Infertility Introduction
Infertility is the inability of a couple to become pregnant (regardless of cause) after 1 year of unprotected sexual intercourse (using no birth control methods).- Infertility affects about 6.1 million people in the United States, about 10% of men and women of reproductive age.
- Infertility affects men and women equally.
- Most infertility cases (85-90%) are treated with medication or surgery. Improvements in fertility treatment have made it possible for many women whose male partner is infertile to become pregnant. These new and advanced technologies include in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and other similar procedures.
MALE INFERTILITY
What is male infertility?
Infertility is defined as the failure to achieve a pregnancy after one year of regular (at least twice weekly) unprotected intercourse with the same partner. Both partners should be evaluated for infertility. Male infertility is indicated when, after evaluation of both partners, problems in reproductive function have been identified in the male partner.
Causes of Male Infertility
Known causes of male infertility
The known causes of male infertility can be subdivided into four areas:
- Hormonal problems. The first group concerns the failure of the pituitary gland at the base of the brain to stimulate the testis. Disorders of this group, usually referred to as endocrine causes of male infertility, are relatively rare, affecting approximately one in 100 patients.
- Sperm production problems. The second category includes disruption of the production of sperm within the testis or the production of antibodies against sperm which block their function. This is the commonest cause affecting about 60 in 100 patients.
- Blockage of sperm transport. The third major category concerns the obstruction (or blockage) of the tubes leading sperm away from the testis, namely in the epididymis and vas deferens, into the ejaculate. This group is the second most common cause affecting about 30 in 100 patients.
- Erection and ejaculation problems. The fourth category relates to problems of erection and ejaculation that are necessary for normal sexual intercourse. These problems affect about 5 in 100 patients.
There are still gaps in our knowledge and for 40% of men with male infertility, the cause of the problem is unknown. This is referred to as 'idiopathic infertility' or 'cause unknown'.
Diagrammatic representation of causes of male infertility:
Hormonal causes of infertility
Hormonal or 'endocrine' causes of infertility are quite rare and represent only 1% of all male infertility disorders. However, it is essential that they are properly diagnosed because effective treatment is available.Hormonal causes of infertility involve problems in producing the hormones that stimulate sperm production by the testis. The pituitary gland sits at the base of the brain and produces hormones called follicle stimulating hormone (FSH) and luteinising hormone (LH) which are responsible for stimulating the testes.
Pituitary tumour and other conditions where the pituitary gland is affected, stop the production of the hormones that are necessary to stimulate the testes.
If the hormones are not produced during puberty, the testes will not fully develop.
If the pituitary gland is not functioning later in life, this will affect the testis and cause an interruption of sperm production.
Sperm Production Problems
Sperm production can be interrupted at various stages in the process for a number of reasons:
Sertoli cell-only syndrome. The testis may completely lack the precursor cells that divide to become sperm. This is a severe form of sperm production disorder making the man sterile.
Maturation arrest. The precursor cells are unable to complete their development to sperm in the testis.
Hypospermatogenesis. Sperm may be made in lower numbers and in some men, so few are made that few, if any, successfully travel through the ducts and into the ejaculated fluid.
Unfortunately, gaps in our knowledge leave approximately 40% of men with disorders of sperm production described as 'cause unknown' (referred to as idiopathic infertility).
The causes known to disrupt sperm production include:
Undescended testis
Genetic causes
Infections
Heat
Sperm antibodies
Torsion
Varicocele
Drugs
Radiation damage
Failure of the testes to descend into the scrotum
In most boys, the testes initially grow in the abdomen and then are lowered or 'descend' into the scrotum before birth. In approximately 6-10% of boys, the testes have not descended into the scrotum at birth but usually descend over the first year of life. However, in approximately 1% of boys the testes remain undescended after the first year. This condition is known as cryptorchidism. Research has shown that damage to sperm production occurs when the testes remain undescended in the abdomen. There is also evidence to suggest that testes that do not descend are at higher risk of testicular cancer. To avoid this problem, attempts are made to bring the testes down surgically into the scrotum within the first 6 to 24 months after birth.
Cryptorchidism is often associated with male infertility. If both testes were cryptorchid after birth and were not brought down into the scrotum before two to four years of age, there is a very high risk of infertility.
Even men with only one cryptorchid testis are at a high risk of later infertility. This may be because the underlying reason for the undescended testis also results in sperm production problems in the other testis. However, some men who have had a single testis that is cryptorchid have normal fertility.
Genetic causes of infertility
Chromosomes are the structures in cells that pass on genetic information. Each cell in our body has 46 chromosomes which contain all the genetic information (genes) for the development and function of our body. Changes to chromosomes and genes can result in abnormal sperm production.
Changes to chromosome number
Changes in the number of chromosomes in cells can result in infertility. The genetic makeup of men normally involves 46 chromosomes, two of which are the sex chromosomes, X and Y. The Y chromosome carries some genetic material that only occurs in males. The sex chromosomes in women normally consist of two X chromosomes.
Klinefelter's Syndrome is the commonest chromosomal disorder in males effecting about 1 in 600 men. It is caused by the presence of an extra X chromosome. Men with Klinefelter's syndrome have 47 chromosomes with the sex chromosome makeup being XXY.
Most men with Klinefelter's syndrome have a zero sperm count, although there is evidence that the first stages of sperm cells may be present in the testes around the time of puberty but then progressively disappear. Recent studies have shown that in a very small number of men with Klinefelter's syndrome, a few small areas of sperm production may be found in the testes, even though there are no sperm in the ejaculate. Men with Klinefelter's syndrome have very small testes (2-6 mls, normal men >15ml). They may also have low levels of the male sex hormone, testosterone. This can result in a failure to have a normal puberty and a lowered sex drive. Other features such as increased body fat, tallness and decreased body and facial hair growth may indicate below normal testosterone production.
Down's Syndrome is a condition where people have an extra copy of chromosome 21, and provides another example of infertility resulting from a change to chromosome number. Men with Down's syndrome are infertile with abnormal sperm production.
Other genetic causes of infertility
Missing genetic material on the Y chromosome has recently been shown to be related to infertility in approximately 6-10% of men with sperm counts of 0 to 5 million/ml. It is thought that areas on the Y chromosome that are missing are important for sperm production. Tests are now available to detect these changes on the Y chromosome, but the exact way in which the missing genetic material impairs sperm production is still unknown.
Congenital absence of the vas deferens occurs in 1 in 2500 men and causes infertility. It is caused by a change in the gene responsible for transportation of material across the lining of many surfaces of the body. Men born with congenital absence of the vas deferens have several parts of their reproductive tract missing (including the vas deferens) which prevents sperm from passing out of the testes into the ejaculate.
Abnormalities in the testosterone (androgen) receptor gene. This is a very rare condition in which the tissues of the body cannot recognise and respond to testosterone in the blood. In its most severe form, this loss of the hormone action results in a male (46XY) child being born with female genital appearance and the failure of sperm production. In mild forms, a normal appearing man may present simply with poor sperm production.
As our knowledge of the human genes improves, it is expected that other genetic causes of infertility may begin to explain a large number of sperm production disorders that are now classified as 'unknown'.
Infections and sperm production
Infection of the testis is called orchitis.
Mumps orchitis is the most well known infection of the testis and is caused by an infection with the mumps virus. Mumps orchitis does not always accompany mumps, but when it occurs after puberty can result in significant swelling and pain, and may lead to a total destruction of the sperm-producing tubes in the testis. Less severe episodes of mumps orchitis can stop sperm production for up to six to twelve months after the attack. No effective treatment exists so it is important that infection be prevented by vaccinating children against mumps.
Epididymo-orchitis is caused by bacterial infection of the testis and epididymis which frequently occur together. Pain and swelling usually last for several days and can be treated by the use of antibiotics. Epididymo-orchitis sometimes accompanies an infection of the urinary tract and can result in permanent blockage to sperm transport causing infertility.
Heat and testicular function
The testes are located in the scrotum where the temperature is approximately 1 to 1.5 degrees Centigrade below the rest of the body's temperature. This is achieved by special mechanisms that cool the blood coming into the testis. The cooler temperature in the testis is necessary for sperm production.
During illnesses that involve a fever, sperm production may be reduced until the fever passes. Similarly, when the testes are exposed to significant external heat on a regular basis, such as the excessive use of hot spa baths, this also appears to reduce sperm production. Failure of the testes to descend into the scrotum can result in damage to sperm production due to the higher body temperature of the abdomen.
There is ongoing debate about the effect of underwear styles on sperm production, and whether or not looser (cooler) boxer shorts should be preferred over tighter (warmer) briefs. Some research has suggested that wearing tight underwear may decrease sperm counts, although other studies have not found this to be the case. Doctors usually advise patients to reduce the possibility of heat stress on sperm production by avoiding regular hot baths and tight-fitting underwear.
Sperm antibodies
Antibodies are substances that the body makes in response to invasion by foreign organisms. For example, when a bacterial infection causes a sore throat, the body recognises that the bacteria are foreign and makes antibodies to coat the bacteria and assist the body's defence systems to get rid of the infection.
The body's ability to tell the difference between what is itself and what is foreign is usually 'programmed' before birth. Because sperm are not produced until the age of puberty, the body recognises them as foreign and therefore produces antibodies to sperm. However, special conditions within the testes normally stop this reaction from occurring.
Approximately 5% to 7% of men with infertility produce antibodies to their own sperm. These antibodies can have a damaging effect on fertility by coating the sperm and interfering with sperm movement within the female reproductive tract. The sperm antibodies may also prevent the interactions that occur between the egg and sperm during fertilisation. In some instances, sperm antibodies cause damage to sperm production within the testis. Antibodies to sperm may occur as a result of testicular surgery or trauma, or following vasectomy when sperm are re-absorbed in the epididymis. In some instances, the presence of sperm antibodies can not be explained.
Torsion of the testis
Torsion of the testis is a condition in which the blood vessels that supply the testis become twisted. This usually occurs because of a structural problem that allows the testis to twist. If torsion occurs in one testis, it is highly likely to happen to the other testis. Torsion produces severe pain and swelling in the testis and needs to be treated as a medical emergency.
The twisting of the blood vessels cuts off the blood supply to the testis, causing damage to the tubes that produce sperm. If the blood supply is interrupted for a long period of time, the testis does not recover. The symptoms of torsion are similar to the symptoms of infection of the testis, so doctors are trained to treat these symptoms as torsion until another reason is found.
Varicocele
A varicocele is a swelling of the veins in the testis, which usually occurs on the left side and results when valves in the veins do not properly drain the blood away from the testis. Blood draining from the testis has to move upwards through the veins against gravity. The valves in the veins help move blood from the testis to the major vein draining blood from the lower part of the body. If the valves are not functioning properly, blood begins to pool in the veins around the testis, forming a varicocele. To detect the presence of a varicocele, it is necessary for the man to be examined standing up. The testis below the varicocele is usually smaller than the other one.
Approximately 15% of men in the general population have varicoceles, but they are more common in men who have problems with sperm production. Studies comparing the sperm counts in men with and without varicoceles show that men with varicoceles have a lower average sperm count, decreased sperm movement and an increase in the number of abnormally shaped sperm. Even so, some men with varicoceles have normal sperm counts and many men with varicoceles have fathered children.
Drugs and other substances causing infertility
There are a number of fairly common drugs, which may have a negative effect on sperm production and or function. They include:
Medications for treatment of cancer
Drugs used in the treatment of cancer are designed to attack the growing cells of the cancer, but can also have an effect on other cells that are growing. The cells in the lining of the sperm-producing tubes in the testis are continually growing to produce the new cells required for sperm production. These cells are therefore open to attack from the drugs for cancer.
