Endocrine System Lecture Notes PDF

Part 1 Hormones, receptors, and signal transduction  Cell communication Gap junctions Facilitate passage of inorganic ions and small molecules (K+, Ca2+, H+, cGMP, IP3, cAMP etc) from one cell to the other. Chemical signals including: Ions (K+, Ca2+, H+, etc) Hormones...

Part 1 Hormones, receptors, and signal transduction  Cell communication Gap junctions Facilitate passage of inorganic ions and small molecules (K+, Ca2+, H+, cGMP, IP3, cAMP etc) from one cell to the other. Chemical signals including: Ions (K+, Ca2+, H+, etc) Hormones (endocrine, paracrine or autocrine) Neurotransmitters Growth factors, etc Chemical signals are transmitted via a secondary messenger except steriods that diffuse across the plasma membrane and interact with cytosolic or nuclear receptors.  Cell communication by hormone A) Endocrine B) Paracrine C) Autocrine  The endocrine system The endocrine system integrates organ function through hormones that are secreted from glands into the extracellular fluid. The hormones are carried through the blood to distant target tissues, where they are recognized by specific, high-affinity receptors. Once a hormone is recognized by its target tissue or tissues, it can exert its biological action by a process known as signal transduction  Chemical Classification of Selected Hormones Hormones may be peptides, metabolites of single amino acids, or metabolites of cholesterol Peptide hormones bind to cell-surface receptors and activate a variety of signal transduction systems Amine hormones are made from tyrosine and tryptophan. They act through surface receptors. Thyroid hormones bind to intracellular receptors as steroids to regulate metabolic rate. Steroid hormones are derived from cholesterol. They bind to intracellular receptors that regulate gene transcription by activating steroid response element.  Hypothalamic and anterior pituitary peptides Hypothalamus Anterior Pituitary Target organs Thyroid gland Ovary and testis Adrenal gland Bone, muscles etc Mammary glands  Dopamine inhibition of prolactin is mediated by G-proteins This inhibition occurs through: A) Gα i protein-mediated inhibition of cAMP production B) Gβ i dimer-mediated: (i) activation of inward rectifier K+ channels and (ii) inhibition of voltage-gated Ca2+ channels. Class-1 cytokine receptors are transmembrane receptors found on the surface of cells to which cytokines bind Activation of protein kinase A (PKA) by cyclic adenosine monophosphate (cAMP) Binding of cAMP to the enzyme protein kinase A (PKA) Separation of the two catalytic subunits of PKA from the two regulatory subunits Phosphorylation of serine and threonine residues on a variety of cellular enzymes and other proteins by the free catalytic subunits of PKA that are no longer restrained and Modification of cellular function by these phosphorylations. NB: The activation of protein kinase G (PKG) by cyclic guanosine monophosphate (cGMP) is similar as described above.  GHRH, CRH, ANG II, PTH Somatostatin, ANG II, a-adrenergic agonist, Dopamine TRH, GnRH, AVP, ANGII ANG II PTH, parathyroid; ANG II, angiotensin II; ANP, atrial natriuretic peptide; EGF, epidermal growth factor; JAK-STAT, Janus kinase/signal transducer and activator of transcription; PDGF, Platelet-derived growth factor. DAG; Diacylglycerol  Receptors of peptide hormones Receptor of guanylyl cyclases The receptor of guanylyl cyclase has an extracellular ligand binding domain. Ligand binding leads to receptor dimerization and activation of guanylyl cyclase activity, which converts GTP to cGMP  Receptors of peptide hormones….continues Extracellular space Receptor serine/threonine kinases Receptor serine/threonine kinases have two subunits, each of which has intrinsic serine/threonine kinase activity. The ligand (e.g., TGF-b;) binds to the type-II subunit, causing it to transphosphorylate the type-I subunit at serine and threonine residues. This phosphorylation, in turn, activates the type-I subunit, which phosphorylates intracellular proteins at serine and/or threonine residues Transforming growth factor beta = (TGF-b) Cytosol  Receptors of peptide hormones….continues Extracellular space Receptor tyrosine kinases (RTKs). There are two classes of RTKs. Ligand binding to two NGF receptors leads to receptor dimerization and activation of tyrosine kinase activity. The monomers in the dimer phosphorylate each other and downstream effectors. Ligand binding to the insulin receptor causes conformational changes in each of the two a:b pairs, which