Continuing Education Activity

Medroxyprogesterone is used to prevent pregnancy in females of reproductive potential and for women experiencing amenorrhea due to hormonal imbalance, excluding organic pathologies such as fibroids and uterine cancer. Additionally, medroxyprogesterone is used for abnormal uterine bleeding due to ovulatory dysfunction, prevention of endometrial hyperplasia, pain related to endometriosis, and in patients with inoperable, recurrent, and/or metastatic endometrial carcinoma as adjunctive and/or palliative treatment. Medroxyprogesterone, a progestin, is similar in structure to naturally occurring progesterone. The mechanism of action of progestin involves binding the progesterone receptor in the hypothalamus, female reproductive tract, and pituitary and inhibiting the secretion of gonadotropin-releasing hormone (GnRH).

This activity highlights medroxyprogesterone as contraception to prevent pregnancy and discusses the mechanism of action, adverse effects, monitoring, and contraindications for medroxyprogesterone, as well as the importance of regularly monitoring patients for adverse effects. An interprofessional team comprising primary care, ob/gyn, or related specialties might provide the best recommendations.

Objectives:

• Identify appropriate indications for medroxyprogesterone, including contraception, hormone replacement therapy, and management of abnormal uterine bleeding.

• Screen patients for contraindications and potential risks associated with medroxyprogesterone use, such as thromboembolic disorders and hormone-sensitive cancers.

• Assess patient response to medroxyprogesterone treatment and monitor for adverse effects or complications.

• Implement effective interprofessional collaboration regarding the benefits, risks, potential adverse effects, and administration of medroxyprogesterone, ensuring informed decision-making.

Indications

Medroxyprogesterone, a synthetic progestin, is commonly prescribed for the medical conditions described below.

Labeled Indications

• Contraception (104 mg/0.65 mL and 150 mg/mL injection): Medroxyprogesterone acetate (MPA) injection is used to prevent pregnancy in females of reproductive potential.[1]

• Amenorrhea, secondary (tablet): Women experiencing amenorrhea due to hormonal imbalance and not because of organic pathologies such as fibroids and uterine cancer.[2]

• Abnormal uterine bleeding (tablet): The American College of Obstetricians and Gynecologists (ACOG) recommends medroxyprogesterone for women experiencing abnormal bleeding due to ovulatory dysfunction; use is not advised for organic pathologies such as fibroids and uterine cancer.[3]

• Endometrial hyperplasia prevention (tablet): Medroxyprogesterone is administered to non-hysterectomized postmenopausal patients receiving a daily oral dose of estrogen of 0.625 mg.[4]

• Endometrial carcinoma (400 mg/mL injection or 100 mg tablet): In patients with inoperable, recurrent, and/or metastatic endometrial carcinoma, medroxyprogesterone acetate is used as adjunctive and/or palliative treatment.[4]

• Endometriosis (104 mg/0.65 mL injection): Used in patients experiencing pain related to endometriosis.[5]

Off-Label Indications

• Acute abnormal uterine bleeding [6]

• Endometrial hyperplasia[7][8]

• Hot flashes [9]

• Paraphilia/hypersexuality [10]

Some research indicates that women with sickle-cell disease are considered good candidates for medroxyprogesterone; the drug has been shown to reduce sickle-cell pain in women.[11] Medroxyprogesterone is also considered to cause a decreased incidence of seizures in women with seizure disorders.[2] Due to its association with respiratory centers, medroxyprogesterone has been used to treat patients with COPD, hypercapnia, sleep apnea, and Pickwickian syndrome.[12]

Mechanism of Action

Medroxyprogesterone is similar in structure to naturally occurring progesterone. The mechanism of action of progestin involves binding the progesterone receptor in the hypothalamus, female reproductive tract, and pituitary and inhibiting the secretion of gonadotropin-releasing hormone (GnRH).[1] By decreasing the frequency of release of GnRH, medroxyprogesterone blunts the midcycle LH surge and prevents follicular maturation and ovulation. Medroxyprogesterone changes a proliferative endometrium to secretory endometrium, making implantation difficult. Finally, medroxyprogesterone also impairs sperm migration into the uterus by increasing the viscosity of the cervical mucus.[1]

In premenopausal women experiencing amenorrhea and irregular uterine bleeding, medroxyprogesterone can be used to establish a normal menstrual cycle. Medroxyprogesterone also decreases endometrial growth in postmenopausal and menopausal women who receive estrogen therapy. Medroxyprogesterone acts on endometrial lesions and decreases endometrial-related pain in patients with endometriosis.[5] 

Pharmacodynamics and Pharmacokinetics

• Absorption
  • Oral: Rapid
  • IM: Slow

• Protein binding: 86% to 90% bound to albumin [5]

• Metabolism: Hepatic through hydroxylation and conjugation

• Bioavailability: 0.6% to 10%

• Half-Life Elimination [13]
  • Oral: 12 to 17 hours
  • IM: approximately 50 days
  • SQ: approximately 43 days

• Time to Peak 
  • Oral: 2 to 7 hours [14]
  • IM: 3 weeks to reach Cmax of 1 to 7 ng/mL
  • SQ: 1 week to reach Cmax of 0.953 ng/mL [5]

• Excretion: Urine as glucuronide conjugates with a small amount excreted as sulfates

Administration

Specific dosing based on formulation and indication can be found in the drug's packaging information.

