Kiln. Wschr. 53, 509-517 (1975) - © by Springer-Verlag 1975
Originalien Spontaneous Changes in Weight, Leg Volume, Renin, Aldosterone and Sex Hormones in Patients with Cyclical Oedema* * * W. Oelkers, B. Marsen, M. Molzahn, and J. Hammerstein Endocrinological Divisions of the Departments of Internal Medicine, and of Gynecology and Obstetrics, Klinikum Steglitz, Freie Universit/it Berlin, Germany.
Sponlanschwankungen yon Gewicht, Beinvolumen, Renin, Aldosleron und Sexualhormonen bei Patienten mit zyklischem Odem. Zusammenjassung. Bei 4 Frauen mit zyklischem Odem wurden das K6rpergewicht, das Beinvolumen, die Ausscheidung yon Natrium, Aldosteron und Oestrogenen, die Plasmakonzentrationen von Progesteron und Angiotensin II und die Plasma-Reninaktivit/it /~ber 4 Wochen w/ihrend der Einnahme einer konstanten Kochsalzmenge gemessen. Bei einer weiteren Patientin wurden regelm/iBige biphasische Temperatur- und Gewichtsschwankungen beobachtet, die nach Ovariektomie verschwanden. Gewichtsschwankungen zwischen 3,5 und 5,5 kg entsprachen annfihernd den )~nderungen der Natriumbilanz. Bei 3 Patientinnen wurden die Gewichtsmaxima in der zweiten, bei einer Patientin in der ersten Zyklush/ilfte beobachtet. Die Plasma-Reninaktivit/it war bei allen Frauen im Normbereich und 5mderte sich tendenziell im gegens/itzlichen Sinne zum Gewicht. Die Aldosteronausscheidung verhielt sich/ihnlich, variierte aber bei 3 Frauen anBerdem parallel zum Plasma-Progesteronspiegel. Die orthostatische .A.nderung des Beinvolumens von morgens bis abends korrelierte nicht signifikant mit der Auderung des Morgen-Gewichtes. Renin, Aldosteron und gesteigerte orthostatische Extravasation von PlasmaFltissigkeit scheinen daher in der Pathogenese der Odeme unserer Patientin keine prim/ire Rolle zu spielen. Die Oestrogenausscheidung war bei 2 Patientinnen mit pr/imenstruellen Oedemen in der zweiten Zyklush/ilfte erniedrigt. Bei keiner der Patientinnen konnte die Natriumretention mit einer fiberschie13enden Oestrogenbildung und/oder einem Progesteronmangel erklfirt werden. Schliisselwgrter: Aldosteron, Odem, Oestrogene, Progesteron, Renin. Summary. In four women with cyclical oedema related to the menstrual cycle, weight, leg volume, urinary excretion of sodium, aldosterone and oestrogens, plasma concentrations of progesterone, angiotensin II and plasma renin activity were measured at intervals during 4 weeks while they were taking a fixed sodium diet. In another patient, regular biphasic changes in weight and basal body temperature, disappearing after ovariectomy, were demonstrated. Changes in weight (varying between 3,5 and 5.5 kg) with corresponding changes in sodium balance were observed. In three patients, the maximum weight occurred in the second half, and in the other patient in the first half of the menstrual cycle. Plasma renin activity was in the normal range in all patients. It tended * Supported by the Deutsche Forschungsgemeinschaft. ** Presented in part at the 7th Annual Meeting of the European Society for Clinical Investigation, April 2 6 - 2 9 , 1973, Rotterdam.
to rise when weight fell and vice versa. Aldosterone excretion behaved similarly and seems to be related to plasma progesterone in three patients. Orthostatic increase in leg volume did not significantly correlate with change in early morning weight. Thus, renin, aldosterone and orthostatic pooling of plasma fluid did not seem to be of primary importance in the pathogenesis of oedema in these patients. Oestrogen excretion in the luteal phase of the cycle was abnormally low in two patients ; both had premenstrual oedema. In none of the patients could sodium retention be explained by excessive oestrogen and/or diminished progesterone production.
Key words: Aldosterone, oedema, oestrogens, progesterone, renin.
