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Fertility, Pregnancy, Research, Stanford News, Women's Health

Oh, baby! Infertile woman gives birth through Stanford-developed technique

Oh, baby! Infertile woman gives birth through Stanford-developed technique

newborn fingerKazuhiro Kawamura, MD, PhD, an associate professor of obstetrics and gynecology at the St. Marianna University School of Medicine in Japan, doesn’t usually cry after performing a caesarean section. The operation itself is routine. But this birth was special.

Kawamura had just delivered the first baby conceived through the use of a new treatment for infertility developed in the Stanford laboratory of Aaron Hsueh, PhD, professor of obstetrics and gynecology. Kawamura headed the clinical aspects of the research, and all the patients received treatment in Japan. Hsueh is senior author of the work, which was published online today in the Proceedings of the National Academy of Sciences (subscription required).

“I couldn’t sleep the night before the operation, but when I saw the healthy baby my anxiety turned to delight,” Kawamura told me. “The couple and I hugged each other in tears.”

The technique, which the researchers refer to as “in vitro activation,” or IVA, requires an ovary (or a portion of an ovary) to be removed from the woman, treated outside the body and then re-implanted near her fallopian tubes. The woman is then treated with hormones to stimulate the growth of specialized structures in the ovaries called follicles in which eggs develop.

As I describe in our release:

Twenty-seven women in Japan took part in the experimental study. The researchers were able to collect mature eggs for in vitro fertilization from five of them. Although it has not yet been tested in women with other causes of infertility, the researchers plan to investigate whether the technique can also help women with early menopause caused by cancer chemotherapy or radiation, and infertile women between the ages of 40 and 45.

The women in the study were suffering from a condition called primary ovarian insufficiency, which affects about 1 percent of women of reproductive age in this country. The ovaries of these women don’t produce normal amounts of estrogen or release eggs regularly. As Hsueh explained:

Women with primary ovarian insufficiency enter menopause quite early in life, before they turn 40. Previous research has suggested that these women still have very tiny, primordial primary and secondary follicles, and that even though they are no longer having menstrual cycles they may still be treatable. Our results obtained with our clinical collaborators in Japan make us hopeful that this is a group of patients who can be helped.

Hsueh’s laboratory has been studying follicle maturation for years. In  2010, he was awarded $1.4 million from the California Institute for Regenerative Medicine to study the maturation of human eggs for stem cell derivation. This birth represents a combination of two treatments known to induce follicle growth: cutting the isolated ovary into small pieces (which disrupts a growth arrest pathway called Hippo) and treating those bits with a substance to modulate a second follicle-development pathway (described by Gina Kolata in the New York Times) previously identified in Hsueh’s lab. The researchers found that the two treatments together had an additive effect, activating many more follicles than either treatment alone.

Valerie Baker, MD, chief of Stanford’s Division of Reproductive Endocrinology and Infertility and medical director of the Stanford Fertility and Reproductive Medicine Center, wasn’t directly involved in the study, but is working with Hsueh to test the treatment on more women. As she described:

These women and their partners come to me in tears. To suddenly learn at a young age that your childbearing potential is gone is very difficult. This technique could potentially help women who have lost their egg supply for any reason.

Photo by Jon Ovington

Ask Stanford Med, Fertility, Women's Health

Ask Stanford Med: Director of Female Sexual Medicine Program responds to questions on sexual health

Ask Stanford Med: Director of Female Sexual Medicine Program responds to questions on sexual health

7058874009_eeff99aae6 (1)In some circles, the term “female sexual health” may elicit more blushing than productive conversation, even between a woman and her gynecologist. So for this installment of Ask Stanford Med, we invited Leah Millheiser, MD, director of Stanford’s Female Sexual Medicine Program, to respond to readers’ questions on the topic. Below are her answers, which we hope will generate more open discussion on a health subject important to both women and men.

Heather asks: Why are there no FDA-approved medications for female sexual disorders and several for men? Will there ever be a Viagra-type drug for women?

That’s an excellent question, Heather, and one that I am frequently asked by my patients. There are two drugs FDA-approved for the treatment of female sexual dysfunction (FSD) compared to the seven available for the treatment of male erectile dysfunction. Premarin vaginal cream has been around for many years for the treatment of vaginal atrophy in postmenopausal women. However, in 2008, the FDA approved Premarin for a new indication – the treatment of postmenopausal sexual pain (dyspareunia). Earlier this year, Osphena was also approved for the treatment of postmenopausal dyspareunia. Osphena is an oral pill taken on a daily basis that belongs to a class of drugs called Selective Estrogen Receptor Modulators (SERMs). Unfortunately, we still have a long way to go when it comes to closing the gap between FDA-approved treatments available to men vs. those available to women. Currently, many women are being treated for sexual dysfunction with off-label treatments. These are medications that have been shown in research to be safe and effective for the treatment of FSD (desire, arousal, orgasm, and pain disorders). The good news is that there are several drugs currently under investigation for the treatment of low libido and arousal disorders. Learn more about female sexual dysfunction here.

