Chronology of Advances

in Neuroendocrine Immunomodulationa
SAMUEL M. MCCANN, ANDREA DE LAURENTIIS,
AND VALERIA RETTORI
Centro de Estudios Farmacologicos y Botanicos, Consejo Nacional de
Investigaciones Cientficas y Tecnicas (CEFYBO-CONICET), Facultad de
Medicina, UBA, Paraguay 2155, CP 1121, Buenos Aires, Argentina

ABSTRACT: This review documents the remarkable progress over the last
50 years of our knowledge of the control of anterior pituitary hormone
release and synthesis by a family of peptidic releasing and inhibiting
hormones, synthesized in hypothalamic neurons and released into the
hypophysial portal vessels. These vessels transport them to the ante-
rior pituitary, where they stimulate release and synthesis of pituitary
hormones or inhibit these processes. In general, there are at least two
hypothalamic hormones for each pituitary hormonevasopressin and
corticotrophin-releasing hormone (CRH) for adrenocorticotropin hor-
mone (ACTH) and growth hormonereleasing hormone (GHRH) and
growth hormoneinhibiting hormone (GIH) for growth hormone (GH).
Some of these hormones have extrapituitary action: for example, luteiniz-
ing hormonereleasing hormone (LHRH) stimulates mating behavior.
High doses of LHRH have an inhibitory action on the growth of prostate
cancer. Proinflammatory and anti-inflammatory cytokines act not only
in the brain, but also on the pituitary and peripheral tissues. All of these
transmitters are controlled by neuronal transmitters. We anticipate fur-
ther rapid progress and clinical application of these transmitters and the
discovery of new ones.

KEYWORDS: vasopressin; oxytocin; corticotropin-releasing hormone

(CRH); LHRH; FSH-RH; GHRH; GH-inhibiting hormone (GHI); so-
matostatin; prolactin-inhibitory factor

I was fortunate to be on the scene as the dramatic developments in neu-

roendocrine immunomodulation took place over the last 55 years. Biologi-
cal science had its birth with the Greeks and the first great physician, Hip-
pocrates; however, his studies were observational, and it remained for Galen
a This paper has been modified with permission from an article by Samuel M. McCann in Physio-
logical Mini-Reviews (Vol. 1, No. 9, April 2006) published by the Argentina Physiological Society.
Address for correspondence: Samuel M. McCann, Facultad de Medicina, UBA, CEFYBO-
CONICET, Paraguay 2155, piso 16, CP 1121, Buenos Aires, Argentina. Voice: 54-11-4508-3680;
fax: 54-11-4508-3680.
e-mail: smmccann2003@yahoo.com

Ann. N.Y. Acad. Sci. 1088: 111 (2006). 

C 2006 New York Academy of Sciences.

