Lecture 1 Physiology and Pharmacology of the Control of Sex Hormone Production MacLeod

REGULATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS: GONADOTROPINS:

FOLLICLE-STIMULATING HORMONE (FSH) & LUTEINIZING HORMONE (LH):
• Produced by specialized cells in the anterior pituitary gland
• Act on FSH and LH receptors in gonads
Females FSH • Stimulates the growth of the developing
ovarian follicles during the first half of the
menstrual cycle, and promotes the synthesis
of estrogen (LH also required)
LH • Induces ovulation, and stimulates
progesterone and estrogen synthesis by the
corpus luteum (formed from the remaining
cells of the ruptured follicle) during the
second half of the menstrual cycle
Males LH • Stimulates synthesis of testosterone by the
Leydig cells of the testes
FSH • Promotes spermatogenesis (testosterone is
also required)

CHORIONIC GONADOTROPIN (CG):

• Produced by fertilized ovum, then by placenta in pregnancy
• Sequence similar to LH, interacts with LH receptors in both men
and women
Females • Acts to maintain the corpus luteum when ovum is
Controls development of Prepares uterus lining
female sex characteristics
and reproductive system
for implantation of a
fertilized egg
fertilized
• NOTE: pre-ovulatory surge of estrogen actually has a stimulatory effect Males • Not produced
on GnRH and Gn production (i.e. positive feedback) • Exogenous CG acts like LH

USE OF GONADOTROPINS: GONADOTROPIN RELEASING HORMONE (GnRH):

• Acts on specific GnRH receptors on anterior pituitary gland to increase
DIAGNOSTIC: Elevated in first trimester (first three months)
Pregnancy blood test production and release of LH and FSH (in pulses):
Pregnancy testing: hCG levels in maternal blood and urine detects progesterone
• Decapeptide with very short half-life (2-4 min)
Prediction of Ovulation occurs about 36 hours after onset of
ovulation: LH surge, and 10-12 hours after peak • Gonadorelin acetate = synthetic GnRH identical to the native hormone
Determining cause • Primary gonadal failure: ovaries or testes o Used to investigate delayed puberty, and treatment of
of impaired sex fail to respond to stimulation by infertility in both men and women
hormone: gonadotropins GnRH ANALOGUES:
• Secondary gonadal failure • Both GnRH agonists and GnRH antagonists now available
(hypogonadotropic hypogonadism): failure
• Both groups of drugs are analogues of GnRH with changes to amino
of hypothalamus to secrete GnRH or
acid sequence that alters their activity
pituitary to secrete gonadotropins
• Both used when want to decrease release of Gn and sex steroids

THERAPEUTIC USE: GnRH AGONISTS: Buserelin, Leuprolide, Nafarelin

• Treatment of infertility in women – component of assisted Compare • ↑ affinity for GnRH on pituitary gland = ↑ potent
reproductive technologies programs in ovulatory patients to GnRH: • Less susceptible to proteolysis = longer duration
o Possible SEs: • Anti-fertility when given continuously
▪ Multiple births o Physiological GnRH = pulsatile (pro-fertility)
▪ Ovarian hyperstimulation syndrome (massive ovarian MOA 1. Initial rise in hormone levels (= “flare” of disease)
enlargement, fluid accumulation leading to pain & 2. Down-regulation of GnRH receptors on pituitary
renal failure) gland
3. ↓ FSH, LH which then ↓ sex steroids
AEs Largely due to suppression of sex steroid production
GONADOTROPIN PREPARATIONS:
• Women: hot flashes, vaginal dryness, memory
• Purified from human urine:
impairment, decreased bone density (can be
o Menotropins: roughly equal amounts FSH and LH
reduced by “add back therapy” with estrogen +
o Chorionic gonadotropin progesterone
• Recombinant versions of FSH, LH and CG have also been developed • Men: hot flashes, decreased libido, erectile
dysfunction, increased risk of osteoporotic
fractures, type 2 diabetes and CVD
Hormones
1. Steroidal hormones Forms SC injection and nasal spray
- gonadal estrogen/ progesterone/ testosterone/ adrenal corticosteroids/ aldosterone/ vit D
- act on receptors inside cell
- consist of fused 17-C atom ring system (steroid structure), in which 3 cyclohexane rings and GnRH ANTAGONISTS: Ganirelix, Cetrorelix, Degarelix
1 cyclopentane ring are present
2. Non-steroidal hormones • Analogues of GnRH that are competitive reversible antagonists of
-insulin/ thyroids/ PTH/ calcitonin GnRH at its receptor on pituitary cells
- act on receptors on cell surface
• Induce a rapid, reversible inhibition of LH and FSH secretion, with
no agonist phase at beginning of treatment
• Approved to prevent premature LH surge and ovulation in in vitro
fertilization cycles and for use in advanced prostate cancer
• Adverse effects appear to be similar to GnRH agonists
 Lecture 1 Physiology and Pharmacology of Androgens and Anti-Androgens MacLeod
Increase synthesis of clotting factors
Decrease HDL
SITES OF ANDROGEN PRODUCTION: ANDROGEN ACTIONS IN MALES: Decrease LH

