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NUCLEAR RECEPTORS
NUCLEAR RECEPTOR

ZINC FINGERS: NUCLEAR RECEPTORS

     Steroids are universally found in organisms, and function as components of the cell membrane, hormones, vitamins, and cytotoxins.  They were probably among the original molecules required by living things (Agarwal, 1993).  Steroids which function as signaling molecules and hormones are not only known in animals;  some bacteria, fungi, algae and plants convert cholesterol into hormones.  Plants have been shown to produce cortisol, mineralcorticoids, progestins, testosterone, estrogens (and estrogen receptors), and ecdysone (Agarwal, 1993; Milanesi, 2004).  These steroid hormones can actually affect animals which ingest them.  For example, grazing mammals can be affected by the plant hormones they ingest (Agarwal, 1993).  A variety of steroids and non-steroid compounds (found in plants) can cause estrogenic activity in the human body (Osterlund, 2001).  Since many nuclear hormone receptors are among animals, hormones from one organism can affect the physiology of another.  Thyroid and steroid hormones from hosts can affect the development of schistosome parasites (de Mendonca, 2000). Fungi possess heterodimer-transcription factors which possess structural similarities to animal nuclear receptors (Phelps, 2006).

     The receptors for steroids in animals are a family of zinc finger transcription factors known as nuclear receptors.  Zinc finger transcription at least as old as eukaryotes and some zinc finger transcription factors are known in bacteria as well.  The origin of the family of nuclear receptors within the family of zinc finger proteins must have been about as ancient as the origin of eukaryotes, given that the steroid receptors in plants are members of the same family as animal receptors (Agarwal, 1993).

      Nuclear receptors include receptors for estrogen, testosterone, glucocorticoids, mineralocorticoid, thyroid hormone, vitamin D and retinoic acid receptors in vertebrates, several receptors from insects (such as ecdysone, ftz regulatory factor 1, and the products of the genes tailless, knirps, and ultraspiracle) and the C. elegans differentiation activating factor.  They all form part of a gene family derived from an ancestral protein with ligand-binding and DNA-binding domains (Amero, 1992, Zilliacus, 1994; Carosa, 1998) and a large number of orphan receptors whose function is not yet known (Detera, 1994). Most nuclear receptors have two zinc finger domains.  Unlike most hormones, steroid and thyroid hormones enter cells rather than binding only to cell membrane receptors.  Once they have bound their intracellular receptor, the steroid hormone-receptor complex travels to the nucleus where it binds DNA and effects gene transcription. The receptor subunits can form homodimers with themselves or heterodimers with other subunits to bind DNA molecules (OMIM). 

     All nuclear receptors possess at least four domains.  The DNA binding domain (C domain) is composed of two zinc fingers and is the most highly conserved region in the family.  The largest domain, the E domain, binds hormones and is required to regulate transcription.  The hinge D region contains a nuclear localization signal, the C terminal region (F domain) which binds the ligand and the N terminal (A/B domain) region which interacts with other proteins involved in transcription/ transcription regulation (Lee, 2002; Laudet, 1992).       Most sex steroid receptors bind to the DNA sequence TGACCT while glucocorticoid receptors bind to the sequence TGTTCT.  There are three amino acids which function in this binding.  A mutation affecting these amino acids can affect hormone binding specificity.  For example, one glucocorticoid receptor mutant can interact with DNA regions recognized by estrogen receptors (Zilliacus, 1994).

     Nuclear hormones and their receptors are widespread in animals, even in the most primitive groups.  Sponges have retinoic acid and its receptor (Schacke, 1994).  Sponge cells are depicted below.

SPONGE

Jellyfish have a receptor which is similar to vertebrate RXR which binds retinoic acid and then binds the DNA of crystallin genes, just as in both vertebrates and invertebrates (Kostrouch, 1998).  Cnidarians and platyhelmenthes possess at least 5 nuclear hormone receptors and gene duplications expanded this number in some coelomate lineages, such as the arthropods and vertebrates (Escriva, 1997). The vertebrate retinoic acid receptor (RXR) is homologous to the receptor for insect juvenile hormone III. In insects, the ecdysone receptor forms a heterodimer with the RXR homolog, Ultraspiracle (USP) in order to function (Hayward, 2003). Like vertebrate steroid hormones, insect steroids can act both by binding DNA and by interacting with membrane proteins (De Loof, 2008).

