Summaries of new peer-reviewed publications
Reviews
“This review addresses the contribution that the "omic" revolution can make to the identification of novel contraceptive targets, as well as the progress that has been made for different target molecules under development… Transcriptomes of individual cells, tissues, and organisms have been quickly deposited into databases and include not only messenger, transfer, and ribosomal RNAs, but also microRNAs, siRNAs, and PIWI-interacting RNAs. In parallel with these advances, new technologies permitting the large-scale characterization of complex protein mixtures (proteomics), and the integration of these proteins into known pathways (systems biology) have had a major impact on the potential for contraceptive development, especially in males.”
As the world grows: contraception in the 21st century.
Aitken RJ, Baker MA, Doncel GF, Matzuk MM, Mauck CK, Harper MJ.
J Clin Invest. 2008 Apr 1;118(4):1330-1343.
PMID: 18382745
“Current barriers to expanded [male hormonal contraceptive] use include limited delivery methods and perceived regulatory obstacles, stymieing introduction to the marketplace. However, advances in oral and injectable androgen delivery are cause for optimism that these hurdles may be overcome. Non-hormonal methods, such as compounds that target sperm motility, are attractive in their theoretical promise of specificity for the reproductive tract. Gene and protein array technologies continue to identify potential targets for this approach.”
Advances in Male Contraception.
Page ST, Amory JK, Bremner WJ.
Endocr Rev. 2008 Apr 24; [Epub ahead of print]
PMID: 18436704
Proteomic/genomic supporting research
“Here, we report that 20,000 clones from a healthy male epididymis cDNA library have been sequenced. The sequencing data provided 8234 known sequences and 650 unknown cDNA fragments… The signals for three of six from [the] unknown group showed as epididymis abundant in a region-specific manner but not in the testis and other tissues tested. All the sequencing data will be available on the website www.sdscli.com.”
Transcriptome Analysis of a cDNA Library from Adult Human Epididymis.
Li JY, Wang HY, Liu J, Liu Q, Zhang JS, Wan FC, Liu FJ, Jin SH, Zhang YL.
DNA Res. 2008 Apr 4; [Epub ahead of print]
PMID: 18390568
“Our data strongly suggest that MILI (miwi-like) and MIWI2 (mouse piwi 2) play essential roles in establishing de novo DNA methylation of retrotransposons in fetal male germ cells.”
DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes.
Kuramochi-Miyagawa S, Watanabe T, Gotoh K, Totoki Y, Toyoda A, Ikawa M, Asada N, Kojima K, Yamaguchi Y, Ijiri TW, Hata K, Li E, Matsuda Y, Kimura T, Okabe M, Sakaki Y, Sasaki H, Nakano T.
Genes Dev. 2008 Apr 1;22(7):908-17.
PMID: 18381894
“Here we demonstrate that inactivation of Nct1/2, two non-coding RNAs encoding piRNAs, leads to de-repression of LINE-1 (L1), but does not affect mouse viability, spermatogenesis, testicular gene expression, or fertility. These findings indicate that piRNAs from a cluster on chromosome 2 are necessary to maintain transposon silencing.”
Mice Deficient for a Small Cluster of Piwi-Interacting RNAs Implicate Piwi-Interacting RNAs in Transposon Control.
Xu M, You Y, Hunsicker P, Hori T, Small C, Griswold MD, Hecht NB.
Biol Reprod. 2008 Apr 9; [Epub ahead of print]
PMID: 18401007
Endocrinological approaches
Under a male hormonal contraceptive regimen of etonogestrel implants and TU injections, “spermatogenesis was suppressed to 1 million/ml or less at week 16 in 89% of men, with approximately 94% in two high release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved </= 1 million/ml… Treatment was well tolerated. As compared to the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating or libido change. Both for spermatogenesis suppression and safety, differences were small between the active treatment groups… Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.”
Male hormonal contraception: a double-blind placebo-controlled study.
Mommers E, Kersemaekers WM, Elliesen J, Kepers M, Apter D, Behre HM, Beynon J, Bouloux PM, Costantino A, Gerbershagen HP, Grønlund L, Heger-Mahn D, Huhtaniemi I, Koldewijn EL, Lange C, Lindenberg S, Meriggiola MC, Meuleman E, Mulders PF, Nieschlag E, Perheentupa A, Solomon A, Väisälä L, Wu FC, Zitzmann M.
J Clin Endocrinol Metab. 2008 Apr 15; [Epub ahead of print]
PMID: 18413423
Endocrinological supporting research
A study of the correlation of CAG polymorphisms in the androgen receptor genes of responders versus non-responders in a study of Chinese men receiving im TU injections as a male hormonal contraceptive. “CAG repeats in the androgen receptor gene presented polymorphism in the subjects, with no significant difference between the responders and non-responders,” although with 29 non-responders and 34 responders, the study may have been underpowered to detect the difference.
Effect of (CAG) n polymorphism of androgen receptor gene on hormonal male contraception. [Chinese]
Li JW, Yuan D, Li H, Liang XW, Lu WH, Gu YQ.
