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Long-term use of an injectable contraceptive: Effect of depot-norethisterone oenanthate on carbohydrate metabolism
CONTRACEPTION
LONG-TERM USE OF AN INJECTABLE CONTRACEPTIVE: EFFECT OF DEPOT-.NORETHISTERONE OENANTHATE OB CARBOHYDRATE METABOLISM M GRIFFIN
D A HEATON*
J A McEWAN
Helen Brook Department of Family Planning and *Department of Medicine and Diabetes King's College Hospital, London SE5 9RS
ABSTRACT In order to determine the metabolic effects of long-term use of the injectable contraceptive norethisterone oenanthate, plasma glucose and serum insulin concentrations were studied in two groups of women who had used the method continuously for at least five years. Group 1 comprised 24 subjects, from whom only fasting blood samples were taken. Despite similar plasma glucose concentrations to those of the controls, the subjects had significantly increased serum insulin concentrations (164.5 (39.9) v 120.3 (34.3) pmol/l, ~(0.01). In addition the insulin:glucose ratios were also significantly increased (34.3 (8.5) Y 24.6 (6.7), p
Submitted for publication September 25, 1987 Accepted for publication January 5, 1988
Reprint requests: Dr J A McEwan, Helen Brook Department of Family Planning, 5th Floor, New Ward Block, King's College Hospital, Denmark Hill, London SE5 gRS
JANUARY
1988 VOL. 37 NO. 1
53
CONTRACEPTION
INTRODUCTION Many studies have been carried out on the effects of oral contraceptives on carbohydrate metabolism. Early studies suggested that the prevalence of abnormal glucose tolerance in oral contraceptive users was increased (l), and that the development of diabetes was more likely in groups of women who displayed glucose intolerance during pregnancy (2, 3). Subsequent studies, however, have produced conflicting results. Possible reasons for these discrepancies include differences in the populations studied, study design and assay methodologies; but perhaps the most critical factor is the oestrogen/ It has been shown that the decrease in progestogen formulation. glucose tolerance is most pronounced when using formulations containing more than 75 micrograms of oestrogen (4). The importance of considering not only the oestrogen dose but also the type and dose of progestogen has recently been emphasised (5), levonorgestrel having been shown to be the most potent progestogen in decreasing glucose tolerance (6). Few reports exist, however, on preparations containing progestogen alone. These are not widely offered as a method of contraception, yet they may have distinct advantages, for example reduced morbidity compared with pills containing oestrogen or with intrauterine devices. Whilst there are difficulties associated with the progestogen-only pill, particularly in relation to compliance and poor cycle control, an alternative methoii of administration involving deep intramusc,rlar Of the two iniection of progestogen may reduce these problems. currently available preparations, medroxyprogesterone acetate (DMPA) has been extensively studied fcr both its short- and long-term effects on glucose tolerance (7, 8, 0). Wowever, no studies have been carried out on the long-term effects of noretnisterone oenanthate (Net-En) on glucose tolerance and insulin secretion. We therefore studied oral giurose tolerance and insulin secretion in a group of women who had used Net-Pn continuously as a method of contraception for at least 5 years.
PATIENTS
AND METHODS
Thirty-one women were identified who had used Net-En (norethisterone Twenty-five oenanthate 200 mg in oil) continuously for at least 5 years. agreed to have blood samples taken, of whom one was a non-insulin-dependent The diabetic prior to taking Net-En and was thus excluded from analysis. mean duration of use of the 24 subjects was 80.3 months (range 63-97 Subjects were compared with a group of 18 controls sought from months). unrelated women currently attending the family planning clinic. and who had not been pregnant or used any hormonal therapy during the previous The proportions with a first degree family history of diabetes 5 years. were the same in the two groups (17%) and the controls were selected to achieve a similar distribution to the subjects for age (subjects mean 35.5 (SD 6.9) v controls 37.6 (5.0) years), and body mass index (mean 25.2 All patients gave informed consent to be (4.5) v 23.7 (3.5) kg/n?). studied and the study was approved by the Camberwell District Ethical Committee.