There were already several different subfamilies of nuclear proteins at the time when protostomes and deuterostomes separated (Laudet, 1992).

     About 170 orphan receptors are known in various genomes.  Some orphan receptors function in the responses to neurotransmitters, retinoic acids, peroxisome regulating signals, and phosphorylation (Lee, 2002).  About 50 nuclear receptor genes are known in mammals, of which slightly over half possess known ligands (Enmark, 2001).  Forty-nine nuclear hormone receptors are known humans, in addition to at least 3 pseudogenes (Robinson, 2001).

     Of the major steroid hormone receptors in mammals (2 estrogen receptors, protesterone receptor, androgen receptor, glucocorticoid receptor, and mineralocorticoid receptor), all seem to have evolved from an ancestral receptor in primitive vertebrates.  None of these receptors have yet to be identified in invertebrates although Drosophila possesses a receptor which is homologous to ERR, a zinc finger steroid receptor related to estrogen receptors and estrogen receptor-like sequences have been identified in coral  (Enmark, 2001; Thornton, 2001).  A single indeterminate steroid hormone receptor is present in hagfish, 3 are known to date from lampreys (named ER, CR, and PR) and sharks (ER, GR, and AR), and all 6 are known in bony vertebrates (lamprey CR is similar to both gnathostome GR and MR) (Thornton, 2001).

 

Progesterone Receptor

   The gene for the progesterone receptor has two separate promoters and translational start sites; this results in two separate isoforms, PRA and PRB.  PRB activates transcription while PRA represses the transcription which would be induced by other steroid hormones such as estrogen.  Progesterone helps to prevent endometrial cancer by opposing the action of estrogen in the uterus.  One polymorphism increases the risk of endometrial cancer.  Progesterone receptors are required for fertility (OMIM).  Progesterone receptors known from fish and amphibians (Wang, 2004).

 

Estrogen Receptor

      Estrogen causes sexual differentiation in many vertebrates (Wu, 2003).        About 60% serum estradiol is bound to albumin, 38% is bound to sex-hormone binding globulin, and about 2% is dissolved in plasma.  Estrogen can be synthesized from testosterone in both men and women by the brain, adipose, and the liver by the aromatase cytochrome P450 19 enzyme (Osterlund, 2001).  Mice without estrogen are infertile (both genders) and have abnormalities of the skeletal system, gonads, and mammary glands.  Mutations in mice also alter lipid metabolism and susceptibility to obesity.    Estrogen affects both the testis and prostate in males.  Estrogens cause growth and differentiation of female reproductive structures, maintain bone mass, serve to lessen cardiovascular disease, and influence mood, cognition, and hormone release (Osterlund, 2001).

     There are two genes for estrogen receptors, ESRA and ESRB.  These receptors are not expressed to the same degree throughout the body: The ovaries and uterus express ESRA more than ESRB; the vagina expresses ERGA only; and the testis expresses ESRB in more regions than ESRA.  Both receptors are expressed in growing bone but with distinct distributions.  The two estrogen receptors can both form homodimers and heterodimers (Osterlund, 2001).

     Variations in ESRA have been linked to bone density variations in women and men and the onset of menopause in women.  Estrogen receptors can vary in the number of TA repeats (ESRA) and CA repeats (ESRB) they contain.  Shorter ESRB receptors are associated with higher levels of circulating androgen. Human mutations suggest that ESRA may offer some protection from heart disease and ESRB may offer some protection from prostate cancer in males (OMIM).  The highest expression of ESRα in the brain occurs in the hypothalamus and amygdale while the highest expression of ESRβ occurs in the hippocampus, thalamus, and entorhinal complex.  Mammals in general express estrogen receptors in the limbic areas of the brain (Osterlund, 2001). 

     Some fish possess a third estrogen receptor, ERg.  This receptor is expressed in a number of tissues, including the testes where it can mediate some of the feminizing affects of environmental estrogens on male fish (Hawkins; 2000)  Two ER1α receptors are known in the tetraploid frog Xenopus  (Wu, 2003).  

