28 results on '"Sheri Ann, Hild"'
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2. Nonhuman primate models for SARS-CoV-2 research: Infrastructure needs for pandemic preparedness
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Sheri Ann, Hild, Michael C, Chang, Stephanie J, Murphy, and Franziska B, Grieder
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Primates ,Disease Models, Animal ,SARS-CoV-2 ,Animals ,COVID-19 ,Humans ,Pandemics - Published
- 2021
3. Nonhuman primate models for SARS-CoV-2 Research: Managing demand for specific-pathogen-free (SPF) animals
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Sheri Ann Hild, Miguel A. Contreras, Stephanie J. Murphy, Franziska B. Grieder, Matthew E. Arnegard, and Michael C Chang
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0303 health sciences ,General Veterinary ,biology ,Coronavirus disease 2019 (COVID-19) ,040301 veterinary sciences ,animal diseases ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,04 agricultural and veterinary sciences ,biochemical phenomena, metabolism, and nutrition ,digestive system ,Virology ,Nonhuman primate ,0403 veterinary science ,03 medical and health sciences ,biology.animal ,Pandemic ,Research studies ,Animal Science and Zoology ,Primate ,Specific Pathogen Free Organism ,skin and connective tissue diseases ,030304 developmental biology ,Specific-pathogen-free - Abstract
The SARS-CoV-2/COVID-19 pandemic has significantly increased the demand for specific-pathogen-free (SPF) nonhuman primates (NHPs) for development of vaccines and therapeutics, thus straining the supply of these animals for biomedical research studies. Non-SPF animals, which are available in greater numbers and include well-characterized primate species, should be considered in lieu of limited SPF animals for appropriate research studies.
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- 2021
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4. Nonhuman primate models for SARS-CoV-2 research: Cryopreservation as a means to maintain critical models and enhance the genetic diversity of colonies
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Sheri Ann Hild and Matthew E. Arnegard
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Genetics ,0303 health sciences ,2019-20 coronavirus outbreak ,Genetic diversity ,General Veterinary ,040301 veterinary sciences ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Treatment outcome ,04 agricultural and veterinary sciences ,Biology ,humanities ,Cryopreservation ,Nonhuman primate ,0403 veterinary science ,03 medical and health sciences ,Genetic variation ,Genetic model ,Animal Science and Zoology ,030304 developmental biology - Abstract
Nonhuman primate (NHP) models, the most predictive preclinical models for human diseases and treatment outcomes, are in high demand and limited supply. There is a need for improved cryopreservation methods and routine storage of gametes and embryos, which are vital to protecting unique genetic models as well as providing resources for enhancing the genetic diversity of NHP colonies.
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- 2021
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5. Nonhuman primate models for SARS-CoV-2 research: Infrastructure needs for pandemic preparedness
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Sheri Ann Hild, Franziska B. Grieder, Stephanie J. Murphy, and Michael C Chang
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0303 health sciences ,2019-20 coronavirus outbreak ,General Veterinary ,Coronavirus disease 2019 (COVID-19) ,040301 veterinary sciences ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pandemic preparedness ,Treatment outcome ,04 agricultural and veterinary sciences ,Biocontainment ,medicine.disease ,Nonhuman primate ,0403 veterinary science ,03 medical and health sciences ,Pandemic ,Medicine ,Animal Science and Zoology ,Medical emergency ,business ,030304 developmental biology - Abstract
The SARS-CoV-2 pandemic has significantly increased the demand for nonhuman primates (NHPs), the preclinical model most predictive of disease and treatment outcomes in humans, and for biocontainment laboratory spaces adjacent to facilities housing NHPs. Accompanying this requirement for biocontainment and research laboratory space is the need for skilled personnel to work in these facilities.
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- 2021
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6. Nonhuman primate models for SARS-CoV-2 research: Consider alternatives to macaques
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Sheri Ann Hild, Franziska B. Grieder, and Michael C Chang
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0303 health sciences ,2019-20 coronavirus outbreak ,General Veterinary ,Coronavirus disease 2019 (COVID-19) ,biology ,040301 veterinary sciences ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,04 agricultural and veterinary sciences ,Disease ,Virology ,Nonhuman primate ,0403 veterinary science ,03 medical and health sciences ,biology.animal ,Pandemic ,Research studies ,Animal Science and Zoology ,Primate ,030304 developmental biology - Abstract
The SARS-CoV-2 pandemic has significantly increased the demand for rhesus macaques, which might outstrip the supply for COVID-19 research and for other biomedical research studies. Baboons, another well-characterized research primate model, should be considered as a promising alternative for COVID-19 disease studies.
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- 2021
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7. N-Butyldeoxygalactonojirimycin Induces Reversible Infertility in Male CD Rats
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Joseph S. Tash, Henry L. Wong, Erick J. Carlson, Vijayalaxmi Gupta, C. Leigh Allen, Gunda I. Georg, Sheri Ann Hild, and Sudhakar Jakkaraj
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0301 basic medicine ,Infertility ,medicine.medical_specialty ,contraceptive ,media_common.quotation_subject ,iminosugar ,Iminosugar ,Fertility ,Catalysis ,Article ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,Internal medicine ,medicine ,NB-DNJ ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,media_common ,chemistry.chemical_classification ,030219 obstetrics & reproductive medicine ,biology ,Organic Chemistry ,General Medicine ,medicine.disease ,In vitro ,Computer Science Applications ,030104 developmental biology ,Enzyme ,Endocrinology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,biology.protein ,Glucosyltransferase ,NB-DGJ - Abstract
This study shows for the first time that an iminosugar exerts anti-spermiogenic effect, inducing reversible infertility in a species that is not related to C57BL/6 male mice. In CD rats, N-butyldeoxygalactonojirimycin (NB-DGJ) caused reversible infertility at 150 mg/kg/day when administered daily as single oral dose. NB-DGJ inhibited CD rat-derived testicular &beta, glucosidase 2 (GBA2) activity at 10 µ, M but did not inhibit CD rat-derived testicular ceramide-specific glucosyltransferase (CGT) at doses up to 1000 µ, M. Pharmacokinetic studies revealed that sufficient plasma levels of NB-DGJ (50 µ, M) were achieved to inhibit the enzyme. Fertility was blocked after 35 days of treatment and reversed one week after termination of treatment. The rapid return of fertility indicates that the major effect of NB-DGJ may be epididymal rather than testicular. Collectively, our in vitro and in vivo studies in rats suggest that iminosugars should continue to be pursued as potential lead compounds for development of oral, non-hormonal male contraceptives. The study also adds evidence that GBA2, and not CGT, is the major target for the contraceptive effect of iminosugars.
