MGEM2015 Flashcards
List Structure & classes of steroids hormones?
- Adrenal Cortical Hormones (Corticoids)
. - sex hormones:
- male: androgens
- female: oestrogens & progesterone
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All Steroid Hormones derive from CHOLESTEROL so all share a common basic ring structure with cholesterol
Compare Different sex hormones? similarity & difference
binding protein? affinity?
secretion site?
Differences:
testosterone: produced in testicles/testes by Leydig cells which rely more heavily on de novo cholesterol synthesis; SHBG binding globulin higher affinity for testosterone than oestrogens; can increase skeletal muscle mass & strength during puberty; can affect erythropoiesis
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progesterone: Produced during luteal phase of menstrual cycle, converted from Pregnenolone in corpus luteum; & produced during pregnency in placenta
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oestradiol: produced in granulosa cells in ovaries; can affect libido (sex desire)
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Similarity:
* both testosterone & oestradiol transported by Sex Hormone Binding Globulin (SHBG), both can affect bones
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* both derived from androgens precursor secreted in zona reticularis of adrenal cortex
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* both testosterone & oestradiol after binding to receptors can initiate intracellular signalling via non-DNA-binding-dependent pathways, by activating secondary messenger like MAPK
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* all 3 sex hormone release stimulated by FSH & LH secreted by pituitary glands
Estradiol main function is to mature and then maintain the reproductive system. During the menstrual cycle, increased estradiol levels cause the maturation and release of the egg, as well as the thickening of the uterus lining to allow a fertilized egg to implant. The hormone is made primarily in the ovaries, so levels decline as women age and decrease significantly during menopause. In men, proper estradiol levels help with bone maintenance, nitric oxide production, and brain function.
Explain Pathway of sex hormones synthesis & role of cholesterol?
cholesterol transported from cytoplasm into mitochondria, facilitated by Steroidogenic Acute Regulatory (StAR) Protein, as steroids biosynthesis requires several mitochondrial Cytochrome P450 enzymes.
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(plasma LDL cholesterol->) pregnenolone converted to androstenedione in theca cells, which in granulosa cells converted to testosterone, then aromatised (in endoplasmic reticulum) to oestradiol; oestradiol in liver is oxidated by17 β-hydroxysteroid dehydrogenase type II to oestrone & then to oestriol
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(50% de novo synthesis of cholesterol in cytoplasm from acetyl-CoA)->pregnenolone->(progesterone->)androstenedione->testosterone
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(cholesterol->) pregnenolone-> progesterone in corpus luteum
Define Principles of hormone-receptor interaction?
androgens/estrogens/progesterone bind to their receptors (AR/ER/PR) respectively, conformational change causing dissociation of chaperone proteins (eg, heat shock proteins). AR^/ER/PR undergo dimerisation, their dimers bind to androgen/estrogen/progesterone response elements (ARE/ERE/PRE)
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^androgen form complex with AR in cytoplasm, complex translocate into nucleus 1st then undergo dimerisation & bind to AREs in target genes
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Non-genomic signalling through sex hormone bind to plasma membrane-bound receptors, initiate secondary messenger signalling like MAPK
Discuss Action of the key sex steroids?
testosterone:
Foetal:male internal genitalia(epididymis,vas deferens, and seminal vesicles) and male externalgenitalia (penis, scrotum,prostate).
Puberty:increase in testosterone production and mature sperm production.Increased secretion of testosterone into the systemic circulationaffects many tissues simultaneously.
Adulthood:gradual developmentof male pattern baldness;gradual development of benign prostatic hyperplasia.
Senescence: serum testosterone concentration gradually declines contributing todecreases in energy, libido, muscle mass and strength , and bone mineral density
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oestrogen:
Growth of uterus, fallopian tubes and vagina
– Mensturation in anovulatory cycles
– Enhances sperm penetration
– Deficiency leads to atrophic changes in female reproductivetract
Secondary Sex Characters: – Breasts: proliferation of ducts and stroma, accumulation of fat
– Pubic and axillary hair appears
– Feminine body contours and behaviours
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progesterone:
Reproductive Tract:
Decreases estrogen-driven endometrial proliferation and leads to the development ofa secretory endometrium.
