WHAT IS FEMALE FERTILITY?

The Reproductive System

• The uterus is a pear-shaped organ located between the bladder and lower intestine. It consists of two parts, the body and the cervix.
  
  
• When a woman is not pregnant the body of the uterus is about the size of a fist, with its walls collapsed and flattened against each other. During pregnancy the walls of the uterus are pushed apart as the fetus grows.
  
  
• The cervix is the lower third of the uterus. It has a canal opening into the vagina with an opening called the os, which allows menstrual blood to flow out of the uterus into the vagina.Leading off each side of the body of the uterus are two tubes known as the fallopian tubes . Near the end of each tube is an ovary.
  
  
• Ovaries are egg-producing organs that hold between 200,000 and 400,000 follicles (from folliculus, meaning "sack" in Latin); these cellular sacks contain the materials needed to produce ripened eggs, or ova.
  
  
• The inner lining of the uterus is called the endometrium, and during pregnancy it thickens and becomes enriched with blood vessels to house and support the growing fetus. If pregnancy does not occur, the endometrium is shed as part of the menstrual flow. Menstrual flow also consists of blood and mucus from the cervix and vagina.

• The hypothalamus (an area in the brain) and the pituitary gland regulate the reproductive hormones. The pituitary gland is often referred to as the master gland because of its important role in many vital functions, many of which require hormones. In women, six key hormones serve as chemical messengers that regulate the reproductive system.
  
  
• The hypothalamus first releases the gonadotropin-releasing hormone (GnRH) .
  
  
• This chemical, in turn, stimulates the pituitary gland to produce follicle-stimulating hormone (FSH ) and luteinizing hormone (LH) .
  
  
• Estrogen, progesterone, and the male hormone testosterone are secreted by the ovaries at the command of FSH and LH and complete the hormonal group necessary for reproductive health.

• With the start of each menstrual cycle, FSH stimulates several follicles to mature over a two-week period until their eggs nearly triple in size. Only one follicle becomes dominant, however, during a cycle.
  
  
• During this period, FSH also signals the dominant follicle to produce estrogen, which enters the bloodstream and reaches the uterus and stimulates the cells in the uterine lining to reproduce, therefore thickening the walls.
  
  
• Estrogen levels reach a peak in about fourteen days and stimulate a surge of LH.

• First, it stimulates ovulation by causing the dominant follicle to burst and release its egg into one of the two fallopian tubes. This occurs around the 14th day of the cycle (counting days beginning with the first day of a period).
  
  
• Next, LH causes the ruptured follicle to develop into the corpus luteum. The corpus luteum is a mound of yellow tissue. (During pregnancy, it serves to produce estrogen and progesterone.)
  
  
• The egg drops into the fallopian tube, where it is ready for fertilization. (Conception is most likely when intercourse occurs at this time, around the day of ovulation.)
  
  
• Once the sperm enters the fallopian tube, it can survive for up to three days and fertilize the egg at any point during that time. The egg, unless fertilized, only survives 12 to 24 hours.
  
  
• If fertilized, two to four days later the egg moves from the fallopian tube into the uterus where it is implanted in the uterine lining and begins its nine-month incubation.
  
  
• The placenta forms at the site of the implantation. The placenta is a thick blanket of blood vessels where the fertilized egg can attach and develop.
  
  
• If the egg is not fertilized, the corpus luteum degenerates to a form called the corpus albicans, and estrogen and progesterone levels drop. Finally, the endometrial lining sloughs off and is shed during menstruation.
  
  
• If fertilization does occur, the fertilized egg attaches to blanket of blood vessels which supplies nutrients for the developing placenta. The corpus luteum continues to produce estrogen and progesterone.

WHEN SHOULD A WOMAN SEEK FERTILITY ADVICE?

WHAT ARE THE RISK FACTORS FOR FEMALE INFERTILITY?

Age

Weight Factors and Excessive Exercise

• Women with eating disorders, such as anorexia or bulimia.
  