Dose Formulations

• IM suspension: 150 mg/mL (1 mL) injection vial or a prefilled syringe

• SQ suspension: 104 mg/0.65 mL (0.65 mL)

• Tablet, oral: 2.5, 5, and 10 mg

Medroxyprogesterone injection inhibits ovulation for 14 weeks and must be administered every 3 months (12 weeks) for continuous contraception. Administration can be either IM or SQ; severe adverse reactions can occur if administered IV.

Oral Administration

Medroxyprogesterone tablets can be ingested sublingually and without regard to meals. 

Injectable Administration

Inspect the product for discoloration and particulate matter before usage. 

Intramuscular Administration (Contraceptive Injection Suspension)

• Administer the injection to the gluteal or deltoid region. 

• Shake the suspension before injecting. 

• Do not dilute the suspension before injecting. 

• Do not administer the drug IV. 

• Exclude the possibility of pregnancy, especially if 14 weeks have passed since the first dose. 

Subcutaneous Administration (Contraceptive Injection Suspension) 

• Inject a prefilled syringe into the anterior thigh or abdomen at a 45-degree angle. Pull the skin away from the body before injecting the drug.

• Shake the tube vigorously for 1 min before usage. 

• Press the area lightly but do not rub it after the injection.

• Avoid giving this IM or IV.

• Administer within 5 days of onset of menstrual bleeding.[15]

Specific Patient Population

Hepatic impairment: Medroxyprogesterone should not be administered to patients with significant liver impairment. If the patient develops jaundice or liver function disturbances, the drug should be stopped.[16]

Renal impairment: No dose adjustment recommendations are studied/provided in the manufacturer's prescribing label. Medroxyprogesterone can cause fluid retention, requiring caution in patients with preexisting kidney disease.

Pregnancy considerations: Three percent of the users experienced an unintended pregnancy, and efficacy was determined to be 99%. The drug is not recommended for women considering pregnancy soon as it may delay the return of fertility after discontinuation. Ectopic pregnancy has been reported with the use of medroxyprogesterone.[17]

Breastfeeding considerations: Breastfeeding women should not use medroxyprogesterone until 6 weeks postpartum in breastfeeding women, as infants are exposed to medroxyprogesterone through breast milk.[18]

Pediatric patients: Medroxyprogesterone use is not advised before menarche. Use is associated with a significant loss of bone mineral density, an important concern during adolescence and early adulthood.

Older patients: Medroxyprogesterone has not been studied in postmenopausal women and is not indicated in this population.

Adverse Effects

Menstrual irregularities and weight gain are the most common adverse effects of medroxyprogesterone.[19] Regarding weight gain, a study reported that medroxyprogesterone use increased by 1.61 in BMI and an average weight gain of 3.23 kg (7.11 lb).[20] Meanwhile, 57.3% of the patients receiving medroxyprogesterone reported irregular menses during the first year. Irregular bleeding decreases to 30% after 24 months and 10% after 24 months. Fifty-five percent of women report amenorrhea after 12 months of therapy, increasing to 68% after 2 years.

The following adverse effects of medroxyprogesterone contraceptive injection have been noted: oligomenorrhea, delayed return to fertility, prolonged anovulation (temporary infertility), unexpected pregnancy, uterine hyperplasia, genitourinary infections, vaginal cysts, vaginal and uterine hemorrhage. In females who utilize medroxyprogesterone tablets without estrogen for hormone replacement therapy, bleeding, spotting, changes in menstrual flow, changes in cervical erosion, and changes in cervical secretions have been reported. 

Both genders reported experiencing changes in breast symptoms and sexual function. Females who used the medroxyprogesterone contraceptive injection reported breast pain (2.8%) and decreased libido (5.5%). Post-market reports with the injection usage determined other adverse effects such as breast lumps, changes in breast size, nipple bleeding, galactorrhea, dyspareunia, lactation suppression, and changes in libido.[21] 

Females who only use medroxyprogesterone (without estrogen) for hormone replacement therapy reported mastodynia or mastalgia (breast pain), galactorrhea, and breast tenderness. Patients who used medroxyprogesterone in addition to estrogen for hormone replacement therapy reported breast tenderness, nipple breast discharge, fibrocystic breast changes, and breast cancer. In males, impotence and a decrease in testosterone levels by 25% were reported when they received medroxyprogesterone for palliative reasons. 

