Testosterone metabolic clearance rate and production rate in the male infant rhesus monkey

The male infant rhesus monkey (Macaca mulatta) undergoes a period of testicular activation similar to that seen in the human infant. Plasma testosterone (T) concentrations rise after birth, reaching levels of about 500 ng/dl at 1-3 mo of age and then fall to approximately 50 ng/dl at 60 mo. The plasma T metabolic clearance rates (MCRT) and production rates (PRT) were measured in two rhesus infants at 1 and 6 mo of age to determine the mechanism of the observed increase in plasma T. While there was little change in the MCRT between 1 and 6 mo, PRT was much higher at 1 mo than at 60 mo of age. These observations are consistent with the hypothesis that the increased plasma testosterone levels in infant rhesus monkeys reflect an increased production of testosterone rather than an altered metabolic disposition of the hormone.     

The effect of exercise on the production and clearance of testosterone in well trained young men

Tritium-labelled testosterone was infused into four well-trained subjects at rest and during one hour of exercise at about 60% of their maximum aerobic power. This exercise regime led to a mean increase of 27% (range 10-51%) in plasma testosterone concentration. At the same time there were significant decreases in the estimated hepatic plasma flow (EHPF) (45%; range 28-67%), metabolic clearance rate of testosterone (MCRT) (29%; range 18-37%) and plasma volume (8.2%; range 3-10%). The production rate of testosterone decreased by 10% (range 9-22%) but this was not statistically significant. The ratio MCRT:EHPF increased in 3 out of 4 subjects in response to exercise but there was considerable inter-subject variation both at rest and during exercise. These findings suggest that the exercise-induced elevation of testosterone level is due solely to the reduction in the rate at which testosterone is cleared from the plasma. The principal cause of the reduction in MCRT is probably the reduction in EHPF but the variation in the ratio MCRT:EHPF suggests that changes in the extrahepatic clearance of testosterone may also be involved.     

Androgen metabolism in hirsute patients treated with cyproterone acetate

Cyproterone acetate (CPA) in association with percutaneously administered estradiol has been used for the treatment of 150 hirsute patients for periods ranging from 6 months to 3 years. A spectacular clinical improvement ensued. Plasma testosterone (T) and androstenedione (A) fell from 69.0 +/- 24 to 33.0 +/- 8 and 210 +/- 103 to 119 +/- 25 ng/dl (mean +/- SD) respectively after 3 months of treatment and remained low thereafter. In contrast, T glucuronide (TG) and 3 alpha-androstanediol (Adiol) remained high during the whole course of treatment: 37 +/- 9 and 115 +/- 43 micrograms/24 h respectively. In vitro T 5 alpha-reductase activity (5 alpha-R) in pubic skin decreased from 147 +/- 34 to 79 +/- 17 fmol/mg skin after 1 year of treatment. To elucidate the discrepancy between plasma and urinary androgens levels, T production rate (PR) and metabolic clearance rate (MCR) were measured with the constant infusion technique in 7 patients before and after 6 months of treatment. PR decreased from 988 +/- 205 to 380 +/- 140 micrograms/24 h (mean +/- SD). In contrast MCRT increased from 1275 +/- 200 to 1632 +/- 360 1/24 h; this increase in MCRT explains the striking plasma T concentration fall and the high TG and Adiol excretion relative to the decrease in PR. Antipyrine clearance rate (n = 8) increased from 36.3 +/- 5.2 to 51.5 +/- 7.4 ml/min whereas 6 beta hydroxycortisol remained unchanged. In conclusion, CPA acts through several mechanisms: (1) it lowers the androgen input to the target cells by (a) depressing T production through its antigonadotropic effect and (b) accelerating T metabolic inactivation due to a partial enzymatic inducer effect on the liver; (2) at the target cell level it competes with any remaining T for the receptor binding sites; (3) the decrease in the androgen-dependent skin 5 alpha-R is a consequence of both actions of androgen suppression and androgen receptor blockade; it reinforces the antiandrogenic effect of CPA.     

