpingography and laparoscopy. •

•

Hysterosalpingography (HSG). This procedure involves a series of X-rays taken of the reproductive organs. A dye is injected into the cervix and travels up to the fallopian tubes. The dye enables the X-ray to reveal if the fallopian tubes are open or blocked. Laparoscopy. In this procedure, a laparoscope (a slender tube fitted with a fiberoptic camera) is inserted into the abdomen through a small incision near the belly button. The laparoscope enables the doctor to view the outside of the uterus, ovaries, and fallopian tubes to detect abnormal growths, as in endometriosis.

How Is Female Infertility Treated? •

•

•

•

Laparoscopy. Women who have been diagnosed with tubal or pelvic disease can either undergo surgery to reconstruct the reproductive organs or try to conceive through in vitro fertilization (IVF, see below). Using a laparoscope inserted through a cut near the bellybutton, scar tissue can be removed, endometriosis treated, ovarian cysts removed, and blocked tubes opened. A hysteroscope placed into the uterus through the cervix can be used to remove polyps and fibroid tumors, divide scar tissue, and open blocked tubes. Medical therapy. Women suffering from ovulation problems may be prescribed medications such as clompiphene citrate (Clomid, Serophene) or gonadotropins such as Gonal F, Follistim, Humegon and Pregnyl, which can lead to ovulation. Gonadotropins can induce ovulation when Clomid or Serophene do not work. These medications also can enhance fertility by causing multiple eggs to ovulate during the cycle (normally, only one egg is released each month). Gonadotropin therapy may be offered for unexplained infertility or when other factors have been corrected without resulting in pregnancy. Metformin (glucophage) is another type of medication that may restore or normalize ovulation in women who have insulin resistance and/or PCOS (polycystic ovarian syndrome). Intrauterine insemination. Intrauterine insemination refers to an office procedure in which semen is collected, rinsed with a special solution, and then placed into the uterus at the time of ovulation. The sperm are deposited into the uterus through a slender plastic catheter that is inserted through the cervix. This procedure can be done in combination with the previously listed medications that stimulate ovulation. In vitro fertilization. In vitro fertilization refers to a procedure in which oocytes (egg cells) are fertilized in a culture dish and placed into the uterus. The woman takes gonadotropins to stimulate multiple oocyte development. When monitoring indicates that the oocytes are mature, the oocytes are collected using a vaginal

•

ultrasound probe with a needle guide. The sperm are collected, washed, and added to the oocytes in a culture dish. Several days later, approximately 3 embryos (fertilized oocytes) are returned to the uterus using an intrauterine insemination catheter. Any extra embryos can be cryo-preserved (frozen) for later use, upon the consent of the couple. Oocyte donation.Oocyte donation helps women who do not have normally functioning ovaries (but who have a normal uterus) to achieve pregnancy. Oocyte donation involves the removal of oocytes from the ovary of a donor who has undergone ovarian stimulation with the use of fertility drugs. The donor's oocytes are then placed together with the sperm from the recipient's husband for in vitro fertilization. The resulting fertilized oocytes (embryos) are transferred to the recipient's uterus.

Medical therapy and in vitro fertilization can increase the chance of pregnancy in women diagnosed with unexplained infertility. Endometriosis and infertility by Ros Wood

Overall, women with endometriosis find it harder to become pregnant than women in general. However, little research has been carried out into this topic, so it is not possible to give you an accurate indication of how much endometriosis will affect your fertility. Nevertheless, studies indicate that women with minimal–mild endometriosis take longer to conceive (become pregnant) and are less likely to conceive than women in general. It also appears that the more severe the woman’s endometriosis, the more likely it is that she will have difficulty becoming pregnant. Thus, women with moderate–severe endometriosis tend to have more difficulty conceiving than women with minimal–mild endometriosis. However, it is important to remember that having endometriosis does not automatically mean that you will never have children. Rather, it means that you may have more problems. Many women with endometriosis have children without difficulty, and many others become pregnant eventually — though it may take time, and may require the help of surgery or assisted reproductive technologies or both. See also: Endometriosis and assisted reproductive technologies In one Australian study involving 3895 women with endometriosis, 54% of the women who tried to become pregnant did not succeed in the first 12 months of trying. However, 70% of them ended up having at least one child [1]*. In comparison, in 1995, the incidence of infertility in US women was 10.2% [2].

* This study included women who tried to conceive in the 1970s and earlier when assisted reproductive technologies were not available or were less successful than today. Therefore, the figure of 70% may be an underestimate.

CAUSES In most cases, it is not understood why it is harder for women with endometriosis to become pregnant. The exception to the rule is when the woman’s endometriosis is severe enough to cause damage to one or more of the organs involved in conception. For example, if the ovaries are covered in thick adhesions, the egg may not be able to escape from the ovary to be fertilised. Similarly, if the ovaries or fallopian tubes are stuck in abnormal places by adhesions, the newly released egg may not be able to ‘find’ the entrance to the fallopian tube. Such damage is usually found only in some women with moderate or severe endometriosis [3]. Many theories have been proposed to explain why it is harder for women with endometriosis to conceive. However, as yet, none have been proven. It is possible that there are several causes and that different causes are relevant in different women. Some of the theories include: •

pelvic adhesions inhibit the movement of the egg down the fallopian tube

•

eggs are of poor quality

•

chemicals produced by the endometriosis inhibit the movement of the egg down the fallopian tube

•

inflammation in the pelvis caused by endometrisis stimulates the production of cells that attack the sperm and shorten their life span

•

eggs are not released from the ovaries each month (also known as anovulation, which may also occur in women without endometroisis [4].