Angioedema, anaphylactic shock, and dermatologic reactions have been reported in users. Between 1% and 5% of the medroxyprogesterone users reported hot flashes and acne vulgaris. Alopecia was reported in 1.1% of patients who received contraceptive injections.

Postmarketing reports of contraceptive injection recipients indicated the following adverse effects: angioedema, dry skin, increased body odor, hyperhidrosis, axillary swelling, melasma, scleroderma, and urticaria. In women who used medroxyprogesterone in addition to estrogen for hormone replacement therapy, the following adverse effects occurred: chloasma or melasma after discontinuation, erythema multiforme, erythema nodosum, and alopecia. In addition, fixed drug eruption to medroxyprogesterone has been reported.[22]

Patients utilizing medroxyprogesterone contraceptive injections have reported dizziness (5.6%), insomnia (1% to 5%), nervousness (10.8%), depression (1% to 5%), anxiety or irritability (1% to 5%) and headaches (9% to 16.5%). If a patient experiences a headache or migraine with focal features consistent with cerebral ischemia, then discontinuation of medroxyprogesterone is recommended.[23] 

CNS adverse effects such as facial palsy, syncope, paralysis, and paresthesia have also occurred with contraceptive injection usage. In women utilizing medroxyprogesterone tablets along with estrogen, chorea and mood disturbances have been reported. Women utilizing the IM depot contraceptive injection reported gastrointestinal effects such as abdominal pain, nausea, and bloating. A rare case of splenic artery thrombosis has been reported.[24] Progestins stimulate the respiratory center and, as a result, during pregnancy and women's luteal phase of the menstrual cycle. Consequently, medroxyprogesterone can cause hyperventilation resulting in hypocapnia due to elevated levels of endogenous progestins. A study conducted in Thailand reported that pregnant women who took medroxyprogesterone had infants with polysyndactyly. The study also determined that the infants of these mothers were at an increased risk of having chromosomal abnormalities.[2][25][2]

Drug-Drug Interactions

• In vitro, medroxyprogesterone is metabolized by CYP3A4. Therefore, inducers and inhibitors of CYP3A4 can affect the metabolism of medroxyprogesterone.[26] Drugs that can reduce the efficacy of medroxyprogesterone include barbiturates, carbamazepine, oxcarbazepine, griseofulvin, bosentan, phenytoin, St. John’s wort, rifampin, and topiramate.[27][28][29]

• Product labeling specifies that significant changes (increase or decrease) in the plasma concentration of progestin have been marked with the coadministration of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) with medroxyprogesterone. Use with caution.[30][31][32]

Drug-Laboratory Interference

• Gonadotropin levels are reduced, and sex hormone-binding globulin is increased.[33]

• Administration of medroxyprogesterone can increase total T4, total T3, and thyroid-binding globulin levels; T3 uptake is also altered.[34]

Contraindications

Medroxyprogesterone is contraindicated in patients with known hypersensitivity to the drug or its excipients. Cases of angioedema and anaphylactic reaction have occurred in patients utilizing medroxyprogesterone.[35] Both forms of the drug (oral and injection) are contraindicated in patients with pre-existing breast cancer. In patients with a history of breast cancer, renal cancer, endometrial cancer, or a family history of breast cancer, medroxyprogesterone is contraindicated. Medroxyprogesterone injection has shown a slightly increased risk of developing breast cancer.[36][37][38] Medroxyprogesterone is contraindicated in patients with undiagnosed vaginal bleeding.

Medroxyprogesterone use requires caution in patients with diabetes. Hormonal contraceptives have been known to alter insulin sensitivity and, as a result, glucose tolerance. Medroxyprogesterone injections are contraindicated in patients with a history of arterial or venous thromboembolic (VTE) diseases or with an increased risk for stroke, heart disease, and arterial vascular disease.[23] Hormonal contraceptives can cause fluid retention and, as a result, should be used with caution in patients with asthma, congestive heart failure, and nephrotic syndrome. 

When using medroxyprogesterone in postmenopausal women along with estrogen therapy, it is associated with cardiovascular and thromboembolic risks.[2] Medroxyprogesterone use requires caution in women with hypertension, and blood pressure requires regular monitoring. Though estrogen-progestin combinations are known to alter serum lipid levels, it is essential to be cautious about medroxyprogesterone, a progestin-only contraceptive. Therefore, clinicians should check HDL and LDL regularly in patients. Although no congenital disabilities have been noted in patients exposed to medroxyprogesterone, it is contraindicated in pregnancy or suspected pregnancy.

