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Ethics, Fertility, Genetics, In the News, Pregnancy, Stanford News

Daddy, mommy and ? Stanford legal expert weighs in about “three parent” embryos

Daddy, mommy and ? Stanford legal expert weighs in about "three parent" embryos

3519855504_9000d95a2aIt’s an interesting question that got a lot of traction in the media last week. Does the contribution of a tiny amount of DNA from a third person during in vitro fertilization really mean that the resulting child would have three genetic parents? Researchers in Oregon have proposed the technique as a way to avoid genetic diseases arising from faulty mitochondrial DNA by replacing an egg’s mitochondria with one from a second, healthy woman either before or after fertilization with a man’s sperm. They’ve shown that it works in monkeys, and the FDA met last week to consider whether the technique is safe enough to be used in humans.

Yesterday, Stanford law professor and bioethicist Hank Greely, JD, posted a great analysis of the topic on the university’s Law and Biosciences blog, complete with an elegant explanation of the problem for women with mitochondrial DNA mutations:

The mitochondria (high school biology’s “energy powerhouses of the cell”) have their own very short stretch of DNA, separate from the 6.8 billion base pairs found on 46 chromosomes in the cell’s nucleus (the nuclear DNA).  The 16,569 base pairs of the mitochondrial DNA (hereafter “mtDNA”) hold 37 (some say 38) genes, providing instructions for making 13 (or 14) proteins and another 24 RNA molecules.  The full importance of these genes is unknown, but it is clear that some (happily rare) variations in the mtDNA cause quite severe illnesses. Unfortunately, each child gets all of its mitochondria (and hence its mtDNA) in the egg from its mother; if the mother’s mtDNA is dangerously flawed, so will be the mtDNA of all her children. With almost all other genetic diseases, no matter how inevitably the “bad” genetic variation leads to a disease (how “penetrant” the genetic variation is), a woman will have only a 50% or 25% chance of passing on the condition.  With these, her genes can give rise to no healthy children.

Greely gets at the heart of the matter when he compares the statistically minute contribution from the donated mitochondria to a hypothetical child he calls Heather:

I have DNA from four people in each of my cells:  my mother’s mother, my mother’s father, my father’s mother, and my father’s father. Actually, my DNA really came from all eight of my great-grandparents, and all 1024 of my great great great great great great great great grandparents, and all roughly one million of my great (18) grandparents. Yes, all that DNA passed through my (genetic) parents before coming to me, but why does that matter?

Heather gets her DNA from more than two people a bit differently from the way the rest of us do, but so what? How does getting what is, in effect, “gene therapy,” where the gene is delivered in a natural package called the mitochondrion, turn our hypothetical (and healthy) child into a powerful argument against the procedure?

It shouldn’t.  Heather will not be getting superpowers, she will not be in any meaningfully way “designed” (except to avoid a nasty genetic disease), and she will not be given a newly made DNA sequence never before found in the human gene pool. She will get mitochondria with mtDNA that will allow her to have normal health, not a grave disease. That mtDNA will have been taken from a woman, who, though not a source of Heather’s nuclear DNA, is certainly a participant in the human gene pool.

“Heather has three parents” is NOT an argument. It is an irrelevant but attention-getting slogan that is uncritically put forward as, and sometimes mistaken for, a real argument. Yes, the proposed process is a way of bringing forth living and healthy babies that is somewhat new and different, but so were obstetric forceps, (safe) C-sections, and in vitro fertilization. Novelty is not, in itself, a respectable argument against it.

Previously: Medical practice, patents and “custom children”: A look at the future of reproductive medicine, Five million babies and counting: Stanford expert offers conversation on reproductive medicine and Stanford researchers work to increase the odds of in vitro fertilization success
Photo by Christian Pichler

Clinical Trials, Fertility, NIH, Research, Women's Health

Testosterone therapy not effective for primary ovarian insufficiency-related depression, study finds

Testosterone therapy not effective for primary ovarian insufficiency-related depression, study finds

Primary ovarian insufficiency (POI), a condition affecting approximately 1 percent of women and teenage girls in the U.S., is characterized by ovaries that stop functioning normally before a woman is 40. POI may be a cause for irregular periods, reduced fertility, or health problems such as osteoporosis, and women with POI may also be at risk for depression and decreased quality of life. Treatments for POI may include hormone replacement therapy to restore estrogen and progesterone levels.

