Recent work has demonstrated that the brain has the capacity to synthe
size impressive amounts of the gases nitric oxide (NO) and carbon mono
xide (GO). There is growing evidence that these gaseous molecules func
tion as novel neural messengers in the brain. This article reviews the
pertinent literature concerning the putative role of NO and CO as cri
tical neurotransmitters and biological mediators of the neuroendocrine
axis. Abundant evidence is presented which suggests that NO has an im
portant role in the control of reproduction due to its ability to cont
rol GnRH secretion from the hypothalamus. NO potently stimulates GnRH
secretion and also appears to mediate the action of one of the major t
ransmitters controlling GnRH secretion, glutamate. Evidence is present
ed which suggests that NO stimulates GnRH release due to its ability t
o modulate the heme-containing enzyme, guanylate cyclase, which leads
to enhanced production of the second messenger molecule, cGMP. A physi
ological role for NO in the preovulatory LH surge was also evidenced b
y findings that inhibitors and antisense oligonucleotides to nitric ox
ide synthase (NOS) attenuate the steroid-induced and preovulatory LH s
urge. CO may also play a role in stimulating GnRH secretion as heme mo
lecules stimulate GnRH release in vitro, an effect which requires heme
oxygenase activity and is blocked by the gaseous scavenger molecule,
hemoglobin. Evidence is also reviewed which suggests that NO acts to r
est rain the hypothalamic-pituitary-adrenal (HPA) axis, as it inhibits
HPA stimulation by various stimulants such as interleukin-1 beta, vas
opressin, and inflammation. This effect fits a proinflammatory role of
NO as it leads to suppression of the release of the anti-inflammatory
corticosteroids from the adrenal. Although not as intensely studied a
s NO, CO has been shown to suppress stimulated CRH release and may als
o function to restrain the HPA axis. Evidence implicating NO in the co
ntrol of prolactin and growth hormone secretion is also reviewed and d
iscussed, as is the possible role of NO acting directly at the anterio
r pituitary. Taken as a whole, the current data suggest that the diffu
sible gases, NO and CO, act as novel transmitters in the neuroendocrin
e axis and mediate a variety of important neuroendocrine functions.