NICHD Research Helps Unravel the Complex Causes of and Treatments for Infertility
According to the Centers for Disease Control and Prevention (CDC), infertility affects about 12% of all people of reproductive age—women and men—in the United States attempting to get pregnant. Other estimates suggest that the numbers are even higher.
Causes of infertility range from: environmental factors, such as exposure to chemicals or smoking; to physical factors, such as blocked fallopian tubes or obesity; to conditions that prevent production of sperm or mature eggs, such as low or high testosterone.
There is also a range of current treatments for infertility, including medication, surgery, and assisted reproductive technologies, such as donor insemination and in vitro fertilization. Although the success of these therapies depends on the individuals and their health status, current therapies enable many people to conceive who would not have been able to do so without assistance.
Addressing issues related to infertility in both men and women is a central part of the NICHD mission. The Institute conducts and funds research on various aspects of infertility, including (but not limited to):
- Causes of infertility
- Therapies for treating infertility
- Demographics of infertility and its treatments
- Economic impact of infertility and its treatments
- Conditions and disorders that cause, contribute to, or are associated with infertility
The NICHD also supports several research networks that study fertility and infertility, as well as programs that train investigators in current techniques and technologies related to infertility research. Several recent studies and ongoing research activities, some described below, illustrate some of the Institute's efforts on this complex topic. Select a link to learn more:
Studies on Overall Fertility
Research on Condition-Specific Infertility
Research on Non-Condition-Specific Infertility
Research on Infertility Outcomes
Other Supported Research and Training Programs on Infertility
Studies on Overall Fertility
The NICHD supports research to understand the causes of fertility, many of which are still unknown, in women and men. Recent studies have examined the relationships among certain environmental factors, lifestyle activities, and reduced fertility. Studies are also under way to identify effective treatments for infertility.
Obesity in Early Adolescence Alters Sex-Specific Hormone Production
Research shows that obesity is associated with increased production of androgens in adult women and during late female puberty or adolescence. Androgens are often called "male hormones" because males' bodies make more of them than do women's bodies, but both males and females need certain levels of androgens for normal health. Changes in hormone levels, including increases in androgens, can disrupt female reproductive cycles and lead to infertility.
In research funded by the NICHD Reproductive Sciences (RS) Branch, investigators studied whether obesity prior to and during early puberty also increased androgen hormone production. Researchers compared androgen levels in normal-weight and obese girls between ages 8 and 14 years. Girls who were obese had higher androgen levels throughout puberty compared with normal-weight girls. The results of this study demonstrate that childhood obesity affects normal hormone production and that these early hormone level changes could influence fertility later in life. For details on this finding, visit PubMed ID: 17118995.
Stress Reduces the Ability to Conceive in Women
Although a few studies have found an association between stress and the probability of conception, it remains unclear whether stress causes fertility problems or fertility problems cause stress. Recently, the NICHD Division of Epidemiology, Statistics, and Prevention Research (DESPR) collaborated with colleagues from the University of Oxford in the United Kingdom to examine this issue by studying alpha-amylase, an enzyme in saliva that has been linked with increased or high levels of stress. In this prospective cohort study, researchers measured the levels of alpha-amylase in the saliva of women who were trying to get pregnant. In the study, the probability of pregnancy was lower for women with higher levels of alpha-amylase than for those with lower concentrations, suggesting that stress reduced the probability of conception. For details on this finding, visit PubMed ID: 20688324.
High Dietary Fiber Intake Reduces Fertility in Women
Increased fiber intake has been a recent focus of women's health efforts because research findings showed that high-fiber diets were connected to lower breast cancer rates. The effect may be the result of fiber reducing levels of the hormone estrogen, which is an important factor not only in breast cancer, but also in reproduction. DESPR researchers aimed to determine the effects of such high-fiber diets on women's reproduction. The researchers evaluated data from the BioCycle Study, a prospective cohort study conducted from 2004 to 2006 that included 250 women. The participants were between 18 and 44 years old, and they contributed daily data over two menstrual cycles.
The researchers found that dietary fiber intake lowered reproductive hormone levels and was associated with ovulation failure. Absence of ovulation is a leading cause of female infertility. This study suggests that diet could be one factor that contributes to infertility in some women. For details on this finding, visit PubMed ID: 19692496.