doi: 10.1196/annals.1366.010

1
2 ANNALS NEW YORK ACADEMY OF SCIENCES

(AD 130200) to initiate studies employing the experimental method. There

were virtually no advances during the subsequent 1,300 years, until Michael
Servetus in the 16th century discovered the valves in veins. His reward was
to be burned at the stake for heresy by Philip II of Spain.1 Descartes (1596
1650) speculated on the function of the pituitary, but modern physiology had its
birth when Walter Cannon (18711945) studied the flight-or-fright response
of animals in stress involving activation of the adrenal medulla, which secreted
sympathin-excitatory (e) and sympathin-inhibitory (i). Unfortunately, he did
not discover the structure of the secreted substances. Presumably, sympathin
was epinephrine. It remained for U.S. von Euler to determine this structure,
and that this compound was norepinephrine.1
Hans Selye discovered the activation of the adrenal cortex by stress, and
demonstrated many other changes produced by stress, such as involution of
lymph nodes and the thymus that were accompanied by lymphopenia, eosinope-
nia, and leukocytosis. He believed that these changes were caused by increases
in plasma histamine activating adrenocorticotropic hormone (ACTH) release
directly from the adenohypophysis. He did not believe that the central nervous
system (CNS) was involved. Actually histamine can activate the hypothalamic
pituitaryadrenal axis, but this is not the major pathway.2
A means by which the brain could control the anterior pituitary gland was
discovered by B. A. Houssay et al. (1933).1 In the living toad, they found that
portal vessels drained blood from a primary capillary plexus in the median
eminence (ME) down the pituitary stalk to the sinusoids in the anterior pituitary
gland. Popa and Fielding1 found these vessels in dead animals but believed
that the blood flow was upward from the pituitary to the ME, a conclusion
also reached in the dead rabbit by G. W. Harris.1 Later, with Green (1947),1 he
found that the flow was downward in the living rat. Because the blood pressure
in the portal vessels is very low, it is likely that, depending on the conditions,
flow can be either upward or downward. In addition, the short portal vessels
carry blood from the neural lobe across the intermediate lobe to the anterior
lobe, thus delivering neural lobe hormones directly in high concentrations to
the anterior lobe of the gland. This fact has been largely neglected.1
Dwight Ingle (1938) carried out pioneering studies that indicated that the
adrenal cortical hormones had a negative feedback at the pituitary gland to
suppress ACTH secretion.3 It was thought at that time that the response of the
cortical hormones to stress was slow; however, Ingle showed that following
unilateral adrenalectomy there was an increase in weight of the remaining
adrenal within 6 h caused by decreased secretion of adrenal steroids. This
decreased negative feedback of these steroids resulted in increased ACTH
secretion, which produced enlargement of the remaining gland.3
In 1943 Li et al.4 and Sayers et al.5 almost simultaneously isolated ACTH,
facilitating studies with this important stress hormone. Sayers6 had shown
that stress caused a decrease in adrenal ascorbic acid concentration within
1 h, which could also be produced by ACTH. The stress-induced decline was
MCCANN et al.: ADVANCES IN NEUROENDOCRINE IMMUNOMODULATION 3

blocked by hypophysectomy. Farrell and I decided to see whether we could

measure ACTH in blood by etherizing rats and withdrawing blood from the
external jugular vein, which was then injected into the external jugular vein
of a hypophysectomized rat. Indeed, detectable ACTH was found. A further
significant increase was induced within 1 min by intravenous (i.v.) injection
of 5 g of epinephrine. This ACTH was purified by the acid acetone method
of Lyons. These studies convinced us that there was a hypothalamicpituitary
axis under minute-to-minute control by hypothalamic releasing factors, which
we named corticotrophin-releasing factors (CRFs).7 This term was coined by
my roommate Al Rothballer, who showed that stress caused a depletion of the
Gomori-positive material from the neurohypophysis. He gave the name CRF
to Murray Saffran, who never acknowledged its origin.
I set about to determine whether ME lesions would block the adrenal cortical
stress response in both cats and rats. I knew that unilateral adrenalectomy in
etherized rats led to a dramatic depletion of adrenal ascorbic acid within 1 h
and showed that ME lesions completely blocked this response (1953).8 With
Walle Nauta, we also showed that arcuate nucleus lesions caused testicular
and accessory sex organ atrophy, an indication that gonadotropin secretion
had been blocked.8 There was atrophy of the neural lobe of the pituitary
accompanied by diabetes insipidus, indicative of deficiency of the neurohy-
pophysial hormone, vasopressin, and hypertrophy of the intermediate lobe
suggesting augmentation of intermediate lobe hormone secretion, which was
later proven. The anterior lobe was usually moderately decreased in size and
was well vascularized, suggesting that portal blood flow was intact. Plasma
and pituitary ACTH was drastically lowered in etherized rats with ME lesions,
providing further evidence for hypothalamic control of synthesis and release of
ACTH.9
Bogdanove (1954)1 did similar studies that were reported later, but did not
study ACTH secretion. Ganong showed that ME lesions blocked compensatory
adrenal hypertrophy in dogs (1954).1 ME lesions also blocked ACTH secretion
in the cat, as evidenced by decreased cortisol in adrenal venous blood and
histological changes in adrenals similar to those following hypophysectomy
(1955).10
We hypothesized that the anterior pituitary was controlled by a family of
releasing factors, one for each pituitary hormone. The assay animal for these
factors would be the rat with ME lesions. Obviously we could not perform
histologic studies to determine whether the lesions were complete, but in the
process of making many such lesions in rats that were allowed to recover for
1014 days, we noticed that rats that drank 200 mL or more of water per
day (those with severe diabetes insipidus), roughly seven times of the normal
intake, did not respond to stress or unilateral adrenalectomy with ascorbic acid
depletion 1 h later. Histologic examination of the brains of these rats indicated
that the supraoptic hypophyseal tract had been interrupted in the ME, which
was itself destroyed.
4 ANNALS NEW YORK ACADEMY OF SCIENCES

