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Editorial |
Chair, Department of Medicine Head of Endocrinology The University of Melbourne Western Hospital Footscray, 3011 Victoria, Australia
Address all correspondence and requests for reprints to: Peter R. Ebeling, Chair, Department of Medicine, Head of Endocrinology, The University of Melbourne, Western Hospital, Footscray, 3011 Victoria, Australia. E-mail: peterre{at}unimelb.edu.au
Estrogen has a pivotal role in maintaining normal bone cellular activity in women and men (1). Postmenopausal osteoporosis is characterized by an imbalance between an increased production of osteoclasts and osteoblasts, favoring the former. This results in increased bone remodeling and bone microarchitectural deterioration. Estrogen deficiency may be responsible for both the accelerated phase of bone loss at the menopause and the slower phase of age-related bone loss later in life.
The menopause transition is also characterized by an increase in serum FSH and a decrease in serum inhibin concentrations. Inhibin, present in ovarian follicular fluid (2), was originally identified because of its ability to suppress pituitary FSH secretion. Two isoforms have subsequently been identified. Inhibin B and inhibin A are heterodimeric proteins in the TGFß superfamily comprising 
ßB and ßA subunits, respectively.
We have previously shown in late premenopausal women that biochemical markers of bone resorption were already increased, despite normal circulating estrogen levels (3). The hormonal variable best correlated with this increase in bone resorption was serum FSH. Using an older RIA that did not differentiate between inhibin isoforms, we could not detect differences in serum inhibin levels in late premenopausal women, but we did demonstrate decreases in inhibin in postmenopausal women and women on hormone therapy. Subsequently, other investigators have shown that a selective decrease in ovarian secretion of the inhibin B isoform is associated with this early rise in FSH in the late premenopause (4).
So does the increase in FSH or the decrease in inhibin levels drive the late-premenopausal increase in bone turnover? Theoretically, at least, the case for inhibin B appears to be stronger as inhibins suppress both osteoblast and osteoclast development in murine bone marrow cultures as shown in the authors’ previous in vitro experiments (5).
To test this hypothesis, in this issue, Perrien et al. (6) have correlated serum concentrations of inhibin A, inhibin B, FSH, and bioavailable estradiol with bone turnover markers in a well-defined population-based cohort of pre-, peri-, and postmenopausal women.
The strongest negative relationships between serum inhibin A and inhibin B levels and markers of bone formation and bone resorption occurred in pre- and perimenopausal women. However, only inhibin A was negatively related with bone formation in postmenopausal women. Serum FSH levels were significantly positively related to bone resorption only in perimenopausal women, as shown in our previous study. Serum inhibin A was the best predictor of both bone formation and bone resorption, independent of changes in either FSH or estradiol.
These clinical data are supported by their in vitro data showing that both inhibin A and inhibin B isoforms suppressed osteoblastogenesis from mesenchymal stem cells, as well as late-stage osteoblast differentiation and mineralization (6). Inhibin A and inhibin B also completely blocked receptor activator of nuclear receptor 
B-ligand (RANK-L)-induced osteoclastogenesis from peripheral mononuclear cells. The case for inhibin having a direct effect on bone turnover therefore appears to be very strong.
Taken together, these clinical and in vitro findings suggest that it is likely that decreases in circulating inhibin levels, due to reduced ovarian function, contribute to perimenopausal bone loss. Alterations of ovarian function throughout reproductive life resulting in oligo- or amenorrhea could also be associated with increases in bone turnover secondary to reductions in inhibin. For example, in the majority of women with functional hypothalamic amenorrhea, FSH levels were within the normal range, whereas inhibin B levels were decreased (7). Less commonly, women with inhibin B-producing granulosa cell tumors of the ovary can present with secondary amenorrhea (8).
Conclusions from the current study are somewhat limited, however, by its cross-sectional design. Large longitudinal studies relating inhibin levels to noninvasive measurements of trabecular and cortical bone microstructure measured by high-resolution peripheral quantitative computerized tomography, as well as bone turnover markers, across the menopause transition are now required. This would allow a better analysis of the relationships between inhibins and the decreases in volumetric bone mineral density occurring in these perimenopausal women. It would also determine whether inhibins preferentially affected the trabecular bone loss that occurs during the menopause transition.
Additional studies would help define the role of inhibin as an important regulator of skeletal health and perhaps offer the tantalizing possibility for a novel therapy to prevent and treat postmenopausal osteoporosis.
Footnotes
The author has nothing to declare.
Received February 23, 2006.
Accepted March 17, 2006.
References
This article has been cited by other articles:
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  D. S. Perrien, N. S. Akel, P. K. Edwards, A. A. Carver, M. S. Bendre, F. L. Swain, R. A. Skinner, W. R. Hogue, K. M. Nicks, T. M. Pierson, et al. Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength Endocrinology, April 1, 2007; 148(4): 1654 - 1665. [Abstract] [Full Text] [PDF]
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