ANTERIOR PITUITARY HORMONES AND FEEDBACK CONTROL
The quantitative and temporal secretion of the pituitary trophic hormones is tightly regulated and controlled at three levels: (1) Adenohypophysiotropic hormones from the hypothalamus are secreted into the portal system and act on pituitary G-protein–linked cell surface membrane binding sites, resulting in either positive or negative signals mediating pituitary hormone gene transcription and secretion. (2) Circulating hormones from the target glands provide negative feedback regulation of their trophic hormones. (3) Intrapituitary autocrine and paracrine cytokines and growth factors act locally to regulate cell development and function. The hypothalamic-releasing hormones include growth hormone–releasing hormone (GHRH), corticotropin- releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH). The two hypothalamic inhibitory regulatory factors are somatostatin and dopamine, which suppress the secretion of growth hormone (GH) and prolactin, respectively. The six anterior pituitary trophic hormones—corticotropin (adrenocorticotropic hormone [ACTH]), GH, thyrotropin (thyroid-stimulating hormone [TSH]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin—are secreted in a pulsatile fashion into the cavernous sinuses and circulate systemically.
Hypothalamic–pituitary–target gland
hormonal systems function in a feedback loop, where the target gland blood
hormone concentration—or a biochemical surrogate—determines the rate of
secretion of the hypothalamic factor and pituitary trophic hormone. The
feedback system may be “negative,” in which the target gland hormone inhibits
the hypothalamic– pituitary unit, or “positive,” in which the target gland
hormone or surrogate increases the hypothalamic– pituitary unit secretion.
These two feedback control systems may be closed loop (regulation is restricted
to the interacting trophic and target gland hormones) or open loop (the nervous
system or other factors influence the feedback loop). All hypothalamic–pituitary–target
gland feedback loops are in part open loop—they have some degree of nervous
system (emotional and exteroceptive influences) inputs that either alter the
setpoint of the feedback control system or can override the closed-loop
controls. Feedback inhibition to the hypothalamus and pituitary is also
provided by other target gland factors. For example, inhibin, a heterodimeric
glycoprotein product of the Sertoli cell of the testes and the ovarian
granulosa cell, provides negative feedback on the secretion of FSH from the
pituitary. Synthesis and secretion of gonadal inhibin is induced by FSH.
Blood levels of trophic and target
gland hormones are also affected by endogenous secretory rhythms. Most hormonal
axes have an endogenous secretory rhythm of 24 hours—termed circadian or
diurnal rhythms—and are regulated by retinal inputs and hypothalamic
nuclei. The retinohypothalamic tract affects the circadian pulse generators in
the hypothalamic suprachiasmatic nuclei. Rhythms that occur more frequently
than once a day are termed ultradian rhythms, and those that have a
period longer than a day are termed infradian rhythms (e.g., menstrual
cycle). Examples of circadian rhythms of pituitary and target gland hormones
include the following: GH and prolactin secretion is highest shortly after the
onset of sleep; cortisol secretion is lowest
at 11 pm and highest between 2 and 6 am; and testosterone secretion is highest
in the morning. In addition, GH, ACTH, and prolactin are also secreted in brief
regular pulses, reflecting the pulsatile release of their respective
hypothalamic releasing factors.
The circadian and pulsatile
secretion of pituitary and target gland hormones must be considered when
assessing endocrine function. For example, because of pulsatile secretion, a
single blood GH measurement is not a good assessment of either hyperfunction or
hypofunction of pituitary somatotropes; the serum concentration of the
GH-dependent peptide insulinlike growth factor 1 (IGF-1)—because of its much
longer serum
half-life—provides a better
assessment of GH secretory status. Circulating hormone concentrations are a
function of circadian rhythms and hormone clearance rates; laboratories
standardize the reference ranges for hormones based on the time of day. For
example, the reference range for cortisol changes depending on whether it is
measured in the morning or afternoon. Normal serum testosterone concentrations
are standardized based on samples obtained from morning venipuncture. Disrupted
circadian rhythms should clue the clinician to possible endocrine
dysfunction—thus, the loss of circadian ACTH secretion with high midnight
concentrations of cortisol in the blood and saliva is consistent with ACTH-dependent Cushing syndrome.
