First the biopsy, then the baby

A common medical procedure may be the key to helping couples who've had no luck with artificial insemination and IVF. Could a common uterine biopsy make pregnancy "stick" for women having trouble conceiving? A small but growing number of couples are embracing an unusual use of biopsies during infertility treatments in the belief that they may help increase the chances of a successful pregnancy.

In a handful of small studies, biopsies of the endometrium, the lining of the uterus, which are usually performed as a diagnostic tool to sample tissue and test for infections, disease or other problems, have been found to boost the pregnancy rates of women who had tried in-vitro fertilization and failed to become pregnant.

One Toronto couple credits the procedure with the first successful pregnancy in 10 years of trying. After 11 artificial inseminations and two IVFs proved fruitless, Roslyn and Howard Kaman had experienced the gamut of failure, from miscarriages to ectopic pregnancies. They had opted to try adoption when they read an article about a lecture at Toronto's Weizmann Science Canada by an Israeli researcher, Nava Dekel.

In 2003, Dr. Dekel found that 45 women who had undergone a uterine biopsy during the menstrual cycle before undergoing IVF had almost twice the rate of pregnancies and births compared with a control group of 89 women. In 27.7 per cent of the women in the biopsy group, the embryo transfer was successful.

The IVF worked for just 14.2 per cent of the control group.

The Kamans wrote to Dr. Dekel, and she connected them with the fertility clinic in Israel that had performed the procedures. Doctors there sent the couple a detailed protocol, which involved three separate biopsies on particular days in the cycle just before an IVF treatment. The Kamans' Toronto fertility specialist, Fay Weisberg, agreed to try it.

Ms. Kaman became pregnant on the first IVF cycle after the procedure and baby Hannah is now three months old.

"I still can't believe it. I think I will go through my whole life and not believe we were successful," says Ms. Kaman, 41.

While broader research is being conducted to confirm the role these biopsies may be playing, anecdotal evidence is starting to mount suggesting that the disruption of the uterus somehow leads to the successful implantation of an embryo. Some practitioners say they'll wait for randomized trial results before they start offering biopsies to IVF patients.

Togas Tulandi, a McGill University medical researcher, is hoping to figure out what role the biopsies might play, if any, in the successful pregnancies of women like Ms. Kaman. He is in the midst of conducting a large randomized study (he hasn't yet reached his goal of 162 participants) and says that if the biopsies are working, the mechanism may be akin to tilling the soil before you plant a tulip bulb.

"Maybe this slight injury to the endometrium makes the environment for implantation better," he says. "If we can prove that it works, we can do it routinely."

Since the procedure carries little risk, other than discomfort and a very small chance of infection or injury to the uterus, many fertility doctors are already incorporating it into their practices. While it is not listed on her menu of services at the First Steps Fertility clinic where she is medical partner, Dr. Weisberg says she now offers it to most of her patients who have failed to conceive with IVF and for most patients before they undergo a frozen embryo transfer.

"I suspect that it will probably soon be a routine for all patients undergoing IVF."

The only reason it's not routine is a paucity of large studies and the fact that it's painful and uncomfortable for most women, she says.

Although she can't unequivocally say whether the biopsies are effective - "the women end up being their own control" - Dr. Weisberg has a hunch that they work.

It could have something to do with increased blood flow, or the way in which the proteins in the uterus heal, she says. "I do believe something changes deep down."

And she's not worried about a stampede for the procedure on the part of desperate couples.

"Not to be cavalier, but this is a procedure already being done on younger women for bleeding of the uterus and other problems," she says. "It's easy, quick, but painful. There's no anesthetic. You can go right back to work."

Other specialists take a more cautious approach. Fertility expert Arthur Leader does not offer it to patients at the Ottawa Fertility Centre where he practises. Until a randomized study such as Dr. Tulandi's can prove that women undergoing these biopsies have a better chance of getting and staying pregnant, "the precautionary principle should apply," he says. "You shouldn't do it until a benefit has been shown."

He points out that there have been many other treatments, including low-dose Aspirin, a blood protein called albumin and a diabetes drug called metformin, that were believed to help women conceive and were routinely prescribed but which, after much study, proved either to do harm or have no effect. And, as far as Dr. Leader is concerned, "No good is harm."