Steroid dynamics in the rabbit

Male rabbits were infused at a constant rate with 3H-androstenedione/14C-estrone (n = 5) or 3H-testosterone/14C-estradiol-17 beta (n = 3) for 3 1/2 hr and blood samples were obtained over the last hour and analyzed for radioactivity as androstenedione (A), testosterone (T), estrone (E1), estradiol-17 beta (E2 beta) and estradiol-17 alpha (E2 alpha). The mean value for the metabolic clearance rate of androstenedione (MCRA) was 85 +/- 10 l/day/kg, which was significantly greater than the mean MCRE1 59 +/- 10 l/day/kg. MCRT, 42 +/- 8 l/day/kg, and MCRE2 beta, 45 +/- 9 l/day/kg were not different. The conversion ratio of androstenedione to testosterone (CRA,T) was greater than CRT,A but for the estrogens, CRE2 beta, E1 was greater than CRE1,E2 beta. CRE2 beta, E2 alpha was greater than CRE1,E2 alpha. The overall aromatization of androstenedione to estrone, the fraction of 3H-androstenedione infused into the blood and measured as 3H-estrone in blood [( rho]A,E1BB) was 0.0005 +/- 0.0001 and for [rho]T,E2 beta BB was 0.0012 +/- 0.0006. In the rabbit both sex hormone binding globulin (SHBG) and albumin binding may effect the MCRs, and peripheral aromatization of androgens occurs to a far lesser degree than in humans and primates.     

Thyroid hormone metabolism in hypermetabolic patients with haematological disorders

Turnover tracer studies of T4 and T3 using the single injection, noncompartmental approach were performed in 6 hypermetabolic patients with haematological disorders (HHD) (basal metabolic rate (BMR): median 141%, range 122-166%), in 10 controls with stable, nonthyroidal illness (NTIC), and in 14 healthy controls (HC). The main finding was an increase of approximately 30% of the production rate (PR) of both T4 and T3 in patients with HHD. Median PR of T4 was 134 nmol/day x 70 kg in HHD, compared to 78 nmol/day x 70 kg in NTIC (P less than 0.05) and 98 nmol/day X 70 kg in HC (p less than 0.1), whereas median PR of T3 was 40.3 nmol/day x 70 kg in HHD, compared to 25.6 nmol/day x 70 kg in NTIC (P less than 0.01) and 31.1 nmol/day x 70 kg in HC (P less than 0.1). An increase of similar magnitude was found for the apparent distribution volume and the pool size of both T4 and T3. In contrast, the mean transit times of the hormones were similar in the 3 groups. Patients with HHD had normal levels of basal serum TSH as well as of the TSH response to TRH. Only PR of T3 correlated to the BMR (R = 1.00, P less than 0.02). The data are compatible with an increased consumption of thyroid hormones by malignant haematologic cells, and the increase of BMR seems to be dependent on the production of T3.     

Effects of beta-blockade on exercise capacity of trained and untrained men: a hemodynamic comparison

To study the effects of cardiovascular fitness on hemodynamic responses to exercise during beta-adrenergic blockade (BAB), submaximal [60% of maximum O2 uptake (VO2max)] and maximal treadmill exercise data were collected in 11 trained (T, VO2max 63.3 ml X kg-1 X min-1, 26.8 yr) and 11 untrained (UT, VO2max 44.5 ml X kg-1 X min-1, 25.0 yr) male subjects. Subjects completed two maximal control tests followed by a randomized, double-blind series of maximal tests after 1-wk treatments with placebo (PLAC), propranolol (PROP, 160 mg/day, beta 1- and beta 2-blockade), and atenolol (ATEN, 100 mg/day, beta 1-blockade). Treatments were separated by 1-wk washout periods. At 60% of control VO2max T and UT subjects experienced no reductions in O2 uptake (VO2) with either drug. Submaximal heart rate (HR, beats/min) was 134.8 PLAC, 107.0 PROP, 107.9 ATEN (P less than 0.05 both drugs vs. PLAC) in T subjects and 141.1 PLAC, 106.1 PROP, and 105.0 ATEN (P less than 0.05 both drugs vs. PLAC) in UT subjects. Cardiac output (1/min) for T was 17.3 PLAC, 16.9 PROP, 16.5 ATEN (P less than 0.05 ATEN vs. PLAC in T only) and for UT it was 12.2 (PLAC), 11.7 (PROP), 11.5 (ATEN) (P less than 0.05 both drugs vs. PLAC in UT). Stroke volume increased from 129.8 ml (PLAC) to 158.6 (PROP) and 156.2 (ATEN) in T (P less than 0.05 both drugs vs. PLAC) and from 86.8 (PLAC) to 110.0 (PROP) and 109.8 (ATEN) (P less than 0.05 both drugs vs. PLAC) in UT. The increases in stroke volume (SV) were similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heart rate and plasma catecholamines during 24 h of everyday life in trained and untrained men.

