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DER BIOLOGIE
HERAUSGEGEBEN VON
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REDIGIERT VON
HANSJOCHEM AUTRUM
ZWEIUNDZWANZIGSTER BAND
MIT 55 ABBILDUNGEN
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BERLIN GOTTINGEN· HEIDELBERG
1960
ISBN-\3: 978-3-540-02510-8 e-ISBN-\3: 978-3-642-94769-8
DOl: 10.1007/978-3-642-94769-8
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Inhal tsverzeichnis
JORGENSEN, C. BARKER, Dr., and LARSEN, LIS OLESEN, mag. sc., Copenhagen
(Denmark). Comparative aspects of hypothalamic-hypophysial relationships.
With 3 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . .
BRAND, THEODOR VON, Professor Dr., Bethesda (USA). Der Stoffwechsel der
Trypanosomen. Mit 3 Abbildungen . . . . . . . . . . . . . . . . . . . 30
HAGBARTH, KARL-ERIK, Dr., Uppsala (Sweden). Centrifugal mechanisms of
sensory control 47
MOHR, HANS, Dr., Tiibingen. Photomorphogenetische Reaktionssysteme in
Pflanzen. 1. Teil: Das reversible Hellrot-Dunkelrot-Reaktionssystem und das
Blau-Dunkelrot-Reaktionssystem. Mit 16 Abbildungen1 • 67
REHM, SIGMUND, Dr., Pretoria (Siidafrikanische "C"nion). Die Bitterstoffe der
Cucurbitaceen. Mit 2 Abbildungen. 108
PANITZ, REINHARD, Gatersleben. Die cytologischen und genetischen Kon-
sequenzen von Inversionen. Mit 27 Abbildungen 138
KARLSON, PETER, Dr., Miinchen. Pheromones . 212
BURKHARDT, DIETRICH, Dr., Miinchen. Die Eigenschaften und Funktionstypen
der Sinnesorgane. Mit 4 Abbildungen . 226
N amen verzeic h n is 268
S ach verzeich nis 282
Berichtigung zum Band XXI
1m Inhaltsverzeichnis des Bandes XXI muB es heiBen:
SCHONE, HERMANN, Dr., SeewiesenjObb. Die Lageorientierung mit Statolith en-
organen und Augen. Mit 5 Abbildungen ................ 161
1 Der 2. Teil dieses Artikels, in dem Reaktionssysteme besprochen werden, bei
denen ausschlieBlich kurzwelliges Licht und nahes Citrav iolett wirksam sind, folgt
im nachsten Band.
Comparative aspects of hypothalamic-hypophysial
relationships
By C. BARKER J0RGENSEN and LIS OLESEN LARSEN
Zoophysiological Laboratory, University of Copenhagen, Denmark
With 3 Figures
Contents
Introduction
Evidence of hypothalamic control of pars distalis function 2
Nervous or humoral hypothalamic control? . . . . . . 5
Chemical nature of hypothalamic hormone-releasing factors 6
Comparative anatomy of the hypothalamic-hypophysial region 10
Neurosecretion and site of formation of neurohypophysial hormones 14
Regeneration of neurohypophysial structures . . . . . . . . . . 17
Comparative physiology and evolution of the functions of the neurohypo-
physis . . . . . . . . 17
Summary and conclusions 21
Literature . . . . . . . 22
Introduction
Until recently studies on hypothalamic-hypophysial relationships
almost exclusively dealt with the hypothalamic control of the release of
the antidiuretic and oxytocic hormones from the pars nervosa of the neuro-
h ypophy sis.1 However, since the late 1940' s a rapidly growing literature has
unequivocally demonstrated a hypothalamic control of at least some
of the functions of the pars distalis in higher vertebrates, for instance
gonadotropic, adrenocorticotropic and thyrotropic functions. Strong
evidence supports the theory that this control is mediated by substances
1 The division and nomenclature of the hypophysial region is similar to that
used by GREEN (1951) and VVINGSTRAND (1951). The vertebrate hypophysis con-
sists of the adenohypophysis and the neurohypophysis. The adenohypophysis can
generally be subdivided into a pars distalis and a pars intermedia. The neurohypo-
physis is closely connected with the hypothalamus through the hypothalamic-
hypophysial tract. It is undivided in cyclostomes and most groups of fishes. In the
higher vertebrates, the neurohypophysis is differentiated into a pars nervosa and a
median eminence (see p. 13).
