Estrogens plus progestin therapy should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens 0.625 mg combined with medroxyprogesterone 2.5 mg relative to placebo.
Estrogens plus progestin therapy should not be used for the prevention of dementia. The Women's Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years and older during 4 years of treatment with daily conjugated estrogens 0.625 mg combined with medroxyprogesterone 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.
In the absence of comparable data, assume these risks to be similar for other doses of conjugated estrogens and medroxyprogesterone and other combinations and dosage forms of estrogens and progestins. Prescribe progestins with estrogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Assisted reproductive technology, luteal phase support:
IM (off label): 50 to 100 mg once daily (Labarta 2020; Pabuçcu 2020; van der Linden 2015; Wu 2021).
Intravaginal :
Gel (8%): 90 mg once daily. In patients with partial or complete ovarian failure, use 90 mg twice daily. If pregnancy occurs, may continue treatment for up to 10 to 12 weeks.
Insert: 100 mg 2 to 3 times daily starting the day after oocyte retrieval and continuing for up to 10 weeks.
Ring: Insert 1 ring on the day after oocyte retrieval; leave in place continuously (for a minimum of 23 hours per day) for 7 days. Replace ring weekly for up to 10 weeks.
Estrogen therapy-associated endometrial hyperplasia, prevention:
Note: Indicated in patients with a uterus receiving estrogen therapy (eg, for vasomotor symptoms associated with menopause or secondary amenorrhea). May be administered either cyclically (preferred in late menopausal transition and early postmenopause or functional hypothalamic amenorrhea) or continuously (preferred if >2 to 3 years postmenopause) (ACOG 2017; ES [Stuenkel 2015]; Gordon 2017; Martin 2022; NAMS 2022; Nelson 2009; Popat 2014). Discontinue when estrogen therapy is discontinued.
Oral: 200 mg once daily for 12 days each month (Ackerman 2019; Ackerman 2020; De Souza 2014; Sophie Gibson 2020) or 100 mg daily continuously (ACOG 2017).
Intravaginal (gel) (alternative agent): Note: Dosing is based on manufacturer’s labeling; however, intravaginal gel route of administration is considered nonpreferred to oral and is infrequently used due to limited data.
45 mg (4% gel) every other day for up to a total of 6 doses; if response is inadequate, may increase to 90 mg (8% gel) at same schedule (Warren 1999).
Secondary amenorrhea, diagnostic aid ("progesterone challenge"):
Oral: 200 mg daily for 10 days (Gordon 2017). Note: Withdrawal bleeding may be expected during therapy or within 7 days after cessation of therapy; absence of withdrawal bleeding suggests low endometrial estrogen exposure and/or uterine or outflow tract abnormality (Gordon 2017; manufacturer’s labeling).
Manufacturer’s labeling: 400 mg once daily at bedtime for 10 days. Note: Higher oral doses (ie, >200 mg/day) are not preferred and infrequently used due to limited data.
IM (alternative agent): Note: Dosing is based on the manufacturer’s labeling; however, IM route of administration is considered nonpreferred to oral and is infrequently used.
5 to 10 mg/day for 6 to 8 consecutive days.
Spontaneous preterm birth, prevention (off-label use): Note: For use in patients with a singleton pregnancy, no prior preterm birth, and a cervical length <25 mm; use may be considered for patients with a singleton pregnancy, prior preterm birth, and a cervical length <25 mm. Data are insufficient regarding the most effective formulation and dose (ACOG 2021a).
Intravaginal (8% gel): 90 mg once daily (Hassan 2011; Kuon 2019; O'Brien 2009). Dosage range: 90 to 200 mg once daily using the 8% vaginal gel, oral capsules administered intravaginally, or compounded vaginal suppositories (EPPPIC Group 2021; Kuon 2019; Norman 2016; Romero 2018). Progesterone is generally continued up to 34 to 36 weeks' gestation (SOGC [Jain 2020]).
Uterine bleeding, abnormal:
IM: 5 to 10 mg/day for 6 doses. Start 2 weeks after estrogen therapy (if also being used). Bleeding should cease within 6 days. Discontinue use if menstrual flow begins during therapy.
Oral (off label): 200 mg once daily for the first 12 days of each month (Jewson 2020; Ramalho 2021).
Injection, oral: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Use with caution.
Intravaginal gel, insert, ring: There are no dosage adjustments provided in the manufacturer's labeling.
