The following two articles from the New York Times
reference GIVF's work on ICSI and NSA.

1. NEW PREGNANCY HOPE: A SINGLE SPERM

2. DISCOVERY MAY BRING PARENTHOOD TO INFERTILE MEN

NEW PREGNANCY HOPE: A SINGLE SPERM

NEW YORK TIMES
Wednesday, August 11, 1993

Belgian scientists have invented a new treatment (ICSI, intracytoplasmic sperm injection) for male infertility that they say may allow virtually any man, no matter how few or misshapen or immobile his sperm cells, to father a child.

The method, developed by a team headed by Dr. Andre' C. Van Steirteghem of the Brussels Free University in Belgium, involves the direct injection of a single human sperm into a human egg in a petri dish. Scientists had thought such a technique would never work, because it bypasses the complex chemical reactions that take place when the membrane of a sperm meets the membrane of an egg and because no one, including Dr. Van Steirteghem, has succeeded in fertilizing animal eggs by directly injecting sperm.

In a telephone interview, Dr. Van Steirteghem reported that in the last year, he had successfully fertilized 65 percent of the eggs he injected. A third of the women who have received the embryos grown from the fertilized eggs have become pregnant, he added. So far 300 pregnancies have been produced through sperm injection, and 100 babies born. Most of the rest are continuing pregnancies.

The new technique's astonishing success is expected to create an entire industry for in vitro fertilization labs, which will now be able to treat couples who had been told that the man was hopelessly infertile.

Infertility affects about two million American men. In about a third of them, the sperm count is so low, or the number of the abnormal sperm so high, that none of the previous methods developed to coax sperm to enter eggs could be used successfully.

Doctors from all over the world have been trekking to Belgium to learn the method. The transfer is done with a pipette to hold the egg and special glass needles for injecting the sperm, which are washed in solutions before they are used. Dr. Van Steirteghem said he was not sure why it works.

Now Dr. Joseph D. Schulman, director of the Genetics & IVF Institute in Fairfax, VA, is expected to announce today what he believes to be the first well-established pregnancy in this country using the Belgian ICSI method. The woman, 28 years old, is entering her third month of pregnancy, carrying twins. A second woman has just become pregnant, and a third was pregnant but miscarried, Dr. Schulman said. The first two pregnancies were achieved in the first 10 cycles tried there.

The woman pregnant with twins said in a telephone interview that she and her 35-year-old husband had spent the previous three years being treated by infertility specialists, with no success. The woman asked that her name be withheld.

Dr. Schulman said he considered sperm injection to be as important an advance as the development of in vitro fertilization 15 years ago. That method allowed women to have babies even if their fallopian tubes were blocked, preventing sperm from reaching their eggs. Sperm injection addresses the male side of the infertility equation.

Dr. Richard Berkowitz, chairman of the department of obstetrics, gynecologic and reproductive medicine at Mount Sinai Medical Center in New York, said, "Everyone who does this work and people like me who are peripherally connected are very excited."

Dr. Arthur Caplan, the director of the Center for Bioethics at the University of Minnesota, said the major policy questions concerned how quickly to make the technique available and whether health-insurance plans should cover it.

The method is very expensive -- Dr. Schulman is charging couples $10,000 for each round of attempts -- and it requires extraordinary skill and equipment costing about $100,000. These include micromanipulators, which scale down hand movements to make a movement of an inch into one that is microscopic.

Dr. Jon Gordon, an expert on fertilization at Mount Sinai Medical School, said infertile couples were so strongly motivated that with sperm injection that "the potential is ripe for taking advantage of patients."

Many observers have warned that doctors who are not proficient in the difficult technique may exploit vulnerable patients, charging them tens of thousands of dollars.

But Dr. Gordon also called Dr. Van Steirteghem's results "very impressive." He said he and other scientists had tried sperm injections for years, using sperm and eggs from laboratory animals, with little success. They concluded that sperm could not fertilize eggs if they were directly injected because fertilization is so complex.

Enormous Complexity

When a sperm touches an egg, its membrane fuses with the egg's membrane, setting off a chain of biochemical events that prevent other sperm from entering the egg and that signal the egg to start the genetic changes necessary to mingle its genes with the sperm's. At the same time, the sperm changes, losing the enzymes it had used to digest its way through the outer layers of an egg. It was thought that if a sperm was injected with its enzymes intact, fertilization would not occur.