Introduction
A considerable percentage of women with unexplained oedema complain of a particularly marked gain in weight in a certain phase of the menstrual cycle, usually in the last few days before menstruation. Although this syndrome was given a special n a m e cyclical or periodic oedema [34J-regular marked changes in weight in those patients have not always been well documented. Reports on the relationship between changes in weight and the secretory cycle of oestrogens and progesterone are also scanty. It is known, however, that large doses of oestrogens cause salt and water retention [8, 20, 27] while progesterone promotes salt loss by antagonizing the effect of mineralocorticoids on the kidney [22, 23, 32]. Exaggerated orthostatic salt and water retention seems to be an important pathogenetic factor in the development of idiopathic oedema [11, 12, 14, 17, 21, 29, 30, 31]. In some of these patients, secondary aldosteronism was observed [11, 12, 14, 17, 21, 24, 29, 30, 37, 25], but according to a recent report by Streeten el at. [32], only 23% exhibited an exaggerated aldosterone response to posture. In the present article we report on spontaneous changes in weight, leg volume and some endocrine factors in women who had been observed to have markedly pronounced oedema in some phase of the menstrual cycle. Three questions are posed:
W. Oelkers et al. : Weight, Leg Volume and Hormones in Cyclical Oedema
510
1. Is it possible to reproduce regular weight changes on a fixed diet in the ward ? 2. Are changes in weight related to the activity of the renin-aldosterone-system and to orthostatic pooling of fluid in the legs? 3. Are changes in weight related to oestrogen excretion and/or plasma progesterone?
Patients, Experimental Procedure, and Laboratory Methods
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1. Patients
Our interest in the problem was stimulated by observations in a woman presenting with an regular increase in body weight and body temperature every 2 weeks (Pat. No. 1). The other 4 patients (No. 2 - 5) whose data are included in this study were seen in the endocrinological clinic from 1970 to 1971. They were subsequently admitted to the metabolic ward for special studies. Clinical data of the patients are summarized in Table 1. Recurrent oedema had first been observed 1 - 8 years earlier. In 3 patients, oedema was observed to be most severe in the mid-cycle and/or premenstrual period, while the weight charts in Pat. No. 4 revealed that maximum weight occurred in the first half of 5 of the 6 menstrual cycles recorded, In this patient, an increase in basal body temperature usually occurred about 1 week before the onset of menstruation. She also had a history of a stone in the right kidney (Table 1), but the excretory function of her kidneys (inulin and PAH-clearances) was normal. Psychiatric diagnoses are based on interviews by the consultant psychiatrist of the Klinikum Steglitz. Routine investigations included physical examinations, red and white blood cell counts, ESR, urine analyses and measurements
4 8 12 16 20 24 28 DAYOFMENSTRUALCYCLE
4 8 12 16 20 24 28 3t DATE
Fig. 1. Basal body temperature (BBT, broken lines) before, and body weight (BW, solid lines) before and after ovariectomy in patient No. 1. Shaded zones =menstrual bleeding
of plasma creatinine and electrolytes, plasma protein concentration, electrophoresis, serum transaminases and alkaline phosphatase, PBI, thyroxin concentration, intravenous or oral glucose tolerance test, chest x-ray, and i.v. pyelogram. The results were normal, except transient hypokalemia in patients No. 2 and 4 some weeks before admission. In Pat. No. 1 no special investigations were done. While in the care of our clinic, she recorded her morning weight and basal body temperature from February 1971 to January 1972, and again from March 1972 until the end of May 1972. On 5 March 1972 her remaining left ovary and uterus were removed because of profuse bleeding from a submucous fibromyoma of the uterus. The record (Fig. I) shows that during 3 menstrual cycles a rather uniform paral-
Table 1. Clinical data of patients studied Patient No. age (years)
1 40
2 28
3 34
4 31
5 39
Onset of oedema (age)
32
21
33
26
31
Maximum oedema
Midcycle and premenstr.
premenstr,
premenstr,
postmenstr.
premenstr.
Menstrual cycle
1962 right ovariectomy, regular menstr, till march 1972 (left ovariectomy + hysterectomy)
1964- 1967 second, amenorreoea, later regular, sometimes anovulatory
almost regular
irregular since 1966 late increase of basal body temperature
regular.
