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Glucose intolerance during ethynodiol diacetate—Mestranol therapy
Glucose Intolerance During Ethynodiol Mestranol -Therapy
Diacetate-
B:/ GEORGEK. HALLING, EDWARD L. MICHALS AND C. ALVIK PAULSEN Administration of a “19-nor” progestinestrogen combination, ethynodiol diacetate and mestranol, produced reversible carbohydrate intolerance in 40 per cent of 15 women tested. No correlation was noted between those subjects with a ge-
S
long-term
INCE poses
change
has
Some have
studies
the
onset
of norethynodrel
treatment
acceptance, Recently,
evaluation.
glucose
control of
for contraceptive
any
reports
during
tolerance
do not specifically
as pretreatment
noted
course
widespread
careful
decreased
of these
alteration
oral progestin-estrogen
attained
warrants
document
netic predisposition to diabetes mellitus by history and the impaired tolerance. The over-all significance of these findings remains to be determined. (Metabolism 16: No. 5, May, 465-468, 1967)
associated have
appeared
progestin-estrogen
relate
treatment
data were 1acking.l.”
impaired
carbohydrate
and mestranol
therapy
tolerance in certain
which therapy.
to this
However,
pur-
metabolic
metabolic
other workers after
patients
a 30-day who were
normal prior to treatment.4,j The patient therapy
demonstration
of a frankly
with monilial prompted
were receiving
vaginitis
us to study
diabetic
while
oral glucose
on cyclic
carbohydrate
tolerance
ethynodiol tolerance
curve
in a
diacetate-mestranol
in those
patients
who
this preparation. METHODS
Fifteen patients on progestin-estrogen therapy were selected from our Endocrine Clinic for stndy. Thirteen women were taking ethynodiol diacetate-mestranol combination’ in cvclic fashion, i.e., one tablet each day from the 5th to the 25th day of the menstrrlal cycle. The indications for treatment were the presence of menstrual irregularities and/or the desire for ovulation inhibition. Two patients were on continuous daily treatment for From the Department of Medicine, Uniuersity of Washington Division of Endocrinology, USPHS Hospital, Se&e, Washington.
School of Medicine
and
Supported in part by NIH grants ROl AM05436 and Tl AM05161 and a grant-in-uid from G. D. Searle and Co. Receiued for pablication December 1.5, 1966. CEOHCE R. HALLING, M.D.: Post-doctoral trainee in endocrinology, currently with the Sunta Barbara Medical Clinic, Santa Barbara, Calif. EDWARD L. MICHALS, M.D.: Senior Surgeon, Assistunt Chief of Medicine, USPHS Hospital, Seattle, Washington. C. ALVIN PAULSEN, M.D.: Associate Professor of Medicine, Dept. of Medicine, Uniuersity of Washington School of Medicine, Seattle. These .stndies confirm and extend obseruations of others which suggest that certain of the newer agettts designed fo regulate oordation commonly cause mild impairment of oral glcrcose tolerance. As the authors point orrt, data are not yet adequate to determine precisely the frequency
of these aberrations. their cause, or their significance.-K.
M. W.
DhletrulenB was supplied by G. D. Searle and Co. Each tah!et contains 2 mg. ethynodiol tliacetate and 0.1 mg. mestranol. 46.5
466
HA.LLING,
MICHALS
AND
PAULSEN
Table l.-Two-Hour Cyclic
Serum Glucose Levels in Patients Receiving Ethynodiol Diacetate-Mestranol Therapy Serum
Patient
Duration of Therapy (No. of Cycles)
Age
J. C.’ P. K.
44
;:: M. M.
50 32 49
G. A. K. A. H.
G.= E. P. C. D.
37 34 41 37 22
B. N. D. M.’
34 24
F. McC. V. B.*
52 30
M. K.
27
17 19
42
Table 2.-Oral
123 -
163 145 168
105 -
-66 107
158 100 120 108 108
-
-
92 104
-
-
12 27
134 113
-
-
3
80
-
-
43 Continuous 48 months
or history of having
Time After 100 Gm. Oral Glucose (min.)
Patient
P. K. (42 yrs.)
NO Medication
Mestranol
a large baby
82
( >9#).
