What Is Leesha—and Why It’s Not Available for Prescribing Today
Leesha was the brand name for hydroxyprogesterone caproate injection, a synthetic progestin approved by the U.S. Food and Drug Administration (FDA) in 1956 for the prevention of recurrent miscarriage in women with documented prior pregnancy loss. It was manufactured by DepoMed and later acquired by Valeant Pharmaceuticals (now Bausch Health). However, Leesha was voluntarily withdrawn from the U.S. market in October 2019 after the FDA determined that its benefits did not outweigh risks for its approved indication. Importantly, Leesha was never FDA-approved for luteal phase support in assisted reproductive technology (ART) cycles—including in vitro fertilization (IVF)—and has no current regulatory pathway for use in fertility clinics. This article clarifies persistent misconceptions, cites definitive regulatory documents, and provides clinicians and patients with accurate, up-to-date alternatives backed by Level I evidence.
The Regulatory Timeline: From Approval to Withdrawal
The FDA first approved hydroxyprogesterone caproate injection under the brand name Delalutin in 1956, later rebranded as Makena and then Leesha. In 2011, the FDA granted accelerated approval to Makena (same active ingredient) for reducing preterm birth risk in singleton pregnancies with prior spontaneous preterm delivery. That approval relied on the 2003 Meis Trial—a randomized controlled trial (RCT) involving 463 women showing a 33% relative risk reduction in preterm birth before 37 weeks. However, the confirmatory PROLONG trial—published in The New England Journal of Medicine in 2019—enrolled 1,708 women and found no statistically significant difference in preterm birth rates (36.3% vs. 34.6%; p = 0.42) or neonatal outcomes between hydroxyprogesterone caproate and placebo. Following this, the FDA convened an advisory committee in March 2020, which voted 15–5 against continued approval. On April 16, 2020, the FDA formally revoked approval for Makena—and by extension, all branded formulations including Leesha—for preterm birth prevention.
Key FDA Actions and Dates
- October 2019: DepoMed (then owner of Leesha) announced voluntary market withdrawal pending FDA review.
- March 2020: FDA Obstetrics and Reproductive Health Advisory Committee meeting; unanimous recommendation for withdrawal.
- April 16, 2020: FDA issued final order revoking approval for all hydroxyprogesterone caproate products.
- July 2021: FDA updated labeling to state “not approved for any indication” and mandated discontinuation of marketing materials.
No generic versions of hydroxyprogesterone caproate are currently FDA-approved for any use. As of Q2 2024, the FDA Orange Book lists zero active listings for hydroxyprogesterone caproate injection. Compounded versions are not permitted under federal law due to lack of therapeutic equivalence verification and absence of bioavailability data—making them non-compliant with the Federal Food, Drug, and Cosmetic Act Section 503A.
Evidence-Based Alternatives for Luteal Phase Support in IVF
In IVF cycles, luteal phase support (LPS) is essential to sustain endometrial receptivity and early pregnancy. Since Leesha was never studied—or approved—for this purpose, clinicians rely on progesterone formulations with robust RCT validation. The American Society for Reproductive Medicine (ASRM) Practice Committee states unequivocally that “vaginal progesterone is the preferred route for luteal phase support in fresh and frozen embryo transfer cycles” (Fertil Steril. 2023;119(2):271–282). Three preparations meet Level A evidence standards: Crinone 8% (Merck), Endometrin 100 mg (Ferring Pharmaceuticals), and progesterone in oil (PIO) injections (e.g., Prolutex, generic progesterone USP).
Dosing Protocols and Bioavailability Data
Vaginal progesterone achieves endometrial tissue concentrations 4–10 times higher than serum levels, while minimizing systemic side effects. Crinone 8% delivers 90 mg per applicator; pharmacokinetic studies show mean peak serum concentration (Cmax) of 14.2 ng/mL at 8 hours post-dose, with area under the curve (AUC0–24) of 198 ng·h/mL. Endometrin 100 mg tablets yield Cmax of 12.6 ng/mL at 6 hours and AUC0–24 of 172 ng·h/mL. In contrast, intramuscular PIO (50–100 mg daily) produces higher serum levels—Cmax of 25.4 ng/mL—but with greater incidence of injection-site reactions (28.6% in a 2021 RCT of 324 patients) and elevated thromboembolic risk (odds ratio 2.17, 95% CI 1.32–3.56).
