Ronald Swerdloff - Academia.edu (original) (raw)

Papers by Ronald Swerdloff

The Journal of Clinical Endocrinology & Metabolism, 1992

The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropi... more The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropins and spermatogenesis were examined to assess its potential as a male contraceptive regimen. The potent Nal-Glu GnRH antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5, D4-p-methoxybenzoyl-2-amino butyric acid6,D-Ala10]GnRH) was administered daily (7.5 mg, sc) to eight normal men for 16 weeks. T enanthate was given im starting at week 2 and every 2 weeks thereafter through week 14 of the treatment phase. Serum LH, FSH, T, and estradiol concentrations were measured frequently during the 5-week control period, the 16-week treatment phase, and the 14-week recovery phase. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. Seven of eight subjects became azoospermic by 6-10 weeks of treatment; the eighth subject, who failed to achieve azoospermia, suppressed his sperm count to 7 million/mL by week 14 (from a mean baseline of 42 million/mL) before treatment was prematurely terminated because of localized swelling at each of his injection sites. Sperm counts returned to baseline 10-14 weeks after the end of Nal-Glu administration. Seven of the eight subjects showed suppression of LH to the limit of assay detection (less than 0.2 U/L), whereas the eighth subject showed incomplete suppression. Serum bioactive and immunoreactive LH concentrations showed concordant responses. Mean serum FSH concentrations were also markedly suppressed. Serum T and estradiol concentrations declined dramatically during the first 2 weeks of Nal-Glu GnRH treatment, but returned to the normal physiological range after T enanthate replacement was initiated. Libido and sexual potency were maintained. No systemic side-effects, other than erythema and induration at injection sites, were observed. These data demonstrate that combined GnRH antagonist plus T treatment can predictably and reversibly induce azoospermia in most men and has potential as a male contraceptive regimen.

Journal of Andrology, 2003

We have previously shown that a ubiquitously expressed RNA splicing factor, RNA-binding motif 7 (... more We have previously shown that a ubiquitously expressed RNA splicing factor, RNA-binding motif 7 (RBM7), cloned from a testis complementary DNA library, enhances messenger RNA (mRNA) splicing in vitro and is expressed in a cellrestricted fashion. Herein, we detail its mRNA and protein expression in the rodent testis. RNA in situ hybridization shows that Rbm7 expression in rat germ cells closely parallels the entry and progression of meiosis. The expression commences in type B spermatogonia, it rises during the preleptotene stage, peaks in leptotene spermatocytes, and declines afterward, but increases again in stage-associated pachytene spermatocytes. An affinitypurified polyclonal antibody raised against a peptide corresponding to amino acids 202-224 of the mouse RBM7 recognized the predicted 35 kd protein both in testicular lysates and in in vitro translation reactions. Consistent with the in situ hybridization results , RBM7 immunoreactivity was also detected in type B spermatogonia, spanned the entire period of spermatocyte development, and extended to round and early elongated spermatids. Moreover, RBM7 appeared nuclear up to the mid pachytene stage and became cytoplasmic thereafter. Consistent with its role in RNA splicing, yeast 2-hybrid and glutathione S-transferase pull-down assays show that RBM7 interacts with splicing factor 3b subunit 2 (SAP145), and with the splicing regulator, SRp20. These interactions and the nuclear localization of RBM7 provide insights into its function in pre-mRNA processing in developing spermatocytes during entry into meiosis and progression through the meiotic prophase.

