Medroxyprogesterone

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Continuing Education Activity

This article highlights medroxyprogesterone as it is used as contraception to prevent pregnancy. This activity discusses the mechanism of action, adverse effects, monitoring, and contraindications for medroxyprogesterone. Also, it highlights the important role that providers play in administering medroxyprogesterone and regularly monitoring patients for side effects.

Objectives:

  • Describe the mechanism of action of medroxyprogesterone.
  • Summarize the potential adverse effects of medroxyprogesterone in its different forms.
  • Review the monitoring necessary for patients on medroxyprogesterone therapy.
  • Outline the importance of appropriate communication with patients and the interprofessional staff to enhance healthcare delivery.

Indications

Labeled Indications

  • Contraception (104 mg per 0.65 mL and 150 mg/mL injection): Medroxyprogesterone acetate 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 drug is indicated for women experiencing abnormal bleeding due to hormonal imbalance and not because of organic pathologies such as fibroids and uterine cancer.
  • Endometrial hyperplasia prevention (tablet): Medroxyprogesterone acetate is administered to non-hysterectomized postmenopausal patients receiving a daily oral dose of estrogen of 0.625 mg.[3]
  • 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.[3]
  • Endometriosis (104 mg/0.65 mL injection): Used in patients experiencing pain related to endometriosis.[4]

Off-Label Indications

  • Acute abnormal uterine bleeding[5]
  • Endometrial hyperplasia 
  • Hot flashes 
  • Paraphilia/hypersexuality[6]

Mechanism of Action

Medroxyprogesterone acetate (MPA), 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 the pituitary and inhibiting the secretion of gonadotropin-releasing hormone (GnRH). By decreasing the frequency of release of GnRH, MPA blunts the midcycle LH surge and prevents follicular maturation and ovulation. MPA changes a proliferative endometrium to a secretory one in the endometrium, making it difficult for implantation. Finally, MPA 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, MPA can be used to establish a normal menstrual cycle. MPA also decreases the endometrial growth in postmenopausal women and menopausal women who receive estrogen therapy. MPA acts on endometrial lesions and decreases endometrial-related pain in patients with endometriosis.[4] Women with sickle-cell disease are considered good candidates for MPA. MPA has been shown to reduce sickle cell pain in women.[7] It is also considered to have decreased incidences 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.[8]

Pharmacodynamics & Pharmacokinetics

  • Absorption
    • Oral: Rapid
    • IM: Slow
  • Protein binding: 86% to 90% bound to albumin[4]
  • Metabolism: Hepatic through hydroxylation and conjugation. 
  • Bioavailability: 0.6% to 10%. 
  • Half-Life Elimination[9]
    • Oral: 12 to 17 hours
    • IM: approximately 50 days
    • SubQ: approximately 43 days
  • Time to Peak 
    • Oral: 2 to 7 hours[10]
    • IM: 3 weeks to reach Cmax of 1 to 7 ng/mL[4]
    • SubQ: 1 week to reach Cmax of 0.953 ng/mL[4]
  • Excretion: Urine as glucuronide conjugates with a small amount excreted as sulfates. 

Administration

Dosage Formulations

  • Intramuscular suspension (medroxyprogesterone acetate):150 mg/mL (1 mL) injection vial or a prefilled syringe
  • Subcutaneous suspension (medroxyprogesterone acetate): 104 mg/0.65 mL (0.65 mL)
  • Tablet, Oral, as acetate: 2.5 mg, 5 mg, and 10 mg

MPA inhibits ovulation for 14 weeks and must be administered every three months (12 weeks) for continuous contraception. Administration can be either intramuscular (IM) or subcutaneous. Severe adverse reactions can occur if administered IV.

Oral Administration

  • MPA tablets can be ingested sublingually and with no regard to meals. 

Injectable Administration

  • Inspect the product for discoloration and particulate matter before usage. 

Intramuscular Administration (Contraceptive injection suspension)

  • The injection must be administered to the gluteal or the deltoid region. 
  • Before injecting, shake the suspension. 
  • Before injecting, do not dilute the suspension. 
  • The injection must not be administered IV. 
  • It is important to exclude the possibility of pregnancy, especially if 14 weeks have passed since the first dose. 

Subcutaneous Administration[11] (Contraceptive Injection suspension) 

  • Inject 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. 
  • After injecting, press the area lightly but do not rub. 
  • Avoid giving this intramuscularly (IM) or intravenously (IV).
  • Must be administered within five days of onset of menstrual bleeding. 

Pregnancy/Breastfeeding 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 in the near future as it may delay the return of fertility after discontinuation. Manufacturers recommend not using MPA until six weeks postpartum in breastfeeding women as infants can suffer exposure through breast milk.[12]

Pediatric Considerations

medroxyprogesterone acetate use is not recommended before menarche. Use is associated with a significant loss of bone mineral density. Which is an important concern during adolescence and/or early adulthood.

Geriatric Patients

Medroxyprogesterone acetate has not been studied in postmenopausal women and is not indicated in this population.

Patients with Renal Impairment

No dose adjustment recommendations are studied/provided in the manufacturer’s prescribing label.

Patients with Hepatic Impairment

Medroxyprogesterone acetate should not be administered to women with significant liver impairment. If women develop jaundice or liver function disturbances, use should be stopped.

