The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis.

BACKGROUND: Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. METHODS: Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. RESULTS: We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions. CONCLUSIONS: In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

The Organization of Frontostriatal Brain Wiring in Healthy Subjects Using a Novel Diffusion Imaging Fiber Cluster Analysis.

To assess normal organization of frontostriatal brain wiring, we analyzed diffusion magnetic resonance imaging (dMRI) scans in 100 young adult healthy subjects (HSs). We identified fiber clusters intersecting the frontal cortex and caudate, a core component of associative striatum, and quantified their degree of deviation from a strictly topographic pattern. Using whole brain dMRI tractography and an automated tract parcellation clustering method, we extracted 17 white matter fiber clusters per hemisphere connecting the frontal cortex and caudate. In a novel approach to quantify the geometric relationship among clusters, we measured intercluster endpoint distances between corresponding cluster pairs in the frontal cortex and caudate. We show first, the overall frontal cortex wiring pattern of the caudate deviates from a strictly topographic organization due to significantly greater convergence in regionally specific clusters; second, these significantly convergent clusters originate in subregions of ventrolateral, dorsolateral, and orbitofrontal prefrontal cortex (PFC); and, third, a similar organization in both hemispheres. Using a novel tractography method, we find PFC-caudate brain wiring in HSs deviates from a strictly topographic organization due to a regionally specific pattern of cluster convergence. We conjecture cortical subregions projecting to the caudate with greater convergence subserve functions that benefit from greater circuit integration.

Costs of potentially inappropriate medication use in residential aged care facilities.

BACKGROUND: The potential harms of some medications may outweigh their potential benefits (inappropriate medication use). Despite recommendations to avoid the use of potentially inappropriate medications (PIMs) in older adults, the prevalence of PIM use is high in different settings including residential aged care. However, it remains unclear what the costs of these medications are in this setting. The main objective of this study was to determine the costs of PIMs in older adults living in residential care. A secondary objective was to examine if there was a difference in costs of PIMs in a home-like model of residential care compared to an Australian standard model of care. METHODS: Participants included 541 participants from the Investigation Services Provided in the Residential Environment for Dementia (INSPIRED) Study. The INSPIRED study is a cross-sectional study of 17 residential aged care facilities in Australia. 12 month medication costs were determined for the participants and PIMs were identified using the 2015 updated Beers Criteria for older adults. RESULTS: Of all of the medications dispensed in 1 year, 15.9% were PIMs and 81.4% of the participants had been exposed to a PIM. Log-linear models showed exposure to a PIM was associated with higher total medication costs (Adjusted ß = 0.307, 95% CI 0.235 to 0.379, p < 0.001). The mean proportion (±SD) of medication costs that were spent on PIMs in 1 year was 17.5% (±17.8) (AUD$410.89 ± 479.45 per participant exposed to a PIM). The largest PIM costs arose from proton-pump inhibitors (34.4%), antipsychotics (21.0%) and benzodiazepines (18.7%). The odds of incurring costs from PIMs were 52% lower for those residing in a home-like model of care compared to a standard model of care. CONCLUSIONS: The use of PIMs for older adults in residential care facilities is high and these medications represent a substantial cost which has the potential to be lowered. Further research should investigate whether medication reviews in this population could lead to potential cost savings and improvement in clinical outcomes. Adopting a home-like model of residential care may be associated with reduced prevalence and costs of PIMs.

A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis.

