INFERTILITY AND FERTILITY

People with certain diseases, disorders, and life events that affect fertility may benefit from fertility preservation. These include people who:

• Have been exposed to toxic chemicals in the workplace or during military duty
• Have endometriosis
• Have uterine fibroids
• Are about to be treated for cancer
• Are about to be treated for an autoimmune disease, such as lupus
• Have a genetic disease that affects future fertility
• Delay having children

A number of fertility-preserving options are available.^1,2

Fertility-preserving options for males include:³

• Sperm cryopreservation (pronounced krahy-oh-prez-er-VEY-shuhn). In this process, a male provides samples of his semen. The semen is then frozen and stored for future use in a process called cryopreservation.
• Gonadal shielding. Radiation treatment for cancer and other conditions can harm fertility, especially if it is used in the pelvic area. Some radiation treatments use modern techniques to aim the rays on a very small area. The testicles can also be protected with a lead shield.

Fertility-preserving options for females include:⁴

• Embryo cryopreservation. This method, also called embryo freezing, is the most common and successful option for preserving a female’s fertility. First, a health care provider removes eggs from the ovaries. The eggs are then fertilized with sperm from her partner or a donor in a lab in a process called in vitro fertilization. The resulting embryos are frozen and stored for future use.
• Oocyte (pronounced OH-uh-sahyt) cryopreservation. This option is similar to embryo cryopreservation, except that unfertilized eggs are frozen and stored.
• Gonadal shielding. This process is similar to gonadal shielding for males. Steps are taken, such as aiming rays at a small area or covering the pelvic area with a lead shield, to protect the ovaries from radiation.
• Ovarian transposition. A health care provider performs a minor surgery to move the ovaries and sometimes the fallopian tubes from the area that will receive radiation to an area that will not receive radiation. For example, they may be relocated to an area of the abdomen wall that will not receive radiation.⁵

Some of these options, such as sperm, oocyte, and embryo cryopreservation, are available only to males and females who have gone through puberty and have mature sperm and eggs. However, gonadal shielding and ovarian transposition can be used to preserve fertility in children who have not gone through puberty.

If you have questions about fertility preservation, talk with your health care provider.

The most common overall cause of female infertility is the failure to ovulate, which occurs in 40% of women with infertility issues.¹ Not ovulating can result from several causes, such as:

• Ovarian or gynecological conditions, such as primary ovarian insufficiency (POI) or polycystic ovary syndrome (PCOS)
• Aging, including “diminished ovarian reserve,” which refers to a low number of eggs in a woman’s ovaries due to normal aging
• Endocrine disorders, such as thyroid disease or problems with the hypothalamus, which affect the hormones produced by the body so that there might be too much or too little of a hormone or group of hormones
• Lifestyle and environmental factors

Problems with the menstrual cycle, the process that prepares the female body for pregnancy, can lead to infertility. The menstrual cycle includes several phases, and problems at any one of the stages can lead to difficulty getting pregnant or to infertility.

To learn about a normal menstrual cycle, visit the Menstruation section of this website.

To learn about common problems that may occur during the menstrual cycle, visit the What are menstrual irregularities? page.

Structural problems usually involve the presence of abnormal tissue in the fallopian tubes or uterus.

If the fallopian tubes are blocked, eggs are not able to move from the ovaries to the uterus and sperm is not able to reach the egg for fertilization. Structural problems with the uterus, such as those that may interfere with implantation, can also cause infertility.

Some specific structural problems that can cause infertility include:

• Endometriosis, when tissue that normally lines the inside of the uterus is found in other places, such as blocking the fallopian tubes
• Uterine fibroids, growths that appear within and around the wall of the uterus, although most women with fibroids do not have problems with fertility and can get pregnant. However, some women with fibroids may not be able to get pregnant naturally or may have multiple miscarriages or preterm labor.
• Polyps, which are noncancerous growths on the inside surface of the uterus. Polyps can interfere with the function of the uterus and make it difficult for a woman to remain pregnant after conception. Surgical removal of the polyps can increase the chances for a woman to get pregnant.
• Scarring in the uterus from previous injuries, infections, or surgery. Scarring may increase the risk of miscarriage and may interfere with implantation, thus leading to infertility.
• An unusually shaped uterus, which can affect implantation and the ability to carry a pregnancy to term

Infections can also cause infertility in men and women.

