72 results on '"Swerdloff, Ronald"'
Search Results
2. Male Contraception Development: Monitoring Effective Spermatogenesis Suppression Utilizing a User-Controlled Sperm Concentration Test Compared with Standard Semen Analysis.
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Lue, Yanhe, Swerdloff, Ronald, Pak, Youngju, Nguyen, Brian T., Yuen, Fiona, Liu, Peter Y., Blithe, Diana L., and Wang, Christina
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SEMEN analysis , *SPERMATOZOA , *CONTRACEPTION , *SPERMATOGENESIS , *MALE contraceptives , *INTRAUTERINE contraceptives , *POSTPARTUM contraception - Abstract
Objective: To determine whether a user-controlled sperm concentration test compared to standard semen analysis can effectively monitor spermatogenesis suppression for male contraception.Design: Single center, prospective sub-study of the ongoing clinical trial: "Study of Daily Application of Nestorone® and Testosterone Combination Gel for Male Contraception."Setting: Research institute at an academic medical center.Participants: Couples participating in the male contraceptive clinical trial.Interventions: None MAIN OUTCOME MEASURE: The ability by participants to monitor sperm suppression to a threshold compatible with contraceptive efficacy utilizing a user-controlled test verified by sperm concentration determined by standard laboratory methods.Results: Thirty-eight men participating in a hormonal male contraceptive clinical trial provided multiple samples during spermatogenesis suppression for this sub-study. Participants, employing a user-controlled test, correctly identified the absence of sperm (a negative test) in 100% of their laboratory-confirmed azoospermic samples (n= 122). Participants also identified 100% of samples (n=73) with sperm >0.2 million/ml as positive. Sperm counts between 0.01 and 0.2 million/ml were identified as negative in 96% of samples. Trial participants noted the overall ease of using the test with respect to sample preparation, test timing, and result interpretation, and that they could accurately use this test at home without difficulty.Conclusion: Participants undergoing spermatogenesis suppression in a hormonal male contraceptive trial performed user-controlled test to determine whether their semen sperm concentration was ≤ or >0.2 million sperm/ml. Compared to standard semen analyses, participants correctly identified 100% of samples with sperm counts >0.2 million/ml as positive (Sensitivity 100%). A positive result when the couple is using a male contraceptive method triggers the need for semen analysis by a laboratory while the couple uses another method of contraception. Participants correctly diagnosed samples ≤0.2 million sperm/ml as negative in 99% of samples (Specificity 99%). A negative result indicates a sperm concentration ≤0.2 million/ml, well below the threshold of ≤1 million/ml offering contraceptive efficacy demonstrated by prior studies. At-home sperm concentration test would minimize the need for users to return to the clinic to monitor suppression of spermatogenesis, decreasing cost and burden of male contraception trials and increasing practicality of the method. [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. Reflections on the T Trials.
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Swerdloff, Ronald and Wang, Christina
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PHYSICAL mobility , *OLDER men , *BONES , *SYMPTOMS , *REFLECTIONS ,GONADAL diseases - Abstract
Background: This manuscript is a review and discussion of the published results of the T Trials. Objective: To re‐examine the efficacy of testosterone replacement of hypogonadal men >65 years of age in the T Trials. Materials and Methods: The T Trials were a complex collection of seven double blind, placebo‐controlled trials of the efficacy of testosterone as replacement therapy for older men with unequivocal hypogonadism. There were three main trials (sexual function; physical function; vitality) and four sub‐trials (cognition; bone; anemia; and cardiovascular). All subjects participated in the main trials while more selective inclusion/exclusion criteria existed for the sub‐trials. Subjects were excluded for perceived higher risk of prostate cancer and recent myocardial or cerebral vascular events. Results: The previously published results are reviewed here as seen in the context of this special issue on late‐onset hypogonadism. In the T Trials, positive benefits were seen in the sexual function, bone, and anemia trials with small but significant benefits in the vitality trial. No benefit was seen in the cognition trial, partial benefit in physical function, and a negative benefit outcome seen in the cardiovascular trial. The later trial was underpowered and the results were described as exploratory. Adverse events were relatively uncommon in the 12‐month treatment phase and additional 12‐month post‐treatment phase. The most frequent adverse effect ascribed to testosterone was erythrocytosis. Conclusions: The T Trials studied the efficacy of testosterone replacement therapy on 788 men with low testosterone and symptoms of hypogonadism. The studies demonstrated benefits in four trials (sexual function, vitality, bone, and anemia); partial benefit in the physical function trial; no effect in the cognition trial; and a negative effect in the exploratory cardiovascular trial. The T Trials were not designed to assess long‐term risks of testosterone in men. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests.
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Wang, Christina and Swerdloff, Ronald S.
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MALE infertility , *SEMEN analysis , *SPERMATOZOA analysis , *PREGNANCY , *FERTILIZATION in vitro , *SPERM motility , *REPRODUCTIVE technology , *DIAGNOSIS - Abstract
Semen analysis is the first step to identify male factor infertility. Standardized methods of semen analysis are available allowing accurate assessment of sperm quality and comparison among laboratories. Population-based reference ranges are available for standard semen and sperm parameters. Sperm numbers and morphology are associated with time to natural pregnancy, whereas sperm motility may be less predictive. Routine semen analysis does not measure the fertilizing potential of spermatozoa and the complex changes that occur in the female reproductive tract before fertilization. Whether assisted reproduction technology (ART) is required depends not only on male factors but female fecundity. Newer tests should predict the success of fertilization in vitro and the outcome of the progeny. [ABSTRACT FROM AUTHOR]
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- 2014
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5. Mouse model for men with klinefelter syndrome: a multifaceted fit for a complex disorder.
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Swerdloff, Ronald S., YanHe Lue, Liu, Peter Y., Erkkilä, Krista, and Christina Wang
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KLINEFELTER'S syndrome , *CHROMOSOMES , *GENES , *PHENOTYPES , *HEREDITY - Abstract
41XXY mouse models share many characteristics of the human 47XXY Klinefelter syndrome (KS). This manuscript discusses the relative role of androgen deficiency and X chromosome genes resulting in the XXY mouse phenotype. The similarities in phenotype between 47XXY men and 41XXY mice suggest that the clinical manifestations in XXY men may be because of gene-dosage effect from genes that escape X inactivation in mouse. The 41XXY mouse is an excellent model for KS. [ABSTRACT FROM AUTHOR]
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- 2011
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6. Recent methodological advances in male hormonal contraception
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Liu, Peter Y., Swerdloff, Ronald S., and Wang, Christina
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MALE contraception , *PROGESTATIONAL hormones , *SEMEN , *ANDROGENS , *PLACEBOS , *SPERMATOGENESIS , *CLINICAL trials - Abstract
Abstract: Landmark WHO-sponsored trials showed decades ago that male hormonal contraception (MHC) is an effective male-directed contraceptive approach. Considerable progress has been made particularly in the last 5 years, establishing for the first time the reversibility of MHC and its short-term safety. Methodological advances in recent years include the pooling of information and individual-level integrated analysis; the first-time use of centralized semen analysis and fluorescence to detect low sperm concentrations; the establishment of sperm quality reference ranges in fertile men; the measurement of blood steroid concentrations by gas chromatography/mass spectrometry; and the inclusion of placebo groups to delineate clearly possible adverse effects of androgens and progestins in men. We report integrated analyses of factors that are important in predicting suppression and recovery of spermatogenesis after MHC clinical trials for the past 15 years. These are the best data available and will provide guidance and reassurance for the larger-scale Phase III specific regimen efficacy studies that will be required to bring MHC to the population (market). [ABSTRACT FROM AUTHOR]
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- 2010
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7. The emerging role of mitochondrial derived peptide humanin in the testis.
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Lue, Yanhe, Swerdloff, Ronald, Jia, Yue, and Wang, Christina
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LEYDIG cells , *GERM cells , *CELLULAR control mechanisms , *TESTIS , *SPERMATOGENESIS , *MITOCHONDRIA , *INFERTILITY , *HEAT stroke - Abstract
The discovery of mitochondrial derive peptides (MDPs) has spotlighted mitochondria as central hubs in control and regulation of cell viability and metabolism in the testis in response to intracellular and extracellular stresses. MDPs (Humanin, MOTS-c and SHLP-2) are present in testes. Humanin, the first MDP, is predominantly expressed in Leydig cells, and moderately in germ cells and seminal plasma. The administration of synthetic humanin peptide agonist HNG protects male germ cells against apoptosis induced by intratesticular hormonal deprivation, testicular hyperthermia, and chemotherapeutic agents in rodent testes. Humanin interacting with IGFBP-3 and/or Bax (pro-apoptotic proteins) prevents the activation of germ cell apoptosis. Humanin participates in the network of IL-12/IL-27 family of cytokines to exert the immune-modulation of the testicular environment. Humanin and other MDPs may be important in the amelioration of testicular stress and prevention of cell injury with possible implications for male infertility, fertility preservation and contraceptive development. [Display omitted] • Humanin interacting with IGFBP-3 or Bax prevents male germ cell apoptosis. • Humanin participates the immune-modulation of testicular environment. • Humanin protects testes against intracellular and extracellular insults. • Mitochondrial derived peptides MOTS-c and SHLP-2 are present in testes. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis.
