Effect of Norethindrone on Sex Hormone-Binding Globulin (SHBG)
Norethindrone decreases SHBG levels, which is opposite to the effect of estrogen-containing contraceptives that typically increase SHBG. 1, 2
Mechanism of Action
Norethindrone, a first-generation progestin, affects SHBG levels through several mechanisms:
- It has androgenic properties that directly suppress SHBG production in the liver 2
- When used alone (without estrogen), it decreases SHBG concentrations 1, 3
- This decrease in SHBG can lead to higher levels of free (unbound) testosterone, despite potentially lowering total testosterone levels 3, 4
Evidence from Clinical Studies
The FDA drug label for norethindrone specifically notes that progestin-only oral contraceptives affect laboratory tests including: "Sex hormone-binding globulin (SHBG) concentrations may be decreased." 1
Research studies confirm this effect:
- In a 1980 study, women treated with norethindrone enanthate showed SHBG levels that fell within the normal range for men 3
- A 2001 randomized trial found that continuous combined estradiol and norethindrone acetate increased SHBG levels, but this was due to the estrogen component counteracting the progestin effect 5
- A 1982 study demonstrated that norethindrone in vaginal rings significantly reduced SHBG binding capacity 4
Comparison with Other Hormonal Contraceptives
The effect of norethindrone on SHBG differs from combined hormonal contraceptives:
- Combined oral contraceptives (COCs) containing ethinyl estradiol typically increase SHBG levels 2, 6
- When norethindrone is combined with ethinyl estradiol in COCs, the estrogen effect predominates, resulting in increased SHBG 4
- A meta-analysis of 42 studies confirmed that all COCs increase SHBG concentrations, though the magnitude varies by estrogen dose and progestin type 6
Clinical Implications
The SHBG-lowering effect of norethindrone has several clinical implications:
- May benefit women with conditions exacerbated by high SHBG levels
- Could potentially worsen androgenic symptoms in some women due to increased free testosterone
- Different from combined hormonal contraceptives that increase SHBG and reduce free testosterone 2
- This effect contributes to norethindrone's mechanism of action in treating acne, as noted in the JAAD guidelines 2
Monitoring Considerations
When prescribing norethindrone:
- Be aware that it may alter laboratory test results for SHBG and thyroid binding globulin 1
- Consider monitoring SHBG levels in patients where androgen status is clinically relevant
- Remember that the decrease in SHBG may affect the interpretation of total testosterone levels
Important Caveats
- The magnitude of SHBG reduction may vary between individuals
- When combined with estrogen (as in combined oral contraceptives), the estrogen effect on SHBG may predominate 4
- Dose-dependent effects may occur, with higher doses potentially causing greater SHBG suppression
- Other factors such as weight, thyroid function, and liver health also influence SHBG levels 7
In summary, norethindrone as a progestin-only medication decreases SHBG levels, which is an important consideration when selecting hormonal therapy for patients with specific hormonal needs or concerns.