Pharmacology of sex hormones

Estrogens
Estrogen is produced primarily by developing follicles in the
ovaries, the corpus luteum, and the placenta
Some estrogens are also produced by other tissues such as
the liver, adrenal glands, and the breasts
The ovaries are the principal source of circulating estrogen
in premenopausal women, 17beta-estradiol is the main
secretory product
In postmenopausal women, the principal hormone is
estrone synthesized from dehydroepiandrosterone and
secreted by the adrenals
 Estrogen Receptors
• nuclear receptors
• estrogen receptor (ER) genes are located on separate
chromosomes: ESR1 encodes ER-alpha and ESR2
encodes ER-beta
• Both ERs are ligand-activated transcription factors that
increase or decrease the transcription of target genes
• ER is an inactive monomer bound to heat-shock
proteins, and upon binding estrogen, a change in ER
conformation dissociates the heat-shock proteins and
causes receptor dimerization
 Estrogen signaling pathway
• Classical nuclear: estrogen binds to receptor,
dimerization, conformational change, ERE, gene
transcription
• ERE-independent: protein-protein interactions using
indirect tethering to transcription factors, DNA
sequence not required, bind to transcription factors
(not at ERE)
• Non-genomic: binds to plasma membrane estrogen
receptor, activates signaling molecules, rapid
phosphorylation
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 Estrogen actions
• stimulation of endometrial growth
• maintenance of blood vessels and skin
• reduction of bone resorption and increase of bone
formation
• increased uterine growth
• increased the hepatic production of binding proteins
• increased circulating clotting factors II, VII, IX, X and
plasminogen
• increased high-density lipoprotein (HDL)
• increased biliary cholesterol
• control salt and water retention
 Estrogens in therapy
• oral contraception
• menopause
• osteoporosis.
• vaginal atrophy
• hypogonadism
• amenorrhea, dysmenorrhea, oligomenorrhoea
• prostate cancer (estramustine)
 Estrogen adverse effects
• nausea and vomiting
• abdominal cramps and bloating
• breast enlargement and tenderness
• premenstrual symptoms
• salt and water retention with edema, hypertension and
heart failure
• endometriosis (without progesterone)
• thromboembolism
• gynecomastia and impotence (in men)

ethinylestradiol, estradiol, estron tbl, gel

 Estrogen antagonists
• Selective Estrogen Receptor • Selective Estrogen Receptor
Downregulators (SERDs)
Modulators (SERMs)
Compounds with tissue-
Pure antagonists selective actions
– clomiphene tbl is for infertility – tamoxifen, raloxifen,
– fulvestrant inj is for breast toremifene tbl
cancer – estrogenic actions (brain,
bone, liver, ovaries,
endometrium, myometrium,
• Aromatase inhibitors cervix) for postmenopausal
hormone therapy; risk of
inhibits the synthesis of endometrial cancer
estrogens – antiestrogenic action in
– anastrozole, letrozole, breast (for ER positive
exemastane (for breast cancer cancers)
in postmenopausal women, the
target is only the breast)
 Progestogens
Progestins include the naturally occurring hormone
progesterone, pregnanes, estranes, and gonanes

All progestogens have anti-estrogenic and anti-

gonadotrophic properties and differ in their potency
and their side effects.
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 Progestogen Receptors
• nuclear receptors
• single gene encodes two isoforms : PR-A and PR-B
• ligand-activated transcription factors that increase or
decrease the transcription of target genes
• PR-B mediates the stimulatory activities of
progesterone, PR-A strongly inhibits this action of PR-B
• the ligand-binding domains of the two PR isoforms are
identical, there is no difference in ligand binding
• acts the same as the estrogen receptor (with similar
signaling)
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 Progesterone actions
• decreases estrogen-driven endometrial proliferation
and leads to the development of a secretory
endometrium
• its decline at the end of the cycle is the determinant of
the onset of menstruation
• suppresses menstruation and uterine contractility
• maintenance of pregnancy
 Progesterone in therapy

• to control anovulatory bleeding;

• to prepare the uterine lining in infertility therapy and to
support early pregnancy;
• for recurrent pregnancy loss due to inadequate
production
• in intersex disorders to promote breast development
 Progestogens in therapy

