This document summarizes basic concepts of endocrine regulation and hormone secretion. It discusses how hormones are classified into peptides, steroids, and amines. It describes the evolution of hormones and their receptors. It then explains the processes of hormone synthesis, processing, storage, and secretion for different hormone types. Key points are that hormone precursors are typically inactive and require processing, and there are mechanisms to precisely regulate hormone production and levels.
This document summarizes basic concepts of endocrine regulation and hormone secretion. It discusses how hormones are classified into peptides, steroids, and amines. It describes the evolution of hormones and their receptors. It then explains the processes of hormone synthesis, processing, storage, and secretion for different hormone types. Key points are that hormone precursors are typically inactive and require processing, and there are mechanisms to precisely regulate hormone production and levels.
This document summarizes basic concepts of endocrine regulation and hormone secretion. It discusses how hormones are classified into peptides, steroids, and amines. It describes the evolution of hormones and their receptors. It then explains the processes of hormone synthesis, processing, storage, and secretion for different hormone types. Key points are that hormone precursors are typically inactive and require processing, and there are mechanisms to precisely regulate hormone production and levels.
BASIC CONCEPTS OF ENDOCRINE REGULATION The unique feature of endocrine physiology is that, unlike other physiological systems, the endocrine system cannot be defined along anatomic lines Rather, the endocrine system is a distributed system of glands and circulating messengers (hormones) that is often simulated by the central nervous system and/or autonomic nervous system Hormones comprise steroids, amines, and peptides Peptides are by far the most numerous BASIC CONCEPTS OF ENDOCRINE REGULATION They include hormones secreted by the anterior and posterior pituitary gland, the pancreas (insulin and glucagon), the parathyroid gland (parathyroid hormone) and many others Steroids are secreted by the adrenal cortex (cortisol and aldosterone), the ovaries (estrogen and progesterone), the testes (testosterone), and the placenta (estrogen and progesterone) Derivatives of the amino acid tyrosine are secreted by the thyroid gland (thyroxine and triodothyronine), and the adrenal medulla (epinephrine and norepinephrine) EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS Many hormones can be grouped into families reflecting their structural similarities as well as the similarities of the receptors they activate However, the number of hormones and their diversity increase as one moves from simple to higher life forms This reflects the added challenges in providing for homeostasis in more complex organisms For example, among the peptides hormones, several are heterodimers that share a common σ chain, with specificity being conferred by the chain EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS In the specific cases of thyroid-stimulating hormone (TSH), follicular-stimulating hormone (FSH), and luteinizing hormone (LH), there is evidence that the distinct chains arose from a series of duplications of a common ancestral gene For these and other hormones, moreover, this molecular evolution implies that hormone receptors also needed to evolve to allow for spreading of hormone actions/specificity EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS This was accomplished by co-evolution of the basic G- protein coupled receptors (GPCR) and receptor tyrosine kinases that mediate the effects of peptide and amine hormones that act on the cell surface The underling ancestral relationship sometimes re- emerge, however, in the cross-reactivity that may be seen when hormones rise to unusually high levels (eg, endocrine tumours) Steroids and thyroid hormones are distinguished by their predominantly intracellular sites of actions, since they can diffuse freely through the cell membranes EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS They bind to a largely cytoplasmic proteins known as nuclear receptors Upon ligand binding, the receptor-ligand complex translocates to the nucleus where it either homodimerizes, or associates with a distinct liganded nuclear receptor to form a heterodimer In either case, the dimer bind to DNA to either increase or decrease gene transcription in the target tissue Individual members of the nuclear receptor family have a considerable degree of homology EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS This, perhaps implying a common ancestral gene, and share many functional domains, such as the zinc fingers that permit DNA binding However, sequence variations allow for ligand specificity as well as