The following abbreviations and synonyms have been used in the text: ACTH =
adrenocorticotropic hormone = corticotropin; CRF = corticotropin-releasing fac-
tor; TSH = thyrotropic hormone.
Ergebnisse der Biologie XXII
2 C. BARKER J 0RGENSEN and LIS OLESEN LARSEN
released in the median eminence and carried with the blood to the pars
distalis. Further evidence obtained during the last few years favours the
concept that these substances are chemically closely related to the pars
nervosa hormones. In the present paper these new discoveries are
considered in the light of previous knowledge of the various aspects of
hypothalamic-hypophysial relationships in vertebrates, and some
consequences to theories on the evolution of neurohypophysial functions
are pointed out.
Evidence of hypothalamic control of pars distalis function
Cyclostomes and fishes. Nothing definite is known about hypothalamic
control of pars distalis function in these groups (see p. 15 and 17).
Amphibians. Investigations on the effect of transplantation of the
pars distalis to other parts of the body have been of great importance in
the elucidation of the hypothalamic control of pars distalis function.
A few experiments of this kind have been performed on amphibians. In
the toad Bufo bufo hypophysectomy immediately causes abnormal
appearance of the skin. Moulting is inhibited and the epidermis hyper-
keratinizes. The condition of the skin can therefore be used to evaluate
hypophysial function. When pars distalis was autografted under the
recessus opticus of the brain the toads behaved like hypophysectomized
animals, whereas when the gland was exstirpated and regrafted onto the
original site, the toads showed normal hypophysial functions as judged
from the appearance of the skin. The graft at the heterotopic site was
richly vascularized and viable, but cytologically dedifferentiated [JACOB-
SOHN and ]0RGENSEN (1956)J. The loss of function of grafts outside the
range of hypothalamic influence is not due to irreversible damage of the
pars distalis tissue, because regrafting of non-functional autografts from
the eye muscle to the original site under the median eminence can result
in resumed functioning of the pars distalis (own unpublished results).
Frogs, Rana temporaria, with autografted pars distalis in the eye muscle
did not reproduce during the spring, whereas frogs with autografts under
the median eminence were capable of normal reproduction. Thus
gonadotropic secretion of the pars distalis depends upon hypothalamic
control. Similar results were obtained with the urodele Triton cristatus
[VIVIAN and SCHOTT (1958)].
Hypothalamic influence on the pars distalis has also been revealed in
experiments using properly placed hypothalamic lesions. In Triton
cristatus lesions in the preoptic area were found to inhibit gonadotropic
secretion as shown by loss of spermatogenesis [MAZZI (1952)J. Toads with
lesions in the same region ceased moulting (SCHARRER (1934)J.
Birds. Hypothalamic control of pars distalis function has not been
investigated in reptiles, but in birds gonadotropic activity has been
Comparative aspects of hypothalamic-hypophysial relationships 3
found to be under nervous control. Increasing light intensity and day
length activate the resting gonads in ducks, but light stimulation (of
testes) was inhibited by lesions in the anterior hypothalamus [ASSEN-
MACHER (1957)] or by transplanting pars distalis to the anterior eye
chamber in hypophysectomized ducks [ASSENMACHER and BENOIT
(1958)]. Obviously stimulation by light depends upon intact hypo-
thalamic structures and upon close connection between the hypo-
thalamus and the pars distalis. In the domestic fowl the timing of
release of the ovulation-inducing hormone is apparently under control
of the central nervous system [FRAPS (1954, 1955)].
Mammals. From the extensive literature on hypothalamic dependance
of pars distalis function in mammals, only a few examples will be cited.