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- 2019
8. Development of Dimethandrolone 17 -Undecanoate (DMAU) as an Oral Male Hormonal Contraceptive: Induction of Infertility and Recovery of Fertility in Adult Male Rabbits
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Barbara J. Attardi, Sheri Ann Hild, David Gropp, and Jean A. Engbring
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Male ,medicine.medical_specialty ,Urology ,Endocrinology, Diabetes and Metabolism ,Biology ,Andrology ,Follicle-stimulating hormone ,Endocrinology ,Internal medicine ,medicine ,Animals ,Nandrolone ,Spermatogenesis ,Infertility, Male ,Testosterone ,Contraceptive Agents, Male ,Dimethandrolone ,medicine.disease ,Spermatozoa ,Sperm ,Contraception ,Fertility ,Reproductive Medicine ,Oligospermia ,Dimethandrolone-undecanoate ,Rabbits ,Luteinizing hormone - Abstract
Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen with progestational activity that is in development for therapeutic uses in men. We hypothesized that because of its dual activity, DMAU might have potential as a single-agent oral hormonal contraceptive. To test this possibility, adult male rabbits (5/group) of proven fertility were treated orally with vehicle or DMAU at 1.0, 2.5, 5.0, or 10.0 mg/kg/d for 12 or 13 weeks. Semen and blood samples were collected every other week through week 30. Sperm were decreased (P.05) in semen samples from DMAU-treated rabbits at 2.5 and 5.0 mg/kg/d at weeks 12, 14, 16, 18, and 20 compared to week 0 (prior to treatment). The percentage of forward progressive motile sperm in those rabbits that still had measurable sperm was also reduced by DMAU treatment at 2.5 mg/kg/d at weeks 14, 16, 18, and 20 and at 5.0 mg/kg/d at week 18 (P.05). At 1.0 mg/kg/d only 1 rabbit had reduced sperm numbers and motility. A mating trial was performed at week 15. The number of bred males that were fertile was 4 of 4 in the vehicle-treated group and 4 of 5, 0 of 4, and 2 of 5 in the 1.0, 2.5, and 5.0 mg/kg/d DMAU treatment groups. By week 22, sperm numbers and forward progressive motility increased, and they returned to pretreatment levels in all DMAU-treated rabbits by week 30. All bred males were fertile at week 31. Serum levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were significantly suppressed in DMAU (1.0, 2.5, or 5.0 mg/kg/d)-treated rabbits during the 12-week dosing interval, but were comparable to pretreatment levels after cessation of dosing. These data indicate that DMAU suppressed the hypothalamic-pituitary-gonadal axis, resulting in severe oligospermia in the majority of rabbits in the 2.5 and 5.0 mg/kg/d dosing groups. Infertility was observed when sperm numbers decreased to about 10% of pretreatment levels. In rabbits dosed with DMAU at 10.0 mg/kg/d, no effect on sperm numbers or motility was observed by week 12. Dosing continued for another week, and the rabbits underwent a gross necropsy on week 13 with removal of testes and epididymides for histology and preparation of testicular cytosol. Serum testosterone, FSH, and LH levels were considerably suppressed in these rabbits as in the lower-dose groups. The lack of oligospermia in the 10.0 mg/kg group as well as in the 2 fertile males in the 5.0 mg/kg group may have been due to high intratesticular levels of 7α,11β-dimethyl-19-nortestosterone, the active metabolite of DMAU. Hence, as observed previously for testosterone, DMAU has a biphasic effect on spermatogenesis. Collectively, these data indicate that DMAU has the potential to be an orally active single-agent male hormonal contraceptive at an appropriate dose level and should be tested for contraceptive efficacy in nonhuman primates.
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- 2010
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9. Relative progestational and androgenic activity of four progestins used for male hormonal contraception assessed in vitro in relation to their ability to suppress LH secretion in the castrate male rat
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Sheri Ann Hild, Barbara J. Attardi, and Sailaja Koduri
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Male ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,Steroid hormone receptor binding ,Down-Regulation ,Pharmacology ,Transfection ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Endocrinology ,Genes, Reporter ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Levonorgestrel ,Luciferases ,Molecular Biology ,Testosterone ,business.industry ,Contraceptive Agents, Male ,Cyproterone acetate ,Norethindrone Acetate ,Luteinizing Hormone ,Androgen ,Rats ,Gonadotropin secretion ,Contraception ,Gene Expression Regulation ,chemistry ,Androgens ,Progestins ,business ,Orchiectomy ,Progestin ,medicine.drug - Abstract
Male hormonal contraceptive regimens are generally combinations of an androgen and a progestin which suppress gonadotropin secretion and, consequently, spermatogenesis. The activities of four synthetic progestins, levonorgestrel (LNG), norethindrone acetate (NETA), cyproterone acetate (CPA), and nestorone (NES), used in combination with testosterone for male hormonal contraception were compared in vitro and in vivo . In vitro assays (steroid hormone receptor binding and transactivation) focused on their relative androgenic vs progestational potencies. The relative androgenic potencies were LNG ≈ NETA > CPA > NES. Their order of potency as progestins was NES > LNG > CPA ≈ NETA. A bioassay was developed using the castrate adult male rat to assess the activity of these progestins in vivo . Rats were treated with several doses (0.1–3.2 mg/kg/day) of LNG, NETA, CPA, or NES for 21 days, and blood was collected at various times for measurement of LH levels in serum. LH was suppressed to baseline by LNG at 0.8 and 1.6 mg/kg/day; NETA was effective at 3.2 mg/kg/day; and NES and CPA showed no or minimal LH suppression at doses up to 3.2 mg/kg/day. We concluded, therefore, that suppression of LH is correlated with androgenic, rather than progestational, potency of the synthetic progestins.
