NEUROENDOCRINOLOGY

 

HORMONES are a heterogenous group of substances whose message is disseminated by the circulation, decoded by specific cell receptors and they exert a prolonged effect upon cell metabolism.

 

1 - They are substances that directly contribute to the regulation of signals between neurons.

 

2 -They are amines or aminoacids that fulfill certain criteria and their message is relayed by anatomical contiguity and activity leads to a propagation of an electrical impulse and the activity lasts a short time.

 

3 -They may not generate post-synaptic spike discharges but rather modify release of the primary neurotransmitter or adjust the receptivity or sensitivity of the post-synaptic elements of the primary transmitter. Their action will be slower and more prolonged. E.G. Cholecystokinin and Dopamine occur together in some neurons.

CCK may have an enhancing  effect on DA.

 

A substance can be both a transmitter and a hormone.  E.G. DA in caudate nucleus and in Pituitary.

 

Neurosecretory neurons -

 

1.  MAGNOCELLULAR  SUPRAOPTIC & PARAVENTRICULAR FOR AVP (ADH) & OXYTOCIN.

 

2.  PARVOCELLULAR TUBERO-INEUNDIBULAR SYSTEM

 

 

HYPOTHALAMUS

 

1   DIRECT PARTICIPATION IN MANY BEHAVIOURS e.g. EATING, SLEEP ETC.

 

Neuropeptides present can not only control hormone release but have behavioural effects.

 

2 .CONTROL OF ANTERIOR PITUITARY HORMONES & PRODUCTION OF POST.PITUITARY HORMONES.

 

3.  AUTONOMIC N.S.

 

 

 

HYPOTHALAMIC HORMONES

 

-           Thyrotrophin Releasing hormone

-              Tripeptide, mainly from dorsomedial, ventromedial & arcuate nuclei

-              Stimulates Pituitary TSH release

-              Also stimulates Prolactin release

 

Gonadotrophin releasing hormone

-              Decapeptide, mainly from arcuate and pre-optic areas

-              Principally to stimulate LH release

-              To a lesser extent F'SR release

-              Release of LH or FSH depends on differential feedback and inhibin.

 

-              Growth Hormone releasing hormone

-              Much larger structure, mainly from arcuate and ventromedial nuclei

 

SOMATOSTATIN - GH inhibition & wide-range of Inhibitory activities mainly from periventricular regions

 

CRF-Stimulates release of PRO OPIO CORTIN PEPTIDES, mainly from paraventricular nuclei

 

-Prolactin inhibiting factor, mainly from arcuate nuclei

 

VASOPRESSIN AND OXYTOCIN

neurohypophyseal peptides mainly formed in supraoptic and paraventricular nuclei.

 

PROLACTIN

 

Single chain polypeptide, similar in structure to GH,  produced by Lactotroph cells in the anterior pituitary.   These cells increase in number during pregnancy and are sensitive to a variety of substances, notably DA, gona~ steroids, TRH etc.

 

There is an episodic secretory pattern and the amplitude of the fluctuations are greater in sleep, with levels reaching a peak early a.m.

 

Main physiological stimulus      SUCKLING.

 

Pregnancy -          Prolactin levels rise up to about 20 times and the rise is related to oestrogen levels.   Oestrogen produced by foeto-placental unit promotes lactotroph hyperplasia.   Without suckling levels return to normal in about 2-6 weeks.  With breast feeding they remain high for several months, with a rise of levels associated with suckling.

 

Release of Prolactin

Main Hypothalamic influence - INHIBITION.        DA main PIP.

 

L-DOPA & DA agonist                                             Bromocriptine inhibit Prolactin secretion

 

DA Antagonist                                                          e.g. Neuroleptics increase~r~lactin secretion

 

GABA increases Prolactin levels by a complex mechanism. ?  Stimulation of Prolactin release or Prolactin Release Factor

 

TRH causes a release of Prolactin

 

Serotonin, Opioids and VIP all increase levels of Prolactin.

 

Auto regulation via DA.

 

                                                          CAUSES OF HYPERPROLACTINAEMIA

 

Drugs: (e.g. butyrophenones  haloperidol);

antiemetics e.g. metoclopramide, domperidone antibypertensives, e.g. reserpine, methyldopa

TRH

opiates, oral contraceptives (oestrogen)

- PITIUITARY -  GONADAL    AXIS

                      Pit. Hormones                   Same in both sexes

                      In females              -           cyclical production of Ovum

                      In males                 -           continuous production of Sperms

 

Hypothalamic Release Hormone - one or more  ?

 

Gn RH  (LH/FSH-RH) pulsatile release mainly from Arcuate & Supraschiasmatic neuclei influenced by 

1.  a range of Neuramines and Neuropeptides

2.  feedback effect of gonadal steroids

3. short loop feed back of gonadotrophins

 

 

HPG  AXIS

 

In early development

 

Foetus is bipotential for sexual differentiation.

 

Sex Chromosomes promote the development and differentiation of primary gonads but the decisive influence is presence or absence of testosterone.

 

Feotal hypothalamus produces GnRH by 8th week of gestation and by 12 weeks Gonadotrophins are produced.

 

 

 

Puberty

 

Episodic secretion of low-amplitude gonadotrophin release continues during childhood.

 

Prepuberty-Hypothalamic output of GnRH is in some way inhibited and with puberty this is released and Pituitry Gonadotr&phins rise.

