Research in a new field called oncofertility has advanced the ability of doctors to preserve the reproductive health of women, men and children who are diagnosed with cancer. Yet, many oncologists aren’t familiar with these new strategies to help their patients.

A leading oncofertility researcher and a breast surgical oncologist from the Northwestern University Feinberg School of Medicine have written a guide to help doctors navigate their patients through the new technologies to preserve their fertility and understand the fertility threats posed by cancer treatments. The guide, based on the latest research, offers strategies based on each kind of cancer, age and gender of the patient.

The article is published in the February 26 issue of the New England Journal of Medicine and is included in the NEJM Audio Summary.

“We hope that physicians who are not used to dealing with fertility threats associated with treatment can now talk confidently with their patients about their options,” said article co-author Teresa Woodruff, chief of fertility preservation and the Thomas J. Watkins Professor of Obstetrics and Gynecology at the Feinberg School. “This is a new tool for them.”

Woodruff and Northwestern colleagues also recently launched www.myoncofertility.org, an interactive web site to educate patients about the potential effect of cancer and treatments on their fertility and options to preserve it.

“Doctors are focused on saving a patient’s life and are not used to thinking about preserving a patient’s fertility and incorporating fertility preservation into her or his care,” said lead author Jacqueline Jeruss, M.D., assistant professor of surgery at Feinberg. Jeruss also is a surgical oncologist at Northwestern Memorial’s Prentice Women’s Hospital and a basic science researcher at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Younger patients in particular are not benefiting from fertility preservation options. A new national survey of pediatric oncologists showed that more than half of them are not using fertility preservation techniques that are available at most medical centers for their adolescent patients. The survey was conducted by Robert Brannigan, M.D., associate professor of urology at the Feinberg School and a physician at Northwestern Memorial Hospital.

“Adolescent oncology patients are at the same risk as adults to become permanently infertile as a result of their cancer or cancer treatment, but they are not getting what they need to save their fertility,” Brannigan said.

When a young patient is diagnosed with cancer, doctors feel like it is a medical emergency, even when there may be time to consider fertility before treatment begins, Jeruss explained. “We aren’t used to taking a step back to look at the big picture of patients’ lives after they survive cancer,” she said.

“Clinicians need to break through old practice patterns,” Jeruss said. “In the past, if I saw a young woman with breast cancer, I would be focused on getting her into surgery and through chemotherapy and radiation. Now we have a better sense that with the improvements we’ve made in cancer management, many of our young patients with cancer are going on to survive and live healthy long lives. We need to do everything possible so patients can look forward to a life that looks as much like the life they had planned on before the day they were diagnosed.”

The survival rate of children with cancer is nearly 80 percent in the United States. Approximately 10,700 children were diagnosed with cancer in 2008. In addition, there are 140,000 young adults (men and women younger than 45 years old) who face a cancer diagnosis each year.

Northwestern has led the emerging field of oncofertility and has provided a template of fertility preservation patient care to other medical centers. Woodruff developed and is principal investigator of the national Oncofertility Consortium, a National Institute of Health- funded network of doctors and scientists working to provide improved fertility preservation options for people diagnosed with cancer and other diseases.

At the Lurie Cancer Center, newly diagnosed men, women and adolescents work with a special Fertility Preservation Patient Navigator to figure out the best options to preserve their reproductive health before starting cancer therapy. The patient navigator then coordinates that plan with the patient’s doctors.

Several fertility preservation techniques are under investigation at Northwestern. One is an entirely new way of growing and preserving a woman’s immature eggs, or young follicles, so they can be fertilized and implanted into the uterus when she is ready to have children. Thus far, this technology has been used successfully in mice to produce live, healthy offspring.

As recently as 10 years ago, all men born with an extra X chromosome — a condition whose classic symptoms are known as Klinefelter syndrome — were thought to be infertile. Now, new research at NewYork-Presbyterian/Weill Cornell, led by Dr. Peter Schlegel, has pioneered a surgical approach — a combination of TESE (testicular sperm extraction) and IVF (in vitro fertilization) — that enables these men to father healthy children approximately 40 percent of the time it is employed.

