Progesterone

Progesterone is the hormone of the second half of the menstrual cycle and the first two trimesters of pregnancy. Its name is literal — pro-gestation, the hormone that makes gestation possible by preparing and holding the endometrium for implantation and suppressing the uterine contractions that would expel an embryo. Outside the reproductive tract, it doubles as a neurosteroid with real effects on sleep, mood, and temperature.

At a glance

What it does

In reproductive-age women, progesterone's dominant job is preparing the endometrium for implantation and sustaining a pregnancy if one occurs. During the luteal phase (the second half of the cycle, after ovulation), the corpus luteum — the transformed remnant of the ruptured follicle — produces progesterone in large amounts. This converts the proliferative endometrium into the secretory endometrium: glands elongate, blood supply expands, and the uterine lining becomes a receptive substrate for an embryo. Progesterone also thickens cervical mucus, damps uterine contractility, and suppresses further ovulation for the rest of that cycle.

If pregnancy occurs, the embryo signals the corpus luteum to persist, progesterone continues rising, and at roughly 8-10 weeks the placenta takes over as the dominant source and sustains the pregnancy through delivery. A sudden drop in progesterone triggers labor; a premature drop drives miscarriage. Every significant reproductive event in a woman's life — menstruation, pregnancy, parturition — is essentially a progesterone trajectory decision.

Outside the uterus, progesterone is a neurosteroid. Its metabolite allopregnanolone is a positive allosteric modulator of GABA-A receptors — the same target as benzodiazepines and alcohol. This is why oral progesterone at reasonable doses reliably produces drowsiness and anxiolysis in most women. It is also why the rapid late-luteal drop in progesterone is implicated in premenstrual mood shifts and PMDD — you are experiencing something functionally analogous to withdrawal from an endogenous GABAergic agent.

Progesterone is also thermogenic. Basal body temperature rises 0.3-0.5°C in the luteal phase and falls back with menstruation. This is the basis of basal body temperature tracking as a rough fertility awareness method — you can see ovulation retrospectively by detecting the temperature shift 24-48 hours after it happens.

How it works

Progesterone synthesis follows the steroid pathway from cholesterol through pregnenolone. The corpus luteum is the dominant post-ovulation producer; in early pregnancy it continues until the placenta takes over in the second trimester and drives levels an order of magnitude higher. Minimal amounts come from the adrenal cortex as an intermediate in cortisol and aldosterone synthesis, and from the testes as a minor byproduct.

Progesterone acts through two main nuclear receptors, PR-A and PR-B, expressed in different patterns across uterus, breast, ovary, and brain. The receptor dimer binds progesterone response elements in DNA and modulates target gene transcription. Some effects — especially neurosteroid actions via allopregnanolone — happen faster through direct GABA-A modulation without requiring transcription.

The menstrual cycle, reduced to its hormonal skeleton: FSH recruits a dominant follicle, granulosa cells produce rising estradiol, estradiol triggers the LH surge, the LH surge triggers ovulation, and the ruptured follicle transforms into the corpus luteum. The corpus luteum produces estradiol and, dominantly, progesterone, driving the luteal phase. If pregnancy does not occur, the corpus luteum dies after about 14 days, progesterone crashes, and menstruation follows. If pregnancy does occur, hCG from the implanting embryo rescues the corpus luteum.

Levels & ranges

Progesterone in reproductive-age women is almost entirely a question of cycle phase. Follicular phase: 0.2-1.5 ng/mL. Mid-luteal (day 21 of a 28-day cycle) peak: 5-25 ng/mL. A mid-luteal progesterone above roughly 3 ng/mL confirms ovulation retrospectively; under 3, ovulation probably did not happen that cycle.

Pregnancy drives progesterone into a different range entirely: roughly 10-40 ng/mL in the first trimester, rising to 30-80 in the second, and 100-300+ in the third as the placenta dominates. Declining progesterone in the third trimester or any significant progesterone drop in a pregnant woman with symptoms is clinically concerning.

Men run a baseline of 0.1-0.5 ng/mL as a byproduct of adrenal and gonadal steroidogenesis. It is not clinically followed as a primary hormone in men.

