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Physiology Monday, July 15, 2024 9:48 PM Puberty Onset Disinhibition of central hypothalamic function Recapitulating a process active in fetal life and in the newborn period 1st measurable hormonal changes are rises in circulating LH at night HSD27B3 mutation - individual stays prepubescent by t...

Physiology Monday, July 15, 2024 9:48 PM Puberty Onset Disinhibition of central hypothalamic function Recapitulating a process active in fetal life and in the newborn period 1st measurable hormonal changes are rises in circulating LH at night HSD27B3 mutation - individual stays prepubescent by targeting process involved in transition from quiescence to activity at puberty of hypothalamus Male puberty 1st sign: testis growth Hypothalamus increase GRH release -> anterior pituitary increase LH/FSH release -> maturation and growth of testis -> increase steroid/testosterone 2 main cell types - Sertoli cells - Leydig cells Female puberty Transition from non-cyclic, quiescent reproductive endocrine system to cyclic reproductive function that allows procreation Menarche - beginning of menstrual cycles Thelarche - breast development Adrenarche - increased adrenal androgen secretion GnRH release from hypothalamus -> LH/FSH output from pituitary -> maturation and growth of ovaries -> estrogens and androgens -> secondary sexual changes + decreased sensitivity of hypothalamic pituitary system to inhibitory effects of estrogen -> subsequent LH surge -> menarche -> period regularity -> cyclic reproductive cycle preparing uterus for implantation and releasing at least one ovum that can be fertilized - Increased estrogen -> ovulation -> suppression of LH/FSH Effects of estrogen on non-pregnant female - At puberty, granulosa cells in the developing follicles of the ovary begin to secrete estrogen -> menarche - Stimulate growth of external genitalia - Subcutaneous fat deposits Physiology of breast Prepubertal breast - most male and female have duct system ending in terminal ducts with minimal lobule formation Female (menarche) - terminal ducts become lobules - Increased interlobular fibrous stroma, paucity of adipose tissue, cyclic changes After ovulation - increased estrogen/progesterone -> cell proliferation -> increased number of acini per lobule -> intralobular stroma -> edematous -> sense of premenstrual fullness Menstruation - decreased estrogen/ progesterone -> epithelial cell apoptosis -> resolution of stromal edema -> regression in size of lobules Pregnancy - great increase in estrogen/progesterone -> increased #/size of lobules with scant stroma -> areola dermal glands become more prominent and function in nipple lubrication -> milk production is inhibited by increased progesterone Hormones - Estrogen - branching of duct system - Progesterone - formation of new lobes and alveoli - Prolactin - hPL - normal breast development during pregnancy - Growth hormone and glucocorticoids Neural endocrine reflex for lactation 1. Stimulus from suckling travels from breast, through the spinal cord to the hypothalamus 2. Neurons from spinal cord inhibit dopamine release from the arcuate nucleus. The decreased Endocrinology 第 1 頁  2. Neurons from spinal cord inhibit dopamine release from the arcuate nucleus. The decreased level of dopamine removes the inhibition that DA normally produces on lactotrophs in the anterior pituitary, leading to prolactin release. Prolactin stimulates milk production in the breast. ○ TRH from hypothalamus → prolactin released from anterior pituitary → enters bloodstream → breasts → increased milk production and secretion by alveolar epithelial cells ○ Increased prolactin inhibits release of GnRH from hypothalamus → decreased LH/FSH from anterior pituitary → decreased development of ovarian follicles, ovulation, menstrual periods 3. Neurons from the spinal cord also stimulate the production and release of oxytocin from the paraventricular and supraoptic nuclei. Oxytocin is released in the posterior pituitary and into the systemic blood, where it then makes it ways to the breast and myoepithelial cells. ○ Myoepithelial cells contract → milk ejection from alveolus → drained by milk collecting ducts → transported to nipple ○ Other triggers for oxytocin release and let down reflex includes sounds/sights/smells connected to infant (e.g. infant crying) 4. Neurons from the spinal cord inhibit neurons in the arcuate nucleus and preoptic area of the hypothalamus, causing a fall in GnRH production. The