There are many factors that can cause infertility, affecting either the female or male partner, or both. It is very important for both partners to be thoroughly evaluated to determine the cause – and best treatment options – for each individual patient. However, in some cases, even with comprehensive testing, a cause cannot be determined.
A female is born with millions of eggs. Each month, several hundred to one thousand eggs are eligible for ovulation. Hormonal changes throughout the menstrual cycle, as well as local events within the ovary, typically allow only one egg to be released during a single menstrual cycle.
Eggs develop inside a water balloon-like structure called a follicle. The release of luteinizing hormone (LH) then triggers ovulation (the release of an egg from a follicle). After ovulation, the dominant follicle produces progesterone, which is critical for maintaining a receptive uterine lining, or endometrium, where a fertilized egg may implant.
If pregnancy is established, the placenta makes the hormone human chorionic gonadotropin (hCG). hCG levels rise sharply during early pregnancy and forces the dominant follicle (now called a corpus luteum) to make progesterone until the placenta takes over making progesterone. This occurs at approximately eight weeks gestation. If pregnancy is not established, the corpus luteum dissolves and progesterone levels fall, triggering a menstrual period.
Most women ovulate every 21 to 35 days. Women with cycles greater than 35 days are considered to have oligo-ovulation. Those who do not ovulate at all have anovulation. Medical therapy is often successful in these cases.
There are a number of reasons why women do not have regular cycles. Some reasons include polycystic ovarian syndrome (PCOS), thyroid disorder and adrenal gland problems. Excessive exercise or weight loss can also cause problems with ovulation. An evaluation including hormone and other blood testing, as well as ultrasound, is performed to determine the cause of the irregular cycles.
Fertility medications help to encourage the development of eggs within the ovaries. These medications – such as clomiphene citrate and injectable gonadotropins – often stimulate the ovaries to mature more than one egg in a cycle. Women undergoing ovulation induction or IVF will frequently be given progesterone during the luteal phase (the two weeks after ovulation) to help support the endometrium.
Tubal disease, one of the many causes of female infertility, is a disorder in which the fallopian tubes are blocked or damaged. Scar tissue resulting from endometriosis, surgery or infection is often the cause of tubal disease.
There are a number of treatment options available to overcome infertility caused by tubal disease, including surgical removal of scar tissue, surgical repair of damaged tubes or in vitro fertilization (IVF).
Tubal disease can result in an ectopic pregnancy, which occurs when an egg is fertilized but is unable to travel to the uterus, growing instead in the wall of the fallopian tube. This condition can result in rupture, internal bleeding and further tubal damage.
In approximately one in 70 pregnancies, the embryo implants in a location outside of the uterus. Almost all ectopic pregnancies are confined to the fallopian tubes. Ectopic pregnancies are best treated when they are diagnosed early. Women experiencing ectopic pregnancy typically have lower levels of the pregnancy hormone, hCG, that rise slowly, and often experience vaginal bleeding and pelvic pain. Ectopic pregnancies can either be treated by laparoscopic surgery or with medication.
Endometriosis is defined as the presence of endometrial tissue (the normal lining of the uterus) outside the uterine cavity. An estimated three to five million American women of reproductive age suffer from endometriosis, which is found in five percent of fertile women, compared to 20 to 30 percent of women with infertility.
While many women with endometriosis complain of painful periods (dysmenorrhea), pain with intercourse (dyspareunia) and premenstrual spotting, many have no symptoms.
Approximately 15 percent of women have moderate or severe endometriosis, which can be detected by pelvic examination and/or ultrasound. In these cases, pelvic adhesions are frequently found, making it difficult for eggs to travel down the fallopian tubes.
Lesser amounts of endometriosis can also interfere with conception. A landmark article published by Dr. Castelbaum and colleagues (Clin Endocrinol Metab.1994 Aug; 79(2):643-9) showed that women with minimal or mild endometriosis have diminished uterine receptivity, making it more difficult for an embryo to attach to the uterine lining. Some women will benefit from laparoscopy to diagnose and treat endometriosis, if present.
Normal ovarian aging begins while the female fetus is still inside the womb. A female fetus has approximately six to seven million eggs before she is born. Several hundred thousand eggs remain when a young woman enters puberty.