Some examples include:
Cyclophosphamide, a drug used for the treatment of some cancers and kidney disorders, can result in permanent infertility if the treatment is given for a prolonged period of time.
Salazopyrine, which is commonly used to treat inflammatory bowel disease such as ulcerative colitis or Crohn's disease, causes infertility that can be reversed. When the drug is stopped, sperm production will restart. The condition requiring treatment can often be managed with alternative medications, which allows the man to remain fertile.
Many young men who have been treated for cancer (for example Hodgkin's disease) with chemotherapy or radiotherapy in the past now have low or absent sperm production and present to infertility clinics for treatment. In some instances, the sperm cells have been totally destroyed and no treatment is possible. In others, low levels of sperm production are present and sperm can be used successfully in assisted reproductive techniques.
Sperm storage is important if a man is to undergo a medical treatment that may permanently affect sperm production.
Environmental and chemical agents
There is evidence that some environmental and chemical agents, such as pesticides, may cause infertility. One striking example was the pesticide called dibromochloropropane that was used to kill worms in pineapple plantations. The men exposed to this pesticide were found to have a zero sperm count and infertile.
There is much debate about the possible long-term effects of pesticides and other industrial agents, such as some heavy metals and glycol ethers, on male fertility. However since it may take some 25 years for an early exposure to such agents to be identified in adulthood as an infertility disorder, common sense points to the need for further research and the use of caution in the widespread use of such agents.
Anabolic steroids
Men who take anabolic steroids either by mouth or injection for body building and competitive sports, put themselves at risk of infertility because these drugs stop pituitary hormone drive to the testes, which results in a reduced testis size and low sperm count.
Radiation damage
Radiation therapy for cancer can cause damage to the testis, causing permanent problems with sperm production. Radiation therapy is designed to attack and destroy rapidly dividing cells, so the sperm-producing tubes in the testis can easily be damaged. Attempts are made to shield the testis from radiation damage during therapy for cancer, but this is not always possible and radiation treatment can result in permanent infertility. Sometimes radiation damage is temporary and some recovery is possible. Radiation has the potential to cause genetic changes, so it is recommended that men wait at least two years after radiation therapy before attempting to achieve a pregnancy.
Sperm storage is important if a man is to undergo a medical treatment that may permanently affect sperm production
Blockage of sperm transport from the testis
Sperm from the testis must pass through the epididymis and vas deferens on their journey to the ejaculate. Blockage, or obstruction, of sperm transport from the testis can cause a zero sperm count, even though the testis continues to produce sperm. Obstruction in one (unilateral) or both (bilateral) sides may be due to either missing or blocked tubes (ducts). Obstruction may occur at any point from the epididymis up to the ejaculatory ducts in the prostatic urethra.
Obstructions can result from a variety of causes and include:
Congenital absence of the vas deferens
Infection
Vasectomy
Obstructions in region of prostate
Congenital absence of the vas deferens
Absence of the vas deferens prevents sperm from passing from the testis into the ejaculate. When men are born with this condition it is known as congenital absence of the vas deferens and these men are usually missing both their vas deferens and two thirds of their epididymis. In most cases, congenital absence of the vas deferens results from a genetic change or mutation to a gene called the 'cystic fibrosis transmembrane regulator' (CFTR). More complex changes (or mutations) of this CFTR gene have also been found to cause cystic fibrosis, a serious condition causing breathing and bowel problems from early infancy. Men with cystic fibrosis also have congenital absence of the vas deferens. However, infertile men with congenital absence of the vas deferens usually have no significant history of respiratory disease. Men with congenital absence of the vas deferens are now regarded as having an extremely mild form of the cystic fibrosis syndrome.
In men with congenital absence of the vas deferens, it is possible to collect sperm directly from the testis or from the small remaining part of the epididymis and achieve pregnancies using assisted reproductive technologies. Due to the genetic basis of this problem, genetic screening of the man and his partner for mutations in the CFTR gene is essential prior to starting treatment because if both partners have CFTR mutations, then there is a high risk of cystic fibrosis in their children born from assisted reproductive technologies.
Absence of the seminal vesicles usually occurs in association with congenital absence of the vas deferens. The prostate and seminal vesicles contribute approximately 90% of the quantity of the ejaculate, so absence of the seminal vesicles can cause a smaller amount of ejaculate (usually about 0.5 ml, normal men > 2 ml). The seminal vesicles also contribute to making the ejaculate alkaline, so when they are absent the acidity of the ejaculate is increased.
Infection
Infections of the reproductive tract may lead to blockage of sperm transport and preventing sperm from being ejaculated.
Sexually transmitted diseases such as gonorrhoea and chlamydia may result in damage and blockage of the epididymis, preventing sperm from passing from the testis to be ejaculated. Because the testis only contributes a small part of the quantity of the normal ejaculate, blockage at this level does not change the ejaculate volume.
Since the ejaculatory duct passes through the prostate gland, infections of the prostate can cause swelling and block off the ejaculatory duct preventing sperm from being ejaculated. Because the prostate and seminal vesicles contribute the majority of fluid to the ejaculate volume, blockage at this level will reduce the volume of ejaculate. Infections of the prostate and seminal vesicles can also cause inflammatory cells to pass into the ejaculate, which may damage the sperm.
Vasectomy
Vasectomy involves the cutting and removal of a section of the vas deferens, the tube which carries sperm from the testis to the urethra at the base of the bladder. Vasectomy is a safe and effective long-term contraceptive option however about 6% of Australian men who have had a now seek to have the operation reversed in order to father more children.
Evidence does not support long term changes in testosterone levels following vasectomy. However with the passage of time, damage to the sperm producing tubes of the testis may occur. In addition, scarring and blockages in the epididymal tubes can also occur. Sperm antibodies develop in 80% of men who have had a vasectomy. For these reasons, vasectomy reversal surgery is less successful if 10 years have elapsed since the original vasectomy.
Storage of sperm before vasectomy
Vasectomy is a safe and effective contraceptive option however all men should consider it irreversible. Unfortunately life is unpredictable. Young men, particularly those who have never had children, should be dissuaded from vasectomy and seek other methods of contraception. Another option is to consider long-term storage of sperm prior to the vasectomy. Sperm can be stored at very low temperatures while still maintaining a reasonable sperm quality. The knowledge that sperm has been stored for the future insemination of a spouse may be reassuring and a reasonable "insurance policy" for couples considering vasectomy.
Obstructions in region of prostate
Infections of the prostate can cause swelling and blockage of the ejaculatory duct as this duct passes through the prostate gland. Blockage in this region will prevent sperm from being ejaculated.
Occasionally, a man may have a congenital abnormality (a problem they have been born with) in which 'cysts' in the prostate gland have formed. By pressing on the ejaculatory ducts, these cysts can also cause blockage of sperm at this level.
Erection and ejaculation problems
In about 5% of couples, infertility may be caused by problems relating to ejaculation and intercourse. These problems may be caused by:
Damage to nerves causing erection and ejaculation
Erections come about by a stimulus arising in the brain. Impulses are relayed down the spinal cord and then to the penis through nerves leaving the lower part of the spinal cord. Spinal cord injury, diabetes or surgery may cause damage to nerves and prevent erection and ejaculation.
Ejaculation problems
Some men may be unable to obtain or maintain an erection or experience premature or lack of ejaculation.
Prostate surgery
Surgery to the prostate can result in damage to the muscular ring at the base of the bladder, leading to a condition called 'retrograde ejaculation' where the semen flows backwards into the bladder.
Surgery to the nerves in the pelvis
Surgery to the nerves in the pelvis that control the muscular ring at the base of the bladder can also result in retrograde ejaculation. These nerves may be damaged during removal of the prostate gland, as well as in major surgery when parts of the bowel are removed because of cancer and other disorders.
Timing of intercourse
Failure to achieve a pregnancy may also occur due to the lack of appropriate timing of intercourse. Infrequency of intercourse is a common problem in infertile couples.
Medication
Some drugs to treat depression or high blood pressure may cause erection and ejaculation problems.
Unknown cause of infertility
Unfortunately, medical research has not yet uncovered all the details of the sperm production process, so many disorders are therefore classified as 'cause unknown'. Forty percent of men with disorders of sperm production have their condition classified as 'cause unknown' or 'idiopathic'.
As medical research continues, it is likely that genetic causes of infertility will explain a large number of the sperm production disorders now classified as cause unknown. Experiments involving gene changes in mice show that disruption of gene function can result in changes to fertility. Further studies are needed to take this experimental information and look for similarities with human infertility.
Prevention of Male Infertility
Can I do anything to prevent male infertility?Lifestyle
- Cigarette smoking: Some reports suggest that cigarette smoking may have a negative effect on semen quality. However, results of studies are unclear but because of this uncertainty, quitting smoking should be considered.
- Alcohol: Moderate alcohol use (1-2 standard drinks per day) does not appear to have an effect on sperm production. However, excessive alcohol use may cause associated liver problems and a negative effect on health in general.
- Sexually transmitted diseases (STDs): Sexually transmitted diseases such as gonorrhoea and chlamydia may lead to damage and blockage of the epididymis, preventing sperm from passing from the testis into the ejaculate. It is important that treatment of STDs is sought from your doctor immediately to prevent the spread of the disease to your female partner and possible blockages of the male reproductive tract.
- Heat stress: There is ongoing debate about the effect of underwear styles on sperm production, and whether or not looser (cooler) boxer shorts should be preferred over tighter (warmer) briefs. Some research has suggested that wearing tight underwear may decrease sperm counts, although other studies have not found this to be the case. Doctors usually advise patients to reduce the possibility of heat stress on sperm production by avoiding regular hot baths and tight-fitting underwear.
- Vaginal Lubricants: Most vaginal lubricants are toxic to sperm. If couples are trying to conceive, the use of vaginal lubricants should be avoided.
- Cryptochidism: Early treatment of undescended testes before the age of two years is recommended.
All men who are considering chemotherapy or radiotherapy should receive advice from their doctors about fertility issues. It is highly recommended that each man produce a semen sample that can be frozen and stored for future use in case his fertility is permanently affected by chemotherapy or radiotherapy. Frozen sperm can be thawed at a later date and used to artificially inseminate a partner.
Sperm storage for early adolescent patients can be a difficult issue and needs careful and delicate handling. Parents may need to be involved in communicating the fertility issues to their child.
Vasectomy is an effective form of contraception. It should however be considered irreversible. For men planning a vasectomy, it may be advisable to make use of sperm storage techniques before having the operation. This storage would remove the need for vasectomy reversals and other techniques that are used when a man wants to become fertile again after a vasectomy.Specialist reproductive centres providing assisted reproductive technologies usually also offer long-term sperm storage facilities. For more information about long-term sperm storage, contact your nearest specialist reproductive clinic or speak to your specialist.
Diagnosis of Male Infertility
Am I infertile?
Infertility is defined as the failure to achieve a pregnancy after one year of regular (at least twice weekly) unprotected intercourse with the same partner. Both partners should be evaluated for infertility.It is important to see a doctor who can do the necessary investigations to see if there is a reason for you and your partner not being able to fall pregnant.
Diagrammatic representation of causes and diagnosis of male infertility:
Should I see a doctor?