Interestingly, as the water intake increased up to 150 mL/day, the adrenal

weight decreased to a minimum. Some rats with ME lesions had much higher
water intakes, as a result of which the adrenal weight increased from the mini-
mum to a maximum. We still do not know the cause of this.11 Ascorbic acid de-
pletion was still blocked.12 ME lesions increase MSH secretion from the pars
intermedia and prolactin release11,13 by obliterating dopaminergic inhibitory
control of prolactin because ME lesions would destroy the tuberoinfundibular
DA neurons.
Therefore, we used these rats with ME lesions and H 2 O intake of 200 mL
or more per day as an assay animal to screen for possible CRFs. Pitressin,
a commercial arginine vasopressin preparation, decreased adrenal ascorbic
acid significantly in a dose-dependent manner in rats with ME lesions. Com-
mercial oxytocin had no effect. There was no action of epinephrine (1954).12
Probably because of the long period between operation and testing, it oc-
curred to us that testing only 48 h after lesions might yield a more sensi-
tive preparation. Indeed, if these rats had a water intake of 100 mL or more
24 h after lesions were made, they were much more sensitive to vasopressin but
did not respond to nonspecific stimuli. We used these rats to demonstrate the
CRF activity of synthetic lysine vasopressin given to us by du Vigneaud,14,15
who had just received the Nobel Prize for synthesizing vasopressin as well as
oxytocin.
Using this more sensitive assay, we demonstrated the CRH activity of rat stalk
median eminence (SME) extracts and SME extracts from sheep. These were
contaminated with ACTH and vasopressin, and we quantified their ascorbic
aciddepleting activity in our animals; roughly 80% of the activity was due to
CRF (1959).16 Royce and Sayers obtained similar results.
Our major competitors were the first to use incubation of quartered ante-
rior pituitaries and confirmed the ability of vasopressin to release ACTH, but
claimed that there was a CRF activity contaminating the vasopressin that could
also stimulate secretion of ACTH. This was also demonstrated in the presence
of norepinephrine. Guillemin and Hearn and Saffran and Schally used paper
chromatographic systems to separate vasopressin from CRF. Using our assay
we found vasopressin with CRF activity, but no CRF using their chromato-
graphic systems. Subsequently Guillemin and Schally claimed to isolate 1
and 2 and CRF. These CRFs were part of the prophetic literature and soon
disappeared from the literature. A major problem of these researchers work
was that they used pituitary and not hypothalamic extracts. Also they did not
preincubate the pituitaries, so that the hormones that leaked from the cut glands
made it very difficult to see a small increment of ACTH possibly released by
neural lobe extracts. Joe Meites was the first to preincubate hemi-anterior pi-
tuitaries to wash out the hormones from the cut glands, which made it possible
to use hemipituitaries as a bioassay for releasing factors. Later both Guillemin
and Schally extracted hypothalami. Schally used porcine and Guillemin used
ovine hypothalami.
MCCANN et al.: ADVANCES IN NEUROENDOCRINE IMMUNOMODULATION 5