Cyclic
Glucose Tolerance Levels in Patients Receiving Ethynodiol Diucetate-Mestranol Therapy
J. C. (44 yrs.)
%)
108 89
Serum
#See footnote
(mg.
210 165
25 10 Continuous 40 months 29 20 10 29 3
*Subjects with a diabetic relative See footnote on page 465.
Glucose
Ethyncdiol Diacetate + Mestranolt
Glucose
(mg.
Ethynodiol Diaeetate + YeBtranol’
%)
No Medication
0
106
100
30 60 90 120 180
172 234 252 210 156
155 175 147 123 120
0 60
68 160
-
120
165
89
on page 465.
estrogen replacement. Duration of therapy is listed in Table 1 for each patient. Glucose tolerance was tested at varying days of the treatment cycle, but always between the 17th and 25th day. After a three-day 300-Gm. carbohydrate diet preparation, serum was obtained two hours following the ingestion of 100 Gm. of glucose, and the true serum glucose was estimated by the autoanalyzer technique. Fasting levels were determined in two
soon after progestin administration
the carbohydrate
abnormality
developed.
patients. The ethynodiol diacetate-mestranol combination was discontinued in those patients who demonstrated a two-hour serum glucose value above 140-mg. per cent. Such patients were then restudied in a similar manner 17 to 25 days later while on either no medication or mestranol alone (0.1 mg. daily).
MESTRANOL
467
THERAPY RESULTS
Six of the fifteen patients (40 per cent) showed an abnormal two-hour glucose level while receiving progestin therapy (Table 1). Two of these patients (J.C., P. K.) had modified glucose tolerance tests which revealed normal fasting levels (Table 2). All of the six patients, when retested, demonstrated normal two hour serum glucose levels (Table 1). The group of patients with impaired glucose tolerance had received hormonal therapy for an average of 23 cycles (range 1040) while the group with normal glucose tolerance had been on therapy for an average of 16 cycles (range 343). Four patients had either a positive family history for diabetes mellitus or gave a history of having large babies, i.e., greater than nine pounds. Two of these patients demonstrated abnormal carbohydrate tolerance, and in the group without such a history, four out of eleven patients demonstrated imparied carbohydrate tolerance while on progestin therapy. DISCXJSSION
A significant number of our patients on long-term ethynodiol diacetatemestranol therapy demonstrated impaired carbohydrate tolerance which reverted to normal when treatment was discontinued. Fasting glucose levels during treatment were unaffected in the two patients so tested; and with the exception of two patients (J. C., G. G.) who had monilial vaginitis, no signs or symptoms consistent with diabetes mellitus were noted. Since our patients were not examined longitudinally during therapy, we are unable to state how soon after progestin administration the carbohydrate abnormality developed. However, when comparing the duration of treatment in those patients with abnormal glucose levels with those whose levels remained normal, there appears to be no significant difference in time. Furthermore, the published data which demonstrated the occurrence of elevated glucose levels during the first cycle of progestin therapy indicate that these changes may occur promptly.4-“i Our patient sample size is too small to tell whether or not individuals with a diabetic family history are more prone to develop carbohydrate intolerance following progestin treatment. Previous studies also fail to clarify this point.” Three patients who demonstrated abnormal serum sugar levels while on the progestin-estrogen combination had normal glucose levels when placed on mestranol alone. This observation indicates that the progestin in some manner was responsible for the abnormality in carbohydrate metabolism. Progesterone administration apparently lacks this ability.7 Since diethylstilbestrol treatment in daily doses of 5 mg. has been shown to cause similar alterations in carbohydrate tolerance,” it may be that estrogenic compounds have this property at certain dose levels. Synthetic progestins of the “19-nor” category are inherently estrogenic .8 Therefore, the addition of progestins of this type to a potent estrogen such as mestranol may merely increase endogenous estrogen levels to that point where carbohydrate intolerance develops. The mechanism by which the progestin-estrogen combinations and estrogens alone elevate blood sugar levels is not clear. Buchler and Warren6 found no change
468
HALLING,
MICHALS
AND
PAULSEN
in the K value after intravenous glucose tolerance testing before and after norethynodrel-mestranol therapy, in spite of the presence of carbohydrate intolerance. On the other hand, Posner et al.’ demonstrated a significant drop in the K value after only one treatment cycle with the same preparation. Moreover, Spellacy and Carlson” demonstrated an increase in radioimmunoassayable insulin in patients receiving norethynodrel-mestranol combination therapy. These data indicate that these compounds do indeed exert a postprandial hyperglycemic effect which may be related to an interference with insulin ac’tivity. Since the consequence of chronically elevated postprandial blood sugar levels are not known, the significance of these findings remains to be determined. In the meantime any patient on long-term estrogen-progestin therapy should be periodically tested for glucose intolerance. REFERENCES 1. Besch, P. K., Vorys, N., Stevens, V., and Barry,
Ullery, J. C., R. D.: Some
systemic effects of a progestational agent. Metabolism 14:387-396, 1965. 2. Gershberg, H., Javier, Z., and Hulse, M.: Glucose tolerance in women on ovulatory suppressants. Diabetes 13:378382, 1964. 3. Peterson, W. F., Steel, M. W., and Coyne, R. V.: Analysis of the effects of ovulatory suppressants on glucose tolerance. Amer. J. Obstet. 488, 1966.