For couples who end up with a healthy pregnancy after uterine biopsies, it's hard not to credit the procedure for their little bundles of joy. Still, Ms. Kaman says that even though she suspects the treatment did work, there may have been some luck involved. When she imagines trying for a second IVF baby, "part of me thinks lightning's not going to strike twice with us."

Anatomy of a biopsy

An endometrial biopsy is performed by inserting a suction catheter through the vagina and cervix, into the uterus. The end is pressed up against the uterine wall where it cuts away a small sample of the lining tissue.

Because of any number of factors, an embryo may not be able to attach itself to the cells that make up the lining of the uterus.

After the biopsy is taken, some researchers and fertility experts believe that the slight damage caused to the wall of the uterus makes it a better environment for implantation, whether because of increased blood flow, the healing process or some other factor.

Adult Stem Cells May Lead To New Infertility Treatment

A special class of adult stem cells, known as human induced pluripotent stem (iPS) cells, has for the first time been reprogrammed into cells that develop into human eggs and sperm. The research, carried out by members of the University of California, Los Angeles (UCLA)'s Broad Stem Cell Research Center, was published in the January 27 online edition of the journal Stem Cells.
Derived from adult body cells that have been engineered to return to an embryonic state, iPS cells have the ability to become every cell type in the human body - a characteristic they share with embryonic stem (ES) cells. In this study the iPS cells were coaxed into forming the germ line precursor cells that are capable of giving rise to sperm and eggs.
'This finding could be important for people who are rendered infertile through disease or injury'. said Amander Clark, the senior author of the study. 'We may, one day, be able to replace the germ cells that are lost, and these germ cells would be specific and genetically related to that patient'. Many infertile couples would see this process as preferable to using eggs or sperm from a donor who would then become one of the child's genetic parents.
However, Clark cautioned that scientists are still many years from offering treatments involving iPS cells to infertile patients. There are many uncertainties and dangers that need to be resolved. For example, the process of reprogramming involves using viruses to deliver genes to the cells, potentially increasing the likelihood of genetic abnormalities and cancers.
Crucially, Clark's team found that the germ line cells derived from iPS cells did not perform certain key regulatory processes as well as those generated from ES cells. The associated increased risk of chromosomal errors, or abnormal growth, could have serious health consequences for any child conceived using egg or sperm obtained in this way.
Therefore Clark believes that it is vital that research using human ES cells continues. These cells can be derived from left over embryos used during in vitro fertilisation, and would otherwise be destroyed, yet their use is controversial and the topic remains fiercely debated. Despite this President Obama is expected to reverse President Bush's restrictive policies on ES cell research in the next few weeks.

Change Has Come

Animals Who Need Help, Too

Does the famously rotund cartoon cat Garfield need a shot of insulin? We may never know, but the fact of the matter is that many household pets have diabetes, and fat cats are at higher risk for diabetes than leaner ones. “Type 2 diabetes is associated with obesity in people, and it’s the same story in cats,” says Margarethe Hoenig, DVM, PhD, professor in the College of Veterinary Medicine at the University of Georgia in Athens. She says that 45 percent of cats are overweight or obese, and as they have gotten bigger, feline diabetes has increased three- to fivefold over the past 30 years.

Canine diabetes, on the other hand, appears to be closely related to human type 1 diabetes. Pancreatic antibodies, the hallmark of human type 1 diabetes, are found in diabetic dogs, indicating that an autoimmune war is being waged on the pancreatic cells that secrete insulin. Diabetic cats, meanwhile, maintain these cells, but produce less insulin and have reduced insulin sensitivity.

Overall, 0.5–1 percent of cats and 0.2 percent of dogs are diabetic. Certain breeds—including Burmese cats and Golden Retrievers— are more prone to diabetes than others. This indicates that there may be genetic factors that predispose certain animals to the disease.

The signs that a pet may have diabetes are the same as in people: They drink more, they urinate more, they want to eat more, and they may become weak. If you suspect diabetes in your pet, make a veterinarian appointment as soon as possible. Diabetic dogs will need to be administered insulin indefinitely. For cats, insulin may be required, but a high-protein diet and exercise are also good ways to help keep blood glucose levels in check. Oral medications may also be included in care regimens.