MISCARRIAGE There is no evidence that endometriosis causes women to have repeated miscarriages [5]. Also, there is no evidence that treating endometriosis results in women having fewer miscarriages [6, 7]. HORMONAL TREATMENT Minimal–mild endometriosis

In women with minimal–mild endometriosis, hormonal drugs are not an effective treatment for endometriosis-related infertility, as none of the drugs leads to better pregnancy rates. Therefore, they should not be used to improve fertility in women with minimal–mild endometriosis [8]. Moderate–severe endometriosis In women with more severe disease, no published studies have looked at the effect of hormonal treatment on infertility. However, it is assumed that they are not effective, so they should not be used to improve infertility in women with moderate–severe disease [9]. SURGICAL TREATMENT Aim Surgery for endometriosis-related infertility aims to remove any endometriosis and adhesions present. If the endometriosis has damaged any organs, or resulted in them being stuck down in abnormal positions, the surgery will also try to repair the damage and restore the anatomy of the organs to as close as possible to their normal positioning [9]. Minimal–mild endometriosis In women with minimal–mild endometriosis, laparoscopic surgery is an effective treatment for endometriosis-related infertility, as it leads to better pregnancy rates than a diagnostic laparoscopy alone [10]. Moderate–severe endometriosis In women with moderate–severe endometriosis, no well designed studies have looked at the effect of surgery on pregnancy rates [9]. However, three studies seem to suggest that the more severe the endometriosis the lower the pregnancy rates following surgery [11, 12, 13]. In other words, it seems that women with severe endometriosis are less likely to become pregnant following surgery than women with mild or moderate endometriosis. Nevertheless, some gynaecologists believe that women with the most severe forms of endometriosis have the greatest improvements in pregnancy rates following surgery [14]. In other words, surgery seems to increase their chances of becoming pregnant proportionally more than women with less severe endometriosis. Ovarian endometriomas There is considerable debate about how large ovarian endometriomas in women with endometriosis-related infertility should be treated [9]. The three main treatments are:

• draining the endometrioma • draining and coagulating (burning the lining of) the endometrioma • excising (remove by cutting out) the endometrioma from the ovary. Several studies indicate that laparoscopically excising large endometriomas greater than 4 cm in diameter leads to increased pregnancy rates and decreased recurrence rates compared with draining and coagulating the endometrioma [15, 16, 17, 18]. Removing an ovarian endometrioma allows the diagnosis of endometriosis to be confirmed by a pathologist, may reduce pain and discomfort, and may make it easier for the gynaecologist to collect follicles (potential eggs) for IVF [9]. However, removing an endometrioma may also result in the removal of some of the adjacent ovarian tissue, including some follicles (potential eggs). This may lead to decreased functioning of the ovary and occasionally even loss of ovarian function, particularly in women who have had previous ovarian surgeries [9]. Thus, the decision to remove or not remove an endometrioma must be carefully considered in the light of your circumstances [9].

Ovulatory Disorder Ovulatory dysfunction is a term that describes a group of disorders in which ovulation fails to occur, or occurs on an infrequent or irregular basis. Ovulatory dysfunction is one of the leading causes of infertility. Anovulation (no ovulation) is a disorder in which eggs do not develop properly, or are not released from the follicles of the ovaries. Women who have this disorder may not menstruate for several months. Others may menstruate even though they are not ovulating. Although anovulation may result from hormonal imbalances, eating disorders, and other medical disorders, the cause is often unknown. Women athletes who exercise excessively may also stop ovulating. Oligo-ovulation (ol-I-go-ov-u-LA-shun) is a disorder in which ovulation doesn't occur on a regular basis, and your menstrual cycle may be longer than the normal cycle of 21 to 35 days.

How Ovulatory Dysfunction is Diagnosed

Your medical history is useful in diagnosing ovulatory dysfunction. However, other tests may be required to confirm the diagnosis. You may need one or more of the following tests: • • •

•

FSH blood level - a blood test that measures the amount of follicle stimulating hormone (FSH) in your blood to see if you are approaching menopause Progesterone blood level - a blood test that measures the amount of progesterone in your blood to diagnose if ovulation has occurred Ultrasound - a scan that uses high frequency sound waves to see if follicles in your ovaries are developing; also used to evaluate ovarian function - for example, small ovaries with a few small follicles may be a sign of approaching menopause Endometrial biopsy - a procedure in which a sample of your endometrial tissue is examined to determine if it is developed enough to support a pregnancy

Common Questions Q How can I tell if I am ovulating? A Ovulation prediction kits are helpful for detecting when you are about to ovulate. They measure the luteinizing hormone (LH) in your urine. An LH surge (high level of LH in your urine) means that you will probably ovulate within the next 24 to 36 hours. The test is performed mid-cycle. (For example, it is performed on days 13 and 15 of your menstrual cycle if you usually get your period every 28 days. Day 1 is the first day of your period.) If you do the test every day during your mid-cycle and do not detect an LH surge, you may not be ovulating. Q How can charting my basal body temperature (BBT) help to diagnose anovulation? A Your BBT should rise about 1¡ just after you ovulate, about 2 weeks before your next period is due to begin. If there is no rise in your BBT at mid-cycle, you may not be ovulating. BBT charting cannot predict ovulation, but it may confirm that ovulation has occurred. Q What treatments are available to me? A If you are not ovulating, your doctor may prescribe a medication to stimulate your ovulation. If you decide to take medication to ovulate, your doctor will want to monitor you carefully to see if and when you are ovulating. Monitoring usually involves ultrasound and blood tests.

Polycystic ovary syndrome

Polycystic ovary shown on ultrasound image ICD-10

E28.2

ICD-9

256.4

OMIM

184700

DiseasesDB

10285

eMedicine

med/2173 ped/2155 radio/565

MeSH

[1]

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects approximately 5% of all women.[1] It occurs amongst all races and nationalities, is the most common hormonal disorder among women of reproductive age, and is a leading cause of infertility.[2][3] The principal features are obesity, anovulation (resulting in irregular menstruation), and excessive amounts or effects of androgenic (masculinizing) hormones. The symptoms and severity of the syndrome vary greatly among women. While the causes are unknown, insulin resistance, diabetes, and obesity are all strongly correlated with PCOS.

