Management of Male Infertility

Treatments for male infertility range from surgical intervention or intrauterine insemination (IUI) to in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Depending on the source of the problem, sperm can be taken from the man's ejaculate for use in assisted fertilization procedures. One treatment option for men who do have sperm in the ejaculate is intrauterine insemination (IUI). Intrauterine insemination is an infertility treatment in which sperm are placed directly into the upper uterine cavity near the time she ovulates. IUIs are commonly performed when there is a low sperm count or low motility. The sperm that will be injected during the procedure are prepared using a process called sperm washing. The sperm are "washed" to remove any extra cells and debris in an effort to obtain the greatest concentration of the highly motile sperm that will be used for the insemination. One of the most common problems affecting male sperm levels is a varicocele, a tangle of swollen veins surrounding the testicle. Surgical correction of large varicoceles may improve sperm DNA quality and semen analysis results, as well as restore fertility in about two-thirds of cases.
In some cases there is no sperm in the ejaculate so surgical options for sperm retrieval are explored. Advanced sperm retrieval techniques, including TESA, PESA testicular microdissection and testicular biopsy, combined with IVF and ICSI, now allow men with either a low sperm count or no sperm in their ejaculate the chance to produce a child. For some couples, the use of donor sperm remains the best option for building a family. Obviously, donor sperm is the only option for men whose testicular biopsy reveals complete azoospermia - no trace of sperm in the testicular tissue. The use of donor sperm may also be considered when genetic screening indicates a possibility of passing on hereditary conditions such as cystic fibrosis to male offspring.
An increased understanding of male factor infertility and the recent advances made in assisted sperm retrieval techniques are now giving men who never thought they could have biological offspring the chance to father a child. Successful fertility outcomes at Rotunda-The Center For Human Reproduction result from a combination of technological advances, scientific expertise and consistent andrology laboratory standards.

Varicocele - Modern Management

Varicocele is a dilation (enlargement) of the internal spermatic veins that drain the testicle (picture on left). It is a very common condition present in 15% of the general male population and 40% of men evaluated for infertility. A varicocele develops because of defective valves that normally allow for blood to flow away from the testicle toward the abdomen. Testicular injury occurs due to abnormal back flow of blood from the abdomen into the scrotum and this creates a hostile environment for sperm development. The significance of this condition has been known for a thousand years. The first century Greek physician Celsius originally described the varicocele: "The veins are swollen and twisted over the testicle, which becomes smaller than its fellow in as much as its nutrition has become defective".
Numerous theories postulate how a varicocele can affect fertility:
1. Testicular temperature increases due to abnormal blood flow in the veins draining the testicle and in the artery entering the scrotum. Prolonged elevated testicular temperature has detrimental effects on sperm production.
2. Abnormal concentrations of adrenal and renal substances may impede development of normal sperm.
3. Abnormal venous blood flow from the scrotum increases metabolic waste products and decreases the availability of oxygen and nutrients required for sperm development.
4. Abnormal blood flow can also interfere with testosterone concentration, which in turn can interfere with sperm production. The long-term effects of compromised circulation may interfere with normal male androgen production.

Left-sided varicoceles are found in 85% of men with this problem and a right-sided varicocele is seen in 15%. The problem involves both sides in 20% of men. A unilateral varicocele may affect both testicles. The most probable explanation for the more frequent development of a varicocele on the left side alone is because the left spermatic vein is longer than the right. The left vein enters the left renal vein at a right angle near a site of compression by the mesenteric artery while the right spermatic vein drains at a softer angle into the vena cava. These anatomical factors (and the aid of gravity) promote backflow of blood in the left spermatic vein, resulting in pooling of blood and increased temperature and congestion in the testicle.

