Hypothalamic Control of Lactation: Monographs on Endocrinology

Hormone

Part I

Physiological Regulation of Lactation

Outline

Chapter 1: Mechanism of Lactation

Chapter 2: Hypothalamus-Pituitary Axis

Chapter 3: Prolactin

Chapter 4: Growth Hormone

Chapter 5: Gonadotropins and Sex Steroids

Chapter 6: Adrenocorticotropin and Corticosteroids

Chapter 7: Thyrotropin and Thyroid Hormones

Chapter 8: Oxytocin and Vasopressin

Chapter 9: Parathormone and Calcitonin

Chapter 10: Insulin and Glucagon

Chapter 11: Pineal Gland

Chapter 12: Placental and Amniotic Fluid

Chapter 1

Mechanism of Lactation

Publisher Summary

This chapter discusses different hormone mechanisms, specifically the mechanism of lactation. The action of the steroids on lactation is only comprehensible if it is assumed that the existence of an acceptor or receptor for them, both in the brain (hypothalamus and hypophysis) and in the mammary gland. A new aspect of hypothalamic lactation is its dependence upon the temporal cortex of the brain. The difficulty of producing lactation by prolactin alone stems from the necessity of a harmonious interplay of all hypophysiotropins. Peripheral hormonal factors are no less important for the regulation of mammary gland growth and function. The most vital for mammary proliferation are the ovarian hormones—estrogen and progesterone. Mammary physiology is similar in all mammals, but hormone requirements for mammary development vary according to species. For experimental mammogenesis, estrogen priming at subthreshold doses is of utmost importance.

The mechanism of lactation is poorly understood. For this reason no hormonal preparation for stimulation of lactation in man or animals has as yet been accepted. The following working hypothesis and nomenclature is proposed by us:

The main problem derives from the fact that, while the common hormone reactions, e. g. ovulation etc., are brought about by hyperemia of the target organ and enzymatical changes involving low-energy processes which can be induced by one hormone alone, lactation additionally requires the action of many metabolic hormones which have to mobilize casein, butter fat, lactose, calcium etc. for the excessive requirements of milk production. It is obvious that this goal cannot be achieved by one hormone alone, i. e. prolactin, without the aid of STH, ACTH, TSH, parathyroid hormone, etc. A harmonious concurrence of all these hormones is apparently only possible through appropriate stimulation by the conductor of such a symphony—the hypothalamus.

With this approach in mind we studied the different hormone mechanisms involved. The three main objectives of that study can be summarized as follows:

a) contribution to the basic knowledge of the mechanism of lactation by interplay of all body hormones;

b) developing exact methods for assay of all hormones involved in the different species;

c) stimulation of lactation in animals and women postpartum.

Experimental data strongly suggest that the mode of action of the ovarian hormones on mammary tissue may be direct as well as indirect. Today we know that high doses of LTH and STH can substitute for the effect of estrogen + progesterone (cf. Chapters 5 and 20).

The action of the steroids on lactation is only comprehensible if we assume the existence of an acceptor or receptor for them, both in the brain (hypothalamus and hypophysis) and in the mammary gland. As we shall show in Chapter 19, these receptors have a striking similarity with those required for the modern psychopharmaca which elicit lactation, with one difference: Lactation elicited in women by psychopharmaca—apparently induced by impairment of a prolactin-inhibiting factor (PIF) in the posterior hypothalamus—cannot be suppressed by steroids, which, as it now seems, cannot enter a receptor occupied by specific psychopharmaca. The same holds for the Chiari-Frommel syndrome and Ahumada-del Castillo syndrome. These are called forth by a disturbance of the PIF center and do not react to steroids (Chapter 28). On the other hand, puerperal lactation is apparently induced by a prolactin-releasing factor (PRF)—its area in the anterior hypothalamus is extremely sensitive to estrogen; it can be stimulated by it and it can also be suppressed by an overdose of estrogens. Thus, it seems that a double-center theory would explain all the manifold problems of hypothalamic lactation described in this monograph. Release or inhibition of additional hypophysiotropins can further contribute to lactation (DIKSTEIN and SULMAN, 1966).

A new aspect of hypothalamic lactation is its dependence upon the temporal cortex of the brain. Bilateral lesions produced by suction in the basal portion of the temporal lobes in ovariectomized estrogen-primed rabbits resulted in milk secretion (MENA and BEYER, 1968). This effect was apparent within one week after the operation. The common area destroyed by these lesions included the entorhinal cortex and the ventral part of the amygdala. Control lesions in the neocortex and olfactory bulbs did not induce this effect. Using stereotaxic approaches, we have not been able to confirm these results which—if correct—would suggest that the temporal lobes influence the hypothalamic pituitary systems.

Summarizing, it seems that the difficulty of producing lactation by prolactin alone stems from the necessity of a harmonious interplay of all hypophysiotropins. This can only be obtained by suitable stimulation (or suppression) originating in the hypothalamus. The importance of the temporal lobe of the cortex and its ability to evoke feelings of motherhood in animals and humans (cf. Solomon’s judgement: I Kings: 3: 16—28) needs further study.

