Melatonin and gonadotropin secretion after acute exercise in physically active males

Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone, testosterone (T) and melatonin were measured in seven physically active male volunteers after exercise on a treadmill using the Bruce protocol. Measurements were made on blood samples obtained before exercise, within 30 s after exercise, at 15 min after exercise, and subsequently at 30-min intervals after exercise for a total duration of 180 min. Serum LH concentration fell from a peak post-exercise level of 15.7 (4.7) IU·l^–1 [mean (SD)] to a nadir of 10.3 (2.4) IU·l^–1 (P<0.004). Nadir values in individual volunteers were seen between 60 and 150 min after exercise. This fall in serum LH was paralleled by a similar fall in the concentration of serum T. Serum melaonin concentrations did not change significantly after exercise. It is concluded that melatonin, despite is reported anti-gonadotropic properties, does not play a role in the depression of serum LH after acute strenuous exercise in physically active males     

Beta-endorphin/beta-lipotropin release and gonadotropin secretion after acute exercise in physically conditioned males

beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) concentrations were measured in the basal state and after acute exercise for 15 min or until exhaustion in 6 physically conditioned male volunteers. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and prolactin were also measured in the basal state. In addition, the concentrations of the gonadotropins (LH and FSH) were determined after exercise and the gonadotropin response to gonadotropin releasing hormone was assessed before and after exercise. The data show that acute exercise stimulates the release of both beta-EP and beta-LPH which return to base-line levels within 60 min after exercise. This is in contrast to our previously described results in physically unconditioned male volunteers in whom only beta-LPH release was noted after exercise. Serum LH concentrations declined after exercise reaching nadir values between 60 to 150 min after exercise. As we previously reported in physically unconditioned male volunteers, serum FSH concentrations did not change with exercise and the gonadotropin response to LRH stimulation was uninfluenced by exercise. Serum testosterone and prolactin concentration were within the normal range for healthy adult males. We speculate that the difference in beta-EP release with exercise in physically conditioned and unconditioned males represents a difference in processing of the opioid precursor molecule (pro-opiomelanocortin, POMC) in the two groups.     

Beta-endorphin/beta-lipotropin release and gonadotropin secretion after acute exercise in normal males

The plasma beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) response to acute exercise and the relationship of these opioid peptides to basal and luteinizing hormone-releasing hormone (LRH)-stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion was studied in eight normal male volunteers. Acute exercise resulted in a rise in plasma beta-LPH levels that returned to base line when measured 60 min after exercise. Plasma beta-EP levels did not demonstrate any rise when measured immediately after 20 min of exercise or at 60 min after exercise. Serum LH concentrations in individual volunteers declined to nadir values 60-180 min after exercise after which they showed a rebound to levels higher than the preexercise values in three of five volunteers in whom nadir LH levels were attained before the final (180 min) measurement. Serum FSH concentrations were unaltered by exercise. Acute exercise similarly did not alter the LH/FSH response to exogenous LRH stimulation. Pretreatment of the volunteers with the narcotic antagonist, naloxone, failed to alter the postexercise or LRH-stimulated LH and FSH release. The data suggest that beta-EP does not exert a suppressive effect on LH secretion after acute exercise in normal human males. Whether the suppression of LH secretion after acute exercise in unconditioned males is due to factor(s) cosecreted with beta-LPH, an increase in brain beta-EP or to alternate mechanisms such as alteration in central dopaminergic or GABAergic tone remains to be established.     

Corticotropin releasing factor stimulates growth hormone secretion in neonatal rats

Corticotropin releasing factor (CRF) both stimulates ACTH secretion from the pituitary and inhibits secretion of growth hormone (GH) in adult rats through actions in the CNS. The purpose of the present study was to evaluate these pituitary and central actions of CRF in neonatal rats, in which the hypothalamo- pituitary adrenal (HPA) axis is relatively hypo-functional. The results of this study show that central or peripheral administration of CRF evokes a marked dose-related rise in serum corticosterone in 6-day old rats. The same doses of CRF stimulate, rather than inhibit GH secretion. These results suggest that CRF has unique central actions early in ontogeny.     

Corticotropin releasing hormone and its function in the skin.