Our CRF was purified and separated on Sephadex G-25 followed by CMC
chromatography17,18 from other releasing and inhibiting factors (19591965).
Because it was a much larger peptide (40 aa [amino acids]) than the other
releasing factors, it defied structural characterization for many years. As late
as the late 1960s, the President of the American Endocrine Society drew a
diagram of the hypophysialadrenal axis leaving out the hypothalamus and
CRF. Later we found that vasopressin potentiates the action of CRFs on the
pituitary.19
Evidence that oxytocin might be a prolactin-releasing factor was provided
by Benson and Foley (1959). We confirmed their finding that oxytocin delayed
the histological involution of mammary glands of rats from which the litter
had been removed. Much later we obtained evidence for a physiological role
of oxytocin in the control of prolactin secretion.20
Reflection made it seem odd that oxytocin, one of the three most abundant
peptides in the body (the others being vasopressin and atrial natriuretic peptide)
would have so little function. As I was flying down to Rio de Janeiro, this
obvious idea occurred to me. Furthermore, I guessed that it was involved in
cardiovascular system function. When I arrived at the office of Jose Antunes
Rodrigues, one of my long-term collaborators, his assistant jumped at the idea
and lo and behold, oxytocin has a physiologically significant role in physiology
of the cardiovascular system to decrease the rate and force of contraction of
the heart and to dilate blood vessels (1997).21 It is present in the heart and
blood vessels and plays a role in the development of the circulation. Oxytocin
can convert stem cells into a sheet of synchronously beating cardiomyocytes
(2002).22 These studies complemented our studies of the role of ANP in the
cardiovascular system and the body fluid homeostasis (1997).23
I felt that there should be both a follicle-stimulating hormone-releasing fac-
tor (FSHRF) and a luteinizing hormone-releasing hormone (LHRH) to control
secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH),
respectively, from the anterior pituitary. What we needed was an assay animal.
Because the gonads are steroid-secreting glands like the adrenal, I hypothe-
sized that LH might cause a depletion of ascorbic acid in the testis or from the
corpus luteum obtained from pseudopregnant rats. I found little if any effect.
That year (1958), the Federation Meeting was held in Philadelphia, a stones
throw away from my office. Amazingly, Al Parlow presented the assay for LH
in young pregnant mares serum (PMS) and human chorionic gonadotropin
(HCG) hormoneinjected female rats. I was amazed and immediately set out
to verify his results. I also injected a 0.1 N HCl extract of rat SMEs, the exact
method used to extract CRF.
There was a dose-related effect of SME extract, in that it depleted ovarian
ascorbic acid, whereas similar extracts from cerebral cortex had no effect. There
was no effect of epinephrine, norepinephrine, serotonin, or substance P. To rule
out LH in the hypothalamic extracts, I had the people at the Hormone Assay
Lab inject PMS followed by HCG either before or after hypophysectomy and
6 ANNALS NEW YORK ACADEMY OF SCIENCES

then send the rats to me by air mail. To my chagrin, hypophysectomy caused

a 23-fold decline in ovarian ascorbic acid and a loss of sensitivity to LH.
I was going to the International Congress of Physiology in Buenos Aires
in 1959 and had planned to give the results. Instead, after meeting Bernardo
Houssay and Luis Leloir, the first a Nobel laureate, and the second as stated
by Houssay to become one (for Chemistry, in 1970), I met Samuel Taleisnik
(director of the Institute in Cordoba), who was to join me in Philadelphia on the
recommendation of Houssay. We took the night train to Cordoba. I asked him
if he could do hypophysectomy in baby rats. He said he could. I showed him the
data and told him that he would be doing hypophysectomy in Philadelphia. He
came to Philadelphia and was working on nine papers in 1 year. We ruled out
LH as a factor in the ascorbic acid depletion and published the first paper on
LH-RF.24 I asked Taleisnik to stay, but he could not because he was director of
the Institute. After he left, I showed that if you inject hypothalamic extract i.v.
into ovariectomized, estrogen-primed rats, blood LH increases. Also, LH-RF
was a peptide according to enzymatic degradation studies.
At this time (1963), Masao Igarashi came from Japan. He brought with him
a new, more sensitive assay for FSH, the mouse uterine weight augmentation
assay. The Steelman-Pohley assay was too insensitive for our studies. I told
him that after a few improvements, his assay would be suitable and we would
discover the FSH-RF. He presented the discovery of FSH-RF at the Endocrine
Meeting in Atlantic City in 1963 and we published in full shortly after in 1964.25
I had no experience and had no luck trying to recruit peptide chemists. Gel
filtration on Shephadex G-25 appeared to be an ideal technique to separate
small peptides. Therefore, I set up a small column of Shephadex G-25 and
collected the fractions overnight in the cold room. The peaks of FSH-RF and
LHRH overlapped completely.
Fortunately, Anand Dhariwal arrived at this point (1965). He set up a tall
skinny Shephadex G-25 column. There was a clear separation of the FSH-RF
eluting just prior to the LHRH. Schally confirmed these results using the FSH
assay, shown to him on the way back to Japan by Igarashi. Now, Schally does
not quote his own work, which was doing severe damage to this field! Not only
did we separate FSH-RF from LHRH but also from other releasing factors.17,26
We believe FSH-RF is lamprey GnRH III. Antibodies against it block the
action of FSH-RF. It is localized to the dorsomedial preoptic area, an area
that controls FSH release and not LH release.27 Mass spectroscopy of puri-
fied FSH-releasing hypothalamic extracts reveals a peptide with its molecu-
lar weight (unpublished data). Biotinylated L-GnRH III binds selectively to
FSH gonadotropes, whereas biotinylated LHRH binds selectively to LH go-
nadotropes.27 FSH-RF mediates separate pulses of FSH.27
It occurred to me that since mating behavior occurred in the rat shortly after
LH was released to induce ovulation, LHRH might induce mating behavior.
I had no experience with mating studies, but Lady Luck came to my aid. I
needed an electrophysiologist for the physiology department. I indicated this
MCCANN et al.: ADVANCES IN NEUROENDOCRINE IMMUNOMODULATION 7

