States of Pituitary Hypofunction


Hypopituitarism is defined as the deficiency of one or more of the anterior pituitary hormones: growth hormone, thyroid stimulating hormone, lutenizing hormone, follicle stimulating hormone, prolactin, and adrenocorticotrophic hormone. The deficiency of posterior pituitary hormones, specifically antidiuretic hormone, may also be present. Hypopituitarism is often a sequela of a previous neurological insult; however, many cases are considered idiopathic.

The development of the pituitary gland has been shown to be a balanced and orchestrated sequence of events dependent on the temporal and spatial appearance of multiple developmental factors that will eventually produce specific pituitary cell types. A disruption in this cascade that leads to the decreased expression of one or more of these factors results in idiopathic hypopituitarism. The identification of proteins responsible for the development of the anterior pituitary gland and their genetic alterations has provided novel insights into the mechanisms responsible for hypopituitarism. Murine models, as well as patients with hypopituitarism due to specific mutations in these developmental proteins, have assisted in the elucidation of mechanisms leading to decreased pituitary gene expression and hormone production. Furthermore, the development of more sophisticated and efficient methods for genome sequencing offers greater promise in delineating the pathogenic mechanisms in patients with idiopathic hypopituitarism.


pituitary development, hypopituitarism, combined pituitary hormone deficiency



Hypopituitarism is a condition that presents clinically with one or more deficiencies of hormones secreted from the adenohypophysis, neurohypophysis, or both. The annual incidence rate has been estimated to be 4.2 cases per 100,000 of the population, along with a prevalence of 45.5 per 100,000 in a 2001 population study from Spain. The etiology of hypopituitarism can be attributed to several causes including head injury, neurosurgical sequelae, infiltrative disorders, and cranial radiotherapy; however, for many patients, in particular for those with congenital or idiopathic hypopituitarism, the etiology for hormone deficiency cannot be identified. There appear to be limited data on the true prevalence of idiopathic hypopituitarism. The advancements in understanding hypothalamic-pituitary development using animal models have helped to identify a cascade of several developmental factors necessary for proper pituitary function. Mutations in these factors found in both animal models and affected patients have been identified and linked to the development of hypopituitarism.

Pituitary hormone deficiency may present in a wide variety of ways; for example, it may manifest acutely in neonates as an adrenal crisis or insidiously in children with a poor growth velocity. The clinical presentation will depend on the deficient hormone(s) and may be relatively nonspecific; symptoms may include increased lethargy, cold intolerance, poor weight gain, decreased appetite, or abdominal pain. An evaluation of pituitary function in the newborn period typically takes place in the setting of persistent hypoglycemia or electrolyte imbalance. Although the phenotype of idiopathic hypopituitarism is varied, infants found to have midline defects and male infants with micropenis should be evaluated for possible pituitary hormone deficiency. In children and adolescents, poor growth or delayed puberty is often an indicator for care providers to evaluate the pituitary for possible deficiencies. It is prudent to recognize that the evaluation of some patients may initially reveal a single pituitary hormone deficiency; however, follow-up evaluations are required, as additional pituitary hormone deficiencies may develop over time.

Genetic pathophysiology

The development of the pituitary occurs early during embryogenesis by the coordinated spatial and temporal expression of signaling molecules and transcription factors. Initially, the primordial Rathke’s pouch develops by the thickening and invagination of the oral ectoderm that comes into contact with the ventral diencephalon. Proliferation of the cells through expression of various signaling factors drives oral ectoderm closure and forms a detached rudimentary gland. The expression of Sonic hedgehog (Shh) from the oral ectoderm and downstream effectors, such as those in the Gli family, are important in orchestrating the proliferation and formation of the gland. In addition, the Wnt family of signaling molecules and bone morphogenetic protein 4 (BMP4), among others, also may have roles in guiding proliferation and specification of pituitary cell types.