Physical training decreases resting heart rate as well as heart rate and catecholamine responses to ordinary physical activity and mental stress. These effects have been speculated to diminish cardiac morbidity. However, the sparing of heartbeats and catecholamine production might be outweighed by exaggerated responses during training sessions. To elucidate this issue, heart rate was measured continuously and plasma catecholamine concentrations were measured frequently during 24 h of ordinary living conditions in seven endurance-trained athletes (T) and eight sedentary or untrained (UT) young males. T subjects had lower heart rates than UT subjects during sleep and during nontraining awake periods. However, because of the increase during training, the total 24-h heartbeat number did not differ between groups (107,737 +/- 3,819 for T vs. 113,249 +/- 6,879 for UT, P = 0.731). Neither during sleep nor during awake nontraining periods were catecholamine levels lower in T than in UT subjects. Peak catecholamine levels during exercise in T were much higher than peak levels in UT subjects, and 24-h average epinephrine and norepinephrine concentrations were twice as high. We concluded that in highly trained athletes the total number of heartbeats per day is not decreased and the catecholamine production is, in fact, increased.     

Effects of exercise training on thermoregulatory responses and blood volume in older men.

We assessed the effects of aerobic and/or resistance training on thermoregulatory responses in older men and analyzed the results in relation to the changes in peak oxygen consumption rate (VO(2 peak)) and blood volume (BV). Twenty-three older men [age, 64 +/- 1 (SE) yr; VO(2 peak), 32.7 +/- 1.1 ml. kg(-1). min(-1)] were divided into three training regimens for 18 wk: control (C; n = 7), aerobic training (AT; n = 8), and resistance training (RT; n = 8). Subjects in C were allowed to perform walking of ~10,000 steps/day, 6-7 days/wk. Subjects in AT exercised on a cycle ergometer at 50-80% VO(2 peak) for 60 min/day, 3 days/wk, in addition to the walking. Subjects in RT performed a resistance exercise, including knee extension and flexion at 60-80% of one repetition maximum, two to three sets of eight repetitions per day, 3 days/wk, in addition to the walking. After 18 wk of training, VO(2 peak) increased by 5.2 +/- 3.4% in C (P > 0.07), 20.0 +/- 2.5% in AT (P < 0.0001), and 9.7 +/- 5.1% in RT (P < 0.003), but BV remained unchanged in all trials. In addition, the esophageal temperature (T(es)) thresholds for forearm skin vasodilation and sweating, determined during 30-min exercise of 60% VO(2 peak) at 30 degrees C, decreased in AT (P < 0.02) and RT (P < 0.02) but not in C (P > 0.2). In contrast, the slopes of forearm skin vascular conductance/T(es) and sweat rate/T(es) remained unchanged in all trials, but both increased in subjects with increased BV irrespective of trials with significant correlations between the changes in the slopes and BV (P < 0.005 and P < 0.0005, respectively). Thus aerobic and/or resistance training in older men increased VO(2 peak) and lowered T(es) thresholds for forearm skin vasodilation and sweating but did not increase BV. Furthermore, the sensitivity of the increase in skin vasodilation and sweating at a given increase in T(es) was more associated with BV than with VO(2 peak).     

