Reproductive Endocrinology - Student Copy.pptx

Reproductive Endocrinology Module Code: Theme 2, Lecture 2 Oliver G. Steele [email protected] Join at slido.com #2322361 Lecture in Context This lecture will build on … • Steroid hormone mechanisms of action and synthesis • Hypothalamic pituitary axis … by introducing and covering … Introduc...

Reproductive Endocrinology Module Code: Theme 2, Lecture 2 Oliver G. Steele [email protected] Join at slido.com #2322361 Lecture in Context This lecture will build on … • Steroid hormone mechanisms of action and synthesis • Hypothalamic pituitary axis … by introducing and covering … Introduction to Endocrinolog y • Testicular and Series of ovarian Endocrin endocrine e function Physiolo • Endocrine control gy of the menstrual Lectures cycle • Hormonal control of fertility You are here! 2 Intended Learning Outcomes To understand the normal hormonal control of the male and female reproductive systems, the effects of hormones on physique and the control of fertility. To appreciate how hormonal contraceptives act on the reproductive system. To appreciate the stages of the ovarian and menstrual cycles, the way the endometrium responds 3during the menstrual cycle and Outline 1. Endocrine function of the testes • Testosterone synthesis and physiology 2. Endocrine function of the ovaries • 17β-estradiol synthesis and physiology • Normal follicular development 3. Endocrine control of the ovarian and menstrual cycles • Interactions of LH, FSH, 17β-estradiol & progesterone in the control of the menstrual and ovariancontrol cycles of fertility and the menopause 4. Hormonal • Endogenous and pharmacological endocrine control of fertility • Endocrine changes during the menopause 4 Endocrine function of the testes Section 1 of 4 5 Testicular anatomy Efferent ductules Blood supply largely from the testicular artery Epididymis Drainage into the pampiniform plexus, then up the right and left Vas Deferens testicular veins Rete testis Seminifero us Tubules Scrotum holds the testes away from the core to control temperature Seminiferous tubules are the major functional unit within the testes synthesising and Testicular Lobules 6 Cells within the seminiferous tubules Leydig cells produce testosterone Myoid Cells Leydig Cells Myoid cells are contractile, help to Spermatogonium form peristaltic waves to move immobile spermatozoa through seminiferous tubules Basal Lamina Lumen Sertoli cells are ‘nurse cells’ which act to support spermatogenesis Spermatogonium are primary germ cells which undergo differentiation into spermatozoa Sertoli Cells 7 Testosterone Synthesis GnRH - LHFSH Testes Testosterone Action of LH at G-protein coupled receptors on Leydig cells promotes cholesterol accumulation and testosterone production FSH acts at Sertoli cells to promote spermatogenesis Leydig cells do express aromatase (enzyme 7), but testosterone production is favoured 8 Context & Interest I do not expect you to learn this whole pathway Cellular Mechanism of Testosterone Action Testosterone is a steroid hormone therefore it … • Is transported in the blood by specific carrier proteins, called sex hormone binding globulin (SHBG) • Passes the membrane freely Testosterone is peripherally converted in tissue to the more potent dihydrotestosterone (DHT) by 5αreductase Testosterone drives protein expression changes in a variety of tissues 9 Physiological effects of testosterone Target Testosterone acts at sertoli cells to further promote spermatogenesis Effect Testes Drives development of secondary sexual characteristics in males; • deepening of voice • increased libido • pubertal hair • Regulation of spermatogenesi s Bone & Muscle Testosterone gradually decreases with age post puberty Testosterone interacts with the brain and is positively correlated with increased aggression levels in males Red Blood Cell 10 • Bone growth at the epiphysial plate • Closure of the epiphysial plate in later puberty • Stimulation of erythropoiesis Which cells in the seminiferous tubules are responsible for the production of testosterone? A. B. C. D. Myoid Cells Leydig Cells Sertoli Cells Spermatogonium Move to reveal answer Correct Answer: B - Leydig 11 Answer slide Leydig cells produce testosterone Myoid Cells Leydig Cells Myoid cells are contractile, help to Spermatogonium form peristaltic waves to move immobile spermatozoa along Basal Lamina Sertoli cells are ‘nurse cells’ which act to support spermatogenesis Lumen Spermatogonium are primary germ cells which undergo differentiation into spermatozoa Sertoli Cells 12 Endocrine function of the ovaries Section 2 of 4 13 Female Reproductive Anatomy Uterus Vaginal pH is acidic (pH 3.8-5) to help separate external and internal environments Fallopian Tubes Endometrium thickens and becomes highly vascularized during implantation and pregnancy, and is shed during the menstrual cycle Ovaries Cervix Myometrium contracts during labor in response to oxytocin Vagina Ovaries are site of both gametogenesis and hormone synthesis 14 Endometrium Myometrium Cell types in the Ovaries Primary follicle has a layer of follicular cells around the oocyte Corpus Corpus Albicans Luteum Corpu s Luteu m Follicle stimulating hormone (FSH) promotes follicular maturation Development of thecal and granulosa cells takes place in the secondary follicle and produce 17β-estradiol Primordia l Follicle Primary Follicle Luteinizing hormone (LH) aids in ovulation and drives the corpus luteum to release progesterone Secondar y Follicle Graafian Follicle 15 Oocyte (Ovulatio n) Estrogen & Progesterone synthesis GnRH - LHFSH Ovaries Estrogen Progesterone LH action at thecal cells drives production of androgens These androgens are transferred to granulosa cells where FSH promotes the conversion of androgens to estrogens Granulosa cells highly express aromatase (enzyme 7), favouring conversion of testosterone to 17βestradiol 16 Context & Interest I do not expect you to learn this whole pathway Estrogen & Progesterone as steroid hormones 17β-estradiol and progesterone are both steroid hormones • Free diffusion across the cell membrane • Driving gene expression changes • Delayed effect 17β-estradiol travels in the blood bound to sex hormone binding protein and binds to the estrogen receptor intracellularly Progesterone travels in the blood bound to corticosteroid-binding protein and binds to the progesterone receptor intracellularly 17 17β-estradiol & progesterone physiology Primary function of both progesterone and 17β-estradiol is to develop the endometrium during the menstrual cycle in preparation for implantation and pregnancy The increased levels of 17βestradiol and progesterone during puberty drive the development of secondary sexual characteristics • Enlargement of breasts • Widening of hips • Pubertal hair Target Endometriu m Bone & Muscle Adipos e Tissue 18 Effect • Development and maintenance of the • endometrium Regulation of remodelling and bone density during puberty and beyond • Fat deposition in the legs, buttocks and hips Which cell type is principally responsible for the steroidogenesis of estrogens in the ovaries? A. B. C. D. Leydig Cells Thecal Cells Granulosa Cells Sertoli Cells Move to reveal answer Correct Answer: C – Granulosa Cells 19 Answer Slide GnRH - LHFSH Ovaries Estrogen Progesterone LH action at thecal cells drives production of androgens These androgens are transferred to granulosa cells where FSH promotes the conversion of androgens to estrogens Granulosa cells highly express aromatase (enzyme 7), favouring conversion of testosterone to 17βestradiol 20 Context & Interest I do not expect you to learn this whole pathway Endocrine control of the ovarian and menstrual cycles Section 3 of 4 21 Menstrual Cycle Overview Ovarian Cycle Ovulation Luteal Phase Hormone Level FS H LH Follicular Phase Estrad iol Progesterone Uterine Cycle Da y Menstruatio n 0 Proliferative Phase Secretory