What Is Polycystic Ovary Syndrome? Polycystic (pronounced: pah-lee-sis-tik) ovary syndrome is a common health problem that affects teenage girls and young women. Although no one really knows what causes PCOS, it seems to be related to an imbalance in a girl's hormones. Both girls and guys produce sex hormones, but in different amounts. In girls, the ovaries produce the hormones estrogen and progesterone, and also androgens. These hormones

regulate a girl's menstrual cycle and ovulationovulation. Even though androgens are sometimes referred to as "male hormones," every female produces them. In girls with PCOS, the ovaries produce higher than normal amounts of androgens, and this can interfere with egg development and release. Some of the eggs develop into cysts, which are little sacs filled with liquid. Instead of being released during ovulation, as an egg is during a normal menstrual cycle, the cysts build up in the ovaries and may become enlarged. Because girls with PCOS are not ovulating or releasing an egg each month, it's common for them to have irregular or missed periods. Although PCOS (which used to be called Stein-Leventhal syndrome) was first recognized in the 1930s, doctors can't say for sure what causes it. Research has suggested that PCOS may be related to increased insulin production in the body. Women with PCOS may produce too much insulin, which signals their ovaries to release extra male hormones. PCOS seems to run in families, too, so if someone on your mom's or dad's side of the family has it, you might be more likely to develop it. If PCOS is not treated properly, it can put a girl at risk for lots of problems. Girls with PCOS are more likely to have infertility, excessive hair growth, acne, obesity, diabetes, heart disease, high blood pressure, abnormal bleeding from the uterus, and cancer. The good news is that, although there's no cure for PCOS, it can be treated. The most important step is diagnosing the condition, because getting treatment for PCOS reduces a girl's chances of having serious side effects.

Tubal Factor Infertility and Reversing Tubal Sterilization Once the follicles reach maturity, the LH surge occurs, which causes ovulation thirty-six hours later. The egg(s) is ovulated into the end of the fallopian tube and travels to the distal end where fertilization occurs. Any condition that impedes, or blocks, egg transport through the tubes can cause tubal factor infertility. In many of these cases IVF is the treatment of first choice. Sometimes endometriosis will attach to the fallopian tubes causing scarring and/or adhesions"on" the tubes leading to obstruction. In addition, severe pelvic infections (pelvic inflammatory disease), caused by a variety of microorganisms including Chlamydia, can severely damage the fallopian tubes. In other cases, women who previously had their tubes tied, seek to have the procedure reversed. While this is sometimes possible, tubal sterilization should be considered a permanent form of birth control. To begin the evaluation of the tubes and uterus, the specialist orders a hysterosalpingogram (HSG). In this test, dye is inserted into the uterus and x-rays are taken as it flows back through the tubes. Blockages are seen as concentrations of dye. The physician may recommend surgery if the tubal blockage is not severe. This is dependent upon a number of patient specific variables including age, where, and how, the tubes were "cut" or damaged, other underlying causes of infertility, etc. Data clearly demonstrates that in vitro fertilization (IVF) produces higher per cycle success rates than does tubal reconstruction. A patient with tubal sterilization may opt for a tubal reversal if she is young and has no other factors contributing to her infertility. The advantage to tubal reversal, in appropriately screened cases, is that even though the per cycle success rates are lower than IVF; numerous natural intercourse cycles can be attempted. Moreover, the patient may not be able to afford multiple IVF attempts. IVF is usually recommended as a first line treatment when moderate to severe tubal damage is present.

Ovulation disorders are a common cause of infertility and are present in up to 30% of cases. Every month a normally ovulating female recruits eggs that develop to maturity and are released according to precise timing governed by hormone relationships in the

menstrual cycle. Lack of ovulation is termed "anovulation" and irregular ovulation is termed "oligoovulation". The fertility specialist will order numerous tests to assess ovulation that may include FSH (follicle stimulating hormone), LH (luteinizing hormone), estrogen, progesterone, androgens, thyroid and adrenal tests. Other tests might include an ultrasound exam to visualize the ovaries and a clomiphene citrate challenge test. In order to understand ovulatory disorders, it is necessary to have a basic understanding of the various hormone relationships involved in the hypothalamic-pituitary-adrenal axis (HPA axis). The hypothalamus is a small gland located at the base of the brain, which can be thought of as a "thermostat". It releases gonadotropin releasing hormone (GnRH), which travels to the pituitary where it stimulates the production of FSH and LH. The hypothalamus signals the pituitary to increase production of FSH during the first few days of the menstrual cycle. FSH is responsible for stimulating the recruitment of ovarian follicles, each of which contains an egg, and supporting their growth. As healthy follicles mature, they begin to produce estrogen, which helps to stimulate the growth of the endometrium (lining of the uterus). The endometrium must thicken to accept and support the growth of an embryo. Estrogen levels are monitored by a part of the brain called the hypothalamus and as they increase, the hypothalamus signals the pituitary to reduce production of FSH. Once the hormone levels indicate that the follicles are mature, the hypothalamus signals the pituitary to release a surge of luteinizing hormone (LH). The spike in LH levels triggers ovulation approximately 36 hours after the surge. The ovaries begin to produce progesterone, which also supports the development of the endometrium. Rising levels of human chorionic gonadotropin (hCG), produced by the placenta, are an indication of pregnancy. If pregnancy does not occur, the lining of the endometrium breaks down and is released during menstruation. There are many causes of oligoovulation (irregular ovulation) and anovulation (no ovulation) including: •

•

Ovarian failure as a Cause of Ovulation Failure- Women are born with all the eggs they will have for a lifetime and one is usually ovulated during each monthly menstrual cycle. As women age, infertility increases as ovarian function begins to decline until the menopause, where no more eggs are released and FSH levels are very high. Ovarian failure means that the ovaries cannot produce eggs that will normally fertilize and develop. Day 3 FSH levels are elevated in these patients and response to the clomiphene citrate challenge test is abnormal. Ovarian failure may occur early in some women and is discussed in detail in our "Age and Fertility" section. These women are often candidates for our donor egg program. Polycystic ovarian syndrome, PCOS- a common condition characterized by elevated androgens (male hormone), reduced insulin sensitivity, and numerous cysts on the ovary. Elevated androgens can lead to oligoovulation.

•

•

• •

•

Thyroid dysfunction- Abnormally high (hyperthyroidism) or low (hypothyroidism) levels of thyroid hormone can cause irregular ovulation thought to be due to the high levels of estrogen associated with these conditions. Hyperprolactinemia - Prolactin is responsible for breast milk production in pregnant women. Elevated levels of the hormone, prolactin, can lead to ovulatory disorders and infertility. Elevated levels in the absence of pregnancy cause irregular ovulation by reducing the levels of FSH and LH. Excessive exercise, stress, and anorexia can lead to irregular ovulation. Adrenal dysfunction- Androgens are produced by the adrenal glands and abnormally elevated levels lead to oligoovulation. Increased androgens are associated with elevated levels of prolactin, and/or tumors on the ovary, pituitary, or adrenal gland. Unexplained- Sometimes eggs will not fertilize and develop into health embryos for unexplained reasons. In many cases, these couples achieve pregnancy with donor egg IVF. Irregular ovulation can usually be treated effectively with medications such as Clomid, Metformin, Bromocriptine, or FSH unless it is due to reduced ovarian reserve or ovarian failure. The best option for patients with ovarian failure is IVF using donor eggs.