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Liu, Peter Y., Swerdloff, Ronald S., Christenson, Peter D., Handelsman, David J., and Wang, Christina
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MALE contraception , *MALE contraceptives , *SPERMATOGENESIS , *ANDROGENS , *MEDICAL research , *SPERMATOZOA , *BIRTH control , *CONTRACEPTION - Abstract
Summary Background Hormonal methods for safe, reliable, and reversible contraception based on the suppression of spermatogenesis could soon become available. We have investigated the rate, extent, and predictors of reversibility of hormonal male contraception. Methods We undertook an integrated multivariate time-to-event analysis of data from individual participants in 30 studies published in 1990-2005, in which sperm output was monitored every month until recovery. The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million per mL, an indicator of fertility. We undertook univariate and multivariate analyses, using Kaplan-Meier and Cox's methods. Findings 1549 healthy eugonadal men who were white (n=965), Asian (almost all Chinese men; n=535), or of other origins (n=49) and aged 18-51 years underwent 1283·5 man-years of treatment and 705 man-years of post-treatment recovery. These data represented about 90% of all published data from individuals using androgen or androgen-progestagen regimens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3·4 months (95% CI 3·2-3·5), 3·0 months (2·9-3·1), and 2·5 months (2·4-2·7), respectively. Multivariate Cox's analysis showed higher rates of recovery with older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of luteinising hormone at baseline. The typical probability of recovery to 20 million per mL was 67% (61-72) within 6 months, 90% (85-93) within 12 months, 96% (92-98) within 16 months, and 100% within 24 months. Interpretation Hormonal male contraceptive regimens show full reversibility within a predictable time course. Various covariables affect the rate but not the extent of recovery, although their effect sizes are minor. These data are crucial for the further safe and practical development of such regimens. [ABSTRACT FROM AUTHOR]
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- 2006
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9. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men.
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Wang, Christina, Swerdloff, Ronald S., Iranmanesh, Ali, Dobs, Adrian, Snyder, Peter J., Cunningham, Glenn, Matsumoto, Alvin M., Weber, Thomas, and Berman, Nancy
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ANDROGENS , *HYPOGONADISM , *HORMONE therapy - Abstract
OBJECTIVE Androgen replacement has been reported to increase bone mineral density (BMD) in hypogonadal men. We studied the effects of 6 months of treatment with a new transdermal testosterone (T) gel preparation on bone turnover markers and BMD. DESIGN This was a prospective, randomized, multicentre, parallel clinical trial where 227 hypogonadal men, mean age 51 years (range: 19–68 years) were studied in 16 academic and research institutions in the USA. Subjects were randomized to apply 1% T gel containing 50 or 100 mg T (delivering approximately 5–10 mg T/day) or two T patches (delivering 5 mg T/day) transdermally for 90 days. At day 91, depending on the serum T concentration, the T gel dose was adjusted upward or downward to 75 mg T/day until day 180. No dose adjustment occurred in the T patch group. MEASUREMENTS Serum T, free T and oestradiol, bone turnover markers and BMD were measured on days 0, 30, 90 and 180 before and after treatment. RESULTS Application of T gel 100 mg/day resulted in serum T concentrations 1·4 and 1·9-fold higher than in the T gel 50 mg/day and the T patch groups, respectively. Proportional increases occurred in serum oestradiol. Urine N-telopeptide/creatinine ratio, a marker for bone resorption, decreased significantly (P = 0·0019) only in the T gel 100 mg/day group. Serum bone osteoblastic activity markers (osteocalcin, procollagen and skeletal alkaline phosphatase) increased significantly during the first 90 days of treatment without intergroup differences but declined to baseline thereafter. BMD increased significantly both in the hip (+1·1 ± 0·3%) and spine (+2·2 ± 0·5%) only in the T gel 100 mg/day group (P = 0·0001). CONCLUSIONS Transdermal testosterone gel application for 6 months decreased bone resorption markers and increased osteoblastic activity markers for a short period, which resulted in a small but significant increase in BMD. Ongoing long-term studies should answer whether the observed increases in BMD are sustained or continue to be dependent on the dose of testosterone administered. [ABSTRACT FROM AUTHOR]
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- 2001
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10. Clinical decisions. Testosterone-replacement therapy.
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Swerdloff, Ronald and Anawalt, Bradley D
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- 2014
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11. Testosterone-Replacement Therapy.
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Swerdloff, Ronald and Anawalt, Bradley D.
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THERAPEUTIC use of testosterone , *ANDROGENS - Abstract
An interactive clinical decisions test with a case vignette followed by specific options on testosterone-replacement therapy is presented.
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- 2014
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12. Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines.
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Wang, Christina, Meriggiola, Maria Cristina, Amory, John K., Barratt, Christopher L. R., Behre, Hermann M., Bremner, William J., Ferlin, Alberto, Honig, Stanton, Kopa, Zsolt, Lo, Kirk, Nieschlag, Eberhard, Page, Stephanie T., Sandlow, Jay, Sitruk‐Ware, Regine, Swerdloff, Ronald S., Wu, Frederick C. W., and Goulis, Dimitrios G.
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CONTRACEPTION , *UNPLANNED pregnancy , *MALE contraceptives , *SEMEN analysis , *FAMILY planning - Abstract
Backgrounds: Despite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male‐directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception. Aim: The present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence‐based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA). Methods: An expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results: Sixty evidence‐based and graded recommendations were produced on couple‐centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non‐hormonal methods, vaccines, and social and ethical considerations. Conclusion: As gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male‐directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non‐hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Aging Results in Attenuated Gonadotropin Releasing Hormone-Luteinizing Hormone Axis Responsiveness to Glutamate Receptor Agonist N-Methyl-d-Aspartate*.
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Bonavera, Juan J., Swerdloff, Ronald S., Sinha Hikim, Amiya P., Lue, Yan H., and Wang, Christina
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LUTEINIZING hormone , *EXCITATORY amino acids , *AGING endocrinology , *METHYL aspartate - Abstract
Reproductive aging in the Brown Norway rat occurs because of testicular as well as hypothalamic-pituitary dysfunction. Excitatory amino acids (EAA) participate in the regulation of pulsatile secretion of hypothalamic GnRH and pituitary LH. In the present study, we studied the EAA-GnRH-LH axis for possible age-related alterations in prepubertal (35 days), young (3–4 months), middle-aged (12–13 months) and old (21–23 months) rats. In the first experiment, an intra-atrial cannula was implanted in rats of different ages to evaluate the pituitary response to small, physiological intravenous bolus administration of GnRH (0.5 or 1.0 nmol/100 g body weight). The results showed no age-related significant differences in in-vivo serum LH or FSH responsiveness to GnRH. In a second experiment, blood samples for the gonadotropins were withdrawn immediately before and 10 min after an iv injection of the glutamate receptor agonist N-methyl-d-aspartate (NMDA; 5 mg/kg, a dose that induces a physiological LH pulse in young rats). Administration of NMDA induced significant increases in LH and prolactin in all groups of animals (P<0.05) and a significant FSH response in young and middle-aged but not old rats. NMDA-induced LH, FSH and prolactin release was higher (P<0.05) in prepubertal rats than in all other age groups. Compared with young rats, NMDA-induced increase in plasma LH and prolactin was lower (P<0.05) in old rats. In the third experiment, to ascertain whether this reduced LH response to NMDA in old rats was exerted at the hypothalamic level, the effects of NMDA on GnRH release in vitro from preoptic area-medial basal hypothalamus (POA-MBH) fragments were compared among rats of different ages. GnRH efflux in response to NMDA was significantly attenuated with increasing age. GnRH release in vitro was higher in prepubertal and lower in old than in young rats (P<0.05). Lastly, we measured amino acid concentrations in hypothalamic tissue (POA-MBH fragments). Prepubertal rats had higher levels of glutamate and taurine than young rats. Significant reductions in glutamate and γ-aminobutyric acid (GABA) levels were found in old compared to young rats. In conclusion, these results showed that the hypothalamic NMDA-GnRH-LH axis was altered in old rats. The decreased hypothalamic content of some of the EAA and the reduced responsiveness of GnRH neurons to NMDA (both in vivo and in vitro) may contribute to an altered LH pulsatile secretion observed in old rats. [ABSTRACT FROM AUTHOR]
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- 1998
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14. Infertility in the Male.
