Reproductive question bank

A. Carbamazepine induces hepatic enzymes, lowering contraceptive hormone levels — Carbamazepine is an enzyme inducer; drugs that induce enzymes such as CYP3A4 lower the plasma concentrations of contraceptive hormones and can cause breakthrough bleeding or contraceptive failure, so an alternative or back-up method is needed. Receptor blockade is how ulipristal acts at the progesterone receptor, not carbamazepine. A gut-flora effect is the antibiotic idea, and most broad-spectrum antibiotics do not affect combined-pill effectiveness (US MEC category 1). Binding globulins are raised by the pill’s own estrogen, and the labeled way that anticonvulsants such as carbamazepine cause contraceptive failure is enzyme induction.

C. Ulipristal, a progesterone receptor modulator that postpones follicular rupture — Ulipristal is taken as soon as possible within 5 days (120 hours) of unprotected sex; as a selective progesterone receptor modulator it postpones follicular rupture, even when LH has already started to rise. Levonorgestrel is labeled within 72 hours and acts by blunting the LH surge — recent studies show no significant endometrial effect. Norethindrone suppresses ovulation in only about half of users and is a regular method, and drospirenone’s antimineralocorticoid action underlies its hyperkalemia risk, whereas most progestins prevent pregnancy by suppressing gonadotropins and ovulation.

B. Reduced serum estrogen levels — Medroxyprogesterone inhibits gonadotropin secretion and reduces serum estrogen, which is associated with significant loss of bone mineral density — the boxed warning. Loss grows with duration, matters most in adolescence, may not fully reverse, and use beyond 2 years is not recommended unless other methods are inadequate. Antimineralocorticoid activity belongs to drospirenone, the injection lowers rather than raises estrogen, and raised clotting factors are the estrogen mechanism of VTE, not of bone loss.

D. Antimineralocorticoid activity of drospirenone, a spironolactone analogue — Drospirenone is a spironolactone analogue with antimineralocorticoid activity that can cause hyperkalemia in high-risk patients; ACE inhibitors also raise potassium, which is why potassium is checked during the first treatment cycle. Activated protein C resistance is an estrogen clotting mechanism, drospirenone is antiandrogenic rather than androgenic, and enzyme induction, the action of drugs such as rifampin, lowers contraceptive hormone levels rather than raising potassium.

D. Adding a progestin to oppose estrogen’s endometrial stimulation — Unopposed estrogen increases the risk of endometrial hyperplasia and cancer in a woman with a uterus, and adding a progestin, which converts the estrogen-primed proliferative endometrium to a secretory one, reduces that risk. Changing the route does not remove it: the transdermal Climara label carries the same warning about unopposed estrogen and endometrial cancer. Fezolinetant acts on NK3 receptors in the thermoregulatory center, not the endometrium, and thyroid-binding globulin affects thyroid replacement needs, not the uterus.

C. Transdermal estradiol, because it bypasses the hepatic first pass that raises activated protein C resistance — Transdermal estradiol bypasses the hepatic metabolism that produces activated protein C resistance and does not change hepatic coagulation proteins at standard doses, so it has minimal impact on VTE risk and is the better choice for most women, especially smokers and women with migraines. Oral estrogen raises clotting factors and VTE risk despite reliable absorption. The Estring ring is labeled for vulvovaginal atrophy, not hot flashes. Bazedoxifene in Duavee protects the endometrium; Duavee is oral conjugated estrogens, and it is labeled for women with a uterus.

B. Its antiglucocorticoid action risks acute adrenal insufficiency during long-term corticosteroid therapy — Besides blocking the progesterone receptor, mifepristone has antiglucocorticoid activity, and concurrent long-term corticosteroid therapy (like chronic adrenal failure) is a contraindication because of the risk of acute adrenal insufficiency. Mifepristone does not induce CYP3A4 — it may raise the levels of CYP3A4 substrates. It acts by competing with progesterone at its receptor, and the bleeding contraindication concerns hemorrhagic disorders and anticoagulants.

A. Neurokinin 3 receptor antagonism at hypothalamic KNDy neurons — Fezolinetant is an NK3 receptor antagonist that blocks neurokinin B on the KNDy neurons of the thermoregulatory center. It is not a hormone and showed no clear changes in sex hormones, so it does not act on estrogen or progesterone receptors; uterine estrogen antagonism describes bazedoxifene. Its boxed warning is hepatotoxicity, with cases within 40 days of starting: she should stop it at once and have hepatic laboratory tests.

