Review of the Role of Medroxyprogesterone Acetate 5 Mg in Hormone Replacement Therapy for Postmenopausal Women

Home , Cyproterone acetate, Dydrogesterone, Medroxyprogesterone, Progestogen, Progestogen (medication)

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

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)

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.

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

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

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.

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Table 1. Systematic reviews evaluating the effectiveness of MPA in HRT

No. Article; Search strategy Selection criteria; Outcomes Conclusions; Comment

1. Furness (2009) Randomised comparisons of Hormone therapy for unopposed estrogen therapy, postmenopausal women with Cochrane Menstrual Disorders and combined continuous estrogen‐ an intact uterus should Subfertility Group trials register, progestogen therapy and/or comprise both estrogen and Cochrane Library, MEDLINE, sequential estrogen‐progesteron progestogen. Risk of EMBASE, Current Contents, therapy with each other or endometrial hyperplasia with Biological Abstracts, Social Science placebo, administered over a HRT comprising low dose Index, PsycINFO and CINAHL were minimum period of twelve estrogen continuosly searched up to May 2008. months. combined with a minimum of 1 mg norethisterone acetate 45 studies were included from OUTCOME: Incidence of or 1.5 mg wich 10 with 5mg MPA: Bruhat endometrial medroxyprogesterone 2001, Chang 2003, Gelfand 1989, hyperplasia/carcinoma assessed acetate is not significantly Heikkinen 2000, Luciano 1993, by a biopsy at the end of different from placebo (1 mg Mattsson 2004, MSG 1994 (Archer treatment NETA: OR=0.04 (95% CI 0 to 1994 and 2000), Nand 1995, 2.8); 1.5 mg MPA: no OGEN‐Provera 1998 (Nand 1998), hyperplasia events). Wu 2002.

Table 2. Clinical trials evaluating bleeding patterns in treatment containing 5mg MPA

BP Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Archer 1994 RCT 1724 Postmenopau 1. 5 mg MPA seq. + 1. Placebo + 0,625 mg Bleeding patterns of HRT 2 continuous regimens Withdrawal sal women 0,625mg CEE CEE produced amenorrhea in bleeding and /or Norfolk, USA 61,4% and 72,8% spotting 2. 5 mg MPA cont. + 2. 10 mg MPA seq. + compared to only 5% of 0,625mg CEE 0,625mg CEE women on sequential regimen.Those women 3.2,5mg MPA cont. + also had withdrawal 0,625mg CEE bleeding or spotting in 81,3% and 77% compared to 75% in women on estrogens only.

2 Archer 2000 RCT 678 Postmenopau 5mg MPA + 0,625mg 2,5 mg MPA + Effect of progestin dose 5 mg MPA group 2 cases of sal women CEE 0,625mg CEE and time since reported no bleeding in endometrial (age 45‐65) menopause on 93,8% vs. 89,5 % in 2,5 hyperplasia in endometrial bleeding mg MPA group, p< 2,5MPA, no cases Philadelphia,USA 0.089. 5 mg MPA is more in 5 MPA but ther suitable for women is no statistical starting therapy and difference. early menopause women.

3 Bruhat 2001 RCT 440 Postmenopau 5mg MPA + 1‐2 mg 1. 2,5 mg MPA + 1‐2 Bleeding control and MPA regiments had Tolerability and sal women E2V mg E2V symptom relief significant fewer endometrial safety Clermond‐ bleeding days then were good, no 8

Ferrand,France 2. 1 mg NETA + 2 NETA. All regiments cases of mg E2 affectively relieved hyperplasia were climacteric symptoms observed. More (no sign.difference women between groups) and discontinued NETA had benefit on lipid regimen then MPA profile (decrease in total (30% in NETA vs cholesterol 5%in NETA 86% in 5MPA) due and 9% in MPA; HDL to bleeding significantly lower in disturbances, NETA vs MPA p>0.001) breast tenderness and weight increase.

4 Buyuk 1999 RCT 86 Postmenopau 5mg MPA (as initial Placebo (prior to HRT) Bleeding patterns Less frequent break‐ No hyperplastic or sal women gestagen tratment through bleeding in MPA malignant Istambul, Turkey prior to HRT) group 34,2% than histology placebo group specimen from 48%(p=0.27) There were endometrial no significant difference biopsy. between groups concerning endometrial thickness and serumlevels during bleeding (p>0.05)

5 Cano 1999 RCT 100 Postmenopau 5mg MPA twice per 2,5 mg MPA daily + Dropping out, bleeding Both similarly effective‐ Irregular bleeding sal women week + 50 mcg E2 50 mcg E2 pattern, endometrial symptom relief in 76% occurred in 14/50 Valencia, Spain transdermal transdermal thickness and plasma intermittent and 77% women from lipids continuous group. intermittent MPA Endometrium thickness group and 13/50 remained <5mm in both from continuous groups‐Lipid levels had group. High rate of no significant change in atrophic both groups. endometria suggests reduction 9

of progestin dose

6 Cumming 2002 RCT 23 Postmenopau 5mg MPA + 0,625 mg 200mg micronized Bleeding control and No effect on mood MPA users sal women CEE ( 2 weeks progesterone + 0,625 symptom relief (depression, vigor, reported more San Francisco, USA mean change: CEE+MPA mg CEE ( 2 weeks fatigue, anger, tension, vaginal bleeding age then only CEE) change: CEE+MPA confusion) in any group (p<0.05) and 52,5 then only CEE) individually, compared breast tenderness with placebo ot between (p<0.05) then groups. progesterone group

7 Huber 2002 RCT 501 Postmenopau 5mg MPA + 0,025 mg 2,5 mg tibolone Effects of HRT on Tibolone treatement had Tolerability: 32,8% sal women CEE bleeding rates, QoL and significantly lower of tibolone women Vienna, Austria tolerability bleeding rate (p=0,004), vs 38,3% in MPA <65 intact improved sexual drive group. Severe uterus (p=0.017) and lower adverse event incidence of breast were 2 in tibolone tenderness (p<0.001). group (stroke and Both regimens improved vaginal bleeding) QoL, well‐being, and 1 in MPA climacteric symptoms (deep and urogenital thrombophlebitis complaints. and pulmonary embolism resulted in death of the patient!). Others reported: breast tenderness, headache, back pain, abdominal pain, hot flushes (tibolone vs MPA p<0.05), depression, weight increase, anxiety,

vaginitis, sinusitis.

8 Mattsson 2004 RCT 393 Postmenopau 2,5 mg MPA + 1mg 1. 1mg NETA + 2mg Bleeding profile and side‐ All regiments provided Significantly higher sal women E2V E2 effects of HRT excellent endometrial rate of adverse Gothenburg, safety. Significantly more events in NETA Sweden 2. 5mg MPH + 1‐2 mg bleeding disturbances group E2V and breast tenderness in (56,8%,p<0.05) NETA group (p < 0.05). than in MPA groups (32,1% and 40,8%, p<0.05)‐ breast tenderness, breast pain and bleeding

9 Nand 1998a RCT 568 Postmenopau 5mg MPA +1,25 E1S 1. 2,5 mg MPA + Bleeding pattern and No statistically No cases of multicenter sal women 1, 25mg E1S endometrial changes significant differences endometrial Randwick NSW, double between groups. hyperplasia. Australia blind 2 1. 10 mg MPA + Approx. 80% A greater number years study 1, 25mg E1S amennorheic by 6 of women months of th. experienced heavy bleeding in the 2.5MPAgroup than in 5MPA and 10MPA groups. This was consistent over time for the first 9 months but was not statistically significant. Adverse events in women in 2.5MPA group decreased over this time from 9.3% to 3.1%. In 11

the 5‐mg group, 5.5% were heavy bleeders at month 1 and 0.6% were heavy bleeders at month 9. In the 10‐mg group, only 4.4% were heavy bleeders at month 1 and this figure decreased to 0.6% by month 9. 10 Odmark 2001 RCT 208 Postmenopau 5mg MPA + 0,625 mg 1 mg NETA+ 2 mg Bleeding patterns MPA group had fewer Not reported sal women CEE 17betaE2 bleeding problems Solna, Sweden p<0.002). Progression to amenorrhea had odds ratio of 1,58 in comparison to other group.