The definition of infertility uses a period of 12 months. But this does not mean that it is wrong to seek medical advice prior to that time. For example, if a couple wishes to get pregnant and is uncertain about intercourse timing or any aspect of the normal reproductive system, then advice should be sought from your local doctor. Some couples will be anxious "that things are not working" after only a few months, and may benefit from talking about their concerns with the local doctor.Clearly if the couple have been trying for a year without success, they should go to their local doctor who can perform some initial tests. Both partners should be evaluated, even if one has already conceived in a previous relationship. In about half the couples seeking assistance, both male and female problems are found to be contributing to the infertility problem.
Treatment of Male Infertility
Deciding on the right treatmentYour doctor will review the findings that he has obtained from talking and examining you, together with the results of the tests that you have undertaken. He will attempt to make a diagnosis and will then assess whether your infertility is due to a treatable cause or whether the cause of your infertility is unknown. Assisted reproductive techniques are available that may still be able to overcome the problem.
In discussing the approach to treatment of your infertility, your doctor should give you an indication of the likelihood of you and your partner conceiving without medical intervention and then should provide you with an indication of the likely success of any treatment options that are being proposed. It is important to realize that you and your partner have the final decision.
As for any medical intervention, there may be risks associated with the type of treatment. It is important to discuss the risks of treatment with your doctor when discussing your treatment options to make the best decision as to your treatment.
Diagrammatic representation of treamtment options for male infertility
Emotional Impact of Male Infertility on Men
How do men respond when told they are infertile?Most men find a diagnosis of infertility to be an unexpected shock. Of course nobody wants such a diagnosis but it seems to be particularly difficult for men. In all of the recent discussions about infertility there is still an assumption that its causes are most likely to be found within women so that when men are told that there is a sperm problem, typically they are quite unprepared. While there are other reactions to male infertility, for most men it comes ‘out of the blue’ and they often don’t have an immediate way of dealing with what they are being told.
It is not unusual for men to feel that they are pretty much alone with this problem and that they can’t easily speak about it to many other people. In this kind of situation men often feel stressed and find it difficult to reduce their stress. This stress comes from feeling some vulnerability because to be told that there is a sperm problem strikes at the core of men’s masculinity. Most infertile men at some time struggle with the idea that now they are not able to do what other men can. Often this leads men to confuse their infertility with their sense of masculinity, sexuality, virility and potency. For example, it is not unusual for these men to experience episodes of erection difficulties while they try to come to terms with their diagnosis.
Infertility is not something that can be discussed with many others. Men with a fertility problem usually rely heavily on their spouses or partners who may be the only people who can be trusted and with whom they can have the kind of deeply personal conversation that might be helpful. However it is also true that for some men their close male relatives or friends are chosen for conversations about the infertility.
There are two other reactions that some men experience. First, some men believe that their most effective response is to immediately find some strategy to solve their infertility problem. To the extent that men feel comfortable taking some action to solve their difficulties, they will try to find something to do, to search for a medical breakthrough that might help or to tackle some physical task.
Second, some men have reason to suspect that there might be something wrong. These men may have had a problem diagnosed in their early life, which they think might mean that they will not be able to be fathers. Examples of this include undescended testes or some childhood infections. These men can experience a feeling of resignation but also frustration and anger that life has not been fair to them.
How do men respond when told they are infertile?
Most men find a diagnosis of infertility to be an unexpected shock. Of course nobody wants such a diagnosis but it seems to be particularly difficult for men. In all of the recent discussions about infertility there is still an assumption that its causes are most likely to be found within women so that when men are told that there is a sperm problem, typically they are quite unprepared. While there are other reactions to male infertility, for most men it comes ‘out of the blue’ and they often don’t have an immediate way of dealing with what they are being told.
It is not unusual for men to feel that they are pretty much alone with this problem and that they can’t easily speak about it to many other people. In this kind of situation men often feel stressed and find it difficult to reduce their stress. This stress comes from feeling some vulnerability because to be told that there is a sperm problem strikes at the core of men’s masculinity. Most infertile men at some time struggle with the idea that now they are not able to do what other men can. Often this leads men to confuse their infertility with their sense of masculinity, sexuality, virility and potency. For example, it is not unusual for these men to experience episodes of erection difficulties while they try to come to terms with their diagnosis.
Infertility is not something that can be discussed with many others. Men with a fertility problem usually rely heavily on their spouses or partners who may be the only people who can be trusted and with whom they can have the kind of deeply personal conversation that might be helpful. However it is also true that for some men their close male relatives or friends are chosen for conversations about the infertility.
There are two other reactions that some men experience. First, some men believe that their most effective response is to immediately find some strategy to solve their infertility problem. To the extent that men feel comfortable taking some action to solve their difficulties, they will try to find something to do, to search for a medical breakthrough that might help or to tackle some physical task.
Second, some men have reason to suspect that there might be something wrong. These men may have had a problem diagnosed in their early life, which they think might mean that they will not be able to be fathers. Examples of this include undescended testes or some childhood infections. These men can experience a feeling of resignation but also frustration and anger that life has not been fair to them.
FEMALE INFERTILITY
Causes of Infertility
Tubal infertility Male infertility Unexplained infertility Egg quantity and quality problems Female age Ovulation disorders Polycystic ovarian syndrome Previous vasectomy Previous tubal ligation Endometriosis Uterine factors Uterine polyps Uterine fibroids Intrauterine adhesions Immune system problems Ectopic pregnancy Pelvic scarring Smoking and fertility
Tubal factor infertility
Tubal factor infertility accounts for about 20-25% of all cases of infertility. This category includes cases in which the woman has completely blocked fallopian tubes and also women who have either one blocked tube or no tubal blockage but tubal scarring or other tubal damage.Tubal factor infertility is usually caused by either pelvic infection, such as pelvic inflammatory disease (PID) or pelvic endometriosis. Sometimes it can be caused by scar tissue that forms after pelvic surgery.
In cases of relatively minor tubal damage it can be difficult to be certain that the infertility problem is solely due to the tubal damage. There may be other significant contributing causes that are resulting in the problem conceiving. In general, the standard infertility testing is performed on all couples and if no other cause of infertility is found, the presumptive diagnosis can be tubal factor. However, if the degree of tubal scarring is very minimal, a diagnosis of unexplained infertility may be warranted.
Pelvic inflammatory disease (PID)
Pelvic inflammatory disease is usually caused by invasion of either gonorrhea or chlamydia from the cervix up to the uterus and tubes. The infection in these tissues causes an intense inflammatory response. Bacteria, white blood cells and other fluids (pus) fill the tubes as the body combats the infection. Eventually, the body wins and the bacteria are controlled and destroyed. However, during the healing process the delicate inner lining of the tubes (tubal mucosa) is permanently scarred. The end of the tube by the ovaries may become partially or completely blocked, and scar tissue often forms on the outside of the tubes and ovaries. All of these factors can impact ovarian or tubal function and the chances for conception in the future. If pelvic inflammatory disease is treated very early and aggressively with IV antibiotics, the tubal damage might be minimized, and fertility maintained.Another problem seen after PID is tubal ectopic pregnancy. The rate of ectopic pregnancy in women with previous known PID is increased 6-10 times higher than in women with no previous history of PID.
A published study of 745 women with one or more episodes of PID that attempted to conceive showed that 16% of the women were infertile from tubal occlusion. Of those that conceived, 6.4% had ectopic pregnancies.
Testing for tubal infertility
HysterosalpingogramThe diagnosis of tubal factor infertility is initially investigated in most cases with a hysterosalpingogram. This is an x-ray examination performed in the radiology department of the hospital in which contrast material (dye) is injected through the cervix to the uterine cavity. If the fallopian tubes are open the dye flows into the tubes and then spills out to the abdominal cavity. This is documented in a series of x-ray images during the procedure.
However, just because the fallopian tubes are found to be open by this "plumbing" test this does not mean that tubal function is normal. The inside lining of the fallopian tube can be severely damaged even though the tube is open and dye spills into the abdominal cavity on the hysterosalpingogram. Open but scarred tubes may not be able to perform the necessary functions to result in establishment of a normal intrauterine pregnancy. Proper tubal function allows egg pickup and transport, fertilization, and subsequent embryo transport from the fallopian tube down into the uterus where the embryo would implant.
If egg pickup, transport, and fertilization occur properly, but the tubal damage does not allow proper transport of the embryo to the uterus, implantation may occur in the tube resulting in a tubal pregnancy.
Other methods of detecting tubal damage
Laparoscopy can be performed to diagnose tubal damage other than complete tubal blockage.
Tubal catheterization utilizing a special scope can also be done to assess the status of the mucosal lining of the inside of the tubes.
Treatment of tubal factor infertility
The treatment for tubal factor infertility is usually either tubal surgery to repair some of the damage or in vitro fertilization (IVF).Pros and cons of surgery versus IVF
The decision to have one of these therapies for tubal infertility should be based on several factors which your reproductive endocrinologist should discuss with you. The most significant issues are the degree of tubal damage, the age of the female, and whether other infertility factors (male or female) are present. Medical insurance issues, economic considerations and success rates with the 2 approaches are also very important.
In vitro fertilization for tubal infertility
In vitro fertilization is a treatment option that bypasses the tubal problem instead of attempting a repair.
With in vitro fertilization, sperm and eggs are mixed together in the laboratory and then the resulting embryos are transferred to the woman's uterus. Pregnancy rates with in vitro fertilization for tubal factor infertility in women under 40 years old are usually relatively good because these women are relatively unlikely to have additional infertility problems.
Infertility due to ovulation problems
Anovulation - "Egg release" disorders
Background
Some women do not properly develop and release a mature egg every month as they should normally. We call this condition anovulation.Some women never develop and release an egg without medication - we say that these women are anovulatory. These women will have no menstrual periods for several months or years at a time. The medical term for this is amenorrhea. Often, when they do have a period it is quite heavy. In some cases, the woman may even require medical attention because of the degree of blood loss.
Some women ovulate once or twice a year and need medication to stimulate egg development to occur in every menstrual cycle to increase the chance for pregnancy.
Diagnostic testing for ovulation disorders
Usually the doctor can tell from discussing the details regarding previous menstrual cycles whether there is likely to be an ovulation disorder. In addition, blood testing at various times of the menstrual cycle and sometimes an ultrasound study of the ovaries can clarify whether ovulation is occurring.Polycystic ovarian syndrome is a very common cause of anovulation and infertility. When it is suspected, additional testing may be indicated.
Treatment for ovulation disorders and pregnancy rates for women with ovulation disorders are discussed on the Induction of ovulation section.
Infertility and Endometriosis
Background
The endometrium is the tissue that lines the inside of the uterine cavity. Endometriosis is a disease state in which some of this tissue has spread elsewhere - such as to the ovaries, or elsewhere in the abdominal cavity.Endometriosis causes pain in some women and can also cause infertility.
5-10% of all women have endometriosis. Most of these women are not infertile.
30-40% of infertile women have endometriosis.
Diagnosis of endometriosis
The only way to be sure whether a woman has endometriosis is to perform a surgical procedure called laparoscopy that allows us look inside the abdominal cavity with a narrow scope.Sometimes we strongly suspect that the disease is present based on the woman's history of very painful menstrual cycles, painful intercourse, etc., or based on the physical examination of the woman or ultrasound findings.
Mild endometriosis
The large majority of cases of endometriosis are mild.Women with any stage of endometriosis (mild, moderate, or severe) can have severe lower abdominal and pelvic pain - or they might have no pain or symptoms whatsoever.
Although mild endometriosis is associated with infertility in some women, many fertile women also have mild endometriosis. A cause and effect relationship between mild endometriosis and infertility has not been established. It might be that infertility and delayed pregnancy predisposes women to developing endometriosis, rather than the endometriosis causing the infertility.