C. Paroxetine inhibits CYP2D6, lowering levels of endoxifen, the potent active metabolite — CYP2D6 forms endoxifen, which has about 100-fold greater affinity for the estrogen receptor than tamoxifen, and strong CYP2D6 inhibitors such as paroxetine and fluoxetine lower endoxifen concentrations; CPIC advises avoiding moderate and strong CYP2D6 inhibitors. CYP3A4 induction is the rifampin interaction, the estrogen receptor is tamoxifen’s own target, and the boxed QT warning belongs to toremifene.

D. Endometrial cancer or uterine sarcoma, tamoxifen’s boxed uterine risk — Tamoxifen increases endometrial hyperplasia and polyps (through its partial estrogenic effect) and endometrial adenocarcinoma and uterine sarcoma — the boxed warning, possibly related to the same estrogen-like effect. Anyone receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding is evaluated promptly. Vaginal dryness can occur on tamoxifen, but bleeding after tamoxifen is evaluated for uterine malignancy; ovarian hyperstimulation is a clomiphene effect, and pulmonary embolism, though also boxed, does not present as vaginal bleeding.

A. Clomiphene blocks hypothalamic estrogen feedback, raising gonadotropins that overstimulate the ovaries — With its hypothalamic estrogen receptors occupied by clomiphene, rising estradiol no longer suppresses FSH and LH, so gonadotropins rise and stimulate the ovaries; ovarian hyperstimulation syndrome can progress rapidly to ascites, pleural effusion and oliguria, and PCOS ovaries may overrespond. Clomiphene acts at estrogen receptors, not on aromatase, and it has no apparent progestational effects; QT prolongation is toremifene’s box.

D. Estrogen-agonist action in the endometrium — In the endometrium ospemifene has estrogen-agonist effects, so its box carries the unopposed-estrogen endometrial-cancer warning (with the estrogen-alone stroke and DVT risks); abnormal genital bleeding is evaluated, including endometrial sampling. Endometrial antagonism describes raloxifene and bazedoxifene, CYP2D6 activation is tamoxifen’s pathway, and blocking hypothalamic feedback is how clomiphene works.

C. Aromatization of adrenal and ovarian androgens in peripheral tissues such as fat — After menopause the principal source of circulating estrogen is aromatase in peripheral tissues — adrenal glands, skin, muscle and fat — converting androstenedione and testosterone to estrone and estradiol; anastrozole inhibits that enzyme and significantly lowers serum estradiol. The ovary is the main estrogen source only before menopause. Anastrozole has no detectable effect on the formation of adrenal corticosteroids or aldosterone, so no replacement is needed. It is an enzyme inhibitor, and in animal studies it has no direct estrogenic activity.

D. Lower estrogen would reduce pituitary feedback, gonadotropins would rise, and her ovaries would be stimulated — In premenopausal women, aromatase inhibitors increase gonadotropin secretion because estrogen’s negative feedback on the pituitary falls, and the ovary is stimulated; aromatization of adrenal androgens is not a significant estradiol source before menopause, so anastrozole would not be expected to lower her estradiol, and the adrenal pathway would not become her main source. That is why the breast cancer labels are postmenopausal. Anastrozole does not affect cortisol or aldosterone secretion, so no glucocorticoid replacement is needed.

B. A steroidal false substrate converted to an intermediate that binds aromatase irreversibly — Exemestane is a steroidal inactivator related to androstenedione: aromatase processes it as a false substrate into an intermediate that binds irreversibly to the active site — suicide inhibition. Competitive heme binding is how letrozole, a nonsteroidal, reversible inhibitor, works. Exemestane does not bind significantly to steroid receptors, apart from a slight affinity for the androgen receptor, so it is not an estrogen receptor antagonist. And it does not suppress gonadotropins — it causes slight rises in LH and FSH through pituitary feedback.

C. It should not be used: tamoxifen lowered anastrozole levels, and the combination added no benefit over tamoxifen alone — Coadministration reduced anastrozole plasma concentration by 27%, and in the adjuvant trial the combination showed no efficacy benefit over tamoxifen, so tamoxifen should not be given with anastrozole. Anastrozole significantly lowers serum estradiol in postmenopausal women on its own. Coadministration did not change the pharmacokinetics of tamoxifen, and anastrozole is unlikely to affect other drugs through cytochrome P450 inhibition.

B. A transient rise in testosterone from initial GnRH receptor stimulation (tumor flare) — GnRH agonists first stimulate the receptor, raising testosterone about 50% above baseline in the first weeks; in prostate cancer this can cause tumor flare with bone pain, neuropathy and spinal cord compression, especially with vertebral metastases. Competitive blockade with no surge describes the antagonists; hyperglycemia and QT prolongation are separate androgen-deprivation warnings that do not explain back pain and leg weakness.