• combined oral contraceptive and progestogen-only pill

• medroxyprogesterone acetate by depot injection is
used for parenteral contraception
• androgen-sensitive tumors (prostate cancer), e.g.
cyproterone acetate
• hormone replacement therapy with an intact uterus to
avoid endometriosis
• endometriosis;
• menstrual disorders (premenstrual tension,
dysmenorrhea, menorrhagia)
 Progestogens in therapy
• common use: norgestrel and derivatives
(norethisterone, levonorgestrel, desogestrel,
norgestimate, gestodene)
• desogestrel and gestodene are associated with an
increased risk of venous thromboembolism
• desogestrel, drospirenone and gestodene should be
considered for women who have side effects (acne,
headache, depression, weight gain, breast symptoms
and breakthrough bleeding) with other progestogens
• norelgestromin + ethinylestradiol for transdermal
contraceptive patch
 Progestogen adverse effects
• abdominal cramps
• depression
• dizziness, headache
• anxiety
• cough
• diarrhea
• fatigue
• musculoskeletal pain
• nausea
• bloating
 Progestogens antagonists
• mifepristone: competitive antagonist, a medical
alternative to surgical termination of early pregnancy
up to 63 days’ gestation (causes decidual
breakdown)
• A single oral dose of mifepristone is followed by
gemeprost (a prostaglandin that ripens and softens
the cervix)
• mifepriston in myoma therapy: reduces myoma size
and bleeding
• ulipristal (selective progesterone receptor modulator
– SPRM) strong effect on myoma and fibroids
 Androgens
The principal hormone is testosterone secreted
by Leydig cells. Testosterone circulates in the
blood, bound to a plasma globulin. Cells in
target tissues convert testosterone into
dihydrotestosterone by a 5-α-reductase enzyme.
Both testosterone and dihydrotestosterone are
inactivated in the liver.
 Androgen Receptor
• nuclear receptor
• the androgen receptor is encoded by the AR gene
located on the X chromosome
• no subtypes
• ligand-activated transcription factors that increase or
decrease the transcription of target genes
• acts the same as the estrogen receptor (with similar
signaling)
 Androgen actions
• development of male secondary sex characteristics
(male distribution of body hair, breaking of the voice,
enlargement of the penis, sebum secretion, male-
pattern balding)
• protein anabolic effects influencing growth,
maturation of bone and muscle development
• spermatogenesis and seminal fluid formation
• FSH acts on the seminiferous tubules and promotes
spermatogenesis
• LH stimulates testosterone production
 Androgens in therapy
• hypogonadism
• female disorders: dysfunctional uterine bleeding,
endometriosis, disseminated breast cancer
• aplastic anemia (recently replaced by recombinant
erythropoietin )
• reconvalescence: anabolic steroids
• osteoporosis

testosterone inj (Nebido), gel, transdermal gel

(Androgel)
Selective androgen receptor modulators
(SARMs)

• a class of compounds that have similar properties to

anabolic agents, but with reduced androgenic
properties
• anabolic effects on the muscle, but not adverse
effects on prostate
• SARMs are illicit ingredients for dietary supplements
• future drugs for sarcopenia and osteoporosis
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 Androgen adverse effects
• virilization in women (acne, facial hair growth,
deepening of the voice, masculinizing effects,
menstrual irregularities)
• increased libido in men (frequent erections or
priapism, aggressive behaviour)
• fusion of epiphyses in childhood
• hepatotoxicity (jaundice, methyl-testosterone is no
longer prescribed!)
• azospermia (inhibition of FSH and LH)
• anorexia, vomiting, bloating, diarrhoea (oral
testosterone preparations)
 Androgen antagonists
• Competitive antagonist
– cyproterone acetate +
strong progestogen effect
– bicalutamide, apalutamide
tbl
– inoperable prostatic
carcinoma
– reduce sexual drive in cases
of sexual deviation
– to treat hyperandrogenic
effects (women)
– abiraterone-acetate –17,20
lyase inhibitor, blocks
androgen synthesis –
prostatic carcinoma
• 5 alpha-reductase
inhibitors
inhibit the formation of
dyhydrotestosterone
– finasteride, dutasteride (+
tamsulosine)
– for benign prostatic
hypertrophy (significantly
enlarged prostate)
– finasteride is licensed for
treating baldness in men
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 Oral contraceptives
-estrogen-progestogen combination – the most common

monophasic 21 or 24
biphasic 21 or 22
triphasic 21 (7-7-7)
tetraphasic 28 (26+2 placebo)
extended cycle 91 (84+7)