The suspension injections can induce temporary infertility at higher concentrations, and patients experience delays in returning to baseline after ceasing treatment. Medroxyprogesterone tablets are also contraindicated in patients with incomplete abortions. In women with hepatic dysfunction or hepatic diseases, medroxyprogesterone usage is contraindicated. Use should be discontinued in women who experience jaundice or disturbances with their liver function. In women with a history of major depression, migraine, or seizure disorder, medroxyprogesterone should be used with caution, as progestin can exacerbate these conditions.  Clinicians should counsel patients that using medroxyprogesterone does not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.[39]

Box Warnings

Estrogens and progestins should not be used for cardiovascular disease prophylaxis.

• An increased risk of myocardial infarction, pulmonary embolism, deep vein thrombosis, and stroke in postmenopausal women (50 to 79 years) is seen with prolonged treatment when medroxyprogesterone is combined with conjugated estrogens.[40][41]

• MPA depot injection can decrease bone mineral density, possibly irreversible in postmenopausal women. Calcium and vitamin D supplementation are recommended.[42]

• MPA injection is not advised as a long-term (ie, older than 2 years) birth control; and should be utilized only when other birth control options are deemed inadequate.

• A risk of dementia in postmenopausal women 65 years and older during 4 years of daily treatment with conjugated estrogen plus medroxyprogesterone is evident.[43][44]

Monitoring

Patients require evaluation regarding their pregnancy status before starting therapy and if 14 weeks have passed since the last injection. Also, weight and bone mineral density should be evaluated regularly; consider bone mineral density in female patients with a strong history of breast cancer and the possibility of developing endometrial cancer, especially with long-term medroxyprogesterone use. Endometrial sampling is recommended every 3 to 5 months to monitor continually for endometrial hyperplasia.[45][7]

For menopausal patients currently using combination hormonal therapy, the risk for breast cancer and cardiovascular disease requires assessment. After initiating medroxyprogesterone therapy, the healthcare team must assess blood pressure and any unscheduled bleeding of greater than 6 months duration to evaluate for endometrial pathology. Additionally, patients should be administered breast exams and pelvic exams, depending on their age. These parameters should be followed even more closely for patients with diabetes, obesity, or a family history of endometrial cancer. Serum triglycerides should be monitored closely and checked 2 weeks after initiating therapy in patients with elevated triglycerides (>200 mg/dL). For patients currently receiving thyroid replacements, TSH levels must also be monitored 6 to 12 weeks after starting on oral medroxyprogesterone tablets.[9] If patients are currently prescribed medroxyprogesterone for paraphilia/hypersexuality, liver function tests (LFTs), complete blood count (CBC), serum testosterone, LH, FSH, and glucose require regular monitoring. Also, consider an annual bone scan if serum testosterone markedly decreases.[46][47]

Toxicity

Patients experiencing medroxyprogesterone overdose may experience nausea, vomiting, seizures, trouble breathing, and altered mental status. Treatment is primarily supportive.

Enhancing Healthcare Team Outcomes

Medroxyprogesterone can be administered via injection or oral tablet. Administering medroxyprogesterone requires communication between all interprofessional healthcare team members. Communication includes providing detailed instructions on different ways of administering IM and SQ injections and avoiding IV administration altogether. Additionally, clinicians and pharmacists must work together to determine appropriate forms of medroxyprogesterone, given the patient's symptoms and diagnosis. This level of collaboration can assist in avoiding adverse effects on patients and the potential development of invasive cancers and involves the entire interprofessional team. Pharmacists should verify the prescription before dispensing, as medroxyprogesterone can be confused with methyltestosterone and methylprednisolone.[48] They should also verify dosing and administration techniques, perform medication reconciliation, and offer patient counseling regarding their prescription.

Nursing staff and other healthcare team members need training in treating contraceptive overdose and the symptoms that could point in the direction of overdose. Nurses and other clinicians in the emergency department (ED) must work together to obtain drug levels in the blood and treat them to prevent any immediate adverse effects resulting from the overdose. To treat any long-term symptoms of the overdose, the healthcare team in the ED should consult with a toxicologist and pharmacist to provide evidence-based medical intervention.[49]

Medical staff should be prepared to inform patients about long-term usage risks and adverse effects. The healthcare team must work together to educate women with accurate information and, in the process, counter the inaccurate information spread through magazines and other patient-friendly lay platforms.[19] Patients should obtain counsel regarding the risk of osteoporosis and be screened regularly for breast cancer. They should also be informed about the likely menstrual disturbances and their length.[50] The interprofessional efforts of primary care clinicians, gynecologists, advanced practice practitioners, pharmacists, nursing staff, and pharmacists can improve therapeutic outcomes while minimizing adverse patient events when using medroxyprogesterone.