D. Cyclosporine is a strong OATP1B1 inhibitor that raises elagolix levels — a contraindication — Elagolix is contraindicated with OATP1B1 inhibitors that significantly increase its plasma concentrations, such as cyclosporine, because of the increased risk of adverse reactions. It is an oral GnRH antagonist that suppresses LH and FSH and lowers estradiol, so it neither causes a flare nor acts as an estrogen.

B. To prevent a premature LH surge by competitively blocking pituitary GnRH receptors — Ganirelix competitively blocks pituitary GnRH receptors, rapidly and reversibly suppressing LH (more than FSH) without an initial release, which inhibits premature LH surges during controlled ovarian hyperstimulation. hCG, not ganirelix, is given to trigger ovulation, and a flare followed by downregulation describes the agonists.

A. Combination with norethindrone acetate add-back and a BMD assessment first — Leuprolide induces a hypoestrogenic state with BMD loss that may not fully reverse; norethindrone acetate add-back reduces that loss, and the label says not to retreat without it and to assess BMD before retreatment. Antagonists cause no flare, CYP3A4 inhibition has no role here, and iron is given with leuprolide to correct fibroid-related anemia, not to protect bone.

D. The testis — primary hypogonadism, a labeled indication for replacement — Low testosterone with gonadotropins above the normal range is primary hypogonadism: the testis fails and loss of negative feedback raises LH and FSH. Klinefelter syndrome is the most common congenital cause and is named in the testosterone labels. Failed GnRH-neuron migration is Kallmann syndrome, which lowers LH and FSH. 5α-reductase deficiency gives normal testosterone and LH with low DHT, and androgen insensitivity gives elevated testosterone and LH.

B. Feedback inhibition of pituitary LH and FSH, so the testis is no longer stimulated — Exogenous androgens inhibit endogenous testosterone release through feedback inhibition of pituitary LH, and at large doses suppress spermatogenesis through feedback inhibition of pituitary FSH; testicular atrophy, subfertility and infertility are reported with anabolic steroid misuse. Elevated testosterone suppresses GnRH rather than stimulating it, and the FSH suppression is precisely what stops spermatogenesis. Testosterone and DHT both bind and activate androgen receptors; neither blocks them.

A. Aromatization of testosterone to estradiol — Gynecomastia on testosterone is due to peripheral aromatization of testosterone to estradiol, one of its two major active metabolites. DHT, made by 5α-reductase, drives the prostate, external genitalia and scalp follicles. Red cell production explains erythrocytosis, not breast growth. 17β-hydroxysteroid dehydrogenase is the step that converts androstenedione to testosterone in testosterone synthesis; the conversion that makes estradiol is aromatization.

D. A sensitive pregnancy test immediately before starting, and a non-hormonal contraceptive during therapy — Danazol is contraindicated in pregnancy: in utero exposure can cause androgenic effects on the female fetus, including clitoral hypertrophy, labial fusion and ambiguous genitalia. Its boxed warning recommends a sensitive pregnancy test immediately before starting and a non-hormonal method of contraception during therapy, and the label says therapy should begin during menstruation. Relying on ovulation suppression or a hormonal method does not meet that requirement.

D. It blocks the androgen receptor so the initial testosterone surge from leuprolide causes no flare — A GnRH agonist first raises testosterone about 50% above baseline in the first weeks, which can cause tumor flare; an antiandrogen such as bicalutamide, started first, blocks the clinical response to that surge by competitively binding androgen receptors. Suppressing LH is what leuprolide itself does over time; bicalutamide acts on androgen receptors in the target tissue. CYP17 inhibition is abiraterone, and 5α-reductase inhibition is finasteride or dutasteride.

A. Abnormal external genitalia in a male fetus, because DHT is needed to form them — Finasteride blocks conversion of testosterone to DHT, which is needed for normal development of male genitalia, so it may cause abnormalities of the external genitalia of a male fetus; females who are or may be pregnant should not handle crushed or broken tablets. Finasteride lowers DHT rather than raising it, and DHT has no significant role in normal female physiology. The coating prevents contact only if tablets are not broken or crushed, and the warning appears on both the finasteride and dutasteride labels.