 

Androgen Receptor

     The gene which codes for the two isoforms of androgen receptor is located on chromosome Xq11.  The receptor protein can be cleaved by caspase 3 to produce fragments which can be toxic to the cell (a “death substrate”) utilized in programmed cell death.

     Some mutations in androgen receptors result in small testis and prostate size.  Some mutations cause constitutive activity of the receptor (in which the receptor is always active even when it has not bound to androgen hormones) and are a cause of prostate cancer.  Two mutations are known resulting in a “promiscuous receptor” which can bind to estrogen and progesterone and these mutations also increase the likelihood of prostate cancer (OMIM; Han, 2005).  

   The normal gene possesses two regions of tandem trinucleotide repeats and (one type of mutation observed in this gene is an amplification of the number of CAG repeats).  While 11 to 33 repeats can be considered normal, those with a larger number of repeats are more susceptible to mutation.  Some repeats have been linked to mental retardation and, as the number of repeats increases, the likelihood of males suffering from partly/unfuses scrotum, micropenis, and azoospermia increases.  Although the number of CAG repeats is not a major cause of infertility, normal men with lower repeat numbers have higher sperm counts than those with higher repeat numbers.  Women who have lower repeat numbers in the androgen receptor gene have higher levels of androgens in the blood and lower levels of LH (OMIM). 

     Shorter androgen receptor proteins increase the activity of the receptor and are associated with an earlier age of onset and increased severity of prostate cancer.  Longer proteins can cause infertility.  There are ethnic differences in the number of repeats found in androgen receptors (OMIM).

 

The human genome has a number of “Orphan Receptors” which have no known ligands.  While some nuclear hormone receptors bind to DNA as homodimers (a complex of two copies of the same gene product, other nuclear receptors bind as heterodimers (Handschin, 2000). 

 

Ftz-F1, a protein which activates the ftz homeodomain gene in Drosophila which is involved in the segmentation of the embryo is a member of the nuclear receptor superfamily.    FTZ-F1 is homologous to steroidogenic Factor I which regulates steroid synthesis in mammals (Lala, ?).  Drosophila possess other members of this family including the retinoid X receptor-related protein, the ultraspiracle product (also called the chorion gene transcription factor CF-1), Embryonic gonald, Tailless (a gap segmentation protein), and Knirps (involved in segmentation).  Some members of the family only contain the DNA-binding region of the mammalian nuclear hormone receptors (such Knirps and Embryonic gonald) while Ftz-F1 possesses both the DNA-binding and ligand binding domains found in the mammalian hormone receptors (Lavorgna, 1991)  In nematodes, the nhr-2 gene is important in early development, as are vertebrate and invertebrate homologs of tailless and FTZ-F1 (Sluder, 1997).

 

RAR-related Orphan Receptor A, RORA, is homologous to the mouse mutant ‘staggerer’ whose mutations cause cerebellar ataxia and abnormal development of Purkinje fibers.

 

RAR-related Orphan Receptor B, RORB, is expressed in the CNS and is involved in the regulation of circadian rhythms.

 

RAR-related Orphan Receptor C, RORC, is needed for the formation of lymph nodes and mutations can cause the absence of lymph nodes, the absence of Peyers patches, and a decrease in the number of thymocytes.

 

 PPAR genes bind prostaglandins, fatty acids, and leukotrienes.

PPAR-γ

 

PPAR-α

 

PPAR-δ

 

Hydroxylated cholesterol receptors

The nuclear receptors of the liver X group (LXR) function in both cholesterol metabolism, development of atherosclerosis, and innate immunity responses to microbes and inflammatory signals. They form heterodimers with retinoid acid receptors before binding DNA (Valledor, 2005).

LXRα

 

LXRβ

 

ESRL1 is an orphan receptor expressed in the kidney, heart, and brown adipose.  It is involved in the metabolism of abdominal fat.

 

ESRL2 is essential for the development of the placenta.

 

ESRRG is involved in development and transcription regulation.

 

NR1H2 receptors bind with retinoid X receptors and regulate the metabolism and transport of lipids.

