Investigating The Infertile Male

It is natural for the attention of the gynecologist and family practitioner to initially turn toward the female in cases of infertility. Although infertility is generally viewed a ‘female problem’, fully 45% of infertile couples have male infertility as a contributing cause. It makes sense then to begin the fertility evaluation with a basic evaluation of the male partner. Because significant male factor infertility is generally treated with in vitro fertilization, needless hysterosalpingograms, laparoscopies and clomiphene cycles can be avoided by early detection of significant dysfunction in the male partner. The savings of time and money can be tremendous. IVF with intracytoplasmic sperm injection (IVF/ICSI) has made it possible to successfully treat virtually all cases of male infertility, even with only a few moving sperm in the entire ejaculate.

The evaluation of the male partner starts with a competent semen analysis. Non-specialized laboratories, such as Ranbaxy and Metropolis, perform a World Health Organization (WHO) semen analysis. This is a crude screening test and should be replaced by the strict semen analysis (Kruger) that is done by most fertility centers. The difference between the WHO and the Kruger test is that, with the Kruger test, sperm morphology is evaluated in a very stringent manner. The results of the Kruger test predict fertilization rates in vitro and presumably in vivo as well. The WHO does not predict outcome and will frequently miss subtle but clinically significant sperm abnormalities. The cost of the Kruger test is the same or less than a WHO analysis at our center.

When male infertility is suspected and tests reveal abnormal semen parameters, the couple should be referred to a fertility physician and/or urologist for further evaluation. Conditions warranting referral for male infertility are: a sperm concentration of less than 20 million per mL, motility less than 35%, and morphology less than 5% (Kruger) or 30% (WHO).

A direct antisperm antibody test should be done in cases where the male has a history of genital trauma, genital surgery or has never initiated a pregnancy. The direct antibody test is done on a semen sample and detects whether antibodies are attached to the sperm themselves. The cutoff for a positive test varies between labs but is usually considered positive when greater than 10%-20% of sperm are bound. Couples with antisperm antibodies should be referred to a fertility physician for further evaluation and treatment.

Genetic evaluation of male infertility is indicated when there is a sperm concentration less that 5 million per milliliter. This male infertility evaluation should consist of a karyotype and a study to look for microdeletions on the long arm of the Y chromosome (Yq deletion study). An assay for DNA fragmentation in the sperm cells may also be helpful in select patients. If azoospermia is present, carrier status for one of the cystic fibrosis mutations should be ruled out. These men should, of course, be referred for a urological evaluation. If surgical treatment of the infertile male is not indicated, a fertility physician can then complete treatment.

Hormonal evaluation of the infertile male is indicated when there is a history of sexual dysfunction, azoospermia or abnormal physical findings. This workup, which consists of testosterone, FSH, LH and prolactin levels, should be accompanied by urological consultation.

Triple Marker Test

The multiple marker test (sometimes referred to as the triple screen) can tell you if your baby is at an increased risk of having certain birth defects and genetic abnormalities. If you choose to have this test, it's important to understand that a "positive" or abnormal result doesn't necessarily mean that your baby has a problem. Infact, only about 10 percent of women with abnormal results have babies with birth defects. In general, an abnormal result means only that you may need further testing, such as ultrasound or amniocentesis, to know for sure. On the other hand, a negative or normal result is not a guarantee that your baby is healthy - but it does mean that your baby's chances of having certain birth defects are much lower. And that's why a lot of women opt to take it. Current research indicates that this test will detect 75 to 80 percent of neural tube defects (such as spina bifida and anencephaly) and 60 percent of Down syndrome in babies of women younger than 35, and 75 percent of neural tube defects and Down syndrome in babies of women 35 and older. Only about 3 to 5 percent of women will receive a positive (abnormal) result on the multiple marker - and on an average, only about 10 percent of those women will actually have a baby with a problem. That adds up to a lot of false positive results. Statistics from one of the companies that offers a multiple marker test show an even higher rate of false positives. If 1000 pregnant women take this test, only about 25 of them will show an increased risk for a baby with neural tube defects, and of those, only one or two will actually have a baby with Down syndrome. On the other hand, some women whose test results are normal will have a baby with one of these problems.