11 Pickar 1998. RCT 972 Postmenopau 1. 5mg MPA 1. 2,5mg MPA Amenorrheic frequency Amenorrheic frequency Bleedins,spotting, sal women continuous + 0,625 continuous + 0,625 increased in 2,5 and 5 endometrial Philadelphia, USA mg CEE mg CEE MPA continuous hyperplasia regimens. 2. 5mg MPA 2. 10 mg MPA sequentionel + 0,625 sequentionel + 0,625 mg CEE mg CEE

3. Placebo + 0,625 mg CEE

12 Raudaskolski 2002 RCT 163 Postmenopau 5mg MPA + 2 mg 1. 10 mg Clinical, endometrial and After 12 months of 3 women in sal women E2V levonogestrel metabolic response therapy, strong levonorgestrel Oulu, Finland intrauterine + 2 mg endometrial suppression group E2V was found in 46/47 and discontinued due 55/55 of the subjects to bleeding, 4 due

2. 20 mg receiving 10mg and to abdominal pain, levonogestrel 20mg of levonorgestrel, endometrial polyp, intrauterine + 2 mg respectively, while the depression and E2V endometrium was pain in the legs. proliferative in 18/47 of 4 in MPA group the subjects in the discontinued due medroxyprogesterone to multiple acetate group. MPA subjective adverse regiment produced cyclic symptoms. The withdraval .Total serum most frequently cholesterol decreased in events were: all groups. unscheduled bleeding, headache, abdominal pain, breast pain and vaginal discharge. MPA group reported bleeding and vaginal discharge less frequently than did those with intrauterine treatments, but otherwise there were no differences between the treatment groups.

MPA and bleeding patterns summary

12 RCT papers were reviewed with total of 5856 postmenopausal women involved in the studies. 7 out of 12 RCTs showed better withdrawal bleeding control and vaginal discharge control together with increase of amenorrhea rates in MPA containing treatment than other regimens compared. 2 out of 12 RCTs showed very good response in regard to bleeding control, but had no significant difference between MPA and other regimens. 3 out of 12 RCTs reported better therapeutic response in comparative treatments (tibolone, micronized natural progesterone and intrauterine levonogestrel) than 5 mg MPA. Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA.

Table 3. Clinical trials evaluating bone density in treatment containing 5mg MPA

BD Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Blake 1993 RCT 74 Postmenopau 5 mg MPA seq.+ 1. 2,5 mg MPA cont + Protection of bone mass HRT prevented bone 2 vaginal bleedings sal women 0,625 mg CE + 0,3 mg CE + Calcium mass loss by increasing in 5 MPA group,10 Calcium lumbar spine mineral in 2,5MPA group. 2. Calcium density (significantly Breast tenderness compared to calcium was increased in only p>0.05) and MPA group. decrease in HDL in both groups (significantly compared to calcium only p>0.05)a

2 el‐Hajj Fuleihan RCT 30 Postmenopau 1. 5 mg MPA seq. + 2,5 mg MPA cont. + Effect on indexes of All groups demonstrated 9 women 1992 sal women 0,625mg CEE 0,625mg CEE mineral metabolism of significant decrease in discontinued HRT. indexes of bone therapy due to 2. 5 mg MPA cont. + formation turnover, severe abdominal 14

Boston, USA 0,625mg CEE including decrements in cramps, bleeding, alkaline phosphatase migraine levels of 11% to 30% and headaches, blood in osteocalcin levels of pressure elevation, 45% to 60%.Intact deep vein parathyroid hormone trombosis and levels rose 10 to 20% vitamin D and there were deficiency significant decrements in 24‐hour urinary Ca‐ creatinine ratios and hydroxyproline‐ creatinine ratios of 13% to 28% (measures of bone resorption).

3 Heikkinen 2000b RCT 296 Postmenopau 1. 5 mg MPA + 1 mg 1. 2,5 mg MPA + 1 Long‐term HRT in Lower dose regimens are No endometrial sal women E2V mg E2V prevention of bone loss effective in increasing hyperplasia was 4 years (age 52‐62) and maintaining bone observed in any study 2. 5 mg MPA + 2 mg 2. 2,5 mg MPA + 2 mineral density and group Oulu, Finland E2V mg E2V provides good endometrial safety profile for the long term prevention of osteoporosis. All regimens were safe and well accepted (80%continuation) and showed prominent beneficial effect on bone.

4 Heikkinen 2008 RCT 279 Postmenopau 1. 5mg MPA +1 mg 1. 2,5 mg MPA + 1 Effect on bone mineral Progressive increase of Long term HRT sal women E2V mg E2V density of long‐term of vertebral Bone Mineral associated effect: Espoo, Finland 10 year HRT Density was observed in myocardial follow 2. 5 mg MPA + 2 mg 2. 2,5 mg MPA + 2 all dosage regimens infarction, deep 15

up E2V mg E2V (discontinued trough out 9 years. venous after 7 years) Mean BMD declined thrombosis, after cessation of HRT pulmonary but remained embolism ,breast substantially above and other cancers baseline levels.

5 Nand 1999 RCT 414 Postmenopau 5mg MPA + 1,25 E1S 1. 2,5 mg MPA + 1,25 Bone density Effective for preventing 146 drop outs sal women mg E1S bone loss P< 0.001 reported in Nand Randvick NSW, with no significant 1998a Australia 2. 10 mg MPA + 1,25 differences between mg E1S groups

6 Tsai 2001 RCT 116 Postmenopau 5mg MPA + 0,625 mg 60mg raloxifene Densitrometric and Reloxifen has favourable 31% women sal Taiwanese CEE biochemical effect results in bone mineral reported vaginal Taipei,Taiwan, ROC Aged women density, bone turnover bleeding (p< 0,05) 47‐66, and serum lipids compared to mean compared to MPA 3,3%in raloxifen 57 group.Both regiments group. increased significantly bone mineral density, HDL and trigyceride levels,but decreased total LDL cholesterol.

7 Webber 1994 RCT 75 Postmenopau 5mg MPA + 0,625 mg 1. Calcium Bone mass, serum lipids HRT reduced whole body Not reported sal women EE + Calcium and lipoproteins bone turnover and Ontario, Canada 2. 0,3mg EE + prevented age related Calcium reductions in bone mass and serum cardiovascular risk profile in comparison to calcium.

8 Yang 1999 RCT 40 Postmenopau 5mg MPA + 0,625 mg 2,5 mg Tibolone Safety and efficacy of Tibolone has higher Uterine bleeding in sal Chinese CEE Tibolone regarding compliance. MPA group 20 MPA patients Taipei, Taiwan ROC women climacteric symptoms, had increased bone vs 6 tibolone bone loss, endometrial density, but also cyclic patients in first 3 stimulation and lipid withdrawal bleeding and months; 20 MPA profile increase in tryglicerides vs 1 tibolone after 6 month of treatment. Others in MPA group: sleeplessness in 3, backpain in 2 patients.

MPA and bone density summary

8 RCT papers were reviewed with total of 1324 postmenopausal women involved in the studies. 3 out of 8 RCTs showed better bone mineral density levels in MPA containing treatment than other regimens compared. 2 out of 8 RCTs showed very good response in regard to preventing bone loss,but without significant difference between MPA and other regimens. 3 out of 8 RCTs reported better therapeutic response in comparative treatments (2,5mg MPA, raloxifene and tibolone) than 5 mg MPA. Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal bleeding and breast tenderness as adverse events.

Table 4. Clinical trials evaluating serum lipid levels in treatment containing 5mg MPA

SL Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Allvers 1999 RCT 56 Postmenopau 5mg MPA + 0,625 mg 2 mg EV + 1 mg CPA Lipid profile Both groups had positive No adverse effects sal women CE effect on lipids on the lipid profile. Bogota, Colombia (increased HDL: MPA 12.9%,CPA 17,8%; decreased LDL: MPA‐ 7,6%, CPA ‐7,2%(no significant difference between groups) and decreased total cholesterol: MPA ‐3% p=0,001,CPA ‐1,9% p=0.004, no significant difference between groups).Triglycerides increased by 13,5% in MPA and 16,7% in CPA group with no differences between groups.

2 Aygen 1998 RCT 37 Postmenopau 5mg MPA + 0,625 mg 2,5mg MPA + Effects of different doses 2,5mg MPA group Not reported sal women‐ CEE 0,625mg CEE of MPA on serum lipids, (significant decrease in intact uterus lipoprotein levels and total cholesterol, atherogenic index. triglyceride and LDL) got better effect on lipid profile than 5mg MPA (significant decrease in triglyceride levels), but no significantly 18

difference between groups p>0,05.