Men • Testes Sex organs Development of male sex organs, prostate, seminal vesicles,
• Also adrenals release small amounts spermatogenesis, sexual function
Women • Very small amounts of androgens derived Voice Larynx growth and voice deepening
from ovaries & adrenal glands Bone Increases linear bone growth; also role in termination of bone growth and
• Role in skin (sebaceous gland), bone maintaining bone density
growth and sexual function Muscles Increases lean muscle strength and volume
Hair Stimulates male-pattern hair growth
REGULATION OF ANDROGEN PRODUCTION: Skin Increases skin thickness and oiliness
Brain Increased libido, altered mood, behavioral effects
Androgens Kidney Stimulates erythropoietin production
- C-19 steroid
- all have anabolic activity
(promote muscle growth) THERAPEUTIC USES:
- if with 17-methyl or ester
groups: PO active ANDROGEN REPLACEMENT THERAPY IN TESTOSTERONE DEFICIENCY: 1o & 2o hypogonadism
• Induce/maintain pubertal development, including secondary sex characteristics
• Permit normal accumulation of bone mass & achieve optimal growth and final height
(if pre-pubertal)
• To develop and/or maintain skin, muscle and sexual organ function
• When used in appropriate doses, not associated with adverse effects
Testosterone 17-enanthate
- resembles estradiol esters (increase
/ testes duration of action when given IM)
(leydig cells)
AGE-ASSOCIATED DECREASE IN ANDROGEN PRODUCTION:
• Decreased testosterone production is a normal consequence of aging in men
• May contribute to decreased sexual function, muscle and bone mass, and other sx
• Sometimes described as late onset hypogonadism, andropause or low T
No ester/
ethinyl group o Clinical definition still not agreed on
TESTOSTERONE REPLACEMENT THERAPY:
Testosterone
• In men > 65 yrs with age-related low serum T, replacement therapy for 12 months
CHANGES IN TESTOSTERONE SECRETION WITH AGE: produced a transient improvement in sexual function BUT no benefit in physical
strength, vitality or cognition
• Emerging evidence of increased risk of CV events, particularly in pre-existing CVD
• Risk of prostate cancer not clear

Danazol (androgen receptor agonist)

OTHER USES OF ANDROGENS: - dose-related androgenic effects
- used in endometriosis/ fibrocystic breast disease precocious
• To stimulate delayed growth and puberty in males puberty in male children
o Due to true hypogonadism or constitutional delay of puberty
o Usually used for relatively short periods (up to 3 months), then re-evaluated
• Catabolic or muscle-wasting conditions
o In general, not particularly effective
o However, AIDS is often associated with low serum T, treatment increases muscle
mass and strength

DIRECT AND INDIRECT ACTIONS OF TESTOSTERONE:

