Hormonal Feedback Regulatory System

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, and (4) IGF-I on the growth hormone–releasing hormone (GHRH)-GH axis These regulatory loops include both positive (e.g.,TRH, TSH) and negative components (e.g., T4, T3), allowing for exquisite control of hormone levels.As an example, a small reduction of TH triggers a rapid increase of TRH and TSH secretion, resulting in thyroid gland stimulation and increased TH production. When the TH 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 (see below). 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 a ten- to twentyfold amplification of LH release.

PARACRINE AND AUTOCRINE CONTROL

  The aforementioned 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 δ cells inhibits insulin secretion from nearby β 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 readily measured.

  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 hypothalamicpituitary 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 from the gastrointestinal tract; and the liver is the proximal target of insulin action because of portal drainage from the pancreas.

HORMONAL RHYTHMS

  The feedback regulatory systems described above are superimposed on hormonal rhythms that are used for adaptation to the environment. Seasonal changes, the daily occurrence of the light-dark cycle, sleep, meals, and stress are examples of the many environmental events that affect hormonal rhythms. The menstrual cycle is repeated on average every 28 days, reflecting the time required for follicular maturation and ovulation.  Essentially all pituitary hormone rhythms are entrained to sleep and to the circadian cycle, generating reproducible patterns that are repeated approximately every 24 hours. The HPA axis, for example, exhibits characteristic peaks of ACTH and cortisol production in the early morning, with a nadir during the night. Recognition of these rhythms is important for endocrine testing and treatment. Patients with Cushing’s syndrome characteristically exhibit increased midnight cortisol levels when compared to normal individuals. In contrast, morning cortisol levels are similar in these groups, as cortisol is normally high at this time of day in normal individuals.The HPA axis is more susceptible to suppression by glucocorticoids administered at night as they blunt the early morning rise of ACTH. Understanding these rhythms allows glucocorticoid replacement that mimics diurnal production by administering larger doses in the morning than in the afternoon. Disrupted sleep rhythms can alter hormonal regulation. For example, sleep deprivation causes mild insulin resistance and hypertension, which are reversible at least in the short term.

Other endocrine rhythms occur on a more rapid time scale. Many peptide hormones are secreted in discrete bursts every few hours. LH and FSH secretion are exquisitely sensitive to GnRH pulse frequency. Intermittent pulses of GnRH are required to maintain pituitary sensitivity, whereas continuous exposure to GnRH causes pituitary gonadotrope desensitization. This feature of the hypothalamic-pituitary-gonadotrope axis forms the basis for using long-acting GnRH agonists to treat central precocious puberty or to decrease testosterone levels in the management of prostate cancer.

  It is important to be aware of the pulsatile nature of hormone secretion and the rhythmic patterns of hormone production when relating serum hormone measurements to normal values.For some hormones,integrated markers have been developed to circumvent hormonal fluctuations. Examples include 24-h urine collections for cortisol, IGF-I as a biologic marker of GH action, and HbA1c as an index of long-term (weeks to months) blood glucose control.

  Often, one must interpret endocrine data only in the context of other hormones. For example, PTH levels are typically assessed in combination with serum calcium concentrations.A high serum calcium level in association with elevated PTH is suggestive of hyperparathyroidism, whereas a suppressed PTH in this situation is more likely to be caused by hypercalcemia of malignancy or other causes of hypercalcemia. Similarly,TSH should be elevated when T4 and T3 concentrations are low, reflecting reduced feedback inhibition. When this is not the case, it is important to consider secondary hypothyroidism, which is caused by a defect at the level of the pituitary.