Important inmaintenance of pregnancy and suppression of menstruation and uterine contractility.
Increasethe viscosity of cervical mucus.
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Mammary Gland:
Proliferation of the acini of the mammary gland during pregnancy and cyclic epithelialproliferation and turnover of acini during luteal phase.
Control of mitotic activity in the breast epithelium.
Preparation of breast for lactation
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Central Nervous System:
Depressant and hypnotic actions.
Increase in basal body temperature.
Increase of the ventilatory responseto carbon dioxide and reduction of arterial and alveolar PCO2.
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Metabolic Effects:
Increases basal insulin levels.
Stimulation of lipoprotein lipase activityandenhancement offat deposition
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Neuroendocrine Actions:
Weak inhibitor of Gonadotrophin secretion.
Control onresetting the hypothalamic-pituitary-gonadal axis to transition from the lutealto thefollicular phase.
Where are major sites of oestrone production?
skeletal muscle & adipose tissue
regulation of oestrogens/progesterone production?
In the theca cells, LH controls 17βHSD activity and androstenedione production, whereas CYP19 (P450arom) activity in the granulosa cells is controlled by FSH and hence estradiol production.
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LH acts on both thecal and granulosa cells; FSH acts only on granulosa cells. FSH and LH stimulate adenylate cyclase via G protein-coupled receptors. Cyclic adenosine monophosphate (cAMP) generated from adenosine triphosphate (ATP) activates protein kinase A, which in turn stimulates steroidogenic enzymes.
In males, Which of the following are Sertoli cells responsible for producing? stimulated by which hormone?
a.Gonadotropin-releasing hormone (GnRH)
b.Androgen binding globulin
c.Testosterone
d.Oestrogen
FSH stimulates Sertoli cells to produce androgen binding globulin
ABG binds to testosterone and keeps it at high concentrations in the seminiferous tubules within testes. This is important as high levels are required here for successful spermatogenesis.
In males which hormone stimulates Leydig cells to produce what?
Leydig produce a sex hormone
Luteinizing hormone (LH) stimulate Leydig cells produce testosterone
Discuss the secretion of the gonadotrophic hormones, luteinizing hormone (LH) & follicle stimulating hormone (FSH)?
Gonadotrophin-releasing hormone (GnRH) through hypophyseal portal systemstimulates LH & FSH release from anterior pituitary gonadotrophic cells
regulation and control of LH and FSH in male & female?
release under control of hypothalamic-pituitary-gonadal (HPG) axis
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1.hypothalamic input:
* More rapid GnRHpulse frequencies favor LH secretion; Slower pulse frequencies favor FSH
2, positive & negative feedback from gonadal sex steroid & peptide hormones:
* =Male: Testosterone negative feedback to hypothalamus to inhibit GnRH & to pituitary to inhibit LH & FSH
* Sertoli cells release inhibin (when spermatogenesis is sufficient), act on pituitary inhibit FSH release
* =Female: As follicles grow, they release estradiol, negative feedback to hypothalamus, inhibit GnRH so inhibit pituitary secrete LH & FSH (in follicular phase)
* At ovulation estradiol positive feedback to hypothalamus, trigger surge of LH & FSH secretion, rising oestrogen level make pituitary more responsive to GnRH
* Luteal phase, Progesterone (secreted by luteinized theca cells in corpus luteum), & estradiol negative feedback to hypothalamus & pituitary
Luteinized granulosa cells secret inhibin which inhibits pituitary FSH secretion
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3.paracrine modulation from local factors produced within pituitary:
* activin stimulate FSH
* follistatin inhibit FSH, which adds to FSH inhibition effect by inhibin, increased expression when at faster GnRH pulse frequencies that favor LH release
sex steroids can control LH/FSH release regulating GnRHR expression and signalling
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Development of the follicles is stimulated by production of follicle stimulating hormone (FSH) by the pituitary gland. Ripening of the follicles then results in an increase in oestrogen levels, as oestrogen is secreted by follicular cells. This increase in oestrogen levels feeds back to the pituitary, and suppresses further release of FSH (negative feedback). The follicles also release a second hormone called inhibin, which also suppresses further production of FHS. As the oestrogen levels rise, this triggers a a mid cycle surge in a second pituitary hormone called Lutenising hormone (LH), which causes the follicle to rupture (ovulation). LH also causes ruptured follicles to lutenise, forming a transitory endocrine organ called the corpus luteum. This looks yellow, due to its pigmented lutein cells (luteus is latin for yellow). The corpus lutein secretes progesterone and oestrogen. The progesterone levels feed back to the pituitary and suppress further release of LH. If fertilisation does not occur, the corpus luteum degenerates into a small white fibrous scar called the corpus albicans. The resulting decline in progesterone (and to some extent oestrogen) levels precipitate menstruation. The decline in oestrogen levels, feeds back to the pituitary and there is a corresponding increase in FSH to being the cycle all over again.