Cigarette Smoking Affects Women's Reproductive Hormones
Research has implicated cigarette smoking in lower fertility in women, specifically in delayed conception, but the reason that this occurs is unknown. In another analysis of data from the BioCycle Study, DESPR researchers examined the effect of cigarette smoking on women's reproductive health. Researchers measured women's reproductive hormones, including estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), across the menstrual cycle. The levels of these hormones, which vary during the menstrual cycle, are critical for a woman's reproductive health. In the study, researchers found that smokers had abnormal increases in FSH and LH. High levels of these hormones are common during menopause and are associated with reduced fertility. This research points to a possible explanation for the adverse effect of smoking on women's fertility and reproductive health. For details on this finding, visit PubMed ID: 20670224.
A Critical Balance of Spermatogonial Stem Cell Populations Is Required for Male Fertility
Studies also aim to understand the critical balance of cell populations that is required for male fertility. An essential requirement for sustaining male fertility is maintaining an adequate number of spermatogonial stem cells (SSCs). To achieve this number, when the SSCs divide, some resulting cells must remain stem cells (a process called self-renewal), while others become sperm through a process called differentiation. The balance between self-renewal and differentiation is critical and an imbalance will result in male infertility. Several investigators, supported by the RS Branch, are examining the regulatory processes that govern SSC self-renewal and differentiation. One of these processes includes the role of micro-RNAs (miRs), which are small molecules that inhibit the process of maintaining the "stemness" of SSCs. In a recent study, the investigators found that miR-21 is important for maintaining the SSC population. For details on this study, visit PubMed ID: 21768389.
Investigators supported by the RS Branch are also examining the mechanisms that regulate germline stem cell (GSC) output. GSCs are the source of the cells needed for the process of sperm formation, so understanding their regulation can help identify processes affecting fertility. In the study, the investigators identified several mechanisms of GSC output, including a novel mechanism of GSC generation. Their results indicated GSC output does not rely on a single pathway. In addition, the investigators found that, under certain conditions, GSCs de-differentiate back into stem cells. For details on this study, visit PubMed ID: 21752931.
Study in Progress: Effects of the Environment on Men's and Women's Fertility
Few comprehensive studies have examined the effects of environmental and lifestyle factors on fertility. One study, the Longitudinal Investigation of Fertility and the Environment (LIFE) Study, conducted by DESPR, is doing just that: examining the long-term effects of ubiquitous environmental and lifestyle factors on fertility among couples. The exposures of interest include persistent chemicals, such as polychlorinated biphenyls, and lifestyle factors, including stress, cigarette smoking, caffeine intake, and alcohol usage. Researchers collected data from 501 couples in two U.S. states, over 12 menstrual cycles, as they tried to get pregnant. Women who conceived were followed to delivery. Researchers are examining a number of measurements of reproduction, including fertility, pregnancy loss, infertility, and infant gestation and birth size.
In a recent publication from the LIFE Study, researchers examined the levels of cadmium and lead in the blood and the incidence of infertility. Cadmium and lead are two metals found in most individuals' environments. Cadmium is present in batteries, plastics, and cigarette smoke, while lead is present in a variety of products, such as paint in older houses. Both are also found in varying amounts in human food sources, including plants and animals. Exposure to these metals is known to have adverse effects on human health, but their effects on human fertility have not been studied extensively. Using data from the LIFE Study, investigators examined the blood levels of cadmium and lead in couples. Researchers examined the number of menstrual cycles couples required to achieve pregnancy and found that higher blood levels of cadmium in women and higher blood levels of lead in men delayed pregnancy. For details on this finding, read the NICHD news release: NIH study links high levels of cadmium, lead in blood to pregnancy delay.
Study in Progress: Effects of Aspirin on Gestation and Reproduction (EAGeR) Study
Previous studies have suggested that some effects of aspirin may provide an advantage for reproductive measures, including conception, implantation of the fertilized egg, early reproductive loss, late fetal death, and low birth weight, among others. While the exact mechanism is not known, aspirin may provide some of its advantages by improving blood flow during conception and egg implantation. The improved blood flow may reduce the risk for adverse pregnancy events by improving placental health. To learn more, the NICHD's DESPR is conducting the EAGeR Study, a randomized placebo-controlled clinical trial designed to evaluate the effect of daily low-dose aspirin on live-birth rates.