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Swerdloff, Ronald S., Overstreet, James W., Sokol, Rebecca Z., and Rajfer, Jacob
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MALE infertility , *PATHOLOGICAL physiology - Abstract
Discusses the physiologic factors involved in male infertility. Definition of infertility; Discussion on the control of spermatogenesis; Description on capacitation and the acrosome reaction; Cause of male factor infertility; Approach to the assessment of infertility in man; Surgery and medical treatment of male infertility.
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- 1985
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15. Comments on 'Low serum sex hormone binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients.
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Wang, Christina and Swerdloff, Ronald S.
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SERUM , *SEX hormones , *PEOPLE with diabetes , *GLOBULINS , *METABOLIC disorders , *FATTY liver - Abstract
The authors discuss the paper "Low serum sex hormone binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients," by X. Hua and colleagues. Topics discussed by the author include the impact of sex-hormone-binding globulin (SHBG) to the delivery of the sex steroid to the body, the relationship of the circulating androgen levels to metabolic disorders and nonalcoholic fatty liver disease (NAFLD), and the role of low SHBG in the development of NAFLD.
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- 2014
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16. Dihydrotestosterone: Hormone or Autocrine--Paracrine Signal?
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Swerdloff, Ronald S. and Wang, Christina
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TESTOSTERONE , *ANDROGENS , *PROSTATE , *STANOLONE , *THERAPEUTICS - Abstract
The authors reflect on the risk-benefit profile of testosterone replacement. They argue that the findings offer insights on the possible efficacy of future synthetic androgen receptor modulators which will share the anabolic effects on muscle and fat as well as the sparing effects on the prostate. An overview of the randomized and controlled trial that studied the long term effects of dihydrotestosterone (DHT) treatment on prostate growth is offered.
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- 2010
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17. Androgens, Estrogens, and Bone in Men.
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Swerdloff, Ronald S.
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BONES , *HEALTH of older men , *TESTOSTERONE , *ESTROGEN - Abstract
Editorial. Comments on a research study by S. Amin et al. on the relations between testosterone and estrogen levels and bone density in elderly men, published in the December 19, 2000 edition of the periodical 'Annals of Internal Medicine.' Role of pharmacologic testosterone treatment of osteopenia in older men; Role of pure androgens in bone metabolism.
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- 2000
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18. In Vitro Generation of Haploid Germ Cells from Human XY and XXY Immature Testes in a 3D Organoid System.
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Galdon, Guillermo, Zarandi, Nima Pourhabibi, Deebel, Nicholas A., Zhang, Sue, Cornett, Olivia, Lyalin, Dmitry, Pettenati, Mark J., Lue, YanHe, Wang, Christina, Swerdloff, Ronald, Shupe, Thomas D., Bishop, Colin, Stogner, Kimberly, Kogan, Stanley J., Howards, Stuart, Atala, Anthony, and Sadri-Ardekani, Hooman
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GERM cell differentiation , *FLUORESCENCE in situ hybridization , *KLINEFELTER'S syndrome , *X chromosome , *GERM cells , *CRYOPROTECTIVE agents - Abstract
Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients. Testicular cells were isolated from cryopreserved human testes tissue stored from XY and XXY prepubertal patients and propagated in a two-dimensional culture. Cells were then incorporated into a 3D human testicular organoid (HTO) system. During a 3-week culture period, HTOs maintained their structure, viability, and metabolic activity. Cell-specific PCR and flow cytometry markers identified undifferentiated spermatogonia, Sertoli, Leydig, and peritubular cells within the HTOs. Testosterone was produced by the HTOs both with and without hCG stimulation. Upregulation of postmeiotic germ cell markers was detected after 23 days in culture. Fluorescence in situ hybridization (FISH) of chromosomes X, Y, and 18 identified haploid cells in the in vitro differentiated HTOs. Thus, 3D HTOs were successfully generated from isolated immature human testicular cells from both euploid (XY) and Klinefelter (XXY) patients, supporting androgen production and germ cell differentiation in vitro. [ABSTRACT FROM AUTHOR]
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- 2024
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19. The humanin analogue (HNG) prevents temozolomide-induced male germ cell apoptosis and other adverse effects in severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma.
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Jia, Yue, Lue, Yanhe, Swerdloff, Ronald S., Lasky, Joseph L., Panosyan, Eduard H., Dai-Ju, Jenny, and Wang, Christina
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GERM cells , *BLOOD cell count , *LEUCOCYTES , *CANCER cells , *APOPTOSIS , *MICE - Abstract
Subfertility is a major concern of long-term cancer survivors at the reproductive age. We have previously demonstrated that a potent humanin analogue, HNG, protected chemotherapy-induced apoptosis in germ cells but not cancer cells in a metastatic melanoma allograft model. In this study, we utilized severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma to study the effect of HNG in Temozolomide (TMZ) induced male germ cell apoptosis and white blood cell (WBC) suppression. Human medulloblastoma DAOY cells were injected subcutaneously into the right flank of male SCID mice. Three weeks later, groups of tumor-bearing mice received one of the following treatments: vehicle, HNG, TMZ, or TMZ + HNG. 24 h after last injection, the tumors weights, complete blood counts, liver and spleen weights, male germ cell apoptosis was assessed. HNG did not affect TMZ's significant anti-tumor action. HNG significantly prevented TMZ-induced germ cell apoptosis and attenuated the suppressed total WBC and granulocyte counts in SCID mice with or without TMZ treatment. HNG also attenuated TMZ-induced body weight loss and decrease of spleen and liver weights. In conclusion, HNG ameliorated TMZ-induced germ cell apoptosis; WBC and granulocytes loss; and decreased body/organ weights without compromising the TMZ's anti-cancer action on medulloblastoma xenografts in SCID mice. [ABSTRACT FROM AUTHOR]
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- 2019
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20. Large divergence in testosterone concentrations between men and women: Frame of reference for elite athletes in sex‐specific competition in sports, a narrative review.
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Clark, Richard V., Wald, Jeffrey A., Swerdloff, Ronald S., Wang, Christina, Wu, Frederick C. W., Bowers, Larry D., and Matsumoto, Alvin M.
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TESTOSTERONE , *ANDROGENS , *PERFORMANCE-enhancing drugs , *ATHLETES' health , *EMERGENCY medicine , *SPORTS medicine - Abstract
Summary: Objective: The purpose of this narrative review was to summarize available data on testosterone levels in normal, healthy adult males and females, to provide a physiologic reference framework to evaluate testosterone levels reported in males and females with conditions that elevate androgens, such as disorders of sex development (DSD), and to determine the separation or overlap of testosterone levels between normal and affected males and females. Methods: A literature review was conducted for published papers, from peer reviewed journals, reporting testosterone levels in healthy males and females, males with 46XY DSD, and females with hyperandrogenism due to polycystic ovary syndrome (PCOS). Papers were selected that had adequate characterization of participants, and description of the methodology for measurement of serum testosterone and reporting of results. Results: In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range being four‐ to fivefold higher than the upper end of the female range(males 8.8‐30.9 nmol/L, females 0.4‐2.0 nmol/L). Individuals with 46XY DSD, specifically those with 5‐alpha reductase deficiency, type 2 and androgen insensitivity syndrome testosterone levels that were within normal male range. Females with PCOS or congenital adrenal hyperplasia were above the normal female range but still below the normal male range. Conclusions: Existing studies strongly support a bimodal distribution of serum testosterone levels in females compared to males. These data should be considered in the discussion of female competition eligibility in individuals with possible DSD or hyperandrogenism. [ABSTRACT FROM AUTHOR]
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- 2019
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21. Safety, Efficacy and Pharmacokinetics of Testosterone Undecanoate Long-Acting Injection in the Treatment of Hypogonadism: Results of a Phase III Clinical Trial.
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Morgentaler, Abraham, Swerdloff, Ronald S., Dobs, Adrian S., Kaufman, Joel, Miner, Martin M., and Shabsigh, Ridwan
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TESTOSTERONE , *HORMONE therapy , *HYPOGONADISM , *SERUM , *PHARMACOKINETICS , *THERAPEUTICS - Abstract
The article discusses a study on the safety, efficacy and pharmacokinetics (PK) of testosterone undecanoate long-acting injection in the treatment of hypogonadism. It mentions the PK parameters used to measure outcomes and indicates the achieved level of serum T concentrations. The conclusion of the study is given.
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- 2008
22. Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity.
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Lue, Yanhe, Chen Gao, Swerdloff, Ronald, Hoang, James, Avetisyan, Rozeta, Yue Jia, Meng Rao, Shuxun Ren, Atienza, Vince, Junyi Yu, Ye Zhang, Mengping Chen, Yang Song, Yibin Wang, and Wang, Christina
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SALINE injections , *INTRAPERITONEAL injections , *CANCER patients , *CARDIOTOXICITY , *HEART fibrosis - Abstract
The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline daily, HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized at 10 wk. In the absence of Dox, HNG, DRZ, or DRZ + HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated the Dox-induced decrease in ejection fraction. HNG + DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG + DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein-2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG + DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Doxinduced cardiotoxicity. [ABSTRACT FROM AUTHOR]
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- 2018
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23. Androgens, lipids, and cardiovascular risk.
