Stimulatory Effects of Recombinant Follicle-Stimulating Hormone on Leydig Cell Function and Spermatogenesis in Immature Hypophysectomized Rats*

Vihko, Kimmo K.; LaPolt, Philip S.; Nishimori, K.; Hsueh, Aaron J. W.

doi:10.1210/endo-129-4-1926

Cited by 72 publications

(31 citation statements)

References 30 publications

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“…A role of Leydig cells in the production of inhibin B, either directly or through induction of spermatogenesis, is in agreement with our findings showing higher inhibin B levels during hCG plus FSH regimen as compared to FSH alone. It is noteworthy that FSH induces LH receptor expression (26). Third, in patient 7 (Table 1), long-term treatment with hCG was associated with a decline in serum inhibin B.…”

Section: Discussionmentioning

confidence: 89%

Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome

Raivio¹,

Wikström²,

Dunkel³

2007

eur j endocrinol

106

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Background: Boys with prepubertal onset of hypogonadotropic hypogonadism (HH) are at a risk of poor testis growth and impaired spermatogenesis. One potential cause for this is deficient proliferation of immature Sertoli cells before and during puberty due to the absence of FSH. Objective: To evaluate the effects of recombinant human FSH (r-hFSH) and human chorionicgonadotropin (hCG) on testicular function and pubertal development in boys with prepubertal onset of HH. Design: Retrospective clinical study. Setting: Two university central hospitals, pediatric referral endocrinology outpatient clinics. Patients: Fourteen boys (aged, 9.9-17.7 years) with prepubertal (testicular volume (TV) !3 ml) onset of HH (idiopathic HH, nZ2; Kallman syndrome, nZ2; idiopathic panhypopituitarism, nZ4; organic panhypopituitarism, nZ6). Intervention: Treatment with r-hFSH alone (2 mo-2.8 years) prior to induction of puberty with the combination of FSH and hCG. Main outcome measures: Progression of puberty, change in serum inhibin B, spermatogenesis. Results: r-hFSH alone increased testicular volume twofold, from 0.9G0.6 ml (meanGS.D.) to 1.8G 1.1 ml (P!0.005), and serum inhibin B threefold, from 27G14 to 80G57 pg/ml (P!0.01). Three boys with an apparent absence of postnatal hypothalamic-pituitary-testicular axis activation displayed attenuated inhibin B responses to long-term (R1 year) r-hFSH (P!0.01). Further significant increase in both TVand inhibin B occurred with induction of puberty with FSH and hCG (P!0.001). Seven boys provided semen samples: one had azoospermia, and others displayed a maximal sperm count range from 2.9 to 92 million/ml (median 8.5 million/ml). Conclusions: (i) r-hFSH induces prepubertal testis growth and increases circulating inhibin B levels, findings suggesting proliferation of immature Sertoli cells. (ii) Puberty was successfully induced with hCG and r-hFSH following r-hFSH priming. (iii) Inhibin B appears useful for monitoring spermatogenetic activity in boys treated with hCG. (iv) Despite the extremely small initial testis volume, six out of seven patients (86%) primed with r-hFSH displayed sperm in the ejaculate suggesting beneficial effect of r-hFSH priming on testicular function later in life.

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Section: Discussionmentioning

confidence: 89%

Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome

Raivio¹,

Wikström²,

Dunkel³

2007

eur j endocrinol

106

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“…Similar observations were described in mammals. FSH treatment upregulated Lhcgr gene expression and steroidogenesis output in the Leydig cells of hypophysectomized immature rats (Vihko et al 1991). In trout, gonadotropins reach their maximum levels just before and during the spawning period at stages VII-VIII (Gomez et al 1999).…”

Section: Discussionmentioning

confidence: 95%

Fsh and Lh have common and distinct effects on gene expression in rainbow trout testis