The EAGeR study will recruit and follow 1,600 women for up to six menstrual cycles while they attempt to get pregnant. Women who get pregnant will be followed through delivery. Researchers will examine the effect of low-dose aspirin in combination with folic acid, which reduces a certain group of problems called neural tube defects, on the incidence of live births compared with either treatment alone. Researchers will also examine early pregnancy loss, preterm delivery, and other measurements of fertility and fetal/infant health. Read more about this study on the EAGeR Study website.
Research on Condition-Specific Infertility
The NICHD also supports research to understand diseases of and conditions that cause infertility. These conditions include (but are not limited to) endometriosis, Polycystic Ovary Syndrome (PCOS), and Primary Ovarian Insufficiency (POI). Recent NICHD-supported research in some of these areas is described in more detail below.
A recent NICHD Spotlight described several research advances and findings on endometriosis, including endometriosis-related infertility. For more information, visit: Molecular Imbalance Harms Fertility.
Researchers in DESPR designed the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study to examine the incidence of endometriosis and factors contributing to its development. Two recent publications from the ENDO Study highlight important concerns about endometriosis. For both publications, researchers used a matched-exposure cohort design to determine the incidence of endometriosis in women (ages 18 to 44) with no history of endometriosis undergoing laparoscopy/laparotomy ("operative" cohort) for other health concerns. Women undergoing laparoscopy/laparotomy at 14 participating clinical centers during the 2007–2009 period were matched to a population (control) cohort of women who did not undergo laparoscopy/laparotomy. The incidence of endometriosis in the control cohort was determined by magnetic resonance imaging. The design of the study allowed researchers to estimate the percentage of women in the general population with undiagnosed endometriosis. Based on the results, the researchers reported that approximately 11% of women in the general population have undiagnosed endometriosis. The researchers concluded that endometriosis incidence is dependent on the method used for the diagnosis and the sampling method. The results of this study indicate that undiagnosed endometriosis exists in a portion of the population. For details on this finding, visit PubMed ID: 21719000.
Previous experimental evidence has suggested a possible link between persistent organochlorine pollutants (POPs) and endometriosis. In the second recent publication from the ENDO Study, researchers examined whether higher concentrations of POPs in the body were associated with a greater incidence of endometriosis. In this study, POP concentrations were measured in belly fat in the operative cohort and in serum in both cohorts. In the operative cohort, a specific POP—gamma-hexachlorocyclohexane—was associated with endometriosis incidence. In the control cohort, another POP—beta-hexachlorocyclohexane—was associated with endometriosis incidence. The results of this study indicated that POPs are associated with an increased incidence of endometriosis. Additionally, the methods used to detect endometriosis are important for interpreting the associated factors, POPs in this case. For details on this finding, visit PubMed ID: 22417635.
In addition, researchers funded through the NICHD Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR) recently identified a key step in the establishment of pregnancy. This step occurs when a protein called Hand2 turns off chemical activity that causes the tissue lining the uterus to grow, allowing a fertilized egg to implant. This finding is important for understanding infertility related to the inability of a fertilized egg to implant in the uterus. The finding also has implications for understanding disorders in which uterine lining tissue grows out of control, including endometrial cancer and endometriosis. For details on this finding, read the NICHD news release: Researchers Identify Protein Essential for Embryo Implantation.
Studies in Progress: PCOS and PCOS-Related Infertility
PCOS is one of the most common causes of female infertility. One its primary features is higher-than-normal levels of androgens. In women, high levels of these hormones interfere with the growth, development, and release of eggs that occurs during ovulation. This disruption can cause the formation of fluid-filled sacs, called cysts, in the ovaries. NICHD-supported researchers are conducting studies to understand and treat PCOS and PCOS-associated infertility.