Untreated gonorrhea and chlamydia in women can lead to pelvic inflammatory disease, which might cause scarring that blocks the fallopian tubes. Untreated syphilis increases the risk for a pregnant woman to have a stillbirth. More information about infections that may affect fertility can be found on the sexually transmitted infections (STIs) health topic page.

Chronic infections in the cervix and surgical treatment of cervical lesions associated with human papillomavirus (HPV) infection can also reduce the amount or quality of cervical mucus. Problems with this sticky or slippery substance that collects on the cervix and in the vagina can make it difficult for women to get pregnant.¹

The Centers for Disease Control and Prevention recommends that all boys and girls age 11 or 12 be vaccinated against HPV. Men and women who weren’t vaccinated as preteens can also get the vaccine into their early to mid-20s.²

Eggs may not mature properly for a variety of reasons, ranging from conditions such as PCOS, to obesity, to a lack of specific proteins needed for the egg to mature.

An immature egg may not be released at the correct time, may not make it down the fallopian tubes, or may not be able to be fertilized.

Implantation failure refers to the failure of a fertilized egg to implant in the uterine wall to begin pregnancy. While the specific cause of implantation failure are often unknown, possibilities include:^3,4,5

• Genetic defects in the embryo
• Thin endometrium (pronounced en-doh-MEE-tree-uhm)
• Embryonic defects
• Endometriosis
• Progesterone resistance
• Scar tissue in the endometrial cavity

Endometriosis occurs when the cells that normally line the uterine cavity, called the endometrium, are found outside the uterus instead. A more detailed description of endometriosis can be found at the NICHD endometriosis topic page.

Research has found a link between infertility and endometriosis. Studies show that between 25% and 50% of infertile woman have endometriosis and between 30% and 40% of women with endometriosis are infertile.^6,7,8 Scientists do not know the exact cause of infertility in women with endometriosis.

Current theories on how endometriosis causes infertility include the follow:

• Changes in the structure of the female reproductive organs may occur. Endometriosis can cause pelvic adhesions made of scar tissue to form between nearby structures, such as between the ovary and pelvic wall. This can obstruct and affect the release of the egg after ovulation. Scarring in the fallopian tube can interrupt block the egg’s movement through the fallopian tube.
• The lining of the abdomen, which is called the peritoneum (pronounced pair-ih-tuh-NEE-uhm), may go through changes that affect its function:
  • In women with endometriosis, the amount of fluid inside the peritoneum often increases.
  • The fluid in the peritoneum contains substances that can negatively affect the functions of the egg, sperm, and fallopian tubes.
• Chemical changes in the lining of the uterus that occur as a result of endometriosis may affect an embryo’s ability to implant properly and make it difficult for a woman to stay pregnant after conception.

PCOS is one of the most common causes of female infertility.⁹ It is a condition in which a woman’s ovaries and, in some cases, adrenal glands produce more androgens (a type of hormone) than normal. High levels of these hormones interfere with the development of ovarian follicles and release of eggs during ovulation. As a result, fluid-filled sacs, or cysts, can develop within the ovaries. A more detailed description can be found on the NICHD PCOS topic page.

Researchers estimate that 5% to 10% of women in the United States have PCOS.¹⁰ The exact cause of PCOS is unknown, but current research suggests that a combination of genetic and environmental factors leads to the disease.

POI is a condition in which a woman’s ovaries stop producing hormones and eggs at a young age. Women with POI ovulate irregularly, if at all, and may have abnormal levels of ovarian and pituitary hormones due to problems with their ovaries.

Women with POI often have trouble getting pregnant. However, pregnancy is still possible, though rare. About 5% to 10% of women with POI get pregnant without medical treatment.¹¹

A more detailed description of POI, including possible causes, can be found on the NICHD POI topic page.

Uterine fibroids are noncancerous growths that form inside the uterus. Uterine fibroids can cause symptoms in some cases, depending on their size and location. Scientists do not know what causes fibroids to form, but it is believed that there may be a genetic basis.

Fibroids can contribute to infertility and are found in 5% to 10% of infertile women.¹² Fibroids located in the uterine cavity (as opposed to those that grow within the uterine wall) or those that are larger than 6 centimeters in diameter are more likely to have a negative effect on fertility. Fibroids are more likely to affect a woman’s fertility if they¹²:

• Change the position of the cervix, which can reduce the number of sperm that enter the uterus
• Change the shape of the uterus, which can interfere with the movement of sperm or implantation
• Block the fallopian tubes, which prevents sperm from reaching the egg and keeps a fertilized egg from moving to the uterus
• Interfere with blood flow to the uterus, which can prevent the embryo from implanting

A more detailed description of uterine fibroids can be found on the NICHD uterine fibroids topic page.