Married
4--
-
Parturitions Psychiatric diagnosis
1 "normal"
0 neurosis, depressive, hysteric
Renal disease
no
Blood- )~ lying pressure f standing
160/100 140/90
no
110/70 110/80
-
+
0 neurosis, depressive, schizoid
0 neurosis, depressive, schizoid
no
1968 right pelvic stone removed.
no
120/80 120/80
110/65 100/80
140/90 135/90
0 "normal" but often ill and absenteeism
W. Oelkers et al. : Weight, Leg Volume and Hormones in Cyclical Oedema lel rise in weight and basal body temperature occurred between the 8th and the 10th day of the cycle and a fall to baseline after 5 - 7 days. 3 to 4 days before the onset of menstruation, weight and basal body temperature rose again with a subsequent fall of both with the onset of menstruation. Weight changes ranged between 1.5 and 2.5 kg. After ovariectomy, regular weight changes did not occur, the largest fluctuations in weight then amounting to 1 kg.
511
radioimmunoassay method of Dfisterdieck and McElwee [9]; (normal range-supine: 5 - 35 pg/ml) and the excretion rate of aldosterone-18-gtucuronide by a radioimmunoassay according to Vecsei [36] ; (normal range - ambulatory : 3 - 16 pg/24 h). Plasma progesterone concentration was measured by a protein binding assay after Johansson [18] and total oestrogen excretion by the method of Brown et aL [4]. tn patients No. 2 and 3 fractionation of the three classical oestrogens was performed, in addition, according to Brown's method [2].
2. Exper#nental protocols
Patients No. 2 - 5 were asked not to take diuretics at least 6 days before admission to the wards. Patients No. 2 and No. 4 admitted later that they had nevertheless continued with furosemide in small doses. All patients were given a diet containing 10 - 15 meq of sodium and 6 0 - 8 0 meq of potassium. 128 meq of sodium chloride were given bringing the total sodium intake within the range of 135-143 meq/day. Patients were upright (watking and standing; sitting at meal times only) from 08.00 until at least 17.00 hrs at the earliest. Weight was measured in night clothes in all patients at 08.00 and at 17.00 hrs. after emptying the bladder. Leg volume was measured at the same times in addition in patients No. 2 and 3.24 h urine samples were collected every day and the excretion of sodium, aldosterone-18-glucuronide, and estrogens was measured, partly in pooled urine samples of 2 or 3 days. On several occasions, blood was drawn in the morning in the recumbent position after at least 8 h of bed rest for the determination of the plasma concentrations of potassium, progesterone and renin activity; in 2 patients an additional sample was taken at 17.00 hrs for renin determination. Body temperature was measured every day. In patients No. 2 - 5 , PAH and inulin clearance studies were performed, once in the follicular and once in the luteal phase (Pat. No. 2 - 4 ) of the menstrual cycle. For these studies, patients remained recumbent in the morning. After injecting a priming dose of PAH and inulin, a constant infusion of PAH and inulin in 5% dextrose solution (5 ml/min) was started. 30 min tater, the patients emptied their bladder. Two clearance periods of 120 rain duration followed, the first in the recumbent, the second in the upright position (standing or walking slowly). Indwelling urinary catheters were not used. Urine volumes and sodium and potassium excretion were measured, and at the end of both clearance periods, blood was drawn for the determination of plasma renin activity and of plasma angiotensin II concentration.
3. Methods
Leg volume as measured by placing the leg, up to the lower thigh, into a large lass cylinder with an inner diameter of 25 cm and a water column exactly 34 cm high. The rise of the water column was read from a mm-scale fixed to the outer wall of the glass cylinder and the leg volume was calculated from the increment in height of the water column. Mean volumes of the right and the left leg are reported in Figs. 2 and 3. Sodium and potassium concentrations in plasma and urine were measured by standard flame photometer techniques. Inulin in plasma and urine was determined using the method of Roe et al. [28] and PAH according to Czok et al. [7]. Plasma renin activity was measured by our own modification of the method of Haber et al. [15] using a radioimmunoassay kit of Schwartz and Mann, Orangeburg, N.Y., USA (normal range - supine : 0.5 - 4.5 ng angiotensin I/ml/h). Our modification consisted of a 4 h dialysis before incubation of plasma against a chloride free phosphate buffer pH 6.0 made isotonic to plasma by adding sodium sulphate. Human plasma angiotensinase activity is minimal at this hydrogen ion concentration [33]. Plasma angiotensin II concentration was measured by a
Results
All observations in patients No. 2 - 5, except clearance studies, are summarized in Figs. 2 - 5.