The multiple marker test measures your blood levels of three substances: alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3). For years, women were screened for AFP alone in a test called the maternal serum AFP or MSAFP, but now most labs check for all three substances because they can tell more that way. Some hospitals screen for the hormone inhibin A as well, in what's called a quadruple screen test. When this compound is added to the test, the detection rate for Down syndrome increases to between 67 and 76 percent in women younger than 35. It's usually done between 15 and 20 weeks of pregnancy, with 16 to 18 weeks (when the hormone levels are the most consistent) being the optimum time. You'll have a blood sample taken and sent to a lab for analysis. The lab analyzes the levels of AFP, hCG and uE3 (and sometimes inhibin A) in your blood and determines whether they fall within a "normal" range for this stage of your pregnancy, based on your age, weight, race, and other factors (such as having diabetes). Having too much or too little of these substances in your blood is considered a positive, or abnormal, result. Results are generally available in one or two weeks. Your level of AFP and the other substances are considered individually and in combination to determine whether you and your baby are at risk for certain problems. The results tell you what your baby's chances are of having each kind of birth defect. For example, on average, a 35-year-old woman has a 1 in 250 to 270 chance of having a baby with Down syndrome. If the results show that your chances of having a baby with any of the defects tested for are higher than average for your age, you'll want to consider further testing. A high AFP can mean several things. Your baby produces AFP throughout your pregnancy, and a certain amount of it should cross the placenta into your bloodstream at each stage. If there's more than expected, it often means that you're carrying more than one baby or that your baby is older than your practitioner thought. But in some cases, it's a sign of an abnormal opening in the baby's spine (spina bifida), head or abdominal wall that's allowing more AFP to leak out. In rare cases, it can also signify a problem with the baby's kidneys. And in some cases, it doesn't mean any of those things. A low AFP, low estriol, and high hCG are associated with a higher risk for Down syndrome (trisomy 21). Low levels of all three mean your baby has an increased risk for trisomy 18, a more severe and less common chromosomal anomaly.

Certain results may also indicate that you yourself are at a somewhat greater risk for problems such as preeclampsia, premature birth, or miscarriage. Knowing this can allow you and your practitioner to be on the lookout for signs of trouble. If you receive an abnormal result, you'll most likely be offered a detailed (level II) ultrasound first. This test can be done right away and can give you immediate information. (If the ultrasound shows that your baby is younger or older than your practitioner thought, your results will be recalculated.) You may also want to meet with a genetic counselor at this point to discuss your risks and your options. If you have a high AFP, a level II ultrasound will confirm your baby's age and show whether you're carrying twins, and will allow your doctor to check your baby's spine and other parts for defects. If your baby is found to have spina bifida and you decide to continue the pregnancy, your medical team will be able to monitor your baby's condition during your pregnancy and prepare to do surgery once your baby's born. If you have a low AFP, the ultrasound can allow your doctor to check for several so-called "soft markers" that may suggest Down syndrome and other chromosomal disorders. These soft markers include cysts in a particular area of the brain (choroid plexus cysts), extra calcium in certain muscles of the heart (hyperechogenic intracardiac foci), a kidney problem (mild pyelectasis), a thickened nuchal fold (also called the nuchal translucency, a clear area between the back of the baby's neck and the overlying skin), an abnormally short thigh bone, and a bright-appearing (hyperechogenic) bowel.

When two or more of these markers are found, the chance that your baby has a chromosomal abnormality may be significantly higher, depending on your age and how far along you are. Also, a baby with a major structural abnormality, such as a defect in the heart or abdominal wall, has a greater chance of having a chromosomal defect. If everything looks normal on the ultrasound, it's not a guarantee that everything is okay, but it does mean that your baby has a lower risk of chromosomal defects than average for a woman your age. You may decide that this small risk is acceptable or you may decide that you'd also like to have amniocentesis to know for sure. If the ultrasound suggests your baby may have a chromosomal problem, your practitioner will usually recommend amniocentesis to determine for sure what's going on. And if the ultrasound detects certain structural defects, you may want amniocentesis to find out whether your baby has a chromosomal problem as well, which is often the case. Amniocentesis can diagnose 99 percent of chromosomal abnormalities, but it does carry a slight risk of miscarriage (one in 200 on average). This test is usually done between 15 and 20 weeks so that the parents will have the option of terminating the pregnancy before 24 weeks if they choose to. Again, you have to wait 10 to 14 days to get the results.