Use is contraindicated in hepatic impairment or disease.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Prometrium: 100 mg [contains fd&c red #40 (allura red ac dye), peanut oil, quinoline yellow (d&c yellow #10)]
Prometrium: 200 mg [contains fd&c yellow #6 (sunset yellow), peanut oil, quinoline yellow (d&c yellow #10)]
Generic: 100 mg, 200 mg
Gel, Vaginal:
Crinone: 4% (1.125 g); 8% (1.125 g)
Insert, Vaginal:
Endometrin: 100 mg (1 ea, 21 ea)
Oil, Intramuscular:
Generic: 50 mg/mL (10 mL)
May be product dependent
Progesterone cream 10% and vaginal suppositories are compounding kits. Refer to manufacturer’s labeling for compounding instructions.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Prometrium: 100 mg [contains soybean lecithin]
Generic: 100 mg, 200 mg
Gel, Vaginal:
Crinone: 8% (1.45 g)
Insert, Vaginal:
Endometrin: 100 mg (21 ea)
Oil, Intramuscular:
Generic: 50 mg/mL (10 mL)
Milprosa: FDA approved April 2020; anticipated availability is currently unknown.
IM: May cause injection-site irritation.
Intravaginal:
Vaginal gel: A small amount of gel will remain in the applicator following insertion. Administer into the vagina directly from sealed applicator. Remove applicator from wrapper; holding applicator on each side, push plunger into applicator until it snaps into place; twist off cap counterclockwise; gently insert into vagina and push plunger. Do not use concomitantly with other local vaginal therapy. If concomitant therapy cannot be avoided, administer other vaginal products at least 6 hours before or 6 hours after progesterone administration. Small white globules may appear as vaginal discharge. If a dose increase from 4% to 8% is needed for the treatment of secondary amenorrhea, the 8% gel must be used. Increasing the volume of the 4% gel does not increase the amount of progesterone absorbed.
Vaginal insert: Insert tablet in vagina using disposable applicator provided. Concomitant use with other vaginal products (eg, antifungals) has not been studied; release and absorption from the insert may be altered.
Vaginal ring: Remove vaginal ring from foil pouch and insert into vagina; save foil pouch to use for disposal. Vaginal ring should remain in place for a minimum of 23 hours each day; can be removed for sexual intercourse, but it is not necessary. If vaginal ring is expelled, removed, or dropped, rinse with cool to lukewarm water and reinsert as soon as possible; if contact with feces occurs, replace with a new ring. Remove vaginal ring after 7 days and replace with a new ring. Concomitant use with other vaginal products (eg, antifungal, vaginal lubricants, diaphragms, condoms) has not been studied; release and absorption may be altered. If possible, avoid use with other vaginal products. Refer to manufacturer's labeling for additional administration instructions.
Capsule (off-label route): When the oral capsule is used for spontaneous preterm birth prevention, doses are administered intravaginally at bedtime (Fonseca 2007; Majhi 2009; Norman 2016).
Oral: Administer at bedtime. For patients who experience difficulty swallowing the capsules, taking with a full glass of water in the standing position may be beneficial.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. For IM preparation, NIOSH recommends double gloving, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator). Double gloving and a protective gown are required during IM administration. NIOSH recommends double gloving, a protective gown, and (if liquid that could splash) eye/face protection for administration of a topical product; if there is potential for inhalation, respiratory protection is recommended (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Assisted reproductive technology: Progesterone replacement or supplementation as part of assisted reproductive technology (ART) for infertile patients with progesterone deficiency (Crinone vaginal gel). To support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of ART (Endometrin vaginal insert, Milprosa vaginal ring)
Limitations of use: Products are indicated for infertile patients to support or maintain a clinical pregnancy. Efficacy of vaginal insert/ring in patients ≥35 years of age has not been established. Use of the vaginal ring in patients with a BMI >38 kg/m2 has not been studied.
Estrogen therapy-associated endometrial hyperplasia, prevention: Prevention of endometrial hyperplasia in patients with a uterus receiving estrogen therapy (eg, for vasomotor symptoms associated with menopause or secondary amenorrhea).
Secondary amenorrhea, diagnostic aid ("progesterone challenge"): For use as a diagnostic aid to determine endometrial estrogen exposure and/or uterine or outflow tract abnormality.
Uterine bleeding, abnormal: Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer (IM injection).
