Endocrine system - University of Babylon



Endocrine system

In physiology, the endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream to regulate the body. The endocrine system is in contrast to exocrine system, which secretes its chemicals using ducts. It words endo meaning inside, within, and crinis for secrete. The endocrine system is an information signal system like the nervous system, yet its effects and mechanism are classifiably different. The endocrine systems effects are slow to initiate, and prolonged in their response, lasting for hours to weeks. The nervous system sends information very quickly, and responses are generally short lived. Hormones are substances (chemical mediators) released from endocrine tissue into the bloodstream where they travel to target tissue and generate a response. Hormones regulate various human functions, including Metabolism, growth and development, tissue function, and mood. The field of study dealing with the endocrine system and its disorders is endocrinology, a branch of internal medicine.

Features of endocrine glands are, in general, their ductless nature, their vascularity, and usually the presence of intracellular vacuoles or granules storing their hormones. In contrast, exocrine glands, such as salivary glands, sweat glands, and glands within the gastrointestinal tract, tend to be much less vascular and have ducts or a hollow lumen.

In addition to the specialised endocrine organs mentioned above, many other organs that are part of other body systems, such as the kidney, liver, heart and gonads, have secondary endocrine functions. For example the kidney secretes endocrine hormones such as erythropoietin and renin.

The endocrine system is made up of a series of glands that produce chemicals called hormones. A number of glands that signal each other in sequence is usually referred to as an axis, for example, the hypothalamic-pituitary-adrenal axis.

Hormone

Epinephrine (adrenaline), a catecholamine-type hormone

A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one cell to another. All multicellular organisms produce hormones; plant hormones are also called phytohormones. Hormones in animals are often transported in the blood. Cells respond to a hormone when they express a specific receptor for that hormone. The hormone binds to the receptor protein, resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses.

Endocrine hormone molecules are secreted (released) directly into the bloodstream, whereas exocrine hormones (or ectohormones) are secreted directly into a duct, and, from the duct, they flow either into the bloodstream or from cell to cell by diffusion in a process known as paracrine signalling.

Recently it has been found that a variety of exogenous modern chemical compounds have hormone-like effects on both humans and wildlife. Their interference with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body are responsible of homeostasis, reproduction, development, and/or behavioural changes sameway as the endogenous produced hormones

Hormones as a signal

Hormonal signaling involves the following:[

1. Biosynthesis of a particular hormone in a particular tissue

2. Storage and secretion of the hormone

3. Transport of the hormone to the target cell(s)

4. Recognition of the hormone by an associated cell membrane or intracellular receptor protein

5. Relay and amplification of the received hormonal signal via a signal transduction process: This then leads to a cellular response. The reaction of the target cells may then be recognized by the original hormone-producing cells, leading to a down-regulation in hormone production. This is an example of a homeostatic negative feedback loop.

6. Degradation of the hormone.

Hormone cells are typically of a specialized cell type, residing within a particular endocrine gland, such as thyroid gland, ovaries, and testes. Hormones exit their cell of origin via exocytosis or another means of membrane transport. The hierarchical model is an oversimplification of the hormonal signaling process. Cellular recipients of a particular hormonal signal may be one of several cell types that reside within a number of different tissues, as is the case for insulin, which triggers a diverse range of systemic physiological effects. Different tissue types may also respond differently to the same hormonal signal. Because of this, hormonal signaling is elaborate and hard to dissect]

Interactions with receptors

Most hormones initiate a cellular response by initially combining with either a specific intracellular or cell membrane associated receptor protein. A cell may have several different receptors that recognize the same hormone and activate different signal transduction pathways, or a cell may have several different receptors that recognize different hormones and activate the same biochemical pathway.

For many hormones, including most protein hormones, the receptor is membrane-associated and embedded in the plasma membrane at the surface of the cell. The interaction of hormone and receptor typically triggers a cascade of secondary effects within the cytoplasm of the cell, often involving phosphorylation or dephosphorylation of various other cytoplasmic proteins, changes in ion channel permeability, or increased concentrations of intracellular molecules that may act as secondary messengers (e.g., cyclic AMP). Some protein hormones also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism.