Explain the control of spermatogenesis & testosterone secretion?
=FSH acts indirectly on Sertoli cells to stimulate spermatogenesis
=testosterone stimulates final stages of spermatogenesis.
=When sufficient spermatogenesis is achieved, Sertoli cell releases inhibin, which inhibits FSH release from pituitary.
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=LH stimulate Leydig cells produce testosterone
=Testosterone negative feedback to hypothalamus to inhibit GnRH secretion & to pituitary to inhibit LH secretion, so reduce Leydig cell secretion of testosterone
Describe the processes involved in ovarian follicles development?
At birth, in primordial follicles, primary oocytes remain arrested in prophase stage of meiotic division 1.
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FSH & LH stimulate primordial follicles to develop. In each ovarian cycle, about 20 primordial follicles containing primary oocytes are activated to begin maturation. However, normally ONLY 1 follicle fully matures, the rest contribute to the endocrine function of ovary
When activated by FSH & LH, 1st meiotic division is completed, the primary follicle has matured into a secondary follicle. Then 2nd division starts, Graafian follicle containing a secondary oocyte is formed. This 2nd division is not completed, unless the ovum is fertilised.
A dominant follicle appears to be selected from a cohort of class 5 antral/Graafian follicles (with diameter 2-5mm) at the end of the luteal phase of menstrual cycle. About 15-20 days are required for a dominant follicle to grow and develop to preovulatory stage (diameter 16-20mm)
essential components of ‘Genotypic Sex’?
genotypic Male: 22 autosomes + XY
genotypic Female: 22 autosomes + XX
Y chromosome determines genotypic sex – conferring ‘Maleness’
Female genotypic sex can be seen as the default sex unless: After approx 6-7 weeks of gestation, the expression of SRY gene on Y chromosome induces changes that result in the development of the testes.
SRY: sex-determining region Y gene (only found on Y chromosome)
Identify the biological processes underlying gonadal differentiation & the central molecular mediators?
The indifferent gonad develops into a testis in response to Testis Differentiation Factor (TDF, a DNA-binding protein/transcription factor) produced/encoded bySRYgene, before week 9 ofdevelopment.
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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 testis.
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molecular mediators: further male sexual differentiation depend on testosterone & Anti-Mullerian hormone (AMH) produced by testis, and dihydrotestosterone (DHT) converted by peripheral tissues from testosterone
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if AMH present (Testes =Male)
if No AMH (Ovary =Female)
around week 10 of development, testosterone secreted by testis Leydig cells in response to human chorionic gonadotropin (HCG)
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embryo= from fertilisation until end of week 8
Outline the physiological differences between male and female fetuses (=from week 9 after fertilisation)?
their developmental origins?
In males, gonadarche (physical & functional maturation of gonads) leads to initiation of sperm production by testes
In females it leads to folliculogenesis & menarche.
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In male foetus, testis develops from the medulla of the indifferent/primordial gonad; the cortex regresses
In female foetus, the medulla of indifferent gonad regresses while the cortex becomes greatly thickened, due to mitotically dividing Primordial Germ Cells which give rise tooogonia.