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Plymate, Stephen R., Swerdloff, Ronald S., Plymate, S R, and Swerdloff, R S
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STEROIDS , *CORONARY disease , *SEX factors in disease , *HIGH density lipoproteins , *ANDROGENS , *LIPIDS - Abstract
Focuses on the concept that sex steroids affect lipid levels and suggest a mechanism by which sex steroids may account for the differences in the incidence of coronary artery disease between men and women. Analysis of the no sex-related differences in serum high-density lipoprotein cholesterol or triglyceride levels in prepubertal children; Comparison between men who had mild type II diabetes and normal men; Risk factor for coronary artery disease.
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- 1992
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24. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety.
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Honig, Stanton, Gittelman, Marc, Kaminetsky, Jed, Wang, Christina, Amory, John K., Rohowsky, Nestor, Dudley, Robert E., Woun Seo, B., Newmark, Jay, and Swerdloff, Ronald
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PROSTATE cancer , *HDL cholesterol , *TESTOSTERONE , *SYSTOLIC blood pressure , *LIVER function tests , *PROSTATE-specific antigen , *HEMATOCRIT - Abstract
Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300–1,000 ng/dL [10–35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P <.0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P <.0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3–6 mm Hg increase in systolic blood pressure (P <.05); a slight increase in hematocrit (P <.0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P <.0001). There were no clinically significant changes from baseline in liver function tests. Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750–1758. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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25. Hypogonadism in the AgingMale Diagnosis, Potential Benefits, and Risks of Testosterone Replacement Therapy.
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Surampudi, Prasanth N., Wang, Christina, and Swerdloff, Ronald
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HYPOGONADISM , *THERAPEUTIC use of testosterone , *AGE factors in disease , *IMPOTENCE , *OSTEOPENIA , *OSTEOPOROSIS - Abstract
Hypogonadism in older men is a syndrome characterized by low serum testosterone levels and clinical symptoms often seen in hypogonadal men of younger age. These symptoms include decreased libido, erectile dysfunction, decreased vitality, decreased muscle mass, increased adiposity, depressed mood, osteopenia, and osteoporosis. Hypogonadism is a common disorder in aging men with a significant percentage ofmen over 60 years of age having serumtestosterone levels below the lower limits of young male adults. There are a variety of testosterone formulations available for treatment of hypogonadism. Data from many small studies indicate that testosterone therapy offers several potential benefits to older hypogonadal men. A large multicenter NIH supported double blind, placebo controlled study is ongoing, and this study should greatly enhance the information available on efficacy and side effects of treatment. While safety data is available across many age groups, there are still unresolved concerns associated with testosterone therapy. We have reviewed the diagnostic methods as well as benefits and risks of testosterone replacement therapy for hypogonadism in aging men. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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26. Interaction of Insulin-like Growth Factor-binding Protein-3 and BAX in Mitochondria Promotes Male Germ Cell Apoptosis.
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Jia, Yue, Kuk-Wha Lee, Swerdloff, Ronald, David Hwang, Cobb, Laura J., Hikim, Amiya Sinha, Lue, YanHe, Cohen, Pinchas, and Christina Wang
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GROWTH factors , *GERM cells , *APOPTOSIS , *CARRIER proteins , *SALINE solutions , *CYTOSOL , *MITOCHONDRIA , *HOMEOSTASIS - Abstract
Germ cell apoptosis is crucial for spermatogenesis and can be triggered by various stimuli, including intratesticular hormone deprivation. This study proposes a role for insulin-like growth factor binding protein-3 (IGFBP-3) in male germ cell apoptosis. Groups of adult Sprague-Dawley male rats received one of the following treatments for 5 days: (i) daily intratesticular (IT) injections with saline (control); (ii) a single subcutaneous injection of the gonadotropin-releasing hormone antagonist (GnRHA), acyline, on day 1 and a daily IT injection of saline; (iii) daily IT injection of IGFBP-3; and (iv) a GnRH-A injection on day 1 and a daily IT injection of IGFBP-3. Germ cell apoptosis increased significantly after IGFBP-3 or GnRH-A treatment which was further enhanced by the combined treatment. After co-immunoprecipitation with BAX antibody, IGFBP-3 association with BAX was demonstrated in total and mitochondrial fractions but not in the cytosol of testis extracts. BAX-associated IGFBP-3 expression was increased in mitochondria after treatment compared with control, which was confirmed by an IGFBP-3 enzyme-linked immunosorbent assay. Dot blot studies further validated the BAX-IGFBP-3 binding in vitro. IGFBP-3 as well as BAX induced release of cytochrome c and DIABLO from isolated testicular mitochondria in vitro. IGFBP-3, when combined with an ineffective dose of BAX, triggered release of these proteins from isolated mitochondria at a 4-fold lower dose than IGFBP-3 alone. Our data demonstrate that the IGFBP-3 and BAX interaction activates germ cell apoptosis via the mitochondriadependent pathway. This represents a novel pathway regulating germ call homeostasis that may have significance for male fertility and testicular disease. [ABSTRACT FROM AUTHOR]
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- 2010
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27. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males.
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Wang, Christina, Nieschlag, Eberhard, Swerdloff, Ronald S., Behre, Hermann, Hellstrom, Wayne J., Gooren, Louis J., Kaufman, Jean M., Legros, Jean-Jacques, Lunenfeld, Bruno, Morales, Alvaro, Morley, John E., Schulman, Claude, Thompson, Ian M., Weidner, Wolfgang, and Wu, Frederick C. W.
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MALES , *HYPOGONADISM , *SEXUAL dysfunction , *TESTOSTERONE , *ANDROGENS , *DISEASES - Abstract
The article features the implication of late-onset hypogonadism (LOH) in males worldwide. It is a clinical and biochemical syndrome associated with advancing age, characterized by deficiency in serum testosterone levels. Data shows that there is an increasing cases of androgen deficiency in males, indicating that testosterone falls progressively with age. It was also found that the percentage of men over 60 years of age have serum testosterone levels which are below the limits of young adults.
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- 2009
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28. Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM, EAU, EAA, and ASA Recommendations
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Wang, Christina, Nieschlag, Eberhard, Swerdloff, Ronald, Behre, Hermann M., Hellstrom, Wayne J., Gooren, Louis J., Kaufman, Jean M., Legros, Jean-Jacques, Lunenfeld, Bruno, Morales, Alvaro, Morley, John E., Schulman, Claude, Thompson, Ian M., Weidner, Wolfgang, and Wu, Frederick C.W.
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- 2009
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29. Acceptability of the oral hormonal male contraceptive prototype, 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), in a 28-day placebo-controlled trial.
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Nguyen, Brian T., Yuen, Fiona, Farrant, Maritza, Thirumalai, Arthi, Fernando, Frances, Amory, John K., Swerdloff, Ronald S., Anawalt, Bradley D., Blithe, Diana L., Long, Jill E., Liu, Peter Y., Page, Stephanie T., and Wang, Christina
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MALE contraceptives , *MALE reproductive health , *CLIENT satisfaction , *DRUG utilization , *CONTRACEPTION , *RESEARCH , *ANDROGENS , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *RANDOMIZED controlled trials , *BLIND experiment , *RESEARCH funding - Abstract
Objective: To determine men's satisfaction with and the potential acceptability of 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC).Study Design: We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11β-MNTDC for male contraception.Results: Of 42 trial participants, 40 (30 11β-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11β-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel.Conclusion: A majority of participants in this short-term trial of daily oral 11β-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects.Implications: Oral 11β-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11β-MNTDC. [ABSTRACT FROM AUTHOR]- Published
- 2021
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30. Aging-Related Increased Expression of Inducible Nitric Oxide Synthase and Cytotoxicity Markers in Rat Hypothalamic Regions Associated with Male Reproductive Function.
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Ferrini, Monica, Wang, Christina, Swerdloff, Ronald S., Sinha Hikim, Amiya P., Rajfer, Jacob, and Gonzalez-Cadavid, Nestor F.
