Gonadal & Ovarian Pharmacology

Correct Answer

A — Norethindrone

Rationale

Norethindrone 0.35 mg (the minipill) is classified as a progestin-only oral contraceptive pill. It contains no estrogen component. Drospirenone is a progestin used in combination with ethinyl estradiol in combined oral contraceptives, not as a standalone progestin-only pill at contraceptive doses. Ethinyl estradiol is a synthetic estrogen, not a progestin. Etonogestrel is a progestin delivered as a subdermal implant (Nexplanon), not as an oral pill.

Correct Answer

C — Ulipristal acetate

Rationale

Ulipristal acetate is classified as a selective progesterone receptor modulator. Its partial progesterone receptor antagonist activity allows it to inhibit or delay follicular rupture even after the luteinizing hormone surge has begun, distinguishing it from progestin-based emergency contraceptives. Levonorgestrel is a progestin, not a selective progesterone receptor modulator. Medroxyprogesterone acetate is a synthetic progestin used for contraception and hormone therapy. Mifepristone is a progesterone receptor antagonist used for medical abortion, not for emergency contraception in the standard sense.

Correct Answer

D — Single-rod subdermal progestin implant

Rationale

Etonogestrel is the active progestin in Nexplanon, a single-rod subdermal implant inserted in the inner upper arm that provides contraceptive concentrations for 3 years. It is not an intrauterine device — that delivery system uses levonorgestrel. It is not an injectable — depot medroxyprogesterone acetate is the intramuscular injectable progestin. It is not an oral tablet — the oral desogestrel pill contains desogestrel, which is converted to etonogestrel after absorption, but the implant delivers etonogestrel directly.

Correct Answer

B — Levonorgestrel-releasing intrauterine system

Rationale

The 52 mg levonorgestrel device (Mirena) is classified as a levonorgestrel-releasing intrauterine system — a hormone-containing intrauterine device that releases levonorgestrel locally into the uterine cavity. The copper-bearing intrauterine device contains no hormone and works through copper ion cytotoxicity on sperm. The subdermal implant (Nexplanon) delivers etonogestrel from a rod inserted under the skin of the upper arm. The depot injectable delivers medroxyprogesterone acetate by intramuscular injection every 12 weeks.

Correct Answer

A — Depot medroxyprogesterone acetate

Rationale

Depot medroxyprogesterone acetate (Depo-Provera) is classified as an intramuscular depot injectable progestin contraceptive, administered as a 150 mg injection every 12 weeks. The depot formulation releases medroxyprogesterone acetate gradually from the injection site over 3 months. Etonogestrel is delivered as a subdermal implant (Nexplanon), not an injection. Levonorgestrel is available as an intrauterine system and as an emergency contraceptive tablet, but not as an intramuscular depot injectable. Norethindrone is an oral progestin available as a daily tablet.

Correct Answer

C — A preparation containing ethinyl estradiol plus a progestin

Rationale

A combined oral contraceptive is defined by its dual hormonal composition: an estrogen component (almost universally ethinyl estradiol in conventional preparations) combined with a progestin. This combination suppresses the hypothalamic-pituitary-ovarian axis more reliably than either component alone. A preparation containing only a progestin is classified as a progestin-only pill or minipill. No approved daily oral contraceptive contains estrogen alone or a gonadotropin-releasing hormone antagonist — the antagonist class (elagolix, relugolix) is used for endometriosis and prostate cancer, not as a daily contraceptive.

Correct Answer

B — Norethindrone prevents pregnancy primarily by thickening cervical mucus, and mucus permeability begins to recover within 3 to 4 hours as norethindrone plasma levels fall below their effective threshold

Rationale

The norethindrone 0.35 mg minipill works primarily through cervical mucus thickening rather than ovulation suppression. At this dose, norethindrone converts the mid-cycle cervical mucus from a fluid, sperm-permeable state to a viscous, impenetrable consistency. This effect depends on maintaining plasma norethindrone above a threshold concentration. When a dose is missed or taken more than 3 to 4 hours late, plasma norethindrone falls below this threshold and cervical mucus begins to recover its permeability, re-opening the path for sperm. Because ovulation suppression is inconsistent with this preparation, the cervical mucus effect is the primary contraceptive mechanism, making the 3-hour window critical.