Journal of Andrology, 2001

To explore the functional role of Bcl-2 in germ cell development, transgenic mice carrying 6 kilo... more To explore the functional role of Bcl-2 in germ cell development, transgenic mice carrying 6 kilobases of the inhibin-␣ promoter were generated to express human bcl-2 gene product in the gonads. Although female transgenic mice demonstrated decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis, the adult males exhibited variable impairment of spermatogenesis. The degree of damage ranged from tubules with intraepithelial vacuoles of varying sizes to near atrophied tubules consisting of Sertoli cells and a few spermatogonia. Although there was no significant change in body weight, an approximately 34% decrease in testicular weights was noted in transgenic animals compared with wild-type mice. Gamete maturation, assessed by determining the percentage of tubules with advanced (steps 13-16) spermatids, was decreased to 44.4% of the values measured in the wild-type animals. The incidence of germ cell apoptosis increased 3.8-fold in the transgenic animals and was associated with a marked loss of germ cells. Electron microscopy of the testes further revealed large vacuoles in the Sertoli cell cytoplasm and dilations of the intracellular spaces between adjacent Sertoli cells, spermatid malformations, and increased germ cell apoptosis in the transgenic animals. There was no evidence of Sertoli cell death either by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TU-NEL) assay or electron microscopy. Leydig cell ultrastructure, cell size and numbers, and plasma levels of testosterone were not different between normal and the transgenic animals. Collectively, these results support the critical role of Bcl-2 in male germ cell development and are consistent with the gender-specific role of the Bcl-2 family members in reproduction.

Male Reproductive Dysfunction, 2007

Coronary artery disease, Jan 9, 2015

Data from prior studies have yielded inconsistent results on the association of serum testosteron... more Data from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression. We designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population. The Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (<275 ng/dl). CCTA performed at baseline and after 12 months of therapy will determine the effects of testosterone on the progression of the total volume of noncalcified plaques. All ...

Archives of Clinical Neuropsychology, 2021

Repeated sports-related concussions have been associated with cognitive deficits, similar to othe... more Repeated sports-related concussions have been associated with cognitive deficits, similar to other forms of traumatic brain injury. We investigated three different measures of executive ability derived from the Trail Making Test part B (TMT-B) in healthy comparison (HC) adults and retired football players. The sample consisted of 32 HC, 15 retired football speed players (FSP; e.g., quarterbacks), and 53 retired football non-speed players (FNP) participants. Participants were administered both TMT part A (TMT-A) and TMT-B, and total time for completion was recorded. A series of ANCOVAs, controlling for age and education were conducted to evaluate group differences in executive abilities. Executive measures included the TMT-B raw score (i.e., seconds to complete TMT-B), the raw score difference (in seconds) between TMT-A and TMT-B (TMT-BA), and the difference between a predicted TMT-B score (TMT-BP) and the obtained TMT-B score (TMT-BBP). Correlations between TMT-B, TMT-BA, and TMT-BB...

Controversies in Testosterone Deficiency, 2021

Accurate and precise measurement of serum testosterone is adequate for the diagnosis and monitori... more Accurate and precise measurement of serum testosterone is adequate for the diagnosis and monitoring of testosterone replacement for most men with testosterone deficiency. Serum testosterone measurement should be obtained in the morning, preferably in fasting state, and a repeat sample for confirmation is advisable. The sample should be sent to a reliable laboratory that practices accuracy-based proficiency tests or external quality control programs and quotes a reference range of serum testosterone levels of adult men between 250 and 1000 ng/dL (8.7–34.7 nmol/L). The use of free testosterone measurements as a primary diagnostic tool for male hypogonadism has remained controversial. Free testosterone measurements may provide additional information if there are issues with the concentration or the binding of testosterone to sex hormone binding globulin (SHBG). Free testosterone should be measured by equilibrium dialysis which is available in reference laboratories or by calculated fre...

Aging

Humanin is a member of a new family of peptides that are encoded by short open reading frames wit... more Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer’s disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