Therefore, some experts consider infertility associated with mild endometriosis to really be "unexplained infertility".
Severe endometriosis
Severe endometriosis causes pelvic scarring and distortion of pelvic anatomy. The tubes can become damaged or blocked and the ovaries often contain cysts of endometriosis (endometriomas) and may become adherent to the uterus, bowel or pelvic side wall. Any of these anatomic distortions can result in infertility.In some cases the eggs in the ovaries can be damaged, resulting in decreased ovarian reserve and reduced egg quantity and quality.
Treatment of endometriosis
Treatment for endometriosis associated with infertility needs to be individualized for each woman. There are no easy answers, and treatment decisions depend on factors such as the severity of the disease and its location in the pelvis, the age of the woman, length of infertility, and the presence of pain or other symptoms. Some general issues regarding treatment are discussed here:Treatment for mild endometriosis
Medical (drug) treatment can suppress endometriosis and relieve the associated pain in many women. Surgical removal of lesions by laparoscopy might also reduce the pain temporarily.
However, several well-controlled studies have shown that neither medical or surgical treatment for mild endometriosis will improve pregnancy rates for infertile women as compared to expectant management (no treatment). There are a few more recent studies that did show a benefit to surgical treatment of mild endometriosis. This is interesting because previous studies have shown no benefit.
For treatment of the infertility associated with mild to moderate endometriosis, controlled ovarian hyperstimulation with intrauterine insemination is often attempted and has a reasonable chance to result in pregnancy if other infertility factors are not present.
If this is not effective after about 6 cycles (maximum), then in vitro fertilization should be considered.
Treatment for severe endometriosis
Several studies have shown that medical treatment for severe endometriosis does not improve pregnancy rates for infertile women.
Some studies have shown that surgical treatment of severe endometriosis does improve the chances for pregnancy as compared to no treatment. However, pregnancy rates remain low after surgery - some studies have reported pregnancy rates of 1.5-2% per month.
Some physicians advocate medical suppression with a GnRH-agonist such as Lupron, Synarel, or Zoladex for up to 6 months after surgery for severe endometriosis before attempting conception. Although at least one published study found this to improve pregnancy rates as compared to surgery alone, other studies have shown it to be of no benefit. This is one of many issues regarding endometriosis that there is not universal agreement about among infertility specialists.
Unfortunately, the infertility in women with severe endometriosis is often resistant to treatment with ovarian stimulation plus intrauterine insemination. If the pelvic anatomy is very distorted, insemination would probably be futile. These women will often require in vitro fertilization in order to conceive.
Although the studies of in vitro fertilization for women with severe endometriosis do not all show similar results, pregnancy rates are usually good if the woman is relatively young (under 40) and if she produces enough eggs during the ovarian stimulation.
Ovarian reserve tests -
evaluation of egg quantity and quality and quantity
Background
Female age is very important in consideration of probability for conception because it is very much related to egg quantity and quality.A 45 year old can have good quality eggs (for her age) and still be fertile, although this is quite uncommon. At the other extreme, a 25 year old can have very poor quality eggs and be infertile - unless she uses donor eggs. These are extreme examples, but the point is that egg quantity and quality tends to decline significantly in the 30s and faster in the early 40s, but egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average.
It would be nice to have a reliable test to determine how good the eggs are in an individual woman at a point in time. We do have some screening tests, however, they are far from perfect. These tests are often referred to as tests of "ovarian reserve". In other words, does the woman have a good reserve of high quality eggs remaining in her ovaries?
Day 3 FSH (follicle stimulating hormone) and estradiol (E2) test
By measuring a baseline FSH on day 3 of the cycle, we can sometimes get an indication that the women is closer to menopause and has relatively less "ovarian reserve". Another way of saying this is that if the baseline FSH is elevated her quantity of eggs remaining for the future is reduced.
Clomiphene challenge test
A clomiphene challenge test is a dynamic type of test that can discover some cases of poor ovarian reserve that are still showing a normal day 3 FSH. It is discussed on the day 3 FSH page.
Response of the ovaries to ovarian stimulation with injectable gonadotropins (FSH)
This is not really a "test" that we do to help us determine egg quantity and quality - it is part of a treatment for infertility. However, the response of the ovaries when the woman takes injectable FSH for stimulation is often very predictive of the egg quantity - and therefore, also the relative chances for success with infertility treatment.Response to stimulation and antral follicle counts are important predictors of outcome, and are discussed in detail on another page.
Other provocative tests of ovarian reserve
We can also challenge the ovaries with drugs (hormones) and assess whether they have responded appropriately in order to distinguish women with good ovarian reserve from women with diminished reserve.For example, the exogenous FSH ovarian reserve test involves giving an FSH injection on day 3 of the cycle and testing both the baseline FSH and baseline and 24 hour post-injection estradiol to see if a normal response has resulted.
If the estradiol response is poor, ovarian reserve and egg quantity are also likely to be poor. The woman is also less likely to be a "normal responder" to gonadotropin stimulation.
In vitro fertilization
This is a treatment for infertility, but at the same time it can give us much useful information about egg and embryo quality. By careful examination of the eggs and embryos during the in vitro incubation process we sometimes get clues about why pregnancy has not occurred previously.For example, the eggs may demonstrate poor morphology, or may have problems with maturation, or with fertilization, proper cleavage, etc...
Treatment options for women with reduced ovarian reserve
In vitro fertilizationLupron "flare" protocol for ovarian stimulation in low responders
In vitro fertilization with assisted hatching
In vitro fertilization with coculture
In vitro fertilization with donor eggs
Infertility and Age
Background
Female age is very important in consideration of probability for conception. The real issue is egg quantity and quality - which translates over to embryo quality after fertilization.The age of the male partner does not appear to matter nearly as much. Sperm from older men does not usually have a substantially reduced fertilizing potential as compared to sperm from younger men. However, older men often have less interest in frequent intercourse, which can be a factor in chances for conception.
Many people are not aware of the decline in fertility as the age of the female partner increases:
There is a slow decline in pregnancy rates in the early 30's. This decline is more substantial in the late 30's and early 40's. Few women over 45 are still fertile.
Miscarriage rates also increase substantially as the mother ages (more on miscarriage below).
One important caveat is that the above numbers apply to populations, not individuals. A given woman can have rapid decline in egg quantity and quality at an early age - even in her teens or twenties in rare cases.
A study published in 1957 examined the relationship between the age of the female partner and fertility. This study found that:
By age 30, 7% of couples were infertile
By age 35, 11% of couples were infertile
By age 40, 33% of couples were infertile
At age 45, 87% of couples were infertile
Reference: Tietze C: Reproductive span and rate of conception among Hutterite women. Fertility and Sterility 1957;8:89-97.
For several reasons, infertility rates are even higher in the general population in the U.S. today than for the population studied by Tietze in the 1950s.
The diagram below is from the 2002 ART Success Rates report published by the CDC (Centers for Disease Control and Prevention) in Atlanta Georgia.
This report was generated from national data from hundreds of clinics and many thousands of IVF cycles. It shows the rate of live births per embryo transfer procedure by the age of the recipient of the embryos. The blue line shows data using the infertile woman's own eggs for IVF, while the black line shows IVF data from using donor eggs.
This chart is very useful in illustrating the decline in live birth rates by female age beginning at about age 30-31. This curve becomes steeper (egg quantity and quality decreasing at a faster rate) starting at about age 37-38. It is very important to remember that each data point on the curve below represents an average live birth rate from many cases. Every couple is unique and could be more fertile, or less fertile as compared to the average for their age.
Another interesting point that is illustrated here is that there is no decline in live birth rates by age of recipient when donor egg IVF is being utilized. In other words, the age of the eggs is very important, but the age of the uterus is not.
Tests to determine whether "age" is a significant factor in an individual couple
"Age" is in quotes here because the real issue is oocyte (egg) quality and not the number in a woman's age.A woman can be 45 with exceptionally good quality eggs and still be fertile, or, she can be 25 with very poor quality eggs and be infertile. These are extreme examples, but the point is that egg quantity and quality tends to decline significantly in the late 30s and faster in the early 40s, but egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average.
It would be nice to have a reliable test to determine how good the eggs are in an individual woman at a point in time. We do have some screening tests for ovarian reserve, however, they are far from perfect. Day 3 FSH testing and antral follicle counts are tests used by infertility specialists to help predict ovarian reserve.
Many infertility specialists recommend that women over about 38 that are infertile should have aggressive treatment and proceed to in vitro fertilization relatively quickly - before all fertility potential is lost.
Miscarriage and female age
Numerous studies have documented the increased risk for miscarriage as women get older. The following table is a summary of information from several studies:
Maternal age
|
Loss rate
|
< 30
|
5%
|
30-34
|
7%
|
35-39
|
15%
|
40-41
|
25%
|
42-43
|
35%
|
44-46
|
50%
|
We do not know exactly why there is an increase in chromosomal abnormalities in the eggs of women as they age. However, research studies have clarified some of the issues involved.
The meiotic spindle is a critical component of eggs that is involved in organizing the chromosome pairs so that a proper division of the pairs can occur as the egg is developing. An abnormal spindle can predispose to development of chromosomally abnormal eggs.
A study published in the medical journal "Human Reproduction" in October of 1996 investigated the influence of maternal age on meiotic spindle assembly in human eggs:D.E. Battaglia, et al: Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Human Reproduction October, 1996; (Vol. 11): Pages 2217-2222.
In this research project, 17% of the eggs studied from women 20-25 years old were found to have an abnormal spindle appearance and at least one chromosome displaced from proper alignment.
In contrast, 79% of the eggs studied from women 40-45 years old were found to have an abnormal spindle appearance and at least one chromosome displaced from proper alignment.
This study illustrates how chromosomally abnormal eggs (and therefore, embryos) are produced more often in older women. When the chromosomes line up properly in a straight line on the spindle apparatus in the egg, the division process would be expected to proceed normally so that the egg would end up with its proper complement of 23 chromosomes. However, with a disordered arrangement on an abnormal spindle, the division could easily be uneven - resulting in an unbalanced chromosomal situation in the egg.
This is illustrated in the drawing below, which is based on the confocal fluorescence microscopy images of eggs stained with special dyes to show the spindles and chromosomes. The excellent article (referenced above) shows the actual images and has a thorough discussion of this topic.
 |  |
| NormalChromosomes line up in straight line on spindle | AbnormalChromosomes line up erratically |
The bottom line of all of this is that as women get older the incidence of chromosomally abnormal eggs increases dramatically. This results in lower chances for conception, as well as increased risk for miscarriage. When moms are 35 or older, amniocentesis is recommended to test the baby's chromosomes because of the increased risk of a chromosomally abnormal child (e.g. Down Syndrome).
Uterine problems causing infertility or miscarriage
A (fairly) normal uterine cavity and endometrial lining are necessary in order to conceive and maintain a pregnancy. There are several conditions related to the cavity or the lining that can cause problems.
When a woman has her menses (period) the endometrial lining of the uterus and some associated blood is shed. Then a new lining is regenerated over the next few weeks or so and eventually becomes receptive to possible implantation of an embryo. If no embryo implants (she is not pregnant) her body recognizes that she is not pregnant at the end of that menstrual cycle and it sheds the lining and starts the regeneration process over again.
Problems of the uterus and uterine lining that can cause or contribute to reproductive problems such as infertility or recurrent miscarriage:
- Uterine Polyps
- Uterine Fibroids (proper medical terminology is myoma or leiomyoma)
- Intrauterine adhesions - scar tissue within the uterine cavity, also called Asherman's Syndrome. This can interfere with conception, or can increase the risk of a miscarriage.