Peripheral hormonal factors are no less important for regulation of mammary gland growth and function. Yet, the most vital for mammary proliferation are the ovarian hormones—estrogen and progesterone. Normal cyclic changes in these two hormonal components govern the normal cyclic changes in mammary gland development associated with estrus or menstrual cycle. The same changes can be reproduced experimentally by exogenous hormonal treatment. In this respect we can distinguish between two different types of reaction: Animals such as the mouse, rat, rabbit or cat will respond to physiological amounts of estrogen by proliferation of the duct system, while for lobulo-alveolar growth progesterone is also required. Detailed studies on the optimal amounts and proportions of the two hormones have been carried out by many researchers (for details cf. D. JACOBSOHN, 1961), and are obviously different according to the species and specific strain studied. A different kind of reaction is observed in the guinea pig, goat and cow. In these species estrogen alone has been shown to cause both ductal and lobulo-alveolar development. Closer observation reveals, however, that even here treatment with estrogen alone results in anomalous gland structures (COWIE, FOLLEY, MALPRESS and RICHARDSON, 1952). For optimal mammary growth a combination of estrogen and progesterone is essential.

In still other species, such as the bitch and the ferret, estrogen alone does not even produce ductal growth.

A further point to be remembered, apart from the species differences, are the differences in the individual response of animals belonging to the same species and strain. This applies both to natural and to experimental mammary development. Lactation studies should, therefore, preferably be carried out on estrogen-primed animals. The dose given varies between 8 and 10 μg daily per rat for 10 days. We prefer the lower dosage since we found that priming with 10 μg per day may give unspecific reactions. Thus, NICOLL, TALWALKER and MEITES (1960) obtained lactation after non-specific stresses, such as injection of formalin, exposure to extreme cold or heat, restraint, etc., using 10 μg for daily priming. They also reported lactation following injection of meprobamate after identical priming, whereas this substance proved negative in our set-up when only 8 μg/day was used for priming (BEN-DAVID, DIKSTEIN and SULMAN, 1965).

In short: mammary physiology is similar in all mammals, but hormone requirements for mammary development vary according to species. For experimental mammogenesis estrogen priming at subthreshold doses is of utmost importance.

Chapter 2

Hypothalamus-Pituitary Axis

Publisher Summary

The hypophysiotropic hormones or releasers diffuse into the capillary plexus of the median eminence and are carried by the veins of the pituitary stalk to the sinusoids of the anterior pituitary gland. In mammals, prolactin is a unique anterior pituitary hormone because the hypothalamus exerts a tonic and chronic inhibition on its pituitary secretion by a prolactin-inhibiting factor (PIF). Psychopharmaca, which depress the PIF center, can induce prolactin release in vivo and initiate mammary secretion in rats, rabbits, or humans. The increase in PIF content of the hypothalamus, while pituitary prolactin content decreases and blood-plasma prolactin rises, can best be interpreted as being caused by the blockage of PIF release from the hypothalamus. The release of prolactin by the pigeon pituitary appears to be controlled differently than in mammals. With regard to prolactin, the existence of a hypothalamic inhibiting factor is well established by prolactin release after hypothalamic lesions, pituitary stalk section, pituitary transplantation, and treatment with hypothalamic depressants and by hypothalamuspituitary co-culture.

a) Hypothalamic Control of Prolactin Secretion

The theory of the anterior pituitary gland being controlled by neurohumors (Fig. 1) carried through the hypophysial portal circulation, advanced mainly by HARRIS (1955), and the concept of neurosecretion, pioneered by SCHARRER and his group (1963), have led to the present, widely held view that the median eminence of the hypothalamus and the adjacent pituitary stalk make up a specialized neurohumoral organ whose function it is to control the anterior lobe (HARRIS and DONOVAN, 1966; BROWN-GRANT AND CROSS, 1966; MARTINI and GANONG, 1966; REICHLIN, 1966). Within the median eminence there are nerve endings containing neurosecretory substances which have the property of regulating the secretion of the cells of the anterior pituitary. These hypophysiotropic hormones or releasers diffuse into the capillary plexus of the median eminence and are carried by the veins of the pituitary stalk to the sinusoids of the anterior pituitary gland. This vascular system has been designated the hypophysial-portal circulation, by analogy with the hepatic-portal system (Fig. 2). The portal vessel chemotransmitter hypothesis has been supported by the demonstration that compounds extracted from the stalk and median eminence region of the hypothalamus possess the property of releasing or inhibiting anterior pituitary tropic hormones.

Fig. 1 Diagram of mammary stimulation by different hormones, drawn by M. BEN-DAVID(1968). Effect of I CNS (hypothalamus) and II pituitary, on III endocrine glands and IV peripheral target organs (mammary gland, etc.). Note absence of feedback from the mammary gland

Fig. 2 Scheme of hypophysial-portal circulation. The sinusoids of the anterior lobe receive their blood supply from the hypophysial portal vessels, which arise from the capillary beds within the median eminence (above) and enter the infundibular stem (below). In the anterior lobe (r) they form a secondary plexus of the pituitary portal system, leading to the venous dural sinuses, which surround the pituitary and connect it to the general peripheral circulation. The releasing or inhibiting factors of the hypothalamus or the median eminence enter the pituitary circulation at the primary plexus of the hypophysial portal system which runs from the median eminence via the infundibular stem to the pars distalis (anterior pituitary lobe). (Copyright: The Ciba Collection of Medical Illustrations by FRANK H. NETTER, M. D.)

In mammals, prolactin is a unique anterior pituitary hormone because the hypothalamus exerts a tonic and chronic inhibition on its pituitary secretion by a prolactin-inhibiting factor (PIF). This fact does not exclude the possibility of the existence of a prolactin-releasing factor (PRF) as will be shown in paragraph c. In the mammalian animal the inhibitory hypothalamic regulation of prolactin secretion is the predominant one; it is, however, reversed by lactation following delivery. With regard to MSH, it seems that it, too, is subject to the regulation by a MSH-releasing factor (MRF) in the median eminence and a MSH-inhibiting factor (MIF) in the supraoptic nucleus area (TALEISNIK and TOMATIS, 1967). Research in this field will be reported in Chapter