TESTOSTERONE PREPARATIONS:
Estradiol • Termination of bone growth
0.3% • Maintenance bone density Testosterone • Fatty acid esterified at 17β-hydroxy position
Aromatase • Gonadotropin regulation esters o Increased lipophilicity
Excretion
Testosterone • Skeletal muscle mass/strength • Depot preparations administered IM every 2-4 weeks
(90%)
o Slowly released from site of injection, hydrolyzed to testosterone
6-8% in prostate • Bone growth, density
5α-reductase • Spermatogenesis
Transdermal Testosterone patch • Applied once/day
• Sexual function
delivery Testosterone gel • 1% testosterone applied
Dihydro- • Hair follicles
systems • Single use packets or metered dose pump
testosterone • Prostate • Both delivery modes give testosterone levels in normal range
• Skin • Potential for secondary exposure of women and children with gel
17α-alkylated • Resistant to hepatic breakdown = effective on oral administration
androgens • Not recommended for clinical use due to risk of hepatotoxicity
MECHANISMS OF ANDROGEN ACTION:
1. Once secreted by testes, testosterone is mainly protein Androgens with relatively selective anabolic activity
ANABOLIC STEROIDS: Increased anabolic activity with nandrolone/ oxandrolone
bound (sex hormone binding globulin).
• Attempt to separate effects of androgens on muscle & bone from other actions of androgens
2. Free hormone enters the cell by diffusion. In some cells, it
is converted to DHT. • Only limited selectivity achieved = very limited clinical use; widely abused Large dose: liver dysfunction
3. Both testosterone and DHT bind to inactive androgen • Most are 17α-alkylated androgens = orally active
receptor (DHT with higher affinity), located in cytoplasm.
ANDROGEN USE BY ATHLETES AND BODY BUILDERS:
4. Binding results in dissociation of corepressor proteins,
• Reasons for use: to increase lean body mass, to decrease fat mass, to enhance performance,
dimerization, translocation to nucleus and binding to
androgen response element of androgen-regulated target to sustain intensive training periods and to improve appearance
genes. • Often used intermittently in very high doses (ex// stacking = using oral and injectable forms
5. Hormone-receptor complex interacts with coactivators to and increasing doses for 6-12 weeks at a time)
produce altered regulation of target genes • Appear to increase muscle mass & strength, especially in combo with wt training but no
evidence for improved indurance
• Mechanisms unclear but include hypertrophy of muscle fibers
 Lecture 1 Physiology and Pharmacology of Androgens and Anti-Androgens MacLeod

ADVERSE EFFECTS OF ANDROGENS: ADVERSE EFFECTS OF VERY HIGH DOSES OF ANDROGENS/

• Virilization of females (any age) Masculinization/ acne/ hirsutism/ deepening voice/ menstrual irregularities ANABOLIC STEROIDS IN MEN:
• Premature termination of bone growth and disturbances in sexual development and childrenInappropriate for long-
term use in children
• Suppression of spermatogenesis
• 17α-alkylated androgens/anabolic steroids carry risk of hepatotoxicity • Testicular atrophy
• Sodium retention leading to edema • Decreased HDL, increased LDL
Male: priapism (continued erection)/ impotency • Gynecomastia
CVD: increased CAD
• Psychological changes

ANDROGEN RECEPTOR ANTAGONISTS: Antiandrogen (inhibit synthesis of androgen)

