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PubMed1985

Effects of flutamide or of supplementation with testosterone in prepubertal male rats prenatally treated with busulfan.

Male rats treated prenatally with busulfan in order to render them aspermatogenic were treated between 23 and 38 days of age either with testosterone, or flutamide. In such aspermatogenic rats, testosterone supplementation stimulated the growth of accessory sex organs, markedly decreased the secretion of gonadotrophins (by 61% for LH and 83% for FSH), decreased testicular weight (-60%) as well as all parameters relating to testicular histology. Flutamide treatment decreased the weight of accessory sex organs, stimulated the secretion of both LH (+200%) and FSH (+63%) by inhibition of the negative feedback of testosterone; endogenous testosterone secretion was increased by 363%. Testicular weight was increased by 44% and the total volume and the cytoplasmic and nuclear area of Leydig cells were increased by 254 and 28%, respectively, but their number per testis was unchanged. The number of Sertoli cells per testis was increased by 49%, but their nuclear area was not modified. In aspermatogenic prepubertal rats, the large increase in plasma FSH demonstrated that FSH release was partly under the control of inhibin, secreted by Sertoli cells when germinal cells were present. Nevertheless, FSH levels after testosterone (inhibition) or flutamide treatment (stimulation) clearly demonstrated that, in the growing rat, FSH secretion is also partly dependent on the negative feedback of testosterone. In the absence of germ cells, FSH was able to re-initiate Sertoli cells mitoses, but not their functional activity. LH secretion was solely controlled by the negative feedback of androgens and, even in the absence of germinal cells, Leydig cells were able to respond to LH stimulation by an increase in testosterone secretion.

Anilides↗
PubMed1987

[Studies on the feedback regulation of gonadotropin concentrations in male rats. (III). The effects of testosterone and its metabolites on gonadotropin secretion from rat pituitary cells in culture].

To determine whether dihydrotestosterone (DHT) or estradiol (E2) exerts negative or positive feedback effects on rat pituitary gland, Testosterone (T) metabolite (T, DHT, 5 alpha-androstane-3 alpha, 17 beta-diol:3 alpha-diol or E2) was added to the cultured pituitary cells. Anterior pituitary glands were obtained from 6-week-old male rats. Pituitary cells were prepared by trypsin digestion and incubated with various concentrations of steroid hormones for 72 h to determine the effects of steroid hormones on basal secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) after 48 h preculture without steroids. Then 10 nM luteinizing hormone-releasing hormone (LH-RH) with appropriate concentrations of these steroid hormones was added to the pituitary cells in culture and incubated for another 6h to determine the effects of steroid hormones on LH-RH induced gonadotropin release. After the incubation, pituitary cells were lysed with 0.1% Triton X100 to measure the intracellular gonadotropin content. The concentration of LH and FSH was determined by radioimmunoassay. T, DHT and 3 alpha-diol stimulated basal FSH but not basal LH secretion, and inhibited both the release of FSH and LH from cultured pituitary cells during incubations with LH-RH in a dose-dependent fashion. Intracellular content of both FSH and LH were increased, and total FSH and not LH was also increased by the addition of DHT in a dose-dependent manner. E2 did not exert any of such effects on pituitary cells in culture. These studies suggest that 5 alpha-reduced metabolites but not aromatized metabolite of T play an important role on feedback regulation of gonadotropin secretion at pituitary level. DHT directly acts on pituitary gland not only to stimulate the production of FSH but also to suppress FSH and LH secretion induced by LH-RH.

Androstane-3,17-diol↗
PubMed1993

Melatonin potentiates testosterone-induced suppression of luteinizing hormone secretion in normal men.