Autoimmune disorders cause the body’s immune system to attack normal body tissues it would normally ignore. Autoimmune disorders, such as lupus, Hashimoto’s and other types of thyroiditis, or rheumatoid arthritis, may affect fertility. The reasons for this are not fully understood and differ between diseases, but they are thought to involve inflammation in the uterus and placenta or medications used to treat the diseases. Both men and women can make antibodies that attack sperm or the reproductive organs.¹³

In evaluating a woman’s fertility, a health care provider will ask specific questions about her health history. These include:^1,2

• Prior pregnancies
• Prior miscarriages
• The regularity of her menstrual period
• The presence of pelvic pain
• Whether she has abnormal vaginal bleeding or discharge
• Whether she has a history of pelvic infection or previous pelvic surgery

Initial screening may also involve a physical exam, including a pelvic exam or pelvic ultrasound, a Pap test, and blood tests to look at overall health. The health care provider may look for signs of milk production in the breasts, which suggests a hormone imbalance, and other physical symptoms of polycystic ovary syndrome and other conditions that affect fertility.

A health care provider may also conduct the following laboratory tests and evaluations:^1,2

• A blood test around day 23 of the woman’s menstrual cycle can measure the amount of a hormone called progesterone. This test can tell whether ovulation has occurred and whether the ovaries are producing a normal amount of this hormone.
• Tests may also measure levels of other hormones that are important for fertility. The levels of follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) in the blood can help determine the quantity of a woman’s remaining egg supply. FSH stimulates egg production and a hormone called estradiol. High FSH levels may mean that a woman has ovarian failure or is in perimenopause or menopause. Low levels of FSH may mean a woman has stopped producing eggs. AMH is produced only in ovarian follicles, so the levels of AMH in the blood indicate the presence of growing follicles.
• Other tests may include those to examine the fallopian tubes and determine whether there is blockage that prevents movement of the egg from the ovaries. These include the following:
  • X-ray hysterosalpingogram (pronounced HISS-tuh-roh-sal-PING-goh-gram). A health care provider injects a radiographic dye into the cervix to fill the uterus. If the fallopian tubes are clear of blockages, the dye will flow out the end of the fallopian tube into the peritoneal cavity. Movement of the dye is monitored by x-ray fluoroscopy.
  • Laparoscopy (pronounced lap-uh-ROS-kuh-pee) is a surgery in which a small viewing instrument, called a laparoscope, is inserted through a small cut in the abdomen to examine the female reproductive organs. If the procedure identifies blockages in the fallopian tubes, the blockages can be surgically treated with instruments attached to the laparoscope.
• A health care provider may examine the inside of the uterus to look for scarring, uterine fibroids, or polyps. The following procedures are used to examine the uterus:
  • Transvaginal ultrasound. An ultrasound looks at the internal organs using sound waves. A wand inserted into the vagina applies sound waves to the body. This provides a health care provider a better view of the female reproductive organs, including the uterus and ovaries.
  • Hysteroscopy (pronounced hiss-tuh-ROS-kuh-pee). A hysteroscope is a long, thin camera that is inserted through the vagina and into the uterus.
  • Saline sonohysterogram (pronounced sah-noh-HISS-tuh-roh-gram). In this procedure, a health care provider injects sterile saline into the cervix to fill the uterus. Once the uterine cavity is full, it is easier to see its inner lining. The pelvic organs are visualized with transvaginal ultrasound. It is also possible to see fluid move into the peritoneal cavity at the same time, which indicates that at least one tube is open.
• Health care providers may test a woman older than age 35 to get a snapshot of the number of remaining follicles or if her follicles mature to the stage of ovulation. This type of testing includes performing a transvaginal ultrasound to look at the ovaries and measuring hormones in the blood on certain days of the menstrual cycle.

The evaluation of a man’s fertility includes looking for signs of hormone deficiency, such as increased body fat, decreased muscle mass, and decreased facial and body hair. The evaluation also includes questions about the man’s health history, including:³

• Past injury to the testicles or penis
• Recent high fevers
• Childhood diseases, such as mumps
• Low sexual desire (libido)

A physical examination of the testes and penis allows for identification of problems, such as:¹

• Infection, signaled by discharge or prostate swelling
• Hernia
• Malformed tubes that transport sperm
• Hormone deficiency as indicated by small testes or lack of facial and body hair
• Presence of a mass in the testicles
• Varicocele (abnormal veins in the scrotum)

A health care provider may also ask a man to provide a sample of semen to assess the health and quality of his sperm. To give a semen sample, the man is requested to refrain from ejaculation for around 48 hours before the test. He then provides a sample by masturbating into a cup or by having intercourse using a special condom (without contraceptive) that collects semen without affecting the sperm. A man may need to provide a semen sample on more than one occasion, because sperm production can vary over time depending on the man’s current health status, activities, and stress level.