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In males, the genital tubercle becomes the glans penis (tip of penis). The urogenital folds fuse to form the shaft of penis. The labioscrotal swellings become scrotum.
In females, the genital tubercle becomes the clitoris. The urogenital folds remain separate as the labia minora. The labioscrotal swellings become the labia majora (around vagina opening) where they remain unfused. Ventrally, the labioscrotal swellings fuse to form the mons pubis (rounded mass of fatty tissue lying over the pubic symphysis)
Provide an overview of gametogenesis?
male: spermatogonium (mitosis)->primary spermatocyte (meiosis 1)->secondary spermatocyte (meiosis 2)-> spermatid (differentiation=cellular reorganisation)->spermatozoon (=mature sperm) detached from Sertoli cells into seminiferous tubule lumen
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female: oogonium (mitosis)->primary oocyte (meiosis 1)->secondary oocyte (meiosis 2)-> ootid (differentiation)->ovum
primary oocytes in primordial follicles are arrested at prophase of meiosis 1 until stimulated by LH & FSH around puberty
describe the structure of the ovary?
Surface – formed by simple cuboidal epithelium (=germinal epithelium). Underlying this layer is a dense connective tissue capsule.
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Cortex – comprised of a connective tissue stroma & numerous ovarian follicles. Each follicle contains an oocyte, surrounded by a single layer of follicular cells.
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Medulla – formed by loose connective tissue and a rich neurovascular network, which enters via the hilum of the ovary.
describe the structure & development of ovarian follicle (folliculogenesis)?
Primordial follicles
Every day, a cohort will start to grow
3 – 4 months primary follicle
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Primary follicles
70 days small antral follicles (2 – 5 mm)
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Small antral follicles
FSH window recruited into ovulatory cycle
No FSH window atresia
Primordial follicle Only 1 layer of flat granulosa cells
b). Primary follicle 2 or more layers of granulosa cells & zona pellucida & theca interna
c). Secondary follicle: antrum (fluid filled space) & theca interna & theca externa
d). Graafian (mature) follicle: with corona radiata (adjacent to zona pellucida) & cumulus oophorus
e). Corpus luteum: The ruptured follicle
Describe the process of follicle selection, recruitment growth & dominance?
Recruitment:In 1 ovarian cycle, several follicles depart from resting pool to begin a well-characterised pattern of growth and development during early follicular phase.
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Selection: select most healthy from maturing antral/Graafian follicle cohort by atresia, highly selective. Depends on follicle size with smaller cells <10mm destined to undergo apoptosis
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Dominance:ONLY 1 dominant follicle destined to ovulate given its presumed key role in regulating the size of the ovulatory quota. Mature Graafian follicle diameter ~2cm at ovulation
explain the two-cell two gonadotropin theory of steroidogenesis in ovary?
The first compartment consists of theca cells, which are stimulated by LH to produce androstenedione. The second compartment consists of granulosa cells, which are stimulated by FSH to convert androstenedione to estrogens like estradiol.
LH binds to luteinizing/chorionic gonadotropin receptor (LH/CGR) on theca cell surface and stimulates the expression of the steroidogenic enzymes necessary for androgen production. Cholesterol is mobilized into mitochondria by steroidogenic acute regulatory protein (STAR) where it is converted to pregnenolone by cholesterol sidechain cleavage enzyme (CYP11A1). Pregnenolone diffuses into the smooth endoplasmic reticulum and is converted to progesterone by 3β-hydroxysteroid dehydrogenase (HSD3B). Progesterone is then converted to androstenedione by 17α-hydroxylase/17,20desmolase (CYP17A1).
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Granulosa cells: follicle-stimulating hormone (FSH) via signaling through follicle-stimulating hormone receptor (FSHR) stimulates the expression of enzymes necessary for estrogen synthesis. Androstenedione produced by theca cells diffuses into granulosa cells and is converted to testosterone by the enzyme 17βhydroxysteroid dehydrogenase (HSD17B) or to estrone by aromatase (CYP19A1). CYP19A1 utilizes testosterone to produce 17β-estradiol. However, HSD17B can also produce 17β-estradiol using estrone as a substrate
Define & distinguish between uterine & ovarian cycle?