Emily asks: Is there any connection between female sexual health disorders and infertility?

There is definitely a connection between female sexual function issues and infertility, Emily. In a 2010 study (subscription required) published in Fertility and Sterility, we demonstrated that women with infertility were at a higher risk for sexual dysfunction compared to women without infertility. Specifically, the women with infertility had greater difficulty with sexual arousal and desire. On the flip side, when a woman is experiencing sexual dysfunction, she may limit or avoid sexual activity altogether. This limitation may prevent a woman from becoming pregnant. In fact, many patients are referred to me from infertility centers with a diagnosis of sexual pain, most commonly vaginismus. Vaginismus occurs when there is an involuntary contraction of the pelvic floor muscles during attempted or actual vaginal penetration. Oftentimes, partners of women with vaginismus will describe the sensation of “hitting a brick wall” whenever they try to enter the vagina. Individuals with this disorder may avoid seeing a gynecologist for yearly exams due to the fear of pain. The treatment for vaginismus is quite successful and, in the motivated patient, can be completed in a relatively short period of time. From a financial perspective, it is often more cost-effective to address the sexual dysfunction prior to embarking on what can end up being very expensive fertility treatments. Learn more about the relationship between infertility and female sexual dysfunction here.

Grace asks: What is the relationship between body image/low self-esteem and low sex drive in women?

When a woman comes to see me for a complaint of low sex drive, we focus on several areas of her health: general medical disorders, medications, surgeries, pregnancy history, mental health, relationship history, as well as psychosocial stressors. When taking a patient’s mental health history, I always screen for depression/anxiety and discuss body image and self-esteem. There are many reasons why a negative body image can affect a woman, including dissatisfaction with body image following pregnancy, menopause, or treatment for cancer (breast, gynecologic). In the case of pregnancy, the data shows that most couples resume intercourse after six weeks; however, the frequency is usually decreased compared to pre-pregnancy, which can be related to low body image. If a woman does not feel comfortable with her own body, she may avoid situations of intimacy with her partner. This avoidant behavior becomes associated with low sex drive. Following menopause, many women find that they gain weight easily, especially in the abdominal area, and have difficulty losing it. Additionally, they may develop low libido and vaginal atrophy, which can lead to painful intercourse. In many cases, women feel as though their bodies have “turned against them” following menopause and, as a result, their body image and sexual self-esteem are impacted. In the setting of breast cancer, women may experience negative body image as a result of chemotherapy-related hair loss or surgical treatment, including mastectomy or lumpectomy. In fact, data shows that premenopausal women who undergo mastectomy experience greater issues related to poor body image compared to postmenopausal women treated with the same surgery.

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Fertility, Pregnancy, Research, Women's Health

Study shows bigger breakfast may help women with PCOS manage symptoms

Study shows bigger breakfast may help women with PCOS manage symptoms

“We’ve had one, yes. But what about second breakfast?” Pippin replied to Aragorn in The Lord of the Rings: The Fellowship of the Rings (2001). How would a hobbit manage with one breakfast if it were a nearly 1,000-calorie affair, and lunch and dinner were eaten in prince and pauper-sized portions, respectively? What about certain human females?

A recent study from Tel Aviv University varied meal timing and calorie distribution for normal-weight women with Polycystic Ovarian Syndrome (PCOS) and measured changes in insulin resistance and fertility rates among them. The 60 participants were randomly assigned to either a “big breakfast” group—consuming 983 calories for breakfast, 684 for lunch, and 190 for dinner—or a “big dinner” group, which kept lunch calories the same and switched the calorie numbers for breakfast and dinner, for 90 days. The study’s lead author, Daniela Jakubowicz, MD, has promoted hobbit-friendly breakfasts for weight loss previously.

Past research has found a link between PCOS and insulin resistance, and between symptoms of PCOS, such as irregular ovulation cycles and high levels of testosterone, and fertility problems. Other studies have focused on lifestyle modifications such as weight loss for insulin and hormone management among overweight women with PCOS, and medications including insulin-sensitizing agents may be used to treat hormonal and metabolic conditions associated with PCOS.