leads to activation of the tyrosine kinases on the b-subunits. The activated b-subunits then phosphorylate each other and downstream effectors. Nerve growth factor = (NGF) Cytosol  Receptors of peptide hormones….continues A) Receptor of guanylyl cyclases Receptor of guanylyl cyclases has an extracellular ligand binding domain. Ligand binding leads to receptor dimerization and activation of guanylyl cyclase activity, which converts GTP to cGMP B) Receptor serine/threonine Kinases Receptor serine/threonine kinases have two subunits, each of which has intrinsic serine/threonine kinase activity. The ligand (e.g., TGF-b;) binds to the type-II subunit, causing it to transphosphorylate the type-I subunit at serine and threonine C) Receptor tyrosine kinases (RTKs). residues. There are two classes of RTKs. Ligand binding to two NGF receptors leads to receptor dimerization and activation of tyrosine kinase activity. The monomers in the This phosphorylation, in turn, dimer phosphorylate each other and downstream effectors. activates the type-I subunit, which phosphorylates intracellular proteins Ligand binding to the insulin receptor causes conformational changes in each of the at serine and/or threonine residues two a:b pairs, which leads to activation of the tyrosine kinases on the b-subunits. The activated b-subunits then phosphorylate each other and downstream effectors.  G-protein acting via adenylyl cyclase (AC)  Activation of a heterotrimeric G protein (αs or αi);  Activation (by αs) or inhibition (by αi) of a membrane-bound adenylyl cyclase;  Formation of intracellular cAMP from ATP, catalyzed by adenylyl cyclase;  Binding of cAMP to the enzyme protein kinase A (PKA)  Separation of the two catalytic subunits of PKA from the two regulatory subunits  Phosphorylation of serine and threonine residues on a variety of cellular enzymes and other proteins by the free catalytic subunits of PKA that are no longer restrained and  Modification of cellular function by these phosphorylations. The activation is terminated in two ways:  Phosphodiesterases (PDE) in the cell degrade cAMP.  Serine/threonine-specific protein phosphatases can dephosphorylate enzymes and proteins that had previously been phosphorylated by PKA. Activation of protein kinase A (PKA) by cyclic adenosine monophosphate (cAMP) Binding of cAMP to the enzyme protein kinase A (PKA) Separation of the two catalytic subunits of PKA from the two regulatory subunits Phosphorylation of serine and threonine residues on a variety of cellular enzymes and other proteins by the free catalytic subunits of PKA that are no longer restrained and Modification of cellular function by these phosphorylations. NB: The activation of protein kinase G (PKG) by cyclic guanosine monophosphate (cGMP) is similar as described above.  G-protein acting via Phospholipase C (PLC)  When a ligand binds to a receptor that is coupled to q, phospholipase C (PLC) is activated. PLC converts PIP2 to IP3 and DAG. The IP3 leads to the release of Ca2+ from intracellular stores. The increase in [Ca2+]I activates Ca2+-dependent kinases (e.g., Ca2+-calmodulin- dependent protein kinases, protein kinase C [PKC]) with alteration of cell function. Similarly, DAG activates protein kinase C (PKC) to alter cellular functions.  G-protein acting via Phospholipase A (PLA2) Binding of the ligand to receptor activates Gαq or Gα11, Stimulation of membrane-bound PLA2 by the activated Gα, Cleavage of membrane phospholipids by PLA2 to produce lysophospholipid and arachidonic acid, and  Arachidonic acidic is converted by cyclooxygenase and lipooxygenase to a variety of biologically active eicosanoids (e.g., prostaglandins, prostacyclins, thromboxanes, and leukotrienes  Part 2 Sex Differentiation  Chromosomes and sexual differentiation Chromosomes are nuclear structure containing a linear thread of DNA which transmit genetic information among other functions. Source: Journal of the Greeff and related families, No 9, May 2008. Judith G. Hall, MD  The human karyotype The full set of chromosomes in a cell is known as the karyotype. Humans have two types of chromosomes: A single pair of sex chromosome 22 pairs of autosomal chromosomes (autosomes). Differences between the female and male karyotype Females have two X chromosomes, while males have one X and one Y. The Y chromosome is small and acrocentric (i.e., the centromere is located at one end of the chromosome).  