to my friend Barry Cross at poolside at a meeting at the Santa Ines Inn off Sunset
Boulevard, looking on the sea. He said Bob Moss, an American, had shown that
oxytocin had a positive feedback on oxytocin neurons and wanted to come back
to the USA. When I saw his CV, I discovered that he had obtained his degree
for sex behavior studies in rats. When he came, I told him my idea and said
that when the structure of LHRH broke we would test it for mating behavior.
It was not long until the structure was elucidated in Schallys laboratory by
Matsuo. I called Schally and asked if we could have some synthetic LHRH.
He said it already was being provided to people in 40 laboratories around the
world. Fortunately, we got it quite without his help soon. I gave some to Moss
and asked him to try it. Several months went by. Finally I called him in. He
said he was sure it would not work, so he had not tried it. I said I think it will
work, so try a high dose in ovariectomized estradiol-primed rats. If it does not
work, you will be finished with it, but if it works, you will be working with it
for the rest of your life. It worked like a charm,28 and he worked on it until his
premature death.
We had earlier studied the effect of cAMP on hypothalamic pituitary function
and since cGMP had no known functions and was a major cyclic nucleotide,
we wondered whether cGMP might have a role to play. Indeed, we found that
cGMP mediated the action of GnRHs on the pituitary.2,29,30 Now we know that
nitric oxide (NO) stimulates gonadotropin release by cGMP.27
Lad Krulich from Prague had been working with us for some years. We
decided to see whether our hypothalamic extracts would stimulate GH release
from the pituitary. He would inject the SME extract intravenously and then
measure the depletion of GH from the pituitary assayed by widening of the
tibial epiphyseal plate of hypophysectomized rats. He quickly found a hypotha-
lamic GH-RF and then switched to a better assay studying the effect of purified
hypothalamic extracts on GH release from rat pituitaries in vitro. With Dhari-
wal, he purified the growth hormoneinhibitory factor (GIF) by gel filtration
and carboxymethylcellulose ion exchange chromatography (CMC), separating
it from the other releasing factors.31,32
Several years later, Guillemins group purified this peptide and synthesized
it, renaming it somatostatin (1972). In the original version of this manuscript
he didnt mention our work. The referees complained, and it was changed to
say that we had found it in crude extracts. That was incorrect because crude
extracts had a GH-releasing action. Somatostatin is a tetradecapeptide that has
never been shown to have growth inhibitory action. The name is a misnomer
but is still used.
We purified and separated all of these peptides, one from another that we
worked on. Gel filtration on Sephadex G-25 separated more or less according
to molecular weight. The larger peptide is the one eluted earlierthe largest
CRF eluted followed by GRF, GIF, FSH-RF, LHRH, and vasopressin.17 We
discovered a peptidic prolactin-inhibiting factor (PIF), but did not pursue this
further since dopamine turned out to be a powerful PIF.27
8 ANNALS NEW YORK ACADEMY OF SCIENCES