Other tests may include:^1,3

• Measurement of hormones in the blood, including testosterone and follicle-stimulating hormone, thyroid hormones, and prolactin
• Biopsy of the testicle. A health care provider uses a needle to extract sperm from the testicle.
• Genetic testing. In cases where no or very few sperm are found in the semen, a health care provider may do genetic testing before starting fertility treatments. Testing can identify chromosome abnormalities that may cause the lack of sperm or lead to developmental problems among offspring.

Intrauterine (pronounced IN-truh-YOO-tuh-rin) insemination (pronounced in-sem-uh-NAY-shun) is the placement of a man’s sperm into a woman’s uterus using a long, narrow tube similar to a thin straw.¹

More information on IUI includes the following:¹

• IUI is most effective for treating infertility in:
  • Women who have scarring or defects of the cervix
  • Men who have low sperm counts
  • Men who have sperm with low mobility
  • Men who cannot get erections
  • Men who have retrograde ejaculation, a condition in which sperm are ejaculated into the bladder instead of out of the penis
  • Couples who have difficulty having intercourse
• IUI can be used in combination with medications that stimulate ovulation. This combination can increase the chance of pregnancy in some cases.
• The success of IUI depends on the cause of the couple’s infertility. If inseminations are performed monthly with fresh or frozen sperm, success rates can be as high as 20% per cycle. These outcomes depend on whether fertility medications are used, the age of the female partner, and the infertility diagnosis, as well as on other factors that could affect the success of the cycle.

During IVF, eggs and sperm from the couple are incubated together in a laboratory to produce an embryo. A health care provider then places the embryo into the woman’s uterus, where it may implant and result in a successful pregnancy.

The steps of IVF are:²

• Superovulation
• Egg Retrieval
• Fertilization
• Embryo Transfer

Superovulation

 

In this process, also known as ovarian stimulation, ovulation induction, or stimulation of egg maturation, a woman takes medication to stimulate the ovaries to make many mature eggs at one time.

These medications are given by injection for 8 to 14 days. A health care provider closely monitors the development of the eggs using transvaginal ultrasound and blood tests to assess follicle growth and estrogen production by the ovaries. When the eggs are mature—as determined by the size of the ovarian follicles and the level of estrogen—an injection of the hormone hCG initiates the ovulation process. A health care provider takes out (egg retrieval) the eggs 34 to 36 hours after the hCG injection.

 

Egg Retrieval

This is the process used to remove the eggs from the ovaries so they can be fertilized. The procedure is performed in a physician’s office as an outpatient procedure. A mild sedative and painkiller are often used during the procedure, and it normally takes about 30 minutes. The steps for egg retrieval are as follows:

• An ultrasound probe is inserted into the vagina to visualize the ovaries and the follicles, which contain the eggs.
• A needle is inserted through the wall of the vagina to the ovaries. Generally, ultrasound is used to guide the placement of the needle.
• Suction is used to pull the eggs from the ovaries into the needle.

 

Fertilization

A man provides a semen sample. If the sperm are healthy, they are centrifuged to concentrate them and reduce the volume, placed in a dish with the egg, and left overnight in an incubator. Fertilization usually occurs on its own. However, sometimes sperm are not able to fertilize the egg on their own. When this is the case, a single sperm is injected into an egg using a needle. This process is called intracytoplasmic (pronounced IN-truh-sahy-tuh-PLAZ-mick) sperm injection (ICSI). About 60% of IVF in the Unites States is performed with ICSI.³ The pregnancy rate is about the same for IVF using natural fertilization or ICSI.

If sperm cannot fertilize the egg without assistance, couples should consider genetic testing. This testing can determine whether the sperm have chromosome problems that might cause development problems in the resulting embryos.

Embryos that develop from IVF are placed into the uterus 1 to 6 days after retrieval.

 

Embryo Transfer

This procedure is performed in a physician’s office. The procedure is normally painless, but some women may experience cramping.

