Transcript Sex Hormones

Sex Hormones
 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.
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 !
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.
Males
LH
FSH
Leydig
cells
Sertoli
cells
Testosterone
synthesis
Spermatogenesis
Females
Females
 LH
 FSH
 Theca Cells
 Granulosa Cells
 Androgen Synthesis
 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
Negative Feedback
 Testosterone inhibits
 Estrogen:
Hypothalamic GnRH and
↓ FSH/ ↓ LH,
pituitary FSH/LH
May also ↓GnRH
secretion
 Estrogen + Progesterone:
estrogen effect multiplied
 Progesterone alone may
↓GnRH pulse frequency
↓ Anterior pituitary
responsiveness to GnRH
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
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
Androgens and derivatives
Uses
 Replacement in
hypogonadism
 Osteoporosis
 Catabolic and wasting
states
 Refractory anaemias
Adverse effects
 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
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:
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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)
 Lipid metabolism
 Clotting :
 ↑ HDL, ↓ LDL
o ↑ production of clotting
 May inhibit oxidation of
factors II, VII, IX, X,
and XII
o ↓ anticoagulation factors
(Protein C, Protein S
and Antithrombin III)
LDL
 Vasodilation
 Retardation of
atherogenesis
Estrogens and derivatives
Uses
 Component of combined
contraceptives
 Hormone replacement
therapy (HRT) in
hypogonadism and post
menopausal women
Adverse effects
 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
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
Progestins and derivatives
Uses
 Contraception (alone and
with Estrogen)
 Emergency contraception
 HRT
 Prevention of Estrogen
mediated endometrial
hyperplasia
 Diagnostically in 2ry
amenorrhea (Provera
challenge)
Adverse effects
 May impair glucose
tolerance
 Counteract the beneficial
effects of Estrogen on lipid
profile
Pathophysiology of reproductive
disorders
Disruption of H-PGonadal axis
Inappropriate
growth of hormone
dependent tissues
Deficiency of
gonadal hormones
PCOS
(Polycystic ovary
syndrome)
Breast Cancer
E/P/PRL
dependent
Primary
Hypogonadism
(e.g: Premature
Ovarian failure)
Prolactinoma*
Prostatic
hyperplasia/cancer
(Androgen
dependent)
Menopause
* Bromocriptine
Carbegoline
Inhibitors of gonadal
hormones
Replacement
hormones
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
↑ Prolactin
 ↓ GnRH
 ↓ Pituitary sensitivity to GnRH
 ↓ Gonadotropins and Sex
Hormones
1. Infertility
2. Erectile dysfunction
3. Gynecomastia
1. Anovulatory infertility
2. Oligorrhea/ Amenorrhea
3. Galactorrhea
4. Double vision(?)
5. Headaches
 Lab values: ↑ PRL, ↓ FSH, ↓ LH, ↓ Estrogen and ↓ Progesterone
 Treatment :
Dopamine analogues
1. Carbegoline
2. Bromocriptine
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)
Pharmacologic classes
1. Inhibitors of gonadal hormones
2. Hormones and analogues :
replacement & Anabolic steroids
3. Hormones and analogues :
Contraception
Discussed in
Anticancer drugs
Synthesis inhibitors
Inhibitors of
gonadal hormones
Discussed in
Anticancer drugs
GnRH agonists and
antagonists
5 α reductase
inhibitors
Aromatase
Inhibitors
Selective Estrogen
Receptor
Modulators
(SERMs)
Receptor
Antagonists
Progesterone
receptor antagonist
Androgen receptor
antagonist
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
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
Estrogen
Tamoxifen
Raloxifene
Breast
+++
Endometrium
+++
Bone
+++
_
_
+
_
+
+
+ = Agonist 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.
_ = Antagonist effect
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
Progesterone Receptor antagonist :
Mifepristone
 Mechanism of action : blocks Progesterone receptors and
hence Progesterone mediated
1. Maintenance of uterine lining during pregnancy
2. Relaxation of Uterine contractions
 Use: Abortifacient (usually accompanied with PG
Misoprostol which also induces uterine contractions)
Androgen Receptor Antagonist :
Flutamide/Cyproterone
 Mechanism of action: Blocks androgen receptor
 Uses:
Metastatic prostate cancer
2. Benign prostatic hyperplasia
3. Acne (Cyproterone)
1.
Hormones and Analogues:
Contraception
Monophasic
Contraceptives
Hormonal
Female
Intrauterine
devices
Hormonal
Male
Spermicide
Combined
Biphasic
Oral Tablets
Progesterone only
Triphasic
Vaginal rings
Emergency
Transdermal
Patches
Injections
Hormones and Analogues:
Contraception : Mechanism
Combined contraceptive
↓GnRH↓ FSH/LH
↓ follicle
maturation/ovulation
2. Progesterone effects
1.
Progestin only
 ↑Viscosity of cervical
secretion:↓sperm
penetration
 ↓ Rate of oocyte transport
through oviducts
 May also ↓GnRH &
Pituitary sensitivity to it
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
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.
Anabolic steroids : Nandrolone &
Stanozolol
 Uses :
Wasting and debilitating conditions (AIDS associated
muscle wasting)
2. Stimulation of erythropoiesis in refractory anaemias
3. Osteoporosis
4. 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
1.
Hypogonadism
(↓sex hormones)
Primary
Central
↑FSH/LH
↓FSH/LH
Genetic , infection,
radiation, surgery,..
Autoimmune
(Premature
Ovarian Failure)
Exogenous steroids
Pituitary Tumors
Hyperprolactinemia
Thyroid dysfunction
Etc…
Premature ovarian failure
 Means loss of normal ovarian function before 40
 Causes:
1. Specific autoimmune disease : antiovarian antibodies causing
accelerated oocyte degeneration
2. 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 :
1. Oral corticosteroid
2. HRT
Final hormone exam is approaching