A total of 12 healthy adult men were recruited to investigate the effect of exogenous melatonin on the sensitivity of the hypothalamo-pituitary axis to sex steroid negative feedback. The experiment consisted of a double-blind, randomized cross-over trial during which all subjects received 100 mg oral melatonin or placebo at 1600 h for 14 days. Midway through each of the two treatments (day 8), 100 mg testosterone propionate i.m. (TP) was given at 0900 h. Blood samples for the measurement of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, testosterone and melatonin were taken at 0900 h on days 1, 3, 5, and daily from days 8-14. An additional blood sample was taken 8 h after the administration of testosterone. The interval between the melatonin and placebo treatment periods was 2 months. The oral administration of melatonin caused a pharmacological increase in the blood plasma concentration of melatonin which was maximum at 2 h and still above normal at 24 h. The daily treatment thus resulted in persistently high circulating levels of melatonin for 14 days. This treatment had no significant effect on the secretion of LH, FSH, prolactin or testosterone based on the first week of each study (melatonin compared with placebo). The injection of TP caused a rapid 3 to 4-fold increase in the plasma concentrations of testosterone which was at a maximum at 8 h and had returned to baseline within 4 days, with a similar pattern in both the melatonin and placebo periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men.

The precise sites of action of the negative feed-back effects of gonadal steroids in men remain unclear. To determine whether testosterone (T) administration can suppress gonadotropin secretion directly at the level of the pituitary, the pituitary responses to physiological doses of GnRH were assessed in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous T infusion (15 mg/day). Their responses were compared with the effects of identical T infusions on spontaneous gonadotropin secretion and the response to a 100-micrograms GnRH bolus in six normal men. Both groups were monitored with 15 h of frequent blood sampling before and during the last day of the T infusion. In the GnRH-deficient men, the first three GnRH doses were identical and were chosen to produce LH pulses with amplitudes in the midphysiological range of our normal men (i.e. a physiological dose), while the last four doses spanned 1.5 log orders (7.5, 25, 75, and 250 ng/kg). The 250 ng/kg dose was always administered last because it is known to be pharmacological. In the GnRH-deficient men, mean LH (P less than 0.02) and FSH (P less than 0.01) levels as well as LH pulse amplitude (P less than 0.05) decreased significantly during T infusion, demonstrating a direct pituitary-suppressive effect of T and/or its metabolites. Mean LH levels were suppressed to a greater extent in the normal than in the GnRH-deficient men (58 +/- 15% vs. 28 +/- 7%; P less than 0.05). In addition, LH frequency decreased significantly (P less than 0.01) during T administration in the normal men. These latter two findings suggest that T administration also suppresses hypothalamic GnRH release. T was unable to suppress gonadotropin secretion in one GnRH-deficient and one normal man. In both groups, the suppressive effect of T administration was present only in response to physiological doses of GnRH. Because the pituitary- and hypothalamus-suppressive effects of T could be mediated by its aromatization to estrogens, five GnRH-deficient and five normal men underwent identical T infusions with concomitant administration of the aromatase inhibitor testolactone (TL; 500 mg, orally, every 6 h). As an additional control, four GnRH-deficient and four normal men received TL alone. TL administration completely prevented the effect of T administration to suppress gonadotropin secretion in both the normal and GnRH-deficient men, and mean LH levels increased significantly in both the GnRH-deficient (P less than 0.01) and the normal (P less than 0.001) men who received TL alone. The increase in mean LH levels was greater (P less than 0.01) in the normal men who received TL alone than in the normal men who received T plus TL, thus revealing a direct effect of androgens in normal men. Measurements of T and estradiol production rates in three men demonstrated that TL effectively blocked aromatization.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1993

Regulation of inhibin secretion in human placental cell culture by epidermal growth factor, transforming growth factors, and activin.