 

NR2C1 is expressed in the testes, seminal vesicle, and prostate and alternate splicing can produce different isoforms. 


NR2C2 can be spliced in different ways; one form is expressed predominantly in the testes.

 

NR2F1 is a homolog of the COUP-TF orphan receptors (chicken ovalbumin upstream promotor-transcription factors).

 

NR2F2 is a COUP-TF homolog involved in organogenesis and embryonic development.

 

NR2F6 is most highly expressed in the liver.  Liver cells are depicted below.

LIVER

NR4A1 is expressed after induction by signals for cell division.  When this receptor is active in the nucleus it can function to stimulate growth (perhaps after dimerization with other receptors such as retinoid X receptors) while when it is active in the cytoplasm, it can induce apoptosis by its action in mitochondria which results in the release of cytochrome c.

 

NR4A2 is expressed after T cells are activated and is involved in inflammation and perhaps rheumatoid arthritis.  It is an essential receptor in the midbrain and certain alleles affect the susceptibility to Parkinsons.

 

NR4A3 mutations can cause chondrosarcomas.  Cartilage cells are depicted below.

CARTILAGE

NR5A1 is the homolog of the Drosophila gene fushi tarazu which is involved in the development of segmentation in the embryo.  In humans, it is expressed in tissues which synthesize steroids and is involved in sex determination and the regression of Muellerian ducts.  It interacts with the DAX protein (which can cause XY sex reversal) and the WT1 protein (the absence of which can result in male pseudohermaphroditism).  Mutations in mice cause abnormalities of the adrenal glands and gonads, XY sex reversal, and the persistence of Muellerian ducts in males (OMIM).

 

Pregnane X Receptor

     The pregnane receptor activates one of the cytochrome P450-3A which is responsible for the metabolism of 60% of drugs and involved in drug interactions.  Other nuclear receptors (androstane receptors [CAR gene] in humans and CXR in chickens) also regulate the P450 cytochromes (Handschin, 2000).

 

GCCR, the glucocorticoid receptor, is related to the erb-A family of oncogenes.  It mediates the response to stress and other changes in internal state.  Mutations can contribute to heart disease, male obesity, infertility, and hypertension.

 

Mineralocorticoid Receptor (NR3C2) mediates the action of hormones such as aldosterone.  Mutations can cause pseudohypoaldosteronism and early onset hypertension.  Some mutant receptors respond to the steroid hormone progesterone and can cause pre-clampsia.

DAX1

There is an X-linked gene DAX-1 which, when present in two copies can cause XY individuals with SRY to develop as females.  It is a nuclear hormone receptor that binds to retinoic acid and regulates transcription.  DAX-1 is not required for normal male development (Zanaria, 1994). In addition to DAX-1 on the X chromosome, autosomal sites on 9q, 10q, and chromosome 17 can cause sex reversal.  The gene on chromosome 17, SOX9 affects gender development in a dosage-specific manner (as does DAX) and may be a vestige of an older dosage-dependent mechanism for sex determination (Foster, 1994).  DAX1 does not have a zinc finger DNA binding domain (Robinson, 2001).


 

Thyroid hormone Subfamily

 

     Retinoic Acid, vitamin D, and thyroid hormone receptors form a subfamily of nuclear hormone receptors and can increase transcription of genes which possess two or more AGGTCA sequences (OMIM).  Thyroid hormone, retinoic acid, and ecdysone receptors can silence transcription when no ligand is present.  Ecdysone receptors can repress transcription in both invertebrate and vertebrate cells, suggesting that this receptor evolved long ago (Thormeyer, 1999). Many nuclear hormones can undergo autoinduction.  This is true in insects and frogs and also applies to retinoid, sex steroid, and vitamin D receptors (Tata, 2000).   It seems that an ancestral cluster of three tandem nuclear receptor genes THR, NR1D (encoding Rev-Erb), and RAR was duplicated early in vertebrate evolution to form alpha and beta members clusters (Koh, 1999).   The following photo is of the thyroid gland.

