ATC Class:G03DA04
VA Class:HS800
Progesterone is a naturally occurring progestin secreted by the corpus luteum and is the prototype of the progestins.
Progesterone is used orally to reduce the incidence of endometrial hyperplasia in postmenopausal women receiving estrogen replacement therapy.103
Progesterone is used orally or intravaginally for the management of secondary amenorrhea.103, 105
Progesterone is used intravaginally to support embryo implantation and early pregnancy by supplementing corpus luteal function as part of assisted reproductive technology (ART) treatment of infertile women.104, 105 Efficacy of progesterone vaginal insert for this indication has not been established in women 35 years of age or older.104
Progesterone is used parenterally for the treatment of amenorrhea and for the treatment of abnormal uterine bleeding caused by hormonal imbalance in patients without underlying organic pathology such as fibroids or uterine cancer.101, 102 Progesterone also is used parenterally to support embryo implantation and early pregnancy by supplementing corpus luteal function as part of ART treatment† of infertile women.106
Progesterone is administered by orally, intravaginally, and by IM injection.101, 102, 103, 104, 105
Progesterone capsules are administered orally once daily at bedtime.103 Women who have difficulty swallowing the capsules should be advised to swallow progesterone capsules while in an upright position and with adequate amounts of fluid (e.g., a glass of water).103 Administration at bedtime may alleviate some of the adverse effects (e.g., dizziness, blurred vision) associated with the drug.103
Progesterone vaginal gel should not be administered concurrently with other intravaginal preparations.105 If therapy with another agent administered intravaginally is needed, such therapy should be administered 6 hours before or 6 hours after progesterone vaginal gel.105
Concomitant use of progesterone vaginal inserts with other preparations that are administered intravaginally is not recommended.104 Although specific studies have not been undertaken, the possibility exists that concomitant administration of a progesterone vaginal insert with another preparation administered intravaginally may alter the release and absorption of progesterone from the vaginal insert.104
When progesterone capsules are used in the management of secondary amenorrhea, the recommended dosage of progesterone is 400 mg once daily at bedtime for 10 days.103
When progesterone vaginal gel is used for the management of secondary amenorrhea, the contents of one prefilled applicator of progesterone 4% vaginal gel (approximately 1.125 g of gel containing 45 mg of progesterone) should be inserted intravaginally every other day for a total of 6 doses.105 Women who do not respond to the 4% gel may be given progesterone 8% vaginal gel.105 For these women, the contents of one prefilled applicator of the 8% vaginal gel (approximately 1.125 g of gel containing 90 mg of progesterone) should be inserted intravaginally every other day for a total of 6 doses.105 Women who require the higher dose should receive the 8% vaginal gel; increasing the volume of the 4% gel will not achieve the same progesterone concentrations as administration of the 8% gel.105
When parenteral progesterone is used for the treatment of amenorrhea, the usual dosage of progesterone is 5-10 mg administered IM daily for 6-8 days.101, 102 When sufficient ovarian activity is present to produce a proliferative endometrium, withdrawal bleeding will usually occur within 48-72 hours after discontinuing therapy with the drug.101, 102 Spontaneous normal cycles may occur in some patients after a single course of therapy.101, 102
Assisted Reproductive Technology Treatment
When progesterone vaginal gel is used as part of an assisted reproductive technology (ART) treatment regimen in women who require progesterone supplementation, the contents of one prefilled applicator of progesterone 8% vaginal gel (approximately 1.125 g of gel containing 90 mg of progesterone) should be inserted intravaginally once daily.105 When progesterone vaginal gel is used in women with partial or complete ovarian failure who require progesterone replacement, the contents of one prefilled applicator of progesterone 8% vaginal gel (approximately 1.125 g of gel containing 90 mg of progesterone) should be inserted intravaginally twice daily.105 If pregnancy occurs, treatment with progesterone gel may be continued until placental autonomy is achieved, up to 10-12 weeks.105
When progesterone vaginal inserts are used as part of an ART treatment regimen in women younger than 35 years of age, one vaginal insert containing 100 mg of progesterone is inserted intravaginally 2 or 3 times daily, starting at oocyte retrieval.104 Therapy may be continued for up to 10 weeks.104 The appropriate dosage for women 35 years of age or older has not been established.104
Prevention of Endometrial Changes Associated with Estrogens
When progesterone capsules are used in conjunction with estrogen replacement therapy, progesterone is administered in a dosage of 200 mg once daily at bedtime for 12 consecutive days (e.g., days 17-28) of the 28-day cycle.103
When parenteral progesterone is used for the treatment of abnormal uterine bleeding, the usual dosage of progesterone is 5-10 mg administered IM daily for 6 days.101, 102 When estrogen therapy is used concomitantly with progesterone, progesterone therapy is usually initiated after 2 weeks of estrogen therapy.101, 102 Therapy with progesterone is usually discontinued if menses occurs during the series of injections.101, 102
Adverse effects reported in patients receiving oral progesterone include dizziness, breast pain, headache, abdominal pain, fatigue, viral infection, abdominal distention, musculoskeletal pain, emotional lability, irritability, and upper respiratory tract infection.103 Extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, and shortness of breath have been reported in a few women receiving the drug.103 Hypotension and syncope have occurred rarely in women receiving progesterone capsules.103
Adverse effects reported in patients receiving progesterone vaginal gel include breast pain/enlargement, somnolence, constipation, nausea, headache, and perineal pain.105
Adverse effects reported in patients receiving progesterone vaginal insert include abdominal pain, nausea, and ovarian hyperstimulation syndrome.104
Adverse effects reported in patients receiving IM progesterone include breakthrough bleeding, spotting, changes in menstrual flow, amenorrhea, changes in cervical erosion and secretions, edema, weight gain or loss, cholestatic jaundice, allergic rash with or without pruritus, breast tenderness, galactorrhea, alopecia, hirsutism, pyrexia, sleep disturbances, nausea, and mental depression.101, 102 Pain and swelling at the site of injection may occur following IM administration of progesterone.101, 102 Large doses (50-100 mg daily) of progesterone may cause a moderate catabolic effect and a transient increase in sodium and chloride excretion.