In this study, the effects of epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), TGF beta 1, and activin-A on inhibin secretion were investigated in primary culture of human placental cells. Immunoreactive inhibin in the culture medium was measured by immunoenzymatic assay. EGF stimulated testosterone-induced inhibin secretion in placental cells. Although testosterone alone induced only a slight enhancement of inhibin release in the culture, treatment of trophoblast cells with EGF and testosterone caused a significant increase in inhibin secretion, with immunoreactive inhibin levels much higher than those of testosterone or EGF alone. TGF alpha combined with human placental lactogen (hPL) had a stimulatory effect on inhibin secretion in placental cell culture. Simple addition of either TGF alpha or hPL to the culture did not show any effect on inhibin secretion in placental cells. A remarkable augmentation of inhibin secretion was obtained after the trophoblasts were exposed to both TGF alpha and hPL simultaneously. TGF beta 1 and activin-A showed synergistic effects to suppress inhibin secretion in placental cells. TGF beta 1 alone did not show any action on inhibin secretion, and activin-A alone induced a small decrease in inhibin release in the culture. In the presence of activin-A, addition of TGF beta 1 to the culture induced a profound decrease in immunoreactive inhibin levels in the medium. Activin-A could also suppress hCG-induced inhibin secretion in placental cells. Addition of hCG alone resulted in a small, but not significant, increase in inhibin release in the cultured cells, whereas the presence of activin-A combined with hCG in the culture conversely decreased inhibin secretion in the culture, with immunoreactive inhibin levels significantly lower than those in the presence of hCG or activin-A alone. These findings suggest that EGF and TGF alpha, alone or in combination with other hormones, may be stimulators, and TGF beta and activin may act as suppressors of inhibin secretion in human placental cells.

Activins↗
PubMed1976

Effect of a new LH-RH analogue (D-Ser(TBU)6-EA10-LH-RH) on gonadotrophin and gonadal steroid secretion in men.

The effect of a new analogue of the gonadotrophin-releasing hormone LH-RH, D-Ser(TBU)6-EA10-LH-RH, on the secretion of LH, FSH, as well as testosterone, oestradiol, HGH, prolactin, TSH, and cortisol was studied in normal men. The same subjects were injected intravenously in 4-day intervals with 1.0, 2.5, 5.0, and 10.0 mug of this substance. A significant LH but no FSH release was seen after doses of 1.0 and 2.5 mug LH-RH analogue, while after 5.0 and 10.0 mug dose-dependent increases of LH and imposed elevations of FSH were observed. Peak levels of LH were reached after 30 min, those of FSH after intravenous injection after 120 min. LH and FSH remained elevated for 8-10 h. LH peak levels after 5 mug of LH-RH analogue were comparable to those seen after injection of 100 mug of the decapeptide LH-RH. Following the release of LH and FSH after doses of 5.0 and 10.0 mug LH-RH analogue, there was a late stimulating effect in testosterone and oestradiol secretion. HGH, TSH, prolactin, and cortisol were not influenced by the LH-RH analogue.

Adult↗
PubMed1991

The interaction of testosterone and gonadotropins in stimulating estradiol and progesterone secretion by cultures of corpus luteum cells isolated from pigs in early and midluteal phase.

The first objective of this research was to define the capacity of corpora lutea of pig to secrete estradiol in the presence of an androgen substrate which was testosterone. The second objective was to define the synergism between gonadotropic hormones such as LH, FSH, and PRL and testosterone as measured by estradiol and progesterone secretion by two types of porcine luteal cells. Luteal cells were collected from newly forming corpora lutea (0-3 days after ovulation) and from mature corpora lutea (8-10 days after ovulation). After dispersion, luteal cells were suspended in medium M199 supplemented with 10% of calf serum and grown as monolayers at 37 degrees C. Control cultures were grown in medium alone while other cultures were supplemented with either testosterone alone at a concentration of 1 x 10(-7) M or with 10, 100, 500 ng LH plus testosterone, 10, 100, 500 ng FSH plus testosterone or 10, 100, 500 ng PRL plus testosterone. After 2 days of cultivation all cultures were terminated and media were frozen at 20 degrees C for further steroid analysis. Testosterone added to the culture medium in the absence of gonadotropins was without effect on estradiol and progesterone secretion by luteal cells collected in the corpora lutea of the early luteal phase. On the other hand testosterone added to the medium significantly increased progesterone and estradiol secretion by cultured luteal cells collected in the midluteal phase of the cycle. No additive stimulatory action of gonadotropins and testosterone on progesterone secretion was observed in cultures of luteal cells from the early luteal phase but this was not the case in cultures of luteal cells from the midluteal phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Photoperiodically induced changes in glutamatergic stimulation of LH secretion in male Syrian hamsters: role of circulating testosterone and endogenous opioids.

