High bone density in hyperandrogenic women: effect of gonadotropin-releasing hormone agonist alone or in conjunction with estrogen-progestin replacement.

We studied 20 hirsute patients with high levels of serum testosterone (T), calculated free T, androstenedione, and dehydroepiandrosterone sulfate and 19 age-matched nonhirsute normoandrogenic control women. The bone mineral density (BMD) in the lumbar spine, femoral neck, and trochanter major region in hirsute patients was higher than that in the controls. BMD in the lumbar spine and proximal femur correlated positively with the body mass index and with serum T and free T in hyperandrogenic women and the whole study group, but not with serum androstenedione or dehydroepiandrosterone sulfate levels. The hirsute women were treated with a GnRH agonist (goserelin, 3.6-mg implant) for 9 months. After the first 3 months of treatment, half of the patients were randomized to receive estrogen-progestin replacement therapy (HRT), and the other half served as controls. After the first 3 months of trial, BMD was unaffected, and the urinary output of collagen pyridinoline, deoxypyridinoline cross-links, and hydroxyproline (all markers of bone resorption) were increased, but serum markers, the carboxy-terminal telopeptide of type I collagen (marker of bone resorption) and that of bone-specific alkaline phosphatase (marker of bone formation) did not change. After 9 months of goserelin treatment, the lumbar spine had lost 5.4% of its BMD (P < 0.01), but regained bone density 6 months after cessation of treatment. Addition of HRT protected the spine and trochanter major against bone loss. The changes in serum telopeptide and urinary output of pyridinoline and deoxypyridinoline after 3 months of treatment (from prestudy levels) correlated with the decrease in BMD in the femoral neck at 9 months. In conclusion, our data show that patients with ovarian androgen excess 1) have high BMD, 2) lose bone during 9 months of treatment with GnRH agonist, 3) show a decrease in bone density preceded by biochemical alterations in bone metabolism at least 6 months earlier, and 4) can have their bone loss prevented by add-back HRT.