How do oral contraceptives (OCs) affect serum hormone levels?

Effects of Oral Contraceptives on Serum Hormone Levels

Combined oral contraceptives (COCs) significantly alter serum hormone levels by suppressing gonadotropins, increasing sex hormone-binding globulin, and reducing free androgen levels, while progestin-only contraceptives have more limited hormonal effects. 1

Primary Hormonal Effects of COCs

Gonadotropin Suppression

• COCs inhibit folliculogenesis through central suppression of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) 2, 1
• FSH levels are rapidly suppressed from day 2 of the pill cycle onward 3
• LH levels progressively decline during active pill days, with significant suppression occurring after day 8 with monophasic pills 3
• The number of LH pulses decreases while pulse amplitude may increase during active pill use 3

Sex Hormone Effects

• COCs significantly increase sex hormone-binding globulin (SHBG) production 1
• Increased SHBG binds to testosterone, reducing free androgen levels 1
• Total testosterone and free androgen index are reduced 1
• COCs suppress ovarian androgen production 2, 1
• Estradiol (endogenous) concentrations decrease during active pill consumption 4
• Ethinyl estradiol (exogenous) levels peak around days 20-21 of active pill ingestion 4

Renin-Angiotensin-Aldosterone System Effects

• The estrogen component of COCs stimulates hepatic production of angiotensinogen, leading to RAAS activation 1
• Higher doses of ethinyl estradiol (50 μg) double plasma angiotensinogen levels, while lower doses (30-35 μg) increase levels by 12-20% 1

Differences Between COC Formulations

Estrogen Component

• Ethinyl estradiol is the most common estrogen in COCs, with daily doses typically ranging from 10-50 μg 2
• Higher estrogen doses have greater effects on the RAAS system and potentially greater risk of thrombosis 2, 1
• Newer formulations containing natural estrogens like estradiol valerate and estetrol may have fewer effects on the RAAS system 1

Progestin Component

• Different generations of progestins have varying androgenic potential 2
• First and second-generation progestins (norethindrone, levonorgestrel) have higher androgenic potential 2
• Third-generation progestins (norgestimate, desogestrel) are less androgenic 2
• Fourth-generation progestins like drospirenone (a spironolactone analogue) have antiandrogenic properties 2

Temporal Hormone Fluctuations During Pill Cycle

• Contrary to previous assumptions, hormone levels are not stable throughout the 28-day pill cycle 4
• During the 7 days of inactive pill ingestion, endogenous estradiol levels rise sharply 4
• Exogenous ethinyl estradiol levels decline during inactive pill days 4
• After the 7-day pill-free interval, a normal early follicular phase pulse pattern returns, even in long-term OC users 3

Clinical Implications and Laboratory Effects

Coagulation System Effects

• COCs increase prothrombin and factors VII, VIII, IX, and X 5
• They decrease antithrombin 3 levels 5
• Increased norepinephrine-induced platelet aggregability occurs 5

Other Laboratory Changes

• Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone 5
• Free T3 resin uptake is decreased, reflecting elevated TBG; free T4 concentration is unaltered 5
• High-density lipoprotein cholesterol (HDL-C) and triglycerides may increase 5
• Low-density lipoprotein cholesterol (LDL-C) and total cholesterol may decrease or remain unchanged 5
• Glucose tolerance may be decreased 5

Important Considerations for Specific Populations

Thrombosis Risk

• Estrogen-containing contraceptives create a procoagulant environment with decreased AT III and protein S 2
• There is a dose-response relationship between estrogens/progestins and venous thrombosis risk 2
• Transdermal and oral contraceptives have similar effects on vascular risk markers 2

Acne Treatment

• COCs are conditionally recommended for acne treatment based on their anti-androgenic properties 2
• Four COCs are FDA-approved for acne treatment in women who desire oral contraception 2
• All COCs yield net antiandrogenic properties when combined with estrogen 2

Metabolic Considerations

• Women being treated for hyperlipidemias should be monitored closely if using OCPs 5
• Some progestogens may elevate LDL levels and complicate hyperlipidemia management 5

By understanding these complex hormonal effects, clinicians can better select appropriate contraceptive options and anticipate potential metabolic changes in their patients.