18th Expert Committee on the Selection and Use of Essential Medicines (21 to 25 March 2011) Section 18: Hormones, other endocrine medicines and contraceptives Section 18.7: Progestogens -- Medroxyprogesterone acetate (Possible deletion) Review of the role of Medroxyprogesterone acetate 5 mg in hormone replacement therapy for postmenopausal women Name of the organization preparing the application School of Medicine, University of Split, Šoltanska 2, 21000 Split, Croatia 1. Pehlic Marina 2. Sambunjak Dario 3. Stipic Ivica 4. Novak Ribicic Kristijana 5. Strinic Tomislav Acknowledgment We thank Ana Utrobicic for her assisstance in conducting literature search and obtaining the needed articles. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1. Pehlic Marina,MD, Research fellow, Department of Medical Biology, School of Medicine, University of Split, Soltanska 2, 21000 Split, CROATIA 2. Sambunjak Dario,MD,PhD, Director, Croatian Branch of the Italian Cochrane Centre, Senior Editor of Croatian Medical Journal, School of Medicine, University of Split, Soltanska 2, 21000 Split 3. Ivica Stipic,MD, Resident doctor, Department of Obstetrics and Gynecology, University Hospital Split, Spinciceva 1, Split, School of Medicine, University of Split, Soltanska 2, 21000 Split 4. Novak Ribicic Kristijana,MD, Resident doctor, Department of Obstetrics and Gynecology, University Hospital Split, Spinciceva 1, 21000 Split 5. Professor Tomislav Strinic, MD,PhD, Specialist in Obstetrics and Gynecology, Department of Obstetrics and Gynecology, University Hospital Split, Spinciceva 1, Split, School of Medicine, University of Split, Soltanska 2, 21000 Split 1 The aim of this review is to evaluate safety and efficacy of per os medroxyprogesterone (MPA) in 5mg dosage regimen for hormonal replacement therapy (HRT) by searching all published papers and reports. MPA is currently listed on the 16th WHO Model List of Essential Medicines in group 18.7 Progestogens (http://www.who.int/medicines/publications/essentialmedicines/Updated_sixteenth_adult_list_en.pdf) 1.Introduction 1.a) MPA Medroxyprogesterone acetate or MPA is a progestin, a synthetic variant of the human hormone progesterone. MPA inhibits secretion of pituitary gonadotropins, thereby preventing follicular maturation and ovulation (contraceptive effect); inhibits spontaneous uterine contraction; transforms proliferative endometrium into secretory endometrium; produces antineoplastic effect in advanced endometrial or renal carcinoma. Trade Names : Amen- Tablets 10 mg Curretab- Tablets 10mg Cycrin- Tablets 2.5 mg - Tablets 5 mg - Tablets 10 mg Depo-Provera- Injection 150 mg/mL - Injection 400 mg/mL Provera - Tablets 2.5 mg - Tablets 5mg - Tablets 10 mg Apo-Medroxy (Canada) Gen-Medroxy (Canada) Provera-Pak (Canada) 2 ratio-MPA (Canada) -mostly used: Provera (http://www.pfizer.com/files/products/uspi_provera.pdf) Indications and Usage Per os (PO) - Treatment of secondary amenorrhea and abnormal uterine bleeding caused by hormonal imbalance; reduction of incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogen 0.625 mg. Parenteral - Prevention of pregnancy; adjunctive and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma. Contraindications Hypersensitivity to progestins; current or history of thrombophlebitis, thromboembolic disorders, cerebrovascular disease, or cerebral hemorrhage; impaired liver function; breast or genital organ cancer; undiagnosed vaginal bleeding; missed abortion; diagnostic test for pregnancy; known or suspected pregnancy. Dosage and Administration Abnormal Uterine Bleeding-Adults -PO 5 to 10 mg/day for 5 to 10 days beginning on 16th or 21st day of menstrual cycle. Contraceptive-Adults -IM 150 mg every 3 mo. Endometrial or Renal Carcinoma-Adult - Initial -IM 400 to 1,000 mg/wk. - Maintenance -IM 400 mg/mo. Reduction of Endometrial Hyperplasia-Adults -PO 5 to 10 mg daily for 12 to 14 consecutive days per month, beginning on the 1st or 16th day of cycle. Secondary Amenorrhea-Adults- PO 5 to 10 mg/day for 5 to 10 days. 3 Adverse Reactions Cardiovascular-Thrombophlebitis; edema. CNS-Depression; headache; nervousness; dizziness; insomnia; fatigue; somnolence. Dermatologic-Rash; acne; melasma; chloasma; alopecia; hirsutism; photosensitivity; pruritus; urticaria. GI-Abdominal pain or discomfort; nausea. Genitourinary-Breakthrough bleeding; spotting; change in menstrual flow; amenorrhea; decrease in libido; changes in cervical erosion and secretions. Hepatic-Cholestatic jaundice. Respiratory-Pulmonary embolism. Miscellaneous-Breast tenderness; masculinization of female fetus; edema; weight changes, especially weight gain; anaphylactoid reactions; bone mineral density changes, increasing risk of osteoporosis; hyperglycemia; pyrexia; galactorrhea 