Sambroni¹,

Rolland²,

Lareyre³

et al. 2012

Journal of Molecular Endocrinology

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The general rules established from mammalian species for the regulation of spermatogenesis by gonadotropins may not be fully relevant in fish. Particularly, Fsh is as potent as Lh to stimulate steroidogenesis and the Fsh receptor is expressed in Leydig cells. In seasonal breeders, Fsh is likely the major gonadotropin involved in spermatogenesis onset and Lh is required to support spermatogenesis progression and gamete release. However, the genes that relay the action of Fsh and Lh have been poorly investigated in fish. The present study was aimed at identifying gonadotropin-dependent genes expressed in the testis during fish puberty. We cultured pubertal trout testicular explants for 96 h, with or without gonadotropin, and analyzed transcriptome variations using microarrays. Fsh and Lh had similar effects on a large group of genes while other genes were preferentially regulated by one or the other gonadotropin. We showed that most of the responsive genes were expressed in somatic cells and exhibited relevant patterns during the seasonal reproductive cycle. Some genes preferentially modulated by Lh could be involved in testicular cell fate (pvrl1 and bty) or sperm maturation (ehmt2 and racgap1) and will deserve further examination. Besides Fsh's effects on the steroidogenic pathway, our study demonstrates that Fsh coordinates relevant stimulatory and inhibitory paracrine factors known to regulate early germ cell proliferation and differentiation. Some of these genes belong to major regulatory pathways including the Igf pathway (igf1b/igf3 and igfbp6), the Tgfb pathway (amh, inha, inhba, and fstl3), the Wnt pathway (wisp1), and pleiotrophin (mdka).

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“…FSH and LH are known to stimulate Sertoli cells to accelerate spermatogenesis and Leydig cells to secret testosterone, respectively, but both LH and FSH have also been reported to stimulate proliferation of Leydig cells [17,18]. Therefore, the elevated levels of FSH and LH have been thought to be the cause of the hyperplasia of Leydig cells in Klinefelter syndrome.…”

Section: Discussionmentioning

confidence: 99%

Leydig Cell Hyperplasia in an ENU-induced Mutant Mouse with Germ Cell Depletion

et al. 2008

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Abstract.Repro22 is an N-ethyl-N-nitrosourea (ENU)-induced mutation in mice showing depletion of both male and female germ cells. In the present study, we investigated the male phenotypes of the mutant mouse at the adult stage. The repro22/repro22 homozygous mice showed reduced body weights as well as markedly reduced testis weights. Histological examination of the testes at 4 and 10 months of age showed no germ cells in the seminiferous tubules of the affected testis while a number of Sertoli cells were observed in the tubules. In addition to the germ cell depletion, the testes of the affected mouse contained expanded intertubular spaces that were filled by Leydig cell-like interstitial cells. These interstitial cells were confirmed to be Leydig cells by immunohistochmical staining using anti-3β-HSD antibody. The estimated number of Leydig cells in the affected testes at 10 months of age increased approximately 2 fold compared with those of normal testes. Furthermore, the plasma testosterone levels of the affected mice at 10 months of age were significantly higher than those of the normal mice. These findings indicated that the repro22/repro22 mouse developed hyperplasia of Leydig cells that was presumably caused by the absence of germ cells in the seminiferous tubules. Key words: ENU mutagenesis, Germ cell, Infertility, Leydig cell, Mouse, Testosterone (J. Reprod. Dev. 54: [225][226][227][228] 2008) nfertility is a major health problem worldwide that influences more than 10% of couples, and approximately 50% of cases of infertility are caused by male factors. In particular, Sertoli cellonly syndrome, a form of non-obstructive azoospermia, is the most serious male infertility, as patients with this disorder show germ cell depletion and are untreatable using assisted reproduction techniques. Although a significant portion of male infertilities is believed to be caused by autosomal recessive mutations [1], the genetic factors that underlay most nonsyndromic male infertilities have not yet been identified, with a few exceptions [2,3]. Mutant mice established by gene targeting technology, chemical mutagenesis and spontaneous mutations [4][5][6][7], showing various features of infertility are expected to be useful animal models for investigating the pathogenesis and genetic factors of human infertilities. However, only a limited number of mouse models for Sertoli cell-only syndrome or germ cell depletion have been reported [8][9][10][11]. Repro22 is a mutation in mice recently produced by N-ethyl-Nnitrosourea (ENU)-induced mutagenesis at The Jackson Laboratory, showing depletion of germ cells in both the male and female. In the present study, we investigated male phenotypes of the mutant mouse at the adult stage and found that the mutant mouse showed Leydig cell hyperplasia and an elevated plasma testosterone level in addition to germ cell depletion. Materials and MethodsThe mice bearing the repro22 mutation were produced and provided by the ReproGenomics Program at The Jackson Laboratory. The mice have a mixed g...

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Stimulatory Effects of Recombinant Follicle-Stimulating Hormone on Leydig Cell Function and Spermatogenesis in Immature Hypophysectomized Rats*

Cited by 72 publications

References 30 publications

Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome

Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome

Fsh and Lh have common and distinct effects on gene expression in rainbow trout testis

Leydig Cell Hyperplasia in an ENU-induced Mutant Mouse with Germ Cell Depletion

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