For hormones such as steroid or thyroid hormones, their receptors are located intracellularly within the cytoplasm of their target cell. To bind their receptors, these hormones must cross the cell membrane. They can do so because they are lipid-soluble. The combined hormone-receptor complex then moves across the nuclear membrane into the nucleus of the cell, where it binds to specific DNA sequences, effectively amplifying or suppressing the action of certain genes, and affecting protein synthesis However, it has been shown that not all steroid receptors are located intracellularly. some are associated with the plasma membrane

An important consideration, dictating the level at which cellular signal transduction pathways are activated in response to a hormonal signal, is the effective concentration of hormone-receptor complexes that are formed. Hormone-receptor complex concentrations are effectively determined by three factors:

1. The number of hormone molecules available for complex formation

2. The number of receptor molecules available for complex formation

3. The binding affinity between hormone and receptor.

The number of hormone molecules available for complex formation is usually the key factor in determining the level at which signal transduction pathways are activated, the number of hormone molecules available being determined by the concentration of circulating hormone, which is in turn influenced by the level and rate at which they are secreted by biosynthetic cells. The number of receptors at the cell surface of the receiving cell can also be varied, as can the affinity between the hormone and its receptor.

Physiology of hormones

Most cells are capable of producing one or more molecules, which act as signaling molecules to other cells, altering their growth, function, or metabolism. The classical hormones produced by cells in the endocrine glands mentioned so far in this article are cellular products, specialized to serve as regulators at the overall organism level. However, they may also exert their effects solely within the tissue in which they are produced and originally released.

The rate of hormone biosynthesis and secretion is often regulated by a homeostatic negative feedback control mechanism. Such a mechanism depends on factors that influence the metabolism and excretion of hormones. Thus, higher hormone concentration alone cannot trigger the negative feedback mechanism. Negative feedback must be triggered by overproduction of an "effect" of the hormone.

Hormone secretion can be stimulated and inhibited by:

• Other hormones (stimulating- or releasing -hormones)

• Plasma concentrations of ions or nutrients, as well as binding globulins

• Neurons and mental activity

• Environmental changes, e.g., of light or temperature

One special group of hormones is the tropic hormones that stimulate the hormone production of other endocrine glands. For example, thyroid-stimulating hormone (TSH) causes growth and increased activity of another endocrine gland, the thyroid, which increases output of thyroid hormones.

A recently identified class of hormones is that of the "hunger hormones" - ghrelin, orexin, and PYY 3-36 - and "satiety hormones" - e.g., cholecystokinin, leptin, nesfatin-1, obestatin.

To release active hormones quickly into the circulation, hormone biosynthetic cells may produce and store biologically inactive hormones in the form of pre- or prohormones. These can then be quickly converted into their active hormone form in response to a particular stimulus.

Effects of hormones

Hormones have the following effects on the body:

• stimulation or inhibition of growth

• mood swings

• induction or suppression of apoptosis (programmed cell death)

• activation or inhibition of the immune system

• regulation of metabolism

• preparation of the body for mating, fighting, fleeing, and other activity

• preparation of the body for a new phase of life, such as puberty, parenting, and menopause

• control of the reproductive cycle

• hunger cravings

A hormone may also regulate the production and release of other hormones. Hormone signals control the internal environment of the body through homeostasis.

Chemical classes of hormones

Vertebrate hormones fall into three chemical classes:

• Peptide hormones consist of chains of amino acids. Examples of small peptide hormones are TRH and vasopressin. Peptides composed of scores or hundreds of amino acids are referred to as proteins. Examples of protein hormones include insulin and growth hormone. More complex protein hormones bear carbohydrate side-chains and are called glycoprotein hormones. Luteinizing hormone, follicle-stimulating hormone and thyroid-stimulating hormone are glycoprotein hormones. There's also another type of hydrophilics hormones. They are called nonpeptide hormones. Although they don't have peptide connections, they are assimilated as peptide hormones.

• Lipid and phospholipid-derived hormones derive from lipids such as linoleic acid and arachidonic acid and phospholipids. The main classes are the steroid hormones that derive from cholesterol and the eicosanoids. Examples of steroid hormones are testosterone and cortisol. Sterol hormones such as calcitriol are a homologous system. The adrenal cortex and the gonads are primary sources of steroid hormones. Examples of eicosanoids are the widely studied prostaglandins.

• Monoamines derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan by the action of aromatic amino acid decarboxylase enzymes. Examples of monoamines are thyroxine and adrenaline.

Pharmacology

Many hormones and their analogues are used as medication. The most commonly prescribed hormones are estrogens and progestagens (as methods of hormonal contraception and as HRT), thyroxine (as levothyroxine, for hypothyroidism) and steroids (for autoimmune diseases and several respiratory disorders). Insulin is used by many diabetics. Local preparations for use in otolaryngology often contain pharmacologic equivalents of adrenaline, while steroid and vitamin D creams are used extensively in dermatological practice.

