A progesterone-like shot failed its big test, and progesterone still helps in a few places

Key takeaways

• In April 2023, the FDA withdrew Makena after a required follow-up trial of 1,708 women found births before 35 weeks in 11.0% of those on the shot and 11.5% on placebo.
• A blood progesterone level above 3 ng/mL, drawn about a week before an expected period, shows that ovulation happened, but levels can swing sevenfold within hours.
• The American Society for Reproductive Medicine says “luteal phase deficiency” has no reliable test and hasn’t been proven to cause infertility or repeated miscarriage.
• In a trial of women bleeding in early pregnancy, those with three or more past miscarriages had 72% live births on progesterone versus 57% on placebo, and since 2021 British guidelines have recommended it for early bleeding after any past miscarriage.
• There’s no evidence the body turns wild yam into progesterone, and two wild yam progesterone creams we checked list lab-made progesterone and carry an FDA notice that they aren’t approved.

On April 6, 2023, the Food and Drug Administration withdrew its approval of Makena, a weekly shot meant to lower the risk of a second preterm birth, along with its generic versions¹².

The FDA had approved Makena in 2011 through a fast-track pathway called accelerated approval¹. That approval rested on a trial showing fewer births before 37 weeks, and it came with a condition: the company had to run a confirmatory trial².

That trial, called PROLONG, was nearly four times larger than the first². It enrolled 1,708 women at 93 centers, 41 of them in the United States³. Births before 35 weeks happened in 11.0% of women on the shot and 11.5% on placebo, a dummy shot³.

By our math, that’s about 5 fewer early births per 1,000 women, a gap small enough to be chance. Serious problems in newborns were no lower either: 5.6% with the drug versus 5.0% without³.

The FDA said the drug wasn’t shown to work in Black women, in other women, or in low-, medium- or high-risk groups². That mattered, because about 60% of the women in the original trial were Black, and FDA leaders noted preterm birth’s disproportionate toll on Black women¹².

If you received these shots in a past pregnancy, you followed the evidence your care team had at the time. The story is a reminder of how hard progesterone science has been. We walk through what the hormone does, what testing can tell you, and where treatment holds up.

Progesterone’s monthly job

Progesterone is the hormone of the second half of the menstrual cycle. After ovulation, a temporary gland called the corpus luteum forms on the ovary and starts making it⁶⁷.

Its main job is to ready the lining of the uterus for a fertilized egg⁶⁷. If no pregnancy starts, progesterone levels drop and the lining sheds as a period⁶.

It does other work, too. Progesterone thickens cervical mucus, which blocks sperm, and that’s the principle behind some birth control⁶. It also acts on the brain’s temperature center, which is why your resting temperature rises about 0.5 to 1 degree Fahrenheit after ovulation⁶.

Men and women both make some progesterone in the adrenal glands⁶. In men, the testes make it too, and it helps sperm mature⁶. It also works alongside estradiol to build bone⁶.

Our companion article on estrogen covers that partner hormone. Premenstrual mood changes, including the severe form called PMDD, get their own article later in this series.

In pregnancy, progesterone keeps the uterus calm

If an egg is fertilized and implants, the corpus luteum keeps making progesterone in early pregnancy. After about week 10, the placenta takes over⁶. Levels climb each trimester and peak in the last one⁷.

During pregnancy, progesterone helps quiet the muscle of the uterus, partly through breakdown products that act on chemical-signal receptors⁶. It also holds back milk production until after birth, when falling levels release that brake⁶.

Progesterone versus progestins. Progestins are lab-made compounds that act like progesterone⁷. They’re used in birth control, menopause hormone therapy and treatment for abnormal bleeding, in pills, shots, vaginal gels and intrauterine devices⁷. Makena’s ingredient, hydroxyprogesterone caproate, was one such progesterone-like drug².

Other products contain progesterone itself, made in a lab from plant starting materials¹³. Our article on “balance your hormones” claims explains the difference between FDA-approved “bioidentical” hormones and custom-mixed versions.

A progesterone test answers one question well

The most useful progesterone blood test answers a single question: did you ovulate this cycle?

The American Society for Reproductive Medicine (ASRM), a professional group of fertility specialists, explains how. The blood is drawn about one week before your next expected period, not on a fixed cycle day⁸. A level above 3 ng/mL is reasonable evidence that you recently ovulated⁸.

One number can’t do much more than that. Progesterone is released in pulses⁹. ASRM’s 2021 opinion says levels can swing sevenfold over a few hours, and its 2026 opinion cites swings of up to eightfold within 90 minutes⁸⁹. If your cycles regularly run 21 to 35 days, ASRM says extra ovulation testing usually isn’t needed⁸.