Types of cell division in reproduction  Mitosis occur in somatic cells for growth, whereas meiosis occurs only in germ cells for the production of male and female gametes. Mitosis  Mitosis results in the formation of two identical daughter cells with same number of chromosomes (i.e., 46 in humans) and same DNA content as the original cell.  Mitosis is a continuum consisting of five phases: prophase, prometaphase, metaphase, anaphase, and telophase. Reasons for genetic identity in mitosis: i) No exchange of genetic material occurs between homologous chromosomes, so sister chromatids (i.e., the two copies of the same DNA on a chromosome) are identical. ii) Sister chromatids of each chromosome split, one going to each daughter cell during anaphase of the single mitotic division.  Mitosis Two identic daughter somatic cells are produced Source: Boron & Boulpaep, Medical Physiology, 2nd Edition  Meiosis Meiosis occurs in the germ cells (spermatogonia in males and oogonia in females), resulting in four haploid daughter cells. Meiosis is a continuum of two divisions in which homologous chromosomes separate during meiosis-1, and the chromatids separate during meiosis-2.  Cell division-1 involves recombination (i.e., crossing over of genetic material between homologous chromosomes) and the reduction to the haploid number of chromosomes.  Cell division-2 separates the chromatids of each chromosome as in mitosis. NB: The genetic sex of a zygote is established at fertilization, when an X- or Y- bearing sperm fertilizes an oocyte.  Meiosis in male (spermatogenesis) A major difference between male and female Meiotic division-I gametogenesis is that one spermatogonium yields four spermatids, whereas one oogonium yields one mature oocyte and two polar bodies. Meiotic division-II Source: Boron & Boulpaep, Medical Physiology, 2nd Edition  Meiosis in female (oogenesis) Meiotic division-I A major difference between male and female gametogenesis is that one spermatogonium yields four spermatids, whereas one oogonium yields one mature oocyte and two polar bodies. Meiotic division-II Source: Boron & Boulpaep, Medical Physiology, 2nd Edition  Genetic aspects of sexual differentiation The genetic sex of a zygote is established at fertilization, when an X- or Y-bearing sperm fertilizes an oocyte. The sex chromosomes from parents contribute to determining the genotypic sex of the offspring. The genotypic sex determines the gonadal sex, which in turn determines the phenotypic sex that becomes fully established at puberty. Thus, sex-determining mechanisms established at fertilization direct all the subsequent ontogenetic events (i.e. processes that lead to the development of an organism) involved in male-female differentiation.  Epigenetics An epigenetic modification is a change in phenotype without a change in genotype.  Epigenetics indicate cellular characteristics that are heritable by daughter cells that does not involve changes to the underlying DNA sequence. Such changes may be triggered by environmental factors).  DNA methylation and histone modification are involved in many epigenetic changes.  Histones are the major protein components of chromatin and they act as spools (reel) around which DNA winds. Histones are important for gene regulation.  Epigenetic changes may be due to chemical modifications of DNA/histone complexes. Importantly, epigenetic changes play a fundamental role to dictate gene activity by rapidly modifying chromatin accessibility to transcription factors.  Although epigenetic changes are regular and natural, they are influenced by many factors such as the environment, lifestyle, age and disease state. Although some epigenetic modifications can be physiological without any damaging effects, recent evidence indicate that a high number of epigenetic changes are amongst the causes of many diseases including type-2, diabetes, hypertension, cancer etc.  Epigenetics…cont’d Epigenetics studies the mechanisms that cause cells with identical DNA to develop, appear and function very differently. In a fetus, epigenomes direct development of undifferentiated stem cells at the right time and sequence. One of the most studied epigenetic mechanisms is DNA methylation where methyl groups attach directly to DNA strands. An equilibrium between methylation and de-methylation directs healthy cell growth and differentiation. An imbalance in DNA methylation has been found in diseases including cancer and autoimmune diseases such as lupus and multiple sclerosis. Studies are exploring whether external factors such as diet, stress or pollutants could influence epigenomes and speed or slow aging, even when the exposure occurred generations earlier. However, as epigenetics is still evolving, we will focus mainly on the traditional genetics and its role in sex determination.  