Summaries of new peer-reviewed publications
A summary of new publications related to andrology and male contraceptive research categorized by contraceptive approach. Don’t see your publication listed here? Do let us know so your colleagues can learn about your work in the next issue.
Cell adhesion targets
A new delivery mechanism for Adjudin (AF-2364) whereby it is conjugated to a mutated FSH. The mutant FSH still binds to Sertoli cell receptors but does not initiate Inhibin B production. Using this mechanism, a dose 1000 times smaller than the orally active dose was effective. Four weeks after treatment, 98% of the seminiferous tubules of treated rats had shed all spermatids and spermatocytes. The contraceptive effect was fully reversed 20 weeks after treatment. Adjudin also cleared Ames , genotoxicity and toxicity testing.
A male contraceptive targeting germ cell adhesion
Mruk DD, Wong CH, Silvestrini B, Cheng CY.
Nature Medicine. 2006 Oct 29; [Epub ahead of print]
PMID: 17072312
Glycolipid metabolism targets
“In contrast to the observations in mice, the oral administration of miglustat does not appear to affect human spermatogenesis. Further elucidation of the mechanism underlying the species specificity of miglustat may improve our understanding of the role of glycosphingolipids in spermatogenesis and result in alternative approaches to male fertility control.”
Miglustat has no apparent effect on spermatogenesis in normal men.
Amory JK, Muller CH, Page ST, Leifke E, Pagel ER, Bhandari A, Subramanyam B, Bone W, Radlmaier A, Bremner WJ.
Hum Reprod. 2006 Oct 25; [Epub ahead of print]
PMID: 17067996
ß-Glucosidase 2 (GBA2) is a glucocerebrosidase located in the ER; mouse GBA2 is 83% homologous to the human enzyme. It is not testis-specific, occuring primarily in mouse “testis and brain, with lesser amounts present in 14 other tissues.” In Sertoli cells, GBA2 “expression… overlapped that of tyrosine-tubulin.” GBA2 KO mice showed undetectable levels of bile acid glucosyltransferase activity, a ~50-85% reduction in bile acid glucosidase activity, and glucosylceramide accumulation in the testes, brain and liver. There were no apparent adverse neurological or longevity effects, no signs of organomegaly, and females showed normal fertility. Male KO mice had 1/3 the fertility rate of WT, with sperm showing “distended round heads that lacked an obvious acrosome, disordered mitochondria in the sheaths and heads, and dense pyknotic nuclei.” Overall sperm count and motility were reduced by 40% each.
Mutation of ß-glucosidase 2 causes glycolipid storage disease and impaired male fertility.
Yildiz Y, Matern H, Thompson B, Allegood JC, Warren RL, Ramirez DMO, Hammer RE, Hamra FK, Matern S, Russell DW.
J. Clin. Invest. 116: 2985-2994.
DOI: 10.1172/JCI29224
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Spermatid formation in GBA2 KO and wild type mice. |
Comment on Yildiz et al. “GBA2 deficiency leaves bile acid and cholesterol metabolism intact, instead causing lipid accumulation in the ER of testicular Sertoli cells, round-headed sperm (globozoospermia), and impaired male fertility… In this context, Gba2 represents a Sertoli cell–expressed gene, the lack of which affects the modeling of the spermatid head. A central question is: How does an ER glucosidase in testicular Sertoli cells affect spermatid head shape?”
Shaping the sperm head: an ER enzyme leaves its mark.
Roy A , Lin YN, Matzuk MM.
J. Clin. Invest. 116: 2860-2863.
DOI: 10.1172/JCI30221
Supporting endocrinological research
Review of the extreme ends of LH action, “from total inactivation to overproduction… thus elucidat[ing] many aspects of the pathophysiology of LH/LHR function… The genetically modified mouse models, including our LuRKO and hCG+ mice, have confirmed many classical concepts of the physiology and pathophysiology of gonadotrophin action. In addition, they have shed light on novel and controversial topics of this field.”
Phenotypic characterisation of mice with exaggerated and missing LH/hCG action.
Ahtiainen P, Rulli S, Pakarainen T, Zhang FP, Poutanen M, Huhtaniemi I.
