Researchers Discover Role Of Estrogen Stimulator In Making Male Hormone; Finding May Help Explain Infertility In Some Women And Men

"The old thought was that follicle stimulating hormone, or FSH, wasn’t necessary for producing testosterone, the male sex hormone, in women or men," said Dr. Lawrence C. Layman, chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics and senior author on an article published in the Oct. 19 edition of the New England Journal of Medicine.

It was believed that FSH was only involved in making estrogen; that the pituitary makes FSH which stimulates ovaries to produce estrogen and it makes luteinizing hormone, or LH, to stimulate the ovaries in women and the testes in men to produce testosterone.

"We thought that FSH was just for making estradiol, the major estrogen, and LH was for making testosterone," Dr. Layman said. "But what we found was that FSH is necessary to make testosterone in women as well."

The newly discovered role of FSH may help explain why some men have a low sperm count and some women don’t ovulate and enable both to get help, Dr. Layman said. It also opens the door for potential new approaches to male contraception with a medication that blocks FSH, lowering sperm count.

It’s been known that male and female sex hormones are produced from cholesterol. LH initiates the conversion of cholesterol to precursors of male hormones, Dr. Layman said. Through a series of biochemical steps, the precursors then become androgens, or male hormones. In men and, to a far greater extent in women, some of the male hormone is then converted to estrogen.

But the researchers found that FSH also plays a role in normal male hormone production in women; the function of testosterone in women is somewhat unclear, but it does appear to be important in libido.

Dr. Layman, working with colleagues at the University of Chicago, discovered the role of FSH in producing needed testosterone by treating a woman with an unusual problem: she was missing FSH and had an elevated level of testosterone-producing LH.

The barely detectable FSH with an elevated LH scenario should have meant the woman had too little estrogen and too much testosterone. Instead, she didn’t seem to have much of either.

The adult patient had under-developed breasts, had never menstruated and was infertile, all clear indicators of her estrogen deficit. But she did not have body and facial hair as expected because of her high levels of testosterone-producing LH.

When they gave the woman gonadotropin releasing hormones, or GnRH, which stimulate the pituitary to make FSH and LH, her LH increased but her FSH didn’t budge. "What that suggested is there was something wrong with the FSH," Dr. Layman said.

Looking further, he found a genetic basis for the scenario: two mutations in the beta subunit of her FSH gene. FSH and LH genes have alpha and beta components; they have the alpha subunits in common, but different beta subunits. "Since she could make LH but not FSH, it was likely to be a beta subunit of FSH that was mutated and not the common alpha subunit," Dr. Layman said. He was the lead author of a study on this finding published in the New England Journal of Medicine in 1997.

The woman then went to the Clinical Research Center at the University of Chicago where she was given human chorionic gonadotropin or hCG, a longer-acting LH-like protein, that should have increased her testosterone level, but it was unchanged.

So they gave her shots of hCG and FSH and her testosterone level tripled into the normal range. "That shows that you also need FSH to make normal testosterone," Dr. Layman said. Her estrogen level also went up slightly because she got one dose of FSH, the missing hormone.

The doctors determined she needed estrogen to enable sexual development and protect her bones. She now takes birth control pills, which contain estrogen and progesterone, Dr. Layman said. If she decides to have a child, she can receive comparatively expensive FSH injections to stimulate ovulation. "When she eventually wants to do that, we hope to measure a variety of other hormones and see what FSH’s normal effect is," he said.

"This patient, a rare patient, who has mutations in her FSH beta gene, already has taught us a lot about normal physiology," Dr. Layman said. "And that often happens when you find something rare."

The researchers’ latest finding indicates that doctors may want to check for mutations of the FSH beta gene in women with unexplained infertility; that’s about 25 percent of infertile women, Dr. Layman said. Most women with the mutation should respond to FSH injections, he said.

Milder mutations of the FSH beta gene may explain why some women experience normal puberty but are still infertile. "We are looking at that now," Dr. Layman said.

But despite his finding in a woman, Dr. Layman theorizes that FSH beta mutations may be even more common in men where it’s responsible for low sperm count. That’s another study he is beginning now by collecting DNA from several hundred males and females with unexplained infertility and looking at the FSH beta gene. They also are screening these patients for other gene mutations that may explain infertility.