Experimental 'IVM' incorporates erroneous Human Embryology 101

Dianne N. Irving
Copyright February 13, 2006
Reproduced with Permission

Aside from obvious ethical issues, the following article on experimental IVM -- a new method used to mature oocytes in vitro for IVF "fertility treatments" -- quotes erroneous human embryology:

"During each monthly menstrual cycle, one egg becomes dominant, accumulates fluid in its sac, and breaks out. About 34 hours before it escapes, the egg gets a hormonal signal to jettison half the chromosomes in its nucleus - just in case a sperm comes along to replace the lost genetic material." [emphases added]

Where the article obtained such scientific mis-information -- that diploid oocytes become haploid by some "hormonal signal" while still maturing in the ovary -- is speculative, but it does raise the question again as to whether or not these IVF/IVM researchers and clinicians are academically credentialed in human embryology and human genetics, and thus really know what they are doing.

In human embryology, "diploid" means the cell contains "46" chromosomes; "haploid" means the cell contains "23" chromosomes. In fact, immature germ line cells (both female and male) are diploid (not haploid) until the last period of their growth and development. Both must pass through two stages of meiosis (meiosis 1 and meiosis 2) before the number of chromosomes in the cell is halved. Spermatogonia are diploid until their last weeks of maturity; and primary oocytes remain diploid until and unless they are fertilized by a sperm (otherwise, they die as diploid). Amazingly, in maturing oocytes, meiosis 1 and meiosis 2 can take up to 50 years and, again, they finally become haploid only if they are fertilized. This can be verified in any human embryology text book. In the passages below, "primary" means diploid; "secondary" means haploid:

Gametogenesis is the production of [gametes], i.e., spermatozoa and oocytes. These cells are produced in the gonads, i.e., the testes and ovaries respectively. ... During the differentiation of gametes, diploid cells (those with a double set of chromosomes, as found in somatic cells [46 chromosomes]) are termed primary, and haploid cells (those with a single set of chromosomes [23 chromosomes]) are called secondary. The reduction of chromosomal number ... from 46 (the diploid number or 2n) to 23 (the haploid number or n) is accomplished by a cellular division termed meiosis. ... Spermatogenesis, the production of spermatozoa, continues from immediately after puberty until old age. It takes place in the testis, which is also an endocrine gland, the interstitial cells of which secrete testosterone. Previous to puberty, spermatogonia in the simiferous tubules of the testis remain relatively inactive. After puberty, under stimulation from the interstitial cells, spermatogonia proliferate ... and some become primary spermatocytes. When these undergo their first maturation division (meiosis 1), they become secondary spermatocytes. The second maturation division (meiosis 2) results in spermatids, which become converted into spermatozoa.

Oogenesis is the production and maturation of oocytes, i.e.; the female gametes derived from oogonia. Oogonia (derived from primordial germ cells) multiply by mitosis and become primary oocytes. The number of oogonia increases to nearly seven million by the middle of prenatal life, after which it diminishes to about two million at birth. From these, several thousand oocytes are derived, several hundred of which mature and are liberated (ovulated) during a reproductive period of some thirty years. Prophase of meiosis 1 begins during fetal life but ceases at the diplotene state, which persists during childhood. ... After puberty, meiosis 1 is resumed and a secondary oocyte ... is formed, together with polar body 1, which can be regarded as an oocyte having a reduced share of cytoplasm. The secondary oocyte is a female gamete in which the first meiotic division is completed and the second has begun. From oogonium to secondary oocyte takes from about 12 to 50 years to be completed. Meiosis 2 is terminated after rupture of the follicle (ovulation) but only if a spermatozoon penetrates. ... The term 'ovum' implies that polar body 2 has been given off, which event is usually delayed until the oocyte has been penetrated by a spermatozoon (i.e., has been fertilized). Hence a human ovum does not [really] exist. Moreover the term has been used for such disparate structures as an oocyte and a three-week embryo, and therefore should be discarded, as a fortiori should 'egg'. (Emphasis added.) [See, Ronan O'Rahilly and Fabiola Muller, Human Embryology & Teratology (New York: Wiley-Liss, 2001, p. 25. See also, William Larsen, Human Embryology (2nd ed.) (New York: Churchill Livingstone, 1997), pp. 3-11; also, Larsen, Essentials of Human Embryology (New York: Churchill Livingstone, 1998); also, Keith Moore and T. V. N. Persaud, The Developing Human: Clinically Oriented Embryology (6th ed. only) (Philadelphia: W.B. Saunders Company, 1998), pp. 18-34 (also, (7th ed., 2003); also, Bruce M. Carlson, Human Embryology and Developmental Biology (St. Louis, MO: Mosby, 1994), pp.3-21.

