Environmental stress is recognized as a major cause of infertility in men and women. However, it is not clear how stressful stimuli interrupt normal reproductive processes. The recent isolation and purification of corticotropin-releasing hormone (CRH) has provided a valuable new tool for investigating the relationship between stress and infertility. CRH is a peptide synthesized in the brain and released into the hypophyseal portal system where it regulates activation of the adrenal cortex by the pituitary. Several recent studies have provided evidence supporting the hypothesis that, in addition to the other suppressive effects of stress on reproductive processes, CRH may directly inhibit the release of gonadotropin- releasing hormone (GnRH), a peptide required for pituitary activation of the gonads. The long-term goal of this investigation is to define the physiological and environmental control of reproductive processes in non-human primate species that demonstrate reproductive patterns similar to those found in humans. This proposal describes experiments that will provide insight into the physiological mechanisms through which stress affects fertility in male and female macaques. The body responds to an environmental stimulus with the release of a variety of chemical signal; the goal of this line of research is to isolate the effects of CRH on gonadotropin secretion.
The first aim i s to analyze and compare the effects of a specific stressful situation (i.e., short-term chair restraint) on male and female ,acacias on different reproductive states. All of the animals used in these studies will have indwelling catheters which will allow blood sampling and delivery of test substances from a remote site.
The second aim of this study is to determine if CRH can inhibit the secretion of pituitary gonadotropins when injected into an unstressed animal. Thirdly, an antagonist to CRH will be administered immediately before exposing an animal to a stressful stimulus to determine if blocking the inhibitory effects of endogenous CRH on gonadotropin secretion will elucidate the physiologic role that CRH has in controlling fertility.
The fourth aim i s to test whether neuroleptic drugs that are known to block the release of gonadotropins from the pituitary do so indirectly by stimulating the release of CRH which then blocks GnRH release. Several neuroleptic drugs are thought to act by inhibiting the action of neurotransmitters on GnRH neurons. Environmental stress is a contributing factor in many human diseases.
The final aim, once the specific agent that inhibits gonadotropin release during stress has been identified, is to determine if chronic administration of this agent will result in infertility. A better understanding of the mechanisms which activate the hypothalamic-pituitary-adrenal axis in response to stress will also clarify the effects of stress on other physiological systems and will allow the development of more effective strategies to cope with everyday stress.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD018591-06A2
Application #
3315667
Study Section
Reproductive Biology Study Section (REB)
Project Start
1983-08-01
Project End
1994-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Texas Tech University
Department
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Lado-Abeal, J; Robert-McComb, J J; Qian, X-P et al. (2005) Sex differences in the neuroendocrine response to short-term fasting in rhesus macaques. J Neuroendocrinol 17:435-44
Lado-Abeal, Joaquin; Clapper, Jeffrey A; Chen Zhu, B et al. (2002) Hypoglycemia-induced suppression of luteinizing hormone (LH) secretion in intact female rhesus macaques: role of vasopressin and endogenous opioids. Stress 5:113-9
Lado-Abeal, Joaquin; Veldhuis, Johannes D; Norman, Reid L (2002) Glucose relays information regarding nutritional status to the neural circuits that control the somatotropic, corticotropic, and gonadotropic axes in adult male rhesus macaques. Endocrinology 143:403-10
Lado-Abeal, J; Clapper, J A; Norman, R L (2001) Antagonism of central vasopressin receptors blocks hypoglycemic stress induced inhibition of luteinizing hormone release in male rhesus macaques. J Neuroendocrinol 13:650-5
Lado-Abeal, J; Hickox, J R; Cheung, T L et al. (2000) Neuroendocrine consequences of fasting in adult male macaques: effects of recombinant rhesus macaque leptin infusion. Neuroendocrinology 71:196-208
Lado-Abeal, J; Lukyanenko, Y O; Swamy, S et al. (1999) Short-term leptin infusion does not affect circulating levels of LH, testosterone or cortisol in food-restricted pubertal male rhesus macaques. Clin Endocrinol (Oxf) 51:41-51
Lado-Abeal, J; Mrotek, J J; Stocco, D M et al. (1999) Effect of leptin on ACTH-stimulated secretion of cortisol in rhesus macaques and on human adrenal carcinoma cells. Eur J Endocrinol 141:534-8
Lado-Abeal, J; Norman, R L (1998) Absence of an inhibitory vasopressinergic tone on LH release in pubertal male rhesus macaques. Neuroendocrinology 67:236-43
Huang, B M; Stocco, D M; Norman, R L (1997) The cellular mechanisms of corticotropin-releasing hormone (CRH)-stimulated steroidogenesis in mouse Leydig cells are similar to those for LH. J Androl 18:528-34
Huang, B M; Stocco, D M; Li, P H et al. (1997) Corticotropin-releasing hormone stimulates the expression of the steroidogenic acute regulatory protein in MA-10 mouse cells. Biol Reprod 57:547-51

Showing the most recent 10 out of 25 publications