Mol Cell Endocrinol. 2006 Oct 6; [Epub ahead of print]
PMID: 17029767
Exploration of androgen dependence of genes in an isolated mouse epididymal principal cell-line using 5α-reductase inhibitors to block DHT. After androgen withdrawal, “of the 167 genes detected in the PC-1 cells, 50 genes changed by at least 1.5-fold (increase or decrease) and 20 genes increased from undetected levels.” DHT administration was mostly able to rescue gene expression after 2 days, but not 4. This cutoff “presumably would have profound consequences at the promoter of many androgen-regulated genes,” with implications for “temporary androgen suppression such as hormonal contraception…”
Time dependent rescue of gene expression by androgens in the mouse proximal caput epididymis (PC-1) cell line after androgen withdrawal.
Seenundun S, Robaire B.
Endocrinology. 2006 Oct 5; [Epub ahead of print]
PMID: 17023530
Gene array analysis after 5α-reductase inhibition using FK143 (“a non-steroidal, non-competitive inhibitor of both the isozymes of 5α-reductase”) led to the selection of epididymal “genes potentially involved in epididymal regulatory mechanisms for further characterization.” Discusses the location of mRNAs for IGFBP-5, IGFBP-6, FGF-10, FGFR-2, TGF-β, VEGF and VEGFR-2.
Region-specific expression of androgen and growth factor pathway genes in the rat epididymis and the effects of dual 5α-reductase inhibition.
Henderson NA, Cooke GM, Robaire B.
J Endocrinol. 2006 Sep;190(3):779-91.
PMID: 17003279
Follistatin, which binds and neutralizes activins, has some functional similarity to inhibins. Given that mice over expressing the activin β A subunit gene showed disrupted spermatogenesis, a role for follistatin in spermatogenesis had been hypothesized. Follistatin KO mice cannot be used to address this hypothesis because they die immediately after birth. This study found that testes of follistatin KO mice transplanted to the external ears of wild-type mice were able to carry out spermatogenesis, indicating that testicular production of follistatin is not required for spermatogenesis. If follistatin plays a role in spermatogenesis, this model must have utilized the heavier circulating form, follistatin 315.
Spermatogenesis does not require the local production of follistatin.
Lin SY, Morrison JR, Matzuk MM, de Kretser DM.
Reproduction. 2006 Oct;132(4):601-5.
PMID: 17008471
Test of hip and spine bone mineral density using dual energy roentgen absorptiometry in women receiving DMPA injections. The decline in DMPA users was 7.7% +/- 0.11% (mean +/- SE) in the hip and 6.4% +/- 0.36% in the spine, whereas the control group declined ≤1.6% +/- 0.30%. “Hip and spine BMD loss slowed to <0.6% after 48 months of depot MPA use. After discontinuation, BMD increased from 0.3% to 2.0% per year depending on length of depot MPA use and bone site.”
Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate.
Clark MK, Sowers M, Levy B, Nichols S.
Fertil Steril. 2006 Nov;86(5):1466-74. Epub 2006 Sep 25.
PMID: 16996507
Supporting motility research
An investigation of the role of proline-directed phosphorylation in mouse and human sperm using phoso-specific monoclonal antibody MPM-2. When sperm were incubated in capacitating conditions, antibody binding of acrosomal proteins occurred within 15 minutes – as opposed to 60-90 minutes required for tyrosine phosphorylation. cAMP agonists had no affect. BSA was required in the capacitation medium, suggesting a relationship between proline-directed phosphorylation and sperm membrane cholesterol efflux.
Evidence for the involvement of proline-directed serine/threonine phosphorylation in sperm capacitation.
Jha KN, Salicioni AM, Arcelay E, Chertihin O, Kumari S, Herr JC, Visconti PE.
Mol Hum Reprod. 2006 Oct 18; [Epub ahead of print]
PMID: 17050774
Measurement of sperm mitochondrial membrane potential (ΔΨ m) using flow-cytometric sorting.
The functionality of mitochondria differentiates human spermatozoa with high and low fertilizing capability.
Gallon F, Marchetti C, Jouy N, Marchetti P.