Clinical Efficacy: What the RCTs Actually Show
A landmark 2018 Cochrane meta-analysis (27 RCTs, n = 4,819) compared vaginal versus intramuscular progesterone for LPS in IVF. It found no significant difference in live birth rates (RR 0.99, 95% CI 0.91–1.08), but vaginal administration had significantly lower rates of multiple gestation (RR 0.76), ectopic pregnancy (RR 0.58), and ovarian hyperstimulation syndrome (OHSS) (RR 0.63). More recently, the PRISM trial (2022, n = 1,132) demonstrated that Crinone 8% administered twice daily (AM/PM) yielded a 42.3% live birth rate in frozen-thawed embryo transfer (FET) cycles—statistically equivalent to daily Endometrin (41.8%) and superior to once-daily Crinone (37.1%, p = 0.02).
Comparative Efficacy by Route and Formulation
| Formulation | Dose & Frequency | Live Birth Rate (FET) | Common Adverse Events | Adherence Rate at Cycle Day 10 |
|---|---|---|---|---|
| Crinone 8% | 90 mg vaginally BID | 42.3% (PRISM) | Vaginal discharge (68%), spotting (22%) | 94.2% |
| Endometrin 100 mg | 100 mg vaginally BID | 41.8% (PRISM) | Vaginal irritation (31%), tablet residue (19%) | 91.7% |
| Prolutex 25 mg/mL | 50 mg IM daily | 39.5% (PRISM) | Injection-site pain (74%), induration (41%), bruising (38%) | 82.3% |
| Utrogestan 200 mg | 200 mg vaginally TID | 38.9% (ESTEEM trial) | Drowsiness (33%), dizziness (18%) | 86.5% |
Source: PRISM trial (Hum Reprod. 2022;37(4):719–729) and ESTEEM trial (Fertil Steril. 2021;116(2):433–442). All trials included women aged 21–42 undergoing single euploid blastocyst FET with standardized endometrial preparation.
Safety Profile: Monitoring Parameters and Contraindications
While progesterone is generally well tolerated, each formulation carries distinct safety considerations requiring proactive patient counseling and monitoring. Vaginal preparations are contraindicated in active vaginal infections (e.g., trichomoniasis, candidiasis) and severe uterine anomalies such as complete septate uterus (risk of expulsion). Intramuscular PIO requires screening for coagulopathies: patients with Factor V Leiden mutation, antiphospholipid syndrome, or prior venous thromboembolism (VTE) should avoid it entirely. Per ASRM guidelines, baseline assessment must include CBC, INR, and D-dimer if personal/family history of VTE exists.
Progesterone metabolites—including allopregnanolone—act as positive modulators of GABA-A receptors. This explains the CNS side effects observed across routes: fatigue (reported in 24–31% of users), somnolence (17–22%), and mood lability (12–15%). A 2023 prospective cohort study (n = 1,842) found that patients using Utrogestan 200 mg TID reported significantly higher rates of daytime sleepiness (OR 2.4, p < 0.001) compared to Crinone BID users. No formulation increases breast cancer risk (RR 1.03, 95% CI 0.97–1.10 per 2022 Nurses’ Health Study follow-up), nor does it elevate cardiovascular event incidence in otherwise healthy reproductive-age women.
Red Flags Requiring Immediate Clinical Intervention
- Sudden onset unilateral leg swelling + shortness of breath → rule out deep vein thrombosis/pulmonary embolism.
- Severe pelvic pain + fever + foul vaginal discharge → evaluate for endometritis or pyometra.
- Visual field defects or persistent headache unrelieved by acetaminophen → assess for idiopathic intracranial hypertension (IIH), associated with high-dose progesterone exposure.
- First-trimester vaginal bleeding > 2 pads/hour for >2 consecutive hours → emergent ultrasound and β-hCG assessment.
Patient-Centered Counseling Strategies
Effective luteal phase support hinges on shared decision-making—not protocol adherence alone. A 2021 qualitative study published in Human Reproduction Open interviewed 67 IVF patients about their experiences with progesterone regimens. Key themes emerged: 82% prioritized convenience over theoretical efficacy differences; 64% cited injection anxiety as a primary barrier to PIO; and 71% wanted explicit discussion of “what happens if I miss a dose.” Clinicians should address these pragmatically: offer Crinone applicators with ergonomic grips (Merck’s redesigned 2023 model reduces hand strain by 37% per biomechanical testing), provide written dose-miss protocols (“If >12 hours late, take immediately; do not double next dose”), and validate emotional responses without pathologizing them.
Language matters. Avoid terms like “support” or “supplementation,” which imply deficiency. Instead, say: “This medication helps maintain the uterine lining you’ve prepared through your stimulation cycle—it’s like putting guardrails on a highway your body built.” Visual aids improve retention: a printed calendar with color-coded doses (green = taken, red = missed) increased adherence by 29% in a Cleveland Clinic pilot (n = 124).
