Menopausal Hormone Therapy, Progestins & Antiprogestins

Estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. Estrogens act by binding nuclear receptors — estrogen receptors α and β, in proportions that vary from tissue to tissue. In cycling women the ovarian follicle supplies the estradiol; after menopause most estrogen comes from peripheral conversion of adrenal androstenedione to estrone, and estrone and estrone sulfate become the most abundant circulating estrogens. Without ovarian estrogen, negative feedback falls away and LH and FSH rise; estrogen therapy lowers them again.

Hot flashes come from the hypothalamus. Estrogen therapy is thought to act there by influencing the neurokinin B signaling pathway, which regulates reproductive and thermoregulatory responses and interacts with the median preoptic nucleus. That same pathway is the target of the non-hormonal drug fezolinetant, below.

Estrogen therapy alone makes the endometrial lining grow unopposed. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times that of non-users and depends on the duration of treatment and the estrogen dose, which is the first item in the boxed warnings. Adding a progestin has been shown to reduce the risk of endometrial hyperplasia, a possible precursor of endometrial cancer, because in the presence of adequate estrogen progesterone transforms a proliferative endometrium into a secretory one. After a hysterectomy, a progestin is unnecessary.

The progestin is not free: compared with estrogen alone, adding it carries possible risks, including an increased risk of breast cancer. Duavee takes another route to the same protection. It pairs conjugated estrogens with bazedoxifene, an estrogen agonist/antagonist that is an antagonist in the uterus, so the bazedoxifene component reduces the hyperplasia the estrogen would cause; women taking it do not add progestins, other estrogens or other estrogen agonist/antagonists. (Raloxifene is on the Bone & Calcium Agents page; the estrogen agonist/antagonist class has its own later page.)

The boxed warnings come from the Women’s Health Initiative. Its estrogen-alone substudy reported increased risks of stroke and DVT; its estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism, myocardial infarction and invasive breast cancer. Estrogen alone was not associated with an increased risk of invasive breast cancer in that substudy. In women 65 or older, both raised the risk of probable dementia, and it is unknown whether this applies to younger postmenopausal women. Estrogen therapy is not used to prevent cardiovascular disease or dementia, and it is given at the lowest effective dose for the shortest duration consistent with the goals and risks.

Age matters: subgroup analyses of women 50 to 59 suggest no increased risk of stroke with estrogen alone. How each product words the box differs. Provera’s box covers cardiovascular disorders, breast cancer and probable dementia with estrogen plus progestin; Duavee’s covers endometrial cancer, cardiovascular disorders and probable dementia; the current Estring and Prometrium labels carry the WHI findings as warnings without a box.

Oral estrogen passes through the liver first. Estrogen labels list the result among their laboratory effects: accelerated prothrombin and partial thromboplastin times, increased factors II, VII, VIII, IX, X and XII and fibrinogen, and decreased antithrombin III. Oral estrogen also increases activated protein C resistance, raising the risk of a clot, and oral estrogen carries a higher chance of VTE and gallstones, raises thyroid-binding globulin, and can sharply raise triglycerides. (The same estrogen–liver clotting story drives the risks of ethinyl estradiol on the Hormonal Contraceptives page.)

Transdermal estradiol bypasses the hepatic metabolism that produces activated protein C resistance and, at standard doses, does not change thyroid-binding globulin or hepatic coagulation proteins; it has minimal impact on VTE risk, which makes it the better choice for most women, especially those who smoke or have migraines. Vaginal delivery also circumvents first-pass metabolism. The boxed clot risk still appears on the patch label, and estrogens remain contraindicated after DVT, PE, stroke or MI and in thrombophilia.

Estrogen receptors in the vagina, vulva, urethra and bladder trigone maintain blood flow, epithelial thickness, elasticity and moisture. Estrogen keeps the vaginal epithelium maturing and rich in glycogen, which lactobacilli convert to lactic acid, holding the pH at 3.5 to 5.0. When estrogen falls, glycogen and lactobacilli decline, the pH rises above 5, and the epithelium thins — the genitourinary syndrome of menopause (GSM), with dryness, painful intercourse, urinary urgency and recurrent urinary tract infections. Unlike hot flashes, it progresses without treatment.

For symptoms limited to the vagina, the labels say a topical vaginal product should be considered first. Vaginal creams, tablets or inserts, and rings are similarly effective, and low-dose local estrogen has not been shown to raise total systemic estrogen levels, and progestin and routine endometrial surveillance are not needed with local estrogen — though any postmenopausal bleeding still requires investigation. The Estring label notes that systemic exposure is lower than with systemic estrogens, so the relevance of the systemic risks to it is not known.

Progesterone comes from the corpus luteum and, after about the tenth week of pregnancy, from the placenta. It binds a nuclear progesterone receptor (isoforms PR-A and PR-B, which oppose each other) and alters gene transcription. In the luteal phase it prepares the endometrium for implantation; if no implantation occurs, progesterone falls and the endometrium sloughs. In pregnancy it reduces myometrial contractility and inhibits lactation, and it thickens cervical mucus — the property progestin contraceptives use (Hormonal Contraceptives page). The progestin-challenge test uses that withdrawal: after a progestin is stopped, failure to bleed points to too little estrogen, an injured endometrium or a blocked outflow tract.

Endogenous progesterone lasts only minutes, while synthetic progestins last hours. Micronized oral progesterone (Prometrium) is chemically identical to ovarian progesterone, with oral bioavailability increased by micronization and by food. It and oral medroxyprogesterone (Provera) are labeled to prevent endometrial hyperplasia during estrogen therapy and to treat secondary amenorrhea; Provera also treats abnormal uterine bleeding from hormonal imbalance, and vaginal progesterone gel (Crinone) supplies progesterone in assisted reproduction. Oral progesterone can cause dizziness and drowsiness.

A pregnancy depends on progesterone. Mifepristone competes with progesterone at its receptor, and in pregnancy it also sensitizes the myometrium to the contractions that prostaglandins cause. Mifepristone is labeled, in a regimen with misoprostol (a prostaglandin, taken after the mifepristone; Uterotonics page), for medical termination of intrauterine pregnancy through 70 days gestation. Together they cause decidual necrosis, myometrial contractions and cervical softening, leading to expulsion, and follow-up confirms that termination is complete.

Its other receptor actions explain several contraindications. At higher doses mifepristone blocks cortisol at the glucocorticoid receptor — the basis of its separate use in Cushing syndrome (Korlym, on the Adrenal Agents page) — so chronic adrenal failure and long-term corticosteroid therapy are contraindications because of the risk of acute adrenal insufficiency. It will not end an ectopic pregnancy, so a confirmed or suspected ectopic pregnancy is a contraindication, and hemorrhagic disorders or anticoagulants are excluded because of heavy bleeding. Its boxed warning is rare but serious infection or bleeding after any abortion, and it is distributed only through a REMS.

Fezolinetant is a neurokinin 3 (NK3) receptor antagonist. It blocks neurokinin B binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neurons to modulate activity in the thermoregulatory center, treating moderate to severe vasomotor symptoms of menopause without any hormone; treatment showed no clear trends in the sex hormones measured. Its affinity for NK3 receptors is more than 450-fold higher than for NK1 or NK2.

Its risks are its own. The boxed warning is hepatotoxicity, with serious cases within 40 days of starting, so liver tests precede and follow initiation. It is cleared mainly by CYP1A2, so CYP1A2 inhibitors — which raise its exposure up to several-fold — are contraindicated, as are cirrhosis and severe renal impairment.