Department of Obstetrics, Gynecology and Reproductive Science

Reproductive Endocrinology and Infertility: Treating Infertility
General Topics

• Infertility: Introduction.
• Recurrent Pregnancy Loss: Two or more occurrences of miscarriage.
• Hyperprolactinemia: Overproduction by the pituitary gland of the hormone prolactin, which interferes with normal reproductive function.
• Polycystic Ovary Syndrome: A common cause of irregular ovulation.
• Pelvic Surgery: Laparoscopy, hysteroscopy, laparotomy, and other surgeries used to evaluate and treat diseases of the female reproductive tract.
• Endometrosis: A condition in which there is a growth of tissues outside of the uterus that can cause pelvic pain or infertility.
• Male-Factor Infertility: Infertility can be caused by disorders of sperm quantity and/or quality.
• Uterine Fibroids: Benign tumors of the uterus that can cause infertility, heavy periods, severe menstrual cramps, and pelvic pressure.
• Reversal of Tubal Ligation
• Ectopic Pregnancy: Pregnancies outside of the uterus, usually within the fallopian tubes, can be life threatening if not treated.
• Multiple Gestation: A frequent complication of fertility medications and procedures is the occurrence of twins and even triplets.
• Endometrial Polyps:Overgrowths of the lining of the uterus may cause infertility and irregular uterine bleeding
• Preimplantation Genetic Diagnosis: Using the technology of IVF with new molecular biology techniques, couples with a known genetic disorder can have their embryos analyzed prior to their being replaced into the uterus.

Infertility
Infertility is the failure of a couple to conceive after one year of regular unprotected sexual intercourse. Nearly one in five couples experiences infertility and seeks treatment. There is a natural decline in fertility that comes with aging. This decline accelerates after age 30. In women over the age of 35, it is often prudent to begin an evaluation of the couple after only 6 months of failing to conceive.

Primary infertility is the term used to describe infertility in a couple who has never conceived, while secondary infertility would be used to classify infertility in a couple who has achieved a pregnancy in the past but is unable to do so again. There are some differences in the evaluation and treatment of the two classes of infertility, since theoretically, a couple who previously achieved a pregnancy had all the basic components of their reproductive systems intact. Secondary infertility indicates that it is likely that one or both partners have recently developed a problem that is responsible for their current infertility.

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Recurrent Pregnancy Loss
Miscarriage, or spontaneous abortion, occurs in 15 to 25% of pregnancies. The rate of miscarriage risk increases markedly when a woman passes the age of 40, in some studies, approaching 50%. Most miscarriages result from chromosomal abnormalities, but other causes may be related to anatomic, hormonal, infectious, or immunological abnormalities.

Recurrent pregnancy loss is usually defined as at least three miscarriages with no more than one pregnancy extending into the third trimester. When a couple presents with this history, the physician attempts to identify any abnormalities that may be causing the frequent losses. A direct cause is found less than half the time these evaluations are performed. Fortunately, couples with unexplained recurrent miscarriage usually have a high chance of a successful subsequent pregnancy.

Few studies have been well done on recurrent pregnancy loss, and many of the suggested treatments are expensive and experimental. In fact, if the woman does get treated for recurrent miscarriage and subsequently gets pregnant, it is difficult to know whether the treatment was responsible for the pregnancy's success. Common tests performed on a couple who have experienced recurrent miscarriages include checking their chromosomes (karyotypes), checking a woman's uterine anatomy (hysterosalpingogram), evaluating common hormonal problems (thyroid, prolactin, glucose), checking for infections (chlamydia and mycoplasma), and checking for common immunologic problems (antibody testing). Treatment can often be simple, ranging from taking a baby aspirin each day or undergoing an outpatient surgical procedure to remove a fibroid (hysteroscopic myomectomy), to more complicated immunotherapy.

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Hyperprolactinemia
Prolactin is a hormone secreted by the pituitary gland (located at the base of the brain). Normally, prolactin is present in the blood stream in low levels in nonpregnant women. During pregnancy, prolactin levels increase approximately tenfold and stimulate milk formation. Hyperprolactinemia is a condition where the gland secretes too much prolactin in a woman who is not pregnant. Hyperprolactinemia can produce a variety of reproductive dysfunctions, including inadequate progesterone production during the luteal phase after ovulation, irregular ovulation and menstruation, absence of menstruation (amenorrhea), and breast milk production by a woman who is not nursing (galactorrhea). Prolactin levels should be measured in women who experience these conditions.

