Testicular sperm results in elevated miscarriage rates compared to epididymal sperm in azoospermic patients

Júnior, Edson Borges; Rossi-Ferragut, Lia Mara; Pasqualotto, Fábio Firmbach; Santos, Daniela Regina dos; Rocha, C.C.; Júnior, Assumpto Iaconelli

doi:10.1590/s1516-31802002000400007

Cited by 16 publications

(3 citation statements)

References 22 publications

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“…Our independent approaches, strongly argue that the described embryonic phenotypes are due to increased Asl levels rather than to other problems stemming from overexpression or mutations. These observations are consistent with indirect observations that centrosome reduction is essential for embryonic development in mammals; for example, in vitro fertilization using human, rabbit, or cat early spermatids, having unreduced centrosomes, provide reduced rates of zygotic aster formation and elevated miscarriage rates [11–13]. …”

Section: Resultssupporting

confidence: 87%

“…Elegant work in mammals by Schatten, Simerly, Manandhar, and colleagues showed that centrosome lose many of their components in a stepwise fashion and identified some proteins that are reduced [25, 26]. Additional studies provided indirect evidence for an essential role of centrosome reduction in embryo development [11–13]. The data disclosed here provide the first insight in to the molecular mechanisms regulating centrosome reduction and the first direct evidence that centrosome reduction is essential for postfertilization development.…”

Section: Resultsmentioning

confidence: 69%

“…It is unclear how and why centrosome reduction occurs even though it is ubiquitous throughout the animal kingdom and several indirect studies suggest it is necessary [11–13]. However, skeptics speculate that centrosome reduction is mediated by general sperm differentiation mechanisms and is inconsequential for male fertility, since centrosome reduction mechanism remains unknown.…”

Section: Resultsmentioning

confidence: 99%

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Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila

et al. 2015

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SUMMARY Centrosome reduction is the decrease in centrosomal components during spermatid differentiation (spermiogenesis) [1, 2]. It is one of several dramatic subcellular reorganizations that leads to spermatozoa formation common to a wide range of animals [3]. However, the mechanism underlying centrosome reduction is unknown and its functions are unclear. Here, we show that in Drosophila melanogaster spermiogenesis, the quantity of centrosomal proteins is dramatically reduced [4, 5];for example, Asterless (Asl) is reduced ~500-fold and is barely detected in spermatozoa. Asl reduction is regulated through a subset of its domains by the master regulator of centriole duplication Plk4[6–8] and by the ubiquitin ligase that targets Plk4 for degradation: Slimb [9, 10]. When Asl reduction is attenuated by Asl overexpression, plk4 mutations, Plk4 RNAi, or Slimb overexpression, Asl levels are higher in spermatozoa, resulting in embryo’s with reduced viability. Significantly, overexpressing Plk4 and Asl simultaneously, or combining plk4 and slimb mutations, balances their opposing effects on Asl reduction, restoring seemingly normal fertility. This suggests that increased Asl levels cause the observed reduced fertility, and not other pleotropic effects. Attenuation of Asl reduction also causes delayed development and a failure to form astral microtubules in the zygote. Together, we provide the first insight into a molecular mechanism that regulates centrosome reduction and the first direct evidence that centrosome reduction is essential for postfertilization development.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

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Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila

et al. 2015

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The Infertile Male-5: Management of Non-Obstructive Azoospermia

et al. 2011

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Traitement de l’azoospermie obstructive par injection Intracytoplasmique d’un spermatozoïde

Lewis

2006

Androl.

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Intracytoplasmic sperm injection (ICSI) allows the treatment of virtually every type of male infertility. Unlike in vitro fertilization (IVF), its success does not depend on sperm concentration, motility or morphology and most of the physical barriers to fertilisation are by-passed. Since ICSl does not require strongly motile sperm, its use has now been expanded to incorporate immature sperm from the testes and epididymides. Successful fertilisation, pregnancies and healthy babies have all been reported. However, concerns about the safety of ICSl remain due to its short clinical history and the lack of testing on animal models.Male fertility potential for assisted reproduction by ICSl cannot be measured by conventional parameters. Sperm DNA integrity is increasingly recognised as a more useful indicator. Studies have shown that sperm with higher levels of DNA damage have lower fertilisation rates after IVF and ICSI. Sperm with DNA damage above a certain threshold are associated with a longer time to conceive in otherwise apparently fertile couples and a higher miscarriage rate. DNA damage has been shown to be associated with impaired embryo cleavage. Our group has shown that sperm DNA from testicular sperm is less fragmented than that from epididymal sperm and suggest its preferred use in ICSI.In addition to nuclear (n) DNA we also assessed the quality of mitochondrial (mt) DNA from testicular sperm from men with obstructive azoospermia undergoing ICSI. We observed that couples achieving a pregnancy had both less mtDNA deletions and less nDNA fragmentation. We found inverse relationships between pregnancy and sperm mtDNA deletion numbers, size and nDNA fragmentation. No relationships were observed with fertilisation rates. With this knowledge, we designed an algorithm for the prediction of pregnancy based on the quality of sperm nDNA and mtDNA.Each year 40,000 men have a vasectomy in the UK but every year 2500 request a reversal to begin a second family. For such men, vasectomy reversal has recently been replaced in part by testicular biopsy via fine-needle testicular sperm aspiration (TESA) or percutaneous epididymal sperm aspiration (PESA) performed at an outpatient clinic and subsequently used in ICSI. Since these were previously fertile men it has been assumed that they had 'fertile' sperm. However the assisted conception success rates of these mens partners has not been assessed until recently. We have shown a significant reduction in the clinical pregnancy rates in the partners of men who had had a vasectomy >10yrs previously. There is also evidence to suggest that spermatogenesis is significantly impaired in vasectomised men. Marked decreases in spermatocytes, spermatids and spermatozoa have been observed. We have found this to be associated with concomitant increases in apoptotic markers, such as Fas, FasL and Bax. The quality of the remaining sperm is also compromised. Sperm DNA from vasectomized men shows substantial damage which increases with time after surgery. This new use of ICSI will be d...

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Testicular sperm results in elevated miscarriage rates compared to epididymal sperm in azoospermic patients

Cited by 16 publications

References 22 publications

Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila

Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila

The Infertile Male-5: Management of Non-Obstructive Azoospermia

Traitement de l’azoospermie obstructive par injection Intracytoplasmique d’un spermatozoïde

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