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PubMed1987

5 alpha-Cholest-8(14)-en-3 beta-ol-15-one. In vivo conversion to cholesterol upon oral administration to a nonhuman primate.

The metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one (I), a potent inhibitor of cholesterol synthesis with marked hypocholesteremic activity, has been studied in a nonhuman primate. A mixture of [2,4-3H]-I and [4-14C]-cholesterol was administered to a male baboon in the form of a feedball. Blood was samples at 4, 8, 12, 16, and 24 hr. Detailed analyses of the plasma lipids indicated very rapid absorption of I (relative to cholesterol) and metabolism to cholesterol, cholesteryl esters, and esters of I. The labeled cholesterol was characterized by chromatographic techniques and by purification by way of its dibromide derivative. The levels of 3H in plasma associated with I, esters of I, cholesterol, and cholesteryl esters each showed a different time course. By 24 hr after the administration of [2,4-3H]-I, most of the 3H in plasma was associated with cholesterol and cholesteryl esters. The levels of total 3H and 14C in plasma at various times after the administration of the mixture of [2,4-3H]-I and [4-14C]-cholesterol differed markedly with 3H showing a maximum value at 4 hr and 14C showing a maximum value at 24 hr.

Administration, Oral↗
PubMed2000

SPECT imaging with the D(4) receptor antagonist L-750,667 in nonhuman primate brain.

The suitability of an (123)I-labeled form of the putative D(4) receptor ligand L750,667 as a radiotracer for single photon emission computed tomography imaging was assessed in nonhuman primates. [(123)I]L750,667, labeled by iododestannylation, was administered to baboons in bolus and bolus plus constant infusion paradigms and imaged for 6 h. Total [(123)I]L750,667 brain uptake peaked (2.3% injected dose) at 15 min postinjection. [(123)I]L750,667 uptake was observed in all brain regions measured including diencephalon, brainstem, basal ganglia, cingulate cortex, and cerebellum, and slightly lower levels were noted in the frontal, parietal, temporoinsular, and occipital cortices. Administration of the D(4) receptor antagonist NGD 94-1 (2 mg/kg) did not displace radioactivity from any of the brain regions examined. Thus, while L750,667 is selective for the D(4) receptor in vitro, because brain [(123)I]L750,667 uptake was not displaced by NGD 94-1 at receptor saturating doses, [(123)I]L750,667 does not appear to be a suitable radiotracer for in vivo imaging of the D(4) receptor.

Animals↗
PubMed1977

Childhood lymphoblastic cancer: subgroups defined by nonhuman primate antisera to human lymphatic leukemia cell antigens.

Lymphoblasts from 23 children with acute lymphocytic leukemia (ALL) and 10 with lymphoblastic lymphoma (LBL) were studied by complement-dependent microcytoxicity tests with two nonhuman primate antisera defining leukemia-associated and lymphoma-associated antigens. Cells form 15 patients with ALL and 1 with LBL reacted only with antiserum to chronic lymphatic leukemia (CLL). These group-I patients were predominantly female. Most were pancytopenic and lacked mediastinal widening and T-cell markers; lymphoblasts from 15 were periodic acid-Schiff-positive. Cells from 8 male patients reacted only with antiserum to converted lymphosarcoma (LS). All these group-II patients expressed T-cell markers; 5 had mediastinal enlargement and 2, an abdominal mass. Six of the 8 were PAS-negative. Cells from 9 patients reacted with both antisera. The group-III patients demonstrated some characteristics of each of the above groups. Patients whose lymphoblasts reacted with CLL antiserum presented with clinical and laboratory features indicative of a good prognosis, i.e., ALL with PAS positivity and no T-cell markers or localized mass. Patients whose cells reacted with LS antiserum often had bad prognostic features: mediastinal or abdominal mass, expression of T-cell markers, and PAS negativity. These antisera appear able to differentiate childhood ALL from LBL. The distinction is important prognostically and perhaps therapeutically.

Adolescent↗
PubMed1988

Neonatal and maternal hair zinc levels in a nonhuman primate model of the fetal alcohol syndrome.