"With all that, everyone was pretty much down on the method of microinjection as a means of conceiving babies," Dr. Gordon said. When Dr. Van Steirteghem announced that he could do it and said that the majority of the eggs had been successfully fertilized, Dr. Gordon went to Belgium to see for himself. "I watched him work," he said, standing by amazed while Dr. Van Steirteghem took a man with so few sperm that no one could have used them and managed to fertilize seven out of eight eggs.

Dr. Gordon, who plans to start sperm injections, sees two lessons in the story. One, he said, is that human fertilization is astonishingly different from that in other mammals. "Their eggs tolerate manipulation much better," Dr. Gordon said.

A second lesson is that misshapen or immobile sperm do not necessarily produce malformed babies. The genes that control sperm shape, size, number and motility appear to have nothing to do with the genes necessary to produce normal, healthy offspring. The chromosomes of the children produced through sperm injection have appeared to be normal.

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DISCOVERY MAY BRING PARENTHOOD TO INFERTILE MEN

Advances in treating male infertility have made it possible for virtually any man who makes even the tiniest amount of sperm to become a father. Even men who have no sperm at all or only dead sperm in their ejaculate or men whose sperm cannot swim or cannot penetrate an egg may be helped.

The most recent discovery builds on the finding that men who have no viable sperm in their semen often have at least a small number in their testes. These sperm are unable to fertilize eggs on their own because they have not undergone maturation and biochemical changes that occur when sperm are transported from the testes through the epididymis, a coiled tube where sperm are stored. They are barely moving because motility also develops during the passage through the epididymis. But they can still fertilize an egg when they are directly injected into it.

The problem has been getting those sperm out of the testes. That required opening up the testes in an operation that cost $10,000 or more, was painful, took place in a hospital and required a month or more of recuperation.

Now, researchers have found a much easier way to extract sperm: by aspirating them through a thin needle in a $1,000 procedure (NSA, non-surgical sperm aspiration) simple enough to be done in a doctor's office. The change in the prospects for infertile men is little short of amazing, investigators say.

Dr. Richard J. Sherins, the developer of the NSA technique, said it "has completely revolutionized our approach to patients with these problems." Dr. Sherins is the director of the male infertility program at the Genetics & IVF Institute in Fairfax, VA.

So far, he and his colleagues at the institute have used the method on nine men, obtained sperm from all them, used the sperm to fertilize eggs and achieved four pregnancies. In the case of two of the couples, the doctors do not yet know the outcome of the procedure because the fertilized eggs were implanted in the women so recently that it is too soon to know if the women are pregnant.

Seven of the nine men had normal sperm production but had blockages that prevented sperm from leaving their testes. Two not only had blockages but also were not making many sperm. Their testes had atrophied to less than half the normal size. And one man was unable to ejaculate.

The method is "a huge leap forward," said Dr. Arnold Belker, a urologist at the University of Louisville School of Medicine. But, he cautioned, "There's a strong caveat and that is the ability of patients to afford the advanced reproductive technologies."

Even though NSA is not terribly expensive, it is used with in vitro fertilization and the direct injection of sperm into eggs, procedures with very high costs. "You're talking about $9,000 to $14,000 per attempt," Dr. Belker said.

Many insurance companies will not pay, and Dr. Belker said that patients often said they could not afford the therapy.

Nonetheless, the advances in treating male infertility have revolutionized the field in recent years. Researchers used to think that male infertility was all but unsolvable. Sperm production is a complex process that takes three months of maturation and chemical modifications. There were so many places where things could go wrong that it seemed almost impossible to find and fix them. It is so difficult for sperm to come through the process and still be viable that even in a normal fertile man, just 15 of the 100 to 300 million sperm produced in an ejaculate are actually capable of fertilizing an egg.

