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
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LH FSH
Leydig Sertoli cells cells
Testosterone Spermatogenesis
synthesis

6. Females
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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]
Cholestatic jaundice
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
(Polycystic ovary syndrome)
PCOS
Prolactinoma*
Inappropriate growth of hormone dependent tissues
E/P/PRL dependent
Breast Cancer
Prostatic hyperplasia/cancer
(Androgen dependent)
Deficiency of gonadal hormones
(e.g: Premature Ovarian failure)
Primary Hypogonadism
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 ↓Testosterone & spermatogenesis
Treatment : Dopamine analogues
Carbegoline
Bromocriptine

21. Compression of the optic chiasm & double vision
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24. 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)

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

26. 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

27. 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

28. 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

29. + = 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

30. 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)

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

32. 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

33. 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

34. 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

35. 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.

36. 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

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

38. 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

39. Final hormone exam is approaching