reduced stimulation of gonadotrophs inhibits the ovarian cycle. Anticipation: oxytocin secretion Nursing: prolactin secretion (preparation for the next feed) Hormonal control of overy Follicular phase - developing a follicle capable of sustaining estrogen and progesterone production (Graafian follicle) - Measured from onset of menstruation - Folliculogenesis: granulosa cells -> increased estradiol production -> rapid growth/ matruation endometrium ○ Follicle -> primary oocyte -> mature follicle -> ovulation -> corpus luteum -> corpus albicans ○ Gondaotropin dependent - one cell selected to become dominant follicle  Other cells grow in size and support cell through steroid genesis or atrophy and disappear  Monthly cycle ○ Gonadotropin independent  Long cycle (85 days)  Commenced in luteal phase 3 cyces prior to ovulation - Proliferative phase - increased estradiol production mid follicular phase -> decreased FSH negative feedback -> increased preovulatory surge estradiol production -> increased positive feedback anterior pituitary -> LH surge -> ovulation - LH surge drives progesterone level - Epithelial differentiation - basalis, spongiosum, stratum compactum Luteal phase - sustaining structure long enough to allow for implantation - After ovulation, follicle becomes corpus luteum, granulosa and theca cells become luteal cells (produce progesterone, inhibin, estrogen) - Estrogen and progesterone stimulate endometrial growth and development, vacuole formation, secretory phase ○ Progesterone is primary steroid hormone - Increased expression of cytochrome P450 cholesterol SCC, 3BHSD - Decreased expression of enzymes that ocnvert progesterone to estrogens (17 a hydroxylase; aromatase cytochrome P450) - High progesterone, estrogen, inhibin -> suppress hypothalamic pituitary system -> decreased FSH and LH secretion -> decreased stimulation of corpus luteum -> decreased estrogen and progesterone -> degeneration of endometrium -> menstrual bleeding - Decreased -ve feedback -> increased gonadotropin secretion -> small increase in FSH -> next cycle Inhibin related proteins - secreted by granulosa cells in response to FSH Endocrinology 第 2 頁 Inhibin related proteins - secreted by granulosa cells in response to FSH - Inhibin - inhibits FSH (luteal phase) - Activin - stimulates FSH Ovary steroid genesis Estrogen production - coordinated enzymatic activities of theca and granulosa cells - Theca cells: cholesterol to androgens (androstenedione -> testosterone) but lack enzymes to convert androgens to estradiol ○ LH -> increased androstenedione via activation of G proteins -> increase AC -> increase cAMP -> increase enzymes required for biosynthesis of testosterone - Granulosa cells: androgens to estradiol but lack enzymes to convert progesterone to androstenedione ○ FSH -> increased inhibin synthesis -> increased aromatase activity -> increased estradiol through activation of G proteins -> increased AC -> increased cAMP Androgenesis Leydig cells - LH -> increased testosterone -> activation of G proteins -> increased AC -> increased cAMP -> increased PKA -> increased enzymes required biosynthesis of testosterone - Androgenesis blocked by transcription inhibitor Sertoli cells - FSH -> increased growth factors -> increased inhibin synthesis -> increased androgen binding protein Cholesterol -> SCC -> pregnenolone -> 17 B hydroxylase -> 17a hydroxy pregnenolone -> 17-20 desmolase -> DHEA -> 17B hydroxysterone dehydrogenase -> androstenediol -> 3HSD -> testosterone - Free plasma testosterone - 2% - Bound: ○ Sex hormone binding globulin/ testosterone binding globulin - 45% ○ Albumin/ corticosteroid binding globulin - 55% Types of androgens - 5a dihydrotestosterone via 5a reductase - stimulation of epididymis, growth of accessory sex organs/ skin - 5B dihydrotestosterone - heme synthesis - 5a androstenodiol - stimulates seminal fluid secretion - Androstenediol - induction of liver enzymes - Estradiol 17B via aromatase - sexual differentiation Dominant source of testosterone production = testis Senescence - gradual decline in serum - LH not elevated and decreased production due to comorbidities (poor diet/obesity, CVD, diabetes) Differential gene expression Gene rearrangement Chromosomal rearrangements - Crossing over during meiosis - Mutational events that change gene locations Regulation of gene expression 3 main stages: transcription, RNA processing post transcription, translation Transcriptional regulation - Promoter sequence (cis elements) on DNA act as