There’s another way their human companions can help cats, by the way. It’s believed that one problem contributing to the increase in feline diabetes may be the cuteness factor: As Hoenig says, “Cat owners like their cats obese.” Of course, fans of a certain lasagna-loving feline already know that.

—Erika Gebel, PhD

Could A Dog Save Your Life?

Devin Grayson’s world was shrinking.

The 36-year-old California comic book author and video game writer had been diagnosed with type 1 diabetes when she was 15, and like many people with insulin-dependent diabetes, she suffered wild swings in her blood glucose. Over time, she’d also developed hypoglycemia unawareness, the inability to recognize symptoms of severe glucose lows. “One night I woke up and my blood sugar was 17,” she recalls. “It’s amazing I woke up at all and didn’t die in my sleep.”

By the summer of 2005, Grayson was restricting her activities because of her fear of hypoglycemic episodes. She gave up many of her favorite pursuits, like hiking in the redwoods north of San Francisco, and became reluctant to go out alone. She even moved into a house with friends because she worried that her diabetes made it dangerous to live alone any longer. And still she felt trapped. “There’s a real psychic burden attached to diabetes,” she says. “You never get a break. Every meal, every day, you have to monitor. It’s lonely. There are days when you would do anything just to have a weekend off.”

Then Grayson met Cody, and everything changed. It was an Internet hook-up, of sorts: Online, Grayson had discovered Dogs for Diabetics, a Concord, Calif.,–based organization that trains dogs to respond to serious blood glucose drops in humans. She registered for classes in the summer of 2005, and in six months she was teamed up with Cody, a male Golden Retriever. Not only has Cody saved Grayson’s life, he’s given her a life to enjoy, she says: “For the first time since I was diagnosed, I feel this enormous burden has been lifted. I’m not alone with it anymore.”

To Learn More… Training groups mentioned in this article

Dogs for Diabetics
Concord, Calif.
Dogs for Diabetics (D4D) is a certified member of Assistance Dogs International, an organization that sets standards for service dog training. D4D is the only ADI member that trains dogs primarily for hypoglycemia alert. The group accepts clients only in Northern California at present. E-mail: info@dogs4diabetics.com

Canine Partners for Life Cochranville, Pa.
Canine Partners for Life trains alert and assistance dogs for people suffering seizures or loss of hearing, sight, or mobility, often resulting from diabetes. The group has placed two dogs trained specifically for hypoglycemia alert. Phone: (610) 869-4902. E-mail: info@k94life.org

All Purpose Canines, Inc.
Aberdeen, S.D.
All Purpose Canines trains hypoglycemia alert dogs for children, although the company’s primary focus has become training dogs for children with autism. Phone: (605) 225-1131. E-mail: apc@allpurposecanines.com

Assistance dogs, such as guide dogs for blind people, dogs that “hear” for the hearing impaired, or dogs that retrieve items for the wheelchair-bound, have been helping humans for decades. But Cody is part of a new trend in which dogs are trained to identify the onset of hypoglycemia in people with insulin-dependent diabetes. For the dogs, it’s a game. Once they alert, they receive their treat, plus lots of positive reinforcement from their owners. But for the humans they live with, the results are nothing short of miraculous.

And yet science tells us nothing about whether dogs can really do this. Or how: “We believe the dogs are picking up on scents that are created by chemical changes going on in the person’s body before we humans see the actual symptoms of the illness,” says Darlene Sullivan, executive director of Canine Partners for Life. But the scent has not been identified. In fact, the first academic study to evaluate how well dogs detect hypoglycemia is being done by Deborah Wells, MD, at Queens Uni versity in Belfast, Northern Ireland. If she verifies that dogs can alert to blood glucose drops, her next project will be to identify the sensory cue the dogs are reacting to.

Part of what is so uncanny about these dogs is their reliability: Trainers say they are right 90 percent of the time. They also seem to have a skill that no test kit or piece of machinery offers: the ability to sense a dangerous drop in blood glucose before the drop occurs. Some dogs become so good at sensing low and high blood glucose that they “diagnose” people around them. At Grayson’s office, for example, a coworker mentioned that Cody had been anxiously pawing the woman’s knee. “Wait a minute,” Grayson said, and went to get her glucose monitor. When she checked the woman, her blood glucose was 180. She was later diagnosed with type 2 diabetes.

