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Sex Hormones.

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Presentation on theme: "Sex Hormones."— Presentation transcript:

1 Sex Hormones

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 hypothalamus GnRH is released in a PULSATILE fashion Rate of GnRH pulse affects subsequent FSH/LH release pattern Continuous administration of GnRH  Decreases FSH/LH !

4 Pituitary factors : Gonadotropins
The anterior pituitary responds to GnRH by secreting gonadotropins: FSH= Follicular Stimulating Hormone LH = Luteinizing Hormone Although 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.

5 Males LH FSH Leydig Sertoli cells cells Testosterone Spermatogenesis

6 Females

7 Females LH Theca Cells Androgen Synthesis FSH Granulosa Cells
Aromatase Activation Estrogen Note: All Estrogen is synthesised from androgen precursors via aromatase enzyme Progesterone is first synthesised then converted to androgen precursors in theca and granulosa cells under the effect of LH

8 Negative Feedback Testosterone inhibits Hypothalamic GnRH and pituitary FSH/LH secretion Estrogen: ↓ FSH/ ↓ LH, May also ↓GnRH Estrogen + Progesterone: estrogen effect multiplied Progesterone 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 reductase Fetal effects: Development of male reproductive organs/ Suppression of female ones Descent of Testes in scrotum

11 Increased size and development of reproductive organs
At Puberty: Increased size and development of reproductive organs Development of secondary sexual characteristics: Body Hair distribution (Baldness?) Male Voice Increased 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 Erythropoeisis Na/ water reabsorption Behavioural effects: Aggressiveness and better spatial functions

12 Androgens and derivatives
Uses Adverse effects Replacement in hypogonadism Osteoporosis Catabolic and wasting states Refractory anaemias All androgens suppress gonadotropin secretion Some can cause gyneacomastia Some can cause hepatotoxicity Some can ↑ LDL and ↓ HDL Some may impair glucose tolerance Virilisation in females

13 Physiologic functions : Estrogen
Development of uterus, vagina, fallopian tubes and breast Increases tubal contractility (enhancing ovum transport to uterus) Increases watery content of cervical mucus to facilitate sperm penetration Development of secondary sexual characteristics: Axillary and pubic hair growth Nipple pigmentation Metabolic effects: Bones: ↑ bone mass and epiphyseal growth growth spurt & epiphyseal closure Proteins: slight ↑ in protein deposition Fats: ↑ 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 LDL Vasodilation Retardation of atherogenesis Clotting : ↑ production of clotting factors II, VII, IX, X, and XII ↓ anticoagulation factors (Protein C, Protein S and Antithrombin III)

15 Estrogens and derivatives
Uses Adverse effects Component of combined contraceptives Hormone replacement therapy (HRT) in hypogonadism and post menopausal women Risk of endometrial, cervical and vaginal cancer Edema and reduced glucose tolerance Risk of Thromboembolism [Short term use: increased blood coagulability] Long term use : hepatic dysfunction : ↓clotting factors and coagulability Feminization 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 oviduct Thickening of cervical mucus and decreased sperm penetration Metabolic effects: ↑ LDL CNS effects: ↑Basal body temperature , with ovulation

17 Progestins and derivatives
Uses Adverse effects Contraception (alone and with Estrogen) Emergency contraception HRT Prevention of Estrogen mediated endometrial hyperplasia Diagnostically in 2ry amenorrhea (Provera challenge) May impair glucose tolerance Counteract the beneficial effects of Estrogen on lipid profile

18 Pathophysiology of reproductive disorders
Disruption of H-P- Gonadal axis PCOS (Polycystic ovary syndrome) Prolactinoma* Inappropriate growth of hormone dependent tissues Breast Cancer E/P/PRL dependent Prostatic hyperplasia/cancer (Androgen dependent) Deficiency of gonadal hormones Primary Hypogonadism (e.g: Premature Ovarian failure) Menopause * Bromocriptine Carbegoline Inhibitors of gonadal hormones Replacement hormones

19 Hyperprolactinemia & fertility
Prolactin is secreted from lactotrophs in anterior pituitary gland However unlike the rest of anterior pituitary hormones, prolactin secretion is under tonic INHIBITION by Dopamine from hypothalamus Decreased or interrupted dopamine supply Increased Prolactin secretion