The effects of 8 weeks of creatine monohydrate and glutamine supplementation on body composition and performance measures

Twenty-nine (17 men, 12 women) collegiate track and field athletes were randomly divided into a creatine monohydrate (CM, n = 10) group, creatine monohydrate and glutamine (CG, n = 10) group, or placebo (P, n = 9) group. The CM group received 0.3 g creatine.kg body mass per day for 1 week, followed by 0.03 g creatine.kg body mass per day for 7 weeks. The CG group received the same creatine dosage scheme as the CM group plus 4 g glutamine.day(-1). All 3 treatment groups participated in an identical periodized strength and conditioning program during preseason training. Body composition, vertical jump, and cycle performances were tested before (T1) and after (T2) the 8-week supplementation period. Body mass and lean body mass (LBM) increased at a greater rate for the CM and CG groups, compared with the P treatment. Additionally, the CM and CG groups exhibited significantly greater improvement in initial rate of power production, compared with the placebo treatment. These results suggest CM and CG significantly increase body mass, LBM, and initial rate of power production during multiple cycle ergometer bouts.     

Effect of physical training on the capacity to secrete epinephrine

Epinephrine responses to hypoglycemia and to identical relative work loads have been shown to be higher in endurance-trained athletes than in untrained subjects. To test the hypothesis that training increases the adrenal medullary secretory capacity, we studied the effects of glucagon (1 mg/70 kg iv), acute hypercapnia (inspired O2 fraction = 7%), and acute hypobaric hypoxia (inspired Po2 = 87 Torr), respectively, on the epinephrine concentration in arterialized hand vein blood in eight endurance-trained athletes [T, O2 uptake = 66 (62-70) ml.min-1.kg-1] and seven sedentary males [C, O2 uptake = 46 (41-50)]. In response to identical increments in glucagon concentrations, plasma epinephrine increased more in T than in C subjects [0.87 +/- 0.11 vs. 0.38 +/- 0.14 (SE) nmol/l, P less than 0.05]. In response to hypercapnia [arterial PCO2 = 56 +/- 0.7 Torr (T) and 55 +/- 0.4 (C), P greater than 0.05], the increment in epinephrine was significant in T (0.38 +/- 0.11 nmol/l) but not (P less than 0.1) in C subjects (0.22 +/- 0.11). Hypoxia [arterial PO2 = 42 +/- 2 Torr (T) and 41 +/- 2 (C), P greater than 0.05] increased epinephrine in T (0.22 +/- 0.10 nmol/l, P less than 0.05) but not in C subjects (0.01 +/- 0.07). The plasma norepinephrine concentration never changed, whereas heart rate always increased, the increase being higher (P less than 0.05) in T than in C subjects only during hypercapnia. The results indicate that training increases the capacity to secrete epinephrine.     

The cardiovascular effects of a chimeric opioid peptide based on morphiceptin and PFRTic-NH2

MCRT (YPFPFRTic-NH₂) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH₂. In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and l-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH₂. When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection.     

Physical performance in kidney transplanted patients: a study on desert trekking

Physical performance of kidney transplanted patients in challenging environments, such as deserts, has been poorly studied. Six kidney transplanted (T: 5 males, 1 female; 45±6 yrs) and 8 control (C: 5 males, 3 females; 49±13 yrs) subjects participated in a 5-day desert trek. Blood pressure, hydration status (Height2/Rz by bioimpedance), heart rate, energy expenditure (by SenseWear Pro Armband) and walking velocities were recorded during each daily trekking stage (GPS-assisted wearable devices). Systo-diastolic blood pressure did not differ between C (119/77±12/8 mmHg) and T (121/77±10/6 mmHg) groups throughout the study. The hydration status was stable from day 1 (Ht2/Rz: 64±13 cm2/Ohm in T and 59±12 cm2/Ohm in C subjects) to day 5 (66±11 cm2/Ohm in T and 61±13 cm2/Ohm in C subjects) in both groups. Two patients on steroid treatment showed a relative hyperhydration. Mean heart rate did not differ between T (135±10 bpm) and C (136±5 bpm) subjects throughout the study, although a reduction from day 1 to day 5 was observed in T subjects only (p<0.05 vs C group). No differences were found between T and C group in walking velocity (1.7±0.6 km/h in T and 1.7±0.5 km/h in C group); mean intensity of physical activity was 3.4±0.5 METs in T and 3.3±0.6 METs in C group during each trekking stage. Negligible differences were observed in cardiovascular, metabolic and hydration status adaptations to desert trekking between selected T and C individuals. T subjects with creatinine clearance > 55 ml/min showed acceptable physical performance and acclimatization to desert environment, suggesting a good long-term outcome of transplantation.     