Journal of the Endocrine Society

Abstract Introduction: Measuring T levels, in addition to monitoring symptoms, during T replaceme... more Abstract Introduction: Measuring T levels, in addition to monitoring symptoms, during T replacement therapy is critical to guide dosing decisions. T levels in blood samples from men receiving oral TU can be elevated substantially above actual circulating T levels due to post-collection conversion of TU to T by esterases in blood. Because erroneous T values can result in inappropriate dose-titration decisions, we identified a method for monitoring T that addresses this problem. Methods: Post-collection conversion of TU to T was evaluated in blood drawn from men who had received oral TU (either JATENZO®, Clarus’s oral TU, or Andriol®) and in blood spiked with TU after collection. Blood was collected in Plain, EDTA or NaF-EDTA tubes and then incubated for selected times (up to 3 hours) at room temperature (RT) or on ice. After incubation, blood was centrifuged and the matrix (serum or plasma) was used for measurement of T and TU concentrations by LC/MS-MS. Regression analysis of rate of change of T concentration during incubation versus TU concentration was used to develop algorithms to correct for T overestimation. Algorithm accuracy was tested using results from the Phase 3 inTUne Trial of JATENZO. Results: T concentrations increase in blood containing TU as the blood sits pre-centrifugation, regardless of whether the TU is in the blood when collected or spiked post-collection. The rate of TU conversion depends on the TU concentration, incubation temperature, and presence of NaF, an esterase inhibitor. Incubation temperature had the greatest impact on conversion - rate at RT >5-fold faster than on ice; NaF had a smaller effect. Most clinic T levels are routinely measured in serum from Plain tubes; however, titration in the inTUne Trial of oral TU was based on T in NaF-EDTA plasma. Based on regression analysis of the TU to T conversion rates measured in serum and NaF-EDTA plasma and the NaF effect on measured T levels, a conversion factor of 1.214 was derived to convert a NaF-EDTA plasma T value to an equivalent serum T value for samples collected 6 hours post-dose (the optimal dose-titration sample point for JATENZO). This conversion factor was tested against T data collected during the final PK Visit of the inTUne Trial (87% of subjects attained eugonadal range based on NaF-EDTA plasma T levels) where serum T levels were also measured. Using the conversion factor to compare the measured serum T value with its matched plasma value, we observed a mean error of only 3.1% (n=155 sample pairs; 95% CI 0.4%, 5.8%). Conclusion: Post-collection conversion of TU to T can cause overestimation of circulating T levels in men dosed with oral TU. By accounting for the conversion with different tube types / handling conditions, a conversion factor was derived to allow monitoring of T concentration in JATENZO patients using serum. This conversion factor was validated for JATENZO against the Phase 3 inTUne data.

Journal of the Endocrine Society

Abstract Background: Macimorelin (MAC), an orally active ghrelin receptor agonist, is indicated f... more Abstract Background: Macimorelin (MAC), an orally active ghrelin receptor agonist, is indicated for the diagnosis of adult growth hormone deficiency (AGHD) in the United States. The efficacy of MAC for AGHD diagnosis was previously demonstrated; comparing MAC at cutpoint values of 2.8 and 5.1 ng/mL with ITT at cutpoint values of 3.0 and 5.1 ng/mL.1,2Objective: This post hoc analysis evaluated the percent agreement and sensitivity and specificity of MAC vs ITT over a range of GH cutpoints. Methods: This analysis included data from a phase 3, open-label, randomized, 2-way crossover study of MAC vs ITT in subjects with high (Group A, n=38), intermediate (Group B, n=37), and low (Group C, n=40) likelihood for AGHD and healthy, matched controls (Group D, n=25).1 Percent agreement (negative, positive, and overall) and estimated sensitivity and specificity were determined using GH cutpoint values of 2.8, 4, 5.1, and 6.5 ng/mL for both MAC and ITT. Results: 74 subjects were classified as GH deficient, and 66 subjects were classified as GH sufficient. These subjects were classified based on the ITT using a cutpoint of 5.1 ng/mL.1 The highest negative, positive, and overall agreements between tests were observed when GH cutpoints chosen for MAC and ITT were identical to each other and were either 2.8 or 5.1 ng/mL. With a GH cutpoint value of 2.8 ng/mL for both tests, negative agreement was 94% (95% CI: 86%, 98%), positive agreement was 87% (95% CI: 76%, 94%), and overall agreement was 91% (95% CI: 85%, 95%). At a GH cutpoint value of 5.1 ng/mL for both tests, negative agreement was 92% (95% CI: 83%, 97%), positive agreement was 82% (95% CI: 72%, 90%), and overall agreement was 87% (95% CI: 80%, 92%). Assuming all Group A participants were cases and all Group D participants were controls, estimated specificities of MAC and ITT were identical (96%) at GH cutpoint values of 2.8, 4, or 5.1 ng/mL. Estimated sensitivity for ITT at GH cutpoint value of 5.1 ng/mL (97%) was higher than for MAC at cutpoint value of 2.8 ng/mL (87%); increasing the test cutpoint to 6.5 ng/mL increased sensitivity to 97% and 100% for MAC and ITT, respectively, but at the expense of specificity decreases to 92% (MAC) and 88% (ITT). Conclusions: Among the cutpoints examined, agreement between MAC and ITT was highest at either 2.8 or 5.1 ng/mL, with positive agreement declining modestly at the higher cutpoint. Sensitivity of MAC was maximal at 6.5 ng/mL but at the expense of a decline in specificity from 96% to 92%, which may be undesirable if the primary consideration is minimization of false-positive diagnosis of AGHD. A MAC cutpoint of 5.1 ng/mL provides maximal specificity (96%) and high sensitivity (92%) with good overall agreement to ITT at the same cutpoint (87%), making it clinically useful for the diagnosis of AGHD. Reference: 1. Garcia JM, et al. J Clin Endocrinol Metab. 2018;103(8):3083-3093. 2. Garcia JM, et al. Presented at ENEA; 17-20 October 2018; Wroclaw, Poland.