An association between pulmonary embolism and cerebral thrombosis and embolism and use of estrogen-progestin combination preparations has been shown.101, 102 (See Thromboembolic Disorders in Cautions: Cardiovascular Effects, in Estrogen-Progestin Combinations 68:12.) The possibility that thromboembolic disorders may occur in patients receiving progesterone should be considered and patients should be carefully observed for these effects during therapy with the drug.101, 102 Although available evidence suggests that an association exists between neuro-ocular lesions such as optic neuritis or retinal thrombosis and use of estrogen-progestin combination preparations, such a relationship has been neither confirmed nor refuted.
Precautions and Contraindications
Progesterone shares the toxic potentials of progestins, and the usual precautions of progestin therapy should be observed. Prior to initiation of therapy with progesterone in women, a physical examination should be performed, including special attention to the breasts and pelvic organs and a Papanicolaou test (Pap smear).101, 102, 105 Women receiving progesterone should be given a copy of the patient labeling for the drug.101, 102, 103, 104, 105
Progesterone should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma, seizure disorders, migraine, or cardiac or renal dysfunction).101, 102, 103, 105 The drug should also be used with caution in patients with a history of mental depression; progesterone should be discontinued if depression recurs to a serious degree during therapy with the drug.101, 102, 103, 104, 105
When breakthrough bleeding or irregular vaginal bleeding occurs during progesterone therapy, nonfunctional causes should be considered.101, 102, 103, 105 Adequate diagnostic procedures should be performed in patients with undiagnosed vaginal bleeding.101, 102, 103, 105
Diabetic patients should be carefully monitored during progesterone therapy, since decreased glucose tolerance has been observed in women receiving estrogen-progestin combinations.101, 102, 103, 105 Progesterone may mask the onset of climacteric in women.101, 102
The clinician and the patient using progesterone should be alert to the earliest signs and symptoms of myocardial infarction, cerebrovascular disorders, thromboembolism (e.g., venous thromboembolism, pulmonary embolism), thrombophlebitis, or retinal thrombosis.101, 102, 103, 104, 105 The drug should be discontinued immediately when any of these disorders occurs or is suspected.101, 102, 104, 105
If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; retinal vascular lesions; or migraine occur during therapy with progesterone, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted.101, 102
Because dizziness has been reported during therapy with oral progesterone, patients receiving such therapy should be advised to use caution while driving or operating machinery.103
Progesterone is contraindicated in patients with thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a history of these conditions.101, 102, 103, 104, 105 The drug is also contraindicated in patients with undiagnosed vaginal bleeding, missed abortion, known sensitivity to the drug or any ingredient in the formulation, markedly impaired liver function or liver disease, or carcinoma of the breast or for use as a pregnancy test.101, 102, 103, 104, 105
Progesterone capsules are contraindicated in individuals with known hypersensitivity to peanuts because the capsules contain peanut oil.103
Mutagenicity and Carcinogenicity
The carcinogenic and mutagenic potentials of progesterone have not been specifically determined.
Administration of medroxyprogesterone to beagles has been associated with the development of mammary nodules, some of which were malignant. Although nodules occasionally occurred in control beagles, they were intermittent in nature; nodules in drug-treated beagles were larger, more numerous, persistent, and occasionally malignant with metastases. The clinical relevance of these findings to humans has not been established. For additional information on the carcinogenic potential of progestins, see Cautions: Mutagenicity and Carcinogenicity, in Medroxyprogesterone Acetate 68:32.