A health care provider inserts a long, thin tube through the vagina and into the uterus and injects the embryo into the uterus. The embryo should implant into the lining of the uterus 6 to 10 days after retrieval.
Sometimes the embryos are frozen and thawed at a later date for embryo transfer. This is often done when fresh embryos fail to implant or when a woman wants to preserve her eggs in order to become pregnant years later. Women either time implantation with their ovulation cycle or receive estrogen and progesterone medications to prepare their uterine linings for implantation.

When couples do not achieve pregnancy from infertility treatments or traditional ART, they may choose to use a third party–assisted ART method to get pregnant.² Assistance can consist of:

• Sperm Donation
• Egg Donation
• Surrogates and Gestational Carriers
• Embryo Donation

Sperm Donation

Couples can opt for donated sperm if a man does not produce sperm, produces very low numbers of sperm, or has a genetic disease. Donated sperm can be used with IUI or with IVF.

Egg Donation

This process may be an option when a woman does not produce healthy eggs that can be fertilized. An egg donor undergoes the superovulation and egg retrieval steps of IVF. The donated egg can then be fertilized by sperm from the woman’s partner. The resulting embryo is placed into the woman’s uterus, which is receptive for implantation because of hormone treatments.

Egg donation may be particularly helpful² for women who:

• Have primary ovary insufficiency
• Have had chemotherapy or radiation therapy
• Have had surgical removal of the ovaries
• Were born without ovaries
• Are carriers of known genetic diseases
• Are infertile because of poor egg quality
• Are menopausal

Surrogates and Gestational Carriers

If a woman is unable to carry a pregnancy to term, she and her partner may choose a surrogate or gestational carrier.

A surrogate is a woman inseminated with sperm from the male partner of the couple. The resulting child will be biologically related to the surrogate and to the male partner. Surrogacy can be used when the female of the couple does not produce healthy eggs that can be fertilized.

A gestational carrier is implanted with an embryo that is not biologically related to her. This alternative can be used when a woman produces healthy eggs but is unable to carry a pregnancy to term. If needed, egg or sperm donation can also be used in this situation.

Embryo Donation

Embryo donation, sometimes called embryo adoption, allows the recipient mother to experience pregnancy and give birth to her adopted child. Couples who have undergone IVF and completed their families sometimes choose to donate their remaining embryos. An embryo donation agency, such as the National Embryo Donation Center, stores these frozen embryos and mediates adoption with the recipient woman or couple.Communication between the donating and adoptive couple can range from anonymous to a fully open relationship.

Reasons a woman may choose embryo adoption include:

• She or her partner is infertile and looking for alternatives to other ART.
• IVF has repeatedly failed.
• She or her partner is concerned about or at high risk for passing on genetic disorders.

The donated embryo is transferred to the recipient’s uterus. According to CDC, 50% of transfers with donated frozen embryos result in pregnancy, and 40% result in a live birth.⁴

The most common medications used to treat infertility help stimulate ovulation. Examples of these types of medications include:^2,3

• Clomiphene or Clomiphene Citrate
• Letrozole
• Gonadotropins or Human Chorionic Gonadotropin (hCG)
• Bromocriptine or Cabergoline

Clomiphene or Clomiphene Citrate

Clomiphene is a medication patients take by mouth (orally). It causes the body to make more of the hormones that cause the eggs to mature in the ovaries.² If a woman does not become pregnant after taking clomiphene for six menstrual cycles, a health care provider may prescribe other fertility treatments.

• Patients take clomiphene in the beginning of the menstrual cycle.
• Clomiphene causes ovulation to occur in 80% of women treated. About half of those who ovulate are able to achieve a pregnancy or live birth.²
• Use of clomiphene increases the risk of having a multiple pregnancy. There is a 10% chance of twins, but having triplets or more is rare—less than 1% of cases.²

Letrozole

Letrozole is an oral pill that decreases the amount of estrogen a woman makes, stimulating her ovaries to release eggs.

• Patients take letrozole toward the end of their menstrual cycle for around 5 days.
• A 2015 study by researchers in the NICHD Reproductive Medicine Network found that about 19% of couples with unexplained infertility went on to have a live birth after using letrozole for 4 months. This rate was slightly lower than the live birth rate for couples using clomiphene (23%).⁴
• Other studies have found that letrozole may work better than clomiphene in women with polycystic ovary syndrome.⁵

Gonadotropins and Human Chorionic Gonadotropin (hCG)

Gonadotropins such as follicle-stimulating hormone (FSH) are hormones that are injected in a woman to directly stimulate eggs to grow in the ovaries, leading to ovulation.² Health care providers normally prescribe gonadotropins when a woman does not respond to clomiphene or to stimulate follicle growth for assisted reproductive technology (ART).

