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 Urinary cortisol/creatinine ratio

Cyclical Cushings JCEM 2004

JCEM 83: , 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