NON-STEROIDAL ANTI-ANDROGENS: Flutamide, bicalutamide, nilutamide, enzalutamide 5α-REDUCTASE (5AR) INHIBITORS: Decrease dihydrotestosterone
• Competitive antagonists of the binding of androgens to nuclear receptors • Types of 5α-reductase:
• Block androgen actions in all target tissues, including hypothalamus/pituitary o Type 1: found in prostate + other organs
o Reduced negative feedback results in increased testosterone production o Type 2: concentrated in male genitals and prostate
Increased circulating testosterone level
• 5α-reductase inhibitors:
THERAPEUTIC USES:
o Dutasteride inhibits Type 1 and 2 5α-reductase
• Treatment of advanced prostatic carcinoma o
Competitively
Finasteride inhibits Type 2 5α-reductase only Has heterocyclic ring
• Most commonly during first 2-4 weeks treatment with GnRH agonist
o Counteracts symptom “flare” resulting from GnRH-agonist induced USES:
increase in testosterone production
BENIGN PROSTATE HYPERTROPHY: Reduce prostate size
Increase peak urinary flow rate
• Decrease circulating DHT levels by 75-90%
ADVERSE EFFECTS: o Growth of prostate requires DHT rather than testosterone
• Hot flashes • Erectile dysfunction • Appear to be equally effective
• Decreased libido • Breast tenderness, gynecomastia
• Used alone in men with enlarged prostate & obstructive sx
o Decrease prostate size with improvement in urinary
CYPROTERONE ACETATE: flow rate and symptoms
• Competitive antagonist at androgen receptors o Decrease risk of long term complications by ~ 50%
• Also has progesterone activity and blocks gonadotropin secretion o Slow onset of action
• Combination therapy with α-blockers more effective than
USES: either alone in reducing the risk of progression
• Treatment of severe cystic acne as component of Diane 35
(combination of ethinyl estradiol + cyproterone acetate) MALE PATTERN HAIR LOSS (ANDROGENETIC ALOPECIA):
o Also has contraceptive effect BUT not approved for this use in Canada • Delay hair loss and promote some re-growth of hair
o Relatively higher risk of VTE than other oral contraceptives • Better on vertex (top of head) than on frontal hair
• Slow onset, effective only as long as drug is given
• (approved use of finasteride only)

C/I: pregnancy (even absorbed

ADVERSE EFFECTS: testicular pain, hirsutism
from skin, thus avoid contact)
Sexual dysfunction
• Dose-dependent decreased libido, erectile dysfxn, gynecomastia
• Decreased PSA levels Finasteride: effective in 3-6 months in reducing serum PSA by 50%
within 6 months of treatment

EFFECT ON DEVELOPMENT OF PROSTATE CANCER:

• Both drugs have been shown to reduce detection of
prostate cancers by 23-25% overall Can cause prostate cancer ADRs
• However, increased risk of detection of serious prostate CA
• Not considered to have favorable risk-benefit for
prevention of prostate cancer Not used for prevention of prostate cancer

Site of action: nucleus

 Diethylstilbestrol (DES) 17-ethinyl group: PO active
Clomiphene - non-steroidal synthetic estrogen (stilbene derivative, (by preventing formation of
- indications: male/ female infertility bioisosters with ethinylestradiol) estradiol to estrone)
- female infertility: induce ovulation (PO daily from 5th to 10th day of menstrual cycle) - x pregnancy: cause infertility and development of
vaginal cancer in female offspring Ethinylestradiol
Lecture 1 Physiology & Pharmacology of Estrogens and Progestins and their Modulators - 17-alpha estradiol MacLeod
- synthetic steroid estrogen

SYNTHESIS OF ESTROGENS AND PROGESTERONE: MAJOR ESTROGENS: C-18 steroid (three 6-membered rings & one 5-membered ring)
17β- • Most potent naturally occurring estrogen
estradiol • Major secretory product of the ovaries & major circulating
Phenolic ring
(E2) estrogen in pre-menopausal women (60% of total)
(aromatic) causes
cancer side effects

Estrone • Produced in ovaries, peripheral tissues and liver; also by

(E1) placenta in pregnancy
• Major estrogen in post-menopausal women, produced in
adipose tissue from adrenal androgens
Estriol • Metabolic product of both estrone and estradiol with
(E3) weak estrogenic activity
• Produced mainly in the liver, also by placenta

REGULATION OF ESTROGEN AND PROGESTIN PRODUCTION: ACTIONS OF ESTROGENS IN FEMALES:

Female Stimulate development of vagina, uterus and fallopian
maturation tubes, as well as secondary characteristics (hair growth,
body fat distribution)
Breasts Stimulate growth and development of the breasts
Endometrium Cause growth of endometrium during first half of the
menstrual cycle
► Action normally opposed by progesterone released
during second half of cycle
► If unopposed, can cause endometrial hyperplasia,
leading to increased risk of endometrial cancer
Brain • Regulate areas that prepare body for reproduction
• May influence behavior and libido
• May help protect memory and cognition
Bone Limited effect to promote linear growth, but promote
MENSTRUAL CYCLE: closure of epiphyses (termination of bone growth) and help
to maintain density by decreasing resorption
CV events • Alterations in serum lipids (↑ HDL, ↓ LDL)
increased estrogen - increased progesterone
- uterine contraction
• Increased blood coagulation, through enhanced
- when premenstrual symptoms occur hepatic production of clotting factors

THERAPEUTIC USES OF ESTROGENS:

• Oral contraception (with progestins)
• Replacement therapy in estrogen deficiency states:
o Primary hypogonadism
o Hypogonadotropic hypogonadism
o In young girls, estrogen therapy at appropriate time replicates
events of puberty and stimulates growth
o Menopause e.g. hot flushes, vaginal dryness

