Hormonal Contraceptives

Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and
progesterone, which may be used either in combination or in progestin-only formulations for
contraception. These formulations act synergistically to produce antiovulatory effects and can also
affect the endometrial lining (typically decreasing bleeding and pain associated with menstruation),
which is why they are also used to treat a variety of gynecologic issues. Available formulations include
oral contraceptive pills (combined and progestin-only), transdermal patches, vaginal rings, progestin
injections, subdermal implants, and intrauterine devices. Common adverse effects include nausea,
headaches, mood changes, and irregular bleeding. Importantly, estrogens increase the risk of venous
thromboembolism (VTE) and are contraindicated in individuals at risk for VTE. Other important
contraindications include pregnancy, liver disease, and breast cancer.

Last updated: February 6, 2023

CONTENTS

Overview
Pharmacodynamics
Classification
Pharmacokinetics
Indications
Adverse Effects and Contraindications
Comparison of Different Contraceptive Methods
References

Overview
Components
Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones
estrogen and progesterone. HCs may contain either:

Progestin + estrogen
Progestin alone

Choice of contraception
The choice of contraceptive method is very individual and often is dictated by a variety of
factors, including:

Ease of access and use (e.g., dosing regimen, required procedures)

Affordability
Efficacy rate
Reversibility or permanence
Prevention of STIs
Adverse effects
Medical contraindications

Comparison of the effectiveness of hormonal and nonhormonal contraceptive methods

Image by Lecturio.

Chemistry
Both estrogens and progestins are steroid hormones, making them fat-soluble.

Ethinyl estradiol (EE):

Very similar in structure to natural estradiol

Addition of an ethynyl group makes it significantly more stable (i.e., steric hindrance resists
metabolic degradation) than estradiol.
↑ Bioavailability as compared with estradiol when taken orally
EE is the only estrogen used in HCs (though dosage varies).
Progestins:
 Similar in structure to natural progesterone
Addition of a triple bond in most cases makes the molecules more stable.
Androgenic effects:
Most are derived from testosterone → have stronger androgenic effects than natural
progesterone
Major exception: drospirenone
Spironolactone analog
Has antiandrogenic activity
Multiple different progestins are used in HCs → different properties of the progestins are
responsible for different side-effect profiles of various HCs

Chemical structures of different progestins

Image A: “Progesterone” by Rhododendronbusch. License: Public Domain

Image B: “Norethisterone acetate” by Fvasconcellos. License: Public Domain
Image C: “Levonorgestrel” by Ayacop. License: Public Domain
Image D: “Etonogestrel” by Edgar181. License: Public Domain
Image E: “Desogestrel” by Fvasconcellos. License: Public Domain
Image F: “Drospirenone” by Fvasconcellos. License: Public Domain
Pharmacodynamics
Normal physiology of the menstrual cycle
Understanding hormonal regulation of ovulation and the menstrual cycle is key to understanding
the mechanisms of HCs. This regulation is primarily by the hypothalamic-pituitary-ovarian (HPO)
axis.
HPO axis:
Hypothalamus secretes gonadotropin-releasing hormone (GnRH).
Pituitary secretes:
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Ovary secretes:
Estrogen
Progesterone
Follicular/proliferative phase (1st phase of menstrual cycle):
GnRH pulse stimulates the release of FSH.
FSH stimulates follicular development within the ovaries.
Developing follicles produce estrogen, specifically estradiol.
Estrogen:
Stimulates endometrial proliferation
Inhibits FSH secretion (feedback inhibition)
Stimulates bone growth
Ovulation:
Triggered by a midcycle surge of LH
Luteal/secretory phase:
The ovulated follicle is now called the corpus luteum.
The corpus luteum produces both estradiol and progesterone.
Progesterone:
Stabilizes endometrium
Causes endometrium to mature into secretory endometrium, capable of sustaining
a pregnancy
Study tip: progesterone = “progestational hormone” → produced only after
ovulation, when gestation is possible
Estradiol and progesterone are secreted for approximately 14 days after ovulation (time
for a fertilized embryo to implant).
If pregnant: corpus luteum continues producing progesterone until the placenta can take
over.
If not pregnant: corpus luteum involutes → estradiol and progesterone levels fall
Menstrual phase:
Loss of stabilizing hormones (particularly progesterone) triggers breakdown of the
endometrium → menses
Key point: Progesterone withdrawal triggers bleeding.
 Diagram showing the correlation between the ovarian cycle and the endometrial cycle

Image by Lecturio.