A recent study from the National Institutes of Health Clinical Center has examined the effect in women with POI of one year of hormone treatment that included testosterone.

From a release:

In the randomized, double-blind, placebo controlled study, 61 women used placebo patches and 67 women used patches that delivered 150 micrograms of testosterone a day, similar to the Intrinsa patch that was rejected by FDA as a treatment for low sexual desire in women.

After 12 months, testosterone levels were back up to normal for the women who got the treatment. The investigators saw no detrimental effects of testosterone, but they found no significant improvement either in measurements of quality of life, self esteem and mood compared with placebo.

Bringing testosterone back to normal doesn’t help these aspects of life, suggesting that it’s something other than testosterone that plays a role in mood problems for women with POI, concluded the researchers.

“This study makes an important contribution toward understanding what testosterone can and cannot do. With all the hype about testosterone and aging, it is important that the public have the facts,” NAMS Executive Director Margery Gass, MD, said in the release.

The study was published online in the journal Menopause.

Previously: An in-depth look at fertility and cancer survivorshipAsk Stanford Med: Expert in reproductive medicine responds to questions on infertility, Researchers describe procedure that induces egg growth in infertile women and Oh, baby! Infertile woman gives birth through Stanford-developed technique

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

An in-depth look at fertility and cancer survivorship

An in-depth look at fertility and cancer survivorship

Pregnant_woman2The physical and emotional after-effects of cancer treatment – things like fatigue, pain and depression – have been well-documented. And because some treatments cause havoc on parts of the body’s reproductive system, younger patients often must also contend with fertility issues.

In a paper recently published online in CA: A Cancer Journal for Clinicians, a group of Stanford researchers review the existing literature on fertility and cancer survivorship. The topic, they explain, is an increasingly important one, given that around 9 percent of patients diagnosed with cancer in the United States are younger than 45 years old and that infertility has been shown to negatively impact quality of life among cancer survivors. They write:

The distress resulting from the interruption of fulfilling one’s reproductive goals as a result of a cancer diagnosis and treatment  persists several years after the diagnosis, particularly for those who never conceive.

The goal of the review, which was led by Lynn Westphal, MD, associate professor of obstetrics and gynecology, was to aid in pre- and post-treatment fertility counseling for patients. In their lengthy article, Westphal and her colleagues summarize what is known about infertility and survivorship – and what we still need to study further. Among the information shared about patients’ reproductive health and the health of their offspring:

  • Since it varies with type of treatment and patient age, among other things, there isn’t an accurate estimate of women’s risk of infertility or primary ovarian insufficiency after cancer treatment. But, the researchers write, studies have shown the incidence of acute ovarian failure or premature menopause among childhood cancer survivors varies from 6 to 12 percent.
  • In the landmark Childhood Cancer Survivor Study, exposure of the ovaries to radiation was shown to be to be one of the highest risks for acute ovarian failure and premature menopause in women.
  • In several studies comparing pregnancies in cancer survivors with those in the general population, “the vast majority of pregnancies occurring in cancer survivors are routine  and uneventful.” But patients who have undergone abdominal or pelvic radiotherapy are known to face a higher risk of preterm birth, low birth-weight offspring, stillbirth and early neonatal death.
  • Testicular and hematologic malignancies are the most common cancers that are associated with impaired sperm production in men.
  • Recent estimates suggest that up to two-thirds of all pediatric cancer survivors will face male germ cell dysfunction.
  • For most cancer survivors, there is no increase in cancer or birth defects in their children. One study comparing more than 2,100 offspring of cancer survivors with more than 4,500 offspring of controls in the United States found no difference in birth defects between the two groups.

The authors discuss specific types of fertility preservation, including egg and embryo freezing, and note that techniques to help survivors have children have improved over the past decade. Yet, they write, only “a subset of oncologists discuss the gonadotoxic effects of cancer treatments with patients of reproductive age, and even fewer refer them for fertility preservation consultations.”