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NITRIC oxide , *LUTEINIZING hormone releasing hormone , *GONADOTROPIN , *APOPTOSIS , *REPRODUCTION , *IMMUNOCYTOCHEMISTRY - Abstract
We have previously demonstrated that the inducible nitric oxide synthase (iNOS) protein and total NOS activity increase in the hypothalamus and other regions of the male rat brain during aging. We have now tested the hypothesis that increased iNOS results in excessive nitric oxide (NO) and peroxynitrite production, and leads to increased apoptosis in CNS cells, including the GnRH and oxytocin hypothalamic neurons involved in the control of male reproductive function. Young (3-month-old) and old (24-month-old) male Brown Norway rats (n = 6) were perfused with 4% formalin. Adjacent coronal paraffin-embedded sections (5 μm) of preoptic area (POA), supraoptic nucleus (SON), paraventricular nucleus (PVN), and arcuate nucleus (ARC) of the hypothalamus were immunostained with antibodies for iNOS, neuronal NOS (nNOS), and nitrotyrosine (a marker of peroxynitrite formation). The intensity of immunostaining was measured using a densitometric image analysis system. Apoptosis was determined by the TUNEL assay. Double immunofluorescence staining with confocal laser scanning microscopy was used for co-localization studies. A significant increase in the iNOS immunostaining measured as optical density (OD) was found in the old compared to the young animals (SON: 0.32 ± 0.02 vs. 0.23 ± 0.03, p < 0.05; PVN: 0.34 ± 0.03 vs. 0.07 ± 0.05, p < 0.001; POA: 0.18 ± 0.02 vs. 0.01 ± 0.02, p < 0.001). Aging did not affect nNOS expression. Nitrotyrosine was elevated in the hypothalamic regions of old compared to young rats (SON: 0.32 ± 0.05 vs. 0.10 ± 0.04, p < 0.05; PVN: 0.32 ± 0.04 vs. 0.13 ± 0.03, p < 0.01; POA: 0.72 ± 0.06 vs. 0.03 ± 0.003, p < 0.001). Increased nitrotyrosine was accompanied by an elevation of the apoptotic index in the old rats (SON: 11.01 ± 3.33 vs. 0.57 ± 0.50, p < 0.001; PVN: 3.08 ± 1.12 vs. 0.42 ± 0.32; POA: 6.60 ± 1.93 vs. 0.18 ± 0.17, p < 0.01; ARC: 0.001 ± 0.0001 vs. 4.33 ± 2.33). iNOS staining co-localized with GnRH and oxytocin staining. In conclusion: The aging-related iNOS increased expression in the hypothalamus of the male rat affects regions known to control the synthesis and release of GnRH (POA, ARC) and oxytocin (PVN, SON), and the factors regulating penile erection (POA, and PVN). These observations suggest that iNOS may play a role in the reduction in GnRH and oxytocin neuronal secretion resulting in reproductive dysfunctions such as lowered serum testosterone, hypospermatogenesis, and diminished copulatory function in the aging male animal.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2001
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31. Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β‐MNTDC in healthy men.
- Author
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Yuen, Fiona, Thirumalai, Arthi, Fernando, Frances A., Swerdloff, Ronald S., Liu, Peter Y., Pak, Youngju, Hull, Laura, Bross, Rachelle, Blithe, Diana L., Long, Jill E., Page, Stephanie T., and Wang, Christina
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- *
INSULIN sensitivity , *ANDROGENS , *INSULIN resistance , *MALE contraceptives , *HDL cholesterol - Abstract
Background: Dimethandrolone (DMA) and 11β‐methyl‐19‐nortestosterone (11β‐MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. Objective: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. Materials/Methods: In two clinical trials of DMA undecanoate (DMAU) and 11β‐MNT dodecylcarbonate (11β‐MNTDC), oral prodrugs of DMA and 11β‐MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non‐parametric Kruskal‐Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. Results: Class effects were seen, with decrease in HDL‐C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA‐IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11β‐MNTDC. An increase in LDL‐C was seen with 11β‐MNTDC but not with DMAU. Discussion: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. Conclusion: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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32. Therapeutic Applications of Luteinizing-Hormone-Releasing Hormone and Its Analogs.
- Author
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Cutler Jr., Gordon B., Hoffman, Andrew R., Swerdloff, Ronald S., Santen, Richard J., Meldrum, David R., and Comite, Florence
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LUTEINIZING hormone releasing hormone , *SPERMATOGENESIS , *THERAPEUTICS - Abstract
Presents information on a study which described the therapeutic applications of luteinizing-hormone-releasing hormone (LHRH) . History of LHRH; Fertility induction in hypothalamic hypogonadism; Induction of spermatogenesis; Ovulation induction; Hormonal control of spermatogenesis.
- Published
- 1985
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33. Memory in repeat sports-related concussive injury and single-impact traumatic brain injury.
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Wright, Matthew J., Monti, Martin M., Lutkenhoff, Evan S., Hardy, David J., Litvin, Pavel Y., Kelly, Daniel F., Guskiewicz, Kevin, Cantu, Robert C., Vespa, Paul M., Hovda, David A., Lopez, Walter D., Wang, Christina, Swerdloff, Ronald, and Fuster, Joaquín M.
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BRAIN concussion , *BRAIN injuries , *HIPPOCAMPUS (Brain) , *LEARNING , *MAGNETIC resonance imaging , *MEMORY , *NEUROANATOMY , *SPORTS injuries , *MEDICAL coding - Abstract
Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods: We sought to determine memory differences between persons with RC/SCI, moderate-to-severe single-impact traumatic brain injury (SI-TBI), and healthy controls. MRI scans from a subsample of participants with SI-TBI were used to identify the neuroanatomical correlates of observed memory process differences between the brain injury groups. Results: Both brain injury groups evidenced worse learning and recall in contrast to controls, although SI-TBI group had poorer memory than the RC/SCI group. Regarding memory process differences, in contrast to controls, the SI-TBI group evidenced difficulties with encoding, consolidation, and retrieval, while the RC/SCI group showed deficits in consolidation and retrieval. Delayed recall was predicted by encoding, with consolidation as a secondary predictor in the SI-TBI group. In the RC/SCI group, delayed recall was only predicted by consolidation. MRI data showed that the consolidation index we used mapped onto hippocampal atrophy. Conclusions: RC/SCI is primarily associated with consolidation deficits, which differs from SI-TBI. Given the role of the hippocampus in memory consolidation and the fact that hyperphosphorylated tau tends to accumulate in the medial temporal lobe in RC/SCI, consolidation deficits may be a cognitive marker of chronic traumatic encephalopathy in athletes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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34. Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype.
- Author
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Nguyen, Brian T., Farrant, Maritza T., Anawalt, Bradley D., Yuen, Fiona, Thirumalai, Arthi, Amory, John K., Swerdloff, Ronald S., Bremner, William J., Liu, Peter Y., Blithe, Diana L., Page, Stephanie T., and Wang, Christina
- Subjects
- *
MALE contraceptives , *PHARMACOKINETICS , *CONTRACEPTION , *CONTRACEPTIVES , *PROTOTYPES , *RESEARCH , *ANDROGENS , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *RANDOMIZED controlled trials , *BLIND experiment , *STATISTICAL sampling - Abstract
Objective: To determine men's satisfaction with and acceptability of a once-daily, oral regimen of dimethandrolone undecanoate (DMAU) versus placebo when used for 28 days.Study Design: After a Phase I double-blind, randomized, placebo-controlled, dose-escalating trial of oral DMAU for 28-days, 57 healthy male volunteers completed a survey assessing their experience and satisfaction with the regimen. In the trial, participants were randomized to receive up to 4 DMAU capsules daily versus placebo and instructed to ingest them within 30 min of consuming a high fat meal. Pharmacokinetic and pharmacodynamic profiles were performed, followed by a 6-week recovery phase. Participants were counseled that they could not rely on the drug for contraception.Results: Fifty-seven participants were offered acceptability surveys (39 DMAU, 18 placebo). Most respondents, 80% (45/56), reported satisfaction with the method; 77% (44/57) would recommend it. 54% (31/57), reported that, if available, they would use the method as their primary contraceptive. More respondents reported satisfaction with active DMAU than placebo (87% vs. 67%; p = 0.05). Most respondents, 91% (52/57), reported no difficulty with having to take up to 4 pills within 30 min of ingesting a high-fat meal.Conclusion: Most participants reported that the study method, daily oral DMAU or placebo, was satisfactory and acceptable. Having to take the drug after a high-fat meal did not detract from acceptability.Implications: Most participants in a 4-week trial of daily DMAU capsules would recommend and use the method. High satisfaction among DMAU and placebo groups affirms acceptability of a daily male contraceptive pill, warranting further study of oral DMAU. [ABSTRACT FROM AUTHOR]- Published
- 2020
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35. A - 151 Assessing the Role of Executive Function in the Memory Performances of Retired National Football League Players.