THYROID

Retinoic Acid Receptors

 

Retinoids bind to two families of nuclear receptors: the RA receptors (RARα, RARβ, and RARγ) and retinoid X receptors (RXRα, RXRβ, and RXRγ).  There is a conservation of retinoic acid response elements (RAREs) in vertebrates (Mainguy, 2003).  Abnormalites of the branchial arches are often due to altered neural crest cell migration and may be induced by changes in retinoic acid (Menegola, 2004).

 

 

RARγ, RARβ, RARα, RORγ, RZR, and RZRβ  bind trans-retinoic acid.

RARγ

RARG is the major RAR receptor expressed in skeletal muscle.

 

RARβ

RARB and RARG are involved in locomotion and dopamine pathways.  Variants may be involved in Parkinsons and schizophrenia.

 

RARα

RARA mutations can cause leukemia. 

RORγ

 

RZRα

 

RZRβ

 

RXR is required for the formation of the ventricles of the heart and the normal functioning of the liver. RXR expression can decrease cholesterol levels and atherosclerosis.  RXRα, RXRβ, and RXRγ bind to 9-cis retinoic acid.

 

RXRα

 

RXRβ

 

RXRγ

  

Vitamin D Receptor

    This receptor is more similar to the thyroid hormone receptors than the steroid hormone receptors.  Calcitrol (the activated form of vitamin D) is needed for the synthesis of osteocalcin, the second most abundant protein in bone (after collagen).  Variations in this gene affect bone density and mutant forms can cause rickets. 

     The nuclear receptor for vitamin D, VDR, activates gene transcription after binding to vitamin D.  Although its major functions in mammals include the absorption of calcium for skeletal formation and regulation of the hair cycle, vitamin D receptors are expressed in lampreys which lack both bones and hair.  Lampreys may use this gene to induce P450 enzymes (Whitfield, 2003).

 

 

      Thyroid hormone regulates the metamorphosis of both fish and amphibians (Marchand, 2004).  Almost all vertebrates secrete thyroid hormones.  Thus, one of the major regulators of endothermic metabolism is present in ectotherms as well.   It is required for metamorphosis in tunicates, fish , and amphibans  (Tata, 2000; Jones, 2002; Carosa, 1998).  A tunicate is pictured below.

SEA SQUIRT

     Tunicates lack steroid hormones (and the P450 enzymes which synthesize them) but they do possess nuclear receptors, such as those which bind thyroid hormones and retinoic acid (which protostomes lack). A nuclear receptor in tunicates (CiNR1) seems close to a sequence which could approximate the ancestral sequences of thyroid receptors.  It is expressed during development and metamorphosis (Carosa, 1998; Dehal, 2002).  Interestingly, there is one member of the estrogen-related receptor family in both flies and tunicates whose ligand is unknown.  Tunicates possess both an iodine-sequestering endostyle, homologs of thyroid peroxidase which synthesizes thyroid hormones in vertebrates, and iodothyronine deiodinases (which convert thyroxine to T3).   As a result, they seem to use hormones homologous to thyroid hormones of vertebrates even though they lack a thyroid gland.  In both tunicates and lancets, the endostyle is thought to be a primitive homolog of the vertebrate thyroid gland (Dehal, 2002).

 

Thyroid Hormone Receptor A, TRA is expressed in most tissues other than the liver.  Some mutations are involved in pituitary adenoma.  THRA gene encodes two alternate transcripts: TRα1 binds thyroid hormones while TRα2 does not bind thyroid hormones and functions as an inhibitor (Koh, 1999).

 

TRB is expressed most in the liver and exists in different isoforms, one is specific for the pituitary gland.  TRB is needed for the development of the ear and some mutations cause deafness or hearing impariment.  In mice, mutations have been shown to lead to abnormalities of the cerebellum and hippocampus.  In humans, mutations cause thyroid hormone resistance and may be involved in some cancers.  Maternal thyroid hormone interacts with fetal brain receptors in the development of the brain. 

 

  After binding with polycyclic hydrocarbons, the AHR receptor binds to an aryl hydrocarbon nuclear translocator and this heterodimer mediates the diverse cellular responses to toxins. Dioxin can bind AHR for long periods of time and the inactivation of this response may be a central component of dioxin’s toxicity (Oesch-Bartlomowicz, 2005).