D. Increased adrenal mineralocorticoid production from CYP17 inhibition — Abiraterone inhibits CYP17, and blocking it can increase adrenal mineralocorticoid production, causing hypertension, hypokalemia and fluid retention; blood pressure is controlled and potassium corrected before and during treatment. Abiraterone is an androgen biosynthesis inhibitor, not a receptor blocker or a 5α-reductase inhibitor. Adrenocortical insufficiency follows interruption of the corticosteroid, infection or stress, and its signs may be masked by mineralocorticoid excess.

C. Doubled, for comparison with normal values in untreated men — Dutasteride reduces serum PSA by about 50% within 3 to 6 months, so an isolated value in a man treated for 3 months or more is doubled for comparison with untreated men. PSA remains useful: a new baseline is set and any confirmed rise from the lowest value is evaluated, because it may signal prostate cancer.

A. Nitrates increase cGMP formation while sildenafil blocks its breakdown, causing severe hypotension — Nitrates are NO donors that increase cGMP formation; sildenafil inhibits PDE5, the enzyme that degrades cGMP, so the combination produces severe, life-threatening hypotension — organic nitrates in any form are contraindicated. Sildenafil does not block guanylate cyclase; NO activates it. Sildenafil has systemic vasodilatory, not vasoconstricting, properties, and it has no direct relaxant effect on isolated corpus cavernosum — it works only by amplifying NO-driven cGMP.

D. Start sildenafil at the lowest dose, since he is already stable on the α-blocker — PDE5 inhibitors and α-adrenergic blockers are both vasodilators with additive blood-pressure lowering that can cause symptomatic hypotension. Patients should be stable on the α-blocker before a PDE5 inhibitor is started, and the PDE5 inhibitor should be started at the lowest dose. Sildenafil also lowers blood pressure further with other antihypertensives, so adding one increases the risk, and the receptor difference does not prevent the additive effect.

B. At least 48 hours should elapse after the last dose before a nitrate is considered, with close hemodynamic monitoring — Tadalafil’s mean terminal half-life is 17.5 hours. If a nitrate is medically necessary in a life-threatening situation, at least 48 hours should elapse after the last tadalafil dose before it is considered, and then only under close medical supervision with hemodynamic monitoring. About 4 hours is sildenafil’s half-life, not a nitrate interval, and even for sildenafil a safe interval has not been determined. The label allows a nitrate after the interval, so it is not permanently ruled out.

D. PDE6 inhibition in the retina — Sildenafil is only about 10-fold more selective for PDE5 than for PDE6, a retinal phototransduction enzyme, and this lower selectivity is thought to underlie the transient blue/green color-discrimination changes. NAION presents as sudden loss of vision, not a transient color tinge. Sildenafil is about 4,000-fold more selective for PDE5 than for PDE3, the cardiac contractility enzyme. PDE11 inhibition is a tadalafil property whose clinical consequence has not been defined.

D. Myometrial oxytocin receptor concentration rises through pregnancy and peaks at term — Oxytocin receptors in the myometrium increase greatly during pregnancy and peak in early labor at term; the uterus’s sensitivity, set by the receptor concentration, determines the response, so before term a higher rate may be needed. The half-life is shorter, not longer, in late pregnancy; oxytocin raises inositol triphosphate and intracellular calcium; and oxytocinase activity rises, peaking near term.

C. Stop the oxytocin and free water and replace them with isotonic saline — Oxytocin and vasopressin differ in only two amino acids, and oxytocin’s intrinsic antidiuretic effect increases water reabsorption; large doses over long periods, especially with oral fluids, cause water intoxication with convulsions. Treatment is to stop the oxytocin infusion and any free water and replace electrolyte-free water with isotonic saline. Continuing or increasing oxytocin keeps the antidiuretic effect going, and the label’s infusion is made in 0.9% sodium chloride or Ringer’s lactate.

A. Stop the oxytocin infusion and give the mother oxygen in a lateral position — Hyperstimulation causes uteroplacental hypoperfusion, variable decelerations and fetal hypoxia, and can rupture the uterus. The label says to stop the infusion immediately in uterine hyperactivity or fetal distress and to give the mother oxygen, preferably in a lateral position; with a plasma half-life of about 1–6 minutes, the effect fades quickly. More oxytocin or waiting prolongs the overstimulation, and an intramuscular dose acts for 2–3 hours.

D. Oxytocin released from the posterior pituitary contracting myoepithelial cells around the alveolar ducts — Suckling triggers oxytocin release from the posterior pituitary, and oxytocin contracts the myoepithelial cells of the alveolar ducts, forcing milk out; like labor, the milk-ejection reflex runs on positive feedback. Oxytocin is stored in the posterior, not anterior, pituitary, and it ejects milk already made by squeezing the ducts rather than by increasing synthesis.