One of these studies, the Pregnancy in Polycystic Ovary Syndrome II study, is investigating the safety and efficacy of two treatments for PCOS-related infertility—an aromatase inhibitor (letrozole) compared to clomiphene citrate—for ovulation, conception, and live births in infertile women with PCOS. This study is nearing completion. For details, visit Clinical Trials.gov ID: NCT00719186.
Another study, which is currently seeking participants, will examine adrenal gland function in women with PCOS. The adrenal glands produce or contribute to the high androgen levels seen in women with PCOS, but it is not known whether there is a problem with the glands themselves. Read more about the study and its eligibility criteria at Women Sought for NIH Study of Infertility Disorder.
A recent study conducted by scientists in the RS Branch-funded Reproductive Medicine Network (RMN) examined progestin treatment for PCOS-related infertility. In the study, 626 women with PCOS were examined for effects on conception and live-birth rates. The investigators found that conception and live-birth rates were significantly higher following treatment with ovulation-inducing medications in anovulatory cycles, in which the ovaries do not release an egg, without progestin-induced withdrawal bleeding compared to similar treatment after a spontaneous menses or progestin-induced withdrawal bleeding episode. Ovulation rates were comparable in all the groups whether or not women were treated with progestin before ovulation induction. The results of the study suggested that the common clinical practice of inducing endometrial shedding with progestin before ovarian stimulation may have an adverse effect on the rates of conception and live birth in anovulatory women with PCOS. For details on this finding, visit PubMed ID: 22525900.
POIdescribes a condition in which a woman's ovaries stop working normally before she reaches the age of 40. The symptoms of POI include infertility and higher risk for health conditions, including osteoporosis, thyroid problems, and heart disease.
In previous NICHD studies, researchers identified an ovarian protein known as maternal antigen that embryos require (MATER) that is essential for cell division following fertilization (see http://www.ncbi.nlm.nih.gov/pubmed/14670992 for more information). More recently, NICHD researchers were able to slow an autoimmune response attack on MATER in mice with POI by "teaching" the immune system to recognize MATER as a non-foreign protein. Because infertility in some cases of POI seems to result from a similar immune response, the study findings could provide a way to identify women who are highly likely to develop autoimmune POI. If these women are identified early, there may be time for them to consider methods of preserving fertility, such as freezing their healthy eggs for later pregnancies. Read more about the finding at: NIH Researchers Slow Immune Attack on Ovaries in Mice.
Research on Non-Condition-Specific Infertility
The NICHD also supports research on infertility that is not related to a specific condition. A current study is examining therapies to treat unexplained (sometimes called idiopathic) infertility in couples.
Study in Progress: Identifying Effective Therapies for Unexplained Infertility in Couples
Infertility can occur in the absence of identifiable factors. The Assessment of Multiple Intrauterine Gestations related to Ovarian Stimulation (AMIGOS) trial seeks to identify an effective treatment, one associated with the lowest rate of multiple gestations, for couples with unexplained infertility. The AMIGOS trial is currently recruiting participants. For details on this study, visit Clinical Trials.gov ID: NCT01044862.
Research on Infertility Outcomes
The NICHD also supports research to understand some of the outcomes of infertility, including stillbirth and miscarriage. Selected NICHD-supported research on these outcomes is described in more detail below.
Research on Stillbirth
Stillbirth, defined as the death of a baby at or after the 20th week of pregnancy, occurs in 1 out of 160 pregnancies in the United States, according to the March of Dimes. Since 2003, the stillbirth rate in the United States has remained at 6.2 stillbirths per 1,000 births, according to the National Center for Health Statistics.
The NICHD's Stillbirth CollaborativeResearch Network (SCRN), funded through the NICHD Pregnancy & Perinatology (PP) Branch, was established to identify causes of stillbirth as well as ways to prevent or reduce its occurrence. Network studies also aim to understand any factors, including race/ethnicity and socioeconomic status, that contribute to differences in stillbirth rates.
Recent results from an SCRN study identified several factors associated with stillbirth that could also explain some cases of infertility. The study also identified key differences in stillbirth risk among different racial/ethnic groups. For details on these findings, read the NICHD news release: Placental, Pregnancy Conditions Account for Most Stillbirths.
