Causes of Infertility

Ovulation Factors
Cervical Factors
Tubal & Peritoneal Factors
Endometriosis
Male Factors
Uterine Fibroids
Unexplained Infertility

Ovulation Factors
Ovulation problems are responsible for about 20 percent of all infertility conditions.

Disorder of ovulation can be detected in several ways. Sometimes a woman has no menses at all (amenorrhea).
At other times she may ovulate sporadically decreasing her chances for pregnancy.

If ovulation dysfunction is the only infertility factor, treatment with clomiphene citrate or with similar medications can restore normal ovulation in about 80% of the patients.

And of those that do ovulate, about 50% will conceive after three cycles of treatment. Side effects attributed to the medication occur in less than 10% of patients and include hot flushes, breast tenderness, and abdominal pain as a result of enlargement of the ovaries. There is also increased incidence of twins (7%) because more than one egg may be released.

In some women the problem with ovulation can be attributed to Polycystic Ovarian Syndrome (PCOS) characterized by irregular cycles, obesity and increased androgen (such as testosterone) hormone levels. Here, adding an insulin sensitizing agent (such as metformin) can improve the quality of ovulation, and consequently increasing pregnancy rates and decreasing miscarriage rates.

Sometimes issues with ovulation can be traced to a high level of a pituitary hormone called prolactin. This condition can be treated medically.  In other patients, the ovulatory disorder may be caused by stress or by abnormal thyroid hormones. An underactive thyroid can be treated medically as well.  It is important to recognize that once an ovulatory issue is identified, proper treatment can result in an excellent pregnancy rate.

In older women, problems with ovulation may result from normal” aging” of their eggs. Other women may experience menopause at a younger age (Premature Ovarian Failure). In these situations, in vitro fertilization (IVF) with donated eggs from younger women (egg donation) may be their only recourse. Delivery rates associated with egg donation can exceed 70%.

Cervical Factors
Once sperm are ejaculated, they must "swim" from the vagina through the cervix and into the uterus. This is facilitated by the cervical mucus which is produced by numerous small glands (endocervical glands) lining the cervix. The amount of cervical mucus, and its consistency, is influenced by the hormone estrogen. When estrogen levels increase, prior to ovulation, more cervical mucus is produced and it becomes "thinner," thus enhancing sperm transport.

Cervical factor infertility results if the sperm cannot travel through the cervical mucus to the uterus. This might be caused by "inadequate sperm", insufficient mucus, mucus that is too thick, or the presence of antisperm antibodies.  Medications, such as clomiphene citrate, can also negatively affect the cervical mucus secondary to anti-estrogen effects.

Antisperm antibody reactions occur when the body mistakes sperm for invading pathogens, such as a virus or bacteria, and seeks to destroy them. Antibodies occur in the female and less commonly in the male. Antibody formation in the male usually results from contact between blood cells and sperm, as through testicular trauma or a varicocele.

Intrauterine insemination (IUI) is often the treatment of first choice for cervical factor infertility. IUI involves placing specially washed and concentrated sperm directly into the uterus, thus bypassing the cervix altogether.  If moderate to severe male factor infertility is present, IUI using donor sperm or IVF with ICSI may be recommended.

Tubal & Peritoneal Factors
Because open, healthy fallopian tubes are necessary for conception, tests to determine tubal patency
(patent = open) are important.  Tubal and/or peritoneal factors account for about 35 percent of all infertility problems. A special x-ray called a hysterosalpingogram (HSG) can be performed.  If the HSG demonstrates blocked fallopian tubes, scar tissue may be present.  Laparoscopy may consequently be performed to determine if adhesions (scar tissue) have formed on the outer surface of the tubes and to what extent they interfere with tubal function. Other tests, such as an office hysteroscopy or a sonohysterogram, may also be recommended.