Genetics aspects of sexual differentiation cont’d The genotypic sex determines the gonadal sex, which in turn determines the phenotypic sex that becomes fully established at puberty.  Determination of gonadal sex The indifferent gonad consists of an outer cortex and an inner medulla  Development of testes and ovary from the undifferentiated gonad During sex differentiation, the testis develops from the medulla, while the cortex regresses. Similarly, during sex differentiation, the ovary develops from the cortex, while the medulla regresses.  Determination of gonadal sex The indifferent gonad consists of an outer cortex and an inner medulla The testis develops from the medulla of the indifferent gonad; the cortex regresses. The ovary develops from the cortex of the indifferent gonad; the medulla regresses.  The differentiated gonads, in turn, determines the sexual differentiation of the genital ducts and external genitalia.  Determination of gonadal sex…..cont.  The Y chromosome exerts a powerful testis-determining effect on the indifferent or developing gonad.  During embryogenesis the male sex is established when the primary sex cords differentiate into seminiferous tubules under the influence of the Y chromosome.  In the absence of a Y chromosome, the indifferent gonad develops into an ovary. The indifferent gonad is composed of an outer cortex and an inner medulla. i) In embryos with XX chromosome, the cortex develops into an ovary, and the medulla degenerates. ii) In embryos with XY chromosome, the medulla differentiates into a testis, and the cortex regresses.  Testis-determining gene  The testis-determining factor (TDF) is a single gene located on the short arm of the Y chromosome. It is also known as SRY (for Sex-determining Region Y).  TDF is necessary for normal testicular development.  Rarely, the TDF may be found translocated on other chromosomes, for example in an XX male. An XX male is an individual whose sex chromosome is XX, but whose phenotype is male. During normal male meiosis, X and Y chromosomes pair and recombine at the distal end of their short arms. XX males arise as a result of an abnormal exchange of genetic material between X and Y chromosomes in the father, causing the TDF to be transferred from a Y chromatid to an X chromatid. If the sperm that fertilizes an ovum contains the defective X chromosome with a TDF, the resultant individual will be an XX male. XX males are sterile, have small testes and may display feminine characteristics.  Gonadal dysgenesis  It is an abnormal gonadal differentiation. In Females:  For example, loss of one of the X chromosomes of the XX pair results in an individual with an XO sex chromosome constitution and ovarian dysgenesis. In an XO individual, the gonads appears as a streak (line) on the pelvic sidewall in the adult.  The most common example of gonodal dysgenesis is Turner syndrome, a disorder of the female sex characterized by short stature, primary amenorrhea, sexual infantilism and other congenital abnormalities. The karyotype of individuals with Turner syndrome is 45,XO.  SRY gene-related anomalies  The testis-determining factor (TDF) is a single gene located on the short arm of the Y chromosome, and is also referred to as SRY (for Sex-determining Region Y). SRY-gene anomaly may cause discordance between genotype and gonadal phenotype. Examples include: 1. Individuals with no recognizable Y chromosome but do have testes. Some of these individuals are 46,XX and are true hermaphrodites; that is, they possess both male and female sex organs. 2. Individuals with mixed gonadal dysgenesis. These individuals have testes and a streak ovary (underdeveloped and non-functional), and a 45,XO karyotype. Some are pseudohermaphrodites because they have only one type of gonadal tissue, but display morphological characteristics of both sexes.  