Drug Interactions

In vitro, MPA is metabolized by CYP3A4. Therefore, inducers and inhibitors of CYP3A4 can affect the metabolism of MPA.[13]

Adverse Effects

Menstrual irregularities and weight gain are the most common adverse effects of MPA.[14] In terms of weight gain, a study reported that MPA resulted in an increase of 1.61 in BMI and an average weight gain of 3.23 kg (7.11 lb). [15] 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% thereafter. Fifty-five percent of women report amenorrhea after 12 months of therapy, and that number goes up to 68% after two 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 hemorrhage, and uterine hemorrhage. (Medroxyprogesterone acetate 104 mg/0.65ml) injection suspension package insert. In females for hormone replacement therapy who utilize medroxyprogesterone tablets without estrogen, the following adverse effects have presented: bleeding, spotting, changes in menstrual flow, changes in cervical erosion, and changes in cervical secretions. 

 Both genders reported experiencing changes in breast and sexual function. Females who used the medroxyprogesterone contraceptive injection reported breast pain (2.8%) and a 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.[16] Females, who only use medroxyprogesterone (without estrogen) for hormone replacement therapy, reported mastodynia or mastalgia (breast pain), galactorrhea, and breast tenderness. As for patients who used medroxyprogesterone in addition to estrogen for hormone replacement therapy, they reported breast tenderness, nipple breast discharge, fibrocystic breast changes, and breast cancer. In males, there were reports of impotence and a decrease in testosterone levels by 25% 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 the 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. 

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. [17] CNS side effects such as facial palsy, syncope, paralysis, and paresthesia have also occurred with the contraceptive injection usage. Women utilizing medroxyprogesterone tablets along with estrogen, chorea, and mood disturbances may occur. 

Women utilizing the IM depot contraceptive injection reported gastrointestinal effects such as abdominal pain, nausea, and bloating. Recipients of the subcutaneous contraceptive injections  

Progestins stimulate the respiratory center and, as a result, during pregnancy and the luteal phase of the menstrual cycle in women. In addition, MPA can cause women to hyperventilate and become hypocapnic due to elevated levels of endogenous progestins.

A study conducted in Thailand reported that pregnant women who took MPA had infants with polysyndactyly. The study also determined that the infants of these mothers were at an increased risk of having chromosomal abnormalities.[2]

Contraindications

Medroxyprogesterone is contraindicated in patients with known hypersensitivity to medroxyprogesterone acetate. Cases of angioedema and anaphylactic reaction have occurred in patients utilizing medroxyprogesterone. 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 to have a slightly increased risk of developing breast cancer.[18][19][20]

Medroxyprogesterone use requires caution in patients with diabetes mellitus. Hormonal contraceptives have 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 diseases or patients with increased risks for stroke, heart disease, and arterial vascular disease.[17] 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. Even though estrogen-progestin combinations are known to alter serum lipid levels, it is essential to be cautious about medroxyprogesterone, a progestin-only contraceptive. Therefore, providers 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 stopping the treatment. Medroxyprogesterone tablets are also contraindicated in patients with incomplete abortions. In women with hepatic dysfunction or hepatic diseases, medroxyprogesterone usage is contraindicated. Usage 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. 

Providers should counsel patients that using medroxyprogesterone does not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.[21]

Additionally, as stated in a boxed warning on medroxyprogesterone depot injections, medroxyprogesterone usage can alter the bone mineral density and may not be reversible in premenopausal women. Recommendations for patients include taking calcium and vitamin D when using medroxyprogesterone depot injections.[22]

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 determined regularly. In female patients with a strong history of breast cancer and the possibility of developing endometrial cancer, consider bone mineral density, especially with long-term usage. Endometrial sampling is recommended every 3 to 5 months to monitor continually for endometrial hyperplasia.[23][24]

For menopausal patients currently using combination hormonal therapy, the risk for breast cancer and cardiovascular disease requires assessment. Following the administration of medroxyprogesterone, it is essential to assess blood pressure and for any unscheduled bleeding greater than six months 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 two weeks after starting therapy in patients with elevated triglycerides (>200 mg/dL). For patients who are currently receiving thyroid replacements, TSH levels must also be monitored 6 to 12 weeks after starting on oral medroxyprogesterone tablets.[25] 

Patients currently using medroxyprogesterone for paraphilia/hypersexuality, LFTs, CBC, serum testosterone, LH, FSH, and glucose require regular monitoring. Also, if serum testosterone shows a marked decrease, consider an annual bone scan.[26][27]

Toxicity

Patients experiencing medroxyprogesterone acetate overdose may experience nausea, vomiting, seizures, trouble breathing, or cannot be awakened. Treatment is mostly supportive.

Enhancing Healthcare Team Outcomes

Administering medroxyprogesterone acetate requires communication between interprofessional staff. Communication includes providing detailed instruction on different ways of administering IM and SubQ injections and avoiding IV administration altogether. Additionally, physicians and pharmacists need to 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 in patients and the potential development of invasive cancers and involves clinicians, nurses, and pharmacists.

Also, nurses and health care teams need training in treating contraceptive overdose and the symptoms that could point in the direction of overdose. Nurses and clinicians in the ED must work together to obtain drug levels in the blood and treat to prevent any immediate adverse side 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 comprehensive care that holistically addresses the concerns based on their expertise. 

Medical staff should be prepared to inform patients about the risk and adverse effects of long-term usage. It is of paramount importance that the healthcare team works together to inform women with accurate information and, in the process, take down the inaccurate information spread through magazines and other patient-friendly platforms.[14] Patients should be educated about the risk for osteoporosis and screened regularly for breast cancer. Patients should also be informed about the likely menstrual disturbances and the length of these disturbances.[28] The interprofessional efforts will improve therapeutic outcomes while minimizing or eliminating adverse events for patients using medroxyprogesterone acetate.[Level 5]


Article Details

Article Author

Abha Sathe

Article Editor:

Valerie Gerriets

Updated:

5/19/2022 2:24:40 PM

PubMed Link:

Medroxyprogesterone

References

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