A "pharmacologic dose" of a hormone is a medical usage referring to an amount of a hormone far greater than naturally occurs in a healthy body. The effects of pharmacologic doses of hormones may be different from responses to naturally occurring amounts and may be therapeutically useful. An example is the ability of pharmacologic doses of glucocorticoid to suppress inflammation.

A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland. The anterior pituitary regulates several physiological processes including stress, growth, and reproduction.

Its regulatory functions are achieved through the secretion of various peptide hormones that act on target organs including the adrenal gland, liver, bone, thyroid gland, and gonads. The anterior pituitary itself is regulated by the hypothalamus and by negative feedback from these target organs.

Disorders of the anterior pituitary are generally classified by the presence of over- or underproduction of pituitary hormones. For example, a prolactinoma is a pituitary adenoma that overproduces prolactin. In Sheehan's syndrome of postpartum hypopituitarism, the anterior pituitary uniformly malfunctions and underproduces all hormones. Proper function of the anterior pituitary and of the organs it regulates can often be ascertained via blood tests that measure hormone levels.

Anatomy

The pituitary gland is a pea-sized gland that sits in a protective bony enclosure called the sella turcica. It is composed of three lobes: anterior, intermediate, and posterior. In many animals, these three lobes are distinct. However, in humans, the intermediate lobe is but a few cell layers thick and indistinct; as a result, it is often considered part of the anterior pituitary. In all animals, the fleshy, glandular anterior pituitary is distinct from the neural composition of the posterior pituitary.

The anterior pituitary is composed of multiple parts:

The pars distalis, or "distal part", comprises the majority of the anterior pituitary and is where the bulk of pituitary hormone production occurs. Occasionally, "pars distalis" is incorrectly used as a synonym for the anterior pituitary.[

Pars tuberalis

The pars tuberalis, or "tubular part", forms a sheath extending up from the pars distalis and wrapping around the pituitary stalk. Its function is poorly understood.

Pars intermedia

The pars intermedia, or "intermediate part", sits between the pars distalis and the posterior pituitary and is often very small in humans.

Hormone secretion

The posterior pituitary as a down growth of the brain, is a neurosecretory organThe secretion of hormones from the posterior pituitary is controlled directly by neurons in the hypothalamus. The connecting stalk between the hypothalamus and the lobes of the pituitary gland, the infundibulum, carries the hormones of the posterior pituitary from nuclei in the hypothalamus. The hypothalmic supraoptic nuclei manufacture anti-diruetic hormone and the hypothalmic paraventricular nuclei manufacture oxytocin. These hormones are then stored in pituitary axons until their release is triggered .

The anterior pituitary is a glandular secretory organ. The secretion of hormones from the anterior pituitary is controlled by inhibiting and releasing factors secreted by neurons in the hypothalamus. These inhibiting and releasing factors are released into a primary capillary plexus where they travel, via portal veins, to a secondary capillary plexus where they stimulate the glandular tissue of the anterior pituitary to release its hormones.

Embryology

The anterior pituitary arises from an invagination of the oral ectoderm and forms Rathke's pouch. This contrasts with the posterior pituitary, which originates from neuroectoderm.

Major hormones secreted

|Hormone |Other names |Symbol(s) |Structure |Secretory cells|Staining |Target |Effect |

|Adrenocorticotropic |Corticotropin |ACTH |Polypeptide |Corticotrophs |Basophil |Adrenal |Secretion of |

|hormone | | | | | |gland |glucocorticoids |

|Beta-endorphin | | |Polypeptide |Corticotrophs |Basophil |Opioid |Inhibit perception of |

| | | | | | |receptor |pain |

|Thyroid-stimulating |Thyrotropin |TSH |Glycoprotein |Thyrotrophs |Basophil |Thyroid |Secretion of thyroid |

|hormone | | | | | |gland |hormones |

|Follicle-stimulating |- |FSH |Glycoprotein |Gonadotrophs |Basophil |Gonads |Growth of reproductive |

|hormone | | | | | | |system |

|Luteinizing hormone |Lutropin |LH, ICSH |Glycoprotein |Gonadotrophs |Basophil |Gonads |Sex hormone production |

|Growth hormone |Somatotropin |GH, STH |Polypeptide |Somatotrophs |Acidophil |Liver, |Promotes growth; lipid |

| | | | | | |adipose |and carbohydrate |

| | | | | | |tissue |metabolism |

|Prolactin |Lactogenic |PRL |Polypeptide |Lactotrophs and|Acidophil |Ovaries, |Secretion of |

| |hormone | | |Mammotrophs | |mammary |estrogens/progesterone; |

| | | | | | |glands |milk production |

The acidophilic cells (GH and PRL) have extensive rough endoplasmic reticulum and produce single chain polypeptides without any glycosylation or phosphorylation. Basophilic staining results from lysosome action modifying the hormones (or prohormones in the case of corticotrophs) by glycosylation.

