Follicle-stimulating hormone increases primordial follicle reserve in mature female hypogonadal mice

Allan, Charles M.; Wang, Y; Jimenez, Mark; Marshan, Benjamin; Spaliviero, Jenny; Illingworth, Peter; Handelsman, David J.

doi:10.1677/joe.1.06614

Cited by 39 publications

(30 citation statements)

References 51 publications

(56 reference statements)

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“…For instance, it has been demonstrated that FSH directly regulate bone mass independently of E2 by activating bone resorption and therefore it might be a potential factor involved in Sema4D −/− bone resorption phenotype [24]. In the same way, we did not completely rule out the possibility that Gnrh1 could act directly on osteoclasts, to promote bone resorption, although it has been shown that Gnrh1 have no effect on osteoclastogenesis [24] and that hypogonadism is currently associated with bone loss [26]. In addition to the FSH direct effect on bone, recent studies have reported that elevated FSH levels increase bone formation, independently of E2, and that this increased bone formation is correlated to the FSH induced ovarian secretion of inhibin and androgens [27].…”

Section: Discussionmentioning

confidence: 75%

Control of Bone Resorption by Semaphorin 4D Is Dependent on Ovarian Function

et al. 2011

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Osteoporosis is one of the most common bone pathologies, which are characterized by a decrease in bone mass. It is well established that bone mass, which results from a balanced bone formation and bone resorption, is regulated by many hormonal, environmental and genetic factors. Here we report that the immune semaphorin 4D (Sema4D) is a novel factor controlling bone resorption. Sema4D-deficient primary osteoclasts showed impaired spreading, adhesion, migration and resorption due to altered ß3 integrin sub-unit downstream signaling. In apparent accordance with these in vitro results, Sema4D deletion in sexually mature female mice led to a high bone mass phenotype due to defective bone resorption by osteoclasts. Mutant males, however, displayed normal bone mass and the female osteopetrotic phenotype was only detected at the onset of sexual maturity, indicating that, in vivo, this intrinsic osteoclast defect might be overcome in these mice. Using bone marrow cross transplantation, we confirmed that Sema4D controls bone resorption through an indirect mechanism. In addition, we show that Sema4D −/− mice were less fertile than their WT littermates. A decrease in Gnrh1 hypothalamic expression and a reduced number of ovarian follicles can explain this attenuated fertility. Interestingly, ovariectomy abrogated the bone resorption phenotype in Sema4D −/− mice, providing the evidence that the observed high bone mass phenotype is strictly dependent on ovarian function. Altogether, this study reveals that, in vivo, Sema4D is an indirect regulator of bone resorption, which acts via its effect on reproductive function.

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Section: Discussionmentioning

confidence: 75%

Control of Bone Resorption by Semaphorin 4D Is Dependent on Ovarian Function

et al. 2011

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“…Serum levels of TgFSH driven by the rat insulin II gene promoter (21,22) were significantly higher in TgFSH H compared with TgFSH m females (Fig. 1A).…”

Section: Tgfsh Stimulates Ovarian Secretion Of Inhibin a And Testostementioning

confidence: 92%

“…Our TgFSH mouse model provides progressively rising circulating levels of FSH with age (18), with distinct transgenic lines allowing dose-dependent analysis of FSH actions in vivo (19)(20)(21). Using this FSH model, we have determined TgFSH actions on bone (i) in isolation of LH actions, using TgFSH expressed in hypogonadal (hpg) female mice lacking gonadotropinreleasing hormone (GnRH) and therefore endogenous FSH and LH secretion (21,22), and (ii) in isolation of intact ovaries, using ovariectomized TgFSH mice (TgFSH-Ovx). In contrast to previous observations, our findings reveal that elevated FSH activity in vivo, regardless of LH and/or estradiol levels, markedly stimulates bone mass via an ovary-dependent pathway.…”

