Title> Steroid Hormones.HTML

INTRODUCTION


Steroid hormones are crucial substances for the proper function of the body. They mediate a wide variety of vital physiological functions ranging from anti-inflammatory agents to regulating events during pregnancy. They are synthesized and secreted into the bloodstream by endocrine glands such as the adrenal cortex and the gonads (ovary and testis). Steroid hormones are all characterized by the steroid nucleus which is composed of three six member rings and one five member ring, ingeniously labeled A, B, C, and D respectively. The steroid nucleus has the following Structure: 7

6 and is known as cyclopentanophenanthrene. This structure, which has six asymmetric cartoons, provides many possible stereo isomers, which one would expect since steroid hormones have an array of functions. Furthermore at C-17, there is a substituent which varies from hormone to hormone, depending on its function. 7


In discussing steroid hormones one is compelled to discuss cholesterol since it is the precursor for steroid hormones, as well as, bile acids and provitamin D. Cholesterol is a sterol which is a natural product derived from the steroid nucleus. Besides being the building block for steroid hormones, cholesterol is also a component of the cell membrane. It is thought that the cholesterol present in the cell membrane is responsible for allowing steroid hormones to enter the cell, bind to the hormone receptor, and ultimately to a specific site on the chromatin, in turn activating the gene in question. 10


Five classes of steroid hormones:

8
Both androgens and estrogens affect sexual development and function. They regulate sexual differentiation, the secondary sex characteristics, and sexual behavior patterns. A second class of ovarian steroids, C-21 compounds called progestins. Progestins help mediate the menstrual cycle and pregnancy. The mineralocorticoids largely function to regulate the excretion of salt and water by kidney. The glucocorticoids affect carbohydrate, protein, and lipid metabolism in manner nearly opposite to that of insulin, and influence a wide variety of other vital functions including inflammatory reactions and the capacity to cope with stress. 7

STRUCTURE / OVERVIEW:


Lets start by defining the words steroid and hormone. Steroid- is a fat soluble organic compound with an origin from plants or animals; it is characterized by its "steroid nucleus" and is a class of lipid. Hormone- a chemical messenger produced by endocrine glands, whose secretion are liberated directly into the bloodstream and transported to a distant part or parts of the body, where they exert a specific effect for the benefit of the body as a whole. 7

Steroid hormones are composed of three six membered rings and one five membered ring. These organic compounds are easily identified from a visual stand point by their "steroid nucleus", which is called cyclopentanophenanthrene. This nucleus looks like this (show transparency), all hormones have an oxygen at C-3 and a varied substituent at C-17. This substituent varies according to the different kind of steroid hormones at hand and can be either Alpha or Beta depending on where they are situated below the plane of the molecule. There are 6-centers of asymmetry, as a result, there are 64 possible compounds (stereoisomers) with this structure. They are located at C-5, C-10, C-8, C-9, C-14, and C-13. The rings adopt or puckered conformation over the boat form beacause its more stable (steric factor). 2


The endocrine glands are responsible for the production of steroid hormones, the adrenal gland, the ovary, and the testies, commonly known as the gonads. Many but not all steroids are hormones, however, not all steroids are hormones. They are target organ hormones meaning they exert a direct effect in peripheral tissue. Some examples of steroid hormones are 1) Estrogens, 2) Androgens (testosterone), 3) Progesterone, 4) Corticoids {Glucocorticoids and Mineral corticoids}. 7


Steroid hormones are made on a basis of need. Whenever the body needs a certain process done or needs a certain protein synthesized, the brain releases a signal to produce a certain type of hormone. The funny thing is, that the signals are transmitted through intermediary hormones. I would like to touch briefly on steroid hormones wide variety of uses. Progesterone- Regulates events during pregnancy Corticoids- Suppress inflammation reactions and regulates mineral and sugar metabolism. Androgens- Promote male sex development and maintain male sex characteristics. Estrogens- Promote female sex development In plants, auxin is an example of a steroid hormone that regulates longitudinal cell structure so as to allow bending of the stalk or stem in phototrophic response. A note: most steroid hormones are neither basic nor acidic, with estradole being an exception, being slightly acidic due to the phenol component. 7


It discussing steroid hormones, one is required to talk about cholesterol; cholesterol is know as a sterol, which is a natural product from the steroid nucleus. CHOLESTEROL Cholesterol is very important, as we learned, in the production of steroid hormones, in fact they are the precursor for bile acids (bile acids aid in fat digestion), steroid hormones, and provitamin D (When irradiated by sunlight it changes to vitamin D3.

