Alterations in sperm characteristics of follicle-stimulating hormone (FSH)-immunized men are similar to those of FSH-deprived infertile male bonnet monkeys.
TL;DR: It appears that in monkeys and men, lack of FSH signaling results in production of sperm that exhibit defective chromatin packaging and reduction in acrosomal glycoprotein content, similar to that exhibited by sperm of some class of infertile men.
Abstract: The quality of sperm ejaculated by bonnet monkeys and normal, healthy proven fertile volunteer men, both actively immunized with ovine follicle-stimulating hormone (oFSH), was examined at different times of study for chromatin packaging and acrosomal glycoprotein concentration by flow cytometry. Susceptibility of sperm nuclear DNA to dithiothreitol (DTT)-induced decondensation, as measured by ethidium bromide binding, was markedly high compared with values at day 0 in men and monkeys during periods when FSH antibody titer was high. Sperm chromatin structure assay yields alphat values, which is another index of chromatin packaging. Higher alphat values, signifying poor packaging, occurred in both species following immunization with heterologous pituitary FSH. The binding of fluorosceinated pisum sativum agglutinin (PSA-FITC) to acrosome of sperm of monkeys and men was significantly low, compared with values at day 0 (control) during periods when cross-reactive FSH antibody titer was high and endogenous FSH was not detectable. Blockade of FSH function in monkeys by active immunization with a recombinant oFSH receptor protein corresponding to a naturally occurring messenger RNA (mRNA) also resulted in production of sperm with similar defects in chromatin packaging and reduced acrosomal glycoprotein concentration. Thus, it appears that in monkeys and men, lack of FSH signaling results in production of sperm that exhibit defective chromatin packaging and reduction in acrosomal glycoprotein content. These characteristics are similar to that exhibited by sperm of some class of infertile men. Interestingly, these alterations in sperm quality occur well ahead of decreased sperm counts in the ejaculate.
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TL;DR: In this paper, the phenotypic changes observed in male FSH receptor knockout (FORKO) mice are summarized and compared with normal healthy mice, showing that FORKO males experience delayed puberty with postponement in the formation of round spermatids.
80 citations
TL;DR: Evidence from both animal models and man supports a need for both follicle-stimulating hormone and testosterone in achieving full spermatogenic potential, but a species difference in their relative roles exists.
75 citations
TL;DR: As determined from human and mouse models, F SH is essential for normal puberty and fertility in females, particularly for ovarian follicular development beyond the antral stage, and in males, FSH is necessary for normal spermatogenesis, but there are differences in human andmouse models.
Abstract: The pituitary gonadotropin follicle-stimulating hormone (FSH) interacts with its membrane-bound receptor to produce biologic effects. Traditional functions of FSH include follicular development and estradiol production in females, and the regulation of Sertoli cell action and spermatogenesis in males. Knockout mice for both the ligand (Fshb) and the receptor (Fshr) serve as models for FSH deficiency, while Fshb and Fshr transgenic mice manifest FSH excess. In addition, inactivating mutations of both human orthologs (FSHB and FSHR) have been characterized in a small number of patients, with phenotypic effects of the ligand disruption being more profound than those of its receptor. Activating human FSHR mutants have also been described in both sexes, leading to a phenotype of normal testis function (male) or spontaneous ovarian hyperstimulation syndrome (females). As determined from human and mouse models, FSH is essential for normal puberty and fertility in females, particularly for ovarian follicular development beyond the antral stage. In males, FSH is necessary for normal spermatogenesis, but there are differences in human and mouse models. The FSHB mutations in humans result in azoospermia; while FSHR mutations in humans and knockouts of both the ligand and the receptor in mice affect testicular function but do not result in absolute infertility. Available evidence also indicates that FSH may also be necessary for normal androgen synthesis in males and females.
70 citations
Cites background from "Alterations in sperm characteristic..."
...Interestingly, these alterations in sperm quality occurred well in advance of decreased sperm counts in the ejaculate.(97) Most of these studies have involved males....
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TL;DR: Recombinant human FSH may be a valuable pretreatment for oligozoospermic patients undergoing ICSI and may influence testicular paracrine activity.
50 citations
TL;DR: Investigation of the neuroendocrine axis involved in estrogen production demonstrated down-regulation of the axis supporting FSH/estrogen secretion in Cnr1-knockout male mice, demonstrating that estrogens, possibly in combination with FSH secretion, play an important role in regulating chromatin remodeling of spermatids.