BACKGROUND: Alemtuzumab (CD52-specific humanized monoclonal antibody) was found to be an effective therapy for treatment-naive patients with relapsing-remitting multiple sclerosis. OBJECTIVE: Evaluate alemtuzumab's effects in patients with treatment-refractory relapsing-remitting multiple sclerosis. METHODS: Forty-five relapsing-remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg i.v. alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g i.v. methylprednisolone on days 1-3 at both times. RESULTS: After 2-year follow-up, the annualized relapse rate was reduced by 94% compared to pre-treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P<0.0001). Moreover, 86% of patients showed stable or improved scores on the Expanded Disability Status Scale, and only 1 experienced an increase in disability lasting ≥6 months. The majority (70-88%) showed stable or improved leg, arm and cognitive function as measured by the Multiple Sclerosis Functional Composite. Serious adverse events observed in single patients were transient neutropenia and pneumonia, pulmonary emboli and deep vein thrombosis. Five patients developed clinical thyroid disorders but no opportunistic infections or cases of immune thrombocytopenic purpura were observed. CONCLUSIONS: Alemtuzumab effectively reduced relapse rates and improved clinical scores in patients with active relapsing-remitting multiple sclerosis not controlled by interferon therapy.

Condom use problems during anal sex among men who have sex with men (MSM): findings from the Safe in the City study.

Our research aims were to: (1) assess the prevalence of two condom use problems: breakage or slippage and partial use (delayed application or early removal) among men who have sex with men (MSM) seeking services in urban US STD clinics; and (2) examine the association between these condom use problems and participant, partner and partnership characteristics. Analysis was restricted to HIV-negative MSM who reported having anal sex at least once in the preceding 3 months and who completed both the baseline and 3 month follow-up assessments. Two models were fitted using the generalized estimating equations (GEE) approach. A total of 263 MSM (median age=32 years) reported 990 partnerships. Partnerships with no condom use 422 (42.6%) were excluded. Thus, 207 MSM and 568 partnerships were included. Among condom users, 100% use was reported within 454 partnerships (79.9%) and <100% within 114 (20.1%), and 21(3.7%) reported both condom use problems, 25 (4.4%) reported only breakage, 67 (11.8%) reported only partial use, and 455 (80.1%) reported no errors. The breakage or slippage and partial use rates per condom used were 3.4% and 11.2%, respectively. A significantly higher rate of breakage or slippage occurred among non-main partnerships. Characteristics associated with increased odds for condom breakage or slippage were: lower education level (OR=2.78; CI: 1.1-7.5), non-main partner status (OR=4.1; CI: 1.5-11.7), and drunk or high during sex (OR=2.0; CI: 1.1-3.8), and for partial use: lower education level (OR=2.6; CI: 1.0-6.6), perceived partner sexually transmitted infections (STI) risk (OR=2.4; CI: 1.3-4.2), and inconsistent condom use (OR=3.7; CI: 2.0-6.6). A high percentage of MSM partnerships reported no condom use and among condom users, a sizable proportion did not use them consistently or correctly. MSM may benefit from interventions designed to increase proficiency for condom use with a particular focus on the behaviors of inconsistent and partial condom use.

Comparable rates of secondary surgery between anterior cruciate ligament repair with suture tape augmentation and anterior cruciate ligament reconstruction.

PURPOSE: The aim of this study was to determine the frequency of secondary surgery following anterior cruciate ligament (ACL) repair with suture tape augmentation in comparison to conventional hamstring ACL reconstruction. We hypothesised that there would be no differences between the groups. METHODS: This was a retrospective comparison study of patients undergoing ACL surgery between September 2011 and April 2018. Two hundred and 73 patients underwent ACL reconstruction using hamstring autograft. During the same timeframe, 137 patients with an acute proximal ACL rupture underwent ACL repair with suture tape augmentation. One patient was lost to follow-up in the ACL reconstruction group leaving 272 patients (99.6%) for the final analysis. In the ACL repair group, three patients were lost to follow-up leaving 134 patents (97.8%) for the final analysis. Secondary surgery was identified by contacting the patients by email/telephone and reviewing patient notes at the time of this analysis. RESULTS: Re-rupture occurred in 32 patients (11.8%) in the ACL reconstruction group compared to 22 patients (16.4%) in the ACL repair group (p = 0.194). Contralateral ACL rupture occurred in four patients (1.5%) in the ACL reconstruction group compared to three patients (2.2%) in the ACL repair group (p = 0.224). In the ACL reconstruction group, nine patients (3.3%) required secondary meniscal surgery whilst five patients (3.7%) required meniscal surgery in the ACL repair group (p = 0.830). Seven other operations were performed in the ACL reconstruction group (2.6%) compared to three other operations in the ACL repair group (2.2%) (p = 0.374). The overall number of patients undergoing secondary surgery in the ACL reconstruction group was 52 (19.1%) in comparison to 30 (22.4%) in the ACL repair group (p = 0.114). CONCLUSION: ACL repair with suture tape augmentation for acute proximal ruptures demonstrated comparable rates of secondary surgery with hamstring ACL reconstruction.