In seasonally breeding mammals, the sensitivity of LH secretion to stimulation by the glutamate agonist N-methyl-D-aspartic acid (NMDA) is lower in the sexually active condition than in animals with testicular regression. One experiment determined if this increased sensitivity to NMDA in the reproductively inactive animal reflects reduced circulating testosterone. Responses to NMDA were determined during long days (LD) and short days (SD) in castrated hamsters bearing silastic testosterone implants, designed to maintain constant serum testosterone concentrations throughout a photoperiodically induced seasonal cycle. As expected, no significant effect of NMDA (50 mg/kg BW, sc) on secretion of LH occurred in testosterone-implanted castrate or intact control hamsters when challenged in LD. In contrast, both groups of hamsters responded to this dose of NMDA after 8 weeks exposure to SD, despite the maintenance of high serum testosterone concentrations in the castrate group. Moreover, the increased response to NMDA was not a reflection of lower LH concentrations associated with this photoperiod, because a response to NMDA persisted after removal of implants when endogenous secretion of LH had increased. Thus, the low circulating concentrations of testosterone in male hamsters exposed to an inhibitory SD photoperiod cannot explain the increased response to glutamatergic stimulation in the sexually inactive state. Photoperiod, acting centrally, is the major determinant of the response to activation of NMDA receptors. Other experiments investigated whether the lack of response to glutamatergic stimulation in the LD sexually active state results from endogenous opioid (EOP) tone that inhibits further increases in LH secretion at this stage of the reproductive cycle. If this is so, then pretreatment with an opioid antagonist would reveal or increase the stimulatory effect of NMDA on secretion of LH. Hamsters in LD were pretreated with the opioid antagonist naloxone (NAL; 5 mg/kg BW sc) before NMDA treatment (50 mg/kg BW sc), and blood samples collected 15 min later. Compared with controls, serum LH was significantly elevated in hamsters pretreated with NAL, but NMDA alone did not elevate LH. Surprisingly, LH concentrations in hamsters pretreated with NAL and then injected with NMDA were significantly lower than in hamsters receiving NAL only. Treatment with a submaximal dose of NAL (0.1 mg/kg) did not increase serum LH, nor did it reveal a stimulatory effect of subsequent NMDA treatment. The results demonstrate that the decreased sensitivity to glutamatergic agonists in the sexually active state is not a reflection of masking by inhibitory EOP mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

The role of calcium in luteinizing hormone/human chorionic gonadotrophin stimulation of Leydig cell immunoactive inhibin secretion in vitro.