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- 2010
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10. Mechanism of action of bolandiol (19-nortestosterone-3β,17β-diol), a unique anabolic steroid with androgenic, estrogenic, and progestational activities
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Barbara J. Attardi, Sheri Ann Hild, Alvin M. Matsumoto, Stephanie T. Page, and Christopher C. Coss
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Male ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,Estrogen receptor ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Anabolic Agents ,Endocrinology ,Nandrolone ,Testosterone ,Enzyme Inhibitors ,Aromatase ,Receptor ,Estradiol ,Estrogen Antagonists ,Prostate ,Seminal Vesicles ,Dihydrotestosterone ,Organ Size ,Recombinant Proteins ,Receptors, Estrogen ,Receptors, Androgen ,Androgens ,Molecular Medicine ,Female ,Receptors, Progesterone ,medicine.drug ,Transcriptional Activation ,medicine.medical_specialty ,medicine.drug_class ,Biology ,Article ,Receptors, Glucocorticoid ,Bolandiol ,Internal medicine ,medicine ,Animals ,Humans ,Molecular Biology ,Uterus ,Androgen Antagonists ,Estrogens ,Muscle, Smooth ,Cell Biology ,Luteinizing Hormone ,Androgen ,Rats ,Androgen receptor ,chemistry ,biology.protein ,Progestins ,Anabolic steroid - Abstract
Bolandiol is a synthetic anabolic steroid that increases lean body mass and bone mineral density without significant stimulation of sex accessory glands in castrate adult male rats. Since bolandiol suppresses gonadotropins and endogenous testosterone (T) production, we investigated its mechanism of action. We compared the potency of bolandiol in vitro and in vivo with T, 5alpha-dihydrotestosterone (DHT), 19-nortestosterone (19-NT) and estradiol (E(2)). Bolandiol bound with lower affinity to the recombinant rat androgen receptor (AR) than the other androgens and had low, but measurable, affinity for recombinant human progestin receptors (PR-A, PR-B), and estrogen receptors (ERalpha and beta-1). Functional agonist activity was assessed in transcription assays mediated by AR, PR, or ER. Bolandiol was stimulatory in all these assays, but only 4-9% as potent as T, DHT, and 19-NT via AR, 1% as potent as progesterone via PR, and 3% and 1% as potent as E(2) acting through ERalpha or ERbeta, respectively. In immature castrate rats, bolandiol was equipotent to T in stimulating growth of the levator ani muscle but less potent than T in stimulating growth of the sex accessory glands. Bolandiol also stimulated uterine weight increases in immature female rats, which were partly blocked by ICI 182,780, but it was not aromatized in vitro by recombinant human aromatase. In contrast to T, stimulation of sex accessory gland weights by bolandiol was not inhibited by concomitant treatment with the dual 5alpha-reductase inhibitor dutasteride. As bolandiol exhibits tissue selectivity in vivo, it may act via AR, PR, and/or ER, utilize alternative signaling pathway(s) or transcriptional coregulators, and/or be metabolized to a more potent selective steroid.
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- 2010
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11. Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase
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Janet Burgenson, Lisa M. Radler, Jerry R. Reel, Trung C. Pham, Sheri Ann Hild, and Barbara J. Attardi
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medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Models, Biological ,Biochemistry ,Chemical synthesis ,Article ,Aromatase ,Endocrinology ,Tumor Cells, Cultured ,medicine ,Humans ,Nandrolone ,Testosterone ,Estrenes ,Molecular Biology ,Aromatase inhibitor ,Estradiol ,biology ,Chemistry ,Letrozole ,Aromatization ,Dimethandrolone ,Cell Biology ,Androgen ,Recombinant Proteins ,Cyclization ,Dimethandrolone-undecanoate ,Androgens ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
Dimethandrolone undecanoate (DMAU: 7alpha,11beta-dimethyl-19-nortestosterone 17beta-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17beta-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11beta-methyl-19-nortestosterone (11beta-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) alpha and beta in competitive binding assays (IC50's: 5-12 x 10(-9) M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E2) (EC50's: 10(-12) to 10(-11) M). C19 androgens (T, 17alpha-methyltestosterone (17alpha-MT), androstenedione (AD), and 16alpha-hydroxyandrostenedione (16alpha-OHAD)), 19-norandrogens (DMA, 11beta-MNT, 19-nortestosterone (19-NT), and 7alpha-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 microM with recombinant human aromatase for 10-180 min at 37 degrees C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16alpha-OHAD was linear for 40-60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11beta-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11beta position.
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- 2008
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12. A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose1
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Gunda I. Georg, Joseph S. Tash, Sudhakar Jakkaraj, Barbara J. Attardi, Ramappa Chakrasali, and Sheri Ann Hild
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Infertility ,Indazole ,medicine.medical_specialty ,Gamendazole ,Male contraceptive ,Cell Biology ,General Medicine ,Biology ,medicine.disease ,Sertoli cell ,In vitro ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,Reproductive Medicine ,chemistry ,Internal medicine ,medicine ,Adjudin ,Spermatogenesis - Abstract
Women have historically been the focus for development of new contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal male contraceptive agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal male contraceptive agent can occur.
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- 2008
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13. Development ofl-CDB-4022 as a Nonsteroidal Male Oral Contraceptive: Induction and Recovery from Severe Oligospermia in the Adult Male Cynomolgus Monkey (Macaca fascicularis)
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Rex A. Hess, Jerry R. Reel, Sheri Ann Hild, Tony M. Plant, David R. Simorangkir, Barbara J. Attardi, Gary R. Marshall, Stefan Schlatt, Sailaja Koduri, and Suresh Ramaswamy
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Male ,medicine.medical_specialty ,Drug Evaluation, Preclinical ,Administration, Oral ,Male contraceptive ,Models, Biological ,Endocrinology ,Piperidines ,biology.animal ,Internal medicine ,Testis ,medicine ,Animals ,Testosterone ,Primate ,Sperm motility ,Epididymis ,biology ,Contraceptive Agents, Male ,Oligospermia ,Recovery of Function ,Luteinizing Hormone ,medicine.disease ,Sperm ,Macaca fascicularis ,medicine.anatomical_structure ,Seminiferous tubule ,Indenes ,Follicle Stimulating Hormone ,Luteinizing hormone - Abstract
The present study was undertaken to examine the antispermatogenic effect of l-CDB-4022 in the adult male cynomolgus monkey. Monkeys (four per group) were dosed via nasogastric tube for 7 d with l-CDB-4022 at 12.5 mg/kg.d or vehicle (d 0=first day of dosing). Plasma levels of l-CDB-4022 and its deesterified metabolite were nondetectable prior to treatment and in all vehicle-treated monkeys. Peak levels of l-CDB-4022 and its metabolite were observed at 4 h after dosing with steady-state levels apparent around d 4. Sperm concentration and total sperm per ejaculate were decreased to levels below 1x10(6) sperm/ml or sperm/ejaculate in l-CDB-4022-treated monkeys by d 17 and remained suppressed through wk 6. Sperm motility also declined to 0% for 6 wk. Testicular volume was reduced in l-CDB-4022-treated monkeys through d 21. The left testis and epididymis were removed from all monkeys on d 24. At this time, the most mature germ cells in the seminiferous tubules of testes from l-CDB-4022-treated monkeys were either spermatocytes or round spermatids. Immature germ cells, but not mature sperm, were found in the efferent ducts and collapsed epididymal lumen of l-CDB-4022-treated monkeys. A steady recovery in sperm motility, concentration, and total sperm per ejaculate was observed in l-CDB-4022-treated monkeys such that these parameters were not different from those of vehicle-treated monkeys by wk 16. Volume of the remaining testis increased in vehicle- and l-CDB-4022-treated monkeys after hemicastration; however, the increase in l-CDB-4022-treated monkeys was delayed compared with that observed in the vehicle-treated monkeys. The morphology of the remaining testis and epididymis, which were removed on wk 17, was normal. Serum inhibin B levels were increased in l-CDB-4022-treated monkeys during the dosing interval; thereafter serum inhibin B levels declined such that there was no difference between the groups by wk 3. l-CDB-4022 treatment did not affect circulating levels of testosterone, LH, FSH, or estradiol. In conclusion, these data indicate that in the cynomolgus monkey, a representative higher primate, l-CDB-4022 exerts a selective antispermatogenic action, which was reversible under the conditions of this study and thus has potential as a nonhormonal oral male contraceptive.
