62 TH E HYP OT HALAM IC HORMON ES

modulates neurosecretory activity (see, e.g., Figure 1.1). Four examples of neuroendo-
crine transducers are: (1) the magnocellular neurons of the PVN and SON that release
oxytocin/vasopressin; (2) the parvicellular neurons that secrete releasing/inhibiting
hormones into the hypophyseal portal system; (3) the adrenal medulla that responds to
sympathetic stimulation with the release of catecholamines; and (4) the pineal gland that
receives adrenergic input to release melatonin.

4.3 Hypothalamic hypophysiotropic hormones

There are six well-established hypothalamic hypophysiotropic hormones that regulate the
release of the anterior pituitary hormones (Table 4.2). These are also called hypothalamic
releasing and inhibiting hormones. A concise description of the structures and functions of
these hormones can be found elsewhere (Squire et al. 2008).
Hypothalamic hormones are sometimes called factors rather than hormones. There is no
hard and fast rule for this, and this book will employ the term “hormone.”
As shown in Table 4.2, there are five identified hypothalamic peptide hormones
(TRH, CRH, GnRH, GHRH and somatostatin). The major control of prolactin secretion is
not a peptide, but the neurotransmitter dopamine which inhibits prolactin secretion.
A prolactin-releasing hormone may be present in the hypothalamus, although it does
not seem to act in the same way as the other releasing hormones; that is, there is no
evidence that it is released into the pituitary portal system (Onaka et al. 2010).
Nevertheless, it is able to stimulate PRL release from the pituitary and may function
as a versatile releasing hormone since it also stimulates LH, ACTH and vasopressin.
Under some circumstances in the human female, TRH will also induce PRL secretion.
For example, in hypothyroidism, when TSH secretion is low, PRL secretion is increased
because of the enhanced release of TRH from the hypothalamus. The regulation of
α-MSH secretion from the intermediate lobe of the pituitary gland may also involve
a neurotransmitter, rather than a releasing hormone stimulation, mediated secretion
(see section 4.3.6, below). Hypothalamic releasing/inhibiting hormones are secreted
from neuroendocrine cells in a number of different hypothalamic nuclei (Table 4.3).

Table 4.2 Hypothalamic hypophysiotropic hormones

Releasing hormones
Thyrotropin-releasing hormone (TRH) = TSH-RH
Corticotropin-releasing hormone (CRH)
Gonadotropin-releasing hormone (GnRH) = LHRH. Thought to release LH and FSH and therefore GnRH
is a more accurate abbreviation.
Paired releasing and inhibiting hormones
Growth hormone releasing hormone (GHRH)
Growth hormone release inhibiting hormone (GH-RIH) = Somatostatin
Prolactin releasing factor (PRF)
Prolactin releasing inhibiting factor (PIF) (probably dopamine)
Melanocyte-stimulating hormone–releasing factor (MSH-RF) (may be CRH and serotonin)
Melanocyte-stimulating hormone–release-inhibiting factor (MSH-RIF) (probably dopamine and GABA)
 4 . 3 H Y P O T H AL A M I C H Y P O P H Y S I O T R O P I C H O R M O N E S 63

Table 4.3 Location of the hypothalamic neurosecretory cells which

synthesize the hypothalamic hormones
The magnocellular neurosecretory cells that synthesize the hormones released from the posterior pituitary
Oxytocin Paraventricular (PVN) and Supraoptic (SON) nuclei
Vasopressin (ADH) Paraventricular (PVN) and Supraoptic (SON) nuclei

The parvicellular neurosecretory cells that synthesize the hypothalamic hypophyseal hormones
TRH (TSH-RH) Primarily in the PVN
CRH Primarily in the PVN
GnRH (LH-RH) POA-AH in rodents

ARC (in humans and monkeys)

FSH-RH (?) Most probably GnRH in ARC or POA
GHRH Primarily in the ARC
Somatostatin (SOM) Periventricular region of AH
PRH Could be TRH or PrRP in the PVN/DMN
PIF (dopamine) ARC (tuberoinfundibular dopaminergic neurons)
MSH-RH Could be CRH or serotonin in PVN or ARC?
MSH-RIH (dopamine or GABA) ARC (tuberofundibular dopaminergic neurons)

Abbreviations are as in Tables 4.1 and 4.2. FSH-RH, follicle-stimulating hormone-releasing hormone; PrRP,
prolactin-releasing peptide.