- Congenital uterine malformations, such as a bicornuate uterus, a T-shaped uterus, or a uterine septum
- Luteal phase defect - an uncommon condition that involves inadequate development of the microscopic and cellular changes in the endometrial lining of the uterus after ovulation and exposure to the hormone progesterone.
- Thin endometrial lining - this is also uncommon. We like to see a lining of at least 8mm in thickness when measured by ultrasound at the time of maximal thickness during the cycle (see above ultrasound images of an 11.5 mm lining). There is some ongoing debate as to "how thin is too thin", as well as to "how thick is too thick". In general, 8-13 mm is good, less than 6 is potentially a problem, and greater than 15 or so could possibly reduce chances for a successful pregnancy.
Uterine septum
A septate uterus can cause reproductive problems such as miscarriage, preterm labor or preterm labor and birth.A septum in the uterus is like extra muscle "pushing down" from the top into the cavity.
Pelvic scarring, pelvic and tubal adhesions and pelvic factor infertility
Background
Pelvic factor infertility accounts for about 25% of all cases of infertility.This category includes cases in which the woman has difficulty conceiving and:
- completely blocked fallopian tubes - tubal factor infertility
- one blocked tube and one open tube
- tubal scarring (internal or external) or other tubal damage
- endometriosis causing infertility
- scar tissue or adhesions in the area of the tubes, ovaries or uterus
In cases with very minor scar tissue, it is not possible to be certain that this is the cause of the infertility problem. In general, the standard infertility testing is performed on all couples and if no other infertility causes are found, the presumptive diagnosis can be pelvic factor. However, if the degree of scarring is very minimal, a diagnosis of unexplained infertility may be more appropriate.
Testing for pelvic infertility
Treatment options for infertility caused by scar tissue, and pelvic or tubal adhesions
Ultrasound
Pelvic ultrasound can sometimes give us evidence of pelvic scarring and tubal damage. We can see blocked tubes that are full of fluid - called a hydrosalpinx (plural is hydrosalpinges). At times we can see that the ovary is fixed in an abnormal location, which indicates adhesions that have glued it in place.The diagnosis of pelvic factor infertility can be made sometimes with a hysterosalpingogram. This is an x-ray examination performed in the radiology department of the hospital in which contrast material (dye) is injected through the cervix to the uterine cavity. If the fallopian tubes are open the dye flows into the tubes and then spills out to the abdominal cavity. This is documented in a series of x-ray images during the procedure.
Open but scarred tubes may not be able to perform the necessary functions to result in establishment of a normal intrauterine pregnancy. Proper tubal function allows egg pickup and transport, fertilization, and subsequent embryo transport from the fallopian tube down into the uterus where the embryo would implant.
If egg pickup, transport, and fertilization occur properly, but the internal tubal damage does not allow proper transport of the embryo to the uterus, implantation may occur in the tube resulting in a tubal pregnancy.
can be performed to look for pelvic scar tissue and endometriosis
Treatment of pelvic factor infertility
The treatment is usually either tubal surgery to repair some of the damage, or ovarian stimulation with intrauterine insemination, or in vitro fertilization (IVF) - depending on the degree of pelvic damage and the wishes of the woman. The decision as to what treatment is most appropriate for the couple requires a detailed discussion with the Reproductive Endocrinology and Infertility specialist of the risks and benefits of the available options in that particular couple's situation.
In vitro fertilization for pelvic factor infertility
In vitro fertilization is a treatment option that bypasses the pelvic problem instead of attempting repair.With IVF, sperm and eggs are mixed together in the laboratory and then the resulting embryos are transferred to the woman's uterus.
Pregnancy rates with in vitro fertilization for pelvic factor infertility in women under 40 years old are usually relatively good because these women are relatively unlikely to have additional infertility problems.
Unexplained Infertility
Background
Unexplained infertility (also called idiopathic infertility) cases are those in which standard infertility testing has not found a cause for the failure to conceive. The definition of what "standard testing" consists of is not agreed upon by all experts.Various studies have reported that 0-26% of infertile couples have unexplained infertility. The most commonly reported figures are between 10-20% of infertile couples.
In reality, there are hundreds (thousands ??) of "causes" of infertility. What I mean by this is that there are a lot of things that have to happen perfectly in order to conceive and have a baby. As a simplified example:
- The hormones that stimulate egg development must be made in the brain and released properly
- The egg must be of sufficient quality and be chromosomally normal
- The egg must develop to maturity
- The brain must release a sufficient surge of the LH hormone to stimulate final maturation of the egg
- The follicle (eggs develop in structures called follicles in the ovaries) must rupture and release the follicular fluid and the egg
- The tube must "pick up" the egg
- The sperm must survive their brief visit to the vagina, enter the cervical mucous, swim to the fallopian tube and "find" the egg
- The sperm must be able to get through the cumulus cells around the egg and bind the shell (zona pellucida) of the egg
- The sperm must undergo a biochemical reaction and release their DNA package (23 chromosomes) into the egg
- The fertilized egg must be able to divide
- The early embryo must continue to divide and develop normally
- After 3 days, the tube should have transported the embryo into the uterus
- The embryo must develop into a blastocyst
- The blastocyst must hatch from its shell
- The endometrial lining of the uterus must be properly developed and receptive
- The hatched blastocyst must attach to the endometrial lining and "implant"
- Many more miracles in early embryonic and fetal development must then follow...
A weak link anywhere in this chain can cause failure to conceive
The above list is very oversimplified, but the point is made. There are literally hundreds of molecular and biochemical events that have to function properly in order to have a pregnancy develop. The standard tests for infertility barely scratch the surface and are really only looking for very obvious factors, such as blocked tubes, abnormal sperm counts, ovulation regularity, etc. These tests do not address the molecular issues at all. That is still for the future...The likelihood of a diagnosis of unexplained infertility is increased substantially in women 35 and over - and greatly increased in women over 38. The reason for this is that there are more likely to be egg quantity and quality problems as women age. Since we do not have a "standard category" called egg factor infertility, these couples sometimes get lumped in to the "unexplained" infertility category.
Some experts would also consider infertility associated with mild endometriosis to be in the "unexplained" category. This is because a cause and effect relationship has not been established betweenmild endometriosis and infertility.
Prognosis for untreated couples with unexplained infertility
The duration of infertility is important:The longer the infertility, the less likely the couple is to conceive on their own. After 5 years of infertility, a couple with unexplained infertility has less than a 10% chance for success on their own.
One study showed that for couples with unexplained infertility of over 3 years duration, the cumulative conception rate after 24 months of attempting conception without any treatment was 28%. This number was found to be reduced by 10% for each year that the female is over 31.
Treatment for unexplained infertility
Ovarian stimulation and/or intrauterine inseminationIntrauterine insemination vs. timed intercourse
This has been studied and a slight improvement found for insemination. However, the difference was not large enough to be statistically significant.
Clomiphene citrate
3-6 months of treatment might improve fertility by as much as 2 times as compared to no treatment. This is a very low level infertility treatment. Infertility specialists do not usually recommend this level of treatment for women over the age of 35-37. Some do not use it on any couples with unexplained infertility.
Injectable gonadotropins plus intrauterine insemination
Several studies showed improved pregnancy rates with this treatment as compared to no treatment.
Injectable gonadotropins plus intercourse
This is less extensively studied. It is not yet known whether the ovarian stimulation and the insemination have independent beneficial effects or whether their beneficial effects are only seen when they are used in combination.
Assisted reproductive technologies as treatment for unexplained infertility
In vitro fertilization (IVF) has high success in young women with normal ovarian reserve testing and unexplained infertility.
Polycystic ovaries and anovulation cause female infertility
Background
Polycystic ovarian syndrome is a common cause of anovulation and infertility in women. Women with this syndrome do not ovulate regularly and have ovaries that contain multiple small cystic structures, usually about 2-9 mm in diameter. This gives the ovaries a characteristic "polycystic" (many cysts) appearance on ultrasound - see images below.Polycystic ovarian syndrome causes irregularities in the menstrual cycle, and sometimes a total lack of periods - amenorrhea.
The basic problem is that although the polycystic ovaries contain many follicles with eggs, the follicles do not develop and mature properly so that they do not ovulate. Women without polycystic ovaries normally develop one mature follicle each month which ovulates (releases) one egg.
Women with polycystic ovaries are often hyperandrogenic as well. This means that their ovaries produce an excess amount of male hormones testosterone and androstenedione which can cause increased hair growth - hirsutism, and sometimes other problems as well.
The typical story seen in women with polycystic ovaries is irregular menstrual cycles, onset of hirsutism in the teens or early 20s, and gradually worsening excess hair growth.
When they attempt to get pregnant, women with polycystic ovaries will usually have difficulty. Some women with this disorder will ovulate (release a mature egg) occasionally, others do not ovulate at all. In order to conceive, sperm must be able to find and fertilize a mature egg. Therefore, they will usually need to undergo induction of ovulation to get pregnant.
The good news is that pregnancy rates are high for women with this condition. The large majority will be able to have a baby, if they will undergo treatment. Details about use of the medications mentioned below are on the induction of ovulation page.
Many will be able to get pregnant using clomiphene citrate tablets to induce ovulation. This is often given by general gynecologists. About 75% of women with polycystic ovaries will ovulate with clomiphene, but only about 40% will get pregnant with it.
If this fails after about 6-9 ovulatory cycles, the next step is usually injectable gonadotropins. About 90% of women that do not ovulate with clomiphene will ovulate with this medication. The majority will get pregnant as well.
If this fails after about 3-6 ovulatory cycles, the next step is usually in vitro fertilization. The majority of women with polycystic ovaries that have not gotten pregnant with the above treatments will conceive with IVF.
A relatively new method of inducing ovulation in women with polycystic ovarian syndrome is to use oral medications such as metformin in conjunction with clomiphene citrate. Metformin has been used in the past as an oral agent to help control diabetes. Recently, it has been found to facilitate ovulation in some women with PCOS. The medication can have side effects and proper monitoring must be performed. We are currently offering this treatment to appropriate candidates.
Infertility associated with immunological problems
This area is very controversial and infertility "experts" do not agree on many related issues. Immunological problems are associated with some recurrent miscarriage cases, but a cause and effect relationship with infertility remains to be proven. This area is very controversial and infertility "experts" do not agree on many related issues. Immunological problems are associated with some recurrent miscarriage cases, but a cause and effect relationship with infertility remains to be proven. This area is very controversial and infertility "experts" do not agree on many related issues. Immunological problems are associated with some recurrent miscarriage cases, but a cause and effect relationship with infertility remains to be proven.Infertility article review and discussion
Title: Antiphospholipid antibodies and pregnancy rates and outcome in in vitro fertilization patientsAuthors: A. Denis, M. Guido, R. Adler, P. Bergh, C. Brenner, R. Scott, Jr.
Source: Fertility and Sterility: June, 1997 (Vol. 67) Pages 1084-1090.
Background
The relationship between "antibodies" and infertility and miscarriage is very controversial. There are some experts who believe that the presence of antiphospholipid antibodies in a woman may cause problems with conception, or may predispose to miscarriage.One of the problems is that there are many healthy, fertile women with no infertility or miscarriages that have elevated levels of some of the same antibodies that are purported to cause problems with conception and/or miscarriage.
This study tried to determine whether there was any relationship between the level of various antiphospholipid antibodies and outcome for in vitro fertilization (IVF). They looked at both initial pregnancy rates as well as miscarriage rates.
