Which of the following disorders is a result of Hyposecretion of hormones?

Publisher Summary

Hyper secretion of endogenous and exogenous growth hormone (GH) can affect all cell systems in the human body. However, beneficial effects on the central nervous system, such as improved cognition, learning capacity, quality of life, or memory are not known. Possible anabolic effects of growth hormone have also been studied in patients with Turner's syndrome who show diminished height and a spectrum of characteristic cognitive disturbances. Long-term GH administration is not associated with abbreviations of these urocognitive deficits nor does long-term growth hormone administration induce improved mental development in patients with Down's syndrome. Furthermore, the chapter discuses treatment approaches for GH-producing tumor. Surgery has been the most commonly chosen first treatment in acromegaly. However, surgery followed by photon irradiation shows significantly lowers quality of life. Other approaches involve somatostatin analogues and genetically engineered GH receptor antagonist pegvisomant or trovert, which inhibits GH action on cells. This GH receptor antagonist is remarkably effective, controlling disease activity and normalizing IGF-I levels in serum in over 90% of patients.

MUCUS HYPERSECRETION AND CHRONIC RESPIRATORY DISEASE

Hypersecretion of mucus into the airways is an important contributor to morbidity and mortality in many patients with severe chronic lung diseases, such as chronic pulmonary obstructive disease (COPD), asthma, and cystic fibrosis.35 Excessive mucus in the airways can limit airflow; and its presence is a particular risk factor for those patients with COPD who are prone to chest infections. COPD is a severe chronic inflammatory disease of the respiratory tract that comprises three conditions, namely chronic bronchitis (long-standing airway mucus hypersecretion), small airways disease, and emphysema.36 It is increasing worldwide in prevalence and economic burden.37,38 In COPD, patients with chronic mucus hypersecretion have a significantly increased risk of hospitalization and death compared with patients without a marked bronchitic component.39,40 Current treatments for COPD are palliative and do not halt disease progression,41 and there is no specific treatment for the mucus hypersecretion.42 In the absence of effective therapy for any aspect of COPD pathophysiology, development of treatments for mucus hypersecretion is warranted. The ability to clear mucus from the lungs, through airway cilia movement, depends on its viscocity and elasticity. These properties are determined by the proportion of mucin glycoproteins, by weight, that the mucus contains.43 MUC5AC and MUC5B are the major mucins in both normal and pathologic human airway secretions.44 In patients with COPD, levels of the mucins MUC5AC and MUC5B are increased in the respiratory mucus, although proportionally more MUC5B is secreted.45 Mucins are secreted into the airways by goblet cells in the epithelium and seromucous glands in the submucosa.43 One possibility for inhibiting mucus secretion is to utilize the inhibitory activity of the clostridial neurotoxin endopeptidases on vesicle fusion, targeted to the mucin-secreting cells of the airway using an appropriate targeting ligand.

To investigate whether a suitably targeted clostridial endopeptidase would cleave SNARE proteins in human respiratory epithelial cells, and thereby inhibit mucus secretion, a fusion protein was generated from a recombinant gene encoding the LHN domain of BoNT/C and EGF, designated EGF-LHN/C, to target EGF receptors on the mucin secreting cells.34 EGF was selected as the prototype ligand for the creation of such a fusion protein because EGF receptors are present on human respiratory epithelial cells46,47 and are upregulated in the airway epithelium of patients with asthma and COPD,48 as well as smokers.49 The recombinant fusion protein EGF-LHN/C cleaved the relevant SNARE protein syntaxin in a human mucoepidermoid metastatic cell line, H292 cells, in vitro in a concentration-dependent fashion.34 Pretreating H292 cells with EGF-LHN/C inhibits the stimulated release of mucin in response to a combined stimulus of EGF and tumor necrosis factor-α (TNFα) in a concentration-dependent manner, with an IC50 of approximately 0.4 nM (Fig. 28-1). This compares very well with the previously reported inhibitory effect of EGF-LHN/C on stimulated mucin release from another respiratory epithelial cell line, the human type II alveolar cell line A549, in response to the same stimulus.34 In both cell types, there was no detectable effect of EGF-LHN/C on the basal level of mucin secretion. The inhibition of mucin secretion by EGF-LHN/C is due to the targeted delivery of its endopeptidase activity through the EGF receptor, and is not the result of cell cytotoxicity or receptor antagonism or downregulation.34 EGF-LHN/C is also able to inhibit stimulated mucin release from A549 cells in response to a stimulatory cocktail of cytokines, a combination of 1 ng/mL interferon (IFN)-γ, TNFα, and interleukin (IL)-1β, called cytomix (Fig. 28-2). Thus, the effect of EGF-LHN/C on stimulated mucin release from respiratory epithelial cells is independent of the precise nature of the stimulus used. Histologic examination shows that the mucin is retained inside the treated cells (Fig. 28-3). Control cells contain stained intracellular mucin, whereas stimulated cells show markedly reduced staining, indicating mucin secretion. Stimulated cells pretreated with EGF-LHN/C show retained intracellular staining, indicating inhibition of secretion by EGF-LHN/C. To assess the response of the cells to such intracellular mucin retention, the effect of EGF-LHN/C pretreatment on MUC5AC mRNA levels was measured as an indicator of mucin synthesis. EGF-LHN/C pretreatment is associated with a concentration-dependent inhibition of EGF-TNFα–induced MUC5AC mRNA expression, with an IC50 value of ∼0.1 nM (Fig. 28-4). As with the inhibition of stimulated mucin release from the cells, this effect of EGF-LHN/C is due to the targeted delivery of its endopeptidase activity through the EGF receptor, because neither an LHN/C lacking an EGF ligand to target it to the EGF receptor nor a mutated form of the fusion protein in which the endopeptidase domain has been inactivated by three residue changes in the catalytic region (EGF-TE-LHN/C) inhibit MUC5AC mRNA expression. This effect of EGF-LHN/C on MUC5AC mRNA expression suggests the existence of a possible negative feedback mechanism between mucin release and mucin synthesis in respiratory epithelial cells, and also that gene expression downregulates in response to inhibition of secretion by a recombinant clostridial endopeptidase.

