Progesterone

Introduction Overview

Generic Name

progesterone

Brand Name

First Progesterone MC10, Menopause Formula Progesterone, Prometrium

Dosage Form

Oral capsules, vaginal gel, vaginal inserts, vaginal rings, injections, topical creams

Drug Class

Progestins

Pharmacokinetics

Absorption:
Progesterone exhibits variable absorption depending on the route of administration. Orally administered progesterone undergoes significant first-pass hepatic metabolism, severely reducing its systemic bioavailability; this has historically limited the effectiveness of oral formulations until micronized progesterone capsules were developed to improve absorption. Vaginal and intramuscular routes bypass first-pass metabolism, resulting in greater systemic availability. The onset of action may be rapid with intramuscular injections, while vaginal gels and inserts provide more sustained local effects with gradual systemic absorption. Factors such as gastrointestinal motility, presence of food, and formulation excipients can influence the rate and extent of oral absorption in clinical use.

Distribution:
Progesterone is highly lipophilic and extensively distributed throughout the body with a large volume of distribution. It readily crosses biological membranes and accumulates in fatty tissues and target organs such as the uterus and brain. Plasma protein binding is moderate, primarily to albumin and corticosteroid-binding globulin (CBG). The hormone’s lipophilicity allows it to cross the blood-brain barrier, exerting central nervous system effects. Tissue concentrations in the endometrium directly correlate with administered dose and route. Binding characteristics and distribution dynamics affect dosing schedules and therapeutic efficacy.

Metabolism:
Progesterone undergoes rapid and extensive hepatic metabolism primarily by reduction and hydroxylation pathways, mediated by cytochrome P450 enzymes such as CYP3A4. Metabolites include pregnanediol and pregnanolone, which are conjugated with glucuronic acid or sulfate before excretion. First-pass metabolism reduces oral bioavailability and produces active metabolites with neuroactive properties, such as allopregnanolone, that contribute to progesterone’s sedative effects. Metabolic clearance rates vary with age, liver function, and concomitant drug use that alters enzyme activity.

Elimination:
The primary route of elimination for progesterone and its metabolites is renal excretion of conjugated metabolites. The half-life after parenteral administration ranges from 5 to 20 minutes, but effects persist longer due to depot formation in adipose tissue. Vaginal and intramuscular routes display prolonged absorption phases, extending duration of clinical effect. Hepatic impairment can reduce clearance leading to increased systemic exposure, necessitating dose adjustments. Excretion kinetics contribute to dosing interval flexibility and timing in clinical protocols.

Dosage Forms

Available Dosage Forms:
- Oral capsules: micronized progesterone capsules (100 mg, 200 mg, 300 mg) [e.g. Prometrium]
- Vaginal gel: 4%, 8% progesterone gel [e.g. Prochieve]
- Vaginal inserts: 100 mg inserts [e.g. Endometrin]
- Vaginal rings: sustained release vaginal rings [e.g. Milprosa]
- Intramuscular injection: progesterone in oil solution (various concentrations)
- Topical creams: variable progesterone content, usually compounded

Dosages for Adults and Adolescents:
- For induction of menstrual period in anovulatory women: oral progesterone 200 mg daily in the luteal phase for 10 to 12 days per cycle
- For prevention of endometrial hyperplasia in postmenopausal women on estrogen therapy: oral 200 mg daily for 10 to 14 days per month
- For luteal phase support in assisted reproductive technology (ART): vaginal gel 90 mg daily or vaginal insert 100 mg daily
- For progesterone deficiency: doses individualized based on indication and clinical response
- Intramuscular injections typically administered as 50 to 100 mg daily or every other day depending on therapeutic goal

Specific Patient Populations:
- In postmenopausal women, lower doses may be used cautiously to avoid cardiovascular risk
- Pregnant women may receive intramuscular or vaginal progesterone for luteal phase support or prevention of preterm birth under specialist guidance
- Patients with hepatic impairment require careful monitoring due to altered metabolism
- Use during breastfeeding requires caution; systemic absorption may transmit progesterone into milk
- Pediatric dosing is rare and only under specialist supervision for specific hormonal indications
- Allergy to peanut oil in certain formulations contraindicates use of products containing it; alternatives should be selected.

Mechanism Of Action

Progesterone is a naturally occurring steroid hormone belonging to the progestin class, functioning primarily by binding to and activating progesterone receptors (PR), which are nuclear hormone receptors expressed in target tissues such as the uterus, breast, and central nervous system. Upon progesterone binding, the receptor undergoes conformational changes allowing it to regulate transcription of genes involved in reproductive and endocrine functions.