binding to specific DNA motifs In this way, the transcription of distinct genes is regulated by individual hormones HORMONE SECRETION SYNTHESIS AND PROCESSING The regulation of hormone synthesis, depends on their chemical nature Polypeptides and protein hormones The synthesis of all of the protein/peptide hormones as well as hormone receptors, is subject to a normal mechanisms of transcriptional control in the cell In addition, there is provision for exquisitely specific regulation by other hormones, since the regulatory regions of many peptide hormone genes contain binding motifs for nuclear receptors HORMONE SECRETION SYNTHESIS AND PROCESSING Peptide are synthesized on the rough end of the endoplasmic reticulum of different endocrine cells in the same fashion as most other proteins They are usually synthesized at first as larger proteins that are not biologically active (preprohormones) and are cleaved to form smaller prohormones in the endoplasmic reticulum by specific proteases In some cases, multiple hormones may be derived from the same initial precursor, depending on the specific processing steps present in a given cell HORMONE SECRETION SYNTHESIS AND PROCESSING Presumably this provides for a form of genetic ‘economy’ Prohormones are then transferred to the Golgi apparatus for packaging into secretory vesicles In this process, enzymes in the vesicles leave the prohormones to produce smaller, biologically active hormones and inactive fragments The vesicles are stored within the cytoplasm, and many are bound to the cell membranes until their secretion is needed HORMONE SECRETION SYNTHESIS AND PROCESSING Secretion of the hormone occurs when the secretory vesicles fuse with the cell membrane and the granular contents are extruded into the interstitial fluid or directly into blood stream by exocytosis The stimulus for exocytosis is an increase in cystolic calcium concentration caused by depolarization of the plasma membrane In other instances, stimulation of endocrine cell surface receptor causes increased cyclic adenosine monophosphate (cAMP) and subsequently activation of protein kinase that initiate secretion of the hormone HORMONE SECRETION SYNTHESIS AND PROCESSING The peptide hormones are water soluble, allowing them to enter the circulation system easily, where they are carried to their target tissues Steroid hormones For steroid hormones, synthesis is controlled indirectly by regulating the production of key synthetic enzymes, as well as by substrate availability The chemical structure of steroid hormones is similar to that of cholesterol, and in most instances they are synthesized from cholesterol itself HORMONE SECRETION SYNTHESIS AND PROCESSING They are lipid soluble and consist of three cyclohexyl rings and one cyclopentyl ring combined into a single structure Although there is usually very little hormone storage in steroid-producing endocrine cells, large amount of cholesterol ester in cytoplasm vacuoles can be rapidly mobilized for steroid synthesis after a stimulus Most of the cholesterol in steroid-producing cells comes from the plasma, but there is also de novo synthesis of cholesterol in steroid-producing cells HORMONE SECRETION SYNTHESIS AND PROCESSING Because the steroids are highly lipid soluble, once they are synthesized, they simply diffuse across the cell membrane and enter the interstitial fluid and then the blood Amine hormones The two groups of hormones derived from tyrosine, the thyroid and the adrenal medullary hormones are formed by the actions of enzymes in the cytoplasmic compartments of the glandular cells HORMONE SECRETION SYNTHESIS AND PROCESSING The thyroid hormones are synthesized and stored in the thyroid gland and incorporated into macromolecules of the protein thyroglobulin which is stored in large follicles within the thyroid gland Hormone secretion occurs when the amines are split from thyroglobulin, and the free hormones (T 3 and T4) are released into the blood stream After entering the blood, most of the thyroid hormones combine with plasma proteins, especially thyroxine- biding globulin, which slowly release the hormones to the target tissues HORMONE SECRETION SYNTHESIS AND PROCESSING Epinephrine and norepinephrine are formed in the adrenal medulla, which secretes about four times more epinephrine than norepinephrine Catecholamines are stored in preformed vesicles and stored until secreted Similar to the protein hormones, catecholamines are also released from adrenal medullary cells by exocytosis Once they enter the circulation, they can exist in plasma in free form or in conjugation with other substances HORMONE SECRETION SYNTHESIS AND PROCESSING Most importantly is that, hormone precursors themselves are typically inactive This may be a mechanism that provides for an additional measure of regulatory control, or, in the case of thyroid hormones, may dictate the site of