Research has demonstrated that the likelihood of establishing a pregnancy begins to decline when a woman reaches age 25. Between the ages of 35 and 40, fertility rates fall significantly, and further accelerate after the age of 40.
Worldwide experience with in vitro fertilization (IVF) has shown a similar decline in fertility beginning in the mid 30s, with a more rapid decline in fertility after the age of 40. This reduced fertility appears entirely due to diminishing egg quality and quantity.
Measuring follicle stimulating hormone (FSH) levels on the second, third or fourth day of a woman’s menstrual period is highly predictive of future fertility. While elevated FSH levels mostly affect women in their late 30s and early 40s, a young woman with an elevated FSH level also has a reduced likelihood of establishing a pregnancy without the use of donor eggs.
There are some women with a normal day three FSH level who still have diminished ovarian reserve. Such women, typically in their late 30s and early 40s, or with prior ovarian surgery, can be diagnosed with the use of a clomiphene citrate challenge test (CCCT). Clomiphene citrate is taken daily, starting on cycle day five for a total of five days. On cycle day ten, an FSH level is again measured. It appears that a single elevated FSH level represents diminished ovarian reserve and a poor prognosis for pregnancy, even if FSH testing in subsequent months is normal.
Another method to assess ovarian reserve and the chance for pregnancy is by assessing the woman’s antral follicles, which are small follicles that can be measured with ultrasound. An antral follicle count is a good predictor of the number of follicles in the woman’s ovaries that may produce a mature egg.
Other tests such as early follicular estradiol gonadotropinreleasing hormone agonist stimulation tests, inhibin levels (a hormone produced in the ovaries), and anti-mullerian hormone levels (secreted by the small follicles on the ovary) are not as thoroughly studied as FSH values for predicting ovarian reserve and, therefore, are not routinely recommended.
The use of donor eggs is the most effective form of therapy for women with elevated FSH testing. At RMA of Philadelphia, our donor egg program has a 70 percent per cycle pregnancy rate. We have also had successful pregnancies using ovulation induction medications in some women with diminished ovarian reserve.
Fibroids (myomas) are benign tumors arising from the muscular wall of the uterus. Fibroids are easily visualized by ultrasound. Their presence and location can be further evaluated by the use of office hysteroscopy, hysterosalpingogram or saline infusion sonography, a simple procedure during which warmed sterile saline is slowly passed into the uterine cavity using a small, soft plastic tube.
Common symptoms of fibroidsinclude an enlarged pelvic or abdominal mass, as well as heavy, frequent and prolonged periods, low blood count (anemia), pain with intercourse, painful periods and bladder pressure with frequent urination. Fibroids located in the uterine cavity can cause recurrent pregnancy loss, infertility and abnormal vaginal bleeding. Many women with fibroids may not have any symptoms, or even know that they have fibroids. Uterine fibroids often do not require treatment, but when problematic, they may be treated surgically or with medication.
In women with multiple fibroids, especially fibroids that are large and symptomatic, abdominal or laparoscopic myomectomy may be indicated. Pregnancy rates following surgery are often very high. Even small fibroids located within the uterine cavity should be removed because they can interfere with achieving or maintaining a pregnancy. This is done through the vagina using hysteroscopy.
A successful pregnancy requires that the embryo attach to the lining of the uterus (endometrium), where it will develop. There is only a narrow window of implantation during the menstrual cycle when the uterus is receptive for an embryo to establish a pregnancy.
To evaluate uterine receptivity, we measure blood levels of progesterone around cycle day 21. Elevated levels of progesterone have been associated with normal corpus luteum function, and by inference, normal uterine receptivity.
Dr. Castelbaum and colleagues have published many of the landmark studies using endometrial integrins, important markers of uterine receptivity. One marker, the avb3 endometrial integrin, has been extensively studied. It abruptly appears in the lining of the uterus on cycle day 20, at the optimal time for implantation. Understanding what regulates endometrial integrins may lead to better treatment and diagnostic strategies for infertility.