Fertil Steril. 2006 Nov;86(5):1526-30. Epub 2006 Sep 25.
PMID: 16996512
An investigation of mu-opioid receptors (MOR) in human sperm, “in order to evaluate the hypothesis of an involvement of the opioid system in modulating sperm fertilization competence.” Findings indicated that the MOR “receptor is predominantly expressed on the sperm head (acrosomal region and neck),” and they advance the hypothesis that MOR plays a role in the prevention of premature capacition: “b-END binding to MOR would inactivate L-type Ca2+ channels.”
Expression and immunolocalization of the mu-opioid receptor in human sperm cells.
Albrizio M, Guaricci AC, Calamita G, Zarrilli A, Minoia P.
Fertil Steril. 2006 Sep 26; [Epub ahead of print]
PMID: 17007854
“Our Western blot and indirect immunofluorescent results demonstrate for the first time the presence and distinct regional distributions of the TREK-1, TRAAK, and TASK-2 K 2P channel isoforms in nonhuman primate sperm… The unique expression of K 2P channels in nonhuman primate sperm and effects of K 2P channel agonists and antagonists on sperm kinematics and acrosome status provide greater insight into the diverse activity of potassium ion channels in sperm biology.”
Expression of two-pore domain potassium channels in nonhuman primate sperm.
Chow GE, Muller CH, Curnow EC, Hayes ES.
Fertil Steril. 2006 Oct 23; [Epub ahead of print]
PMID: 17067589
Semen parameter standardization
Analysis of nearly 1,200 semen samples from a wide demographic and geographic range within China. Statistically significant differences in parameters were found among age cohorts, period of abstinence groups, province of residence, season of sample collection and time from ejaculation to analysis. “The main findings that Chinese men had lower values of semen parameters according to WHO standard… could be useful in the practice of reproductive medicine and policy development regarding male reproductive health.”
Semen quality in a residential, geographic and age representative sample of healthy Chinese men.
Gao J, Gao ES, Yang Q, Walker M, Wu JQ, Zhou WJ, Wen SW.
Hum Reprod. 2006 Oct 10; [Epub ahead of print]
PMID: 17023488
Continuous case study of one man’s semen parameters from age 40 to 50. “Compared with TUNEL data, sperm chromatin structure assay parameters (DNA fragmentation index and high DNA stainability) showed less variation over the data collection period… [I]n this healthy fertile volunteer, semen parameters and sperm DNA integrity remained normal, and no trend was observed over the study period.”
Ten-year variation in semen parameters and sperm deoxyribonucleic acid integrity in a healthy fertile man.
Sergerie M, Mieusset R, Daudin M, Thonneau P, Bujan L.
Fertil Steril. 2006 Nov;86(5):1513.
PMID: 17070200
Proteomic/Genomic supporting research
A study aiming to “find the proteins involved in the regulation of sperm motility” by comparing normozoospermic to asthenozoospermic samples. “Half of the proteins identified in this study are enzymes associated with sperm energy metabolism”: isocitrate dehydrogenase subunit α (IDH-α), phosphoglycerate mutase 2, triosephosphate isomerase, glutamate oxaloacetate transaminase-1 and carbonic anhydrase. Rho GDP-dissociation inhibitor 1 and 4 semenogelin precursors were also identified.
Identification of several proteins involved in regulation of sperm motility by proteomic analysis.
Zhao C, Huo R, Wang FQ, Lin M, Zhou ZM, Sha JH.
Fertil Steril. 2006 Oct 27; [Epub ahead of print]
PMID: 17074334
“300 genes were significantly down-regulated in Sertoli cell only syndrome or maturation arrest samples, and 10 novel sterility-related genes were identified. Of the 10 novel genes, 6 genes encode proteins with predictable functional domains… believed to correlate with spermatogenesis and/or spermiogenesis.” Functional descriptions of the 6 genes are in the Discussion section.
Identification of ten novel genes involved in human spermatogenesis by microarray analysis of testicular tissue.
Lin YH, Lin YM, Teng YN, Hsieh TY, Lin YS, Kuo PL.
Fertil Steril. 2006 Oct 27; [Epub ahead of print]
PMID: 17074343