Progesterone is used to support embryo implantation and maintain pregnancy as a component of assisted reproductive technology (ART) treatment in infertile women.104, 105, 106 Such use is associated with increased ongoing pregnancy rates.104, 105, 106
Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during the first 4 months of pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. Masculinization of the female fetus has reportedly occurred when progestins were used during pregnancy. Clitoral hypertrophy has been reported in a few female neonates born to women who had received medroxyprogesterone during pregnancy. An association between intrauterine exposure to female sex hormones and congenital anomalies, including cardiovascular and limb defects, has been suggested. (See Cautions: Pregnancy, Fertility, and Lactation, in Estrogen-Progestin Combinations 68:12.) Use of progestins generally is not recommended during the first 4 months of pregnancy.
Progesterone should not be used to induce withdrawal bleeding as a test for pregnancy.
Progestins are reportedly distributed into milk. The manufacturers warn that the possible effects of progestins in milk on nursing infants have not been determined.102, 104, 105
The manufacturers caution that estrogen-progestin combinations have caused abnormal thyroid function test results. (See Effects on Thyroid in Cautions: Endocrine and Metabolic Effects, in Estrogen-Progestin Combinations 68:12.) The manufacturers also caution that estrogen-progestin combinations have altered the metyrapone test (see Laboratory Test Interferences in Estrogen-Progestin Combinations 68:12), and that these combinations have altered liver function test results (see Cautions: Hepatic Effects, in Estrogen-Progestin Combinations 68:12). These combinations have also caused decreased pregnanediol excretion.
The manufacturers state that the pathologist should be advised of progesterone use when relevant specimens from a patient exposed to the drug are submitted.101, 102, 103, 105
Progesterone is a progestinic hormone secreted mainly from the corpus luteum of the ovary during the latter half of the menstrual cycle. Progesterone is formed from steroid precursors in the ovary, testis, adrenal cortex, and placenta. Luteinizing hormone (LH) stimulates the synthesis and secretion of progesterone from the corpus luteum. Progesterone is necessary for nidation (implantation) of the ovum and for maintenance of pregnancy. Although the hormone is secreted mainly during the luteal phase of the menstrual cycle, small amounts of progesterone are also secreted during the follicular phase. High concentrations of the hormone are secreted during the latter part of pregnancy. Amounts comparable to those secreted in women during the follicular phase have been shown to be secreted in males.
Progesterone shares the pharmacologic actions of the progestins. In women with adequate endogenous estrogen, progesterone transforms a proliferative endometrium into a secretory one. The abrupt decline in the secretion of progesterone at the end of the menstrual cycle is principally responsible for the onset of menstruation. Progesterone also stimulates the growth of mammary alveolar tissue and relaxes uterine smooth muscle. Progesterone has minimal estrogenic and androgenic activity.
Progesterone has a short plasma half-life of several minutes. The hormone is reduced to pregnanediol in the liver and conjugated with glucuronic acid, and then excreted mainly in urine.
Progesterone is a naturally occurring progestin secreted by the corpus luteum. Progesterone is the prototype of the progestins. The drug may be obtained from animal ovaries but is usually prepared synthetically from stigmasterol or from diosgenin (extracted from Dioscorea mexicana , a Mexican yam).
Progesterone occurs as a white or creamy white, crystalline powder and is practically insoluble in water, soluble in alcohol, and sparingly soluble in vegetable oils. Progesterone injection is a sterile solution of the drug in a suitable solvent.
Progesterone is stable when exposed to air. The drug should be stored in tight, light-resistant containers. Parenteral progesterone preparations, progesterone capsules, progesterone vaginal inserts, and progesterone vaginal gel should be stored at 15-30°C.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder* | |||
Oral | Capsules | 100 mg | ||
200 mg | Prometrium® | Abbott | ||
Parenteral | Injection | 50 mg/mL* | Progesterone Injection | |
Vaginal | Gel | 4% | Crinone® (available in prefilled, disposable applicators) | |
8% | Crinone® (available in prefilled, disposable applicators) | Watson | ||
Insert | 100 mg | Endometrin® (with disposable applicators) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
101. Abraxis Pharmaceutical Partners, Inc. Progesterone injection prescribing information. Schaumburg, IL; 2006 Jun.
102. Watson Laboratories. Progesterone injection prescribing information. Corona, CA; 2007 Jan.
103. Solvay Pharmaceuticals, Inc. Prometrium®(progesterone) capsule prescribing information. Marietta, GA; 2004 Dec.
104. Ferring Pharmaceuticals, Inc. Endometrin®(progesterone) vaginal insert prescribing information. Suffern, NY; Jun 2007.
105. Columbia Laboratories, Inc. Crinone® (progesterone) bioadhesive vaginal gel prescribing information. Livingston, NJ; 2006 Dec.
106. Daya S, Gunby J. Luteal phase support in assisted reproductive cycles. Cochrane Database of Systematic Reviews . 2004, Issue 3. Art. no.:CD004830. DOI: 10.1002/14651858. CD004830.