Neurovascular Hypothesis: Harris (1955) postulated that regulation of pituitary hormone secretion was controlled by “humoral” factors from the hypothalamus that reached the pituitary through the hypophysial portal system. The following observations supported this hypothesis:
1. End organ atrophy followed ectopic grafting of the pituitary.
2. Transection of pituitary stalk (or placement of a barrier) also led to atrophy.
3. Revascularization restores function.
4. Crude hypothalamic extracts could stimulate or inhibit pituitary function.

Structure of the Hypothalamus

 The hypothalamus is the basal part of the diencephalon, below the thalamus. It includes the walls and floor of the third ventricle of the brain, the optic chiasma, tuber cinereum, infundibulum, and mammilary bodies. The tuber cinereum is that portion of the floor of the third ventricle extending down toward the infundibulum. The lowest portion of the tuber cinereum, richly vascularized, is the median eminence. The hypothalamo-hypophysial (or simply the hypophysial) portal system forms the vascular link between the median eminence and the pituitary.

Clusters of neurons (hypothalamic nuclei) are symmetrically located around the third ventricle. The supraoptic (SON) and paraventricular (PVN) nuclei have axonal projections which extend down the infundibulum into the pars nervosa. Together, these axons form a tract known as the supraopticoparaventriculohypophysial tract. This is also known as the magnocellular neurosecretory system. Other hypothalamic nuclei of interest include the ventromedial, arcuate, lateral tuberal and dorsomedial.

The Endocrine Hypothalamus

 The endocrine hypothalamus is composed of those nuerons which release neurohormones (called hypophysiotropic hormones) which, in turn, regulate the activity of the anterior pituitary. These form the parvocellular nuerosecretory system.
The parvocellular system have axons that form the tuberoinfundibular tract and terminate on capillaries in the median eminence. The term hypophysiotrophic area refers to the median basal hypothalamus (MBH) because this area can support grafts of pituitary tissue. The MBH extends from the median eminence upward and forward to include the suprachiasmatic region.

Hypophysiotropic Hormones

1. Thyrotropin releasing hormone (TRH): Tripeptide containing glutamic acid, histidine and proline. In the brain TRH is formed by post-translational clevage of proTRH (multiple copies). TRH stimulates the release of thyroid stimulating hormone (TSH) from the anterior pituitary. Under certain conditions, and in some species, it can also stimulate the release of PRL and GH (STH). The ability of TRH to stimulate TSH release is restricted to homeotherms: even though fish have TRH in their CNS, it lacks TSH stimulating activity. TRH is also present in the amphibian hypothalamus and plasma. Much higher concentrations can be found in the skin of some frogs. TRH may have an older function with TSH stimulating activity a late evolutionary adaptation. It is also found in the larval lamprey, amphioxus and in the nervous system of snails.

2. Somatostatin (SS): Somatotropin (GH) release-inhibiting hormone is another name for this. Growth hormone is released episodically in all species, including man. Pulsitile release depedns upon two hypothalamic hormones: somatostatin and GH-RH. Although first isolated from the hypothalamus, somatostatin has widespread occurrence and effects in gut, brain, and pancreas. SS is a 14 a.a. peptide produced by clevage of the last 14 a.a.’s of prosomatostatin. Prosomatostatin will also inhibit PRL release. Since somatostatin can inhibit TRH induced TSH secretion but does not interfere with TRH induced PRL release, it acts specifically on thyrotrophs, not on lactotrophs. Frog skin is also a source of somatostatin.

3. Gonadotropin-releasing Hormone (Gn-RH): 10 a.a. peptide whose primary structure is similar across species lines. Hypothalamic Gn-RH levels decrease after deafferentiation of the hypothalamus suggesting that higher levels of the brain may regulate its release. Pulsatile release of Gn-RH allows gonadotrophs which release both FSH and LH to respond differently to Gn-RH: low pulsatile release favors FSH release while high pulsatile Gn-RH favors release of LH.

4. Somatocrinin (GH-RH): 44 a.a. peptide which stimulates release of growth hormone. First found in a human pancreatic tumor.

5. Corticotropin-releasing Hormone (CRH): 41 a.a. peptide which is highly conserved. Stimulates release of ACTH.

6. Prolactin-inhibiting Hormone  (PIH): Shown by McLeod to be dopamine. Regulates the tonic inhibition of prolactin release.

7. Prolactin-releasing Hormone: Some evidence suggests this substance may exist and promote prolactin release.

8. Melanocyte Stimulating Hormone- Inhibiting Hormone: Also likely to be dopamine.