Thus clearly, the haploidization of a mature oocyte has nothing whatsoever to do with some "hormonal signal" while the diploid oocyte is still in the woman's ovary. Rather, the diploid oocyte, which has not yet completed meiosis 2, must erupt from the ovary, be passed into the woman's fallopian tube, and be fertilized there by a sperm before becoming haploid.

Furthermore, when such scientific mis-information is incorporated into laws and regulations concerning IVF or other artificial reproductive technologies, human embryo research, human cloning, human embryonic stem cell research, and human genetic engineering, etc., it renders them meaningless and supplies nothing more than legislative loopholes to be exploited. Yes, the "devil's in the details", and as such cannot be dumbed down without serious consequences.

[For a clear scientific explanation of sexual -- as distinct from asexual -- human reproduction, using only text books in concert with the international nomenclature on human embryology, please see Irving, "When does a human being [normally] begin? 'Scientific' myths and scientific facts", International Journal of Sociology and Social Policy (Feb.1999), 19:3/4:22-47, (subscription); and at http://www.lifeissues.net/writers/irv/irv_01lifebegin1.html


The Tribune San
February 10, 2006

Experimental in vitro fertility option may be safer, cheaper

Knight Ridder Newspapers

PHILADELPHIA - Last June, after a week of fertility-drug shots, Christine Mozes' ovaries went into overdrive, literally bursting with eggs ripening in their watery sacs.

If she were to have taken the full course of drugs, her hyperstimulated ovaries could have triggered life-threatening breathing problems, kidney failure, and blood clots.

George Taliadouros, her avuncular physician at Delaware Valley Institute of Fertility and Genetics in Marlton, N.J., cut off the treatment she needed to get pregnant.

"He said, `We just can't do this,'" recalled Mozes, 37.

Her plight was one of the most common and vexing in infertility treatment. Like an estimated three million U.S. women, she has polycystic ovarian syndrome, a hormonal disorder that disrupts ovulation. It's a leading cause of female infertility - but it makes infertility treatment extremely risky because the ovaries can easily be overstimulated.

The good news is that this reproductive double whammy is promoting the development of technology that may someday reduce the complications and cost of all high-tech baby-making. Instead of removing fully mature eggs from the ovaries and promptly fertilizing them, physicians remove immature eggs, ripen them in a lab dish, then add sperm. With this approach, the woman requires only three days of fertility drugs to gently stimulate her ovaries - compared with up to two weeks under the conventional method.

Lab-dish or in vitro egg maturation - IVM for short - is experimental, and has produced only about 300 babies worldwide, too few to firmly establish its safety. Even so, for Mozes and her husband, John, it was a godsend. She is now four months pregnant.

"This is just overwhelming," she said. "It was great because I only needed three days of shots. And no misery."

In vitro egg maturation is not really new. In 1994, Australian researchers reported the first birth after IVM in a patient with polycystic ovaries.

Since then, conventional in vitro fertilization - uniting a mature egg and sperm in a dish, growing embryos, then implanting some in the uterus - has become increasingly successful. About two million IVF babies have been born worldwide. But IVM remains a challenge.

Human eggs - the largest cells in the body - are constantly changing, from the moment a woman is born with more than a million of them, until puberty, when about 300,000 remain, through menopause, when the supply is gone.

