Levonorgestrel

How levonorgestrel works

Levonorgestrel is a second-generation synthetic progestogen derived from 19-nortestosterone. It binds to progesterone receptors and, in part, to androgen receptors. This binding delays the release of GnRH by the hypothalamus and blunts the LH surge that normally precedes ovulation. By dampening this hormonal signal, it inhibits or delays the release of the egg, which is its main mode of action.

A local effect adds to this first lever: levonorgestrel thickens the cervical mucus, which hinders the movement of sperm and their passage into the uterus. A third mechanism, an action on the endometrium, was long put forward. For use in emergency contraception, recent data do not show an endometrial effect capable on its own of preventing a pregnancy: this point remains debated and is not accepted as the main mechanism.

Its fate in the body

Taken by mouth, levonorgestrel is absorbed rapidly and almost completely, with a bioavailability close to 85 to 100 percent and without any notable first-pass hepatic effect. The peak in the blood occurs at about 1.6 hours after the dose. Once in the circulation, it is 97.5 to 99 percent bound to plasma proteins, mainly to the globulin that binds sex hormones, SHBG, and to albumin.

The liver then takes over: levonorgestrel is metabolised there mainly by the cytochrome CYP3A4, through hydroxylation, reduction and conjugation into glucuronides. It is eliminated for about 45 percent in the urine and 32 percent in the stool. Its half-life is about 24 hours after a single dose. Within a combined pill, the kinetics become non-linear, because ethinylestradiol raises the level of SHBG and therefore the bound fraction of the hormone: the steady-state half-life then reaches about 36 hours.

How to take it

For emergency contraception, levonorgestrel is taken as a single dose, as early as possible and within the 72 hours following unprotected intercourse. Its efficacy decreases as the dose is delayed: every hour gained counts. The effect of a meal on the speed and extent of absorption has not been assessed, so there is no established instruction to take it with or without food.

Used as regular hormonal contraception, it is taken continuously, without stopping on one's own decision, because stopping exposes to the risk of pregnancy. Certain signals call for speaking with a professional rather than waiting: a period delayed by more than a week, lower abdominal pain or irregular bleeding that persists warrant a gynaecological evaluation.

The effects to know about

In the clinical trial of emergency contraception with levonorgestrel 1.5 mg, the most commonly reported effects concerned first the cycle and general condition. Heavier menstrual bleeding affected 30.9 percent of women, nausea 13.7 percent, lower abdominal pain 13.3 percent, fatigue 13.3 percent, headache 10.3 percent and dizziness 9.6 percent. These effects follow the dose.

In hormonal contraception, cycle disturbances are the most common effect: irregular bleeding, infrequent bleeding, absence of periods or painful periods. Serious events such as ectopic pregnancy, stroke and anaphylaxis have been reported, but rarely.

On the plate

The documented nutritional impact concerns combined oral contraceptives, those that combine an oestrogen, ethinylestradiol, with a progestogen such as levonorgestrel. It is mainly attributed to the oestrogenic component. Reviews report in users lower serum levels of B-group vitamins, of vitamin C and of vitamin E, as well as of zinc, magnesium and selenium, with decreases sometimes proportional to the duration of use. These nutrients are found in a varied plate: legumes and spinach for folate, pumpkin seeds and red meat for zinc, almonds and dark chocolate for magnesium.

The case of vitamin B12 deserves a nuance: it appears significantly lower in users, but this decrease could reflect a redistribution rather than a true deficiency, and its mechanism remains to be clarified. For vitamin B6 and folate, the differences are not always found. Eggs, salmon and animal products cover B12, while green vegetables provide folate. When a regular dietary intake struggles to keep up over time, a targeted supplement makes sense, in addition to your treatment, never in its place.

A plate built around these nutrients supports the same ground that contraception draws on. Relying on green vegetables, nuts, seeds and a regular source of protein gives the body what it needs to maintain its reserves of B vitamins, magnesium and zinc.

Interactions and monitoring

Certain medicines reduce the efficacy of levonorgestrel by speeding up its breakdown. Inducers of CYP3A4 and of the P-glycoprotein transporter lower its concentrations: rifampicin, phenytoin, carbamazepine, barbiturates and St John's wort. St John's wort illustrates the risk well: between 2000 and 2014, the British agency MHRA received 19 reports of suspected interactions, including 15 unwanted pregnancies and 4 breakthrough bleedings. In women treated with efavirenz or rifampicin, doubling the dose, that is 3 mg instead of 1.5 mg, largely compensates for the loss of exposure; in practice, an adjusted dose or another contraceptive method is recommended under these treatments.

Monitoring supports these situations. It includes liver function tests, in particular in case of liver impairment, and heightened vigilance when a CYP3A4 inducer is associated. On the gynaecological side, an evaluation is needed if a period is delayed by more than a week, in case of lower abdominal pain or of irregular bleeding that persists. These markers help to distinguish an expected effect from a signal that calls for medical advice.