54
JANUARY
1988 VOL. 37 NO. 1
CONTRACEPTION
Basal Blood Samples A fasting venous blood sample was obtained from the 24 subjects and 18 controls for the analysis of plasma glucose and serum insulin concentrations. For the subjects, the range from the previous injection was 53-63 days, mean 56.6 days, and the sample was taken on the day that a further injection of Net-En was due. Oral Glucose
Tolerance
Tests
Thirteen of the subjects and 10 controls (similarly distributed for age (mean 36.2 (7.5) v 35.6 (6.0) y ears) and body mass index (mean 23.9 (3.9) v 23.9 (4.2) kg/m2) also had an oral glucose tolerance test. Following a fast of at least 12 hours,the subjects were studied in a supine position. A basal blood ssmple was taken at time 0, after which 75 g of glucose dissolved in 0.33 litres of water was consumed over four minutes. Further samples were taken at 30, 60, 90 and 120 minutes after the glucose load, for the measurement of plasma glucose and serum insulin concentrations. Plasma glucose was measured by a glucose Serum insulin was estimated oxidase method (Yellow Springs Analyser). by a modified double antibody radioimmunoassay technique (10): sensitivity (lower limit of detection p = 0.99) for this method being 5 microunits per ml and reproducibility as assessed by inter- and coefficient of intra-assay variation (expressed as a percentage variation over the linear range of the standard curve) were 4.9% and 3.6%,respectively. Insulin responses were calculated as areas under the curve above basal values, using a method of least squares from time 0 to 120 minutes after oral glucose. Statistics Results have been expressed as the mean and standard deviation (SD) of the mean. Changes were compared using both two-tailed Student's T The tests for unpaired observations and 95% confidence intervals. significant variables approximated normal distribution in that 66% of Results were considered the values fell within one SD of their mean. significant at ~(0.05.
RESULTS Fasting
Concentrations
The 24 subjects and 18 controls had similar mean plasma glucose concentrations (4.9 (0.4) v 4.8 (0.6) mmol/l). Mean serum insulin concentrations, however, were significantly increased in the subjects (164.5 (39.9) v 120.3 (34.3) pmol/l, ~(0.01; mean difference 44.2; 95% confidence interval 19.9 to 68.3), as were the mean insulin: glucose ratios (34.3 (8.5) v 24.6 (6.7), p
to Oral Glucose
Basally the 13 subjects and 10 controls had similar mean plasma glucose concentrations (4.8 (0.8) v 4.9 (0.5) mmol/l). Mean serum insulin concentrations, although higher in the subjects, were not significantly
JANUARY 1988 VOL. 37 NO. 1
55
CONTRACEPTION
different from control values (166.2 01.6) v 139.9 (29.9) pmol/l). However, the insulin:glucose ratios were significantly increased mean difference 6.3; 95% confidence (35.0 (7.‘7) v a.7 (5.6), p
Ar. acceptable contraccptivc method :;h~~)u;J carry a low risk of clinically significant metaboiic 'change:;. This study has shown that long-term use of Met-En is not associated with any evidence of oral glucose intolerance, but is associated with relative hyperinsulinaemia, cnnsistent with a decrease in peripheral insulin sensitivity. These findings are in agreement with dither reports on the metabolic effects of Jet-En. Giwa-Osagie and Newton (111 showed that short-term us -5 of Net-En (:‘!I weeks) bar! :10 effort on glucose tolerance; while in a similar study of Thai women, Virutamaser, et al. (12) in spite of 3 rise i:. plasma glucoses ,at 30 minute:; showeti I.oast two ~$2al-:; t.reni,mentthere was ii0 significant change ir. urn1 glucose tolerar,,:c. Fiovuri -L,t ai. (l;-) had formerly st.udied the ei‘frct on an intravenous gl~~cosc tolerance test after a single dose of lict-En and found :10 signi,*icant differences :at two and i2 weeks after the injection from the pre-treatment test. Bamji -et al. (15) examined the effects q!' a monthly injection of Net-En at a tenth of the dosage, 20 mg per month, at s,x and 1:~ months. at six months There j waci a transient deterioration levels by 12 months; which was largely -,or:eitcd almost tL? pre-treatment In none of these 3C it was felt Lhat there wan no sigl,lflcant effect. ::tulics, however, were thi ! ns11lin c~:nccntrntions measured. insulin concentrations following Net-En Orlly two studies have mt-asitr,_xi Lrontment . In India, Dhall -et al. (7 j weri~ unable to detect any significant change in post-prandial inscllin concentrations following a single injection of Net-En. In a more detailed study Amatayajul and Suriyonan (16) reported that after 15 months of Net-En treatment, there vas no significant impairment of intravenous glucose tolerance. However, plasma insulin levels were significantly elevated compared with pretreatment control levels both basally anti throughout the whole go-minute period of observation; results consistent with decreased insulin sensitivity. Our own observations have confirmed and extended the findings of these short-term studies iuring longer term use of this injectable contraceptive.
