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Unexplained infertility

 

INTRODUCTION

“Unexplained” infertility is the inability to achieve pregnancy, for no apparent reason, after one year or more of unprotected intercourse. Almost 60-80 million have difficulty conceiving. During this time, couples may experience frustration, jealousy, guilt, and anger. However, recent breakthroughs in diagnostic tests and treatments including assisted reproductive technologies (ART) offer more hope than ever before for a successful pregnancy. Pregnancy is now possible for more than half the couples pursuing treatment. For about 84 percent of couples, experts can identify the male and female factors that reduce fertility. For the other 16 percent of infertile couples, no explainable cause for the inability to conceive has been discovered. This section will explain how the diagnosis of unexplained infertility is reached, the chances that it can be overcome (both spontaneously and in response to treatment), and the various treatments that are used in unexplained infertility.

NORMAL REPRODUCTIVE FUNCTION

In women, at least one of the ovaries must be working properly in order for ovulation to occur, and at least one of the fallopian tubes must be intact and open in order to pick up the egg released during ovulation. The egg is usually fertilized by the male’s sperm inside the fallopian tube. After fertilization, the fertilized egg, or embryo, travels through the tube to the uterus, where it implants in the uterine lining and grows (Figure 1).

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Figure 1: Female Reproductive Tract. Arrows indicate path sperm must travel to reach the egg.

In men, at least one testis and its accompanying duct system must produce and transport sperm (Figure 2). Sperm are formed in the seminiferous tubules and then enter the epididymis, a coiled tube attached to the top of each testis. The epididymis leads into a larger duct about 14 inches long called the vas deferens. Behind the bladder is a pair of pouches called seminal vesicles, which secrete fluid for the sperm’s nourishment. Each one is joined to a vas to form an ejaculatory duct. The two ducts lead into the prostate gland and direct the ejaculate (semen containing sperm) into the urethra, a tube leading from the bladder to the end of the penis.
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Figure 2 : Male Reproductive tract. Arrows indicate sperm’s path at ejaculation
THE DIAGNOSIS OF UNEXPLAINED INFERTILITY
Female Evaluation

The standard infertility work-up for the female consists of a medical history, a physical examination, a test of blood hormone levels, a test of sperm in the cervical mucus after intercourse (postcoital test), a sample of the endometrial lining in the second half of the cycle (endometrial biopsy) for a blood progesterone level, and an x-ray of the uterus and fallopian tubes (hysterosalpingogram [HSG]). A laparoscopy, an outpatient surgical procedure, may be performed on the woman to insure that her tubes, ovaries, and pelvis are normal, and to look for endometriosis (a condition where endometrial tissue has implanted in various spots throughout the pelvis) and pelvic adhesions (scar tissue).

The diagnosis is termed unexplained infertility if conditions impeding the woman’s ability to conceive, such as pelvic adhesions, tubal blockage, or hormonal problems, are excluded after all of these tests have been performed and the male’s reproductive system is functioning normally.

Male Evaluation

A qualified specialist evaluates the male by obtaining a complete medical history, physical examination, and a semen analysis. Hormonal testing is performed as deemed necessary. Problems that can be detected after this initial evaluation include varicocele, obstruction (partial or complete), hormonal problems, ejaculatory dysfunction, and infection. Unexplained infertility is diagnosed only when the entire male partner’s evaluation is normal,including the semen analysis. However, antisperm antibody testing should also be performed to rule out an autoimmune problem before establishing this diagnosis. Additional tests of the male partner’s sperm, including strict morphological assessment and hamster egg penetration tests, are sometimes performed to completely exclude a sperm abnormality.

The Chances for Pregnancy in Unexplained Infertility

Fortunately, over time there is a significant spontaneous pregnancy rate in couples with unexplained infertility. This spontaneous pregnancy rate depends on the man’s sperm count and the woman’s age. Couples with unexplained infertility of less than three years duration have a 60 percent chance of spontaneously conceiving in the next three years. The spontaneous conception rates fall by 25 percent each year thereafter. The spontaneous pregnancy rate may be even higher in patients who have had a previous pregnancy and are diagnosed with what is termed secondary infertility.

Treatments for unexplained infertility are directed toward increasing the chance of achieving a pregnancy by increasing the number of eggs and sperm and by getting the eggs and sperm closer to each other. However, since the long-term prognosis is good without treatment in couples with unexplained infertility, and since treatments may be expensive and have side effects and risks, it is not uncommon, particularly in younger women, to delay treatment for a limited period of time to allow the couple to conceive naturally.