Journal of Steroid Biochemistry

The lancet. Diabetes & endocrinology, 2018

The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of whic... more The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff m...

Clinical endocrinology, Jan 23, 2018

The purpose of this narrative review was to summarize available data on testosterone levels in no... more 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. 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. In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range be...

The Journal of clinical endocrinology and metabolism, May 17, 2018

To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guidelin... more To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) defi...

The Journal of clinical endocrinology and metabolism, Feb 14, 2017

Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. To determ... more Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. To determine the effect of testosterone treatment on cardiovascular (CV) biomarkers in older men with low testosterone. Double-blind, placebo-controlled trial. Twelve academic medical centers in the United States. 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Testosterone treatment, compared to placebo, significantly decreased total cholesterol (adjusted mean difference -6.1 mg/dL, p<0.001), high density lipoprotein (HDL) cholesterol (adjusted mean difference -2.0 mg/dL, p<0.001) cholesterol and low density lipoprotein (LDL) cholestero...

Pituitary, Jan 9, 2017

Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes f... more Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course. The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ("second round") an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: "agreement" if no more than two responses were outside a 2 week window around the median response; "disagreement" if more than two responses were outside a 2 week window around the median response. Recommendations were developed...

The Journal of Clinical Endocrinology & Metabolism, 1992

The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropi... more The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropins and spermatogenesis were examined to assess its potential as a male contraceptive regimen. The potent Nal-Glu GnRH antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5, D4-p-methoxybenzoyl-2-amino butyric acid6,D-Ala10]GnRH) was administered daily (7.5 mg, sc) to eight normal men for 16 weeks. T enanthate was given im starting at week 2 and every 2 weeks thereafter through week 14 of the treatment phase. Serum LH, FSH, T, and estradiol concentrations were measured frequently during the 5-week control period, the 16-week treatment phase, and the 14-week recovery phase. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. Seven of eight subjects became azoospermic by 6-10 weeks of treatment; the eighth subject, who failed to achieve azoospermia, suppressed his sperm count to 7 million/mL by week 14 (from a mean baseline of 42 million/mL) before treatment was prematurely terminated because of localized swelling at each of his injection sites. Sperm counts returned to baseline 10-14 weeks after the end of Nal-Glu administration. Seven of the eight subjects showed suppression of LH to the limit of assay detection (less than 0.2 U/L), whereas the eighth subject showed incomplete suppression. Serum bioactive and immunoreactive LH concentrations showed concordant responses. Mean serum FSH concentrations were also markedly suppressed. Serum T and estradiol concentrations declined dramatically during the first 2 weeks of Nal-Glu GnRH treatment, but returned to the normal physiological range after T enanthate replacement was initiated. Libido and sexual potency were maintained. No systemic side-effects, other than erythema and induration at injection sites, were observed. These data demonstrate that combined GnRH antagonist plus T treatment can predictably and reversibly induce azoospermia in most men and has potential as a male contraceptive regimen.

