Download Physiologic and Metabolic effects

Drugs for Reproductive
Endocrinology:
Focus on OCP therapeutics
Ma. Stephanie Fay S. Cagayan, MD, FPOGS
General Objective
To acquire an understanding of the
action of the different sex hormones
and other hormones utilized in the
pharmacology of hormonal
contraception
Reference: Chapter 40, Basic and Clinical
Pharmacology 1th edition (Katzung)
Specific Objectives
1.
2.
3.
4.
To be able to review the physiology of
normal menstrual cycle
To list the different sex hormones, know
their biosynthesis (chemical
compositions), mechanism of action,
pharmacokinetic properties, physiologic
and metabolic effects
To describe clinical/therapeutic
applications of these hormones
To list side effects and/or adverse
reactions to these drugs
Outline
I.
II.
Physiology of Reproductive Hormones
Female Gonadal Hormones
Estrogen and Progesterone
ORAL CONTRACEPTION
Different Hormones in
Reproductive Endocrinology
Biosynthesis (chemical compositions)
 Mechanism of action
 Pharmacokinetic properties
 Physiologic and Metabolic effects
 Clinical / Therapeutic Application
 Adverse Effects

Outline
I.
II.
Physiology of Reproductive
Hormones
Female Gonadal Hormones
Estrogen and Progesterone
ORAL CONTRACEPTION



Sex hormones = gonadal hormones
estrogens
progestins
androgens
Gonadotropins
LH
FSH
GnRH
Gonadal Hormones

SYNTHESIS OF
SEX STEROIDS
Gonadal Hormones
SEX HORMONES:
1. 21 carbon series – PROGESTINS
(pregnane nucleus)
2. 19 carbon series - ANDROGENS
(androstane nucleus)
3. 18 carbon series - ESTROGENS (estrane
nucleus)

What regulates the synthesis of sex hormones?
Hypothalamic-Pituitary-Gonadal
Axis
Hypothalamic-Pituitary-Reproductive Axis: TWO CELLSYSTEMS
(Testosterone)
(Androstenedione)
Hypothalamic-Pituitary-Reproductive Axis: TWO CELLSYSTEMS
MALE
LH
FSH
Leydig
Sertoli
Testosterone
Increases
production of ABP
synthesis
FEMALE Theca
Spermatogenesis
Granulosa
Androstenedione Increases
synthesis
aromatase activity
Prerequisites of Normal
Menstruation





an intact HPO axis
estrogen-induced
proliferative endometrium
ovulation at midcycle
progesterone-induced
secretory endometrium
if pregnancy does not
occur, the hormones
decline, and withdrawal
bleeding occurs
CH 3
OH
H
H
H
CH3
HO
ESTRADIOL
O
H
H
H
CH3
OH
HO
H
ESTRONE
H
OH
H
HO
ESTRIOL


The Estrogens
Major natural estrogens in human
Actions mediated by ESTROGEN RECEPTORS (alpha and
beta) which are ligand-regulated transcription factors
Some synthetic estrogens
The Estrogens
Biosynthesis (chemical compositions)
 Mechanism of action
 Pharmacokinetic properties
 Physiologic and Metabolic effects
 Clinical / Therapeutic Application
 Adverse Effects

Steroid Hormone and its
Receptor
Estrogen Receptor

Actions mediated by ESTROGEN
RECEPTORS (alpha and beta) which are
ligand-regulated transcription factors
The Estrogens:
Pharmacokinetics



Estradiol (E2) binds STRONGLY to α globulin (SHBG)
LOWER affinity to albumin
E2 (liver) → Estrone (E1) and Estriol(E3) → hydroxylated
derivatives and conjugated metabolites
Orally administered estrogens have HIGH ratio of hepatic
to peripheral effects
→ responsible for the increased clotting factors and
increased renin substrate

Clinical / Therapeutic
Application

Primary hypogonadism

Hormonal contraception

Post-menopausal hormonal therapy
The Estrogens
Biosynthesis (chemical compositions)
 Mechanism of action
 Pharmacokinetic properties
 Physiologic and Metabolic effects
 Clinical / Therapeutic Application
 Adverse Effects