• Gonadotropins are injected in the early part of the menstrual cycle for 7 to 12 days.
• While a woman is treated with gonadotropins, a health care provider uses transvaginal ultrasound to monitor the size of the developing eggs, which grow inside tiny sacs called follicles. The health care providers also draw blood frequently to check the ovarian production of estrogen.
• The chance of a multiple birth is higher with gonadotropins than with clomiphene, and 30% of women who conceive a pregnancy with this medication have multiple births.² About two-thirds of multiple births are twins. Triplets or larger multiple births account for the remaining third.

hCG is a hormone similar to luteinizing hormone that can be used to trigger release of the egg after the follicles have developed.

Bromocriptine or Cabergoline

Bromocriptine and cabergoline are pills taken orally to treat abnormally high levels of the hormone prolactin, which can interfere with ovulation.² Pituitary growths; certain medications, including antidepressants; kidney disease; and thyroid disease can cause high levels of prolactin.

• Bromocriptine or cabergoline allow 90% of women to have normal prolactin levels.¹
• Once prolactin levels become normal, 85% of women using bromocriptine or cabergoline ovulate.¹

If disease of the fallopian tubes is the cause of infertility, surgery can be used to repair the tubes or remove blockages in the tubes. Success rates of these types of surgery, however, are low (approximately 20%, depending on the skill of the surgeon).

These surgeries involving the fallopian tubes also increase the risk of ectopic (pronounced ek-TAH-pik) pregnancy, which is a pregnancy that occurs outside of the uterus.¹ Ectopic pregnancies are also called “tubal pregnancies,” because they most often occur in a fallopian tube.⁶

Surgery to remove patches of endometriosis has been found to double the chances for pregnancy. Surgery can also be used to remove uterine fibroids, polyps, or scarring, which can affect fertility.

Researchers at and supported by NICHD are investigating the causes of infertility and identifying new effective treatments. One line of research examines the contributions of environmental factors to infertility. Another explores how the physical changes associated with diseases, such as endometriosis, relate to infertility. Investigators are also studying why African American women have lower success rates using assisted reproductive technology (ART). In addition, research is being conducted to determine new ways to preserve fertility and to better understand the effect of aspirin on live-birth rates.

Research on the effects of environmental factors on infertility is conducted in NICHD’s Division of Intramural Population Health Research (DIPHR). For example, researchers in the Division collaborated with scientists at the University of Buffalo to study the relationship between hormone levels and oxidative stress during the menstrual cycle to elucidate the effects of diet, smoking, and caffeine on fertility. DIPHR scientists also studied the link between psychological stress and infertility in women. Additionally, DIPHR scientists are looking at the effect of environmental toxins and lifestyle factors on men and women’s fertility. The Longitudinal Investigation of Fertility and the Environment (LIFE) Study is examining the long-term effects of lifestyle factors, including stress, cigarette smoking, caffeine intake, and alcohol usage, on fertility. These researchers found that men who worked in physically demanding jobs or took two or more medications had lower sperm counts. Men with high blood pressure, but not those with diabetes or high cholesterol, had less normally shaped sperm. Lower sperm quality or number can make it harder for a couple to conceive.

The Epidemiology Branch within DIPHR conducts research and provides services and training. Its epidemiologic research focuses on reproductive, perinatal, and pediatric health endpoints to identify underlying etiologic mechanisms, at-risk subgroups, and interventions aimed at diagnosing or treating disease. An ongoing investigation, called the Effects of Aspirin on Gestation and Reproduction (EAGeR) Study, is investigating the effects of aspirin on blood flow and placental health to reduce the risk for adverse pregnancy events, such as early pregnancy loss and preterm birth.

The Unit on Reproductive Endocrinology and Infertility (UREI) in the Division of Intramural Research (DIR) is also actively researching both treatments for and causes of infertility. For example, women and girls with cancer who undergo chemotherapy treatments are exposed to chemicals that can affect the ovaries and lead to infertility. Studies conducted by UREI scientists have examined ways to prevent this damage. Another study conducted by UREI scientists examined procedural differences in ART that might account for differences in pregnancy rates among African American women and whether access to care and economic issues affect use of the technologies by minority women.