The NICHD's Prenatal Alcohol and Sudden Infant Death Syndrome (SIDS) and Stillbirth (PASS) Network, also funded through the PP Branch, aims to find ways of improving pregnancy outcomes and infant health within the context of alcohol intake during pregnancy and SIDS. PASS Network researchers conduct community-linked studies to investigate the role of prenatal alcohol exposure in the risk for SIDS and adverse pregnancy outcomes, such as stillbirth and fetal alcohol spectrum disorders (FASDs), and how they may be interrelated.
The Safe Passage Study, currently the main study of the PASS Network, aims to understand some of the causes of SIDS, stillbirth, and FASD, especially those related to alcohol exposure during pregnancy. The Safe Passage Study plans to enroll approximately 12,000 pregnant women from the United States and South Africa. The study will follow them through pregnancy and the infants' first year of life.
Other Supported Research and Training Programs on Infertility
The NICHD supports several networks that conduct infertility-related research, as well as individual research projects on societal and other influences on and predictors of fertility.
For example, the RMN, funded through the RS Branch, carries out large, multicenter clinical trials of diagnostic and therapeutic interventions for male and female infertility and reproductive diseases and disorders.
The SCCPIR, also funded by the RS Branch, is a national network of research-based centers that aims to improve human reproductive health. The portfolio of research in the SCCPIR includes studies to understand the complex causes of male and female fertility and infertility and the regulation of male and female reproductive processes. SCCPIR investigators also study assisted reproductive therapies, as well as diseases and conditions that affect fertility, such as obesity, endometriosis, and PCOS.
The SCRN and the PASS Network, described above, aim to understand why some pregnancies end in stillbirth. Network studies seek to identify risk factors for stillbirth, including environmental and geographical factors.
The NICHD supports research on fertility, infertility, and reproductive health to understand social, cultural, economic, and policy factors that contribute to disparities in fertility. DBS-supported research examines fertility in older couples and societal influences to have families at older ages because of increased work, education, and other responsibilities at younger ages. Other studies examine racial, ethnic, and socioeconomic disparities in both infertility status and access to treatment. Supported research also includes studies of the short- and long-term consequences of infertility or infertility-associated treatments and the psychological processes that occur during infertility experiences and treatment. This research recently led to a new method for predicting changes in countries' fertility rates, an important factor in planning for service and infrastructure needs. Read more about the method in the news release: NIH-funded Study Proposes New Method to Predict Fertility Rates.
Training the next generation of researchers to study topics related to infertility is also a critical part of the NICHD's activities. Several programs focus specifically on infertility researchers, including (but not limited to):
- Division of Intramural Research (DIR) Reproductive Endocrinology and Infertility Training Program. The Program, accredited by the American Board of Obstetrics and Gynecology (ABOG), sponsors 3-year clinical fellowships, with a strong emphasis on research. Upon completion of the curriculum, fellows may apply to the ABOG for certification in the Subspecialty of Reproductive Endocrinology.
- Male Reproductive Health Research Career Development Program. The Program provides the opportunity for clinicians who specialize in male reproductive health to advance their careers and clinical research capacity through mentored training. The Program, which was established in 2006, is supported by the RS Branch.
- Reproductive Scientist Development Program. The Program is a national career development program with the goal of developing a cadre of reproductive physician-scientists who are highly competitive for funding. The Program, launched in 1988, is supported by the RS Branch and uses mentored research to assist junior faculty in their transition to independent physician-scientists.
- Women's Reproductive Health Research Career Development Program. The Program provides the opportunity for obstetricians/gynecologists who recently completed their postgraduate clinical training to advance their research experience through mentored training. The Program, which was established in 1998, is supported by the RS Branch.
- Clinical Research/Reproductive Scientist Training (CREST) Program. This Program—led by the American Society for Reproductive Medicine, in collaboration with the NICHD and the Clinical Research Training Program at Duke University, trains reproductive endocrinologists in clinical practice to obtain the skills necessary to plan and undertake clinical trials in infertility. For more information on the CREST Program, visit http://www.asrm.org/Apply_for_CREST.
For more information on infertility research at the NICHD, select one of the following links:
Originally Posted: June 15, 2012
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