Abstract: The type 1-cannabinoid receptor, CNR1, regulates differentiation of spermatids. Indeed, we have recently reported that the genetic inactivation of Cnr1 in mice influenced chromatin remodeling of spermatids, by reducing histone displacement and then sperm chromatin quality indices (chromatin condensation and DNA integrity). Herein, we have studied, at both central and testicular levels, the molecular signals potentially involved in histone displacement. In particular, investigation of the neuroendocrine axis involved in estrogen production demonstrated down-regulation of the axis supporting FSH/estrogen secretion in Cnr1-knockout male mice. Conversely, Cnr1-knockout male mice treated with 17beta-estradiol showed a weak increase of pituitary Fsh-beta subunit mRNA levels and a rescue of sperm chromatin quality indices demonstrating that estrogens, possibly in combination with FSH secretion, play an important role in regulating chromatin remodeling of spermatids. cannabinoid receptor, chromatin remodeling, DNA damage, endocannabinoids, epigenetic, estrogens, FSH, GnRH, gonadotropins, hypothalamus, spermatids, spermatogenesis, spermiogenesis, testis
46 citations
Cites background from "Alterations in sperm characteristic..."
...Interestingly, it is still a matter of debate whether FSH and/or estrogen affect chromatin remodeling in SPT in either a synergistic or an independent way with androgens [42, 49, 58, 71, 72]....
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References
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TL;DR: To generate animal models for human diseases involving the gonadotropin signal transduction pathway, mice deficient in the FSHβ subunit are produced and therefore in FSH using ES cell technology.
Abstract: Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinzing hormone (LH), thyroid stimulating hormone, and chorionic gonadotropin. These heterodimeric hormones share a common alpha subunit and differ in their hormone-specific beta subunit. The biological activity is conferred only by the heterodimers. FSH and LH are synthesized in the same cells of the pituitary, the gonadotrophs. FSH receptors are localized to Sertoli cells of the testes and granulosa cells of the ovary. Minimal data has been accumulated so far involving human mutations in the FSH beta, LH beta, or the gonadotropin receptor genes. There are no known mouse strains with mutations in the FSH beta gene. To generate animal models for human diseases involving the gonadotropin signal transduction pathway, we produced mice deficient in the FSH beta subunit and therefore in FSH using ES cell technology. FSH-deficient females are infertile due to a block in folliculogenesis prior to antral follicle formation. Although FSH was predicted to be necessary for spermatogenesis and Sertoli cell growth in males, FSH-deficient males are fertile despite having small testes. Our findings have important implications for male contraceptive development in humans.
1,269 citations
TL;DR: Although FSH signaling is not essential for initiating spermatogenesis, it appears to be required for adequate viability and motility of the sperms and mice lacking FSH-R are generated by homologous recombination.
Abstract: Pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone stimulate the gonads by regulating germ cell proliferation and differentiation. FSH receptors (FSH-Rs) are localized to testicular Sertoli cells and ovarian granulosa cells and are coupled to activation of the adenylyl cyclase and other signaling pathways. Activation of FSH-Rs is considered essential for folliculogenesis in the female and spermatogenesis in the male. We have generated mice lacking FSH-R by homologous recombination. FSH-R-deficient males are fertile but display small testes and partial spermatogenic failure. Thus, although FSH signaling is not essential for initiating spermatogenesis, it appears to be required for adequate viability and motility of the sperms. FSH-R-deficient females display thin uteri and small ovaries and are sterile because of a block in folliculogenesis before antral follicle formation. Although the expression of marker genes is only moderately altered in FSH-R −/− mice, drastic sex-specific changes are observed in the levels of various hormones. The anterior lobe of the pituitary gland in females is enlarged and reveals a larger number of FSH- and thyroid-stimulating hormone (TSH)-positive cells. The phenotype of FSH-R −/− mice is reminiscent of human hypergonadotropic ovarian dysgenesis and infertility.
812 citations
"Alterations in sperm characteristic..." refers background in this paper
...These mutant males also have reduced fertility (Dierich et al, 1998; Sairam et al, unpublished material)....
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TL;DR: Sperm nuclei contain a unique structure termed the sperm nuclear annulus to which the entire complement of DNA appears to be anchored when the nuclear matrix is disrupted during decondensation, and the structural organization of sperm DNA is likely to be just as vital to the proper functioning of the spermatozoa.
