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Hormone replacement therapy: benefits and adverse effects
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Numerous studies have shown that estrogen replacement therapy (ERT) is an effective treatment for vasomotor symptoms, insomnia and vaginal dryness. Beneficial effects have also been shown on lipid patterns and on the incidence of osteoporotic fractures. As ERT increases the risk of endometrial adenocarcinoma, combinations with various progestogens have been developed in order to protect the endometrium. However, the addition of progestogens tends to reduce the beneficial effects of estrogens on mood, cognition and lipid metabolism. The added progestogen often causes side effects such as irritability and depression. There is evidence that the effect on wellbeing varies between women and with the type of progestogen used. Women who prefer to avoid withdrawal bleedings can be given continuous combined hormone replacement therapy (HRT). Unfortunately, irregular bleedings are common at the beginning of treatment and reduces compliance. Recently, several studies have reported an increased risk of breast cancer and venous thrombosis, and therefore long-term treatment with HRT for women without climacteric symptoms is no longer recommended. The ongoing debate has, for the time being, resulted in a recommendation that improving quality of life (QoL) by treatment of climacteric symptoms should be the only indication for prescribing HRT.

Aims and methods: The aims of the study were to investigate bleeding patterns, changes in wellbeing at onset and during long-term treatment, and lipid and lipoprotein profiles with two different types of continuous combined HRT. In addition, women starting, and women switching from mainly sequential HRT were compared. The design was a randomised, double-blind, one year, prospective, multicentre study including 249 healthy postmenopausal women who were given continuous daily oral treatment with either combined 0.625mg conjugated estrogen (CE) and 5mg medroxyprogesterone acetate (MPA) or combined 2mg 17β - estradiol (E2) and 1mg norethisterone acetate (NETA). Bleedings, if any, were recorded daily throughout the study. The main outcome measures (changes in wellbeing and climacteric symptoms) consisted of daily ratings of 12 items on a validated symptom scale. Serum concentrations of lipids and lipoproteins were measured at baseline and after one year of treatment.

Results and conclusions: The majority of drop-outs were confined to the first three months, and the main reasons were bleedings and/or decreased wellbeing. Drop-outs were three times more common in the E2/NETA group. During the first month, 67% of the women reported irregular bleedings. The number of bleeding days decreased on both treatments during the first four months. Treatment with CE/MPA resulted in less irregular bleedings and a shorter time to amenorrhoea compared to E2/NETA.

As expected, "starters" experienced more sweats than "switchers" at the onset of treatment, but both groups improved significantly. Side effects such as breast tenderness, swelling, depression and irritability appeared during the first treatment week in both groups. The side effects of HRT appeared much more quickly than the benefits and were more frequent in women with a history of premenstrual syndrome (PMS). Breast tenderness was more common in the E2/NETA group throughout the whole study period. Apart from that, there were no differences between the two treatment regimens as regards effects on well-being at the end of the study.

Lipoprotein(a) levels, an important risk factor for cardiovascular disease, decreased in both treatment groups. Triglyceride levels increased in women treated with CE/MPA, and levels of total cholesterol, high density lipoprotein and low density lipoprotein fell in the E2/NETA group.

In conclusion, treatment with E2/NETA caused more bleeding problems than treatment with CE/MPA. CE/MPA was better tolerated than E2/NETA at the beginning of the study, but among the women remaining in the study there was no difference in QoL between the two treatment groups. HRT counselling should take into account that a history of PMS increases the likelihood of side effects and that these may precede any beneficial effects. Both treatments produced beneficial effects on lipid and lipoprotein levels, and neither of the regimens was superior in this respect.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2004. , 90 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 888
Keyword [en]
hormone replacement therapy (HRT), bleeding pattern, progestogen, wellbeing, side effects, lipoprotein(a)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-243ISBN: 91-7305-635-9 (print)OAI: oai:DiVA.org:umu-243DiVA: diva2:142789
Public defence
2004-04-29, Betula, Lecturer Hall, 6M, NUS, Umeå, 09:15
Opponent
Available from: 2004-04-22 Created: 2004-04-22 Last updated: 2010-08-31Bibliographically approved
List of papers
1. Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate or with 17β-estradiol and norethindrone acetate
Open this publication in new window or tab >>Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate or with 17β-estradiol and norethindrone acetate
2001 (English)In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 184, no 6, 1131-1138 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: We studied bleeding patterns in postmenopausal women who were using 2 types of continuous combination regimens.