  
• Women on very low-calorie or restrictive diets are at risk, especially if their periods are irregular.
  
  
• Strict vegetarians might also have difficulties if they lack important nutrients, such as vitamin B12, zinc, iron, and folic acid.
  
  
• Marathon runners, dancers, and others who exercise very intensely. (Lower body fat contributes to menstrual irregularities in competitive athletes, but other mechanisms are also involved.)

Lifestyle Factors

Environmental Risks

• High exposure to chemicals (particularly those that have estrogen-like effects, including certain pesticides, aldrin, dieldrin, PCPs, dioxins, and furans).
  
  
• Diethylstilbestrol (DES). DES, an estrogen compound, was used by pregnant women in the 1940s and 1950s. The daughters of these women face a higher risk for cervical cancer, genital tract abnormalities, and miscarriage. The effect on the daughter's reproductive capabilities is not entirely clear, although one 1999 study found little adverse effect on quality or development of eggs.
  
  
• Cancer treatments (radiation or chemotherapy).
  
  
• Agricultural work. (Exposure to pesticides may increase the risk for infertility. Specific products, particularly tobacco, also increase risk.)
  
  
• Heavy exposure to electromagnetic wave or microwave emissions has been linked to some reduced fertility in men. Although it is impossible to prove no risk on a developing fetus, research is very reassuring about ordinary exposure to low level emissions, such as those produced by small appliances.

Stress and Emotional Factors

WHAT CAUSES FEMALE INFERTILITY?

Pelvic Inflammatory Disease

• Sexually transmitted diseases (cause of most PIDs). Chlamydia trachomatis is an infectious organism that causes 75% of salpingitis cases. Gonorrhea is responsible for most of the remaining cases.
  
  
• Pelvic tuberculosis (a growing global problem as tuberculosis cases increase).
  
  
• Nonsterile abortions.
  
  
• Ruptured appendix.
  
  
• Herpesvirus (suggested for some cases, but not confirmed as a causal agent).

Endometriosis

• Endometrial cysts in the fallopian tubes may block the egg's passage or they may grow in the ovaries and prevent the release of the egg. (Even mild endometriosis can cause infertility if implants occur in these areas.)
  
  
• Endometriosis can cause rigid webs of scar tissue between the uterus, ovaries, and fallopian tubes, thereby preventing the transfer of the egg to the tube.
  
  
• Some studies have observed poor egg implantation in women with endometriosis that may be due to deficiencies in substances that enable the fertilized egg to adhere to the endometrial lining.
  
  
• Researchers are also focusing on defects in the immune system that may cause endometriosis, and in turn, can lead to infertility.

Hypothalamic-Pituitary Disorders (Hypogonadotropic Hypogonadism)

• Direct injuries to the hypothalamus or pituitary gland.
  
  
• Medical conditions that disturb their regulation (kidney failure, cirrhosis, pituitary tumors).
  
  
• Excessive exercise.
  
  
• Anorexia nervosa.

Polycystic Ovarian Syndrome

Ovarian Cysts

Premature Ovarian Failure (Early Menopause)

• Adrenal, pituitary, or thyroid deficiencies.
  
  
• Low levels of certain growth factors, called inhibins, that are produced by the ovaries.
  
  
• A general genetic condition called hypergonadotropic hypogonadism. The condition overproduces gonadotropic hormones so that functional ovaries do not develop. (The most common disorder belonging to this category is Turner's syndrome, in which one of the two X-chromosomes is missing.)
  
  
• Radiation therapy and anti-cancer agents.
  
  
• Rare causes include sarcoidosis, mumps, some sexually transmitted diseases, and tuberculosis.
  
  
• Autoimmune diseases, including diabetes type 1 and autoimmune hypothyroidism, are associated with a higher risk for early menopause. Autoimmunity, however, may also play a role in some cases of premature ovarian failure without the presence of autoimmune diseases. In such cases, antibodies attack a person's own cells.
  
  
• Some cases of unexplained infertility may result in loss of ovarian function that causes such subtle hormonal alterations that they are not picked up using routine laboratory tests.