ASRM calls temperature charting often unreliable, and a medical reference hosted by the National Library of Medicine notes that some studies found it detected ovulation only about 22% of the time⁶⁸. Fertility awareness methods for avoiding or planning pregnancy get their own article later in this series.

What about “low progesterone”? The medical label is luteal phase deficiency, usually meaning a second half of the cycle that lasts 10 days or less⁹. In 2026, ASRM concluded that no test for it has proven reliable⁹.

Dating a biopsy of the uterine lining varied between reviewers and cycles, and ASRM doesn’t recommend it⁹. Short luteal phases also turn up in fertile women. In one study, 13% of ovulating cycles had a luteal phase under 10 days⁹.

ASRM also concluded that luteal phase deficiency hasn’t been proven to cause infertility or repeated miscarriage on its own⁹. No treatment has been shown to raise pregnancy rates in natural cycles⁹.

Fertility treatment is a different story. There, ASRM notes, progesterone does help⁹.

If you’re trying to conceive, ASRM’s timeline is a more useful guide than one hormone number. It suggests an evaluation after 12 months of trying if you’re under 35, after 6 months at 35 or older, and sooner after 40⁸.

Miscarriage: two large trials and one narrow yes

If you’ve lived through a miscarriage, wanting to do something different next time is natural. Progesterone has been tested carefully for exactly that wish, in two large trials.

PROMISE tested women with repeated, unexplained early miscarriages. Results from 826 women at 45 hospitals in the United Kingdom and the Netherlands appeared in the New England Journal of Medicine in 2015¹⁰. Women used vaginal progesterone or a placebo through 12 weeks of pregnancy¹⁰.

Live births were 65.8% with progesterone and 63.3% with placebo, a difference that could easily be chance¹⁰. By our math, that’s about 25 more births per 1,000 women. The trial found no harm to women or babies¹⁰.

PRISM asked a different question: does progesterone help women who are bleeding in early pregnancy? From 2015 to 2017, 48 hospitals in the United Kingdom enrolled 4,153 women aged 16 to 39¹¹. Each had a scan showing a pregnancy sac inside the uterus¹¹. Chance decided who used vaginal progesterone suppositories twice daily through 16 weeks and who used a look-alike placebo¹¹. The UK’s National Institute for Health Research, a government body, paid for the trial¹¹.

Among the 4,038 women with results, 75% on progesterone had a live birth, versus 72% on placebo, a gap that narrowly missed the usual test for ruling out chance¹¹. The picture changed for one group. For women with three or more earlier losses, the live birth figures were 72% with progesterone and 57% with placebo¹¹.

By our math, that’s about 15 more babies per 100 women in that group. Results within a subgroup are less certain than a trial’s main result, and a physician-written summary called the subgroup findings generally inconclusive¹¹. Side effects for mothers and newborns didn’t differ between the groups¹¹.

In November 2021, NICE, the British agency that sets national care guidelines, acted on this evidence. It recommends vaginal micronized progesterone for women with early pregnancy bleeding who have had a previous miscarriage, once a scan shows the pregnancy is in the uterus¹². If a heartbeat is seen, treatment continues to 16 weeks¹². In June 2025, NICE updated the wording because that use is no longer off-label in the United Kingdom¹².

We did not find a matching U.S. guideline in the sources we reviewed. If you’ve had a miscarriage before and you’re bleeding in a new pregnancy, it’s a fair question for your obstetric clinician.

Grief after a pregnancy loss can be heavy, and it doesn’t follow a schedule. If it turns into hopelessness or thoughts of harming yourself, call or text 988, the Suicide & Crisis Lifeline, at any hour.

Preterm birth: the short cervix exception

Makena’s withdrawal didn’t end progesterone’s role in preventing early birth. It narrowed it.

In April 2023, the American College of Obstetricians and Gynecologists (ACOG) said the shots, known as 17-OHPC, are not recommended for people with a past spontaneous preterm birth⁴. ACOG advises repeat ultrasound checks of cervical length in those pregnancies, using a vaginal probe⁴.

The cervix is the neck of the uterus. ACOG says vaginal progesterone may be considered when a person with a past preterm birth carrying one baby develops a short cervix⁴. Without a short cervix, ACOG says vaginal progesterone should not be offered to prevent early birth⁴.