The reincorporation and redistribution of trace geoforensic particulates on clothing: an introductory study.

Two experimental studies were undertaken to investigate the processes of reincorporation and redistribution of trace evidence on garments when worn by a suspect or a victim (reincorporation) or after the garments have been seized and packaged for subsequent forensic analysis (redistribution). The first experiment utilised UV powder, an established proxy for geoforensic trace particulates and the second experiment utilised daffodil pollen transferred onto garments under conditions that mimicked forensic reality. It was demonstrated that reincorporation of trace particulates occurs from upper to lower parts of the same garment and also from upper garments to lower garments. Reincorporation also occurred to all areas of the lower garments, however the highest concentration of particulates was found to be the lap area of the jeans. Particulates also tended to be preserved around technical details such as stitching or relief design features of the garments. Thus the decay of particulates after a contact has been made does not necessarily involve a loss of those particulates from the entire system. These findings have implications for the interpretation of trace evidence when seeking to establish the source of initial contacts or the chronology of pertinent events. The second study demonstrated that folding and packaging items of clothing leads to a redistribution of any trace particulate evidence that is present thereby eliciting an alteration in the spatial distribution of that evidence. There is therefore a necessity to take the context of trace evidence into account and also to follow protocols that are sensitive to these aspects of trace evidence behaviour as a failure to do so may have consequences for the correct interpretation of such evidence.

Estrogen and spermatogenesis.

Although it has been known for many years that estrogen administration has deleterious effects on male fertility, data from transgenic mice deficient in estrogen receptors or aromatase point to an essential physiological role for estrogen in male fertility. This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action. The review also discusses the many studies that have used models employing the administration of estrogenic substances to show that male fertility is responsive to estrogen, thus providing a mechanism by which inappropriate exposure to estrogenic substances may cause adverse effects on spermatogenesis and male fertility. The reproductive phenotypes of mice deficient in estrogen receptors alpha and/or beta and aromatase are also compared to evaluate the physiological role of estrogen in male fertility. The review focuses on the effects of estrogen administration or deprivation, primarily in rodents, on the hypothalamo-pituitary-testis axis, testicular function (including Leydig cell, Sertoli cell, and germ cell development and function), and in the development and function of the efferent ductules and epididymis. The requirement for estrogen in normal male sexual behavior is also reviewed, along with the somewhat limited data on the fertility of men who lack either the capacity to produce or respond to estrogen. This review highlights the ability of exogenous estrogen exposure to perturb spermatogenesis and male fertility, as well as the emerging physiological role of estrogens in male fertility, suggesting that, in this local context, estrogenic substances should also be considered "male hormones."

A single center's experience using four different front line mobilization strategies in lymphoma patients planned to undergo autologous hematopoietic cell transplantation.