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confidence: 99%

Follicle-stimulating hormone increases bone mass in female mice

Allan

Kalak

Dunstan

et al. 2010

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

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Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarianderived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells. ) were protected from bone loss despite estradiol deficiency, whereas haploinsufficient Fshb +/− females exhibited increased bone mass (9). By inference, it was proposed that elevated circulating FSH levels caused the bone loss observed in estrogen deficient peri-and postmenopausal women (9, 10). Mechanisms proposed for this putative FSH-induced bone loss included direct FSH stimulation of osteoclastic bone resorption via the FSHR (9) and FSH-induced TNFα production by bone marrow granulocytes and macrophages by as-yet-undefined pathways (11). However, elevated androgens in Fshb −/− and Fshr −/− female mice provide an alternate explanation for the preservation of bone mass in these estradiol-deficient mouse models (12). Although direct regulation of bone remodeling through FSH would have major clinical implications, such a mechanism has yet to exclude roles of FSH-regulated ovarianderived factors, which, on a biological basis, are more likely to control bone turnover, such as sex steroids (12-15) or inhibins (16, 17).In the current study, we have directly determined the effects of elevated FSH activity on bone mass and structure by using pituitary-independent, transgenic expression of human FSH (TgFSH) in female mice. Our TgFSH mouse model provides progressively rising circulating levels of FSH with age (18), with distinct transgenic lines allowing dose-dependent analysis of FSH actions in vivo (19)(20)(21). Using this FSH model, we have determined TgFSH actions on bone (i) in isolation of LH actions, using TgFSH expressed in hypogonadal (hpg) female mice lacking gonadotropinreleasing hormone (GnRH) and therefore endog...

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“…Yet, the number of competent oocytes in hpg mice was reduced markedly, and exogenous gonadotropin increased the number of competent oocytes (57). Accordingly, FSH increased follicular growth in hpg mice (58). Studies with ArKO mice or preantral follicles cultured with an aromatase inhibitor resulted in normal follicular growth, and the oocytes matured in vitro (35,59,60).…”

Section: Discussionmentioning

confidence: 99%

Are Steroids Obligatory Mediators of Luteinizing Hormone/Human Chorionic Gonadotropin-Triggered Resumption of Meiosis in Mammals?

2007

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Steroids mediate the gonadotropic stimulus of oocyte maturation in fish and amphibians. Such a role of steroids in mammals has not been confirmed until recently. A series of studies presented data suggesting that steroids might be involved in meiosis of mouse oocytes. Here we examined this suggestion using in vitro cultures of rat and mouse follicle-enclosed oocytes (FEOs) and cumulus-enclosed oocytes (CEOs). In FEOs that mature only in response to gonadotropins or other stimuli, we tested the ability of steroids to trigger meiosis and whether addition of steroid receptor antagonists blocks LH/human chorionic gonadotropin stimulation of meiosis. In CEOs that mature spontaneously, we tested whether steroid antagonists block maturation and whether steroids overcome the inhibition of maturation by hypoxanthine (Hx), a mild inhibitor of meiotic resumption. The progesterone antagonists mifepristone (RU 486) and Organon 31710 as well as the estrogen antagonist faslodex did not prevent LH-triggered maturation of rat or mouse FEOs or the spontaneous maturation of CEOs. In accordance, the progesterone agonist promegestone (R5020) and estradiol did not stimulate the resumption of meiosis in rat and mouse FEOs, and both did not overcome the Hx inhibition of meiosis in rat and mouse CEOs. Flutamide, an androgen antagonist, did block meiosis in rat FEOs, but this action could not be affected by adding dihydrotestosterone, suggesting that it was not androgen receptor mediated. Flutamide did not affect spontaneous maturation of rat CEOs, and dihydrotestosterone could not stimulate meiosis inhibited by Hx. Thus, in contrast to lower vertebrates, in mammals, steroids do not seem to serve as an obligatory signal by which the somatic cells of the follicle transfer the gonadotropic stimulation of meiosis to the oocyte.

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Follicle-stimulating hormone increases primordial follicle reserve in mature female hypogonadal mice

Cited by 39 publications

References 51 publications

Control of Bone Resorption by Semaphorin 4D Is Dependent on Ovarian Function

Control of Bone Resorption by Semaphorin 4D Is Dependent on Ovarian Function

Follicle-stimulating hormone increases bone mass in female mice

Are Steroids Obligatory Mediators of Luteinizing Hormone/Human Chorionic Gonadotropin-Triggered Resumption of Meiosis in Mammals?

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