In other words:
- Does the presence of these antibodies cause a lower chance for pregnancy from IVF?
- Does the presence of these antibodies cause an increased chance for miscarriage in a pregnancy from IVF?
How the study was done
This study was performed by drawing and freezing blood from 793 women having IVF at one center. Women with a history of recurrent pregnancy loss were excluded from the study.After all of the IVF cycles were completed, the blood was assayed for levels of 21 different antibodies. In this way, the results of the assays could not influence treatment decisions for the IVF cycle.
No "immunity-related" treatments were used: no women were given glucocorticoids (e.g. Prednisone), aspirin, heparin, or immunoglobulin (Ig) therapy.
Pregnancy and miscarriage rates were then compared according to the antibody status of the women to determine if any relationship existed between antibody levels and IVF outcome.
Results
There was no difference in pregnancy rates according to the antibody status.There was no difference in miscarriage rates according to the antibody status.
In other words, the pregnancy rates for the 323 women with no antibodies detected was not different from the 470 women with positive tests for at least 1 of the antibodies. Also, the pregnancy rate was not different according to how many antibodies were detected in the woman - even for those women having 5 or more positive results.
The same was seen for miscarriage and delivery rates.
Conclusion:
The authors concluded that "there is no relationship between antiphospholipid antibody levels and clinical pregnancy rates or pregnancy loss rates".They further stated that "the clear lack of a relationship between these antibodies and reproductive outcome suggests that patients should not be treated based solely on the results of these assays. The expense and risks associated with the various agents used to treat this 'disorder' cannot be justified by the presence of an antibody that does not predict or compromise outcome".
Comments about the study
This is a much-needed study in the field of reproductive medicine. As the authors of this article point out, although some programs are testing for antibodies and "treating" according to the results, there have not yet been well-controlled trials of treatment for "immune-related" infertility. Such research is needed.Smoking Tobacco and Fertility and Infertility
There are many known causes of infertility. Some are more absolute than others. For example, if a woman has blocked fallopian tubes, or a man has a very low sperm count or motility, then we know the cause of the couples infertility problem (or at least one of the causes). However, there are other fertility issues that are difficult to characterize as "the problem" - but we know that often they are at least factors contributing to the infertility.This page is not meant to be a complete discussion of this issue. However, here are some general comments about our knowledge of the relationship between female tobacco smoking and reproduction:
- Over 20 published studies in the medical literature have detailed the adverse effects of tobacco smoking on fertility
- Tobacco smoke contains several hundred substances, many of which are toxic
- A study done in mice showed that nicotine had disruptive effects on egg maturation, ovulation rates, and fertilization rates. The study also showed more chromosomal abnormalities in the eggs exposed to nicotine.
- Ovarian reserve and egg quantity and quality are reduced in women who smoke
- Smokers have lower numbers of follicles when stimulated for in vitro fertilization
- Smokers have lower numbers of eggs retrieved with in vitro fertilization
- Smokers have lower rates of fertilization of the eggs with in vitro fertilization
- Smokers have increased rates of miscarriage with in vitro fertilization pregnancies
- One study showed that the chance for an IVF pregnancy was 2.7 times higher for women who have never smoked as compared to women that do (or have previously). The same study showed that if the woman smoked for over 5 years, the risk was increased to 4.8
- There is also some evidence that male smoking decreases success rates with IVF. It is not known whether this effect would be caused directly by the sperm, or whether it represents a negative effect on the egg and embryo quality through passive exposure (second hand exposure).
Infertility Testing
| Basic infertility evaluation | Day 3 FSH testing |
| Hysterosalpingogram | Antral follicle counts |
| Egg quantity and quality tests | Laparoscopy for infertility |
| Male fertility tests | Hysteroscopy for infertility |
Basic infertility evaluation
What should be included in the initial infertility evaluation?
History
The doctor will ask questions about your past to try to get clues as to the cause of your infertility. These questions will be regarding your medical, surgical, gynecological, and obstetric history, as well as some "lifestyle" questions.A review of fertility-related records from other doctors that you have seen is also important.
Physical exam
A directed physical exam that may include a pelvic ultrasound should be performed. Ultrasound can help us discover abnormalities with the uterus, fallopian tubes and/or ovaries. We can sometimes see evidence of pelvic scarring, such as when an ovary appears to be stuck to the uterus. We can also get some information regarding the woman's potential for adequate ovarian stimulation for infertility treatment cycles by counting antral follicles.
Assessment of ovarian reserve
This is a very important assessment of a woman's remaining egg supply. It is generally done with day 3 FSH and estradiol testing and a vaginal ultrasound assessment of ovarian volume and antral follicle counts.
Assessment of adequacy of ovulation
This can be done in a variety of ways.About 25% of all infertility is caused by an ovulation disorder. One type of ovulation problem, polycystic ovarian syndrome, is usually quite amenable to treatment with medications.
Semen analysis
This is a very important test and should be done early in the evaluation process. If a severe sperm defect is discovered, the testing on the female partner might be modified, and therapy can be immediately directed to the problem.About 25% of all infertility is caused by a sperm defect and 40-50% of infertility cases have a sperm defect as the main cause, or a contributing cause.
Blood tests
Depending on the individual couple's situation, various blood tests on either the female or the male may be needed.Blood tests that might be needed include day 3 follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone (T), estradiol (E2), progesterone (P4), 17-hydroxyprogesterone (17-OHP), thyroxin (T4), thyroid stimulating hormone (TSH), lupus anticoagulant (LAC), anti-cardiolipin (ACL), and possibly other tests
Immunological testing has not been proven to have any value in infertility patients without a history of 2 or more miscarriages.
Hysterosalpingogram (HSG)
This test is done in order to assess the anatomy of the endometrial cavity of the uterus and the fallopian tubes. The HSG is usually scheduled to be done between days 6 and 13 of the cycle - this also depends on the specifics of the woman's normal cycle.This test is usually performed in the radiology department of a hospital.
About 25% of all infertility is due to a tubal factor.
Laparoscopy
This is a surgical procedure and should not be performed until the basic testing has been done on both partners. In some cases, laparoscopy will be indicated to look for pelvic scarring or endometriosis
Hysterosalpingogram (HSG)
What is a hysterosalpingogram?A hysterosalpingogram is an important test that is part of the basic infertility evaluation.
The test is usually done in the radiology department of a hospital in which radiographic contrast (dye) is injected into the uterine cavity through the vagina and cervix. The uterine cavity fills with dye and if the fallopian tubes are open the dye will then fill the tubes and spill out into the abdominal cavity. In this way it can be determined whether the fallopian tubes are open or blocked and whether the blockage is located at the junction of the tube and the uterus (proximal) or whether it is at the end of the fallopian tube (distal). These two areas where the tube is most commonly blocked have different causes. Effective treatment for tubal factor infertility is available.
There are other things that potentially can be seen on a hysterosalpingogram other that whether the tubes are open or blocked. The uterine cavity is evaluated for the presence of polyps or fibroid tumors or scar tissue. The fallopian tubes are also examined for any defects within the tube or suggestion of a partial blockage.
What to expect during a hysterosalpingogram
The hysterosalpingogram study only takes about 5 minutes to actually perform. However as the test is usually done in the radiology department of a hospital there is additional time for the woman to register at the facility and fill out a questionnaire and answer some questions regarding allergies to medication etc. The way the test is done is the following:
- The woman lies on the table on her back and brings her feet up into a "frog leg" position.
- The doctor places a speculum in the vagina and visualizes the cervix.
- Either a soft, thin catheter is placed through the cervical opening into the uterine cavity or an instrument called a tenaculum is placed on the cervix and then a narrow metal cannula is inserted through the cervical opening.
- Contrast is slowly injected through the cannula or catheter into the uterine cavity. An x-ray picture is taken as the uterine cavity is filling and then additional contrast is injected so that the tubes should fill and begin to spill into the abdominal cavity. Additional x-rays are taken as this "fill and spill" occurs.
- When both tubes are demonstrated to be patent (or blocked), the woman is usually asked to roll to one side or the other slightly to give a slightly oblique x-ray image which may help to further delineate her anatomy.
- The procedure is now complete. The instruments are removed from the cervix and vagina. The woman usually remains on the table for several minutes to recover from the cramping which usually accompanies injection of the contrast.
- After several minutes the woman can get dressed and leave the hospital.
Pregnancy rates in several studies have been reported to be slightly increased in the first months following a hysterosalpingogram. This may be due to the fact that the flushing of the tubes with the contrast could open a minor blockage or clean out some debris that may be a factor that is preventing the couple from conceiving. Some of these studies suggest that using oil based contrast provides a greater increase in pregnancy rates after a hysterosalpingogram than does the use of water based contrast.
Complications
Complications associated with a hysterosalpingogram include the possibility of an allergic reaction to the dye, which is uncommon. This usually manifests as a rash, but can rarely be more serious.
Pelvic infection or uterine perforation are also possible complications. Both of these are very uncommon.
If a woman has multiple sexual partners or is otherwise at risk for sexually transmitted diseases, she should be screened with cervical cultures before doing an HSG. Some physicians prescribe several days of antibiotics for their patients to attempt to reduce the risk of infection after HSG.
HSG showing multiple "filling defects" in uterine cavity
These represent numerous endometrial polyps
The polyps were then removed by hysteroscopic resection
These represent numerous endometrial polyps
The polyps were then removed by hysteroscopic resection
HSG showing a normal uterus and blocked tubes
No "spill" of dye is seen at the ends of the tubes
This woman then had successful in vitro fertilization
No "spill" of dye is seen at the ends of the tubes
This woman then had successful in vitro fertilization
Ovarian reserve tests - evaluation of egg quantity and quality
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Background
Female age is very important in consideration of probability for conception because it is very much related to egg quality.A 45 year old can have good quality eggs (for her age) and still be fertile, although this is quite uncommon. At the other extreme, a 25 year old can have very poor quality eggs and be infertile - unless she uses donor eggs. These are extreme examples, but the point is that egg quantity and quality tends to decline significantly in the 30s and faster in the early 40s, but egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average.
It would be nice to have a reliable test to determine how many eggs remain and how good the eggs are in an individual woman at a point in time. We do have some screening tests, however, they are far from perfect. These tests are often referred to as tests of "ovarian reserve". In other words, does the woman have a good number (reserve) of good quality eggs remaining in her ovaries?
Day 3 FSH (follicle stimulating hormone) and estradiol (E2) test
By measuring a baseline FSH on day 3 of the cycle, we can sometimes get an indication that the women is closer to menopause and has relatively less "ovarian reserve". Another way of saying this is that if the baseline FSH is elevated the egg quantity is reduced from what is expected.
Clomiphene challenge test
A clomiphene challenge test is a dynamic type of test that can discover some cases of poor ovarian reserve that are still showing a normal day 3 FSH. It is discussed on the day 3 FSH page.
Response of the ovaries to ovarian stimulation with injectable gonadotropins (FSH)
This is not really a "test" that we do to help us determine egg quantity and quality - it is part of a treatment for infertility. However, the response of the ovaries when the woman takes injectable FSH for stimulation is often very predictive of the egg quantity - and therefore, also the relative chances for success with infertility treatment.Response to stimulation and antral follicle counts are important predictors of outcome, and are discussed in detail on another page.
Other provocative tests of ovarian reserve
We can also challenge the ovaries with drugs (hormones) and assess whether they have responded appropriately in order to distinguish women with good ovarian reserve from women with diminished reserve.For example, the exogenous FSH ovarian reserve test involves giving an FSH injection on day 3 of the cycle and testing both the baseline FSH and baseline and 24 hour post-injection estradiol to see if a normal response has resulted.