By cutting frozen sections horizontally and frontally we localized the various

releasing factors in the preoptic and hypothalamic areas,33 results later con-
firmed by immunocytochemistry. Martini postulated that pituitary hormones
would have a short-loop negative feedback and that hypothalamic hormones
would have an ultrashort negative feedback. We have found many examples of
these actions,27 which probably act for all transmitters.
In the ovariectomized estrogen-primed female rat, the negative feedback of
estrogen to decrease LHRH release is reversed and becomes positive to increase
LHRH release by NO, which stimulates LH release from the adenohypophysis
but also acts in the brain stem to augment mating behavior by inducing lordosis.
It also activates pelvic neurons, which act by releasing NO in the corpora
cavernosa of the penis to cause penile erection.27 This is but one example of
the ubiquitous role of NO as a synaptic transmitter.
Acetylcholine, dopamine, NE, serotonin, glutamic acid, gamma amino bu-
tyric acid, and NO interact in complex ways to participate in the hypothalamic
control of hormone release and inhibiting hormone release.27
In 1966, we published our first study on neuroimmunomodulation, which
was a comparison of the effect of environmental and preoptic heating with that
of fever induced by purified bacterial lipopolysaccharide (LPS), which caused
an increase in the cortisol release in dogs.34 Twenty years later we determined
the ability of proinflammatory cytokines to induce the pattern of pituitary
hormone release during infection.35 With Valeria Rettori and Les Dees we
showed with immunocytochemistry that there were some neurons containing
IL-1  among the dorsomedial preoptic temperature-sensitive neurons and
that they were dramatically induced by LPS.36 Ma Li Wong showed that IL-1
mRNA could be induced in neurons in the paraventricular and arcuate nucleus
by LPS.37
With Omid Khoram and Jim Lipton we showed that alpha melanocyte-
stimulating hormone (MSH) had an antipyretic effect on LPS-induced fever.
Indeed -MSH is an anti-inflammatory cytokine.38
With Tibor Wenger and Valeria Rettori we studied the hypothalamic action
of 9-tetrahydrocannabinol, the active ingredient of marijuana.39 We believed
that there must be an endogenous cannabinoid with appropriate receptors.
We were pleased to see the discovery of an endogenous ligand, anandamide
(AEA) with two receptors, CB1r and CBb2r. With Valeria Rettori and her
group we have carried out extensive studies indicating that many drugs act by
endocannabinoids activating CB1r or CB2r. For example the action of alcohol
to suppress LHRH release can be blocked by a CB1r blocker.40
With Ramirez, we found that immature rats were excruciatingly sensitive
to the negative feedback of gonadal steroids. After puberty the sensitivity
declined several-fold.41 Some time later Coleman discovered dwarfed obese
sterile mice. The defect was in a single gene named obese (Ob). Only homozy-
gous Ob-Ob mice showed the defects. Coleman parabiosed a thin mouse to an
Ob-Ob mouse, resulting in the fat mouses becoming thin. It was hypothesized
MCCANN et al.: ADVANCES IN NEUROENDOCRINE IMMUNOMODULATION 9

that there was a hormonal defect in the fat mouse. People looked in vain for
the hormone in the blood and in the urine. Nothing happened until Zhang and
Friedmann obtained its structure by positional cloning, making possible the
synthesis of leptin.
With Wen Yu we determined that leptin acted in the basal tuberal region to
release LHRH via NO. It also acted on the anterior pituitary to stimulate LH and
to a lesser extent FSH with the same potency as LHRH. Surprisingly, leptin was
present in adipocytes in large amounts and secretion could be stimulated within
10 min. There was a circadian rhythm of plasma leptin with a peak at 1:30 AM
and a nadir at 7:30 AM in man and rats. Finally, plasma leptin throughout the
24 h paralleled that of NO 2 -NO 3 , suggesting that leptin stimulated NO. Indeed,
leptin stimulated NO 2 -NO 3 and TNF- release from incubated epididymal fat
pads.42 Finally, Julio Licinio demonstrated that Ob-Ob humans failed to go
into puberty, but that it could be induced by leptin, indicating that leptin is the
major inducer of puberty.43
In conclusion, it has been a wonderful ride. I believe scientists can be in-
creasingly productive in the next 50 years if we continue to provide money to
productive people. Money should be provided on the basis of merit and not
age. When productivity declines, money should be reallocated. We must be
open to new ideas. Almost every new idea we had met with a barrier. One must
take time to go over a problem considering all the possibilities for its solution.
This is the way to get new ideas. The most important thing for progress is the
new idea. Without it progress ceases.

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