• Sign Up

Medroxyprogesterone


Medroxyprogesterone

Article Author:
Abha Sathe
Article Editor:
Valerie Gerriets
Updated:
6/5/2020 1:22:46 PM
For CME on this topic:
Medroxyprogesterone CME
PubMed Link:
Medroxyprogesterone

Indications

Labeled Indications:

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

Amenorrhea, secondary (tablet): When women are 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 who are 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 who are receiving a daily oral dose of estrogen 0.625 mg.[3]

Endometrial carcinoma (400 mg/mL injection) (100 mg tablet): In patients who have 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. In the endometrium, MPA changes a proliferative endometrium to a secretory one, which makes 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. In patients with endometriosis, MPA acts on endometrial lesions and decreases endometrial related pain.[4]

Three percent of the users experienced an unintended pregnancy, and efficacy was determined to be 99%. Manufacturers recommend not using MPA until six weeks postpartum in breastfeeding women as infants can suffer exposure through breast milk.[7] Women with sickle-cell disease are considered good candidates for MPA. MPA has shown to reduce sickle cell pain in women.[8] It is also considered to have decreased incidences of seizures in women with seizure disorders.[2] Medroxyprogesterone, due to its association with respiratory centers, has been used to treat patients with COPD, hypercapnia, sleep apnea, and Pickwickian syndrome.[9]

Administration

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: [10]
    • Oral: 12 to 17 hours
    • IM: approximately 50 days
    • SubQ: approximately 43 days
  • Time to Peak 
    • Oral: 2 to 7 hours [11]
    • 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. 

In vitro, MPA is metabolized by CYP3A4. Therefore, inducers and inhibitors of CYP3A4 can affect the metabolism of MPA. [12]

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. MPA formula is available in a 150 mg/ml injection vial or a prefilled syringe for IM injections. 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 [13]

 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. 

Adverse Effects

Menstrual irregularities and weight gain are the most common adverse effect of using 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 who were received medroxyprogesterone reported irregular menses during the first year. Irregular bleeding decreases to 30% after 24 months and then to 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 for 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 headache or migraine with focal features that are 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 as well as the luteal phase of the menstrual cycle in women. 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

The drug is not recommended for women considering pregnancy in the near future as it may delay the return of fertility after discontinuation. 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 should be monitored regularly. 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 birth defects have been noted in patients exposed to medroxyprogesterone, it is contraindicated in pregnancy or suspected pregnancy. At higher concentrations, the suspension injections can induce temporary infertility, 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 the usage of 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. Every 3 to 5 months, endometrial sampling is recommended to monitor continually for endometrial hyperplasia.[23][24]

For menopausal patients, who are 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 6 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 diabetic, obese, or have 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 who are currently using medroxyprogesterone for paraphilia/hypersexuality, LFTs, CBC, serum testosterone, serum LH, FSH, and glucose require regular monitoring. Also, if serum testosterone shows a marked decrease, then 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 symptoms and diagnosis of the patient. This level of collaboration can assist in avoiding adverse effects in patients and the potential development of invasive cancers. 

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 as a result of 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 in terms of 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]


References

[1] Mishell DR Jr, Pharmacokinetics of depot medroxyprogesterone acetate contraception. The Journal of reproductive medicine. 1996 May     [PubMed PMID: 8725700]
[2] Westhoff C, Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety. Contraception. 2003 Aug     [PubMed PMID: 12954518]
[3] Tamauchi S,Kajiyama H,Utsumi F,Suzuki S,Niimi K,Sakata J,Mizuno M,Shibata K,Kikkawa F, Efficacy of medroxyprogesterone acetate treatment and retreatment for atypical endometrial hyperplasia and endometrial cancer. The journal of obstetrics and gynaecology research. 2018 Jan     [PubMed PMID: 29121428]
[4]     [PubMed PMID: 29617576]
[5] Munro MG,Mainor N,Basu R,Brisinger M,Barreda L, Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstetrics and gynecology. 2006 Oct;     [PubMed PMID: 17012455]
[6]     [PubMed PMID: 2529006]
[7] Koetsawang S,Nukulkarn P,Fotherby K,Shrimanker K,Mangalam M,Towobola K, Transfer of contraceptive steroids in milk of women using long-acting gestagens. Contraception. 1982 Apr;     [PubMed PMID: 6213373]
[8]     [PubMed PMID: 6178915]
[9]     [PubMed PMID: 1101759]
[10]     [PubMed PMID: 2524303]
[11]     [PubMed PMID: 6946675]
[12] Mimura N,Kobayashi K,Nakamura Y,Shimada N,Hosokawa M,Chiba K, Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo. Life sciences. 2003 Nov 7;     [PubMed PMID: 14561525]
[13]     [PubMed PMID: 23993431]
[14]     [PubMed PMID: 10454658]
[15]     [PubMed PMID: 11975135]
[16] ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstetrics and gynecology. 2006 Jun;     [PubMed PMID: 16738183]
[17] Curtis KM,Tepper NK,Jatlaoui TC,Berry-Bibee E,Horton LG,Zapata LB,Simmons KB,Pagano HP,Jamieson DJ,Whiteman MK, U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2016 Jul 29;     [PubMed PMID: 27467196]
[18] Li CI,Beaber EF,Tang MT,Porter PL,Daling JR,Malone KE, Effect of depo-medroxyprogesterone acetate on breast cancer risk among women 20 to 44 years of age. Cancer research. 2012 Apr 15;     [PubMed PMID: 22369929]
[19] Cobin RH,Goodman NF, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON MENOPAUSE-2017 UPDATE. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2017 Jul;     [PubMed PMID: 28703650]
[20] The 2017 hormone therapy position statement of The North American Menopause Society. Menopause (New York, N.Y.). 2017 Jul;     [PubMed PMID: 28650869]
[21] Tepper NK,Krashin JW,Curtis KM,Cox S,Whiteman MK, Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2016: Revised Recommendations for the Use of Hormonal Contraception Among Women at High Risk for HIV Infection. MMWR. Morbidity and mortality weekly report. 2017 Sep 22;     [PubMed PMID: 28934178]
[22] Bahamondes L,Perrotti M,Castro S,Faúndes D,Petta C,Bedone A, Forearm bone density in users of Depo-Provera as a contraceptive method. Fertility and sterility. 1999 May;     [PubMed PMID: 10231044]
[23] Trimble CL,Method M,Leitao M,Lu K,Ioffe O,Hampton M,Higgins R,Zaino R,Mutter GL, Management of endometrial precancers. Obstetrics and gynecology. 2012 Nov;     [PubMed PMID: 23090535]
[24] The American College of Obstetricians and Gynecologists Committee Opinion no. 631. Endometrial intraepithelial neoplasia. Obstetrics and gynecology. 2015 May;     [PubMed PMID: 25932867]
[25] Stuenkel CA,Davis SR,Gompel A,Lumsden MA,Murad MH,Pinkerton JV,Santen RJ, Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2015 Nov;     [PubMed PMID: 26444994]
[26] Guay DR, Drug treatment of paraphilic and nonparaphilic sexual disorders. Clinical therapeutics. 2009 Jan;     [PubMed PMID: 19243704]
[27] Reilly DR,Delva NJ,Hudson RW, Protocols for the use of cyproterone, medroxyprogesterone, and leuprolide in the treatment of paraphilia. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 2000 Aug;     [PubMed PMID: 10986575]
[28]     [PubMed PMID: 8492647]