The skin, as the largest organ of the body, is strategically located as a barrier between the external and internal environments, being permanently exposed to noxious stressors such as bursts of radiation (solar, thermal), mechanical energy, or chemical and biological insults. Because of its functional domains and structural diversity, the skin must have a constitutive mechanism for dealing with the stressors. Activities of the skin are mostly regulated by local cutaneous factors and stressed skin can generate signals to produce rapid (neural) or slow (humoral) responses to local or systemic levels. Thus, the skin neuroendocrine system is comprised of locally produced neuroendocrine mediators that interact with corresponding specific receptors through para- or autocrine mechanisms. Furthermore, it is known for several years that the corticotropin-releasing hormone (CRH)/ pro-opiomelanocorticotropin (POMC) skin system fulfils analogous functions to the hypothalamic-pituitary-adrenal (HPA) stress axis. Additionally, skin cells produce hormones, neurotansmitters and neuropeptides, having the corresponding receptors and the skin itself is able to fulfill a multidirectional communication between endocrine, immune and central nervous systems as well as other internal organs. In summary, the skin expresses an equivalent of the prominent hypothalamic-pituitary-adrenal stress axis that may act as a cutaneous defense system, operating as a coordinator and executor of local responses to stress, in addition to its normal function: the preservation of body homeostasis.     

Conformation of gonadotropin releasing hormone.

The conformation of the gonadotropin releasing hormone (Gn-RH), whose primary sequence is pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-GlyNH2, and of several of its structural analogues has been studied by circular dichroism, optical rotatory dispersion, and fluorescence spectroscopy. The effects of pH, guanidine, and temperature on fluorescence emission have also been examined. Titration data demonstrate that the histidine and tyrosine residues are free of any mutual interactions. The similarity of emission spectra in water and in guanidine hydrochloride solutions precludes significant interactions between the fluorescent groups and other residues. Neither the temperature nor the pH profiles of the emission intensities of either tyrosine or tryptophan reveal any fixed secondary structure in Gn-RH. Both the extent of alkaline quenching and the distance of 10-11 A calculated from F?rster energy transfer theory are in accord with a randomly coiled structure with only one residue between tyrosine and tryptophan. Furthermore, the circular dichroism spectrum and optical rotatory dispersion do not exhibit any contributions from peptide bonds in an ordered structure, although there is a perturbation of the peptide absorption region due to overlapping bands from side-chain chromophores. Gn-RH, therefore, appears to behave as a random coil polypeptide in water devoid of any intrachain residue interactions. This nonordered structure in Gn-RH and the lack of any significant differences in the physical-chemical properties of the hormone analogues indicate that a predetermined solution conformation is not required for biological activity. In contrast to its behavior in water, Gn-RH in trifluoroethanol exhibits a conformational transition, with the formation of a beta structure. Differences in conformational changes exhibited by several analogues in trifluoroethanol may be relevant to their relative biological activities at the receptor site.     

Luteinizing hormone release by gonadotropin releasing hormone before and after castration in bulls

The magnitude of gonadotropin releasing hormone (GnRH) induced lutei nizing hormone (LH) release prior to castration, following castration, a nd during testosterone replacement in males, was compared, using 6 9-mon th-old Holstein bulls. Also, the effects of castration and testosterone replacement on patterns of episodic changes in serum LH were studied. Blood samples were collected at hourly intervals for 24 hours prior to castration, at 21 days after castration, and at 23 days postcastration a fter testosterone, 20 mg thrice daily, has been given for 24 hours. Each animal was given GnRH, 40 mcg iv, at 24 hours before castration, at 7 and 14 days after castration, and at 28 days postcastration following 6 days of testosterone treatment. GnRH caused LH release before and after castration. The LH increase was 2.5-fold at 14 days postcastratio n. Testosterone replacement did not reduce the magnitude of LH response to GnRH to precastration levels. The number of episodic increases in serum LH prior to castration averaged 3.7 daily and increased to 6.5 daily at 21 days after castration (p less than .05). The magnitude of increase in LH concentration in these epidsodic events was not affected by castration. Testosterone replacement failed to restore either the average number or change the magniture of LH increase above precastratio n levels. It was shown that LH is normally released episodically in bulls. The peaks of LH release were followed by increased testosterone in serum. Results suggest that LH release in bulls is controlled by gonadic factors other than testosterone.     