In an otherwise eligible patient with relapsed lymphoma, inadequate mobilization of hematopoietic stem cells (HSCs) is a limiting factor to proceeding with an autologous hematopoietic cell transplantation (auto-HCT). Multiple strategies have been used to mobilize an adequate number of HSCs with no obvious front-line strategy. We report a single institutional experience mobilizing HSCs using four different approaches in lymphoma patients. We prospectively collected mobilization outcomes on patients planned to undergo auto-HCT at Ohio State University. We report results of first mobilization attempts for all relapsed or refractory lymphoma patients between 2008 and 2014. We identified 255 lymphoma patients who underwent mobilization for planned auto-HCT. The 255 lymphoma patients underwent the following front line mobilization strategies: 95 (37%) G-CSF alone, 38 (15%) chemomobilization (G-CSF+chemotherapy), 97 (38%) preemptive day 4 plerixafor, and 25 (10%) rescue day 5 plerixafor. As expected, there were significant differences between cohorts including age, comorbidity indices, histology, and amount of prior chemotherapy. After controlling for differences between groups, the odds of collecting 2 × 106/kg HSCs on the first day of collection and 5 × 106/kg HSCs in total was the highest in the cohort undergoing chemomobilization. In conclusion, our experience highlights the effectiveness of chemomobilization.

FSH regulates the formation of adherens junctions and ectoplasmic specialisations between rat Sertoli cells in vitro and in vivo.

Spermatogenesis is dependent on the ability of Sertoli cells to form mature junctions that maintain a unique environment within the seminiferous epithelium. Adjacent Sertoli cells form a junctional complex that includes classical adherens junctions and testis-specific ectoplasmic specialisations (ES). The regulation of inter-Sertoli cell junctions by the two main endocrine regulators of spermatogenesis, FSH and testosterone, is unclear. This study aimed to investigate the effects of FSH and testosterone on inter-Sertoli cell adherens junctions (as determined by immunolocalisation of cadherin, catenin and actin) and ES junctions (as determined by immunolocalisation of espin, actin and vinculin) in cultured immature Sertoli cells and GnRH-immunised adult rat testes given FSH or testosterone replacement in vivo. When hormones were absent in vitro, adherens junctions formed as discrete puncta between interdigitating, finger-like projections of Sertoli cells, but ES junctions were not present. The adherens junction puncta included actin filaments that were oriented perpendicularly to the Sertoli cell plasma membrane, but were not associated with the intermediate filament protein vimentin. When FSH was added in vitro, ES junctions formed, and adjacent adherens junction puncta fused into extensive adherens junction belts. After hormone suppression in vivo, ES junctions were absent, while FSH replacement restored ES junctions, as confirmed by electron microscopy and confocal analysis of ES-associated proteins. Testosterone alone did not affect adherens junctions or ES in vitro or in vivo. We conclude that FSH can regulate the formation of ES junctions and stimulate the organisation and orientation of extensive adherens junctions in Sertoli cells.

Effect of oral clarithromycin on gall-bladder motility in normal subjects and those with gall-stones.

BACKGROUND: Motilin receptor stimulation with erythromycin has been shown to have a prokinetic effect on gall-bladder motility in human beings. AIM: To find out whether oral clarithromycin has similar prokinetic activity to erythromycin on fasting and postprandial gall-bladder emptying in normal humans and those with gall-stone disease. METHODS: In a blinded two-way crossover study clarithromycin 500 mg and a placebo were administered to 10 normal subjects and 10 subjects with gall-stone disease. Gall-bladder volumes were assessed in the fasting and postprandial state. RESULTS: Fasting volumes were significantly less following clarithromycin administration in both normal subjects and subjects with gall-stones compared with placebo (12.1 +/- 1.8 mL vs. 17.8 +/- 2.0 mL, P < 0.05 and 16.7 +/- 2 mL vs. 26.8 +/- 7.2 mL, P < 0.02, mean +/- S.E.M). Postprandial volumes were also significantly less following clarithromycin administration. Ejection fraction significantly increased following clarithromycin in both normal subjects (66 +/- 5.8% vs. 37 +/- 5.9%, P = 0.02) and subjects with gall-stones (45 +/- 3.2 vs. 20 +/- 1.6%, P < 0.02). CONCLUSION: Clarithromycin enhances both fasting and postprandial gall-bladder contraction in normal humans and also in those with gall-stone disease.