A study published in Diabetic Medicine in 1992 showed that as many as one-third of the pets living with people with diabetes—usually dogs, but also cats, rabbits, and even birds—exhibit dramatic changes in behavior when they sense a drop in their owners’ blood glucose. A British Medical Journal article in 2000 further piqued the interest of both dog trainers and diabetes experts. It reported the experiences of three women with insulin-dependent diabetes, one with type 1 diabetes and two with type 2, whose pet dogs predicted the onset of a hypoglycemic episode. The dogs dramatically changed their behavior when they sensed their owners’ drop in blood glucose—jumping up, running around the house, hiding under a chair, rousting them out of bed, pacing, or putting their heads or paws in their owners’ lap until their owners ingested carbohydrates to normalize their glucose levels.

“The three patients who I wrote about in the British Medical Journal paper all had impaired awareness of hypoglycemia,” says Gareth Williams, MD, a professor of medicine at the University of Bristol in England. “Their lives were made miserable by their fear of going hypo.” That is, until their dogs began to help them out.

Still, many people who experience hypoglycemic episodes may do well to try further diabetes education on how to safely adjust insulin and diet to activity, and to talk to their doctor about new regimens including insulin-pump therapy or continuous glucose monitoring, counsels Diabetes Forecast Editor-in-Chief Paris Roach, MD, of the Indiana University School of Medicine. “While these dogs apparently have an amazing ability, much remains to be learned about how sensitive they are in detecting hypoglycemia,” he adds.

A forensic scientist who has type 1, Mark Ruefenacht had trained dogs for law enforcement, and worked as a volunteer “puppy raiser” and supervisor for Guide Dogs for the Blind in Northern California. While on a business trip to New York, Ruefenacht ate a chocolate doughnut one night before bedtime, and took extra insulin to compensate. But he didn’t check his blood glucose. He happened to have brought along Benton, a dog he was training to be a guide dog, and that night Benton recognized that Ruefenacht’s blood glucose had plunged, and frantically tried to wake him. “He had difficulty getting me up, and getting me going. But he stayed with me until I got up and ate something to raise my blood sugar,” Ruefenacht says. “This was not a dog that knew me, or my diabetes. I started thinking, ‘Can I train a dog to do this?’ ”

Ruefenacht was given Armstrong, a yellow Labrador Retriever, from Guide Dogs for the Blind. The organization felt Armstrong had a great nose for scents, but his penchant for walking around puddles made him inappropriate as a guide dog. Ruefenacht trained Armstrong to alert consistently to drops in his own blood glucose, but could he sense others’? He asked Kaiser Permanente diabetes educator Jeanne Hickey, who also has diabetes, to come over wearing clothing from a time she had experienced low blood glucose. When she walked in, Armstrong alerted. “That was our bingo day,” Ruefenacht says.

Ruefenacht founded Dogs for Diabetics, or D4D, as it is known, in 2004. At first, he tried to train the dogs to alert to a specific blood glucose number, one at which many people have hypoglycemic symptoms. “But what we found is that dogs were not alerting to a static number. They may alert at 150, but within 20 or 30 minutes, the person is down to 70 or lower. They are recognizing a scent emitted when a diabetic begins to experience a rapid drop in blood sugar.” Ruefenacht realized that this was far more useful. It allows time to treat the condition before it turns into a crisis. Now, after three years of placing trained dogs, he says, “Clients are coming back saying ‘I have never had better control of my blood sugar in my life as I have since I got this dog.’ ”

The number of people using alert dogs is limited by the expense and time it takes to train both dog and client. Training may require two years and costs at least $20,000. “It’s very time-consuming and intense to get the dog to be at least 85 percent accurate,” says Beverly Schwartz of All Purpose Canines. Most assistance dog organizations are supported by grants and donations, so funding limits the number of dogs they can provide, and most ask the clients to cover a portion of the costs.