 

Pregnancy

 

1 -                                 Very low maternal FSH & LH.

2.                                  Placental gonodotrophins (HCG) rise early and maintains the cor~us luteum.

3.                                  Oestrogen produced by foeto-placental unit induces lactotroph hy~rplasi,a.

4.                                  Pit.   in size and Prolactin levels rise.

 

Puerperium

 

1.                                  Ra id fall of oestrogens removes peripheral blockade and there is galactorrhoea.

2.                                  In first post-natal week concentration of oestradiol and progesterone decline 100-fold.   The significance of this in relation to post-natal depression is unclear.

3.                                  Pit. gonadotrophins remain low during lactation with cycles suppressed.   Increased Prolactin - helps feed back on pituitary. Once suckling diminishes Prolactin levels fall and cycling begins.

 

Menopause

 

The production of oocytes declines and the levels of progesterone and oestrogen fall with diminishing - v e feedback LH & FSH rise. Less  otent - oestrone  roduced b  adrenals circulates.

 

HPG AXIS in Anorexia Nervosa

 

1.In the acute phase, at low weight reduced Blood and Urinary levels of Gonadotrophins.

2.Gonadal steroids, Oestrogen and Testosterone are also low.

3. With regaining of weight circulating Hormone levels return to normal.

4. But - CYCLICAL Pattern ofhorm6nelevels is delayed.

5. The LH secretory pattern resembles that found in pre-pubertal girls, with small pulses and low concentrations.

6. To exotenous LHRH there is a normal FSH response but an impaired  LH response.

7.Clomiphene does not elicit the normal LH augmentation response. Even when weight is restored the response does not return to normal.

 

Other features in Anorexia Nervosa include a normal or increased GH level.

Increased Costisol and increased Prolactin levels, lowered T.14.

 

Bulimia

 

Menstrual irregularities are common, despite the fact that body weight of most of the patients~4Łe~thin the normal range.  This suggests that abnormal eating habits may disrupt menstrual function irrespective of body weight.

 

HYPOTHALAMIC - PITUITARY - ADRENAL AXIS

Three main mechanisms:-

 

1.  negative feedback of glucocorticoids

2.  circadian rhythm

3.  aversive, 'stress' factors, pain, exercise, surgery etc.

 

CRF -   cells secreting CRF mainly in para-ventricular nuclei (parvo cellular neurones)

Apart from stimulating release of ACTH, wide ranging behavioural effects

 

Vasopressin     greatly potentiates the ACTH releasing activity of CRF.

 

Neurotransrnitter influences vary from stimulatory effects of A Ch and possibly an inhibitory effect by NA on CRF release.

 

Feedback due to Cortisol both at the level of Hypothalamus and Pituitary. Long and short loop feedback mechanisms operate.

 

circadian Rhythm

 

There are during the 24 hours, a number of secretory episodes. Peak secretion between 07.00 and 0800 and Cortisol follows an

identical pattern -

 

Stress Induced Release Of ACTH

 

Both psychological and physiological stresses cause rapid elevation of ACTH and cortisol which can over-ride feedback control and circadian rhythms.

 

REPORTED CHANGES IN CORTISOL SECHETION IN DEPRESSION

 

 

1.       24 hr. secretion - urinary free cortisol

 

2.       CSF Cortisol conc.

 

3.       Plasma 214 hour cortisol  with frequency of secretory episode

 

4.       Reduced amplitude of normal circadian rhythm

 

5.       Relative resistance to suppression by Oral Dexamethasone

 

“DST Non. suppression”

 

(These changes do not appear to be as specific as they used to be thought.)

 

TWO MAIN FINDINGS RE ACTH IN DEPRESSION

 

1.       Basal Conon. (i.e. resting levels) - normal in depression

2.   relatively resistant to suppression by Dexamathasone

 

HPA AXIS  IN DEPRESSION

 

1.       central activation  CRF

2.        P1asma ACTH not  increased

           Despite cortisol levels

           and increased CSF CRF levels

 

CRE' effect an restrained by  cortisol.

 

 

 

Evidence in Endogenous Depression

 

1.       CSF CRF is  increased

 

2.       Changes reproducible in volunteers with CRF

 

3.       ACTH response LO CRF is reduced.

 

4.       Cortisol responses to ACTH increased

          ie Hyper responsive AD. cortex.

 

 

Although CRF -> behav. effects -  'Depression1 CRF changes non specific to depression.

 

? cause or co-existing defect in depression.

 

 

 

FACTORS ALTERING GH SECRETION

                                

Stimulatory Factors

Inhibitory Factors

Postprandial hyperglycemia

Episodic, spontaneous

Elevated free fatty acids

 

Serotonin antagonists, e.g. cyproheptadine,

Exercise

   methysergide

Physical and psychologic stress

-  adrenergic stimulation

Hypoglycemia

Glucocorticoids

L-dopa

 progesterone

Apomorphine

Growth hormone

Clonidine

Obesity

Se'rotonin precursors

Hypothyroidism

Amino acid infusion, e.g.  argine, leucine

Possibly emotional deprivation

 

  (i.e. psychosocial dwarfism)

2 -deoxyglucose

 

Insulin-induced hypoglycemia

 

Opiates

 

Oestrogens

 

Vasopressin

 

Glucagon

 

Thyroid hormones

 

Acromegaly

 

Starvation

 

Anorexia nervosa

 

Renal failure

 

Hepatic cirrhosis