The main advantage of the multiple marker is that it can give you some information about your baby's risk of having certain birth defects without subjecting you to the slight risk of miscarriage associated with amniocentesis or the CVS test. If you're going to be 35 or older by your due date, your practitioner may suggest that you skip this test and go right to those more accurate tests. After you reach this age, your risk of having a baby with a chromosomal problem such as Down syndrome is higher than your risk of miscarrying because of amniocentesis. Still, if you're uncomfortable with this risk, you may choose to have the multiple marker with a detailed ultrasound instead. If the results of these are both normal, you may not want to go through with the amnio because the small chance that the baby will have a defect may now be less than the chance that an amnio would cause a miscarriage, just as it would be if you were younger than 35. Even if you know that you would never terminate a pregnancy for any reason, knowing in advance that your baby may have special needs allows you to prepare for the challenges you'll face. You might want to switch to a better-equipped hospital with specialists. Knowing what's going on with your baby will allow your medical team to monitor your pregnancy as needed and to bring a neonatologist or pediatric surgeon on board to prepare to help your baby after birth.

On the other hand, a false positive result can worry you needlessly (this is the most common complaint about the test) and make you decide to undergo amniocentesis for no reason. A false negative result could make you decide to avoid further tests that would have revealed a birth defect. Before making a decision, you'll want to discuss all of these issues with your partner, your health practitioner, and possibly a genetic counselor.

Sperm Bank

The Female Evaluation

The infertility workup of the female partner has undergone several changes over the years but the basics have remained the same. The well-orchestrated female workup can be completed in a single menstrual cycle. At the end of this workup, along with the male data, the clinician should be able to plot a definitive course of treatment. The workup will be divided between female patients who are ovulatory by history and those that are not. Ovulation is presumed if the female has had regular menses every 26-32 days for the last six months. It is important to organize the workup to prevent unnecessary testing. The female workup should start with an initial intake that includes a thorough history, physical examination and a transvaginal pelvic ultrasound. Important historical details include those that might indicate previous exposure to STDs (such as a history of abnormal pap smears), recurrent pregnancy loss and the duration of infertility. Physical examination and pelvic ultrasound will identify patients that have gross pathology requiring surgical treatment prior to further fertility evaluation. For example, a dermoid cyst requiring surgery would allow the surgeon to evaluate tubal patency at the time of surgery rather than ordering an HSG.

Ovarian Reserve Testing
After the initial intake, the next step in the evaluation of the ovulatory female is the evaluation of ovarian reserve. The level of ovarian reserve and the age of the female partner are the most important prognostic factors in the fertility workup. Ovarian reserve is evaluated with a cycle day three FSH and estradiol level. On the third day of bleeding, a simple blood test yields a lot. Normal ovarian function is indicated when the FSH is <10 mIU/mL and the estradiol is <65 pg/mL. If the FSH is >15 mIU/mL, the patient will require egg donation. If the FSH is 10-15 mIU/mL or the E2 is >65 pg/mL, the more sensitive clomiphene citrate challenge test (CCCT) should be performed to further define ovarian reserve.