In the recent study, published in Clinical Science, participants’ BMI stayed the same, as expected, while other measures differed between the two groups. From a release:

While participants in the “big dinner” group maintained consistently high levels of insulin and testosterone throughout the study, those in the “big breakfast” group experienced a 56 percent decrease in insulin resistance and a 50 percent decrease in testosterone. This reduction of insulin and testosterone levels led to a 50 percent rise in ovulation rate, indicated by a rise in progesterone, by the end of the study.

According to Prof. Jakobowicz, these results suggest that meal timing – specifically a meal plan that calls for the majority of daily calories to be consumed at breakfast and a reduction of calories throughout the day – could help women with PCOS manage their condition naturally, providing new hope for those who have found no solutions to their fertility issues, she says. PCOS not only inhibits natural fertilization, but impacts the effectiveness of in vitro fertilization treatments and increases the rate of miscarriage.

Study authors indicated that a high-calorie breakfast followed by reduced caloric intake throughout the day could also lessen the impact of common PCOS symptoms, such as unwanted body hair, acne, and an elevated risk of developing type-2 diabetes.

Lynn Westphal, MD, is co-director of Women and Sex Differences in Medicine (WSDM) and an associate professor of obstetrics and gynecology at Stanford whose research interests include infertility and fertility preservation. I asked her for comment on this study. She replied:

I think it’s a really interesting study. I would not have thought that the timing of meals would make that big of a difference in the PCOS patients. A lot of patients don’t eat breakfast or don’t think it’s important, so having a study that shows it has an impact on fertility will help us counsel patients to modify their lifestyle in a way that also benefits their overall health. As a follow up, it would be interesting to see if this benefit is seen during pregnancy, too.   We know that the health of the mother during pregnancy can have a significant impact on the long-term health of the child.

Previously: NIH study suggests progestin in infertility treatment for women with PCOS may be counterproductivePatients turning to acupuncture to boost fertility and The pill works just as well for heavier women, study finds

Fertility, Pregnancy, Research, Women's Health

Survey captures thoughts of women who undergo egg freezing

Survey captures thoughts of women who undergo egg freezing

There’s some interesting research out of Europe on the mindset of women who have undergone egg freezing. The survey, conducted by physicians at Free University in Belgium – one of Europe’s largest reproductive centers - focused on 140 healthy women considering egg banking as insurance against age-related infertility (not for medical reasons). It showed that while only one-third of the women who wound up preserving their eggs thought they’d ever use the eggs, 96 percent of them said they would do it again – though at a younger age. (The median age of the women surveyed was 37 years.)

The work was presented yesterday at the European Society of Human Reproduction and Embryology, and the researchers say the findings “suggest oocyte freezing to preserve fertility provides important psychological reassurance for those opting to use the technology.”

Previously: Programs help cancer patients at risk of losing their fertility

Cancer, Fertility, Men's Health, Research, Sexual Health, Stanford News

Low sperm count can mean increased cancer risk

Low sperm count can mean increased cancer risk

Men who are diagnosed as azoospermic , or infertile due to an absence of sperm in their semen, are at higher risk of developing cancer than the general population, Stanford urologist Mike Eisenberg, MD, PhD, has found. A diagnosis of azoospermia before age 30 carries an eight-fold cancer risk.

Eisenberg, who is director of male reproductive medicine and surgery at Stanford Hospital & Clinics, is lead author of a just-published study in Fertility and Sterility concluding that an azoospermic man’s risk for developing cancer is similar to that for a typical man 10 years older.

(Eisenberg is the same physician/scientist who discovered, a few years ago, that childless men are at higher cardiovascular risk than their counterparts with kids.)

About 4 million American men – 15 percent of those ages 15-45 – are infertile. Of these, some 600,000 (an estimated 15 percent) are azoospermic, usually because their testes don’t produce enough sperm for any to reach their ejaculate – most likely, Eisenberg says, because of genetic deficiencies of one sort or another.

That may explain the azoospermia/cancer link. As I wrote in my news release on this study, fully one-fourth of all the genes in the human genome play some role in reproduction:

The findings suggest that genetic defects that result in azoospermia may… broadly increase a man’s vulnerability to cancer, Eisenberg said, supporting the notion that azoospermia and cancer vulnerability may share common genetic causes.

Although men diagnosed as azoospermic before age 30 appear to have a particularly pronounced cancer risk compared with their same-age peers, Eisenberg notes that the absolute cancer risk for any apparently healthy man under age 30, regardless of whether or not he is azoospermic, nevertheless remain very small. Still, he advises young men who’ve been diagnosed as azoospermic to be aware of their heightened risk and make sure to get periodic checkups with that in mind.