Ovarian cycle= Interval between successive ovulations, ovum maturation & release, follicle->corpus luteum, follicular phase & luteal phase
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Uterine cycle= Effects of ovarian hormones on uterus, especially Endometrium
Proliferative->Secretory phase(=menses)
Describe the endocrinology of the menstrual cycle?
Describe feedback control of HPO axis during menstrual cycle?
low level progesterone (P4) & estrodiol (E2) due to (no fertilisation) corpus luteum death feeback to hypothalamus & anterior pituitary to increase FSH
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As dominant follicle matures, secrete more estradiol, E2 circulating levels exceed certain threshold, positive feedback to anterior pituitary increase LH
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High P4 level secreted by corpus luteum suppress LH & FSH release
Explain the temporal events of the menstrual cycle?
Day 1-4, FSH increase leads to recruitment of a cohort of follicles from the pool of non-proliferating follicles.
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After menses/menstrual bleeding (Day 0-4), FSH levels begin to decline due to E2 negative feedback & inhibin B produced by developing follicles.
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Day 5-7, dominant follicle selection: only 1 follicle is selected from the cohort of recruited follicles to ovulate, the remaining follicles will undergo atresia. By day 8, dominant follicle promote its own growth & suppress other follicles maturation
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Day 8-14, serum E2 increase as dominant follicle size & number of granulosa cells increase. In presence of increased E2, (FSH stimulates formation of LH receptors on granulosa cells allowing for secretion of small quantities of progesterone & 17-hydroxyprogesterone), positive feedback to anterior pituitary increase LH release. LH surge induced, ~24-36hrs later, follicle rupture to release oocyte =OVULATION
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Day 15-28, LH cause empty follicle converted into corpus luteum→ secretes mostly P4 but also E2
P4 maintains endometrium; induces decidualisation
P4 causes differentiation of endometrial glands to prepare for implantation
High P4 levels negative feedback inhibit LH & FSH release
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(no fertilisation) corpus luteum degenerate to corpus albicans, cause lower P4 & E2 levels feedback to hypothalamus & pituitary increase FSH in last few days of cycle, allowed by sharp decrease of inhibin A. This increase in FSH allows for recruitment of follicles in each ovary for next cycle. cycle start again
Day 1-14 of menstrual cycle: follicular/proliferative phase
15-28: luteal/secretory phase
P4: progesterone
E2: estradiol
Describe the function and effects of sex steroids on endometrial structure and function?
endometrium Proliferation & differentiation stimulated by estrogen (day 5-14)
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progesterone (P4) maintains endometrium & induces decidualisation: spindle-shaped stromal cells become rounded decidual cells via cAMP. decidual cell provide nutrition to early embryo, secrete prolactin, rich in uterine natural killer cells help immune tolerance (so embryo not rejected by mother). Multiple foci of decidual cells spread throughout endometrial upper dense layer =zona compacta. endometrial glands become more prominent in zona spongiosa.
P4 causes differentiation of endometrial glands to prepare for implantation of embryo (blastocyst).
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(no fertilisation) decreasing E2 & P4 level as corpus luteum degenerate. As hormonal support of endometrium is withdrawn, vascular & glandular integrity of endometrium degenerates, tissue breaks down, menstrual bleeding ensues (day 0-4)
Give examples of conditions associated with menstrual cycle dysregulation?
Secondary amenorrhoea (=no menstruation for 6 months without pregnancy) & anovulation commonly caused by stress/excessive exercise (suppress hypothalamic–pituitary–ovarian HPO axis, low LH/FSH), excessive weight loss, Polycystic Ovary Syndrome (PCOS) & hyperprolactinaemia (prolactin affect gonadotrophins release)
Excessive weight can also have an adverse effect on ovulation cause anovulation. This probably results from excess estrone, generated in the adipose tissue by conversion from androgens, interfering with the normal feedback mechanism to the pituitary gland
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anovulation: Prolonged ovarian cycles are frequently associated with failure of ovulation, presumably because of insufficient secretion of LH at the time of the preovulatory surge of LH, which is necessary for ovulation.