Phase 22 14 28 Ovarian Cycle dictates the menstrual cycle Luteal Phase Average duration is 28 +/- 7 days Corpus Corpus Albicans Luteum Corpu s Luteu m Follicle stimulating hormone (FSH) promotes follicular development Luteinising hormone (LH) degrades follicular wall and promotes ovulation and later the formation of the corpus luteum Corpus luteum secretes progesterone and degrades over time if not maintained Primordia l Follicle Primary Follicle Secondar y Follicle Graafian Follicle Follicular Phase 23 Oocyte (Ovulatio n) Hormones during Follicular Phase Primordial follicle (oocyte) develops into a primary follicle when a layer of follicular cells surround the oocyte Ovarian Cycle Ovulation Estrad iol Progesterone Uterine Cycle Da y Menstruatio n 0 Luteal Phase FSH stimulates follicular cells to transition the follicle from primary to secondary follicle • Granulosa & thecal cell proliferation Hormone Level FS H LH Follicular Phase Proliferative Phase 24 Secretory Phase Joint action of thecal and granulosa cells produce increasing amounts of 17βestradiol 14 28 Hormones during Ovulation 17β-estradiol from the graafian follicle increases negative feedback onto FSH Ovarian Cycle Once 17β-estradiol surpasses a certain level, feedback switches and becomes positive Hormone Level FS H LH Ovulation Estrad iol Progesterone Uterine Cycle Da y Proliferative Phase 14 LH surge weakens the wall of the follicle and stimulates ovulation LH stimulates the remaining thecal and granulosa cells to produce progesterone instead of 17β25 Hormones during the Luteal Phase Ovarian Cycle Ovulation Luteal Phase Corpus luteum produces progesterone for ~ 10 days following ovulation Hormone Level FS H LH Remaining cells form the corpus luteum producing progesterone and a little 17β-estradiol Estrad iol Progesterone erativeUterine e Cycle Da y Progesterone maintains the endometrium and increases vascularisation, whilst also thickening the cervical mucus Secretory Phase 14 28 26 Corpus luteum degrades so Menstrual Cycle Overview Ovarian Cycle Ovulation Luteal Phase Hormone Level FS H LH Follicular Phase Estrad iol Progesterone Uterine Cycle Da y Menstruatio n 0 Proliferative Phase Secretory Phase 27 14 28 Which hormone is most prominently elevated during the luteal phase of the ovarian cycle? A. B. C. D. Follicle Stimulating Hormone Luteinising Hormone Estradiol Progesterone Correct Answer: D – Progesterone Move to reveal answer 28 Answer Slide Ovarian Cycle Ovulation Luteal Phase Corpus luteum produces progesterone for ~ 10 days following ovulation Hormone Level FS H LH Remaining cells form the corpus luteum producing progesterone and a little 17β-estradiol Estrad iol Progesterone erativeUterine e Cycle Da y Progesterone maintains the endometrium and increases vascularisation, whilst also thickening the cervical mucus Secretory Phase 14 28 29 Corpus luteum degrades so Hormonal control of fertility and the menopause Section 4 of 4 30 Male Control of Fertility Subfertility in males can arise from a disruption in any of the following - Normal spermatogenesis - Sperm transport - Production of seminal plasma - Penetration of cervical mucus by sperm Leydig Cells Spermatogoniu Lumen Spermatogenesis depends on the joint action of FSH and testosterone Sertoli Cells Myoid Cells Endocrine subfertility, male hypogonadism, usually arises from dysfunction at the testes (primary hypogonadism) or at the hypothalamus/pituitary (secondary hypogonadism) Seminiferous Tubule Cross Section 31 Female Control of Fertility Luteal Phase Subfertility in females can arise from a disruption in any of the following - Ovulatory defects - Pelvic disorders Ovulation depends on fine hormonal control through the menstrual and ovarian cycles Corpus Corpus Albicans Luteum Corpu s Luteu m Primordia l Follicle Primary Follicle Secondar y Follicle Graafian Follicle Age is a controlling factor due to age-dependent loss of Follicular ovarian follicles Phase 32 