STUDY DESIGN: A prospective, double-blind, randomized study of 208 postmenopausal women treated with conjugated estrogen, 0.625 mg, and medroxyprogesterone acetate, 5 mg, or with 17beta-estradiol, 2 mg, and norethindrone acetate, 1 mg.

RESULTS: The mean number of bleeding days decreased during the first 4 months of treatment (P <.002) but not thereafter. The number of bleeding days was fewer (P <.002) and the time until amenorrhea was shorter (P <.02) in patients receiving conjugated estrogen and medroxyprogesterone acetate than in patients receiving 17beta-estradiol and norethindrone acetate. The odds ratio for progression to amenorrhea with the use of conjugated estrogen and medroxyprogesterone acetate was 1.58, in comparison with the use of 17beta-estradiol and norethindrone acetate. A thick endometrium at the start of treatment resulted in more bleeding days than were found for a thin endometrium (P <.03). Body mass index, age, and blood pressure had no predictive value for bleeding problems.

CONCLUSIONS: Treatment with continuous combined conjugated estrogen and medroxyprogesterone acetate resulted in fewer bleeding problems than did treatment with 17beta-estradiol and norethindrone acetate. Endometrial thickness may help to predict the chance of achieving amenorrhea during early hormone replacement therapy.

Keyword
Postmenopausal, continuous combined hormone replacement therapy, bleeding
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-3888 (URN)10.1067/mob.2001.112561 (DOI)11349178 (PubMedID)
Available from: 2004-04-22 Created: 2004-04-22 Last updated: 2010-08-31Bibliographically approved
2. Well-being at onset of hormone replacement therapy: comparison between two continuous combined regimens
Open this publication in new window or tab >>Well-being at onset of hormone replacement therapy: comparison between two continuous combined regimens
2004 (English)In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 7, no 1, 92-102 p.Article in journal (Refereed) Published
Abstract [en]

Objectives To compare the effect on well-being of two continuous combined hormone replacement therapies (HRTs) in women starting treatment (‘starters’) and women switching from mainly sequential HRT (‘switchers’).

Methods This was a randomized, double-blind, 1-month trial, in which 249 postmenopausal women were treated with either conjugated estrogen plus medroxyprogesterone acetate (CE/MPA 0.625 mg/5 mg) or 17β-estradiol plus norethisterone acetate (E2/NETA 2 mg/1 mg) continuously. Twelve items for measuring climacteric symptoms and well-being were reported daily on a validated symptom scale.

Results Women taking CE/MPA reported lower scores for breast tenderness (p = 0.005), depression (p = 0.019), irritability (p = 0.004) and tension (p = 0.048), compared with women taking E2/NETA. Compared with pretreatment, both groups developed side-effects during the first week: breast tenderness, swelling and depression (p < 0.05). Starters, but also switchers, improved in sweats (p < 0.001 and p = 0.030). Compared with pretreatment ratings, switchers reported higher scores for breast tenderness (p < 0.001), depression (p = 0.050) and negative effects on daily life (p < 0.001), whereas starters reported only physical side-effects (p < 0.05). A history of premenstrual syndrome (PMS) predicted high scores for swelling (p = 0.023), depression (p = 0.024), tension (p = 0.009), irritability (p = 0.027), headache (p < 0.001) and negative effects on daily life (p < 0.001).

Conclusions CE/MPA 0.625 mg/5 mg is better tolerated than E2/NETA 2 mg/1 mg, and starters react differently from switchers. Side-effects occur more quickly than benefits with HRT, and are more frequent in women with previous PMS.