Journal of Andrology, 2003

We have previously shown that a ubiquitously expressed RNA splicing factor, RNA-binding motif 7 (... more We have previously shown that a ubiquitously expressed RNA splicing factor, RNA-binding motif 7 (RBM7), cloned from a testis complementary DNA library, enhances messenger RNA (mRNA) splicing in vitro and is expressed in a cellrestricted fashion. Herein, we detail its mRNA and protein expression in the rodent testis. RNA in situ hybridization shows that Rbm7 expression in rat germ cells closely parallels the entry and progression of meiosis. The expression commences in type B spermatogonia, it rises during the preleptotene stage, peaks in leptotene spermatocytes, and declines afterward, but increases again in stage-associated pachytene spermatocytes. An affinitypurified polyclonal antibody raised against a peptide corresponding to amino acids 202-224 of the mouse RBM7 recognized the predicted 35 kd protein both in testicular lysates and in in vitro translation reactions. Consistent with the in situ hybridization results , RBM7 immunoreactivity was also detected in type B spermatogonia, spanned the entire period of spermatocyte development, and extended to round and early elongated spermatids. Moreover, RBM7 appeared nuclear up to the mid pachytene stage and became cytoplasmic thereafter. Consistent with its role in RNA splicing, yeast 2-hybrid and glutathione S-transferase pull-down assays show that RBM7 interacts with splicing factor 3b subunit 2 (SAP145), and with the splicing regulator, SRp20. These interactions and the nuclear localization of RBM7 provide insights into its function in pre-mRNA processing in developing spermatocytes during entry into meiosis and progression through the meiotic prophase.

Journal of Andrology, 2001

To explore the functional role of Bcl-2 in germ cell development, transgenic mice carrying 6 kilo... more To explore the functional role of Bcl-2 in germ cell development, transgenic mice carrying 6 kilobases of the inhibin-␣ promoter were generated to express human bcl-2 gene product in the gonads. Although female transgenic mice demonstrated decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis, the adult males exhibited variable impairment of spermatogenesis. The degree of damage ranged from tubules with intraepithelial vacuoles of varying sizes to near atrophied tubules consisting of Sertoli cells and a few spermatogonia. Although there was no significant change in body weight, an approximately 34% decrease in testicular weights was noted in transgenic animals compared with wild-type mice. Gamete maturation, assessed by determining the percentage of tubules with advanced (steps 13-16) spermatids, was decreased to 44.4% of the values measured in the wild-type animals. The incidence of germ cell apoptosis increased 3.8-fold in the transgenic animals and was associated with a marked loss of germ cells. Electron microscopy of the testes further revealed large vacuoles in the Sertoli cell cytoplasm and dilations of the intracellular spaces between adjacent Sertoli cells, spermatid malformations, and increased germ cell apoptosis in the transgenic animals. There was no evidence of Sertoli cell death either by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TU-NEL) assay or electron microscopy. Leydig cell ultrastructure, cell size and numbers, and plasma levels of testosterone were not different between normal and the transgenic animals. Collectively, these results support the critical role of Bcl-2 in male germ cell development and are consistent with the gender-specific role of the Bcl-2 family members in reproduction.

Male Reproductive Dysfunction, 2007

Coronary artery disease, Jan 9, 2015

Data from prior studies have yielded inconsistent results on the association of serum testosteron... more Data from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression. We designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population. The Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (<275 ng/dl). CCTA performed at baseline and after 12 months of therapy will determine the effects of testosterone on the progression of the total volume of noncalcified plaques. All ...

Archives of Clinical Neuropsychology, 2021

Repeated sports-related concussions have been associated with cognitive deficits, similar to othe... more Repeated sports-related concussions have been associated with cognitive deficits, similar to other forms of traumatic brain injury. We investigated three different measures of executive ability derived from the Trail Making Test part B (TMT-B) in healthy comparison (HC) adults and retired football players. The sample consisted of 32 HC, 15 retired football speed players (FSP; e.g., quarterbacks), and 53 retired football non-speed players (FNP) participants. Participants were administered both TMT part A (TMT-A) and TMT-B, and total time for completion was recorded. A series of ANCOVAs, controlling for age and education were conducted to evaluate group differences in executive abilities. Executive measures included the TMT-B raw score (i.e., seconds to complete TMT-B), the raw score difference (in seconds) between TMT-A and TMT-B (TMT-BA), and the difference between a predicted TMT-B score (TMT-BP) and the obtained TMT-B score (TMT-BBP). Correlations between TMT-B, TMT-BA, and TMT-BB...

