60 YEARS OF NEUROENDOCRINOLOGY: The posterior pituitary, from Geoffrey Harris to our present understanding

Geoffrey Harris pioneered our understanding of the posterior pituitary, mainly with experiments that involved the electrical stimulation of the supraoptico-hypophysial tract. In the present essay, we explain how his observations included clues to the pulsatile nature of the oxytocin signal – clues that were followed up by subsequent workers, including his students and their students. These studies ultimately led to our present understanding of the milk-ejection reflex and of the role of oxytocin in parturition. Discoveries of wide significance followed, including: the recognition of the importance of pulsatile hormone secretion; the recognition of the importance of stimulus-secretion coupling mechanisms in interpreting the patterned electrical activity of neurons; the physiological importance of peptide release in the brain; the recognition that peptide release comes substantially from dendrites and can be regulated independently of nerve terminal secretion; and the importance of dynamic morphological changes to neuronal function in the hypothalamus. All of these discoveries followed from the drive to understand the milk-ejection reflex. We also reflect on Harris's observations on vasopressin secretion, on the effects of stress, and on oxytocin secretion during sexual activity.

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The pituitary and the maintenance of milk secretion

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1958.0073 ◽

1958 ◽

Vol 149 (936) ◽

pp. 330-336 ◽

Cited By ~ 5

Keyword(s):

Anterior Pituitary ◽

Causal Factor ◽

Complete Inhibition ◽

Posterior Pituitary ◽

Milk Secretion ◽

Milk Ejection ◽

Complete Cessation ◽

Lack Of Information ◽

Milk Ejection Reflex

Following the demonstration by Strieker & Grüter (1928) of the lactogenic effects of anterior-pituitary extracts, the importance of the role of the pituitary in maintaining lactation was further emphasized by observations that removal of the pituitary in the lactating animal resulted in a rapid and complete cessation of lactation (for references, see Folley 1952). For a time it was generally assumed that the loss of the anterior pituitary was the causal factor in the cessation of lactation, but when the role of the posterior pituitary in milk ejection was established it became obvious that interference with the milk-ejection reflex could well be the cause of the failure of lactation after hypophysectomy. It therefore seemed desirable to repeat some of the earlier studies on the effect of hypophysectomy on lactation, in order to determine whether the restoration of milk-ejection by the regular administration of oxytocin would affect the results and possibly allow us to distinguish a failure of milk ejection from a failure of milk secretion. In this connexion it may be noted that reports on the maintenance of lactation after hypophysectomy, by administering anterior-pituitary preparations, have been remarkably few, and this lack of information possibly reflects the unsuccessful outcome of attempts which may have failed because milk ejection was not restored. At Shinfield we have studied the effect of hypophysectomy in the lactating rat, both in the presence and absence of adequate oxytocin therapy, and have confirmed that hypophysectomy results in a rapid and complete inhibition of milk secretion (see Cowie 1957), and there seems to be no reason to doubt that this will also be true for other species.

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NEUROHORMONAL MECHANISMS IN EMOTIONAL INHIBITION OF MILK EJECTION

Journal of Endocrinology ◽

10.1677/joe.0.0120029 ◽

1955 ◽

Vol 12 (1) ◽

pp. 29-37 ◽

Cited By ~ 68

Author(s):

B. A. CROSS

Keyword(s):

Emotional Disturbance ◽

Posterior Pituitary ◽

Milk Ejection ◽

Emotional Inhibition ◽

Conscious Animal ◽

Adrenal System ◽

Oxytocin Release ◽

Posterior Pituitary Gland ◽

Milk Ejection Reflex ◽

Main Factor

SUMMARY 1. Fifteen lactating rabbits were maintained on a regime of one daily nursing in which litter weights, milk yields and duration of nursing were recorded. 2. Sodium pentobarbitone anaesthesia blocked the milk-ejection reflex and prevented the removal of more than 15% of the full milk yield by the young. Intravenous injection of 50 mU oxytocin regularly restored normal milk removal; 10 and 20 mU did not. 3. In thirty-five out of forty-two experiments in which the does were suckled while under forcible restraint the amount of milk removed was reduced by 20–100%. In twenty-nine cases injection of 50 mU oxytocin restored normal milk removal. In the remaining six experiments this replacement therapy was fully effective only after the does had been anaesthetized. 4. Kymograph records of milk-ejection responses showed that normal milk removal was associated with a reflex milk-ejection response similar to that produced by 50 mU oxytocin, and incomplete milk removal with a reduced (=5 mU oxytocin) or absent milk-ejection response. Where injection of 50 mU oxytocin failed to restore normal milk removal in the conscious animal, the resulting milk-ejection response was reduced by an amount similar to that produced by injection of 1μg adrenaline. 5. The results indicate that, while activation of the sympathetico-adrenal system does occur, the main factor in emotional disturbance of the milk-ejection reflex is a partial or complete inhibition of oxytocin release from the posterior pituitary gland.

