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

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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