The strongest evidence applies to a different group. In 2024, the Society for Maternal-Fetal Medicine (SMFM), the professional society for high-risk pregnancy specialists, issued advice for people with no past preterm birth⁵. It defines a short cervix as 25 millimeters or less on a mid-pregnancy ultrasound⁵.

When the cervix measures 20 millimeters or less before 24 weeks in a pregnancy with one baby and no symptoms, SMFM recommends vaginal progesterone, giving that advice its highest grade⁵. For 21 to 25 millimeters, it suggests deciding together with your clinician⁵.

SMFM also advises against 17-OHPC for a short cervix, including compounded versions mixed by pharmacies⁵. It recommends against a cervical stitch or a cervical pessary in this situation, and against routine progesterone for twins outside of research⁵.

Creams and wild yam: what’s in the jar

Some creams sold for menopause are marketed as wild yam products¹⁴. The plant’s root contains diosgenin, and chemists have used diosgenin as a raw material to make progesterone in the lab¹³.

That lab fact underlies a popular idea: that rubbing on wild yam lets your body make its own progesterone. The herb database at Memorial Sloan Kettering Cancer Center (MSKCC) finds nothing showing that people can carry out that chemistry inside their bodies¹³. Human research is thin, and in small menopause studies, a wild yam formula applied to the skin didn’t help¹³.

Some creams solve the problem by adding the hormone. We looked at two progesterone creams listed in DailyMed, the National Library of Medicine’s database of product labels¹⁴. Both list micronized progesterone USP as the active ingredient, with wild yam named beside it¹⁴. In other words, the hormone in the jar is progesterone itself, made in a lab¹³¹⁴.

What else their labels say, as company claims:

• Both are listed as “unapproved drug other,” with an FDA notice that the agency hasn’t found them safe and effective and hasn’t approved the labeling¹⁴.
• One claims 2% progesterone, yet its ingredient table lists 20 mg in 58 grams, about 0.03% by our math, and its directions say about 20 mg per quarter teaspoon¹⁴.
• Both are labeled for external cosmetic use only, while saying they may help “balance your hormones” and ease menopause symptoms such as hot flashes¹⁴.
• Both warn against using them with any other progesterone or progestin¹⁴.

Natural-health values point in a useful direction here. The same skepticism that the Makena story earned, about a drug that stayed on the market for years without confirmed benefit¹², applies to a jar whose own label can’t agree on its dose. Wanting gentler, plant-based care is reasonable. It works best when the label tells you what’s inside and someone has tested whether it helps.

Progesterone: what the evidence supports

Our summary of the sources above, using the library’s four-level scale:

Use	Evidence	Who says so	Notes
Blood test about a week before a period to confirm ovulation	Strong evidence	ASRM, 20218	Above 3 ng/mL confirms ovulation; one value can’t grade the cycle
Diagnosing “low progesterone” or luteal phase deficiency	Not enough evidence	ASRM, 20269	No reliable test; not proven to cause infertility
Progesterone to boost fertility in natural cycles	Not enough evidence	ASRM, 20269	No treatment shown to raise pregnancy rates
Progesterone for repeated unexplained miscarriage, without bleeding	Evidence says no, or unsafe	PROMISE trial10	65.8% vs. 63.3% live births; no harm found
Vaginal progesterone for early bleeding after a past miscarriage	Promising but early	NICE, 202112	Largest gain with three or more past losses11
Vaginal progesterone for a cervix 20 mm or less, no past preterm birth	Strong evidence	SMFM, 20245	Highest-grade recommendation
Vaginal progesterone after a past preterm birth, normal cervix	Evidence says no, or unsafe	ACOG, 20234	ACOG says don’t offer it for prevention without a short cervix
17-OHPC (Makena-type) shots	Evidence says no, or unsafe	FDA, ACOG, SMFM145	No benefit in a 1,708-woman trial3
Wild yam cream as a progesterone source	Evidence says no, or unsafe	MSKCC13	No sign the body converts it; a skin formula failed in small studies
Over-the-counter progesterone creams	Not enough evidence	DailyMed listings14	Unapproved; conflicting doses on labels

When to get help

In pregnancy, Cleveland Clinic advises contacting your provider about spotting or cramping⁷. NICE advises that women with early bleeding in a confirmed pregnancy return for another check if bleeding gets worse or lasts beyond 14 days¹².

NICE lists belly or pelvic pain, vaginal bleeding, dizziness or fainting, and pain at the tip of the shoulder as possible signs of an ectopic pregnancy, one growing outside the uterus¹². It also says women should be told when and how to seek help if symptoms get worse or new ones appear¹².

