also called NR5A1) is a critical mediator of endocrine organ formation. Without it, the anterior pituitary gonadotrophs, adrenal gland and gonad fail to develop. It is also critical for the ongoing expression of many important genes within these cell types (e.g. the enzymes that orchestrate steroidogenesis; Figure 2.6). A variant receptor with a similar expression profile is DAX1 (also called NROB1), mutation of which causes X‐linked congenital adrenal hypoplasia (i.e. under‐development). Duplication of the region that includes the gene encoding DAX1 causes male‐to‐female sex reversal (Chapters 6 and 7). Increasingly, endogenous compounds are being identified that occupy the three‐dimensional structure created by the ligand‐binding domain. Whether these substances are the true hormone ligands remains debatable.
Figure 3.16 Hormonal stimulation of intracellular phospholipid turnover and calcium metabolism. Phosphatidylinositol (PI) metabolism includes the membrane intermediaries, PI monophosphate (PIP) and PI bisphosphate (PIP2). Hormone action stimulates phospholipase C, which hydrolyzes PIP2 to diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 mobilizes calcium, particularly from the endoplasmic reticulum. DAG activates protein kinase C and increases its affinity for calcium ions, which further enhances activation. Collectively, these events stimulate phosphorylation cascades of proteins and enzymes that alter intracellular metabolism.
Figure 3.17 Eicosanoid signalling. Arachidonic acid, released by phospholipase A2, is the rate‐limiting precursor for generating eicosanoid signalling molecules by cyclo‐oxygenase (COX) and lipoxygenase pathways. This example produces prostaglandin E2 (PGE2), but there are at least 16 prostaglandins, all structurally related, 20‐carbon, fatty acid derivatives. They are released from many cell‐types and exert paracrine and autocrine actions (e.g. the inflammatory response and contraction of uterine smooth muscle). Their circulating half‐life is short (3–10 min). Aspirin inhibits prostaglandin production at sites of inflammation. There are different forms of COX; until withdrawn due to side‐effects, inhibitors of COX‐2 were used as anti‐inflammatory agents.
Figure 3.18 Simplified schematic of nuclear hormone action. (a) Free hormone (a steroid is shown), in equilibrium with protein‐bound hormone, diffuses across the target cell membrane. (b) Inside the cell, free hormone binds to its receptor (
Endocrine transcription factors
Other transcription factors play roles in development and regulating mature function comparable to some of the orphan and variant nuclear receptors although they are not part of the nuclear receptor superfamily (Table 3.4). This is important because inactivating mutations in these transcription factors cause endocrine pathology, particularly in the paediatric setting. For instance, pituitary‐specific transcription factor 1 (PIT1) regulates expression of the genes encoding GH, PRL and the β‐subunit of TSH. People with inactivating PIT1 mutations show loss of these hormones, causing short stature, and a developmental secondary hypothyroidism accompanied by severe learning disability. Via whole‐exome and, increasingly, whole‐genome sequencing, clinical genetics and genomics can provide increasingly precise diagnostic answers to these developmental endocrinology problems (Chapter 4).
Figure 3.19 The nuclear hormone receptor superfamily. The receptors, named according to their ligands (shown to the right), range in size from 395 to 984 amino acids.
Table 3.2 Examples of modifications to hormones, their precursors or metabolites within the cell prior to nuclear receptor action
| Modification that increases activity | Modification that decreases activity |
|---|---|
| Deiodination of thyroxine (T4) to tri‐iodothyronine (T3) by type 1 and type 2 selenodeiodinase (Figure 8.7) | Inactivation of T4 and T3 by the formation of reverse T3 and di‐iodothyronine (T2) by type 3 selenodeiodinase (Figure 8.7) |
| Reduction of testosterone to dihydrotestosterone (DHT) by 5α‐reductase (Figure 7.7); sex steroid function in males by local conversion of testosterone to oestradiol by the action of aromatase (CYP19; e.g. in bone; Figure 2.6) | Loss of androgenic activity by conversion of testosterone to oestradiol by the action of aromatase (CYP19; Figure 2.6) |
| Conversion of 25‐hydroxyvitamin D to 1,25‐dihydroxyvitamin D (calcitriol) by 1α‐hydroxylase (Figure 9.2) |
Conversion of 25‐hydroxyvitamin D to 24,25‐dihydroxyvitamin D or the inactivation of 1,25‐dihydroxyvitamin D to 1,24,25‐trihydroxyvitamin D by 24α‐hydroxylase (Figure 9.2)
|