D. Carboprost — Carboprost is labeled for postpartum hemorrhage from atony that has not responded to oxytocin and massage, and its main cautions — asthma and active cardiopulmonary, renal or hepatic disease — do not apply here. Methylergonovine is contraindicated in hypertension and toxemia because of its vasoconstriction. Dinoprostone is labeled for cervical ripening before induction, and misoprostol’s only labeled indication is reducing NSAID-induced gastric ulcers; its use in postpartum hemorrhage is outside that indication.

B. A PGF2α analog contracting bronchial smooth muscle — Carboprost is a 15-methyl analog of PGF2α; besides the myometrium it contracts other smooth muscle and may cause transient bronchoconstriction, which is why asthma calls for caution. Vasoconstriction is the effect of the ergot methylergonovine, not carboprost; large doses of carboprost raise rather than lower blood pressure, by contracting vascular smooth muscle; and it stimulates rather than relaxes gastrointestinal smooth muscle — the cause of its vomiting and diarrhea.

C. Remove the insert and start oxytocin at least 30 minutes later — Dinoprostone stimulates PGF2α production, which sensitizes the myometrium to oxytocin, and prostaglandins potentiate oxytocin. Cervidil is removed at the onset of active labor, and at least 30 minutes is allowed before an oxytocic is started; concurrent IV oxytocics are contraindicated. Waiting for tachysystole, or starting oxytocin with the insert in place, invites the hyperstimulation the interval is meant to prevent.

B. Confirm a negative serum pregnancy test within 2 weeks, use effective contraception, and start on the second or third day of a period — Misoprostol is labeled to reduce NSAID-induced gastric ulcers in high-risk patients, but it also contracts the pregnant uterus and its boxed warning covers birth defects, abortion, premature birth and uterine rupture. A woman of childbearing potential at high risk may use it after a negative serum pregnancy test within 2 weeks, with effective contraception, starting on the second or third day of her next period — so it is not banned outright. Magnesium-containing antacids increase its diarrhea and are avoided.

A. Stop the infusion and give IV calcium gluconate — Disappearance of the patellar reflex is a sign of magnesium intoxication, and respiratory paralysis can follow as levels rise; falling urine output reduces magnesium’s only route of excretion. The magnesium is stopped and IV calcium gluconate given as the antidote, which antagonizes magnesium’s effects immediately but temporarily. Increasing or continuing the infusion worsens the toxicity, and furosemide only adds to removal once the magnesium has been stopped.

D. Fetal hypocalcemia and bone abnormalities such as demineralization and osteopenia — The label warns that continuous administration beyond 5–7 days can cause fetal hypocalcemia and bone abnormalities, including skeletal demineralization, osteopenia and neonatal fractures, and that its use for preterm labor is unapproved. Magnesium reaches the fetus — newborns can show neuromuscular or respiratory depression after an infusion, especially one lasting more than 24 hours before delivery — and given within 24 hours of early preterm birth it reduces, rather than increases, the risk of cerebral palsy.

C. Magnesium sulfate is contraindicated because neuromuscular function can worsen even at low concentrations — In myasthenia gravis, neuromuscular function can deteriorate even at lower magnesium concentrations, so magnesium sulfate is contraindicated; magnesium and phenytoin both cause muscle weakness that can lead to a myasthenic crisis, so levetiracetam or valproic acid is used instead. Magnesium blocks neuromuscular transmission by reducing acetylcholine release, and neuromuscular blocking agents add to that block rather than preventing weakness.

A. Additive CNS depression and excessive neuromuscular block, so these drugs are dosed with caution — Magnesium has additive CNS depressant effects with opioids, hypnotics and anesthetics, so their doses are adjusted with caution, and excessive neuromuscular block has occurred when parenteral magnesium is given with a neuromuscular blocking agent. Magnesium itself blocks neuromuscular transmission, so it adds to these drugs rather than antagonizing or shortening them, and its actions extend well beyond the uterus.

C. β-adrenergic stimulation — cardiac β1 activity and β-agonist metabolic effects — Terbutaline is a β-adrenergic agonist; its maternal cardiac complications are suggested to stem from β1 activity in cardiac muscle, and β-agonists cause transient hyperglycemia and hypokalemia, possibly from intracellular potassium shifting. It stimulates rather than blocks β2 receptors. Calcium channel blockade is how nifedipine works, and prostaglandin synthesis inhibition is indomethacin’s mechanism.

