Understanding the differentiation of the five endocrine cells of the pars distalis from a single precursor cell has seen significant progress. Soon after the formation of Rathke's pouch, which is the embryological precursor of the adenohypophysis, the homeodomain transcription factor PROP-1 is expressed. PROP-1 promotes the cell lineages of somatotropes, lactotropes, thyrotropes, and gonadotropes. In humans, rare mutations in the PROP1 gene lead to a type of combined pituitary hormone deficiency. Individuals with these mutations display dwarfism due to a lack of growth hormone, cognitive deficits due to hypothyroidism, and infertility due to a lack of gonadotropins. Another pituitary-specific homeodomain transcription factor called POU1F1, also known as Pit-1, is required for the differentiation of thyrotropes, somatotropes, and lactotropes. It directly stimulates the transcription and expression of TSH, GH, and prolactin. Affected individuals with POU1F1 mutations also have dwarfism and intellectual disability. The nuclear hormone receptor-related transcription factor steroidogenic factor-1 (SF-1) was originally identified in the adrenal cortex and gonads as a regulator of steroidogenic enzyme gene expression. SF-1 is also expressed in GnRH neurons in the hypothalamus and in pituitary gonadotropes, where it regulates the transcription of LH and FSH. Mutations in the SF1 gene disrupt adrenal and gonadal function, including the loss of gonadotropes in the pituitary gland. TPIT is a transcription factor involved in the differentiation of corticotropes. Acting with other transcription factors, TPIT promotes the differentiation of corticotropes and the expression of the POMC gene. Mutations in the human TPIT gene result in isolated ACTH deficiency, leading to a form of secondary adrenal insufficiency that requires lifelong replacement with glucocorticoids. The hypothalamic regulation of anterior pituitary function is neurohormonal. The hypophysiotropic region of the hypothalamus contains small cell bodies that project axons to the median eminence. These cells are distinct from the magnocellular neurons that project to the pars nervosa. Releasing hormones are secreted by parvocellular neurons from their axonal termini at the median eminence. The releasing hormones then enter a primary plexus of fenestrated capillaries and are conveyed to a second capillary plexus in the pars distalis by the hypothalamohypophyseal portal vessels. At the secondary capillary plexus, the releasing hormones diffuse out of the vasculature and bind to their cognate receptors on specific cell types within the pars distalis. The connection between the hypothalamus and pituitary, known as the pituitary stalk, can be disrupted by physical trauma, surgery, or hypothalamic disease. Damage to the stalk and subsequent functional isolation of the anterior pituitary result in a decline in all anterior pituitary tropic hormones except prolactin.
Significantprogresshasbeenmadeinunderstandingthedifferentiationofthefiveendocrinecellsoftheparsdistalisfromoneprecursorcell.ThehomeodomaintranscriptionfactorPROP-1 isexpressedsoonafterRathke’spouch(embryologicalprecursoroftheadenohypophysis)formsandpromotesthecelllineagesofsomatotropes,lactotropes,thyrotropes,andgonadotropes.Inhumans,raremutationsinthePROP1 generesultinatypeofcombined pituitary hormone deficiency. TheseindividualsdisplaydwarfismduetolackofGH,cognitivedeficitssecondarytohypothyroidism,andinfertilityduetolackofgonadotropins.Asubsequentlyexpressedpituitary-specifichomeodomaintranscriptionfactorcalledPOU1F1 (formerlyknownasPit-1)isrequiredfordifferentiationofthyrotropes,somatotropes,andlactotropes,anditdirectlystimulatestranscriptionandexpressionofTSH,GH,andprolactin.AffectedindividualswithPOU1F1 mutationshavedwarfismandintellectualdisability.Thenuclearhormonereceptor–relatedtranscriptionfactorsteroidogenic factor-1 (SF-1) wasoriginallyidentifiedintheadrenalcortexandgonadsasaregulatorofsteroidogenicenzymegeneexpression.SF-1isalsoexpressedinGnRHneuronsinthehypothalamusandinpituitarygonadotropes,whereitregulatestranscriptionofLHandFSH.MutationsintheSF1 genedisruptadrenalandgonadalfunction,includinglossofgonadotropesinthepituitarygland.TPIT isatranscriptionfactorinvolvedinthedifferentiationofcorticotropes.TPIT,actingwithothertranscriptionfactors,promotesdifferentiationofcorticotropesandexpressionofthePOMC gene(seeCorticotropessection).MutationsinthehumanTPIT generesultinisolated ACTH deficiency. Thisresultsinaformofsecondary adrenal insufficiency thatrequireslifelongreplacementwithglucocorticoids(see
The hypothalamic regulation of anterior pituitary function is neurohormonal. An area of the hypothalamus collectively referred to as the hypophysiotropic (i.e., stimulatory to the hypophysis) region contains nuclei composed of small, or parvocellular, cell bodies that project axons to the
Transcription, excision, splicing •Fig. 41.4 Synthesisandprocessingofpreprovasopressinorpreprooxytocin.
median eminence. They are distinct from the magnocellular neurons of the PVN and SON that project to the pars nervosa. Parvocellular neurons secrete releasing hormones from their axonal termini at the median eminence (Fig.
41.7 ). The releasing hormones enter a primary plexus of fenestrated capillaries and are then conveyed to a second capillary plexus located in the pars distalis by the hypothalamohypophyseal portal vessels (a portal vessel is defined as a vessel that begins and ends in capillaries without going through the heart). At the secondary capillary plexus, the releasing hormones diffuse out of the vasculature and bind to their cognate receptors on specific cell types within the pars distalis. The neurovascular link (i.e., pituitary stalk) between the hypothalamus and pituitary is somewhat fragile and can be disrupted by physical trauma, surgery, or hypothalamic disease. Damage to the stalk and subsequent functional isolation of the anterior pituitary result in a decline in all anterior pituitary tropic hormones except prolactin (discussed later).