Lect 16 Reproduction Endocrinology PDF

Reproductive endocrinology Recommended reading Rang and Dales Pharmacology – Chapter 34 Tortora and Derrickson’s Anatomy and Physiology – Chapter 28 Practice MCQ questions on Moodle Topics to cover: Hormonal regulation of male reproductive...

Reproductive endocrinology Recommended reading Rang and Dales Pharmacology – Chapter 34 Tortora and Derrickson’s Anatomy and Physiology – Chapter 28 Practice MCQ questions on Moodle Topics to cover: Hormonal regulation of male reproductive system Hormonal regulation of female reproductive system Contraceptive pill Reproductive pathology and treatment Pregnancy/birth/lactation Teratogens MALE REPRODUCTIVE SYSTEM  Cells of the testes  Leydig cells (interstitial endocrinocytes) found in the spaces between adjacent seminiferous tubules secrete the male hormone testosterone  Embedded among the spermatogenic cells in the tubules are large Sertoli cells SERTOLI CELLS - form blood testes barrier - nourish spermatocytes - mediate the effects of testosterone and FSH on spermatogenesis - phagocytose excess spermatids - secrete the hormone inhibin which helps regulate sperm production by inhibiting production of FSH Copyright 2009, John Wiley & Sons, Inc.  Hormone control of Spermatogenesis Main hormones involved are: 1. GnRH (gonadotrophin-releasing hormone) 2. FSH (follicle stimulating hormone) 3. LH (luteinising hormone) - in the male is also known as interstitial cell-stimulating hormone (ICSH) 4. Testosterone and DHT (dihydrotestosterone) - 5 alpha-reductase converts testosterone into DHT in external genitals and prostate 5. Inhibin Copyright 2009, John Wiley & Sons, Inc.  Hormone control of Spermatogenesis At puberty GnRH secretion↑ Stimulates anterior pituitary to secrete FSH and LH LH stimulates Leydig cells to produce testosterone - synthesised from cholesterol in testes Suppresses secretion of LH by negative feedback FSH acts to stimulate spermatogenesis FSH and testosterone act on Sertoli cells to stimulate secretion of androgen-binding protein (ABP) -binds testosterone keeping concentrations high Testosterone stimulates final stages of spermatogenesis When enough sperm have been produced Sertoli cells release inhibin which inhibits FSH Copyright 2009, John Wiley & Sons, Inc.  Control of Testosterone Production Negative feedback system controls blood levels of testosterone Receptors in hypothalamus detect increased blood level of testosterone Inhibits secretion of GnRH from hypothalamus Reduced secretion of LH from anterior pituitary Leydig cells secrete less testosterone Blood level returns normal Copyright 2009, John Wiley & Sons, Inc.  Male Hypogonadism Primary congenital (inherited) - testicular agenesis (failure to develop) - Klinefelter’s syndrome (47XXY) - most common sex chromosome disorder Primary acquired - bilateral orchitis (inflamation of testes), mumps, irradiation or cytotoxic drugs Secondary (not testicular) - pituitary disorders e.g. tumours - hypothalamic disorders e.g. Kallman’s syndrome – GnRH deficiency  Aging in the male reproductive system Enlargement of prostate (benign hyperplasia) – 1/3 of males over 60 – frequent urination, decreased force of stream, bed- wetting & sensation of incomplete emptying  Prostate cancer Leading male cancer death Blood test for prostate-specific antigen (PSA) Antiandrogens such as flutamide or cyproterone are used as part of treatment - block testosterone/DHT actions - prevents them from stimulating prostate cancer cells to grow  Erectile Dysfunction - Treatment Viagra (Sildenafil citrate) – PDE5 inhibitor Nitrergic nerves release nitric oxide (NO) Diffuses into smooth muscle cells activating guanylate cyclase cGMP-specific ↑ synthesis of cGMP phosphodiesterase type V (PDE5) activates protein kinase G (PKG) breaks down cGMP _ ↓[Ca2+]i sildenafil vasodilation, ↑penile blood flow, constriction of penile vein - PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis - sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body FEMALE REPRODUCTIVE SYSTEM  The Female Reproductive Cycle Encompasses ovarian and uterine cycle, hormonal changes that regulate them, and related changes in breast and cervix controlled by monthly hormone cycle of anterior pituitary, hypothalamus and ovary Ovarian cycle changes in ovaries that occur during and after maturation of oocyte Uterine (menstrual) cycle concurrent series of changes in uterine endometrium preparing it for arrival of fertilized ovum if implantation does not occur the stratum functionalis is shed during menstruation Hormonal control of the female reproductive cycle – Gonadotropin-releasing hormone (GnRH) Secreted by hypothalamus controls ovarian and uterine cycle Stimulates release of FSH and LH from anterior pituitary – Follicle stimulating hormone (FSH) Initiate follicular growth Stimulate ovarian follicles to secrete estrogens – Luteinising hormone (LH) Stimulates further development of ovarian follicles Stimulate ovarian follicles to secrete estrogens Triggers ovulation Promotes formation of corpus luteum – produces estrogens, progesterone, relaxin and inhibin  Ovarian hormones – Estrogens secreted by ovarian follicles (mainly β- estradiol) Promote development and maintenance of female reproductive structures and secondary sex characteristics Increases protein anabolism including building strong bones Lowers blood cholesterol Inhibit release of GnRH, LH and FSH – Progesterone Secreted mainly by corpus luteum Works with estrogens to prepare and maintain endometrium for implantation and mammary glands for milk production Inhibits secretion of GnRH and LH  Ovarian hormones – Relaxin Produced by corpus luteum Relaxes uterus by inhibiting contraction of myometrium At end of pregnancy, increases flexibility of pubic symphysis and dilates uterine cervix – Inhibin Secreted by granulosa cells of growing follicles and by corpus luteum Inhibits secretion of FSH and LH Secretion and physiological effects of hormones in the female reproductive cycle  Phases of the female reproductive cycle 1. Menstrual phase 2. Pre-ovulatory phase 3. Ovulation 4. Post-ovulatory phase (1) Menstrual phase or menstruation (days 1-5) – First day of menstruation is day 1 of new cycle – Events in ovaries follicles begin to develop – Follicle that begins to develop in one cycle may not mature for several cycles – Events in uterus ↓ oestrogens and progesterone stimulate release of prostaglandins causing uterine spiral arterioles to constrict menstrual discharge  (2) Pre-ovulatory phase (days 6-13) Events in ovaries (follicular stage) Secondary follicle(s) begin to secrete oestrogens and inhibin Decrease secretion of FSH by negative feedback  (2) Pre-ovulatory phase (days 6-13) – Events in uterus Oestrogens stimulate repair of endometrium Cells of stratum basalis undergo mitosis to form new stratum functionalis In uterine cycle, pre-ovulatory phase is the proliferative phase  (3) Ovulation (day 14) High levels of oestrogen exert a positive feedback effect to increase secretion of LH and GnRH Under the influence of LH, the corpus hamorrhagicum becomes the corpus luteum  (4) Postovulatory phase (day 15-28) - Events in ovary – Luteal Phase After ovulation, mature follicle collapses to form corpus luteum under the influence of LH Secretes progesterone and oestrogen in large quantities Also secretes relaxin and inhibin  Corpus luteum If oocyte not fertilised it lasts 2 weeks – Degenerates in corpus albicans – ↓ progesterone, oestrogen and inhibin – ↑release of GnRH, FSH, and LH due to loss of negative feedback – Follicular growth resume as new ovarian cycle begins  Corpus luteum If oocyte is fertilised - Human chorionic gonadotropin (hCG) produced by chorion of embryo - Like LH, hCG stimulates corpus luteum to secrete hormones - hCG levels in the blood form the basis of the pregnancy test  (4) Postovulatory phase (day 15-28) - Events in uterus – secretory phase Progesterone and oestrogens produced by corpus luteum promote growth of endometrium If fertilization does not occur; - ↓ levels of progesterone and oestrogens causes menstruation Hormonal interactions in the ovarian and uterine cycles  Causes of female hypogonadism Primary congenital (inherited) – problem in ovaries Turner’s syndrome (45XO) – absence of an entire sex chromosome Noonan’s syndrome (46XX) – multiple gene mutations Primary acquired chemotherapy irradiation Secondary – indirect pituitary disorders hypothalamus disorders Treatment with CLOMIPHENE  Aging in the female reproductive system menopause - hot flushes, copious sweating, headache, vaginal dryness, depression, weight gain, and emotional fluctuations Treat short term (2-5 years) with HRT (oestrogen/progesterone) – Tibolone Drawbacks of long term therapy: – ↑ risk of endometrial cancer – ↑ risk of breast cancer – ↑ risk of venous thromboembolism  Endometriosis Growth of endometrial tissue outside of the uterus – can cover ovaries, outer surface of uterus, colon, kidneys and bladder – (GnRH) analogues – taken continuously prevent oestrogen production (buserelin, goserelin, nafarelin, leuprorelin) – Progesterone without oestrogen (medroxyprogesterone acetate) – Danazol  Breast cancer Breast cancer is the leading cause of cancer in UK – Two genes increase susceptibility to breast cancer: BRCA1 (breast cancer 1) and BRCA2 – Mutation of BRCA1 also confers high risk for ovarian cancer TREATMENT – hormone therapy, lumpectomy, mastectomy – radiation treatment and chemotherapy may follow – Pre-menopausal women may have ovarian ablation – Tamoxifen – Herceptin® – Anastrazole – Raloxifene  Summary  There are four phases to the female reproductive cycle 1. Menstrual phase 2. Pre-ovulatory phase 3. Ovulation 4. Post-ovulatory phase  Varying levels of oestrogen and progesterone