Pars distalis grafts placed under the median eminence of hypo-
physectomized rats often showed normal gonadotropic activity as
judged by oestrus cycles and pregnancy in females and spermatogenesis
in males. Even pars distalis tissue of immature donors or of adult male
donors was capable of maintaining normal oestrus cycles and pregnancy
when placed under the median eminence of female rats. By way of
contrast, grafts placed under the temporal lobe of the brain, even when
richly vascularized, showed no gonadotropic activity [HARRIS and
JACOBSOHN (1952)]. Gonadotropic activity likewise ceased in hypo-
physes transplanted to the kidney in female rats. The grafts, however,
could resume functioning, as shown by a recurrence of sexual cycles,
when retransplanted under the median eminence. In rats with grafts
retransplanted from the kidney to the temporal lobe, sexual cycles never
recurred. Histologically, the grafts under the temporal lobe, like the
kidney grafts, were dedifferentiated, whereas the grafts under the
median eminence became redifferentiated with basophils of normal
appearance. The loss of cytological differentiation and gonadotropic
secretion in pars distalis transplanted to other parts is therefore not due
to injury of the tissue but to its loss of contact with the hypothalamus
[NIKITOVITCH-WINER and EVERETT (1957)]. The nature of the hypo-
thalamic control of gonadotropic activity of the pars distalis in the
spontaneously ovulating rat has been studied by means of agents capable
of blocking the nervous activation of the pars distalis [EVERETT and
SAWYER (1950, 1953), EVERETT (1956)]. In order to block gonadotropin
release and accordingly normal ovulation a blocking agent, e. g. atropin,
has to be administered within a period of two hours on the day before the
expected ovulation. Administration prior to or after this period does not
prevent the hypothalamic activation of the pars distalis.
Hypothalamic influence on the adrenocorticotropic activity of the
pars distalis is obvious from the following examples. Normal rabbits
respond to such stimuli as restraint or exposure to cold by releasing ACTH
1*
4 C. BARKER J0 RGENSEN and LIS OLESEN LARSEN
from the pars distalis as is evidenced by a reduction of the number of
circulating lymphocytes. This lymphopenic response is reduced or
abolished by effective separation of the pars distalis from the hypothalamus
by section of the hypophysial stalk and insertion of a waxed-paper plate
between the cut ends [FORTIER et al. (1957)J. In dogs hypothalamic
lesions can reduce the normal rate of adrenal corticoid secretion as is
shown by measurements on blood drawn from a permanent canula in the
adrenal vein. Less ACTH is released following operative trauma [HUME
(1958)]. Appropriate hypothalamic lesions in guinea pigs likewise reduce
normal levels of ACTH secretion and abolish the increased secretion
which normally follows administration of diphtheria-toxin [SCHMID et al.
(1957), WINKLER et al. (1958)J. Liberation of ACTH can also be induced
by electrical stimulation of hypothalamus [ENDROCZI et al. (1957), rats;
MASON (1958), monkeys].
In normal mammals exposure to cold stimulates the thyrotropic
activity of the pars distalis, causing increased release of thyroid hormone.
This response to cold was abolished in hypophysectomized rabbits with
grafts of pars distalis in the anterior eye chamber [VON EULER and HOLM-
GREN (1956a and b)J and in hamsters with grafts in the cheek pouch
[KNIGGE and BIERMAN (1958)]. In rabbits, stalk sections that effectively
destroyed connections between hypothalamus and pars distalis, also
abolished the inhibition of TSH secretion as was shown by normal rabbits
in response to restraint ("psychic stress") [BROWN-GRANT et al. (1957)J.
It is thus evident that gonadotropic, adrenocorticotropic and thyro-
tropic function of the pars distalis is under hypothalamic control. It
remains to be discussed whether, and to what extent, these pars distalis
functions are independent of the central nervous system. The question
is still a matter of controversy and will not be treated in detail here.
Probably gonadotropic activity of the pars distalis is low or absent
when the gland is deprived of its normal hypothalamic connections.
However, it is generally agreed that the transplanted pars distalis or the
pars distalis isolated from hypothalamic control by stalk section or
hypothalamic lesions, possesses considerable ability to autonomously
produce ACTH and TSH. Thus certain forms of stress ("systemic stress")
can still induce ACTH release. The thyroids function at a level much
above that of hypophysectomized controls [BROWN-GRANT et al. (1957),
D'ANGELO (1958), FLORSHEIM (1958), FORTIER et al. (1957), GREER
(1957), Scow and GREER (1955), VON EULER and HOLMGREN (1956 a
and b)J.