SF-1

SF-1 is a orphan nuclear hormone receptor.  Mutations can result in sex reversal and agenesis of the adrenal glands and gonads.  Sex reversal can occur in heterozygous humans.  SF-1 is also involved in the production of the original undifferentiated gonad (Vaiman, 2000).  Orphan nuclear factor SF1 has a similar pattern of expression in marsupials and placental mammals.  It is involved in the development of the adrenal glands, anterior pituitary, and hypothalamus.  It also regulates cytochrome 450 genes which are involved in steroid metabolism in ovaries and testes (Whitworth, 2001). Some turtles have a gender specific SF1 expression pattern similar to mammals. (Whitworth, 2001).

     In mammals, the first step in sex determination is the differentiation of the gonads controlled by genes followed by a second step of phenotypic changes induced by hormones.  Anti-Muellerian hormone is a member of the TGF-B family which is required for male development (without which they develop as pseudphermaphrodites).   Females exposed to AMH undergo partial sex reversal.  Four transcription factors are known to bind to the AMH promoter: SF-1, WT1, SOX-9, and GATA-4 (Vaiman, 2000).

 

TR2 and TR4 represent a subfamily within the NR family.  The genes in humans include TR2, TR2-5, Tr2-7, TR2-9, TR2-11.  TR4 genes in humans include TR4, TR4a1, TR4a2, and TAK1.  Androgens, radiation, p53 and dopamine can affect the expression of TR2 and TR4 receptors which in turn affect apoptosis, the expression of receptor genes, and hormone signaling pathways.  TR4 deletions may cause retardation   Homologs of the human orphan receptors TR2 and TR4 are known in nematodes, flies, sea urchins, and diverse vertebrates (Lee, 2002).

 

GCNF is the only nuclear receptor in mammals which is the only member of its subfamily.  Homologs of GCNF are known in nematodes and insects (Enmark, 2001).

 

The TLX/tailless receptors in vertebrates/invertebrates is an important factor in the establishment of and anterior-posterior axis and in the development of the nervous system (Enmark, 2001).

 

DSF (dissatisfaction) receptors are known in nematodes and flies although no homolog is known in mammals.  In flies mutations affect sexual preference (Enmark, 2001).

 

Other transcription factors such as the nuclear hormone receptor Nurr1 and the LIM protein Lmx1b are also involved in the development of midbrain dopaminergic neurons (Nunes, 2003). 

 

Nurr1

 

NGFI-B

 

nor1

 

Orphan receptors BmE75A and BmE75C in insects are involved in oogenesis and egg development (Swevers, 2002).

 

FXR binds to bile acids.  FXRβ may be a pseudogene (Robinson, 2001).

 

RevErbAα

 

RevErbAβ

 

PNR

 

TLX

 

Ear2

 

SHP

 

FTF/LHR-1

 

 

Androstenol

CAR

 

 

 

Trithorax is not a nuclear receptor but it does contain a sequence similar to the DNA-binding domain of nuclear receptors (Robinson, 2001).

                                                                       

Farnesoid X receptor (FXR) (NR1H4) and RevErbA (NR1D1) are newly discovered nuclear receptors (Enmark, 2001).  Ancestral eukaryotic cells evolved the ability to synthesize cholesterol and modern organisms utilize cholesterol in cell membranes and as a precursor for other molecules.  Eukaryotes also acquired the need to metabolize cholesterol.  In animals the liver converts cholesterol to bile acids in a 14-step pathway.  Of the cholesterol secreted as bile, 5% is lost in feces, the rest is reabsorbed   A number of orphan nuclear receptors, LXR, FXR, RXR, and PPAR, respond to oxysterol levels by controlling the amount of cholesterol released from cells through ABC transporters.  This cholesterol is transported to the liver by HDL proteins where it is metabolized.  LXR/RXR also activate the synthesis of CYP7A1 which increases the conversion of cholesterol to bile salts.  FXR regulates liver bile acid levels, PXR and VDR regulate the excretion of bile acids, and LXR and PPAR control the amount of cholesterol and bile salts excreted from the small intestine (Redinger, 2003).