If the tubes are found to be blocked, scarred, or damaged, surgery can sometimes correct the problem. Although many tubal problems can be corrected by surgery, women with severely damaged tubes are so unlikely to become pregnant that laparoscopic repair is seldom attempted.  If this is the case, in vitro fertilization (IVF) offers the best hope for a successful pregnancy.

Endometriosis
The term endometriosis refers to a benign and common disease in which cells that line the inside of the womb (the endometrium) are established outside the womb, such as on the ligaments supporting the uterus, on the ovaries, tubes, pelvis, bowels, or bladder.  In patients with endometriosis, these cells, like the endometrium, respond to the monthly hormonal changes. When the woman with endometriosis menstruates, the endometriosis breaks down in the same way that the lining of the uterus does, which can lead to inflammation and scarring. 

Some patients with endometriosis may have no symptoms.  Others may experience considerable pain during their periods or during intercourse.

On pelvic examination, women with endometriosis may exhibit tenderness and thickening of the supporting ligaments of the uterus in women. Ovarian cysts may be observed as well.
While the majority of women with endometriosis are fertile, many women with pelvic endometriosis may experience difficulty becoming pregnant.

In many cases, endometriosis leads to anatomical distortion of the pelvic, thus causing infertility.  In other cases, it is likely that substances secreted by the endometriosis adversely affect egg development, sperm binding to the egg, fertilization, tubal function and embryo implantation.

The only means of diagnosis of endometriosis is by laparoscopy, which assesses the severity of endometriosis and the condition of the fallopian tubes. There are a number of different classification systems for endometriosis, but the most widely used is that of the American Society for Reproductive Medicine (ASRM), in which endometriosis is classified into four stages: minimal, mild, moderate and severe.  There is little correlation between the severity of symptoms and extent of the endometriosis.

The exact cause of endometriosis is not known for certain.  However, the most widely accepted explanation for endometriosis is that viable cells from the lining of the womb pass backwards (retrograde) into the fallopian tube and out into the pelvic (peritoneal) cavity.  In most women, these cells will be destroyed by the woman's immune system. However, in some women, these cells implant and proliferate, and for reasons unknown, cannot not be cleared.

Male Factors
The following is a list of risk factors related to male infertility (also called male factor or male factor infertility):

• history of prostatitis or genital infection
• testicular trauma or torsion
• history of precocious puberty (puberty occurring at a young age) or delayed puberty (puberty occurring at an older age)
• exposure to toxic substances or hazards on the job, such as lead, cadmium, mercury, ethylene oxide, vinyl chloride, radioactivity, and x-rays
• cigarette or marijuana smoke
• heavy alcohol consumption
• exposure of the genitals to high temperatures
• hernia repair
• undescended testicles
• prescription drugs for ulcers or psoriasis
• DES taken by mother during pregnancy
• mumps after puberty

Problems with the production and maturation of sperm are the most common causes of male infertility.  Sperm may be immature, abnormally shaped, or unable to move properly.  Or, normal sperm may be produced in abnormally low numbers (oligospermia) or seemingly not at all (azoospermia).  This problem may be caused by many different conditions including the following:

• infectious diseases or inflammatory conditions such as the mumps virus
• endocrine or hormonal disorders such as Kallman's syndrome or pituitary problem
• immunological disorders in which some men produce antibodies to their own sperm
• environmental and lifestyle factors
• genetic diseases (most are associated with sperm abnormalities, either directly or indirectly):
1. cystic fibrosis - an inherited condition that typically involves the lungs and pancreas, but can present also as a cause of infertility with or without mild sinus problems; 6 to 10 percent of men with obstructive azoospermia have congenital bilateral absence of the vas deferens (CBAVD), which means they were born without the vas deferens; of these, 70 percent may have cystic fibrosis or carry a mutation in the cystic fibrosis gene.
2. Noonan syndrome - an inherited condition which can occur in either males or females. In males, this syndrome can cause abnormal gonadal (testicular) function.
3. myotonic dystrophy - an inherited condition with progressive multi-system involvement, resulting in infertility (underdeveloped testes and abnormal sperm production), in some cases.
4. hemochromatosis - an inherited condition affecting iron storage. Eighty percent of men with hemochromatosis have testicular dysfunction.
5. sickle cell disease - an inherited condition affecting the normal production of hemoglobin.
6. sex reversal syndrome - a male who has the sex chromosomes of a genetic female (XX, instead of XY), resulting in azoospermia and other characteristics.
7. androgen receptor gene mutations - an inherited condition in which a man is genetically male (46,XY), but has infertility due to a defect in receptors for testosterone.
8. chromosomal abnormalities - men with an extra X sex chromosome, known as Klinefelter syndrome, often do not produce sperm or produce very low quantities of sperm.
9. chromosome rearrangements - in some persons, there are the usual number of chromosomes (46) in the nucleus (center) of cells, but rearrangements in the chromosome material, where a piece of a chromosome has exchanged places with another, has taken place; men with either azoospermia or oligospermia have a higher frequency of chromosome rearrangements than is found in the general population.
10. deletions in the Y chromosome - in some persons, there are the usual number of chromosomes (46) in the body cells, but small sections of the Y chromosome are missing or deleted; anywhere from 3 to 30 percent of men with either azoospermia or oligospermia have deletions in the Y chromosome.
    
    It is important to understand that men who have genetic problems which cause their infertility, such as a deletion in the Y chromosome, can pass this problem to their sons, who would also have infertility, if they elect to use their own sperm in achieving a pregnancy.

• anatomical abnormalities
  Obstructions of the genital tract can cause infertility by partially or totally blocking the flow of seminal fluid. Some of these abnormalities may be of congenital (present at birth) origin or the result of a genetic defect. Others could have occurred due to infection or inflammation of the urogenital tract, surgery that left scar tissue in the genital tract, or the presence of varicose veins in the scrotum (scrotal varicoceles).
• immotile cilia syndrome
  In this condition, the sperm count is normal but the spermatozoa are non-motile such as in Kartagener's syndrome, an inherited disorder.
• mitochondrial deletions
  Mitochondria are structures in the cell responsible for energy production. There are actually a set of genes in the mitochondria, separate from the normal chromosome set contained in the nucleus. Recently, it has been discovered that these genes, when altered or deleted, can affect a person's health and/or fertility.
• liver disease, renal disease, or treatment for seizure disorders
• other factors
  Other factors may arise from the defective delivery of sperm into the female genital tract, which could be caused by impotence or premature ejaculation.

In addition to a complete medical history and physical examination, diagnostic testing for male factor infertility may include the following:

• multiple semen analysis - at least two semen examples are collected on separate days to examine the semen and sperm for various factors, such as semen volume, consistency, and pH, and the sperm count, motility, and morphology (shape).
• other tests - (to determine the cause of sperm abnormalities or diseases of the male reproductive system)

There is a range of treatment options currently available for male factor infertility. Treatment may include:

• assisted reproductive technologies (ART)
  This type of treatment may include the following:
• intrauterine insemination (IUI)
  Artificial insemination involves the placement of relatively large numbers of healthy sperm either at the entrance of the cervix or into the partner's uterus, bypassing the cervix, to have direct access to the fallopian tubes.
• In vitro fertilization (IVF) and other related techniques
  IVF has been used for the treatment of male infertility. As is the case with artificial insemination, IVF and similar techniques offer the opportunity to prepare sperm in vitro, so that oocytes are exposed to an optimal concentration of high quality, motile sperm.
• Introcytoplasmic sperm injection (ICSI)
  This treatment is used to facilitate sperm penetration by injection of a single sperm into the oocyte. Fertilization then takes place under the microscope.
  
