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Effect of postmenopausal estrogen therapy on diastolic blood pressure and bodyweight
hlaturitas.1 (1978) 3-8 B ElsevierlNorth-Holland BiomedicalPress
3
EFFECTOF POSTME:YOPAUSAL ESTROGENTHERAPYON DIASTOLIC BLOODPRESSUREANDBODYWEIGHT
WULF H. UTIAN Department
ofRepmduc~iveBlology.
MacDonald House.
else Western Reserve University School
of Medicine,
UniverslryHospitals. Cleveland. OH 44104. USA
(J~eceived 9 August,1977, acce.ptcd 2 Novembc:1978)
The e%xt of two formsof exogenous estrogenand a placeboon diastolicblwd prr%sure and bodyweightwasevaluatedin 50 oophorectomized women.There was no significantchangein bodyweight on any formoftreatment, norwasthereany dgniflcantelevationin meandiastolicbloodpressure.How* ever. 2 out of 49 femaleson conjugatedestrogenshoweda markedelevationof the diastolicblood pressure.It is therefore recommendedthat alJ women on exogenousestrogentreatmenthavetheir blood preuurc checkeda1 least cncc every6 months.Providedthisprecautionis observed,changesin bodyweightor diistolicbloodpr~ure neednot be consideredaspotentialdisdvantagesin the evaluation of indicationsfor long-termc;trogentreatment. (Key words:Pustmenopause, Estrogentherapy. Bloodpressure.Bodyweight)
INTRODUCTION
Increase in blood pressure and bodyweight are two undesirable clinical effects that have been related to the use of oral contraceptives [l-3] and possibly to exol:enous estrogen therapy after the menopause [Z]. Spontaneous or artificial menopause itself may be diicctly related to increase in blood pressure and bodyweight, but reporls have been conflicting. Moreover, weight gain and predisposition to hypertension may be age-related, a factor that needs to be borne In mind In evaluatingor planning any study. The clinical implications of an estrogen-induced increase in blood pressure and/or bodyweight remain unsettled, but arc potentially disturbing. It was therefore considered pertinent to review personal previously unpublished data, taken from a detailed menopausal study [4], and to determine whether any direct clinical effect was produced by estrogen therapy on blood pressure and bodyweight when administered to oophorectomizcd women. MATERIAL ANDMETHODS Fifty females were investigated through a Menopause Clinic established for &&al research purposes at Groote Sohuur Hospital, Cape Town. ‘!%ep&ients were selscted accordlng to ihe followblgcriteria: (1) Femalesaged 45-55 yr.
TABLE I
Aamumentschcduk Assessment no.
DeSatpttOn
1 2
Controlrcsdtng- vsrtabtetime W y) Jfter oophorec+omy Folbwing 3 mth centimmrues!mdtalvatmate4 m@ 1
: 5
FoUowir&6 mth continuouscstndiolvakntc 4 ny/uay Folkw& 3 mth continuouspkcebo therapy- singk blind Following3 mth continuousconjugatedestrogen5 m&lay
-___-
-
(2) Ah patients had undergone hysterectomy with bilateral oophorectomy within 2 yr of their fust visit. (3) Absence of gynaecoh+al or other diagnosedmaltgnancy. (4) No hormonal, vitamht or digitalis therapy ht the preceding 6 mth. (5) No symptoms of general dii. (6) The patients were ah Caucasians (White) of sbnilar soctoeconomic group. The patients were each assessed on 5 occasions over a period of 1 yr. There were no patient defaulters during the study. However, 1 patient died following intesthtat obstruction (volvulus) before the last visit, and so the results of the fmal assessment represent
measurementsin 49 patients. At each visit the clhrical evaluation was repeated before treatment was prescribed or changed. Thus each assessment was representattve of a particular stage of therapy according to the schedule in Table 1. Hence the treatment protocol, lasting 1 yr for each patient, was to administer estradiol valerate (Rogynova; Scherhtg AC. Berlin) 4 mg orahy for 6 mth following control evahmtion. Repeat evaluation5were taken at 3mth intervals. Thereafter a single-blindcrossover to an identical phrcebo for 3 mth was made and finally the placebo was replaced by continuous oral conjugated equine estrogen (Remarin; Ayerst Laboratories, New York) 5 mg datly. The dosage of the estrogens selected was cab culated to be equivalent to the relative proliferative dose (estradiol valerate = 60 mg; conjugated equine estrogen = 80 mg). In all instances the drtqp were administered continuously with no cyclical variation.