In light of research showing that treatment-related infertility is significantly associated with depressive symptoms among survivors, Westphal and her colleagues encourage clinicians to address these issues – and the options – with their patients.

“Discussion of the changes to a patient’s reproductive health after cancer treatment is essential to providing comprehensive quality care,” they conclude.

Previously: Study highlights fertility-related concerns of young cancer survivorsUnique challenges face young women with breast cancer and A need to provide infertility counseling to cancer patients
Photo by Canwest News Service

Aging, Fertility, Genetics, Research, Science, Stanford News

Male roundworms shorten females’ lifespan with soluble compounds, say Stanford researchers

Male roundworms shorten females' lifespan with soluble compounds, say Stanford researchers

2927367197_d663f8af63_zIt’s almost too good to be true. A Thanksgiving story about sex, death, gender conflict and… roundworms. A Stanford study published today in Science Express suggests that, in some species of worms and flies, males secrete compounds specifically to shorten the lifespan of nearby females. As a result, their mere presence initiates an inexorable early death sequence that the researchers call “male-induced demise.”

(Let’s all pause here for a deeply satisfying comparison to certain relationships in our own lives…)

The researchers, including Stanford geneticist and longevity expert Anne Brunet, PhD, and postdoctoral scholar Travis Maures, PhD, studied the laboratory roundworm, C. elegans, which has hermaphrodites rather than true females. Their research indicates that male roundworms secrete as-yet-unidentified molecules that act on hermaphrodites sequestered on the other side of a laboratory dish, or those added to a laboratory dish from which a batch of males had recently been evicted. Those hermaphrodites have a lifespan more than 20 percent shorter than controls not exposed to males.

The finding appears to counteract previous theories suggesting that the act of mating (which in worms can be – shall we say – quite rowdy) is responsible for the hermaphrodites’ early demise. As I wrote in our press release:

For several years, it’s been known that the presence of some male worms and flies can shorten the lifespan of their female or hermaphroditic counterparts. But it’s not been clear why. Some researchers have speculated that the physical stress of mating may lead to their early death.

The Stanford research, however, suggests something more than sex is to blame — specifically, that the males are carrying out a calculated plan at the molecular level to off the baby-makers after they’ve done their jobs.

The motive? Brunet and Maures speculate the murderous spree could be triggered by a need to conserve resources for newly produced young, or to prevent other males from mating with the same female. From the release:

“In worms, once the male has mated and eggs are produced, the hermaphrodite mother can be discarded,” Brunet said. “The C. elegans mother is not needed to care for the baby worms. Why should it be allowed to stay around and eat? Also, if she dies, no other male can get to her and thus introduce his genes into the gene pool.”

The researchers found that the continuous presence of young males shortened the average lifespan of C. elegans hermaphrodites by more than 20 percent. This effect persisted even when the genders were prevented from co-mingling, or when the hermaphrodites were sterile — indicating that neither the physical stress of copulation nor the energy demands of producing offspring were entirely responsible for early death. Affected hermaphrodites also displayed symptoms of aging, including slower movement, an increased incidence of paralysis, general decrepitude and structural decline.

It’s almost unbearably tempting to extend these findings to mammals or even humans.The presence of males leads to general decrepitude and structural decline in nearby females? I’ll go with it. And they exert this lifespan shortening effect over both space and time? Check. (In my house this is accomplished by my husband’s refusal to put his dishes in the dishwasher before leaving the house, but your trigger may vary.)

However, such nefarious tactics are likely to seriously backfire when a mother (or a set of parents) is needed to care for helpless offspring. In that case, males would appear to have little incentive to kill off their partners. Even so, the results indicate that this tactic has been going on for millions of years:

Although the researchers first studied a domesticated strain of C. elegans, they were also able to observe male-induced demise in a wild strain of C. elegans, as well as in two other, distantly related species of worm — confirming that the phenomenon has been conserved over about 20 to 30 million years of evolution. The male-induced demise even occurred in species of roundworm that have true males and true females in an equal mix (similar to mammals), suggesting that this phenomenon is not just due to idiosyncrasies of C. elegans such as hermaphroditism or a low proportion of males.

