Developmental causes of hypopituitarism are present before or around birth. They range from damage acquired in the newborn period to inherited disorders that impair how the pituitary forms and how its cells differentiate (become specialised hormone-producing cells).
Pituitary damage in the newborn can be acquired in the first days of life, through breech delivery, cranial haemorrhage and asphyxia. The main cause of hypopituitarism in newborns, however, is inherited disorders, and these fall into two broad kinds.
Disorders of the whole gland
The first kind affects the whole gland and its position. The anterior pituitary is built by cells that migrate from Rathke’s pouch, and HESX1 is one of the earliest genes in that process. A HESX1 mutation can produce a triad of optic nerve hypoplasia, midline neurological abnormalities such as agenesis of the corpus callosum, and pituitary hypoplasia, with panhypopituitarism (deficiency of all the pituitary hormones) as the endocrine consequence. An aplastic, hypoplastic or ectopic pituitary gland belongs to the same group.
Disorders of individual hormone lineages
The second kind affects only some of the hormone-producing lineages, and the phenotype depends on which transcription factor (a protein that switches on the genes a cell lineage needs) is lost. The lineages are named for their hormones: somatotrophs make GH, lactotrophs prolactin, thyrotrophs TSH and gonadotrophs LH and FSH.
- Pit-1 (POU1F1) is needed in somatotrophs, lactotrophs and thyrotrophs, so its mutation causes combined deficiency of GH, prolactin and TSH; growth failure appears in the first years of life, while the TSH deficiency becomes evident later.
- PROP-1 is required for the activity of the Pit-1 product, so its mutation causes combined deficiency of GH, prolactin, TSH and the gonadotropins, with growth retardation and delayed puberty. A recessive PROP1 mutation is the most frequent genetic cause of combined pituitary hormone deficiency and is more common than a POU1F1 mutation.
- TPIT (TBX19) is needed for the POMC lineage, so its mutation causes isolated ACTH deficiency.
- NR5A1 impairs the development of gonadotropic cells together with the adrenal and gonadal development that depends on the same factor.
Inherited pituitary dysfunction therefore ranges from isolated hormone deficiency, through combined pituitary hormone deficiency (CPHD), to diabetes insipidus, and the age at which each deficiency appears differs between genes. Everything so far concerns the developing pituitary itself; the hypothalamus above it, which controls the anterior lobe, can also be the site of the fault.