THE TREATMENT OF UNEXPLAINED INFERTILITY

Intrauterine Insemination (IUI)

Catheter loaded with sperm

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Figure 3: Intrauterine Insemination . sperm are washed and inserted directly into the uterine cavity uterine cavity

Sperm inserted into
uterine cavity

cervix

Catheter loaded with sperm

Vagina

Figure 3: Intrauterine Insemination . sperm are washed and inserted directly into the uterine cavity

Clomiphene Citrate and IUI

Clomiphene citrate is often given to the female to facilitate ovulation. This method of empirically increasing a couple’s monthly fertility, while relatively inexpensive, has only marginal success rates, approximately 5 to 10 percent per cycle. Particularly in older women where time is of the essence lengthy trials of clomiphene citrate alone or clomiphene combined with IUI may be counterproductive. This leads to a delay in the implementation of more effective therapies, which may become less effective with increasing age. The combination of clomiphene and IUI enhance fertility more than either clomiphene or IUI alone. A pregnancy rate of 10 to 20 percent per cycle may be achieved in couples with unexplained infertility, depending upon the age of the female partner. If this approach is not successful within three to four cycles, more advanced reproductive treatments may be advisable.

Follicle Stimulating Hormone or Human Menopausal Gonadotropins and IUI

With follicle stimulating hormone (FSH) or human menopausal gonadotropin (hMG)/IUl therapy, aggressive multiple ovulation induction is performed with injectable medications in order to obtain multiple eggs per cycle. At the time of ovulation, which may be triggered by human chorionic Gonadotropin (hCG), IUI is performed to increase the number of sperm in the woman’s fallopian tubes. Multiple studies have shown between a 15 to 20 percent per cycle pregnancy rate using this technique for couples with unexplained infertility where the female partner is younger than 35 years of age. It is often the first advanced therapy chosen for unexplained infertility. However, it has not been absolutely proven effective. Most physicians recommend three or four of these treatment cycles prior to implementing more advanced technologies.
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Figure 4: Egg retrieval is usually performed through the vagina with an ultrasound guided needle.
In Vitro Fertilization

In vitro fertilization (IVF) is increasingly utilized in the treatment of unexplained infertility. Pregnancy rates for this complex procedure are improving nationally and it appears effective for the treatment of unexplained infertility. The goal of IVF is to increase the number of sperm and eggs in direct proximity to each other, thus increasing the chances of a successful fertilization. At times, a clearer reason for the cause of unexplained infertility is discovered during IVF. Some couples may have poor or absent fertilization in vitro (outside the body), thus suggesting a sperm and/or egg problem as a cause for infertility.With follicle stimulating hormone (FSH) or human menopausal gonadotropin (hMG)/IUl therapy, aggressive multiple ovulation induction is performed with injectable medications in order to obtain multiple eggs per cycle. At the time of ovulation, which may be triggered by human chorionic Gonadotropin (hCG), IUI is performed to increase the number of sperm in the woman’s fallopian tubes. Multiple studies have shown between a 15 to 20 percent per cycle pregnancy rate using this technique for couples with unexplained infertility where the female partner is younger than 35 years of age. It is often the first advanced therapy chosen for unexplained infertility. However, it has not been absolutely proven effective. Most physicians recommend three or four of these treatment cycles prior to implementing more advanced technologies.
During the IVF cycle, the woman is given medications to induce multiple egg development. The eggs are retrieved from the ovary by transvaginal ultrasound aspiration (Figure 4) and individually incubated with the partner’s sperm. Fertilization and early embryo development occur in the laboratory. Two or three days later the resulting embryos (often more than one) are placed into the woman’s uterus through her cervix, in a procedure known as embryo transfer (Figure 5). National average delivery (“take home baby”) rates are 22.5 percent per retrieval (1995 data), although they vary considerably for individual programs. IVF is expensive and involves the use of multiple medications with unknown long-term effects. IVF has several possible side effects, including a condition known as ovarian hyperstimulation syndrome, and a 37 percent chance of multiple pregnancy.

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Gamete Intrafallopian Transfer

Gamete intrafallopian transfer (GIFT) is performed as an attempt to increase the chances of fertilization by increasing the number of eggs and sperm in direct proximity to each other in the woman’s fallopian tube. The woman is given FSH and/or hMG to induce multiple egg development, and the eggs are removed from the ovary either by laparoscopy or transvaginal ultrasound aspiration. A large number of moving sperm and one or more eggs are then placed into the woman’s fallopian tube(s) where fertilization will hopefully occur (Figure 6). If all goes well, a fertilized egg will travel to the uterus and implant in the uterine lining, thus establishing a pregnancy.
GIFT had a delivery rate of 27 percent per retrieval in 1995. The success of GIFT depends in part on the condition of the fallopian tubes. Many centers no longer perform GIFT because of the added cost and invasiveness of laparoscopy and usually proceed directly to IVF, with comparable delivery rates and much lower costs. A fundamental difference between IVF and GIFT is that fertilization is performed in the laboratory with IVF, rather than in the fallopian tube with GIFT. The “diagnostic” benefit of being able to directly assess the fertilization with IVF is another reason for selecting IVF over GIFT.
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Figure 6. In GIFT, eggs (are retrieved from the ovaries (step I) and mixed with
sperm (step 2). The sperm-egg mixture is loaded into a catheter and injected
directly into the fallopian tube(s) (step 3).