Blood pressure and bodyweight were accurately evaluated and recorded at each visit. Blood pressure was taken with the patient sitting after a period of rest. The patient5 were not given any medication during the period of study, other than the abovementioned specific treatment. Nor were they advised to aiter the%regular eating habits in any way at all. The diitolic blood pressure was compared in rwo ways: (l)lndftirar~ response: Each patient served as her own control, and the patient5 were then divided into 3 groups as follows: (a) diastolic blood pregure <90 nun &; (b) diitolic blood pressure of 90-120 nun I-&;(c) diastolic blood pressure X20 mm W. (2) Group response: The mean diastolic blood pmssums for the group on each therapeutic modality were compared stattsttcally using the matched p&s t&at. The change in bodyweight was evahrated stattstically by use of the matched pairs r-test.
5
The effecl of estrogen and placebo therapy on the diastolic blood pressure of oophorectomized females. Body weight
Control
3 mth estradiol valerate
6 mth estradiol vakrate
3 mth placebo
3 mtt conjugated estro8:ns
No. of patients
50
50
50
50
49
Mean diastolic presaura(mm Hg)
90.34
88.62
8 .80
90
91.10
Standard deviation
14.3037
13.9867
11.7906
13.6695
14.5971
2.n228
1.9780
Standard en~r
_.
1.6674 -_
1.9331
--_-
2.0853
RESULTS
The effect of estrogen and placebo therapy on the diastolic blood pressure of oophorectomized females is indicated in Table II. Although a marginrd decrease in pressure occurred on estradiol valerate and a slight increase on conjugated estrogen therapy, statistical comparison between all the groups revealed no significant differences. It was therefore considered pertinent to regroup the readings from each patknt within each treatment group into those with normal (<90 mm Hg), elevated [90-120 mm Hg) and erossly elevated diastolic pressures (>120 mm Hg). The totals for !he three subditisions withii exh treatment group are depicted in Table III. Once again, the estradiol valerate appeared to be associated with a decrease in diastolic blood pressure,and conjugated estrogen with an kcrease. Indeed, the conjugated estrogen treatment group was the only one to have patients with grossly elevated c’iastolic pressures. Statistical evaluation ?:“s unhelpful, as no significant differences were demon-
TABLE 111 The dialtoiic blood Pnuun
(mm Hg) of oophomctumizcd females and the effect of cstro4en and
plaabo therapy. Diadolk blood Pr=a=
Control
Pmth ertradiol v&rate
6 mlh estradiol valetate
no. *
no. %
no. J
no. a.
no. %
SO
SO
50
50
49
3mtb placebo
3 mth uonjugstod cstro8ens
---.
Totalno.of
100
100
100
100
100
pstknts treated >90
28
90-120 >120
22 0
56.0 44.0 0
35 1s 0
70.0 30.0 9
33 17 0
66.0 34.0 0
31 19 0
62.0 38.0 0
27 20 2
55.1 40.8 4.1
TABLE IV The effect of estrogenani placebothempyon the bodyweightof aophorectomizedfemales.
_50
_.__~ 3 mth estmdbl vslerate -.50
6 mth eHmdkJ1 vale&e
66.28
66.77
65.88
65.80
66.75
12.04 1.72
11.38 1.63 -___--
11.28 1.61
11.11 1.59
11.38 1.63
Body weight
Control
--.-No. of patients Meanbodyweight inkg Standarddeviation Standardernx
50
3mth plaC&Ll ______ 50
3 mth conjugated estrogens 49
straied to exist between the groups. The difference between ertrsdiol valerate and conjugated estrogen reached possibk significance (P
difference. It can be concluded that the administration of estrogen to oophorcctomized females doer not result in any sign&ant change in the bodyweight.
