BRASILIA, Brazil -- A newly found mutation in one of the genes involved in sexual development prevents puberty in males but allows it to occur in females, researchers here said.
BRASILIA, Brazil, Aug. 29 -- A newly found mutation in one of the genes involved in sexual development prevents puberty in males but allows it to occur in females, researchers here said.
Lack of luteinizing hormone because of defects in the LH beta-subunit gene (LHB) is a rare cause of hypogonadism usually seen in males, according to Adriana Lofrano-Porto, M.D., of the University Hospital of Braslia, and colleagues.
But in a case report in the Aug. 30 issue of the New England Journal of Medicine, Dr. Lofrano-Porto and colleagues describe what they say is the first known case of a woman affected by such a defect.
The study began when doctors treated a Brazilian man born to consanguineous parents.
At 38, he was six feet tall and weighed 191 pounds, but had bilateral gynecomastia, a juvenile voice, and no facial hair. His penis was 1.8 inches long, or Tanner stage one, although his pubic hair was in Tanner stage four. His testicles were descended but small.
Tests showed that LH was completely absent and therapy with intramuscular testosterone (at 250 mg every three weeks) was started. Over a year, the hormone induced virilization, doubled the penis length (to 3.5 inches), and increased the testicular volume.
Genetic testing showed that the man was homozygous for a LHB gene defect - a guanine to cytosine substitution in position one of intron two. Both his parents had the same defect, but carried only one copy each and were fertile, as were other heterozygous relatives.
Further testing showed that the man's 30-year-old bother and 29-year-old sister also carried two copies of the defect.
The brother had been treated with testosterone for hypogonadism since the age of 25. He had normal male genitalia but no measurable level of sperm in his semen.
The sister, on the other hand, had had a normal pubertal development, with menarche at 13, followed by several years of light and irregular periods. She weighed 123 pounds and was five feet, five inches tall.
Her breast and pubic-hair development were normal (Tanner stage five for both mammary glands and pubic hair). She had a normal uterus with atrophic endometrium. The ovaries were normal in size and contained multiple antral follicles.
Nevertheless, she had secondary amenorrhea and infertility, the researchers said. As with her siblings, levels of LH were undetectable.
Treatment began with 0.625 mg of estrogen daily for three months, followed by combined estrogen-progestagen. Follow-up ultrasound showed progressive endometrial thickening and follicle enlargement.
The findings "corroborate the essential roles of luteinizing hormone in ovulatory function," the researchers said.
The effect of the mutation, the researchers said, would be to create a messenger-RNA transcript with an extra 236 nucleotides - an aberration so great that a protein based on the gene probably "would not be secreted," the researchers said.
Such a "rare experiment of nature" offers new clues to the complicated machinery surrounding human reproduction, according to Shalender Bhasin, M.D., of the Boston University.
In an accompanying editorial, Dr. Bhasin said the "new insight" from the report is that luteinizing hormone isn't needed for normal puberty in women, including breast development and menarche.
On the other hand, he said, the hormone is essential for ovulation.