The mechanism by which luteinizing hormone (LH) stimulates Leydig cell immunoactive inhibin (I-inhibin) secretion was investigated using Percoll-purified adult rat Leydig cells. Using a maximally stimulating dose of LH (16 ng/ml). Leydig cell I-inhibin secretion was non-detectable at 1-2 h of incubation, but subsequently increased at all time points during a 25 h incubation period. LH stimulated both Leydig cell content and release of I-inhibin. Increasing concentrations of LH stimulated both inhibin and testosterone immunoactivity in the incubation media over a similar dose-response range, with a 2- to 4-fold rise in I-inhibin secretion at maximal doses of LH. Dibutyryl cAMP stimulated testosterone secretion in a manner similar to that of LH, but I-inhibin secretion was less sensitive than testosterone and a significant stimulation was observed only at the highest doses (200-1000 micrograms/ml). LH-stimulated I-inhibin secretion was significantly decreased when Leydig cells were incubated in calcium-depleted (0.15 mM Ca2+ + 1 mM EGTA) or low [Ca2+] media (0.15 mM) as compared to normal (1.15 mM) or high [Ca2+] (2-5 mM) media. In contrast, LH-stimulated testosterone secretion remained unchanged by altering extracellular [Ca2+], and although decreased in the presence of EGTA, testosterone secretion remained significantly greater than basal levels. Furthermore both diltiazem and verapamil completely blocked the LH and dibutyryl cAMP-stimulated increase in Leydig cell I-inhibin, but did not reduce either LH or dibutyryl cAMP-stimulated testosterone production to basal levels. We conclude that LH stimulates both I-inhibin synthesis and release by adult rat Leydig cells in culture, by mechanisms involving calcium.

Animals↗
PubMed1977

Lysosomal enzyme secretion in rat ventral prostate. Secretagogue action of testosterone and dibutyryl cyclic AMP.

Rat ventral prostate slices, when incubated in vitro, secrete protein, lysosomal enzymes and newly phosphorylated components in a time- and temperature-dependent manner. Testosterone and dibutyryl cyclic AMP immediately stimulate secretion and 32Pi incorporation. Acid phosphatase and beta-N-acetylhexosaminidase are secreted as acidic isoenzymes presumably contained within primary lysosomes.

Acid Phosphatase↗
PubMed1987

Unilateral orchidectomy of ram lambs: acute, chronic and hCG-stimulated androgen levels.

1. The objectives of this study were to determine whether compensation of androgen secretion occurred acutely, chronically or after hCG-stimulation in unilaterally orchidectomized (ULO) rams. 2. Testosterone (T) concentrations were not significantly different (P greater than 0.10) between ULO and sham-operated ram lambs during the period immediately following ULO. 3. Chronically, testosterone concentrations were not significantly different (P greater than 0.10) between ULO and sham-operated ram lambs. 4. After hCG injection, the testosterone response of chronic ULO ram lambs was approx. half the response of the sham-operated ram lambs. 5. These data indicate that a rapid and sustained compensatory response of basal secretion of testosterone but not hCG-inducible testosterone secretion occurred in the ULO'd ram lambs.

Animals↗
PubMedDate not supplied

[Hormonal regulation of the processes of growth and sexual maturation in girls with accelerated physical development].

The peculiarities of physical growth and sexual maturity were investigated in 300 girls with accelerated physical development aged 9 to 17 years. It was found, that maximum rates of the somatic formation, a high level of the growth hormone and testosterone as well as low estradiol secretion are seen during the prepubescent stage of maturity. After the menarche the somatic formation rates, the growth hormone and testosterone secretion decrease, whereas estradiol secretion progressively rises.

Adolescent↗
PubMedDate not supplied

Expression of 17 beta-hydroxysteroid dehydrogenase type 5 in human ovary: a pilot study.

OBJECTIVE: Conversion of androstenedione to testosterone, the most potent androgen secreted by the ovary, is carried out by androgenic 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity. The molecular basis for this is unclear. We tested the hypothesis that type 5 17 beta-HSD (17 beta-HSD5) is responsible for testosterone formation from androstenedione in the human ovary. METHODS: We used primers specific for each type of 17 beta-HSD to identify quantitatively and directly sequence the polymerase chain reaction products of a human ovary library. RESULTS: 17 beta-HSD1, 17 beta-HSD4, and 17 beta-HSD5 were detected in the library lysate, but not 17 beta-HSD2 or 17 beta-HSD3. 17 beta-HSD5 was the predominant androgenic form of 17 beta-HSD expressed in human ovary. CONCLUSION: These data suggest that 17 beta-HSD5 may play a major role in testosterone biosynthesis by the human ovary. Further investigation of the regulation of 17 beta-HSD5 gene expression is warranted with regard to ovarian testosterone secretion in normal and abnormal states of ovarian function, such as polycystic ovary syndrome.