Recombinant clostridial endopeptidase fusion proteins that can inhibit mucus secretion, as exemplified by EGF-LHN/C, have the potential for development as therapeutic proteins for the treatment of COPD, chronic bronchitis, cystic fibrosis, and other chronic respiratory conditions involving excess airway mucus production. The longevity of the protein's activity would mean that the product would only need to be inhaled infrequently, making it well suited to the treatment of chronic respiratory diseases of this type.

Hyperprolactinemia

Hypersecretion of PRL is among the most common of pituitary disorders. Medications that elevate PRL secretion and may cause hyperprolactinemia include commonly used antiemetics, antipsychotics, antidepressants, and narcotics. These medications alter PRL secretion by antagonizing DA action, or by elevating serotonin or endorphin bioactivity. Reserpine and methyldopa increase PRL secretion as a result of DA depletion. DA receptor antagonists, such as haloperidol and phenylthiazines, increase PRL secretion. Serotonin reuptake inhibitors, such as fluoxetine, elevate serum PRL.59 It is uncommon for any of these medications to cause clinical signs of hyperprolactinemia, because the levels of PRL seldom reach more than 30 to 50 ng/mL with these drugs. One might imagine that subtle hormonal effects may be noted after long-term treatment.

Hyperprolactinemia that manifests clinical symptoms is most commonly a consequence of a lactotroph adenoma (see Chapter 22). These tumors may secrete high levels of PRL alone or of both PRL and GH. Any intracranial mass or trauma that causes compression or disruption of the pituitary stalk can cause hyperprolactinemia because of the loss of dopaminergic tone from the hypothalamus. Pituitary adenomas have been discovered to be much more common than was previously believed, with more than 20% of individuals harboring tumors measuring at least 3 mm at autopsy.46 Tumors that do not hypersecrete hormones are usually of gonadotroph or lactotroph origin. Tumor mass effects may cause some symptoms of prolactinomas. These include visual field defects, associated with pressure on the medial aspect of the optic chiasm, and alterations in temperature regulation, feeding patterns, or other effects caused by hypothalamic compression. However, effects associated with the physiologic actions of the hormone are the more common presenting symptoms.

Galactorrhea (breast milk secretion in an individual who is not postpartum) and amenorrhea are the result of PRL actions directly on the breast and the hypothalamic-pituitary-ovarian axis. In men, galactorrhea and impotence are the most common presenting symptoms of a hypersecreting prolactinoma. The causes of impotence in hyperprolactinemia, whether hormonal or neurogenic, are unclear. Hyperprolactinemia is treated medically by administration of DA agonists, including bromocriptine and cabergoline, or it is treated surgically by resection of the tumor tissue.

Adrenocorticotropic Hormone-Secreting Adenomas

ACTH hypersecretion leads to Cushing's disease. Three-quarters of patients with Cushing's disease are women, and they present with typical features including moon facies, central obesity, buffalo hump, and abdominal striae. They frequently have hirsutism, thinning of the skin, and steroid myopathy, and they may develop hypertension, diabetes, and osteoporosis. The disorder has a 5-year mortality rate of approximately 50% if untreated. The diagnosis is established by elevated ACTH levels, elevated 24-h urinary free cortisol, and loss of ACTH suppression by glucocorticoids. Frequently, the tumors are too small to identify on MRI scan, but bilateral inferior petrosal sinus catheterization can lateralize and confirm the pituitary origin of excess ACTH secretion when imaging studies are negative. Transsphenoidal surgical resection is the treatment of choice. Occasionally, refractory Cushing's disease may be treated with bilateral adrenalectomy; however, ACTH hypersecretion and pituitary enlargement continue to cause diffuse-skin hyperpigmentation (Nelson's syndrome) in approximately 25% of patients. Pharmacological blocking agents, such as mitotane, ketoconazole, and metyrapone, have some effect, but they are used only after surgical failure. Future therapies may include drugs that block the glucorticoid receptor and somatostatin analogs that inhibit ACTH secretion. Radiation therapy is also reserved for postsurgical treatment and patients who are not candidates for initial surgery.