Some men with major varicoceles may show no evidence of testicular injury, while others with small or "subclinical" (detected only by radiological tests) varicocele may be infertile. The effects of a varicocele on sperm quality and quantity are thus difficult to define and predict. The so-called "stress pattern" frequently found in men with a varicocele consists of an increase in tapered abnormal sperm forms and decreased motility. The diagnosis of a varicocele can usually be made on physical examination of the scrotum while the patient is standing. The varicocele feels like a "bag of worms" and disappears or becomes significantly reduced when the patient lies down. The patient is asked to bear down and frequently the backflow of blood can be felt in these veins. Occasionally a varicocele may be so prominent that it can be seen through the skin. Often the testicle on the side of the varicocele is smaller than the other side. Ancillary tests such as the Doppler stethoscope and technetium isotope study may id in the diagnosis. Recently the scrotal ultrasound has been found to be an accurate way of confirming the presence of a varicocele. The size of the veins and abnormal blood flow can be seen and measured using the ultrasound.
Repair of the varicocele is indicated when the couple has documented infertility with normal or potentially normal female partner but a male with one or more abnormal semen parameters and the presence of a varicocele on physical exam. Repair should be done when a varicocele causes testicular pain or discomfort or there is a significant discrepancy between the size of the two testicles. Treatment options to aid with fertility include surgical varicocele repair, angiographic embolization, intrauterine insemination, in-vitro fertilization and medical therapy with clomiphene citrate. Surgical repair offers the best results. Semen improvement is expected in up to 70% of men and pregnancy in up to 60% of couples within the first two years after successful repair. Even in men with worst case scenarios who were not candidates for In Vitro Fertilization because they had no sperm in the ejaculate or no moving sperm, varicocele repair restored sperm or motility in 55-69% of patients. Twenty percent of these men were able to father children after varicocele repair without any other assistance.
Surgery is performed through a one and one half inch incision made below the belt line with a technique called microsurgical inguinal varicocele repair. The abnormal veins are identified using an operating microscope and are interrupted so blood can no longer pool around the testicle. The testicular artery and small lymphatic channels are identified using the microscope and are preserved. This limits potential complications. Surgery is performed on an outpatient basis and generally takes 30-45 minutes to complete. Using this approach the success rates for varicocele repair are close to 95% and the complication rate is about 1%.
Depending on the individual circumstances and the severity of the sperm abnormalities, multiple approaches to this problem can be taken. Surgical correction, intrauterine insemination and clomiphene citrate therapy can be used simultaneously to achieve a pregnancy. A recent study published in the Journal of Urology in May 2001 showed that varicocele repair improves intrauterine insemination success rates by almost double in men who have varicoceles. The most severe cases of male infertility may require in-vitro fertilization. The varicocele remains the most treatable cause of poor semen parameters and male infertility.

Acupuncture Shoots Up IVF Success Rates

Women undergoing fertility treatment could have their chances of success shooting up with acupuncture. German researchers said they have increased success rates by almost 50% in women having in vitro fertilization (IVF). The theory is that acupuncture can affect the autonomic nervous system, which is involved in the control of muscles and glands, and could therefore make the lining of the uterus more receptive to receiving an embryo. But the scientists admit they do not know for certain why the complementary therapy helped, and plan to carry out more studies in a bid to find out. Fertility techniques are used to help couples who cannot conceive naturally.
The theory of acupuncture is based on pathways called meridians. Research has shown it can help relieve nausea caused by anaesthetics during surgery or chemotherapy and to relieve dental pain. It may also help relieve other conditions including headaches and menstrual cramps. A report published in the journal Fertility and Sterility found the pregnancy rate in the group receiving acupuncture group was 42.5%, compared to the group which did not receive the therapy, where the rate was 26.3%. The German researchers worked with doctors at the Department of Traditional Chinese Medicine at Tongji Hospital in Wuhan, China. Of 160 women undergoing IVF, half received standard in vitro fertilization, while half were given acupuncture treatments before and after. The researchers chose acupuncture points which traditional Chinese medicine says relax the uterus. They also used needles to stimulate meridians involving the spleen, stomach and colon, to improve blood flow and create "more energy in the uterus." Key relaxation points were also stimulated. The research team, led by Dr. Wolfgang Paulus and colleagues at the Christian-Lauritzen-Institut in Ulm, Germany, wrote in the journal: "Acupuncture seems to be a useful tool for improving pregnancy rate after assisted reproductive techniques. They add: "To rule out the possibility that acupuncture produces only psychological or psychosomatic effects, we plan to use a placebo needle set as a control in a future study."
Such a study would involve people having needles inserted in the same way as in acupuncture, but not at the acupuncture points. Dr. Sandra Carson, president-elect of the American Society of Reproductive Medicine, which publishes the journal, said: "If these findings are confirmed, they may help us improve the odds for our (in vitro fertilization) patients' achieving pregnancy." We had a doctor couple from the US with multiple previous failed IVF cycles who came in for Surrogacy. The husband used to stick in the acupuncture needles into the spouse’s body couple of hours before the oocyte retrieval. They are proud parents of a bonny baby boy now. The gestational surrogate conceived on the second attempt early this year.