The role of zinc deficiency in the etiology of ethanol-associated fetotoxicity was assessed by measurement of maternal and newborn hair zinc content in a nonhuman primate model of the fetal alcohol syndrome. The model best approximates the human situation for length of gestation and type of placentation, coupled with the ability to control for nutritional factors. All mothers received 110% of their minimum daily caloric requirements as a balanced, nutritionally complete diet, including a minimum of 3.5 mg zinc per day. Over a 2-year period, maternal hair samples from 17 pregnancies (using 12 females) were obtained at term. There were 16 live, full-term neonates (nine ethanol exposed and seven control) from whom samples were taken within 1 hr of birth. The ethanol-exposed infant monkeys had a significantly higher incidence of craniofacial dysmorphology and developmental delay compared to the controls. There was no difference in hair zinc levels between ethanol-exposed and control animals for either the mothers or the newborns. Neonatal levels were, however, consistently higher than corresponding maternal. Although the findings cannot exclude transient or early gestational zinc deficiency as a factor, they provide further evidence that ethanol (and/or its metabolites) is the proximate toxin in the type of fetal injury seen in the fetal alcohol syndrome.

Animals↗
PubMed2002

Induction of donor-specific tolerance to islet allografts in nonhuman primates.

Pancreatic tissue grafting is by far the most physiological therapeutic solution to the insulin deficiency of diabetes. Recent clinical trials have indicated somewhat successful use of nonsteroidal immunosuppressive regimens and a successful nonhuman primate trial using CD154 for costimulation blockade was reported. However, these protocols need to be replaced with safe and efficacious ones in which long-term allotolerance would make these treatments routine in a clinical setting. With the specific objective of testing whether peripheral infusions of stem cells or stem cell fractions in conjunction with islet allografting would induce allograft tolerance, we have established a macaque diabetic model. The macaques were rendered diabetic by streptozotocin and required daily doses of insulin to maintain lower blood glucose levels. The diabetic macaques then received islets and stem cells from unrelated and MHC-mismatched donors without any immunosuppression. In our initial analysis, 5 of 7 macaques that received stem cell infusions at the time of islet allografting have shown allograft survival longer than the group of macaques that received islets without the stem cell infusion. One of these five macaques has been normoglycemic for 10 months, with no exogenous insulin. This macaque received stem cell population enriched for CD34+ cells with depletion of CD18 cells, which have shown low or no allostimulatory potential in mixed lymphocyte cultures. Increased levels in insulin and C-peptide levels were shown in the macaques after islet transplantation.

Animals↗
PubMed2004

Recognition of ESAT-6 sequences by antibodies in sera of tuberculous nonhuman primates.

Previous work in our laboratory showed that the ESAT-6 protein of Mycobacterium tuberculosis and Mycobacterium bovis induces strong antibody responses in a large proportion ( approximately 90%) of experimentally or naturally infected nonhuman primates. Here, the antibody response to ESAT-6 in tuberculous monkeys was characterized at the epitope level by measuring antibodies to overlapping, synthetic peptides spanning the ESAT-6 sequence. The antibody response against the COOH-terminal portion of the protein was the strongest in both experimentally and naturally infected animals. Moreover, these antibodies became detectable the earliest during experimental infection, suggesting an ordered expansion of ESAT-6-specific B-cell clones in the course of infection. The data support use of synthetic peptides in lieu of the full-length ESAT-6 protein in diagnostic antibody detection assays.

Amino Acid Sequence↗
PubMed2003

Infection and inflammation in skeletal muscle from nonhuman primates infected with different genospecies of the Lyme disease spirochete Borrelia burgdorferi.

