By David N. Leff

Everyone in the Air Force knows the parable of the ignorant bumblebee. "The bumblebee," it goes, "is incapable of flying, because, according to the laws of aerodynamics, the ratio of its wingspread to its body weight makes flight impossible. But the bumblebee, being ignorant of the laws of aerodynamics, flies anyway."

A parallel piece of received wisdom concerns follicle-stimulating hormone (FSH). Physicians and endocrinologists know that men who fail to make FSH * which initiates and sustains spermatogenesis * cannot father children. That infertility rap on FSH populates medical textbooks to this day.

But perhaps not tomorrow.

It turns out that both mice and men who have absent or inactive FSH remain able to produce pups and babies, respectively. Reports of their infertility have been greatly exaggerated. This unexpected finding is having adverse effects on worldwide efforts to develop a male contraceptive.

In females, however, human and murine alike, absence of follicle-stimulating hormone effects does indeed spell absolute infertility.

At the University of Oulu, in Finland, molecular and clinical geneticists studied 22 women with inactivating cytosine-to-thymine point mutations in their FSH-receptor genes. These patients, by established definition infertile, came from 13 families, and had 25 male siblings.

Five of those brothers had inherited the mutant FSH receptor gene from both parents. By the bumblebee law, all of them, being homozygous for the lack of FSH receptor, should have been infertile. Yet two of the five had two children each

An article in the February 1997 issue of Nature Genetics by the Finnish researchers tells that story. It bears the title: "Men homozygous for an inactivating mutation of the follicle-stimulating hormone [FSH] receptor gene present variable suppression of spermatogenesis and fertility."

Their article reports, "All five men appeared healthy and normally masculinized; the only aberrant finding was the low-normal to clearly low testicular volume [range 4.0 to 15.8 milliliters]."

In Men And Mice: Unexpected Fertility

Immediately adjacent to this human experiment of nature, in Nature Genetics, is a report of its murine counterpart, titled: "Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility." Its senior author is molecular endocrinologist Martin Matzuk, at Baylor College of Medicine, in Houston.

Matzuk and his co-workers have created a sizable colony of transgenic mice, in which a gene essential to expression of FSH is missing. (Normal FSH enables ovarian cells to ovulate, and the testicular Sertoli cells to make sperm.)

All 33 of the homozygous FSA-deficient mice in the initial Baylor batch were fertile by six weeks of age, but had testes only one-fourth the size of those equipping their wild-type litter mates.

But 20 FSA-minus female rodents, bred to male controls for six to 12 months, failed to produce any offspring.

Putting together these mouse results with the Finnish findings, Matzuk concluded, "Homozygous FSH-deficient mice phenocopy the human FSH receptor mutation, and confirm that FSH-mediated signaling is essential for normal ovarian follicular maturation, but dispensable for male fertility in mammals.

"The textbooks say," Matzuk told BioWorld Today, that FSH is necessary for spermatogenesis, and that's why the Finnish companion paper is also very important. A person could argue that our findings are just applicable to mice. But since the receptor is also missing in humans, and those human males also appear to be fertile, the role of FSH appears to be consistent in both mice and men."

He added: "Our observations also suggest that the long-sought anti-FSH-based vaccines would not be feasible as immunocontraceptive reagents in human males."

Matzuk has confirmation of that suggestion from at least two key sources, who have heard his lectures to scientific audiences, presenting this data.

Male Contraceptive Set-Back

"A while back," he recalled, "the World Health Organization contacted me. They wanted to confirm our finding that FSA-minus mice are fertile. In consequence, they are now changing their policy on funding that type of research.

"Last November," he continued, "I was also invited to speak at Organon International BV, in Oss, the Netherlands. They are the major manufacturers of recombinant FSH, which is used in fertility research. Based on my talk, Organon decided not to initiate research on a male contraceptive aimed at blocking FSA."

Matzuk foresees that, "Now the approach many people will take, if they want to design male contraceptives, is to block the spermatogenesis process by other mechanisms, combined with FSH. But I think that anything combined with FSH is not going to be as effective as might have been expected initially."

Matzuk's creation of transgenic mice is funded by the National Institutes of Health's National Cancer Institute, with a four-year grant ending in 2001. This year, it amounts to some $240,000.

"We had two reasons for generating these FSA-minus mice," he explained. "The first was to determine what the essential functions of FSH were in mammals, male and female. The hormone was thought to be essential to male fertility, until we reported these studies.

"Second, the reason we generated the FSH-deficient animals, and why we have NCI funding for this research, is to determine what role FSH plays in ovarian and testicular cancers."

Responding to the unexpected Finnish and Baylor findings, research endocrinologist Richard Blye told BioWorld Today: "This is a perplexing area. We're in an area here that we don't know a helluva lot about."

Blye is a research pharmacologist at the Contraceptive Development Branch, National Institute of Child Health and Human Development. (See BioWorld Today, May 30, 1995, p. 1.)

Commenting on the WHO and Organon reactions to the news that FSH is not a sine qua non of male fertility, Blye said, "I've never been a proponent of the FSH approach to male contraception. But a lot of people have taken that avenue, and nothing has ever come of it." *