highest hormone availability In addition, there is provision for exquisitely specific regulation by other hormones, since the regulatory regions of many peptide hormone genes contain binding motifs for nuclear receptors HORMONE SECRETION SYNTHESIS AND PROCESSING For example, thyroid hormone directly suppresses TSH expression via the thyroid hormone receptor These specific mechanisms to regulate hormone transcription are essential to the function of feedback loops In some cases, the abundance of selected hormones may also be regulated via effects on translation For example, elevated levels of circulating glucose stimulate the translation of insulin mRNA HORMONE SECRETION SYNTHESIS AND PROCESSING These effects are mediated by the ability of glucose to increase the interaction of insulin mRNA with specific RNA binding proteins, which increase its stability and enhances its translation The net effect is a more precise and timely regulation of insulin levels, and thus energy metabolism, than could be accomplished with transcriptional regulation alone HORMONE SECRETION SYNTHESIS AND PROCESSING The precursor for peptide hormones are processed through the cellular machinery that handles proteins destined for export, including trafficking through special vesicles where the propeptide form can be cleaved to the active hormones Mature hormones are also subjected to a variety of posttranslational processing steps, such as glycosylation, which can influence their ultimate biological activity and/or stability in the circulation Ultimately, all hormones enter either the constitutive or regulated secretory pathway SECRETION The secretion of many hormones is via a process of exocytosis of stored granules The exocytotic machinery is activated when the cell type that synthesizes and stores the hormone in question is activated by a specific signal, such as a neurotransmitter or peptide releasing factor One should, however, contrast the secretion of stored hormones with that of those that are continuously released by diffusion (eg, steroids) SECRETION Control of secretion of the later molecule occurs via kinetic influence on synthetic enzymes or carrier proteins involved in the hormone production For example, the steroidogenic acute regulatory protein (StAR) is a labile protein whose expression, activation, and deactivation are regulated by intracellular signaling cascades and their effectors, including a variety of protein kinases and phosphates StAR traffics cholesterol form the outer to the inner membrane leaflet of the mitochondrion SECRETION Because this is a rate-limiting first step in the synthesis of the steroid precursor, pregnenolone, this arrangement permits changes in the rate of steroid synthesis, and thus secretion, in response to homeostatic cues such as trophic hormones, cytokines and stress (Figure 16-1) An additional complexity related to hormone secretion relates to the fact that some hormones are secreted in a pulsatile fashion SECRETION Pulsatile secretion is the normal pattern for the gonadotrophins, LH and FSH, with major pulses released every 1-2 hours depending on the phase of the menstrual cycle Growth hormone is also secreted in pulsatile fashion, with undetectable levels between pulses Secretion rates may peak and ebb relative to circadian rhythms, in response to the timing of meals, or as regulated by other pattern generators whose periodicity may range from milliseconds to years SECRETION Circadian means changes over 24 hours of the day- night cycle and is best shown by the pituitary-adrenal axis For example, cortisol levels are highest in the morning and lowest in overnight Additionally, cortisol release is pulsatile, following the pulsatility of pituitary ACTH The menstrual cycle is an example of a longer and more complex (28-day biological rhythm) SECRETION Pulsatile secretion is often related to the activity of oscillators in the hypothalamus that regulate the membrane potential of neurons Which in turn secret bursts of hormone releasing factors into the hypophysial blood flow that then cause the release of pituitary and other downstream hormones in a pulsatile fashion There is evidence that these hormones pulses convey different information to the target tissues that they act upon than steady exposure to a single concentration of the hormone SECRETION Therapeutically, pulsatile secretion may pose challenges if, due to deficiency, it proves necessary to replace a pulsatile hormone that is normally secreted in this way Continuous secretion is typical of thyroid hormones, with a half-life of 7-1o days for T4 and 6-10 hours for T3, and with little variation over the day, month and year FIGURE 16-1 Regulation of steroid biosynthesis by StAR Extracellular signals activate intracellular kinases that, in turn, phosphorylate transcription factors that upregulate StAR expression StAR is activated by phosphorylation, and