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. 2. 3. 4. 5.
Pehlic Marina,MD, Research fellow, Department of Medical Biology, School of Medicine, University of Split, Soltanska 2, 21000 Split, CROATIA 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 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 Novak Ribicic Kristijana,MD, Resident doctor, Department of Obstetrics and Gynecology, University Hospital Split, Spinciceva 1, 21000 Split 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
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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 10 mg 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 5 mg - 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.
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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
Identification
Figure 1. Flow Diagram
Records identified through database searching(CCRCT) (n =624)
Additional records identified through other sources(CDSR+DARE) (n =15+7)
Included
Eligibility
Screening
Records after duplicates removed (n =624+15+7)
Records screened (n =624+15+7)
Records excluded, with reasons* (n =531+14+7)
Articles assessed for eligibility (n =93+1)
Articles excluded (n =12)
Studies included (n =81+1)
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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, CEEconjugated 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
1.
Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen‐ progestogen therapy and/or sequential estrogen‐progesteron therapy with each other or placebo, administered over a minimum period of twelve months.
Furness (2009) Cochrane Menstrual Disorders and Subfertility Group trials register, Cochrane Library, MEDLINE, EMBASE, Current Contents, Biological Abstracts, Social Science Index, PsycINFO and CINAHL were searched up to May 2008. 45 studies were included from wich 10 with 5mg MPA: Bruhat 2001, Chang 2003, Gelfand 1989, Heikkinen 2000, Luciano 1993, Mattsson 2004, MSG 1994 (Archer 1994 and 2000), Nand 1995, OGEN‐Provera 1998 (Nand 1998), Wu 2002.
Conclusions; Comment
Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen. Risk of endometrial hyperplasia with HRT comprising low dose estrogen continuosly combined with a minimum of 1 mg norethisterone acetate OUTCOME: Incidence of or 1.5 mg endometrial medroxyprogesterone hyperplasia/carcinoma assessed acetate is not significantly by a biopsy at the end of different from placebo (1 mg treatment NETA: OR=0.04 (95% CI 0 to 2.8); 1.5 mg MPA: no hyperplasia events).
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Table 2. Clinical trials evaluating bleeding patterns in treatment containing 5mg MPA
BP
Citation and setting
Study design
No. of partici pants
Age range Intervention(incl. and formulation and stratification dose)
Comparator(s)
1
Archer 1994
RCT
1724
Postmenopau sal women
1. 5 mg MPA seq. + 0,625mg CEE
1. Placebo + 0,625 mg Bleeding patterns of HRT CEE
2. 5 mg MPA cont. + 0,625mg CEE
2. 10 mg MPA seq. + 0,625mg CEE
Norfolk, USA
Outcome(s) being assessment
3.2,5mg MPA cont. + 0,625mg CEE
2
Archer 2000
Clermond‐
2 continuous regimens Withdrawal produced amenorrhea in bleeding and /or 61,4% and 72,8% spotting compared to only 5% of women on sequential regimen.Those women also had withdrawal bleeding or spotting in 81,3% and 77% compared to 75% in women on estrogens only.
678
Postmenopau sal women (age 45‐65)
5mg MPA + 0,625mg CEE
2,5 mg MPA + 0,625mg CEE
Effect of progestin dose and time since menopause on endometrial bleeding
5 mg MPA group reported no bleeding in 93,8% vs. 89,5 % in 2,5 mg MPA group, p0.001)
cases of hyperplasia were observed. More women discontinued NETA regimen then MPA (30% in NETA vs 86% in 5MPA) due to bleeding disturbances, breast tenderness and weight increase.
RCT
86
Postmenopau sal women
5mg MPA (as initial gestagen tratment prior to HRT)
Placebo (prior to HRT) Bleeding patterns
Less frequent break‐ through bleeding in MPA group 34,2% than placebo group 48%(p=0.27) There were no significant difference between groups concerning endometrial thickness and serumlevels during bleeding (p>0.05)
No hyperplastic or malignant histology specimen from endometrial biopsy.
RCT
100
Postmenopau sal women
5mg MPA twice per week + 50 mcg E2 transdermal
2,5 mg MPA daily + 50 mcg E2 transdermal
Both similarly effective‐ symptom relief in 76% intermittent and 77% continuous group. Endometrium thickness remained