-only progestogen („minipill”)

lactation, estrogen CI 28

-postcoital 1 (within 72 h) or 1+1 (after 12-16 h and

24h) LNG
24 h 95%, 48h 85%, 72h 58%
0-72h 100%, 48-120 h 97% 1 (within 120 h) ULIPR
2 dark yellow tablets: 3 mg estradiol valerate
5 medium red tablets: 2 mg estradiol valerate + 2 mg dienogest
17 light yellow tablets: 2 mg estradiol valerate + 3 mg dienogest
2 dark red tablets: 1 mg estradiol valerate
2 white tablets: inert
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 Advantages of COCs

-99% efficacy
-withdrawal bleeding: less pain and blood loss (important in
coagulation disorders), less risk for anemia
-milder PMS
- lower risk for cancer (ovary, cervix, myometrium, colon)
-do not increase the risk of breast cancer even in case of genetic
predominance (BRCA1/2),
-lower risk for pelvic inflammation
-lower risk for ovary and breast cysts and fibromas
-lower risk for ectopic pregnancy
-dermatological advantages (e.g., acne)
-reduced risk for endometriosis
-inhibit the bone loss (above the age 40)
 Risks of COCs

-adverse effect with low risks:

nausea, reduced libido, headache, breast sensitivity,
irregular bleedings (in the first 2 months), weight gain,
mood alteration

- adverse effect with high risks:

hypertension – water retention, steroid action
thromboembolism – estrogen increases the synthesis of
coagulation factors (deep vein thrombosis, stroke, MI)
 Advantages of extended cycle COCs

-infrequent bleedings or total lack of bleedings

-simpler use (1 tablet every day)
-efficacy is practically 100%
-reduced risk for endometriosis, improvement in active disease
-no PMS
-significantly reduced frequency of headaches

Risks
-irregular, spotting bleedings
-risks of COCs
New COC
drospirenone + estetrol; 24 - 4 (Drovelis, Lydisilka)
estetrol: SERM, produced by fetal liver, terminal half life (after 5
days dosage): 24 h, does not influence the CYP450 system
No danger for water ecosystem
drospirenone: also antiandrogen and antialdosterone effects
(spironolactone analogue), no effect on glucocorticoid receptor,
half life (after 10 days dosage): 32 h
Slight antihypertensive effect as compared with other COCs
Minipill: (Slinda) 24-4, long efficacy (24 h „missed dose” window)
 Advantages of minipills
-ideal during lactation (estrogen inhibits the milk secretion)
-proper in estrogen contraindication (risk of thrombosis,
hypertension, smoking, migraine with aura)
-milder bleeding and cramps
-lower risk for tumors (ovary, cervix, myometrium)
-lower risk for pelvic inflammation

Risks
-24 h efficacy (necessity of precise dosage)
-irregular bleedings, no cycle, endometrium thinning
-adverse effects: reduced libido, hot flush, insomnia, mood
alteration, fatigue
 Advantages of emergency contraception
-possible avoid of unwanted pregnancies
-no risk for the already existing pregnancy

Risks
-short efficacy
-adverse effects: breast sensitivity, altered mood, fatigue, migraine,
dysmenorrhea
Hormone replacement therapy (HRT)
 Menopause

• Marks the end of reproductive life

• Cessation of menses for 12 months
• Diagnosis by clinical symptoms
• Result of egg depletion and estrogen
production by the ovary due to natural aging
or surgery
Summary of Key Physical Changes

• Vasomotor instability Brain

Eyes
• Metabolic Changes
Teeth
• Coronary Artery Disease Vasomotor
Heart
• Accelerated bone loss
Breast
• Skin changes Colon

• Urogenital atrophy Urogenital

tract
• Cognition (?) Skin

• Libido (?) Bone

 Hot Flushes
• “Sudden onset of reddening of the skin over the head,
neck, and chest accompanied by a feeling of intense
body heat and sometimes concluded by profuse
perspiration”
• Number one complaint
• Few seconds to several minutes
• Most severe at night and during times of stress
• More common among overweight women
• Usually last for 1-2 years
• 25% will last for more than 5 years
 The Menopausal Metabolic Syndrome
◼ Lipid Triad
– Hypertriglyceridemia ▪  HDL Cholesterol
–  LDL Cholesterol

◼ Abnormalities in Insulin
– Insulin resistance ▪  insulin secretion
–  insulin elimination ▪ Hyperinsulinemia

◼ Other Factors
– Endothelial dysfunction
▪  SHBG
–  visceral fat
▪  blood pressure
–  uric acid
▪  PAI-1
 Duration of therapy
There are no reasons to place mandatory
limitations on the duration of HRT. Whether or
not to continue therapy should be decided at
the discretion of the well-informed woman and
her health professional, dependent upon the
specific goals and an objective estimation of
ongoing benefits and risks.
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