& Gynecol.
95:484-
4. Posner, N. A., Silverstone, F. A., Pomerante, W., and Baumgold, D.: Oral contraceptives and intravenous glucose tolerance. I. Data noted in early treatment. Obstet. & Gynecol. 29:79, 1967. 5. Spellacy, W. N., and Carbon, K. L.:
Plasma insulin and blood glucose levels in patients taking oral contraceptives. Am. J. Obstet. 1966.
& Gynecol.
95:474478,
6. Buchler, D., and Warren, J. C.: Effects of estrogen on glucose tolerance. Am. J. Obstet. and Gynecol. 95:479-483, 1966. 7. Lloyd, C. W.: The Ovaries. In Textbook of Endocrinology, R. H. Williams, Ed. Philadelphia, Pa., W. B. Saunders Co., 1963, p. 452. 8. Paulsen, C. A., Leach, R. B., Lanman, J., Goldston, N., Maddock, W. O., and Heller, C. G.: Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone. J. Clin. Endocrinol. 22:1033-1039, 1962.
Diacetate-
B:/ GEORGEK. HALLING, EDWARD L. MICHALS AND C. ALVIK PAULSEN Administration of a “19-nor” progestinestrogen combination, ethynodiol diacetate and mestranol, produced reversible carbohydrate intolerance in 40 per cent of 15 women tested. No correlation was noted between those subjects with a ge-
S
long-term
INCE poses
change
has
Some have
studies
the
onset
of norethynodrel
treatment
acceptance, Recently,
evaluation.
glucose
control of
for contraceptive
any
reports
during
tolerance
do not specifically
as pretreatment
noted
course
widespread
careful
decreased
of these
alteration
oral progestin-estrogen
attained
warrants
document
netic predisposition to diabetes mellitus by history and the impaired tolerance. The over-all significance of these findings remains to be determined. (Metabolism 16: No. 5, May, 465-468, 1967)
associated have
appeared
progestin-estrogen
relate
treatment
data were 1acking.l.”
impaired
carbohydrate
and mestranol
therapy
tolerance in certain
which therapy.
to this
However,
pur-
metabolic
metabolic
other workers after
patients
a 30-day who were
normal prior to treatment.4,j The patient therapy
demonstration
of a frankly
with monilial prompted
were receiving
vaginitis
us to study
diabetic
while
oral glucose
on cyclic
carbohydrate
tolerance
ethynodiol tolerance
curve
in a
diacetate-mestranol
in those
patients
who
this preparation. METHODS
Fifteen patients on progestin-estrogen therapy were selected from our Endocrine Clinic for stndy. Thirteen women were taking ethynodiol diacetate-mestranol combination’ in cvclic fashion, i.e., one tablet each day from the 5th to the 25th day of the menstrrlal cycle. The indications for treatment were the presence of menstrual irregularities and/or the desire for ovulation inhibition. Two patients were on continuous daily treatment for From the Department of Medicine, Uniuersity of Washington Division of Endocrinology, USPHS Hospital, Se&e, Washington.