Increased epinephrine response and inaccurate glucoregulation in exercising athletes

Epinephrine responses to insulin-induced hypoglycemia have indicated that athletes have a higher adrenal medullary secretory capacity than untrained subjects. This view was tested by an exercise protocol aiming at identical stimulation of the adrenal medulla in the two groups. Eight athletes (T) and eight controls (C) ran 7 min at 60% maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. Plasma epinephrine both at rest and at identical relative work loads [110% VO2max: 8.73 +/- 1.51 (T) vs. 3.60 +/- 1.09 mmol X l-1 (C)] was higher [P less than 0.05) in T than in C. Norepinephrine, as well as heart rate, increased identically in the two groups, indicating identical sympathetic nervous activity. Lactate and glycerol were higher in T than in C after running. Glucose production peaked immediately after exercise and was higher in T than in C. Glucose disappearance increased less than glucose production and was identical in T and C. Accordingly plasma glucose increased, more in T than in C (P less than 0.01). In T glucose levels approached the renal threshold greater than 20 min postexercise. Glucose clearance increased less in T than in C during exercise and decreased postexercise to or below (T, P less than 0.05) basal levels, despite increased insulin levels. Long-term endurance training increases responsiveness of the adrenal medulla to exercise, indicating increased secretory capacity. During maximal exercise this may contribute to higher glucose production, lower clearance, more inaccurate glucoregulation, and higher lypolysis in T compared with C.     

Cocrystallization model for synthetic biodegradable poly(butylene adipate-co-butylene terephthalate)

Synthetic biodegradable poly(butylene adipate-co-butylene terephthalate), P(BA-co-BT), with 56 mol % butylene adipate, BA, was characterized by solid-state NMR spectroscopy, thermal analysis, X-ray diffraction, computer modeling, and polarization microscopy. The NMR study showed the presence of BA and butylene terephthalate, BT. T(1C) NMR measurements proved that some BA and BT units were in crystalline regions. Thermal analysis showed one glass-transition temperature and a single diffuse melting endotherm corresponding to a large melting-point depression of about 100 degrees C compared with poly(butylene terephthalate), PBT. These results suggest that there is only one crystalline phase. An X-ray fiber diagram of a stretched film could be indexed with the same unit cell as that for PBT. Computer modeling showed that the adipate unit fits into the crystal structure of PBT by adopting a TTGTG dihedral angle sequence in the crystalline conformation proposed for the cocrystallization model. The predicted fiber diagram from the proposed model qualitatively agrees with the experimental one. Polarization microscopy revealed that the spherulite growth rate of P(BA-co-BT) was similar to that for poly(butylene adipate), PBA.     

Blood pressure and metabolic effects of 18-oxo-cortisol in sheep

18-Oxo-cortisol (18-oxo-F) has been isolated from the urine of subjects with primary aldosteronism. This study examines the pressor, mineralocorticoid and glucocorticoid effects of 18-oxo-F in conscious sheep--a well studied species for the assessment of the pressor effect of steroid hormones. 18-oxo-F (24 mg/day i.v. for 5 days, n = 3) increased mean arterial pressure MAP (64 +/- 2 mmHg control and 75 +/- 6 mmHg on day 5 P less than 0.001). There was no change in heart rate. Plasma [K+] decreased from a control of 4.3 +/- 0.1 mmol/l control to 2.9 +/- 0.3 mmol/l on day 5 (P less than 0.001). Urinary Na+ excretion decreased on the first infusion day (233 +/- 18 mmol/day control and 124 +/- 20 mmol/day on infusion day 1 P less than 0.001). Urinary K+ excretion was reduced on days 1, 4 and 5 of the infusion. Thus in sheep, 18-oxo-F increased blood pressure associated with in vivo evidence of mineralocorticoid activity.     

