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During puberty,prolactin stimulates breast development, acting in concertwith other hormones. In pregnancy, the final alveolar andductal development of breasts is stimulated by prolactin,estrogen, and progesterone. The high prolactin levels duringpregnancy are promoted by estrogen, which is not a directprolactin secretagogue, but rather, enhances prolactin secretion in response to other factors.After parturition, suckling promotes prolactin synthesis andrelease. Whereas the high levels of estrogen inhibit lactationduring pregnancy, after parturition, estrogen levels arereduced and the lactogenic action of prolactin is unopposed.Binding of prolactin to its receptors in the mammary glandsresults in tyrosine kinase activation, transcriptional regulation, and ultimately, synthesis of milk proteins.
One of theactions of prolactin is inhibition of gonadotropin-releasinghormone and therefore suppression of the female reproductive cycle, which accounts for the reduced likelihood ofanother conception during breastfeeding.Breastfeeding acts as a partially effective contraceptivemeasure in the first 6 months after parturition becauseof its inhibitory effects on the reproductive endocrine axis ofthe mother. If the baby is fed exclusively by breastfeeding, conception is unlikely during this period as long as the mother hasnot had a menstrual period. In developing nations, birthrateshave sometimes risen early in the process of industrialization,due to an increase in formula feeding of infants.321CHAPTER27Thyroid HormonesThyroid hormones (TH) have biologic actions in every organin the body and are critical to proper fetal, postnatal, andpubertal growth and development.
In addition, the action ofthyroid hormones to maintain basal metabolic rate (BMR)makes states of thyroid excess and deficiency in adults readilyevident—this is one reason that treatment for “enlarged neck,”or goiter (hypothyroid-induced), was described in Chineseherbal medicine almost 5000 years ago.Reverse T3 (rT3) is also synthesized in the thyroid gland,but in small amounts. It differs from T3 by the positionof the iodine moiety. rT3 has little biologic activity; there is littlerT3 present under normal conditions, but high amounts arepresent in chronic diseases, in the fetus, and during starvation.rT3 is made in larger amounts when T4 is processed at end organtissues.STRUCTURE OF THE THYROID GLANDSteps in Thyroid Hormone SynthesisThe thyroid is a shield-shaped gland located on the anteriorside of the trachea, below the thyroid cricoid cartilages(Fig. 27.1).
It is composed of right and left lobes and anisthmus and weighs ∼20 grams. As with all endocrine glands,it is highly vascularized to supply nutrients for hormone synthesis and blood flow for hormone transport. The functionalunits of the gland are the follicles, which are filled with thyroglobulin (Tg). Tg is the glycoprotein precursor to thyroidhormones, and modified Tg is collectively known as colloid.The follicle cells are surrounded by an epithelial cell layer.Scattered between the follicles are parafollicular cells, whichare calcitonin-producing cells (see “Main Areas of CalciumRegulation” in Chapter 30). On the follicular cell basal membrane, there are G protein–coupled receptors for thyroidstimulating hormone (TSH).Within the follicular cells, the elements necessary for thyroidhormone synthesis are combined in the following steps(Fig.
27.3):SYNTHESIS OF THYROID HORMONESThe thyroid gland synthesizes two main types of TH: triiodothyronine (T3) and thyroxine (T4) (Fig. 27.2). Although T3 isabout four times more biologically active than T4, the amountof T4 produced and secreted is about 20 times greater than themore potent T3. When T4 is secreted and enters a tissue, it isthen converted to T3, and thus, T4 acts as a prohormone. Thisis an important concept to understand—because thyroidhormone is active in most organs, the amount available forimmediate biologic action is regulated by several differentmechanisms (discussed in detail later). Limiting the amountof highly active T3 released into the blood is one of the safetymechanisms.1.
Thyroglobulin molecules rich in tyrosine are producedin the endoplasmic reticulum, packaged in vesicles bythe Golgi, and exocytosed into the lumen of thefollicle.2. Iodide (I-) enters the follicle cell via basolateral Na+/Icotransporters (the I-trap). The iodide exits the cell onthe apical side into the lumen via I-/Cl- antiporters.3. In the follicular lumen, I- is oxidized to iodine by thyroidperoxidase and substituted for H+ on the benzene ringof tyrosine residues of thyroglobulin.4. Binding of one iodine will form monoiodotyrosine(MIT), and binding of two iodine moieties will formdiiodotyrosine (DIT). This reaction is termed organification. Thyroid peroxidase also catalyzes the binding ofDIT to another DIT, forming T4. Some DIT will alsobind to an MIT, forming T3.