But this is just the beginning. “Our Department has five scientists who are leading research into Klinefelter’s and other chromosomal variations. We are very pleased to join forces with KS&A to raise awareness for these conditions,” says Dr. Schlegel, chairman of the Department of Urology and professor of urology and reproductive medicine at Weill Cornell Medical College, and urologist-in-chief at NewYork-Presbyterian/Weill Cornell.

KS&A presented Dr. Schlegel with a “Lifetime Achievement Award” at its recent meeting to honor his infertility treatment advances — which are rewriting the textbook on Klinefelter syndrome.

“Our current research in the laboratory focuses on understanding the mechanism by which the presence of an additional X chromosome affects sperm production and testosterone synthesis in males with Klinefelter syndrome. These critical and unique studies will allow us to provide improved treatment and management recommendations based on solid understanding of underlying pathophysiology,” says Dr. Darius A. Paduch, assistant professor of urology and reproductive medicine at Weill Cornell Medical College and assistant attending urologist at NewYork-Presbyterian/Weill Cornell.

Dr. Paduch, who leads NewYork-Presbyterian/Weill Cornell’s translational research into the molecular biology and genetics of 47XXY and Klinefelter syndrome, has assembled a diverse group of scientists from Cornell-Ithaca and Rockefeller University to create a center of excellence in research on Klinefelter syndrome. The Center will be one of the first nationally comprehensive resources for patients of all ages dedicated to variations in the X and Y chromosomes.

The unique meeting brought together national expertise in molecular biology and genetics of reproduction and molecular endocrinology. Each of the scientists who participated in the conference — Weill Cornell’s Dr. Matthew Hardy, an adjunct professor of urology, and Cornell-Ithaca’s Dr. Paula Cohen, associate professor of genetics, as well as Dr. Alex Travis, assistant professor of reproductive biology — offer unique expertise in basic science, which, combined with access to patients seen in the Department of Urology, will allow for multidisciplinary collaborations focused on basic scientific research to improve patient care.

“We are very pleased to join with NewYork-Presbyterian/Weill Cornell, whose important research is a cornerstone for a growing body of knowledge that will help transform the lives of individuals who have X and Y chromosome variations,” says Robert Shelton, chairman of the Board of Directors of KS&A. “There is a high likelihood that research into these chromosomal variations will make substantial contributions to knowledge about breast cancer, learning disabilities and other seemingly unrelated phenomena as more is discovered concerning the relevance of genes located on the X and Y chromosomes.”

Most individuals have a total of 46 chromosomes. Commonly, men have one X and one Y chromosome; and women have two X chromosomes. But this is not true for everyone. The most common variation is 47XXY in boys and Trisomy X in girls. Without proper interventions, boys born with an extra X chromosome are at a significantly heightened risk of developing the signs and symptoms of Klinefelter syndrome as adults. Unlike other genetic syndromes such as Down’s or Fragile X, comparatively little is known about X and Y chromosome variations. NewYork-Presbyterian/Weill Cornell and KS&A are working diligently to change that.

As recently as 10 years ago, all men born with an extra X chromosome — a condition whose classic symptoms are known as Klinefelter syndrome — were thought to be infertile. Now, new research at NewYork-Presbyterian/Weill Cornell, led by Dr. Peter Schlegel, has pioneered a surgical approach — a combination of TESE (testicular sperm extraction) and IVF (in vitro fertilization) — that enables these men to father healthy children approximately 40 percent of the time it is employed.

But this is just the beginning. “Our Department has five scientists who are leading research into Klinefelter’s and other chromosomal variations. We are very pleased to join forces with KS&A to raise awareness for these conditions,” says Dr. Schlegel, chairman of the Department of Urology and professor of urology and reproductive medicine at Weill Cornell Medical College, and urologist-in-chief at NewYork-Presbyterian/Weill Cornell.

