Understanding Estrogen Action during Menopause

Iqbal, Jameel; Zaidi, Mone

doi:10.1210/en.2009-0449

Cited by 34 publications

(21 citation statements)

References 29 publications

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“…This is because luperide alters multiple hormones within the hypothalamic-pituitary-ovarian axis, whereas our antibody permits the identification of a specific FSH effect on bone in the presence of severe hypoestrogenemia. In this situation, and consistent with the profound effect of estrogen deprivation on both bone resorption and bone formation (14), the FSH antibody attenuated, but did not abolish the bone loss after ovariectomy. It is also possible that the luperide study (15) points to important differences in the human skeletal response to FSH inhibition, but our hypothesis is, on the other hand, compatible with crosssectional studies in amenorrheic women: those with serum FSH levels ∼8 IU/mL did suffer bone loss, but this bone loss was less marked than that in women with higher serum FSH levels of >35 IU/mL (7).…”

Section: Discussionsupporting

confidence: 70%

“…Through this mechanism, FSH enhances osteoclastogenesis, bone resorption, and osteoclast survival (9-11). We also identified FSHRs on mesenchymal stem cells (MSCs), but their functional significance has not been established (9).Despite demonstrable receptor-mediated effects of FSH on bone, it has been difficult to separate the action of estrogen on bone resorption, which is inhibitory, from that of FSH, which we and others show is stimulatory (9)(10)(11)14). This is because FSH stimulates estrogen production, hitherto considered its sole action, and the estrogen so produced, opposes FSH action.…”

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confidence: 99%

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Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Zhu

Blair

Cao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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145

143

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Low estrogen levels undoubtedly underlie menopausal bone thinning. However, rapid and profuse bone loss begins 3 y before the last menstrual period, when serum estrogen is relatively normal. We have shown that the pituitary hormone FSH, the levels of which are high during late perimenopause, directly stimulates bone resorption by osteoclasts. Here, we generated and characterized a polyclonal antibody to a 13-amino-acid-long peptide sequence within the receptor-binding domain of the FSH β-subunit. We show that the FSH antibody binds FSH specifically and blocks its action on osteoclast formation in vitro. When injected into ovariectomized mice, the FSH antibody attenuates bone loss significantly not only by inhibiting bone resorption, but also by stimulating bone formation, a yet uncharacterized action of FSH that we report herein. Mesenchymal cells isolated from mice treated with the FSH antibody show greater osteoblast precursor colony counts, similarly to mesenchymal cells isolated from FSH receptor (FSHR) −/− mice. This suggests that FSH negatively regulates osteoblast number. We confirm that this action is mediated by signaling-efficient FSHRs present on mesenchymal stem cells. Overall, the data prompt the future development of an FSH-blocking agent as a means of uncoupling bone formation and bone resorption to a therapeutic advantage in humans.osteoporosis | sex steroids | skeletal anabolic | gonadotropin W omen lose over 3% of bone mass during late perimenopause at which time estrogen levels remain relatively unperturbed (1, 2). This bone loss begins 3 y before the last menstrual period (3), and arises from a profound elevation in bone resorption, which is not compensated by parallel increases in bone formation (4). Inhibiting bone resorption during this period with an anticatabolic agent, such as a bisphosphonate, selective estrogen receptor modulator, or estrogen itself, attenuates bone loss (5). However, estrogen use can be associated with increased breast cancer risk and designer estrogens have undesirable side effects. Further, growing concerns regarding oversuppression of bone turnover by bisphosphonates limit their use as early as perimenopause (5). The relatively small armamentarium for osteoporosis therapies, particularly for early and rapidly progressing bone loss, makes the advent of newer preventative strategies very desirable.A close examination of hormonal changes in women during late perimenopause shows that, whereas estrogen levels remain unperturbed, FSH levels have begun to rise, likely to compensate for failing ovaries (3). Strong correlations between rising serum FSH levels and bone loss have been documented, particularly in the Study of Women's Health Across Nations (SWAN) (2, 6). Furthermore, amenorrheic women with high FSH levels >35 IU/L display greater decrements in bone density than those with a mean FSH of ∼8 IU/L (7). Likewise, women having activating FSH receptor (FSHR) polymorphisms have a low bone mass and high bone turnover (8). Together, these findings suggest that a rising ...

