Journal of Human Hypertension (2001) 15, 313–321 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Dose response effect of cyclical medroxyprogesterone on blood pressure in postmenopausal women PJ Harvey1, D Molloy2, J Upton2 and LM Wing1 Departments of 1Clinical Pharmacology and 2Medicine, Flinders University of South Australia, Bedford Park, Adelaide, South Australia, Australia 5042 Objective: This study was designed to compare with mean values of weeks 3 and 4 of each phase used for placebo the dose-response effect of cyclical doses of analysis. Ambulatory BP was performed in the final the C21 progestogen, medroxyprogesterone acetate week of each phase. (MPA) on blood pressure (BP) when administered to Results: Compared with the placebo phase, end of normotensive postmenopausal women receiving a fixed phase clinic BP was unchanged by any of the proges- mid-range daily dose of conjugated equine oestrogen togen treatments. There was a dose-dependent (CEE). decrease in ambulatory daytime diastolic and mean Materials and methods: Twenty normotensive post- arterial BP with the progestogen treatments compared menopausal women (median age 53 years) participated with placebo (P Ͻ 0.05). in the study which used a double-blind crossover Conclusion: In a regimen of postmenopausal hormone design. There were four randomised treatment phases, replacement therapy with a fixed mid-range daily dose each of 4 weeks duration. The four blinded treatments of CEE combined with a cyclical regimen of a C21 pro- were MPA 2.5 mg, MPA 5 mg, MPA 10 mg and matching gestogen spanning the current clinical dose range, the placebo, taken for the last 14 days of each 28 day treat- progestogen has either no effect or a small dose-depen- ment cycle. CEE 0.625 mg was also administered once dent reduction in clinic and ambulatory BPs over one daily as open labelled tablets to all subjects throughout treatment cycle. the study. Clinic BP was measured weekly with the Journal of Human Hypertension (2001) 15, 313–321 Keywords: menopause; progestogen; oestrogen; blood pressure; ambulatory blood pressure; arterial pulse waveform Introduction The one notable exception is the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.5 This Reliable data regarding the effects of ‘hormone study in healthy, normotensive postmenopausal replacement therapy’ (HRT) on blood pressure women provided the first definitive evidence using a remain deficient. Collectively, previous studies have randomised, placebo-controlled design, that a single variably shown no change,1–12 a decrease1,2,13–29 or 4,9,11,21,30–35 mid-range dose of conjugated equine oestrogen an increase in blood pressure with vari- administered with randomised progestogen treat- ous combinations of HRT. Unfortunately, few of the ments or placebo had no significant effect on blood previous studies have been designed to differentiate pressure.5 In addition to the PEPI study, limited data between the effects on blood pressure of the individ- on the effects of progestogens on blood pressure are ual oestrogen (‘natural’, conjugated equine or available from studies of progestogen-only contra- semisynthetic) and progestogen (C21 or C19 deriva- ceptive formulations administered to normotensive tives administered as cyclical or continuous premenopausal women. From these studies there is therapy) components of the regimen when these little evidence to suggest that contraceptive doses of preparations have been administered in combi- progestogens given alone to normotensive premeno- nation. pausal women are associated with a pressor effect on blood pressure.31,36–38 However, results of some studies have suggested that, while progestogen Correspondence: Dr Paula Harvey, Division of Cardiology, administered alone does not have a demonstrable Toronto General Hospital, 12 Eaton South, Room 414, 200 Eliza- beth Street, Toronto, Ontario, M5G 2C4, Canada pressor effect, when administered in combination E-mail: paula.harveyȰutoronto.ca with oestrogen in combined contraceptive formu- Received 1 September 2000; revised 27 October 2000; accepted lations the progestogen may have a synergistic 4 December 2000 effect, thereby enhancing the pressor effect of the oestrogen.37,39 Postmenopausal progestogen and blood pressure PJ Harvey et al 314 From the currently available data a number of performed to assess endometrial thickness and to questions remain unanswered. Although the results exclude the presence of endometrial hyperplasia in of the PEPI study were reassuring, the study did not women with an intact uterus. Women over the age provide information regarding the different types, of 50 years who had not had a mammogram within doses and regimens of progestogen ‘replacement’ the last 2 years were required