Lyme borreliosis is a multisystemic disease caused by various genospecies of the spirochete Borrelia burgdorferi. To investigate muscle involvement in the nonhuman primate (NHP) model of Lyme disease, 16 adult Macaca mulatta animals inoculated with strain N40 of B. burgdorferi sensu strictu by syringe or by tick bite or with strain Pbi of B. burgdorferi genospecies garinii by syringe were studied. Animals were necropsied while immunosuppressed on day 50 (two animals each inoculated with B. burgdorferi N40 by syringe and with B. garinii Pbi by syringe) or on day 90, 40 days after immunosuppression had been discontinued (four animals each inoculated with strain N40 by syringe, with strain N40 by tick bite, and with strain Pbi by syringe). Skeletal muscles removed at necropsy were studied by (i) microscopic examination of hematoxylin-eosin-stained sections for inflammation and tissue injury; (ii) immunohistochemical and digital image analyses for antibody and complement deposition and cellular inflammation; (iii) Western blot densitometry for the presence of antibodies; and (iv) reverse transcription-PCR for measurement of the spirochetal load or C1q (the first component of the complement cascade) synthesis. The results showed that N40 was more infectious for NHPs than Pbi. NHPs inoculated with N40 but not with Pbi developed myositis. The inflammation in skeletal muscle was more severe in NHPs inoculated with N40 by syringe than in those inoculated by tick bite. The predominant cells in the inflammatory infiltrate were T cells and plasma cells. The deposition of antibody and complement in inflamed muscles from N40-inoculated NHPs was significantly higher than that in Pbi-inoculated NHPs. The spirochetal load was very high in the two N40-inoculated NHPs examined while they were immunosuppressed but decreased to minimal levels in the NHPs when immunocompetence was restored. We conclude that myositis can be a prominent feature of Lyme borreliosis depending on the infecting organism and host immune status.

Animals↗
PubMed1994

Dexamethasone resistance among nonhuman primates associated with a selective decrease of glucocorticoid receptors in the hippocampus and a history of social instability.

We have studied some of the neuroendocrine and social correlates of dexamethasone resistance in a nonhuman primate population. Subjects were 51 male Macaca fascicularis monkeys with known behavioral histories and who had been given dexamethasone (DEX) suppression tests a week prior to killing. We compared the subset of monkeys who were most DEX responsive (post-DEX cortisol values of 3.1 +/- 0.5 micrograms/dl) versus a DEX-resistant subset (cortisol values of 9.2 +/- 2.0 micrograms/dl); we found two features that distinguished these groups: (a) DEX-resistant monkeys had significantly fewer available glucocorticoid receptor (GR) binding sites in the hippocampus; they did not differ in numbers of mineralocorticoid receptor (MR) sites in the hippocampus, nor in numbers for either receptor in the cortex or hypothalamus as a whole. (b) Animals had resided for a number of years in social groups that were either stable or were repeatedly destabilized by changing of group membership; the latter has been shown to constitute a sustained stressor. DEX-resistant animals were more than twice as likely to have come from an unstable group as were DEX-responsive monkeys. Rodent studies have shown that sustained stress can cause a selective downregulatory decrease in the numbers of hippocampal corticosteroid receptors, and that such a loss is associated with DEX resistance. The present data suggest similar associations in the primate, and may be of relevance to the DEX resistance observed in a subset of human depressives.

Animals↗
PubMed1987

Development of a nonhuman primate model for spontaneous hypertension. Blood pressures in first-generation offspring.

A breeding colony of two subspecies of African green monkeys has been established in an attempt to develop a strain of nonhuman primates with inherited spontaneous hypertension. Selective breeding of normotensive and hypertensive feral animals has produced over 300 first-generation, colony-born offspring of nine possible types, which were grouped according to parentage. Blood pressures were measured by indirect methods in 335 unanesthetized animals aged 0.5 to 6 years. Analysis of variance and covariance of mean blood pressures of animals aged 0.5 to 6 years indicated significant differences between control and experimental offspring groups (p less than .001) both before and after adjusting for sex, subspecies, age, and body weight. Mean blood pressures of control and experimental (p less than .02) offspring were significantly different from 0.5 to 5 years of age. The slopes of the regression of mean blood pressure on age were significantly different between the control and experimental groups (p less than .001). Multiple linear regression analysis indicated significant differences among blood pressure, body weight, and age (p less than .001) and also between age and weight (p less than .001) between the groups. The relative contributions of age and weight to determining the mean blood pressure differed, however. The results indicate that elevated blood pressures can be detected in offspring with even one parent having elevated blood pressure from as early as 1 year of age and that the tendency to develop elevated blood pressure is transmitted from parent to offspring in this species, thereby providing a strong indication that a hypertensive strain of monkeys can be developed through selective breeding.

Age Factors↗
PubMed1993

SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT: pharmacological characterization of brain uptake in nonhuman primates.