Extracellular matrix conditions T cells for adhesion to tissue interstitium

The activation and differentiation of peripheral blood T cells (PBT) are known to correlate with increased surface expression and adhesive capacity of beta(1) integrins, which mediate adhesion to the extracellular matrix (ECM). However, little is known about the regulation of integrin expression, affinity, and avidity on tissue T cells after they are embedded in the interstitial ECM. In this study we show that tissue T cells, freshly isolated from their residence in the interstitial ECM of the intestinal lamina propria, express a distinct subset of functionally active integrins that contribute to enhanced adhesion to purified collagen, fibronectin, and cell-derived ECM when compared with freshly isolated, short term activated, and long term cultured PBT. Furthermore, integrin usage is distinct between circulating and tissue-derived T cells, in that lamina propria T cells prefer to bind to collagen, while PBT lymphoblasts choose fibronectin when presented with a complex, three-dimensional, cell-derived matrix. To identify the extrinsic factors that regulate the conversion from a nonadhesive PBT to highly adhesive tissue T cell, we demonstrate that activation of PBT in the presence of fibronectin or collagen rapidly generates a surface integrin expression profile, an integrin usage pattern, and adhesive capacity mirroring that of a tissue T cell. These results indicate that the tissue ECM microenvironment instructs newly arrived T cells for further interactions with the underlying matrix and thereby imprints them with a signature tissue adhesive phenotype.     

Capsicum ethanol extracts and capsaicin enhance interleukin-2 and interferon-gamma production in cultured murine Peyer's patch cells ex vivo

We investigated the effects of red pepper (Capsicum annuum Lin.) extracts (capsicum extract) and its main pungent capsaicin on T helper 1 (Th1) and 2 (Th2) cytokine production in cultured murine Peyer's patch (PP) cells in vitro and ex vivo. Direct administration of capsicum extract (1 and 10 mug/ml) and capsaicin (3 and 30 muM) resulted in suppression of interleukin (IL)-2, interferon (IFN)-gamma, IL-4 and IL-5 production. In an ex vivo experiment using PP cells removed from the mice after oral administration of capsicum extract (10 mg/kg/day for 4 consecutive days), IL-2, IFN-gamma and IL-5 increased in response to concanavalin A (Con A). Oral administration of 3 mg/kg/day capsaicin, one active constituent of the extract, also enhanced IL-2, INF-gamma and IL-4 production in response to Con A stimulation but did not influence the production of IL-5. Orally administered capsazepine (3 mg/kg/day), a selective transient receptor potential vanilloid 1 (TRPV1) antagonist, slightly enhanced IL-2 production also irrespective of Con A stimulation. The capsaicin-induced enhancement of both IL-2 and IFN-gamma production was not reduced by oral administration of capsazepine (3 mg/kg/day), suggesting a TRPV1 receptor-independent mechanism. Flow cytometric analysis revealed that the population of CD3(+) cells in the PP cells was significantly reduced while CD19(+) cells increased after oral administration of capsicum extract (1 and 10 mg/kg/day) and capsaicin (0.3 and 3 mg/kg/day). Capsazepine (3 mg/kg/day) weakly but significantly reversed these effects. Orally administered capsicum extract and capsaicin did not change the T cell subset (CD4(+) and CD8(+)), Th1 (IFN-gamma(+)) and T2 (IL-4(+)) ratio. These findings indicate that capsicum extract and capsaicin modulate T cell-immune responses, and their immunomodulatory effects on murine PP cells are partly due to both TRPV1-dependent and -independent pathway.     

Effects of gonadotropin-releasing hormone treatment on ovarian steroid production during midpregnancy

