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Infertility in women - InDepth

Highlights

Risk factors for female infertility include:

Female infertility may be caused by an underlying medical condition that damages the fallopian tubes, interferes with ovulation, or causes hormonal complications. These medical conditions include:

Infertility may also be due to an infertile male partner.

For women under the age of 35, if you have been unable to conceive after 1 year of unprotected sex, talk with your health care provider about having your fertility evaluated. If you are age 35 or older, you should talk to a fertility specialist if you do not conceive within six months of unprotected sex. Fertility testing should especially be performed if a woman is over 35 years old or if either partner has known risk factors for infertility. An analysis of the man's semen should be performed before the female partner undergoes any invasive testing.

Treatment for infertility should first address any underlying medical condition that may be contributing to fertility problems. If this step does not restore fertility, there are several treatment approaches:

The American Society for Reproductive Medicine (ASRM) has guidelines for how couples can increase the likelihood of achieving pregnancy (these recommendations apply to couples who have no evidence of infertility):

Introduction

Infertility is the failure of a couple to become pregnant after 1 year of regular, unprotected sexual intercourse. In most cases, infertility is actually decreased fertility due to a number of treatable conditions and not genuine sterility, which is a rare.

About a third of infertility problems are due to female infertility, and another third are due to male infertility. In the remaining cases, infertility affects both partners or the cause is unclear.

Female infertility may occur when:

In order to understand infertility, it is important to know the organs and structures of the female reproductive system:

Uterus

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus.

During a woman's monthly menstrual cycle, her body prepares for conception and pregnancy. The average menstrual cycle is about 28 days but a normal cycle can range from 21 to 35 days. The menstrual cycle is divided into three phases: follicular, ovulatory, and luteal.

Follicular Phase (Days 1 to 13)

The follicular phase begins with the first day of menstrual bleeding:

Ovulatory Phase (Day 14)

The ovulatory phase occurs halfway through the menstrual cycle. During the ovulatory phase:

Luteal Phase (Days 15 to 28)

The luteal phase begins immediately after ovulation and ends when the next menstrual period starts. The luteal phase lasts about 12 to 16 days. During the luteal phase:

Follicle development

Click the icon to see an image of the corpus luteum.

Conception occurs when an egg is fertilized by a sperm. When fertilization occurs:

Placenta

Click the icon to see an image of the placenta.

Causes

Most cases of female infertility are due to medical conditions that cause:

Ovulation is the release of the egg that occurs during the monthly menstrual cycle. Problems that affect ovulation, and the hormones involved with ovulation, are the most common cause of female infertility. These conditions include:

Overproductive ovaries

Click the icon to see an image of polycystic ovarian syndrome.

A blocked fallopian tube can prevent sperm from reaching and fertilizing the egg. Blockage in the fallopian tubes can also prevent a fertilized egg from traveling to the uterus for implantation. Conditions that can block or damage fallopian tubes include:

Endometriosis

Endometriosis is a noncancerous condition in which cells that normally line the uterus (endometrium) also grow on other areas of the body, causing pain and abnormal bleeding.

Structural problems in a women's reproductive system may be caused by:

Fibroid tumors

Click the icon to see an image of uterine fibroids.

Cervical Mucus

Low amounts of cervical mucus or poor quality cervical mucus can contribute to infertility by interfering with the sperm's ability to reach and fertilize the egg.

Ovarian Reserve

Ovarian reserve refers to the quality and quantity of a woman's eggs. As a woman ages, the number and quality of her eggs diminish. Younger women can also have problems with ovarian reserve, usually because of medical conditions or treatments that affect the ovaries.

Hypothyroidism (underactive thyroid gland) and type 1 diabetes are some of the medical conditions that can contribute to infertility. Other autoimmune diseases such as multiple sclerosis and rheumatoid arthritis can affect fertility.

Risk Factors

Fertility declines as a woman ages. Fertility begins to decrease when a woman reaches age 32, and rapidly declines after age 37. As a woman ages, her ovaries produce fewer eggs. In addition, the quality of the eggs is poorer than those of younger women. Older women also have a higher risk of miscarriage. Older women are also more likely to have health problems that may interfere with fertility.

Although most of a woman's estrogen is manufactured in her ovaries, smaller amounts are produced by fat cells, which transform male hormones produced by the adrenal glands into estrogen. Because a normal hormonal balance is essential for the process of conception, extreme weight levels (either high or low) can contribute to infertility.