The relationship between estrogen, endogenous and exogenous, and blood pressure is unclear. Arterial blood pressure tends to increase with age until late in life [S]. Young women have similar blood plessurc levels to young men. The increase with age in women, however, is more rapid, and after middle age their levels cxeccd those of males [S]. Menopause,and supposedly estrogen dcfklenoy, has been a natural target of suspicion for the sexual difference in blood pressure. Data from the U&cd States Health Sxamination Survey of Adults contimt that women whose menstrual periods had stopped had bier levels of diastolic blood pressure, but not systolic blood pressure, than premenopausal women. The blood pressure levels were not related to type of menopause (spontaneous vs. operative) or time interval since mcnopausc. Although thcsc results were. suggestivethat menopause precedes the rise in diastohe blood pressure. it was not possible to be certain of the temporal sequence of events [6]. Von Eiff attempted to explain the incnase in blood pressure after menopause as being due to the loss of a prcmenopausal “protcotivc” cffcet of estrogen [7]. fik studkr suggest that both exogenous and endogcnous estrogens play a rok in protecting premcnopausal womzn from essential hypertension. Unfortunately a paradox seems to exist. Use of the oral cmtraccptive is a&o&cd with a slight, but usually reversibk. rise in the mean blood prcssum. Fiseh and Frank reported the contraccptive-induccd blood pressure elevation to be about S-6 mm Hg
systo%c and l-2 mm diastolic, that is slight but statistically significant [I 1. Stern et al. reported similar fmdings [3]. Moreover, the Royal College of General Practitioners prospective study on 46,ooO women reported that oral contraceptive users where 2 to 2.5 times more likely to develop hypertension than nonusers [g]. Notelowitz found conjugated estrogens to increase the mean systolic and diastolic blood pressures when administered to postmenopausal women, but only the tllastollc was significantly elevated [9]. Spellacy and Birk found oral contraceptives with synthetic estrogens to induce blood pressure elevations, but not conjugated estrogens [lo]. Pallas et al. could discern no effect of conjugated estrogens on the blood pressun!, when corrected for age and relative weight, of $75 women on no medication compared to that of 82 on conjugated estrogen [I I]. The paradox thus appears to be at an impasse. The present study is of interest in that no significant differences in diastolic blood pressure were demonstrated on either estradiol valerate or conjugated estrogen. Nonetheless, the conjugated estrogen treatment group was the only one to be associated with extreme elevations or the diastolic blood pressure, a fmding that occurred in 2 out of 49 patients. The lack of association of natural estrogens with statistically significant elevation of diastolic blood pressure, is reassming. No apparent reason therefore exists for wltholding estrogen therapy on this basis alone. Nevertheless, Notelowitz’ observation that some postmenopausal women have an idiosyncratic response to conjugated estrogens with blood pressure elevations has been confirmed and is worthy of emphasis. His recommendation that women on such therapy have blood pressure check-ups every 6 mth merits attention [9]. Bodyweight was unaffected by treatment with two types of estrogen therapy, and this Finding has been confirmed [9]. This should be reassuring for women about to embark on estrogen therapy. In conclusion, it can be stated that weight gain i:i not a concurrent feature or problem of exogenous estrogen therapy. Indeed, nor is any significant increase in diastolic blood pressure. Conjugated estrogens, however, do appear to be associated with occasional significant elevations of diastolic blood pressure. In view of the potential adverse effects of such a blood pressure increase, all women on long-term estrogen treatment should have blood pressure readings taken every 6 mth as part of their routine medical follow-up examination. REFERENCES 111 Fisck, I.R. and Rank, J. (1977) Oral contraceptives and blood pressure.I. Am. Med. Assoc. 237, 2499-2503. Spe&y. W.N.. Buhi, WE. and Birk, %A. (1972) The affect of estrogens on carbohydrate metabolism. Am. J. Obstat. Gynccal. 114,378-390. 13) Stern, P.M., Bmwn, B.W.. Hatkell, W.L., Farquhar, I., Wehrle, C.I. and Wood, P.D. (1976)Cw
[2]
diovucuLr risk and use of erlrqwu 01 ertrogenproaestsp,ea combinations J. Am. Med. Assoc. 235,811-815. [4] Uthn, W.H. fi970) Clinical and metabolic effects of the menopause end the role of rc;placement oectro@t~ thaapy. PhD Thepia. University of Cape Town.