Luteal Phase Defect (Implantation Failure)

Benign Uterine Fibroids

Surgical Problems

Other Causes of Infertility

WHAT WILL CONFIRM THE DIAGNOSIS OF FEMALE INFERTILITY?

Medical History and Physical Examination

Laboratory Tests

• High FSH and LH levels and low estrogen levels suggest premature ovarian failure or hypogonadotropic hypogonadism.
  
  
• High LH and low FSH may suggest polycystic ovary syndrome or luteal phase defect.
  
  
• High FSH on the third day of the cycle may predict a poorer success rate with standard doses of fertility drugs and the need for higher doses.
  
  
• LH surges indicate ovulation.
  
  
• Blood tests for prolactin levels and thyroid function are also measured.

Testing for Fallopian Tube and Uterine Abnormalities

• The physician inserts a tube into the cervix through which a radio opaque dye is injected. (The patient may experience some cramping and discomfort.)
  
  
• The dye passes into the uterus and up through the fallopian tubes.
  
  
• An x-ray is taken of the dye-filled uterus and tubes.
  
  
• If the dye is seen emerging from the end of the tube, no blockage is present. (In some cases, hysterosalpingography may even restore fertility by clearing away tiny tubal blockages.)
  
  
• If results show blockage or abnormalities, the test may need to be repeated. In case of blockage, hysterosalpingography may reveal a number of conditions, including endometrial polyps, fibroid tumors, or structural abnormalities of the uterus and tubes.

• The physician makes two small incisions, one at the navel and one above the pubic bone. (The procedure is usually done under general anesthetic.)
  
  
• Carbon dioxide gas is injected into the abdomen, distending it and pushing the bowel away.
  
  
• It employs a laparoscope, a hollow tube equipped with a tiny camera, lenses and a fiberoptic light source, which is inserted through the umbilical incision.
  
  
• A probe is then inserted through the second incision allowing the physician to directly view the outside surface of the uterus, fallopian tubes, and ovaries.
  
  
• Endometriosis, pelvic scar tissue, and blockage at the ends of the fallopian tubes can all be identified using laparoscopy. Some of these conditions can be corrected during the procedure by cutting away any scar tissue that may be binding organs together or by destroying endometrial implants.
  
  
• There are small risks of bleeding, infection, and reactions to anesthesia. Many patients experience temporary discomfort in the shoulders after the operation due to residual carbon dioxide that puts pressure on the diaphragm. The wound itself is minimally painful.

Investigative Tests to Determine Remaining Eggs

• Calculating the volume of the ovaries. In general, the smaller the ovaries, the fewer the remaining eggs.
  
  
• Counting antral follicles. Antral follicles are those that develop but do not become dominant follicles. Instead, they form a fluid-filled space called an antrum. Women who have fewer than three to five antral follicles appear to have a poor chance of fertility.
  
  
• Measuring inhibin B. Inhibin B is a growth factor produced in the ovaries. Low levels suggest fewer eggs.

Genetic Testing

WHAT ARE THE GENERAL GUIDELINES FOR FERTILITY TREATMENTS?

Fertility Treatment Approaches

• Lifestyle measures (healthy life style, planning sexual activity with ovulation cycle, managing stress and emotions).
  
  
• Treatments for endometriosis, fibroids, or menstrual disorders. [For other details see the Well-Connected Reports #100, Menstrual Disorders: Cramps (Dysmenorrhea) , #101, Menstrual Disorders: Absence of Periods (Amenorrhea) , #80, Menstrual Disorders: Heavy Periods (Menorrhagia) , #73, Fibroids: Uterine , or #74, Endometriosis.]
  
  
• Use of anti-estrogen agents, such as clomiphene, to induce ovulation in women with ovarian dysfunction.
  
  
• Surgery (standard or laparoscopic) to unblock fallopian tubes.
  
  
• Use of hormone treatments (clomiphene or progestins) for luteal phase defect.
  