Single photon emission computed tomography (SPECT) studies of regional kinetic uptake and pharmacological specificity of [123I]methyl 3 beta-(4-iodophenyl) tropane-2 beta-carboxylate ([123I]beta-CIT) were performed in nonhuman primates (n = 41). In control experiments, activity was concentrated in striatum and in hypothalamic/midbrain regions. Striatal uptake increased for 140-180 min and displayed stable levels thereafter. Striatal to cerebellar activity ratios were 7.3 +/- 0.9 (mean +/- SEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive beta-CIT. Hypothalamic/midbrain activity reached maximal levels at approximately 45 min. A slow washout phase followed this peak activity. Activities in frontal, occipital, and cerebellar regions were characterized by an early peak (20-30 min), followed by rapid washout. Displacement studies demonstrated that striatal uptake was associated with dopamine (DA) transporters, as it was displaced by GBR 12909, a selective DA uptake inhibitor, but not by citalopram, a selective serotonin (5-HT) uptake inhibitor. The inverse was true in the hypothalamic/midbrain area, suggesting that the uptake in this area was associated primarily with 5-HT transporters. Maprotiline, a selective norepinephrine uptake inhibitor, did not affect [123I]beta-CIT uptake. In vivo site occupancy ED50 values of cocaine, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT), and beta-CIT were measured in the striatum with a stepwise displacement paradigm. In vivo ED50 values correlated strongly with in vitro IC50 values for binding to DA transporters. Infusion of high dose of L-DOPA (250 mumol/kg) failed to displace striatal [123I]beta-CIT binding, suggesting that the binding would not be affected by L-DOPA administration in Parkinsonian patients. However, studies performed with injection of d-amphetamine indirectly suggested that high synaptic levels of DA may compete with [123I]beta-CIT binding. These studies suggest that [123I]beta-CIT will be a useful SPECT tracer of DA and 5-HT transporters in living human brain.

Animals↗
PubMed1993

Arcobacter (Campylobacter) butzleri-associated diarrheal illness in a nonhuman primate population.

After DNA hybridization identified an isolate from an ill rhesus macaque (Macaca mulatta) as Arcobacter (Campylobacter) butzleri, we initiated a study to determine whether A. butzleri was associated with diarrheal disease in nonhuman primates at the Yerkes Primate Research Center. By using Campy-CVA medium incubated at 35 degrees C, 15 A. butzleri isolates were obtained from 14 macaques; 7 macaques were coinfected with Campylobacter coli and Campylobacter jejuni. A. butzleri was not isolated from normal feces, despite the fact that feces from 76 macaques were cultured at necropsy. Histologic evaluation of colonic specimens from three macaques from which A. butzleri had been isolated showed mild to moderately severe chronic, active colitis. Ribotype analysis of the 15 A. butzleri isolates revealed nine different strains; these data suggest that A. butzleri may be endemic in this primate population and that a point source of infection is unlikely. This is the first report of the presence of A. butzleri in juvenile and adult macaques with diarrhea, and it may present an opportunity to study the pathogenesis of this organism, which appears to be associated with persistent diarrhea in humans.

Animals↗
PubMed2001

Morphological differences between minicolumns in human and nonhuman primate cortex.

Our study performed a quantitative investigation of minicolumns in the planum temporale (PT) of human, chimpanzee, and rhesus monkey brains. This analysis distinguished minicolumns in the human cortex from those of the other nonhuman primates. Human cell columns are larger, contain more neuropil space, and pack more cells into the core area of the column than those of the other primates tested. Because the minicolumn is a basic anatomical and functional unit of the cortex, this strong evidence showed reorganization in this area of the human brain. The relationship between the minicolumn and cortical volume is also discussed.

Adaptation, Physiological↗
PubMed1990

Renal hemodynamics and prostaglandin E2 excretion in a nonhuman primate model of septic shock.