151 National Center for Health Statistics. Blood pressure of adults by age and sex: United States 1960-1962. PHS Publication No. 1000, Series 11, No. 4, 1964. U.S. Government Printing Offi, Washiion, D.C.
8 161 Weiss, N.S. (1972) Beletionship of -to serum ckolesterol and art&al blood tmsswe: The United States health examination rwey of idults. Am. J. Epktemiol. 96.237-241. [7] Van Eiff, A.W. (1975) Blood pressure and estrqenr In: Et&gem in the postmenop~usee,pp. 177-1S4. Editors: PA. van Keqa and C. Irtitzea. Karget, BataL [S] &al cmtrawptives andhedthzAn interimrepmtftom tke oral contraception study of the Royal Cc~e of General Pmctitbms (1974). pit&n Medii London. 191 Notebwitz, Id. (1975) Effect of n&ml ocstqem on blood p~crsurcand weight in postmenopausal women. S. Afr. Med. 1.49.2251-2254. [IO] Spcllpcy, W.N. and Birk, S.A. (1972) ‘The cffwt of I.U.D.‘s. oral ooattacaptivcs, estrogens ad prqertogear on blood prrcrurc.Am. J. ObsM. Gyaced. 112.912-919. [I1 ] PaUPs,K.G., Hohwarth, GJ., Stem, M.P. ad Lucas, CR. (1977) The effect of mnjuyted estrogenron the rcnb-la~tensin system. 1. Cm EndoaiIKd. Metab. 44,1061-1068.
3
EFFECTOF POSTME:YOPAUSAL ESTROGENTHERAPYON DIASTOLIC BLOODPRESSUREANDBODYWEIGHT
WULF H. UTIAN Department
ofRepmduc~iveBlology.
MacDonald House.
else Western Reserve University School
of Medicine,
UniverslryHospitals. Cleveland. OH 44104. USA
(J~eceived 9 August,1977, acce.ptcd 2 Novembc:1978)
The e%xt of two formsof exogenous estrogenand a placeboon diastolicblwd prr%sure and bodyweightwasevaluatedin 50 oophorectomized women.There was no significantchangein bodyweight on any formoftreatment, norwasthereany dgniflcantelevationin meandiastolicbloodpressure.How* ever. 2 out of 49 femaleson conjugatedestrogenshoweda markedelevationof the diastolicblood pressure.It is therefore recommendedthat alJ women on exogenousestrogentreatmenthavetheir blood preuurc checkeda1 least cncc every6 months.Providedthisprecautionis observed,changesin bodyweightor diistolicbloodpr~ure neednot be consideredaspotentialdisdvantagesin the evaluation of indicationsfor long-termc;trogentreatment. (Key words:Pustmenopause, Estrogentherapy. Bloodpressure.Bodyweight)
INTRODUCTION
Increase in blood pressure and bodyweight are two undesirable clinical effects that have been related to the use of oral contraceptives [l-3] and possibly to exol:enous estrogen therapy after the menopause [Z]. Spontaneous or artificial menopause itself may be diicctly related to increase in blood pressure and bodyweight, but reporls have been conflicting. Moreover, weight gain and predisposition to hypertension may be age-related, a factor that needs to be borne In mind In evaluatingor planning any study. The clinical implications of an estrogen-induced increase in blood pressure and/or bodyweight remain unsettled, but arc potentially disturbing. It was therefore considered pertinent to review personal previously unpublished data, taken from a detailed menopausal study [4], and to determine whether any direct clinical effect was produced by estrogen therapy on blood pressure and bodyweight when administered to oophorectomizcd women. MATERIAL ANDMETHODS Fifty females were investigated through a Menopause Clinic established for &&al research purposes at Groote Sohuur Hospital, Cape Town. ‘!%ep&ients were selscted accordlng to ihe followblgcriteria: (1) Femalesaged 45-55 yr.