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Section: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Zhu

Blair

Cao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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145

143

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“…However, the rapid loss of bone during the late perimenopausal transition, particularly when estrogen levels are relatively normal, is proposed to be mediated, at least in part, by rising follicle-stimulating hormone levels (FSH levels) (2,3). Nonetheless, these hormonal changes do not fully explain the increased bone formation, high BM T cell counts, or macrophage activation that have been noted across the menopausal transition (4). Alterations in immune cell function have largely been attributed to increased production of TNFα, which further enhances osteoclast formation and function (5,6).…”

Section: A New Player In Sex Steroid Deficiency-related Bone Lossmentioning

confidence: 99%

From the gut to the strut: where inflammation reigns, bone abstains

Iqbal¹,

Yuen²,

Sun³

et al. 2016

Journal of Clinical Investigation

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C o m m e n t a r y2 0 4A new player in sex steroid deficiency-related bone lossOsteoporosis is a leading cause of morbidity in the increasing population of aging adults. In postmenopausal women, fracture incidence far exceeds the combined incidence of breast cancer, stroke, and myocardial infarction. Bone loss arises from accelerated resorption by osteoclasts, which outpaces the accompanying increase in bone formation by osteoblasts (1). Postmenopausal osteoporosis has traditionally been solely attributed to declining estrogen levels. However, the rapid loss of bone during the late perimenopausal transition, particularly when estrogen levels are relatively normal, is proposed to be mediated, at least in part, by rising follicle-stimulating hormone levels (FSH levels) (2, 3). Nonetheless, these hormonal changes do not fully explain the increased bone formation, high BM T cell counts, or macrophage activation that have been noted across the menopausal transition (4). Alterations in immune cell function have largely been attributed to increased production of TNFα, which further enhances osteoclast formation and function (5, 6). Consistent with this, ablation of the Tnfa gene in mice prevents gonadectomy-induced bone loss, osteoclast and osteoblast activation, and accompanying immune cell abberations (5). However, the mechanisms that drive TNFα production during hypogonadal states remain relatively unclear. In this issue, Li et al. (7) show that gut microbiota play a fundamental role in the enhanced TNFα production that occurs upon the induction of estrogen deficiency in mice. It has previously been shown that lowering the inflammatory burden does suppress the effects of estrogen deficiency. For example, TNFα or IL-1 blockade in early postmenopausal women decreases bone resorption markers (8). Likewise, mice in which Tnfa or Il6 is deleted are relatively resistant to ovariectomy-induced bone loss (9). Li et al. evaluated how gut microbiota contribute to the inflammation seen with estrogen deficiency by using a strategy in which mice raised in an environment devoid of gut bacterial colonization (germ-free mice) were chemically castrated with leuprolide (7). Impressively, these hypogonadal, germ-free mice did not experience the marked bone loss that occurred in hypogonadal mice with unperturbed gut flora. Likewise, osteoclast numbers were not increased in germ-free mice. Even more impressive was the observation that the reintroduction of flora into germ-free mice reversed the osteoprotection exerted by an absence of microbiota; this, in essence, proved a fundamental role for gut microbiota in regulating skeletal integrity. Mice raised in a germ-free environment are indeed known to have increased bone mass and fewer osteoclasts (10). The findings of Li et al. now suggest that the same pathways are responsible for the bone loss accompanying sex steroid deficiency. Germ-free mice maintain barrier functionWhat is the mechanism through which gut microbiota mediate bone loss during sex steroid deficiency? It is widely acce...

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“…His hypothesis linking the loss of sex steroids to bone loss led to estrogen hormone replacement therapy (HRT) becoming the first successful treatment for osteoporosis [2]. More recently, however, a finer re-examination of menopausal bone loss has revealed that nearly half of lifetime loss occurs within the first 5 years [3,4].…”

Section: Introductionmentioning

confidence: 99%