Being Overweight

Being overweight or obese can contribute to infertility in various ways. Obesity is also associated with PCOS, an endocrine disorder that can cause infertility.

Being Underweight

Being extremely underweight is a risk factor for infertility. Body fat levels that are significantly below normal can completely shut down the ovulation process.

Cigarette smoking can harm a woman's ovaries and contribute to a decrease in eggs. The cells that line the fallopian tubes may also slow down their ability to move the fertilized egg into the uterine cavity for implantation, resulting in abnormal pregnancies. Smoking may also interfere with the success of fertility treatments.

Alcohol and caffeine use may contribute to infertility. If you are trying to become pregnant, it is best to avoid alcohol. Alcohol use in early pregnancy can contribute to birth defects. Moderate coffee intake does not increase the risk for infertility and does not decrease the success rate of IVF. However, try to limit consumption to no more than 2 cups of coffee a day. Drinking more than 5 cups of coffee a day may reduce fertility.

Exposure to environmental hazards (such as herbicides, pesticides, and industrial solvents) may affect fertility. Estrogen-like chemicals that interfere with normal hormones are of particular concern for infertility in men and for effects on offspring of women. Phthalates, chemicals used to soften plastics, are under particular scrutiny because they may disrupt hormones.

Neurotransmitters (chemical messengers in the brain) act in the hypothalamus gland, which controls both reproductive and stress hormones. There is no conclusive evidence that stress has any significant effect on fertility or fertility treatments.

Diagnosis

Both male and female partners should get tested for infertility if pregnancy fails to occur after 1 year of regular unprotected sexual intercourse. If a woman is over age 35, fertility testing is recommended if she fails to conceive after 6 months of unprotected sex

Most couples who do not have fertility problems conceive within the first 6 months of attempting pregnancy, and typically within the first 3 months.

An analysis of the man's semen should be performed before the female partner undergoes any invasive testing.

Before beginning an expensive fertility work-up, you can try the following steps at home. They are free or low-cost and may be helpful:

The first step in any infertility work-up is a complete medical history and physical examination. Your provider will ask about:

The provider may feel your thyroid gland to check for signs of nodules or enlargement. A pelvic exam will evaluate any signs of masses or structural abnormalities.

Hormone Levels

Various tests are used to evaluate hormone function and ovarian reserve (the number of follicles and quality of the eggs). These include blood tests for FSH, antimullerian hormone (AMH), progesterone, and estradiol, and urine tests for LH. You may also receive tests to check your thyroid hormone and prolactin levels. Blood tests for previous infections with chlamydia may also be considered and can help women avoid more invasive procedures like laparoscopy.

Clomiphene Challenge Test

Clomiphene citrate (Clomid, Serophene, generic), a standard fertility drug, may be used to test for ovarian reserve. With this test, blood is drawn to measure FSH on day 3 of the menstrual cycle. The woman takes clomiphene on days 5 to 9 of the cycle. FSH is tested again on day 10. A normal response to clomiphene is a moderate increase in FSH levels followed by a return to baseline. High levels of FSH on day 3 or day 10 indicate problems with ovarian function. However, a normal result of the clomiphene test does not necessarily guarantee a good response to fertility treatments.

Imaging tests are used to examine the uterus and fallopian tubes.

Ultrasound and Sonohysterography

Ultrasound is the standard imaging technique for evaluating the uterus and ovaries. It uses a probe placed in the vagina to send out sound waves, which produce an image of the organs. Transvaginal sonohysterography uses ultrasound along with saline infused into the uterus. This helps enhance the image and improve the detection of potential problems.

Hysterosalpingography

Hysterosalpingography is an x-ray procedure performed to discover possible blockage in the fallopian tubes and abnormalities in the uterus:

Hysteroscopy

Hysteroscopy uses a long flexible or rigid tube called a hysteroscope, which is inserted into the vagina and advanced through the cervix to reach the uterus. A fiber-optic light source and a tiny camera in the tube allow the doctor to view the uterus, ovaries, and fallopian tubes.

Hysteroscopy may be done in a medical office or in a hospital operating room, depending on whether local or general anesthesia is used. The uterus is filled with saline or carbon dioxide to inflate the cavity and provide better viewing. This can cause cramping.