Regulation

Hormone secretion from the anterior pituitary gland is regulated by hormones secreted by the hypothalamus. Neuroendocrine neurons in the hypothalamus project axons to the median eminence, at the base of the brain. At this site, these neurons can release substances into small blood vessels that travel directly to the anterior pituitary gland (the hypothalamo-hypophysial portal vessels).

Tropic hormone

Tropic hormones are hormones which have other endocrine glands as their target. Most tropic hormones are produced and secreted by the anterior pituitary. The hypothalamus secretes tropic hormones that target the anterior pituitary, and the thyroid gland secretes thyroxine, which targets the hypothalamus and therefore can be considered a tropic hormone

Tropic hormones from the anterior pituitary include:

• Thyroid-stimulating hormone (TSH or thyrotropin) – stimulates the thyroid gland to make and release thyroid hormone.

• Adrenocorticotropic hormone (ACTH or corticotropin) – stimulates the adrenal cortex to release glucocorticoids.

• Luteinizing hormone (LH) – stimulates the release of steroid hormones in gonads—the ovary and testes. Follicle-stimulating hormone (FSH) – stimulates the maturation of eggs and production of sperm.

• Growth hormone (GH)has both tropic and non-tropic effects. Growth hormone's major tropic effect is it releases insulin-like growth factors (IGFs) from the liver which causes bone growth. The hypothalamus controls the release of hormones from the anterior pituitary by secreting a class of hypothalamic neurohormones called releasing and release-inhibiting hormones—which are released to the hypothalamo-hypophyseal portal system and act on the anterior pituitary.

Non-tropic hormone

Non-tropic hormones are hormones that directly stimulate target cells to induce effects. This differs from the tropic hormones which act on another endocrine gland.

Most endocrine glands, such as the gonads, pancreas, and adrenal glands , produce non-tropic hormones. Those released from the pituitary gland in the brain include:

• Oxytocin (posterior lobe)- stimulates milk letdown in females.

• Prolactin (PRL) (anterior lobe) - is remarkable for the diversity of its effects among vertebrate species. The varied roles suggest that prolactin is an ancient hormone with functions that have diversified during the evolution of vertebrate groups.

• Melanocyte-stimulating hormone (MSH) (intermediate lobe) - regulates the activity of pigment-containing cells in the skins of some amphibians. In mammals, MSH act on neurons in the brain, inhibiting hunger and make skin colour dark it also can protect body form uv-ray

• Growth hormone (GH)has both tropic and non-tropic effects. GH directly stimulates muscle growth, a non-tropic effect. [1]

Estrogen

Estriol. Note two hydroxyl (-OH) groups attached to the D ring (rightmost ring)

Estradiol. Note one hydroxyl group attached to the D ring. The 'di' refers both to this hydroxyl and the one on the A ring (leftmost).

Estrone. Note the ketone (=O) group attached to the D ring.

Estrogens (AmE), oestrogens (BE), or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals, and functioning as the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal. Their name comes from the Greek words estrus/οίστρος = sexual desire + gen/γόνο = to generate.

Estrogens are synthesized in all vertebratesas well as some insects. Their presence in both vertebrates and insects suggests that estrogenic sex hormones have an ancient history.

Estrogens are used as part of some oral contraceptives, in estrogen replacement therapy for postmenopausal women, and in hormone replacement therapy for trans women.

Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the expression of many genes.[3] Additionally, estrogens have been shown to activate a G protein-coupled receptor, GPR30.[4]

Types

Steroidal

The three major naturally occurring oestrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Oestradiol (E2) is the predominant form in nonpregnant females, estrone is produced during menopause, and estriol is the primary oestrogen of pregnancy. In the body these are all produced from androgens through actions of enzymes.

• From menarche to menopause the primary oestrogen is 17β-estradiol. In postmenopausal women more estrone is present than oestradiol.

• Oestradiol is produced from testosterone and estrone from androstenedione by aromatase.

• Oestrone is weaker than estradiol.

Premarin, a commonly prescribed estrogenic drug, contains the steroidal oestrogens equilin and equilenin. There are oestradiol skin patches such as Estraderm (the original brand, introduced in the late 1980s) that offer a completely natural alternative. (A skin patch rather than pill also has the advantage of direct transmission into the blood stream without going through the liver.)