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Lopez Hernandez, Daniel W, Cantu, Robert, Guskiewicz, Kevin M, Kelly, Daniel F, Swerdloff, Ronald, Woo, Ellen, and Wright, Matthew J
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FOOTBALL players , *EXECUTIVE function , *TRAIL Making Test , *RECOLLECTION (Psychology) , *VERBAL memory , *SPORTS psychology - Abstract
Objective: We evaluated the relationship between retired National Football League players executive functioning (EF) abilities on verbal memory performance and subprocesses. Method: Fifty-eight participants were divided into two groups: intact executive functioning (IEF) and deficit executive functioning (DEF). Participants completed the California Verbal Learning Test, Second Edition (CVLT-II) to evaluate verbal memory performance. Additionally, the Item Specific Deficit Approach (ISDA) was applied to the CVLT-II to quantify verbal memory subprocesses (i.e., encoding, consolidation, & retrieval). Next, we determined which ISDA indices predicted long-delayed free recall (LDFR) for both groups. We then computed hierarchal regressions to determine which ISDA indices were predictive of LDFR for each group. Next, we retained significant predictors from the ISDA and correlated them with measures of executive function in both groups with and without partialling out cognitive reserve (CR). Results: We found the IEF group outperformed the DEF group on the CVLT-II learning trials and LDFR, and demonstrated better encoding abilities. Hierarchical regression revealed that the ISDA was predictive of LDFR in both groups. The DEF group LDFR issues were only predicted by encoding problems. In contrast, LDFR deficits in the IEF were primarily driven by consolidation problems. The ISDA encoding index correlated with Trail Making Test part B and Phonemic Fluency Test. However, after partialling out the variance accounted for by CR, the associations between the encoding index and executive function were nonsignificant. Conclusions: Our results suggest that greater executive function results in better memory performances in retired football players. Lastly, improved executive function is related to greater CR. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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36. Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone).
- Author
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Amory, John K., Blithe, Diana L., Sitruk-Ware, Regine, Swerdloff, Ronald S., Bremner, William J., Dart, Clint, Liu, Peter Y., Thirumalai, Arthi, Nguyen, Brian T., Anawalt, Bradley D., Lee, Min S., Page, Stephanie T., and Wang, Christina
- Subjects
- *
MALE contraceptives , *UNPLANNED pregnancy , *TESTOSTERONE , *CONTRACEPTION , *ACETATES - Abstract
Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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37. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials.
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Wang, Christina, Stephens-Shields, Alisa J., DeRogatis, Leonard R., Cunningham, Glenn R., Swerdloff, Ronald S., Preston, Peter, Cella, David, Snyder, Peter J., Gill, Thomas M., Bhasin, Shalender, Matsumoto, Alvin M., and Rosen, Raymond C.
- Subjects
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SEXUAL health , *SEXUAL desire disorders , *HYPERSEXUALITY , *TESTOSTERONE , *SEXUAL dysfunction - Abstract
Background Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function. Aim To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains. Methods Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set. Outcomes Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials. Results Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men. Clinical Implications The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T. Strengths & Limitations Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity. Conclusion Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997–1009. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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38. Testosterone protects high-fat/low-carbohydrate diet-induced nonalcoholic fatty liver disease in castrated male rats mainly via modulating endoplasmic reticulum stress.
- Author
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Yue Jia, Yee, Jennifer K., Wang, Christina, Nikolaenko, Liana, Diaz-Arjonilla, Maruja, Cohen, Joshua N., French, Samuel W., Liu, Peter Y., YanHe Lue, Lee, Wai-Nang P., and Swerdloff, Ronald S.
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FATTY liver , *TESTOSTERONE , *ENDOPLASMIC reticulum - Abstract
We previously showed that testosterone (T) deficiency enhanced high-fat/low-carbohydrate diet (HFD)-induced hepatic steatosis in rats independent of insulin resistance and that T replacement reduced hepatic macrovesicular fat accumulation and inflammation. The present report explores the mechanism of T's protective effects on HFD-induced steatohepatitis. Adult male rats were randomized into four treatment groups for 15 wk: intact rats on regular chow diet or HFD, and castrated rats on HFD with or without T replacement. Fatty acid β-oxidation and de novo synthesis were not changed by castration and T replacement, but expression of lipid export proteins ApoB100 and microsomal triglyceride transfer protein (MTP) was suppressed by HFD in both intact and castrated rats but restored by T replacement. Macrovesicular lipid droplet-related proteins perilipin 1 and fat-specific protein 27 were increased by HFD in castrated rats and suppressed by T replacement. Higher activation/expression of ER stress proteins (PERK, IRE-1α, JNK, NF-κB, and CHOP) was demonstrated in castrated rats fed HFD compared with intact animals, and T replacement suppressed these changes. We conclude that 1) HFD leads to ApoB100/MTP suppression reducing export of lipids; 2) castration promotes progression to steatohepatitis through activation of the ER stress pathway and enhancement of macrovesicular droplet protein expression; and 3) testosterone suppresses ER stress, inhibits the formation of macrovesicular lipid droplets, promotes lipid export, and ameliorates steatohepatitis induced by HFD and castration. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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39. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone.
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Budoff, Matthew J., Ellenberg, Susan S., Lewis, Cora E., Mohler III, Emile R., Wenger, Nanette K., Bhasin, Shalender, Barrett-Connor, Elizabeth, Swerdloff, Ronald S., Stephens-Shields, Alisa, Cauley, Jane A., Crandall, Jill P., Cunningham, Glenn R., Ensrud, Kristine E., Gill, Thomas M., Matsumoto, Alvin M., Molitch, Mark E., Rine Nakanishi, Nezarat, Negin, Suguru Matsumoto, and Xiaoling Hou
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THERAPEUTIC use of testosterone , *CORONARY disease , *ATHEROSCLEROTIC plaque , *OLDER men , *CARDIOVASCULAR diseases risk factors , *HYPOGONADISM , *ARTERIOGRAPHY , *COLLOIDS in medicine , *PATIENTS , *DISEASES in older people - Abstract
Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.Trial Registration: clinicaltrials.gov Identifier: NCT00799617. [ABSTRACT FROM AUTHOR]- Published
- 2017
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40. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment.
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Resnick, Susan M., Matsumoto, Alvin M., Stephens-Shields, Alisa J., Ellenberg, Susan S., Gill, Thomas M., Shumaker, Sally A., Pleasants, Debbie D., Barrett-Connor, Elizabeth, Bhasin, Shalender, Cauley, Jane A., Cella, David, Crandall, Jill P., Cunningham, Glenn R., Ensrud, Kristine E., Farrar, John T., Lewis, Cora E., Molitch, Mark E., Pahor, Marco, Swerdloff, Ronald S., and Cifelli, Denise
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THERAPEUTIC use of testosterone , *COGNITIVE ability , *OLDER men , *COGNITION in old age , *AGE factors in disease , *MEMORY disorders in old age , *PLACEBOS , *VISUAL memory , *PSYCHOLOGY , *ANDROGEN drugs , *CLINICAL trials , *COGNITION , *COMPARATIVE studies , *PHARMACEUTICAL gels , *RESEARCH methodology , *MEDICAL cooperation , *MEMORY , *MEMORY disorders , *REFERENCE values , *RESEARCH , *RESEARCH funding , *TESTOSTERONE , *TIME , *EVALUATION research , *TREATMENT effectiveness , *BLIND experiment , *EXECUTIVE function - Abstract
Importance: Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.Objective: To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI).Design, Setting, and Participants: The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014.Interventions: Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.Main Outcomes and Measures: The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months.Results: Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89).Conclusions and Relevance: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.Trial Registration: clinicaltrials.gov Identifier: NCT00799617. [ABSTRACT FROM AUTHOR]- Published
- 2017
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41. Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials.
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Stephens-Shields, Alisa J., Wang, Christina, Preston, Peter, Snyder, Peter J., and Swerdloff, Ronald S.
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LUST , *OLDER men , *RECEIVER operating characteristic curves , *CUMULATIVE distribution function - Abstract
A recent study of older men participating in the Testosterone Trials (TTrials) defined a clinically meaningful change in the Psychosexual Daily Questionnaire (PDQ) question 4 in hypogonadal men age ≥65 years. This study defines clinically meaningful change in the same population for sexual desire assessed by PDQ question 1. To determine a clinically meaningful change in the answers to question 1 of the PDQ in hypogonadal older men. Participants in the Sexual Function Trial of the TTrials were randomly divided into a training and test set. Anchor-based methods, including regression analysis, receiver operating characteristic curves, and empirical cumulative distribution functions, were used to determine a clinically meaningful change on question 1 in the training set, and the selected threshold was evaluated in the test set for an effect of testosterone treatment. A clinically meaningful increase in question 1 of the PDQ was determined to be ≥0.7 points. Question 1 of the PDQ can be used to assess sexual desire in response to testosterone treatment. Data were obtained from a single large study of older hypogonadal men. Clinically meaningful improvement of sexual desire is a change of ≥0.7 in the score of question 1 of the PDQ. Stephens-Shields AJ, Wang C, Preston P, et al. Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials. J Sex Med 2019;16:951–953. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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42. Male sex matters.
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Liu, Peter Y., Wang, Christina, and Swerdloff, Ronald S.
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TESTOSTERONE , *ANDROGENS , *SEXUAL dysfunction , *IMPOTENCE , *TREATMENT of sexual dysfunction , *THERAPEUTICS - Abstract
The article cites a meta-analysis of randomized placebo-controlled trials examining the effect of testosterone therapy on sexual dysfunction. The evidence suggests that testosterone may improve sexual function in men with low-normal blood testosterone concentrations. Another important conclusion of the meta-analysis is that testosterone can alter both libido and erectile function.