Laparoscopy

Laparoscopy is a minimally invasive surgical procedure. It requires general anesthesia and is performed in an operating room. The surgeon makes a very small incision below the belly button and inserts an instrument called a laparoscope, which is similar to a hysteroscope. (The difference is that a laparoscope is inserted through the abdomen, while a hysteroscope is inserted through the vagina and cervix.)

Through the laparoscope, the surgeon can view the uterus, fallopian tube, and ovaries. Laparoscopy is most helpful for identifying endometriosis or other adhesions that may affect fertility.

Treatment

Several approaches are used to treat infertility:

Advanced fertility procedures and medications are expensive and often not covered by insurance. Choosing a good fertility clinic is important. You should ask the fertility clinic questions about:

Women undergoing cancer treatments who are concerned about preserving their fertility should see a reproductive specialist to discuss their options These discussions should take place as early as possible, and before cancer treatment starts.

According to the American Society of Clinical Oncology's guidelines, the best fertility preservation methods for women with cancer are embryo and oocyte (egg) cryopreservation. This procedure involves harvesting and freezing a woman's eggs (oocytes), and can be followed by IVF and freezing of embryos for later use. It requires several weeks of pretreatment with ovarian stimulation drugs, so planning is very important.

Ovarian transposition, which involves moving one or both ovaries outside of the treatment field, may be an option for some women who are undergoing pelvic radiation. If you are going to be having gynecological surgery or radiation as part of your cancer treatment, discuss with your cancer care team any options for procedures that may help conserve fertility. And, be sure your doctors clearly explain to you how various cancer treatments could affect your fertility.

Embryo and oocyte cryopreservation are well-established methods that have excellent chances for success. At this time, other fertility preservation methods such as ovarian tissue cryopreservation, are still considered experimental and the American Society of Clinical Oncology does not recommend them.

Fibroids originate from the thick wall of the uterus and are categorized by where they grow. Treatment recommendations are based on the size and type of the fibroid.

Uterine artery embolization is a less invasive treatment for fibroids. This procedure blocks blood supply to a fibroid, causing it to shrink. However, this treatment is generally not recommended for women seeking future pregnancies.

Medications

Medications to treat infertility can be divided into three main categories:

Other drugs may also be used, for example:

Clomiphene citrate (Clomid, Serophene, generic) is usually the first fertility drug prescribed for women who have ovulation problems. (It is less likely to work for women who have normal ovulation.)

Unlike more potent drugs used in superovulation, clomiphene is gentler and works by blocking estrogen, which tricks the pituitary into producing the hormones FSH and LH. This process boosts follicle growth and the release of the egg.

Clomiphene can be taken by mouth, is relatively inexpensive, and the risk for multiple births is lower than with other drugs. One or two tablets are taken each day for 5 days, usually starting 2 to 5 days after the period starts. If successful, ovulation occurs about a week after the last pill has been taken. If ovulation does not occur, then a higher dose may be given for the next cycle.

If this regimen is not successful, treatment may be repeated or additional drugs may be added. Health care providers usually do not recommend more than 6 cycles.

Mood swings are a very common side effect of clomiphene. Other side effects include hot flashes, breast tenderness, nausea, pelvic discomfort, and ovarian cysts.

If clomiphene does not work or is not an appropriate choice, gonadotropin drugs are a second option. Gonadotropins include several different types of drugs that contain either a combination of the hormones FSH and LH, or only FSH.

Whereas clomiphene works indirectly by stimulating the pituitary gland to secrete FSH, which prompts follicle production, gonadotropin hormones directly stimulate the ovaries to produce multiple follicles.

Gonadotropins are given by injection. Your doctor may show you how to self-administer the injection. Gonadotropins include:

Human Menopausal Gonadotropin (hMG)

The hMG drugs contain a mixture of both FSH and LH. These drugs (Menopur, Repronex, and Humegon) are all derived from the urine of postmenopausal women. hMG is administered as a series of injections 2 to 3 days after the period starts. Injections are usually given for 7 to 12 days, but the time may be extended if ovulation does not occur. In such cases, a shot of hCG may trigger ovulation.

Human Chorionic Gonadotropin (hCG)

The hCG drugs are similar to LH. It mimics the LH surge, which stimulates the follicle to release the egg. Natural hCG drugs, derived from the urine of pregnant women, include Pregnyl, Profasi, and Novarel. Ovidrel is a genetically modified hCG drug. Ovidrel has fewer side effects and its quality can be better controlled than the natural drugs. It is generally used after hMG or FSH to stimulate the final maturation stages of the follicles. Ovulation, if it occurs, does so about 36 to 72 hours after administration.