Tubal Patency
The next step in the ovulatory patient is to confirm tubal patency. This has been done traditionally with the hysterosalpingogram (HSG) and nothing has really improved on this. The HSG is performed at the outpatient radiology department. It involves injecting dye into the uterus and monitoring its "flow back" through the fallopian tubes. Blockages appear as concentrations of dye at the point of the obstruction. This test should be done in the follicular phase of the cycle after bleeding has stopped and before possible ovulation. The ordering physician should personally review the films to confirm findings of the study. Loculation of spill and tubal phimosis indicate that laparoscopy may be helpful. If large hydrosalpinges are identified, they should be clipped or removed laparoscopically prior to in vitro fertilization. Several large studies as well as a recent metanalysis, have confirmed the pregnancy rates with IVF are reduced by half in the presence of hydrosalpinges and that the rates are normalized with salpingectomy. The exact etiology of the phenomenon is not known.

Confirmation of Ovulation
Confirmation of ovulation is unlikely to be helpful in women when a careful history is consistent with ovulation. If there is doubt, a cycle day 21 progesterone with a level greater than 4 ng/mL is indicative of ovulation with most conceptions cycles having levels greater than 10 ng/mL. Alternately, sonographic confirmation of follicle rupture with serial ultrasound can be performed. Some programs use the basal body thermometer (BBT) to predict ovulation. The BBT measures the slight rise in temperature that occurs immediately prior to ovulation. Most physicians prefer to use the urinary ovulation predictor kits as they are more accurate and easy to administer.

Anovulatory Patients
The apparently oligomenorrheic patient should have the cause of their anovulation evaluated thoroughly prior to the initiation of treatment. The initial physical examination should note the presence or absence of goiter, acanthosis nigricans, striae, normal secondary sexual characteristics, Turner’s stigmata, galactorrhea, hirsuitism and abnormalities of the reproductive tract. Ultrasound should note the thickness of the endometrial lining as well as whether the ovaries are polycystic in nature. An endometrial biopsy should be considered if the uterine lining measures greater than 15mm.

Endocrine Evaluation
In anovulatory patients, the initial laboratory evaluation should include random levels of FSH, LH, prolactin, TSH, DHEAS and testosterone. Insulin resistance should be considered in patients that have any of the following: obesity, hirsuitism or acanthosis nigricans on physical exam; polycystic ovaries on ultrasound; inverted FSH/LH ratio or androgen excess on laboratory examination. Evaluation for insulin resistance can be accomplished simply with a 12 hour fasting serum insulin level. A 12 hour fasting serum insulin level of more than 10 mIU/ml signifies hyperinsulinemia in that PCOS subject.

Oocyte Retrieval (Follicle Puncture)

The first IVF baby was born as a result of collecting an egg by laparoscopy. Patrick Steptoe had pioneered the use of the laparoscope in gynaecology - a procedure which is now used extensively but was considered in the late 1970's to be 'a dangerous procedure'. Patrick Steptoe and Robert Edwards achieved the first IVF birth on July 25th 1978, although they had achieved an ectopic pregnancy some time before that. That pregancy was the result of a single egg being collected. The photographs on the right (taken by Patrick Steptoe down the laparoscope) shows a single follicle as a shiny structure towards the bottom left of the ovary. We ocassionally have to yet resort to laparoscopic oocyte retrievals when the ovaries are not accessible with transvaginal ultrasound eg. Meyer-Rokitansky-Kustner-Hauser Syndrome.
Oocyte retrieval is performed approximately 34-36 hours after the hCG injection, immediately before each follicle releases its oocyte. Oocyte retrieval involves a short procedure (lasting 20 to 45 minutes depending on the number of follicles having reached maturity) which is performed transvaginally under ultrasound control (the same way as during the ultrasound monitoring during the stimulation phase). There is therefore no incision or scar involved since the needle is inserted in each follicle by puncturing the ovary directly through the lateral wall at the top of the vagina. Each follicle is punctured and emptied of its fluid by aspiration. The eggs are collected through the vagina under ultrasound control, using a fine needle that is passed through the vagina into the ovary. Fluid from the follicles is sucked through the needle into a test tube and is passed immediately to the adjacent laboratory where the scientist checks for eggs under the microscope. After each aspiration, the sterile test tube containing the aspirated fluid is forwarded to the IVF laboratory, which will do a microscopic search of the fuid for the presence of oocytes. Most eggs are reasonably easy to find as a jelly like mass of cells known as the cumulus surrounds them(see picture). The eggs are then placed in culture fluid (a water based salt solution with added nutrients) in special dishes and put into the incubator at body temperature. If no oocyte is identified, repeated rinsing of the follicle with some millilitres of culture medium generally permits recovery of the oocyte. Oocyte retrieval can be done under a light general anesthesia (usually Propofol) at Rotunda.
The procedure takes 15-30 minutes and most women will have one or several eggs recovered. It is rare for no eggs to be found. After OPU the woman usually remains in the recovery area for about two hours before discharge. Due to the drugs used during the procedure, driving for the next 24 hours is not advisable. Your co-ordination and perception may be impaired and insurance companies may decide not to cover claims that occur during this time. It is not unusual to have some vaginal bleeding, from where the needle passes through the vaginal wall, for the next 24 hours. Mild lower abdominal cramping for the next day or two, due to swelling of the ovaries, is also common and paracetamol can safely be used.