The mature anterior pituitary gland ultimately contains five cell types regulated by trophic hormones produced by the hypothalamus, as well as positive and negative feedback from peripherally secreted hormones. The cell types and hormones they secrete include: somatotrophs, growth hormone (GH); thyrotrophs, thyroid-stimulating hormone (TSH), lactotrophs, prolactin (PRL), gonadotrophs, lutenizing hormone (LH), and follicle-stimulating hormone (FSH), and corticotrophs, adrenocorticotrophic hormone (ACTH). The development of these pituitary cell types is regulated by the expression of transcription factors including Hesx homeobox 1, LIM homeobox protein 3 (Lhx3), paired-like homeodomain 1 (Pitx1), and POU1F1, among others. These factors play significant roles in the coordinated temporal and spatial development of specific pituitary cell types ( Fig. 6.1 ). Since several of the pituitary cell types require common factors for their development, the early disruption in the cascade of events may ultimately affect several cell types. This may lead to loss of pituitary gene expression and secretion as well as abnormal structural development of the pituitary gland.

Figure 6.1

An overview of major transcription and signaling factors involved in pituitary development.

Several signaling factors are expressed to regulate the development of the primordial pituitary associated with contact of the ventral diencephalon (neural epithelium) and oral ectoderm. The subsequent expression of transcription factors occurs in an orchestrated temporal and spatial sequence that leads to the development of Rathke’s pouch and ultimately the mature anterior pituitary, which will contain the five mature pituitary cell types. The figure illustrates the major transcription factors involved in the cascade leading to the mature pituitary. The arrows represent the relative temporal appearance of these factors over the course of development as well as the attenuation of some of these factors (depicted as dashed lines), which have been shown to be important for appropriate development. The disruption of any of these factors has been suggested as a potential etiology for hypopituitarism.

Although a large part of our knowledge regarding pituitary organogenesis is based on nonhuman studies, careful clinical investigation of patients with hypopituitarism has yielded important insights into pituitary development. For example, murine studies of the Ames dwarf mouse, which bears a mutation in the PROP1 gene, revealed a hypocellular anterior pituitary generally lacking somatotrophs, lactotrophs, and thyrotrophs. These findings led to studies in patients with a similar phenotype and the identification of human mutations in the PROP1 gene. Two other naturally occurring inbred murine models, the Jackson and Snell dwarf mice, illustrated the importance of POU1F1 (formerly Pit1) in normal pituitary development. Mutations in the POU1F1 gene were subsequently identified in patients and revealed the importance of heterozygous point mutations encoding proteins acting as dominant negative inhibitors of pituitary gene expression.

Over the last several decades, several research laboratories have shown that mutations in specific transcription factors can disrupt the balanced orchestration of pituitary development and ultimately the expression and function of the five pituitary cell types. This progress has resulted in the genetic characterization of hypopituitarism in many patients whose condition had been labeled as idiopathic or “congenital.” Mutations in several of these factors leads to multiple pituitary hormone deficiencies, whereas mutations in others may only lead to loss of a single hormone. Table 6.1 contains an outline of several genetic factors that have importance in anterior pituitary development. For each factor, the following are listed: a brief description of its function, the pituitary cell types affected by its disruption, a brief summary of the clinical features noted in patients with reported mutations, and the mode of inheritance. Several of these factors are associated with syndromes or are affected as a result of chromosomal abnormalities; thus, hypopituitarism may be one of the clues suggesting a genetic etiology. Finally, these factors are crucial to pituitary development, but may also be important for pituitary cell survival; therefore, the initial clinical phenotype in some patients may progress and additional pituitary hormone deficiencies can develop over time.