The effect of luteinizing hormone releasing hormone and anti-luteinizing hormone releasing hormone antibodies on chorionic gonadotropin and progesterone secretion by human placental villiin vitro

Gonadotropin releasing hormone has been located and found to be secreted by the human placenta in culture. Addition of the releasing hormone upto 1μg concentration in the placental cultures brings about stimulation of chorionic gonadotropin and progesterone secretion. Higher amounts of the decapeptide has an inhibitory influence on both the gonadotropin and the steroid production. The action of the releasing hormone on the placenta could be blocked by the anti-luteinizing hormone releasing hormone monoclonal antibodies indicating a possible site of action of the antibodies for control of fertility     

Corticotropin releasing hormone concentrations in umbilical cord blood of preterm fetuses.

Corticotrophin releasing hormone (CRH), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured in umbilical cord plasma obtained from 90 preterm and 98 term fetuses. Maternal plasma was obtained from 23 women who delivered preterm and from 23 women matched for gestational age who ultimately delivered term infants. Mean umbilical cord plasma CRH concentration was significantly higher in the preterm fetuses (n = 69, 538 +/- 63 pg/ml) compared to the term fetuses (n = 98, 280 +/- 22 pg/ml, P < 0.01). Mean DHEAS level in the preterm fetuses was 208 +/- 22 mg/dl (n = 56), cortisol level was 7 +/- 1 mg/dl (n = 58). Umbilical plasma CRH concentrations (808 +/- 170 pg/ml) were significantly higher at 24-27 weeks than at 28-31 or 31-34 weeks gestation. Cortisol levels (12 +/- 3 micrograms/dl) were highest at 24-27 weeks. Mode of delivery and the presence of labor did not affect fetal CRH levels. The highest fetal CRH levels were measured in the pregnancies complicated by hypertension as well as prematurity; however, fetal CRH levels remained higher in the preterm group compared to the term group when hypertensive pregnancies were excluded. Maternal plasma CRH levels were significantly higher in the group that delivered preterm compared to women who delivered at term matched for gestational age (1058 +/- 184 pg/ml compared to 456 +/- 71 pg/ml, P < 0.00).(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle ubiquinone in healthy physically active males

Thirty-five (35) healthy physically active males had muscle biopsies taken from their vastus lateralis muscle to analyze for ubiquinone (vitamin Q, UQ), oxidative (muscle fiber types expressed as %ST and citrate synthase activity, CS) and fermentative (lactate dehydrogenase, LD) profiles. Graded cycle ergometer exercise to determine the intensities corresponding to onset of blood lactate accumulation set to 4.0 mmol × 1^–1 (W_OBLA) and symptom limited exercise (maximal, W_SL) were also undertaken. Eleven (11) subjects had also recently participated in a marathon race. UQ was positively related to CS (r = 0.67, p < 0.001) and %ST (r = 0.60, p < 0.001) but not to LD. UQ was also positively related to exercise capacity and/or marathon performance (e.g. W_OBLA × kg^–1 BW, r = 0.70, p < 0.001). It was suggested that muscle UQ allocation in man was related to variables describing molecular oxygen availability, respiratory activity and oxidative energy releasing processes but not to fermentation activity. UQ allocation to ST fibers/CS activity was suggested to be due to the double role of UQ: 1) as a mitochondrial coenzyme (CoQ₁₀) and 2) as a nonspecific antioxidant.     

Corticotropin releasing hormone: therapeutic implications and medicinal chemistry developments

Corticotropin releasing hormone (CRH, sometimes known as CRF) is an endogenous 41 amino acid peptide that has been implicated in the onset of pregnancy, the 'fight or flight' response, in addition to a large number of physiological disorders. Recently, medicinal chemists have developed a number of potent and selective compounds that show promise in a vast array of therapeutic uses. Herein we review the current status of research.     

Effect of infusion of gonadotropin releasing hormone upon plasma concentrations of sex hormones in prepubertal and pubertal males.

Plasma testosterone (T), dihydrotestosterone (DHT), 17-hydroxyprogesterone (17OHP), androstenedione (A), estradiol (E2), and dehydroepiandrosterone sulfate (DHAS) were measured by radioimmunoassay after celite chromatography prior to and after a 3-hour infusion of the synthetic gonadotropin releasing factor, GnRH, in normal prepubertal and pubertal boys. Plasma T levels rose (p less than 0.001) in the pubertal but not prepubertal boys. 17OHP concentrations increased in those boys who had an increment of T. A, DHT, E2 or DHAS levels did not increase after GnRH. Basal levels of T, DHT, A and DHAS correlated with the peak and mean serum LH levels attained during the GnRH infusion. These data confirm the greater Leydig cell responsivity to transient rises of endogenous gonadotropin in pubertal males and also suggest that there may be a relationship between adrenal androgen production and maturation of the hypothalamic-pituitary-gonadal system.     