Adverse Effects
Uterine bleeding
 Endometrial cancer
 Other effects: nausea, breast
tenderness

The Natural Progestins:
Progesterone
 The most important progestin in human
 Serves as a precursor to the estrogens,
androgens and adrenocortical steroids
 Synthesized in the ovary, testis and adrenal
from circulating cholesterol; large amounts
are also synthesized and released by the
placenta during pregnancy
The Synthetic Progestins
21 carbon
compounds




Hydroxyprogesterone
acetate
Medroxyprogesterone
acetate
Megestrol
Dimethisterone
* Most closely related to
progesterone
19-nor, 13 ethyl
compounds



Desogestrel
Gestodene
Norgestimate
** claimed to have lower
androgenic activity
than older synthetic
progestins
The Progestins
Actions are mediated by progesterone receptors (A and B
isoforms) which are ligand-activated transcription factors
 The concentration of progesterone receptors is dependent on
previous estrogen action

The Progestins
Biosynthesis (chemical compositions)
 Mechanism of action
 Pharmacokinetic properties
 Physiologic and Metabolic effects
 Clinical / Therapeutic Application
 Adverse Effects

The Progestins: Pharmacokinetics
Progesterone





is rapidly absorbed following administration by any
route
t ½ is 5minutes
Almost completely metabolized in one passage
through the liver
In the liver, it is metabolized to pregnanediol and
conjugated with glucuronic acid
It is excreted into the urine as pregnanediol
glucuronide
The Progestins
Biosynthesis (chemical compositions)
 Mechanism of action
 Pharmacokinetic properties
 Physiologic and Metabolic effects
 Clinical / Therapeutic Application
 Adverse Effects

Physiologic Effects
 Decreases amount of
cervical mucus and
increases its viscosity

Promote endometrial
development during luteal phase
 Increases basal body
temperature
The Physiologic Effect of
Progestins
Progesterone
ATTENUATES
estrogen action
on the
endometrium in
3 ways:



By reducing the rate of
synthesis of ER
molecules
By increasing the rate of
enzymatic inactivation
By effecting estrogen
inactivation through
sulfuration
The Physiologic Effect of
Progestins
Physiologic Effects:
Progesterone
Has little effect on protein metabolism
 Has more marked effect on
carbohydrate metabolism:
progesterone INCREASES basal
insulin levels and the insulin response
to glucose
 Antagonize actions of aldosterone

Physiologic Effects:
Progesterone
Increases body temperature
 Has depressant and hypnotic effects on
the brain
 Increases ventilatory response to CO2
 Stimulate growth and development of
breasts during pregnancy
 Its effects on the uterus are essential
for maintenance of pregnancy

Clinical Application
THERAPEUTIC APPLICATION:
 Hormonal contraception
 Hormonal replacement therapy
 Endometriosis
Clinical Application:
D
I
A
G
N
O
S
T
I
C

A test of estrogen secretion:
Progesterone challenge test MPA 10mg/d for 5 days
- when endometrium has been
stimulated by estrogens  
(+) withdrawal bleeding
Adverse Effects
Headache
 Dizziness
 Bloating
 Weight gain
 Reversible reduction of glucose
tolerance

Hormonal contraception in
women
Combination of progestins and
estrogens – Combination oral
contraceptives (COCs)
 Progestin only pills (POPs)

The Pharmacology of the Estrogen
Component of COCs
E2 is the most potent natural estrogen --inactive orally
 E2 + ethinyl group at the 17 position =
Ethinyl Estradiol
--orally active

The Pharmacology of the Estrogen
Component of COCs



Metabolism of EE VARIES SIGNIFICANTLY
from individual to individual, and from one
population to another
ESTROGEN CONTENT of the pill is of major
clinical importance ---- THROMBOSIS is doserelated
DOSE OF ESTROGEN – a critical issue in
selecting an oral contraceptive
42
COMBINATION ORAL
CONTRACEPTIVES (COCS) –
PROGESTIN COMPONENT
The Pharmacology of the Progestin
Component of COCs
2 major types of synthetic progestins
1. Derivatives of 19 nortestosterone
2. Derivatives of 17α acetoxyprogesterone