  
• Assisted procedures, which are generally known as artificial insemination or assisted reproductive technologies (ART, with or without superovulation agents). [ See Boxes Typical Regimen for Hyperstimulation and In Vitro Fertilization and Gentler Alternatives to Superovulation .]
  
  
• Treating the male partner for infertility, including artificial or intrauterine semination with donor or partner sperm. [For more information see the Well-Connected Report #67, Infertility in Men .]

Choosing a Fertility Clinic

• The live-birth rate (not just pregnancy success rate) for other couples with similar infertility problems. (Multiple births, such as twins or triplets, are counted as one live birth.)
  
  
• Such statistics should include high-risk women, such as those who are older or fail to produce eggs. (Some disreputable clinics give success percentages that exclude high-risk women from their total, thereby making the percentage of success much higher.)

WHAT ARE LIFESTYLE MEASURES FOR FEMALE INFERTILITY?

Maintaining a Healthy Lifestyle

• Maintain a healthy weight. Women who are either over- or underweight are at risk for fertility failure, including a lower chance for achieving success with fertility procedures. Everyone should have a diet rich in fresh fruits and vegetables, and whole grains and that is also low in saturated fats.
  
  
• Stop smoking. Smoking increases the risk for infertility in both men and women, and poses a future health risk for the mother and infant. Everyone should quit.
  
  
• Avoid caffeine and alcohol.
  
  
• Avoid excessive exercise if it causes menstrual irregularity. It should be strongly noted that moderate and regular exercise is essential for good health. Few women exercise to the extent that their periods are affected. For those that do, one study found that simply adding calories can restore menstruation in many cases. Competitive athletes, then, may not have to stop exercising to restore fertility, although more research is needed to confirm this.
  
  
• Don't use electric blankets. In one study, a 74% higher incidence of spontaneous abortion was associated with using an electric blanket during the month of conception. There was no association with heated waterbeds or electromagnetic waves.
  
  
• Avoid any unnecessary medications.
  
  
• There is no evidence of harm to a developing fetus from low exposure to microwaves or electromagnetic waves. Women who remain anxious may derive comfort by avoiding some of these devices (such as cellular phones or electric blankets) and remaining a foot or so away from others (such as computers or microwave ovens).

Planning Sexual Activity and Monitoring Basal Body Temperature

• Each morning before rising, the woman takes her temperature with a specialized basal body thermometer and marks the result on a graph-paper chart. (Of interest is a wrist-watch like device under investigation that measures skin changes to predict ovulation.)
  
  
• The woman also notes the days of menstruation and sexual activity.
  
  
• The so-called "fertile window" is six days long and starts five days before ovulation and ends the day of ovulation.
  
  
• The chances for fertility are considered to be highest between days 10 and 17 in the menstrual cycle (with day 1 being the first day of the period and ovulation occurring about two weeks later). It should be noted, however, that a 2000 study reported that only 30% of women were fertile within the period of time. In the study women had a 10% chance of ovulating on each day between day 6 and 21. Researchers who conducted the study suggested that each woman track the length of her cycle, which in the general population of women actually runs between 19 and 60 days. A long cycle, for example, suggests a delayed ovulation date.
  
  
• Immediately after ovulation the body temperature increases sharply in about 80% of cases. (Some women can be ovulating normally, however, but not show this temperature pattern.)
  
  
• After maintaining the chart over several menstrual cycles, a couple can often anticipate the rise in temperature and so time their sexual activity for those days when fertility is most likely.
  
  
• Couples must try to avoid becoming fixated on the chart, however, in scheduling their sexual activity. Spontaneity can be lost, and the stress on the relationship can be quite severe, possibly impeding fertility.
  
  
• Common folk wisdom advises women to lie quietly after sexual intercourse. This advice was given some support by a 2000 study on women being treated with intrauterine insemination. Women who lay quietly for 10 minutes after sperm were implanted had a significantly higher rate of pregnancy than those who got up immediately. (This does not necessarily apply to natural intercourse.)
  