Transformation of the genital ducts In the indifferent duct system, the mesonephric or wolffian ducts and the paramesonephric or müllerian ducts are clearly distinguished. In the differentiated female In the differentiated male duct system, the duct system, the mesonephric or wolffian paramesonephric or duct degenerates and the müllerian duct paramesonephric or degenerates and the müllerian ducts develops mesonephric or wolffian (Mesonephric) into the oviducts (fallopian duct develops into the vas tube), uterus, and upper deferens, seminiferous third of the vagina. tubules and ejaculatory duct. (Paramesonephric) (Paramesonephric) (Mesonephric)  Differentiation of the internal genital ducts Embryos of both sexes have a double set of genital ducts: In males, the mesonephric or wolffian ducts develops into the vas deferens, seminiferous tubules and ejaculatory duct; and In females, the paramesonephric or müllerian ducts develops into the oviducts (fallopian tube), uterus, and upper third of the vagina. The development of the the mesonephric or wolffian ducts requires testosterone.  Differentiation of the internal genital ducts Wolffian duct remains Mullerian duct remains Müllerian ducts or Wolffian or (mesonephric) paramesonephric mesonephric degenerates degenerates (paramesonephric) Source: Boron & Boulpaep, Medical Physiology, 2nd Edition Panel A: During the early development, both the wolffian (mesonephric) and the paramesonephric or müllerian ducts are present in parallel. Panel B: In a normal male, the wolffian duct develops into the vas deferens, the seminal vesicles, and the ejaculatory duct. In males, the müllerian ducts degenerate. Panel C:, In a normal female, the paramesonephric or müllerian ducts develop into the fallopian tubes, the uterus, the cervix, and the upper one third of the vagina. In females, the wolffian (mesonephric) ducts degenerate.  Factors affecting differentiation of the internal genital ducts Are the testes important? (Removal of testes) müllerian duct Source: Boron & Boulpaep, Medical Physiology, 2nd Edition Panel D: The bilateral removal of the testes deprives the embryo of both testosterone and anti-müllerian hormone (AMH), also known as müllerian inhibiting substance (MIS), two important testicular products. The absence of AMH causes the müllerian ducts to develop in a female pattern. In the absence of testosterone, the wolffian ducts degenerate. Thus, the genetically male fetus develops female internal and external genitalia.  Factors affecting differentiation of the internal genital ducts Are the ovaries important? (Removal of ovaries) Müllerian duct Source: Boron & Boulpaep, Medical Physiology, 2nd Edition Panel E: After bilateral removal of the ovaries, müllerian development continues along normal female lines indicating that the ovary is not required for female duct development.  Factors affecting differentiation of the internal genital ducts Wolffian duct Müllerian duct Source: Boron & Boulpaep, Medical Physiology, 2nd Edition Panel F: Unilateral removal of the testis results in female duct (müllerian) development on the same (ipsilateral) side as the castration. The duct develops in a male pattern on the side with the remaining testis and virilization of the external genitalia proceeds normally.  Factors affecting differentiation of the internal genital ducts Wolffian duct Müllerian duct Source: Boron & Boulpaep, Medical Physiology, 2nd Edition Panel G: In the absence of both testes, administering testosterone preserves development of the wolffian ducts. However, because of the absence of AMH- which is a product of the testis, no müllerian regression occurs.  Factors affecting differentiation of the internal genital ducts Wolffian duct Müllerian duct Source: Boron & Boulpaep, Medical Physiology, 2nd Edition Panel H: In the presence of both ovaries, testosterone promotes development of the wolffian ducts. Without testes, no AMH is present and so the müllerian ducts develop normally.  Male pattern of sexual differentiation  The testis-determining factor (TDF) is contained in the short arm of the Y chromosome and, is a single gene called SRY (for "sex-determining region Y"). The SRY gene triggers development of the testis, which then makes androgens like testosterone and a glycoprotein like anti-müllerian hormone necessary for the male pattern of sexual differentiation.  Male pattern of sexual differentiation depends on the presence of three hormones, testosterone, dihydrotestosterone (DHT), and anti-müllerian hormone (AMH). The testis directly produces both testosterone and AMH. Peripheral tissues convert testosterone to DHT via the enzyme 5 reductase.  Testicular development occurs in the presence of TDF, the gene product of the SRY gene before 9 weeks of gestation. If TDF is not present or if TDF is present only after the critical window of 9 weeks has passed, an ovary will develop instead of a testis.  