recognition sites for trans elements (transcription factors) to bind and initiate transcription Promoter - DNA sequence upstream of TSS that specify where transcription starts and if/when it occurs Core promoter - BRE sequence - immediately upstream of TATA box; recognized by TFIIB component - TATA box - upstream of TSS; bound by TFIIB - Initiator sequence - located at TSS; bound by TFIID - Downstream promoter element - downstream of TSS; recognized by TFIID Proximal promoter elements Endocrinology 第 3 頁 Proximal promoter elements - CAAT box - associated with genes that require high levels of expression - GC box - stabilize promoter complexes; role in assembling transcription complexes in genes lacking TATA box; bind SP1 TF Alternative promoters - Allow tissue/developmental stage specific gene expression - Isoforms can provide tissue specificity, developmental stage specificity, differential subcellular localization, differential functional capacity - Ex. dystrophin gene - Dp427 main variant Promoter mutations - change expression levels of gene rather than coding sequence changes - Ex. B thalassemia - HBB gene codes for beta globin protein Other regulatory sequences - Enhancers - located 100s of kb from core promoter; bind TFs to activate transcription; regulate strength of gene expression in a cell - Silencers - act in opposition to enhancers; bind TFs that repress transcription - Boundary elements and insulators - function to block a region of DNA from the influence of nearby enhancers or silencers - Looping of DNA btw enhancer/silencer and promoter sequences enables direct interaction of mediator proteins Distance activation - insulator elements prevent inappropriate gene activation by inhibiting binding btw enhancers and other promoters Transcription factors DNA binding proteins that regulate gene expression by binding to promoter, enhancer, and response elements to initiate transcription Trans-acting elements - Can travel into nucleus and act on multiple diff genes on diff chromosomes General - required for binding of RNA pol II to promoter Specific - increase or decrease transcription in certain cells or in response to signals Structure - DNA binding domain - Signal sensing domain - senses and transmits external signals to transcriptional complex - Trans-activation domain - contains binding sites for coregulators Mutation examples - c-Myc and p53 in cancer - AIRE in autoimmune disease - NFkB in chronic inflammation - SWI/SNF chromatin remodeling complex in intellectual disability Response element DNA sequence that binds ligand and receptor complexes; results in transcriptional activation in response to ligand entry to the cell Post transcriptional regulation RNA processing - RNA splicing - removal of introns prior to RNA translation - Polyadenylation - addition of poly A tail to 3' end of transcript; stabilizes mRNA Alternative splicing - Allows production of multiple diff RNA sequences from a single primary transcript Alternative polyadenylation - alteration in size and position of poly A tail - Type I - single poly A signal - Type II - multiple poly A signal -> changes in mRNA stability but no diff in protein produced - Type III - multiple poly A signals -> diff mRNAs/proteins Translational control Global regulation promotes or inhibits interaction of mRNA with ribosomes Regulatory sequences within mRNA can control translation - Usually in 3'UTR - Interaction btw cis acting regulatory sequences and trans acting RNA binding proteins RNA trafficking - Transport of RNA to specific cellular locations Translational regulation by iron status Endocrinology 第 4 頁 Translational regulation by iron status - IRE binding protein binds to IRE sequence in 3'UTR of transferrin receptor mRNA ○ Binding prevents degradation -> increased receptor made -> increased ability for cellular uptake of iron - IRE binding to protein binds to IRE sequence in 5'UTR of ferritin mRNA ○ Binding inhibits translation -> decreased ferritin produced -> decreased storage of iron Regulatory non coding RNAs Functional RNAs that are not translated Interact with complementary mRNA sequences to reduce level of gene expression Act by - Inhibiting translation of mRNA - Triggering of mRNA destruction by dsRNAses - Transcriptional silencing of promoters microRNAs, siRNAs - post transcriptional gene silencing, RNA interference Small RNAs - modification of target RNAs, synthesis of telomeric DNA, chromatin structure dynamics, transcription modulation, structural role, gametogenesis Medium