During each monthly menstrual cycle, one egg becomes dominant, accumulates fluid in its sac, and breaks out. About 34 hours before it escapes, the egg gets a hormonal signal to jettison half the chromosomes in its nucleus - just in case a sperm comes along to replace the lost genetic material.

Scientists have long struggled to make eggs perform this nuclear split, called "meiosis," in a lab dish instead of an ovary. But even when they succeeded, the eggs resisted fertilization because their outer membranes had hardened; sperm just bounced off. When eggs did manage to fertilize, the embryos usually died soon afterward.

On the encouraging side, studies have found that when IVM works, babies are healthy and develop normally.

"The principle behind this is great. It has potential and promise," said Christos Coutifaris, head of the University of Pennsylvania's IVF program. "But it's still experimental."

Danish researchers have led the way in developing better chemical solutions to nurture egg maturation. In November, Denmark-based Medicult became the first company to win FDA approval of its IVM culturing medium.

That medium is now being used by eight U.S. infertility clinics, including Delaware Valley Institute. A clinic in Florida and another in Illinois have each achieved a single IVM pregnancy, although one patient miscarried, according to Medicult and the clinics.

The new method may increase laboratory costs, as embryologist Jennifer Macdonald must closely monitor the eggs during their 32-hour sojourn in the culture medium. Fertilization also is a bit more expensive; to overcome the hardened-membrane problem, the egg is carefully punctured and a single sperm is injected.

Still, experts believe that maturing eggs outside the body could dramatically cut costs because the woman's ovaries would need minimal stimulation and she would need fewer ultrasounds and blood tests. Taliadouros estimates patients would need $900 worth of fertility drugs, instead of $5,000.

If science usurps yet another small but critical step in the creation of life, could abnormalities or defects turn up?

"We worry about that," he said. "But right now, we're doing it for patients for whom Nature doesn't do it better."

Women such as Mozes.

She didn't know she had polycystic ovarian syndrome until she first tried to get pregnant about eight years ago.

The syndrome, which affects an estimated 6 percent of women of childbearing age, is a complex set of metabolic and hormonal malfunctions that can vary in severity and symptoms. Basically, the ovary doesn't make all the hormones needed for eggs to fully mature. Even though eggs may start to grow and accumulate fluid, they remain trapped and eventually die in their sacs, turning into fibrous cysts. Without the release of an egg, the menstrual cycle is irregular or missing - the hallmark symptom.

Mozes, a child-welfare administrator, often missed periods. But then, so did her mother and sisters, and they had no apparent fertility problems.

When Mozes couldn't get pregnant, she and her husband resorted to in vitro fertilization. They succeeded on their very first try - daughter Riley is now 4 1/2 - but the fertility drugs made Mozes extremely ill.

Her ovaries ballooned, causing fluids to shift from her blood vessels into her belly and chest. That erroneously signaled her kidneys to stop making urine, which made the swelling even worse. Even after the drug treatment was over, and 30 eggs had been removed from her ovaries, she spent a week in bed, massively bloated, short of breath, with severe abdominal pain and nausea.

And that bout of hyperstimulation was not nearly as severe as what she was headed for last summer, when her treatment was halted.

Although deaths are rare, severe hyperstimulation can cause strokes and other long-term complications.

Some patients can endure the treatment if drug doses are reduced or briefly interrupted, but it's a dicey balancing act.

"If you give too little medication, the patient may not respond," Taliadouros said. "Give too much, the patient hyperstimulates."

In Denmark, Anne Lis Mikkelsen, an IVM pioneer at Herlev University Hospital's fertility clinic, has been offering IVM not only to polycystic patients, but also to couples in which the man has fertility problems.

Pregnancy rates of 24 percent per IVM attempt - one out of every four patients - have been achieved, she wrote in a journal article in May.

Others say the technology has a long way to go. But it's only a matter of time.

In vitro egg maturation "is not ready for prime time. But you have to start somewhere," said Carolyn Coulam, a reproductive endocrinologist at the Rinehart Center for Reproductive Medicine in Chicago.

"I think it is the wave of the future."