These products remainlinked to the Tg.5. The mature thyroglobulin, containing MIT, DIT, T4,and T3 (in order of greater to lesser abundance), is endocytosed back into the follicle cell and can be stored ascolloid until secreted. TH can be stored several weekswhile bound to Tg—this is different than seen withother hormones.6. Proteolysis of the colloid is stimulated by TSH andreleases the constituent molecules. MIT and DIT reenterthe synthetic pool, and T3 and T4 exit the basolateralmembrane into the blood.322Endocrine PhysiologyHyoid boneThyroid cartilageSuperior thyroidartery and veinThyroid cartilagePyramidal lobe(often absent or small)Common carotid arteryThyroid glandTracheaInternal jugular veinMiddle thyroid veinRight lobeLeft lobeInferior thyroid veinsIsthmusThyroidglandInferior thyroid arteryVagus nerve (X)Right recurrent laryngeal nerveHyoid boneLeft recurrent laryngeal nerveSuperior vena cavaAortic archThyroid gland and surroundinganatomy: anterior viewEpiglottisInferior pharyngeal constrictor muscle (cut)Superior thyroid arteryCommon carotid arteryCommon carotid arterySuperior parathyroid glandSuperior parathyroid glandRight lobe of thyroid glandLeft lobe of thyroid glandInferior parathyroid glandInferior parathyroid glandInferior thyroid arteryRecurrent laryngeal nerveEsophagusTransverse cervical arteryRecurrent laryngeal nerveTracheaThyroid and parathyroid glands: posterior viewFigure 27.1 Thyroid Gland Structure The thyroid gland is a highly vascularized structure locatedanterior to the trachea and inferior to the cricoid cartilage.
In about 15% of the population, a small pyramidallobe is present (as seen).Thyroxine (T4)Triiodothyronine (T3)IIOHOIIHOOCOOHCOOHIIINH2Figure 27.2 Structure of T3 and T4 The two main types of thyroid hormones (TH), thyroxine (T4) andtriiodothyronine (T3), differ from each other by the addition of one iodine in T4. The majority of circulating THis T4, and almost all of the circulating TH is bound to a thyroxine-binding protein.NH2Thyroid HormonesHypothalamusSomatostatinDopamineTRHT3PituitaryTSHT4T3DeiodinationTSHThyroidFollicular Epithelial CellThyroid FollicleLumenGolgiapparatusVesicle4MIT DITT33TGPeroxidaseTGEndoplasmicmRNAThyroglobulin reticulumAminoacids1T4I–I–I–DeiodinaseNa+2I–IodidetrapNa+MIT DITMIT DITT4EndocytosisApicalmembraneMIT DITTGTGT35T3ProteolysisT4T3T3T4T46ColloiddropletsLysosomesBasalmembraneFigure 27.3 Synthesis and Regulation of Thyroid Hormones The thyroid gland is composed offollicular epithelial cells that synthesize and store thyroxine (T4) and triiodothyronine (T3) and release thesehormones into the circulation.
The synthesis is controlled by release of thyroid-stimulating hormone (TSH),which is under negative feedback control by the thyroid hormones. Synthesis and storage of the thyroidhormones is outlined here and in the figure: (1) In the endoplasmic reticulum, thyroglobulin molecules areproduced, packaged in vesicles by the Golgi, and exocytosed into the lumen of the follicle. (2) Iodide (I−)(from the diet) enters the follicle cell via basolateral Na+/I− cotransporters (the I-trap). The iodide exits thecell on the apical side into the lumen via I−/Cl− antiporters. (3) In the follicular lumen, I− is oxidized to iodineby thyroid peroxidase and substituted for H+ on the benzene ring of tyrosine residues of thyroglobulin. (4)Binding of one iodine will form monoiodotyrosine (MIT), and binding of two iodine moieties will form diiodotyrosine (DIT). This reaction is termed organification.
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