School of Medicine
and
Supported in part by NIH grants ROl AM05436 and Tl AM05161 and a grant-in-uid from G. D. Searle and Co. Receiued for pablication December 1.5, 1966. CEOHCE R. HALLING, M.D.: Post-doctoral trainee in endocrinology, currently with the Sunta Barbara Medical Clinic, Santa Barbara, Calif. EDWARD L. MICHALS, M.D.: Senior Surgeon, Assistunt Chief of Medicine, USPHS Hospital, Seattle, Washington. C. ALVIN PAULSEN, M.D.: Associate Professor of Medicine, Dept. of Medicine, Uniuersity of Washington School of Medicine, Seattle. These .stndies confirm and extend obseruations of others which suggest that certain of the newer agettts designed fo regulate oordation commonly cause mild impairment of oral glcrcose tolerance. As the authors point orrt, data are not yet adequate to determine precisely the frequency
of these aberrations. their cause, or their significance.-K.
M. W.
DhletrulenB was supplied by G. D. Searle and Co. Each tah!et contains 2 mg. ethynodiol tliacetate and 0.1 mg. mestranol. 46.5
466
HA.LLING,
MICHALS
AND
PAULSEN
Table l.-Two-Hour Cyclic
Serum Glucose Levels in Patients Receiving Ethynodiol Diacetate-Mestranol Therapy Serum
Patient
Duration of Therapy (No. of Cycles)
Age
J. C.’ P. K.
44
;:: M. M.
50 32 49
G. A. K. A. H.
G.= E. P. C. D.
37 34 41 37 22
B. N. D. M.’
34 24
F. McC. V. B.*
52 30
M. K.
27
17 19
42
Table 2.-Oral
123 -
163 145 168
105 -
-66 107
158 100 120 108 108
-
-
92 104
-
-
12 27
134 113
-
-
3
80
-
-
43 Continuous 48 months
or history of having
Time After 100 Gm. Oral Glucose (min.)
Patient
P. K. (42 yrs.)
NO Medication
Mestranol
a large baby
82
( >9#).
Cyclic
Glucose Tolerance Levels in Patients Receiving Ethynodiol Diucetate-Mestranol Therapy
J. C. (44 yrs.)
%)
108 89
Serum
#See footnote
(mg.
210 165
25 10 Continuous 40 months 29 20 10 29 3
*Subjects with a diabetic relative See footnote on page 465.
Glucose
Ethyncdiol Diacetate + Mestranolt
Glucose
(mg.
Ethynodiol Diaeetate + YeBtranol’
%)
No Medication
0
106
100
30 60 90 120 180
172 234 252 210 156
155 175 147 123 120
0 60
68 160
-
120
165
89
on page 465.
estrogen replacement. Duration of therapy is listed in Table 1 for each patient. Glucose tolerance was tested at varying days of the treatment cycle, but always between the 17th and 25th day. After a three-day 300-Gm. carbohydrate diet preparation, serum was obtained two hours following the ingestion of 100 Gm. of glucose, and the true serum glucose was estimated by the autoanalyzer technique. Fasting levels were determined in two
soon after progestin administration
the carbohydrate
abnormality
developed.
patients. The ethynodiol diacetate-mestranol combination was discontinued in those patients who demonstrated a two-hour serum glucose value above 140-mg. per cent. Such patients were then restudied in a similar manner 17 to 25 days later while on either no medication or mestranol alone (0.1 mg. daily).