Zhonghua Nan Ke Xue. 2008 Feb;14(2):126-30.
PMID: 18390176
“Profound suppression of circulating serum dihydrotestosterone induced by 5α-reductase inhibitors during 1 year does not adversely impact bone, serum lipoproteins or hemoglobin, and has a minimal, reversible effect on serum prostate specific antigen and sexual function in normal men. Circulating dihydrotestosterone does not appear to have a clinically significant role in modulating bone mass, hematopoiesis or lipid metabolism in normal men.”
The Effect of 5 α-Reductase Inhibition With Dutasteride and Finasteride on Bone Mineral Density, Serum Lipoproteins, Hemoglobin, Prostate Specific Antigen and Sexual Function in Healthy Young Men.
Amory JK, Anawalt BD, Matsumoto AM, Page ST, Bremner WJ, Wang C, Swerdloff RS, Clark RV.
J Urol. 2008 Apr 17; [Epub ahead of print]
PMID: 18423697
“This review article provides an overview of the literature concerning the hormonal pathways regulating spermatogenesis,” Including the roles of Sertoli cells, growth factors and apoptotic pathways.
Hormonal regulation of spermatogenesis and spermiogenesis.
Sofikitis N, Giotitsas N, Tsounapi P, Baltogiannis D, Giannakis D, Pardalidis N.
J Steroid Biochem Mol Biol. 2008 Mar 6; [Epub ahead of print]
PMID: 18400489
“Measurement of Sertoli cell-specific transcript levels showed that about a third were independent of hormonal action on the Sertoli cell while others were predominantly androgen-dependent or showed redundant control by FSH and androgen… [The] Sertoli cell retains a significant capacity for activity which is independent of direct hormonal regulation.”
Spermatogenesis and Sertoli cell activity in mice lacking Sertoli cell receptors for follicle stimulating hormone and androgen.
Abel MH, Baker PJ, Charlton HM, Monteiro A, Verhoeven G, de Gendt K, Guillou F, O'Shaughnessy PJ.
Endocrinology. 2008 Apr 10; [Epub ahead of print]
PMID: 18403489
“[In] the seminiferous tubules, FSH suppression induces spermatogonial apoptosis predominantly via the intrinsic pathway, while spermatocyte apoptosis occurs via both the intrinsic and extrinsic pathways.”
Pathways involved in testicular germ cell apoptosis in immature rats after FSH suppression.
Ruwanpura SM, McLachlan RI, Stanton PG, Loveland KL, Meachem SJ.
J Endocrinol. 2008 Apr;197(1):35-43.
PMID: 18372230
“In this study, we provide compelling evidence for the expression, putative hormonal regulation and direct effects of adiponectin in the rat testis… [specifically in] interstitial Leydig cells. Testicular levels of adiponectin mRNA were marginally regulated by pituitary gonadotropins, but overtly modulated by metabolic signals, such as glucocorticoids, thyroxine and PPAR-γ, whose effects were partially different from those on circulating levels of adiponectin… [Adiponectin] might operate as endocrine integrator linking metabolism and gonadal function.”
Novel Expression and Direct Effects of Adiponectin in the Rat Testis.
Caminos JE, Nogueiras R, Gaytán F, Pineda R, González CR, Barreiro ML, Castaño JP, Malagón MM, Pinilla L, Toppari J, Dieguez C, Tena-Sempere M.
Endocrinology. 2008 Apr 10; [Epub ahead of print]
PMID: 18403483
Immunological approaches
“This is the first study to report the use of phage display technology to obtain antisperm scFv antibodies of defined antigen specificity. These antibodies will find clinical applications in the development of novel immunocontraceptives, and specific diagnostics for immunoinfertility.”
Isolation of human single chain variable fragment antibodies against specific sperm antigens for immunocontraceptive development.
Samuel AS, Naz RK.
Hum Reprod. 2008 Mar 26; [Epub ahead of print]
PMID: 18372255
Supporting motility research
While their testis appeared morphologically normal and sperm production occurred at a normal rate, “the targeted disruption of Ldhc severely impaired fertility in male Ldhc(-/-) mice… Although initially motile when isolated, there was a more rapid reduction in the level of ATP and in motility in Ldhc(-/-) sperm than in wild type sperm. Moreover, Ldhc(-/-) sperm did not acquire hyperactivated motility, were unable to penetrate the zona pellucida in vitro, and failed to undergo the phosphorylation events characteristic of capacitation.”
Expression of the Gene for Mouse Lactate Dehydrogenase C (Ldhc) Is Required for Male Fertility.
Odet F, Duan C, Willis WD, Goulding EH, Kung A, Eddy EM, Goldberg E.
Biol Reprod. 2008 Mar 26; [Epub ahead of print]
PMID: 18367675
“Indirect immunofluorescence also documented the presence of Kir6.2 (KCNJ11) and SUR2 (ABCC9) in the epididymal epithelium, as well as in spermatozoa, of canine, feline, bovine and human origin… Although their physiological roles need to be fully characterized, it is tempting to propose that such types of K + channels might be involved in protein secretion and fluid-electrolytes transport occurring along the epididymal epithelium, leading to spermatozoa maturation.”
