Review of the role of Medroxyprogesterone acetate 5 mg in hormone replacement therapy for postmenopausal women

  18th Expert Committee on the Selection and Use of Essential Medicines (21 to 25 March 2011) Section 18: Hormones, other endocrine medicines and cont...
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  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) 



 

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 

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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) 



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 



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 

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