An ectopic pregnancy that bursts is an emergency. MedlinePlus, the National Library of Medicine’s health site, says it needs emergency medical help¹⁵. Signs include sudden, severe, sharp pain low in the belly, shoulder pain, strong pressure in the rectum, and fainting or feeling faint¹⁵.

If you used Makena or a generic in a past or current pregnancy and have questions, the FDA advises talking with your health care provider¹. Don’t start, stop or change any hormone in pregnancy without your obstetric clinician.

If a cream or supplement seems to have harmed you, report it to the FDA through MedWatch and keep the container. After a loss, call or text 988 any time if you’re struggling to cope.

Questions readers ask

The bottom line

Progesterone readies the uterus each month, raises your temperature after ovulation and helps keep a pregnancy calm. A well-timed blood test can confirm ovulation, but popular “low progesterone” diagnoses rest on tests that don’t hold up.

Treatment has real but specific uses. Vaginal progesterone helps when a short cervix is found, and it may help women who bleed in early pregnancy after past miscarriages. Makena failed its big test, and wild yam can’t do the work of the hormone. When a claim about progesterone comes your way, ask which test, which trial and which guideline back it.

Related reading

• One man’s bones proved estrogen matters for men as well as women
• Real hormone problems have names and tests, which “balance your hormones” claims lack
• A few herbs are known pregnancy risks, and most were never tested
• How clinical trials decide, when most treatments tested in people fail
• Why one flagged lab number is not a diagnosis

Sources

1. U.S. Food and Drug Administration. “FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena.” News release, April 6, 2023. fda.gov
2. U.S. Food and Drug Administration. “Makena (hydroxyprogesterone caproate injection) Information.” Accessed October 2026. fda.gov
3. Blackwell SC, Chauhan SP, Gyamfi-Bannerman C, et al. “17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial.” American Journal of Perinatology, 2020;37(2):127–136 (UT Health San Antonio and UTMB records). scholars.uthscsa.edu and researchexperts.utmb.edu
4. American College of Obstetricians and Gynecologists. “Updated Clinical Guidance for the Use of Progesterone Supplementation for the Prevention of Recurrent Preterm Birth.” Practice Advisory, April 2023.
5. Society for Maternal-Fetal Medicine. “Consult Series #70: Management of Short Cervix in Individuals Without a History of Spontaneous Preterm Birth.” 2024. publications.smfm.org
6. Cable JK, Grider MH. “Physiology, Progesterone,” updated May 1, 2023; and Steward K, Raja A. “Physiology, Ovulation and Basal Body Temperature,” updated July 17, 2023. StatPearls, NCBI Bookshelf, National Library of Medicine. ncbi.nlm.nih.gov and ncbi.nlm.nih.gov
7. Cleveland Clinic. “Progesterone: Natural Function, Levels and Side Effects.” Reviewed December 29, 2022. my.clevelandclinic.org
8. American Society for Reproductive Medicine Practice Committee. “Fertility Evaluation of Infertile Women: A Committee Opinion.” Fertility and Sterility, 2021;116:1255–65. asrm.org
9. American Society for Reproductive Medicine Practice Committee. “Diagnosis and Treatment of Luteal Phase Deficiency: A Committee Opinion.” Fertility and Sterility, 2026;126:633–9. asrm.org
10. The Miscarriage Association. “The PROMISE Trial” (on Coomarasamy A, et al., New England Journal of Medicine, 2015;373:2141–8).
11. Coomarasamy A, et al. “A Randomized Trial of Progesterone in Women With Bleeding in Early Pregnancy” (PRISM). New England Journal of Medicine, 2019 (University of Glasgow Enlighten record); subgroup figures via Chibber S, McMillan D, 2 Minute Medicine, May 9, 2019. eprints.gla.ac.uk and 2minutemedicine.com
12. National Institute for Health and Care Excellence. “Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management” (NG126), PDF last updated August 23, 2023, and “Update Information” page listing 2021, 2025 and 2026 changes. nice.org.uk and nice.org.uk
13. Memorial Sloan Kettering Cancer Center. “Wild Yam.” About Herbs, updated July 12, 2022. mskcc.org
14. DailyMed, National Library of Medicine. Labels for two progesterone creams marketed as derived from wild yam: “Wild Yam and Progesterone” cream (April 2026) and “P50 Progesterone Cream” (June 2025). dailymed.nlm.nih.gov and dailymed.nlm.nih.gov
15. MedlinePlus Medical Encyclopedia, National Library of Medicine. “Ectopic Pregnancy.” Reviewed March 17, 2026. medlineplus.gov