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- 2005
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43. An index predictive of cognitive outcome in retired professional American Football players with a history of sports concussion.
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Wright, Mathew J., Woo, Ellen, Birath, J. Brandon, Siders, Craig A., Kelly, Daniel F., Wang, Christina, Swerdloff, Ronald, Romero, Elizabeth, Kernan, Claudia, Cantu, Robert C., and Guskiewicz, Kevin
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FOOTBALL players , *RETIREES , *COGNITIVE ability , *BRAIN concussion , *NEUROPSYCHOLOGICAL tests , *FOOTBALL injuries , *WECHSLER Individual Achievement Test - Abstract
Objective: Various concussion characteristics and personal factors are associated with cognitive recovery in athletes. We developed an index based on concussion frequency, severity, and timeframe, as well as cognitive reserve (CR), and we assessed its predictive power regarding cognitive ability in retired professional football players.Method: Data from 40 retired professional American football players were used in the current study. On average, participants had been retired from football for 20 years. Current neuropsychological performances, indicators of CR, concussion history, and play data were used to create an index for predicting cognitive outcome.Results: The sample displayed a range of concussions, concussion severities, seasons played, CR, and cognitive ability. Many of the participants demonstrated cognitive deficits. The index strongly predicted global cognitive ability (R2= .31). The index also predicted the number of areas of neuropsychological deficit, which varied as a function of the deficit classification system used (Heaton:R2= .15; Wechsler:R2= .28).Conclusions: The current study demonstrated that a unique combination of CR, sports concussion, and game-related data can predict cognitive outcomes in participants who had been retired from professional American football for an average of 20 years. Such indices may prove to be useful for clinical decision making and research. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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44. Association of endogenous testosterone with subclinical atherosclerosis in men: the multi-ethnic study of atherosclerosis.
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Khazai, Bahram, Golden, Sherita Hill, Colangelo, Laura A., Swerdloff, Ronald, Wang, Christina, Honoris, Lily, Gapstur, Susan M., Ouyang, Pamela, Cushman, Mary, Li, Dong, Kopp, Peter, Vaidya, Dhananjay, Liu, Kiang, Dobs, Adrian, and Budoff, Matthew
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TESTOSTERONE , *ATHEROSCLEROSIS , *SEX hormones , *CARDIOVASCULAR diseases risk factors , *GLOBULINS , *DEHYDROEPIANDROSTERONE - Abstract
Objectives Whether endogenous sex hormones play a role in cardiovascular disease ( CVD) risk in men is unclear. Few studies have examined associations of sex hormones with atherosclerosis measured by coronary artery calcium score ( CACS) and carotid intima-media thickness ( cIMT). We evaluated the association of testosterone (T) and other sex hormones with CACS and cIMT. Methods Using the large multi-ethnic cohort of 3164 men without known CVD in the Multi-Ethnic Study of Atherosclerosis ( MESA), cross-sectional associations of tertiles of endogenous sex hormones with CACS and cIMT were analysed. Results In regard to CAC, there was a significant negative trend (P-trend = 0·02) for CACS>0 over tertiles of free T ( FT) with RRs (95% CI) for the lowest to highest tertiles. There was also a marginally significant positive trend (P-trend = 0·06) for CACS>0 over tertiles of sex hormone-binding globulin ( SHBG) with RRs for the lowest to highest tertiles. There were no significant associations with CACS >0 for tertiles of TT (Total T), bioavailable T ( BT), oestradiol (E2) and dehydroepiandrosterone ( DHEA). There was significantly higher log CACS after adjustment for CVD risk factors for lower TT levels, compared to higher levels, using 9·54 and 10·4 nmol/l as cut-off points. In regard to cIMT, there was a significant positive trend ( P = 0·003) in mean cIMT over the tertiles of BT, but not for TT, FT, E2, DHEA and SHBG. There was significantly lower cIMT after adjustment for CVD risk factors for lower TT levels compared to higher levels. Conclusion In a population of male subjects with no known CVD, lower FT is associated with higher RR of CACS>0 and lower TT is associated with higher log CACS. Lower BT and TT are associated with lower cIMT. While these findings support the positive correlation between low T and coronary atherosclerosis, the opposite findings on cIMT warrant further evaluation. [ABSTRACT FROM AUTHOR]
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- 2016
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45. Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies.
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Raznahan, Armin, Lue, YanHe, Probst, Frank, Greenstein, Deanna, Giedd, Jay, Wang, Christina, Lerch, Jason, and Swerdloff, Ronald
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NEURAL development , *SEX chromosomes , *BRAIN imaging , *NEUROANATOMY , *THALAMIC nuclei ,SEX differences (Biology) - Abstract
Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study-XO, XX, XY and XXY-to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ('forebrain cholinergic' and 'cerebelo-pontine-thalamo-cortical'), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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46. Recruitment and Screening for the Testosterone Trials.
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Cauley, Jane A, Fluharty, Laura, Ellenberg, Susan S, Gill, Thomas M, Ensrud, Kristine E, Barrett-Connor, Elizabeth, Cifelli, Denise, Cunningham, Glenn R, Matsumoto, Alvin M, Bhasin, Shalender, Pahor, Marco, Farrar, John T, Cella, David, Rosen, Raymond C, Resnick, Susan M, Swerdloff, Ronald S, Lewis, Cora E, Molitch, Mark E, Crandall, Jill P, and Stephens-Shields, Alisa J
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THERAPEUTIC use of testosterone , *TREATMENT of sexual dysfunction , *HYPOGONADISM , *VITALITY , *CLINICAL trials - Abstract
Background: We describe the recruitment of men for The Testosterone (T) Trials, which were designed to determine the efficacy of T treatment.Methods: Men were eligible if they were ≥65 years, had an average of two morning total T values <275 ng/dL with neither value >300 ng/mL, and had symptoms and objective evidence of mobility limitation, sexual dysfunction, and/or low vitality. Men had to be eligible for and enroll in at least one of these three main trials (physical function, sexual function, vitality).Results: Men were recruited primarily through mass mailings in 12 U.S. communities: 82% of men who contacted the sites did so in response to mailings. Men who responded were screened by telephone to ascertain eligibility. Of 51,085 telephone screens, 53.5% were eligible for further screening. Of 23,889 initial screening visits (SV1), 2,781 (11.6%) men were eligible for the second screening visit (SV2), which 2,261 (81.3%) completed. At SV2, 931 (41.2%) men met the criteria for one or more trials, the T level criterion and had no other exclusions. Of these, 790 (84.6%) were randomized; 99 (12.5%) in all three trials and 348 (44%) in two trials. Their mean age was 72 years and mean body mass index (BMI) was 31.0 kg/m(2). Mean (standard deviation) total T (ng/dL) was 212.0 (40.0).Conclusion: Despite the telephone screening to enrollment ratio of 65 to 1, we met the recruitment goals for each trial. Recruitment of symptomatic older men with low testosterone levels is difficult but feasible. [ABSTRACT FROM AUTHOR]- Published
- 2015
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47. Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial.
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Roth, Mara Y., Shih, Grace, Ilani, Niloufar, Wang, Christina, Page, Stephanie T., Bremner, William J., Swerdloff, Ronald S., Sitruk-Ware, Regine, Blithe, Diana L., and Amory, John K.
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MALE contraceptives , *TRANSDERMAL medication , *BIRTH control , *CONDOMS , *TESTOSTERONE , *HORMONES , *RANDOMIZED controlled trials - Abstract
Objective Fifty percent of pregnancies in the United States are unintended despite numerous contraceptive methods available to women. The only male contraceptive methods, vasectomy and condoms, are used by 10% and 16% of couples, respectively. Prior studies have shown efficacy of male hormonal contraceptives in development, but few have evaluated patient acceptability and potential use if commercially available. The objective of this study is to determine if a transdermal gel-based male hormonal contraceptive regimen, containing testosterone and Nestorone® gels, would be acceptable to study participants as a primary contraceptive method. Study Design As part of a three-arm, 6-month, double-blind, randomized controlled trial of testosterone and nestorone gels at two academic medical centers, subjects completed a questionnaire to assess the acceptability of the regimen. Of the 99 men randomized, 79 provided data for analysis. Results Overall, 56% (44/79) of men were satisfied or extremely satisfied with this gel-based method of contraception, and 51% (40/79) reported that they would recommend this method to others. One third of subjects (26/79) reported that they would use this as their primary method of contraception if it were commercially available today. However, men with concerns about sexually transmitted disease were significantly less satisfied than men without such concerns (p=0.03). Conclusions A majority of the men who volunteered to participate in this trial of an experimental male hormonal contraceptive were satisfied with this transdermal male hormonal contraceptive. If commercially available, a combination of topical nesterone and testosterone gels could provide a reversible, effective method of contraception that is appealing to men. Implications A substantial portion of men report they would use this transdermal male contraceptive regimen if commercially available. This method would provide a novel, reversible method of contraception for men, whose current choices are limited to condoms and vasectomy. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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48. Prevalence of Pituitary Hormone Dysfunction, Metabolic Syndrome, and Impaired Quality of Life in Retired Professional Football Players: A Prospective Study.