Spontaneous preterm birth, prevention
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Intramuscular injection:
Frequency not defined:
Cardiovascular: Edema
Dermatologic: Acne vulgaris, allergic skin rash, alopecia, hirsutism, pruritus, skin rash, urticaria
Endocrine & metabolic: Amenorrhea, change in menstrual flow, galactorrhea not associated with childbirth, weight gain, weight loss
Gastrointestinal: Nausea
Genitourinary: Breakthrough bleeding, breast tenderness, cervical erosion, change in cervical secretions, spotting
Hepatic: Cholestatic jaundice
Hypersensitivity: Anaphylactoid shock
Local: Erythema at injection site, irritation at injection site, pain at injection site
Nervous system: Depression, drowsiness, insomnia
Miscellaneous: Fever
Oral (percentages reported when used in combination with or cycled with conjugated estrogens):
>10%:
Endocrine & metabolic: Breast tenderness (27%), mastalgia (6% to 16%)
Gastrointestinal: Abdominal pain (20%), bloating (12%)
Genitourinary: Urinary tract abnormality (11%)
Infection: Viral infection (12%)
Nervous system: Depression (19%), dizziness (15% to 24%), headache (16% to 31%)
Neuromuscular & skeletal: Musculoskeletal pain (12%)
1% to 10%:
Cardiovascular: Chest pain (7%)
Gastrointestinal: Cholecystectomy (2% to <5%), constipation (3% to <5%), diarrhea (7% to 8%), nausea and vomiting (≤8%)
Genitourinary: Vaginal discharge (10%)
Hematologic & oncologic: Malignant neoplasm of breast (2% to <5%)
Nervous system: Anxiety (8%), fatigue (8%), irritability (8%)
Respiratory: Cough (8%)
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cerebrovascular accident, deep vein thrombosis, pulmonary embolism
Nervous system: Dementia
Vaginal gel (percentages reported with Assisted Reproductive Technology):
>10%:
Gastrointestinal: Abdominal pain (12%), constipation (27%), muscle cramps (15%), nausea (7% to 22%)
Genitourinary: Breast hypertrophy (40%), mastalgia (13%), nocturia (13%), perineal pain (17%)
Nervous system: Depression (11%), drowsiness (27%), headache (13% to 17%), nervousness (16%)
1% to 10%:
Dermatologic: Genital pruritus (5%)
Endocrine & metabolic: Decreased libido (10%)
Gastrointestinal: Bloating (7%), diarrhea (8%), vomiting (5%)
Genitourinary: Dyspareunia (6%), genital candidiasis (5%), vaginal discharge (7%)
Nervous system: Dizziness (5%), pain (8%)
Neuromuscular & skeletal: Arthralgia (8%)
Vaginal insert (percentages reported with Assisted Reproductive Technology):
>10%: Gastrointestinal: Abdominal pain (12%)
1% to 10%:
Endocrine & metabolic: Ovarian hyperstimulation syndrome (7%)
Gastrointestinal: Abdominal distention (4%), constipation (2% to 3%), nausea (7% to 8%), vomiting (2% to 3%)
Genitourinary: Urinary tract infection (1% to 2%), uterine spasm (3% to 4%), vaginal hemorrhage (3%)
Nervous system: Fatigue (2% to 3%), headache (3% to 4%)
Vaginal ring (percentages reported with Assisted Reproductive Technology):
1% to 10%:
Gastrointestinal: Abdominal distension (3%), abdominal pain (3%), constipation (3%), nausea (4%)
Genitourinary: Breast tenderness (4%), pelvic pain (3%), vaginal discharge (4%)
Nervous system: Headache (7%)
<1%, postmarketing, and/or case reports (all formulations): Abnormal gait, abnormal uterine bleeding, acute pancreatitis, aggressive behavior, alopecia, anaphylaxis, arthralgia, asthma, blurred vision, choking sensation, cholestasis, cholestatic hepatitis, circulatory shock, cleft lip, cleft palate, confusion, congenital heart disease, depersonalization, diplopia, disorientation, drowsiness, dysarthria, dysphagia, dyspnea, endometrial carcinoma, facial edema, feeling abnormal, heavy menstrual bleeding, hepatic failure, hepatic necrosis, hepatitis, hypersensitivity reaction, hypertension, hypospadias, hypotension, impaired consciousness, increased liver enzymes, increased serum glucose, intoxicated feeling, jaundice, loss of consciousness, menstrual disease, muscle cramps, ovarian cyst, paresthesia, peripheral edema, pruritus, sedation, seizure, slurred speech, spontaneous abortion, stupor, suicidal ideation, syncope, tachycardia, tinnitus, tongue edema, transient ischemic attacks, urticaria, vaginal discomfort, vertigo, visual disturbance, vulvovaginal burning, vulvovaginal irritation, vulvovaginal pruritus, weight gain, weight loss
Oral: Hypersensitivity to progesterone or any component of the formulation, including peanuts/peanut oil; undiagnosed abnormal genital bleeding; breast cancer (known, suspected, or history of); active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or history of arterial thromboembolic disease (eg, stroke, MI); hepatic impairment or disease; pregnancy.