The secretion of a single hypothalamic hormone may be regulated through a number of

different neural pathways (see Chapter 6). A concise outline of the hypothalamic
hormones and their sites of secretion can be found elsewhere (Squire et al. 2008;
Boron and Boulpaep 2005).

4.3.1 Thyrotropin releasing hormone (TRH)

TRH is also known as TRF (releasing factor) or thyroid-stimulating hormone-releasing
hormone (TSH-RH). TRH is released from TRH neuron nerve terminals in the median
eminence into the pituitary portal system from which it stimulates the thyrotroph cells of
the anterior pituitary to produce and release TSH. TRH also acts as a neuromodulator in the
brain (see section 12.7.3). TRH is synthesized primarily in the paraventricular nucleus
(PVN). Like most hypothalamic releasing/inhibiting hormones, TRH secretion from
hypothalamic neurons is regulated by inhibitory neurotransmitters such as dopamine,
and by opiates such as morphine, as well as by cold and food intake (see Figure 6.6).
Another important regulator of TRH release is CART (cocaine- and amphetamine-regulated
transcript), a brain peptide implicated in food intake (Fekete and Lechan 2006). In addition,
there are environmental factors which stimulate the release of TRH, including acute cold
exposure and when babies suckle at their mother’s breast (see Figure 8.3; Sanchez et al.
2001). Sensitive molecular biology techniques have also localized TRH gene expression in
cells in the suprachiasmatic nuclei (SCN; Fliers et al. 1998), suggesting that TRH may be
important in the control of circadian rhythms, distinct from its involvement in TSH
secretion from the pituitary (see Chapter 12).
64 TH E HYP OT HALAM IC HORMON ES

4.3.2 Corticotropin-releasing hormone (CRH)

CRH stimulates the release of ACTH and β-endorphin from the corticotroph cells of the
anterior pituitary. CRH is synthesized primarily in PVN neurons and is released from nerve
terminals in the median eminence into the portal circulation in response to pain and stress.
CRH secretion from nerve terminals is regulated by the negative feedback of glucocorti-
coids as well as a number of neurotransmitters and neuropeptides. β-endorphin stimulates
CRH release, whereas GABA is inhibitory (Yamauchi et al. 1997; Kovacs et al. 2004). CRH
secretion also shows a circadian rhythm, and in humans there is an increase in CRH/ACTH/
cortisol release in the morning hours (see Figure 6.5). The CRH peptide is also synthesized
and released elsewhere in the brain, where it acts as a neuromodulator in addition to its role
in the regulation of ACTH secretion (see Chapter 12). Thus, CRH gene expression is
detectable in a wide variety of brain sites, including the cerebral cortex, amygdala and
lateral hypothalamus, in addition to the PVN (Alon et al. 2009).

4.3.3 Gonadotropin-releasing hormone (GnRH)

It is generally accepted that release of both gonadotropins, FSH and LH, from the gonado-
troph cells of the anterior pituitary is regulated by a single hypothalamic-releasing hor-
mone, GnRH. In contrast, there is some evidence that there may be two different
gonadotropin-releasing hormones: LHRH and FSH-RH. It is beyond the scope of this
book to fully discuss this issue, given that a single releasing hormone, GnRH, can account
for all the release of both LH and FSH. Nonetheless, for those interested in this topic, the
views of the late S. M. McCann may be compelling (McCann et al. 2001).

Location of GnRH neurons: regulation of GnRH release

Rodent and monkey brains have been carefully mapped to identify the neuroanatomical
location of GnRH-positive neuron cell bodies (Spergel et al. 2001; Standish et al. 1987).
Unlike the neurons responsible for the synthesis of vasopressin and oxytocin, which are
tightly grouped together in discrete nuclei (i.e. SON and PVN), GnRH neurons are relatively
few in number (approx. 600 to 800 per brain) and are scattered through several brain areas.
Herbison and colleagues (2008) have estimated that as few as 80 GnRH neurons are
required for normal fertility in males, and only 200 for reproductive function in females,
indicating a high level of redundancy within the reproductive system. In the mouse, GnRH
cell bodies occur in a continuum from the olfactory bulbs at the front of the brain to the
preoptic area (POA) of the hypothalamus. It is the POA neurons that send axons to the
median eminence where GnRH is released into the portal system (Spergel et al. 2001).
In monkey and human brains, there are some GnRH cell bodies in the POA, but the
primary neurons that secrete GnRH into the portal system are found in the arcuate nucleus
(Standish et al. 1987).
GnRH release is regulated by many different neurotransmitters and neuropeptides, many
of which interact with each other and with feedback from gonadal steroid hormones such as
estradiol (female) or testosterone (male), to modulate GnRH release (Figure 4.3). This
multiple control system enables a wide variety of external and internal stimuli to influence
GnRH release. For example, GnRH secretion is modulated by neurons projecting from the
suprachiasmatic nucleus, which regulates circadian rhythms; by neurons from the PVN,
which process visceral afferent input and may activate stress-induced changes in GnRH
 4 . 3 H Y P O T H AL A M I C H Y P O P H Y S I O T R O P I C H O R M O N E S 65