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Functional role of intrahypothalamic release of oxytocin and vasopressin: consequences and controversies

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.268.4.e537 ◽

1995 ◽

Vol 268 (4) ◽

pp. E537-E545 ◽

Cited By ~ 3

Author(s):

M. Ludwig

Keyword(s):

Milk Ejection ◽

In Vitro Techniques ◽

Hypothalamic Nuclei ◽

Peptide Release ◽

Functional Consequences ◽

Milk Ejection Reflex ◽

And Behavior

This brief review of vasopressin (VP) and oxytocin (OT) release into the extracellular space of the supraoptic (SON) and paraventricular (PVN) nuclei focuses on recent data illustrating the significance of their intranuclear release and the potential functional consequences. With the use of in vitro techniques, it has been demonstrated that administration of exogenous OT causes local peptide release and that, in vivo, this facilitates the milk ejection reflex. These findings lead to the idea that endogenous peptides are released into the hypothalamic nuclei. Microperfusion techniques have been used to monitor the dynamics of intranuclear OT and VP release in response to distinct stimuli. It is clear that intranuclear release of OT plays a role during reproductive states (parturition and lactation) and that intranuclear release of VP and OT is involved in osmoregulation. This review discusses 1) the origin of the intranuclearly released peptides, 2) stimuli which cause release into the hypothalamic nuclei, and 3) the function of intranuclear VP and OT, e.g., regulation of local morphology, feedback mechanisms and synchronization, and the possible role in regulating autonomic function and behavior.

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SYMPATHETICO-ADRENAL INHIBITION OF THE NEUROHYPOPHYSIAL MILK-EJECTION MECHANISM

Journal of Endocrinology ◽

10.1677/joe.0.0090007 ◽

1953 ◽

Vol 9 (1) ◽

pp. 7-18 ◽

Cited By ~ 36

Author(s):

B. A. CROSS

Keyword(s):

Electrical Stimulation ◽

Inhibitory Effect ◽

Posterior Pituitary ◽

Pituitary Extract ◽

Milk Ejection ◽

Emotional Inhibition ◽

Adrenal System ◽

Ejection Mechanism ◽

Milk Ejection Reflex ◽

Stimulation Of

1. Emotional inhibition of the milk-ejection reflex in rabbits is described. 2. Injection of 5–50 μg adrenaline intravenously into does before nursing interfered with milk ejection, as shown by the failure of the young to withdraw more than three-quarters of the normal yield of milk. Injection of 150 mU (=milliunits) 'Pitocin' immediately after the adrenaline did not restore normal milk ejection. 3. Intravenous injection of 5 μg adrenaline suppressed the milk-ejection response to 50 mU posterior pituitary extract in anaesthetized rabbits with cannulated teats, provided the injection of adrenaline preceded that of the posterior pituitary extract. The inhibitory effect had not entirely disappeared in 2 min. 50μg adrenaline prevented the occurrence of milk ejection for 3½ min. 4. Intravenous doses of 5 μg adrenaline, but not smaller amounts, inhibited the milk-ejection response to electrical stimulation of the supraoptico-hypophysial tract, if injected before stimulation or during the latent period of the response. When injected after the commencement of milk ejection 5 μg adrenaline was without effect, but 50 μg abolished the response. 5. Electrical stimulation of the posterior hypothalamus produced inhibition of the milk-ejection response to injected oxytocic extract, together with pupillary dilatation and exophthalmos. The inhibition closely resembled that resulting from injection of adrenaline. 6. It is concluded that one mechanism involved in the emotional inhibition of milk ejection is an activation of the sympathetico-adrenal system, resulting in antagonism of the action of the neurohypophysial milk-ejection hormone on the contraction process within the mammary gland.

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THE ROLE OF THE NEUROHYPOPHYSIS IN THE MILK-EJECTION REFLEX

Journal of Endocrinology ◽

10.1677/joe.0.0080148 ◽

1952 ◽

Vol 8 (2) ◽

pp. 148-161 ◽

Cited By ~ 116

Author(s):

B. A. CROSS ◽

G. W. HARRIS

Keyword(s):