Prolactin secretion may increase mildly with sleep, stress, intercourse, exercise, nipple stimulation, ingestion of certain foods and drugs, and pregnancy. If a woman's prolactin level is elevated the first time it is tested, a second sample should be checked when she is fasting and non-stressed. If the prolactin level continues to be markedly elevated, it is important to look for a cause. Confirmed elevations of prolactin need to be evaluated. In some cases, magnetic resonance imaging (MRI) or computerized tomography (CT) of the brain will be performed to look for small tumors that might be stimulating production of prolactin. Low thyroid hormone production is a common medical condition that can cause hyperprolactinemia. In approximately 30 percent of cases, the hyperprolactinemia is unexplained. Parlodel and Dostinex are the two drugs commonly used to treat prolactin excess. They both work by suppressing prolactin production. Ovulation and menstruation generally return within six weeks of normalizing prolactin levels. Galactorrhea takes more time and is less certain to resolve. The side effects of these medications (including lightheadedness, nausea, and headache) usually resolve within the first month of use. Hyperprolactinemia is a common problem found in up to one-third of patients with absence of menstruation and in up to 90 percent of women with galactorrhea. Observation and expectant management is appropriate for some of these women, and medical management is highly successful in others.

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Polycystic Ovary Syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is a condition in which the ovaries accumulate tiny "cysts," which are actually little follicles, two to five millimeters in diameter, each of which contains an egg. Instead of the follicles' growing and going on to ovulate, they stall and secrete male hormone into the blood. Ovulation can be rare without the help of medications. In some women, there will be a long history of irregular periods and, perhaps, an increase in facial and body hair caused by more than the normal amount of male hormone in the blood. There are estimates that about 20 percent of all women have mild polycystic ovaries (PCO). The condition is probably genetic - often coming down the male side of the family. When a woman is not trying to get pregnant, oral contraceptive pills are a good treatment: they stop follicles and male hormone-producing tissue from accumulating, stop complications such as abnormal hair growth from taking place, give regular periods, provide contraception, and protect future fertility.

If a patient is attempting pregnancy, then the drug clomiphene (Clomid) is the first choice to induce ovulation. If clomiphene does not work, physicians often use injectable medications such as Pergonal, Humegon, Gonal-F, Follistim, and Repronex. Inducing ovulation in preparation for getting pregnant naturally is often complicated; however, it is most challenging in women with PCO, since often up to 10 or 20 follicles will respond and try to ovulate. It is important that if this happens, the cycle be cancelled, and that the next month it be started with lower doses of medications.

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Pelvic Surgery
Certain diseases require surgery for correction. Oftentimes, the treatment of abnormalities of the uterus, ovaries, and fallopian tubes can be performed safely as an outpatient or "same-day" surgical procedure. It is important that your physician have advanced training and extensive experience in performing laparoscopic and hysteroscopic surgery to make your surgery safe, convenient, and minimally invasive. Other pelvic surgeries such as myomectomies, laparoscopically-assisted vaginal hysterectomies, and endometrial ablations also require significant surgical expertise.

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Endometriosis
Endometriosis, or growth of endometrial tissue outside the uterus, is without question one of the most baffling conditions that affect women. An estimated 10 million women in the United States are affected by this disease, and it is one of the leading causes of infertility in women. Though there are many effective treatments, there is no known cure. The diagnosis is confirmed when uterine or endometrial cells are identified outside their usual location inside the uterus. Endometrial tissue may be found on the outside of the uterus, inside and outside the ovaries, or implanted upon the fallopian tubes, bowel, urinary tract, and anywhere in the abdomen. When a woman gets her period, the endometriosis often responds to the menstrual cycle's hormonal signals. When the endometrial tissue outside the uterus bleeds, the woman may have sensations of deep pain or cramping because the body responds to the bleeding by surrounding it with inflammation, often causing adhesions and leaving scar tissue.

Endometriosis is estimated to be present in 15% of all reproductive-age women, but as many as 30-40% of all infertile women. The exact ways that endometriosis affects infertility are not fully understood. Scar tissue and adhesions are known to interfere with the path the egg and sperm must travel to unite and become fertilized and implanted. In some women, endometriomas (a special type of ovarian cyst that contains endometrial cells that grow and bleed during menstruation) may form inside the ovaries, causing enlargement of the ovaries and thereby interfering with normal ovarian functions such as ovulation. There also may be links between endometriosis and hormonal imbalances or immune system abnormalities that can also interfere with fertility. Some women with endometriosis experience severe pain during their menstrual cycle or during intercourse, excessive or irregular bleeding during menstruation, or urinary or bowel problems in conjunction with menstruation. Other symptoms may include fatigue, painful bowel movements with periods, lower back pain with periods, diarrhea and/or constipation, and other intestinal upset with periods. The amount of pain is not necessarily related to the extent or size of growths. Other women experience no symptoms, and their endometriosis goes undiagnosed until they seek medical help to explain their inability to conceive. Because endometriosis is progressive, the key to preserving fertility in women who have endometriosis is early diagnosis and treatment of the symptoms that interfere with conception and pregnancy.