Controversies in Testosterone Deficiency, 2021

Accurate and precise measurement of serum testosterone is adequate for the diagnosis and monitori... more Accurate and precise measurement of serum testosterone is adequate for the diagnosis and monitoring of testosterone replacement for most men with testosterone deficiency. Serum testosterone measurement should be obtained in the morning, preferably in fasting state, and a repeat sample for confirmation is advisable. The sample should be sent to a reliable laboratory that practices accuracy-based proficiency tests or external quality control programs and quotes a reference range of serum testosterone levels of adult men between 250 and 1000 ng/dL (8.7–34.7 nmol/L). The use of free testosterone measurements as a primary diagnostic tool for male hypogonadism has remained controversial. Free testosterone measurements may provide additional information if there are issues with the concentration or the binding of testosterone to sex hormone binding globulin (SHBG). Free testosterone should be measured by equilibrium dialysis which is available in reference laboratories or by calculated fre...

Aging

Humanin is a member of a new family of peptides that are encoded by short open reading frames wit... more Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer’s disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

Journal of the Endocrine Society

Abstract Introduction: Measuring T levels, in addition to monitoring symptoms, during T replaceme... more Abstract Introduction: Measuring T levels, in addition to monitoring symptoms, during T replacement therapy is critical to guide dosing decisions. T levels in blood samples from men receiving oral TU can be elevated substantially above actual circulating T levels due to post-collection conversion of TU to T by esterases in blood. Because erroneous T values can result in inappropriate dose-titration decisions, we identified a method for monitoring T that addresses this problem. Methods: Post-collection conversion of TU to T was evaluated in blood drawn from men who had received oral TU (either JATENZO®, Clarus’s oral TU, or Andriol®) and in blood spiked with TU after collection. Blood was collected in Plain, EDTA or NaF-EDTA tubes and then incubated for selected times (up to 3 hours) at room temperature (RT) or on ice. After incubation, blood was centrifuged and the matrix (serum or plasma) was used for measurement of T and TU concentrations by LC/MS-MS. Regression analysis of rate of change of T concentration during incubation versus TU concentration was used to develop algorithms to correct for T overestimation. Algorithm accuracy was tested using results from the Phase 3 inTUne Trial of JATENZO. Results: T concentrations increase in blood containing TU as the blood sits pre-centrifugation, regardless of whether the TU is in the blood when collected or spiked post-collection. The rate of TU conversion depends on the TU concentration, incubation temperature, and presence of NaF, an esterase inhibitor. Incubation temperature had the greatest impact on conversion - rate at RT >5-fold faster than on ice; NaF had a smaller effect. Most clinic T levels are routinely measured in serum from Plain tubes; however, titration in the inTUne Trial of oral TU was based on T in NaF-EDTA plasma. Based on regression analysis of the TU to T conversion rates measured in serum and NaF-EDTA plasma and the NaF effect on measured T levels, a conversion factor of 1.214 was derived to convert a NaF-EDTA plasma T value to an equivalent serum T value for samples collected 6 hours post-dose (the optimal dose-titration sample point for JATENZO). This conversion factor was tested against T data collected during the final PK Visit of the inTUne Trial (87% of subjects attained eugonadal range based on NaF-EDTA plasma T levels) where serum T levels were also measured. Using the conversion factor to compare the measured serum T value with its matched plasma value, we observed a mean error of only 3.1% (n=155 sample pairs; 95% CI 0.4%, 5.8%). Conclusion: Post-collection conversion of TU to T can cause overestimation of circulating T levels in men dosed with oral TU. By accounting for the conversion with different tube types / handling conditions, a conversion factor was derived to allow monitoring of T concentration in JATENZO patients using serum. This conversion factor was validated for JATENZO against the Phase 3 inTUne data.