3 Cano 1999 RCT 100 Postmenopau 5mg MPA twice per 2,5 mg MPA daily + Dropping out, bleeding Both similarly effective‐ Irregular bleeding sal women week + 50 mcg E2 50 mcg E2 pattern, endometrial symptom relief in 76% occurred in 14/50 Valencia, Spain transdermal transdermal thickness and plasma intermittent and 77% women from lipids continuous group. intermittent MPA Endometrium thickness group and 13/50 remained <5mm in both from continuous groups‐Lipid levels had group. High rate of no significant change in atrophic both groups. endometria suggests reduction of progestin dose

4 de Kraker 2004 RCT 275 Postmenopau 5 mg MPA + 0,625 5mg dydrogesterone Effect on lipids, Significant difference 21/362 sal women CEE + 1mg 17bE2 apolipoproteins and between two groups for discontinued Utrecht, (Age lipoprotein. total cholesterol (D‐ therapy due to Netherlands 39‐74 1,7%, MPA‐7,3%), LDL vaginal bleeding, intact (D‐4,5%, MPA‐11,3%), 55 /362 because of uterus) HDL (D+15,3%, adverse events MPA+7,5%), triglyceride (not specified), (D+9,8%, MPA+16,6%), 6/362 due to lack VLDL (D‐3,3%, of effect, 5/362 MPA+10,0%) and LPa (D due to other 0%, MPA‐25,2%) reasons.

5 Hermenegildo 2001 RCT 33 Postmenopau 5mg MPA + 1 or 2mg 300mg natural Effect on lipoprotein MPA group had reduced Not reported sal women E2 for 2 months, then Progesterone + 1 or profile, resistance of LDL size of LDL particles Valencia, Spain 2mg E2 for 14 days 2mg E2 for 2 months to oxidation and LDL (p<0.05 vs baseline) and ,then 2mg E2 for 14 particle size decreased triglycerides days (p<0.001 vs natural progesterone) without limiting E2 positive action on LDL oxidation. Estradiol reduced LDL 19

levels, increased HDL and triglycerides and protected LDL from oxidation in a dose‐ dependent manner (1mcM or higher).

6 Kim 1994 RCT 184 Postmenopau 5 mg MPA + 0,625mg 1. Placebo Effect on lipoprotein and All groups had lower Adverse effect of sal women CEE lipids of HRT lipoproteins by 20%. ERT progesterone on Seoul, South Korea 2. 10 mg MPA + raised HDL and HDL (lower levels) 0,625mg CEE decreased LDL without changing total 3. 0,625mg CEE cholesterol. HRT with MPA abolished effect of estrogen on HDL and lowered PL levels

7 Mc Manus 1997 RCT 56 Postmenopau 5mg MPA cont. + 2 1. 1 mg EV Effect of HRT on oxidation MPA group: Reduction in 2 of 10 women on sal women t mg EV of LDL free cholesterol, MPA had slight Belfast, Northern 2. 0,625 CEE significant decrease in vaginal bleeding Ireland, UK total cholesterol 9,3 % 3. 50 mcg E2 (p<0,01), reduction in transdermal mean serum LDL levels of 12,7 % (p<0,05). 4. 50 mg E2 implant

5. 2 mg EV + 1 mg NETA

8 Odmark 2004b RCT 62 Postmenopau 5 mg MPA + 0,625 1mg NETA + 2mg Effects on lipids and MPA group showed no 15 dropped out,6 sal women CEE 17bE2 lipoproteins significant changes in mainly due to Umea, Sweden total cholesterol, HDL bleeding and LDL, but significant problems. Other increase of triglyceride reasons level – NETA group had were headache, significantly lower total abdominal pain cholesterol afraid to use HRT, 20

(p < 0.001, HDL (p < constipation/breas 0.001)and LDL (p < t tenderness, 0.025)but no significant depression, upper increase of triglyceride respiratory infection and palpitations 9 Onalan 2005 RCT 286 Postmenopau 5 mg MPA + 0,625mg 1. 2,5 mg MPA + Effect of HRT and 5 MPA group preserved Not reported sal women CEE 0,625mg CEE cholesterol levels on normal mood scores and Ankara, Turkey mood scores 2,5 MPA increased. 2. 2,5 mg tibolone Serum lipids and BMI were similar between 3. 1000 mg Calcium these 2 groups. Beck Depression Inventory scores decreased significantly in all HRT groups vs.Calcium group (p<0,05).

10 Pan 2002 RCT 40 Postmenopau 5 mg MPA + 0,625 2,5 mg tibolone Flow resistance in carotid No difference between Iirregular vaginal sal women CEE and middle cerebral groups in pulsatily and bleeding, fear of Tainan, Taiwan arteries and serum lipids resistance index of the cancer carotid arteried and middle brain artery. Both treatments effectively reduced total cholesterol level, no difference between regiments. MPA group had significantly higher triglyceride levels.

11 Ulloa 2002 RCT 30 Postmenopau 5 mg MPA + 0,625 Placebo Effect on cholesterol HRT group had increased Not reported sal women CEE efflux capacity and key LPA (27%), HDL (21%), Concepcion, Chile proteins regulating HDL triglyceride (45%) and levels. free cholesterol (43%) (results represent mainly 21

the estrogenic effect)

12 Webber 1994 RCT 75 Postmenopau 5mg MPA + 0,625 mg 1. Calcium Bone mass, serum lipids HRT reduced whole body Not reported sal women EE + Calcium and lipoproteins bone turnover and Ontario, Canada 2. 0,3mg EE + prevented age related Calcium reductions in bone mass and serum cardiovascular risk profile in comparison to calcium.

13 Yancey 1990 RCT 60 Postmenopau 5mg MPA 1. 10 mg MPA Effects on serum lipids No difference in total Regular sal women sequentially + 0,625 continuously + 0,625 cholesterol, HDL, withdrawal Tacoma, USA mg CEE mg CEE triglycerides, bleeding, break apolipoproetins I and II, through bleeding, 2. 10 mg MPA sex hormone‐binding secretory sequentially + 0,625 protein or serum MPA endometrium, mg CEE levels were noted subjective between sequential and symptoms: continuous 5 MPA dizziness, nausea, group. 10 MPA group asthma had no effect on HDL exacerbation, and LDL. 5 MPA more weight gain, beneficial then 10 MPA mastalgia,bloating, headache

14 Yang 1999 RCT 40 Postmenopau 5mg MPA + 0,625 mg 2,5 mg Tibolone Safety and efficacy of Tibolone has higher Uterine bleeding in sal Chinese CEE Tibolone regarding compliance. MPA group 20 MPA patients Taipei, Taiwan ROC women climacteric symptoms, had increased bone vs 6 tibolone bone loss, endometrial density, but also cyclic patients in first 3 stimulation and lipid withdrawal bleeding and months; 20 MPA profile increase in tryglicerides vs 1 tibolone after 6 month of treatment. Others

in MPA group: sleeplessness in 3, backpain in 2 women.

MPA and serum lipid levels summary

14 RCT papers were reviewed with total of 1334 postmenopausal women involved in the studies. 7 out of 14 RCTs showed higher beneficial effect on serum lipid levels in MPA containing treatment than other regimens compared. 3 out of 14 RCTs showed very good response in regard to lowering the serum lipid parameters, but without significant difference between MPA and other regimens. 4 out of 14 RCTs reported better therapeutic response in comparative treatments (2,5mg MPA, 1mg NETA and tibolone) than 5 mg MPA. Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal bleeding, breast tenderness, headache, abdominal pain and weight gain as adverse events. These data pointed out that addition of MPA to HRT regimen has beneficial effect mostly on total cholesterol levels, but can also increase trygliceride levels.

Table 5. Clinical trials evaluating mammografic breast density in treatment containing 5mg MPA

MBD Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Christodoulakus RCT 132 Postmenopau 5mg MPA with 0,625 1. 2mg 17bE2 + 1 mg Mammographic breast 13,2% women in MPA Not reported 2006 sal women mg CEE NETA density (changes group, 31,8% 1 mg NETA non according to Wolfe and 12,2% 0,5 NETA Athens, Greece hysterectomis 2. 1mg 17bE2 +0,5mg classification) group showed increase ed NETA in breast density Signifficant difference between MPA and 1 NETA group (p=0,04).

2 Lundstrom 2001 RCT 158 Postmenopau 5mg MPA + 0,625 mg 1. 2 mg estrogen Mammografic breast MPA group had 40% Increase in sal women CEE density increased mammographic Stockholm, (age 44‐57) 2. 50 mcg E2 mammographic density density Sweden transdermal in comparison to 6% estrogen and 2% transdermal treatment (p<0,0001)

3 Marchesoni 2006 RCT 103 Postmenopau 5mg MPA + 0,625 mg 1. 2,5 mg Tibolone Mammographic breast Highly significant Not reported sal women CEE density difference HRT vs Udine, Italy 2. placebo placebo in increase of breast density (p<0,001).

MPA and mammographic breast density summary

3 RCT papers were reviewed with total of 393 postmenopausal women involved in the studies. 3 out of 3 RCTs showed higher mammografic breast density parameters (according to Wolfe classification) in MPA regimen than in comparative treatments (0,5mg/1mg NETA, estrogen only and tibolone). All studies reported no adverse events and had significant difference between regimen groups.