“Most reproductive aged men (20s-40s) don’t have primary care doctors or really ever see the doctor,” Eisenberg says.

Previously: Men with kids are at lower risk of dying from cardiovascular disease than their childless counterparts

Fertility, Myths, Pediatrics, Pregnancy, Sexual Health, Women's Health

Research supports IUD use for teens

Research supports IUD use for teens

A large body of scientific research supports the safety and effectiveness of intrauterine devices and other forms of long-acting, reversible contraception (LARC) for adolescents, and physicians should offer these birth control methods to young women in their care. That’s the message behind a series of review articles published this week in a special supplemental issue of the Journal of Adolescent Health.

Stanford ob/gyn expert Paula Hillard, MD, who edited the supplement, explained to me that doctors are missing a great opportunity to prevent unwanted pregnancies by not offering young women the LARC birth control methods, which include IUDs and hormonal implants. Not only are the LARC methods very safe, the rate of unintended pregnancy with typical use of these techniques is 20 times lower than for alternate methods such as the Pill or a hormone patch.

But a design flaw in one specific IUD used in the 1970s – the Dalkon Shield – increased women’s risk for pelvic infections and gave all IUDs a bad rap. Use of IUDs among adult American women has been low ever since; it’s even lower in teens.

“Long after it was proven that the Dalkon Shield was particularly bad and newer IUDs were much safer, women were just scared,” Hillard said. “Not only did women stop asking for for them, many doctors also stopped using IUDs.”

The new review articles that Hillard edited are targeted at physicians but contain some interesting tidbits for general readers as well. The article titled “Myths and Misperceptions about Long Acting Reversible Contraception (LARC)” provides scientific evidence to refute several common myths, concluding, for instance, that IUDs don’t cause abortions or infertility, don’t increase women’s rates of ectopic pregnancy above the rates seen in the general population, and can be used by women and teens who have never had children.

And, as Hillard put it for me during our conversation, “These birth control methods are very safe and as effective as sterilization but completely reversible. They work better than anything else, and they’re so easy to use.”

Previously: Will more women begin opting for an IUD?, Promoting the use of IUDs in the developing world, and Study shows women may overestimate the effectiveness of common contraceptives
Photo, by ATIS547, shows a public sculpture on the campus of the University of California, Santa Cruz that is affectionately known as the “Flying IUD”

Fertility, Imaging, Pregnancy, Stanford News, Women's Health

Stanford researchers work to increase the odds of in vitro fertilization success

Stanford researchers work to increase the odds of in vitro fertilization success

Updated 12-6-12: In the video above, Shawn Chavez, PhD, first author of the study, describes the work and its significance.


12-4-12: Couples who turn to in vitro fertilization, or IVF, are desperate to have a family. But, despite many advances, the odds of a successful pregnancy from each round of costly, emotionally demanding embryo transfer are only about 30 percent. The problem stems from the fact that many human embryos are faulty from the earliest stages and will never develop successfully.

Stanford researchers Renee Reijo Pera, PhD, and Barry Behr, PhD, have been working to find out why – and to develop ways to increase the odds of a successful pregnancy through IVF. They report findings from some of their work in today’s Nature Communications, which I describe in a release:

The research suggests that fragmentation — a common but not well-understood occurrence in the early stages of human development in which some of the cells in an embryo appear to break down into smaller particles — is often associated with a lethal loss or gain of genetic material in an embryo’s cells. Coupling a dynamic analysis of fragmentation with an analysis of the timing of the major steps of embryonic development can significantly increase the chances of selecting an embryo with the correct number of chromosomes, the researchers found.

“It is amazing to me that 70 to 80 percent of all human embryos have the wrong number of chromosomes,” said [Reijo Pera], professor of obstetrics and gynecology. “But less than 1 percent of all mouse embryos are similarly affected. We’re trying to figure out what causes all these abnormalities.”

Reijo Pera and Behr started a company called Auxogyn to investigate ways to bring these findings into the clinic. The company, which is now privately held, is currently conducting clinical trials of an earlier version of the technique. Reijo Pera and Behr hold stock in the company.

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Fertility, Genetics, Research, Stanford News

Whole-genome sequencing of human sperm done by Stanford researchers

Whole-genome sequencing of human sperm done by Stanford researchers

Bioengineer Stephen Quake, PhD, has been in the news a lot lately. Earlier this month, his lab reported the first non-invasive whole-genome sequencing of a fetus using only the mother’s blood. Now he’s broken new ground again by sequencing the whole genomes of single sperm cells. The research is published today in Cell. As I explain in our release:

The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete — the only cells that become a child and through which parents pass on physical traits.