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- 2007
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14. The Ability of a Gonadotropin-Releasing Hormone Antagonist, Acyline, to Prevent Irreversible Infertility Induced by the Indenopyridine, CDB-4022, in Adult Male Rats: The Role of Testosterone1
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Jerry R. Reel, Barbara J. Attardi, and Sheri Ann Hild
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Infertility ,medicine.medical_specialty ,medicine.drug_class ,Antagonist ,Cell Biology ,General Medicine ,Gonadotropin-releasing hormone ,Biology ,medicine.disease ,Androgen ,Gonadotropin-releasing hormone antagonist ,Endocrinology ,Reproductive Medicine ,Internal medicine ,medicine ,Implant ,Spermatogenesis ,Testosterone - Abstract
Intratesticular testosterone (ITT) is known to play a critical role in the maintenance of spermatogenesis. We have used acyline, a GnRH antagonist, to suppress testosterone (T) production, and acyline and T implants to study the prevention of irreversible infertility induced by CDB-4022. Vehicle or acyline was administered to proven fertile male rats (n 5 5/group) at a dose (210 mg/day) that completely suppressed (P , 0.05) T production, as measured by serum T, and testicular function, either before, concurrent with, or after vehicle or a single oral dose of 2.5 mg CDB-4022/kg (Week 0). Vehicle-treated males remained fertile, whereas acyline-treated males exhibited transitory infertility. CDB-4022 alone caused irreversible infertility in all males. Importantly, CDB-4022-treated males recovered fertility when acyline was started before CDB-4022 (Weeks 24 to 0; Weeks 24‐9), but not when acyline was administered concurrently with or after CDB-4022 (Weeks 0‐9; Weeks 10‐19). At the end of this study (Week 34), testes weights, spermatid head counts (SHC), and tubule differentiation indices (TDI) were suppressed (P , 0.05) in infertile CDB-4022-treated males, but in rats that recovered fertility, these parameters were similar (P . 0.05) to those in vehicle-treated males. In addition, serum inhibin B and epididymal androgen-binding protein levels were nondetectable in infertile CDB-4022-treated rats. To test whether suppression of ITT was critical for prevention of CDB-4022-induced infertility, proven fertile rats (n 5 7‐8/group) received vehicle, acyline alone, or acyline and a T implant for 4 wk before CDB-4022 (Week 0). The T implant increased ITT in acyline-treated rats. Although ITT was lower (P , 0.05) in the T-implanted males than in untreated rats, it was sufficient to sustain spermiogenesis. Serum rFSH levels were also elevated in rats treated with acyline 1 T as compared with acyline alone during the treatment interval, but rFSH was still lower than in vehicle-treated rats. Rats in all treatment groups were rendered infertile initially, but the acyline 1 CDB-4022-treated rats recovered fertility by Week 10. In contrast, rats treated with CDB-4022 alone or acyline 1 T 1 CDB-4022 remained infertile until at least Week 16. Testes weights, SHC, and TDI were within normal ranges for acyline 1 CDB-4022-treated rats, but were decreased (P , 0.05) in CDB4022- or acyline 1 T 1 CDB-4022-treated rats. Serum inhibin B levels were nondetectable by Week 1 in males rendered irreversibly infertile by CDB-4022; levels increased transiently and
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- 2004
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15. Disruption of Spermatogenesis and Sertoli Cell Structure and Function by the Indenopyridine CDB-4022 in Rats1
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Richard P. Blye, Janice M. Larner, Sheri Ann Hild, and Jerry R. Reel
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endocrine system ,medicine.medical_specialty ,Leydig cell ,Efferent ducts ,Cell Biology ,General Medicine ,Biology ,Epididymis ,Sertoli cell ,Endocrinology ,medicine.anatomical_structure ,Seminal vesicle ,Reproductive Medicine ,Internal medicine ,medicine ,Spermatogenesis ,Germ cell ,Testosterone - Abstract
The present studies were undertaken to determine the testicular cell type(s) affected by the antispermatogenic indenopyridine CDB-4022. At the oral threshold dose (2.5 mg/kg), CDB-4022 induced infertility in all males. CDB-4022 did not alter (P > 0.05) Leydig cell function as assessed by circulating testosterone, seminal vesicle, and ventral prostate weights or body weight gain compared to controls. Conversely, CDB-4022 reduced (P 0.05), compared to controls. CDB-4022 and DPP increased (P < 0.05) the percentage of tubules with apoptotic germ cells, particularly differentiating spermatogonia and spermatocytes, by 12 h after dosing. Microscopic examination of the testis indicated a greater degree of vacuolation in Sertoli cells and initial signs of apical germ cell sloughing/shedding by 3 or 12 h after CDB-4022 or DPP treatment, respectively. In a third study, prepubertal male rats were treated with vehicle, 12.5 mg/kg of CDB-4022, or 2200 mg/kg of DPP, and the efferent ducts of the right testis were ligated 23 h before necropsy. Seminiferous tubule fluid secretion (difference in weight of testes), serum inhibin B levels, and ABP levels in the unligated epididymis were reduced (P < 0.05) at 24 and 48 h after dosing in CDB-4022- and DPP-treated rats compared to controls. Collectively, these data suggest that CDB-4022 disrupts spermatogenesis by inducing apoptosis in early stage germ cells via a direct action on the Sertoli cell.