Table 6. Clinical trials evaluating cardiovascular effect of treatment containing 5mg MPA

CV Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Barnes 2002 RCT 43 Postmenopau 5mg MPA cont. + 2.5mg tibolone Effects of 2 HRT regimens MPA+CEE therapy Abdominal pain, sal women 0,625 mg CEE on cardiovascular risk caused significant weight gain, breast Glasgow, Scotland , factors reduction in LDL tenderness, UK (p<0.001) and total headache and cholesterol (p<0.01), but inadequate difference between 2 symptom control groups in triglyceride, were reasons for HDL, LDL oxidation and discontinuation in LDLI+I I : LDLIII ratio was 10 women. significantly in favour to tibolone (all p<0,05).

2 Cagnacci 2000 RCT 31 Postmenopau 1. 5 mg MPA + 50 1. 1 mg melatonin Different circulatory HRT group has Not reported sal women mcg E2 transdermal response to melatonin conserved circulatory Modena, Italy 2. placebo with or without HRT response to melatonin 2. placebo (reduced systolic pressure ‐8,1mmHg p=0.054, diastolic preassure ‐5,0mmHg p=0.049, mean blood preassure for –6mmHg p=0.037, heart rate ‐3,2 bpm p=0.025) and norepinephrine levels ‐ 50,1pg/mL p=0.019. No effect in non HRT group.

3 Chen 2001 RCT 41 Postmenopau 5mg MPA + 1,5 mg 1 mg CPA + 2 mg E2V Effect on cardiovascular MPA regiments showed Increased risk of sal women E2 transdermal risk factors more pronounced venous thrombotic Kellung, Taiwan, reduction of triglyceride events in women ROC (21‐31% p<0.05, on this oral between groups p<0.01) regimen in first and factor VII (6‐10% year of oral p<0.05, no significant treatment difference between groups). CPA showed stronger increase in HDL (2‐8%). Both groups show reduced total cholesterol, LDL, tissue plazminogen activator inhibitor I, antithrombin III and protein S.

4 de Kraker 2009 RCT 48 Postmenopa 5mg MPA + 0,625 mg 1. 1mg 17bE2 + 5 mg Short‐tem effects on Compared with the No dropouts. No usal women CEE dydrogesterone cardiovascular risk control group, 12‐week reported side Amsterdam, (age 41‐58) markers treatment with E/D or effects. Netherlands 2. placebo CEE/MPA reduced fibrinogen (_7.7%, p = 0.004 and _3.3%, p = 0.083, respectively), factor VII‐ act (_8.7%, p = 0.14 and _9.7%, p = 0.06, respectively), homocysteine (_20.5%, p = 0.02 and _26.7%, p = 0.005, respectively), and IGF‐1 (_27.9%, p < 0.001 and _18.1%, p = 0.002, respectively), but increased factor VII‐ ag (+10.1%, p = 0.03 and 26

+4.4%, p = 0.46, respectively), endothelin‐1 (+15.2%, p = 0.12 and +20.0%, p = 0.13, respectively) and C‐ reactive protein (+88.8%, p = 0.18 and +71.0%, p = 0.44, respectively). Fibrinolytic factors were not affected by either hormone therapy (HT).

5 Harvey PJ 2001 RCT 20 Postmenopau 5mg MPA + 0,625 mg 1. 2,5mg MPA + Dose response effect on MPA had either no effect Headache, hot sal women‐ CEE 0,625mg CEE blood pressure or small dose‐dependent flushes, mastalgia Adelaide, SA, normotensive reduction in daily and fatigue were Australia 2. 10mg MPA + diastolic blood pressure reported in all (age 46‐60) 0,625mg CEE (significant for 10MPA groups and do not p<0,05 vs placebo) appear to be dose‐ 3. placebo + 0,625mg related. CEE

6 Manwaring 2000 RCT 17 Postmenopau 5 mg MPA + 0,625mg 0,625 mg CEE Effect of HRT on Both groups had Not reported sal women CEE ambulatory blood reduction in diastolic Kogarah, NSW aged between pressure and systolic blood Australia 45 to 60 pressure and heart rate (p < 0.05)

7 Pan 2002 RCT 40 Postmenopau 5 mg MPA + 0,625 2,5 mg tibolone Flow resistance in carotid No difference between Iirregular vaginal sal women CEE and middle cerebral groups in pulsatily and bleeding, fear of Tainan, Taiwan arteries and serum lipids resistance index of the cancer carotid arteried and middle brain artery. Both treatments effectively reduced total cholesterol

level, no difference between regiments. MPA group had significantly higher triglyceride levels.

8 Tentolouris 2005 RCT 65 Postmenopau 5mg MPA with 0,625 placebo Elastic properties of No significant difference One woman sal women mg CEE arteries, pulse wave and between groups in dropped out Athens, Greece central aortic pressure central systolic aortic because of analysys pressure, augmentation unscheduled and percentage of vaginal bleeding augmentation index.

9 Tuomikoski 2009 RCT 143 Postmenopau 5mg MPA + 2 mg E2 1. 2 mg E2 Effects of hot flushes on Oral estradiol only 2 women left sal women vascular functions regimen caused because of Helsinki, Finland (mean age 2. 1 mg E2 a decrease of 13.2% uterine bleeding 52,4) transdermal (p=0.028) in the time to the first 3. placebo systolic peak after nitroglycerin. In addition, the time to the reflected wave after nitroglycerin was decreased by 8.4% (p=0,018). These effects were not seen in women with intolerable hot flushes or with the other treatment regimens.

MPA and cardiovascular effects summary

9 RCT papers were reviewed with total of 448 postmenopausal women involved in the studies. 3 out of 9 RCTs showed higher beneficial effect on cardiovascular risk markers and circulatory parameters in MPA containing treatment than other regimens compared. 3 out of 9 RCTs showed beneficial 28

effect on cardiovascular system, but without significant difference between MPA and other regimens. 3 out of 9 RCTs reported better therapeutic response in comparative treatments (10mg MPA, estrogen only and tibolone). Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal bleeding, breast tenderness, headache, fatigue and weight gain as adverse events.

Table 7. Clinical trials evaluating menopausal symptoms in treatment containing 5mg MPA

MS Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Bruhat 2001 RCT 440 Postmenopau 5mg MPA + 1‐2 mg 1. 2,5 mg MPA + 1‐2 Bleeding control and MPA regiments had Tolerability and sal women E2V mg E2V symptom relief significant fewer endometrial safety Clermond‐ bleeding days then were good, no Ferrand,France 2. 1 mg NETA + 2 NETA. All regiments cases of mg E2 affectively relieved hyperplasia were climacteric symptoms observed. More (no sign.difference women between groups) and discontinued NETA had benefit on lipid regimen then MPA profile (decrease in total (30% in NETA vs cholesterol 5%in NETA 86% in 5MPA) due and 9% in MPA; HDL to bleeding significantly lower in disturbances, NETA vs MPA p>0.001) breast tenderness and weight increase.

2 Cumming 2002 RCT 23 Postmenopau 5mg MPA + 0,625 mg 200mg micronized Bleeding control and No effect on mood MPA users sal women CEE ( 2 weeks progesterone + 0,625 symptom relief (depression, vigor, reported more San Francisco, USA mean change: CEE+MPA mg CEE ( 2 weeks fatigue, anger, tension, vaginal bleeding age then only CEE) change: CEE+MPA confusion) in any group (p<0.05) and 52,5 then only CEE) individually, compared breast tenderness with placebo ot between (p<0.05) then 29

groups. progesterone group

3 Gelfand 1989 RCT 95 Postmenopau 1. 5 mg MPA seq. + 1. 0,625 mg CEE + Effects on clinical 1 year of therapy with Endometrial sal women 0,625mg CEE placebo symptoms and lipoprotein cee and 5MPA provided hyperplasia in Montreal , Canada lipids the most satisfactory MPA groups (0% 2. 5 mg MPA seq. + 2. 1,25 mg CEE + endometrial protection and 10% 1,25mg CEE placebo and low rates of (compared to braketrough bleeding placebo groups ( 30% and 57%). Irregular bleeding occurred in 14% of MPA users and 54% of pla cebo users.

4 Mattsson 2007 RCT 262 Postmenopau 1. 5mg MPA + 1 mg 1. 2,5 mg MPA + 1 Efficacy and tolerability of Significantly lower rates Adverse events sal women E2 mg E HRT (change in frequency of amenorrhoea in 5 declined in (Indivina 321 Study and severity of hot MPA group, and frequency over Group) 2. 5 mg MPA + 2 mg 2. 2,5 mg MPA + 1 flushes, number of significantly different time with all E2 mg E2 bleeding days and from other groups regimens but evaluation of tolerability) (p<0,05). throughout the study were more Gothenburg, numerous with the Sweden highest‐dose regimen than with lower doses (P = 0.0002). Those above >1% of patients were: bleeding(spotting, brest tenderness, uterine fibroids and nausea.