1. Menstrual cycles Patients No. 2 - 5 were admitted on days 16, t, 4, and 4 respectively of their menstrual cycles. As judged by basal body temperature and plasma progesterone levels, normal biphasic cycles were observed in patients No. 2, 3, and 5. In Pat. No. 4, a rise in basal body temperature occurred on the 27th day of the menstrual cycle with a short and low plasma progesterone peak. Menstrual bleeding commenced 5 days later.
2. Changes in weight related to menstrual cycle Different patterns of weight fluctuation were observed in patients No. 2 to 5. Weight gain started at the time of ovulation in patients No. 2 and 3, a few days before menstruation in patients No. 5, and in the early follicular phase in patient No. 4. Maximum changes in weight of 5.5 kg, 3.5 kg, 4.8 kg, and 5.5 kg occurred in patients No. 2 to 5 respectively on the fixed sodium diet. In patients No. 2 and 3, two weight maxima or sharp rises in weight were observed, while in patients No. 4 and 5 the second weight maximum was much smaller than the first one observed. Postdiuretic sodium retention may have contributed to the first weight gain in patients No. 2 and 4, but hypokalemia was not observed on admission.
3. Orthostatic changes in weight and leg volume The orthostatic increase in weight and in leg volume tended to be larger when the early morning measurements were on the increase. On the other hand, when the early morning weights were decreasing, the measurements in the later part of the day after standing were sometimes lower than in the morning of the same
Weight kg
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Fig, 4
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Fig. 2
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Estrogen 406o Excretion 3o
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513
W. Oelkers et at. : Weight, Leg Volume and H o r m o n e s in Cyclical Oedema Table 2. Coefficients of correlation between orthostatic changes in weight and leg volume Subject n No.
2 3 4 5
30 29 13 29
Coefficient of Correlation • weight change 8 a.m ~ 5 p.m versus
• leg voI. change 8 a.m ~ 5 p.m versus • leg voL change 8 a.m -~ 5 p.m versus
• weight change 8 a . m --+ 8a.m next day
• leg vol. change 8a.m -~ 8a.m next day • weight change 8 a.m ~ 8 a.m next day
r
p(2:0
n
r
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Originalien Spontaneous Changes in Weight, Leg Volume, Renin, Aldosterone and Sex Hormones in Patients with Cyclical Oedema* * * W. Oelkers, B. Marsen, M. Molzahn, and J. Hammerstein Endocrinological Divisions of the Departments of Internal Medicine, and of Gynecology and Obstetrics, Klinikum Steglitz, Freie Universit/it Berlin, Germany.