Quake and his colleagues, including Barry Behr, PhD, HCLD, the director of Stanford’s In Vitro Fertilization Laboratory, were able to identify places in each sperm genome where sections of chromosomes had been swapped in a natural process called recombination. The exact locations and number of times the swaps occur vary in each cell. When the process goes well, it’s an important way to add genetic variation and ensure that a child is a blend of DNA from all four grandparents. When it goes awry, it can lead to infertility or genetic problems in the fetus.

More from the release:

The Stanford study showed that the previous, population-based estimates were, for the most part, surprisingly accurate: on average, the sperm in the sample had each undergone about 23 recombinations, or mixing events. However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. Two sperm were missing entire chromosomes. The study has long-ranging implication for infertility doctors and researchers.

“For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person,” said [Behr]. “Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems.”

Previously: New techniques to diagnose disease in a fetus

Fertility, NIH, Public Health, Women's Health

NIH study suggests progestin in infertility treatment for women with PCOS may be counterproductive

Polycystic ovarian syndrome (PCOS) affects as many as 5 million women in the United States and can occur in girls as young as 11 years old, according to the most recent data from the federal Office on Women’s Health.

Women with PCOS produce excessive amounts of the hormone androgen, which inhibits ovulation and can cause fluid-filled sacs to develop on the ovaries. The conditions is the most common cause of female infertility. For women with PCOS who are undergoing infertility treatment, physicians may administer the hormone progestin in a single course before drug treatment begins.

But new research from the National Institutes of Health (NIH) shows using progestin in infertility treatment for women diagnosed with PCOS may decrease the odds of becoming pregnant. In the study, researchers analyzed data from a 2007 study and compared the effectiveness of ovulation induction combined with advance progestin treatment to that of ovulation induction alone. According to an NIH release:

The researchers found…that women who skipped the progestin treatment before receiving fertility drugs were four times more likely to conceive than were women given progestin. Ultimately, 20 percent of the women who did not receive progestin gave birth, compared with about 5 percent of the women who received progestin.

Interested to know more about the implication of the findings on fertility research and treatments, I contacted Lynn Westphal, MD, associate professor of obstetrics and gynecology at Stanford. She commented on the study, saying:

These are very interesting findings that need to be confirmed with a prospective study. If confirmed, these results will change how we manage our PCOS patients, and perhaps other infertile women, needing ovulation induction.

Previously: Patients turning to acupuncture to boost fertility, New York Times shows how Stanford researchers solved the “egg maturation puzzle” and Stanford researchers help awaken sleeping egg-producing cells

Ethics, Fertility, Genetics, Medicine and Society, Parenting

The end of sex? Maybe not just yet

Will in vitro fertilization gradually morph from a blessing for infertile couples to a preferred pathway to parenthood?

In January, I wrote about a talk given by Stanford law professor Hank Greely, JD. In that talk, Greely noted science’s steady advances in the genetic analysis of living embryos; the production of gametes (egg and sperm cells) from other easily accessed cell types; the matching of genetic variations to not only disease predispositions but also behavioral and physiognomic traits; and gene therapy, which could in theory modify those characteristics in gametes. Greely followed up with a stark prediction: Within the next 50 years or so, the majority of babies in developed countries will be spawned in IVF clinics.

As I wrote then, quite apart from some cautionary arguments regarding the ethics of such interventions, there were some strictly scientific grounds for skepticism. This report of a recent meta-analysis of IVF’s effects, which concludes that babies conceived this way are at increased risk of having birth defects, reinforces those concerns:

Zhibin Hu at Nanjing Medical University and colleagues collected the results of 46 studies that compared the number of birth defects among children conceived using an IVF technique to children conceived normally. For more than 124,000 children born through IVF or using [an associated technique] in which a single sperm is injected directly into the egg, the risk of having a birth defect was 37 percent higher than that of the other children, they found.

This is by no means proof that IVF is, in itself, a dangerous procedure. It may merely be that the people who tend to use IVF are already more likely to have children with birth defects.

Still, the could be another flashing yellow light for birthing technocracy. The medical trade-offs of IVF and related technologies are such, and likely to remain such for a long time, that people without fertility problems per se will likely opt to go the old-fashioned route rather than high-tech option. A prominent exception: people who are carriers for a single-gene disorder they don’t want transmitted to their kids.

Previously: The end of sex?, Sex without babies, and vice versa: Stanford panel explores issues surrounding reproductive technologies, and Stanford’s IVF research on Time’s top ten list

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