Reference ranges for the blood content of estradiol, the primary type of estrogen, during the menstrual cycle.[5]

Nonsteroidal

A range of synthetic and natural substances have been identified that also possess estrogenic activity.[6]

• Synthetic substances of this kind are known as xenoestrogens.

• Plant products with estrogenic activity are called phytoestrogens.

• Those produced by fungi are known as mycoestrogens.

Unlike estrogens produced by mammals, these substances are not necessarily steroids.

Biosynthesis

Steroidogenesis, showing estrogens at bottom right as in pink triangle.

Oestrogens are produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. Luteinizing hormone (LH) stimulates the production of estrogen in the ovaries. Some oestrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts. These secondary sources of oestrogens are especially important in postmenopausal women. Fat cells also produce oestrogen, potentially being the reason why underweight or overweight are risk factors for infertility. In females, synthesis of oestrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to oestrone or oestradiol, either immediately or through testosterone. The conversion of testosterone to oestradiol, and of androstenedione to oestrone, is catalyzed by the enzyme aromatase.

Oestradiol levels vary through the menstrual cycle, with levels highest just before ovulation.

Function

The actions of estrogen are mediated by the Estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls gene expression. Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor. The estrogen:ER complex binds to specific DNA sequences called a Hormone response element to activate the transcription of some 137 ER-regulated genes, of which 89 are direct target genes Since estrogen enters all cells, its action are dependent on the presence of the ER in the cell. The ER is expressed in specific tissues including the ovary, uterus and breast.

While oestrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, and are also involved in the thickening of the endometrium and other aspects of regulating the menstrual cycle. In males, oestrogen regulates certain functions of the reproductive system important to the maturation of sperm and may be necessary for a healthy libido.[13][14] Furthermore, there are several other structural changes induced by oestrogen in addition to other functions.

• Structural

o promote formation of female secondary sex characteristics

o accelerate metabolism

o reduce muscle mass

o increase fat stores

o stimulate endometrial growth

o increase uterine growth

o increase vaginal lubrication

o thicken the vaginal wall

o maintenance of vessel and skin

o reduce bone resorption, increase bone formation

o morphic change (endomorphic -> mesomorphic -> ectomorphic)

• protein synthesis

o increase hepatic production of binding proteins

• coagulation

o increase circulating level of factors 2, 7, 9, 10, plasminogen

o decrease antithrombin III

o increase platelet adhesiveness

• Lipid

o increase HDL, triglyceride

o decrease LDL, fat deposition

• Fluid balance

o salt (sodium) and water retention

o increase cortisol, SHBG

• Gastrointestinal tract

o reduce bowel motility

o increase cholesterol in bile

• Melanin

o increase pheomelanin, reduce eumelanin

• Cancer

o support hormone-sensitive breast cancers (see section below)

• Lung function

o promotes lung function by supporting alveoli (in rodents but probably in humans). Sexual desire is dependent on androgen levels rather than estrogen levels Fetal development

In mice, oestrogens (which are locally aromatized from androgens in the brain) play an important role in psychosexual differentiation, for example, by masculinizing territorial behavior the same is not true in humans.] In humans, the masculinizing effects of prenatal androgens on behavior (and other tissues, with the possible exception of effects on bone) appear to act exclusively through the androgen receptor As a result, the utility of rodent models for studying human psychosexual differentiation has been questioned

Mental health

Oestrogen is considered to play a significant role in women’s mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained oestrogen low levels correlates with significant mood lowering. Clinical recovery from postpartum, perimenopause, and postmenopause depression has been shown to be effective after levels of oestrogen were stabilized and/or restored.[21][22]

Low oestrogen levels in male lab mice may be one cause of obsessive–compulsive disorder (OCD). When oestrogen levels were raised through the increased activity of the enzyme aromatase in male lab mice, OCD rituals were dramatically decreased. Hypothalamic protein levels in the gene COMT are enhanced by increasing oestrogen levels which is believed to return mice that displayed OCD rituals to normal activity. Aromatase deficiency is ultimately suspected which is involved in the synthesis of oestrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder.[23]

Medical applications

Oral contraceptives

Since oestrogen circulating in the blood can negatively feed-back to reduce circulating levels of FSH and LH, most oral contraceptives contain a synthetic oestrogen, along with a synthetic progestin. Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.

Hormone replacement therapy

As more fully discussed in the article on Hormone replacement therapy, oestrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flushes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50-70% and spinal bone density increases by ~5% in those women treated with estrogen within 3 years of the onset of menopause and for 5–10 years thereafter.