 

 

STEROID HORMONES AND MOOD

ESTROGEN

 

     Although estrogen (and testosterone) affect the tissues of the reproductive system, they also affect other tissues including the brain.  The receptors for sex steroids are more abundant in certain parts of the brain including the hypothalamus, amygdala, and hippocampus (Steiner, 2003).   Since the regions of the brain include those which control emotions and drives, it is not surprising that the secretion of steroid hormones are implicated in both normal fluctuations in mood and in mood disorders (affective disorders).  In females, secretion of estrogen seems to begin after birth and is maintained at a low level throughout childhood.  With the onset of puberty, the secretion of estrogen generally increases and undergoes monthly fluctuations (Ramirez, 2003). 

     Affective disorders are the most common mental disorders and women are afflicted at twice the rate as men (with an 8% lifetime risk as opposed to 4% in males).    Decreased estrogen levels are a factor in postnatal depression and post-menopausal depression (Steiner, 2003).  Low concentrations estrogen have been associated with PMS, postnatal depression, and postmenopausal depression and estrogen can be used to treat the latter two.  About 75% women experience some form of PMS and 3-8% of these women suffer from the more serious emotional and behavioral symptoms of PMDD (premenstrual dysphoric disorder) (Steiner, 2003; Osterlund, 2001).  PMDD affects 5% of women in reproductive years (Shors, 2003).

     A number of studies show that estrogen can relieve depression.  Reduction of serotonin (or the tryptophan it is derived from) increases irritability and the severity of PMS.  Estrogen increases serotonin synthesis, uptake and receptor number, and functions as an antidepressant .  Evidence suggests that estrogen decreases the expression of 5-HT1A serotonin receptors and increases the expression of 5-HT2A receptors. (Steiner, 2003; Osterlund, 2001; Genazzani, 2002).  Estrogen affects synthesis of serotonin through TH (tryptophan hydrozxylase) and can increase serotonin receptors in areas of the brain known to affect mood (Shors, 2003).  Given that estrogen can both increase body fat and fight depression, there actually may have been some observational evidence  which gave rise to past sterotypes linking body size and disposition (Oinonen, 2001).

     In general, estrogen seems to offer some protection from schizophrenia. Schizophrenia symptoms are milder in women and onset occurs about 4 years later in women than men.  Estrogen also seems to decrease susceptibility to Alzheimer’s disease (Osterlund, 2001).  Estrogen in mice affects learning (Shors, 2003).  Estrogen improves some cognitive functions, such as memory, which is not surprising given that it increases ACh formation in neurons, such as ACh neurons which project to the hippocampus (Genazzani, 2002).

          The loss of gonadal hormones at menopause affects mood, libido, and some aspects of cognition.  The mood and emotional changes also seem to involve changes in the serotoin, noradrenaline, dopamine, and opiate pathways. (Genazzani, 2002). After menopause, the rate of depression in females approaches that seen in men (Shors, 2003).  A polymorphism in the estrogen receptor alpha is associated with variation in some of the characteristics of menopause such as vaginal dryness and hot flashes (Malacara, 2004).

 

PROGESTERONE

Progesterone can cause depression and increases monoamine oxidase activity (which breaks down serotonin) (Steiner, 2003).  Progesterone opposes estrogen’s effects in the brain and can alter mood, increasing the risk of depression (Genazzani, 2002).

 

ADRENAL HORMONES

Individuals suffering from depression have higher levels of adrenal hormones and corticotrophin releasing factor (CRF).  Male and female mice react to stressful stimuli with different hormones (Shors, 2003).

 

ANDROGENS

     The production of testosterone increases in the male fetus early in the third month of development through birth.  It mediates effects on the male genetalia and hypothalamus during this time.  About 2 months after birth there is another surge in testosterone production which last several months although its significance is not understood.  The final surge in testosterone production occurs during puberty where it contributes to growth, development of the primary sex organs and secondary sexual characteristics, and influences sexuality, personality, violence, and other cognitive aspects (Ramirez, 2003).