Uterine Factor Infertility The uterus must be able to accept and support a developing embryo which implants in its lining. Abnormalities of the uterus can cause infertility by interfering with embryo implantation and fetal growth. Uterine factor infertility is relatively uncommon occurring in less than 5% of women. Sometimes a woman will be born with a misshapen uterus, such as the bicornuate or horned uterus, which will sometimes be corrected surgically. Large polyps and fibroids can also interfere with fetal growth and are removed usually via the laparoscopy. Severe pelvic infections (pelvic inflammatory disease) caused by a variety of microorganisms can permanently damage the uterus and tubes. Cancer treatment may also require the removal of the uterus. When the uterus is absent or severely damaged the only option is to use the services of a surrogate using IVF. A surrogate is a woman who carries the baby to term and delivery. See our section on surrogacy for more information.

Cervical Factor Infertility Sperm must swim in the cervical mucus traveling from the vagina through the cervix and into the uterus. Cervical mucus is produced by small glands that line the cervix. The

mucus must provide nutritional support for sperm and be of the correct consistency. Too little or "sticky" mucus can interfere with sperm transport causing infertility. When estrogen levels increase prior to ovulation it causes increased mucus production and the mucus becomes "watery" thus enhancing sperm movement. Certain medications, such as Clomid can adversely affect the mucus by causing it to thicken. Sometimes antisperm antibodies are found in the cervical mucus. These are antibodies produced by the female that mistake sperm for invading pathogens. When these antibodies are present numerous "dead" or immobile sperm are seen in the post coital test. Rarely, a man will produce antibodies to his sperm. Cervical factor infertility is often treated via intrauterine insemination (IUI). Using this procedure, specially prepared sperm are inserted directly into the uterus using a small catheter. This avoids exposure of the sperm to the cervical mucus and insures it reaches the uterus.

Uterine Factor Infertility The uterus must be able to accept and support a developing embryo which implants in its lining. Abnormalities of the uterus can cause infertility by interfering with embryo implantation and fetal growth. Uterine factor infertility is relatively uncommon occurring in less than 5% of women. Sometimes a woman will be born with a misshapen uterus, such as the bicornuate or horned uterus, which will sometimes be corrected surgically. Large polyps and fibroids can also interfere with fetal growth and are removed usually via the laparoscopy. Severe pelvic infections (pelvic inflammatory disease) caused by a variety of microorganisms can permanently damage the uterus and tubes. Cancer treatment may also require the removal of the uterus. When the uterus is absent or severely damaged the only option is to use the services of a surrogate using IVF. A surrogate is a woman who carries the baby to term and delivery. See our section on surrogacy for more information.

Cervical Factor Infertility Sperm must swim in the cervical mucus traveling from the vagina through the cervix and into the uterus. Cervical mucus is produced by small glands that line the cervix. The mucus must provide nutritional support for sperm and be of the correct consistency. Too little or "sticky" mucus can interfere with sperm transport causing infertility.

When estrogen levels increase prior to ovulation it causes increased mucus production and the mucus becomes "watery" thus enhancing sperm movement. Certain medications, such as Clomid can adversely affect the mucus by causing it to thicken. Sometimes antisperm antibodies are found in the cervical mucus. These are antibodies produced by the female that mistake sperm for invading pathogens. When these antibodies are present numerous "dead" or immobile sperm are seen in the post coital test. Rarely, a man will produce antibodies to his sperm. Cervical factor infertility is often treated via intrauterine insemination (IUI). Using this procedure, specially prepared sperm are inserted directly into the uterus using a small catheter. This avoids exposure of the sperm to the cervical mucus and insures it reaches the uterus.

Endometriosis Endometriosis is a common cause of infertility (up to 40%) and pelvic pain in women. Endometriosis appears to be more common in daughters of women who had endometriosis suggesting a genetic link. It produces symptoms such as pain during menstruation, intercourse, bowel movements, or emptying the bladder. It is also often present with no symptoms. Endometriosis is caused when the cells that normally line the uterine cavity (the endometrium) enter the pelvic cavity and attach to various organs. It is commonly seen on the rectum, ovary, uterus, and tubes, during the laparoscopy. Endometrial lesions present in many forms including the classical dark blue, dark brown, or black lesions. It may also present in a "non classical" lesion that may be white, red. or yellow. Endometriosis occurs when endometrial cells enter the pelvic cavity through a back flow of blood during the menstrual cycle and attach to internal organs. Menstrual blood is rich in endometrial cells since it results from a breakdown of the endometrium. Once in the bloodstream, endometrial cells can travel throughout the body. This explains why endometrial lesions been documented in many organs distant to the pelvic cavity, including the lungs and the brain. Endometriosis is typically "staged" according to its severity and likelihood of causing infertility. The stages include minimal-stage 1, mild-stage 2, moderate-stage 3, and severe-stage 4.

Endometriosis- Effects on Fertility Endometriosis can affect fertility in many different ways: •

Failed or irregular ovulation

• • • •

Causing inflammatory processes within the pelvic cavity Failed or impaired fertilization Chronic pelvic inflammation leading to inhibition of embryonic development It can cause physical damage to important reproductive organs such as the fallopian tubes.