56
JANUARY
1988 VOL. 37 NO. 1
Y
FIGUBE,
1 and
(-
users
oral
to
120
controls
glucose
90
(mins)
Responses
Time
--- 1.---.-7-r--r--r 0 30 60
(~----.a).
tolerance
0
.
h -
Bars
test
O-
700
310
are
SD.
in Net-En
d
Time
r 60
90 (mins)
---I 120
CONTRACEPTION
Similar decreases in peripheral insulin sensitivity have been reported for medroxyprogesterone acetate (9) and the triphasic, low dose oral contraceptive pill (17). Whether loss of normal insulin sensitivity in target tissues could precipitale the development of impaired glucose tolerance and possibly diabetes, is at present unclear. Some reports have suggested that long-term hyperinsulinaemia may be harmful, while in general non-insulin-dependent diabetics, whether obese or not, are insensitive to insulin (18). However, It remains uncertain whether the decreased insulin sensitivity found in such diabetics precedes the onset of hyperglycaemia or is a result of it. Regarding the use of hormonal contraception, a number of recent stludies have reported that decreased insulin sensitivity was not associated with any evidence of a deterioration in oral glucose tolerance (7, 9, 191, suggesting that decreased insulin sensitivity per se does not precipitate the development of impaired glucose tolerance. In summary, long-term use of norethisterone oenanthate injection as a method of contraception is associated with a decrease in peripheral insulin sensitivity. However, these changes are not associated with any evidence of glucose intolerance. We conclude that glucose tolerance is not adversely affected by long-term use of this progestogen-only contraceptive.
ACKNOWLEDGEMENTS The authors wish to thank Dr David Leslie for his advice and Schering Chemicals for the supply of norethisterone oenanthate over many years.
REFERENCES Spellacy, W.N. contraceptives.
2.
Glucose tolerance in Szabo, A.J., Coles, H.S., Grimaldi, R.D. gestational diabetic women during and after treatment with a combination type oral contraceptive. N.Eng. J. Med. 282:
646-50
58
A review of carbohydrate metabolism and the oral Amer. J. Obstet. Gynecol. 104: 448-60 (1969)
1.
(1970)
3.
Comparison of the mechanisms underlying Beck, P., Wells, S.A. carbohydrate intolerance in subclinical diabetic women during pregnancy and during post-partum oral contraceptive steroid J. Clin. Endocrinol. Metab. 29: 807-13 (1969) treatment.
4.
Wynn, V., Adams, P.W., Godsland, I., Melrose, J., Niththyananthan, Comparison of effects of different R., Oakley, N.W., Seed, M. combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1: 1045-9 (1969)
5.
Perlman, J.A., Russell-Briefel, R., Eggati, R., Lieberknecht, G. Oral glucose tolerance and the potency of contraceptive progestins. J. Chronic. Dis. 10: 857-64 (1985)
JANUARY
1988 VOL. 37 NO. 1
CONTRACEPTION
6.
Effect of low dose oral contraceptive administration Wynn, V. on carbohydrate metabolism. Amer. J. Obstet. Gynecol. 142: 739-46 (1982)
7.