KS&A presented Dr. Schlegel with a “Lifetime Achievement Award” at its recent meeting to honor his infertility treatment advances — which are rewriting the textbook on Klinefelter syndrome.

“Our current research in the laboratory focuses on understanding the mechanism by which the presence of an additional X chromosome affects sperm production and testosterone synthesis in males with Klinefelter syndrome. These critical and unique studies will allow us to provide improved treatment and management recommendations based on solid understanding of underlying pathophysiology,” says Dr. Darius A. Paduch, assistant professor of urology and reproductive medicine at Weill Cornell Medical College and assistant attending urologist at NewYork-Presbyterian/Weill Cornell.

Dr. Paduch, who leads NewYork-Presbyterian/Weill Cornell’s translational research into the molecular biology and genetics of 47XXY and Klinefelter syndrome, has assembled a diverse group of scientists from Cornell-Ithaca and Rockefeller University to create a center of excellence in research on Klinefelter syndrome. The Center will be one of the first nationally comprehensive resources for patients of all ages dedicated to variations in the X and Y chromosomes.

The unique meeting brought together national expertise in molecular biology and genetics of reproduction and molecular endocrinology. Each of the scientists who participated in the conference — Weill Cornell’s Dr. Matthew Hardy, an adjunct professor of urology, and Cornell-Ithaca’s Dr. Paula Cohen, associate professor of genetics, as well as Dr. Alex Travis, assistant professor of reproductive biology — offer unique expertise in basic science, which, combined with access to patients seen in the Department of Urology, will allow for multidisciplinary collaborations focused on basic scientific research to improve patient care.

“We are very pleased to join with NewYork-Presbyterian/Weill Cornell, whose important research is a cornerstone for a growing body of knowledge that will help transform the lives of individuals who have X and Y chromosome variations,” says Robert Shelton, chairman of the Board of Directors of KS&A. “There is a high likelihood that research into these chromosomal variations will make substantial contributions to knowledge about breast cancer, learning disabilities and other seemingly unrelated phenomena as more is discovered concerning the relevance of genes located on the X and Y chromosomes.”

Most individuals have a total of 46 chromosomes. Commonly, men have one X and one Y chromosome; and women have two X chromosomes. But this is not true for everyone. The most common variation is 47XXY in boys and Trisomy X in girls. Without proper interventions, boys born with an extra X chromosome are at a significantly heightened risk of developing the signs and symptoms of Klinefelter syndrome as adults. Unlike other genetic syndromes such as Down’s or Fragile X, comparatively little is known about X and Y chromosome variations. NewYork-Presbyterian/Weill Cornell and KS&A are working diligently to change that.

KS&A

KS&A is the nation’s oldest, largest and best-known organization supporting individuals born with one or more extra X and/or Y chromosomes, including Klinefelter syndrome, Trisomy X and XYY syndrome. KS&A’s mission is to help individuals with one or more extra X and/or Y chromosomes and their families lead fuller and more productive lives.

NewYork Presbyterian Hospital/Weill Cornell Medical Center

NewYork-Presbyterian Hospital/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital NewYork-Presbyterian and Weill Cornell Medical College, the medical school of Cornell University. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, education, research and community service. Weill Cornell physician-scientists have been responsible for many medical advances — from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson’s disease, the first indication of bone marrow’s critical role in tumor growth, and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. NewYork-Presbyterian, which is ranked sixth on the U.S.News & World Report list of top hospitals, also comprises NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/Westchester Division and NewYork-Presbyterian Hospital/The Allen Pavilion. Weill Cornell Medical College is the first U.S. medical college to offer a medical degree overseas and maintains a strong global presence in Austria, Brazil, Haiti, Tanzania, Turkey and Qatar. For more information, visit http://www.nyp.org and http://www.med.cornell.edu.

