Hormones feedback control

As with any body system, there is the possibility of disease and malfunction glands can secrete too much (hypersecretion) or too little (hyposecretion) of their hormones cells in tissues can have altered sensitivity to hormones feedback control systems can break down. In these cases, hormones or their synthetic analogues are used as drugs. In other cases, hormones are used as drugs in ways that differ from their physiological role. 

FIGURE 2.2 Illustration of the complexity of hormonal feedback control (-h indicates a positive or augmenting effect — indicates a negative or inhibiting effect). 

Obviously, regulation of food intake depends on many neurotransmitters and hormones but this final section will outline the role played by central 5-HT transmission in this process. It had been the belief for some time that increased 5-HT transmission in the brain reduces food intake (Blundell 1977) and this certainly explains the satiety in rats that follows infusion of 5-HT into the paraventricular nucleus (PVN) of the hypothalamus. However, recent studies using microdialysis have found that 5-HT efflux in the lateral hypothalamus is itself increased by food intake, suggesting the existence of a feedback control system. In fact, because the increase in 5-HT efflux is greater in genetically obese rats than in their lean counterparts, it has been proposed that there is a deficiency in the 5-HT inhibition of food intake in obesity. 

When the concentration of the free form of a hormone decreases, then more of this hormone will be released from the binding proteins. The free hormone is the biologically active form. It binds to the target tissue to cause its actions and is involved with the negative feedback control of its secretion. The binding of hormones to plasma proteins has several beneficial effects, including ... 

Thyroid hormone production is regulated by TSH secreted by the anterior pituitary, which in turn is under negative feedback control by the circulating level of free thyroid hormone and the positive influence of hypothalamic thyrotropin-releasing hormone. Thyroid hormone production is also regulated by extrathyroidal deiodination of T4 to T3, which can be affected by nutrition, nonthyroidal hormones, drugs, and illness. 

TSH-secreting pituitary tumors release biologically active hormone that is unresponsive to normal feedback control. The tumors may cosecrete... 

T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form. Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels of free hormone generally remain normal, reflecting feedback control. 

The more classical Itinehoii of parathyroid hormone is concerned with its control of the maintenance of constant circulating calcium levels. Its action is on 11) Ihe kidney, where it increases the phosphate in the urine. (2) the skeletal system, where it causes calcium resorplion from bone, and t3l the digestive system, where it accelerates (stimulates) calcium absorption into the hitskI The hormone and gland exhibit characteristics of feedback control when the concentration of calcium tons in the blood falls, the secretion of the hormone increases, and when their concentration rises, the secretion of hormone decreases... 

There are also a few examples of positive feedback mechanisms in the endocrine system.25 43 In a positive feedback loop, rising concentrations of one hormone cause an increase in other hormones, which, in turn, facilitates increased production of the first hormone. The primary example of this type of feedback occurs in the female reproductive system, where low levels of estrogen production increase the release of pituitary hormones (LH, FSH).10 43 Increased LH and FSH then facilitate further estrogen production, which further increases pituitary hormone secretion, and so on (see Chapter 30). Positive feedback mechanisms are relatively rare, however, compared with negative feedback controls in the endocrine system. 

FIGURE 28-1 Negative feedback control in the hypothalamic-pituitary-endocrine pathways. Excitatory and inhibitory effects are indicated by (+] and H, respectively. Negative feedback loops occur owing to inhibition of the endocrine hormone on the pituitary and hypothalamus. 

FIGURE 29-2 Negative feedback control of glucocorticoid synthesis. Cortisol limits its own synthesis by inhibiting the release of corticotropin-releasing hormone [CRH] from the hypothalamus and adrenocorticotropic hormone [ACTH] from the anterior pituitary. 

Thyroid hormone release is subject to the negative feedback strategy that is typical of endocrine systems controlled by the hypothalamic-pituitary axis. Increased circulating levels of the thyroid hormones (T4, T3) serve to limit their own production by inhibiting TRH release from the hypothalamus and TSH release from the anterior pituitary.30,35 This negative feedback control prevents peripheral levels of thyroid hormones from becoming excessively high. 

Increased clearance of steroid hormones due to induction of hepatic biotransformation enzymes following chemical exposure often has been cited as a possible mechanism by which toxicants could lower circulating testosterone or 17/3-estradiol levels. While enhanced clearance of sex steroids has been demonstrated following chemical exposure and induction of hepatic biotransformation enzymes, elegant feedback control mechanisms tend to ensure that more hormone is produced and homeostasis is maintained (Figure 17.2). Enhanced clearance of sex steroids can contribute to endocrine disruption if the toxicity also results in impaired hormone synthesis (i.e., gonadal toxicity or interference with the feedback control of hormone synthesis). 2,3,7,8-Tetrachlorodibenzodioxin appears to lower circulating sex steroid levels via this dual effect. 

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

The thyroid-pituitary-hypothalamus axis controls thyroid hormone homeostasis. Thyrotropin-releasing hormone (TRH), released from the hypothalamus, stimulates the synthesis and release of thyroid-stimulating hormone (thyrotropin, TSH) from the anterior pituitary. TSH increases the release of thyroid hormones by several mechanisms, including stimulation of the I pump. While lower than normal levels of T3 and T4 cause an exaggerated response of the pituitary to TRH, released thyroid hormones, in feedback control, blunt the stimulating action of TRH on the pituitary. For further discussion of TSH and TRH biochemistry, see, for example, the review by Kannan48. 

Smith, W., Hypothalamic regulation of pituitary secretion of luteinizing hormone. II. Feedback control of gonadotropin secretion, Bulletin of Mathematical Biology, Vol. 42, No. 1, 1980, pp. 57-78. 

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