Table 6.1

II Genetic Pathophysiology: Developmental Factors Associated with Pituitary Development

Factor Gene function Affected cell types Clinical phenotype Mode of inheritance
One of more pituitary hormone deficiencies

  • Paired-like homeobox gene

  • Early marker for pituitary primordium found in oral ectoderm of Rathke’s pouch

  • Requires Lhx3 for maintenance and Propi for repression

  • Involved in development of forebrain, hypothalamus, optic nerve, and posterior pituitary

Somatotrophs, thyrotrophs, gonadotrophs, corticotrophs, posterior pituitary may also be affected

  • Isolated GH deficiency or multiple hormone deficiency

  • Puberty may be unaffected or delayed

  • Associated with septooptic dysplasia

  • Possibly associated with Kallman syndrome

  • Abnormal MRI findings: anterior pituitary hypoplasia, ectopic posterior pituitary, midline forebrain abnormalities

Lhx3 (Lim3, P-LIM)

  • Member of LIM-homeodomain (LIM-HD) family of gene regulatory proteins

  • Required for survival/proliferation of Rathke’s pouch cells and spinal cord motor neurons

  • Binds and activates α -GSU promoter

  • Acts with Pit-1 to activate TSH-β gene promoter

  • Three isoforms: Lhx3a, Lhx3b, M2-Lhx3

Somatrotrophs, lactotrophs, thyrotrophs, gonadotrophs, possibly corticotrophs

  • Vertebral and skeletal malformations, including rigid cervical spine causing limited neck rotation

  • Hypoplastic anterior/intermediate pituitary lobe

  • Possible sensorineural hearing loss and/or intellectual disability


  • A LIM protein with close resemblance to Lhx3 important for proliferation and differentiation of cell lineages

  • May have overlapping function with PROP1 and POU1F1

  • Expressed during development of hindbrain, cerebral cortex, Rathke’s pouch, and spinal cord

Somatrotrophs, lactotrophs, thyrotrophs, gonadotrophs, corticotrophs

  • Combined pituitary hormone deficiencies with predominant GH deficiency

  • Severe anterior pituitary hypoplasia, ectopic neurohypophysis

  • Cerebellar abnormalities

Six6 ( Optx2 )

  • Member of the SIX sine oculis family of homeobox genes

  • Expressed early in hypothalamus, later in Rathke’s pouch, neural retina and optic chiasma

Somatotrophs, gonadotrophs

  • Microphthalmia or anophthalmia

  • Pituitary hypoplasia

  • Associated with deletion at chromosome 14q22-23

Pitx2 (RIEG1)

  • Bicoid-related homeobox gene expressed early in the nascent Rathke’s pouch

  • Importance in maintaining expression of Hesx1 and Prop1

Somatrotrophs, lactotrophs, thyrotrophs, corticotrophs, reduced expression of gonadotrophs

  • Associated with Rieger syndrome:

    • Anterior chamber eye anomalies

    • Craniofacial dysmorphism

    • Cardiovascular anomalies

    • Dental hypoplasia

    • Protuberant umbilicus

    • Mental retardation

    • Pituitary dysfunction

Prop1 (prophet of Pit 1)

  • Paired-like homeodomain transcription factor required for Pit1 expression

  • Blocks expression of Hesx1

  • Important for FSHβ expression, possibly even into adulthood

Somatrotrophs, lactotrophs, thyrotrophs, gonadotrophs, corticotrophs (delayed)

  • Most common genetic cause of combined pituitary hormone deficiency (GH, TSH, PRL, and late onset ACTH reported)

  • Gonadotropin insufficiency or normal puberty with later onset of deficiency

  • Several mutations noted in nonconsanguineous families

  • Enlarged or hypoplastic anterior pituitary

POU1F1 (Pit1)

  • A member of the POU transcription factor family

  • Important for activation of GH1, PRL, and TSHIβ genes

Somatotrophs, lactotrophs, thyrotrophs

  • GH deficiency along with PRL and TSH dysregulation (TSH secretion may initially be normal)

  • Anterior pituitary hypoplasia


  • Bicoid-type homeodomain gene required for forebrain, ear, nose, and eye development