Endometriosis is supported by the hormones estrogen and progesterone which stimulates rapid endometrial cell growth. These hormones also stimulate the lining of the uterus (endometrium) which must thicken and become more vascular to provide support and nourishment for a developing embryo. As estrogen levels rise, development of the endometrium follows. Unfortunately, it also stimulates endometrial cell growth on other body structures. Endometriosis is dependent on estrogen for growth so drug treatments aim at reducing estrogen levels. It is commonly treated with Lupron, a gonadotropin releasing hormone (GnRH) agonist. It competes with GnRH causing a drop in the production of FSH and LH by the pituitary leading to lowered estrogen levels. Once the estrogen levels decline the patient can experience all of the side effects normally associated with the menopause. However, endometrial cell growth will be slowed. Endometriosis is often surgically removed during the laparoscopy. Fertility specialists meticulouslyremove all endometriosis lesions as there is some evidence that even small amounts of endometriosis can lower pregnancy rates. A reproductive endocrinologist should perform the laparoscopy for the evaluation of infertility. These highly trained specialists can often treat the disease during the diagnostic laparoscopy. When a fertility specialist is chosen, it is usually not necessary to repeat the diagnostic laparoscopy for treatment thus reducing patient inconvenience, cost, and potential surgical side effects. If endometriosis has penetrated the fallopian tubes, IVF may be the best treatment option. Tubal damage may be so severe that surgical treatment may not be a viable option. There may also be severe damage to the ovaries or other internal organs.

Tubal Factor Infertility and Reversing Tubal Sterilization Once the follicles reach maturity, the LH surge occurs, which causes ovulation thirty-six hours later. The egg(s) is ovulated into the end of the fallopian tube and travels to the distal end where fertilization occurs. Any condition that impedes, or blocks, egg transport through the tubes can cause tubal factor infertility. In many of these cases IVF is the treatment of first choice. Sometimes endometriosis will attach to the fallopian tubes causing scarring and/or adhesions"on" the tubes leading to obstruction. In addition, severe pelvic infections

(pelvic inflammatory disease), caused by a variety of microorganisms including Chlamydia, can severely damage the fallopian tubes. In other cases, women who previously had their tubes tied, seek to have the procedure reversed. While this is sometimes possible, tubal sterilization should be considered a permanent form of birth control. To begin the evaluation of the tubes and uterus, the specialist orders a hysterosalpingogram (HSG). In this test, dye is inserted into the uterus and x-rays are taken as it flows back through the tubes. Blockages are seen as concentrations of dye. The physician may recommend surgery if the tubal blockage is not severe. This is dependent upon a number of patient specific variables including age, where, and how, the tubes were "cut" or damaged, other underlying causes of infertility, etc. Data clearly demonstrates that in vitro fertilization (IVF) produces higher per cycle success rates than does tubal reconstruction. A patient with tubal sterilization may opt for a tubal reversal if she is young and has no other factors contributing to her infertility. The advantage to tubal reversal, in appropriately screened cases, is that even though the per cycle success rates are lower than IVF; numerous natural intercourse cycles can be attempted. Moreover, the patient may not be able to afford multiple IVF attempts. IVF is usually recommended as a first line treatment when moderate to severe tubal damage is present.

Obesity and Reproductive Health Reproductive health and infertility have gained much notoriety and public awareness has skyrocketed since the first test tube baby in 1978. The same can be said about the impact lifestyle-namely the relationship between diet, exercise and heredity-may have on overall health risk and infertility. However, only recently in the medical community, and less so within the lay public, has an association been described between one's weight, nutritional status and reproductive health. There appears to be a direct association between body weight and death from all causes between the ages of 30-55. When the BMI* exceeds 30, the relative risk of death, as relates to obesity, increases by 50%. Moreover, there are ethnic differences with a prevalence of increased obesity in African Americans, Hispanics and Caucasian females of 50.8, 40.1 & 30.6 respectively.

Being overweight is associated with 400,000 deaths per year with significant increases in many health related disorders like cardiovascular disease, diabetes, hypertension and stroke, arthritis, fragile X syndrome, gout, sleep apnea, liver and gallbladder disease and colon cancer. Additionally, overweight and/or obese (compared to normal weight) females have a greater incidence of reproductive-related disorders, cancer of the breast, cervix, ovary and uterus, adverse pregnancy outcome and pregnancy-related disorders, reproductive endocrinologic problems, infertility and urogynecologic disorders, to name a few. In that vein, although a thorough review of the literature describing the association between obesity and reproductive health is needed, the brief format of this communication doesn't lend itself to such an article. Therefore, the major areas will be highlighted and conclude with some recommendations. Cancer The incidences of certain types of cancer are significantly increased in the overweight population. In women, those of the reproductive system are more common. Epidemiologic studies in the past suggested that populations whose diets were high in fat have an increased incidence in breast cancer. More recently, there not only appears to be a relationship between total body fat and breast cancer, but the increase in central (visceral) body fat assessed by CAT scan, may have a greater impact on the overall risk. Similarly, the risk of developing endometrial (uterine) cancer is also increased in overweight women, thought to be a consequence of an overproduction of estrogen by the adipose (fat) tissue cells. This increase in the estrogen production by the adipose tissue cells in the postmenopausal female is primarily related to the amount of excess body fat. Obstetrical Outcome A number of studies have shown the relationship between being overweight or obese and adverse obstetrical outcome. A recent study of 2,459 Danish women, divided into three groups based on their pre-pregnancy BMI: normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), obese (BMI>30) were evaluated in terms of their clinical obstetrical outcomes. After adjustments for other factors, both overweight and obese subjects were found to have significant increases in hypertensive complications, caesarian section, induction of labor and excessive fetal size for gestational age in the presence of a normal glucose tolerance. An associated byproduct of the increased caesarian rate is the higher perioperative morbidity, including anesthetic difficulties, infection, problems with wound healing, blood loss and lengthy hospitalizations. Other studies have shown a direct relationship with an increased BMI of >30 & >40 both showing increased rates of gestational diabetes and pregnancy induced hypertension. Reproductive Performance & Endocrine Changes