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- 2001
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16. Long-term effects of dimethandrolone 17β-undecanoate and 11β-methyl-19-nortestosterone 17β-dodecylcarbonate on body composition, bone mineral density, serum gonadotropins, and androgenic/anabolic activity in castrated male rats
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Sheri Ann Hild, Sailaja Koduri, Barbara J. Attardi, Alvin M. Matsumoto, and Brett T. Marck
- Subjects
Male ,medicine.medical_specialty ,Anabolism ,medicine.drug_class ,Urology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Rats, Sprague-Dawley ,Endocrinology ,Absorptiometry, Photon ,Anabolic Agents ,Prostate ,Bone Density ,Internal medicine ,medicine ,Animals ,Nandrolone ,Testosterone ,Bone mineral ,business.industry ,Seminal Vesicles ,Dimethandrolone ,Organ Size ,Luteinizing Hormone ,Androgen ,Rats ,medicine.anatomical_structure ,Reproductive Medicine ,Lean body mass ,Androgens ,Body Composition ,Androgen replacement therapy ,Follicle Stimulating Hormone ,business ,Orchiectomy - Abstract
The potent androgens dimethandrolone 17β-undecanoate (DMAU) and 11β-methyl-19-nortestosterone 17β-dodecylcarbonate (11β-MNTDC) are in development for androgen replacement therapy and hormonal contraception in men. They can be delivered either orally or as long-acting injectables. In the current study, their long-term effects on body composition (percentage lean and fat mass); bone mineral density (BMD); serum gonadotropin levels; and weights of the prostate, seminal vesicles, and levator ani muscle were assessed. Four-week-old male rats were sham-operated (intact) or castrated (Cx) and treated subcutaneously for 16 weeks postsurgery with vehicle (Cx, intact), DMAU, or 11β-MNTDC every 4 weeks; testosterone enanthate (TE) every 2 weeks; or a testosterone (T) implant. There were significant differences in body weights over time with a general trend of intact = Cx + T = Cx + TECx + 11β-MNTDCCxCx + DMAU. At week 18, rats were evaluated by dual-energy x-ray absorptiometry using the whole-body function of the Hologic software. The percentage lean body mass and BMD were lower (P.05) in Cx rats than intact rats but equivalent in all groups of androgen-treated Cx rats and intact rats (P.05). The highest percentage body fat was observed in Cx rats. Only DMAU- and 11β-MNTDC-treated rats had lower percentage body fat compared with Cx rats (P.05). Prostate, seminal vesicles, and levator ani muscle weights, corrected for final body weight, were decreased (P.05) in Cx compared with intact rats and increased to varying extents in androgen-treated Cx rats compared with Cx rats (P.05). The most marked increases were observed in the DMAU-treated rats in which prostate and seminal vesicle weights/kg body weight were 2.4 to 2.7 times those of intact rats, and levator ani muscle weights were increased approximately 1.5-fold. Blood was collected from the tail vein at weeks 4, 8, 12, and 16 for measurement of serum levels of androgens and at necropsy at week 18 for measurement of serum gonadotropins. Serum levels of luteinizing hormone and follicle-stimulating hormone were greatly elevated in Cx rats at week 18 and suppressed to levels comparable to those in intact rats by DMAU, 11β-MNTDC, and T implants (P.05). Collectively, our data indicate that androgen replacement with DMAU or 11β-MNTDC in Cx rats resulted in favorable changes in body composition and maintenance of BMD comparable to those of T.
- Published
- 2010
17. The Potent Synthetic Androgens, Dimethandrolone (7α,11β-Dimethyl-19-Nortestosterone) and 11β-Methyl-19-Nortestosterone, Do Not Require 5α-Reduction to Exert their Maximal Androgenic Effects*
- Author
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Sheri Ann Hild, Sailaja Koduri, Bruce A. Till, David Gropp, Trung C. Pham, Laurent Pessaint, Jerry R. Reel, Anne Semon, Barbara J. Attardi, and Jean A. Engbring
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Stimulation ,Biology ,Antiandrogen ,Biochemistry ,Article ,Rats, Sprague-Dawley ,Endocrinology ,3-Oxo-5-alpha-Steroid 4-Dehydrogenase ,In vivo ,Internal medicine ,medicine ,Animals ,Humans ,Nandrolone ,Testosterone ,Molecular Biology ,Testosterone Congeners ,Prostate ,Seminal Vesicles ,Dimethandrolone ,Dihydrotestosterone ,Cell Biology ,Organ Size ,Androgen ,medicine.disease ,Rats ,Receptors, Androgen ,Molecular Medicine ,Male-pattern baldness ,medicine.drug - Abstract
Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent androgens in development for hormonal therapy in men. As 5α-reduced androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22-day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least threefold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was four- to eightfold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T+DUT, serum T was significantly higher (P
- Published
- 2010
18. Effects of synthetic androgens on liver function using the rabbit as a model
- Author
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Jerry R. Reel, Sailaja Koduri, Barbara J. Attardi, Sheri Ann Hild, and Bruce A. Till
- Subjects
Male ,medicine.medical_specialty ,L-Iditol 2-Dehydrogenase ,medicine.drug_class ,Sorbitol dehydrogenase ,Urology ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Article ,Sulfobromophthalein ,Endocrinology ,Internal medicine ,Methyltestosterone ,medicine ,Animals ,Nandrolone ,Testosterone ,Dosing ,Aspartate Aminotransferases ,Testosterone Congeners ,media_common ,No-Observed-Adverse-Effect Level ,Lagomorpha ,biology ,Alanine Transaminase ,gamma-Glutamyltransferase ,biology.organism_classification ,Androgen ,Reproductive Medicine ,Liver ,Liver function ,Rabbits ,Reproduction ,medicine.drug - Abstract
The objective of this study was to determine whether the rabbit was a suitable model to test new synthetic androgens for potential liver toxicity within a short dosing interval. Adult male rabbits were dosed orally daily on days 0–13 with 17α-methyltestosterone (MT) as a positive control and testosterone (T) as a negative control to validate this model. Synthetic androgens tested were: 7α-methyl-19-nortestosterone (MENT), dimethandrolone-undecanoate (DMAU), and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and sorbitol dehydrogenase (SDH), as well as clearance of intravenous injected bromsulfonphthalein (BSP) from serum on days 0, 7, and 14, were determined. As expected, T (10 mg/kg/d) did not adversely affect BSP retention or serum liver enzymes. MT (10 mg/kg/d) increased BSP retention, and AST, ALT, GGT, and SDH levels, indicating that this model could detect androgens known to be hepatotoxic. DMAU and MENT (10 mg/kg/d) increased BSP retention and all 4 serum liver enzymes as well, but the effects were less than those observed with MT at the same dose. All parameters returned to baseline 2 weeks after cessation of dosing. 11β-MNTDC at 10 mg/kg/d did not have an effect on BSP retention or liver enzymes, but a slight increase in serum GGT levels was observed in rabbits treated with 25 mg/kg/d. For the androgens that exhibited liver toxicity at 10 mg/kg/d (MT, DMAU, and MENT), a no-observed-effect level of 1 mg/kg/d was established. Overall ranking of the synthetic androgens from most to least hepatotoxic on the basis of percent BSP retention was: MT & DMAU > MENT > 11β-MNTDC. Hence, the rabbit appears to be a promising model for detection of potential liver toxicity by synthetic androgens using BSP clearance and serum liver enzyme levels as early indicators of injury.