Abstract: Mammalian sperm DNA is the most tightly compacted eukaryotic DNA, being at least sixfold more highly condensed than the DNA in mitotic chromosomes. To achieve this high degree of packaging, sperm DNA interacts with protamines to form linear, side-by-side arrays of chromatin. This differs markedly from the bulkier DNA packaging of somatic cell nuclei and mitotic chromosomes, in which the DNA is coiled around histone octamers to form nucleosomes. The overall organization of mammalian sperm DNA, however, resembles that of somatic cells in that both the linear arrays of sperm chromatin and the 30-nm solenoid filaments of somatic cell chromatin are organized into loop domains attached at their bases to a nuclear matrix. In addition to the sperm nuclear matrix, sperm nuclei contain a unique structure termed the sperm nuclear annulus to which the entire complement of DNA appears to be anchored when the nuclear matrix is disrupted during decondensation. In somatic cells, proper function of DNA is dependent upon the structural organization of the DNA by the nuclear matrix, and the structural organization of sperm DNA is likely to be just as vital to the proper functioning of the spermatozoa.
679 citations
TL;DR: Two methods for detecting acrosome reactions of human sperm at the light microscopic level are described, rapid, give similar results, and detect an increase in acrosomes reactions following exposure to the ionophore A23187.
Abstract: We describe two methods for detecting acrosome reactions of human sperm at the light microscopic level. The techniques include the use of a supravital stain to detect dead sperm in order to differentiate between “physiological” and “degenerative” acrosome reactions. Sperm are incubated with the supravital stain Hoechst 33258 (a fluorescent DNA-binding dye with limited membrane permeability), washed, suspended in 95% ethanol for fixation and permeabilization, and dried onto slides. The sperm are then labeled either by indirect immunofluorescence using rabbit anti-human sperm antiserum or with fluoresceinated Pisum sativum agglutinin (PSA). Both probes intensely label the acrosomal region of acrosome-intact sperm. Electron microscopy revealed the major site of PSA binding to be the acrosomal contents. Acrosome-reacted sperm have diminished acrosomal labeling by both probes; sperm with nuclei labeled by Hoechst stain are considered nonviable, and are excluded from the assay. Both assays are rapid, give similar results, and detect an increase in acrosome reactions following exposure to the ionophore A23187.
593 citations
"Alterations in sperm characteristic..." refers background or methods in this paper
...Ethanol-permeabilized monkey and human sperm have been used to detect acrosomal content by staining with fluorescenated 319Krishnamurthy et al · FSH Deprivation Affects Sperm Quality lectin (Cross et al, 1986)....
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...Use of ethanol-permeabilized sperm in this assay provides, despite disruption in sperm membrane, an index of glycoprotein concentration of acrosome and other cytoplasmic remnants (Cross et al, 1986)....
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...…such as defective chromatin packaging and reduced acrosomal glycoprotein concentration, have been correlated to infertility in men and monkeys (Cross et al, 1986; Acosta et al, 1992; Engh et al, 1992; Kosower et al, 1992; Moudgal et al, 1992; Bartoov et al, 1994; Bianchi et al, 1996; Sakkas…...
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TL;DR: It is demonstrated that FSH is more important for female than for male fertility, and questions the essential role of FSH for the initiation of spermatogenesis, and shows a clear-cut reduction in ligand binding and signal transduction by the mutated receptor.
Abstract: Gonadal function is controlled by the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). While LH mainly regulates gonadal steroidogenesis, FSH is considered essential for folliculogenesis in the female and spermatogenesis in the male. We recently discovered that an inactivating point mutation in the FSH receptor (R) gene causes a recessively inherited form of hypergonadotropic ovarian failure in homozygous females. This 566C-->T mutation, predicting an alanine to valine substitution, is located in exon 7 of the FSHR gene, in the region encoding the extracellular domain of the receptor molecule. Functional testing showed a clear-cut reduction in ligand binding and signal transduction by the mutated receptor. Hence, lack of FSH function is incompatible with ovarian follicular maturation and female fertility. In the male, FSH is generally considered essential for the pubertal initiation of spermatogenesis and maintenance of quantitatively normal sperm production in adults. We report here the first characterization of males homozygous for an inactivating FSHR mutation. They have variable degrees of spermatogenic failure, but, surprisingly, do not show azoospermia or absolute infertility. These results question the essential role of FSH for the initiation of spermatogenesis, and demonstrate that FSH is more important for female than for male fertility.
527 citations