Intravenous Injection ◽

Mammary Glands ◽

Posterior Pituitary ◽

Pituitary Extract ◽

Active Process ◽

Milk Ejection ◽

Marked Diminution ◽

Milk Ejection Reflex ◽

Stimulation Of

1. Nursing and suckling behaviour of rabbits is described, and evidence given that an active process of milk ejection ('let-down') occurs in this as in other species. 2. Intravenous injection of posterior pituitary extracts in anaesthetized rabbits resulted in ejection of milk from a cannulated teat duct. The threshold dose was about 5 mU. and maximal responses were produced by 200 mU. of extract. Whole posterior pituitary extract was more effective than the oxytocic fraction, which was in turn more effective than the vasopressor fraction. 3. Stimulation of the supraopticohypophysial (s.o.h.) tract in anaesthetized rabbits also resulted in ejection of milk from a cannulated duct. Kymographic records of this response were similar to those obtained after injection of appropriate doses of posterior pituitary extract. 4. Lesions in the s.o.h. tract in lactating rabbits caused a marked diminution in the quantity of milk obtained by their litters in standard suckling tests, and incomplete evacuation of the mammary glands. Intravenous injection of posterior pituitary extract (30–200 mU.) into the does immediately before nursing gave a marked increase in the amount of milk obtained by the young and complete evacuation of the mammary glands. Stimulation of the region of the s.o.h. tract in these animals failed to elicit milk ejection from cannulated teat ducts. 5. Rabbits with hypothalamic lesions that did not involve the s.o.h. tract showed a normal milk-ejection reflex when suckled by their young, and a milk-ejection response after electrical stimulation of the s.o.h. tract.

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LACTATION IN THE RAT AFTER HYPOPHYSIAL POSTERIOR LOBECTOMY

Journal of Endocrinology ◽

10.1677/joe.0.0140054 ◽

1956 ◽

Vol 14 (1) ◽

pp. 54-65 ◽

Cited By ~ 25

Author(s):

G. K. BENSON ◽

A. T. COWIE

Keyword(s):

Diabetes Insipidus ◽

Pituitary Hormone ◽

Posterior Lobe ◽

Posterior Pituitary ◽

Milk Ejection ◽

Milk Ejection Reflex ◽

Posterior Pituitary Hormone

SUMMARY Ablation of the posterior lobe of the pituitary in the lactating rat abolished the milk-ejection reflex so that the pups could only be reared if injections of oxytocin were given to the mothers twice daily. When, however, these posterior lobectomized rats became pregnant a second time, parturition was normal and the milk-ejection reflex was sufficiently restored for the rats to rear their litters without oxytocin being administered. The animals, however, continued to exhibit diabetes insipidus. Measurements of residual neurohypophysial tissue showed that hypertrophy of the neural stalk had occurred after posterior lobectomy. These findings are discussed in relation to recent studies on the site of formation and the liberation of posterior-pituitary hormone(s) after hypophysectomy.

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MESENCEPHALIC AREAS CONTROLLING PULSATILE OXYTOCIN RELEASE IN THE SUCKLED RAT

Journal of Endocrinology ◽

10.1677/joe.0.0910233 ◽

1981 ◽

Vol 91 (2) ◽

pp. 233-244 ◽

Cited By ~ 42

Author(s):

T. S. JUSS ◽

J. B. WAKERLEY

Keyword(s):

Medial Geniculate Body ◽

Milk Ejection ◽

Ventral Tegmentum ◽

Irregular Pattern ◽

Oxytocin Release ◽

Medial Geniculate ◽

Radiofrequency Lesions ◽

Milk Ejection Reflex ◽

Bilateral Lesions ◽

And Control

Experiments were performed on anaesthetized lactating rats to investigate the effects of radiofrequency lesions of the mesencephalon on the milk-ejection reflex. In lesioned and control rats, intramammary pressure recordings were used to estimate oxytocin release (number and relative amplitude of the intermittent milk-ejection responses) during a 3-h suckling test with ten pups. Bilateral lesions (diameter 0·5–1·5 mm) of the lateral tegmentum (near the brachium of the inferior colliculus and medial geniculate body) seriously disrupted the milk-ejection reflex, reducing the number of rats ejecting milk (two out of ten v. all 12 controls, P<0·001) and the amount of oxytocin they released (1·35±0·35 (s.e.m.) v. 15·52±2·19 mu. for controls, P<0·05). Unilateral lesions of the lateral tegmentum also impaired milk ejection and, if the suckling stimulus was restricted only to the contralateral nipples, oxytocin release was virtually abolished. Bilateral lesions placed more medially in the intermediate tegmentum were far less disruptive (eight out of nine rats ejected milk), though the amount of oxytocin released in this group (8·64±1·88 mu.) was still significantly (P<0·05) lower than controls. All rats with lesions of the central grey (nine) or ventral tegmentum (eight) displayed reflex milk ejection, as did those with multiple lesions of the tectum, central grey and ventral tegmentum (seven); in these three groups the amounts of oxytocin released (13·88±2·68, 13·10±1·90 and 11·04±1·95 mu. respectively) did not differ significantly from controls. Damage to the ventral tegmentum produced an irregular pattern of milk ejection characterized by occasional abnormally short (<2 min) milk-ejection intervals, though the overall number of responses in 3 h was less than that of controls (20·83±1·82 v. 14·50±1·30 mu., P<0·05). In conclusion, these results delineate two mesencephalic areas of particular importance in the milk-ejection reflex: (a) the lateral tegmentum, which appears to be concerned with transmission of the suckling stimulus from the contralateral nipples and is indispensable for oxytocin release, and (b) the ventral tegmentum which, although not an essential component of the reflex, may contribute to the timing of the intermittent milk-ejection responses.

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