Intramural scientists within the Reproductive Endocrine and Gynecology Group at NICHD are examining possible causes and treatments for infertility associated with primary ovarian insufficiency (POI). Animal studies have explored molecular pathways involved in the loss of ovarian function and ways to intervene within the pathways to prevent loss of ovarian function. These investigators have studied women with POI to better understand the features of the disease, how it causes infertility, and how infertility can be treated in these women.

The NICHD Fertility and Infertility (FI) Branch, within the Division of Extramural Research (DER), supports research on a variety of topics related to fertility and infertility. This Branch supports the Reproductive Medicine Network, which studies new and effective ways to evaluate and treat infertility in males and females. Findings include new treatments for ovulation induction in infertile women with polycystic ovary syndrome (PCOS) and the optimal treatment for unexplained infertility that results in fewest multiple gestations.

Preserving fertility is also topic of considerable interest for the FI Branch. Current investigations address the concerns of fertility preservation for men, women, and children, for circumstances covering cancer treatment and certain non-cancer conditions. Specifically, Institute-sponsored research investigates measures to prevent gamete damage, options to restore fertility after damage, developing biomarkers of gamete reserve, and the developing technologies that will enable reproductive-age adults to have biological children. One FI Branch-supported study identified a variant of a gene that helps explain why women with PCOS produce higher levels of male hormones. Women with PCOS produced higher levels of a specific gene variant in cells in their ovaries, and these cells then produced higher levels of androgen.

Other FI Branch research areas related to fertility and infertility include:

• Early pregnancy loss (EPL) with emphasis on developing methods to predict those at risk for EPL and understanding the role of oocyte aneuploidy, sperm quality, and pre-placental processes
• Genetics of male and female infertility, including idiopathic infertility
• Improvement of fertility preservation outcomes through developing novel technologies
• Ovarian aging, with special focus on understanding factors that affect egg quality; how the primordial follicle pool is established, regulated, and altered over time; and new methods to assess and predict the ability of the ovary to supply eggs for fertilization
• The relationship between male fertility status and health of their offspring
• The requirements of ovulation, egg fertilization, and embryo implantation
• The effects and mechanisms of diseases such as endometriosis and PCOS on fertility and effective treatments for these disorders
• Growth and development of sperm and factors that affect sperm development, function, and quality

Research related to infertility supported by the NICHD Pregnancy and Perinatology Branch (PPB) focuses on maternal health and healthy pregnancy, as well as on pregnancy loss and stillbirth.

Other DER research supported by the Populations Dynamics Branch focuses on understanding changing patterns of family formation, including cohabitation, marriage, non-marital fertility, infertility, and low fertility.

Institute advances in infertility research include the following:

• Identification of a potential nonsurgical method for diagnosing endometriosis. Endometriosis, a painful condition that can cause infertility, is currently diagnosed using a surgical procedure, termed laparoscopy. Researchers compared which genes were turned on in uterine tissue of women with and without endometriosis. Using these differences, researchers were able to predict which women had endometriosis and distinguish between endometriosis and other uterine problems. The researchers are testing the method in a larger population of women and hope to eventually develop a non-surgical test for endometriosis. Visit High-Tech Analysis of Genetic Data May Yield New Test for Endometriosis for more information.
• Discovery that a chlamydia test can predict chances for pregnancy.Chlamydia trachomatis infection might cause few or no symptoms, but it can cause inflammation and scarring in the fallopian tubes, leading to infertility. An NICHD-funded study looked at the link between C. trachomatis and pregnancy outcomes in women whose infertility is not explained by having blocked fallopian tubes. Researchers used a blood test to detect a previous or existing C. trachomatis infection and followed these women as they underwent fertility treatment. Women who tested positive were less likely to become pregnant or have a live birth and more likely to have an ectopic pregnancy. The researchers suggest it is important to screen infertile women for C. trachomatis infection and screen for other forms of tubal damage besides blockages. See Blood test for chlamydia may predict pregnancy outcomes for more information.
• Discovery that a cancer drug improves pregnancy outcomes for women with PCOS. PCOS is a leading cause of infertility in women. Although the drug clomiphene is used to treat PCOS infertility, it has side effects and is not greatly effective. NICHD-supported researchers compared clomiphene to the cancer drug letrozole. Women treated with letrozole were more likely to have live births than those treated with clomiphene. Letrozole also led to higher rates of ovulation than clomiphene. See Drug Improves Birth Rates for Women with Fertility Disorder for details.