TABLE I
Aamumentschcduk Assessment no.
DeSatpttOn
1 2
Controlrcsdtng- vsrtabtetime W y) Jfter oophorec+omy Folbwing 3 mth centimmrues!mdtalvatmate4 m@ 1
: 5
FoUowir&6 mth continuouscstndiolvakntc 4 ny/uay Folkw& 3 mth continuouspkcebo therapy- singk blind Following3 mth continuousconjugatedestrogen5 m&lay
-___-
-
(2) Ah patients had undergone hysterectomy with bilateral oophorectomy within 2 yr of their fust visit. (3) Absence of gynaecoh+al or other diagnosedmaltgnancy. (4) No hormonal, vitamht or digitalis therapy ht the preceding 6 mth. (5) No symptoms of general dii. (6) The patients were ah Caucasians (White) of sbnilar soctoeconomic group. The patients were each assessed on 5 occasions over a period of 1 yr. There were no patient defaulters during the study. However, 1 patient died following intesthtat obstruction (volvulus) before the last visit, and so the results of the fmal assessment represent
measurementsin 49 patients. At each visit the clhrical evaluation was repeated before treatment was prescribed or changed. Thus each assessment was representattve of a particular stage of therapy according to the schedule in Table 1. Hence the treatment protocol, lasting 1 yr for each patient, was to administer estradiol valerate (Rogynova; Scherhtg AC. Berlin) 4 mg orahy for 6 mth following control evahmtion. Repeat evaluation5were taken at 3mth intervals. Thereafter a single-blindcrossover to an identical phrcebo for 3 mth was made and finally the placebo was replaced by continuous oral conjugated equine estrogen (Remarin; Ayerst Laboratories, New York) 5 mg datly. The dosage of the estrogens selected was cab culated to be equivalent to the relative proliferative dose (estradiol valerate = 60 mg; conjugated equine estrogen = 80 mg). In all instances the drtqp were administered continuously with no cyclical variation.
Blood pressure and bodyweight were accurately evaluated and recorded at each visit. Blood pressure was taken with the patient sitting after a period of rest. The patient5 were not given any medication during the period of study, other than the abovementioned specific treatment. Nor were they advised to aiter the%regular eating habits in any way at all. The diitolic blood pressure was compared in rwo ways: (l)lndftirar~ response: Each patient served as her own control, and the patient5 were then divided into 3 groups as follows: (a) diastolic blood pregure <90 nun &; (b) diitolic blood pressure of 90-120 nun I-&;(c) diastolic blood pressure X20 mm W. (2) Group response: The mean diastolic blood pmssums for the group on each therapeutic modality were compared stattsttcally using the matched p&s t&at. The change in bodyweight was evahrated stattstically by use of the matched pairs r-test.
5
The effecl of estrogen and placebo therapy on the diastolic blood pressure of oophorectomized females. Body weight
Control
3 mth estradiol valerate
6 mth estradiol vakrate
3 mth placebo
3 mtt conjugated estro8:ns
No. of patients
50
50
50
50
49
Mean diastolic presaura(mm Hg)
90.34
88.62
8 .80
90
91.10
Standard deviation
14.3037
13.9867
11.7906
13.6695
14.5971
2.n228
1.9780
Standard en~r
_.
