Sex Hormones & Hormonal Contraceptives

The hypothalamus secretes GnRH in pulses. GnRH activates its G protein–coupled receptor on the anterior pituitary, which releases FSH and LH; LH drives theca cells to make progesterone and androstenedione, and FSH drives granulosa-cell aromatase to convert it, through testosterone, to 17-β estradiol. At the pituitary these sex steroids provide negative feedback, reducing FSH and LH. The exception is ovulation: once estradiol reaches a critical level it switches to positive feedback, LH rises about 10-fold in the LH surge, and ovulation follows about 36 to 44 hours after the surge begins.

Combined hormonal contraceptives act by suppressing gonadotropins. Progestogen negative feedback at the hypothalamus slows GnRH pulse frequency, which lowers FSH and LH; with no developing follicle, estradiol does not rise. Progestogen negative feedback and the lack of estrogen positive feedback stop the mid-cycle LH surge, so no follicle develops and none is released. Estrogen adds a weaker brake by slowing FSH secretion. The progestin also makes cervical mucus unfriendly to sperm, and the estrogen component controls menstrual bleeding.

Most progestins prevent pregnancy by suppressing hypothalamic GnRH and pituitary LH and FSH, which suppresses ovulation, and they add secondary effects: thicker cervical mucus, slowed tubal motility and endometrial atrophy. How completely ovulation is blocked depends on the method. The norethindrone progestin-only pill suppresses ovulation in only about half of users, so it also relies on thickened mucus, lower mid-cycle LH and FSH peaks, slower ovum transport and endometrial change. The etonogestrel implant works by suppressing ovulation, increasing cervical-mucus viscosity and altering the endometrium. The medroxyprogesterone injection inhibits gonadotropin secretion, which prevents follicular maturation and ovulation, and thickens cervical mucus. The levonorgestrel IUS acts locally — thicker mucus, impaired sperm capacitation or survival, and an altered endometrium — although its mechanism has not been conclusively demonstrated.

Long-acting reversible contraceptives — IUDs and the subdermal implant — fail in fewer than 1 woman per 100 per year, making them the most effective form of contraception available, and the implant heads the effectiveness ranking. Etonogestrel is the biologically active metabolite of desogestrel. Progestin-only methods are the usual fallback when estrogen is a problem: most women with medical comorbidities are candidates for progestin-only pills, and epidemiological studies have not linked progestin-only preparations to myocardial infarction, stroke or VTE. The implant and injection labels still list current or past thrombosis or thromboembolic disorders among their contraindications.

Estrogen raises hepatic protein synthesis, increasing coagulation factors — the same mechanism that makes pregnancy a hypercoagulable state — and the hepatic metabolism of oral estrogen produces activated protein C resistance. Combined pills therefore raise the risk of VTE, highest in the first year of use and when restarting after a break of 4 weeks or longer, although pregnancy raises it as much or more. Moving the estrogen to the vagina does not avoid this: ethinyl estradiol from the ring has a bioavailability comparable to oral dosing, and ring users had a VTE risk similar to combined-pill users.

Combined pills also raise the risk of arterial thrombosis — stroke and myocardial infarction — especially with other risk factors. That is the basis of the boxed warning on every combined pill and ring: cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptives, the risk rises with age, particularly over 35, and with the number of cigarettes smoked, so women over 35 who smoke should not use them. The §4 list follows the same logic — a high risk of arterial or venous thrombosis, such as DVT or PE now or in the past, inherited or acquired hypercoagulopathies, cerebrovascular or coronary artery disease, uncontrolled hypertension, or migraine with aura — and adds liver tumors or liver disease and breast cancer.

Drospirenone is a spironolactone analogue with antimineralocorticoid and antiandrogenic activity. Its mild aldosterone blockade raises plasma renin activity and aldosterone and can cause hyperkalemia in high-risk patients — the same mechanism as the potassium-sparing diuretics (Potassium-Sparing Diuretics page). Drospirenone products are therefore contraindicated in conditions that predispose to hyperkalemia: renal impairment, hepatic impairment and adrenal insufficiency. Women on long-term drugs that can raise potassium — ACE inhibitors, angiotensin II receptor blockers, potassium-sparing diuretics, potassium supplements, heparin, aldosterone antagonists and NSAIDs — have their potassium checked during the first treatment cycle.