facilitates transfer of cholesterol from the outer to inner mitochondrial membrane leaflet This then allows entry of cholesterol into the steroid biosynthetic pathway, beginning with pregnenolone HORMONE TRANSPORT IN BLOOD In addition to the rate of secretion and its nature (steady vs pulsatile), a number of factors influence the circulating levels of hormones These include the rates of hormone degradation and/or uptake Receptor binding and availability of receptors, and the affinity of a given hormone for plasma carriers Stability influences the circulating half-life of a given hormone and has therapeutic implications for hormone replacement therapy, in addition to those posed by pulsatile secretion HORMONE TRANSPORT IN BLOOD Plasma carriers for specific hormones have a number of important physiological function First, they serve as a reservoir of inactive hormone and thus provide a hormonal reserve Bound hormones are typically prevented from degradation or uptake Ultimately, plasma carriers may be vital in modulating levels of the free hormones HORMONE TRANSPORT IN BLOOD Typically, it is only the free hormone that is biologically active in target tissues or can mediate feedback regulation since it is the only form able to access the extravascular compartment Thus, the bound hormone reservoir can allow fluctuation in hormonal levels to be smoothed over time Plasma carriers also restrict the access of the hormone to some sites HORMONE TRANSPORT IN BLOOD Catecholamines and most peptide hormones are soluble in plasma and are transported as such Norepinephrine and epinephrine, are secreted within seconds after the gland is stimulated, and they may develop full action within another few seconds to minutes In contrast steroid hormones are hydrophobic and are mostly bound to large proteins called steroid binding proteins (SBP), which are synthesized in the liver HORMONE TRANSPORT IN BLOOD As a result, only small amounts of the free hormone are dissolved in plasma Specifically, sex hormone-binding globulin (SHBG) is a glycoprotein that binds to the sex hormones, testosterone and 17β-estradiol Progesterone, cortisol, and other corticosteroids are bound by transcortin The SBP hormone complex and the free hormone are in equilibrium in the plasma, and only the free hormone is able to diffuse across cell membranes HORMONE TRANSPORT IN BLOOD SBP have three main functions: they increase the solubility of lipid based hormone in the blood They reduce the rate of hormone loss in the urine by preventing the hormone from being filtered in the kidney And they provide a source of hormone in the bloodstream that can release free hormone as the equilibrium change HORMONE TRANSPORT IN BLOOD An additional way to regulate the availability of hormones that bind to a carrier proteins, such as steroids, is to regulate the expression and secretion of the carrier proteins themselves This is a critical mechanism that regulates the bioavailability of thyroid hormones, for example Thyroid hormones are transported in the circulation by a carrier protein thyroxine-binding globulin In a pathophysiological setting, some medications can alter the levels of binding proteins or displace hormones that are bound to them HORMONE TRANSPORT IN BLOOD This is a critical mechanism that regulates the bioavailability of thyroid hormones, for example In addition, some binding proteins are promiscuous and bind multiple hormones (eg, SHBG) These observations may have clinical implications for endocrine homeostasis, since free hormones are needed to feedback and control their rates of synthesis and secretion Finally, the anatomic relationship of sites of release and action of hormones may play a key role in their regulation HORMONE TRANSPORT IN BLOOD For example, a number of hormones are destroyed by passage through the pulmonary circulation or the liver This may markedly curtail the temporal window within which a given hormone can act Concentration of hormones in the circulation The concentration of hormones required to control most metabolic and endocrine functions are incredibly small Their concentration in the blood range from as little as 1 picogram in each millilitre of blood up to at most a few milligrams per millimetre of blood HORMONE TRANSPORT IN BLOOD Similarly, the rates of secretion of various hormones are extremely small, measured in micrograms or milligrams per day The rate of action of hormones also varies Norepinephrine and epinephrine may develop full action within seconds to minutes after being secreted, the actions of other hormones, such as thyroxine or growth hormones, may require months for full effect CLINICAL BOX 16-1 Breast cancer Breast cancer is the most common malignancy of women, with about 1 million new cases diagnosed each year world-wide The proliferation of more than two-thirds of breast tumours are driven by the ovarian