Not by Testosterone Alone

By Sarah Richardson
Apr 1, 1995 6:00 AMNov 12, 2019 5:14 AM


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Making a man is the complex task of culture. Making a male-- nature’s job--is also none too simple. The first requirement is the sex- determining gene on the Y chromosome, called the SRY gene: it enables a fetus to build testes, which manufacture the sine qua non of maleness, testosterone. But testosterone alone is not enough; a second hormone is required to produce a normal, fertile male. Molecular geneticist Richard Behringer and his colleagues at the University of Texas M. D. Anderson Cancer Center in Houston have shown just how important this hormone is in male mice. When it is absent, the males develop as infertile pseudohermaphrodites--meaning they have the internal reproductive ducts of a female as well as those of a male. They look like a regular male, says Behringer. You wouldn’t know unless you look inside that something is funny.

In mammals, Behringer explains, male and female embryos are identical in the early stages of development. Each fetus has one set of gonads--reproductive glands that develop into either testes or ovaries. If the gonads receive the signal from the SRY gene, they develop into testes. Otherwise they become ovaries.

But this unisex blueprint includes two sets of reproductive ducts that extend from the gonads to the embryonic urinary tract. One set of ducts can develop into three female parts: the oviducts (or fallopian tubes in humans), which convey the egg to the uterus; the uterus itself; and the upper portion of the vagina. Very close by lies a second set of ducts that can develop into a male transport system: the epididymis, where sperm cells mature; the vas deferens, the tube that carries mature sperm cells from testes to penis; and the seminal vesicles, which secrete a fluid into the vas deferens that helps rush the sperm on their way. It’s not like the gonads, where you have one pair that have to become one or the other, says Behringer. You’ve got two sets of ducts, and you’ve got to make one set differentiate and one regress, depending on whether it’s a male or a female. That takes a bit more coordination.

Making a female is still relatively straightforward, though: in the absence of testosterone the embryonic male ducts wither away. But researchers have long suspected that to make a male, a second hormone must actively suppress the development of the female reproductive ducts, known as müllerian ducts. The hormone, which is made in the gonads, is called müllerian-inhibiting substance, or MIS. Curiously, the MIS gene is on an ordinary chromosome, not on the Y, so both males and females have it.

To pinpoint the role of the MIS gene in embryonic development, Behringer and his colleagues knocked it out: they mutated the gene in embryonic mouse cells, transferred the embryos into a host mother, and bred the resulting offspring until they had mice in which both copies of the MIS gene were mutated. Then they studied the mutants. The mutant females, the researchers found, didn’t miss MIS; the gene is turned off in a female embryo anyway, so the mutation had no effect. The mutant males also appeared to be normally equipped. But they had some extras--oviducts, uterus, and the upper bit of a vagina. The lack of MIS had permitted the female ducts to flourish.

Surprisingly enough, that didn’t interfere much with the males’ conduct. They could still produce normal sperm and copulate with females. What they couldn’t do was fertilize a female. Although the mutant males manufactured normal amounts of sperm, 90 percent couldn’t father offspring. The presence of the female reproductive duct, Behringer suspects, somehow blocks the path of the sperm cells before they reach their destination. The two ducts come together, he says, and you have a plumbing problem.

The same problem has been observed in humans, although it is extremely rare: a man may have fallopian tubes and a uterus, and be sterile, as a result of a mutation in the MIS gene. What fascinates me is how this delicate balance in normal development is maintained, says Behringer. At the molecular or embryological level, there’s not much difference between men and women. We all start off similar, and a little hormone here or there and you end up being a male or a female.

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