Recurrent Miscarriage - The Immunologic Causes

Immunologic causes of recurrent pregnancy loss are poorly understood. The theories proposed by authorities in this field appear to be constantly evolving and most of the theories that have been proposed to date have been proven to be either incorrect or largely incomplete. Two major categories of immunologic causes of recurrent pregnancy loss are Autoimmune, in which the woman's immune system attacks her own organs and tissues. 
Alloimmune, in which the immune system attacks tissues considered foreign. The immune system is designed to protect oneself against infectious organisms and their toxins. The system identifies, immobilizes and eliminates invaders. The two major mechanisms of surveillance are Nonadaptive immunity, in which cells respond nonspecifically to foreign molecules or material via either phagocytosis and lysis (by macrophages), lysozyme secretion (by lachrymal cells) or cell lysis (by natural killer cells). This type of response does not adapt and so its efficiency is not improved with further exposure . Adaptive immunity, in which action against specific foreign molecules (antigens) is enhanced by re-exposure. This is mediated by lymphocytes which produce highly specific antibodies that bind to the foreign molecules to further elicit (amplify) an immune response. The immune system is constantly operational (turned on) since it must synthesize an enormous catalog of different antibodies and cell surface receptors to deal with the wealth of foreign material that it is presented with.
An important feature of the immune system is its ability to distinguish foreign (unwanted) material from its own (desired) self. If this ability to distinguish non-self from self fails, then the system produces an immune response against itself (or its own tissues). This is called autoimmune disease.
Autoimmune disease or dysfunction may play a role in up to 20% of recurrent pregnancy loss. Phospholipids are molecular building blocks that help to make up a large portion of the walls around the cells of the body, including placental cells. Anti-phospholipid syndrome (APS) is the autoimmune dysfunction that is classically associated with recurrent pregnancy loss.
APS is associated with pregnancy loss in any trimester, placental thrombosis (blood clots), and small placentae. The interruption of the circulation to the fetus via these blood clots is a possible reason for the fetal losses. Identifying the mechanism behind the fetal losses would allow specific treatment to be developed. Clotting mechanisms are difficult to understand without a background in this area. Thrombosis may be caused by a relative deficiency in prostacyclin production within the cells that line the blood vessels (endothelial cells) since prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. Thrombosis may also be caused by a relative insufficiency of the active form of the endogenous anticoagulant protein C, which normally degrades certain clotting factors to limit thrombosis, since phospholipids are required to activate protein C. At this time, the mechanism of thrombosis and fetal loss with APS is largely unknown.
Establishing the diagnosis of APS is important since most of the treatment options involve considerable expense and some added risk. Antiphospholipid antibodies are a large varied group of immunoglobulins directed against several different negatively charged cell surface phospholipids. Many of these phospholipids have been identified, with the best known being cardiolipin. Tests for APS can be divided into coagulation based tests and tests that detect the presence of the antibodies directly.
A group of phospholipid dependent coagulation tests are available (such as the kaolin clotting time, the plasma clotting time, dilute Russell viper venom time, and activated partial thromboplastin time) and serve as popular screening tests for antiphospholipid antibodies. Each of these coagulation tests relies on the activation of a prothrombin activator complex to allow for clot formation. Antiphospholipid antibodies block this activation to delay clot formation, such that in the presence of these antibodies there will be a prolongation of the time required for clotting and an abnormal result for these coagulation tests.
There are several available sensitive and specific assays for anti-cardiolipin antibodies, one of which should be obtained when there is a history of recurrent pregnancy loss. The classic assay for anti-cardiolipin antibodies is the Loizou ELISA, which has been modified over the years. Results that are negative or low positive are generally considered clinically irrelevant and do not require treatment. There are commercial assays for some of the other phospholipids such as phosphatidyl-serine, phosphatidyl-inositol, phosphatidyl-ethanolamine, phosphatidly-choline and phosphatidyl-glycerol. Rather than testing for each phospholipid individually, the more cost efficient test is one that detects a panel (usually all) of these phospholipids (such as an antiphospholipid antibody package). If the panel is positive then more specific detection of specific phospholipids can be considered. Clinically, it is not necessary to test for each of these specific antibodies since the treatment is the same for any of them. Specific testing is most appropriate in a research setting.
To summarize, all couples with recurrent pregnancy loss should be screened for APS. The tests that we routinely order include one of the coagulation tests (aPTT) that relies on the activation of the prothrombin activator complex and which will be appropriately diluted with normal plasma when abnormal,the anti-cardiolipin antibody test (positive in 2-3% of the general population, 7-45% of women with recurrent pregnancy loss- depending on what level is considered abnormal) 