and large RNAs - DNA imprinting, X inactivation, DNA demethylation, gene transcription, generation of other RNA classes miRNAs in disease - miR-15 and 16 induce apoptosis by decreasing BCL2 expression -> deletion -> decreased apoptosis -> absence of oncogene regulation -> proliferation of abnormal blood cells Long ncRNA - Gene regulation - Genomic imprinting (epigenetics) (H19) - X inactivation (Xist) - Disease Reproductive system Male Spermatogonia (46C/2n) -> mitotic division -> spermatogonia (4n) -> mitotic division -> primary spermatocyte (diploid 4n) -> 1st meiotic division -> secondary spermatocyte (haploid 2n) -> 2nd meiotic division -> spermatid (haploid n) Spermatozoa not fully matured in seminiferous tubules - Must spend 1-10 days in epididymis to increase maturity and mobility Composition of semen - volume: 2-6 mL; pH 7,2-7,6 - Seminal vesicles - fructose, fibrinogen, prostaglandins - Prostate gland - alkaline, clotting enzyme - Bulbourethral gland - mucoprotein - Spermatozoa Sperm survival - survive 24-72 hours in female reproductive tract Sperm undergoes morphological, physiological, and biochemical changes during transport through female reproductive tract Capacitation - capacity of sperm to fertilize an ovum is enhanced if they spend some time in the female reproductive tract - Makes sperm able to adhere to ovum - Remove corona penetrating inhibitor and acrosin inhibitor Female Mitotic proliferation of germ cells take place before birth Meiotic divisions -> one mature ovum 2nd meiotic division is completed upon fertilization Sex determination Genetic sex Determined at conception Presence of SRY essential for male development Barr body - inactivated X chromosome Primary sex characteristics Male hormones Endocrinology 第 5 頁 Male hormones - Mullerian inhibiting substance, testosterone, insulin like growth factor 3 - Degeneration of mullerian duct and development of wolffian duct -> vas deferens, seminal vesicle, epididymis - Leydig cells - differentiation of wolffian duct, development of primary organs, spermatogenesis - Sertoli cells - degeneration of Mullerian duct, spermatogenesis No male hormones - Degeneration of wolffian duct and development of mullerian ducts -> uterus, fallopian tubes, proximal vagina - Female development - primarily due to absence of testosterone/DHT Key genes in sexual differentiation DAX1 - on X chromosome - inhibits differentiation of testes SF1 - on chromosome - interacts with SOX9 to induce expression of AMH by Sertoli cells; in interstitial Leydig cells, SF1 induces expression of gene that is needed for androgen production SOX9 - on chromosome 17 - activate AMH SRY - on Y chromosome - TF that initiates testis and other male sex organ formation AMH - on chromosome 19 - responsible for atrophy of Mullerian duct; expression requires united action of SF1, SOX9, DAX1 WT1 - on chromosome 11 - morphogenesis of urogenital system Secondary sex Higher levels of estrogen (females) or testosterone (male) -> puberty Epigenetics Types of modification DNA methylation - methyl group replaces a hydrogen on cytosine residues - Occurs in CG pairs - CH3 addition interrupts TF binding to promoters/ enhancers - CpG islands regulate transcription - Global methylation decreases across lifespan, but CpG methylation increases Histone modification - DNA packaged into nucleosomes - Tight packaging decreases accessibility for transcription - Euchromatin - less compact -> transcriptionally active - Heterochromatin - more compact -> transcriptionally inactive - Histone protein tails can be modified by methylation, acetylation, phosphorylation, ubiquitination, citrullination - Repressive marks = H3K27me3 Non coding RNA - Act by inhibiting translation of mRNA, triggering of mRNA destruction by dsRNAses, transcriptional silencing of promoters Ex. Xist - an RNA transcribed from inactive X chromosome -> coats one X chromosome making it transcriptionally inactive (undergoes DNA methylation and histone modification) Genomic imprinting Some inherited epigenetic marks are parent of origin specific Monoallelic expression; overrides law of dominance IGF2/H19 locus - Regulates fetal growth during development - Maternal H19 -> decreased growth (survival of offspring but not risk future offspring) - Paternal IGF -> increased growth (health and survival of offspring) Nutrition and lifestyle - Folic acid intake - H19 DMR decrease methylation with increased folic acid intake -> altered IGF2/H19 ratio during development - Maternal nutrition - decrease methylation with periconceptual exposure Drug/toxin exposure - Ex. hydralazine (antihypertensive) - DNA methylation inhibitor; valproate - histone deacetylase inhibitor - Drug induced SLE - dysregulated methylation patterns in CD4 proliferation -> increased autoimmune activity Endocrinology 第 6 頁  autoimmune activity Drug Epigenetic effects Methotrexate DNA methylation Tricyclic/SSRI DNA methylation General anesthetics DNA/histone methylation/deacetylation Statins miRNA Procainamide DNA methylation Pregnancy Early pregnancy events Miscarriage, transmission of infections causing fetopathy - Toxoplasmosis - Other agents such as varicella, zoster virus, HPV, Hep B, syphilis - Rubella - Cytomegalovirus - Herpes simplex virus/ HIV Transmissible at birth/ transcervical - candidiasis, gonorrhea, listeriosis Cell mediated immunodeficiency of late pregnancy - Listeriosis, cytomegalovirus, influenza Breastfeeding complications - TB, HIV Newly acquired disease Gestational diabetes and hypertension, preeclampsia (lower levels of IL10), acute liver disease, gestational pemphigus, pregnancy urticaria pruritus syndrome Chronic disease in pregnancy Asthma, arthritis, hypertension, diabetes, obesity Normal changes in pregnancy NK cells - CD16-/ CD56+: marked increased in 1st trimester, decrease in 3rd trimester, marked increase after delivery T cells - CD8 cells increase in 1st trimester, all other decrease in pregnancy B cells - profoundly decrease in pregnancy Menopause (12 months of amenorrhea after final menstrual period) Apoptosis is the mechanism responsible for oocyte depletion and follicular atresia Reflects complete or near complete ovarian follicular depletion and absence of ovarian estrogen secretion Age: average 51 years Factors determining menopause Genetics - genetic variation in estrogen receptor gene, family history Ethnicity - Hispanic women earlier and Japanese later compared to Caucasian women Smoking - age of menopause reduced by 2 years Reproductive history - tendency of earlier menopause for women who never had children and had shorter cycle length during adolescence Premature menopause Menopause in women younger than 40 years of age Menopausal transition (Perimenopause and climacteric) Progressive decline in ovarian function results in cycle disruption Can last for several years (usually 3-5) Early menopausal transition - Menstrual irregularity - risk of endometrial hyperplasia (unopposed estrogen from anovulation and progesterone deficiency in transition period) - Decline in follicular number -> decrease inhibin B and AMH -> increase serum FSH levels - Estradiol secretion relative preservation due to an increase in aromatase activity - Luteal phase progesterone concentrations low Late menopausal transition Endocrinology 第 7 頁 Late menopausal transition - Cycle variability increases - Striking fluctuations of FSH and estradiol - High FSH and low estradiol values suggestive of menopause After menopause Ovarian follicles are depleted; ovaries no longer secrete estradiol and continues to produce and secrete androgens under continued stimulation of LH Clinical manifestations - Loss of menstrual periods - may be first indicator of early ovarian failure - Symptoms of estrogen deficiency ○ May occur while women still having menstrual periods ○ Onset may be gradual or sudden ○ Symptoms include hot flushes, mood change, sleep disturbance, dry vagina, poor lubrication during sexual intercourse - Emotional turmoil - Long term consequences - osteoporosis, accelerated hardening of arteries, breast cancer risk may be reduced slightly Embryonic development Week Developmental Milestones 1 Fertilization, blastulation starts 2 Blastulation continues, bilaminar embryo (endoderm, ectoderm) 3 Gastrulation (trilaminar embryo), muscle and vertebrae begin to form 4 Neural folds fuse, early organogenesis - sensory placodes and limb buds, heartbeat apparent 5 Eyes and hands develop, circulatory system begins to operate 6 Decent of heart and lungs to thorax, olfactory nerve enters the brain 7 Bone formation, eyelids form 8 Ovaries and testes can be distinguished, all major organ systems formed Cell differentiation: activation of gene expression Embryonic cells are totipotent During development, cells specialize and lose flexibility (housekeeping genes remain active) Node - human organizer Gene expression begin with node during gastrulation Left sided rise in intracellular Ca2+ -> cascade of gene expression involving lefty/nodal/TGFB Endocrinology 第 8 頁