Fertility Tests

Laparoscopy
The laparoscopy is a common outpatient surgical procedure that allows the physician to view reproductive organs such as the tubes, ovary, and uterus, and diagnose conditions causing infertility including endometriosis and tubal blockage(see picture). The laparoscope is a small "telescope like" instrument that is placed through a small incision in the abdomen, usually at the belly button(see picture). Small operative tools are inserted through another small incision at the pubic hairline. The laparoscope usually does not produce noticeable scarring. The abdomen is filled with gas causing it to expand making the internal organs more accessible. Reproductive surgeons undergo extensive advanced microsurgical training with the laparoscope. They are able to perform many, if not most, fertility operations using the laparoscope, which dramatically reduces recovery time, pain cost, and adhesions/scarring. Fertility specialists will usually treat conditions such as endometriosis during the diagnostic laparoscopy. This is one reason that a specialist should perform the laparoscopy when infertility is suspected.

Hysteroscopy
The hysteroscopy is an important tool in the study of infertility, recurrent miscarriage, or abnormal uterine bleeding. Diagnostic hysteroscopy is used to examine the inside of the uterus, also known as the uterine cavity, and is helpful in diagnosing abnormal uterine conditions such as internal fibroids, scarring, polyps, and congenital malformations(see picture). A hysterosalpingogram (an x-ray of the uterus and fallopian tubes) or an endometrial biopsy may be performed before or after a diagnostic hysteroscopy. The first step of diagnostic hysteroscopy involves slightly stretching the canal of the cervix with a series of dilators. Once the cervix is dilated, the hysteroscope, a narrow lighted viewing instrument, similar to but smaller than the laparoscope, is inserted through the cervix and into the lower end of the uterus(see picture). Carbon dioxide gas or special clear solutions like normal saline or glycine are then injected into the uterus through the hysteroscope. This gas or solution expands the uterine cavity, clears blood and mucus away, and enables the physician to directly view the internal structure of the uterus. Diagnostic hysteroscopy is usually conducted at Rotunda under propofol anesthesia. Diagnostic hysteroscopy is usually performed soon after menstruation because the uterine cavity is more easily evaluated and there is no risk of interrupting a pregnancy. A mock transfer or trial transfer may also be done at this time.

Ultrasound
Ultrasound measurements have many applications in the infertility evaluation and are also used for monitoring during in vitro fertilization stimulation cycles. The transvaginal ultrasound (through the vagina) is used frequently because it allows the physician to view the ovaries, uterus, and many other internal organs. The ultrasound produces images similar to an x-ray; however, sound waves are used instead of radiation. Many times dense structures, such as uterine fibroids, are clearly visible on transvaginal ultrasound. The ultrasound is also able to show the follicles on the ovaries as they develop and are ovulated(see picture). The fertility specialist must know the number and size of the follicles during drug-stimulated IVF cycles as this information helps in adjusting medication dosages. Ultrasound is used to measure the width of the endometrium, which must thicken and become more vascular to accept a developing embryo(see picture). It is also used as a means to document pregnancy by visualizing the fetal heartbeat.

CV of the Year

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