The long-term objective of this research is to determine the neuroendocrine mechanisms by which estrogen (E) and progesterone (P) control the preovulatory surge release of luteinizing hormone (LH). Although LHRH neurons do not concentrate E or P, they act as the final common pathway by which multiple neurotransmitter systems translate information from the ovary into signals which modulate LH release. The ovarian hormone modulation of LHRH release has been studied intensively; however, little is known about the effects of E and P on LHRH biosynthesis. This information has been previously unattainable, largely because the LHRH gene had not been described, and the structure of LHRH prohormone was unknown. The present studies will use newly-developed methods and probes specific for LHRH prohormone and LHRH mRNA to determine whether LHRH biosynthesis is increased around the time of the LH surge release. The working hypothesis is that ovarian hormones stimulate de novo synthesis of LHRH before the LH surge and that LHRH hypersecretion during the surge is accompanied by elevated LHRH gene transcription. The studies proposed to test this hypothesis will also provide information regarding the relationships among LHRH transcription, steady-state LHRH mRNA levels, and LHRH translation. This information will help explain apparent discrepancies in the literature regarding the effect of E on LHRH mRNA levels. To obtain this information, we will evaluate the effects of ovarian steroids on changes in LHRH gene transcription (using nuclear run-on assays and measurements of nuclear transcripts of LHRH mRNA), cellular levels of LHRH mRNA (using in situ hybridization histochemistry and solution hybridization) and LHRH mRNA translation (by measuring ratios of LHRH prohormone and decapeptide throughout the LHRH neuronal system. These studies will provide important new information on the mechanisms by which E and P act in the hypothalamus to modulate LH release. Such information is important to the development of treatments for infertility, delayed puberty and menopausal symptoms, as well as for the development of better and safer contraceptives.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29HD027305-03
Application #
2200361
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1992-03-01
Project End
1997-02-28
Budget Start
1994-03-01
Budget End
1995-02-28
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
153223151
City
Amherst
State
MA
Country
United States
Zip Code
01003
Del Pino Sans, J; Krishnan, S; Aggison, L K et al. (2015) Microarray analysis of neonatal rat anteroventral periventricular transcriptomes identifies the proapoptotic Cugbp2 gene as sex-specific and regulated by estradiol. Neuroscience 303:312-22
Petersen, Sandra L; Krishnan, Sudha; Aggison, Leah K et al. (2012) Sexual differentiation of the gonadotropin surge release mechanism: a new role for the canonical Nf?B signaling pathway. Front Neuroendocrinol 33:36-44
Porteous, Robert; Petersen, Sandra L; Yeo, Shel Hwa et al. (2011) Kisspeptin neurons co-express met-enkephalin and galanin in the rostral periventricular region of the female mouse hypothalamus. J Comp Neurol 519:3456-69
Intlekofer, K A; Petersen, S L (2011) 17?-estradiol and progesterone regulate multiple progestin signaling molecules in the anteroventral periventricular nucleus, ventromedial nucleus and sexually dimorphic nucleus of the preoptic area in female rats. Neuroscience 176:86-92
Liu, Xinhuai; Porteous, Robert; d'Anglemont de Tassigny, Xavier et al. (2011) Frequency-dependent recruitment of fast amino acid and slow neuropeptide neurotransmitter release controls gonadotropin-releasing hormone neuron excitability. J Neurosci 31:2421-30
Intlekofer, K A; Petersen, S L (2011) Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience 172:55-65
Moura, Paula J; Petersen, Sandra L (2010) Estradiol acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: implications for hormone replacement therapy. Rev Neurosci 21:363-80
Hudgens, Edward D; Ji, Lan; Carpenter, Clifford D et al. (2009) The gad2 promoter is a transcriptional target of estrogen receptor (ER)alpha and ER beta: a unifying hypothesis to explain diverse effects of estradiol. J Neurosci 29:8790-7
Krishnan, Sudha; Intlekofer, Karlie A; Aggison, Leah K et al. (2009) Central role of TRAF-interacting protein in a new model of brain sexual differentiation. Proc Natl Acad Sci U S A 106:16692-7