The Pharmacology of the Progestin
Component of COCs
TESTOSTERONE
ETHISTERONE
NORETHINDRONE
Removal of 19-carbon from ethisterone formed
NORETHINDRONE → changed major hormonal effect
from an androgen to progestational agent
→ 19 nortestosterone - all progestational agents have
some degree of androgenic activity

The Pharmacology of the Progestin
Component of COCs
19 NORTESTOSTERONE
GONANES
ESTRANES
 Levonorgestrel
 Norethindrone
 Norgestimate*
 Norethynodrel
 Gestodene*
 Norethindrone
acetate
 Desogestrel*
 Ethynodiol acetate
* With greater
progestational
activity
The Pharmacology of the Progestin
Component of COCs
Other progestins
 Levonorgestrel is the active isomer of
norgestrel
New progestins
•


Desogestrel, gestodene, norgestimate are derivatives of
levonorgestrel
Reduced androgenicity (increased sex
hormone binding globulin, decreased free
testosterone)
Drospirenone – analogue of spironolactone,
has affinity for mineralocorticoid receptor and
antimineralocorticoid effect (Yasmin)
The Pharmacology of the Progestin
Component of COCs
17 α ACETOXYPROGESTERONE





C21 progestins
PREGNANES
Structurally related to progesterone
Medroxyprogesterone acetate and megestrol
acetate
Marketed for noncontraceptive usage
COCs
“ Current formulations of
COCs are made from
SYNTHETIC steroids and
contain no natural
estrogens or progestins.”
Ethinyl estradiol
synthetic progestins
Definitions
Low Dose Oral Contraceptives – products with
<50ug of EE
1st generation COCs – products with > 50ug of EE
2nd generation COCs – products with
levonorgestrel,norgestimate, and other
members of the norethindrone family and <50ug
EE
3rd generation COCs – products with desogestrel
or gestodene and <50ug of EE
Types of COCs





Usually containing ethinyl estradiol and
norethindrone
Administered with interruption (21 days on, 7 days
off)
Monophasic: All 21 active pills contain same
amount of Estrogen/Progestin (E/P)
Biphasic: 21 active pills contain 2 different E/P
combinations (e.g., 10/11)
Triphasic: 21 active pills contain 3 different E/P
combinations (e.g., 6/5/10)
COCs Mechanism of Action
Estrogen suppresses FSH secretion
Suppress ovulation
Progestin suppresses LH secretion
Reduce sperm transport in
upper genital tract
(fallopian tubes)
Change endometrium making
implantation less likely
Thicken cervical mucus
(preventing sperm
penetration)
P
r
o
g
e
s
t
i
n
the effect of a progestational agent will always take precedence over estrogen
Estrogen in the COCs
ESTROGEN serves 2 other purposes:
1)
2)
it provides STABILITY to the endometrium so that
irregular shedding and unwanted breakthrough
bleeding can be minimized
It potentiates the action of the progestational agents -allowed reduction of the progestational dose in the pill
 increasing the concentration of intracellular
progestational receptors.
* Therefore a minimal pharmacologic level of estrogen is
necessary to maintain the efficacy of the COCs
Oral Contraceptive Pills
COCs: Efficacy





Perfect use failure rate: 0.1%
Typical use failure rate: 7.6%
Pregnancies usually occur because initiation of
the next cycle is delayed
Strict adherence to 7-pill free days is critical to
obtain contraception
If with vomiting & diarrhea → back-up method for
7days→ put pill in the vagina
COCS: METABOLIC
EFFECTS
COCs: Metabolic Effects Thrombosis
Thrombosis can be divided into 2 major
categories:
1. Venous thromboembolism
deep vein thrombosis
pulmonary embolism
2. Arterial
thrombosis
myocardial infarction
stroke
COCs: Metabolic Effects Thrombosis




Pharmacologic estrogen increases the production of
clotting factors (II, VII, IX, X)
Progestins have no significant impact on clotting
factors
Past users of oral contraceptives DO NOT have an
increases incidence of cardiovascular disease
Hypertension is a very important additive risk factor
for stroke in OC users
COCs: Metabolic Effects Thrombosis




