I= STUDIES ON FASTING-INDUCED SUPPRESSION OF HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS IN A NON-HUMAN PRIMATE
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Title of Thesis
STUDIES ON FASTING-INDUCED SUPPRESSION OF HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS IN A NON-HUMAN PRIMATE

Author(s)
Waheed-Uz-Zaman
Institute/University/Department Details
Department of Biological Sciences/ Quaid-i-Azam University, Islamabad
Session
2004
Subject
Biological Sciences
Number of Pages
166
Keywords (Extracted from title, table of contents and abstract of thesis)
fasting-induced suppression, hypothalamic-pituitary-testicular axis, non-human primate, luteinizing hormone, testosterone, leydig cells, gonadal functions, hypothalamic-pituitary-testicular, gonadotropin-releasing hormone, excitatory amino acid, hypo glycemia, , amino acid neurotransmitters, gamma amino butyric acid

Abstract
Short term fasting leads to a significant suppression of plasma luteinizing hormone (LH) and testosterone (T) concentrations in male rhesus monkeys, while refeeding after fasting immediately reverts the negative effects of restricted food intake on pituitary-testicular axis. Testosterone secretion by Leydig cells is mainly under the influence of the pituitary gland and the proper frequency and amplitude of LH pulses are essential for appropriate stimulation of gonadal functions. Fasting induced suppression of T secretion is mediated through a decrease in central drive to the hypothalamic-pituitary-testicular (HPT) axis, since fasting is known to cause a decrease in gonadotropin-releasing hormone (GnRH) secretion. However, there is no decrease in responsiveness of the pituitary-testicular axis to exogenous GnRH administration indicating that this axis can function adequately during fasting-induced hypogonadism. Fasting-induced suppression of the HPT axis is either due to a decrease in excitatory or/and inhibitory drives to GnRH neurons. The present study investigated these central mechanisms underlying nutritional modulation of the HPT axis.

Intact adult male rhesus monkeys were used in this study. The monkeys were kept under standard colony conditions in individual cages. The monkeys were habituated to chair-restraint and were trained to finish their meals within 5-10 min. The appetite of the animals was monitored for a month prior to the beginning of experiments. For the ease of fixing or removing from the chair, animals were sedated with ketamine hydrochloride (3-4 mg/kg BW, im). The blood samples and infusions were initiated when the animals were fully recovered from ketamine sedation. The different drugs or normal saline were administered through a teflon cannula implanted in the saphenous vein. The blood samples were collected for 4-5 h at 15 min intervals. Different drugs were dissolved in 0.9% normal saline immediately before use. All blood samples were taken between 2:00 pm and 7:00 pm to minimize diurnal variations. A period of 1-2 weeks intervened between each experiment. The plasma T concentrations were determined by using highly specific radioimmunoassay while blood glucose levels were measured in whole blood using haemo-glucotest.

In the first set of experiments the effect of spontaneous feeding and 24-h fasting on plasma T concentrations was determined. The involvement of excitatory amino acid (EAA) neurotransmitters in fasting-induced suppression of the HPT axis was also studied. In the preliminary experiment animals were subjected to either normal feeding or 24-11 fasting. All the animals showed higher levels of plasma T concentrations within 1-2 h after feeding, while in 24-h fasted monkeys this feeding associated rise in plasma T levels was absent. Mean plasma T concentrations in 24-h fasted monkeys were significantly less (P <0.001) than normally fed monkeys. N-methyl-D,L-aspartate (NMA, 15 mg/kg BW, iv) ), an EAA analogue, administration caused a significant increase (P< 0.001) in plasma T concentrations in both normally fed as well as 24-11 fasted monkeys. This suggests that the HPT axis remains sensitive to excitatory input under restricted food conditions. However the increase in plasma T concentrations in response to NMA administration was significantly higher (p< 0.01) in normally fed monkeys as compared to the 24-h fasted monkeys, indicating that availability of food alters the responsiveness of the HPT axis being more sensitive under conditions of normal feeding.