- Published
- 2010
19. Mechanism of action of l-CDB-4022, a potential nonhormonal male contraceptive, in the seminiferous epithelium of the rat testis
- Author
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Jerry R. Reel, Sailaja Koduri, Laurent Pessaint, Sheri Ann Hild, and Barbara J. Attardi
- Subjects
MAPK/ERK pathway ,Male ,medicine.medical_specialty ,endocrine system ,MAP Kinase Signaling System ,Stem cell factor ,Apoptosis ,Testicle ,Biology ,Microtubules ,Fas ligand ,Article ,Rats, Sprague-Dawley ,Endocrinology ,Piperidines ,Internal medicine ,medicine ,Animals ,fas Receptor ,Extracellular Signal-Regulated MAP Kinases ,Stem Cell Factor ,Body Weight ,Contraceptive Agents, Male ,Sertoli cell ,Fas receptor ,Rats ,medicine.anatomical_structure ,Seminiferous Epithelium ,Indenes ,Follicle Stimulating Hormone ,Germ cell - Abstract
The present study was conducted to elucidate the possible molecular mechanisms involved in the antispermatogenic activity of l-CDB-4022, an indenopyridine. In this study 45-d-old male Sprague-Dawley rats were treated with a single oral dose of l-CDB-4022 (2.5 mg/kg) or vehicle, and blood and testes were collected at various time points. The rate of body weight gain was not affected, but a significant loss of testes weight was induced by l-CDB-4022. Serum hormones were assayed using specific RIAs or ELISAs, and testicular protein and RNA were analyzed by Western blotting and RT-PCR, respectively. There was a significant decrease in inhibin B and concomitant increase in FSH in serum from l-CDB-4022-treated rats, but serum levels of activin A, testosterone, and LH were unchanged. Western analysis of testicular lysates from l-CDB-4022-treated rats exhibited phosphorylation of ERK1/2 at 4 h and later time points. Loss of nectin/afadin complex occurred at 48 h, but there was an increase in levels of integrin-β1, N-cadherin, α-catenin, and β-catenin protein at 24 h and later time points. Increase in expression of Fas ligand and Fas receptor was detected 8 and 24 h after l-CDB-4022 treatment. The ratio of the membrane to soluble form of stem cell factor mRNA was decreased. Immunohistochemical analysis of testicular sections indicated a dramatic disruption of the Sertoli cell microtubule network in l-CDB-4022-treated rats. Collectively, these results suggest that l-CDB-4022 activates the MAPK pathway, reduces expression of prosurvival factors such as the membrane form of stem cell factor, alters expression of Sertoli-germ cell adherens junction proteins, disrupts Sertoli cell microtubule structure, and induces the proapoptotic factor, Fas, culminating in germ cell loss from the seminiferous epithelium.
- Published
- 2008
20. Acute adverse effects of the indenopyridine CDB-4022 on the ultrastructure of sertoli cells, spermatocytes, and spermatids in rat testes: comparison to the known sertoli cell toxicant Di-n-pentylphthalate (DPP)
- Author
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Sheri Ann Hild, Michael J. Dykstra, Jerry R. Reel, Gary R. Marshall, and Peter C. Mann
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Urology ,Endocrinology, Diabetes and Metabolism ,Phthalic Acids ,Spermatocyte ,Testicle ,Biology ,Rats, Sprague-Dawley ,Endocrinology ,Piperidines ,Spermatocytes ,Internal medicine ,Testis ,medicine ,Animals ,Blood–testis barrier ,Sertoli Cells ,Spermatid ,urogenital system ,Endoplasmic reticulum ,Sertoli cell ,Spermatids ,Cell biology ,Rats ,medicine.anatomical_structure ,Reproductive Medicine ,Indenes ,Cytoplasm ,Ultrastructure - Abstract
Acute effects of CDB-4022 on testicular ultrastructure were determined. Rats were treated orally with vehicle or a maximally effective single dose of CDB-4022 or Di-n-pentylphthalate (DPP). Preserved testes were processed for transmission electron microscopy. Sertoli and germ cells of vehicle-treated rats demonstrated normal morphological characteristics. Disruption of Sertoli cell ultrastructure was apparent in CDB-4022-treated rats by 3 hours. A decrease in the presence of nucleoli, an increase in the amount and diameter of swollen smooth endoplasmic reticulum, and decreases in cytoplasmic ground substance were observed. The severity of these degenerative effects increased at 6 and 12 hours: Vacuoles were apparent; increased cellular debris, swollen mitochondria, and phagocytic structures were observed; and membranes became more disorganized. Similar ultrastructural changes were observed in the Sertoli cells of DPP-treated rats. By 3 hours, spermatocytes and spermatids were adversely affected by CDB-4022 treatment with swelling of the nuclear envelope. The Step 8 spermatids were especially noteworthy; chromatin was more diffuse and rarefied, the nuclear envelopes were incomplete or broken, and the position of the spermatid nucleus within the cell and relative to Sertoli cell cytoplasm was unusual. Fusion of spermatids to form giant cells was observed by 12 hours. CDB-4022 acts acutely on Sertoli cells to induce marked cellular rarefaction and degeneration, but not necrosis. A rapid and direct effect of CDB-4022 on spermatocytes and spermatids was observed. The antispermatogenic activity of CDB-4022 appears to be a consequence of direct effects on Sertoli and germ cells.