All low dose OCs, regardless of progestin type,
have an increased risk of VTE, concentrated in the
1st 2 years of use
Recent studies reinforce the belief that the risks of
arterial and venous thrombosis are a consequence
of the ESTROGEN component of COCs
Smoking has a lesser effect on the risk of venous
thrombosis compared with arterial thrombosis
Smoking and estrogen have an additive effect on
the risk of arterial thrombosis
COCs: Metabolic Effects Thrombosis

Low dose OCs DO NOT increase the risk of MI
or stroke in healthy, non-smoking women,
regardless of age

Almost all MI and strokes in OC users occur in
users of HIGH dose products or users WITH
CARDIOVASCULAR RISK FACTORS

Cardiac deaths occurred in only in women who
smoked >15 cigarettes per day
COCs: Metabolic Effects Thrombosis


New studies emphasize the importance of good
patient screening
- arterial thrombosis is limited to older women
who smoke or have cardiovascular risk factors
- no increase in mortality due to MI or stroke
in healthy,non-smoking women
If a patient has a family history of idiopathic
thromboembolism, an evaluation to search for an
underlying abnormality in the coagulation system
is warranted
COCs: Metabolic Effects - Conclusion
“ LOW DOSE oral contraceptives
are VERY SAFE
for healthy young women.”
COCs : Carbohydrate
Metabolism




Older high dose OCs – (+) impaired glucose
tolerance
Insulin sensitivity is affected mainly by the
PROGESTIN component of the pill
Glucose intolerance is dose-related
Insulin and glucose changes with low dose
monophasic and multiphasic OCs are so
minimal and clinically insignificant
COCs : Carbohydrate
Metabolism
“ It can be stated definitely that
oral contraceptive use
DOES NOT produce an
increase in diabetes mellitus.”
COCs: The Risk of Breast
Cancer
Current and recent (1-4years) use of OCs
may be associated with 20% increased risk
of early (<35) premenopausal breast cancer,
essentially limited to localized and a very
small increase in the number of actual cases
May be due to:
1.) detection/surveillance bias
2.) accelerated growth of already present
malignancies

COCs: The Risk of Breast
Cancer




NO EFFECT of past use or duration of OC use (up
to 15 years of continuous use)
NO INCREASED RISK on use of high dose OCs
Previous use may be associated with a REDUCED
RISK of metastatic cancer LATER in life, and
REDUCED RISK of postmenopausal breast cancer
NO INCREASED RISK in women with positive
family history for breast cancer/women with benign
breast disease
68
COCs: Contraceptive Benefits







Most important use is for ORAL
CONTRACEPTION
Pelvic examination not required to initiate use
Do not interfere with intercourse
Few side effects
Convenient and easy to use
Client can stop use
Can be provided by trained non-medical staff
COCs: Noncontraceptive
Benefits
1.
2.
Incidental benefits
Benefits to treat and manage problem
and disorders
69
COCs: Incidental Benefits

LESS ENDOMETRIAL CANCER
Use for 12 months reduces the risk by
50%
Greatest protective effect if use for >3
years

LESS OVARIAN CANCER
Risk is reduced by 40% (3 years) to 80% (>10 years of
use)
COCs: Incidental Benefits






Fewer ectopic pregnancies
More regular menses – less flow,
dysmenorrhea, anemia
Less salpingitis
Increased bone density
Possibly less benign breast disease
Possibly fewer ovarian cysts
COCs: Noncontraceptive
Benefits
1.
2.
Incidental benefits
Benefits to treat and manage problem
and disorders
Dysmennorhea
Endometriosis
Replacement therapy in ovarian dysfunction
DUB
Postmenopausal symptoms
72
COCs: Absolute
Contraindications
1.
2.
3.
4.
5.
6.
7.
8.
Thrombophlebitis, thromboembolic disorders,
cerebrovascular disease, coronary occlusion
or past history of these conditions
Severe hypercholesterolemia or
hypertriglyceridemia
Untreated hypertension
Smokers over the age of 35
Known or suspected breast cancer
Markedly impaired liver function
Undiagnosed abnormal vaginal bleeding
Known or suspected pregnancy
COCs: Relative
Contraindications
1.
2.
3.
4.
5.
6.
7.
8.
9.
Systemic lupus erythematosus
Sickle cell disease
Gestational diabetes mellitus
Diabetes mellitus
Hyperlipidemia
Controlled hypertension
Smoking
Migraine headaches
Seizure disorder
COCs: Relative
Contraindications
10.
11.
12.
13.
14.
15.
Hepatic disease
Obstructive jaundice in pregnancy
Gallbladder disease
Mitral valve prolapse
Uterine leiomyomas
Elective surgery
Clinical Decisions: Surveillance