Before the specific dangers of conjugated equine oestrogens were well understood, standard therapy was 0.625 mg/day of conjugated equine oestrogens (such as Premarin). There are, however, risks associated with conjugated equine oestrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally administered conjugated equine oestrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of oestrogen supplement, a high oral dose of conjugated equine oestrogens (Premarin alone and with medroxyprogesterone acetate as PremPro).

In a study by the NIH, esterified oestrogens were not proven to pose the same risks to health as conjugated equine oestrogens. Hormone replacement therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause may reduce the incidence of cardiovascular disease, although this hypothesis has yet to be tested in randomized trials. Estrogen appears to have a protector effect on atherosclerosis : it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.

Research is underway to determine if risks of oestrogen supplement use are the same for all methods of delivery. In particular, estrogen applied topically may have a different spectrum of side-effects than when administered orally and transdermal estrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of thrombo-embolic disease.

Oestrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism, castration, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Oestrogens can also be used to suppress lactation after child birth.

Breast cancer

About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers. Suppression of production of estrogen in the body is a treatment for these cancers.

Recently researchers have discovered that the common table mushroom has anti-aromatase] properties and therefore possible anti-estrogen activity. Clinical trials have begun in the United States looking into whether the table mushroom can prevent breast cancer in people A recent study has highlighted the importance of this research. In 2009, a case-control study of the eating habits of 2,018 women, revealed that women who consumed mushrooms had an approximately 50% lower incidence of breast cancer. Women who consumed mushrooms and green tea had a 90% lower incidence of breast cancer

Hormone-receptor-positive breast cancers are treated with drugs which suppress production of estrogen in the body This technique, in the context of treatment of breast cancer, is known variously as hormonal therapy, hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy). Certain foods such as soy may also suppress the proliferative effects of estrogen and are used as an alternative to hormone therapy.

Prostate cancer

Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.

Miscellaneous

In humans and mice, estrogen promotes wound healing. At one time, estrogen was used to induce growth attenuation in tall girls. Recently, estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size

Most recently, estrogen has been used in experimental research as a way to treat patients suffering from bulimia nervosa, in addition to Cognitive Behavioral Therapy, which is the established standard for treatment in bulimia cases. The estrogen research

Estrogen has also been used in studies which indicate that it may be an effective drug for use in the treatment of traumatic liver injury.

Health risks and warning labels

Hyperestrogenemia (elevated levels of estrogen) may be a result of exogenous administration of estrogen or estrogen-like substances, or may be a result of physiologic conditions such as pregnancy. Any of these causes is linked with an increase in the risk of thrombosis.

The estrogen-alone substudy of the WHI reported an increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using 0.625 mg of Premarin conjugated equine estrogens (CEE). The estrogen-plus-progestin substudy of the WHI reported an increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and DVT in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using PremPro, which is 0.625 mg of CEE with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).

The labeling of estrogen-only products in the U.S. includes a boxed warning that unopposed estrogen (without progestagen) therapy increases the risk of endometrial cancer. Based on a review of data from the WHI, on January 8, 2003 the FDA changed the labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to include a new boxed warning about cardiovascul and other risk

Progesterone

Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.

Progesterone is commonly manufactured from the yam family, Dioscorea. Dioscorea produces large amounts of a steroid called diosgenin, which can be converted into progesterone in the laboratory.

Chemistry

Progesterone was independently discovered by four research groups.

Willard Myron Allen co-discovered progesterone with his anatomy professor George Washington Corner at the University of Rochester Medical School in 1933. Allen first determined its melting point, molecular weight, and partial molecular structure. He also gave it the name Progesterone derived from Progestational Steroidal ketone

Like other steroids, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone contains ketone and oxygenated functional groups, as well as two methyl branches. Like all steroid hormones, it is hydrophobic.

Sources

[

Progesterone is produced in the ovaries (to be specific, after ovulation in the corpus luteum), the adrenal glands (near the kidney), and, during pregnancy, in the placenta. Progesterone is also stored in adipose (fat) tissue.

In humans, increasing amounts of progesterone are produced during pregnancy:

• At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCG) from the conceptus.

• However, after the 8th week, production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.

• An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bioavailable progesterone goes up

[edit] Plants

In at least one plant, Juglans regia, progesterone has been detected. In addition, progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana is a plant that is part of the yam family native to Mexico It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone Diosgenin and progesterone are found in other Dioscorea species as well.

Another plant that contains substances readily convertible to progesterone is Dioscorea pseudojaponica native to Taiwan. Research has shown that the Taiwanese yam contains saponins — steroids that can be converted to diosgenin and thence to progesterone. Many other Dioscorea species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are Dioscorea villosa and Dioscorea polygonoides. One study showed that the Dioscorea villosa contains 3.5% diosgenin.[11] Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry.[12] Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.[13]

BiosySynthesis

Top: Conversion of cholesterol (1) into pregnenolone (3) to progesterone (6).

