In Vivo FSH Actions

Allan, Charles M.; Handelsman, David J.

doi:10.1016/b978-012647751-1/50012-x

Cited by 8 publications

(7 citation statements)

References 244 publications

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“…Because residual FSH activity may influence the pattern of testicular regression observed in this pharmacological model, we further examined the spermatogenic and steroidogenic effects of FSHR* during testicular regression in the Gnrh1 À/À mouse, which has complete postnatal functional FSH/LH deficiency [16,35,36]. Using an established T treatment to stimulate maximal androgen-specific spermatogenic completion in Gnrh1 À/À testes [26][27][28], subsequent withdrawal of T for 6 wk was predicted to produce testicular regression, manifest as loss of testis weight and, in particular, loss of androgen-dependent meiotic and postmeiotic germ cells [26].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, targeted disruption of mouse Fshr or Fshb genes preserved male fertility despite reducing testis size, whereas all females remained sterile [7][8][9]. In contrast, infertility occurs in men lacking normal circulating FSH [10][11][12][13][14][15], which suggests that FSH is necessary for human male fertility (reviewed in [16]). The requirement for FSH activity to support human spermatogenesis was further highlighted by the identification of a mutated FSHR (FSHR*D567G, denoted FSHR*) in a hypophysectomized man who retained spermatogenesis and fertility despite receiving testosterone (T) but with uncorrected complete gonadotropin deficiency [17].…”

Section: Introductionmentioning

confidence: 93%

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Maintenance of Spermatogenesis by the Activated Human (Asp567Gly) FSH Receptor During Testicular Regression Due to Hormonal Withdrawal1

Allan¹,

García²,

Spaliviero³

et al. 2006

Biology of Reproduction

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The first activating mutation of the FSH receptor (FSHR*D567G) was identified in a gonadotropin-deficient hypophysectomized man who exhibited persistent spermatogenesis and fertility with only androgen replacement. We have determined the ability of FSHR* activity to maintain spermatogenesis and/or steroidogenesis during gonadotropin and androgen deprivation in mature transgenic FSHR* mice (Tg(Abpa-FSHR*D567G)1Cmal), hereafter referred to as Tg-FSHR* mice. Testes of untreated adult Tg-FSHR* males were equivalent in weight to nontransgenic controls but exhibited increased total Sertoli cell (24%) and spermatogonia (34%) numbers and nonsignificantly elevated spermatocyte-spermatid numbers (13%-17%). During sustained GNRH1 agonist treatment that markedly reduced (96%-98%) serum LH and testosterone (T) and decreased serum FSH (68%-72%), the testes of GNRH1 agonist-treated Tg-FSHR* mice remained significantly larger than treated nontransgenic controls. After 4 wk of gonadotropin suppression, Sertoli cell numbers were reduced in Tg-FSHR* testes to levels comparable with nontransgenic testes, whereas spermatogonia numbers were maintained at higher levels relative to nontransgenic testes. However, after 8 wk of GNRH1 agonist treatment, the total spermatogonia, spermatocyte, or postmeiotic spermatid numbers were reduced to equivalent levels in Tg-FSHR* and nontransgenic mice. FSHR* effects were further examined in gonadotropin-deficient hypogonadal Gnrh1hpg/Gnrh1hpg (Gnrh1(-/-)) mice during testicular regression following withdrawal of T after maximal T-stimulated spermatogenesis. After 6 wk of T withdrawal, spermatogonia, spermatocyte, and postmeiotic spermatid numbers in Tg-FSHR* Gnrh1(-/-) testes decreased to levels found in untreated Tg-FSHR* Gnrh1(-/-) testes. Basal serum T levels in untreated Tg-FSHR* Gnrh1(-/-) males were 2-fold higher than Gnrh1(-/-) controls, but following T treatment/withdrawal, serum T and epididymal weights declined to basal levels found in nontransgenic Gnrh1(-/-) mice. Therefore, FSHR* was unable to sustain circulating T or androgen-dependent epididymal size or postmeiotic spermatogenic development. We conclude that FSHR* activity enhances Sertoli and spermatogenic development in normal testes but has limited ability to maintain spermatogenesis during gonadotropin deficiency, in which the testicular response provided by the FSHR*D567G mutation resembled typical FSH-mediated but not steroidogenic activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Maintenance of Spermatogenesis by the Activated Human (Asp567Gly) FSH Receptor During Testicular Regression Due to Hormonal Withdrawal1

Allan¹,

García²,

Spaliviero³

et al. 2006

Biology of Reproduction

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“…Despite the fact that various roles for FSH in the seminiferous epithelium are emerging (see Allan & Handelsman (2005) and O'Donnell et al (2005)), reports on interSertoli cell junctions in various transgenic models of FSH, LH and androgen action deficiency are limited. However, ultrastructural studies in FSH receptor-deficient (FORKO) mice show various defects in Sertoli cell ultrastructure, particularly fluid-filled cytoplasm indicative of disturbed fluid dynamics (Grover et al 2004).…”

Section: Figurementioning

confidence: 99%

“…Although FSH is not required for fertility or the restoration of qualitatively normal spermatogenesis, it is now becoming clear that FSH has an important role in establishing the Sertoli cell population and supporting its function (reviewed in Allan & Handelsman (2005)). Despite the fact that various roles for FSH in the seminiferous epithelium are emerging (see Allan & Handelsman (2005) and O'Donnell et al (2005)), reports on interSertoli cell junctions in various transgenic models of FSH, LH and androgen action deficiency are limited.…”