- Published
- 2007
21. Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity
- Author
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Sheri Ann Hild, Jerry R. Reel, and Barbara J. Attardi
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Administration, Oral ,Pharmacology ,Biology ,Endocrinology ,In vivo ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Luciferase ,Receptor ,Dose-Response Relationship, Drug ,Dimethandrolone ,Biological activity ,Luteinizing Hormone ,Androgen ,Alkaline Phosphatase ,Flutamide ,Rats ,Androgen receptor ,Mifepristone ,Dimethandrolone-undecanoate ,Androgens ,Rabbits ,Progestins ,Receptors, Progesterone - Abstract
Dimethandrolone (DMA), the 17beta-undecanoic acid ester of dimethandrolone (DMAU; 7alpha,11beta-dimethyl-19-nortestosterone) is a potent androgen currently in development for therapeutic uses in men. Cleavage of the 17beta-ester bond liberates the biologically active DMA. In this study we investigated the activity of DMAU and DMA both in vivo and in vitro. DMAU was active orally in castrate rat bioassays, and when administered sc, a single dose produced prolonged androgenic activity and suppression of LH with sustained circulating levels of DMA. DMA, other 19-norandrogens, and C-19 androgens bound to recombinant rat androgen receptor with high affinity and were equipotent in stimulating luciferase activity (EC50, 10(-10) -10(-9) M) in CV-1 cells cotransfected with a human androgen receptor expression vector and a luciferase reporter plasmid with three hormone response elements. Because various 19-norandrogens are also known to bind to progestin receptors (PR) and to possess progestational activity in vivo, we evaluated the binding affinity of DMA for rabbit PR and recombinant human PR-A and PR-B and its ability to induce PR-mediated transcription and endogenous alkaline phosphatase activity in T47DCO human breast cancer cells. DMA and related 19-norandrogens bound with high affinity to both rabbit and human PR, whereas the less active 11alpha-methyl stereoisomer of DMA and C-19 androgens showed low or negligible binding to PR. In T47DCO cells, 10(-8) M DMA and other 19-norandrogens stimulated transcription of a progestin/glucocorticoid/androgen response element-thymidine kinase-luciferase reporter plasmid to the same extent as R5020, the potent progestin promegestone (EC50, approximately 10(-9) M), but C-19 androgens had no effect. Antiprogestins were potent inhibitors of transactivation and alkaline phosphatase activity induced by DMA and other 19-norandrogens in T47DCO cells, whereas antiandrogens were weak inhibitors. DMA and DMAU also exhibited dose-dependent progestational activity in the estrogen-primed immature female rabbit, as assessed by induction of endometrial gland arborization. The dual androgenic and progestational activities of DMA make it a potential candidate for a single-agent male contraceptive as well as for androgen therapy in men, pending a successful outcome of pharmacokinetic and toxicity studies currently in progress.
- Published
- 2006
22. The ability of a gonadotropin-releasing hormone antagonist, acyline, to prevent irreversible infertility induced by the indenopyridine, CDB-4022, in adult male rats: the role of testosterone
- Author
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Sheri Ann, Hild, Barbara J, Attardi, and Jerry R, Reel
- Subjects
Male ,Rats, Sprague-Dawley ,Indenes ,Piperidines ,Testis ,Animals ,Female ,Testosterone ,Recovery of Function ,Oligopeptides ,Infertility, Male ,Rats - Abstract
Intratesticular testosterone (ITT) is known to play a critical role in the maintenance of spermatogenesis. We have used acyline, a GnRH antagonist, to suppress testosterone (T) production, and acyline and T implants to study the prevention of irreversible infertility induced by CDB-4022. Vehicle or acyline was administered to proven fertile male rats (n = 5/group) at a dose (210 microg/day) that completely suppressed (P0.05) T production, as measured by serum T, and testicular function, either before, concurrent with, or after vehicle or a single oral dose of 2.5 mg CDB-4022/kg (Week 0). Vehicle-treated males remained fertile, whereas acyline-treated males exhibited transitory infertility. CDB-4022 alone caused irreversible infertility in all males. Importantly, CDB-4022-treated males recovered fertility when acyline was started before CDB-4022 (Weeks -4 to 0; Weeks -4-9), but not when acyline was administered concurrently with or after CDB-4022 (Weeks 0-9; Weeks 10-19). At the end of this study (Week 34), testes weights, spermatid head counts (SHC), and tubule differentiation indices (TDI) were suppressed (P0.05) in infertile CDB-4022-treated males, but in rats that recovered fertility, these parameters were similar (P0.05) to those in vehicle-treated males. In addition, serum inhibin B and epididymal androgen-binding protein levels were nondetectable in infertile CDB-4022-treated rats. To test whether suppression of ITT was critical for prevention of CDB-4022-induced infertility, proven fertile rats (n = 7-8/group) received vehicle, acyline alone, or acyline and a T implant for 4 wk before CDB-4022 (Week 0). The T implant increased ITT in acyline-treated rats. Although ITT was lower (P0.05) in the T-implanted males than in untreated rats, it was sufficient to sustain spermiogenesis. Serum rFSH levels were also elevated in rats treated with acyline + T as compared with acyline alone during the treatment interval, but rFSH was still lower than in vehicle-treated rats. Rats in all treatment groups were rendered infertile initially, but the acyline + CDB-4022-treated rats recovered fertility by Week 10. In contrast, rats treated with CDB-4022 alone or acyline + T + CDB-4022 remained infertile until at least Week 16. Testes weights, SHC, and TDI were within normal ranges for acyline + CDB-4022-treated rats, but were decreased (P0.05) in CDB-4022- or acyline + T + CDB-4022-treated rats. Serum inhibin B levels were nondetectable by Week 1 in males rendered irreversibly infertile by CDB-4022; levels increased transiently and returned to baseline in rats protected by acyline pretreatment. These data indicate that pretreatment with acyline was able to prevent irreversible infertility in CDB-4022-treated rats, whereas posttreatment with acyline did not promote spermatogonial differentiation, as has been observed by others in rats that received GnRH analogs and various other testicular toxicants. Suppression of ITT and possibly rFSH by acyline appeared to be crucial in preventing irreversible infertility induced by CDB-4022. In this regard, our results are similar to those of investigators who have studied other testicular toxicants. Continued development of CDB-4022 as a potential male contraceptive will depend largely on its safety profile and whether its antispermatogenic activity is reversible in primates.