Bottom: Progesterone is important for aldosterone (mineralocorticoid) synthesis, as 17-hydroxyprogesterone is for cortisol (glucocorticoid), and androstenedione for sex steroids.

In mammals, progesterone (6), like all other steroid hormones, is synthesized from pregnenolone (3), which in turn is derived from cholesterol (1) (see the upper half of the figure to the right).

Cholesterol (1) undergoes double oxidation to produce 20,22-dihydroxycholesterol (2). This vicinal diol is then further oxidized with loss of the side chain starting at position C-22 to produce pregnenolone (3). This reaction is catalyzed by cytochrome P450scc. The conversion of pregnenolone to progesterone takes place in two steps. First, the 3-hydroxyl group is oxidized to a keto group (4) and second, the double bond is moved to C-4, from C-5 through a keto/enol tautomerization reaction This reaction is catalyzed by 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase.

Progesterone in turn (see lower half of figure to the right) is the precursor of the mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone (another natural progestogen) of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone and estradiol.

Pregenolone and progesterone can also be synthesized by yeast

Laboratory

The Marker semisynthesis of progesterone from diosgenin.

An economical semisynthesis of progesterone from the plant steroid diosgenin isolated from yams was developed by Russell Marker in 1940 for the Parke-Davis pharmaceutical company (see figure to the right).[16] This synthesis is known as the Marker degradation. Additional semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, cortisone can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in chloroform to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone

Levels

In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.

Progesterone levels are relatively low in children and postmenopausal women. Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.

Progesterone levels during the menstrual cycle

- The ranges denoted By biological stage may be used in closely monitored menstrual cycles in regard to other markers of its biological progression, with the time scale being compressed or stretched to how much faster or slower, respectively, the cycle progresses compared to an average cycle.

- The ranges denoted Inter-cycle variability are more appropriate to use in non-monitored cycles with only the beginning of menstruation known, but where the woman accurately knows her average cycle lengths and time of ovulation, and that they are somewhat averagely regular, with the time scale being compressed or stretched to how much a woman's average cycle length is shorter or longer, respectively, than the average of the population.

- The ranges denoted Inter-woman variability are more appropriate to use when the average cycle lengths and time of ovulation are unknown, but only the beginning of menstruation is given.

Effects

Micrograph showing changes to the endometrium due to progesterone (decidualization) H&E stain.

Progesterone exerts its primary action through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated In addition, progesterone is a highly potent antagonist of the mineralocorticoid receptor (MR, the receptor for aldosterone and other mineralocorticosteroids). It prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and other corticosteroids such as cortisol and corticosterone.

Progesterone has a number of physiological effects that are amplified in the presence of estrogen. Estrogen through estrogen receptors upregulates the expression of progesterone receptors Also, elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.

Reproductive system

Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female tract before fertilization occurs, though the receptor(s) as yet remain unidentified. Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes, slow calcium oscillations,] now thought to possibly regulate motility. Interestingly progesterone has also been shown to demonstrate effects on octopus spermatozoa

Progesterone modulates the activity of CatSper (cation channels of sperm) voltage-gated Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis). Hence substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.

Progesterone is sometimes called the "hormone of pregnancy and it has many roles relating to the development of the fetus:

• Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impenetrable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding.

• During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.

• Progesterone decreases contractility of the uterine smooth muscle

• In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.

• A drop in progesterone levels is possibly one step that facilitates the onset of labor.

The fetus metabolizes placental progesterone in the production of adrenal steroids.t] Nervous system

Progesterone, like pregnenolone and dehydroepiandrosterone, belongs to the group of neurosteroids. It can be synthesized within the central nervous system and also serves as a precursor to another major neurosteroid, allopregnanolone.

Neurosteroids affect synaptic functioning, are neuroprotective, and affect myelination.[34] They are investigated for their potential to improve memory and cognitive ability. Progesterone affects regulation of apoptotic genes.

Its effect as a neurosteroid works predominantly through the GSK-3 beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar mood stabilizers, lithium and valproic acid.)

Other syndromes

• It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.

• It increases core temperature (thermogenic function) during ovulation.

• It reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (Progesterone receptors are widely present in submucosal tissue.)

• It acts as an antiinflammatory agent and regulates the immune response.

• It reduces gall-bladder activity

• It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.

• It may affect gum health, increasing risk of gingivitis (gum inflammation) and tooth decay.

• It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.