KATP Channel Subunits Are Expressed in the Epididymal Epithelium in Several Mammalian Species.
Lybaert P, Vanbellinghen AM, Quertinmont E, Petein M, Meuris S, Lebrun P.
Biol Reprod. 2008 Apr 23; [Epub ahead of print]
PMID: 18434629
A presentation of findings that the “mammalian protein SPAG16L,… an axoneme central apparatus protein necessary for flagellar motility” is a substrate for the testis-specific kinase, TSSK2.
Phosphorylation of Mouse Sperm Axoneme Central Apparatus Protein SPAG16L by a Testis-Specific Kinase, TSSK2.
Zhang Z, Shen X, Jones BH, Xu B, Herr JC, Strauss III JF.
Biol Reprod. 2008 Mar 26; [Epub ahead of print]
PMID: 18367677
“Here we report that ERK1/2 and p38MAPK are primarily localized to the tail of mature human spermatozoa… ERK1/2 stimulates and p38 inhibits forward and hyperactivated motility, respectively.”
Identification of extracellular signal-regulated kinase 1/2 and p38MAPK as regulators of human sperm motility and acrosome reaction and as predictors of poor spermatozoa quality.
Almog T, Lazar S, Reiss N, Etkovitz N, Milch E, Rahamim N, Dobkin-Bekman M, Rotem R, Kalina M, Ramon J, Raziel A, Breitbart H, Seger R, Naor Z.
J Biol Chem. 2008 Apr 2; [Epub ahead of print]
PMID: 18372245
“After capacitation, asthenozoospermic L45 and L90 cells failed to increase their membrane fluidity in opposition to normozoospermic cells. Interestingly, membrane hydration significantly correlated with the main sperm motion parameters analysed, being a low membrane hydration associated with poor sperm movement.”
Capacitation-associated changes in membrane fluidity in asthenozoospermic human spermatozoa.
Buffone MG, Doncel GF, Calamera JC, Verstraeten SV.
Int J Androl. 2008 Apr 9; [Epub ahead of print]
PMID: 18399983
Vas-based approaches
“We previously showed that the human epididymal expression pattern of two genes is altered after vasectomy. To complete the list of epididymal genes affected by vasectomy, we analysed the epididymal gene expression pattern of three vasectomised donors, using the affymetrix human GeneChip U133 Plus 2. These results were compared with gene expression pattern of three "normal" donors. The data generated allowed the identification of many human epididymal genes for which the expression is modified after vasectomy.”
Effects of Vasectomy on Gene Expression Profiling along the Human Epididymis.
Thimon V, Calvo E, Koukoui O, Legare C, Sullivan R.
Biol Reprod. 2008 Apr 23; [Epub ahead of print]
PMID: 18434627
Gamete binding/fusion targets
“[Our] data indicate that ADAM15 is present in the testis and in spermatozoa from the caput, corpus and cauda epididymal, as well as in non-capacitated and acrosome-reacted gametes. Results also indicate that ADAM15 is processed during epididymal maturation and acrosome reaction and that it may play a role during sperm-egg binding.”
Presence, processing and localization of mouse ADAM15 during sperm maturation and the role of its disintegrin domain during sperm-egg binding.
Pasten-Hidalgo K, Hernandez-Rivas R, Roa-Espitia A, Sanchez-Gutierrez M, Martinez-Perez F, O-Monroy A, Hernandez
Gonzalez E, Mujica A.
Reproduction. 2008 Apr 4; [Epub ahead of print]
PMID: 18390692
Heat-based approaches
“[The] heat-induced expression of the three types of heat shock protein in [in vitro] monkey Sertoli cells might be regulated by ERK and/or PI3K signal pathways, but the profile of their expression is different, suggesting that they might have different regulatory functions in Sertoli cells.”
Effect of 43 degrees treatment on expression of heat shock proteins 105, 70 and 60 in cultured monkey Sertoli cells.
Chen M, Yuan JX, Shi YQ, Zhang XS, Hu ZY, Gao F, Liu YX.
Asian J Androl. 2008 May;10(3):474-85.
PMID: 18385910
Andrology training standards
“Directors of the generalist residencies in the United States (emergency medicine, family medicine, internal medicine, and pediatrics), directors of urology residencies, medical student educators in urology, and applicants to the 2006 urology residency match were invited to complete an online survey… [asking them] to select the 5 most important topics to be included in a core urology curriculum for all medical students.” The most commonly cited topics were: urinary stone disease, hematuria, urinary tract infections in adults, benign prostatic hyperplasia, urinary incontinence, prostate cancer, screening with prostate-specific antigen, and testicular torsion. Only some elements of a basic male reproductive health curricula were identified by these stakeholders.
What every graduating medical student should know about urology: the stakeholder viewpoint.
Kerfoot BP, Turek PJ.
Urology. 2008 Apr;71(4):549-53.
PMID: 18387383