• The FI Branch supports research networks that address issues related to infertility, including:
  • The Reproductive Medicine Network (RMN) carries out large, multicenter clinical trials of diagnostic and therapeutic interventions for male and female infertility and reproductive diseases and disorders. Among other topics, the RMN conducts research on:
    • Polycystic ovary syndrome
    • Optimal conditions for in vitro fertilization
    • Medications to stimulate ovulation in infertile women and factors that influence multiple pregnancies
    • Ongoing monitoring of babies born in RMN clinical studies
  • The NICHD National Centers for Translational Research in Reproduction and Infertility (NCTRI), formerly the Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR), also supports various research resources:
    • The Human Endometrial Tissue and DNA Bank  at the University of California, San Francisco, contains information on genes associated with the uterus in humans, mice, pigs, sheep, goats, cows, and horses. The information is taken from published microarray data.
    • The Ovary Bank at the University of California, San Diego
    • A tissue bank of male reproductive tissues and fluids at Johns Hopkins University
    • A tissue bank of nonhuman primate tissues at the Oregon National Primate Research Center
    • The Ligand Assay & Analysis Core  at the University of Virginia
    • The Ovarian Kaleidoscope Database  contains information regarding the biological function, expression pattern, and regulation of genes expressed in the ovary. It also provides information on gene sequences, chromosomal localization, human and murine mutation phenotypes, and biomedical publication links.
• The PPB supports the following networks and studies to advance knowledge of the causes of pregnancy loss from miscarriage and stillbirth:
  • The Stillbirth Collaborative Research Network (SCRN) was established to find the causes of stillbirth as well as ways to prevent or reduce its occurrence. SCRN studies also aim to understand any racial/ethnic factors that contribute to differences in stillbirth rates.
  • The Prenatal Alcohol and SIDS and Stillbirth (PASS) Network aims to find ways of improving pregnancy outcomes and infant health. The PASS Network’s key research program is the Safe Passage Study. Its purpose is to understand some of the causes of sudden infant death syndrome (SIDS), stillbirth, and fetal alcohol spectrum disorders, especially those related to alcohol exposure during pregnancy.

There are specific treatments for PCOS that may help a woman get pregnant. A more detailed description of PCOS and its symptoms is available from the NICHD PCOS topic page.

Treatments for infertility in women with PCOS include¹:

• Weight loss. Women with PCOS who lose weight are more likely to have restored ovulation and improved pregnancy rates.²
• Medication to promote ovulation. Clomiphene is the most common treatment for infertility in women with PCOS. Studies have shown that in women with PCOS, those who took clomiphene were six times more likely to get pregnant than those who did not. However, a recent study found that a newer drug, letrozole, also known as Femara, improves the receptivity of the uterus lining in women with PCOS.³
• Insulin-sensitizing medication. A medication called metformin treats diabetes and can also help improve menstrual cycles and ovulation in women with PCOS. Use of metformin may help regulate the hormones that affect the menstrual cycle, but so far there is no evidence that metformin treatment increases the rate of pregnancy in women with PCOS.
• A combination of clomiphene and metformin. In women with PCOS who do not respond to clomiphene by itself, adding metformin may slightly increase the rate of pregnancy.
• Hormone therapy. Gonadotropins and hCG are types of hormones used to treat women who do not respond to clomiphene and/or metformin.^4,5
• Fertility treatments. ART, such as IVF, also may help women with PCOS get pregnant.
• Surgery. Ovarian drilling is a surgical treatment that can stimulate ovulation in women with PCOS. The procedure is usually done through a small incision near the belly button, with the woman under general anesthesia. A laser or electrocautery (a process that destroys tissue using heat current) is used to destroy parts of the ovaries. This surgery is not commonly used. But it can be an option for women who are still not ovulating after losing weight and trying fertility medicines. Studies of women with PCOS have shown that ovarian drilling results in an 80% ovulation rate and a 50% pregnancy rate.⁶

There are specific treatments for endometriosis. A more detailed description of this topic can be found on the NICHD topic page on endometriosis.

Treatments for the infertility that can occur with endometriosis include:^7,8

• Surgery to remove the patches of tissue caused by endometriosis can improve a woman’s chances of getting pregnant. Some studies suggest that surgical treatment of endometriosis can double the pregnancy rate.
• ART, which can improve the chances for getting pregnant among women with endometriosis.

There are currently no treatments that increase fertility among women with POI.⁶ However, women with POI can use ART and become pregnant with the help of an egg donor.⁹ More information about this condition is available on the NICHD POI topic page, which includes a discussion of treatments for POI symptoms and associated conditions.