There are a significant number of overweight and obese females who suffer infertility. This could be a consequence of irregular menses and frequently anovular cycles. A large percentage of those infertile patients have Polycystic Ovarian Syndrome (PCOS), a disorder often associated with obesity, chronic anovulation, and menstrual irregularity with or without hyperandrogenism and hyperinsulinemia. Anovulation is also seen in patients with a BMI > 30 due to abnormal secretion of hypothalamic GnRH, pituitary LH and FSH. The hyperinsulinemia seen with an insulin resistant state without PCOS can impact on fertility independently. Although the exact mechanisms of how obesity affects fertility are not well understood, there is an apparent insulin-mediated hyperstimulation of ovarian steroid production and decreased sex hormone-binding globulin. Obesity has also been associated with an increased risk of early pregnancy loss after IVF, decreased pregnancy rate, decreased fertilization, higher gonadotropins requirements, as well as an impaired response to gonadotropins. The cause of a poor IVF treatment outcome may be due to poor oocyte quality with subsequent lower fertilization and/or implantation defects caused by a qualitatively poor endometrial milieu. Finally, there are a number of endocrine changes that are associated with being overweight or obese. Conclusions The conventional approach in the past has been to carefully monitor patients who have high-risk pregnancies; e.g. gestational diabetes, multiple gestations, etc. Based on more recent data, it seems that overweight/obese individuals represent another high-risk group. Yet, widespread routine high risk screening of obese patients has not become the standard of care. Additionally, due to the greater incidence of clinical problems in the infertile obese population, these patients should also be considered high risk and treated accordingly To that end point, our initial treatment of the infertile, overweight/obese patient should include a multidisciplinary approach to weight management that fosters lifestyle change through proper diet, exercise, behavior modification and stress reduction in concert with pharmacologic approaches (e.g. Metformin) when indicated. By providing a more holistic approach to obesity and reproductive health preconceptually, we may be able to have a powerful impact on our patients by enhancing their chances of conception, achieving a healthy obstetric outcome and possibly enhancing their overall health.

The decrease in female fecundity beginning after the age of 30 and exaggerated after 40, is a well documented finding. This age related decline in fertility is the result of several factors that contribute to overall reproductive failure. Women over 35 require a longer period to achieve conception than younger individuals, and a higher percentage of older than younger women will never achieve pregnancy. In addition, the rate of early pregnancy wastage increases substantially during the 30s, and is over 50% after age 40.

With the aging of the baby boom generation and social trends to delay childbearing, the treatment of women ³ 40 years of age who desire fertility has become a major challenge of today's infertility specialists. For many women, the option to exercise other choices while deferring their reproduction, has resulted in the need to use new reproductive technologies while treating their infertility. These technologies include controlled ovarian hyperstimulation (COH), intrauterine insemination (IUI), and assisted reproductive techniques such as IVF , PGD, and the use of donor eggs. Though the age related decline in pregnancy is seen in ART, there are few reports of COH-IUI results with respect to age. I would like to share my report of a large series of COH-IUI in women 40 years and older. LITERATURE REVIEW Over the past 15 years, there has been a surge in the assisted reproductive technologies available to treat infertility. Huntington Reproductive fertility clinics are at the cutting edge for all assisted reproductive technologies. Given such a vast array of treatments, infertility specialists are faced with uncertainty about the optimal technique for an individual patient with functional fallopian tubes. The optimal choice depends on the IVF success rates per cycle (cycle fecundity) and costs, as well as the degree of invasiveness associated with each of these procedures. Recently, some authors have suggested superovulation with hMG, combined with IUI as an alternative treatment for couples with non tubal causes of infertility.

Reproductive Technology Successful pregnancy requires ovulation (when an ovary releases an egg into a fallopian tube), transport of the egg partway down the fallopian tube, movement of sperm from the vagina to the fallopian tube, penetration by the sperm of the egg's protective layer, and implantation of the fertilized egg in the uterus. In the United States, infertility is an issue of great concern to many couples of childbearing age. More than 15 percent of all such couples are estimated to be infertile. In a 1995 study by the Centers for Disease Control and Prevention, 10 percent of 10,847 women interviewed, a percentage that represents 6.1 million women of childbearing age nationwide, reported having experienced some problems getting pregnant or carrying a baby to term. Of this group, about half were fertile themselves but had infertile partners. The number of women seeking professional assistance to deal with infertility problems is increasing every year (600,000 in 1968, 1.35 million in 1988, 2.7 million in 1995), and it is reasonable to believe that this trend will continue unabated well into the twenty-first century.

Pregnancy and Infertility There are many causes of infertility. Abnormal semen causes the infertility problems of about 30 percent of couples seeking treatment. Tubal disease and endometriosis in the female partner account for another 30 percent. A female partner's failure to ovulate accounts for 15 percent, and the inability of sperm to penetrate the woman's cervical

mucus accounts for another 10 percent. The final 15 percent of couples seeking treatment are infertile for reasons that cannot be diagnosed. Many couples can be helped to overcome infertility through hormonal or surgical interventions. Women experiencing ovulation disorders may benefit from treatment with oral drugs such as clomiphene citrate, or through the injection of gonadotropins, such as follicle-stimulating hormone, which has about a 75 percent success rate. Women with tubal disease can be helped by various types of reconstructive surgery, but the success rate is only about 33 percent. However, many infertile couples cannot be helped by such standard methods of treatment. Instead, as a last resort, couples that want children must turn to newer techniques that bypass one or more steps in the usual physiological processes of ovulation, fertilization, and implantation. Commonly referred to as "assisted reproductive technology," these techniques include in vitro fertilization (IVF), gamete intrafallopian transfer, zygote intrafallopian transfer, donor insemination, egg donation, embryo cryopreservation, intracytoplasmic sperm injection, tubal embryo stage transfer, and intrauterine insemination.

In vitro Fertilization When performed by an experienced practitioner and in an experienced clinic, IVF generally results in pregnancy rates of about 28 percent after one attempt and 51 percent after three. One study has reported the pregnancy rate after six attempts as being 56 percent. Another has reported it as being 66 percent. Generally, one attempt at IVF is made per menstrual cycle. The IVF process begins when couples are first screened. Clinicians first must rule out infertility in the male partner. If the problem is with the female partner, various courses of treatment may be available. Generally, couples are expected to try to achieve pregnancy for a year after the initial screening before intervention is attempted. However, if a woman is in her late thirties or older, or if she is experiencing irregular menstruation, a clinical investigation may begin earlier. Especially in older women, the blood level of follicle-stimulating hormone, a hormone that acts on the ovary to stimulate the maturation of viable eggs, is measured. If the hormone's level is found to be elevated early in a woman's menstrual cycle (after the first week of the new cycle), her ovaries may not be responding to it. In that case, hormonal treatment to stimulate ovulation would be ineffective, and assisted reproductive technology would be unable to help achieve pregnancy. Elevated estrogen levels at day three would also indicate that the ovaries are not responding correctly to estrogen or hormones. In women whose ovaries are capable of generating viable eggs, the first step in IVF is referred to as "superovulation." To increase the chance of success, the woman's ovaries are stimulated to develop many follicles. Normally, only one or perhaps two follicles