A. Premature closure of the fetal ductus arteriosus — NSAIDs, including indomethacin, at about 30 weeks of gestation and later increase the risk of premature closure of the fetal ductus arteriosus, and from about 20 weeks they can cause fetal renal dysfunction leading to oligohydramnios. Neonatal hypoglycemia and fetal tachycardia are terbutaline’s fetal and neonatal effects, and hypokalemia is a maternal effect of β-agonists such as terbutaline, not a fetal risk of indomethacin.

C. A short delay of two to seven days to allow antenatal corticosteroids and transfer — Tocolysis is intended to prolong gestation for two to seven days, providing a window for transfer, antenatal corticosteroids for fetal lung maturity and GBS prophylaxis; it is not intended to reach term. Tocolytics are not recommended as prophylaxis. Oral terbutaline is boxed against any tocolysis, and terbutaline should not be used for maintenance tocolysis at home.

D. Calcium channel blockade causing vasodilation and hypotension — Nifedipine blocks calcium entry to relax the myometrium, and it also has a hypotensive effect: flushing, headache, dizziness and hypotension are its maternal risks, and occasional patients have excessive, poorly tolerated hypotension. β2 stimulation is terbutaline’s mechanism, COX inhibition is indomethacin’s, and oxytocin-receptor antagonism belongs to atosiban and retosiban, which are not approved in the United States.

A. Methylergonovine — Methylergonovine is labeled after delivery of the placenta for uterine atony and hemorrhage, and its contraindications — hypertension, toxemia — do not apply to a normotensive patient. Carboprost can cause transient bronchoconstriction and is avoided in asthmatics. Dinoprostone is labeled for cervical ripening before induction, and terbutaline, a β2 agonist, relaxes rather than contracts smooth muscle.

B. To provide fetal neuroprotection — Magnesium sulfate given within 24 hours of early preterm birth provides neuroprotection for the neonate, reducing the risk of cerebral palsy. Its continuous use for preterm labor is an unapproved treatment, and tocolysis aims only at a short delay, not term. Eclamptic seizure prevention is its labeled use in preeclampsia, which she does not have, and cervical ripening is the role of dinoprostone.

C. Indomethacin — pregnancy at about 30 weeks or later — NSAIDs, including indomethacin, are avoided at about 30 weeks of gestation and later because they increase the risk of premature closure of the fetal ductus arteriosus. Asthma is a caution for carboprost, not methylergonovine, whose contraindications are hypertension and toxemia. Oxytocin is labeled to control postpartum bleeding, and terbutaline’s box is against prolonged tocolysis beyond 48–72 hours and any oral tocolysis.

A. Carboprost — Strong and moderate CYP3A4 inhibitors such as clarithromycin should not be coadministered with methylergonovine, because ergots with potent CYP3A4 inhibitors have caused vasospasm with cerebral or limb ischemia. Carboprost is labeled for hemorrhage from atony unresponsive to conventional management, and her history has none of its cautions or contraindications. Nifedipine inhibits calcium entry and relaxes the uterus, and misoprostol’s labeled indication is NSAID-induced gastric ulcers.

D. Etonogestrel implant — Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptives, particularly over 35, so combined methods — including the ring — should not be used by women over 35 who smoke; the ring’s VTE risk is similar to that of pills. The medroxyprogesterone injection carries a boxed warning for loss of bone mineral density. Epidemiological studies have not linked progestin-only preparations to MI, stroke or VTE, and the implant is among the most effective methods.

A. Copper IUD — The copper IUD is a postcoital option that does not involve progestins; a meta-analysis found it more effective than levonorgestrel-containing methods for emergency contraception, and it increases continued contraceptive use. Levonorgestrel is a progestin that binds progesterone and androgen receptors, ulipristal is a selective progesterone receptor modulator, and a combined pill contains both a progestin and an estrogen.

B. Fezolinetant — Fezolinetant, a neurokinin 3 receptor antagonist, blocks neurokinin B signaling on KNDy neurons in the thermoregulatory center and is indicated for moderate to severe vasomotor symptoms due to menopause; it showed no clear trends in sex hormones. Oral estradiol acts on nuclear estrogen receptors, and a woman with a uterus takes it with a progestogen because unopposed estrogen raises endometrial cancer risk. Medroxyprogesterone is itself a progestin, added to estrogen to reduce endometrial hyperplasia. Conjugated estrogens with bazedoxifene pairs estrogens with an agent that is an agonist in some estrogen-sensitive tissues and an antagonist in the uterus.