A method for clustering white matter fiber tracts.

BACKGROUND/PURPOSE: Despite its potential for visualizing white matter fiber tracts in vivo, diffusion tensor tractography has found only limited applications in clinical research in which specific anatomic connections between distant regions need to be evaluated. We introduce a robust method for fiber clustering that guides the separation of anatomically distinct fiber tracts and enables further estimation of anatomic connectivity between distant brain regions. METHODS: Line scanning diffusion tensor images (LSDTI) were acquired on a 1.5T magnet. Regions of interest for several anatomically distinct fiber tracts were manually drawn; then, white matter tractography was performed by using the Runge-Kutta method to interpolate paths (fiber traces) following the major directions of diffusion, in which traces were seeded only within the defined regions of interest. Next, a fully automatic procedure was applied to fiber traces, grouping them according to a pairwise similarity function that takes into account the shapes of the fibers and their spatial locations. RESULTS: We demonstrated the ability of the clustering algorithm to separate several fiber tracts which are otherwise difficult to define (left and right fornix, uncinate fasciculus and inferior occipitofrontal fasciculus, and corpus callosum fibers). CONCLUSION: This method successfully delineates fiber tracts that can be further analyzed for clinical research purposes. Hypotheses regarding specific fiber connections and their abnormalities in various neuropsychiatric disorders can now be tested.

Effect of catecholamines on the hepatic rate-limiting enzymes of cholesterol metabolism in normally fed and cholesterol-fed rabbits.

Adrenergic control of liver cholesterol metabolism was studied in the rabbit. The effects of noradrenaline (alpha 1, alpha 2, beta 2 agonist) and isoprenaline (beta 1, beta 2 agonist) on 3-hydroxy-3-methylglutaryl coenzyme A reductase, acyl-coenzyme A: cholesterol-o-acyltransferase (cholesterol acyltransferase) and cholesterol 7 alpha-hydroxylase, the rate-limiting enzymes of cholesterol biosynthesis and esterification and bile acid synthesis, respectively, were examined in the normally fed and cholesterol-fed male New Zealand White rabbit. Isoprenaline increased the activities of hydroxymethylglutaryl CoA reductase and cholesterol acyltransferase approx. 12-fold and 5-fold, respectively, in normally fed rabbits. Noradrenaline, by contrast, produced an effect only on hydroxymethylglutaryl CoA reductase, the activity of which was increased 3-fold in these animals. Neither catecholamine had an effect on hydroxymethylglutaryl CoA reductase in the cholesterol-fed rabbit. Isoprenaline decreased the activity of cholesterol acyltransferase by approx. 40% and increased the activity of cholesterol 7 alpha-hydroxylase 2-fold in the cholesterol-fed rabbit compared to cholesterol-fed controls. Noradrenaline had no effect on either cholesterol acyltransferase or cholesterol 7 alpha-hydroxylase in either the normally fed or the cholesterol-fed rabbit. We suggest that beta 2-adrenergic stimulation by isoprenaline in the normally fed rabbit may enhance cholesterol synthesis and storage, but that in the cholesterol-fed rabbit, it facilitates the elimination of cholesterol from the body by increasing the rate of bile acid synthesis.

Two-dimensional echocardiographic detection and diagnostic features of tricuspid papillary fibroelastoma.

Cardiac papillary fibroelastomas are rare and benign primary tumors in the cardiac valves or occasionally the mural endocardium. Before 1977, these tumors were diagnosed exclusively at postmortem examination. Over the last few years, a handful of cases have been diagnosed in vivo by echocardiography. In this report, we describe the first tricuspid valve papillary fibroelastoma detected by echocardiography in an adult. Clinical and echocardiographic features are discussed.

The role of local estrogen biosynthesis in males and females.