1.b) HRT Hormone replacement therapy (HRT)- also known as Hormone therapy (HT), is a system of medical treatment for surgically menopausal, perimenopausal and postmenopausal women. Prescription drugs used most often when treating menopause symptoms include both Estrogen therapy (ET) and combination of hormones- Estrogen plus progestogen therapy (EPT). Menopause is defined as the final menstrual period (FMP). It represents the permanent cessation of menses resulting from loss of ovarian follicular function due to aging. Menopause can occur naturally on average around age 51 or it can be induced by a medical intervention (surgery, chemotherapy, pelvic radiation therapy).Women are said to be postmenopausal when menstruation has ceased for 6 to 12 months and blood serum levels of follicle stimulating hormone (FSH) increase to at least 49 IU/L. The decline in circulating estrogen around the time of the menopause can induce symptoms that affect the well being and health of women: hot flushes, insomnia, declining bone mass, night sweats, mood disturbances and vaginal dryness have all been reported. Estrogen therapy has been used for 4 the treatment of many of the menopausal symptoms, particulary hot flushes and vaginal dryness. Variety of progestogens are used in HRT, classified according to their structure or bioactivity. The main reason for combining estrogen and progestogen in HRT is to protect the endometrium from developing endometrial hyperplasia,which is regarded as a precursor of endometrial cancer. The risk of hyperplasia and/or carcinoma appears to increase with higher doses and increased duration of unopposed estrogen treatment. Adding a progesteron to estrogen therapy significantly reduces the risk of hyperplasia (Furness 2009) but can result in premenstrual symptoms which cause problems for some women. These symptoms and increased bleeding and spotting are often given as a reason to discontinue HRT. HRT is an effective treatment for women with menopausal symptoms of hot flushes, night sweats and vaginal dryness and the duration of therapy shoud be decided for individual women based on an assessment of both benefits, in terms of menopausal symptom managment and harms of therapy, such as venous thromboembolism. The duration of treatment with HRT shoud be reviewed by a woman with her doctor, because for most women hot flushes resolve within a year of onset of the menopause. 2.Search strategy Inclusion criteria: -Subjects: Healthy postmenopausal women (incl.surgical menopause) -Intervention: Medroxyprogesterone acetate 5mg per os (alone or in combination with other substances) -Indication: Hormone Replacement Therapy (HRT) -Included study designs: Systematic Review Articles and Randomised Controlled Trials (RCT) -Outcomes: Safety and Efficacy Search History: 1. exp Hormone Replacement Therapy/ 2. hormone replacement.mp. 3. exp Medroxyprogesterone/ 4. medroxyprogesterone acetate.mp. 5. MPA.mp. 6. 1 or 2 7. 3 or 4 or 5 5 8. 6 and 7 9. exp Hormone Replacement Therapy/ 10. hormone replacement.mp. 11. exp Medroxyprogesterone/ 12. medroxyprogesterone acetate.mp. 13. MPA.mp. 14. 9 or 10 15. 11 or 12 or 13 16. 14 or 15 Figure 1. Flow Diagram Records identified through Additional records identified database searching(CCRCT) through other sources(CDSR+DARE) (n =624) (n =15+7) Identification Records after duplicates removed (n =624+15+7) Screening Records screened Records excluded, with (n =624+15+7) reasons* (n =531+14+7) Articles assessed for Articles excluded (n =12) eligibility (n =93+1) Eligibility Studies included Included 6 (n =81+1) Identification of clinical evidence Ovid SP Database resources were searched: EBM Reviews- Cochrane Database of Systematic Reviews (2005 to September 2010), EBM Reviews- Cochrane Central Register of Controlled Trials (4th Quarter 2010) and EBM Reviews-Database of Abstracts of Reviews of Effects ( 3rd Quarter 2010) were searched to identify all published papers and reports evaluating the effectiveness of MPA in Hormone Replacement Therapy. *reasons for articles exclusion: non-english, different hormone (only estrogen therapy or another progesterone), comorbidity in postmenopausal women, different dosage and/or aplication, different indication (contraception, endometriosis, hyperandrogenism). **abbreviations used: MPA-medroxyprogesterone acetate, E2-estradiol, EV-estradiol valerate, CEE- conjugated equine estrogen,TE-transdermal estrogen, E1S- estriol sulfate , 17bE2- 17beta estradiol, CPA- cyproterone acetate, QoL-Quality of life. ------------------------------------------------------------ Table 1. Systematic reviews evaluating the effectiveness of MPA in HRT No. Article; Search strategy Selection criteria; Outcomes Conclusions; Comment 1. Furness (2009)