D. Her VTE risk is highest in the first year of use and when restarting after a break of 4 weeks or longer — The risk of VTE is highest during the first year of combined-pill use and when restarting after a break of 4 weeks or longer. Pregnancy increases VTE risk as much as or more than the pill does, and ring users have a VTE risk similar to pill users. Elevated estrogen levels mediate the increased synthesis of coagulation factors.

D. Toremifene (Fareston) — Toremifene, a SERM for metastatic breast cancer in postmenopausal women, carries a boxed warning for dose- and concentration-related QT prolongation that can lead to torsade de pointes, and it should not be prescribed with congenital or acquired long QT syndrome. Tamoxifen’s box is uterine malignancies, stroke and pulmonary embolism; raloxifene’s is venous thromboembolism and death from stroke; and anastrozole’s labeled risks are arthralgia, bone loss and raised cholesterol.

A. Bone density tends to fall on anastrozole, whereas it rose on tamoxifen — Aromatase inhibitors lower circulating estrogen and so reduce bone mineral density, with more fractures; compared with tamoxifen, bone density fell on anastrozole while it rose on tamoxifen, which acts as an estrogen agonist in bone after menopause. Anastrozole is an enzyme inhibitor, not a bone agonist, and bone status is managed as for other postmenopausal women at similar fracture risk.

C. Goserelin (Zoladex) — Goserelin, a GnRH agonist, downregulates pituitary GnRH receptors with continuous exposure and suppresses ovarian estradiol; it is labeled for palliative treatment of advanced breast cancer in pre- and perimenopausal women. Anastrozole alone would raise gonadotropins and stimulate the ovary before menopause, which is why aromatase inhibitors are labeled for postmenopausal women; clomiphene raises gonadotropins to induce ovulation; and raloxifene is labeled for postmenopausal osteoporosis and breast-cancer risk reduction.

B. Tadalafil — Tadalafil is labeled for erectile dysfunction, for the signs and symptoms of BPH, and for both together. Finasteride treats symptomatic BPH, but impotence and decreased libido are among its common adverse reactions; sildenafil (Viagra) is labeled for erectile dysfunction; and bicalutamide is an androgen receptor inhibitor for metastatic prostate cancer.

D. Enzalutamide — Seizure occurred in 0.6% of patients on enzalutamide and in 2.2% of those with predisposing factors for seizure; it is permanently stopped if a seizure occurs. Abiraterone’s signature risk is mineralocorticoid excess; degarelix is a GnRH antagonist whose label warns of QT prolongation; and dutasteride is a 5α-reductase inhibitor for BPH.

C. Abiraterone — Abiraterone inhibits CYP17, the enzyme required for androgen biosynthesis that is expressed in testicular, adrenal and prostatic tumor tissue; it is given with a corticosteroid and a GnRH analog. Finasteride blocks the conversion of testosterone to DHT rather than androgen synthesis, bicalutamide blocks the androgen receptor, and spironolactone is a mineralocorticoid receptor antagonist that also binds androgen receptors.

B. Anastrozole — Anastrozole is indicated for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, and in the ATAC trial it had fewer venous thromboembolic events than tamoxifen. Tamoxifen increases thromboembolic events, including deep vein thrombosis and pulmonary embolism. Tamoxifen should not be given with anastrozole: the combination showed no efficacy benefit over tamoxifen and lowered anastrozole concentrations.

C. Failure of GnRH-producing neurons to migrate — Pulsatile GnRH drives LH and FSH secretion. In Kallmann syndrome, GnRH-producing neurons fail to migrate, so LH, FSH, testosterone and sperm count fall, and olfactory dysfunction such as anosmia distinguishes it from other causes of hypogonadotropic hypogonadism. Testicular failure, as in Klinefelter syndrome, raises LH and FSH above the normal range through lost negative feedback. Androgen insensitivity shows elevated testosterone and LH, and 5α-reductase deficiency shows normal testosterone and LH with low DHT.

A. IV oxytocin — WHO recommends IV oxytocin as the first-line uterotonic for treating postpartum hemorrhage, including when the woman has already received it for prevention; a rapid IV bolus is avoided. Carboprost is labeled for hemorrhage from atony that has not responded to conventional management, including IV oxytocin and uterine massage. Methylergonovine should not be given IV routinely, because it can cause sudden hypertensive and cerebrovascular accidents. Treating serious postpartum hemorrhage with misoprostol is outside its approved indication, which is reducing the risk of NSAID-induced gastric ulcers.