5 Nand 1998b RCT 568 Postmenopau 5mg MPA + 1,25 mg 1. 2,5 mg MPA + Menopausal symptom All 3 regimens provided Breast tenderness sal women ES 1,25 mg ES control and side‐effects of similar menopausal Randwick , NSW, HRT symptom control Australia 2. 10 mg MPA + (headache, depression, 1,25 mg ES nausea, bloating and irritability). Side effects decreased markedly after first 3 months (no significant difference between groups.

6 Ryan 2001 RCT 189 Postmenopau 5mg MPA + 0,625 mg 200mg micronized Quality of life, Both groups had better 9 patients in the sal women CEE Progesterone + menopausal symptoms quality of life scores, no MPA group Burlington, Ontario, 0,625mg CEE and costs significant differencies in withdrew because Canada costs. Micronized of adverse events. Progesterone gruop The most showedd better frequently improvement in reported menstrual problems and were abdominal cognitive domains. pain, general pain, viral infection, back pain, dizziness, and pharyngitis.

7 Tuomikoski 2009 RCT 143 Postmenopau 5mg MPA + 2 mg E2 1. 2 mg E2 Effects of hot flushes on Oral estradiol only 2 women left sal women vascular functions regimen caused because of Helsinki, Finland (mean age 2. 1 mg E2 a decrease of 13.2% uterine bleeding 52,4) transdermal (p=0.028) in the time to the first 3. placebo systolic peak after nitroglycerin. In addition, the time to the reflected wave after nitroglycerin was decreased by 8.4% 31

(p=0,018). These effects were not seen in women with intolerable hot flushes or with the other treatment regimens.

MPA and manopausal symptoms summary

8 RCT papers were reviewed with total of 1760 postmenopausal women involved in the studies. 3 out of 8 RCTs showed greater beneficial effect in increasing of menopausal symptoms (hot flushes, depression, irritability, nausea, headache, anger, tension etc.) in MPA containing treatment than other regimens compared. 1 out of 8 RCTs showed good menopausal symptom control, but without significant difference between MPA and other regimens (2,5mg MPA and 10mg MPA). 4 out of 8 RCTs reported better therapeutic response in comparative treatments (micronized natural progesterone, estrogen

only therapy and tibolone). Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal uterine bleeding, breast tenderness, headache, fatigue and weight gain as adverse events. Those adverse effects declined in frequency over time of therapy.

Table 8. Clinical trials evaluating effects on metabolism in treatment containing 5mg MPA

M Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Barnes 2005 RCT 43 Postmenopau 5 mg MPA cont. + 2,5 mg tibolone Effect on C‐reactive CRP was increased by In MPA group 6 sal women 0,625 CEE protein and homocysteine tibolone 76% (p<0,0001), women were Glasgow, Scotland and CEE MPA 81% withdrew from the (p<0,001). Significant treatment because reduction of vitamin B12 of breast levels (tibolone 11%, tenderness, p<0,001), and CEE MPA inadequate 8% (p<0,01). No symptom control statistical significance on and headaches. folate levels and homocystein levels.

2 De Souza 1996 RCT 41 Postmenopau 1. 5mg MPA + 0,625 1. 2,5 mg MPA Effect on coagulation Increase in plasminogen Uterine bleeding in sal women mg CEE sequentially continuously + 0,625 parameters levels 12,9% and 23% in all women on mg CEE both 5 MPA groups sequential 2. 5mg MPA + 0,625 (p<0.05) and large therapy. mg CEE continuously 2. 0,625 mg CEE increase of factors VII (27‐42%) and X (10‐ 20,4%) in all groups (p<0.05). Total protein S decreased only in 2.5MPAcont an CEE groups (p<0.03).

Addition of MPA resulted in dose‐ dependent favourable changes in coagulation parameters‐more protective against thromboembolic occurrences.

3 Demirol 2000 RCT 110 Spontaneus 5mg MPA + 0,625mg placebo Effects of HRT on HRT group had Not reported postmenopau CEE hemostasis significantly decreased Ankara, Turkey sal women fibrinogen p=0.000, lipoprotein A p=0.039 and activated protein C p=0.003. Antithrombin 3 p=0.027, prothrombin time p=0.009 and activated partial thromboplastin p=0.001 time were increased suggesting cardioprotective effect of HRT

4 Edwards 2008 RCT 43 Postmenopa 5mg MPA + 2 mg E2 1. 2 mg E2 Effects on cortisol and ERT significantly Not reported usal women interleukin‐6 levels increased cortisol levels Birmingham, UK 2. placebo (p =0 .002), while the HRT group showed only a trend toward increased cortisol levels (p =0 .094). In the placebo group there was no difference in cortisol levels at baseline pre and post treatment.No 34

changes were observed in IL‐6 levels.

5 Farag 2003 RCT 39 Postmenopau 5 mg MPA + 2mg 1. Placebo Renal kallikrein excretion Urinary kallikrin Not reported sal women 17bE2 increased significantly in San Diego, USA 2. 2mg 17bE2 MPA (p<0,01) and in ERT group (p<0.001). No significant blood pressure changes (possible cardio protective properties of HRT)

6 Hermenegildo 2008 RCT 61 Postmenopau 5 mg MPA +300mg 1. 50mcg E2 Effect of HRT on plasma Significant reduction in Not reported sal women micronized transdermal levels of F2alpha‐ the levels of F2alpha‐ Valencia, Spain progesterone isoprostanes. isoprostanes was 2. 2mg E2 detected only in women receiving transdermal estradiol, alone or in combination with MPA, wich indicates on beneficial effect of estradiol on oxidative stress(p<0,05).

7 Keramaris 2007 RCT 216 Postmenopa 5mg MPA + 0,625 mg 1. 0,625 mg CEE Effect on coagulation MPA group: significant 48 patients usal women CEE inhibitors decrease in withdrew because Aydin, Turkey 2. 2,5 mg tibolone antithrombine levels of vaginal p=0,009; decrease in bleeding, breast 3. 1 mg 17bE2 + 0,5 protein C, p=0,001; and tenderness, mg NETA decrease in protein S, bloating or weight p=0,005. gain 4. placebo

8 Kesim 2005 RCT 124 Postmenopau 5 mg MPA + 0,625 1. 2,5 mg tibolone Effect on nitric oxide All HRT groups had One woman from increased serum nitric MPA group had 35

Istanbul, Turkey sal women CEE 2. 50mcg transdermal levels oxide levels significantly new venous estrogen compared to the placebo thrombus group(p<0,001), but no formation. No 3. placebo difference between the breast carcinoma HRT groups. after 12 months in all HRT groups.

9 Lambrinoudaki 2004 RCT 84 Postmenopau 5 mg MPA + 0,625 1. 2,5 tibolone Serum leptin levels MPA treatment had no Not reported sal women CEE effect on serum leptin Athens, Greece (age 2. 0,625 mg CEE levels (overweight 43‐63) women p=0,1, lean women p=0,31) as well as other two groups.

10 Odmark 2006 RCT 102 Postmenopau 5mg MPA + 0,625 mg 1. 0,625 CEE Effects on carbohydrate No effect on insulin, CEE MPA 5 group sal women CEE metabolism and serum glucose. SHBG increased increased BMI Umea, Sweden 2. 2,5mg MPA + sex hormone‐binding significantly in all groups 0,625 mg CEE globulin except CEE MPA 5. 3. tibolone

11 Orr‐Walker 1999 RCT 39 Postmenopau 1. 5mg MPA 1. 0,625 mg CEE Effect on respiratory Significantly decreased Changes in acid‐ sal women alkalosis serum bicarbonate base status in MPA Auckland, New 2. 5 mg MPA + 0,625 2. placebo concentration in MPA groups Zealand mg CEE groups, p=0,008 (possible role in osteoporosis development)

12 Raudaskolski 2002 RCT 163 Postmenopau 5mg MPA + 2 mg 1. 10 mg Clinical, endometrial and MPA regiment produced Endometrial sal women E2V levonogestrel metabolic response cyclic withdraval hyperplasia was Oulu, Finland intrauterine + 2 mg bleeding and not observed in E2V endometrium was any of the proliferated in 18/47 treatment groups 2. 20 mg subjects. Total serum during the levonogestrel cholesterol decreased in 12‐month study. 3 intrauterine + 2 mg women in 36

E2V all groups. levonorgestrel group discontinued due to bleeding, 4 due to abdominal pain, endometrial polyp, depression and pain in the legs. 4 in MPA group discontinued due to multiple subjective adverse symptoms. The most frequently events were: unscheduled bleeding, headache, abdominal pain, breast pain and vaginal discharge. MPA group reported bleeding and vaginal discharge less frequently than did those with intrauterine treatments, but otherwise there were no differences between the treatment groups. 13 Saavedra 2004 RCT 15 Postmenopau 5 mg MPA + 2mg 2mg 17bE2 Pharmacokinetic study No significant Not reporteded differences between 37

Santiago, Chile sal women 17bE2 groups, no pharmacokinetic interaction.