Many causes of infertility result in diminished uterine receptivity, including minimal and mild endometriosis, blocked and dilated fallopian tubes, unexplained infertility and polycystic ovarian disease. Women experiencing recurrent miscarriage may also have decreased uterine receptivity. Interestingly, when blockages in the fallopian tubes are removed prior to in vitro fertilization, normal uterine receptivity is restored. It is our practice to offer this procedure, prior to IVF, to women with dilated fallopian tubes.
Women who do not ovulate due to polycystic ovarian disease, hypothalamic amenorrhea and premature menopause can be easily treated with medications to create a receptive endometrium. This is critically important for successful frozen embryo transfers and for women using donor eggs.
A common misconception is that infertility is primarily a woman’s “problem.” In fact, infertility affects women and men equally.
To identify male infertility, a semen sample is analyzed to determine the amount or volume of semen, the concentration of sperm, percent of actively moving sperm and the number of normally shaped sperm. However, a semen analysis alone cannot fully predict a couple’s fertility. At RMA of Philadelphia, we also recommend a complete evaluation of the female partner.
The World Health Organization (WHO) has defined a normal semen analysis as a volume of greater than two cc’s (this is less than ½ teaspoon), sperm count greater than 20 million per cc, and 50 percent motility with 30 percent normal appearance (morphology).
Causes of male infertility include hormonal abnormalities, varicocele (blockage or absence of the duct which carries the sperm from the testes) and difficulty with ejaculation. Often there is no identifiable cause for abnormal sperm production, motility or appearance.
Most men with mild to moderate decreases in sperm count and motility can establish pregnancies through treatment with intrauterine insemination. The semen is washed with special media and the sperm are concentrated. A very thin, flexible catheter with the prepared sample is then placed through the woman’s cervix into her uterine cavity. This very brief, painless procedure places all of the motile sperm in the uterine cavity, close to the entrances to the fallopian tubes, where fertilization can take place.
If the semen analysis is very abnormal, more aggressive treatment is often indicated. In vitro fertilization (IVF) with intracytoplasmic sperm injection, or ICSI, is used in cases of very low sperm count, if sperm do not swim properly or have an abnormal shape that prevents them from penetrating the egg. To perform ICSI, an embryologist injects a single healthy sperm into a mature egg. This process takes less than ten minutes and does not damage either the egg or the sperm.
When there is complete absence of sperm in the ejaculate (azospermia), either due to a blockage or severely reduced sperm production by the testicle, a simple surgical procedure can be used to retrieve sperm to be used in IVF or ICSI. This procedure involves retrieval of the sperm using a thin needle.
Miscarriage is both traumatic and relatively common. Many pregnancies are lost even before a woman knows she is pregnant. It is estimated that 30 percent of pregnancies miscarry. Most pregnancy losses occur prior to eight weeks gestational age. Only three percent of pregnancies will miscarry after eight weeks.
Having two to three consecutive miscarriages has been termed recurrent pregnancy loss. It is important to recognize the likelihood of having a successful pregnancy remains high in couples who have experienced multiple miscarriages. Among women who have had three consecutive, unexplained miscarriages, there is a 70 percent chance that the subsequent pregnancy will be entirely normal. That is because the majority of all miscarriages are due to random chromosomal abnormalities of the fetus that typically do not recur.
For women experiencing several miscarriages, we routinely perform a hysteroscopy to look inside the uterine cavity for the presence of fibroids, polyps, congenital malformations or scar tissue. Both female and male partners are also tested for chromosomal abnormalities called balanced translocations. Extensive blood testing on the female partner is also performed, evaluating for immunologic disorders, abnormalities of blood clotting and hormonal imbalances. Even with a very thorough evaluation, a cause for recurrent pregnancy loss can be found in less than half of the couples evaluated.
Therapies for treatment of recurrent pregnancy loss are determined by the underlying disorder found through diagnostic testing. For example, women who are found to have a disorder of blood clotting will be treated with a blood thinner. Many women with unexplained recurrent pregnancy loss are treated with ovulation induction medication or luteal phase progesterone support. In vitro fertilization (IVF) with PGD (preimplantation genetic diagnosis), which tests the embryos for chromosomal abnormalities, is also an effective treatment options for many.