Factors involved in male pattern of sexual differentiation Androgens [e.g. testosterone, dihydrotestosterone (DHT)] direct the male pattern of sexual differentiation of the internal ducts, the urogenital sinus, and the external genitalia. Androgens have two major roles in male phenotypic differentiation: 1) They trigger conversion of the wolffian ducts to the male ejaculatory system, and 2) They direct the differentiation of the urogenital sinus and external genitalia. The wolffian phase of male sexual differentiation is regulated by testosterone and does not require conversion of testosterone to DHT by 5 reductase. On the contrary, virilization of the urogenital sinus, the prostate, the penile urethra, and the external genitalia during embryogenesis requires DHT, as does sexual maturation at puberty.  Factors that influence differentiation of the Duct System After formation of the testicular cords, the Sertoli cells produce anti-müllerian hormone (AMH), which causes the müllerian ducts to regress. Shortly after the initiation of AMH production, the fetal Leydig cells begin producing testosterone. The embryonic mesenchyme contains androgen receptors and is the first site of androgen action during formation of the male urogenital tract. In the absence of adequate androgen production or functioning androgen receptors, sexual ambiguity occurs. Factors that influence differentiation of the Duct System…cont’d The Sertoli cells also produce androgen-binding protein (ABP) to bind and maintain a high concentration of testosterone locally for the stimulation of growth and differentiation of the wolffian ducts into the epididymis, the vas deferens, the seminal vesicles, and the ejaculatory duct as well as differentiation of the medulla of the gonad into the rete testes. Testosterone also promotes development of the prostate. Cells of the wolffian ducts lack 5α-reductase and therefore cannot convert testosterone to DHT. Thus, the internal male ducts respond to testosterone per se and do not require the conversion of testosterone to DHT. In the absence of testosterone, the wolffian system remains rudimentary (underdeveloped), and normal male internal ductal development does not occur.  Differentiation of the external genitalia The cells of the external genitalia, unlike those of the wolffian duct, contain 5α-reductase and are capable of converting testosterone to DHT. The conversion of testosterone to DHT is required for normal male development of the external genitalia. The congenital absence of 5α-reductase is associated with normal development of the wolffian duct system but impaired virilization of the external genitalia.  Female pattern of sexual differentiation The female pattern of sexual differentiation occurs in the absence of testes. In fact, the embryo follows the female pattern even in the absence of all gonadal tissue, suggesting that the male pattern of sexual differentiation is directed by endocrine and paracrine control mechanisms. Hormones and Sex Determination  Congenital Adrenal Hyperplasia Ambiguous genitalia in genotypic females may result from disorders of adrenal function. Several forms of congenital adrenal hyperplasia have been described, including the deficiency of several enzymes involved in steroid synthesis. Deficiencies in 21α-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase all lead to virilization in females and thus ambiguous genitalia as a result of the hypersecretion of adrenal androgens. 21α-Hydroxylase deficiency is the most common and accounts for ∼95% of cases.  Congenital Adrenal Hyperplasia….. 21α-hydroxylase deficiency reduces the conversion of progesterone to 11-deoxycorticosterone, which goes on to form aldosterone and also reduces the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol which is the precursor of cortisol.  Congenital Adrenal Hyperplasia….. 21 α-hydroxylase deficiency reduces the conversion of progesterone to 11-deoxycorticosterone, which goes on to form aldosterone and also reduces the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol which is the precursor of cortisol. As a result, adrenal steroid precursors are shunted into androgen pathways. In female infants, the result is sometimes called the adrenogenital syndrome. The external genitalia are difficult to distinguish from male genitalia on visual inspection. The clitoris is enlarged and resembles a penis, and the labioscrotal folds are enlarged and fused and resemble a scrotum. The genitalia thus have a male phenotype in an otherwise normal female infant.  