Correct Answer

D — Bone mineral density reduction, which is reversible after discontinuation but is of concern in adolescents who have not yet achieved peak bone mass

Rationale

Depot medroxyprogesterone acetate produces bone mineral density reduction with prolonged use. The mechanism involves suppression of the hypothalamic-pituitary-ovarian axis, resulting in low circulating estradiol levels. Because estradiol is a key driver of bone mineral accrual, prolonged hypoestrogenism from depot use reduces bone density. In adults, this bone mineral density loss is reversible after discontinuation and does not increase fracture risk. In adolescents who have not yet achieved peak bone mass — which typically occurs in the late teens — prolonged suppression of estradiol during this critical window of bone accrual raises more concern. The World Health Organization therefore advises caution with use beyond 2 years in this age group.

Correct Answer

A — Ulipristal acetate can inhibit follicular rupture even after the luteinizing hormone surge has already begun, whereas levonorgestrel has no consistent effect once the surge starts

Rationale

The critical mechanistic distinction is timing relative to the luteinizing hormone surge. Levonorgestrel inhibits or delays ovulation only when given before the surge begins — once the surge has started, levonorgestrel has no consistent effect on follicular rupture. Ulipristal acetate, as a selective progesterone receptor modulator, can inhibit follicular rupture even after the luteinizing hormone surge is already underway, because progesterone receptor signaling participates in the final steps of follicle rupture. This extended window of action allows ulipristal acetate to remain effective for up to 120 hours, compared to the effectively 72-hour window of levonorgestrel.

Correct Answer

C — It inhibits or delays ovulation when taken before the luteinizing hormone surge, with no consistent effect after ovulation has occurred

Rationale

Levonorgestrel emergency contraception works by inhibiting or delaying ovulation when taken before the luteinizing hormone surge. Studies consistently show it has no reliable post-ovulatory effect — it does not prevent fertilization of an egg that has already been released, and it does not consistently alter endometrial receptivity or prevent implantation. Efficacy is highest within 24 hours, when the pre-ovulatory window is most likely to be intact, and decreases substantially by 48 to 72 hours as the probability that ovulation has already occurred increases. Understanding this mechanism is clinically important: it means the drug has no contraceptive effect if the patient has already ovulated at the time of administration.

Correct Answer

B — Fertility typically returns within 3 to 4 weeks of implant removal

Rationale

The etonogestrel subdermal implant delivers etonogestrel continuously from a depot rod; once the rod is removed, etonogestrel release stops immediately and plasma concentrations fall rapidly. Ovulation typically resumes within 3 to 4 weeks of removal, and fertility returns promptly. This is one of the major advantages of the implant compared to depot medroxyprogesterone acetate, which has an average 9 to 10-month fertility delay after the last injection due to its large intramuscular depot. The implant is highly effective during use but does not compromise future fertility, making it well suited for women who want reliable long-term contraception with rapid reversibility.

Correct Answer

D — The levonorgestrel intrauterine device acts locally at the endometrium and cervix, with systemic absorption that is minimal compared to oral progestin preparations

Rationale

The levonorgestrel intrauterine device delivers levonorgestrel directly to the uterine cavity, producing very high local concentrations at the endometrium and cervix that are responsible for its contraceptive effects: endometrial atrophy and cervical mucus impermeability. Systemic absorption of levonorgestrel from the device is minimal — plasma levonorgestrel levels with the 52 mg device are substantially lower than with oral levonorgestrel-containing pills. This low systemic exposure is why users experience far fewer systemic progestogenic effects (mood changes, acne, reduced libido) than women taking oral progestins. The drug is the same; the delivery route determines systemic exposure.

Correct Answer

A — Ulipristal acetate partially antagonizes the progesterone receptor, and co-administration with a progestin-containing method reduces ulipristal acetate efficacy

Rationale

Ulipristal acetate is a selective progesterone receptor modulator with partial antagonist activity. When co-administered with a progestin-containing contraceptive method such as the etonogestrel implant, the exogenous progestin competes at the progesterone receptor and reduces the receptor antagonism that underlies ulipristal acetate’s ability to inhibit follicular rupture. The result is reduced emergency contraceptive efficacy. For this reason, women currently using any progestin-containing method who need emergency contraception should not rely on ulipristal acetate. The copper intrauterine device is the preferred choice because its mechanism — copper ion cytotoxicity on sperm — is entirely independent of hormonal status and is unaffected by concurrent progestin use.