MESTRANOL
467
THERAPY RESULTS
Six of the fifteen patients (40 per cent) showed an abnormal two-hour glucose level while receiving progestin therapy (Table 1). Two of these patients (J.C., P. K.) had modified glucose tolerance tests which revealed normal fasting levels (Table 2). All of the six patients, when retested, demonstrated normal two hour serum glucose levels (Table 1). The group of patients with impaired glucose tolerance had received hormonal therapy for an average of 23 cycles (range 1040) while the group with normal glucose tolerance had been on therapy for an average of 16 cycles (range 343). Four patients had either a positive family history for diabetes mellitus or gave a history of having large babies, i.e., greater than nine pounds. Two of these patients demonstrated abnormal carbohydrate tolerance, and in the group without such a history, four out of eleven patients demonstrated imparied carbohydrate tolerance while on progestin therapy. DISCXJSSION
A significant number of our patients on long-term ethynodiol diacetatemestranol therapy demonstrated impaired carbohydrate tolerance which reverted to normal when treatment was discontinued. Fasting glucose levels during treatment were unaffected in the two patients so tested; and with the exception of two patients (J. C., G. G.) who had monilial vaginitis, no signs or symptoms consistent with diabetes mellitus were noted. Since our patients were not examined longitudinally during therapy, we are unable to state how soon after progestin administration the carbohydrate abnormality developed. However, when comparing the duration of treatment in those patients with abnormal glucose levels with those whose levels remained normal, there appears to be no significant difference in time. Furthermore, the published data which demonstrated the occurrence of elevated glucose levels during the first cycle of progestin therapy indicate that these changes may occur promptly.4-“i Our patient sample size is too small to tell whether or not individuals with a diabetic family history are more prone to develop carbohydrate intolerance following progestin treatment. Previous studies also fail to clarify this point.” Three patients who demonstrated abnormal serum sugar levels while on the progestin-estrogen combination had normal glucose levels when placed on mestranol alone. This observation indicates that the progestin in some manner was responsible for the abnormality in carbohydrate metabolism. Progesterone administration apparently lacks this ability.7 Since diethylstilbestrol treatment in daily doses of 5 mg. has been shown to cause similar alterations in carbohydrate tolerance,” it may be that estrogenic compounds have this property at certain dose levels. Synthetic progestins of the “19-nor” category are inherently estrogenic .8 Therefore, the addition of progestins of this type to a potent estrogen such as mestranol may merely increase endogenous estrogen levels to that point where carbohydrate intolerance develops. The mechanism by which the progestin-estrogen combinations and estrogens alone elevate blood sugar levels is not clear. Buchler and Warren6 found no change
468
HALLING,
MICHALS
AND
PAULSEN
in the K value after intravenous glucose tolerance testing before and after norethynodrel-mestranol therapy, in spite of the presence of carbohydrate intolerance. On the other hand, Posner et al.’ demonstrated a significant drop in the K value after only one treatment cycle with the same preparation. Moreover, Spellacy and Carlson” demonstrated an increase in radioimmunoassayable insulin in patients receiving norethynodrel-mestranol combination therapy. These data indicate that these compounds do indeed exert a postprandial hyperglycemic effect which may be related to an interference with insulin ac’tivity. Since the consequence of chronically elevated postprandial blood sugar levels are not known, the significance of these findings remains to be determined. In the meantime any patient on long-term estrogen-progestin therapy should be periodically tested for glucose intolerance. REFERENCES 1. Besch, P. K., Vorys, N., Stevens, V., and Barry,
Ullery, J. C., R. D.: Some
systemic effects of a progestational agent. Metabolism 14:387-396, 1965. 2. Gershberg, H., Javier, Z., and Hulse, M.: Glucose tolerance in women on ovulatory suppressants. Diabetes 13:378382, 1964. 3. Peterson, W. F., Steel, M. W., and Coyne, R. V.: Analysis of the effects of ovulatory suppressants on glucose tolerance. Amer. J. Obstet. 488, 1966.
& Gynecol.
95:484-
4. Posner, N. A., Silverstone, F. A., Pomerante, W., and Baumgold, D.: Oral contraceptives and intravenous glucose tolerance. I. Data noted in early treatment. Obstet. & Gynecol. 29:79, 1967. 5. Spellacy, W. N., and Carbon, K. L.:
Plasma insulin and blood glucose levels in patients taking oral contraceptives. Am. J. Obstet. 1966.
& Gynecol.
95:474478,
6. Buchler, D., and Warren, J. C.: Effects of estrogen on glucose tolerance. Am. J. Obstet. and Gynecol. 95:479-483, 1966. 7. Lloyd, C. W.: The Ovaries. In Textbook of Endocrinology, R. H. Williams, Ed. Philadelphia, Pa., W. B. Saunders Co., 1963, p. 452. 8. Paulsen, C. A., Leach, R. B., Lanman, J., Goldston, N., Maddock, W. O., and Heller, C. G.: Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone. J. Clin. Endocrinol. 22:1033-1039, 1962.