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Principles of Neuroendocrinology
• Anatomy of the hypothalamic-pituitary axis• Neurohumoral secretion• Brain as endocrine organ and target• Endocrine servomechanisms• Chronobiology and endocrinology• Stress• Hormone pulsatility
Hypothalamic-Hypophyseal Circulation
• Anterior pituitary: fed by plexus of portal veins which drain median eminence of the hypothalamus.
• Portal circulation contains high concentration of hypothalamic hormones
Developmental Biology of the Pituitary
Anatomy of Hormone-Producing Cells in the Anterior Pituitary Gland
Hypothalamic Hormones-1• Gonadotropin releasing
hormone (GnRH, LHRH)
• Thyrotropin releasing hormone (TRH)
• Corticotropin releasing hormone (CRH)
Stimulates LH and FSH release
Stimulates TSH release (also prolactin)
Stimulates ACTH release
Hypothalamic Hormones-2• Growth hormone
releasing hormone (GHRH)
• Somatostatin (SRIH)
• Dopamine
Stimulates GH release
Inhibits release of GH and TSH
Inhibits release of prolactin
Brain as a Target Organ• Testosterone may be metabolized to
– Androgen: dihydrotestosterone (DHT)– Estrogen: estradiol
• Estrogen may be metabolized to– Estrogenic steroid: estriol– Catecholestrogen: ?activity
• Neurosteroids– Steroid hormones can interact with cell surface receptors
(progesterone metabolites and GABA receptors)
Endocrine Servomechanisms• Homeostatic feedback
loops:– Hormone A regulates
secretion of hormone B
• Closed feedback:– Hormone B also regulates
hormone A
• Negative feedback loops– Long, short, “ultashort”
• Positive feedback loops
Neuroendocrine Feedback Loops
Chronobiology
• Rhythms may reflect passive adjustment to the environment (exogenous rhythm) or may originate from within the organism itself (endogenous rhythm; e.g., circadian rhythms).
• Rhythms may or may not be sleep-entrained.• Effectiveness of feedback mechanisms may vary
with periodicity.• Disturbances of rhythms may result in dis-ease
Adrenarche Adrenopause
Cyclical Cushing Syndrome
Urin
ary
corti
sol/c
reat
inin
e ra
tio
Cyclical Cushings JCEM 2004
JCEM 83: 1827 - 1834, 1998
Acute and Prolonged Critical Illness as Different Neuroendocrine Paradigms
Stress overcomes the effects of negative feedback and over-rules the circadian
oscillator
Pituitary Hormones are Released in a Pulsatile Fashion• Pulsatile secretion may reflect underlying
neuronal rhythms• Time to synthesize and store new
hormones• Internalization of peptide/receptor• Avoid spill-over of CNS neurohormones
into general circulation
Kallmann Syndrome
• Hypogonadotropic hypogonadism– failure to enter or progress through puberty– low serum LH, FSH, and testosterone
suggesting defect in hypothalamic GnRH• Anosmia• Midline defects, including cleft palate• Misc. neurologic abnormalities
Knobil’s Experiment to Replace GnRH in Rhesus Monkey
• Remove endogenous GnRH by ablating medial basal hypothalamus
• GnRH replacement therapy– Hourly bolus (physiologic rhythm)– Continuous infusion
Knobil Experiment with GnRH Replacement Therapy
• Physiologic pulsatile GnRH infusion stimulates hormone secretion from gonadotroph
• Continuous (nonphysiologic) infusion inhibits gonadotroph
Sine qua non for pulsatility: the hormone must have a
relatively short half-life compared to the interval
between injections or secretion of hormone
GnRH Agonist Therapy: Chemical Castration
• Hormone-sensitive tumors– Prostate cancer– Uterine fibroids (leiomyomata)
• Menstrual cycle related diseases– Endometriosis– Catamenial syndromes
• Preparation for in vitro fertilization• Precocious puberty