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In the first prospective cohort study to examine the relationship between body mass index (BMI) and pregnancy chances in women who have no obvious reasons for infertility but who have spent a year or more trying unsuccessfully to conceive, the study found that for every BMI unit above 29 kg/m2, the probability of pregnancy was reduced by four per cent compared to women with a BMI between 21-29 kg/m2. Very obese women (BMI 35-40) had a probability of pregnancy that was between 26 and 43 per cent lower than women with a BMI between 21-29.

Dr Jan Willem van der Steeg, the lead author of the study [1], which is published in Europe’s leading reproductive medicine journal, Human Reproduction, today (Wednesday 12 December) said: “This reduction in fertility is comparable to the increment of one year in female age. This study tells us that not only obese women with anovulation have lower chances of conception, but also obese women with a regular cycle. Given the increased prevalence of obesity, this is a worrying finding.” The incidence of obesity is reckoned to be 12 per cent in women of child-bearing age in Western Europe and 25 per cent in North America.

As women in developed countries are tending to have their babies later in life, a woman aged 30 or over, who is also obese, would have an even greater reduction in her chances of becoming pregnant.

Obesity is known to be a risk factor for anovulation (absence of ovulation) and NICE [2] guidelines recommending that obese women should be told that they are likely to take longer to conceive are based on studies that looked at BMI and time to pregnancy in women who were pregnant or had delivered a child, and on a study analysing fat distribution and chances of conception in women in a donor insemination programme. However, this new study is the first to show that obesity also affects the chance of spontaneous pregnancy in women who are ovulating normally, but are subfertile [3], and to analyse BMI as a continuous variable that shows the steady decline in pregnancy rates in women with BMIs over 29.

Dr van der Steeg, a medical researcher and resident in obstetrics and gynaecology at the Academic Medical Center, Amsterdam, The Netherlands, and colleagues investigated the effects of obesity on spontaneous pregnancy in 3,029 subfertile couples between 2002 and 2004 in 24 hospitals in The Netherlands. The women had to be ovulating and have at least one, correctly functioning fallopian tube; the men had to have a normal semen analysis. A fertility history and other details, including height, weight and smoking habits, were taken at the start of the study and the couples were followed until pregnancy or the start of fertility treatment within 12 months. Timing and frequency of sexual intercourse was not documented, but Dr van der Steeg believes that this did not affect the results of the study.

“Most studies on subfertility do not report on frequency of intercourse. We assume that most people suffering from subfertility have no problems with the timing and frequency of intercourse, which is an integral part of the history taking in the basic fertility work-up. Couples with serious sexual problems are usually excluded from studies like this one,” he said.

The World Health Organization (WHO) defines overweight as a BMI of between 25-29.9, and obesity as a BMI of 30 or over. In this study 3.7 per cent of women had a BMI below 18.5, 67 per cent had a BMI between 18.5-25, 19 per cent had a BMI between 25-30, 6.7 per cent had a BMI between 30-35, and 3.8 per cent had a BMI of 35 or more. The researchers used the women with a BMI between 21 and 29 as their reference group and found that BMI above 29 was associated with a statistically significant lower probability of spontaneous pregnancy than the reference group.

“In the case of a woman with a BMI of 35, the probability of spontaneous pregnancy was 26 per cent lower, and in the case of a woman with a BMI of 40 it was 43 per cent lower compared to the reference group,” said Dr van der Steeg.

The researchers believe that a possible mechanism to explain the relationship between BMI and pregnancy probability is the hormone leptin that regulates appetite and energy expenditure and is secreted by fatty tissues. “It is possible that obese women may have disturbed hormone levels, which decrease the chances of successful fertilisation and implantation,” said Dr van der Steeg. “The level of leptin in the body is positively related with the amount of fat in individuals without any mutations in their leptin regulation genes. Leptin levels are increased in obese people, suggesting a relative resistance to leptin. It is unclear whether or not obesity causes a resistance to leptin or vice versa. There is evidence that leptin may influence the process of steroid production by the ovaries.”