Mechanism of action of hormonal contraceptives

Both estrogens and progestins cause an antiovulatory effect. When used together, this effect is
synergistic.

Estrogen component:
Inhibits FSH release → prevents the selection and maturation of the dominant follicle =
no ovulation
Would stimulate endometrial proliferation if given alone/without progestins (this is why EE
is not given alone)
Progestin component:
Inhibits LH surge that is necessary for ovulation
Effects on the endometrium:
Natural progesterone is required to make the endometrium healthy for pregnancy;
however, the androgenic nature of synthetic progestins thins the endometrial
lining, making it unsuitable for implantation.
All HCs are “progestin-dominant” as compared to estrogen → overall endometrial
effect of HCs is endometrial atrophy
↑ Cervical mucus viscosity → inhibits sperm transport into the uterus
↓ Cilia motility in the fallopian tube
Classification
Hormonal contraceptives can be grouped by the length of their action and route of
administration. These contraceptives are then classified in different ways, including by their
components and dosages.

Short-acting contraceptives
This category includes pills, patches, rings, and injections. Several common combinations and
brand names in each category are given as examples, though there are many different brand
names for each.
Combined oral contraceptive pills (COCP; EE + progestin):
Daily administration
Classification by progestin:
1st generation (estranes): EE/norethindrone acetate
2nd generation (gonanes): EE/norgestrel, EE/levonorgestrel
3rd generation: EE/desogestrel, EE/norgestimate
4th generation/unclassified: EE/drospirenone (e.g., Yaz®)
Classification by number of “phases”:
Monophasic: Each pill in the pack contains the same amount of hormone.
Triphasic: The amount of hormone varies from pill to pill in the pack.
Many different EE/progestin combinations can come in both monophasic and
triphasic packs.
Progestin-only pills (POPs):
Daily administration
Hormones: norethindrone acetate, drospirenone
Transdermal patch:
Weekly administration (i.e., 1 patch applied per week)
Hormones: EE/norelgestromin
Vaginal ring:
“Monthly” administration (i.e., 1 ring inserted for 3 weeks)
Hormones: EE/etonorgestrel (e.g., NuvaRing®)
Progestin contraceptive injections:
“Quarterly” administration (i.e., 1 injection every 3 months)
Hormones: depot medroxyprogesterone acetate (DMPA, e.g., Depo-Provera®)

Long-acting reversible contraceptives (LARCs)

 Subdermal contraceptive implants (etonogestrel implant):
Nexplanon®: lasts 3 years
Intrauterine device (IUDs): levonorgestrel IUDs
Mirena®, Liletta® (52 mg of levonorgestrel): last 5–7 years
Kyleena® (19.5 mg of levonorgestrel): lasts 5 years
Skyla® (13.5 mg of levonorgestrel): lasts 3 years

Emergency contraception
Refers to contraception administered after unprotected intercourse (UPI; called “the morning
after pill”). These options act to prevent fertilization and/or implantation and are not used as
postimplantation abortifacients.
Insertion of an IUD:
More effective than oral methods
Provide ongoing contraception
Not impacted by BMI or risk of pregnancy (e.g., UPI midcycle, multiple episodes of UPI)
Options:
Copper IUD (Paragard®)
Levonorgestrel 52-mg IUD
Oral methods:
Less effective in individuals with BMI > 30
Less effective in individuals at higher risk of pregnancy
Options:
Ulipristal acetate (can be used up to 5 days after UPI)
Oral levonorgestrel (can be used up to 3 days after UPI)

Pharmacokinetics
Methods of administration
 Hormone-free interval:
Pills/patches/rings containing hormones are typically used for 21–24 days in a row (
ovulation and endometrial growth are suppressed during this time).
This is followed by a hormone-free interval (HFI):
Typically 4–7 days in length
Pill packs include placebo pills during the HFI; the patch/ring is withheld during this
time.
Withdrawal of the progestin triggers a withdrawal bleed (similar to menses), which
is why skipping pills can lead to irregular bleeding.
Cyclic administration:
Hormones taken for 21–24 days followed by 4–7-day HFI
Results in monthly withdrawal bleeding
Prolonged cyclic administration:
Hormones taken for up to 84 days (12 weeks) followed by a 4–7-day HFI
Results in withdrawal bleeding only during the HFIs (typically 4 times per year)
Some brands are designed this way, though any monophasic pill, the patch, and the ring
can be used this way.
Hormone use can be extended beyond 12 weeks if tolerated by the patient.
Continuous administration:
Hormones are taken continuously, with no HFI.
Monophasic pills, the patch, and vaginal ring can all be administered this way.
Completely suppresses menstruation and symptoms associated with hormone
fluctuations (e.g., menstrual migraines)
Higher risk of breakthrough bleeding owing to prolonged endometrial atrophy
Emergency contraception:
Taken as a single course as soon as possible after UPI
Specific regimens depend on days from UPI and medications/methods chosen.