GIFT had a delivery rate of 27 percent per retrieval in 1995. The success of GIFT depends in part on the condition of the fallopian tubes. Many centers no longer perform GIFT because of the added cost and invasiveness of laparoscopy and usually proceed directly to IVF, with comparable delivery rates and much lower costs. A fundamental difference between IVF and GIFT is that fertilization is performed in the laboratory with IVF, rather than in the fallopian tube with GIFT. The “diagnostic” benefit of being able to directly assess the fertilization with IVF is another reason for selecting IVF over GIFT.

Intracytoplasmic Sperm Injection

Recent technical advances have made progress in assisting fertilization of the egg by the sperm. Patients with unexplained infertility who have undergone IVF with poor or no fertilization may benefit from micromanipulation techniques such as intracytoplasmic sperm injection (ICSI). In this procedure, a sperm is injected directly into the egg to facilitate fertilization. Micromanipulation of eggs and sperm requires great expertise and is not performed in all IVF programs. As more experience is obtained, potentially more patients will be candidates for this form of assisted reproductive technology.

OTHER OPTIONS FOR HAVING A FAMILY

Third party reproduction, using the couple’s own sperm and eggs or donor sperm and eggs, is an option for some couples with unexplained infertility. Surrogacy is also an option.

PSYCHOLOGICAL SUPPORT

Infertility is a difficult experience under the best of circumstances. The cyclical nature of testing and treatment can be physically, emotionally, and financially exhausting. When no cause can be found as to why conception has not occurred, infertility takes on an added stress, the pain of not knowing. Unexplained infertility may feel like a roller coaster ride as each new test and treatment brings hope, and possibly, disappointment. To help with the stress, couples may want to find ways to communicate their feelings with others who understand, such as caring family or friends, or other couples or with a mental health professional who specializes in infertility. Taking time to exercise, eat healthy, and enjoy recreational activities or hobbies is also important. In addition, some couples have found it useful to take a break from treatment to “regroup” and regain control in their lives. Despite the emotional difficulties of infertility, many couples say that the experience strengthened their relationship and helped them learn adaptive coping mechanisms for life.

POTENTIAL IMPACT OF ENVIRONMENTAL TOXINS ON INFERTILITY

Environmental toxins commonly encountered in modern life have been increasingly implicated as a source of reduced fertility. It is clear that smoking, and the toxins in cigarette smoke, have adverse effects on human eggs and sperm. For these reasons, smoking is strongly discouraged during fertility treatment. In addition, the use of marijuana is associated with significant deleterious effects on human sperm. Excesses of caffeine and alcohol are also strongly discouraged in couples pursuing fertility. In addition, environmental toxins such as nickel, lead, and mercury are associated with adverse health effects, and may negatively affect human fertility. If couples or indi- viduals being treated for unexplained infertility feel that they are exposed to environmental toxins in excessive amounts, they should discuss this with their physician.

COMPLICATIONS OF TREATMENT

A major complication of all treatments (except IUI alone), especially those involving FSH or hMG, is the incidence of multiple pregnancy. While the infertile couple’s first reaction to the increased probability of multiple pregnancy may be positive, the results of high-order multiple pregnancies can be tragic. Sometimes if a woman is pregnant with a multiple pregnancy greater than twins, the physician may recommend multifefal pregnancy reduction. This procedure reduces the number of embryos early in the pregnancy to give the remaining embryo(s) a better chance of survival. This decision lies with the infertile couple and their physician, who will explain the risks and benefits of the various therapeutic options.

CONCLUSION

Patients with unexplained infertility are often very frustrated with the lack of a definitive diagnosis. However, there is a significant spontaneous pregnancy rate in couples with unexplained infertility, and there are a number of treatments of varying cost, invasiveness, and success which the physician may prescribe. Most of these treatments increase the number of eggs and sperm in proximity to each other either inside the fallopian tube or outside the body (in the laboratory), thus increasing the chance of conception. The majority of couples who have unexplained infertility will see their initial frustration eventually change into happiness after achieving a pregnancy spontaneously or following successful treatment.