17-Hydroxysteroid Dehydrogenases↗
PubMed2000

Testosterone, androstenedione and dihydrotestosterone concentrations are elevated in female patients with major depression.

Hyperactivity of the HPA-system in major depression is reflected by an increased secretion of adrenal hormones especially cortisol and dehydroepiandrosterone (DHEA). In women for whom androgenicity is associated with cardiovascular disorders the dominant source of androstenedione and testosterone secretion are the adrenal glands. To date, there is only sparse information about the regulation of androstenedione, testosterone and dihydrotestosterone (DHT) concentrations in women with severe major depression.Therefore, 11 pre- and postmenopausal, severely depressed, hypercortisolemic women (Hamilton Depression Scale, 31.3+/-5.9; age, 28-77 yrs; mean, 48. 1+/-18.1 yrs) and 11 age-matched healthy female controls (age, 24-81 yrs; mean, 47.9+/-21.5 yrs) underwent a 24 hour (h) blood sampling starting at 0800 h with 30-minute sampling intervals. By applying multivariate analysis of covariance with age as covariate, androstenedione, testosterone and DHT plasma levels at 0900 h show a trend for elevated concentrations in depressed women compared to controls (F(1,19)=2.7; P=0.057). Univariate F tests reveal a significant difference between the groups for androstenedione (4. 19+/-1.571 vs 2.584+/-1.257 nmol/l; P<0.05) testosterone (1.110+/-0. 278 vs 0.833+/-0.347 nmol/l; P<0.05) and DHT (0.656+/-0.207 vs 0. 483+/-0.242 nmol/l; P<0.05). Mean ACTH (16.4+/-10.4 vs 10.4+/-2.4 pmol/l; P=0.89), LH (13.5+/-11.8 vs 8.9+/-9.2 IU/l; P=0.12), FSH (35. 2+/-33.1 vs 31.3+/-35.7 IU/l; P=0.67) and estradiol (135.4+/-157.4 vs 82.2+/-85.1 pmol/l; P=0.20) plasma levels did not differ between patients and controls. Further, there was a trend towards an age related decline in testosterone secretion in healthy controls (r=-0. 24; P=0.08) which did not occur in depressed patients (r=0.17; P=0. 96), while the calculated ratio of DHEA to testosterone was similar in both groups (0.2+/-0.14 vs 0.13+/-0.7; P=0.21, unpaired t-test). In conclusion, androstenedione, testosterone and DHT concentrations all were increased in hypercortisolemic women with severe major depression. These findings are best explained as a consequence of an overstimulation of the adrenal glands through pituitary and hypothalamic sites of the HPA-system.

Adrenocorticotropic Hormone↗
PubMed1992

Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male.

Of the gonadal steroids in the male, testosterone is the most important regulator of gonadotrophin secretion. However, whether testosterone affects gonadotrophin secretion directly or whether it must first be aromatized to estrogens is controversial. We have reported extensively on the endocrine and anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS 20267 in adult female rats. In these animals, both inhibitors potently and selectively inhibit estrogen biosynthesis. Thus these agents can be effectively used in studying estrogen-dependent processes. CGS 16949A was administered for 14 days to adult male rats, over a dose range which in females suppresses estradiol and elevates LH. In male rats a suppression of estradiol was seen, however, there was no significant effect on either serum LH or on the weights of androgen-dependent organs. CGS 16949A, when administered to healthy men at a dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol and significant elevations of plasma FSH and testosterone. Dose-dependent suppression of serum estradiol and an increase in serum testosterone and LH are seen after administration of single oral doses of CGS 20267. These results indicate that in the male rat, inhibition of aromatization of testosterone to estrogens does not influence gonadotrophin secretion whereas in men the negative feedback exerted by testosterone on gonadotrophin secretion is dependent on the aromatization of testosterone to estrogens.