Dr van der Steeg believes that obesity is a factor in the increasing numbers of couples seeking fertility treatments. “Nowadays, one out of six couples will deal with subfertility once in their life. Adult obesity levels have increased four-fold over the last 25 years, with two-thirds of adults deemed overweight. Professor William Ledger has stated that obesity is a key factor in predictions that the number of couples seeking infertility treatments will double over the next ten years,” he said. Prof Ledger is professor of obstetrics and gynaecology at the University of Sheffield, UK, and made this statement in 2005 at the annual conference of the European Society of Human Reproduction and Embryology.

Dr van der Steeg continued: “We think that women should be informed about their lower pregnancy chances due to their overweight. Although this study does not show whether women’s chances of conceiving rise if they lose weight, because of the size of the cohort, with comparable women in different weight groups, we hypothesise that losing weight will increase the chance to conceive without treatment. Therefore, we would advise women to lose weight. Although the effect on better fertility is not proven, it is shown that the chance of a serious complication during pregnancy and labour is reduced.”

The researchers are developing a new model for predicting pregnancy chances and which includes factors such as BMI. The original prediction model without the BMI is available on the internet (http://www.freya.nl/probability.php) and can be used by couples and their doctors to help them decide whether to go for fertility treatment or not. Dr van der Steeg said the next step would be to perform a trial in which obese subfertile couples are allocated to a weight losing programme or no intervention, with the number of pregnancies without treatment being the primary outcome.

The authors found that female mice injected under the skin with polycyclic aromatic hydrocarbons (PAHs) — environmental toxins found in cigarette smoke — pre-pregancy or while lactating were found to have normal sized litters. However, their female offspring had markedly reduced numbers of resting and early growing follicles — cell clusters that each contain a single egg. Further analysis indicated that the effects of PAHs on the number of follicles in female offspring were mediated through the aryl hydrocarbon receptor (Ahr), which upregulated expression of the gene Harakiri that makes a protein that causes cells to die by a process known as apoptosis. The potential importance of these findings for women of child-bearing age was demonstrated by the observation that PAHs triggered similar molecular pathways in human ovarian tissue transplanted into immunocompromised mice.

The objective of this study was to investigate the association among genotype and phenotype for AR mutations found in infertile males by conventional functional assays and additional in-depth studies performed with several gene-reporters. To this aim we selected 4 AR missense mutations associated with isolated male infertility (L547F and two novel mutations A474V and S650G) or partial AIS (Y571H). After introduction of the specific mutations in AR expression plasmid we performed classical in vitro studies (western immunoblotting, electrophoretic mobility shift assay, hormone-response curves) and transactivation assays with different reporter constructs (MMTV, Sc-ARU-TK, TAT-GRE-2X, Slp-ARU-TK, PEM).

Our results showed that standard functional tests (hormone dose-response curve and western immunoblotting) provide sufficient information only for severe AR mutations, found almost exclusively in CAIS and in some PAIS patients, whereas for AR mutations found in MAIS patients only an extensive analysis with different in vitro systems can lead to a comprehension of the “functional trend” of the receptor’s response and therefore it can assess the association among the mutation and the infertile phenotype. If we would limit the analysis of AR mutations to the standard functional tests, we would lose the significance of 3 out of 4 mutations, and in particular of all the 3 mutations associated with male infertility. In the cases of mild AR mutations associated with male infertility, such a large number of different functional assays is needed because seminological, clinical and laboratory data cannot distinguish between patients with and without AR mutations. In fact, only 25% of the patients (2 out of showed an elevated androgen insensitivity index which is considered the best parameter of androgen sensitivity. Among the different in vitro functional studies, transactivation assays with PEM promoter seems to be the most informative in these cases.

Written by:

D. Zuccarello, A. Ferlin, C. Vinanzi, E. Prana, A. Garolla, L. Callewaert, F. Claessens, A.O. Brinkmann, C. Foresta.

Reference:

Clin Endocrinol (Oxf). 2007 Oct 29; [Epub ahead of print]

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