Ultrasound scans may detect the presence of endometriomas in the ovaries, while laparoscopy is typically the definitive way endometriosis is diagnosed. Laparoscopy is typically performed as an outpatient surgical procedure in which a fiber optic telescope is inserted into the patient's abdomen below the navel to look for endometriosis, scarring, and adhesions. In general, surgery and hormonal treatments may be helpful for the treatment of pain related to endometriosis. For infertility, there may be a need for other types of treatment following surgery to increase the number of eggs ovulated in a given month. In extreme cases, in which the endometriosis has caused extreme tubal damage, in vitro fertilization may be needed to bypass the scarred fallopian tubes.

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Male-Factor Infertility
Infertility in the male factor may be responsible for 40% of couples presenting for infertility evaluation. Current diagnostic and advanced treatment modalities have significantly improved prognosis and created a new era in the treatment of male-factor infertility. The initial male fertility evaluation consists of a thorough history and physical examination. Semen analysis forms the basis of the initial evaluation for assessing male-factor infertility. Sperm motility is evaluated both quantitatively and qualitatively. Sperm morphology, determing the percentage of normally shaped sperm, is also an important factor in semen analysis.

Semen Analysis: Minimal Standards of Adequacy
(Apply to at least two specimens)

• Ejaculate volume 1.5 to 5.0 ml.
• Sperm count >20 million sperm/ml.
• Sperm motility >50%
• Forward progression >2 (scale 0 to 4)
• Sperm morphology (WHO) >50% normal
• pH 7.2 to 7.8
• No significant white blood cells

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Uterine Fibroids
Uterine fibroids are abnormal growths in the uterus that almost always are noncancerous. These abnormal growths are one of the most common causes of infertility in women. There are no known causes for uterine fibroids, though the explanation appears to be an absence of a signal to turn off division of the muscle cells that make up the walls of the uterus. While traditionally hysterectomy has been recommended for women with fibroids, women with fibroid tumors are now being offered more conservative treatments such as myomectomies. A myomectomy is a surgical procedure in which the fibroid tumor is removed, yet the uterus is left in place. Reconstruction of the uterus is a vital part of this procedure. Specialists who perform myomectomies are often able to save a woman from needing a hysterectomy, enabling her to retain her child-bearing ability. For some fibroids, the myomectomy can be done on an outpatient basis (laparoscopically or hysteroscopically). Medications are an option for treating fibroid tumors in some women. Prescription medications are available that can shrink the size of the fibroid and lessen heavy bleeding and pain. These medications can only be used for a limited period of time, however, and require careful monitoring by a physician.

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Reversal of Tubal Ligation
Patients who have undergone previous tubal sterilization are candidates for either tubal reconstructive surgery or IVF. The ideal candidates for tubal reconnection are women in whom investigations reveal that the subsequent total tubal length following reconnection will be greater than 4 cm., and cases where the tubes have been divided relatively close to the uterus. The statistical chance of ideal candidates for microsurgical tubal reconnection subsequently to become pregnant within two years is in the range of 60-75 percent with a subsequent ectopic pregnancy incidence of about 10 percent.

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Ectopic Pregnancy
Ectopic pregnancies, pregnancies that occur outside of the uterus, account for 2-3% of all pregnancies. The majority of ectopic pregnancies occur in the fallopian tubes. Traditional treatment included removal of the entire fallopian tube. More recently, these tubal pregnancies have been managed conservatively, either by laparoscopic surgery or by medical treatment (Methotrexate). Any infertility patient with abnormal bleeding and pelvic pain should consider ectopic pregnancy as a real possibility and should have a pregnancy test performed.

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Multiple Gestation
A frequent complication of fertility treatments, multiple pregnancies may cause preterm labor, pregnancy-induced hypertension, and diabetes Early diagnosis is vital in order to provide preventive care and explore all medical options, including multifetal reduction in cases of higher order multiple gestations (triplets, quadruplets, etc.). The key to the treatment of multiple pregnancies is to avoid their occurrence by carefully monitoring patients who are receiving fertility drugs and by minimizing the embryos transferred in patients undergoing in vitro fertilization.

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Endometrial Polyps
Overgrowths of the uterine lining are called endometrial polyps. Some polyps are found incidentally and do not require treatment. Others may cause irregular bleeding and, at times, infertility, and should be surgically removed. When performed by an experienced surgeon, the treatment of endometrial polyps can be performed hysteroscopically as an outpatient procedure and should be safe and effective.

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Preimplantation Genetic Diagnosis
Traditional methods used to identify genetic disease require prenatal diagnosis through amniocentesis or CVS, followed by potential termination of the pregnancy if the fetus is found to be affected. Recent scientific advances now allow the diagnosis of some genetic disorders before pregnancy is established using the technique of preimplantation genetic diagnosis, or PGD. PGD combines the technology of in vitro fertilization (IVF) with new molecular biology techniques. Following fertilization of an egg, a single cell is removed from an embryo in a procedure called an "embryo biopsy." If the embryo is found not to contain the genetic disorder for which it is being tested, the embryo is transferred into the uterus and allowed to develop. Couples with a known genetic disorder can now have unaffected children without some of the emotional and ethical challenges associated with traditional prenatal diagnosis.

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