Sex Steroids, Not FSH, Influence Bone Mass

Hypogonadism, whether caused by the failure of gonadal development or function, frequently results in bone loss. In a research article in the April 21, 2006 issue of Cell, Sun et al. investigated the role of follicle-stimulating hormone (FSH) in the bone loss that is characteristic of hypogonadal mice. They report that female mice lacking either FSHβ or its receptor (FSHR) are resistant to bone loss despite hypogonad-ism. Sun et al. conclude that FSH is directly responsible for bone loss in hypogonadal female mice with unimpaired FSH action (Sun et al., 2006). We challenge the proposal that FSH is required for hypogo-nadal bone loss. We suggest that the two mouse models used in the Sun et al. study have hormonal fea-tures—raised levels of luteinizing hormone (LH) and testosterone as a secondary consequence of FSH loss—that could explain the preservation of bone, without any need to invoke additional bone-specific actions of FSH. LH stimulates ovarian theca cells to produce testosterone (Kumar, 2005). This effect is especially pronounced in the absence of FSH sig-naling when LH levels are increased due to overlapping negative feedback pathways in the hypothala-mus and pituitary. The increased LH levels in turn boost testosterone production by theca cells. Previous work in mice lacking FSHR showed that blood testosterone levels are increased up to 10-fold in immature and mature female mice (Balla et al., 2003; Danilovich et al., 2000; Abel et al., 2003). Moreover, uterine hypertrophy and other defects in mice lacking either FSHR or FSHβ are likely due to increased testoster-one that is of ovarian origin (Abel et al., 2003). We argue that changes in the production of these sex ster-oids and not the loss of FSH sign-aling account for the observations by Sun et al. Unfortunately, Sun et al. did not report the concentration of serum LH or testosterone in their two mouse models. We have shown that in the hpg hypogonadal mouse, marked bone loss is present in males (Sims et al., 2005). Sun and colleagues reported similar findings in female hpg mice in another recent study (Rajen-dren et al., 2006). The hpg mouse is a naturally occurring model of hypogonadism caused by a mutation in the gene encoding gonado-tropin-releasing hormone (GnRH) (Cattanach et al., 1977; Mason et al., 1986a). These mice have post-natal deficiencies in FSH, LH, and gonadal sex steroid hormones. As a consequence, the reproductive system fails to mature, rendering hpg mice a valuable …