Sponlanschwankungen yon Gewicht, Beinvolumen, Renin, Aldosleron und Sexualhormonen bei Patienten mit zyklischem Odem. Zusammenjassung. Bei 4 Frauen mit zyklischem Odem wurden das K6rpergewicht, das Beinvolumen, die Ausscheidung yon Natrium, Aldosteron und Oestrogenen, die Plasmakonzentrationen von Progesteron und Angiotensin II und die Plasma-Reninaktivit/it /~ber 4 Wochen w/ihrend der Einnahme einer konstanten Kochsalzmenge gemessen. Bei einer weiteren Patientin wurden regelm/iBige biphasische Temperatur- und Gewichtsschwankungen beobachtet, die nach Ovariektomie verschwanden. Gewichtsschwankungen zwischen 3,5 und 5,5 kg entsprachen annfihernd den )~nderungen der Natriumbilanz. Bei 3 Patientinnen wurden die Gewichtsmaxima in der zweiten, bei einer Patientin in der ersten Zyklush/ilfte beobachtet. Die Plasma-Reninaktivit/it war bei allen Frauen im Normbereich und 5mderte sich tendenziell im gegens/itzlichen Sinne zum Gewicht. Die Aldosteronausscheidung verhielt sich/ihnlich, variierte aber bei 3 Frauen anBerdem parallel zum Plasma-Progesteronspiegel. Die orthostatische .A.nderung des Beinvolumens von morgens bis abends korrelierte nicht signifikant mit der Auderung des Morgen-Gewichtes. Renin, Aldosteron und gesteigerte orthostatische Extravasation von PlasmaFltissigkeit scheinen daher in der Pathogenese der Odeme unserer Patientin keine prim/ire Rolle zu spielen. Die Oestrogenausscheidung war bei 2 Patientinnen mit pr/imenstruellen Oedemen in der zweiten Zyklush/ilfte erniedrigt. Bei keiner der Patientinnen konnte die Natriumretention mit einer fiberschie13enden Oestrogenbildung und/oder einem Progesteronmangel erklfirt werden. Schliisselwgrter: Aldosteron, Odem, Oestrogene, Progesteron, Renin. Summary. In four women with cyclical oedema related to the menstrual cycle, weight, leg volume, urinary excretion of sodium, aldosterone and oestrogens, plasma concentrations of progesterone, angiotensin II and plasma renin activity were measured at intervals during 4 weeks while they were taking a fixed sodium diet. In another patient, regular biphasic changes in weight and basal body temperature, disappearing after ovariectomy, were demonstrated. Changes in weight (varying between 3,5 and 5.5 kg) with corresponding changes in sodium balance were observed. In three patients, the maximum weight occurred in the second half, and in the other patient in the first half of the menstrual cycle. Plasma renin activity was in the normal range in all patients. It tended * Supported by the Deutsche Forschungsgemeinschaft. ** Presented in part at the 7th Annual Meeting of the European Society for Clinical Investigation, April 2 6 - 2 9 , 1973, Rotterdam.
to rise when weight fell and vice versa. Aldosterone excretion behaved similarly and seems to be related to plasma progesterone in three patients. Orthostatic increase in leg volume did not significantly correlate with change in early morning weight. Thus, renin, aldosterone and orthostatic pooling of plasma fluid did not seem to be of primary importance in the pathogenesis of oedema in these patients. Oestrogen excretion in the luteal phase of the cycle was abnormally low in two patients ; both had premenstrual oedema. In none of the patients could sodium retention be explained by excessive oestrogen and/or diminished progesterone production.
Key words: Aldosterone, oedema, oestrogens, progesterone, renin.
Introduction
A considerable percentage of women with unexplained oedema complain of a particularly marked gain in weight in a certain phase of the menstrual cycle, usually in the last few days before menstruation. Although this syndrome was given a special n a m e cyclical or periodic oedema [34J-regular marked changes in weight in those patients have not always been well documented. Reports on the relationship between changes in weight and the secretory cycle of oestrogens and progesterone are also scanty. It is known, however, that large doses of oestrogens cause salt and water retention [8, 20, 27] while progesterone promotes salt loss by antagonizing the effect of mineralocorticoids on the kidney [22, 23, 32]. Exaggerated orthostatic salt and water retention seems to be an important pathogenetic factor in the development of idiopathic oedema [11, 12, 14, 17, 21, 29, 30, 31]. In some of these patients, secondary aldosteronism was observed [11, 12, 14, 17, 21, 24, 29, 30, 37, 25], but according to a recent report by Streeten el at. [32], only 23% exhibited an exaggerated aldosterone response to posture. In the present article we report on spontaneous changes in weight, leg volume and some endocrine factors in women who had been observed to have markedly pronounced oedema in some phase of the menstrual cycle. Three questions are posed:
W. Oelkers et al. : Weight, Leg Volume and Hormones in Cyclical Oedema
510
1. Is it possible to reproduce regular weight changes on a fixed diet in the ward ? 2. Are changes in weight related to the activity of the renin-aldosterone-system and to orthostatic pooling of fluid in the legs? 3. Are changes in weight related to oestrogen excretion and/or plasma progesterone?
