Sex Hormones & Hormonal Contraceptives

The ovary makes two sex hormones — estrogen and progesterone — under the command of the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamus releases GnRH, which drives the pituitary to release FSH and LH, which in turn ripen a follicle and trigger ovulation (the LH surge). The hormones the ovary makes feed back to the brain to regulate the next cycle.

Hormonal contraceptives exploit that feedback loop. By supplying steady synthetic hormone from the outside — a synthetic estrogen (ethinyl estradiol) plus a synthetic progesterone called a progestin — they convince the brain the ovary is already active. GnRH, FSH, and LH stay suppressed, so no follicle matures and the LH surge that causes ovulation never happens.

The progestin is the workhorse of contraception: it suppresses the LH surge, thickens cervical mucus (blocking sperm), and thins the endometrium (hostile to implantation). Progestin-only methods (the "minipill," implants, hormonal IUDs, Depo-Provera) rely on these effects and are the safer choice when estrogen is dangerous — epidemiological studies have not linked progestin-only preparations to the clot risk below, although the implant (Nexplanon) and medroxyprogesterone injection labels still list current or past thrombosis as a contraindication.

The estrogen mainly stabilizes the endometrium to prevent breakthrough bleeding and adds a second brake on FSH. It is medically useful but it is also the source of the whole safety problem: estrogen is what makes a combined contraceptive raise the risk of dangerous blood clots.

The etonogestrel implant (Nexplanon) prevents pregnancy for up to 5 years by suppressing ovulation, increasing the viscosity of cervical mucus and altering the endometrium. Its boxed warning is about the device: improper insertion raises the risk of complications, proper training before first use minimizes that risk, and it is available only through a restricted program, the NEXPLANON REMS. The medroxyprogesterone injection (Depo-Provera CI, depo-subQ provera 104) inhibits gonadotropin secretion, preventing follicular maturation and ovulation, and thickens cervical mucus. It lowers serum estrogen and is associated with loss of bone mineral density, its boxed warning, and return to ovulation and fertility is likely to be delayed after it is stopped.

The etonogestrel/ethinyl estradiol vaginal ring (NuvaRing, EluRyng, EnilloRing) is a combined method: it suppresses gonadotropins like the combined pill and carries the same smoking boxed warning. Ulipristal (ella), a progesterone agonist/antagonist, is emergency contraception taken as soon as possible within 5 days of unprotected sex or a known or suspected contraceptive failure; taken just before ovulation, it postpones follicular rupture. It is not for routine use, and it is not indicated to end an existing pregnancy.

Estrogen travels to the liver and increases production of clotting factors, and oral estrogen’s passage through the liver also produces resistance to the body’s natural anticoagulant (activated protein C resistance). The blood becomes hypercoagulable — more likely to form clots. That is why combined contraceptives raise the risk of venous thromboembolism (VTE): deep-vein thrombosis and pulmonary embolism, highest in the first year of use.

Now add the boxed warning: cigarette smoking further damages vessels and stacks arterial risk on top of the venous risk. The FDA boxed warning states smoking increases the risk of serious cardiovascular events (stroke, MI, clots) from combined oral contraceptives, and that this risk climbs with age and number of cigarettes — so combined pills are contraindicated in anyone over 35 who smokes. The same estrogen-driven clotting is why combined methods are also avoided with a personal history of VTE, clotting disorders, or migraine with aura (which independently raises stroke risk).