Contraceptive steroids are cleared by the liver — etonogestrel, levonorgestrel and ulipristal by CYP3A4 — so enzyme inducers lower their plasma levels and can cause breakthrough bleeding or contraceptive failure. Labeled examples include rifampicin and rifabutin, the anticonvulsants phenytoin, carbamazepine, barbiturates, oxcarbazepine, topiramate, felbamate and rufinamide, griseofulvin, bosentan, efavirenz, aprepitant and St. John’s wort. Women taking them are counseled to use an alternative method or a back-up method, continued for 28 days after the inducer is stopped when the method is a combined pill.

Ordinary antibiotics are different: most broad-spectrum antibiotics do not affect combined-pill effectiveness, which US MEC rates category 1, whereas rifampin or rifabutin is category 3. The interaction also runs the other way, because hormonal contraceptives alter the metabolism of other drugs: they can lower lamotrigine levels and raise cyclosporine levels.

Levonorgestrel binds progesterone and androgen receptors, delays GnRH release from the hypothalamus and blunts the LH surge, so it delays or inhibits ovulation by inhibiting follicular rupture; it also thickens cervical mucus, and recent studies show no significant effect on the endometrium. It works best when taken before ovulation. Sold over the counter, it is taken as soon as possible within 72 hours of unprotected sex — the sooner the better — and it will not work if the woman is already pregnant. Efficacy is lower with a BMI above 30 kg/m², though not enough to restrict its use.

Ulipristal is a selective progesterone receptor modulator, with antagonistic and partial agonistic effects, that binds the progesterone receptor and prevents progesterone from occupying it. Taken immediately before ovulation it postpones follicular rupture — in label data, for at least 5 days in every woman who took it before the LH surge and in 79% of those who took it once LH had already started to rise, but not on the day of the LH peak. It is taken as soon as possible within 5 days. CYP3A4 inducers such as rifampin lower its levels and should not be combined with it, and strong inhibitors raise them. Ulipristal and progestins act at the same receptor, and progestin contraception started soon afterward can impair its ability to delay ovulation, so regular hormonal contraception starts no sooner than 5 days later, with a barrier method until the next period. Ulipristal is not indicated to end an existing pregnancy. (Mifepristone, a progesterone-receptor antagonist at low doses, is a different drug that a later page covers.)

Not every emergency method is hormonal: the copper T 380A IUD is an emergency option that involves no progestin, and a meta-analysis found the copper IUD more effective than levonorgestrel-containing methods for emergency contraception.

Depot medroxyprogesterone inhibits gonadotropin secretion and reduces serum estrogen, which is associated with significant loss of bone mineral density — its boxed warning. Bone loss grows with the duration of use and may not be completely reversible. It matters most in adolescence and early adulthood, a critical period of bone accretion: in adolescents treated for more than 2 years, hip BMD had not fully recovered 5 years after stopping. Use for longer than 2 years is not recommended unless other methods are inadequate, and other methods are weighed for women with osteoporosis risk factors such as anorexia nervosa, chronic alcohol or tobacco use, or chronic anticonvulsant or corticosteroid use.

The depot is also slow to leave. The apparent half-life is about 50 days, return to ovulation and fertility is likely to be delayed — the median time to conception is 10 months after the last injection, with a range of 4 to 31 months — so it is a poor choice for someone considering pregnancy within the next 2 years. Women also tend to gain weight on it.

The CDC US Medical Eligibility Criteria grade each condition against each method in four categories: 1, no restriction; 2, advantages generally outweigh the theoretical or proven risks; 3, the risks usually outweigh the advantages; 4, an unacceptable health risk — in effect, a contraindication. For combined methods the category 4 list follows the estrogen-thrombosis logic: age 35 or older with 15 or more cigarettes a day, migraine with aura, and fewer than 21 days postpartum. Fewer cigarettes after 35 is category 3, and smoking under 35 is category 2. Migraine without aura is category 2, a classification that holds only without other stroke risk factors. Rifampin is category 3 not because the combination is harmful but because it is likely to reduce effectiveness.

Combined pills lower the risk of endometrial and ovarian cancer, and the medroxyprogesterone injection has also been shown to reduce both. NCI reports endometrial risk reduced by at least 30%, more with longer use, with protection that persists for many years after stopping, and colorectal cancer risk 15% to 20% lower. Against that, ever-use carries a slight (7%) increase in breast cancer risk — 24% while currently using — which declines after stopping and is no longer evident by 10 years, and 5 or more years of use raises cervical cancer risk, which also declines after stopping.

Pills are also used for menstrual pain, irregular menstruation, endometriosis-related pain and menstrual-related migraines, and specific drospirenone and norgestimate products are indicated for acne. Progestins combined with estrogen are also used for menopausal hormone therapy, which a later page covers.