Patients, Experimental Procedure, and Laboratory Methods
BBTCC)
BW (kg)
36, 21'5536~~//' q'~_~Z/~ _
"~'-IApril \MARCH/ ~ , 2£)~y APRt~70VARI LI9 . E. CTOMYI .V . £71
RCH ~ 1972
375 ~//~'"
] 61 62 60
APRIl 1972
37
:'
37.5 ' , ,
f
365!",.,
,/
MAY 1972
,972 /
i
/
~
-
~
o
-62 -61
1. Patients
Our interest in the problem was stimulated by observations in a woman presenting with an regular increase in body weight and body temperature every 2 weeks (Pat. No. 1). The other 4 patients (No. 2 - 5) whose data are included in this study were seen in the endocrinological clinic from 1970 to 1971. They were subsequently admitted to the metabolic ward for special studies. Clinical data of the patients are summarized in Table 1. Recurrent oedema had first been observed 1 - 8 years earlier. In 3 patients, oedema was observed to be most severe in the mid-cycle and/or premenstrual period, while the weight charts in Pat. No. 4 revealed that maximum weight occurred in the first half of 5 of the 6 menstrual cycles recorded, In this patient, an increase in basal body temperature usually occurred about 1 week before the onset of menstruation. She also had a history of a stone in the right kidney (Table 1), but the excretory function of her kidneys (inulin and PAH-clearances) was normal. Psychiatric diagnoses are based on interviews by the consultant psychiatrist of the Klinikum Steglitz. Routine investigations included physical examinations, red and white blood cell counts, ESR, urine analyses and measurements
4 8 12 16 20 24 28 DAYOFMENSTRUALCYCLE
4 8 12 16 20 24 28 3t DATE
Fig. 1. Basal body temperature (BBT, broken lines) before, and body weight (BW, solid lines) before and after ovariectomy in patient No. 1. Shaded zones =menstrual bleeding
of plasma creatinine and electrolytes, plasma protein concentration, electrophoresis, serum transaminases and alkaline phosphatase, PBI, thyroxin concentration, intravenous or oral glucose tolerance test, chest x-ray, and i.v. pyelogram. The results were normal, except transient hypokalemia in patients No. 2 and 4 some weeks before admission. In Pat. No. 1 no special investigations were done. While in the care of our clinic, she recorded her morning weight and basal body temperature from February 1971 to January 1972, and again from March 1972 until the end of May 1972. On 5 March 1972 her remaining left ovary and uterus were removed because of profuse bleeding from a submucous fibromyoma of the uterus. The record (Fig. I) shows that during 3 menstrual cycles a rather uniform paral-
Table 1. Clinical data of patients studied Patient No. age (years)
1 40
2 28
3 34
4 31
5 39
Onset of oedema (age)
32
21
33
26
31
Maximum oedema
Midcycle and premenstr.
premenstr,
premenstr,
postmenstr.
premenstr.
Menstrual cycle
1962 right ovariectomy, regular menstr, till march 1972 (left ovariectomy + hysterectomy)
1964- 1967 second, amenorreoea, later regular, sometimes anovulatory
almost regular
irregular since 1966 late increase of basal body temperature
regular.
Married
4--
-
Parturitions Psychiatric diagnosis
1 "normal"
0 neurosis, depressive, hysteric
Renal disease
no
Blood- )~ lying pressure f standing
160/100 140/90
no
110/70 110/80
-
+
0 neurosis, depressive, schizoid
0 neurosis, depressive, schizoid
no
1968 right pelvic stone removed.
no
120/80 120/80
110/65 100/80
140/90 135/90
0 "normal" but often ill and absenteeism
W. Oelkers et al. : Weight, Leg Volume and Hormones in Cyclical Oedema lel rise in weight and basal body temperature occurred between the 8th and the 10th day of the cycle and a fall to baseline after 5 - 7 days. 3 to 4 days before the onset of menstruation, weight and basal body temperature rose again with a subsequent fall of both with the onset of menstruation. Weight changes ranged between 1.5 and 2.5 kg. After ovariectomy, regular weight changes did not occur, the largest fluctuations in weight then amounting to 1 kg.