- very high LH
MENOPAUSE:
- increased FSH • Defined as the cessation of menstrual cycles for 12 months
1) At the beginning of the cycle, gradual increase in FSH initiates follicular • Preceded by an interval known as perimenopause, during which symptoms
growth and development. Estradiol, secreted in increasing amounts by such as hot flashes and night sweats begin
the follicles, first inhibits the secretion of LH and FSH. At the peak of its • Results from depletion of ovarian follicles, associated with a reduction in
secretion, however, there is a sudden surge in the production of LH and oocyte quality – since follicles are responsible for secretion of hormones,
to a lesser extent, FSH. estrogen and progesterone levels fall
2) In response to LH, follicular cells decrease production of estradiol and • Onset: late 40 – early 50s (median age is 51)
begin production of progesterone. LH also results in ovulation, and
POTENTIAL CONSEQUENCES OF MENOPAUSE:
formation of the corpus luteum.
Early sx • Hot flashes, night sweats (up to 75%)
3) The corpus luteum produces increasing amounts of progesterone and
o Most severe during first 2 post-
estrogens, which inhibit secretion of FSH and LH. In the absence of LH and menopausal years
if the ovum is not fertilized, the corpus luteum regresses, levels of o Sudden onset of upper body vasodilation
estrogen and progesterone fall, and menstruation occurs. associated with feeling of intense heat and
4) When levels of progesterone and estrogen fall, the hypothalamus is sweating
released from the negative feedback and levels of FSH and LH slowly o Frequency up to 1/hour, last for 2-3 mins
begin to rise. The cycle then repeats itself. o Due to re-setting of hypothalamic
thermostat
MECHANISM OF ESTROGEN ACTION: • Insomnia, irritability, mood disturbances
• Most effects produced through interaction with nuclear receptors Physical • Urogenital atrophy (thinning of tissues lining
o Two types now known: ERα and ERβ changes vagina and bladder)
o Both located in nucleus in inactive form (intermediate) o Predisposes to dryness, itching, painful
• Binding of hormone causes dissociation of corepressor proteins and intercourse (dyspareunia), infection
dimerization of receptor, which then binds to specific DNA sites, called • Skin atrophy
estrogen response elements (ERE)
Diseases • Osteoporosis
(chronic) • Cardiovascular disease
• The estrogen-receptor complex then recruits coactivator proteins,
allowing transcription to be initiated, leading to mRNA & protein synthesis
 Estrogen ADRs
- GI: nausea/ GI upset/ gallstone formation
- CVD:VTE/ HTN/ stroke/ MI
- weight gain
- depression
- breast tenderness/ feminization
Lecture 1 Physiology & Pharmacology of Estrogens and Progestins and their Modulators - endometrial cancer (prolonged use) MacLeod
HORMONE REPLACEMENT THERAPY (HRT) IN MENOPAUSE: ESTROGEN USED IN RELIEF OF VASOMOTOR SYMPTOMS OF MENOPAUSE:
• Vasomotor & GU menopausal symptoms result from low estrogen levels ORAL • Conjugated equine estrogens (Premarin)
o Estrogen replacement is most effective therapy o Mix of estrogens, mainly estrone
• Hot flashes generally transient (1-2 years) • Estradiol hemihydrate (Climara)*
o Local administration may be more effective than other routes for • 17 β-estradiol (Activelle, Estrace)*
vaginal symptoms * some preparations also contain a progestin
TRANSDERMAL • 17 β-estradiol patch (Estradot) applied 2x/week
Benefits of post-menopausal Increased risks associated with post- o Also available in combo w/ Progestin (Estralis)
HRT use menopausal HRT • 17 β-estradiol gel (Estrogel 0.06%) applied daily
• Relief of vasomotor and • Venous thromboembolism
GU symptoms of • Non-fatal ischemic stroke ► Transdermal route avoids first pass metabolism
► Some evidence that risk of VTE is lower, but risk of
menopause • Breast cancer
• breast cancer is similar, to oral route
Decreased risk of o Risk increased with longer
osteoporotic fractures duration of use and with use LOCAL ADMIN For relief of vaginal symptoms, such as vaginal dryness,
(both vertebral and hip) of progestin painful intercourse, etc
• Decreased risk of • Endometrial cancer Vaginal 17 β-estradiol, conjugated equine estrogens,
colorectal cancer o E alone but not E + P creams esterified estrogens – applied daily
• CHD * Vaginal 17 β-estradiol (Estring) – SR for 90 days
o With E + P, but not E alone ring
• Cognitive decline and dementia* Vaginal Estradiol hemihydrate (Vagifem) – initial daily,
tablet then 2x/week for maintenance
* current evidence suggests that these risks increased in women starting HRT
at > 63 years old & > 10 years past menopause, but not in women aged 50-59 COMPARISON OF ESTROGEN AND SERMS:
Oral Raloxifene Tamoxifen
SELECTIVE ESTROGEN RECEPTOR MODIFIERS (SERMs): Antiestrogens estrogen
Hot flashes ↓↓↓ ↑ ↑
MECHANISM OF ACTION: Primary site of action: hypothalamus
Prevention of post-menopausal ↑↑↑ ↑↑ ↑
• Bind to nuclear estrogen receptors (ER) and competitively inhibit the
bone loss
binding of estrogen, antagonizing the actions of estrogen in some
Favorable pattern of serum lipids ↑↑↑ ↑ ↑
tissues but mimicking the actions of estrogen in others Risk of endometrial cancer ↑↑* - ↑
• On binding, change the conformation of the ER differently than Thrombosis ↑↑ ↑↑ ↑↑
estradiol, and depending on the tissue: Breast cancer ↑ ↓ ↓
o Change its interaction with coactivators or allow it to interact * prevented by concurrent use of progestins
with corepressors (preventing transcription)
o Allow it to interact with non-ERE in some tissues, producing an AROMATASE INHIBITORS: Reduce estrogen
estrogen-like effect
TYPES:
IDEAL SERM WOULD: • Type 1: Exemestane – steroidal, irreversible
Mimic estrogen to: • Strengthen bone • Type 2: Anastrozole – non-steroidal, competitive
Letrozole (as fertility enhancer)
• Raise HDL and lower LDL
• Suppress hot flashes USE:
Antagonize estrogen to: • Reduce breast cancer risk • As adjunctive txt in early stage breast cancer in post-menopausal
• Reduce risk of endometrial cancer women (improve survival compared to other endocrine therapy)
• Reduce risk of thrombosis • Advanced breast cancer in post-menopausal women
CYP2D6 inhibitors
- amiodarone/ bupropion/ chloroquine/
• Exemestane reduced risk of breast cancer by 65% in healthy post-
diphenhydramine