Cholesterol, if we recall, is incorporated into the cell membrane by lipoproteins. There it plays a role in the regulation of membrane fluidity. It has been stated that cholesterol is probably responsible for permitting steroid hormones to enter the cell. 10

Since cholesterol is of major importance for steroid hormones, I would like to mention its biosynthesis. Believe it or not, this complex structure is derived from this simple structure, acetate ( give structure). Three molecules of acetate, derived metabolically combine to form isoprene, a 5-Carbon molecule, which then is used to compose squalene, a six unit isoprene molecule. Squalene can cyclisize and transform to form the 27 carbon structure of cholesterol. 4


FUNCTION / ROLE:


While all steroids contain the four-ring structure of the sterol nucleus and are remarkably similar in structure, they have enormous differences in their physiological effects. In vertebrates, steroid hormones function as genetic regulators, controlling the rate of synthesis of a particular protein. Steroid hormones are crucial for many enzymatic reactions, the glucocorticoids trigger a variety of cellular responses including the synthesis of second messengers such as cAMP in the short term and the modulation of protein synthesis in the long term. On the molecular level, the enzymatic reaction rates are controlled by phosphorylation and dephosphorylation by increasing the reaction cascades. The administration of estrogens (female sex hormone) such as B- estradiol causes chicken oviducts to increase their ovalbumin mRNA level from ~ 10 to ~ 50,000 molecules per cell. Similarly in insects, the steroid hormone ecdysone mediates several aspects of larval development. 8

Steroid hormones, which are non-polar molecules, simply pass through the plasma membranes of their target cell to the cytosol where they bind to their respective receptors. The steroid hormone penetrates the cell membrane and moves through the cytoplasm to the nucleus; it then couples with the receptor protein, forming a hormone receptor complex.

The steroid receptor complexes, in turn enter the nucleus where they bind to specific chromosomal enhancers so they can induce or repress, the transcription of their associated gene. The action of eukaryotic steroid receptors therefor appear to resemble that of transcriptional regulators such as E. coli complex. 9

For instance, different cell types may have the same receptor for a given steroid hormone and yet synthesize different proteins in response to the hormone. Only some genes are made available for activation by that steroid. 9


The following steroid hormones (glucocorticoids, mineralocorticoids, estrogens, androgens, progestines, and vitamin D) will be defined according to their origin and their major effects.


Glucocorticoids

Glucocorticoids originate in the adrenal cortex and affect mainly metabolism in diverse ways; decrease inflammation and increase resistance to stress.

Mineralocorticoids

Mineralocorticoids originate in adrenal cortex and maintain salt and water balance.

Estrogens

Estrogens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (female sexual determination).

Androgens

Androgens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (male sexual determination).

Progestins

Progestins originate from both ovaries and placenta, and mediate menstrual cycle and maintain pregnancy. 8

Androgens and estrogens play a major role in the development of both sexes secondary characteristics. Androgens, or testosterone and androsterone give the male its sex characteristics during puberty and for promoting tissue and muscle growth. Estrogens, or estrone and estradiol are forms of testosterone synthesized in the ovaries, which control female secondary characteristics and regulation of the menstrual cycle. Another sex hormone is needed for preparing the uterus for implantation of the ovum, this hormone is progesterone. 8

Hormones are needed throughout the body for various functions, however, just as important as these function is the regulation and control of these steroids.


REGULATION / CONTROL:


The production and secretion of steroid hormones are controlled by trophic hormones, which themselves are either proteins or peptides. For example, the target-organ steroid, cortisol, secreted by the adrenal is released by the action of the tropic peptide hormones work indirectly by stimulating other organs or, in this case, glands.7

I didn't find a lot of detailed processes by which steroid hormones are regulated but I did not find how cholesterol is controlled. I reasoned that since cholesterol is the precursor for steroid hormones, then by regulating how much cholesterol is synthesized, then that in turn controls the production of steroid hormones. Cholesterol is controlled by targeting the rate-limiting enzyme, HMG-CoA reductase.4

