2 Although Sex Hormones contribute to the major differences between males and females, their endocrine axis follows the same basic principles.Therefore the male and female reproductive axes can be more easily understood when considered as one system with certain differences rather than two different ones.
3 Hypothalamic factor : GnRH The first step in sex hormone formation is the release of the Gonadotropin Releasing Hormone from the hypothalamusGnRH is released in a PULSATILE fashionRate of GnRH pulse affects subsequent FSH/LH release patternContinuous administration of GnRH Decreases FSH/LH !
4 Pituitary factors : Gonadotropins The anterior pituitary responds to GnRH by secreting gonadotropins:FSH= Follicular Stimulating HormoneLH = Luteinizing HormoneAlthough the effects of FSH and LH are quite different in males and females, a certain analogy exists : Gonadotropins act via two-cell system in males and females.
7 Females LH Theca Cells Androgen Synthesis FSH Granulosa Cells Aromatase ActivationEstrogenNote: All Estrogen is synthesised from androgen precursors via aromatase enzymeProgesterone is first synthesised then converted to androgen precursors in theca and granulosa cells under the effect of LH
8 Negative FeedbackTestosterone inhibits Hypothalamic GnRH and pituitary FSH/LH secretionEstrogen: ↓ FSH/ ↓ LH, May also ↓GnRHEstrogen + Progesterone: estrogen effect multipliedProgesterone alone may ↓GnRH pulse frequency ↓ Anterior pituitary responsiveness to GnRH
10 Physiologic functions : Testosterone Testosterone is essentially a prohormone with modest androgenic activity!Must first be converted to the more potent dihydrotestosterone via enzyme 5 α reductaseFetal effects:Development of male reproductive organs/ Suppression of female onesDescent of Testes in scrotum
11 Increased size and development of reproductive organs At Puberty:Increased size and development of reproductive organsDevelopment of secondary sexual characteristics:Body Hair distribution (Baldness?)Male VoiceIncreased skin thickness and sebaceous gland secretions (Acne?)Metabolic effects:Anabolic : increases protein and muscle formation (50% > women)Bones: epiphyseal bone growth acceleration growth spurt and epiphyseal closure. Also increased thickness of bones and Ca deposition.↑BMR and ErythropoeisisNa/ water reabsorptionBehavioural effects: Aggressiveness and better spatial functions
12 Androgens and derivatives UsesAdverse effectsReplacement in hypogonadismOsteoporosisCatabolic and wasting statesRefractory anaemiasAll androgens suppress gonadotropin secretionSome can cause gyneacomastiaSome can cause hepatotoxicitySome can ↑ LDL and ↓ HDLSome may impair glucose toleranceVirilisation in females
13 Physiologic functions : Estrogen Development of uterus, vagina, fallopian tubes and breastIncreases tubal contractility (enhancing ovum transport to uterus)Increases watery content of cervical mucus to facilitate sperm penetrationDevelopment of secondary sexual characteristics:Axillary and pubic hair growthNipple pigmentationMetabolic effects:Bones: ↑ bone mass and epiphyseal growth growth spurt & epiphyseal closureProteins: slight ↑ in protein depositionFats: ↑ deposition in characteristic female areas (eg: buttocks and breasts)BMR: ↑ (lower than males)Na/ water reabsorption : slight, but ↑ ↑ in pregnancy (↑ ↑ estrogen from placenta)
14 Lipid metabolism Clotting : ↑ HDL, ↓ LDL May inhibit oxidation of LDLVasodilationRetardation of atherogenesisClotting :↑ production of clotting factors II, VII, IX, X, and XII↓ anticoagulation factors (Protein C, Protein S and Antithrombin III)
15 Estrogens and derivatives UsesAdverse effectsComponent of combined contraceptivesHormone replacement therapy (HRT) in hypogonadism and post menopausal womenRisk of endometrial, cervical and vaginal cancerEdema and reduced glucose toleranceRisk of Thromboembolism[Short term use: increased blood coagulability]Long term use : hepatic dysfunction : ↓clotting factors and coagulabilityFeminization in males
16 Physiologic effects: Progestins Reproductive tract: (maintenance of Pregnancy)Decreases estrogen mediated endometrial proliferation↑ Secretory functions of uterus↓ Uterine contraction↓ Rate of oocyte transport through oviductThickening of cervical mucus and decreased sperm penetrationMetabolic effects:↑ LDLCNS effects:↑Basal body temperature , with ovulation
17 Progestins and derivatives UsesAdverse effectsContraception (alone and with Estrogen)Emergency contraceptionHRTPrevention of Estrogen mediated endometrial hyperplasiaDiagnostically in 2ry amenorrhea (Provera challenge)May impair glucose toleranceCounteract the beneficial effects of Estrogen on lipid profile
18 Pathophysiology of reproductive disorders Disruption of H-P- Gonadal axisPCOS(Polycystic ovary syndrome)Prolactinoma*Inappropriate growth of hormone dependent tissuesBreast CancerE/P/PRL dependentProstatic hyperplasia/cancer(Androgen dependent)Deficiency of gonadal hormonesPrimary Hypogonadism(e.g: Premature Ovarian failure)Menopause* BromocriptineCarbegolineInhibitors of gonadal hormonesReplacement hormones
19 Hyperprolactinemia & fertility Prolactin is secreted from lactotrophs in anterior pituitary glandHowever unlike the rest of anterior pituitary hormones, prolactin secretion is under tonic INHIBITION by Dopamine from hypothalamusDecreased or interrupted dopamine supply Increased Prolactin secretion