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Kelly, Daniel F., Chaloner, Charlene, Evans, Diana, Mathews, Amy, Cohan, Pejman, Wang, Christina, Swerdloff, Ronald, Sim, Myung-Shin, Lee, Jihey, Wright, Mathew J., Kernan, Claudia, Barkhoudarian, Garni, Yuen, Kevin C.J., and Guskiewicz, Kevin
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PITUITARY hormones , *DISEASE prevalence , *METABOLIC syndrome , *RETIREES , *FOOTBALL players , *HYPOPITUITARISM , *BRAIN injuries , *DISEASES - Abstract
Hypopituitarism is common after moderate and severe traumatic brain injury (TBI). Herein, we address the association between mild TBI (mTBI) and pituitary and metabolic function in retired football players. Retirees 30-65 years of age, with one or more years of National Football League (NFL) play and poor quality of life (QoL) based on Short Form 36 (SF-36) Mental Component Score (MCS) were prospectively enrolled. Pituitary hormonal and metabolic syndrome (MetS) testing was performed. Using a glucagon stimulation test, growth hormone deficiency (GHD) was defined with a standard cut point of 3 ng/mL and with a more stringent body mass index (BMI)-adjusted cut point. Subjects with and without hormonal deficiency (HD) were compared in terms of QoL, International Index of Erectile Function (IIEF) scores, metabolic parameters, and football career data. Of 74 subjects, 6 were excluded because of significant non-football-related TBIs. Of the remaining 68 subjects (mean age, 47.3±10.2 years; median NFL years, 5; median NFL concussions, 3; mean BMI, 33.8±6.0), 28 (41.2%) were GHD using a peak GH cutoff of <3 ng/mL. However, with a BMI-adjusted definition of GHD, 13 of 68 (19.1%) were GHD. Using this BMI-adjusted definition, overall HD was found in 16 (23.5%) subjects: 10 (14.7%) with isolated GHD; 3 (4.4%) with isolated hypogonadism; and 3 (4.4%) with both GHD and hypogonadism. Subjects with HD had lower mean scores on the IIEF survey ( p=0.016) and trended toward lower scores on the SF-36 MCS ( p=0.113). MetS was present in 50% of subjects, including 5 of 6 (83%) with hypogonadism, and 29 of 62 (46.8%) without hypogonadism ( p=0.087). Age, BMI, median years in NFL, games played, number of concussions, and acknowledged use of performance-enhancing steroids were similar between HD and non-HD groups. In summary, in this cohort of retired NFL players with poor QoL, 23.5% had HD, including 19% with GHD (using a BMI-adjusted definition), 9% with hypogonadism, and 50% had MetS. Although the cause of HD is unclear, these results suggest that GHD and hypogonadism may contribute to poor QoL, erectile dysfunction, and MetS in this population. Further study of pituitary function is warranted in athletes sustaining repetitive mTBI. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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49. Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents.
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Lue, Yanhe, Wang, Christina, Lydon, John P, Leung, Andrew, Li, James, and Swerdloff, Ronald S.
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SPERMATOGENESIS , *SYNTHETIC progestagens , *PROGESTERONE receptors , *APOPTOSIS , *PHARMACOLOGY , *LABORATORY rodents , *CLINICAL trials - Abstract
Synthetic progestins such as levonorgestrel (LNG) are used in combination with testosterone (T) in male contraceptive clinical trials to suppress gonadotropins secretion, but whether progestins have additional direct effects on the testis are not known. This study aimed to examine the effect of a potent progestin, (LNG), alone or in combination with testosterone (T) on spermatogenesis in adult rats, and to evaluate the functional role of the progesterone receptors (PRs) in the testis. In comparison with a low dose of LNG treatment in adult rats for 4 weeks, T and T + LNG treatment decreased testicular sperm count to 64.1 and 40.2% of control levels respectively. LNG induced germ cell apoptosis at stages I-IV and XII-XTV; T increased apoptosis at stages VII-VIII; LNG + T treatment induced greater germ cell apoptosis at a wider range of seminiferous epithelial stages. RT-PCR and Western Blots showed that PR was present in testes and up-regulated during suppression of spermatogenesis induced by testicular hormonal deprivation. PR knockout (PRKO) mice had larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells. Suppression of gonadotropin and intratesticular T by GnRH-antagonist treatment induced PR promoter driven LacZ expression in Leydig cells of PRKO mice. This suggests that GnRH-antagonist treatment while inducing germ cell apoptosis also up-regulates PR. We conclude that (i) LNG + T induced greater suppression of spermatogenesis through increase in germ cell apoptosis involving a wider range of seminiferous epithelial stages than either treatment alone, (ii) up-regulation of PR was associated with inhibition of spermatogenesis, (iii) PR knockout mice showed increased sperm production suggesting that testicular PR activated events play a physiological and pharmacological inhibitory role in the testis. These data support the hypothesis that in addition to its known suppressive effects on gonadotropins, progestins may have direct inhibitory actions on the testis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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50. Integrity of the blood-testis barrier in healthy men after suppression of spermatogenesis with testosterone and levonorgestrel.
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Ilani N, Armanious N, Lue YH, Swerdloff RS, Baravarian S, Adler A, Tsang C, Jia Y, Cui YG, Wang XH, Zhou ZM, Sha JH, Wang C, Ilani, Niloufar, Armanious, Nancy, Lue, Yan-He, Swerdloff, Ronald S, Baravarian, Sima, Adler, Alex, and Tsang, Christina
- Abstract
Study Question: Do exogenous male hormonal contraceptives that suppress intratesticular testosterone and spermatogenesis interfere with the blood-testis barrier integrity in men?Summary Answer: When spermatogenesis was suppressed by testosterone alone or combined with levonorgestrel (LNG) treatment in men, the structural appearance of Sertoli cell tight junctions remained intact in the human testis.What Is Already Known: Testosterone promotes the integrity of the blood-testis barrier. Intratesticular androgen deprivation induced by exogenous testosterone plus a progestin to suppress spermatogenesis in a contraceptive regimen may disturb the structural and functional integrity of the blood-testis barrier.Study Design, Size and Duration: Testicular biopsies were obtained from a sub-study of a randomized clinical trial of 36 healthy Chinese men who were treated for 18 weeks and followed for at least a 12-week recovery period.Participants/material, Setting, Methods: Healthy Chinese male volunteers (27-48 years) were randomized to two treatment groups (n = 18/group) for 18 weeks: (1) testosterone undecanoate (TU) 1000 mg i.m. injection followed by a 500 mg injection every 6 weeks and (2) TU + LNG 250 μg orally daily. Blood samples were obtained from all participants before and during treatment and at the end of the recovery phase. Open testicular biopsies for this study were obtained from four men before treatment and from four men in each of the TU and TU + LNG groups at 2 and 9 weeks of treatment. The presence of antisperm antibodies was checked in the archived serum samples of the subjects at baseline, during treatment and at the end of the recovery period. Stored testicular biopsy samples from cynomolgus monkeys treated with either sub-cutaneous testosterone or placebo for 12 weeks were used for additional protein expression studies.Main Results and Role Of the Chance: Expression of blood-testis barrier associated proteins quantified by immunohistochemistry (claudin 3, claudin 11, junctional adhesion molecule-A, zonula occludens-1) remained unchanged despite a significant decrease in the numbers of pachytene spermatocytes and round spermatids in the seminiferous tubules at 9 weeks in the TU + LNG group. This was confirmed by immunoblots showing a lack of quantitative change in these tight junction proteins in monkeys after testosterone treatment. There were no increases in serum antisperm antibodies in the volunteers during the study.Limitations/reasons For Caution: The duration of the study was short and the long-term effects of male hormonal contraceptive treatments on the integrity of the blood-testis barrier remain to be determined.Wider Implications Of the Findings: This study supports the safety of male hormonal contraceptive treatment and does not corroborate the previous findings of disturbed immunological integrity of the blood-testis barrier from animal studies such as androgen receptor knockout mice and exogenous hormonal treatment in rats.Study Funding/competing Interest: The study was supported by grants from the Contraceptive Research and Development Program and the Mellon Foundation (MFG-02-64, MFG-03-67), Endocrine, Metabolism and Nutrition Training Grant (T32 DK007571), the Clinical and Translational Science Institute at Los Angeles Biomedical and Harbor-UCLA Medical Center (UL1RR033176 and UL1TR000124) and the Los Angeles Biomedical Research Institute Summer High School Student Program. [ABSTRACT FROM AUTHOR]- Published
- 2012
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