20 ↓ Pituitary sensitivity to GnRH
↑ Prolactin ↓ GnRH ↓ Pituitary sensitivity to GnRH ↓ Gonadotropins and Sex Hormones Infertility Erectile dysfunction Gynecomastia Anovulatory infertility Oligorrhea/ Amenorrhea Galactorrhea 4. Double vision(?) 5. Headaches Lab values: ↑ PRL, ↓ FSH, ↓ LH, ↓ Estrogen and ↓ Progesterone Treatment : Dopamine analogues Carbegoline Bromocriptine

21 Different mechanisms for hyperprolactinemia
Prolactinoma Macroadenoma: functioning secreting tumours Diameter>10mm, PRL>200ng/ml Direct Secretion Microadenoma : non functioning, non secreting tumours Diameter <10mm< PRL<200ng/ml Block dopamine flow from brain Pituitary tumours (eg Cushing, Acromegaly) Block Dopamine flow from the brain 1ry Hypothyrodism : ↑TRH lactotrophs hypertrophy Physiological (Pregnancy, breastfeeding. Mental stress) Drugs (SSRI, MAOis)

22 Pharmacologic classes
Inhibitors of gonadal hormones Hormones and analogues : replacement & Anabolic steroids Hormones and analogues : Contraception

23 Inhibitors of gonadal hormones Synthesis inhibitors
GnRH agonists and antagonists 5 α reductase inhibitors Aromatase Inhibitors Receptor Antagonists Selective Estrogen Receptor Modulators (SERMs) Progesterone receptor antagonist Androgen receptor antagonist Discussed in Anticancer drugs Discussed in Anticancer drugs

24 5αReductase Inhibitor: Finasteride
Mechanism of action : Blocks conversion of Testosterone to Dihydrotestosterone Testosterone is a prohormone with modest androgenic activity, but DHT is much more potent Prostate tissue depends on androgen stimulation for growth & survival Use: 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/antagonists Block Estrogen action in some tissues Stimulating Estrogen receptors in other tissues Recall effects of Estrogen on endometrium, breasts and bones

26 + = Agonist effect _ = Antagonist effect
Breast Endometrium Bone Estrogen +++ Tamoxifen _ + Raloxifene + = Agonist effect _ = Antagonist effect Tamoxifen: Estrogen antagonist in breasts Estrogen agonist in endometrium and bones Use: treatment and prevention of breast cancer But: Increased incidence of endometrial cancer administered for no more than 5 years. Raloxifene Estrogen antagonist in breasts and endometrium Estrogen agonist in bones Use: prevention of breast cancer and osteoporosis with no increase in incidence of endometrial cancer Clomiphene: 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 males Use: Unovulatory & oligospermic infertility But: Multiple follicular growth and ovulation

27 Progesterone Receptor antagonist : Mifepristone
Mechanism of action : blocks Progesterone receptors and hence Progesterone mediated Maintenance of uterine lining during pregnancy Relaxation of Uterine contractions Use: Abortifacient (usually accompanied with PG Misoprostol which also induces uterine contractions)

28 Androgen Receptor Antagonist : Flutamide/Cyproterone
Mechanism of action: Blocks androgen receptor Uses: Metastatic prostate cancer Benign prostatic hyperplasia Acne (Cyproterone)

29 Hormones and Analogues: Contraception
Contraceptives Female Hormonal Oral Tablets Combined Monophasic Biphasic Triphasic Progesterone only Emergency Vaginal rings Transdermal Patches Injections Intrauterine devices Male Spermicide

30 Hormones and Analogues: Contraception : Mechanism
Combined contraceptive Progestin only ↓GnRH↓ FSH/LH ↓ follicle maturation/ovulation Progesterone effects ↑Viscosity of cervical secretion:↓sperm penetration ↓ Rate of oocyte transport through oviducts May 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 events Progesterone only pills (minipills) are used when Estrogen is contraindicated or when its side effects become evident Unopposed 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/LH Symptoms include: hot flashes, anxiety ,decreased density and calcification of bones (osteoporosis?) Combination and Progesterone only preparations are available Due 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 anaemias Osteoporosis Enhancing 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

34 Hypogonadism (↓sex hormones) Primary ↑FSH/LH Central ↓FSH/LH
Genetic , infection, radiation, surgery,.. Autoimmune (Premature Ovarian Failure) Central ↓FSH/LH Exogenous steroids Pituitary Tumors Hyperprolactinemia Thyroid dysfunction Etc…

35 Premature ovarian failure
Means loss of normal ovarian function before 40 Causes: Specific autoimmune disease : antiovarian antibodies causing accelerated oocyte degeneration Part 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 syndrome Treatment : Oral corticosteroid HRT

36 Final hormone exam is approaching

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