If the estradiol response is poor, ovarian reserve and egg quantity are also likely to be poor. The woman is also less likely to be a "normal responder" to gonadotropin stimulation.
In vitro fertilization
This is a treatment for infertility, but at the same time it can give us much useful information about egg and embryo quality. By careful examination of the eggs and embryos during the in vitro incubation process we sometimes get clues about why pregnancy has not occurred previously.For example, the eggs may demonstrate poor morphology, or may have problems with maturation, or with fertilization, proper cleavage, etc...
Treatment options for women with reduced ovarian reserve
In vitro fertilizationLupron "flare" protocol for ovarian stimulation in low responders
In vitro fertilization with assisted hatching
In vitro fertilization with coculture
In vitro fertilization with donor eggs
Day 3 FSH Testing - Follicle Stimulating Hormone
Background
It would be nice to have a reliable test to determine how good the eggs are in an individual woman at a point in time - as well as how many she still has remaining. We have some screening tests, however, they are far from perfect. This page will focus on day 3 FSH and estradiol testing. The ovarian reserve page has more overview information on egg quantity and quality issues, as well as other screening tests. Antral follicle counts and response of the ovaries to stimulation with injectable gonadotropins are other variables that affect the overall chance for conception markedly when we attempt in vitro fertilization.
There are several ways that we try to predict "egg quantity and quality" as well as trying to estimate chances for conception with various forms of treatment. Female age is an important variable.However, a woman can be 45 with exceptionally good quality eggs and still be fertile, or, she can be 25 with very poor quality eggs and be infertile. These are extreme examples, the main point is that egg quantity and quality on the average tends to decline slowly starting in the early 30's, then more significantly in the late 30s and much more dramatically in the early 40s. However, egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average.
It would be nice to have a reliable test to determine how good the eggs are in an individual woman at a point in time. We do have some screening tests, however, they are far from perfect.
These tests are often referred to as tests of ovarian reserve. In other words, does the woman have a good reserve of high quality eggs remaining in her ovaries?
Day 3 follicle stimulating hormone: FSH
Follicle stimulating hormone (FSH) is one of the most important hormones involved in the natural menstrual cycle as well as in pharmacological (drug-induced) stimulation of the ovaries. It is the main hormone involved in producing mature eggs.FSH is the same hormone that is contained in the injectable gonadotropins which are used to produce multiple eggs for infertility treatment.
When a women goes into menopause she is essentially running out of eggs in her ovaries. The brain senses that there is a low estrogen environment and more FSH is released from the pituitary gland in an attempt to stimulate the ovaries enough to produce a good follicle and estrogen.
You can think of it like stepping on the gas pedal in the car to get going. The FSH is the gas, and the pituitary gland releases FSH to get a follicle "going" at the beginning of every menstrual cycle. If there are less follicles left (and perhaps lower quality follicles) the "gas" has to be increased to get a follicle to start developing. In a menopausal woman, the gas pedal is on the floor for the rest of her life - even though there are no follicles (or eggs) left that are capable of developing, the woman's body never gives up trying and FSH levels are permanently elevated.
Women in menopause usually have FSH levels that are above 40 mIU/ml. As women approach menopause their baseline FSH levels (day 3 of their cycle) will tend to gradually increase over the years. When they run out of follicles capable of responding, their FSH will be quite high (over 30-40 mIU/ml) and they will stop having menstrual periods.
By measuring a baseline FSH on day 3 of the cycle (we do it on either day 2, 3, or 4), we can often get an indication that the women is closer to menopause and has relatively less "ovarian reserve". Another way of saying this is that if the baseline FSH is elevated the ovarian reserve (how many eggs are left) is reduced and sometimes also the egg quality is reduced. In other words, an elevated FSH represents a reduced egg supply (in numbers of eggs remaining) and it might also reflect a compromise of egg quality. However, in general, the best quick and easy "test" for egg quality is looking at the woman's drivers license - her age.
There are some practical problems associated with this test:
1. The cut off values used to say that egg quantity is good, ok, or poor is very laboratory dependent. What this means is that a given level of, for example, 12 in one laboratory may reflect good ovarian reserve and egg quantity - whereas the same level in another laboratory using a different assay may reflect poor ovarian reserve, poor egg quantity, and low live birth rates with IVF. See below for more on interpretation of results.2. While an abnormal result (high baseline FSH) tends to be very predictive of poor egg quantity and quality, a normal result does not necessarily mean that the egg quantity and quality is good. There are a significant number of women with normal baseline FSH values that do have poor egg quantity and quality that is not being reflected in their FSH value.
This is particularly true for women in their 40s. An infertile 44 year old woman with a normal FSH (for example 6) still has a very low probability of conceiving and delivering with in vitro fertilization - or with any other fertility treatment. The fact that she is 44 greatly diminishes her chances - even if her FSH is normal. This is why IVF programs have age cutoffs. The oldest women accepted by IVF programs varies somewhat - most programs have a cutoff somewhere between age 42-45. Infertile women older than this will rarely be successful using their own eggs. However, women in their 40s are excellent candidates for in vitro fertilization with donor eggs.
Interpretation of day 3 FSH levels
In our center we are currently using a DPC assay run on an Immulite machine. We consider normal for this assay to be under 8. As levels go above 8.0 we often see a reduction in response as illustrated in the table below. If your levels were run with a different assay, you can not compare the results to those shown here with any confidence at all! For example, with some assays, a level of 14 is normal...
| Day 3 FSH level | Interpretation (DPC Immulite only) |
| Less than 9 | Reassuring level. Expect a good response to ovarian stimulation. |
| 9 - 10 | Fair. Response is between completely normal and somewhat reduced (response varies widely). Overall, a somewhat reduced live birth rate. |
| 10 - 12 | Reduced ovarian reserve. Usually show a reduced response to stimulation and some reduction in egg and embryo quality with IVF. Reduced live birth rates on the average. |
| 12 - 17 | Generally show a more marked reduction in response to stimulation and usually a further reduction in egg and embryo quality with IVF. Low live birth rates. |
| Over 17 | "No go" level in our center. Very poor (or no) response to stimulation. No live births. "No go" levels must be individualized for the particular lab assay and IVF center. |
In general, your ovarian reserve and your egg quantity is as bad as your worst FSH. If you have an FSH of 15 in one cycle and have it repeated in another cycle and get a 7 - the situation is not improving. Some women do "bounce around" with FSH levels in the normal to abnormal range - but they will generally respond and have chances for pregnancy more like those women who are consistently at their higher FSH level.
Waiting for a menstrual cycle with a lower FSH level and then stimulating quickly for IVF is probably of no benefit at all.
Young (e.g. under 35) women with elevated FSH levels stimulate better and have a higher pregnancy potential than "older" women.
Day 3 estradiol
A blood estradiol level on day 3 (we do it on any day between days 2 and 4) of the menstrual cycle is a way to potentially discover some of those women with a normal day 3 FSH that may in fact have decreased egg quantity and quality. What we would like to see on day three is a low FSH level in conjunction with a low estradiol level. If the FSH is normal but the estradiol level is elevated, the elevated estradiol may be artificially suppressing the FSH level in to the normal range.
The idea of using day 3 estradiol levels as an adjunct in evaluating egg quantity and quality is relatively new. Clearly defined cutoff values for normal and abnormal are not well defined and are also lab-dependent. I like to see the day 3 estradiol less than about 80. In our experience, levels of 80-100 are borderline, and over 100 is abnormal. We like to repeat any borderline results in another cycle.
There is not much data that suggests that an elevated day 3 estradiol is a problem in itself. The problem is more so that it is potentially "masking" the detection of the poor ovarian reserve by suppressing an FSH level that would otherwise be elevated.
Clomiphene challenge test
A clomiphene challenge test is a dynamic type of test that can discover some cases of poor ovarian reserve that are still showing a normal day 3 FSH.This test is done by:
1. Obtaining a day 3 FSH and estradiol
2. The woman takes two tablets of clomiphene (100 mg) on days 5-9 of the cycle
3. Repeat an FSH level on day 10 of the cycle
The normal test would show a low FSH on day 3, a low estradiol on day 3 and also a low FSH on day 10.
Cut off values for the day 3 and the day 10 FSH values are very lab dependent and must be determined by experience with the laboratory being used. In other words, only your infertility specialist can interpret your results.
In vitro fertilization
This is a treatment for infertility, but at the same time it can give much useful information about egg and embryo quality. By careful examination of the eggs and embryos during the in vitro incubation process we can sometimes get clues about why pregnancy has not occurred previously.
For example, the oocytes may demonstrate poor morphology, or may have problems with maturation, or with fertilization, proper cleavage, etc..
Treatment options for women with elevated FSH and reduced ovarian reserve
Lupron "flare" protocol for ovarian stimulation in low respondersIn vitro fertilization with assisted hatching
In vitro fertilization with coculture
In vitro fertilization with donor eggs
Antral Follicle Counts, Resting Follicles and Ovarian Volume
Methods to help predict female fertility, IVF cancellation risk, response to ovarian stimulation drugs, and number of eggs retrieved for IVF
Another measure of egg quantity, quality and "ovarian reserve"
Background
Women are born with all of the eggs that they will ever have, and they lose them constantly throughout life until menopause, when none remain. It would be helpful to have a reliable test that would tell us how many eggs a woman has remaining at a point in time - as well as telling us about the quality of those eggs. The term "ovarian reserve" is useful in the field of reproductive medicine. It is an estimate of the reserve of the woman's ovaries - remaining egg supply - to be able to make babies in the (near) future. In other words, a woman's ovarian reserve is her remaining fertility potential.While there are some ovarian reserve screening tests, they are far from perfect. This page will focus mainly on on antral follicle counts, but will also address ovarian volume and ovarian response to injectable FSH stimulation. The ovarian reserve page has more overview information on egg quantity and quality issues, as well as other screening tests.
There are several ways that we try to predict "egg quantity and quality" as well as trying to estimate chances for conception with various forms of fertility treatment. Female age and "day 3 FSH" levels are 2 very important variables. The response of the ovaries to ovarian stimulation with injectable gonadotropins (FSH) is another very important variable that affects the overall chance for conception when we attempt in vitro fertilization.
Antral follicles are small follicles (about 2-8 mm in diameter) that we can see - and measure and count - with ultrasound. Antral follicles are also referred to as resting follicles. Vaginal ultrasound is the best way to accurately assess and count these small structures. In my opinion, the antral follicle counts (in conjunction with female age) are by far the best tool that we currently have for estimating ovarian reserve and/or chances for pregnancy with in vitro fertilization.
Presumably, the number of antral follicles visible on ultrasound is indicative of the relative number of microscopic (and sound asleep) primordial follicles remaining in the ovary. Each primordial follicle contains an immature egg that can potentially develop in the future. In other words, when there are only a few antral follicles visible, there are less eggs remaining as compared to when there are more antral follicles visible. As women age, they have less eggs (primordial follicles) remaining, therefore they have less antral follicles visible on ultrasound.
Antral follicle counts are a good predictor of the number of mature follicles that we will be able to stimulate in the woman's ovaries when we administer the injectable FSH medications that are used for in vitro fertilization. The number of eggs retrieved correlates with IVF success rates.
1. When there are an average (or high) number of antral follicles, we tend to get a "good" response with many mature follicles. We tend to get a good number of eggs at retrieval in these cases. Pregnancy rates are higher than average.