  • Antagonizes Fgf8 and Shh expression

  • May have importance in activation of Hesx1

Somatotrophs, thyrotrophs, corticotrophs, gonadotrophs

  • Severe ocular malformations including anophthalmia

  • Developmental delay

  • Combined pituitary hormone deficiencies

  • Anterior pituitary hypoplasia with ectopic posterior pituitary


  • Member of SOXB1 subfamily as Sox1 and Sox3 expressed early in development

Somatotrophs, gonadotrophs, and in animal models thyrotrophs

  • Hypogonadotrophic hypogonadism

  • Anterior pituitary hypoplasia

  • Bilateral anophthalmia/microphthalmia

  • Mid-brain defects including corpus callosum and hippocampus

  • Sensorineural hearing loss

  • Genital abnormalities

  • Esophageal atresia and learning difficulty

  • Associated with hypothalamic and pituitary tumors

De novo

  • Member of SOX (SRY-related high mobility group (HMG) box)

  • Developmental factor expressed in developing infundibulum and hypothalamus

Somatrotrophs and/or possible deficiency in gonadotrophs and thyrotrophs

  • Duplications of Xq26-27 in affected males (female carriers unaffected)

  • Variable mental retardation

  • Hypopituitarism with abnormal MRI:

    • Anterior pituitary hypoplasia

    • Infundibular hypoplasia

    • Ectopic/undescended posterior pituitary

    • Abnormal corpus callosum

  • Murine studies suggest SOX3 dosage critical for normal pituitary development

Isolated hormone deficiency

  • Member of the Gli gene family; transcription factors that mediate Sonic hedgehog signaling

Somatotrophs (possible association with CPHD)

  • Heterozygous loss-of-function mutations in patients with holoprosencephaly

  • Variable penetrance

  • Pituitary dysfunction accompanied by craniofacial abnormalities


  • Encodes GHRH receptor


  • Short stature

  • Anterior pituitary hypoplasia


  • Encodes GH peptide

  • Several heterozygous mutations shown to affect GH secretion or function

  • Mutations reported leading to aberrant splicing


  • Short stature

  • Abnormal fades

  • Associated with Kowarski syndrome (bioinactive GH)

AR, AD, or X-linked

  • Encodes protein anosmin-1

  • Important in migration of both olfactory and GnRH neurons


  • Failed or arrested puberty

  • Anosmia

  • Renal abnormalities

  • Mutations implicated in hearing deficit

  • Associated with CPHD

FGFR-1 (KAL-2)

  • Encodes fibroblast growth factor receptor

  • May interact with anosmin-1 (encoded by KAL1)


  • Failed or arrested puberty; typically less severe impairment of gonadotropin secretion vs. KAL-1 mutations

  • Associated with normosic hypogonadism

  • Associated with Pfeiffer syndrome (OMIM #101600)

  • Associated with Hartsfield syndrome (triad: holoprosencephaly, ectrodactyly, and cleft/lip palate; OMIM #615465)

  • Associated with CPHD


  • Critical role in formation of anterior/midline border

  • Regulates development of GnRH neurons

  • Animal studies demonstrate important role in midfacial integration and optic capsular development


  • Hypogonadotropic hypogonadism

  • Associated with CPHD


  • Encodes G protein-coupled prokineticin receptor-2

  • Ligand is prokinectin-2


  • Hypogonadotropic hypogonadism and anosmia (Kallman syndrome)

  • Majority of patients have heterozygote mutations

  • Associated with CPHD


  • Encodes GnRH receptor in gonadotroph


  • Associated with broad range of reproductive phenotypes

  • May account for large proportion of familial and sporadic cases

  • No defects in olfaction


  • Member of T-box family of transcription factors that contain a homologous DNA binding domain (the T-box)

  • Specific role in differentiation of POMC lineage

  • Several types of identified mutations leading to loss of function


  • Neonatal isolated ACTH deficiency


  • Encodes for peptide proopiomelanocortin (POMC)

  • Functional role in skin pigmentation

  • Control of adrenal growth

  • Regulation of obesity and energy balance


  • POMC deficiency syndrome:

    • Severe early-onset obesity

    • Adrenal insufficiency

    • Red hair


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Sep 7, 2019 | Posted by in ENDOCRINOLOGY | Comments Off on States of Pituitary Hypofunction
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