Adverse effects

Pill form of progesterone (actually a synthetic version such as Progestogen) taken at 400 mg as cited by the following patent can cause increased fluid retention, which may result in epilepsy, migraine, asthma, cardiac or renal dysfunction. Blood clots that can result in strokes and heart attacks, which may lead to death or long-term disability, may develop; pulmonary embolus or breast cancer can also develop as a result of progesterone therapy. Progesterone is associated with an increased risk of thrombotic disorders such as thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis

Common adverse effects include cramps, abdominal pain, skeletal pain, perineal pain, headache, arthralgia, constipation, dyspareunia, nocturia, diarrhea, nausea, vomiting, breast enlargement, joint pain, flatulence, hot flushes, decreased libido, thirst, increased appetite, nervousness, drowsiness, excessive urination at night. Psychiatric effects including depression, mood swings, emotional instability, aggression, abnormal crying, insomnia, forgetfulness, sleep disorders. Less frequent adverse effects that may occur include allergy, anemia, bloating, fatigue, tremor, urticaria, pain, conjunctivitis, dizziness, vomiting, myalgia, back pain, breast pain, genital itching, genital yeast infection, upper respiratory tract infection, cystitis, dysuria, asthenia, xerophthalmia, syncope, dysmenorrhea, premenstrual tension, gastritis, urinary tract infection, vaginal discharge, pharyngitis, sweating, hyperventilation, vaginal dryness, dyspnea, fever, edema, flu-like symptoms, dry mouth, rhinitis, leg pain, skin discoloration, skin disorders, seborrhea, sinusitis, acne.

Current research suggests that progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes It has been shown that women with high levels of progesterone during pregnancy are more likely to develop glucose abnormalities.

Medical applications

The use of progesterone and its analogues have many medical applications, both to address acute situations and to address the long-term decline of natural progesterone levels. Because of the poor bioavailability of progesterone when taken orally, many synthetic progestins have been designed with improved oral bioavailability.[40] Progesteone was approved by the United States Food and Drug Administration as vaginal gel on July 31, 1997 an oral capsule on May 14, 1998] in an injection form on April 25, 2001[] and as a vaginal insert on June 21, 2007. In Italy and Span, Progesterone is sold under the trademarkProgeffik.

Bioavailability

The route of administration impacts the effect of the drug. Given orally, progesterone has a wide person-to-person variability in absorption and bioavailability while synthetic progestins are rapidly absorbed with a longer half-life than progesterone and maintain stable levels in the blood.

Progesterone does not dissolve in water and is poorly absorbed when taken orally unless micronized in oil. Products are often sold as capsules containing micronised progesterone in oil. Progesterone can also be administered through vaginal or rectal suppositories or pessaries, transdermally through a gel or cream, or via injection (though the latter has a short half-life requiring daily administration).

"Natural progesterone" products derived from yams, do not require a prescription but there is no evidence the human body can convert its active ingredient (diosgenin, the plant steroid that is chemically converted to produce progesterone industrially[16]) into progesterone.

Specific uses

• Progesterone is used to support pregnancy in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration, PIO injections are not FDA-approved for use in pregnancy. A recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections In addition, a recent case-matched study comparing vaginal progesterone with PIO injections showed that live birth rates were nearly identical with both methods.

• Progesterone is used to control anovulatory bleeding. It is also used to prepare uterine lining in infertility therapy and to support early pregnancy. Patients with recurrent pregnancy loss due to inadequate progesterone production may receive progesterone.

• Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop.

• Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth.

A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.] In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline. An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment. Progesterone is used in hormone therapy for male-to-female transsexuals and other women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic, the breast shape conical and the areola immature]. Progesterone can correct those even after years of inadequate hormonal treatment[d]. Research usually cited against such value was conducted using Provera, a synthetic progestin[citation needed]. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphic proportions of those.

• Progesterone receptor antagonists, or selective progesterone receptor modulators (SPRM)s, such as RU-486 (Mifepristone), can be used to prevent conception or induce medical abortions.

Note that methods of hormonal contraception do not contain progesterone but a progestin.

Progesterone may affect male behavior. Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa.[citation needed]

Aging

Since most progesterone in males is created during testicular production of testosterone, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagens (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.

The tendency for progesterone to have a regulatory effect, the presence of progesterone receptors in many types of body tissue, and the pattern of deterioration (or tumor formation) in many of those increasing in later years when progesterone levels have dropped, is prompting widespread research into the potential value of maintaining progesterone levels in both males and females.

Brain damage

Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to traumatic brain injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury. Encouraging results have also been reported in human clinical trials.

The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma

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