In the second set of experiments the effect of insulin-induced hypoglycemia (IIH) on plasma T concentrations and involvement of EAA neurotransmission in the mediation of hypo glycemia-induced suppression of the HPT axis were studied. Insulin (1 U/kg, BW, iv) caused an acute and significant decrease (P

In the third set of experiments the involvement of adrenergic pathways in the feeding-induced rise in plasma T concentrations was investigated. In a control experiment 4 intact adult male rhesus monkeys were subjected to spontaneous feeding. The animals showed higher levels of plasma T concentrations within 1-2 h of feeding. In the next experiment, the same group of monkeys was administered with phentolamine, an a-adrenergic receptor antagonist, immediately after feeding. Phentolamine administration (5 mg/kg BW, iv) prevented the feeding associated rise in plasma T concentrations, which was observed in the control group. This suggests that an adrenergic pathway be involved in the feeding-induced rise in the HPT axis.

In the fourth set of experiments the involvement of gamma-amino butyric acid (GABA) in fasting-induced suppression of the HPT axis was investigated. In the preliminary experiment the same group of four monkeys used in expo 3 was subjected to 24-h fasting. The plasma T concentration in 24-h fasted monkeys remained significantly less than plasma T levels in the same animals under conditions of normal feeding. Administration of the GABA antagonist, bicuculline (5 mg/kg BW, iv), in 24-h fasted monkeys failed to prevent fasting-induced suppression of the HPT axis. The plasma T levels in 24-h fasted monkeys after bicuculline administration remained as low as those observed in simple fasted monkeys and significantly less (p< 0.01) than the plasma T levels in normally fed monkeys during the comparable time duration. This suggests that GABA is not involved in fasting-induced suppression of the HPT axis.

Plasma T concentrations remained low in both 24-h fasted and insulin-induced hypoglycemic monkeys as compared to the normally fed monkeys which indicates that availability of metabolic fuel is necessary for normal working of the HPT axis. NMA administration prevented the fasting- and hypoglycemia-induced suppression of the HPT axis. However, the increase in plasma T concentration by NMA administration was significantly higher in normally fed monkeys as compared to the T response to NMA administration in 24-h fasted and hypoglycemic monkeys. Phentolamine administration prevented the feeding-induced increase in plasma T levels, while bicuculline administration failed to prevent fasting-induced suppression of the HPT axis.

In conclusion the present study suggests that different mechanisms are involved in neuroendocrine regulation of the HPT axis under different metabolic conditions. Fasting-induced suppression of the HPT axis is most likely mediated through a decrease in EAA neurotransmission to GnRH neurons, while GABA is not found, at least under present experimental conditions, to be involved in this process. The study also demonstrates that feeding-induced stimulation of the HPT axis is mediated through an adrenergic pathway, although the other excitatory pathways could also be involved. Another important finding is that the HPT axis remains functional under metabolic stress conditions. However, the sensitivity of this axis is decreased when appropriate amount of metabolic fuel is not available. The decreased response to NMA in hypoglycemic conditions indicates that glucose acts as a major metabolic fuel in nutritional regulation of the HPT axis.

Download Full Thesis
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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents/ Introduction
1602.74 KB
2 1 Fasting-Induced Suppression Of Hypothalamic-Pituitary-Testicular Axis In Adult Male Monkeys: Involvement Of Excitatory Amino Acid Neurotransmitters 19
2996.63 KB
3 2 Effect Of Insulin-Induced Hypo Glycemia On Hypothalamic-Pituitary-Testicular Axis In Adult Male Monkeys: Involvement Of Excitatory Amino Acid Neurotransmitters 46
2390.97 KB
4 3 Effect Of Spontaneous Feeding On Hypothalamic-Pituitary-Testicular Axis In Adult Male Monkeys: Involvement Of Adrenergic Pathways 77
2965.7 KB
5 4 Study Of The Role Of Gamma Amino Butyric Acid In Mediating Fasting-Induced Suppression Of Hypothalamic-Pituitary-Testicular Axis In Adult Male Monkeys 90
1559.59 KB
6 5 General Discussion 109
8687.55 KB
  5.1 References 114