- Published
- 2004
23. Steroid hormonal regulation of growth, prostate specific antigen secretion, and transcription mediated by the mutated androgen receptor in CWR22Rv1 human prostate carcinoma cells
- Author
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Jerry R. Reel, Janet Burgenson, Sheri Ann Hild, and Barbara J. Attardi
- Subjects
Male ,Transcriptional Activation ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Transplantation, Heterologous ,Mice, Nude ,Biology ,urologic and male genital diseases ,Biochemistry ,Binding, Competitive ,Steroid ,Transactivation ,Prostate cancer ,Mice ,Endocrinology ,Hormone Antagonists ,Prostate ,Internal medicine ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Testosterone ,Luciferases ,Molecular Biology ,Cell Nucleus ,Prostatic Neoplasms ,Androgen Antagonists ,Prostate-Specific Antigen ,Androgen ,medicine.disease ,Androgen receptor ,medicine.anatomical_structure ,Tumor progression ,Receptors, Androgen ,Mutation ,Androgens ,Progestins ,Hormone - Abstract
CWR22Rv1 (22Rv1) is an androgen-responsive human prostate carcinoma cell line derived from a primary prostate tumor that expresses mutant (H874Y) androgen receptors (AR) and secretes low levels of prostate specific antigen (PSA). In this study, we examined the effects of various androgens and other steroid hormones on proliferation of 22Rv1 cells, PSA secretion, and transactivation. Incubation of 22Rv1 cells with various concentrations of testosterone resulted in a dose-dependent 50–80% increase in growth over 72 h. PSA release and transactivation of PRE 2 -tk-LUC in 22Rv1 cells were stimulated by low concentrations of natural and synthetic androgens (EC 50 s = 10 −10 to 10 −9 M) and a broad range of other classes of steroid hormones, albeit with lower potency. Uniform positive immunocytochemical staining was observed in 22Rv1 cell nuclei with mouse monoclonal antibodies to human AR. Competitive binding assays indicated that the mutant AR in 22Rv1 cytosol is more promiscuous than a wild-type AR (ARLBD: rat AR ligand binding domain). Testosterone (10 −8 M)-induced PSA release and transactivation were blocked by both antiandrogens and antiprogestins with IC 50 s of 10 −7 to 10 −6 M. At high concentration (10 −6 M), these antagonists showed partial agonist activity in terms of PSA secretion but not transactivation. In conclusion, the mutant AR in 22Rv1 cells binds and responds to low levels of androgens and a wide spectrum of other natural and synthetic steroid hormones, mechanisms proposed to contribute to tumor progression following androgen ablation.
- Published
- 2003
24. CDB-2914: anti-progestational/anti-glucocorticoid profile and post-coital anti-fertility activity in rats and rabbits
- Author
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Loren H.Hoffman, Sheri Ann Hild, Richard P. Blye, and Jerry R. Reel
- Subjects
Male ,medicine.medical_specialty ,Norpregnadienes ,Agonist-antagonist ,Uterus ,Rats, Sprague-Dawley ,Hormone Antagonists ,Pregnancy ,Internal medicine ,Copulation ,medicine ,Endocrine system ,Animals ,Glucocorticoids ,Contraceptives, Postcoital, Synthetic ,biology ,Rehabilitation ,Haptoglobin ,Obstetrics and Gynecology ,Biological activity ,Mifepristone ,medicine.disease ,Rats ,Endocrinology ,medicine.anatomical_structure ,Reproductive Medicine ,biology.protein ,Female ,Rabbits ,Progestins ,Glucocorticoid ,medicine.drug - Abstract
Our goal was to determine the endocrine and post-coital anti-fertility activity of CDB-2914. Concurrent administration of progesterone to rats on day 4 post-mating blocked the anti-fertility activity of a single oral 2 mg dose of CDB-2914. CDB-2914 did not exhibit progestational activity in the oestradiol-primed immature female rabbit at doses that exhibited anti-progestational activity. CDB-2914 antagonized exogenous and endogenous progesterone-stimulated uterine haptoglobin synthesis and secretion in immature and adult mated rabbits respectively. Neither CDB-2914 nor mifepristone exhibited glucocorticoid activity as determined by thymus involution in rats; mifepristone was twice as potent as CDB-2914 in antagonizing glucocorticoid action. Post-coital CDB-2914 treatment resulted in a dose-dependent reduction in implantation sites and pregnancy rates in rabbits. CDB-2914-induced inhibition of uterine weight increase, endometrial glandular arborization and uterine haptoglobin synthesis/secretion correlated with inhibition of pregnancy in mated rabbits. A single oral dose of 64 mg CDB-2914/rabbit was effective at blocking pregnancy when administered on day 4, 5, or 6 post-mating, whereas 32 mg/rabbit was only partially effective in this regard. These data demonstrate that CDB-2914 is a potent, orally active anti-progestin with weak anti-glucocorticoid activity. CDB-2914 inhibited implantation in adult rats and rabbits demonstrating its potential as a post-coital contraceptive drug.
- Published
- 2000
25. LOSS OF SPERMATOCYTES AND SPERMATIDS UNDERLIES THE ACTION OF l-CDB-4022 TO INDUCE SEVERE OLIGOSPERMIA IN ADULT MALE CYNOMOLGUS MONKEYS (Macaca fascicularis)
- Author
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Sheri Ann Hild, Barbara J. Attardi, Jerry R. Reel, Gary R. Marshall, and Tony M. Plant
- Subjects
Reproductive Medicine ,Adult male ,Physiology ,Cell Biology ,General Medicine ,Severe oligospermia ,Biology - Published
- 2007
- Full Text
- View/download PDF
26. In Vitro Versus In Vivo Effects of NB-DGJ and NB-DNJ as Lead Compounds for Development of Non-Hormonal Reversible Oral Male Contraceptives
- Author
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Joseph S. Tash, Sudhakar Jakkaraj, Vijayalaxmi Gupta, Gunda I. Georg, and Sheri Ann Hild
- Subjects
Reproductive Medicine ,In vivo ,Non hormonal ,Cell Biology ,General Medicine ,Pharmacology ,Biology ,In vitro - Published
- 2010
- Full Text
- View/download PDF
27. Long-Term Effects of Dimethandrolone 17Beta-Undecanoate (DMAU) and 11Beta-Methyl-19-Nortestosterone 17Beta-Dodecylcarbonate (11Beta-MNTDC) on Body Composition, Bone Mineral Density (BMD), Serum Gonadotropins, and Androgenic/Anabolic Activity in Castrated Male Rats
- Author
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Barbara J. Attardi, Sheri Ann Hild, Sailaja Koduri, Alvin M. Matsumoto, and Brett T. Marck
- Subjects
Bone mineral ,medicine.medical_specialty ,Endocrinology ,Reproductive Medicine ,Anabolism ,Internal medicine ,Male rats ,medicine ,Composition (visual arts) ,Dimethandrolone ,Cell Biology ,General Medicine ,Biology - Published
- 2009
- Full Text
- View/download PDF
28. Development of Dimethandrolone 17β-Undecanoate (DMAU) as an Oral Male Hormonal Contraceptive: Induction of Infertility and Recovery of Fertility in Adult Male Rabbits
- Author
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Barbara J. Attardi, Jean A. Engbring, David Gropp, Sailaja Koduri, Sheri Ann Hild, and Jerry R. Reel
- Subjects
Infertility ,medicine.medical_specialty ,Adult male ,media_common.quotation_subject ,Physiology ,Dimethandrolone ,Fertility ,Cell Biology ,General Medicine ,Biology ,medicine.disease ,Endocrinology ,Reproductive Medicine ,Internal medicine ,medicine ,Hormone ,media_common - Published
- 2008
- Full Text
- View/download PDF
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