14 Sunar 2008 RCT 32 Postmenopau 1. 5 mg MPA + 1. Placebo Effect of low dose zinc No significant difference Not reported sal women 0,625mg CEE supplementation to was found between the Konya, Turkey 2. 15mg ZnSO4 serum estrogen and estrogen and 2. 5 mg MPA + progesterone levels of progesterone levels of 0,625mg CEE + 15mg HRT placebo and ZnSO4 ZnSO4 groups. Other two groups with 5MPA had higher estrogen ans progesterone levels than first 2 groups (p<0,05), but not different between two MPA groups.

15 Svensson 1994 RCT 12 menopausal 1. 5mg MPA 1. 2mg 17betaEV + Plasma concentration of No statistically No serious adverse women (Provera) 10mg MPA (Divina) MPA, E2 and estrone significant difference events were Vasteras,Sweden Single‐blind between drugs. reported during 2. 5mg MPA + 2mg 2. 2mg 17betaEV (in the study period. Triple 17betaE2 (Klimaxil) first phase of There cross‐over Trisequence) were more or less unspecific complaints, such as indisposition, headache, general discomfort, and tiredness. In 1 case swollen hands were reported, and in another petechia.

16 Tutuncu 2005 RCT 80 Postmenopau 5 mg MPA + 0,625 1. 2,5 mg MPA + Effect on plasma In MPA group plasma 1 dropped because sal women CEE 0,625 CEE homocysteine levels homocystein of new breast Istanbul, Turkey concentration decreased carcinoma, 1 new 2. 0,625 CEE by 19,56% (p<0,05), and hypertension and in placebo group 3 refractory 3. placebo increased by 11,66%, but vasomotor no significant difference symptoms between HRT groups.

17 Vural 2006 RCT 75 Postmenopau 5mg MPA cyclic + 1. 2,5 mg MPA cont. Effects on plasma pro‐ HRT groups had Not reported sal women 0,625 mg CEE + 0,625 mg CEE inflammatory and anti‐ significant decrease in Istanbul ,Turkey (premenopaus inflammatory cytokines TNF alpha, IL1‐beta, and al women as 2. placebo and some bone turnover urinary HYP control group) (premenopausal markers concentrations, but no women) effect on IL‐10 levels.

MPA and metabolism summary

17 RCT papers were reviewed with total of 1279 postmenopausal women involved in the studies. 6 out of 17 RCTs showed higher beneficial effect on metabolism (coagulation parameters, hemostasis, renal kallikrein excretion, pro‐and anti‐inflammatory cytokines etc.) in MPA containing treatment than other regimens compared. 5 out of 17 RCTs showed positive effects on metabolism (nitric oxide levels, homocysteine levels etc.), but without significant difference between MPA and other regimens (tibolone, estrogen only therapy, 2,5mg MPA and 10mg MPA). 4 out of 17 RCTs reported negative effect on metabolism (icreased CRP and cortisol, decreased bicarbonates) than in comparative treatments (intrauterine levonogestrel, estrogen only therapy and tibolone). 2 out of 17 had no effect on metabolism(serum leptin, insulin, glucose and SHBG levels). Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal uterine bleeding, breast tenderness, headache, fatigue, weight gain and change in acid‐base status as adverse events.

Table 9. Clinical trials evaluating psychological effects in treatment containing 5mg MPA

PE Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Bukulmez 2001 RCT 60 Postmenopau 5 mg MPA + 0,625mg 1.Tibolone Short term effect of HRT Both CEE MPA regimens Probable sal women CEE platelet tritiated and Tibolone attenuation of Ankara, Turkey 2.5mg MPA + 0,625 imipramine binding significantly increased positive effects on CEE (Bmax) and mood Bmax ,5MPA group Bmax by doubling p=0.01(no significant the dosage of MPA (3. alendronate‐ difference between (2,5 to 5 mg) separate analysis) groups) and improved mood with no differences between groups p=1.00

2 Heikkinen 2006 RCT 198 Postmenopa 1. 5mg MPA +1 mg 1. 2,5 mg MPA + 1 Update on safety and Depressed mood, During the one usal women E2V mg E2V quality‐of‐life findings anxiety, scores on daily year follow‐up, Oulu, Finland 10‐year functioning and only severe events follow‐up 2. 5 mg MPA + 2 mg 2. 2,5 mg MPA + 2 enjoyment, health potentially E2V mg E2V (discontinued perception and sexual associated long after 7 years) interest improved term study HRT irrespective of dosage. were recorded, They deteriorated in including women not continuing myocardial HRT in follow up (year 7 infarction, deep – year 9, continued HRT: venous p=0,0003, discontiunued thrombosis, HRT: p=0,2717). pulmonary embolism, breast and other cancers

3 Huber 2002 RCT 501 Postmenopau 5mg MPA + 0,025 mg 2,5 mg tibolone Effects of HRT on Tibolone treatement had Tolerability: 32,8% bleeding rates, QoL and significantly lower of tibolone women 40

Vienna, Austria sal women CEE tolerability bleeding rate (p=0,004), vs 38,3% in MPA improved sexual drive group. Severe <65 intact (p=0.017) and lower adverse event uterus incidence of breast were 2 in tibolone tenderness (p<0.001). group (stroke and Both regimens improved vaginal bleeding) QoL, well‐being, and 1 in MPA climacteric symptoms (deep and urogenital thrombophlebitis complaints. and pulmonary embolism resulted in death of the patient!). Others reported: breast tenderness, headache, back pain, abdominal pain, hot flushes (tibolone vs MPA p<0.05), depression, weight increase, anxiety, vaginitis, sinusitis.

4 Inan 2005 RCT 61 Postmenopau 5 mg MPA seq. + 2,5 mg tibolone Psychological effect of Statistically significant No adverse effects sal women 0,625 CEE HRT difference in Becks in MPA group. Ankara, Turkey depression scores in tibolone group 21,3 vs. 17,1 (p=0,038), and MPA group 15,7 vs. 13,0 (p=0,04). MPA group increased HDL level 49,1 vs 56,8 (p=0,023).

5 Montplaisir 2001 RCT 21 Postmenopau 5mg MPA + 0,625 mg Micronised Effect of nocturnal sleep MPA group – no increase Not reported Progesterone 200 mg in sleep efficienency and 41

Montreal, Canada sal women CEE + 0,625 mg CEE time spent awake after sleep onset but significant improvement in micronised progesterone group (p = 0.014. Menopausal symptoms and subjective measures of sleep improved (questionnaire) in both groups

6 Myers 1990 RCT 40 Postmenopau 5 mg MPA + 0,625mg 1. 0,625mg CEE Effects on sexual HRT groups had Not reported sal women CEE psychophysiology and significantly reduced hot 2. 0,625mg CEE + behavior flushes (p<0.046), but 5 mg not alter mood ratings, methyltestosterone sexual behaviours and arousal 3. Placebo

7 Odmark 2004a RCT 249 Postmenopau 5 mg MPA + 0,625 1 mg NETA + 2mg E2 Effect of HRT on well‐ MPA group had lower Headache was the sal women CEE being scores for breast reason Umea, Sweden tenderness p=0,005, for discontinuation depression p=0,019, in three cases, one irritability p=0,004 and suffered from tension p=0,048 negative mood compared to NETA changes. Other group. MPA better reasons were tolerated than NETA. bleedings, 'not feeling well', constipation, paresthesia/anest hesia and palpitations

8 Onalan 2005 RCT 286 Postmenopau 5 mg MPA + 0,625mg 1. 2,5 mg MPA + Effect of HRT and 5 MPA group preserved Not reported sal women CEE 0,625mg CEE cholesterol levels on normal mood scores and Ankara, Turkey mood scores 2,5 MPA increased. 2. 2,5 mg tibolone Serum lipids and BMI were similar between 3. 1000 mg Calcium these 2 groups. Beck Depression Inventory scores decreased significantly in all HRT groups vs.Calcium group (p<0,05).