& the lupus anticoagulant test (positive in 1-2% of the general population, 10% of women with recurrent pregnancy loss) We do not routinely order specific anti-phospholipid antibody tests since ourmy management is not altered by the results. Some research centers may order these tests to determine experimental treatment protocols.
APS is classically defined as a triad of recurrent pregnancy loss, thrombosis and autoimmune thrombocytopenia (decreased platelet concentration). For those couples with recurrent pregnancy loss, the positive finding (on 2 separate occasions) of either an appropriately performed coagulation based test or a direct antibody test is generally all that is required to propose treatment. Without treatment, couples with APS have a poor chance of carrying a fetus to term. The worst prognosis appears to occur when there is a prior fetal loss and high anti-cardiolipin antibodies. Treatment options for APS include 1)Low dose aspirin (75-81 mg per day) starting prior to pregnancy. Rationale for this treatment is based on the theory that a relative decrease in prostacyclin is the cause for thrombosis. Aspirin at these low doses has the effect of increasing the prostacyclin to thromboxane (its natural competitor) ratio to enhance the effect of prostacyclin. 
2)Prednisone (30-60 mg per day) to suppress the immune system. This corticosteroid can have several potentially serious complications. When given during pregnancy for this indication, prednisone has been associated with preterm premature rupture of the fetal membranes, preterm delivery and pregnancy-induced hypertension. This medication should only be given by physicians experienced in its use for this indication and typically in a research setting. 
We avoid this approach completely.3)Low molecular weight Heparin (2750 IU s/c per day in the first trimester after fetal viability is seen on ultrasound, continued through to the second trimester). Typically the aPTT test is used to monitor LMW heparin dosing but these test results are abnormal in APS so cannot be used. We generally go by the platelet count (If less than 100,000, we give LMWH on every second or third day). Use of LMW heparin is based on the theory that decreased levels of activated protein C may be responsible for the thrombosis seen, and acts as an anti-coagulant. We have treated over 300 patients using this approach over the last 10 years. 4)Immunoglobulin (Ig) therapy, with intravenous injections of Igs, has been used for several decades in the treatment of immunodeficiency conditions and more recently in the treatment of autoimmune disorders. The mechanism of action is not known, the dosing is not standardized for recurrent pregnancy loss, and this treatment is very expensive. I believe that it is important for this treatment to be administered in a research facility until it is better understood.
Alloimmune dysfunction resulting in recurrent pregnancy loss has also been proposed. Allogeneic antigens are molecular structures that occur in different members of the same species and have the ability to elicit an immune response. Normally, a person will reject dissimilar (non-self) tissues or structures from the body using the immune system. In pregnancy, the placenta and growing embryo are not entirely self but rather are a result of both the maternal and paternal genetic heritages (referred to as a semi-allograft). The placenta (and pregnancy) has a privileged relationship with the pregnant woman that allows it to escape rejection. The mechanism for this privilege is not known.There have been several interesting and complex theories attempting to describe how the normal pregnancy achieves its privileged status in the maternal uterus. Thus far, none of these theories has been generally accepted and proven. Some of the theories are based on
Increased sharing of HLA types (genes encoding antigens that distinguish and mark tissue as self) within the maternal and paternal chromosomes. With increased sharing the placenta may not trigger the production of special blocking antibodies which confer privilege . Decreased numbers of blocking factors that normally allow the placenta to be retained as a privileged site, either due to increased HLA sharing or other factors such as decreased numbers of natural suppresser cells in the uterus, which may control the activity of the natural killer cells and allow for placental survival within the uterus. The diagnosis of alloimmune recurrent pregnancy loss is one of exclusion. That is, when all other tests have been performed and the findings have come back normal then some of those with unexplained losses are thought to fall into this category. Several physicians refuse to treat alloimmune recurrent pregnancy loss since there are no direct diagnostic tests, treatment options are expensive and their benefits are largely unproven, and treatment options potentially involve risk. I think that it is prudent to limit treatment to a research facility with expertise in these therapies. Also, you must consider that there is reportedly up to a 60-70% chance of carrying a pregnancy to term even after 3 spontaneous abortions without treatment. The two main treatment options include 1)Unified leukocyte (white blood cell, WBC) immunization with paternal or donor blood cells, using 200-300 million mononuclear cells from the isolated buffy coat of blood, once the woman is pregnant and prior to 6 weeks gestation on one occasion only . 2)Immunoglobulin (Ig) therapy, with intravenous injections of Igs. The mechanism of action is not known, the dosing is not standardized for recurrent pregnancy loss, and this treatment is very expensive. With treatment, viable pregnancy rates of 70-80% have been reported in uncontrolled studies. In my experience, better candidates for this treatment are couples who have no other treatment options available and are willing to commit themselves to the time, energy (especially emotional) and money required to pursue experimental techniques.