Ethinyl Estradiol
Absorption:
Rapid absorption via any route (e.g., oral, topical, and vaginal)
Oral bioavailability: approximately 50% (estradiol is only approximately 5%)
Distribution:
Highly protein-bound: approximately 98% (primarily albumin; unlike estradiol, EE does not
bind well to sex hormone–binding globulin (SHBG))
Steroid hormones → distributed throughout the body
Metabolism:
High 1st-pass metabolism (though significantly less than for estradiol)
Conjugated via glucuronidation and sulfation to inactive metabolites
Also hydroxylated via CYP3A4
Enterohepatic recirculation occurs
Excretion:
Oral half-life: approximately 10–16 hours
Fecal: 60%
Urine: 40%

Progestins
 Absorption:
High oral bioavailability
IUD components have low (but some) systemic absorption.
LARCs secrete decreasing amounts of progestins daily the longer they are in place.
Distribution:
Highly protein-bound
Some bind more to albumin; others bind more to SHBG.
Metabolism:
Most undergo 1st-pass hepatic metabolism to inactive metabolites.
Some are metabolized by the CYP450 system.
Enterohepatic recirculation can occur.
Excretion:
In both urine and feces
Oral half-life: approximately 20–40 hours

Indications
Contraception
Abnormal uterine bleeding (e.g., heavy, prolonged, or frequent bleeding)
Good options:
COCPs/patch/ring
Levonorgestrel IUDs
Generally avoided owing to higher risks of abnormal bleeding:
POPs
DMPA
Etonorgestrel implant
Dysmenorrhea and/or endometriosis
Polycystic ovarian syndrome
Premature ovarian insufficiency (i.e., premature menopause)
Other specific indications:
Menstrual symptoms (especially menstrual migraines and premenstrual syndrome (PMS)):
continuous COCPs/patch/ring
Hirsutism: COCPs containing the antiandrogenic progestin drospirenone
Endometrial hyperplasia: levonorgestrel 52-mg IUDs

Adverse Effects and Contraindications

Adverse effects
Most of the adverse effects can be seen with either EE or progestins and are possible with any
of the HC methods.
 Risk of venous thromboembolism (VTE):
Significantly greater risk with EE than with progestins
Ethinyl estradiol should be avoided in people at risk for VTE; progestin-only methods are
recommended for these individuals.
Note: Most progestins list VTE as a potential risk/contraindication as well, though large
studies suggest that there is no significantly increased risk in progestin-only
contraceptive users.
Abnormal bleeding (e.g., unscheduled bleeding, prolonged bleeding)
Estrogen tends to stabilize bleeding patterns, so this is more often associated with
progestin-only methods
Worst with etonogestrel implant
Nausea/vomiting
Acne
Headaches/migraines
Mood changes
Decreased libido
Altered lipid metabolism and insulin effects
Breast symptoms:
Fibrocystic breast changes
Mastalgia (breast pain), especially cyclic
Decreased breast milk production during breastfeeding (EE only)
Ovarian cysts (progestin-only methods, since EE generally suppresses cyst formation)
Unique adverse effects:
Vaginal ring: ↑ vaginal discharge
DMPA injections: bone loss (reversible)
Implant: high association with irregular bleeding as compared with other methods
IUDs:
Pelvic pain
Endometritis
Uterine perforation
If pregnancy occurs, significantly ↑ risk of that pregnancy being ectopic (though the
absolute rate of ectopic pregnancy is lower in IUD users than in individuals on no
contraception)

Drug interactions of combined oral contraceptive pills and

progestin-only pills
The metabolism of COCP and POPs is increased by any drugs that increase liver microsomal
enzyme activity, resulting in reduced contraceptive efficacy. These drugs include:
 Anticonvulsants:
Phenytoin
Carbamazepine
Barbiturates
Topiramate
Felbamate
Oxcarbazepine
Lamotrigine (HC retains efficacy but concentrations of lamotrigine are ↓ )
Antimicrobials:
Rifampin
Rifabutin
The vast majority of antibiotics do not interact with HCs.
Antiretroviral drugs
Nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz)
Protease inhibitors (e.g., ritonavir)

Contraindications
The “Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use” by the Centers for
Disease Control and Prevention (CDC) notes the specific risks of each contraceptive method and
> 100 different conditions. This document is a critical resource when determining the safety of a
particular method for a specific individual. The most important contraindications are noted below.