9 Pitkin 2007 RCT 459 Postmenopau 1. 5mg MPA + 1 mg 1. 2,5 mg MPA + 1 Effect on health related Reduction in hot flushes, Not reported sal women E2V mg E1 quality of life (HRQoL) sweating and sleep (Indivina 321 Study (average age disturbances in all Group) 51,5 yrs) 2. 5 mg MPA + 2 mg groups, p<0,05; and E2V highly significant relief in Harrow, Middlesex, all groups, p<0,0001. UK

10 Ryan 2001 RCT 189 Postmenopau 5mg MPA + 0,625 mg 200mg micronized Quality of life, Both groups had better 9 patients in the sal women CEE Progesterone + menopausal symptoms quality of life scores, no MPA group Burlington, Ontario, 0,625mg CEE and costs significant differencies in withdrew because Canada costs. Micronized of adverse events. Progesterone gruop The most showedd better frequently improvement in reported menstrual problems and were abdominal cognitive domains. pain, general pain, viral infection, back pain, dizziness, and pharyngitis.

11 Uygur 2005 RCT 72 Postmenopau 5mg MPA with 0,625 2,5 mg tibolone Effects on sexual life Tibolone group had Not reported sal women mg CEE (sexual desire, sexual significantly higher

Ankara, Turkey excitement, sexual scores for sexual desire, arousal, orgasm capacity, sexual excitement, vaginal lubrication during intercourse frequency sexual activity and and vaginal dryness dyspareunia) (p<0,05)

MPA and psychological effects summary

11 RCT papers were reviewed with total of 2136 postmenopausal women involved in the studies. 2 out of 11 RCTs showed greater beneficial effect on psychological health and quality of life findings in MPA containing treatment than other regimens compared. 5 out of 11 RCTs showed improved quality of life and mood fingings , but without significant difference between MPA and other regimens (2,5mg MPA and tibolone). 3 out of 11 RCTs reported better therapeutic response in comparative treatments (micronized natural progesterone and tibolone). 1 out of 11 RCTs had no effect on sexual psychophysiology and behavior. Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal uterine bleeding, breast tenderness, headache, fatigue and weight gain as adverse events. Those adverse effects declined in frequency over time of therapy. Severe adverse effects in 10 year follow up includeed: myocardial infaction, deep venous thrombosis, pulmonary embolism, breast and other cancers;one patient died of deep thrombophlebitis and pulmonary embolism.

Table 10. Clinical trials evaluating efficacy and safety in treatment containing 5mg MPA

ES Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Doren 1995 RCT 280 Postmenopau 5mg MPA seq. + 2mg 1. 2mg E2 + 1mg Compliance and efficacy NETA therapy is superior Uterine bleeding in sal women EV Estriol + 1mg NETA of 3 HRT regimens to MPA in compliance ( 24% of patients in Munster, Germany cont. 93%vs.66% after 1 MPA and 3% in year,73%vs.49 after 2 NETA group was 2. placebo years) but not regarding the most frequent relief of climacteric reason for symptoms and change in discontinuation of bone loss. Only NETA 44

increased bone mineral drug intake. density after 1 and 2 years compared with baseline: 13% and 17% ( p = 0.01).

2 Heikkinen 2000a RCT 419 Postmenopau 1. 5mg MPA +1 mg 1. 2,5 mg MPA + Optimization of 6 Marked improvement of No cases of sal women E2V 1 mg E2V different HRT treatments climacteric symptoms, hyperplasia were Oulu, Finland 24‐month for efficacy and safety most women had better observed. Overall double 2. 5 mg MPA + 2 mg 2. 2,5 mg MPA + bleeding patterns(1‐2EV <3% had blind phase E2V 2 mg E2V group vs 2/5MPA group abdominal pain, II study p=0.31 vs.p=010) and anxiety and lesser bleeding days depression. All between those 2 groups regimens were in favour to 2,5 MPA safe and well p=0.32‐ tolerated with 84% of continuation rate. All treatments equally effective for menopausal symptoms with no increase in weight

3 Heikkinen 2004 RCT 275 Postmenopau 1. 5mg MPA + 1mg 1. 2,5 mg MPA + Long‐term safety and All regimens provided All regimens were sal women E2V 1mg E2V tolerability of HRT good bleeding control well tolerated with Oulu, Finlad 7 year and endometrial a low frequency of 2. 5 mg MPA + 2 mg 2. 2,5 mg MPA + protection. No cases of adverse effects, E2V 2 mg E2V endometrial hyperplasia mostly occurring or carcinoma. No serious within first 2 years. cardiovascular events, Most common incidence of stroke lower adverse events than national incidence were: and incidence of braest Breakthrough cancer was comparable bleeding, with national level headache, 45

(95%CI). The results abdominal pain, support the use of lower mood changes doses for longterm (only 2,5 MPA hormone therapies. group, p<0,009).,

4 Huber 2002 RCT 501 Postmenopau 5mg MPA + 0,025 mg 2,5 mg tibolone Effects of HRT on Tibolone treatement had Tolerability: 32,8% sal women CEE bleeding rates, QoL and significantly lower of tibolone women Vienna, Austria tolerability bleeding rate (p=0,004), vs 38,3% in MPA <65 intact improved sexual drive group. Severe uterus (p=0.017) and lower adverse event incidence of breast were 2 in tibolone tenderness (p<0.001). group (stroke and Both regimens improved vaginal bleeding) QoL, well‐being, and 1 in MPA climacteric symptoms (deep and urogenital thrombophlebitis complaints. and pulmonary embolism resulted in death of the patient!). Others reported: breast tenderness, headache, back pain, abdominal pain, hot flushes (tibolone vs MPA p<0.05), depression, weight increase, anxiety, vaginitis, sinusitis.

5 Luciano 1993 RCT 29 Postmenopau 1. 5 mg MPA seq. + 2,5 mg MPA cont. + Efficacy and safety of low‐ Vasomotor and Cyclic menstrual sal women 0,625mg CEE 0,625mg CEE dose HRT urogenital symptoms bleeding occurred Farmington, USA improved in all women. in all patients on 2. 5 mg MPA cont. + Cyclic bleeding occurred sequential therapy in all patients on and proliferative 46

0,625mg CEE sequential therapy and endometrium was all endometrial biopsies noted in two were atrophic or women. Reasons inactive. All patients in for withdrawing both continuous from the study regimens had included cyclic amenorrhea after 5th bleeding, cycle. Lumbar BMD exacerbation of improved significantly migraine (p<0,05) by average of headache, 6,41%in all patients. exacerbation of hypertension and recurrence of depression. Other side effects were transient mastodynia, water retention and premenstrual symptoms, all equally distributed among the three groups.

6 Siseles 1995 RCT 24 Postmenopau 5mg MPAseq. + 2,5 mg Tibolone Safety and efficacy Both equally efective in No hyperplastic sal women 0,625mg CEE variables of 2 HRT the treatment of changes on Buenos Aires, regimens climacteric symptoms endometrium Argentina (no sign.difference between groups), serum lipids significantly p<0,05, vasomotor episodes not significantly and safe with respect to effects on endometrium.

MPA and efficacy and safety summary

6 RCT papers were reviewed with total of 1528 postmenopausal women involved in the studies. 1 out of 6 RCTs showed greater beneficial effect on eficacy and safety findings in MPA containing treatment than other regimens compared. 2 out of 6 RCTs showed improved effect on tolerability, but without significant difference between MPA and other regimens (2,5mg MPA and tibolone). 3 out of 6 RCTs reported better therapeutic response in comparative treatments (2,5mg MPA and tibolone). Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal uterine bleeding, breast tenderness, headache, fatigue and weight gain as adverse events. Those adverse effects declined in frequency over time of therapy. One study reported one severe adverse effect‐ patient died of deep thrombophlebitis and pulmonary embolism.

Table 11. Clinical trials evaluating other effects in treatment containing 5mg MPA

OE Citation and Study No. of Age range Intervention(incl. Comparator(s) Outcome(s) being Results Adverse events setting design partici and formulation and assessment pants stratification dose)

1 Chang 2003 RCT 241 Postmenopau 5 mg MPA + 0,625 1. 10mg MPA+ 0,625 Histopatology and cell 5 mg MPA group had the 2 cases of sal women CEE CEE cycle kinetics of only two cases of endometrial Thaipei, Taiwan endometrium. endometrial hyperplasia hyperplasia in 5 2. 20mg but no significant MPA group dydrogestrone + diference between effect (0,08%) 0,625 CEE of MPA and dydrogesterone on cycle kinetics of endometrium.

2 Dahmoun 2004 RCT 43 Postmenopau 5 mg MPA + 0,625 1mg NETA + 1mg Apoptosis, proliferation, MPA increased stromal No development sal women CEE 17bE2 and sex steroid receptors proliferation and of hyperplasia or Sundsvall, Sweden of endometrium decreased ER carcinoma. expression.