1.6674 -_
1.9331
--_-
2.0853
RESULTS
The effect of estrogen and placebo therapy on the diastolic blood pressure of oophorectomized females is indicated in Table II. Although a marginrd decrease in pressure occurred on estradiol valerate and a slight increase on conjugated estrogen therapy, statistical comparison between all the groups revealed no significant differences. It was therefore considered pertinent to regroup the readings from each patknt within each treatment group into those with normal (<90 mm Hg), elevated [90-120 mm Hg) and erossly elevated diastolic pressures (>120 mm Hg). The totals for !he three subditisions withii exh treatment group are depicted in Table III. Once again, the estradiol valerate appeared to be associated with a decrease in diastolic blood pressure,and conjugated estrogen with an kcrease. Indeed, the conjugated estrogen treatment group was the only one to have patients with grossly elevated c’iastolic pressures. Statistical evaluation ?:“s unhelpful, as no significant differences were demon-
TABLE 111 The dialtoiic blood Pnuun
(mm Hg) of oophomctumizcd females and the effect of cstro4en and
plaabo therapy. Diadolk blood Pr=a=
Control
Pmth ertradiol v&rate
6 mlh estradiol valetate
no. *
no. %
no. J
no. a.
no. %
SO
SO
50
50
49
3mtb placebo
3 mth uonjugstod cstro8ens
---.
Totalno.of
100
100
100
100
100
pstknts treated >90
28
90-120 >120
22 0
56.0 44.0 0
35 1s 0
70.0 30.0 9
33 17 0
66.0 34.0 0
31 19 0
62.0 38.0 0
27 20 2
55.1 40.8 4.1
TABLE IV The effect of estrogenani placebothempyon the bodyweightof aophorectomizedfemales.
_50
_.__~ 3 mth estmdbl vslerate -.50
6 mth eHmdkJ1 vale&e
66.28
66.77
65.88
65.80
66.75
12.04 1.72
11.38 1.63 -___--
11.28 1.61
11.11 1.59
11.38 1.63
Body weight
Control
--.-No. of patients Meanbodyweight inkg Standarddeviation Standardernx
50
3mth plaC&Ll ______ 50
3 mth conjugated estrogens 49
straied to exist between the groups. The difference between ertrsdiol valerate and conjugated estrogen reached possibk significance (P
difference. It can be concluded that the administration of estrogen to oophorcctomized females doer not result in any sign&ant change in the bodyweight.
The relationship between estrogen, endogenous and exogenous, and blood pressure is unclear. Arterial blood pressure tends to increase with age until late in life [S]. Young women have similar blood plessurc levels to young men. The increase with age in women, however, is more rapid, and after middle age their levels cxeccd those of males [S]. Menopause,and supposedly estrogen dcfklenoy, has been a natural target of suspicion for the sexual difference in blood pressure. Data from the U&cd States Health Sxamination Survey of Adults contimt that women whose menstrual periods had stopped had bier levels of diastolic blood pressure, but not systolic blood pressure, than premenopausal women. The blood pressure levels were not related to type of menopause (spontaneous vs. operative) or time interval since mcnopausc. Although thcsc results were. suggestivethat menopause precedes the rise in diastohe blood pressure. it was not possible to be certain of the temporal sequence of events [6]. Von Eiff attempted to explain the incnase in blood pressure after menopause as being due to the loss of a prcmenopausal “protcotivc” cffcet of estrogen [7]. fik studkr suggest that both exogenous and endogcnous estrogens play a rok in protecting premcnopausal womzn from essential hypertension. Unfortunately a paradox seems to exist. Use of the oral cmtraccptive is a&o&cd with a slight, but usually reversibk. rise in the mean blood prcssum. Fiseh and Frank reported the contraccptive-induccd blood pressure elevation to be about S-6 mm Hg