hormone, oestrogen, and about one-third of patients, the breast cancer will express receptors for oestrogen and progesterone This is by virtue of the fact that the tumour cells express high levels of posttranslationally modified oestrogen receptors (ER) CLINICAL BOX 16-1 Breast cancer The clinical significance of these molecular findings has been known for more than 100 years, since the Scottish surgeon, Sir Thomas Beatson, reported delayed disease progression in patients with advanced breast cancer following removal of their ovaries in premenopausal women The extent of exposure to ovulatory cycles is one of most important endogenous causes associated with a high risk for development of sporadic breast cancer CLINICAL BOX 16-1 Breast cancer However, although the association of oestrogen in the development of breast cancer is well established, the fundamental mechanism(s) by which this hormone modulate cell growth and tumour development are not yet clear It is known from in vitro and in vivo studies that the mechanism of oestrogen action is mediated through the binding to the ER Oestrogen receptors in turn binds specific enhancer regions on the DNA and regulates gene transcription CLINICAL BOX 16-1 Breast cancer The interaction of oestrogen and its receptors and the recruitment of accessory cofactor proteins has been the focus of intense recent research In modern times, determination of whether a given breast cancer is, or is not, ER-positive is a critical diagnostic test that guides treatment decisions, as well as an important prognosticator ER-positive tumours are typically of lower grade, and patients with such tumours have improved survival CLINICAL BOX 16-1 Breast cancer The latter is likely due, at least in part, to the availability of excellent treatment options for ER- positive tumours compared with those that are ER- negative On the other hand, the oestrogen receptor negative, progesterone receptor (R) negative, mutated EGFR (Her2) negative, triple negative phenotype (basal type) is associated with a poor prognosis than the luminal types A and B THERAPEUTIC HIGHLIGHTS Oestrogen-responsive breast tumours are dependent on the presence of the hormone for growth In modern times, cells can be deprived of the effects of oestrogen pharmacologically, rather than resorting to oophorectomy Premenopausal women In premenopausal women, a reduction in oestrogens can be achieved via pituitary downregulation using gonadotropin-releasing hormone (GnRH) analogues such as goserelin or leuprorelin THERAPEUTIC HIGHLIGHTS Tamoxifen a mixed agonist and antagonist of oestrogen action on the ER, and related agents that specifically inhibit the oestrogen receptor may hasten its degradation The more recent drug fulvestrant is a more selective oestrogen modulator (SERM) and is also used for the treatment of breast cancer Synthetic progestogens, eg, medroxyrogesterone acetate and megestrol, have a direct effect on breast tumour cells through progesterone receptors They can be as effective as tamoxifen in metastatic breast cancer THERAPEUTIC HIGHLIGHTS Postmenopausal women In postmenopausal women, where oestrogen is derived from the metabolism of testosterone to estrone in extragonadal tissues (ie, subcutaneous fat) rather than from the ovaries, aromatase inhibitors inhibits the conversion of androgens to oestrogen The aromatase inhibitors, anastrozole, letrozole and exemestane, reduce circulating oestrogen levels and synthesis in tumour cells THERAPEUTIC HIGHLIGHTS They have shown greater efficacy than tamoxifen in the treatment of metastatic breast cancer and equivalent in adjuvant setting In general, treatment of breast cancer includes surgery: local excission, segmental mastectomy or simple mastectomy with or without reconstruction, radiation therapy, chemotherapy and hormone-modulating therapy, e.g., taxomifen Patients with established metastatic disease may require endocrine therapy, chemotherapy and radiotherapy THERAPEUTIC HIGHLIGHTS The anti-oestrogen drug taxomifen is effective when used as a single agent or when used in combination with other chemotherapeutic agents in patients who are postmenopausal Chemotherapy is used for patients who lack features of hormone responsive disease or who fail to respond to endocrine therapy or who require rapid response if at risk of, eg, liver or respiratory failure There is no advantage in combining more than two drugs at a time THERAPEUTIC HIGHLIGHTS There is very little difference in efficacy between the different regimens for metastatic disease, with response rates varying from 40% to 60% for median duration of 8-10 months The most common regimens with either single agent or doublet combination include: MM: mitoxantrone and methotraxate AC/EC: doxorubicin or epirubicin and cyclophosphamide DC: docetaxel and gemcitabine PG: paclitaxel and gemcitabine Vinorelbine, carbolatin, mitomycin and eribulin