[14] Hydroxyprogesterone caproate is a progestin medication which was used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological disorders.

[26] However, hydroxyprogesterone caproate was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011 until the FDA banned 17α-OHPC in 2023.

A study published in February 2016, found amongst other findings:[38] OPPTIMUM strongly suggests that the efficacy of progesterone in improving outcomes is either non-existent or weak.

Given the heterogeneity of the preterm labour syndrome we cannot exclude benefit in specific phenotypic or genotypic subgroups of women at risk.

However, the subgroups of women who might benefit do not appear to be easily identifiable by current selection strategies, including cervical length measurement and fibronectin testing.

Follow-up of other babies exposed in utero to vaginal progesterone would be helpful in determining whether the increased rate of some renal, gastrointestinal, and respiratory complications is a real effect or a type I error.The journal reviewer made the following notable commentary on the OPPTIMUM study: "That's it.

[9] In addition, hydroxyprogesterone caproate is used in the treatment of endometrial cancer and has been found to be significantly effective in extending life in both premenopausal and postmenopausal women with the disease.

Hydroxyprogesterone caproate is available alone in the form of ampoules and vials of 125 and 250 mg/mL oil solutions for intramuscular injection (brand names Proluton, Makena).

[67][68] Contraindications of hydroxyprogesterone caproate include previous or current thrombosis or thromboembolic disease, known or suspected breast cancer, past or present history of other hormone-sensitive cancer, undiagnosed abnormal vaginal bleeding unrelated to pregnancy, cholestatic jaundice of pregnancy, liver tumors or active liver disease, and uncontrolled hypertension.

[1] Injection site reactions such as pain, soreness, swelling, itching, bruising, and lumps are the most common side effect of hydroxyprogesterone caproate.

[3] Hydroxyprogesterone caproate has been studied in humans at high doses of 2,000 to 5,000 mg per week by intramuscular injection, without safety concerns.

[21][22] However, hydroxyprogesterone caproate has improved pharmacokinetics compared to progesterone, namely a much longer duration with intramuscular injection in oil solution.

[22] In accordance, hydroxyprogesterone caproate has been found not to alter cortisol levels in humans even with very high doses by intramuscular injection.

[7] This is of relevance because medications with significant glucocorticoid activity suppress cortisol levels due to increased negative feedback on the hypothalamic–pituitary–adrenal axis.

[56][109][110] Hydroxyprogesterone caproate has been studied in humans at doses as high as 5,000 mg per week by intramuscular injection, with safety and without glucocorticoid effects observed.

[90][112] Due to its lack of androgenic properties, similarly to progesterone, hydroxyprogesterone caproate does not have any teratogenic effects on the fetus, making it safe for use during pregnancy.

[114][116][117] As examples, 5β-dihydroprogesterone has been found to play an important role in suppressing myometrial activity while allopregnanolone has potent sedative and anesthetic effects in the mother and especially the fetus and is involved in fetal nervous system development.

[23] Further clinical research is anticipated to provide additional data to help clarify the issue of safety with hydroxyprogesterone caproate.

[17] In any case, it has been recommended by the American College of Obstetricians and Gynecologists that pregnant women treated with hydroxyprogesterone caproate receive counseling about its risks and benefits.

[4] However, a novel oral formulation of hydroxyprogesterone caproate (developmental code name LPCN-1107) is under development and has been found to be effective, though it required administration twice a day in a clinical study.

[125][126][127] A depot effect occurs when hydroxyprogesterone caproate is injected intramuscularly or subcutaneously, such that the medication has a prolonged duration of action.

[7][128] The pharmacokinetic parameters of 250 mg hydroxyprogesterone caproate once per week by intramuscular injection have also been studied in pregnant women with singleton and multiple (twin and triplet) gestation.

[129] A single intramuscular injection of 65 to 500 mg hydroxyprogesterone caproate in oil solution has been found to have a duration of action of 5 to 21 days in terms of effect in the uterus and on body temperature in women.

[5] Progesterone and 17α-hydroxyprogesterone have low affinity for sex hormone-binding globulin, and for this reason, only a very small fraction of them (less than 0.5%) is bound to this protein in the circulation.

[23][96] Hydroxyprogesterone caproate has been found to have an elimination half-life of 7.8 days when given by intramuscular injection in an oil-based formulation to non-pregnant women.

[29] With follow-up data showing no evidence of harmful effects on the offspring, the FDA approved the medication Makena, sponsored by KV Pharmaceutical, as an orphan drug in February 2011 to reduce the risk of premature birth in women prior to 37 weeks gestation with a single fetus who had at least one previous premature birth.

The pharmaceutical company is required to conduct confirmatory studies to show the drug provides a clinical benefit.

[27] The FDA subsequently announced that compounding pharmacies could continue to sell hydroxyprogesterone caproate at their usual cost of approximately US$10 to US$20 per dose without fear of enforcement action by the agency.

[66][155][156][157] Conversely, the combination of estradiol valerate and hydroxyprogesterone caproate has been found to be effective in the treatment of breast cancer in women.

[66][113][158] Initial research based on limited clinical data reported that the breast-cancer response rate with a combination of estradiol valerate and hydroxyprogesterone caproate seemed to be greater than with an estrogen alone (35% vs.