“The observation that this male-induced demise is present in several species of worms and has also been shown in flies suggests that it could have some adaptive benefits,” Brunet said. “It will be interesting, of course, to determine whether males also affect the lifespan of females in other species, particularly mammals.”

Previously Longevity gene tied to nerve stem cell regulation, say Stanford researchers and NIH awards nine Stanford faculty funding for innovative research
Photo by Ryan Somma

Applied Biotechnology, Ethics, Fertility, Genetics, Medicine and Society, Parenting

Medical practice, patents, and “custom children”: A look at the future of reproductive medicine

Medical practice, patents, and "custom children": A look at the future of reproductive medicine

black and white baby

Recently, 23andMe, the direct-to-consumer genetic diagnostic company, announced it had been issued a patent for a system of applying genetic testing – and, consequently, genetic screening – to egg and sperm banks. (Full disclosure: I am a 23andMe consumer.) In brief, 23andMe’s system involves receiving information from would-be parents about which traits they’d like their children to possess, and then determining which egg or sperm donations would be the best genetic fit to create those children. While egg and sperm banks currently allow would-be parents to sort through the traits of egg and sperm donors – such as race, height, athleticism, and even SAT scores – 23andMe’s patent envisions applying statistics to the genetic profiles of both donors and recipients to create something of a “custom child.”

To be clear, 23andMe’s patent is just that: a patent. There’s no indication that 23andMe has put its system into implementation or even made a serious business attempt to do so. Nonetheless, others have discussed the ethics behind 23andMe’s system, the propriety of the patent, and 23andMe’s ultimate plans with its intellectual property. But one question I’m particularly intrigued by is: Assuming 23andMe’s vision comes to pass – one easily within our technological if not cultural grasp – what will the future of reproductive medicine look like?

First, it would be a tremendous boon to the medical care of those “custom children,” as it would likely eliminate many common gene variants responsible for disease. These range from simple, single-gene diseases, such as Marfan syndrome, spinal muscular atrophy, and Huntington’s disease, to complex multi-gene diseases, such as breast and ovarian cancer, for which certain gene variants play a significantly large etiological role. And, as is demonstrated by the list above, these diseases need not be limited to the traditional fatal-in-childhood diseases, such as Tay-Sachs or Niemann-Pick syndrome, that are currently screened for. Rather, as is the case with Huntington’s disease, which only afflicts its sufferers in mid-life, the method could quash those genetic variants that cause disease through all stages of life.

Second, the robustness of the technology behind the 23andMe patent may spur demand for  in vitro fertilization. Few couples capable of conceiving without technological intervention undergo IVF today. But some of that is ultimately a matter of choice: that there are few benefits to be had through IVF relative to natural conception. The possibilities for customization described in the 23andMe patent – choosing a child possessing hundreds of hand-picked traits, from curly hair down to caffeine metabolism – may, at least for some, change that calculus. The potential for customization drives demand in other enterprises – smartphones, cheeseburgers, insurance policies, even house paint. It’s culturally naïve to think it will have no effect on reproductive technology.

And lastly, I suppose it also means that reproductive medicine will increasingly come within the ambit of patent law. Since its inception in the 1970s, IVF has largely been free of the destructive and costly patent litigation seen in other industries, such as smartphones. If 23andMe’s patent is indicative of a future norm, reproductive medicine may very well operate in a world controlled by licensing agreements and cowered by threats of litigation. Whether one is entitled to a particular genetic screening method may have little to do with the quality of the institution – as it generally does now – but more with whether an institution has agreed to pay the appropriate royalties. At least this aspect of reproductive medicine is not so futuristic: The current set of patent infringement lawsuits among Verinata, Sequenom, Natera, and Ariosa has held up much non-invasive, prenatal screening for Down’s syndrome.

These issues are both fascinating and complex, and the larger concerns raised by the system described in the 23andMe patent only touch a small fraction of the ethical and practical quandaries involved. For a discussion of the remainder, Stanford’s own Hank Greely, JD, will attempt to address them in his upcoming book, “The End of Sex“. Let us at least hope that that institution’s end is not because of patents.