Until recently, most advances in infertility involved treatments for women. Researchers focused on ways to get women to produce eggs and on fertilizing the eggs in the laboratory, creating the lucrative business of in vitro fertilization. Yet problems with sperm loomed large at infertility clinics. An estimated one of every five American couples are infertile and 40 percent of them are unable to have a baby because of a problem with the man's sperm. In 20 percent of infertile couples, both the man and the woman have reproductive difficulties and in the remaining 40 percent the man is fully fertile but the woman is not.

The first breakthrough in treating men occurred two years ago, when researchers discovered that it did not matter whether sperm could swim vigorously to reach an egg. Nor did it matter if the sperm could even enter an egg, dissolving the egg's outer layer and burrowing in. All that mattered was that the sperm, however feeble, were alive. And if they were alive, they could be injected directly into an egg, where they could often fertilize it.

This technique, called intracytoplasmic sperm injection, or ICSI suddenly made previous research, on how to identify viable sperm and how to enhance sperm production, less important. It stripped fertilization down to the basics: getting the sperm's genes into an egg.

The method was so successful that despite its cost of more than $10,000 per pregnancy attempt, it has already resulted in a diminishing market for sperm donors both in the United States and Europe, said Dr. Joseph Schulman, director of the Genetics & IVF Institute.

Two years ago, Dr. Robert Schoysman of Van Helmont Hospital in Vivoorde, Belgium, took the next step and reported that he could obtain sperm from men who had none in their semen by cutting open the men's testicles, removing sperm and using them for ICSI. Now, with the fine needle aspiration, Dr. Sherins and his colleagues believe they have taken the next leap forward.

Dr. Sherins believes that NSA with ICSI should be of greatest use to the 10 million or so American men who have had vasectomies. Many of these men later change their minds, often because they remarry, and want to father children. It is possible to reverse a vasectomy surgically, but if it has been more than a few years since the vasectomy was done, the results are poor.

Dr. Sherins said that although "we are now quite good at getting the plumbing corrected, if it has been more than 15 years since the vasectomy, there is just a 20 to 25 percent pregnancy rate." Rather than have an operation to reverse the vasectomy, with its slim odds of success, these men could have a fine needle aspiration of sperm from their testes, he said.

Others who could benefit include the 10 percent of infertile men who have no sperm in their semen because the pathway out of the testes is blocked. These men have congenital obstructions or have blockages that resulted from an infection. Another 10 percent of infertile men have pockets of sperm in their testicles but none in their ejaculate. Others are unable to ejaculate because they had spinal cord injuries or neurological diseases like multiple sclerosis.

Another group have necrospermia - dead sperm in the semen - but live sperm can often be obtained from their testes. Still others have had their prostates removed and so do not ejaculate but nonetheless make sperm.

Dr. Sherins said about 5 to 10 percent of the sperm he aspirated were moving, an indicator that they were alive, and that he needed to remove only 100 to 200 sperm, a pittance compared with the 100 million to 300 million in a normal ejaculate. Once he gets those sperm, he said, the chances of successful fertilization and pregnancy depend almost entirely on the woman's eggs. Younger women have eggs that are more likely to be fertilized and have a greater chance of becoming pregnant.

Yet even the extraction and successful use of such tiny numbers of feebly moving sperm is not the end of the story. The next challenge is to help men whose testes do not even contain sperm.

Dr. Marc Goldstein, who directs the Center for Male Reproductive Medicine and Microsurgery at New York Hospital-Cornell Medical Center, is working on what he says is "the only treatment available for men who don't make sperm." Some men, he said, start to make sperm, but then the process halts. They are left with round spermatids, the precursors of sperm. These cells "don't look anything like sperm," Dr. Goldstein said. "They don't have heads or tails, they can't swim," he added. But they do have nuclei with the right number of chromosomes.

Dr. Goldstein is removing these immature sperm from men's testes and injecting them directly into eggs. So far, he and colleagues have produced four pregnancies, but all four women had miscarriages. Two of those miscarriages were at five months of pregnancy, he said. One was in a woman with diabetes and one seemed to be caused by problems with the umbilical cord. In both cases, the fetuses looked normal, so he is optimistic that the method will succeed.

Dr. Goldstein is also studying ways to induce testicular cells to undergo meiosis, the chromosome reduction that occurs when the sperm and eggs are made, to treat men who do not make even the most immature sperm. "We hope eventually to help them," he said.

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