Several attempts have been made by means of lesions to localize the
hypothalamic areas or structures that may take part in the neural control
of the release of the various tropic hormones from the pars distalis.
Lesions mostly inhibit secretion of more than one of the hormones. The
Comparative aspects of hypothalamic-hypophysial relationships 5
structures therefore seem to overlap. However in the rat, the preferred
experimental animal, lesions in the anterior hypothalamus mainly
inhibit thyroid function [BOGDANOVE (1957), D'ANGELO (1958), FLORS-
HElM (1958), GREER (1957), SLUSHER (1958)J, whereas ACTH-regulating
structures are generally supposed to be placed in the mid hypothalamus
[GREER (1957), SLUSHER (1958)]. In the guinea pig SCHMID et al. (1957)
found the ACTH-regulating structures localized around the nucleus
hypothalamus ventromedialis and dorsomedialis. Gonadotropin secretion
has been inhibited by lesions in the median hypothalamus. These lesions
did not influence TSH secretion [BOGDANOVE (1957), D'ANGELO (1958),
SLUSHER (1958)]. However, the anterior hypothalamus may also contain
structures involved in the sexual cycle of the rat [GREER (1957), FLERKO
and SZENTAGOTHAI (1957)].
Nervous or humoral hypothalamic control?
Some investigators state that the vertebrate pars distalis is richly
innervated and that consequently its function is probably under direct
nervous control [METUZALS (1956, 1958), VAZQUES-LoPEZ (1948)].
However, only a scanty nerve supply is generally found, and it is argued
that when a dense net of fibres has been observed it has not been sub-
stantiated that these fibres are nerves and not reticular fibres [GREEN
(1951), HARRIS (1955), SMITH (1956), WINGSTRAND (1951)J. The negative
results of direct electrical stimulation of the hypophysis certainly does not
support the claim that there are secretory nerves whereas stimulation of
the hypothalamus or median eminence can cause release of ACTH, TSH
or gonadotropins [HARRIS (1948b), HARRIS and WOODS (1958), MARKEE
et al. (1946)].
If the pars distalis does not contain secretory nerves its function must
be controlled humorally. Peculiar vascular connections between hypo-
thalamus and pars distalis are, indeed, suitable for such humoral control
(Fig. 2 and 3, p. 12 and 14). In higher vertebrates blood passing through a
dense capillary plexus in the median eminence is drained through portal
vessels directly into the blood sinuses of the pars distalis. POPA and
FIELDING (1930) discovered this hypophysial portal system in mammals
and WISLOCKI (1937) described the true direction of the blood flow. The
portal circulation is also characteristic of birds [WINGSTRAND (1951)J and
amphibians [GREEN (1947), HOUSSAY et al. (1935), anurans; MAZZI and
PEYROT (1957), urodelesJ. In lower vertebrates the vascular connections
between hypothalamus and pars distalis are simpler, but fundamentally
similar. Blood flows through capillaries of the neurohypophysis into the
pars distalis (and pars intermedia) before passing into the systemic
circulation [GREEN (1951)].
6 C. BARKER J 0RGENSEN and LIS OLESEN LARSEN
The hypophysial portal circulation has therefore been assumed to
mediate the hypothalamic control by carrying hormone-releasing factors
to the pars distalis. In higher vertebrates the factors are supposed to be
liberated in the median eminence from the nerve endings of the hypo-
thalamic tract and to diffuse into the primary plexus of the portal
system [HARRIS (1948a)]. A corticotropin-releasing factor (CRF) has in
fact been demonstrated in brain blood from rats subjected to stress.
CRF was not present in brain blood from non-stressed rats nor in blood
drawn from the carotid of stressed rats [SCHAPIRO et al. (1958)]. Blood
from the portal region, but not from the carotid, of the dog likewise
stimulated ACTH secretion when injected into intact rats. In hypo-
physectomized rats no effect was observed [PORTER and JONES (1956)J.