  
• Other factors that might affect fertility are seasonal changes. Different studies have reported higher sperm counts in the winter than in the summer in men who live in temperate climates. (It is not clear where this variation occurs in men who live in the tropics.) For women, fertility rates as measured by treatment success are highest in months when days are longest.

Planning for Stress and Depression

• Decide in advance how many and what kind of procedures will be emotionally and financially acceptable and attempt to determine a final limit. Fertility treatments are expensive and often not covered, and a successful pregnancy often depends on repeated attempts. (Some couples become addicted to treatment, and continue with fertility procedures until they are emotionally and financially drained.)
  
  
• Determine alternatives (adoption, donor sperm or egg, or having no children) as early as possible in the fertility process. This can reduce anxiety during treatments and feelings of hopelessness in case conception does not occur.
  
  
• Locate support groups or counseling services for help before and after treatment to help endure the process and ease the grief should treatment fail.

• Talking to one's spouse, family, and friends is very beneficial. The best support comes from the spouse. It should be noted, however, that men and women may cope differently with the stress and each should understand the other's special needs. Women tend to want greater personal space and also to want to share the burden with their husbands. Men tend to cope by seeking to improve themselves (for example being strong, or being the "best").
  
  
• Almost half of women seeking fertility treatments practice good-luck rituals, including prayer and wearing charms or special jewelry. No evidence exists that these talismans increase fertility, but they may help reduce anxiety and enhance a sense of control.
  
  
• Cognitive-behavioral therapy, which uses methods that include relaxation training and stress-management, have been associated with higher pregnancy rates. (In one study, 42% became pregnant without medical intervention.)
  
  
• Support groups have also been associated with better pregnancy rates. One study indicated that pregnancy rates were twice as high in women who coped with their depression by reaching out to others rather than repressing guilt or rage. (These results held only in cases in which women, not their mates, were infertile.)

• Effects of Failure. Needless to say, the emotional stress of failure can be devastating even on the most loving and affectionate relationships and even in those who have prepared for the possibility of failure. Neither the male or female partner should hesitate to seek professional help if the emotional burdens are too heavy.
  
  
• Effects of Successful Treatments. Some studies have indicated that even if successful, women experience increased stress and fear of failure during pregnancy. According to one 2000 study, however, women who achieved pregnancy using fertility treatments felt increasingly better and had higher self esteem and less anxiety as the pregnancy progressed than women whose pregnancies were not due to medical intervention.
  
  
• Effects of Multiple Births. A successful pregnancy that results in a multiple birth introduces new complexities and emotional problems. One study reported a very high rate of depression in women with triplets, particularly if they had little help from others, and especially if their husbands weren't involved.
  
  
• Effect on Parenting. Once the fertility treatment-assisted child arrives, parents (both men and women) are more likely to have less self esteem, to be anxious, and less confident.

WHAT ARE FERTILITY DRUGS?

General Overview

Clomiphene

• Polycystic ovaries.
  
  
• Ability to menstruate but irregular menstrual cycle.

• Infertility but with normal ovulation.
  
  
• Women with low estrogen levels.
  
  
• Premature ovarian failure (ie, early menopause).

Superovulation with Gonadotropins and GnRH Agonists

• The standard agents are menotropins, which are hormones extracted from urine of postmenopausal or pregnant women. Menotropins contain high concentrations of FSH or LH. The specific agents that are administered either in combination or as FSH.
  
  
• Genetically developed hormones (called recombinant drugs) are proving to be very effective. These are pure hormonal agents and they are allowing the physician to better tailor the regimen to the unique needs of the patient.

• GnRH agonists include leuprolide (Lupron), nafarelin (Synarel), goserelin (Zoladex), and buserelin.
  
  
• GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). These are newer agents that are proving to simplify the procedure because of their quicker action compared to GnRH agonist. They appear to pose less of a risk for complications and side effects in the treatment process.

Complications of Superovulation

WHAT ARE COMMON FERTILITY PROCEDURES?

Artificial Insemination

• When the cervical mucus is unreceptive.
  
  
• When donor sperm are required.
  