Journal of the Endocrine Society

Abstract Background: Macimorelin (MAC), an orally active ghrelin receptor agonist, is indicated f... more Abstract Background: Macimorelin (MAC), an orally active ghrelin receptor agonist, is indicated for the diagnosis of adult growth hormone deficiency (AGHD) in the United States. The efficacy of MAC for AGHD diagnosis was previously demonstrated; comparing MAC at cutpoint values of 2.8 and 5.1 ng/mL with ITT at cutpoint values of 3.0 and 5.1 ng/mL.1,2Objective: This post hoc analysis evaluated the percent agreement and sensitivity and specificity of MAC vs ITT over a range of GH cutpoints. Methods: This analysis included data from a phase 3, open-label, randomized, 2-way crossover study of MAC vs ITT in subjects with high (Group A, n=38), intermediate (Group B, n=37), and low (Group C, n=40) likelihood for AGHD and healthy, matched controls (Group D, n=25).1 Percent agreement (negative, positive, and overall) and estimated sensitivity and specificity were determined using GH cutpoint values of 2.8, 4, 5.1, and 6.5 ng/mL for both MAC and ITT. Results: 74 subjects were classified as GH deficient, and 66 subjects were classified as GH sufficient. These subjects were classified based on the ITT using a cutpoint of 5.1 ng/mL.1 The highest negative, positive, and overall agreements between tests were observed when GH cutpoints chosen for MAC and ITT were identical to each other and were either 2.8 or 5.1 ng/mL. With a GH cutpoint value of 2.8 ng/mL for both tests, negative agreement was 94% (95% CI: 86%, 98%), positive agreement was 87% (95% CI: 76%, 94%), and overall agreement was 91% (95% CI: 85%, 95%). At a GH cutpoint value of 5.1 ng/mL for both tests, negative agreement was 92% (95% CI: 83%, 97%), positive agreement was 82% (95% CI: 72%, 90%), and overall agreement was 87% (95% CI: 80%, 92%). Assuming all Group A participants were cases and all Group D participants were controls, estimated specificities of MAC and ITT were identical (96%) at GH cutpoint values of 2.8, 4, or 5.1 ng/mL. Estimated sensitivity for ITT at GH cutpoint value of 5.1 ng/mL (97%) was higher than for MAC at cutpoint value of 2.8 ng/mL (87%); increasing the test cutpoint to 6.5 ng/mL increased sensitivity to 97% and 100% for MAC and ITT, respectively, but at the expense of specificity decreases to 92% (MAC) and 88% (ITT). Conclusions: Among the cutpoints examined, agreement between MAC and ITT was highest at either 2.8 or 5.1 ng/mL, with positive agreement declining modestly at the higher cutpoint. Sensitivity of MAC was maximal at 6.5 ng/mL but at the expense of a decline in specificity from 96% to 92%, which may be undesirable if the primary consideration is minimization of false-positive diagnosis of AGHD. A MAC cutpoint of 5.1 ng/mL provides maximal specificity (96%) and high sensitivity (92%) with good overall agreement to ITT at the same cutpoint (87%), making it clinically useful for the diagnosis of AGHD. Reference: 1. Garcia JM, et al. J Clin Endocrinol Metab. 2018;103(8):3083-3093. 2. Garcia JM, et al. Presented at ENEA; 17-20 October 2018; Wroclaw, Poland.

Journal of Steroid Biochemistry

The lancet. Diabetes & endocrinology, 2018

The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of whic... more The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff m...

Clinical endocrinology, Jan 23, 2018

The purpose of this narrative review was to summarize available data on testosterone levels in no... more 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. 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. In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range be...

The Journal of clinical endocrinology and metabolism, May 17, 2018

To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guidelin... more To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) defi...

The Journal of clinical endocrinology and metabolism, Feb 14, 2017

Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. To determ... more Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. To determine the effect of testosterone treatment on cardiovascular (CV) biomarkers in older men with low testosterone. Double-blind, placebo-controlled trial. Twelve academic medical centers in the United States. 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Testosterone treatment, compared to placebo, significantly decreased total cholesterol (adjusted mean difference -6.1 mg/dL, p<0.001), high density lipoprotein (HDL) cholesterol (adjusted mean difference -2.0 mg/dL, p<0.001) cholesterol and low density lipoprotein (LDL) cholestero...

Pituitary, Jan 9, 2017

Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes f... more Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course. The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ("second round") an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: "agreement" if no more than two responses were outside a 2 week window around the median response; "disagreement" if more than two responses were outside a 2 week window around the median response. Recommendations were developed...