Natural (human) and experimental (mouse) models of estrogen insufficiency have revealed hitherto unexpected roles for estrogens in both males and females. In postmenopausal women, and in men, estrogen no longer has a major role as a circulating hormone, but rather it functions locally as a paracrine or even 'intracrine' factor in tissue sites where it is formed. As a consequence, the tissue-specific nature of aromatase production assumes physiological and pathophysiological significance. The availability of circulating precursors is also important in sites where there is no local supply of C19 precursors, particularly in elderly women. The potential clinical significance of these findings in terms of the development of new therapeutic modalities is discussed.

Cost-effectiveness of a brief video-based HIV intervention for African American and Latino sexually transmitted disease clinic clients.

BACKGROUND AND OBJECTIVES: Decisions about the dissemination of HIV interventions need to be informed by evidence of their cost-effectiveness in reducing negative health outcomes. Having previously shown the effectiveness of a single-session video-based group intervention (VOICES/VOCES) in reducing incidence of sexually transmitted diseases (STD) among male African American and Latino clients attending an urban STD clinic, this study estimates its cost-effectiveness in terms of disease averted. METHODS: Cost-effectiveness was calculated using data on effectiveness from a randomized clinical trial of the VOICES/VOCES intervention along with updated data on the costs of intervention from four replication sites. STD incidence and self-reported behavioral data were used to make estimates of reduction in HIV incidence among study participants. RESULTS: The average annual cost to provide the intervention to 10 000 STD clinic clients was estimated to be US$447 005, with a cost per client of US$43.30. This expenditure would result in an average of 27.69 HIV infections averted, with an average savings from averted medical costs of US$5 544 408. The number of quality adjusted life years saved averaged 387.61, with a cost per HIV infection averted of US$21 486. CONCLUSIONS: This brief behavioral intervention was found to be feasible and cost-saving when targeted to male STD clinic clients at high risk of contracting and transmitting infections, indicating that this strategy should be considered for inclusion in HIV prevention programming.

Local estrogen biosynthesis in males and females.

It is now apparent that in men and in postmenopausal women, estrogens have important physiological and pathophysiological roles. However, importantly, these actions are at a local level, namely paracrine, autocrine, and even 'intracrine' rather than endocrine in the classical sense. Thus for example local estrogen biosynthesis in the bones of men plays a hitherto unsuspected role in the maintenance of bone mineralization and in epiphyseal fusion; and in the testes, estrogen is essential for male germ cell development. On the other hand, in postmenopausal women, the mesenchymal cells of the breast are the major source of estrogen responsible for breast cancer development. This realization points to the importance of circulating C19 precursors in the maintenance of adequate estrogen biosynthesis in extragonadal sites and suggests the possibility of new therapies to block estrogen synthesis in a tissue-specific fashion.

Spermiation failure is a major contributor to early spermatogenic suppression caused by hormone withdrawal in adult rats.

Spermiation is the process by which mature sperm are released from the Sertoli cell into the lumen of the seminiferous tubule. Previous studies have shown that FSH and LH/testosterone suppression causes a significant increase in the degeneration of mature elongated spermatids. The purpose of this study was to investigate the extent to which spermiation failure contributes to the overall failure of spermatogenesis during hormone suppression. We used in vivo models to selectively suppress either FSH, by passive immunization, and or testosterone, by administration of SILASTIC brand (Dow Corning) testosterone and estradiol implants to suppress LH and testicular testosterone production. Stereological quantitation of the number of step 17-18 spermatids before spermiation and the number of step 19 spermatids retained within the epithelium after spermiation showed that 2% of spermatids failed to spermiate in control animals, and 11% and 14% of spermatids failed to spermiate after 1 week of FSH inhibition or testosterone suppression, respectively. After 1 week of combined FSH and testosterone withdrawal, 50% of the spermatids in the testis failed to be released. A time course of testosterone suppression showed that after 4-5 weeks over 90% of spermatids failed to spermiate. We conclude that spermiation is highly sensitive to hormone suppression, with T and FSH acting synergistically to support spermiation, and that spermiation inhibition is a potential target for contraception.