Functions of androgens  Androgens play two major roles in male phenotypic differentiation: – 1 They trigger conversion of the wolffian ducts to the male ejaculatory system and – 2 They direct the differentiation of the urogenital sinus and external genitalia.  Feminization syndrome: Testicular descent is an androgen-dependent process, and development of the structures involved in testicular descent is dependent on testosterone. In testosterone-deficient states caused by inadequate secretion or disordered androgen action, the testes of genetic males often fail to descend. This abnormality can be seen in individuals with both 5α-reductase deficiency and complete androgen resistance (i.e., testicular feminization syndrome).  Male pseudohermaphroditism: Any defect in the mechanisms by which androgens act on target tissues in genotypic males may lead to a syndrome of male pseudohermaphroditism. Affected individuals have a normal male karyotype (46, XY) and unambiguous male gonads but ambiguous external genitalia or may phenotypically appear as females.  5α-reductase deficiency: The activity of 5α-reductase is necessary for the conversion of testosterone to dihydrotestosterone (DHT). This may lead to ambiguous genitalia in males.  Dihydrotestosterone formation In certain target tissues, cytoplasmic 5α-reductase converts testosterone to dihydrotestosterone (DHT) which binds to the same androgen receptor as testosterone. However, DHT binds to the androgen receptor with an affinity that is about 100-fold greater than the binding of testosterone to the androgen receptor. Moreover, the DHT-receptor complex binds to chromatin more tightly than does the testosterone- receptor complex. The androgen receptor Androgens diffuse into target cells and act by binding to androgen receptors, which are present in genital tissues. In the absence of adequate androgen production or functioning androgen receptors, sexual ambiguity occurs. The androgen receptor functions as a homodimer (AR/AR) and is a member of the family of nuclear receptors The AR/AR receptor complex is a transcription factor that binds to hormone-response elements on DNA located 5' from the genes that the androgens control. Interaction between the receptor-steroid complex and nuclear chromatin causes increased transcription of structural genes, the appearance of mRNA, and subsequent translation and production of new proteins. Congenital absence of the androgen receptor, or the production of abnormal androgen receptor, leads to a syndrome known as testicular feminization Antimüllerian hormone The Sertoli cells of the testis produce antimüllerian hormone (AMH), also known as müllerian-inhibiting substance (MIS). It inhibits the development of the Mullerian duct which is responsible for the formation of fallopian tube, uterus, cervix, vagina. AMH is a homodimer of two monomeric glycoprotein subunits that are linked by disulfide bonds.  Steroid and thyroid hormone receptors Receptor Full name Dimeric arrangement GR Glucocorticoid receptor GR/GR MR Mineralocorticoid MR/MR receptor Steroids PR Progesterone receptor PR/PR ER Estrogen receptor ER/ER AR Androgen receptor AR/AR VDR Vitamin D receptor VDR/RXR THR Thyroid hormone THR/RXR receptor RAR Retinoic acid receptor RAR/RXR In contrast, the other "steroid" receptors (VDR, THR, RAR) preferentially bind to DNA as heterodimers formed with RXR, the receptor for 9-cis-retinoic acid. Thus the dimers are VDR/RXR, THR/RXR, and RAR/RXR. Interestingly, these heterodimers work even in the absence of the ligand of RXR (i.e., 9-cis-retinoic acid).  Steroid Hormones The activated steroid hormone receptor binds to specific stretches of DNA called steroid response elements(SREs), thus stimulating the transcription of appropriate genes. Steroid hormones enter their target cell by simple diffusion across the plasma membrane. Once within the cell, steroid hormones are bound with high affinity to receptors located in the cytosol or the nucleus. The binding of steroid hormone to its receptor results in a change in the receptor conformation so that the active receptor-hormone complex now binds with high affinity to specific DNA sequences called hormone response elements or steroid response elements (SREs).  Endocrine and paracrine control mechanisms in sexual differentiation Generally, intercellular communication can involve the production of a "hormone" or chemical signal by one cell type that acts on distant tissues (endocrine), on a neighboring cell in the same tissue (paracrine), or on the same cell that released the signaling molecule (autocrine). Source: Boron & Boulpaep, Medical Physiology, 2nd Edition