Dhall, K., Kumar, M., Rastogi, G.K., Devi, P.K. Short-term effects of norethisterone oenanthate and medroxyprogesterone acetate on glucose, insulin, growth hormone and lipids. Fertil. Steril. 28: 156-8 (1977)
a.
9.
Amatayajul, K., Swassomboon, B., Singkamani, medroxyprogesterone acetate on serum lipids, tolerance and liver function in Thai women. 283-97 (1980)
R. Effects of protein, glucose Contraception 21:
Fraser, I.S., Weisberg, E. A comprehensive review of injectable contraception with special emphasis on depot-medroxyprogesterone acetate. Med. J. Australia 1: 3-19 (1981)
10.
Yalow, R.S., Berson, S.A. Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 1157-1175 (1960)
11.
Giwa-Osagie, O.F., Newton, J.R. Injectable norethisterone oenanthate contraception: Absence of an effect on oral glucose tolerance. Contraceptive Delivery Systems 3: 61-2 (1982)
12.
Virutsmasen, P., Nitichai, Y., Tangkeow, P., Kankeerati, W., Rienprayura, D., Boonsiri, B. A clinical and metabolic study of norethisterone oenanthate in Thai women. Contraception 22: 397-408 (1980)
13.
Howard, G., Blair, M., Trayner, I., Hamawi, A., Elder, M.G. Some metabolic effects on long-term use of the injectable contraceptive norethisterone oenanthate. Lancet 1: 423-5 (1982)
14.
Howard, G., Myatt, L., Elder, M.G. The effects of intramuscular norethisterone oenanthate used as a contraceptive on intravenous glucose tolerance and on blood coagulation factors VII and X. Brit. J. Obstet. Gynaecol. 84: 618-21 (1977)
15.
Bamji, M.S., Safaya, S., Prema, K. Low dose injectable contraceptive norethisterone enanthate 20 mg monthly - II. Metabolic side effects. Contraception 23: 23-36 (1981)
16.
Amatayajul, injectable
J. Gynae.
JANUARY
The effects of long-acting K., Suriyanan, V. Inter. contraceptives on carbohydrate metabolism. Obstet. 23: 361-8 (1985)
1988 VOL. 37 NO. 1
59
CONTRACEPTION
17.
Skouby, S.O., Anderson, O., Saurbrey, N., Kuhl, C. ception and ins;:lin sensitivity: In viva assessment -women and women with previous gestational diabetes. Endo. Metab. 64: 519-23 (1987)
id.
Leslie, R.D.G. Causes of Non-Insulin Dependent Diabetes. Medicine International 1985, vol. 2, No. 13, 533-4
19.
Skouby, S.O., Kuhl, C., Mblsted-I'edersen, L. Triphasic oral contraception: Metabolic effects in normal women and those with previous gestational diabetes. Amer. J. Obstet. Gynecol. 153: 495-500 (1985)
60
JANUARY
Oral contrain normal J. Clin.
