HORMONAL FEEDBACK REGULATORY SYSTEMS

Feedback control, both negative and positive, is a fundamental feature of endocrine systems. Each of the major hypothalamic-pituitary-hormone axes is governed by negative feedback, a process that maintains hormone levels within a relatively narrow range . Examples of hypothalamic-pituitary negative feedback include  (1) thyroid hormones on the TRH-TSH axis (2) cortisol on the CRH-ACTH axis (3) gonadal steroids on the GnRH-LH/FSH axis (4) IGF-I on the growth hormone–releasing hormone (GHRH)-GH axis.  These regulatory loops include both positive (e.g., TRH, TSH) and negative (e.g., T4, T3) components, allowing for exquisite control of hormone levels. As an example, a small reduction of thyroid hormone triggers a rapid increase of TRH and TSH secretion, resulting in thyroid gland stimulation and increased thyroid hormone production. When thyroid hormone reaches a normal level, it feeds back to suppress TRH and TSH, and a new steady state is attained. Feedback regulation also occurs for endocrine systems that do not involve the pituitary gland, such as calcium feedback on PTH, glucose inhibition of insulin secretion, and leptin feedback on the hypothalamus. An understanding of feedback regulation provides important insights into endocrine testing paradigms. Positive feedback control also occurs but is not well understood. The primary example is estrogen-mediated stimulation of the midcycle LH surge. Though chronic low levels of estrogen are inhibitory, gradually rising estrogen levels stimulate LH secretion. This effect, which is illustrative of an endocrine rhythm , involves activation of the hypothalamic GnRH pulse generator. In addition, estrogen-primed gonadotropes are extraordinarily sensitive to GnRH, leading to amplification of LH release. Paracrine and Autocrine Control The previously mentioned examples of feedback control involve classic endocrine pathways in which hormones are released by one gland and act on a distant target gland. However, local regulatory systems, often involving growth factors, are increasingly recognized.  Paracrine regulation refers to factors released by one cell that act on an adjacent cell in the same tissue. For example, somatostatin secretion by pancreatic islet delta cells inhibits insulin secretion from nearby beta cells. Autocrine regulation describes the action of a factor on the same cell from which it is produced. IGF-I acts on many cells that produce it, including chondrocytes, breast epithelium, and gonadal cells. Unlike endocrine actions, paracrine and autocrine control are difficult to document because local growth factor concentrations cannot be measured readily. Anatomic relationships of glandular systems also greatly influence hormonal exposure: the physical organization of islet cells enhances their intercellular communication; the portal vasculature of the hypothalamic-pituitary system exposes the pituitary to high concentrations of hypothalamic releasing factors; testicular seminiferous tubules gain exposure to high testosterone levels produced by the interdigitated Leydig cells; the pancreas receives nutrient information and local exposure to peptide hormones (incretins) from the gastrointestinal tract; and the liver is the proximal target of insulin action because of portal drainage from the pancreas.