Hormone function

a.) Describe how agonists and antagonists act to disrupt normal hormone function. Use examples and describe the resulting disease states that may result
Humans are exposed to thousands of chemicals during their lifetime, through the air, food, and water. A significant number of these chemicals can be toxic since they can disrupt the endocrine system. Over the past decade, the list of chemicals with endocrine disrupting activity has dramatically increased. Natural hormones are themselves agonists and, in many cases, more than one distinct hormone binds to the same receptor. For a given receptor, different agonists can have dramatically different potencies. Antagonists are molecules that bind the receptor and block binding of the agonist, but fail to trigger intracellular signalling events. Receptors can be activated or inactivated by either endogenous (such as hormones and neurotransmitters) or exogenous (such as drugs) agonists and antagonists, resulting in the stimulation or inhibition of a biological response. A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor. Bisphenol A (BPA) is an industrial compound and a well-known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism.
Many known obesogens are Endocrine disrupting chemicals (EDCs) that can act as direct ligands for nuclear hormone receptors, or affect components in metabolic signaling pathways under hormonal control. Environmental chemicals such as tributyltin (TBT) and triphenyltin (TPT) are known to stimulate adipogenesis in vitro and in vivo. Hence these agonists can trigger obesity.
Uterine fibroids (leiomyomas) are the most common tumor of the female reproductive system, occurring in 25–50% of all women. The risk of the development of uterine fibroids increases with age during premenopausal years, but tumors typically regress with the onset of menopause. Obesity, age at menarche and unopposed estrogen signaling have been shown to increase the risks for fibroids. Both animal and human studies suggest a role of EDCs in altering female reproductive development. Data from animal experiments show that EDC exposure during critical periods of development, both prenatal and neonatal, can induces functional changes that appear later in life.
One of the most prominent examples for a human endocrine disruptor is the potent estrogen receptor modulator diethylstilbestrol (DES) which has formerly been marketed as a drug for several indications, including the prevention of miscarriages in the 1940s to 1960s. In utero exposure to DES has been linked to an increased risk for reproductive tract abnormalities in the offspring of women treated with pharmacological doses during pregnancy, particularly an increased risk for vaginal clear cell adenocarcinoma in daughters.
Hence agonists and antagonists can disrupt normal endocrine activity, and result in abberations and diseases.

b.) Chose examples of one agonist and one antagonist that have been heavily studied. Use these examples to explain the biochemical differences between agonists and antagonists that cause them to affect receptor function differently. Be as specific as possible.
A major antagonists is Bisphenol A. BPA is a synthetic monomer used in the production of polycarbonate plastics and epoxy resins and is one of the highest production synthetic compounds worldwide. It has high antagonistic effects on thyroid receptors. It is detectable in serum of pregnant women and cord serum taken at birth; is 5-fold higher in amniotic fluid at 15-18 wk gestation, compared with maternal serum; and was found in concentrations of up to 100 ng/g in placenta. Thus, the human population is widely exposed to BPA and it appears to accumulate in the fetus. BPA inhibits TR-mediated transcription by acting as an antagonist. A major agonist would be Dopamine. Dopamine agonists are important tools in the management of endocrine disorders. The potency and favourable side effect profile of cabergoline has made it the preferred dopamine agonist of many endocrinologists. Dopamine agonists remain the first-line agents for the management of hyperprolactinaemia and a useful adjunct in the management of acromegaly. In keeping with good clinical practice, the lowest effective dose of dopamine agonist should be used to achieve the therapeutic goal. Dopamine agonists are the initial treatment of choice for patients with giant prolactinomas and those with hyperprolactinemia desiring restoration of normal sexual function and fertility. Dopamine agonists are given at bedtime to minimize side effects of fatigue, nausea, dizziness, and orthostatic hypotension.
In our body
The regulation of blood glucose concentration (through negative feedback) illustrates how the endocrine system maintains homeostasis by the action of antagonistic hormones. The glucose metabolism has been extensively studied and it can be used as an example to demonstrate the difference in agonist-antagonist activity. Bundles of cells in the pancreas called pancreatic islets contain two kinds of cells, alpha cells and beta cells. The alpha and beta cells control blood glucose concentration by producing the antagonistic hormones insulin and glucagon:
Beta cells secrete insulin. Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. When the concentration of blood glucose rises (after eating, for example), beta cells secrete insulin into the blood. Insulin stimulates the liver and most other body cells to absorb glucose. Liver and muscle cells convert the glucose to glycogen (for short-term storage), and adipose cells convert the glucose to fat. In response, glucose concentration decreases in the blood, and insulin secretion discontinues (through negative feedback from declining levels of glucose).
Alpha cells secrete glucagon. It is biochemically different from insulin. Glucagon is a 29-amino acid polypeptide. When the concentration of blood glucose drops (during exercise, for example), alpha cells secrete glucagon into the blood. Glucagon stimulates the liver to release glucose. The glucose in the liver originates from the breakdown of glycogen and the conversion of amino acids and fatty acids into glucose. When blood glucose levels return to normal, glucagon secretion discontinues (negative feedback).

Graves' disease can also be an example. It is caused by persistent, unregulated stimulation of thyroid cells by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor.

c.) Describe at least two assays that are used to screen for agonists and antagonists. Illustrate the results you would receive from these assays for an agonist and an antagonist.
There are many screen tests available for agonist and antagonists. A significant amount of effort over the past few years has been focused towards the development of test methods (particularly a wide range of in vitro assays) to detect endocrine disrupting chemicals. One of them would be the use of vitellogenin as a biomarker for endocrine disruption. We can also state the famus yeast recombinant assay Another example would be the In vivo measurement of aromatase inhibition.
Vitellogenin as a biomarker: Chemical pollutants in effluents , such as oestradiols, phthalates, alkyl-phenols, and alkyl-ethoxylates, influence sex differentiation in fish. The presence of vitellogenin in male fish can be used as an indicator of exposure to oestrogenic compounds. Male fish exposed to effluents can, therefore, be employed to monitor endocrine disruptions through multiple measurements of vitellogenin production, which is easily detected in their blood serum. The determination of vitellogenin is accomplished by means of a non-competitive enzymatic immunoassay (EIA) using monoclonal antibodies.
Yeast recombinant assay: To measure the endocrine disrupting chemicals (EDCs) in wastewater and evaluate the EDCs removal efficiencies in the wastewater treatment. Recombinant yeast cells can also be constructed to express the human androgen receptor and yeast enhanced green fluorescent protein, the latter in response to androgens. This new yeast androgen bioassay is fast, sensitive, and very specific and also suited to detect compounds that have an antiandrogenic mode of action.
In water, endocrine disruptors exert physiological effects at very low concentrations. Surface waters present often a mixture of high concentrations of low-potency disruptors and low amounts of very powerful ones, making their chemical analysis complicated and expensive. The indirect estrogenic, anti-androgenic, anti-progesteronic, and anti-thyroidic activities were observed in the influent. The removal efficiencies of EDCs were above 74%, suggesting that the present wastewater treatment processes were good enough to remove most of these indirect endocrine disrupting chemicals.
Aromatase inhibitors (AIs) is not used to screen, but can be used to determine the effects on changes in estrogen metabolism: Aromatase is the enzyme that synthesizes estrogen. As breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors. Letrozole is a known inhibitor. In most studies, the patients were then randomly assigned to one of the two doses, and measurements of aromatization were repeated after a period of time. Plasma estrogen levels were also measured before and during treatment. On an average, at the dose of 2.5 mg/ day, the estrogens fell by 80% in most studies.