Jake Sherkow, JD, is a fellow at Stanford Law School’s Center for Law and the Biosciences. His current research focuses on the intersection of patent law, biotechnology, and agency regulation.

Previously: Whole-genome fetal sequencing recognized as one of the year’s “10 Breakthrough Technologies”Stanford bioethicists discuss pros, cons of biotech patents, The end of sex? Maybe not just yet, New techniques to diagnose disease in a fetus, and Sex without babies, and vice versa: Stanford panel explores issues surrounding reproductive technologies
Photo by Lisa Williams

Ask Stanford Med, Fertility, Men's Health, Pregnancy, Stanford News, Women's Health

Ask Stanford Med: Expert in reproductive medicine responds to questions on infertility

Ask Stanford Med: Expert in reproductive medicine responds to questions on infertility

couple sitting2Infertility is a reality faced by 10 to 15 percent of U.S. couples. For some, the topic is emotionally charged. And while many may have questions related to reproductive endocrinology, research and treatment options may not be favorite table topics for a night out with friends. So for this edition of Ask Stanford Med, we’ve asked Valerie Baker, MD, the division chief of reproductive endocrinology and infertility and director of Stanford’s Program for Primary Ovarian Insufficiency, to respond to such questions about infertility. Her answers appear below.

@giasison asks: Can you name the 3 top causes of #infertility in your current practice?

Age-related decline in fertility (particularly decline in egg quantity and egg quality with age), sperm problems, and lack of ovulation.

Charmaine asks: Is it true that infertility could be a side effect of vaccination? Why?

No, vaccinations do not cause infertility.

Michelle asks: How have treatments for infertility evolved over the last 10 years? And what might treatments look like 10 years from now?

The biggest advance since the mid-90s has been our ability to help couples with extremely poor sperm quality to conceive. I hope that 10 years from now we will have treatments that help couples where a woman is suffering from premature loss of her egg supply to conceive with her own eggs. Right now, the main choice for women with extremely low egg supply and low egg quality is oocyte donation, where the egg comes from a donor.

Shabba92 asks: What are the most common treatments in your clinic? What percentage of patients wind up undergoing IVF?

The most common treatments are intrauterine insemination (IUI) and in vitro fertilization (IVF). We also do ovulation induction for women who are not ovulating on their own and surgery if needed to correct certain problems. Many couples are able to conceive with simpler treatments and do not need IVF. Fewer than half need IVF.

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Ask Stanford Med, Fertility, Pregnancy, Stanford News, Women's Health

Five million babies and counting: Stanford expert offers conversation on reproductive medicine

Five million babies and counting: Stanford expert offers conversation on reproductive medicine

newbornEarlier this week, an international group announced that reproductive medicine techniques, such as in vitro fertilization, have led to the birth of 5 million babies since 1978. “This is a great medical success story,” a member of the International Committee for the Monitoring of Assisted Reproductive Technology said in a statement, pointing out that the number of these babies equals the population of the state of Colorado.

At Stanford, Valerie Baker, MD, heads up the academic division that focuses on reproductive medicine. From now until Monday evening, she’s taking questions on the topic, as well as on infertility in general. Readers can share what’s on their mind with her in the comments section of this blog entry or by sending a tweet that includes the hashtag #AskSUMed.

Previously: Ask Stanford Med: Expert in reproductive medicine taking questions on infertility, Oh, baby! Infertile woman gives birth through Stanford-developed technique, Stanford researchers work to increase the odds of in vitro fertilization success, Sex without babies, and vice versa: Stanford panel explores issues surrounding reproductive technologies and New test predicts the success of IVF treatment
Photo by Emery Co Photo

Ask Stanford Med, Fertility, Men's Health, Pregnancy, Stanford News, Women's Health

Ask Stanford Med: Expert in reproductive medicine taking questions on infertility

Ask Stanford Med: Expert in reproductive medicine taking questions on infertility

4223909842_e028c12f28An estimated 10 to 15 percent of couples in the United States are infertile. One or a number of factors may render a couple unable to conceive, including hormone imbalances or blockages of sperm movement in men, and ovulation problems arising from a variety of causes in women. Those who turn to fertility treatments, a recent study showed, can expect to pay more than $5,000 out of pocket on average, or upwards of $19,000 for in vitro fertilization (IVF).