IM: Hypersensitivity to progesterone or any component of the formulation, including sesame oil/seeds; active or history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy; undiagnosed vaginal bleeding; hepatic impairment or disease; known or suspected malignancy of the breast or genital organs; missed abortion.
Vaginal gel: Hypersensitivity to progesterone or any component of the formulation, including palm oil; undiagnosed vaginal bleeding; hepatic impairment or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders.
Vaginal insert, ring: Hypersensitivity to progesterone or any component of the formulation; undiagnosed vaginal bleeding; known missed abortion or ectopic pregnancy (Endometrin); hepatic disease; known or suspected malignancy of the breast or genital organs; active or history of arterial or venous thromboembolism or severe thrombophlebitis.
Canadian labeling: Additional contraindications (not in the US labeling):
Capsules: Hypersensitivity to soya; endometrial hyperplasia; classical migraine; partial or complete loss of vision due to ophthalmic vascular disease.
Intravaginal gel: Acute porphyria, cerebral apoplexy.
Vaginal insert/tablet: Porphyria; undiagnosed vaginal bleeding.
Documentation of allergenic cross-reactivity for progestins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Breast cancer: The risk of breast cancer in patients who are postmenopausal on hormone therapy may depend upon type of estrogen and/or progestogen, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2022). Hormone therapy may be associated with increased breast density (NAMS 2022); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestogen therapy.
• CNS depression: Oral progesterone may cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Dementia: Do not use progestogen plus estrogens for the prevention of dementia. Hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2022).
• Endometrial cancer: Progesterone is used to reduce the risk of endometrial hyperplasia in patients who are postmenopausal with a uterus receiving conjugated estrogens. The use of unopposed estrogen in patients with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestogen to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer.
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestogen in patients with residual endometriosis posthysterectomy.
• Eosinophilic pneumonia: Cases of acute eosinophilic pneumonia have been reported with use of progesterone injection in sesame oil; symptoms have included fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates and generally develop 2 to 4 weeks after treatment initiation. Discontinue immediately and undergo prompt medical evaluation if symptoms of eosinophilic pneumonia occur.
• Fluid retention: May cause fluid retention; use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, cardiac or renal impairment, epilepsy, and migraine.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestogen therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2022).
• Retinal thrombosis: Discontinue pending examination in cases of sudden partial or complete vision loss, sudden onset of proptosis, diplopia, or migraine; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
• Toxic shock: Toxic shock syndrome (TSS) has been reported in patients using vaginal systems with and without tampon use; discontinue use if TSS is suspected and initiate appropriate treatment.
Disease-related concerns:
• Cardiovascular disease: Do not use progestogen plus estrogen for the prevention of cardiovascular disease. In the Women's Health Initiative studies, an increased risk of deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction was observed in patients taking conjugated estrogens combined with medroxyprogesterone. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, systemic lupus erythematosus, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Manage risk factors appropriately; discontinue immediately if adverse cardiovascular events occur or are suspected.
• Depression: Use with caution in patients with a history of depression; discontinue if serious depression recurs.
• Diabetes: May impair glucose tolerance; use caution in patients with diabetes. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
Special populations:
• Surgery: Whenever possible, discontinue progestogens in combination with estrogens at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Palm oil: Some products may contain palm oil.
• Peanut oil: Some products may contain peanut oil.
• Sesame oil: Some products may contain sesame oil.
Other warnings/precautions:
• Risks vs benefits: When used for the relief of menopausal symptoms, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Consider cardiovascular disease risk factors when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2022). Use at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual patient. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral conjugated estrogens with medroxyprogesterone relative to placebo in patients who are postmenopausal. Other combinations and dosage forms of estrogens and progestogens were not studied; assume outcomes to be similar for other doses and other dosage forms of estrogens and progestogens until comparable data becomes available.
Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antifungal Agents (Vaginal): May diminish the therapeutic effect of Progesterone. Risk X: Avoid combination
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Capsule: Food increases oral bioavailability.
Progesterone is indicated for use in assisted reproductive technology to support embryo implantation. In addition, some products are used for the treatment of amenorrhea; spontaneous menstrual cycles are expected following therapy.
Use of the vaginal ring (Milprosa) in patients with a BMI >38 kg/m2 has not been studied. Use of the vaginal ring with other vaginal products (eg, vaginal lubricants, diaphragms, condoms) has not been studied; avoid concomitant use.
In transgender patients undergoing masculinizing hormone therapy, progesterone has been used as an alternative to hysterectomy or endometrial ablation to induce amenorrhea when testosterone therapy does not suppress menstruation (ACOG 2021b; Ahmad 2017).