2. When there are few antral follicles, we tend to get a poor response with few mature follicles. Cancellation of the IVF cycle is much more common when there is a low antral count. Pregnancy rates are lower overall in this group. The reduction in success rates is more pronounced in women over 35 years old.
3. When the number of antral follicles is intermediate, the response is not as predictable. In most cases the response is intermediate. However, we could also have either a low or a very good response when the antral counts are intermediate. Pregnancy rates are pretty good overall in this group.
At least in some women, the antral follicle count may be a good predictor of the number of eggs remaining in the ovaries, as well as the quality of those eggs. This i not true for all women.
For example, we see some women in their early 20's that want to be egg donors at our center that when we do ultrasound on them we see only 3 antral follicles per ovary - and the volume of the ovary is low. Although we no longer accept these women into our egg donor program, I am not convinced that they have an egg quality or quantity problem (my best guess is that they have reduced quantity, butquality is probably fine). Often the young woman is concerned about her future fertility when we tell them that their ovaries are small and do not look like they will make sufficient eggs to be a good donor candidate. However, I am not aware of any data (medical research, etc.) that shows that women in that particular scenario are going to have a fertility problem. They might - but we just don't know. Some of those women already have 3 kids and are more fertile than they would prefer - so we really can't say that all women with low antral follicle counts have a fertility problem (reduced egg quality or quantity).
However, fertile women applying to be egg donors with few antral follicles are probably very different from women that have had difficulty conceiving. Many infertile women with low antral follicle counts do have a problem with both egg quality and quantity. The younger they are, the more likely that the problem is just quantity of eggs, whereas for women in their late 30's and early 40's with reduced antrals, there is often a problem with both quantity and quality.
How many antral follicles is "good"?
There is not a perfect answer to this excellent question. Unfortunately, we do not live in a perfect world, and some ovaries have not yet read up on antral follicle counts to know how they are supposed to respond to stimulation. Antral follicle counts can also be somewhat "observer-dependent". This means that if we had several different trained ultrasonographers do an antral count on a woman, they would not all get exactly the same result. Therefore, what we decide looks like 6 antral follicles, at another clinic might have been read as 4 or 8, etc.
| Total number of antral follicles | Expected response to injectable ovarian stimulating drug (FSH product) and chances for success |
| Less than 4 | Extremely low count, very poor (or no) response to stimulation and a cancelled cycle expected. Should seriously consider not attempting IVF at all. Rare pregnancies if IVF attempted. |
| 5-7 | Low count, we are concerned about a possible/probable poor response to the stimulation drugs. Likely to need high doses of FSH product to stimulate ovaries adequately. Higher than average rate of IVF cycle cancellation. Lower than average pregnancy rates for those cases that make it to egg retrieval. The reduction in success rates is more pronounced beyond age 35. |
| 8-11 | Somewhat reduced count. Slightly higher than average rate of IVF cycle cancellation. Slightly reduced chances for pregnancy as a group. |
| 12-14 | Normal (but intermediate) count, the response to drug stimulation is sometimes low, but usually good. Very small increased risk for IVF cycle cancellation. Pregnancy rates as a group only slightly reduced compared to the "best" group. |
| 15-30 | Normal antral count, should have an excellent response to ovarian stimulation. Likely to respond well to low doses of FSH product. Very low risk for IVF cycle cancellation. Some risk for ovarian overstimulation. Best pregnancy rates overall as a group. |
| Over 30 | High count, watch for polycystic ovary type of ovarian response. Likely to have a high response to low doses of FSH product. Much higher than average risk for overstimulation. Very good pregnancy rate overall as a group, but a small percentage of cases in the group have egg quality issues and lower chances for pregnancy. |
This graph shows how ongoing pregnancy rates with IVF go up with increasing antral follicle counts
It also indicates (usually) better outcomes in women under 35 (red) compared to those 35-39 (yellow)
Women 40 and older have substantially lower success rates (not shown here)
It also indicates (usually) better outcomes in women under 35 (red) compared to those 35-39 (yellow)
Women 40 and older have substantially lower success rates (not shown here)
The level of response of the ovaries when the woman takes injectable FSH for stimulation is often predictive of the egg quantity and quality - and therefore, also the relative chances for success with infertility treatment.
There are no absolute and accepted cutoffs for defining "low", "normal", or "high-responders". However, here are some general guidelines:
Low responder: When stimulated aggressively with injectable FSH will develop less than 5 mature follicles - often requiring high doses of the medications. Some women will only develop 1 or 2 mature follicles - even on very high doses of the medications. These women are not good candidates for IVF using their own eggs - but are good candidates for in vitro fertilization with donor eggs.
"Normal" or "average" responder: When stimulated aggressively with injectable FSH will develop 5-8 mature follicles as well as several smaller ones.
High responder: When stimulated aggressively with injectable FSH will develop about 8 or more mature follicles as well as many more small and medium-sized follicles. These women usually respond briskly to low doses of the medications. They are also at the highest risk for ovarian hyperstimulation syndrome.
In general, normal and high-responders to stimulation have better egg quantity and quality and have significantly higher pregnancy rates with treatment.
In general, low-responders to stimulation have lower-quality eggs (as well as quantity) and have significantly lower pregnancy rates with treatment.
Other provocative tests of ovarian reserve
We can also challenge the ovaries with drugs (hormones) and assess whether they have responded appropriately in order to distinguish women with good ovarian reserve from women with diminished reserve.
For example, the exogenous FSH ovarian reserve test involves giving an FSH injection on day 3 of the cycle and testing both the baseline FSH and baseline and 24 hour post-injection estradiol to see if a normal response has resulted.
If the estradiol response is poor, ovarian reserve and egg quantity are also likely to be poor. The woman is also less likely to be a "normal responder" to gonadotropin stimulation.
In vitro fertilization
This is a treatment for infertility and is never done as a "test", but at the same time it gives much useful information about egg and embryo quality. By careful examination of the eggs and embryos during the in vitro incubation process we sometimes
For example, the oocytes may demonstrate poor morphology, or may have problems with maturation, or with fertilization, proper cleavage, etc.
Treatment options for women with low antral follicle counts and low response to stimulation
Lupron "flare" protocol for ovarian stimulation in low responders
In vitro fertilization with assisted hatching
In vitro fertilization with donor eggs
Laparoscopy for infertility
What is laparoscopy?Laparoscopy is a procedure that involves insertion of a narrow telescope-like instrument through a small incision in the belly button. This allows visualization of the abdominal and pelvic organs including the area of the uterus, fallopian tubes and ovaries.
What is laparoscopy used for in women with infertility?
This procedure allows us to determine whether there are any defects such as scar tissue, endometriosis, fibroid tumors and other abnormalities of the uterus, fallopian tubes and ovaries.
If any defects are found then they can often be corrected with operative laparoscopy which involves placing instruments through ports in the scope and through additional, narrow (5 mm) ports which are usually inserted at the top of the pubic hair line in the lower abdomen.
Laparoscopy has traditionally been a part of the female infertility work-up. However, this tradition has recently been challenged by some as potentially being a questionable procedure when assessed by its cost-effectiveness. The issue is complicated, and there are no easy answers. Certainly, some women will have a correctable problem found at laparoscopy that would not have been discovered with other methods.
Because of the cost and invasive nature of laparoscopy it should not be the first procedure or diagnostic test performed as part of the couples infertility diagnostic evaluation. In general, semen analysis, hysterosalpingogram and documentation of ovulation should be assessed prior to consideration of laparoscopy. For example, if the woman has a clear ovulation problem or her male partner has a severe sperm defect then it is unlikely that laparoscopy will provide additional useful information that will help them to conceive.
Most reproductive endocrinology and infertility specialists advocate doing laparoscopy at some time prior to using gonadotropins for superovulation as an infertility treatment.
Laparoscopy in the hospital vs. laparoscopy in the office
Traditionally laparoscopy has been performed in the hospital operating room. Recently there has been a substantial push in the U.S. for medical cost-cutting. One of the many changes that has come about as part of this is that some physicians have done laparoscopy in their office rather than in the hospital operating room. Thus far, this has been performed by a small percentage of physicians nationally.
There are cost advantages for the insurance companies and for the patient as laparoscopy in the office could be done for approximately $1500 total cost for the patient or insurance company as compared to total cost when performed in a hospital setting or sugicenter of about $4000-$10,000.
The only advantage to performing laparoscopy in an office setting is reduced cost. The potential advantages to performing the procedure in the hospital or surgicenter setting includes the fact that when general anesthesia is used, larger instruments can be used and operative correction of problems can be readily performed.
Very little operative laparoscopic work can be performed in the office setting because the pain associated with any dissection performed using local anesthesia and IV sedation. Therefore, if a woman undergoes diagnostic laparoscopy in the office and severe endometriosis, or pelvic adhesions, or tubal damage is discovered - it is likely that the woman will require a second procedure in a hospital or surgicenter setting if an attempt at surgical repair is desired. This is an advantage of hospital laparoscopy over office laparoscopy.
Is it a big procedure? How much work would I miss?
In this country laparoscopy is usually done with general anesthesia (you go to sleep) although it can be done with local anesthesia and in many parts of the world local is the preferred technique.
The procedure usually takes between 20 minutes to 2 hours depending upon how much operative corrective work is required. A complicated case could take up to 4 hours or more.
The woman is generally discharged home from the hospital approximately two hours after completion of the surgery. The woman will usually need to take off an additional 1-2 days from work following the procedure. Mild to moderate pain should be expected to last for up to 7 days or so after the procedure.
Complications
Complications associated with laparoscopy include the possibility of damage to other structures in the pelvis such as the bladder, ureter, bowel and blood vessels. Unexpected open surgery (larger incision) is always a possibility, but is very uncommon.
Any surgery can have an anesthesia-related complication or be associated with post-operative infection, such as a skin infection at an incision site.
Fortunately, all of these complications are very unusual when laparoscopy is expertly performed on young, healthy women.
Hysteroscopy
What is hysteroscopy?Hysteroscopy is a procedure that involves insertion of a narrow telescope-like instrument through the vagina and cervix into the cavity of the uterus (endometrial cavity). The uterine cavity is then distended with fluid and visualized.
What is hysteroscopy used for?
This procedure allows us to determine whether there are any defects such as fibroid tumors, endometrial polyps, intrauterine scar tissue, a uterine septum, or other uterine problems inside the cavity.
If any defects are found then they should be corrected with operative hysteroscopy which involves placing instruments through ports in the scope that allow us to cut, cauterize, etc., to correct the problem.
Is it a big procedure? How much work would I miss?
Hysteroscopy is an out-patient procedure that is usually done in a hospital but can also be done in the office. The actual procedure (diagnostic) usually takes 2-5 minutes.No anesthesia at all is needed for most cases of diagnostic hysteroscopy if a microhysteroscope is used.
General anesthesia or local anesthesia can be used if any operative work is required.
Usually the woman is discharged home approximately 15-30 minutes after the procedure. She can return to work the next morning if general anesthesia was used, or immediately if no anesthesia (or local) was used. Mild pain and cramping is common after operative hysteroscopy, but it usually is brief (lasting perhaps 30 minutes, possibly up to 8 hours).
What problems can defects of the uterine cavity cause?
Abnormalities of the endometrial cavity can be responsible for infertility or problems with recurrent miscarriage.
Hysteroscopy and other methods, such as a hysterosalpingogram, ultrasound, or ultrasound with saline test are useful in diagnosing and correcting these defects.
Complications
Complications associated with hysteroscopy include the possibility of infection, uterine perforation, vaginal bleeding, and fluid overload.
source : Dr Mahmoud Ahmad Fora
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