At the molecular level, progesterone modulates gene expression that regulates the menstrual cycle by preparing the endometrium for potential implantation of a fertilized ovum. It transforms the proliferative endometrium induced by estrogen into a secretory lining capable of supporting embryo implantation. Additionally, progesterone decreases the contractility of uterine smooth muscle, thus supporting pregnancy maintenance.

Progesterone also exhibits multiple systemic effects including modulation of the hypothalamic-pituitary-gonadal axis by negative feedback, reducing luteinizing hormone surge and ovulation. It influences the central nervous system by interacting with neurosteroid-sensitive receptors such as GABA-A receptors via its metabolites like allopregnanolone, contributing to sedative and anxiolytic effects.

Compared to synthetic progestins, natural progesterone has a distinct receptor binding profile resulting in relatively fewer adverse metabolic and cardiovascular effects. Clinical studies have demonstrated progesterone’s utility in hormone replacement therapy to counterbalance estrogen-induced endometrial hyperplasia and its role in fertility treatments for luteal phase support. Ongoing research examines its neuroprotective properties and potential applications in neurological disorders.

Pharmacological Actions

Regulation of the menstrual cycle by preparing endometrium for implantation
Support of pregnancy by maintaining uterine quiescence
Negative feedback inhibition on hypothalamic-pituitary axis reducing gonadotropin release
Modulation of breast tissue development and differentiation
Neurosteroid effects through GABA-A receptor modulation causing sedation and mood alteration
Prevention of endometrial hyperplasia when used with estrogen therapy
Reduction of uterine smooth muscle contractility to prevent preterm labor
Influence on lipid metabolism with less adverse cardiovascular impact compared to synthetic progestins
Immunomodulatory effects aiding in maternal-fetal tolerance
Potential neuroprotective properties under investigation
Induction of secretory transformation in endometrial glands
Stimulation of cervical mucus changes affecting sperm penetration

Therapeutic Or Clinical Uses

Treatment of anovulatory menstrual disorders to induce regular menstrual cycles
Prevention of endometrial hyperplasia in postmenopausal women receiving estrogen therapy
Luteal phase support for infertility treatments such as in-vitro fertilization
Management of secondary amenorrhea related to progesterone deficiency
Adjunct therapy in hormone replacement therapy regimens
Reduction of risk of endometrial cancer in women on unopposed estrogen therapy
Support of early pregnancy to prevent miscarriage in select cases
Treatment of abnormal uterine bleeding due to hormonal imbalance
Use in assisted reproductive technologies to improve implantation rates
Therapeutic trial in certain gynecologic conditions like endometriosis
Potential off-label use for menopausal symptom management when combined appropriately
Adjunctive therapy after incomplete miscarriage or threatened abortion under specialist supervision
Neuropsychiatric indications related to progesterone deficiency are emerging areas of research
Prevention of preterm birth through maintenance of uterine quiescence in at-risk pregnancies
Use in hormone-sensitive cancers is limited and contraindicated in breast cancer patients

Side Or Adverse Effects

Drowsiness and dizziness commonly reported with oral or injectable forms
Breast tenderness and pain
Mood changes including depression, irritability, and mood swings
Headache including migraine exacerbation
Gastrointestinal disturbances such as constipation, diarrhea, and heartburn
Bloating and peripheral edema presenting as swelling in hands or feet
Joint pain or arthralgia
Hot flashes especially during regimen initiation or withdrawal
Vaginal discharge or irritation with vaginal formulations
Increased risk of thromboembolic events including deep vein thrombosis and pulmonary embolism
Potential for increased risk of stroke and myocardial infarction particularly in women with cardiovascular risk factors
Allergic reactions including rash, urticaria, and rare anaphylaxis – importantly consider peanut oil allergy in injectable forms
Abnormal vaginal bleeding requiring evaluation
Vision disturbances and severe headaches warrant urgent attention
Liver function abnormalities manifesting as jaundice or elevated hepatic enzymes

Precautions

Assessment for history of thromboembolic disorders prior to initiation
Cautious use in patients with cardiovascular disease or risk factors
Screening for breast cancer history; contraindicated in active or past breast malignancy
Monitoring for abnormal vaginal bleeding during therapy
Consider alternative formulations in patients allergic to peanut oil present in some preparations
Evaluate hepatic function before and during therapy due to hepatic metabolism
Avoid use in pregnancy unless specifically indicated and supervised
Inform patients of potential sedation and advise on activities requiring alertness
Regular breast examinations for early detection of lumps or changes
Use with caution in patients with seizure disorders or epilepsy
Monitor mood and psychiatric status given risk of depression or mood instability
Adjust dose or discontinue in cases of severe adverse reactions
Review concomitant medications to avoid pharmacokinetic interactions
Use effective contraception during treatment to avoid unplanned pregnancy
Careful consideration in lactating women due to potential drug excretion in breast milk

