Oral Contraceptives: Their Mode of Action and Dermatologic Applications

Milena Pitashny, MD; Helena Martinez de Morentin, MD; Sarah Brenner, MD


Skinmed. 2005;4(2):101-104, 106. 

In This Article

Antiandrogenic Effect of Oral Contraceptives

Estrogen and progesterone combined in OCs act in a synergistic manner in the gonadotropin axis. They decrease the secretion of hypophysial-luteinizing hormone and follicle-stimulating hormone by negative feedback, thereby inhibiting ovulation. Gonadotropin inhibition also has the effect of reducing the androgen production of ovarian theca cells and adrenal gland. An additional antiandrogenic effect of estrogens comes from their stimulation of liver production of sex hormone binding globulin (SHBG), a globulin that binds free-circulating androgens and reduces free available testosterone to peripheral tissues. High doses of estrogens may decrease sebum production, but apparently greater doses than those in OC are required for such an effect.[2]

The role of progestins in androgen metabolism is complex. Synthetic progestins derived from testosterone (19-nortestosterone derivatives) or progesterone (19-norprogesterone or 17-OH-progesterone derivatives) not only bind to the progesterone receptor, they also have the ability to bind other steroid receptors. These include androgen receptors having androgenic or antiandrogenic effects, estrogen receptor, and glucocorticoid receptor and mineralocorticoid receptor, which interfere with water metabolism. Most OCs contain testosterone-derived progestins, with the exception of drospirenone, which is a new progestin derived from 17-α-spirolac-tone with pharmacology resembling that of endogenous progesterone.[2,4,5] These progestin compounds were proposed to aggravate acne, hirsutism, or AGA by increased intrinsic androgenic effect.

When studied separately from estrogen, the different progestin compounds have variable androgenic effect by their linkage with the androgenic receptor. On the other hand, progestins counter the beneficial estrogen effect on SHBG by reducing this binding protein in serum, thus being "antiestrogenic" and androgenic. Although some progestins have more androgenic effect than others, when combined with estrogens they synergistically depress the gonadotropin secretion, decreasing androgen secretion. The counteraction of estrogens and progesterone in SHBG results in the enhancement of this binding protein, with a net reduction in free available androgen. Thus, regardless of the type of progestin involved in combined formulations, all OCs are antiandrogenic.[2]

Even norethindrone, a first generation progestin known to have a marked intrinsic androgenic effect, has the net effect of enhancing SHBG when given in proper doses and in combination with low-dose ethinyl estradiol, resulting in reduction of free testosterone. Further studies are needed to assess the androgenic skin end point effects.[6]

The classification of OC progestins in the literature is confusing. Generations are not standardized, and one compound may appear in different groups. Most of the available OCs contain derivatives of 19-nortestosterone, which may be classified into two families: estrane and gonane. The estrane group (first generation OC) is composed of norethindrone and other progestins that metabolize to norethindrone (including norethynodrel, the progestin component of the first pill). The gonane group is subdivided into two groups: Norgestrel, or its biologically active derivate, levonorgestrel, known as second generation OC, derivate from norethindrone, and have varying degrees of androgenic, estrogenic, and antiestrogenic activities; and the "new" gonanes (or third generation) -- desogestrel, gestodene, and norgestimate -- which are reported to have the least androgenic intrinsic activity of the progestin compounds.[1]

New progestins have been synthesized in the past decade with no intrinsic androgenic effects but potent antiandrogenic activity, including cyproterone acetate, chlormadinone acetate, and dienogest. Their antiandrogenic activity is induced by blocking the androgen receptors in the skin target and by reducing the activity of 5 α-reductase in sebaceous gland and hair follicles. Cyproterone acetate and chlormadinone acetate also have potent antigonadotrophin activity, which, as noted above, reduces ovarian and adrenal androgen production.[7] Dienogest slightly affects the gonadotrophic secretion; its inhibition of ovulation is mainly due to its activity in the peripheral tissues, reducing serum progesterone to anovulatory levels.[8] Combination OCs containing this group of antiandrogenic progestins have been shown to improve seborrhea, acne, hirsutism, and androgen-related alopecia.

Another progestin is drospirenone, derived from 17-α-spirolactone and pharmacologically resembling endogenous progesterone. It has both antiandrogenic and antimineralocorticoid activities. It is antiandrogenic by inhibiting ovarian androgen production like other progestins, and it also blocks androgen receptors in the skin.

Estrogen stimulates angiotensin synthesis and enhances aldosterone-mediated water and sodium retention, making it responsible for such unpleasant symptoms as bloating, breast tenderness, and weight gain.

Drospirenone counters estrogen effect by blocking the aldosterone receptor, thus being antimineralocorticoid. This unique progestin attenuates the aforementioned bothersome estrogenic effects that some women report with the use of OC. It is also reported to improve androgen-related skin disorders, including acne, hirsutism, and seborrhea.[5]