The induction of divergent gonadotropin secretion in vitro by variations in luteinizing hormone releasing hormone pulse regimen

The effects of luteinizing hormone releasing hormone (LHRH) pulse amplitude, duration, and frequency on divergent gonadotropin secretion were examined using superfused anterior pituitary cells from selected stages of the rat estrous cycle. Cells were stimulated with one of five LHRH regimens. With low-amplitude LHRH pulses (regimen 1) in the presence of potentially estrogenic phenol red, LH response in pituitary cells from proestrus 1900, estrus 0800, and diestrus 1,0800 were all significantly larger (P less than 0.05) than the other stages tested. In the absence of phenol red, responsiveness at proestrus 1900 was significantly larger than proestrus 0800, proestrus 1500, and estrus 0800 (P less than 0.01, 0.05, and 0.05, respectively); other cycle stages tested were smaller. No significant differences were observed between cycle stages for follicle-stimulating hormone (FSH) secretion in the presence or absence of phenol red. Because pituitary cells at proestrus 1900 were the most responsive to low-amplitude 4 ng LHRH pulses, they were also used to study the effects of LHRH pulses of increased amplitude or duration and decreased frequency. Increasing the amplitude (regimen 2) or the duration (regimens 3 to 5) increased FSH secretion; this effect was greatest with regimens 3 and 5. When regimens 3 and 5 were studied in pituitary cells obtained at proestrus 1500, FSH was significantly increased by both regimes, but most by regimen 5; furthermore, LH release was significantly reduced. When regimens 3 and 5 were studied in pituitary cells obtained at estrus 0800, FSH release was elevated most significantly by regimen 5. Thus, variations in LHRH pulse regimen were found to be capable of inducing significant divergence in FSH release from superfused anterior pituitary cells derived from specific stages of the estrous cycle.     

Effect of a potent gonadotropin releasing hormone antagonist on pulsatile testosterone and gonadotropin secretion in the male nonhuman primate

A potent gonadotropin releasing hormone (GnRH) antagonist [Ac-delta 3Pro1, pFDPhe2, DTrp3,6]-GnRH was given to adult male monkeys to determine the acute effect on pulsatile testosterone and gonadotropin secretion. Blood was drawn at 30 min intervals over 54 h without anesthesia using a mobile vest and tether assembly to support an indwelling catheter. After a 6 h control period, 0.1, 1.0, 2.0, 4.0 mg GnRH antagonist/kg bw in 1 ml corn oil sc, was given to intact adult male monkeys. The highest dose of GnRH antagonist decreased circulating testosterone within 6 h and for approximately 24-36 h duration. These data demonstrate that this GnRH antagonist can reduce serum testosterone both acutely and for intervals greater than 24 h and that the effective dose in intact animals is several-fold (up to 20 times) greater than in castrate animals.     

Biphasic effect of gonadotropin releasing hormone on progestin secretion by rat granulosa cells

The effect of an agonistic gonadotropin releasing hormone (GnRH)-analog (D-Ala6, des-Gly10-NH2-GnRH-ethylamide, GnRHa) on granulosa cell steroidogenesis in the presence or absence of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) was studied. Granulosa cells, isolated from preovulatory follicles of pregnant mare's serum gonadotropin (PMSG)-treated immature rats or from the less mature follicles of untreated immature rats, were cultured for a period of 72 h with daily changes of medium, and progesterone and its metabolite, 20 alpha-dihydro-progesterone (20 alpha-OHP), were assayed in the medium. In granulosa cells from preovulatory follicles, LH and FSH caused a much greater stimulation of steroidogenesis than did GnRHa. There appeared to be no interaction between GnRHa and FSH during the first 10 h, but at 24 h and later the presence of GnRHa clearly inhibited the steroidogenic response to LH and FSH. Steroidogenesis in granulosa cells from immature rats was considerably lower and the effects of GnRHa and FSH alone less pronounced. In these cells, FSH-stimulated progesterone secretion was inhibited by GnRHa only at 72 h. In contrast, 20 alpha-OHP secretion in the same cultures was potentiated by the combined presence of FSH and GnRHa. In conclusion, it seems as though the effects of GnRHa on granulosa cell steroidogenesis varies with exposure time, the initial response being stimulatory and the later inhibitory. Furthermore, the response is also to some extent determined by the maturational stage of the granulosa cells.     