Testosterone promotes the conversion of round spermatids between stages VII and VIII of the rat spermatogenic cycle.

Several spermatogenic cell types have been reported to be responsive to testosterone (T) in vivo. We have proposed that the principal action of T is to facilitate the maturation of round to elongated spermatids during spermiogenesis. To identify T-dependent cell types during spermiogenesis, round spermatid populations were counted using stereological techniques in adult rats after T withdrawal and replacement. The number of round spermatids per testis in stages I-III, IV-VI, VII, and VIII of the spermatogenic cycle were determined and, based on the known duration of each stage, the hourly production rates of round spermatid populations calculated. Sprague-Dawley rats received 3 cm T and 0.4 cm estradiol implants (TE treatment) for 11 weeks to suppress LH, testicular T levels, and spermatogenesis. To restore sperm production, high-dose T (24 cm) implants were then given, and animals were perfused 0, 2, 4, and 7 days later. Total testicular T levels were suppressed to 2.9% of control levels by TE treatment and significantly increased (P < 0.05) after 2 days of high-dose T, to remain between 7-12% of control. The hourly production rates of round spermatids between stages I and VII were suppressed to 29-35% of control by TE treatment and remained unchanged by high-dose T administration. Stage VIII round spermatid hourly production rates however, were markedly reduced to 5% of control by TE treatment and increased significantly (P < 0.05) to 27% of control after 4 days of high-dose T. The efficiency of conversion of spermatids through spermiogenesis was estimated from the ratios of the hourly production rates of successive spermatid groups. The conversion of spermatids between stages I-VII of the cycle did not differ from control regardless of the treatment. However, the conversion of round spermatids between stages VII and VIII was markedly suppressed to 16% of control by TE treatment and was then normalized after 4 days of high-dose T administration. We conclude that the conversion of round spermatids between stages VII and VIII is a highly T-dependent step during spermiogenesis.

Inhibition of 5 alpha-reductase activity impairs the testosterone-dependent restoration of spermiogenesis in adult rats.

Testosterone (T) is required for spermatogenesis, particularly in the conversion of round spermatids between stages VII and VIII of spermatogenesis. T is generally thought to be the major androgen involved in adult spermatogenesis due to the high local concentration within the testis, whereas its more potent 5alpha-reduced metabolite dihydrotestosterone (DHT) is thought to be the active androgen in peripheral tissues. The current study investigated whether 5alpha-reduction of T to DHT is involved in the restoration of spermiogenesis in vivo in a setting in which testicular T levels were markedly reduced. Adult male rats were given 3-cm T plus 0.4-cm estradiol implants for 9 weeks to suppress serum LH and testicular T levels and thereby inhibit spermatogenesis. Increasing doses of T (3-, 6-, 10-, and 24-cm implants) were then given for 4 days to restore spermatogenesis in the presence or absence of a 5alpha-reductase inhibitor (L685,273). The hourly production rates of round spermatids in stages I-III, IV-VI, VII, and VIII were assessed using stereological techniques, and the conversion of round spermatids between stages VII and VIII was then assessed as an index of androgen action on spermiogenesis. Testicular androgen levels were measured by HPLC and RIA. The 5alpha-reductase inhibitor significantly suppressed (P < 0.05) the hourly production rate of round spermatids at the 3- and 6-cm T doses, but not at the 10- and 24-cm doses. The conversion of round spermatids between stages VII and VIII was suppressed (P < 0.05) by the inhibitor only at the 3- and 6-cm doses. The 5alpha-reductase inhibitor had no effect on testicular T levels, but suppressed (P < 0.05) DHT levels at the 6-, 10-, and 24-cm doses. We conclude that the 5alpha-reduction of T is involved in the restoration of spermiogenesis at the lower administered doses of T and that these data are the first description of a role for 5alpha-reduced androgens in adult spermatogenesis.