Contraceptive Research and Development Looking to the Future (1996) / Chapter Skim
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Appendix B: Male Methods
Appendix B: Male Methods
Pages 381-400
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From page 381... ...
The biology of the male reproductive tract puts certain limitations on the development of novel contraceptive strategies yet, because of the unique features of cells in the male reproductive tract, new possibilities are presenting themselves that need to be carefully addressed. Current Options Contraceptive options for men are extremely limited.
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From page 382... ...
The contraceptive strategy employed, therefore, will depend upon where in the male reproductive tract intervention occurs. Gross Structure Sperm are produced in the seminiferous tubule of the testis; are then released into the lumen of the tubule as immature cells, unable to fertilize eggs; and are carried by bulk flow through the rete testis and efferent ductule into the single,
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From page 383... ...
Three additional cell types -- myoid cells, Leydig cells, and "immune cells" -- surround the epithelium. Sertoli cells are tall, columnar somatic cells that extend from the base of the epithelium to the lumen of the duct.
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From page 384... ...
. In addition, as described above, interstitial cells produce factors that affect Sertoli cells and possibly germ cells.
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From page 385... ...
. Regulation of Function in the Male Reproductive Tract In addition to the regulation of function at the level of the seminiferous tubule through short-loop mechanisms mentioned above, there are endocrine feedback loops that support sperm development in the seminiferous tubule.
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From page 386... ...
The receptor exists in the membrane of the Sertoli cell as a homotetramer, and ligand-blot studies indicate that FSH binds only to the tetrameric form of the FSH receptor. Molecular details of the interaction of FSH with its receptor have been studied through the use of synthetic peptides corresponding to regions of the primary sequence of either FSH or its receptor, as well as by site-directed mutagenesis.
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From page 387... ...
Direct Interference with Hormone-Receptor Interaction Current evidence suggests that the extracellular domain of the FSH receptor contains unique sequences that could be selectively targeted by antibodies or mimetopes so as to prevent FSH binding. This target is located at an accessible site since, although the sperm-producing portion of the testis is protected by the blood–testis barrier, the basal surface of Sertoli cells bears the FSH receptors and is available to the circulation.
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From page 388... ...
Indirect Interference with Hormone-Receptor Interaction As indicated above, FSH binding studies indicate that the hormone binds only to tetrameric FSH receptors. This means that any strategies that would prevent proper assembly of receptor subunits would effectively block receptor action.
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From page 389... ...
As an alternative to targeting spermatogonia, it may be possible to use Sertoli cells as a route of delivery to postmeiotic germ cells. This would be fairly complex since a twostage delivery system would be necessary (targeting first to Sertoli cell, and then to germ cell)
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From page 390... ...
In essence, this would be a "Sertoli cell knockout." Since the number of Sertoli cells limits the number of germ cells undergoing differentiation, the efficiency of this approach might not have to be near 100 percent to achieve a large impact on sperm numbers. The important task of identifying germ cell processes that are amenable to this strategy remains; several possible sites of contraceptive attack are described below.
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From page 391... ...
During spermiogenesis, selected vesicles in the transGolgi network begin to accumulate a granular content and fuse into a large acrosomic body that moves from the Golgi to attach to the nucleus. The remaining Golgi is partially lost in residual bodies and phagocytosed by Sertoli cells, although portions of Golgi membranes remain in the cytoplasmic droplet found on the sperm tail.
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From page 392... ...
Presumably these unique events require unique processes to bring them about, which can be targeted for contraceptive intervention. Alteration of Sperm Surface Proteins During Spermatogenesis and Post-Testicular Development During spermatogenesis, sperm acquire a highly polarized morphology, with a quadripartite structure consisting of a head, which contains the haploid genome, a midpiece, a principal piece, and an end piece.
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From page 393... ...
Many of these fertilization-related proteins are inserted into the plasma membrane during spermatogenesis and display a restricted distribution from the start, whereas others are more uniformly distributed in testicular sperm but are directed into domains during epididymal passage. Both fertilin and PH-20 represent sperm proteins important for fertilization that fall into the latter category (Myles and Primakoff 1991)
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From page 394... ...
Much of the sperm surface appears to be remodeled during maturation and modifications have been detected in all types of plasma membrane components, including lipids, proteins, and carbohydrates. Several theories have been advanced with regard to the mechanisms involved in these changes, including (1)
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From page 395... ...
Sperm surface changes are mediated by products of the epididymal epithelium secreted into the lumen of this tubule. Although the specific components of the epididymal fluid that are responsible for maturing sperm have not been fully identified, it is clear that the composition of the fluid is complex and changes dramatically along the length of the tubule, suggesting that different components of the sperm surface may be modified at different locations along the length of the epididymis.
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From page 396... ...
Delivery of such a mimic could occur in the epididymis and thus potentially be present on sperm for a relatively long period of time. Alternatively, the ZP3 mimic could be targeted to any of the accessory organs of the male reproductive tract -- seminal vesicles,
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From page 397... ...
One is that sperm binding to the natural ligand ZP3 normally occurs after sperm capacitation, which is a poorly defined final maturational phase accomplished within the female reproductive tract during which both the intrinsic (e.g., increased membrane fluidity) and the extrinsic (e.g., glycosylation)
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From page 398... ...
The largest obstacle to targeting the male reproductive tract is its biology. Approaches to inhibition of spermatogenesis (for example, work with the long-loop feedback system)
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From page 399... ...
Hamilton DW. Local immunity and sperm processing in the male reproductive tract.
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From page 400... ...
Testicular cells secrete a protein under androgen control that modulates Sertoli cell function. Proceedings of the National Academy of Sciences, USA 82:114–118, 1985.
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