  
• drug therapy
  A small percentage of infertile men have a hormonal disorder that can be treated with hormone therapy. Hormonal imbalances caused by a dysfunction in the mechanism of interaction between the hypothalamus, the pituitary gland, and the testes directly affect the development of sperm (spermatogenesis). Drug therapy may include gonadotrophin therapy, antibiotics, or another medication deemed appropriate.
  
• surgery
  Surgical therapy in male infertility is designed to overcome anatomical barriers that impede sperm production and maturation or ejaculation. Surgical procedures to remove varicose veins in the scrotum (varicocele) can sometimes serve to improve the quality of sperm.

Uterine Fibroids
Fibroids are benign uterine tumors originating from the uterine muscle (myometrium). They begin as small seedlings in women with genetic predisposition and increase in size during the reproductive life and especially during pregnancy. A very small percentage of fibroid tumors, usually those that grow rapidly, may become cancerous.

Fibroid tumors may be very small or very large.  They may be located outside of the uterus (subserosal), in the wall of the uterus (intramural), in the uterine cavity (submucosal or intracavitary), or anywhere in between. The symptoms vary depending upon size and location of the fibroids. Some women may be totally asymptomatic. Others may have pelvic pain and pelvic pressure symptoms as well as symptoms from the urinary or gastrointestinal systems. With submucosal or intracavitary fibroids, heavy menstrual bleeding, clotting, and/or hemorrhaging may be present.

Submucosal or intracavitary fibroids may prevent normal embryo implantation and contribute to infertility.  Intramural fibroids may also decrease fertility and may be removed to improve chances for pregnancy.  In women of reproductive age, large fibroids larger may contribute to infertility, may increase the risk of a miscarriage, or may lead to premature delivery or other pregnancy-related complications.

Uterine fibroids can be detected by pelvic ultrasound, computerized tomography (CT) scans, or magnetic resonance imaging (MRI).  Submucosal or intracavitary fibroids can be evaluated by hysteroscopy, hysterosalpingogram, or sonohysterogram.  Laparoscopy allows visualization of the size and location of intramural and subserosal fibroids.

Surgical excision is the only way to permanently remove fibroids.  Fibroids that rapidly increase in size are suspect of being cancerous and should be removed without delay. Treatment of other fibroids depends on their size, location, and associated symptoms. Small and asymptomatic fibroids in a woman who is approaching menopause may be observed without specific treatment; they will begin to decrease in size after menopause occurs.  Symptomatic fibroids in a woman who wants to preserve her uterus for future childbearing should be removed via myomectomy, leaving the uterus in place and its anatomy restored. In a woman who has completed her childbearing, fibroids may be removed along with the uterus (hysterectomy).

Fibroids are estrogen-dependent tumors; they decrease in size with a decrease in the estrogen levels.  Medications such as GnRH analogues (leuprolide acetate) decrease the size of the fibroids by suppressing estrogen levels.  However, within six months after the end of treatment with GnRH analogs, the fibroids usually grow back to their original size.

Unexplained Infertility
Unexplained infertility suggests that a conventional battery of fertility testing for both partners fails to reveal a specific cause for infertility.   Approximately 10% of reproductive-aged couples are diagnosed with unexplained infertility.  In addition to reviewing the medical history and performing a physical examination, the following tests are often performed to rule out possible causes for subfertility:

• Baseline endocrine laboratory testing
• Ovulation testing
• Transvaginal ultrasound
• Hysterosalpingogram (HSG)
• Sonohysterogram (SHG)
• Hysteroscopy
• Laparoscopy
• Semen analysis

The following treatments are often used to treat couples with unexplained infertilty:

• Drugs to promote superovulation, such as clomiphene citrate, human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) drugs
• Intrauterine insemination (IUI)
• In vitro fertilization (IVF)

The emotional reaction to a diagnosis of unexplained infertility can be difficult and frustrating, especially since couples usually enter into testing with the expectation that they will receive a diagnosis.  Fortunately, fertility treatments are often able to help patients with unexplained infertility conceive in a timely manner