     Androgens increase sex drive in both men and women and also increase irritability.  High levels of androgens may be associated with some of the increased drive and irritability of some parts of the menstrual cycle in females (Steiner, 2003).  In men, chemical castration is linked to increased risk of depression and anxiety. Ending chemical castration coincides with improved performance in memory.  Decreased testosterone levels are linked to depression (Almeida, 2004).  Testosterone supplementation improves some types of cognitive ability (Almeida, 2004).  Androgens are used to treat the loss of libido in postmenopausal women (Genazzani, 2002).  The “feminine”/“masculine” behavior of young girls has been linked in some studies to both non-biological phenomena (such as the existence of older male siblings) and to levels of testosterone.  Maternal testosterone levels may increase later in life (or at least the ratio of testosterone to estrogen can increase) and this may have an effect on fetal development (Ramirez, 2003).

 

VIOLENCE

     Although it can reasonably be expected that increased levels of testosterone in humans correlate with increased violence given such observations in other mammals, this correlation seems to be weak in humans.  Testosterone levels are higher in adolescent boys perceived to be socially dominant.  In other species, aggressive acts are often initiated by males of lower social status in an attempt to be more socially dominant.  Therefore, the lack of strong evidence for a direct correlation between testosterone levels and aggression may be influenced by the aggression committed by adolescents of a lesser perceived social status (with lower levels of testosterone) who are trying to become more dominant (Ramirez, 2003).

    There are studies which have concluded that males who commit violent acts (including domestic violence) have higher testosterone levels and some males with high testosterone levels display high irritability (George, 2001). In humans, high doses of anabolic steroids has been linked to indiscriminate violence sometimes referred to as “’roid rage”.  Studies have shown that anabolic steroids increase the incidence of verbal aggression, fighting, homicidal behavior and violence towards women.  Studies with rats also indicate that anabolic steroids increase aggression (McGinnis, 2002).

 

     There are a number of hormones which can affect aggression and violence in addition to testosterone.  Increased aggressive behavior may also be linked to lower levels of DHEAS, a lower ratio of testosterone to estrogen, lower levels of FSH, and higher levels of LH, androstenedione, and DHEA. 

     The adrenal gland secretes several hormones which are called androgens because of the similarities of their actions to those of testosterone, androstenedione, DHEA (dehyroepiandrostenedione), and DHEAS (dehyroepiandrostenedione sulfate).  Their effects are more easily observed in females since in males their effects are overshadowed by the testosterone secreted by the testes.   There is some evidence suggesting that higher levels of adrenal androgens are factors in increased aggression and antisocial behavior (Ramirez, 2003).

 

    Low levels of cortisol are associated with increased aggression.  This reduction in cortisol secretion can be observed in children and may thus be a predictor of aggressive behavior.  Interestingly, there seems to be an interaction between culture and cortisol levels.  For example, differences in the rise of cortisol levels after experiencing insult have been observed between adolescents raised in the Northern U.S. compared to the Southern U.S.  (Ramirez, 2003).

 

     Pituitary hormones may also be factors in aggression.  Studies have linked increased aggression to lower levels of FSH and prolactin and higher levels of LH and DHEA (Ramirez, 2003).

 

     In primates, lower cholesterol levels are associated with increased aggression.  In humans, a number of studies have shown lower cholesterol levels are linked to increased levels of violence and death by violence (Golomb, 2000).

 

     Nitric oxide serves three main functions in the body.  Outside of the nervous system, macrophages can synthesize it to destroy tumor cells and endothelial cells can secrete it to relax blood vessels.  In the brain, nitric oxide can affect the activity of neurons and the enzyme which synthesizes it, nitric oxide synthase (NOS), is concentrated in regions of the brain which determine emotions.  In animal studies, mutations in NOS greatly increase male aggression, but not female aggression.  Testosterone is required for this increase; no such increase is observed in castrated males.  In fact, normal female mice do display maternal aggressiveness toward intruders which is reduced in NOS mutant females.   Thus it appears that the activity of NOS affects aggression but has opposite effects in males and females.  Androgens tend to inhibit NOS and estrogens tend to increase its activity (Chiavegatto, 2003).  In mice, absence of the gene nitric oxide synthase affects violence and sexual behavior, in part through effects on the serotonergic pathways and serotonin receptors (Reif, 2003).

 

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