Keyword
breast/physiopathology, contraceptive Agents, female/therapeutic use, depression/drug therapy/psychology, double-Blind method, edema/physiopathology, estrogen replacement therapy/*methods, estrogens/therapeutic use, estrogens, conjugated (USP)/therapeutic use, female, humans, irritable mood, medroxyprogesterone 17-acetate/therapeutic use, middle aged, norethindrone/*analogs & derivatives/therapeutic use, pain/physiopathology, postmenopause/physiology/*psychology, predictive value of tests, prospective studies, quality of life, sleep initiation and maintenance disorders/drug therapy/psychology, sweating/drug effects/physiology
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-9362 (URN)10.1080/13697130310001651526 (DOI)15259288 (PubMedID)
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2011-04-12Bibliographically approved
3. Long-term effects of two different continuous combined regimens of hormone replacement therapy on well-being
Open this publication in new window or tab >>Long-term effects of two different continuous combined regimens of hormone replacement therapy on well-being
2004 (English)In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 18, no 6, 305-317 p.Article in journal (Refereed) Published
Abstract [en]

Our aim was to compare the effect on well-being of two different continuous combined hormone replacement therapies (HRT) in women starting treatment (‘starters’) and women switching from mainly sequential HRT (‘switchers’). The design was a randomized, double-blind, 1-year, prospective study, including 249 postmenopausal women treated with 0.625 mg conjugated estrogen (CE)/ 5 mg medroxyprogesterone acetate (MPA) or 2 mg estradiol/1 mg norethisterone acetate (NETA) continuously. The main outcome measure was well-being, reported daily on a validated symptom scale during treatment cycles 1, 2, 6 and 13. Both treatment groups, starters and switchers, improved significantly in episodes of sweating during the first 6 months (p50.05). Women treated with estradiol/NETA experienced more breast tenderness compared to women using CE/MPA during the whole study period (p50.001), whereas there were no differences in negative mood symptoms between treatment groups. Starters experienced improved wellbeing during the whole study, whereas switchers experienced a transient improvement during the first 2 months. Overall, negative mood symptoms were more frequently reported by women with a history of premenstrual syndrome (PMS) (p50.05). Progestogen side-effects were more pronounced with estradiol/NETA than with CE/MPA combinations. Individual factors, such as previous PMS and previous HRT use, should be taken into consideration when prescribing HRT.

Keyword
Double-Blind Method, Drug Administration Schedule, Estradiol/administration & dosage, Estrogen Replacement Therapy, Estrogens; Conjugated (USP)/administration & dosage, Female, Humans, Medroxyprogesterone 17-Acetate/administration & dosage, Menopause/*psychology, Middle Aged, Norethindrone/administration & dosage/*analogs & derivatives, Prospective Studies, Quality of Life, Sweden
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-9363 (URN)10.1080/09513590410001667265 (DOI)15497493 (PubMedID)
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2011-04-12Bibliographically approved
4. Effects of continuous combined conjugated estrogen/medroxyprogesterone acetate and 17beta-estadiol/norethisterone acetate on lipids and lipoproteins
Open this publication in new window or tab >>Effects of continuous combined conjugated estrogen/medroxyprogesterone acetate and 17beta-estadiol/norethisterone acetate on lipids and lipoproteins
Show others...
2004 (English)In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 48, no 2, 137-146 p.Article in journal (Refereed) Published
Keyword
Cholesterol/blood, Cholesterol; HDL/blood, Cholesterol; LDL/blood, Double-Blind Method, Estradiol/*administration & dosage, Estrogen Replacement Therapy, Estrogens; Conjugated (USP)/*administration & dosage, Female, Humans, Medroxyprogesterone 17-Acetate/*administration & dosage, Middle Aged, Norethindrone/*administration & dosage/*analogs & derivatives, Postmenopause, Prospective Studies, Treatment Outcome, Triglycerides/blood
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-16945 (URN)10.1016/j.maturitas.2003.08.004 (DOI)15172088 (PubMedID)
Available from: 2007-10-22 Created: 2007-10-22 Last updated: 2011-04-12Bibliographically approved

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