develop and are released by an ovary during a single menstrual cycle, which is why usually only one or, on rare occasions, two children are born. In superovulation, a doctor forces multiple follicles to develop so that many oocytes can be collected. To stimulate the ovaries to develop many follicles, the woman undergoes the "long protocol." The action of the pituitary gland is suppressed hormonally, and ten days later the woman is treated with follicle-stimulating hormone. To see how well her ovaries are responding to the hormone, doctors measure estrogen blood levels and observe the ovaries with ultrasound scans. The number and size of the follicles can be visualized. When the doctors judge that the time is right (that is, when the follicle is enlarged to the point that it protrudes above the surface of the ovary), they give the woman human chorionic gonadotropin, wait thirty-six hours, and collect the oocytes from the mature follicles. In the past, to collect follicles, doctors performed laparoscopy, in which a thin optical tube with a light (called a laproscope) is inserted through a very small incision in the abdominal wall, and the pelvic organs are viewed with fiber optics. Today, the use of a needle guided by ultrasound makes the procedure much faster. The ovary is visualized, mature follicles are located, the needle is inserted, and the follicular fluid that contains the mature oocyte (the unreleased egg) is aspirated. The doctors may collect up to eleven oocytes from a single patient. Viable sperm are collected from the man and washed in a special solution that activates them so they can fertilize the egg. The process of sperm activation is called "capacitation" and normally occurs when sperm are ejaculated and enter the female reproductive tract. Capacitation involves activating enzymes in the sperm's acrosomal cap, allowing the sperm head, which contains the sperm's genetic material, to penetrate the outer and inner membranes of the egg (zona pellucida and vitelline membrane). For males with azoospermia, microsurgical or aspiration techniques can directly extract sperm from either the epididymis or the testicles. Azoospermia is the most severe form of male infertility, caused by obstructions in the genital tract or by testicular failure. To allow fertilization to take place, a single egg and about 100,000 sperm are placed together in special culture medium and incubated for about twenty-four hours. Doctors then use a microscope to see if there are two pronuclei (one from the egg and one from the sperm) in the egg, indicating that fertilization occurred. In some cases, the sperm are unable to penetrate the egg. They may be unable to swim correctly, or they may not have been capacitated successfully. In the past, the only solution was to use sperm from another man. Now, however, sperm can be injected directly into the egg's cytoplasm, in a process called microassisted fertilization. There are three ways used successfully by doctors and researchers to micro-fertilize the egg. The first is "zona drilling," in which a hole is punched into the zona pellucida, letting sperm penetrate the egg. The second method is called "subzonal sperm insertion," in which a sperm is injected directly under the zona pellucida. A third, related method is "intracytoplasmic sperm injection," in which a sperm is injected directly into the egg

cytoplasm. The second method is reported to have a higher fertilization success rate (59%) than the third (13%).

The Risks of IVF In some women, the drugs used to promote superovulation may cause side effects, including mood swings. Some investigators have suggested that procedures used in assisted reproductive technology may not be safe because of the potential for increased ovarian hyperstimulation syndrome and bone loss from the hormone treatments. Ovarian hyperstimulation syndrome occurs at mild levels in 23 percent of women undergoing the treatments, at moderate levels in 3 percent, and at severe levels in 0.1 percent. Complications also may arise as a result of the surgical procedures involved in egg retrieval and embryo transfer. Such complications include pelvic and other infections, which occur in 0.15 percent to 1.2 percent of women, complications from anesthesia, which occur in 0.2 percent, and internal injuries, which occur in 0.38 percent. Although the incidence of such complications is low, every chemical or surgical intervention is associated with risks, and potential patients should be aware of this. Other concerns regarding the long-term effects of assisted reproductive technology include the increased incidence of spontaneous abortions, which occur in 20 percent of women, and ectopic and heterotopic pregnancies, which occur in 5.5 and 1.2 percent of women, respectively. In heterotopic pregnancies, an embryo is implanted outside the uterus. There have been conflicting reports as to whether there is a link between the use of fertility drugs and ovarian cancer. Overall, results from many studies do not seem to support such a connection. Some researchers have suggested that the use of the drugs may increase the risk of ovarian cancer later in life, but this is difficult to prove or disprove because the techniques have not been around long enough to assess long-term effects. There have been no reports of any increase in abnormalities in children born using micro-assisted fertilization, though critics have questioned whether the techniques might increase the incidence of such abnormalities.

Embryo Transfer Techniques Once the egg is fertilized, the two pronuclei fuse to form the early embryo, or "zygote." The zygotes are placed in culture media, where they undergo cell division, cleaving repeatedly and passing through the two-cell, four-cell, and eight-cell stages. Within seventy-two hours, the zygote develops into the morula, the solid mass of blastomeres formed by the cleavage of the fertilized ovum (egg). After about three to five days in culture, the zygote has become a hollow ball of cells called the blastocyst. During normal embryogenesis, it is the blastocyst that is implanted in the endometrial lining of the uterus. While the embryos are in culture, problems in their development may become apparent. After embryos with evident problems are discarded, one or more cultured embryos are

transferred into the uterus, where, it is hoped, one will become implanted and develop into a healthy, full-term baby. Embryo transfer replaces the natural process in which the embryo passes down the fallopian tube and into the uterus, prior to implantation. Although this transfer is relatively simple and often takes only a few minutes, the rate of successful implantation is low. Usually, two embryos are transferred, but still only one of five women become pregnant. Most doctors who perform IVF procedures adhere to the limit of two embryos per woman to minimize the risk of multiple pregnancies. In most cases, three embryos are transferred in women older than thirty-five. In the United Kingdom, it is illegal for an IVF doctor to transfer more than three embryos at a time into a woman. A number of factors play a role in whether embryo transfer leads to a baby being born. Success rate is higher if embryo transfer takes place between forty-eight and seventy-two hours after oocyte collection. When more than one embryo is transferred at the same time, the success rate increases, but so does the chance for multiple pregnancies. As noted above, the maximum number transferred should never exceed three. Probably the single most important factor determining whether or not a successful embryo implantation will take place is the donated egg's age. Embryos formed from eggs donated by younger women have a higher implantation success rate than do embryos formed from eggs donated by older women. The age of the host uterus appears to have little or no effect on outcome.