throughout the cycle provide both negative and positive feedback effects - High levels of oestrogen stimulate GnRH, LH and FSH release (positive feedback) and bring about ovulation - Moderate levels of oestrogen secreted by secondary follicles inhibit release of GnRH, LH and FSH preventing the development of new follicles - Low levels of oestrogen and progesterone after the formation of the corpus albicans promote GnRH, LH and FSH release to bring about menstruation and a new cycle  Hormonal birth control – oral contraceptives _ Hypothalamus Combined Pill - oestrogen/progesterone GnRH + _ _ oestrogen inhibits FSH and follicle Anterior pituitary development FSH LH + + progesterone inhibits LH preventing Ovary ovulation and makes mucus inhospitable for sperm together make endometrium unsuitable for implantation Oestrogens Progesterone  Hormonal birth control – oral contraceptives Progesterone-only Pill _ - e.g. levonorgestrel Hypothalamus GnRH + makes cervical mucus inhospitable for _ _ sperm (less and more viscous) Anterior pituitary inhibits ovulation by ↓LH FSH LH + + Ovary Morning-after Pill (emergency) - effective if taken within 72 hours, repeated after 12 hours - either combined or progestin alone - Inhibit FSH and LH - ovary secretes less oestrogen and Oestrogens Progesterone progesterone - induce menstruation  Teratogens  Chemicals and Drugs  Cigarette Smoking  Irradiation Stage Gestation Period Main cellular Affected by process Blastocyst formation 0 - 16 days Cell Division Cytotoxic drugs - alcohol Organogenesis 17 - 60 days Division, Migration, Teratogens Differentiation Maturation 60 days to term As above Drugs – alcohol, nicotine, steroids  Teratogenic Drugs Agent Targets/Treats Effects on foetus Thalidomide Antiemetic – morning sickness Phocomelia, heart defects Warfarin Vitamin K antagonist - Anticoagulant – Retarded growth, defects of limbs, deep vein thrombosis, thrombosis on CNS, eyes heart valves Corticosteroids Anti-inflammatory Cleft palate Stilbestrol Synthetic non-steroidal oestrogen - Vaginal adenosis in female foetus (Diethylstilbestrol) miscarriage (abnormal glandular development) Phenytoin Antiepileptic Cleft lip/palate, mental retardation Valproate Antiepileptic, anticonvulsant Neural tube defects (spina bifida) Carbamazepine Antiepileptic Retardation of foetal head growth Cytotoxic drugs - Folate antagonist – cancer Neural tube defects, Hydrocephalus methotrexate chemotherapy Aminoglycosides Antibiotics – gentamycin, neomycin, Deafness streptomycin Tetracycline Antibiotic Impaired bone growth, staining of bones and teeth Ethanol CNS depressant Foetal alcohol syndrome Retinoids - etretinate Vitamin A derivatives Hydrocephalus etc.. Treat skin diseases (acne, psoriasis) accumulates in subcutaneous fat  Thalidomide  Treat morning sickness  If taken in weeks 3-6 causes virtually 100% infant malformation  Phocomelia – absence of development of limb bones PREGNANCY AND LABOR Hormone changes during pregnancy Starts at week 12 ↑ end of pregnancy Human placental Normally is secreted only Lactogen (hPL) by neurosecretory cells of the hypothalamus Cortisol is needed for maturation of lungs and production of surfactant (more glucose available for foetus)  Labor (Parturition) Progesterone prevents uterine contractions ↑ corticotrophin-releasing hormone secretion ↑ ACTH* release from foetal anterior pituitary ↑ cortisol and DHEA* secretion from foetal adrenal gland placenta converts DHEA into oestrogen ↑ oestrogen (overcomes progesterone inhibition) Stimulates placenta to release prostaglandins ↑ oxytocin receptors in uterine muscle Induces production of enzymes *ACTH = adrenocorticotrophic hormone which digest collagen fibres *DHEA = dehydroepiandrosterone and soften cervix (major adrenal androgen)  Contractions – positive feedback mechanism ↑ oestrogen softens cervix ↑ relaxin from placenta dilates cervix Activation of stretch receptors in cervix ↑ oxytocin release from posterior pituitary + Syntocinon Oxytocin receptor Contraction of uterine muscle agonist Pushes baby towards cervix  Lactation (milk secretion and ejection) ↑ Prolactin produced by anterior pituitary (but progesterone inhibits prolactin effects) birth ↓ progesterone and oestrogen levels suckling Initiates nerve impulse from stretch receptors in nipples to hypothalamus ↓ hypothalamic release of ↑ hypothalamic release of prolactin-inhibiting hormone (PIH) prolactin-releasing hormone (PRH) (Dopamine) - Bromocriptine ↑ Prolactin produced by anterior pituitary - D2 receptor agonist To prevent lactation Treat prolactinoma’s (pituitary tumours) ↑ milk secretion The milk ejection reflex Oxytocin stimulates contraction of the myoepithelial cells in the breasts, which squeezes the glandular and duct cells and causes milk secretion Suckling stimulation ↑ oxytocin and ↓ PIH ↓ PIH results in ↑ secretion of prolactin Maintains lactation