Adverse events following oral maternal use in pregnancy (eg, hypospadias, congenital heart disease, cleft lip/palate) have been noted in postmarketing data; however, a causal relationship has not been clearly established. Adequate progesterone concentrations are required for embryo implantation and maintenance of pregnancy. Based on available data, increased risks of birth defects or adverse neurodevelopment have not been observed following maternal use for the prevention of preterm birth or when used as indicated as part of assisted reproductive technology (ART) (Coomarasamy 2020; Cuijpers 2021; Czyzyk 2017; Simons 2021).
Progesterone is used to maintain pregnancy as part of ART.
Intravaginal progesterone is recommended to reduce the risk of spontaneous preterm birth in patients with a singleton pregnancy, no prior preterm birth, and a cervical length <25 mm. Intravaginal progesterone may also be offered to patients with a singleton pregnancy, prior preterm birth, and a cervical length <25 mm. Although the exact timing and schedule for treatment is not well defined, use is generally started after diagnosis following scheduled transvaginal ultrasound. Patients with no prior preterm birth generally undergo cervical ultrasound between 18 and 22 weeks' gestation; patients with prior spontaneous preterm birth generally undergo serial cervical ultrasounds between 16 and 24 weeks' gestation (ACOG 2021a; EPPPIC Group 2021; Romero 2018). Although not available as an FDA-approved dosage form in the United States, some studies used the vaginal gel off-label for this indication; others used oral capsules intravaginally (off-label route and indication) or compounded vaginal suppositories (Romero 2018). Orally administered progesterone has also been evaluated to reduce the risk of spontaneous preterm birth. However, additional data are needed to make recommendations (Boelig 2019; Care 2022; EPPPIC Group 2021). Data are insufficient to recommend routine use in patients with multiple gestations (ACOG 2021a; EPPPIC Group 2021; Romero 2018).
Progesterone has been studied in patients with a history of miscarriage. Current evidence is conflicting regarding whether progesterone increases live birth rates in patients with threatened or recurrent miscarriages; use may be beneficial for patients with previous miscarriages and early pregnancy bleeding or with a high number of previous miscarriages (Coomarasamy 2021a; Coomarasamy 2021b; Devall 2021).
Progesterone is present in breast milk.
In transgender patients undergoing feminizing hormone therapy, case reports describe the use of progesterone (in combination with other therapies) to induce lactation in patients who wish to breastfeed (Reisman 2018; Wamboldt 2021).
Breastfeeding recommendations vary by manufacturer; the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Vaginal bleeding.
Assisted reproductive technology: Consider monitoring serum progesterone, particularly with intravaginal administration (Labarta 2020).
Menopause: Prior to combination hormonal therapy, baseline risk for breast cancer and CVD. During therapy, age appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement); efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).
Natural steroid hormone that induces secretory changes in the endometrium, promotes mammary gland development, relaxes uterine smooth muscle, blocks follicular maturation and ovulation, and maintains pregnancy. When used as part of an ART program in the luteal phase, progesterone supports embryo implantation.
Absorption: Vaginal gel: Prolonged.
Absorption half-life: Vaginal gel: ~25 to 50 hours.
Protein binding: ~96% to 99%, primarily to albumin (50% to 54%) and cortisol-binding protein (43% to 48%).
Metabolism: Hepatic to pregnanediols and pregnanolones, which are then conjugated to glucuronide and sulfate metabolites; metabolites excreted in the bile may be deconjugated and further metabolized in the intestine via reduction, dehydroxylation, and epimerization.
Half-life elimination: Vaginal gel: 5 to 20 minutes; Vaginal ring: 10.82 ± 4.27 hours.
Time to peak: Oral: Within 3 hours; IM: ~8 hours; Intravaginal gel: 3.55 ± 2.48 hours to 7 ± 2.88 hours; Vaginal insert: 17.3 to 24 hours; Vaginal ring: 134.8 ± 49.17 hours to 206.15 ± 56.33 hours.
Excretion: Urine (50% to 60% as metabolites); bile, feces (~10%).
Capsules (Progesterone Oral)
100 mg (per each): $2.05 - $5.17
200 mg (per each): $3.89 - $9.82
Capsules (Prometrium Oral)
100 mg (per each): $13.92
200 mg (per each): $26.44
Gel (Crinone Vaginal)
4% (per gram): $19.11
8% (per gram): $31.88
INST (Endometrin Vaginal)
100 mg (per each): $16.36
Oil (Progesterone Intramuscular)
50 mg/mL (per mL): $3.59 - $5.01
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