The mechanisms responsible for renal insufficiency in septic shock (SS) have not been well characterized. We therefore investigated renal hemodynamics and the renal excretion of prostaglandin E2 (PGE2) in a nonhuman primate model of severe, low systemic vascular resistance (SVR) SS. In 18 cynomolgus monkeys, SS was induced by an infusion of 3 x 10(10) live Escherichia coli per kg; five saline-treated animals served as nonseptic controls. Systemic and renal hemodynamics, and urine PGE2 concentrations were determined over the 3 h after the induction of sepsis. The septic group demonstrated a significant (p less than .001) and sustained depression in both mean arterial pressure and SVR. Septic animals also had significantly lower effective renal plasma flow (ERPF) (p less than .01) and glomerular filtration rate (GFR) (p less than .01) compared to controls. Furthermore, the renal hemodynamic response to SS was biphasic, with significant increases in ERPF and GFR in the second hour postsepsis, followed by a pronounced decrease in the third postseptic hour. The septic group also demonstrated an increase in the renal excretion of PGE2 (p less than .001) that was temporally associated with the transient recovery in renal hemodynamics during the second postseptic hour. These sepsis-induced renal alterations may be important in the pathogenesis of renal insufficiency complicating clinical SS.

Acute Kidney Injury↗
PubMed2001

Long-term islet allograft function in the absence of chronic immunosuppression: a case report of a nonhuman primate previously made tolerant to a renal allograft from the same donor.

UNLABELLED: Development of mixed chimerism by donor bone marrow transplantation (DBMT) has led to long-term tolerance of solid organ allografts in nonhuman primates. As an initial attempt to extend this approach to cellular transplant, islet transplant from the same donor was attempted in the recipient previously made tolerant to a kidney allograft. METHODS: After the conditioning with ATG, total body irradiation, thymic irradiation, and splenectomy, DBMT was performed followed by 4 weeks of cyclosporine. Kidney transplantation and native nephrectomies were subsequently performed on day 89. After 2.8 years of DBMT, diabetes was induced by streptozocin (STZ) and islets from bone marrow and kidney donor were transplanted without immunosuppression. RESULTS: After DBMT, the recipient developed chimerism and no evidence of kidney rejection for more than 1000 days. STZ induced diabetes was reversed after the islet transplantation. Islet biopsies demonstrated insulin staining without rejection. Although the recipient became diabetic 300 days after islet transplantation, viable transplanted islets were found in the liver and under the kidney capsule without any evidence of rejection. CONCLUSION: Tolerance with a nonmyeloablative conditioning can allow successful pancreatic islet transplantation without immunosuppression. Because no histological evidence of rejection was identified, recurrent diabetes is presumed to be inadequate islet mass.

ABO Blood-Group System↗
PubMed2005

Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates.

BACKGROUND: Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). METHODS: Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. RESULTS: Mean survival time (+/-SEM) in animals treated with MMF alone (23+/-1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5+/-9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2+/-8.7 days) than animals that received less CP-690,550 (33.3+/-12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. CONCLUSIONS: Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

Animals↗
PubMed1987

Cytotoxic and immunoregulatory function of intestinal lymphocytes in Chlamydia trachomatis proctitis of nonhuman primates.

To study the role of natural killer cells and immunoregulatory T cells in the pathogenesis of proctitis due to Chlamydia trachomatis (L2 serovar), lymphocytes were obtained from the rectal mucosa and other sites of nonhuman primates and studied by using phenotypic and functional assays. In animals with lymphogranuloma venereum (LGV) proctitis, the percentage of lymphocytes with the natural killer cell phenotype (Leu-11+) was not significantly higher at any site in LGV infection, and natural killer cell function of lymphocytes isolated from the rectum was lower during LGV infection. This was not due to the suppressive effect of factors in serum, rectal lymphocytes, or LGV elementary bodies. In studies of regulatory T cells, the Leu-3+/Leu-2+ ratio was lower in the peripheral blood and the spleen during LGV infection, but the ratio did not decrease in lamina propria T cells. Both peripheral blood and rectal lymphocytes had higher helper T-cell function for polyclonal immunoglobulin G (IgG) synthesis in pokeweed mitogen-stimulated cultures 2 weeks following LGV infection. Increased suppressor T-cell function for pokeweed mitogen-stimulated IgG synthesis was found only in the peripheral blood of animals 2 weeks after infection, but not in isolated rectal lymphocytes. These results indicate that in LGV proctitis natural killer cells are not an important component of the inflammatory infiltrate at the site of infection, and helper T-cell function increases in peripheral blood and rectal lymphocytes.

Animals↗
PubMed2002

Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.