Can be prescribed without a clinical breast and
pelvic examination
Patients need be seen only every 12months
Perform yearly breast and pelvic examination on
follow up
Reassess new users within 1-2months
“ COCs are safer than most people think. ”
FEAR OF SIDE EFFECTS: most common reason
why patients discontinue oral contraception
Clinical Decisions: Surveillance


Laboratory surveillance should be used only
when indicated
The ff patients should be monitored with blood
screening tests for glucose, lipids and
lipoproteins:
Young women, at least once
Women >35 y/o
Women with strong family history of heart disease, DM,HPN
Women with GDM
Obese women
Diabetic women
COCs: Choice of Pill

The therapeutic principle remains:
“ Utilize the formulations that give
effective contraception and the
greatest margin of safety.”


Current data support that there is GREATER
safety with low dose preparations
There is LITTLE difference between the low
dose monophasics and the multiphasics
89
Progestin-Only Pills
(POPs)
POPs: Mechanisms of Action
Suppress ovulation
(not consistently suppressed)
? Reduce sperm transport in upper
genital tract (fallopian tubes)
Change endometrium making
implantation less likely
Thicken cervical mucus
(preventing sperm penetration)
POPs: Mechanisms of Action




Contains a small dose of a progestational agent
Must be taken daily in a continuous fashion
Must be taken every day of the SAME TIME
Change in cervical mucus
- requires 2-4hours to take effect
- impermeability diminishes 22 hours after
administration
- by 24hours sperm penetration is essentially
unimpaired
POPs: Contraceptive Benefits









Pelvic examination not required prior to use
Do not interfere with intercourse
Do not affect breastfeeding
Immediate return of fertility when stopped
Few side effects
Convenient and easy-to-use
Client can stop use
Can be provided by trained nonmedical staff
Contain no estrogen
93
POPs: Noncontraceptive
Benefits
May decrease menstrual cramps
 May decrease menstrual bleeding
 May improve anemia
 Protect against endometrial cancer
 Decrease benign breast disease
 Decrease ectopic pregnancy
 Protect against some causes of PID

94
POPs: Clinical Decisions

1.
2.
2 situations in which excellent efficacy is achieved:
Lactating women
- no evidence of any adverse effect on
breastfeeding
- women breastfeed longer and add
supplementary feeding at a later time
- can be started IMMEDIATELY after delivery
Women age over 40
Postcoital contraception
Types:
estrogen (ethinyl estradiol) + progestin
(norgestrel); estrogen alone
progestin alone
 High doses but for a few days
 Effectiveness: 90-98% if taken within 72
hours of unprotected intercourse

Post-coital contraception

Mechanism of action
• If fertilization has occurred: prevents
•

implantation, promotes menstrual bleeding
If fertilization has not occurred: decrease the
amount and increase the viscosity of cervical
mucus, suppress the hypothalamic-pituitarygonadal axis, impair ovum transport
Adverse effects
• nausea and vomiting, headache, dizziness,
breast tenderness, abdominal and leg cramps
Schedules for Use of Post-coital
Contraceptives
Conjugated
Estrogens
10mg TID for 5 days
Ethinyl Estradiol
2.5mg BID for 5 days
Mifepristone
L-Norgestrel
600mg once (with Misoprostol 400
ucg once)
0.75mg BID for 1 day
Norgestrel
EE
0.5mg 2 tab and
0.05mg 2 tabs in 12 hours