Strides in research to overcome barriers to conception have included a recent Stanford-developed technique to promote egg growth in infertile women who have experienced early menopause. Senior author Aaron Hsueh, PhD, professor of obstetrics and gynecology at Stanford, collaborated with scientists here and at the St. Marianna University School of Medicine in Kawasaki, Japan on a procedure known as “in virto activation,” in which a portion of a woman’s ovary is removed, treated outside the body, and then returned near her fallopian tubes. Through this specialized structure, a participant in the study recently gave birth.

For this edition of Ask Stanford Med, we’ve asked Valerie Baker, MD, to respond to your questions about infertility. Baker, who offered insights on Hsueh’s study and its possible implications for patients in a video and article last month, is division chief of reproductive endocrinology and infertility and director of Stanford’s Program for Primary Ovarian Insufficiency. Her research and clinical interests include primary ovarian insufficiency, and assisted reproductive technology and hormone therapy for fertility and reproduction.

Questions can be submitted to Baker by either sending a tweet that includes the hashtag #AskSUMed or posting your question in the comments section below. We’ll collect questions until Monday, October 21 at 5 PM.

When submitting questions, please abide by the following ground rules:

  • Stay on topic
  • Be respectful to the person answering your questions
  • Be respectful to one another in submitting questions
  • Do not monopolize the conversation or post the same question repeatedly
  • Kindly ignore disrespectful or off topic comments
  • Know that Twitter handles and/or names may be used in the responses
  • Baker will respond to a selection of the questions submitted, but not all of them, in a future entry on Scope.

Finally – and you may have already guessed this – an answer to any question submitted as part of this feature is meant to offer medical information, not medical advice. These answers are not a basis for any action or inaction, and they’re also not meant to replace the evaluation and determination of your doctor, who will address your specific medical needs and can make a diagnosis and give you the appropriate care.

Previously: Researchers describe procedure that induces egg growth in infertile womenOh, baby! Infertile woman gives birth through Stanford-developed technique and Sex without babies, and vice versa: Stanford panel explores issues surrounding reproductive technologies
Photo by Dylan Luder

Fertility, Image of the Week, Stanford News

Image of the Week: Baby born after mom receives Stanford-developed fertility treatment

Image of the Week: Baby born after mom receives Stanford-developed fertility treatment

infertility baby

Every birth is a miracle, but some births are a bit more miraculous than others. In this case, the phrase “the miracle of birth” couldn’t possibly be more fitting – this child was born to an infertile woman.

Earlier this week, my colleague described how this birth came to be. The mother of this child was successfully treated for a condition called primary ovarian insufficiency. The treatment was developed in the lab of Stanford professor of obstetrics and gynecology Aaron Hsueh, PhD, and the man shown in the image above, Kazuhiro Kawamura, MD, PhD, of the St. Marianna University School of Medicine, managed the clinical component of this trial.

This is the first baby conceived though a treatment of this kind.

Previously: Oh, baby! Infertile woman gives birth through Stanford-developed technique and Researchers describe procedure that induces egg growth in infertile women
Photo by Kazuhiro Kawamura, MD, PhD

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

Researchers describe procedure that induces egg growth in infertile women

Researchers describe procedure that induces egg growth in infertile women

Earlier today, my colleague Krista Conger reported on a technique that induces egg growth in infertile women with primary ovarian insufficiency. In the video above, the researchers – along with Valerie Baker, MD, chief of Stanford’s Division of Reproductive Endocrinology and Infertility - further describe the work and its significance.

“This particular treatment does appear to be a real breakthrough – we’re just cautious not to give false hope because [it] hasn’t been done for large numbers of women yet,”  Baker notes. “But I think it really does hold much more potential than so many of the things that have been tried in the past.”

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

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