OBJECTIVE: Some of the statin-induced reduction in cardiac events in patients with atherosclerosis may be derived from mechanisms independent of lipid lowering. This study tested in nonhuman primates whether statins can influence inflammation (indicated by vascular cell adhesion molecule-1, interleukin-1beta, tissue factor, and macrophages) and features of plaque stability (indicated by collagen and smooth muscle cells) independent of their effect on plasma cholesterol level. METHODS AND RESULTS: Adult male cynomolgus monkeys (n=12 per group) consumed an atherogenic diet for 12 months while receiving (1) no treatment (control), (2) pravastatin (Prava, 40 mg/kg per day), or (3) simvastatin (Simva, 20 mg/kg per day). Dietary cholesterol was adjusted to equalize plasma cholesterol levels among groups. Although the intima/media ratio in the abdominal aorta did not differ among groups, drug treatment reduced inflammation and features of plaque vulnerability. Macrophage content in the lesions of statin-treated animals was lowered (2.4-fold with Prava and 1.3-fold with Simva; both P<0.001 versus control). Furthermore, lesions had approximately 2-fold less vascular cell adhesion molecule-1, interleukin-1beta, and tissue factor expression in statin-treated versus control animals (P<0.005). Lesional smooth muscle cell and collagen content was 2.1-fold greater in the Prava-treated group (P<0.001) and 1.5-fold greater in the Simva-treated group (P<0.005) than in the control group. CONCLUSIONS: In primates, these results provide further support for the beneficial effect of statins on plaque inflammation and stability in addition to cholesterol lowering.

Animals↗
PubMed1988

Testosterone prevents complete suppression of spermatogenesis in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis).

We studied the effects of administration of a GnRH antagonist combined with testosterone (T) as an approach to male contraception as well as the role of intratesticular androgens in spermatogenesis using a nonhuman primate model. Three groups of five adult cynomolgus monkeys (Macaca fascicularis) received daily sc injections of 420-460 micrograms/kg GnRH antagonist ([Ac-D2Nal1,D4ClPhe2,DPal3,Arg5,DGlu6(AA), DALa10]GnRH) for a period of 15 weeks. T supplementation, commencing on the first day of GnRH antagonist administration, was provided by single im injection of 40 mg (group 2) or 200 mg (group 3) of the long-acting testosterone ester testosterone-trans-4-n-butylcyclohexancarboxylate (20-Aet-1). Serum LH bioactivity was undetectable within 1 week of GnRH antagonist administration in all monkeys. GnRH antagonist administration alone (group 1) reduced serum T levels into the castrate range. Forty milligrams of 20-Aet-1 maintained serum T levels in the upper range of normal monkeys, while 200 mg 20-Aet-1 maintained serum T levels about 1.5-fold above normal. The response to electroejaculation was fully maintained in all T-treated monkeys. Sperm counts in the ejaculates dropped to zero among group 1 animals within 7-10 weeks of GnRH antagonist administration. In groups 2 and 3 consistent azoospermia could not be induced, and the sperm counts were significantly (P less than 0.05) higher in group 3 than in group 2. Histologically, spermatogenesis in group 1 was arrested at the spermatogonial level in 75% of seminiferous tubules. In group 2, spermatogenesis proceeded to spermatocytes in 50% of tubules and to elongated spermatids in 10% of tubules, while in group 3 elongation of spermatids occurred in 75% of tubules. The mean T and dihydrotestosterone concentrations in baseline testicular biopsies (n = 15) were 43.8 +/- 6.8 (+/- SE) and 5.7 +/- 1.5 ng/g, respectively. After GnRH antagonist with or without T administration, the mean (n = 15) intratesticular T and dihydrotestosterone levels were reduced to 20.3 +/- 4.9 and 3.2 +/- 0.5 ng/g, respectively, and differed little among the three groups. No correlation, however, could be established between testicular androgen levels and spermatogenic status (P greater than 0.30) or sperm counts (P greater than 0.60). These results demonstrate that administration of a GnRH antagonist in the presence of constant serum T levels does not induce consistent azoospermia, and that the supporting effects of T on spermatogenesis cannot be explained exclusively on the basis of the testicular androgen concentrations.

Androgens↗