B. Manage her bone status as for other postmenopausal women at similar fracture risk, for example with a bisphosphonate — Women on anastrozole should have their bone status managed by the guidelines for postmenopausal women at similar risk of fragility fracture, and bisphosphonate treatment preserved bone density in most patients at risk of fracture. Estrogen-containing therapies should not be used with anastrozole, because they may diminish its action. Bone mineral density loss is an estrogen-deprivation effect of the aromatase inhibitors as a class, and ospemifene should not be used in women with a history of breast cancer.

A. After an initial stimulation, chronic exposure downregulates pituitary GnRH receptors — After an initial stimulation of GnRH receptors, chronic leuprolide downregulates them, reducing LH and FSH release and the ovarian and testicular production of estradiol and testosterone; the effect reverses when it is stopped. Competitive receptor blockade with no detectable initial gonadotropin release describes antagonists such as ganirelix. A progestogen slows GnRH pulse frequency through negative feedback at the hypothalamus, whereas leuprolide acts at the pituitary receptor. Blocking the conversion of androgens to estrogens is the action of aromatase inhibitors.

D. Oxytocin acts through positive feedback, whereas ADH shows negative feedback — Oxytocin is one of the few hormones with positive feedback — its release leads to actions that stimulate more release, as the fetal head on the cervix does until delivery — whereas ADH shows negative feedback. Oxytocin and vasopressin differ in only two of their eight amino acids, which is why oxytocin has an intrinsic antidiuretic effect that can cause water intoxication. Oxytocin is made in the paraventricular nucleus of the hypothalamus and released from the posterior pituitary.

A. Conjugated estrogens with bazedoxifene — Conjugated estrogens with bazedoxifene is indicated in women with a uterus for moderate to severe vasomotor symptoms; bazedoxifene acts as an estrogen antagonist in the uterus and reduces the risk of endometrial hyperplasia, and women taking it should not take progestins. Estrogen alone would grow her endometrial lining unopposed, raising endometrial cancer risk in a woman with a uterus. Ospemifene is indicated for dyspareunia and vaginal dryness from menopausal vulvar and vaginal atrophy and has estrogen agonist effects in the endometrium. Tamoxifen has an estrogen-agonistic effect on the uterus and a boxed warning for uterine malignancies.

C. The estrogen component raised thyroxine-binding globulin, and her replacement may need to increase — The estrogen component of combined pills may raise serum thyroxine-binding globulin. Women with normal thyroid function compensate by making more thyroid hormone, so their free T4 and T3 stay normal, but women who depend on thyroid replacement may need increased doses. Transdermal estradiol avoids liver metabolism and causes no change in thyroxine-binding globulin at standard doses.

D. Methylergonovine — Methylergonovine’s contraindications include pregnancy, along with hypertension and toxemia; it is given after delivery of the placenta for uterine atony, hemorrhage and subinvolution. Oxytocin is indicated for medically indicated induction of labor, Cervidil for cervical ripening at or near term before induction, and magnesium sulfate for the prevention and control of seizures in preeclampsia and eclampsia.

C. A postmenopausal woman taking tamoxifen — In bone, tamoxifen stimulates estrogen receptors — an agonist effect that may help prevent osteoporosis in postmenopausal women — and in the ATAC bone substudy women on tamoxifen had a mean increase in spine and hip bone density, while women on anastrozole had a mean decrease. In premenopausal women, adjuvant tamoxifen has been associated with significant bone loss, particularly in the lumbar spine. Leuprolide induces a hypoestrogenic state that causes bone loss, some of which may not be reversible.

D. Estrogen solely for prevention is considered only at significant risk, and a non-estrogen medication should be carefully considered — When estrogen is prescribed solely to prevent postmenopausal osteoporosis, it should be considered only for women at significant risk, and non-estrogen medication should be carefully considered. Hormone therapy is not supported for preventing cardiovascular disease, dementia or other chronic diseases. Raloxifene has estrogen-agonistic effects on bone and is indicated for the treatment and prevention of postmenopausal osteoporosis.

B. It lowers estrogen, so reduced negative feedback raises gonadotropin secretion — In premenopausal women, aromatase inhibitors increase gonadotropin secretion because estrogen’s negative feedback on the pituitary falls, which stimulates the ovaries; they may be used off-label to induce ovulation. Occupying hypothalamic estrogen receptors so that rising estradiol gives no negative feedback is clomiphene’s mechanism. Letrozole is a nonsteroidal, reversible competitive inhibitor, whereas irreversible inactivation as a false substrate is exemestane’s action. Aromatase in the granulosa cells converts theca-cell androgens to estrogens, so premenopausal ovaries do express it.