SERMS TREATMENT:
- CAT.D: fluoxetine/ haloperidol/ imatinib/
paroxetine/ propoxyphene/ propafenone/
menopausal women at high risk
quinidine/ terbinafine/ thioridazine
Can have effect in ER -ve patients as well
Tamoxifen Use • First line hormonal treatment of breast
cancer in pre-menopausal women MAJOR ADVERSE EFFECTS:
- full anti-estrogens
- bioisosters
- non-steroidal geometric isomer
o As adjunct (with surgery or chemo) in • Early: GI disturbances, headache, hot flashes
- equally effective in PO/ inj early stage breast cancer • Delayed: ↓ bone density  ↑ risk of osteoporosis & fracture;
o Alone in advanced breast cancer polyarthralgia
Clomiphene • Used prophylactically – lowers incidence of
- interfere with -ve feedback of estrogen on hypothalamus
and pituitary, thus increase secretion of GnRH and cause breast cancer in both pre- and post-
ovulation
- for infertility related to anovulatory cycles menopausal women at high risk ANTI-ESTROGEN (AKA selective estrogen receptor downregulator (SERD)
- ADRs: ovarian enlargement/ vasomotor flushes/ visual
disturbances AEs • Hot flashes , vaginal bleeding, menstrual irregularities, N/V MECHANISM:
• Increased risk of VTE, endometrial cancer • Binds to the ER; competitively inhibits binding of estrogen and
Raloxifene Use • Reduces risk of invasive breast cancer in prevents ER dimerization, which leads to its rapid degradation
- estrogen agonist: bone/ lipid profile
- estrogen antagonist: uterine/ breast post-menopausal women at high risk
• In post-menopausal osteoporosis – reduces
FULVESTANT block estrogen receptors in all target tissues
risk of vertebral fracture, but not hip fracture
• Used in txt of metastatic breast cancer in post-menopausal women
AEs • Hot flashes, weight gain
who have disease progression following prior endocrine therapy
• Increased risk of VTE
• No increased risk of endometrial cancer • AEs: nausea, hot flashes, arthralgias
o Effect on bone density and osteoporotic fracture risk is unclear
• Requires IM administration

Estrogen enhance blood coagulability (VTE) by

- increasing coagulation factors
- increasing platelet production and aggregation
- decreasing antithrombin III
 Drospirenone: the only progestin with antihypertensive properties (can increase Na excretion)
Progestin precipitates porphyrias (red urine) in patients with relevant genetic deficiency disease

Lecture 1 Physiology & Pharmacology of Estrogens and Progestins and their Modulators MacLeod
No aromatic
ring and ketone
PROGESTINS: at position 3

PHYSIOLOGICAL FUNCTION OF PROGESTERONE: C-21 steroid (basic

nucleus: pregnane)
THERAPEUTIC USES:
• Essential for oocyte release from follicle at ovulation Norethylnodrel & norethindrone
CONTRACEPTION (alone and with estrogen): -- more commonly used in OCP
• Decreases estrogen-induced endometrial proliferation and promotes potent PO activity/ more lipid-soluble/ less first pass metabolism
Mechanisms of combined estrogen-progestin oral contraceptives:
secretory changes in the endometrium in preparation for implantation
1. Negative feedback suppression of gonadotropin secretion
of a fertilized ovum during the luteal phase of the menstrual cycle
(synergistic effect of estrogen and progestin)
• Influences secretion of gonadotropins during the menstrual cycle
• Decreased production of FSH (to < 70% normal)
• Essential for maintenance of pregnancy
• No LH surge at mid-cycle
o High levels secreted by corpus luteum and placenta suppresses
 Minimal follicular development, and NO OVULATION
menstruation and decreases uterine contractility Increased progesterone can decrease estrogen
o Role in preparing breasts for lactation
2. Abnormal endometrial development
• Endometrium atrophic  impaired implantation
MECHANISM OF ACTION OF PROGESTERONE AND SELECTIVE PROGESTERONE
RECEPTOR MODIFIERS:
3. Abnormal cervical mucus
• Becomes thicker and more viscous  impairs penetration

4. Abnormal muscular activity of fallopian tubes and uterine smooth

muscle  impairs sperm and ovum transport

COMBINED WITH ESTROGEN IN HRT OF POST-MENOPAUSAL WOMEN:

• Oppose effects of estrogen on endometrium, decreasing the risk of
endometrial cancer Added to estrogen during menopause to reduce irregular bleeding and risk
of endometrial cancer
• May enhance the positive effect of estrogen on bone
• May actually increase the risk of breast cancer*
• Tend to oppose the effects of estrogen on lipoprotein-cholesterol
levels *

* may be affected by the type of progestin used – micronized

progesterone may be less likely to have these effects

OTHER USES:
• For ovarian suppression (ex// in dysfunctional uterine bleeding due
to relative excess estrogen effect, endometriosis)
• Adjunct or palliative treatment of breast cancer (4th line) and
Types
PROGESTIN PREPARATIONS: -- 17-alpha hydroxyprogesterone e.g. medroxyprogesterone acetate, megestrol acetate
17-alpha ethinyl androgens (more potent)
endometrial cancer
• Progesterone & derivatives: used mainly in menopausal symptoms GI reflux
o Micronized progesterone 100 mg cap (powder suspended in peanut oil/ glycerine)
Lack androgenic activity
ADVERSE EFFECTS: edema, weight gain, nausea, menstrual irregularities
mood change / depression, headache, unusual fatigue, loss/ change in speech or coordination
Depo- - amenorrhea
oProvera Medroxyprogesterone acetate - abnormal uterine bleeding/ endometriosis
inj - contraceptive 150 mg q3mth
o Megestrole acetate Levonorgestrel: 17-alpha ethinyl progesterone (6 cap subdermal
implanted onto upper arm for long-term contraception) SELECTIVE PROGESTERONE RECEPTOR MODIFIER: Ulipristal acetate
• Synthetic progestins: used mainly in contraceptive preparations
o Varying degrees of progestin potency MECHANISM: binds to progesterone receptor; has partial agonist activity
o Varying amounts of other hormonal activity
► Therefore, variation between preparations based on both type TREATMENT OF UTERINE FIBROIDS (MYOMAS):
and dose of progestin Myomas • Estrogen-sensitive benign fibrous growths
• Can cause menorrhagia with anemia & pelvic pain
ANTI-PROGESTIN: Mifepristone (RU-486) Potent antiprogestin + weak antiglucocorticoid MOA • Reduces proliferation and fibrosis, and increases
apoptosis of myoma cells (but not normal
MOA: competitive inhibitor of progesterone receptors
myometrial cells)
• Blocks ovulation if given in follicular phase of menstrual cycle
Induces menstruation • Suppress proliferation of endometrium
• Induces menstrual bleeding if given in luteal phase SEs • Increase in endometrial thickness, but not
• Results in decidual (endometrial) breakdown in early pregnancy, hyperplasia
leading to detachment of the embryo • Amenoarrhea, hot flashes, headache
First term abortion
Dosage • Fibristal 5 mg tablet
USE: terminate early pregnancy Interfere with progesterone and decrease production of hCG
Both
• PO Combined with misoprostol to improve efficacy Without combining with estrogen EMERGENCY CONTRACEPTIVE:
• Success rate approx. 95% if used within first 49 days MOA • Major action is anti-ovulatory
• Inhibits LH release from pituitary as well as LH-
MIFEGYMISO: combination of mifepristone (200 mg, PO) plus induced follicular rupture within the ovary
misoprostol (4 x 200 mcg buccal, 24-48 hours later) Use • More effective than levonorgesterol (plan B) * –
approx. 60%
ADVERSE EFFECTS: • May retain efficacy for up to 5 days
• Headache, NVD SEs • Headache, abdominal discomfort, and slight delay
• Risk of: in onset of menstrual bleeding (2-3 days)
o Infections and sepsis (rare) Dosage • Ella 30 mg tablet (single dose)
o Prolonged heavy bleeding if incomplete * Plan B delays or inhibits the LH peak by -ve feedback, if given before
o Embryotoxicity if ineffective the start of the LH surge
* there is NO delay in return of fertility