Gamete Intrafallopian Transfer An alternative to IVF and intrauterine embryo transfer is gamete intrafallopian transfer (GIFT), introduced more than twenty years ago. In this procedure, the egg and sperm are collected as they would be for IVF procedures. However, instead of allowing fertilization to take place in a culture dish, the egg and sperm are transferred surgically into the woman's fallopian tube. This allows fertilization to occur in the fallopian tube, just as occurs in a natural pregnancy. The transfer can only be performed in women with healthy and functional fallopian tubes, and the sperm used for fertilization must be completely normal and capable of swimming. After the transfer is made, doctors have no way of knowing if normal fertilization actually takes place until an embryo has implanted in the uterine wall. However, the procedure's success rate (35%) is higher than the success rate for IVF. Another related technique is zygote intrafallopian transfer, in which the egg is fertilized in vitro and the zygote is transferred surgically into the fallopian tube. Other techniques include tubal embryo transfer, in which an embryo already undergoing cleavage is transferred.

Intrauterine Insemination Intrauterine insemination is used when a couple's inability to conceive a child is caused by the sperm's inability to reach the egg. Sperm must move through the uterus and enter the fallopian tube before they can fertilize the egg. Anything that prevents the sperm from

making this trip will block conception. Coital or ejaculatory disorders can limit the sperm's travels, sperm antibodies in the female reproductive tract can kill the sperm, and sperm may be unable to penetrate the cervical mucus. To help the sperm reach the egg, the female is treated with human chorionic gonadotropin to induce multiple ovulation. The number of follicles that are induced is monitored by ultrasound. Washed sperm from the male partner are injected through the cervical opening, into the uterus. The pregnancy rate using this procedure is about 10 percent.

Donor Insemination and Egg Donation Donor insemination is used when sperm are incapable of fertilizing the egg. Usually this occurs if the male produces very little or no sperm. Sometimes, donor sperm is used when the male partner is the carrier of a genetic disorder that could be transmitted to the baby. Sperm donors should be between ages eighteen and fifty-five, and all should be screened for genetic disorders, such as cystic fibrosis, and for various types of chromosomal abnormalities and infectious disease, including hepatitis, syphilis, cytomegalovirus, and HIV. As with the use of intrauterine insemination, the female partner undergoes ovarian stimulation to maximize the number of follicles released during ovulation. Pregnancy rates resulting from the use of donor insemination are between 32 percent and 50 percent after ten inseminations. As with donor insemination, egg donation is used when the woman cannot ovulate or is the carrier of a genetic disease. Egg donors must be younger than thirty-five years and must be screened for the same set of conditions as sperm donors. Donors are treated with drugs to stimulate ovulation, after which the eggs are fertilized with the sperm from the male partner and the embryos are transferred to the uterus of the female partner (other procedures can also be used). Growth and development of the embryos then follow the natural processes.

Surrogacy and Cryopreservation Surrogacy, in which pregnancy occurs in another woman, can supply a couple with an alternative if the woman partner cannot carry the baby to term in her own uterus. In some cases, if the woman cannot supply the egg, sperm from the male partner can be used to inseminate the surrogate mother, who carries the baby to term. Alternatively, if the female partner can produce her own egg, sperm from the male partner can be used to fertilize the egg, and the resulting pre-embryo can be transferred to the uterus of the surrogate mother to grow and develop. Legal controversies resulting from these arrangements have become common in the last few years, so the arrangements should be carefully reviewed by all parties, along with experts in the field, before any final decisions are made. Frozen sperm and embryos effectively retain their viability for many years. The use of frozen human blastocysts is associated with a 10 percent successful pregnancy rate. Oocyte freezing is much less successful, possibly because oocytes may be genetically damaged or killed in the freezing and thawing. Embryos produced from such

cryopreserved eggs have a high incidence of aneuploidy, and they are slow to cleave and develop even if they appear to be genetically undamaged. Various research groups are trying to solve this problem.

Age as a Factor Age must be taken into account when couples are considering assisted reproductive technology. In humans, the age of the oocyte, not the age of the uterus, is the main cause of reproductive failure in IVF and embryo transfer techniques. Embryos formed from older oocytes demonstrate an increased incidence of aneuploidy. In some other species, such as in rabbits, an aging uterus can keep an embryo from being implanted. The use of cryopreservation to circumvent reproductive failure in humans, cattle, and horses has already been successfully employed and is likely to be developed further. Sperm generated by older men are capable of successfully producing normal embryos. However, as sperm age, they are exponentially more likely to contain new gene mutations. Older oocytes, on the other hand, do not appear to be more likely to contain new mutations. Scientists are unsure exactly how age affects oocyte integrity. Oocyte maturation takes place only before birth in the female, so no new oocytes are produced during the entire reproductive life of the female. This is quite different from spermatogenesis, which can continue into old age. Thus, oocytes from older women may be forty or more years old when they are collected and used to form the embryos. Oocytes must reach full maturity before they can be ovulated normally and before they can be fertilized, even artificially, to form embryos. If immature oocytes could be artificially forced to mature in vitro, follicles could be taken from the ovaries of dying or dead women, or from cancer patients planning on undergoing chemotherapy treatments, which can damage oocytes. Unlike immature oocytes, immature sperm can effectively be used in fertilization. Additional research is needed in this area of assisted reproductive technology.

Legal, Ethical, and Moral Considerations The use of these powerful techniques to facilitate reproduction in both humans and animals (the techniques can be used in cattle and pigs, and in the conservation of endangered wildlife) must be balanced against legal, ethical, and moral concerns. For example, would it be permissible to revive extinct animal species? Although a Jurassic Park-like scenario to reanimate extinct dinosaurs is not scientifically credible at this time, what if it became possible to use this technology to form embryos and clone an extinct mammoth, or the passenger pigeon? And what if we can do this for extinct humans? Just because we can develop the capability, would it be acceptable? What are the ethics involved? Other concerns include questions about how long embryos should remain frozen and who owns frozen embryos not used by the parents. What happens if the parents separate, divorce, or die? What about the legal entanglements involved with surrogacy? Already in

the media there have been a number of such cases reported. With the expected increase of these procedures in the future, it is likely that such complex questions will only escalate. Finally, there are basic concerns about helping people sidestep the natural birth process to bring into the world a new human.