During the second half of pregnancy, ovarian testosterone (T) through its conversion to estradiol (E) promotes progesterone (P) synthesis by the ovary which maintains the pregnancy. To determine if the administration of gonadotropin-releasing hormone (GnRH) disrupts pregnancy by suppressing ovarian production of T or its conversion to E, rats were treated from Day 11 through Day 18 of pregnancy with 50 or 100 micrograms/day of GnRH or 1, 5, or 10 micrograms/day of a GnRH agonist (GnRH-Ag; WY-40972) using an osmotic minipump. Rats were bled daily from the jugular vein under light ether anesthesia and on Days 14 or 18 of pregnancy both jugular and ovarian blood samples were obtained. While the GnRH-Ag treatment at the dose of 5 or 10 micrograms/day terminated pregnancy within 48 hr as indicated by vaginal bleeding, 1 microgram/day terminated pregnancy more slowly. Neither dose of GnRH was effective in terminating pregnancy through Day 18. By Day 14, peripheral levels of plasma P in rats treated with 0, 1, 5, or 10 micrograms of GnRH-Ag were 97 +/- 9, 24 +/- 1, 13 +/- 3, and 8 +/- 1, respectively. In the same groups, levels in the ovarian vein were 3205 +/- 633, 1317 +/- 273, 360 +/- 113, and 228 +/- 73 ng/ml. By Day 18, serum P levels in the peripheral circulation and in the ovarian vein were declining even more dramatically. Daily administration of P (4 mg) and E (0.5 micrograms) simultaneously with GnRH-Ag at the dose of 5 micrograms/day from Days 11 through 14 reversed the abortifacient effect of GnRH-Ag and maintained pregnancy indicating that the GnRH-Ag effect is not directly on the uterus. Ovarian vein levels of T on Days 14 or 18 of pregnancy were either not different from controls at 1407 +/- 163 or 1476 +/- 122 pg/ml, respectively, or increased dramatically in certain groups. Ovarian vein levels of E were either not different from controls at 292 +/- 13 pg/ml on Day 14 or increased significantly in rats treated at the dose of 1 microgram/day of GnRH-Ag. However by Day 18, treatment with GnRH-Ag at all doses suppressed ovarian secretion of E. These results suggest that while the GnRH-Ag induces abortion in rats by suppressing ovarian production of P, this abortifacient effect is not due to a fall in ovarian T levels nor to its aromatization to E in the ovary.     

The effects of l-thyroxine and dexamethasone on steroid dynamics in male cynomologous monkeys

Male cynomologous monkeys (M. fascicularis) were infused with [3H]androgens, [14C]estrogens and [3H]cortisol before and after the administration of l-thyroxine, (l-T4) 150 micrograms/day for 6 wk, dexamethasone 8 mg every 8 h for 3 doses and dexamethasone 1.0 mg/day for 8 days. Blood samples were obtained before each of the infusions and analyzed for endogenous T, A, E1, E2 and F concentrations, % free T and % free E2, sex hormone-binding globulin (SHBG) and cortisol binding globulin (CBG) capacity. When l-T4 was being administered, T4 and triiodothyronine (T3) concentrations were also measured. Blood samples were obtained during the infusions and analyzed for radioactivity as testosterone (T), androstenedione (A), dihydrotestosterone (DHT), estradiol (E1), estrone (E2), and cortisol (F). All urine was collected for 96 h and an aliquot of the pooled urine was analyzed for radioactivity as estrone and estradiol glucuronide. The administration of l-T4 for 6 wk to 3 monkeys resulted in a marked rise in T4 and T3 levels, from 4.8 +/- 0.4 micrograms/dl and from 136 +/- 6 to 515 +/- 71 ng/dl, respectively. MCRT, MCRE2 and MCRE1 did not change, but MCRA values increased slightly and MCRF increased 2-3 fold. [rho]T.E2 did not change but [rho]A.E1BM showed a slight but significant increase. The inter-conversions between the androgens and between the estrogens were not altered. There was a 2-3-fold increase in SHBG and a decrease in %FT but no change in %FE2 or CBG. The concentrations of T, A and DHT rose but there was no trend in the levels of the estrogens. The administration of dexamethasone 8 mg every 8 h for 3 doses or 1 mg/day for 8 days caused no changes in the MCRs for T, A, E1 and E2 but did cause a significant decrease in MCRF. Measurement of splanchnic and peripheral tissue extractions before and after acute dexamethasone administration in 1 monkey showed that the decrease in MCRF was the result of a marked decrease, 11-2%, in splanchnic extraction of F. The extractions of T and E2 were relatively unaffected. The concentrations of T and F fell but E2 remained the same. % FT and % FE2 rose slightly and the concentrations of SHBG and CBG were unchanged. The androgen interconversions and estrogen interconversions were not affected but [rho]T,E2BM and [rho]A,E1BM showed slight decreases.(ABSTRACT TRUNCATED AT 400 WORDS)