Animals↗
PubMed2006

Effects of ghrelin and its analogues on chicken ovarian granulosa cells.

The aim of these in vitro experiments was (1) to examine the effects of ghrelin on the basic functions of ovarian cells (proliferation, apoptosis, secretory activity); (2) to determine the possible involvement of the GHS-R1a receptor and PKA- and MAPK-dependent post-receptor intracellular signalling cascades; (3) to identify the active part of the 28-amino acid molecule responsible for the effects of ghrelin on ovarian cells. We compared the effect of full-length ghrelin 1-28, a synthetic activator of GHS-R1a, GHRP6, and ghrelin molecular fragments 1-18 and 1-5 on cultured chicken ovarian cells. Indices of cell apoptosis (expression of the apoptotic peptide bax and the anti-apoptotic peptide bcl-2), proliferation (expression of proliferation-associated peptide PCNA), and expression of protein kinases (PKA and MAPK) within ovarian granulosa cells were analysed by immunocytochemistry. The secretion of progesterone (P(4)), testosterone (T), estradiol (E(2)) and arginine-vasotocin (AVT) by isolated ovarian follicular fragments was evaluated by RIA/EIA. It was observed that accumulation of bax was increased by ghrelin 1-28, GHRP6 and ghrelin 1-18, but not by ghrelin 1-5. Expression of bcl-2 was suppressed by addition of ghrelin 1-28, GHRP6 and ghrelin 1-5, but promoted by ghrelin 1-18. The occurrence of PCNA was reduced by ghrelin 1-28, GHRP6, ghrelin 1-18 and ghrelin 1-5. An increase in the expression of MAPK/ERK1, 2 was observed after addition of ghrelin 1-28, GHRP6 and ghrelin 1-18, but not ghrelin 1-5. The accumulation of PKA decreased after treatment with ghrelin 1-28 and increased after treatment with GHRP6 and ghrelin 1-18 but not ghrelin 1-5. Secretion of P(4) by ovarian follicular fragments was decreased after addition of ghrelin 1-28 or ghrelin 1-5 but stimulated by GHRP6 and ghrelin 1-18. Testosterone secretion was inhibited by ghrelins 1-28 and 1-18, but not by GHRP6 or ghrelin 1-5. Estradiol secretion was reduced after treatment with ghrelin 1-28 but stimulated by ghrelins 1-18 and 1-5; GHRP6 had no effect. AVT secretion was stimulated by ghrelin 1-28, GHRP6 and ghrelin 1-18, but inhibited by ghrelin 1-5. The comparison of the effects of the four ghrelin analogues on nine parameters of ovarian cells suggest (1) a direct effect of ghrelin on basic ovarian functions-apoptosis, proliferation, steroid and peptide hormone secretion; (2) that the majority of these effects can be mediated through GHS-R1a receptors; (3) an effect of ghrelin on MAPK- and PKA-dependent intracellular mechanisms, which can potentially mediate the action of ghrelin at the post-receptor level; (4) that ghrelin residues 5-18 may be responsible for the major effects of ghrelin on the avian ovary.

Animals↗
PubMed1996

Interactions between nutrition, testosterone and inhibin in the control of gonadotrophin secretion in mature rams.