to have a mammogram therapy currently used clinically. The effect on to exclude breast carcinoma prior to study entry. blood pressure and other cardiovascular parameters Subjects were excluded if they had any chronic of a particular oestrogen-progestogen combination medical illness, a history of breast cancer, clinical may depend not only on the type and dose of the evidence of pelvic disease, evidence of endometrial oestrogen administered, but also on the type and hyperplasia (defined as endometrial thickness dose of the progestogen.37 The magnitude of any Ͼ5 mm),46 previous intolerance of oestrogen or pro- progestogen-related effect may also be influenced by gestogen in ‘replacement’ doses, the need for any the relative androgenicity of the progestogen prep- chronic medication likely to impact on blood press- aration used.40–44 ure, 24-h urinary sodium excretion Ͻ70 mmol/day In the present study in normotensive postmeno- or Ͼ250 mmol/day and a body mass index of pausal women, a randomised, double-blind cross- Ͼ30 kg/m2. Subjects were also excluded if they had over design was used to compare with placebo the a disturbance of heart rhythm (atrial fibrillation, fre- effects on blood pressure and other cardiovascular quent (Ͼ10/min) atrial or ventricular extrasystoles) parameters of cyclical doses spanning the clinical which rendered blood pressure measurement by dose range of the C21 progestogen, medroxyproges- oscillometry inaccurate. terone acetate, in normotensive women receiving a The study was approved by the Committee on fixed mid-range daily dose of conjugated equine oes- Clinical Investigation and the Drug and Thera- trogen. The study tested the null hypothesis that peutics Advisory Committee at Flinders Medical there would be no significant effect on blood press- Centre. Prior to entry, all subjects were informed ure from the addition of ‘replacement’ doses of about the study both verbally and by an information exogenous semi-synthetic progestogen as cyclical sheet and were asked to provide written consent therapy to daily oestrogen supplementation in post- to participation. menopausal normotensive women. Study design Materials and methods The study was conducted using a randomised, double- Subjects blind placebo controlled crossover design. Each phase was of 4 weeks duration. For each subject the Subjects included in this study were recruited by order of the treatments was allocated according to a public advertisements in the Consulting Clinics at 4 × 4 balanced Latin square. Each subject was allo- Flinders Medical Centre, a general teaching hospital cated a sequence of the treatments denoted by a row of Flinders University of South Australia, and by of the Latin square with individual treatments occu- advertisement in local news media. They were to be pying the cells of the row. Subjects were allocated healthy postmenopausal women aged 60 years or randomly (by random numbers) in blocks of four to less as determined by medical history, physical and the rows of the square and thus a treatment gynaecological examination and screening haemato- sequence. The columns of the square represented logical and biochemical testing. Postmenopausal the treatment phases in chronological order. (A bal- status was defined as either a history of at least 12 anced Latin square is one in which each treatment months of amenorrhoea prior to study entry in occurs only once in each cell in the square and in women with an intact uterus, or a history of pre- addition occurs only once after any other treatment.) vious hysterectomy with or without oophorectomy, There was no washout period between phases, but combined with biochemical evidence of menopause only the measurements recorded in either the last 2 defined as a serum follicle-stimulating hormone weeks (blood pressure and heart rate) or at the end (FSH) concentration у20 IU/L.45 Subjects were of each phase (ambulatory blood pressure, arterial required to be normotensive, defined as having a waveform and biochemical parameters) were used mean clinic sitting blood pressure of р140 mm Hg for comparison, giving an effective washout period systolic and р90 mm Hg diastolic measured using a of at least 2 weeks in each phase. The active phases mercury sphygmomanometer on at least two separ- of the study were preceded by an open 4-week run- ate occasions at least 1 week apart. They were not in phase in which screening examinations were con- to be currently receiving any hormone replacement ducted, exclusion criteria were assessed and patient therapy and any previous hormone replacement consent obtained. therapy was required to have been ceased at least 1 month prior to entry into the active phases of the Treatments and dosage regimens study. Each subject was