Birds are especially suitable. for demonstrating the significance of
humoral control of the pars distalis, because it is possible to sever the
portal vessels without interrupting the nervous connections between the
hypothalamus and hypophysis. Section of the portal vessels abolishes
the hypothalamic control of the gonadotropic function of the pars
distalis in the duck as judged from the failure of the operated birds to
respond to light. Section of the nervous connections to the hypophysis
does not prevent light-induced sexual maturation [BENOIT and ASSEN-
MACHER (1953)J. Substances that can release hormones from the pars
distalis and thus be the mediators of hypothalamic control are therefore
most probably transmitted with the portal blood. Their number, chemical
nature, and site of origin are not yet definitely known, but are the
subject of much current research.
Chemical nature of hypothalamic
hormone-releasing factors
Several well known physiologically active substances such as hist-
amine, adrenaline and serotonine are present in high concentrations in the
hypothalamus or neurohypophysis and have been considered as possible
natural factors causing hormone release from the pars distalis.
Histamine was found to stimulate ACTH release in the rabbit;
injection of histamine solutions caused lymphopenia. The response was
abolished by hypophysectomy [FUCHE and KAHLSON (1957)J. Apparently,
however, histamine acts indirectly via the hypothalamus because the
ACTH-releasing effect could be abolished in rats by hypothalamic lesions
[MCCANN (1957)J or by transplanting the pars distalis to the anterior
eye chamber [MARTINI (1958)J. Adrenaline, too, induced ACTH release
from the pars distalis in the rat, but, as in the case of histamine, the
response disappeared after lesion of the hypothalamus or median
eminence [MCCANN (1957), SMELIK and DE WIED (1958)J. Injection of
Comparative aspects of hypothalamic-hypophysial relationships 7
adrenaline or nor-adrenaline into the primary plexus of the portal
vessels of female rabbits frequently produced ovulation. The effect was
apparently not due to adrenaline itself, however, but to the acidity of the
solution injected, because after adjustment to neutrality only one of
eight rabbits ovulated after receiving the large dose of 150 y of adrenaline
[DONOVAN and HARRIS (1955)J. Adrenaline is, therefore, most probably
not a natural ACTH-or gonadotropin-releasing agent. Acetylcholine has
also been investigated as to its pars distalis-stimulating activity. No
ACTH-releasing effect was found on the pars distalis tissue transplanted
to the anterior eye chamber in the rat [MARTINI (1958)J. On theoretical
grounds, acetylcholine is unlikely to be a humoral transmitter in the
portal blood, because it is rapidly broken down in the blood stream
[HARRIS (1955)J. Serotonine caused ACTH release in normal rats, but
not after destruction of the median eminence [SMELIK and DE WIED
(1958)J or after transplantation of the pars distalis to the anterior eye
chamber of hypophysectomized rats [MARTINI (1958)]. Also substance P
[see GUILLEMIN (1957)J is stated to release ACTH, but the response
could be abolished byhypothalamiclesions [MCCANN (1957)]. Serotonine
and substance P are therefore presumably ruled out as natural ACTH-
releasing factors.
A lipid extracted from the hypothalamus was found to cause eosino-
penia and adrenal ascorbic acid depletion - other symptoms of ACTH
release - when injected into intact rats, but not when injected into
hypophysectomized rats [SLUSHER and ROBERTS (1954)J. The lipid was
not found in the cortex of the brain. It is stated to cause release not only
of ACTH, but also of TSH and gonadotropins from the pars distalis of
several mammals [CURRI (1958)]. It is doubtful, however, whether this
interesting lipid fraction represents natural humoral links between the
hypothalamus and the pars distalis since its ACTH-releasing activity can
be abolished by destruction of the median eminence [DE WIED et al.
(1958) ].
Special interest attaches to the mammalian antidiuretic hormone
which has been found to stimulate the pars distalis directly. The hormone
acts not only in mammals but also in amphibians. Injections of synthetic
vasopressin induced moulting in toads (Bufo bufo) in which moulting
had been inhibited by isolation of the pars distalis from the hypo-
thalamus. Presumably, vasopressin caused moulting by stimulating the
inactivated pars distalis, because the hormone had no effect in hypo-
physectomized toads [J0RGENSEN and NIELSEN (1958)].
In mammals the ACTH-releasing activity of vasopressin has been
extensively studied. In rats pitressin or synthetic vasopressin causes
adrenal ascorbic acid depletion even in animals with hypothalamic
lesions [MCCANN (1957), MCCANN and FRUIT (1957), SMELIK and DE WIED