The role of negative feedback by two testicular hormones, testosterone and inhibin, in the gonadotrophin responses of mature male sheep to changes in nutrition was tested. Six days after castration, 24 Merino rams were assigned to groups that were fed either a diet that maintained their initial liveweight (Intermediate diet), or about half of the Intermediate diet (Low diet), or the Intermediate diet with a supplement of lupin grain (High diet). One week after the change of diet, all animals were given subcutaneous testosterone implants, providing plasma testosterone concentrations of 3.06 +/- 0.14 ng mL-1 (mean +/- s.e.m.; n = 24). The implants were left in place for 7 days, during which time all the rams were also injected subcutaneously with 2 mL steroid-free bovine follicular fluid (bFF) every 8 h, to provide inhibin at mean plasma concentrations of 0.40 +/- 0.04 ng mL-1 (n = 24; compared with 1.50 +/- 0.12 ng mL-1 when the animals were intact). Five days after castration, there were significant increases in the frequency of luteinizing hormone (LH) pulses (from 1.83 +/- 0.23 to 17.3 +/- 0.96 pulses per 12 h; mean +/- s.e.m.; n = 24) and concentrations of FSH (from 0.45 +/- 0.07 to 14.19 +/- 2.7 ng mL-1; n = 24). Dietary treatment did not significantly affect these responses. Treatment with bFF and testosterone for 7 days reduced LH-pulse frequencies and follicle-stimulating hormone (FSH) concentrations in all groups. The degree of reduction was least in the group on the High diet, for which the FSH concentration (6.49 +/- 1.96 ng mL-1) and frequency of LH pulses (7.00 +/- 2.31 pulses per 24 h) were significantly higher than those observed in the other groups. The mean frequency of LH pulses did not differ significantly between the Intermediate group (0.88 +/- 0.61 pulses per 24 h) and the Low group (0.25 +/- 0.25 pulses per 24 h). Similarly, FSH concentrations did not differ significantly between these two groups (1.78 +/- 0.46 for the Intermediate group v. 1.33 +/- 0.26 ng mL-1 for the Low group). It is concluded that there is no response to diet in the absence of testicular hormones and the effects of nutrition on LH secretion in castrated rams given exogenous testosterone and inhibin are similar to those observed in intact rams.

Animal Nutritional Physiological Phenomena↗
PubMed1984

Inhibition of luteinizing hormone (LH)-releasing hormone-induced secretion of LH in rat anterior pituitary cell culture by testosterone without conversion to 5 alpha-dihydrotestosterone.

The role of 5 alpha-reduction of testosterone in the inhibition of LH secretion was investigated in rat anterior pituitary cell cultures. Pituitary cells were preincubated with testosterone or dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) for 17 h and then with LHRH for an additional 4 h. Dihydrotestosterone was 6-fold more potent than testosterone in the inhibition of LHRH-induced LH release. Basal LH secretion was not affected by either androgen. The inhibition curves of testosterone and dihydrotestosterone were not shifted by the presence of the 5 alpha-reductase inhibitors 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) and 17 beta-N,N-diisopropylcarbamoyl-4-aza-androstan-3-one (DIPA). Neither 4-MA nor DIPA alone had an effect on either basal or LHRH-induced LH release. When pituitary cells were incubated with [3H]testosterone for 17 h, the radioactivities were found to be unmetabolized testosterone (66.9 +/- 2.4%), dihydrotestosterone (13.3 +/- 0.5%), androstenedione (15.9 +/- 1.3%), 5 alpha-androstane-3,17-dione (2.8 +/- 0.3%), and 3 alpha (beta), 17 beta-androstanediol (less than 1%). In the presence of 4-MA or DIPA, 5 alpha-reduction of testosterone was completely inhibited; androstenedione was the only metabolite. Androstenedione was only 12% as potent as testosterone in the inhibition of LHRH stimulation of LH release, and conversion of [3H]androstenedione to testosterone and dihydrotestosterone did occur in these cells. When [3H]dihydrotestosterone was incubated with pituitary cells, the radioactivities were dihydrotestosterone (64.4 +/- 0%), 5 alpha-androstanedione (19.3 +/- 1%), 3 alpha (beta), 17 beta-androstanediol (7.7 +/- 1.7%), and unknown polar metabolites. 4-MA and DIPA had no effect on the metabolism of dihydrotestosterone. These results indicate that both testosterone and dihydrotestosterone inhibit LHRH-induced LH release and that this activity of testosterone does not depend on its 5 alpha-reduction.

5-alpha Reductase Inhibitors↗