Aberrant Mucus Production in Disease

Mucus hypersecretion is a feature of many chronic inflammatory diseases in mucosal tissues, particularly in the respiratory tract. This is unsurprising given the regulation of goblet cell differentiation and secretory mucin gene expression by inflammatory factors, as discussed earlier in the chapter. There is good reason to believe that excess mucus production, sometimes in combination with altered properties of the mucus, contributes to pathology and is a rational target for therapy. The classical genetic disease, CF, is a good exemplar where the primary defect is in a Cl− ion transport gene, CFTR, yet altered mucus is an integral component of the CF phenotype in the lung, intestine, and pancreas. CF mucus has increased viscosity and is more difficult to clear from the lungs, and simple reduction of disulfide bonds in mucins (that depolymerizes the mucins) via aerosol-reducing agents helps clear mucus and relieve disease symptoms. CF patients have chronic infection and subsequent inflammation, and elucidation of the factors contributing to altered mucus is complex. However, as introduced earlier, it has been proposed that reduced extracellular bicarbonate ion concentration due to defective CFTR function leads to inappropriate unpacking and hydration of secreted mucins released from goblet cells, thus explaining the change in mucus quality in the disease (Garcia et al., 2009; Gustafsson et al., 2012). Another example is asthma, where, at least in a subset of asthmatics, the Th2 cytokines, IL-4 and IL-13, produced during allergic responses drive goblet cell hyperplasia and increased mucin biosynthesis and secretion via activation of SPDEF (Whittaker et al., 2002; Park et al., 2007). Mucus hypersecretion combines with bronchoconstriction to reduce the effective size of airways producing the wheezing symptoms of asthma. While blocking mucin production appears an attractive option in some of these diseases, it is important to consider that this could conceivably, in some situations, lead to exacerbation of pathogen-initiated damage to the mucosa.

Neurogenic Disorders of Corticotropin Regulation

Hypothalamic CRH hypersecretion is the likely cause of sustained pituitary-adrenal hyperfunction in at least two situations: Cushing syndrome caused by the rare CRH-secreting gangliocytomas of the hypothalamus410 and severe depression. Severe depression is associated with pituitary-adrenal abnormalities, including inappropriately elevated ACTH levels, abnormal cortisol circadian rhythms, and resistance to dexamethasone suppression.143,147,148,411 The dexamethasone suppression test has, in fact, been used as an aid to the diagnosis of depressive illness. Another possible example of disordered neurogenic control of CRH associated with stress is the dysmetabolic syndrome.412,413 This syndrome is characterized by mild hypercortisolism, blunted dexamethasone suppression of the HPA axis, visceral obesity, and hypertension and may be strongly associated with greater risks for cardiovascular disease and stroke.

A unique syndrome of ACTH hypersecretion termed periodic hypothalamic discharge (Wolff syndrome) has been described in one young man. The patient had a recurring cyclic disorder characterized by high fever, paroxysms of glucocorticoid hypersecretion, and electroencephalographic abnormalities.414

Incoming signals

Mucus hypersecretion is one of the main features of several hypersecretory respiratory diseases including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma. In asthma, mucus forms plugs that are difficult to dislodge from the airways (Rogers, 2004).

Airway mucus is a heterogeneous mixture of secreted polypeptides (termed mucins), cells, and cellular debris that may tether together at the fluid surface by oligomeric mucin protein complexes. The most abundant gel-forming mucins in the human tracheobronchial epithelium are mucin 5AC (MUC5AC), produced by surface epithelial mucus-secreting cells (mainly by goblet cells), and mucin 5B (MUC5B), produced by submucosal glands (Bonser and Erle, 2017).

TNF and other cytokines released by Th2 cells and epidermal growth factor receptor (EGFR) signaling pathway induce goblet cell hyperplasia and the expression of mucins. Activation of TLRs by pathogens also stimulates mucin synthesis.

The increase of goblet cell numbers is a common feature observed in both asthma and COPD. Hyperplasia of goblet cells or increased levels of goblet cell differentiation from club cells (mucus metaplasia) both may lead to mucus overproduction.

A well-balanced airway surface liquid (ASL) system is required for normal mucus clearance. In asthma, fluids overflow into the lumen increasing ASL thickness leading to airway dysfunction.

What are disorders of Hyposecretion of hormones?

Which of the following disorders is caused by hypersecretion of a hormone?

Which of the following is a Hyposecretion disorder?

What disorders are caused due to Hyposecretion and hypersecretion of growth hormone?