Figure 4.3 Control of GnRH secretion

Schematic diagram highlighting the role of
GnRH neurons in the control of mammalian repro-
duction. Pink arrows (A) indicate the positive feedback
effects of serum estradiol and progesterone on GnRH,
LH and FSH release in the proestrous LH surge in
female rodents (see also Figure 4.6). Note that this
type of steroid feedback is normally negative (e.g. see
Figure 4.10). Blue arrows (B) illustrate the negative
feedback effects of testosterone on GnRH, LH and FSH
release. Note that GnRH neurons are subjected to
many neurochemical inputs (C), both stimulatory and
inhibitory. A few examples are shown here. GnRH
neurons are also sensitive to light, stress, mating, etc.
(D).
Abbreviations: CRH, corticotropin-releasing hor-
mone; FSH, follicle-stimulating hormone; GABA, γ-
aminobutyric acid; Glu, glutamate; GnRH,
gonadotropin-releasing hormone; LH, luteinizing hor-
mone; NE, norepinephrine.

release; and by neural input from the olfactory and vomeronasal pathways, through which
pheromones can influence GnRH release. Another neuropeptide, kisspeptin, produced by
the kiss1 gene, is an important regulator of GnRH secretion (see Chapter 6).

Extra-hypothalamic GnRH release

The GnRH peptide, and its receptor, has been localized to many brain regions in
addition to those implicated in the hypothalamic-pituitary system (Skinner et al. 2009;
66 TH E HYP OT HALAM IC HORMON ES

Albertson et al. 2008). As occurs in the CRH system (section 4.3.2), GnRH neurons release
GnRH in other brain areas, including the hippocampus, amygdala, olfactory system,
cerebellum and spinal cord, where it has neuropeptide/neuromodulator actions and
may play a role in sexual behavior, motor control and Alzheimer’s Disease (see
Chapter 12).
It is possible that release of GnRH in non-hypothalamic regions occurs simultaneously
with the release of GnRH into the portal system to facilitate female sexual receptivity
(Pfaff et al. 1987; Sakuma 2002). Also, the high concentration of GnRH associated with the
olfactory pathways could explain why pheromones have such potent “primer effects” on
the neuroendocrine system. Further details on the functions of GnRH as a neuromodulator
are discussed in Chapter 12. That GnRH may be a particularly versatile neuropeptide is also
emphasized by reports of effects outside the brain (e.g. in heart, kidney, lymphocytes,
adrenal and skin) (Skinner et al. 2009).

Tonic and pulsatile secretion of GnRH and generation

of the ovulatory LH/FSH surge
As described above, GnRH is synthesized in neurons of the preoptic area in rodents,
whereas in primates and humans the corresponding cell bodies are primarily located in
the mediobasal hypothalamus (MBH) (Plant 2008). These neurosecretory cells extend
their axons to the median eminence where they release GnRH into the pituitary portal
system to regulate the “tonic,” or basal, secretion of LH and FSH from the anterior
pituitary. However, GnRH neurons release GnRH in an episodic, or pulsatile, fashion that
results in a corresponding pulsatile secretion of LH and FSH from the anterior pituitary.
Figure 4.4 illustrates the pattern of basal secretion of LH in an adult human male
with normal levels of testosterone. The neurosecretory neurons that release GnRH fire
in discrete bursts every 1.5 to 2 hours to secrete GnRH and stimulate the anterior
pituitary to release LH in pulses. This pattern of LH secretion is also seen in human
females and in rodents, sheep and monkeys of both sexes, but the absence of LH pulses

Figure 4.4 Pulsatile secretion

of luteinizing hormone (LH) in a
normal male
Blood levels of LH (mIU per ml)
measured during a 24-hour per-
iod in a 36-year-old adult male
with normal levels of
testosterone.
Key: *Indicates significant
pulses above the background.
Pulses occur approximately
every 2 to 3 hours. Reproduced
with permission and redrawn
(Besser and Thorner 2002).