Dual intracellular pathways in gonadotropin releasing hormone (GNRH) induced desensitization of luteinizing hormone (LH) secretion.

The mechanisms of GnRH-induced desensitization of LH secretion are poorly understood. Protein kinase C (PKC) and protein kinase A (PKA) desensitize some receptors of the 7-membrane type, and the GnRH receptor has consensus phosphorylation sites for PKC in the first and third intracellular loops, and a site for PKA in the first intracellular loop. In the first set of experiments we determined whether synthetic peptides representing the three intracellular loops of the receptor could be phosphorylated in vitro by purified PKC and PKA. As compared with a model substrate peptide for PKC, the third intracellular loop was phosphorylated 74% and the first intracellular loop 21%; PKA-phosphorylated the first intracellular loop peptide 17% as well as a model peptide substrate. In the second set of experiments, we used phorbol 12-myristate 13 acetate (PMA), an established PKC stimulator, and cholera toxin (CTX), established to activate the Gs protein and presumed to activate PKA, to treat cultured rat pituitary cells followed by LH measurements. Treatment with both drugs severely impaired GnRH-stimulated LH secretion whereas neither drug alone reduced LH secretion. Dibutyryl cAMP did not duplicate the effects of cholera toxin suggesting that the CTX action could not be explained by an increase in cAMP. These results suggest that more than one intracellular signaling pathway requires activation in order to induce desensitization; one pathway involves PKC and the other involves a pathway stimulated by cholera toxin, presumably Gs protein, which does not involve PKA.     

Effects of testosterone, dihydrotestosterone and estradiol on gonadotropin release after gonadotropin releasing hormone administration in cyclic mares

Sixteen intact cyclic mares were treated on the fourth day of estrus and then every other day for a total of six injections with 1) testosterone propionate, 2) dihydrotestosterone (DHT) benzoate, 3) estradiol (E2) benzoate or 4) safflower oil. Mares were given gonadotropin releasing hormone (GnRH) on Day 3 of estrus (pretreatment) and again 24 h after the last steroid or oil injection. Treatment with testosterone propionate resulted in a greater (P less than 0.05) follicle-stimulating hormone (FSH) response to the second injection of GnRH compared with all other treatments. Treatment with DHT benzoate also resulted in greater (P less than 0.05) FSH response to GnRH compared with control and E2 benzoate-treated mares. Testosterone propionate and E2 benzoate administration suppressed (P less than 0.05) the normal diestrous rise in FSH concentrations exhibited by the control and DHT benzoate-treated mares. Steroid treatment did not affect the luteinizing hormone (LH) response to GnRH, although testosterone propionate treatment did suppress concentrations of LH in daily blood samples during Days 3 to 6 of treatment. It is concluded that testosterone's effect on FSH after GnRH treatment observed in this and previous experiments can be attributed to two different properties of the hormone or its metabolites acting simultaneously. That is, testosterone increased the secretion of FSH in response to GnRH as did DHT (an androgenic effect). At the same time, testosterone suppressed FSH concentrations in daily blood samples in a manner identical to that of E2 benzoate (an estrogenic effect).     

Induction of ovulation in gonadotropin treated gilts with synthetic gonadotropin releasing hormone

Four consecutive trials were conducted to investigate the possibility of controlling the time of ovulation in prepuberal gilts pretreated with PMS and HCG. In trial 1 it was shown that the GnRH analog Hoe 766 was superior to other compounds tested. The following trial revealed that 10 mug of that analog is the optimal dose to elicit an ovulatory response. In trial 3 it was found that the majority (73%) of gilts had started ovulating by 39 h after Hoe 766 injection. Individual gilts started ovulating up to 4 h sooner or up to more than 5 h later. Apparently the ovulatory process of an individual gilt extends over a period of 4 - 5 h. Double insemination of 9 gilts at 34 and 41 h after Hoe 766 resulted in fertilization rates and litter sizes that compared favourably with those of corresponding gilts treated with HCG.