Warnings

Progesterone use in pregnancy may cause harm to the unborn baby; contraindicated unless specifically prescribed
Increases risk of blood clots, deep vein thrombosis, pulmonary embolism, stroke, and heart attack especially in women with predisposing factors
Not to be used for prevention of heart disease or dementia due to potential increased risk
Avoid use in patients with recent heart attack, stroke, or venous thromboembolism within the past year
May increase the risk of breast cancer with long-term use or in patients with family history
Some formulations contain peanut oil; contraindicated in peanut allergy
Potential for severe allergic reactions including anaphylaxis
Use caution with hepatic impairment due to altered metabolism and clearance
Not recommended in women with abnormal vaginal bleeding of undiagnosed origin
May cause dizziness and drowsiness; caution advised when operating machinery or driving
Discontinue prior to surgery or immobilization to minimize thromboembolic risk
Monitor for symptoms of stroke such as sudden numbness, weakness, severe headache, or slurred speech
Seek immediate medical attention for signs of blood clots in lung or leg such as chest pain or leg swelling
Avoid unmonitored use or off-label indications without specialist consultation
Regular monitoring recommended to assess risk-benefit profile during prolonged therapy

Contraindication

Known hypersensitivity to progesterone or any component of the formulation
Pregnancy unless otherwise directed by a specialist
Active or history of breast cancer
Severe liver dysfunction or disease
Unexplained abnormal vaginal bleeding
Recent history (within one year) of stroke, myocardial infarction, or thromboembolic disorders
Allergy to peanut oil present in certain injectable preparations
History of or current venous thromboembolism or pulmonary embolism
Incomplete miscarriage or missed abortion without medical clearance
Concurrent use with medications or conditions that are contraindicated due to interaction or exacerbation of side effects
Undiagnosed genital bleeding
Breastfeeding mothers unless benefits outweigh risks and monitored closely
Use with caution in epilepsy or seizure disorders
Not to be used as sole therapy for prevention of cardiovascular or neurodegenerative diseases
Severe psychiatric disorders without specialist supervision

Drug Interactions

CYP3A4 inducers such as rifampin, phenytoin, carbamazepine may decrease progesterone plasma levels reducing efficacy
CYP3A4 inhibitors such as ketoconazole may increase progesterone levels, enhancing side effects
Concomitant use with anticoagulants may affect coagulation parameters and increase bleeding risk
Potential interaction with seizure medications leading to altered plasma concentrations
Estrogen-containing medications can have additive prothrombotic risk when combined with progesterone
Drugs that affect hepatic enzyme activity such as St. John's Wort may alter progesterone metabolism
Co-administration with sedatives or CNS depressants may exacerbate drowsiness or dizziness
Herbal supplements affecting cytochrome P450 enzyme system may impact progesterone levels
Potentiation of hypotensive effects when used with antihypertensive agents
Possible interaction with corticosteroids altering adrenal function
Interactions with drugs affecting gastrointestinal motility may influence oral progesterone absorption
Synergistic effects with other hormonal therapies require monitoring for adverse effects
Monitoring required when combined with anticoagulant therapy due to bleeding risk
Concomitant use with other progestational agents can increase side effect frequency
Avoid abrupt discontinuation when used with interacting drugs to prevent withdrawal effects

Preparations Of The Drug

Micronized progesterone oral capsules (Prometrium) designed for improved bioavailability
Progesterone vaginal gels (Prochieve) for local endometrial effects and luteal support
Progesterone vaginal inserts (Endometrin) enabling sustained local drug delivery
Intramuscular progesterone in oil formulations for deep tissue injection and prolonged release
Topical progesterone creams commonly compounded though variable absorption limits standardized use
Progesterone vaginal rings (Milprosa) providing sustained hormone release over weeks
Injectable progesterone preparations requiring aseptic technique and medical supervision
Various compound formulations for specialized indications under physician guidance
Capsules typically contain excipients like peanut oil; alternative formulations available for allergies
Combination hormone therapies with progesterone and estrogen for menopausal symptom management
Suppositories delivering controlled progesterone dosing via vaginal mucosa
Commercially available standardized formulations with quality control and FDA approval
Freeze-dried powder formulations reconstituted for injection in clinical settings
Progesterone implants (less common) for long-term hormone replacement
Variable strengths marketed to cater to diverse clinical needs from menstrual regulation to fertility treatment