Suppression of follicle-stimulating hormone does not affect postmenopausal bone resorption
Changes in serum follicle-stimulating hormone (FSH) levels over time
Serum levels of the bone resorption marker carboxy-terminal telopeptide of type I collagen
The decline in estrogen levels that begins with the menopausal transition is well recognized as an important contributor to postmenopausal bone loss. Other hormonal changes, however, also occur with menopause, including reductions in circulating levels of progesterone, androgens, and inhibins A and B.
Matthew T. Drake, M.D., Ph.D., of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic in Rochester, Minn., says: "Follicle-stimulating hormone (FSH) has received the most recent interest among potential candidate factors (other than estrogen) for mediating menopausal bone loss. Indeed, in perimenopausal women, increases in bone resorption markers best correlate not with serum estradiol levels, but with FSH levels.
"Further, the Study of Women's Health Across the Nation showed that losses in spine and hipbone mineral density during the menopausal transition correlated most strongly with the interaction between the initial FSH level and longitudinal FSH changes, rather than with estradiol or androgen levels."
Whether FSH has direct effects on bone, however, continues to be unclear. Dr. Drake explains: "Evidence both for and against direct FSH effects in bone has been provided from rodent studies. One study found that mice lacking the FSH receptor were hypogonadal but had normal bone mass. Further, they found that in these mice, osteoclasts and their precursors had FSH receptors, and FSH increased osteoclast formation and function in vitro. These findings led the authors to conclude that high circulating FSH levels caused hypogonadal bone loss.
"In contrast, another group of investigators found that the same FSH receptor-null mice had reduced bone mass and that bilateral ovariectomy reduced their elevated circulating testosterone levels and decreased bone mass to levels indistinguishable from those in ovariectomized normal controls. Accordingly, these investigators came to the opposite conclusion — namely, that sex steroids (and not FSH) were responsible for regulating bone turnover in these mice."
Given the correlative human data and the conflicting mouse data regarding a potential role for FSH in mediating bone resorption, Dr. Drake, in collaboration with Sundeep Khosla, M.D., used a direct interventional human study to test whether FSH suppression in postmenopausal women reduced bone resorption marker levels.
Dr. Drake highlights the study: "Because of the myriad of hormonal changes in the perimenopausal and early menopausal years, we studied women well past the menopausal transition, in whom hormonal levels other than FSH would be stable and low.
"To suppress FSH levels, the experimental group received a gonadotropin-releasing hormone (GnRH) agonist while endogenous estrogen levels were controlled by aromatase inhibitor treatment of all patients. In GnRH-treated patients, FSH levels dropped rapidly into the premenopausal range, where they remained throughout the four months of the study. In contrast, FSH levels stayed elevated in control subjects.
"Despite the groups having markedly different circulating FSH levels, however, bone resorption (as assessed by serum carboxy-terminal telopeptide of type I collagen levels) was not different between the groups when assessed at the study endpoint. In fact, both the control subjects and the GnRH-treated patients had slightly increased bone resorption, likely due to the concomitant suppression of endogenous estrogen by aromatase inhibitor therapy in both groups."
Dr. Drake concludes: "Taken together, these findings clearly demonstrate that in postmenopausal women, suppression of serum FSH levels into the premenopausal range does not reduce bone resorption and strongly supports the assertion that the rise in FSH that occurs with the menopause does not itself lead to bone loss. Therefore, the development of pharmacologic approaches to diminish FSH secretion or action, or both, is unlikely to be a viable future approach to limit postmenopausal bone loss."