3 Kublickiene 2008 RCT 55 Postmenopau 1. 5mg MPA 1. 2mg E2 Effect on resistance artery Therapy with estrogens Not reported sal women function and endothelial or in combination with Stockholm, Sweden 2. 5mg MPA + 2mg 2. Placebo morphology and MPA may benefit the E2 movement of HRT function of resistance arteries and may preserve the morphological integrity of endothelial cells by regulatory actions on the cytoskeleton. MPA or placebo had no effect on artery flow‐mediated dilatation.

4 Maia 2006 RCT 40 Postmenopau 5mg MPA + 0,625 mg 2 mg E2 + 1 mg CPA Skin thickness Significant increase in Not reported sal women CEE skin thickness in group Sao Paolo, Brasil CPA (+ 3,14, p<0,001) but no change in 5 MPA group (‐0,27, p=0,8340)

5 Mattsson 2004 RCT 393 Postmenopau 2,5 mg MPA + 1mg 1. 1mg NETA + 2mg Bleeding profile and side‐ All regiments provided Significantly higher sal women E2V E2 effects of HRT excellent endometrial rate of adverse Gothenburg, safety. Significantly more events in NETA Sweden 2. 5mg MPH + 1‐2 mg bleeding disturbances group E2V and breast tenderness in (56,8%,p<0.05) NETA group (p < 0.05). than in MPA groups (32,1% and 40,8%, p<0.05)‐ breast tenderness, breast pain and

bleeding

6 Woodruff 1994 RCT 1385 Postmenopau 1. 5 mg MPA seq. + 1. 2,5mg MPA cont + Incidence of endometrial Incidence of hyperplasia No endometrial sal women 0,625mg CEE 0,625 mg CEE hyperplasia developed in 20% in carcinoma in Baltimore, USA estrogen and 1% in all 4 follow‐up biopsies 2. 5 mg MPA cont. + 2. 10 mg MPA seq. + MPA groups. No of the women with 0,625mg CEE 0,625 mg CEE significant difference hyperplasia. between MPA regimens. 3. 2,5mg MPA cont. + Addition of MPA 0,625 mg CEE effectively reduced incidence of hyperplasia.

7 Yuksel 2007 RCT 59 Postmenopau 5mg MPA + 50 mcg 1. 50 mcg E2 Effects on body fat All three HRT regimens Not reported sal women, E2 transdermal transdermal + 0,25 composition caused significant Aydin, Turkey age 41‐57 continuous mcg NETA decrease in WC, subcutaneous fat 2. 1 mg E2+m 0,5 mg (p<0,01), and WHR NETA (p<0,05). No significant difference between groups (p>0,05).

MPA and other effects summary

7 RCT papers were reviewed with total of 2216 postmenopausal women involved in the studies. 3 out of 7 RCTs showed greater beneficial effect on incidence of endometrial hyperplasia, endothelial morphology and side effects in MPA containing treatment than other regimens compared. 2 out of 7 RCTs showed improved effect on body fat distribution and histopathological findings of endometrium, but without significant difference between MPA and other regimens (10mg MPA and dydrogesterone). 1 out of 7 RCTs reported better therapeutic response in endometrial histopathology in NETA treatment group. 1 out of 7 RCT showed no effect of HRT on skin thickness. Most of the studies reported no endometrial hyperplasia events and very good tolerability of MPA with withdrawal uterine bleeding, breast tenderness, headache, fatigue and weight gain as adverse events.

Summary of results Total of 81 randomized control trial and 1 systematic review articles have been identified and reviewed for 5mg per os medroxyprogesterone acetate used alone or in combination with other treatment for hormone replacement therapy in healthy postmenopausal women. This search combined results for different outcomes regarding hormone repolacement therapy: menopausal symptom control, uterine withdrawal bleeding management, serum lipid level change , bone density protection, cardiovascular effects, psychological effects, effects on metabolism of a woman, breast mammograpgic density, efficacy and safety of MPA and other effects. There is summary of every aspect of treatment in detail below table for each one. Adverse events were mostly represented by irregular withdrawal bleeding, breast tenderness, headache, backpain, nausea and bloating. Very good endometrial protection with fewer cases of endometrial hyperplasia were observed. These data also showed increased breast density and good bone loss prevention. Overall benecifial effect of MPA can be concluded.

Risk of bias assessment Risk of bias in the included clinical studies was assessed by using The Cochrane Collaboration's risk of bias tool, which addresses the following domains: sequence generation, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (Figs. 1 and 2). Information extracted from each report for the risk of bias tool is presented in the accopmanying Excel spreadsheet, along with a judgement of low, high or unclear risk of bias, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions version 5.0.2 (updated September 2009). The Cochrane Collaboration, 2009. Available from: www.cochrane‐ handbook.org.). In the Excel spreadsheet, “yes” designates a low risk of bias, and “no” designates a high risk of bias.

Most of the studies did not provide any details of randomization procedures, so their risk of bias for the “Generation of allocation sequence domain” was judged unclear. Even smaller number of studies reported procedures to conceal the allocation sequence.

Blinding was judged for researcher‐assessed outcomes and/or self‐reported outcomes. If there was no detailed description of blinding procedures, or if the described procedure was judged inadequate, risk of bias for these domains was considered “unclear”. If a study was described as open‐label or no blinding was mentioned, the risk of bias was considered “high”.

For the “Incomplete outcome data” domain, we looked for data on attrition (dropout, loss to follow up) and we also checked if studies have reported full data for all the outcomes mentioned in the methods section. If attrition was high and/or poorly explained, the risk of bias for that particular 51

study was judged “unclear”. If, in addition to that, some outcomes were not fully reported, the risk of bias in this domain was judged “high”.

For the “Selective outcome reporting” domain, we have not searched for study protocols, but only checked the outcomes stated in the Methods section against those mentioned or reported in Results. In majority of studies there was no discrepancies between the two, so our judgment was most frequently that there is no riks of bias concerning this domain.

Two aspects were assessed under the domain of “Other potential threats to validity”: compliance to the treatment protocol and financial support. We are aware that Cochrane Handbook does not recommend including data on financial support in the risk of bias assessment, but we considered it important to present this piece of data in our report. A great majority of studies have either not assessed compliance to the treatment or had industry‐related support, or both, so our judgement was mostly “unclear” for this domain. For cross‐over trials we also checked if the carry‐over effect was addressed. In this domain we also reported when studies included very small number of patients, which may have not introduced bias, but may have caused a low study power and imprecision of estimates.

Figure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Green, yellow, and red colour designates low, unclear, and high risk of bias, respectively. A cell was left empty if there was no researcher‐assessed or self‐reported outcome in the study.

Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Conclusion

Hormone replacement therapy is an effective treatment for women with menopausal symptoms and 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. 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. Low dose HRT has less side effects, and women mostly continue with HRT. For women with an intact uterus, HRT comprising estrogen and progestogen is recommended to minimize the risk of endometrial hyperplasia which can develop into endometrial cancer. Different dosage and progesterone regimens are currently being used with different effects regarding safety and efficacy of therapy. Our findings suggest that medroxyprogesterone acetate in dosage of 5mg can be recommended for hormone replacement therapy in healthy postmenopausal women with an intact uterus and should be listed in WHO List of Essential Medicines.

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Apendix-Hormone Therapy Statistics(http://www.menopause.org/hormonetherapystats.aspx)

Hormone Therapy Statistics As of July 10, 2009

IMS Health, a healthcare information company, compiles one of the most complete, national-level prescription databases in the United States. NAMS relies on this database for statistics regarding the prescription menopause hormone therapy market, defined by IMS Health as estrogens, progestogens, and estrogen-progestogen and estrogen-androgen combinations both indicated and used for menopausal use.

Prescriptions

The National Prescription Audit, derived from IMS Health’s Xponent, captures roughly 70% market share of all prescriptions, then uses projection methodology from a stratified and geographically balanced sample to represent 100% market share coverage of US prescription activity at retail, mail service, long-term care, and managed care outlets. Highlights include:

During each of the last several years, fewer prescriptions have been dispensed in the United States for menopause hormone therapy (HT). In 2008, 42.262 million prescriptions were dispensed, down 6.2% from 45.054 million during 2007. This compares to 57.861 million HT prescriptions dispensed in 2004. Oral Premarin (conjugated estrogens) remained the most dispensed estrogen therapy during 2008, responsible for 23.3% of all dispensed scripts, down 13% versus 2007. Oral medroxyprogesterone acetate (MPA) remained the most dispensed progestogen. Estrogen-progestogen combinations were responsible for 14.8% of dispensed prescriptions during 2008, about even with 2007 levels. The most dispensed combination remained Prempro (low- dose). Estrogen-androgen combinations were responsible for 4.3% of dispensed prescriptions during 2008.