My Daily Routine

Twin Trouble

Do We Really Need To Use Immunosuppressant Therapy For Antiovarian Antibodies?

Over three decades ago researchers observed a high rate of premature ovarian failure associated with poly-endocrine autoimmune disease and suggested that there might be an autoimmune disease of the ovary. At about the same time IVF workers observed auto-antibodies to eggs in the ovary in women with infertility and also suggested there might be an autoimmune disease of the ovary. Since that time, the concept of ovarian autoimmune disease has become more widely recognized but significant advances in our understanding are only just beginning to occur.
Such antibodies would bind to important functional sites in the ovary and granulosa cells and impair the normal response. The anti-ovarian antibodies were found fairly recently, and their complete function is not well known yet. It is believed that these antibodies cause disturbances that are a cause of ovarian failure/non-ovulation or poor ovulation. They are believed also to be a cause of less-than-expected response to various medications to stimulate proper ovarian function, and possibly even formation of less-than-excellent and normal eggs. The treatment of this condition is more or less experimental. Very infrequently, this condition can be helped through in vitro fertilization and if everything else fails an egg donation from a fertile donor is the evidence based-medicine’s answer to this disorder. When such a pregnancy is properly supported by administration of exogenous hormones – progesterone and sometimes even estrogen – it has an excellent chance to lead to normal delivery.
Ovarian autoimmune disease is principally associated with Premature Ovarian Failure (POF) and with unexplained infertility. It is possible that autoimmune unexplained infertility is an early stage of autoimmune POF but this remains to be demonstrated conclusively. POF is the onset of menopause before age 40 and occurs in one to two percent, or about one to two million women. Like natural menopause around age 50, premature menopause is identified by cessation of menstrual cycles for one year, accompanied by elevated follicle stimulating hormone (FSH) and reduced estradiol levels in blood . While some cases of POF have a genetic cause (such as Turner syndrome), or are due to chemotherapy, recent studies suggest that about half the cases of premature menopause are due to an autoimmune attack on ovarian follicles and the eggs (oocytes).
There is still a lack of information on the specific features of autoimmune POF. Some women with POF may have a family history of POF but most do not. However, women with POF have a higher risk for other autoimmune endocrine diseases, such as thyroid disease, Addison disease, type 1 diabetes, and autoimmune poly-glandular syndromes.
Women with infertility and ovarian auto-antibodies tend to have lower than expected estradiol responses to gonadotropin hormone stimulation (i.e. poor responders) and lower pregnancy rates following infertility treatment. Poor responders with ovarian antibodies were younger than poor responders without ovarian antibodies. This suggests that although some poor responses are associated with early stages of the menopause progression and reduced number of functional follicles, others are associated with an autoimmune process.
Ovarian autoimmunity is identified by the presence of anti-ovarian antibodies. There are several different types of tests and consequently different names for these antibodies. Antibodies specifically to eggs and to the zona pellucida (an area surrounding the eggs), or to ovarian cells have been described (9). Some women have antibodies to both ovarian cells and to eggs and others have only one of these antibodies. Ovarian autoimmunity is not identified by traditional tests for ovarian function, such as elevated pituitary follicle stimulating hormone in POF. Although the cause may differ, the symptoms of autoimmune and non-autoimmune POF are the same as in a normal menopause, including hot flashes, dry vaginal tissues, painful sex, infertility, bone loss, and an increased risk of cardiovascular disease. Likewise, autoimmune infertility can only be distinguished from non-autoimmune infertility by specific antibody tests.
As with other endocrine disorders, POF is treated by replacing the lost hormone, in this case hormone replacement therapy (HRT) with estrogen and progesterone to protect the heart, bones, genital and urinary tract tissues, and the nervous system. However, if a woman with infertility or POF wants to become pregnant, treatment with hormones that stimulate ovarian follicles to grow and produce eggs can be tried. If hormone stimulation alone does not result in a pregnancy, women may be treated by more aggressive methods such as in vitro fertilization (IVF). There have been reports of success in combination with low dose immunosuppression. However, success rates are relatively low and there are concerns about the side effects of immunosuppressant therapy. We, at Rotunda do not believe in Immunosuppression with steroids. This sort of approach has not been helpful or useful for any patients in our experience. In some rare cases of POF, follicular function may spontaneously resume, and a pregnancy can occur.
The next significant advance in characterizing ovarian autoimmune disease will be identification of the specific ovarian proteins recognized by the auto antibodies. Once we have tests that detect specific auto-antigens, we will be moving closer to some evidence-based medicine answers. This will permit development of tests based on use of specific antigens, which will improve clinical diagnosis. An understanding of how these proteins become targets of an autoimmune attack would be a significant step toward designing therapies for reversing the effects of this disorder.
As of now, the only known treatment which gives results for this disorder is Donor Egg IVF.