  
• When the male partner's semen contains very low numbers of sperm.
  
  
• When unexplained infertility exists in both partners.

Pregnancy Rates

The Artificial Insemination Procedure

• A woman usually (but not always) takes fertility drugs in advance.
  
  
• The man must produce sperm at the time the woman is ovulating.
  
  
• The sperm are subjected to certain so-called "washing" procedures.
  
  
• The sperm are then inserted into the uterine cavity through a long, thin catheter.

Assisted Reproductive Technologies

In Vitro Fertilization

• The physician first induces superovulation using fertility drugs so that several eggs can be harvested from the ovary before they have been released from the follicles. Some women prefer to try a natural cycle, which produces only one egg but has a lower success rate. Higher doses of fertility drugs for subsequent cycles do not appear to add any advantage in women who have a poor response the first time.
  
  
• To harvest eggs, the physician generally uses a probe inserted into the vagina and guided by ultrasound. A needle is then used to drain the liquid from the follicles, and several eggs are retrieved.
  
  
• The eggs and sperm are combined in a Petri dish. Between 48 to 72 hours later the eggs are usually fertilized.
  
  
• The resulting embryos (the first stage toward the development of the fetus) are reimplanted into the woman's uterus. (Thinning the membrane of the fertilized egg before implanting (assisted hatching) may increase egg implantation rates in certain women, such as those over age 40.)
  
  
• It takes about two weeks to determine if the process is successful.

Gamete/Zygote Intrafallopian Transfer

• The eggs are harvested as in IVF.
  
  
• They are mixed with the sperm but not actively fertilized.
  
  
• They are immediately injected back into the woman. Laparoscopy is used with this procedure to guide the placement of the embryos or egg through a long, thin catheter into the fallopian tubes.
  
  
• The sperm and egg are placed exactly where they would be in natural fertilization.

• The eggs are harvested as in IVF.
  
  
• They are then mixed with the sperm and, in this case, are fertilized in the laboratory.
  
  
• They are then implanted in the fallopian tubes as in GIFT. (The advantage of this procedure over GIFT is that the physician and couple are assured that fertilization has taken place and the eggs can be examined for defects before implantation.)

Intracytoplasmic Sperm Injection

• A tiny glass tube (called a holding pipet) stabilizes the egg.
  
  
• A second glass tube (called the injection pipet) is employed to penetrate the egg's membrane and deposit a single sperm into the egg.
  
  
• The egg is released into a drop of cultured medium.
  
  
• If fertilized, the egg is allowed to develop for one or two days and then is either frozen or implanted.

Success Rates

WHAT ARE THE EFFECTS OF FERTILITY DRUGS AND ASSISTED REPRODUCTIVE TECHNOLOGIES ON THE OFFSPRING AND MOTHERS?

Multiple Births

• Higher rates of cesarean sections.
  
  
• Low birth weight.
  
  
• Higher mortality rates (13 times that of single births).
  
  
• Higher risks for later lung and heart problems.
  
  
• Higher risk for mental retardation or learning disabilities.

• Carry all them to term, which increases health risks for both the mother and the developing fetuses.
  
  
• Complete abortion.
  
  
• Embryo reduction, in which the physician removes one or more embryos (possibly endangering the remaining embryos).

• Most centers now implant two to three embryos at a time, and the remainder can be frozen for future use. (To date, frozen eggs do not appear to pose a risk for developmental problems in children conceived using them, but follow-up studies are needed.) This limits the chance for success, but implanting more than three embryos only increases success rates very slightly, whereas the risk for multiple births increases significantly.
  
  
• Reducing the dosage of fertility drugs also reduces the risk for multiple births, but not significantly and it too reduces the chance for successful outcome.
  
  
• Blastocyst transfer may help reduce the chances for multiple births. [ See above. ]

Risks to the Woman

Risk for Birth and Genetic Defects in Children

WHERE ELSE CAN HELP BE FOUND FOR INFERTILITY IN WOMEN?

Other Internet Sites.

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