Section: Figurementioning

confidence: 99%

FSH regulates the formation of adherens junctions and ectoplasmic specialisations between rat Sertoli cells in vitro and in vivo

Sluka

O’Donnell

Bartles

et al. 2006

Journal of Endocrinology

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Spermatogenesis is dependent on the ability of Sertoli cells to form mature junctions that maintain a unique environment within the seminiferous epithelium. Adjacent Sertoli cells form a junctional complex that includes classical adherens junctions and testis-specific ectoplasmic specialisations (ES). The regulation of inter-Sertoli cell junctions by the two main endocrine regulators of spermatogenesis, FSH and testosterone, is unclear. This study aimed to investigate the effects of FSH and testosterone on interSertoli cell adherens junctions (as determined by immunolocalisation of cadherin, catenin and actin) and ES junctions (as determined by immunolocalisation of espin, actin and vinculin) in cultured immature Sertoli cells and GnRH-immunised adult rat testes given FSH or testosterone replacement in vivo. When hormones were absent in vitro, adherens junctions formed as discrete puncta between interdigitating, finger-like projections of Sertoli cells, but ES junctions were not present. The adherens junction puncta included actin filaments that were oriented perpendicularly to the Sertoli cell plasma membrane, but were not associated with the intermediate filament protein vimentin. When FSH was added in vitro, ES junctions formed, and adjacent adherens junction puncta fused into extensive adherens junction belts. After hormone suppression in vivo, ES junctions were absent, while FSH replacement restored ES junctions, as confirmed by electron microscopy and confocal analysis of ES-associated proteins. Testosterone alone did not affect adherens junctions or ES in vitro or in vivo. We conclude that FSH can regulate the formation of ES junctions and stimulate the organisation and orientation of extensive adherens junctions in Sertoli cells.

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“…FSH alone cannot initiate completion of spermatogenesis in androgen-deficient men (44), but prepubertal FSH administration may enhance subsequent FSHϩhCG (human chorionic gonadotropin)-induced pubertal onset and testis function in hypogonadotropic hypogonadal boys (41), suggesting that FSH has a key role in human spermatogenesis (reviewed in Ref. 4). In addition, FSH increases Sertoli, spermatogonia, and meiotic spermatocyte numbers and has synergistic effects with androgen on postmeiotic development in hypogonadal hpg mouse testes (3,5,18), which fail to develop due to a functional deletion in the Gnrh1 gene (29,49).…”

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confidence: 98%

Transgenic mutant D567G but not wild-type human FSH receptor overexpression provides FSH-independent and promiscuous glycoprotein hormone Sertoli cell signaling

Allan

Lim²,

Robson³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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We have characterized the in vivo actions of human wild-type FSH receptor (FSHR) overexpressed in Sertoli cells of transgenic (Tg) mice (TgFSHRwt) compared with transgenic overexpression of the human activated mutant FSHR*D567G (TgFSHR*D567G). Testicular TgFSHRwt expression significantly elevated specific FSH binding (>2-fold, P < 0.01) relative to nontransgenic testes, similar to increased FSH binding in TgFSHR*D567G testes. Isolated TgFSHRwt Sertoli cells exhibited higher FSH-stimulated cAMP levels compared with non-Tg or TgFSHR*D567G cells but did not display the elevated FSH-independent basal cAMP levels found in TgFSHR*D567G Sertoli cells. Furthermore, Sertoli cell overexpression of TgFSHR*D567G but not TgFSHRwt allowed promiscuous cAMP responses to human chorionic gonadotropin (300 IU/ml) and TSH (30 mIU/ml), demonstrating increased constitutive signaling and altered glycoprotein hormone specificity via the intracellular D567G substitution rather than FSHR overexpression. Despite elevating Sertoli cell FSH sensitivity, overexpression of TgFSHRwt had no detectable effect upon normal testis function and did not stimulate Sertoli and germ cell development in testes of gonadotropin-deficient hypogonadal (hpg) mice, in contrast to the increased meiotic and postmeiotic germ cell development in TgFSHR*D567G hpg testes. Increased steroidogenic potential of TgFSHR*D567G hpg testes was demonstrated by elevated Cyp11a1 and Star expression, which was not detected in TgFSHRwt hpg testes. Androgen-regulated and Sertoli cell-specific Rhox5 gene expression was increased in TgFSHR*D567G but not TgFSHRwt hpg testes, providing evidence of elevated LH-independent androgen activity due to mutant FSHR*D567G. Hence, transgenic FSHR overexpression in Sertoli cells revealed that the D567G mutation confers autonomous signaling and steroidogenic activity in vivo as well as promiscuous glycoprotein hormone receptor activation, independently of FSHR overexpression alone.

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In Vivo FSH Actions

Cited by 8 publications

References 244 publications

Maintenance of Spermatogenesis by the Activated Human (Asp567Gly) FSH Receptor During Testicular Regression Due to Hormonal Withdrawal1

Maintenance of Spermatogenesis by the Activated Human (Asp567Gly) FSH Receptor During Testicular Regression Due to Hormonal Withdrawal1

FSH regulates the formation of adherens junctions and ectoplasmic specialisations between rat Sertoli cells in vitro and in vivo

Transgenic mutant D567G but not wild-type human FSH receptor overexpression provides FSH-independent and promiscuous glycoprotein hormone Sertoli cell signaling

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