EE-containing HCs (COCPs/patch/ring):

Pregnancy
Current, history of, or risk factors for, VTE, including:
< 21 days postpartum
Smoking in women > 35 years
Certain coagulopathies
Systemic lupus erythematosus (SLE)
Cardiovascular disease:
Hypertension
Ischemic heart disease
Peripartum cardiomyopathy
Valvular heart disorders with complications
Migraines with aura
Undiagnosed abnormal uterine bleeding (AUB)
Current or past breast cancer
Liver disease, including:
Decompensated liver cirrhosis
Hepatocellular adenoma
Liver cancer
Diabetes > 20 years or with vascular disease (neuropathy, nephropathy, retinopathy)
Hypertriglyceridemia
Solid-organ transplantation with complications

Progestin-only HCs:

Generally preferred methods in patients at risk for VTE. Beyond that, contraindications are similar
to EE-containing HCs and include:
 Pregnancy
Current or past breast cancer
Undiagnosed AUB
Liver disease
Additional contraindications specific to IUDs:
Uterine anomalies
Pelvic inflammatory disease (PID) or endometritis
Acute cervicitis or vaginitis (e.g., Chlamydia trachomatis or bacterial vaginosis infections
at the time of planned IUD insertion)

Comparison of Different Contraceptive Methods

Table: Comparison of different contraceptive methods

Method Major downsides Reasons to pick this method

Method Major downsides
COCPs More contraindications,
especially:
VTE risk
Migraines with aura
Cardiovascular disease,
including hypertension
Requires daily administration
to be most effective
Side effects are common.
Patch Same contraindications as
COCPs
Some find the patch irritating
to the skin or find that it
comes off easily.
Vaginal ring Same contraindications as
COCPs
↑ Risk of physiologic vaginal
discharge
Vaginal insertion may be
difficult for individuals who
are virgins
May fall out more easily in
multiparous individuals
POPs Least effective HC
Higher risk of irregular
bleeding
DMPA injection Higher association with
mood disturbances
Causes bone loss → avoid
using for > 2 years
consecutively
Requires an appointment
every 3 months
Reasons to pick this method
↑ Degree of patient
control
Easy to use, accessible,
and affordable
Well tolerated by many
Decreases the risk of
ovarian cancer
Control of menstrual
cycles
Same reasons as COCPs,
but:
Individual doesn’t like
taking pills.
Individual likes the idea of
weekly rather than daily
administration
Same reasons as COCPs,
but:
Individual prefers monthly
rather than daily
administration.
Potentially fewer systemic
side effects than COCPs
Same benefits as COCPs,
but without the risks
associated with EE
Good option in
breastfeeding individuals
If individuals can make it to
appointments, does not
require additional effort.
Lasts 3 months
May be a good option in
teenagers and individuals
immediately postpartum
Method Major downsides
Etonogestrel Highest risk of undesirable
implant irregular bleeding
Requires a procedure
Levonorgestrel Risk of uterine perforation
IUDs Requires a procedure that
may be uncomfortable
(especially in nulliparous
patients)
Copper IUD Same as levonorgestrel IUDs
Plus: ↑ menstrual bleeding
(periods should be regular,
but they are often heavier
and/or longer)
Sterilization Requires surgery
Permanent
Still not 100% effective
Reasons to pick this method
The most effective
reversible contraceptive
available
Lasts up to 3 years
(evidence suggests
effective up to 5 years)
Requires no additional
effort by patient
Highly effective, including
as emergency
contraception
Lasts 3–7 years
Requires no additional
effort by patient
Can significantly reduce
menstrual bleeding
Systemic side effects are
much less common (e.g.,
headaches, nausea, mood
symptoms).
The only highly effective
hormone-free reversible
contraceptive option
Essentially no systemic
side effects
Lasts 10–12 years
Permanent
Hormone-free (no systemic
side effects)
No effect on bleeding
profile
↓ Risk of ovarian cancer
 Method Major downsides Reasons to pick this method

Barrier method Least effective method Provides protection

Requires consistent, correct against STIs
use Easy to use, accessible,
and affordable
Hormone-free option
Good when combined with
another method (e.g.,
lactational amenorrhea in
breastfeeding mothers)

References