Postmenopausal women running on endogenous hormones have progesterone near zero — the ovaries have stopped producing it along with estradiol. Women on menopause hormone therapy with progesterone added (to protect the endometrium from unopposed estrogen) have pharmacologic levels that depend on route, formulation, and dose.

When it goes wrong

Luteal phase deficiency — a cycle that ovulates but produces inadequate progesterone and thus an insufficient secretory endometrium — is a controversial diagnosis in reproductive endocrinology. Some women with recurrent early miscarriage benefit from luteal progesterone supplementation; the larger randomized trials (PROMISE, PRISM) have shown benefit specifically in women with bleeding in early pregnancy and a history of prior loss, but not in unselected populations. It is a real but narrowly indicated intervention.

Perimenopause is partly a progesterone story. As ovulation becomes less reliable in a woman's 40s, cycles without ovulation produce no corpus luteum and no meaningful progesterone. Estrogen continues and may even run high in some cycles, producing a "progesterone deficient" hormonal environment — often experienced as heavier or more erratic periods, breast tenderness, sleep disruption, anxiety, and mood changes several years before any estradiol decline is obvious. The framing of perimenopause as "low estrogen" is often wrong in this phase; it is frequently low progesterone with relatively intact or high estrogen.

PMDD (premenstrual dysphoric disorder) is a more severe form of PMS that causes real disability. It is not about absolute progesterone levels but about individual sensitivity to the normal cyclic changes — particularly the rapid late-luteal drop in progesterone and allopregnanolone. Treatment options include SSRIs (effective luteal-phase dosing), hormonal contraceptives that suppress the cycle entirely, and in severe cases GnRH agonist-induced chemical menopause.

Progesterone excess, when not iatrogenic or pregnancy-related, is uncommon and usually traces to ovarian or adrenal tumors or to congenital adrenal hyperplasia variants.

Interactions

Oral micronized progesterone (Prometrium, Utrogestan) is not pharmacologically equivalent to the synthetic progestins in most oral contraceptives and older HRT formulations. Oral micronized progesterone is bioidentical, produces meaningful allopregnanolone metabolites (hence the reliable sedating effect), and has a different risk profile for breast and cardiovascular outcomes than synthetic progestins like medroxyprogesterone acetate (MPA). The WHI findings that damaged HRT's reputation were with MPA specifically; subsequent observational work suggests micronized progesterone has a more favorable breast cancer and thromboembolism profile. This distinction is important and is often flattened in lay discussion.

Vaginal progesterone (gel or suppositories) reaches the uterus with first-pass to local tissue and achieves endometrial concentrations higher than the serum level suggests. It is the preferred route for luteal support in IVF and for certain preterm labor prevention indications. Transdermal progesterone creams are popular in wellness circles but have not reliably demonstrated adequate endometrial protection in women taking systemic estrogen — do not rely on them for that purpose.

Progestin-only contraceptives (pills, IUDs, implants) suppress ovulation, thicken cervical mucus, and thin the endometrium. Levonorgestrel IUDs (Mirena, Kyleena) deliver progestin primarily to the uterus with low systemic exposure, which is why they produce very different side effect profiles from systemic progestins.

SSRIs modulate PMDD symptoms likely through effects on allopregnanolone metabolism and serotonin-GABA crosstalk. Brexanolone (IV allopregnanolone) and its oral analogue zuranolone are FDA-approved for postpartum depression and represent a direct pharmacologic validation of the neurosteroid hypothesis of perimenstrual and peripartum mood.

Honest take

Sources

• Coomarasamy et al., NEJM (2019) — the PRISM trial on progesterone for threatened miscarriage, defining when luteal support genuinely helps.
• Fournier et al., Breast Cancer Research and Treatment — the E3N cohort data comparing micronized progesterone with synthetic progestins on breast cancer risk.
• Schumacher et al., Progress in Neurobiology — on progesterone and allopregnanolone as neurosteroids with GABA-A receptor effects.
• Prior, Endocrine Reviews — on perimenopause as a primarily progesterone-driven phase with distinct hormonal dynamics from menopause proper.
• Meltzer-Brody et al., Lancet (2018) — on brexanolone for postpartum depression, the proof-of-concept for neurosteroid therapy in mood disorders.