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.