20 ↓ Pituitary sensitivity to GnRH ↑ Prolactin↓ GnRH↓ Pituitary sensitivity to GnRH↓ Gonadotropins and Sex HormonesInfertilityErectile dysfunctionGynecomastiaAnovulatory infertilityOligorrhea/ AmenorrheaGalactorrhea4. Double vision(?)5. HeadachesLab values: ↑ PRL, ↓ FSH, ↓ LH, ↓ Estrogen and ↓ ProgesteroneTreatment :Dopamine analoguesCarbegolineBromocriptine
21 Different mechanisms for hyperprolactinemia ProlactinomaMacroadenoma: functioning secreting tumours Diameter>10mm, PRL>200ng/ml Direct SecretionMicroadenoma : non functioning, non secreting tumours Diameter <10mm< PRL<200ng/ml Block dopamine flow from brainPituitary tumours (eg Cushing, Acromegaly)Block Dopamine flow from the brain1ry Hypothyrodism : ↑TRH lactotrophs hypertrophyPhysiological (Pregnancy, breastfeeding. Mental stress)Drugs (SSRI, MAOis)
22 Pharmacologic classes Inhibitors of gonadal hormonesHormones and analogues : replacement & Anabolic steroidsHormones and analogues : Contraception
23 Inhibitors of gonadal hormones Synthesis inhibitors GnRH agonists and antagonists5 α reductase inhibitorsAromatase InhibitorsReceptor AntagonistsSelective Estrogen Receptor Modulators (SERMs)Progesterone receptor antagonistAndrogen receptor antagonistDiscussed in Anticancer drugsDiscussed in Anticancer drugs
24 5αReductase Inhibitor: Finasteride Mechanism of action :Blocks conversion of Testosterone to DihydrotestosteroneTestosterone is a prohormone with modest androgenic activity, but DHT is much more potentProstate tissue depends on androgen stimulation for growth & survivalUse:Benign Prostatic Hyperplasia
25 SERMs: Tamoxifen, Raloxifene and Clomiphene Selective Estrogen Receptor Modulators: Estrogen receptor antagonists that are not pure antagonists but rather mixed agonists/antagonistsBlock Estrogen action in some tissuesStimulating Estrogen receptors in other tissuesRecall effects of Estrogen on endometrium, breasts and bones
26 + = Agonist effect _ = Antagonist effect BreastEndometriumBoneEstrogen+++Tamoxifen_+Raloxifene+ = Agonist effect _ = Antagonist effectTamoxifen:Estrogen antagonist in breastsEstrogen agonist in endometrium and bonesUse: treatment and prevention of breast cancerBut: Increased incidence of endometrial cancer administered for no more than 5 years.RaloxifeneEstrogen antagonist in breasts and endometriumEstrogen agonist in bonesUse: prevention of breast cancer and osteoporosis with no increase in incidence of endometrial cancerClomiphene:Partial agonist in ovaries, antagonist in hypothalamus and pituitary glands blocks negative feedback of endogenous Estrogen↑ FSH/LH ↑Follicular Growth and ovulation in females, ↑ spermatogenesis in malesUse: Unovulatory & oligospermic infertility But: Multiple follicular growth and ovulation
27 Progesterone Receptor antagonist : Mifepristone Mechanism of action : blocks Progesterone receptors and hence Progesterone mediatedMaintenance of uterine lining during pregnancyRelaxation of Uterine contractionsUse: Abortifacient (usually accompanied with PG Misoprostol which also induces uterine contractions)
30 Hormones and Analogues: Contraception : Mechanism Combined contraceptiveProgestin only↓GnRH↓ FSH/LH ↓ follicle maturation/ovulationProgesterone effects↑Viscosity of cervical secretion:↓sperm penetration↓ Rate of oocyte transport through oviductsMay also ↓GnRH & Pituitary sensitivity to it
31 Notes on female hormonal contraception Combined Contraception (Estrogen + Progesterone)Increase risk of deep vein thrombosis , pulmonary embolism impaired glucose tolerance and lipid profile (↑LDL, ↓HDL)Avoided in females over 35 years of age who smoke due to increased incidences of thrombotic cardiovascular eventsProgesterone only pills (minipills) are used when Estrogen is contraindicated or when its side effects become evidentUnopposed Estrogen use (i.e. without concomitant progesterone) increases the incidence of endometrial cancer
32 Hormones and Analogues: Replacement : Menopause ‘’Burning out ‘’ of ovarian follicles No more Estrogen produced increased levels of FSH/LHSymptoms include: hot flashes, anxiety ,decreased density and calcification of bones (osteoporosis?)Combination and Progesterone only preparations are availableDue to increased risk of cardiovascular events, breast cancer and stroke, the current recommendation is to use post menopausal hormone replacement only for severe symptoms, using the lowest effective dose for the shortest period of time.
33 Anabolic steroids : Nandrolone & Stanozolol Uses :Wasting and debilitating conditions (AIDS associated muscle wasting)Stimulation of erythropoiesis in refractory anaemiasOsteoporosisEnhancing athletic performance (abuse!)Note: all anabolic steroids do have a certain degree of androgenic activity: their use in high doses suppression of gonadotropin secretion decrease Testosterone production and spermatogenesis may lead to infertility
35 Premature ovarian failure Means loss of normal ovarian function before 40Causes:Specific autoimmune disease : antiovarian antibodies causing accelerated oocyte degenerationPart of a polyglandular autoimmune syndrome(poly endocrine syndrome) characterized by the obligatory occurrence of autoimmune Addison disease in combination with thyroid autoimmune disease and/or type 1 diabetes mellitus. Primary hypogonadism, myasthenia gravis, and celiac disease also are commonly observed in this syndromeTreatment :Oral corticosteroidHRT