511
radioimmunoassay method of Dfisterdieck and McElwee [9]; (normal range-supine: 5 - 35 pg/ml) and the excretion rate of aldosterone-18-gtucuronide by a radioimmunoassay according to Vecsei [36] ; (normal range - ambulatory : 3 - 16 pg/24 h). Plasma progesterone concentration was measured by a protein binding assay after Johansson [18] and total oestrogen excretion by the method of Brown et aL [4]. tn patients No. 2 and 3 fractionation of the three classical oestrogens was performed, in addition, according to Brown's method [2].
2. Exper#nental protocols
Patients No. 2 - 5 were asked not to take diuretics at least 6 days before admission to the wards. Patients No. 2 and No. 4 admitted later that they had nevertheless continued with furosemide in small doses. All patients were given a diet containing 10 - 15 meq of sodium and 6 0 - 8 0 meq of potassium. 128 meq of sodium chloride were given bringing the total sodium intake within the range of 135-143 meq/day. Patients were upright (watking and standing; sitting at meal times only) from 08.00 until at least 17.00 hrs at the earliest. Weight was measured in night clothes in all patients at 08.00 and at 17.00 hrs. after emptying the bladder. Leg volume was measured at the same times in addition in patients No. 2 and 3.24 h urine samples were collected every day and the excretion of sodium, aldosterone-18-glucuronide, and estrogens was measured, partly in pooled urine samples of 2 or 3 days. On several occasions, blood was drawn in the morning in the recumbent position after at least 8 h of bed rest for the determination of the plasma concentrations of potassium, progesterone and renin activity; in 2 patients an additional sample was taken at 17.00 hrs for renin determination. Body temperature was measured every day. In patients No. 2 - 5 , PAH and inulin clearance studies were performed, once in the follicular and once in the luteal phase (Pat. No. 2 - 4 ) of the menstrual cycle. For these studies, patients remained recumbent in the morning. After injecting a priming dose of PAH and inulin, a constant infusion of PAH and inulin in 5% dextrose solution (5 ml/min) was started. 30 min tater, the patients emptied their bladder. Two clearance periods of 120 rain duration followed, the first in the recumbent, the second in the upright position (standing or walking slowly). Indwelling urinary catheters were not used. Urine volumes and sodium and potassium excretion were measured, and at the end of both clearance periods, blood was drawn for the determination of plasma renin activity and of plasma angiotensin II concentration.
3. Methods
Leg volume as measured by placing the leg, up to the lower thigh, into a large lass cylinder with an inner diameter of 25 cm and a water column exactly 34 cm high. The rise of the water column was read from a mm-scale fixed to the outer wall of the glass cylinder and the leg volume was calculated from the increment in height of the water column. Mean volumes of the right and the left leg are reported in Figs. 2 and 3. Sodium and potassium concentrations in plasma and urine were measured by standard flame photometer techniques. Inulin in plasma and urine was determined using the method of Roe et al. [28] and PAH according to Czok et al. [7]. Plasma renin activity was measured by our own modification of the method of Haber et al. [15] using a radioimmunoassay kit of Schwartz and Mann, Orangeburg, N.Y., USA (normal range - supine : 0.5 - 4.5 ng angiotensin I/ml/h). Our modification consisted of a 4 h dialysis before incubation of plasma against a chloride free phosphate buffer pH 6.0 made isotonic to plasma by adding sodium sulphate. Human plasma angiotensinase activity is minimal at this hydrogen ion concentration [33]. Plasma angiotensin II concentration was measured by a
Results
All observations in patients No. 2 - 5, except clearance studies, are summarized in Figs. 2 - 5.
1. Menstrual cycles Patients No. 2 - 5 were admitted on days 16, t, 4, and 4 respectively of their menstrual cycles. As judged by basal body temperature and plasma progesterone levels, normal biphasic cycles were observed in patients No. 2, 3, and 5. In Pat. No. 4, a rise in basal body temperature occurred on the 27th day of the menstrual cycle with a short and low plasma progesterone peak. Menstrual bleeding commenced 5 days later.
2. Changes in weight related to menstrual cycle Different patterns of weight fluctuation were observed in patients No. 2 to 5. Weight gain started at the time of ovulation in patients No. 2 and 3, a few days before menstruation in patients No. 5, and in the early follicular phase in patient No. 4. Maximum changes in weight of 5.5 kg, 3.5 kg, 4.8 kg, and 5.5 kg occurred in patients No. 2 to 5 respectively on the fixed sodium diet. In patients No. 2 and 3, two weight maxima or sharp rises in weight were observed, while in patients No. 4 and 5 the second weight maximum was much smaller than the first one observed. Postdiuretic sodium retention may have contributed to the first weight gain in patients No. 2 and 4, but hypokalemia was not observed on admission.