systo%c and l-2 mm diastolic, that is slight but statistically significant [I 1. Stern et al. reported similar fmdings [3]. Moreover, the Royal College of General Practitioners prospective study on 46,ooO women reported that oral contraceptive users where 2 to 2.5 times more likely to develop hypertension than nonusers [g]. Notelowitz found conjugated estrogens to increase the mean systolic and diastolic blood pressures when administered to postmenopausal women, but only the tllastollc was significantly elevated [9]. Spellacy and Birk found oral contraceptives with synthetic estrogens to induce blood pressure elevations, but not conjugated estrogens [lo]. Pallas et al. could discern no effect of conjugated estrogens on the blood pressun!, when corrected for age and relative weight, of $75 women on no medication compared to that of 82 on conjugated estrogen [I I]. The paradox thus appears to be at an impasse. The present study is of interest in that no significant differences in diastolic blood pressure were demonstrated on either estradiol valerate or conjugated estrogen. Nonetheless, the conjugated estrogen treatment group was the only one to be associated with extreme elevations or the diastolic blood pressure, a fmding that occurred in 2 out of 49 patients. The lack of association of natural estrogens with statistically significant elevation of diastolic blood pressure, is reassming. No apparent reason therefore exists for wltholding estrogen therapy on this basis alone. Nevertheless, Notelowitz’ observation that some postmenopausal women have an idiosyncratic response to conjugated estrogens with blood pressure elevations has been confirmed and is worthy of emphasis. His recommendation that women on such therapy have blood pressure check-ups every 6 mth merits attention [9]. Bodyweight was unaffected by treatment with two types of estrogen therapy, and this Finding has been confirmed [9]. This should be reassuring for women about to embark on estrogen therapy. In conclusion, it can be stated that weight gain i:i not a concurrent feature or problem of exogenous estrogen therapy. Indeed, nor is any significant increase in diastolic blood pressure. Conjugated estrogens, however, do appear to be associated with occasional significant elevations of diastolic blood pressure. In view of the potential adverse effects of such a blood pressure increase, all women on long-term estrogen treatment should have blood pressure readings taken every 6 mth as part of their routine medical follow-up examination. REFERENCES 111 Fisck, I.R. and Rank, J. (1977) Oral contraceptives and blood pressure.I. Am. Med. Assoc. 237, 2499-2503. Spe&y. W.N.. Buhi, WE. and Birk, %A. (1972) The affect of estrogens on carbohydrate metabolism. Am. J. Obstat. Gynccal. 114,378-390. 13) Stern, P.M., Bmwn, B.W.. Hatkell, W.L., Farquhar, I., Wehrle, C.I. and Wood, P.D. (1976)Cw
[2]
diovucuLr risk and use of erlrqwu 01 ertrogenproaestsp,ea combinations J. Am. Med. Assoc. 235,811-815. [4] Uthn, W.H. fi970) Clinical and metabolic effects of the menopause end the role of rc;placement oectro@t~ thaapy. PhD Thepia. University of Cape Town.
151 National Center for Health Statistics. Blood pressure of adults by age and sex: United States 1960-1962. PHS Publication No. 1000, Series 11, No. 4, 1964. U.S. Government Printing Offi, Washiion, D.C.
8 161 Weiss, N.S. (1972) Beletionship of -to serum ckolesterol and art&al blood tmsswe: The United States health examination rwey of idults. Am. J. Epktemiol. 96.237-241. [7] Van Eiff, A.W. (1975) Blood pressure and estrqenr In: Et&gem in the postmenop~usee,pp. 177-1S4. Editors: PA. van Keqa and C. Irtitzea. Karget, BataL [S] &al cmtrawptives andhedthzAn interimrepmtftom tke oral contraception study of the Royal Cc~e of General Pmctitbms (1974). pit&n Medii London. 191 Notebwitz, Id. (1975) Effect of n&ml ocstqem on blood p~crsurcand weight in postmenopausal women. S. Afr. Med. 1.49.2251-2254. [IO] Spcllpcy, W.N. and Birk, S.A. (1972) ‘The cffwt of I.U.D.‘s. oral ooattacaptivcs, estrogens ad prqertogear on blood prrcrurc.Am. J. ObsM. Gyaced. 112.912-919. [I1 ] PaUPs,K.G., Hohwarth, GJ., Stem, M.P. ad Lucas, CR. (1977) The effect of mnjuyted estrogenron the rcnb-la~tensin system. 1. Cm EndoaiIKd. Metab. 44,1061-1068.