“The first time that dog gets you up in the middle of the night because your child is dropping into a serious low, rapidly,” says Donna Cope, of Miami, “you realize it’s worth every penny you spent and every minute you had to wait.” Her daughter, Hunter Cope, 11, was diagnosed with diabetes when she was 7 years old. Diva, Hunter’s German Shepherd, was trained by All Purpose Canines and placed with the Copes last year. “This dog is incredible,” Donna Cope says. “She’ll come running to us in the middle of the night with the test kit in her mouth.”

Brianna Mountain, a 10-year-old with diabetes in Walla Walla, Wash., suffers from a condition called hemiplegic migraine, which coincides with her hypoglycemic episodes. “It’s like she’s had a stroke,” her mother, Tammy, says. “She can’t speak or move the right side of her body.” Two months ago, the Mountain family got Kay-Dee, a Golden Retriever trained by All Purpose Canines. Already Kay-Dee has saved Brianna at least once from this ordeal. “If I don’t wake up right away, Kay-Dee will stand on me,” Tammy Mountain says. “Then I say, ‘Show me,’ and she runs to Brianna’s bed, nudges her, and looks for her treat.” The dog also alerts when Brianna’s glucose is too high. “At about 200, Kay-Dee gets restless, and paces. If Brianna gets over 250, Kay-Dee pants so hard she heaves.”

As important as the dogs can be for the parents of insulin-dependent children, they offer something equally significant to adults like Devin Grayson: a new chance at health. Before Cody, Grayson says, “I let myself run high, around 170. That felt safe to me, because the alternative of going low was so frightening.” But chronic hyperglycemia has caused Grayson to develop proliferative retinopathy, a severe form of eye disease. Laser surgery may stop progression of the condition, but will not restore lost vision. “I’ve had to do laser treatments six times, already,” Grayson says. “But with Cody, I don’t feel the need to hedge my bets by keeping my blood sugar too high. I can try to maintain a healthy blood sugar now.”

And as Grayson is speaking, Cody begins licking her hand, and pacing. Grayson gets her glucose monitor and tests. “It’s 211,” she says. She pops a piece of dried liver in Cody’s mouth, and gets out her insulin. “In the past, I wouldn’t have checked for hours.”

Amanda Spake is a freelance writer from Churchton, Md.

Australian First For Melbourne Stem Cell Scientists

Melbourne scientists have created Australia's first induced pluripotent stem (iPS) cell lines.Scientists from the Monash Institute of Medical Research (MIMR) have derived the cells from skin cells, and reprogrammed them to behave as embryonic stem cells; a breakthrough that will allow Australian scientists unlimited access to study a range of diseases.
Until now, Australian scientists have had to import human iPS cells from America or Japan.
Program leader, Dr Paul Verma, said the significance of developing iPS cells 'in-house' cannot be underestimated. "We now have the capability to investigate any human disease we wish, rather than relying on iPS cells from specific diseases that have been generated elsewhere."
"In addition, each iPS cell line generated from the same adult cells appears to be subtly different. We are keen to investigate these differences between iPS lines, which would be impossible to do if we had to rely on cells provided by other laboratories," Dr Verma said.
Dr Verma and his team are working with Professor Bernie Tuch from the Sydney Cell Therapy Foundation, and will now generate iPS cells from type 1 diabetes patients to help understand the disease and develop better drugs.
Creating iPS cells does not require donated excess IVF embryos or human eggs; therefore, no human embryos are destroyed in the process. However, Dr Verma said it is still too early to assume iPS cells are the preferable alternative to working with embryonic stem cells.
"While the iPS cells we have created appear in an identical manner to embryonic stem cells, iPS cell lines show great variability in their potential to produce mature cells. If, through our research, we can overcome this, iPS cells would certainly pose a great alternative to embryonic stem cells," he said.
Dr Verma's research is funded by a joint Victorian and NSW Government grant. The Victorian Minister for Innovation, Gavin Jennings, said that Dr Verma's creation of iPS cells will greatly assist Victorian researchers to progress their research into serious diseases, and to develop better treatments.
"Creating Australia's first iPS cell line is another example of how Victoria's world-leading stem cell research capabilities have the potential to improve our quality of life he said.

Octuplet Sunday