3. Orthostatic changes in weight and leg volume The orthostatic increase in weight and in leg volume tended to be larger when the early morning measurements were on the increase. On the other hand, when the early morning weights were decreasing, the measurements in the later part of the day after standing were sometimes lower than in the morning of the same
Weight kg
70
Weight kg
69
51
68
t
49
67
48t
66
7"7"-~"--
47-
65 64 Na
Leg Vol. ml Na
3200 V
f
~
~Se,m
...Spin
+
Excretion meq/24 h
,
120 100 -
2 40:
2800 2700
20,
266
+
Excr. meq/ 24 h
I50 130 II0 90 70 50
PRA ng/mt • h
....
Atdosterone Excretion gg/24 h
It;'
............. T,'), , I, ') I ,If : ]l
)!
Aldosterone Excret gg/24 h Progesterone ng/ml Estrog. Excret. gg/24 h Bas. Temp, °C
PRA ng ml h
IT Progesterone ng/ml
rV71-
Estrogen Excretion gg/24 h
6
_1
l
40 30
•
,
,
~
2o
,
t
L
Basal Temp. oC
~)
d ~
40 30 20 10
"
4 50
37,5 i ~ ~
Fig, 4
36,5
7 8 9 101112131415161718192021222324252627282930311
2 3 4 5 6 7 8 910111213
Day of Menstrual Cycle
16171819202t 2223242526 1 2 3 4 5 6 7 8 9 I0 11 I2 I0 14 15 16 17 18 19 20 21 22 23
Fig. 2
Day of Menstrual Cycle
Weight kg ~2i'-" %
Weight kg
,'k
,,"-.
0o!
/
63
Leg Vol. ml
~eom
3103
..stem lNa
2~oo~°°~7oIoO8~ ~ " % / ' ' '
"
" ......... ". . . . . . "" "
Excretion meq/24 h
/" ......
222i Excret, 19o 170 150 meq/ 130 24 h 110
Na
+
PRA ng/ml, h . . . . .
90 70 50~
PRA ng/ml • h
,
,
,,
,,
,:
)
I~
I
,
)i
4 3 2~ 1
5~ 3:
__rS-I
Progesterone - ~ io 8
fILL,_
o
42
l~w~
~g/24 h
2~
Basal Temp.
~7,~ ~3~,8
0C
36
g~, o n e
~
d~o~
ng/ml
[
~
..,l.lI
11 ]
I I
l__) .........
Estrogen Excretion p.g/24 h Basal Temp. °C
36,5 • [..~
36
1213141516171810202]
Day of Menstrual Cycle
222324252627
~ _
4 5 6 7 8 91011121314151617181920212223
] 2 3 4 5
Fig. 5
,.
37,8
~nstruam~ 123456?891011
_., I ....
kl_1
Aldosterone 29 Excretion 13 1l gg/24 h 97
6 5 4
Estrogen 406o Excretion 3o
Fig. 3
160 i4o 120 I00 00
+
Aldosterone Excret gg/24 h Progesterone ng/ml
200 180
Day of Menstrual Cycle
"'*
MenstruaIMflow k~ IIiillll
.
.
. .. .
513
W. Oelkers et at. : Weight, Leg Volume and H o r m o n e s in Cyclical Oedema Table 2. Coefficients of correlation between orthostatic changes in weight and leg volume Subject n No.
2 3 4 5
30 29 13 29
Coefficient of Correlation • weight change 8 a.m ~ 5 p.m versus
• leg voI. change 8 a.m ~ 5 p.m versus • leg voL change 8 a.m -~ 5 p.m versus
• weight change 8 a . m --+ 8a.m next day
• leg vol. change 8a.m -~ 8a.m next day • weight change 8 a.m ~ 8 a.m next day
r
p(2:0
n
r
+0,557 +0,658 +0,784 +0,774