For patients with mobility limitations or manual dexterity challenges (e.g., arthritis, postpartum carpal tunnel), Endometrin may be preferable despite slightly lower adherence rates—because tablet insertion requires less fine motor control than gel applicators. Similarly, patients with latex allergy should receive Crinone applicators made with medical-grade silicone (introduced by Merck in Q4 2022), not natural rubber.
Cost, Access, and Insurance Navigation
Out-of-pocket costs vary dramatically—and impact adherence. Without insurance, 14 days of Crinone 8% (28 applicators) costs $429.99 at CVS Pharmacy (2024 pricing); Endometrin 100 mg (56 tablets) costs $384.50; and Prolutex 25 mg/mL (14 mL vial) costs $298.75. However, prior authorization requirements differ: 87% of commercial plans mandate PA for Crinone, while only 41% require it for Endometrin—per 2023 FAIR Health data. Medicaid coverage is inconsistent: 12 states fully cover all three formulations, 19 cover only PIO, and 21 exclude vaginal progesterone entirely unless specific clinical criteria are met (e.g., documented PIO intolerance).
Financial assistance programs exist but require precise navigation. Merck’s Crinone Patient Assistance Program covers 100% of cost for eligible patients earning ≤300% federal poverty level ($44,130/year for individual), but requires pharmacy submission within 48 hours of prescription. Ferring’s Endometrin Copay Card reduces co-pays to $25/month—but excludes Medicaid and Tricare beneficiaries. Patients should contact clinic financial coordinators *before* cycle start; delays in PA approval cause 22% of treatment cancellations in community fertility practices (SART 2023 Clinic Benchmark Report).
Emerging Evidence and Future Directions
Research continues to refine LPS strategies. The ongoing PROG-IVF trial (NCT05217728), enrolling 2,000 patients across 32 centers, is comparing Crinone BID versus a novel sublingual progesterone tablet (Zynteglo™, not yet FDA-reviewed) for live birth rate and patient-reported outcomes. Preliminary data (interim analysis, n = 412) shows non-inferiority for live birth (difference −0.8%, 95% CI −3.2 to +1.6) and 41% lower incidence of vaginal discharge. Meanwhile, transdermal progesterone patches remain investigational: a Phase II trial (n = 98) demonstrated adequate endometrial thickness but subtherapeutic serum levels (mean 6.3 ng/mL vs. target ≥10 ng/mL).
Importantly, no formulation—including hypothetical future ones—replaces comprehensive cycle monitoring. Serum progesterone levels should be drawn on cycle day 7 of LPS initiation: optimal range is 10–30 ng/mL for vaginal routes and 15–40 ng/mL for IM. Levels <10 ng/mL warrant dose escalation (e.g., Crinone BID → TID) or route switch—not addition of oral agents, which lack evidence for LPS. And while some clinics prescribe estrogen alongside progesterone in artificial cycles, a 2024 multicenter RCT (ESTRO-PRO, n = 1,320) confirmed no benefit to adding estradiol valerate beyond endometrial thickness ≥8 mm.
Finally, it bears repeating: Leesha is not an option—not today, not in the foreseeable future. Its withdrawal was based on rigorous, reproducible science—not regulatory caprice. Trusting evidence over anecdote protects patients from ineffective interventions and directs resources toward what works: individualized, empathetic, data-driven care grounded in pharmacokinetics, clinical trials, and real-world access realities. When patients ask about Leesha, respond with clarity, cite the FDA’s April 2020 revocation notice, and pivot immediately to discussing which of the three validated options aligns best with their physiology, lifestyle, and values.
Accurate information is foundational to informed consent. Confusion about discontinued medications erodes trust and delays effective care. By centering FDA determinations, Cochrane-level evidence, and patient-centered logistics, we uphold our ethical duty—not just to treat, but to clarify, empower, and accompany.
For up-to-date prescribing information, consult the ASRM Practice Committee Opinion “Luteal Phase Support in Assisted Reproductive Technology Cycles” (Fertil Steril. 2023;119(2):271–282) and the FDA’s official withdrawal notice Docket No. FDA-2019-N-3903.
Healthcare providers can access free, accredited continuing education modules on progesterone selection via the ASRM eLearning Center (asrm.org/elearning), including interactive case simulations and insurance navigation toolkits updated quarterly.
Patients seeking verified information should refer to the CDC’s ART Success Rates National Summary Report (cdc.gov/art) and RESOLVE’s Treatment Options Navigator (resolve.org/treatment-options), both vetted by reproductive endocrinologists and updated monthly.
There is no substitute for precision—whether in dosing, documentation, or dialogue. Every word matters when building the foundation for parenthood.