Follicle Stimulating Hormone (FSH)

Urofollitropin (Bravelle, Fertinex) is a purified form of FSH, derived from the urine of postmenopausal women. Follitropin drugs (Gonal-F, Follistim) are synthetic versions of FSH. These FSH drugs are sometimes given in combination with an hCG drug.

GnRH Analogs (Agonists or Antagonists)

Gonadotropin-releasing hormone (GnRH) is a hormone produced in the hypothalamus part of the brain. GnRH stimulates the pituitary gland to produce LH and FSH.

GnRH analogs are synthetic forms of GnRH. They are similar to natural GnRH but have very different actions. These drugs actually prevent the LH and FSH surge that occurs right before ovulation. This action helps prevent the premature release of the eggs before they can be harvested for ART.

GnRH analogs are classified as either agonists or antagonists:

Superovulation is the process of using fertility drugs to stimulate the development of multiple follicles (eggs) in the ovaries. Superovulation is also called controlled ovarian stimulation.

Potential risks and complications of superovulation include:

Assisted Reproductive Technologies (ART)

ART are medical techniques that help couples conceive. These procedures involve either:

Fertilization may occur either in the laboratory or in the uterus. In the United States, over 68,000 live births (deliveries of one or more infants) occur each year using ART. According to the Centers for Disease Control (CDC), approximately 1.7% of all babies born in the United States every year are conceived using ART.

Technically, the term ART refers only to fertility treatments, such as IVF and its variants, which handle both egg and sperm.

Artificial insemination (AI) involves placing the sperm directly in the cervix (called intracervical insemination) or into the uterus (called intrauterine insemination, or IUI).

IUI is the standard AI procedure. It involves placing washed sperm into the woman's uterine cavity through a long, thin catheter. The washing procedure produces high quality sperm by removing seminal fluid and non-motile (not moving) cells, infectious agents, and chemicals used in the cryopreservation of semen. The sperm can come from the woman's male partner or from a donor (third party). The procedure is usually performed for cases of male infertility or unexplained female infertility. It may also be used if a woman has cervical scarring that prevents sperm from entering the uterus.

An IUI procedure is performed close to the time of ovulation. If a woman ovulates naturally, she may have ultrasound or other imaging tests performed to monitor for signs of ovulation. She may also use an ovarian prediction kit at home to test for the LH surge that occurs a few days before ovulation.

IUI is also frequently performed in combination with fertility drugs in a process called controlled ovarian stimulation. These drugs include clomiphene and letrozole, which may be used along with an injection of hCG. The sperm is inserted 1 to 2 days after the hCG injection.

You will take a pregnancy test a few weeks after the procedure. If pregnancy was not achieved, the cycle may be repeated.

IUI is the least complex and least expensive of fertility procedures and is often tried first in uncomplicated cases of infertility. However, it may pose a greater risk for multiple births and have a lower chance for pregnancy success than IVF. For these reasons, some fertility specialists recommend that couples who fail to conceive after 2 to 3 cycles proceed directly to IVF.

Most ART procedures use IVF. An in vitro procedure is one that is performed in the laboratory. Advances in these procedures have dramatically increased the rate of live births. IVF can be performed with a woman's own eggs and sperm, or with donor eggs and sperm.

A standard IVF cycle is divided into the following steps:

The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technologies (SART) have joint guidelines on the number of embryos that should be transferred during IVF procedures. The 2017 guidelines distinguish between cleavage-stage embryos (2 to 3 days after fertilization) and blastocyst embryos (5 to 6 days after fertilization). Apart from young age, the guidelines define the following characteristics as favorable prognosis: 1) expectation of one or more high-quality embryos available for cryopreservation; 2) euploid embryos; and 3) previous live birth after an IVF cycle. In people who do not meet criteria for a favorable prognosis in each of the below age groups, an additional embryo transfer may be considered.

For women with favorable prognosis, the 2017 guidelines recommend:

These embryo numbers are recommended for women with favorable prognoses. For women who have failed to become pregnant after at least 2 IVF cycles, or who have a less favorable prognosis, the doctor may consider adding 1 additional embryo. The guidelines apply to both fresh and frozen embryos.

Success Rates

Not all IVF cycles result in pregnancy, and not all IVF-achieved pregnancies result in live births. When a woman's own eggs are used, results are better with fresh embryos than frozen embryos. Success rates depend on many factors, especially the age of the woman.