Oocyte (Ovulatio n) Endocrine function during menopause With decreasing follicular number there is an increasing likelihood of; Oocyte # Terminal Differentiation ~ 1,000,000 Gestation Birth al Wk 1218 Stage of Life - FSH not locating a follicle and therefore thecal and granulosa cells are not matured properly ~ 1,000 Menopau se 90% experience menopause at an average age of 51.2 years - LH fails to stimulate ovulation (anovulatory cycle) 33 - Lack of negative feedback from low estrogen so LH/FSH Endocrine consequences of menopause Target Characterised by decreased production of 17β-estradiol 17β-estradiol deprivation can results in; - Bone density loss - Loss of fertility - Genital atrophy Menstrual Cycle Consequence • Disrupted menstrual cycle and inability to conceive Bone & Muscle • Decreasing bone density and osteoporosis Genital Atroph y • Thinning, drying and inflammation of vaginal walls Genital atrophy - Lack of physiological 17βestradiol signalling impairs normal functioning of the reproductive tract 34 Hormonal Contraceptives Act through negative feedback on the hypothalamic-pituitary-gonadal axis Progestogen only contraceptives (POCs) • Progestogens are progesterone analogues acting at the same receptor • Thickens cervical mucus, impairing sperm transport • Predominantly impairs LH production, which supresses ovulation but not consistently • Administration: • Subdermal or intrauterine implants • Intramuscular injections • Oral pills FS H 35 LH Hormonal POCs CHCs Contraceptives Progestogen Oocyte (Ovulatio n) EstrogensProgesterone Hormonal Contraceptives Act through negative feedback on the hypothalamic-pituitarygonadal axis Combined hormonal contraceptives (CHCs) • Provide release of 17β-estradiol and progesterone (mono- or multi-phasic) • Administration: FS H • Vaginal ring • Transdermal patches • Oral pills 36 LH Hormonal POCs CHCs Contraceptives Progestogen Oocyte (Ovulatio n) EstrogensProgesterone The onset of menopause is typically caused by which of the following? A. B. C. D. Elevated LH/FSH levels High levels of 17β-estradiol Decreasing number of follicles Occurrence of anovulatory cycles Correct Answer: C –reveal Decreasing Move to answernumber of follicles 37 Answer Slide With decreasing follicular number there is an increasing likelihood of; Oocyte # Terminal Differentiation ~ 1,000,000 Gestation Birth al Wk 1218 - FSH not locating a follicle and therefore thecal and granulosa cells are not matured properly ~ 1,000 Menopau se 90% experience menopause at an average age of 51.2 years - LH fails to stimulate ovulation (anovulatory cycle) 38 - Lack of negative feedback from low estrogen so LH/FSH What you need to know • Understand the physiological endocrine roles of the testicles and ovaries • Appreciate the stages of the ovarian and menstrual cycles • Know how the endometrium develops during the menstrual cycle • Describe the endocrine control of fertility • To appreciate how hormonal contraceptives act on the reproductive system • Understand the endocrine changes occurring during the 39 Suggested Additional Reading Greenspan’s Basic and Clinical Endocrinology. “Chapter 12 for the testes, Chapter 13 for the ovaries, menstrual cycle and menopause. Good for clinical cases too.” Tenth Edition. Gardner & Shoback. McGraw-Hill Medical; 2018. ISBN: 978-0071622431. “Chapter 6 for testicular function, and Chapter 7 for ovarian function in a more condensed form.” Integrated Endocrinology First Edition. Laycock & Meeran. Wiley-Blackwell; 2013. ISBN: 978-0470688120. 40 An alternate menstrual cycle explanation https://www.youtube.com/watch?v=L4adODFmmtI 41 Feedback Opportunity If you have any feedback for me on this lecture, please either scan the QR code or follow the link below Questionnaire is short (~2 mins) and anonymous All feedback helps me to improve, and as a result improve the quality of your teaching. https://universityofsussex.eu.qualtrics.com/jfe/form/SV_3wVeRAhOFt bXjee 42