Studies have shown that dietary cholesterol (polyunsaturated fatty acids) suppresses synthesis of cholesterol: Two mechanisms exist. 1. Synthesis of enzymes is inhibited at transcription level. This makes sense since this conserves energy by stopping the production of synthesis at the start and not by going through useless processes that would waste energy. 2. Activity of the enzyme is modulated through a mechanism involving cyclic phosphorylation and dephosphorylation of the reductase protein (enzyme) itself. Levels of steroid hormones present at any given time is regulated by its rate of synthesis, which is ultimately controlled by brain signals.4


Estrogene and testosterone are very useful steroid hormones, however, excessive amounts of both can have serious effects. For example; we are aware that estrogen regulates female characteristics just as testosterone does for males. However, estrogen is also a crucial risk factor in breast cancer. There is a component known as indole-3-carbinol (I3C for short) that regulates the production of the malignant estrogen by altering the process by which the body synthesizes this. I3C causes the body to produce the benign byproduct instead of the highly estrogenic and potentially carcinogenic one. I3C is found in cabbage and broccoli, so better eat your vegetables.1


Circulating testosterone is not beneficial and needs to be controlled; it can cause prostate cancer. This problem has been treated with a luteinising hormone (LHRH) against it, however, this has not been proven completely effective since the adrenals also produce testosterone to a certain extent. Therefor, the concept of total androgen ablation or maximum androgen blocked has been created. This concept combines LHRH against an anti-androgen (such as flutamide) to suppress production of residual testosterone. This process works by antagonizing the androgen receptor in the hypothalamus, preventing it from binding to the androgen steroid hormone and producing stimulating production of testosterone.3

Other processes exist to inhibit production of certain steroid hormones. Inhibition of enzymes of androgen biosynthesis [e.g. Ketoconazole (a drug) suppresses synthesis of testosterone by inhibiting the enzyme, 17 (alpha- hydroxylase / {c.sub. 17,20}- Lyase). 5 (alpha)-dihydrotesterone main androgen causing prostate cancer, its derived from testosterone by testosterone-5 (alpha)-reductase. Inhibitors (flutamide, cypoterone aceterte, or rilutamide are known as anti-androgens) of this enzyme could prove essential in treating this disease.5

Works Cited

1 "Broccoli inhibits cancer - mostly". Science News Dec 24, 1994: p 442

2 Considine, Douglas M. Encyclopedia of Chemistry. 4th ed, 1984.

3 Jarman, M. "Drug development" The Lancet Oct 9, 1993: p 904

4 Mathews, Christopher and van-Holde, K.E. Biochemistry. Redwood City, California: The Benjamin/Cummings Publishing Co., 1990.

5 "Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients". The Lancet. July 29, 1995: p 265.

6 McMurry, John. Organic Chemistry. Pacific Grove, California: Brooks Cole Publishing Co., 1990.

7 "Steroids." McGraw- Hill Encyclopedia of Science and Technology. 1992 ed.

8 Voet, Donald and Judith. Biochemistry. New York: John Wiley and Sons, 1990.

9 Weaver, Robert and Hedrick, Philip. Genetics. Kansas: Wm. C. Brown publishers, 1989.

10 Witzmann, Rupert. Steroids: Keys to life. New York: Van Norstrand Reinhold Co., 1977

PRECISE on REGULATION


If cholesterol is to behave as the building block for all the steroid hormones then cytochrome P-450 needs to be present and fully functional. Cytochrome P-450 is an enzyme that oxidizes/reduces and is responsible for the oxidation of cholesterol, which is a necessary step if it is to become progesterone. Progesterone is the species that ultimately converts to the other steroid hormones through a variety of reactions. Therefore, the regulation of steroid hormones can be indirectly tied to the inhibition of l;this enzyme, known as cytochrome P-450. The mechanism by which this occurs is not detailed specifically; however, one can reason that the inhibition of this enzyme will indeed have an effect on the regulation of cholesterol and ultimately on all the steroid hormones. It is no surprise to find that by inhibition cytochrome P-450, which is present at the beginning of the complex process of producing steroid hormones, the body avoids wasting energy. This stands to be a very effective and reasonable mechanism by which steroid hormones can be regulated. Some may state that this mechanism is a rather crude process; however, nature enjoys simplicity and tries to avoid making regulation of any species terribly difficult and complex.


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