Does progesterone have androgenic effects?

Does Progesterone Have Androgenic Effects?

Natural progesterone itself does not have androgenic effects, but many synthetic progestins (synthetic progesterone derivatives) do possess varying degrees of androgenic activity depending on their chemical structure.

Natural Progesterone vs. Synthetic Progestins

Natural progesterone and its close derivatives lack androgenic properties 1, 2. However, the synthetic progestins commonly used in contraceptives and hormone therapy are structurally diverse and exhibit markedly different androgenic profiles 2.

Structural Basis of Androgenic Activity

The androgenic effects of progestins depend entirely on their parent molecule:

• 19-nortestosterone derivatives (derived from testosterone) retain varying degrees of androgenic activity 1, 2, 3

  • These include norethisterone, levonorgestrel, and their metabolites
  • Removing carbon-19 from testosterone changes the primary effect from androgenic to progestogenic, but residual androgenic activity persists 3
  • At low doses, these are considered "mild androgens" 4

• Progesterone derivatives (17-OH progesterone and 19-norprogesterone derivatives) are essentially non-androgenic 1, 2

  • These "pure" progestational molecules bind almost exclusively to progesterone receptors
  • Examples include trimegestone, nomegestrol acetate, and Nestorone 2

Progestins with Anti-Androgenic Properties

Several newer progestins actually possess anti-androgenic effects rather than androgenic effects:

• Drospirenone has partial anti-androgenic activity and is derived from spironolactone 5, 1, 2
• Dienogest is a hybrid progestin with partial anti-androgenic effects 1, 2
• These progestins should be avoided in patients with hypoandrogenism, as they could worsen low testosterone symptoms 4

Clinical Manifestations of Androgenic Activity

When synthetic progestins with androgenic properties are used, they can cause 6, 3:

• External manifestations: oily skin, acne, hirsutism, android obesity, androgenic alopecia
• Metabolic disturbances: unfavorable lipid profiles, increased diabetes and hypertension risk
• These effects are dose-related and opposed by estrogen 3

Selectivity Index

The degree of androgenic activity is measured by the selectivity index: the ratio of affinity for progesterone receptors to androgen receptors 7. Third-generation progestins (norgestimate, desogestrel, gestodene) have higher selectivity indexes than older agents, meaning greater progestational activity relative to androgenic activity 7.

Clinical Implications

When prescribing progestins, avoid treating them as a class effect 2. The choice matters significantly:

• For patients requiring contraception with minimal androgenic effects: consider newer generation progestins or those with anti-androgenic properties 6, 7
• For patients with hypoandrogenism or low libido: avoid anti-androgenic progestins 4
• Normethyltestosterone derivatives at higher doses (10 mg daily) have mild androgenic activity and can cause metabolic and vascular side effects 4