Data from SART in 2015 indicate that the chances of ART resulting in live birth are about:

Complications

Data have been conflicting on whether IVF increases the risk for genetic abnormalities and birth defects. In general, the overall risks for birth defects appear to be small. Studies indicate that most children conceived through IVF are healthy and have normal cognitive development and school performance. However, recent studies suggest that fetuses conceived with ICSI and IVF may have a higher risk of congenital heart defects.

The main risk of IVF is the consequences of multiple pregnancies. Multiple pregnancies increase the chance of health problems for a mother and her babies. In particular, there is increased risk for premature delivery and low birth weight. These factors can cause heart and lung problems and developmental disabilities in children.

GIFT is a laparoscopic procedure by which both washed sperm from the male partner and eggs from the female partner are transferred to the fallopian tubes at the same time. Egg retrieval precedes GIFT in the same surgical event. GIFT is not an IVF procedure, since fertilization occurs in the fallopian tubes.

ZIFT is the laparoscopic transfer of zygotes (single cell stage of the embryo) to the fallopian tubes, 24 hours after IVF. ZIFT following all but the last step of IVF as described above.

GIFT and ZIFT are rarely performed due to the requirement for laparoscopy. Studies have not proven them to be more successful compared to traditional IVF.

ICSI is an ART used for couples when male infertility is the main problem. It involves injecting a single sperm into an egg obtained from IVF.

The procedure is very simple:

The greatest concern with this procedure has been whether it increases the risk for birth defects. Many, but not all, studies have reported no higher risks of birth defects in children born using ICSI procedures. However, if the father's infertility was due to genetic issues, this genetic defect may be passed on to male children conceived through ICSI.

Another concern has been whether the ICSI procedure is being overused. Some doctors recommend ICSI for women who have failed prior IVF attempts or who have few or poor-quality eggs, even if their male partners have normal semen measurements. According to the SART, there is little evidence that ICSI helps improve pregnancy success for couples who do not have a problem with male factor infertility.

Lifestyle Changes

Although there are no dietary or nutritional cures for infertility, a healthy lifestyle is important. Some ovulatory problems may be helped by changing behavioral patterns. Some tips include:

The Fertile Window

An egg survives only 12 to 24 hours after it is released from the ovary. For conception to occur, a sperm must be able to fertilize the egg during this time. Couples can optimize their chances for conception by planning sexual intercourse during the woman's fertile window:

To determine when the fertile window occurs, women should track their menstrual cycles. They can also try methods such as charting BBT to monitor ovulation (see Diagnosis section of this report).

Frequency of Intercourse

Evidence indicates that chances are best for conception when sexual intercourse occurs every 1 to 2 days, especially during the fertile window. Less frequent sexual intercourse (2 to 3 times a week) also achieves good results. However, couples need to make their own personal choices about what amount of sexual activity is appropriate, comfortable, and desirable. Data suggests that abstinence (not having sex) of more than 5 to 10 days may adversely affect sperm health.

Sexual Practices

There is no evidence that any particular sexual positions, or resting after sex, help increase the chances for pregnancy. There is also no evidence that whether or not a woman achieves orgasm affects the likelihood of her becoming pregnant. Couples should be aware that water-based vaginal lubricants (Astroglide, K-Y Jelly, saliva) can damage sperm's ability to swim and should not be used. For lubrication, try mineral oil, canola oil, or commercially available "fertility friendly" products such as Pre-Seed, which do not harm sperm.

The fertility treatment process presents a roller coaster of emotions. There are almost no sure ways to predict which couples will eventually conceive. Some couples with multiple problems will overcome great odds, while other, seemingly fertile, couples fail to conceive. Many of the new treatments are remarkable, but a live birth is never guaranteed. The emotional burden on the couple is considerable, and some planning is helpful. You should:

On a reassuring note, studies on infertility in women indicate that stress levels do not affect the outcome of fertility treatments. There appears to be no difference in stress levels between women who become pregnant and those who do not. Women who are feeling stressed by problems with fertility or the challenges of the fertility treatment process should not feel additionally concerned that their emotional state may affect their chances of becoming pregnant.

Resources

References

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Review Date: 3/23/2020
Reviewed By: John D. Jacobson, MD, Professor of Obstetrics and Gynecology, Loma Linda University School of Medicine, Loma Linda Center for Fertility, Loma Linda, CA. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.
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