Correct Answer

C — Ethinyl estradiol amplifies the baseline two-fold elevated ischemic stroke risk associated with migraine with aura, producing a multiplicative increase in absolute stroke risk that constitutes an unacceptable safety threshold

Rationale

Migraine with aura independently doubles the baseline risk of ischemic stroke in otherwise healthy reproductive-age women, through mechanisms including cortical spreading depression and associated vasomotor instability. Ethinyl estradiol in combined oral contraceptives further increases stroke risk through its prothrombotic effects on coagulation factors synthesized by the liver after first-pass portal exposure. When these risks are combined in a woman with migraine with aura, the resulting absolute stroke risk is judged to constitute an unacceptable health risk — the definition of World Health Organization Category 4. Progestin-only methods, which contain no ethinyl estradiol and do not carry independent stroke risk, are Category 2 in women with migraine with aura and are the appropriate hormonal contraceptive option.

Correct Answer

A — Levonorgestrel-releasing intrauterine system, because it is a progestin-only method and does not deliver systemic ethinyl estradiol that could reduce milk supply or expose the infant

Rationale

Ethinyl estradiol in combined hormonal contraceptives is classified as World Health Organization Category 4 (absolute contraindication) in the first 6 weeks postpartum for breastfeeding women. The mechanism is twofold: ethinyl estradiol reduces milk volume by suppressing prolactin-driven lactogenesis, and estrogen passes into breast milk, exposing the newborn during a important developmental period. Progestin-only methods — including the levonorgestrel intrauterine system, the etonogestrel implant, depot medroxyprogesterone acetate, and progestin-only pills — do not suppress lactation and are Category 1 or 2 during breastfeeding. The levonorgestrel intrauterine system is particularly well suited because its local mechanism minimizes systemic progestin exposure to both mother and infant.

Correct Answer

C — Ulipristal acetate 30 mg, because it shows less weight-dependent attenuation of efficacy than levonorgestrel at this body mass index

Rationale

Levonorgestrel emergency contraception shows substantial body weight-dependent attenuation of efficacy. At body mass index above approximately 26 kilograms per square meter, plasma levonorgestrel concentrations are lower and ovulation suppression becomes less reliable; at body mass index above 35 the impairment is substantial. Ulipristal acetate 30 mg shows less weight-dependent attenuation than levonorgestrel and is the preferred pharmacological emergency contraceptive in women above this weight threshold. With a body mass index of 30, this patient falls in the range where ulipristal acetate is the appropriate oral choice. The copper intrauterine device would be even more effective and is weight-independent, but ulipristal acetate is the correct pharmacological selection when an oral method is chosen.

Correct Answer

B — Levonorgestrel-releasing intrauterine system, because it acts locally at concentrations that far exceed systemic levels regardless of any enzyme induction effect

Rationale

Carbamazepine is a potent cytochrome P450 3A4 inducer. Combined oral contraceptives, the contraceptive patch, the vaginal ring, and the etonogestrel implant all depend on systemic hormone concentrations that can be reduced to subtherapeutic levels by enzyme induction. The norethindrone minipill is similarly vulnerable to induction at its already-marginal plasma concentrations. The levonorgestrel intrauterine system is the preferred option because it works locally: levonorgestrel concentrations at the endometrium and in cervical mucus far exceed the threshold for contraceptive effect regardless of systemic levonorgestrel levels. Even if carbamazepine induction reduces systemic levonorgestrel modestly, the local intrauterine concentrations remain far above what is needed. Depot medroxyprogesterone acetate is also acceptable due to its large depot buffer against induction.

Correct Answer

D — Anovulation, because sustained hormone levels are required to suppress the mid-cycle luteinizing hormone surge, and 3 missed pills allow follicular development and ovulation to resume

Rationale

Combined oral contraceptives prevent pregnancy through three mechanisms in a hierarchy: anovulation is primary, cervical mucus thickening is secondary, and endometrial atrophy is a tertiary backup. Anovulation is the most reliable mechanism and the one most severely disrupted by missed pills. Sustained exogenous estrogen and progestin are required to suppress the hypothalamic-pituitary-ovarian axis and prevent the mid-cycle luteinizing hormone surge that triggers ovulation. When three consecutive active pills are missed, hypothalamic-pituitary-ovarian axis suppression may fail, allowing follicular development and ovulation to resume. Because pregnancy requires an egg to fertilize, disruption of anovulation creates the greatest pregnancy risk. Cervical mucus and endometrial effects do not compensate adequately once ovulation has occurred.