1988 VOL.
37 NO. 1
LONG-TERM USE OF AN INJECTABLE CONTRACEPTIVE: EFFECT OF DEPOT-.NORETHISTERONE OENANTHATE OB CARBOHYDRATE METABOLISM M GRIFFIN
D A HEATON*
J A McEWAN
Helen Brook Department of Family Planning and *Department of Medicine and Diabetes King's College Hospital, London SE5 9RS
ABSTRACT In order to determine the metabolic effects of long-term use of the injectable contraceptive norethisterone oenanthate, plasma glucose and serum insulin concentrations were studied in two groups of women who had used the method continuously for at least five years. Group 1 comprised 24 subjects, from whom only fasting blood samples were taken. Despite similar plasma glucose concentrations to those of the controls, the subjects had significantly increased serum insulin concentrations (164.5 (39.9) v 120.3 (34.3) pmol/l, ~(0.01). In addition the insulin:glucose ratios were also significantly increased (34.3 (8.5) Y 24.6 (6.7), p
Submitted for publication September 25, 1987 Accepted for publication January 5, 1988
Reprint requests: Dr J A McEwan, Helen Brook Department of Family Planning, 5th Floor, New Ward Block, King's College Hospital, Denmark Hill, London SE5 gRS
JANUARY
1988 VOL. 37 NO. 1
53
CONTRACEPTION
INTRODUCTION Many studies have been carried out on the effects of oral contraceptives on carbohydrate metabolism. Early studies suggested that the prevalence of abnormal glucose tolerance in oral contraceptive users was increased (l), and that the development of diabetes was more likely in groups of women who displayed glucose intolerance during pregnancy (2, 3). Subsequent studies, however, have produced conflicting results. Possible reasons for these discrepancies include differences in the populations studied, study design and assay methodologies; but perhaps the most critical factor is the oestrogen/ It has been shown that the decrease in progestogen formulation. glucose tolerance is most pronounced when using formulations containing more than 75 micrograms of oestrogen (4). The importance of considering not only the oestrogen dose but also the type and dose of progestogen has recently been emphasised (5), levonorgestrel having been shown to be the most potent progestogen in decreasing glucose tolerance (6). Few reports exist, however, on preparations containing progestogen alone. These are not widely offered as a method of contraception, yet they may have distinct advantages, for example reduced morbidity compared with pills containing oestrogen or with intrauterine devices. Whilst there are difficulties associated with the progestogen-only pill, particularly in relation to compliance and poor cycle control, an alternative methoii of administration involving deep intramusc,rlar Of the two iniection of progestogen may reduce these problems. currently available preparations, medroxyprogesterone acetate (DMPA) has been extensively studied fcr both its short- and long-term effects on glucose tolerance (7, 8, 0). Wowever, no studies have been carried out on the long-term effects of noretnisterone oenanthate (Net-En) on glucose tolerance and insulin secretion. We therefore studied oral giurose tolerance and insulin secretion in a group of women who had used Net-Pn continuously as a method of contraception for at least 5 years.
PATIENTS
AND METHODS
Thirty-one women were identified who had used Net-En (norethisterone Twenty-five oenanthate 200 mg in oil) continuously for at least 5 years. agreed to have blood samples taken, of whom one was a non-insulin-dependent The diabetic prior to taking Net-En and was thus excluded from analysis. mean duration of use of the 24 subjects was 80.3 months (range 63-97 Subjects were compared with a group of 18 controls sought from months). unrelated women currently attending the family planning clinic. and who had not been pregnant or used any hormonal therapy during the previous The proportions with a first degree family history of diabetes 5 years. were the same in the two groups (17%) and the controls were selected to achieve a similar distribution to the subjects for age (subjects mean 35.5 (SD 6.9) v controls 37.6 (5.0) years), and body mass index (mean 25.2 All patients gave informed consent to be (4.5) v 23.7 (3.5) kg/n?). studied and the study was approved by the Camberwell District Ethical Committee.
54
JANUARY
1988 VOL. 37 NO. 1
CONTRACEPTION
Basal Blood Samples A fasting venous blood sample was obtained from the 24 subjects and 18 controls for the analysis of plasma glucose and serum insulin concentrations. For the subjects, the range from the previous injection was 53-63 days, mean 56.6 days, and the sample was taken on the day that a further injection of Net-En was due. Oral Glucose
Tolerance
Tests
Thirteen of the subjects and 10 controls (similarly distributed for age (mean 36.2 (7.5) v 35.6 (6.0) y ears) and body mass index (mean 23.9 (3.9) v 23.9 (4.2) kg/m2) also had an oral glucose tolerance test. Following a fast of at least 12 hours,the subjects were studied in a supine position. A basal blood ssmple was taken at time 0, after which 75 g of glucose dissolved in 0.33 litres of water was consumed over four minutes. Further samples were taken at 30, 60, 90 and 120 minutes after the glucose load, for the measurement of plasma glucose and serum insulin concentrations. Plasma glucose was measured by a glucose Serum insulin was estimated oxidase method (Yellow Springs Analyser). by a modified double antibody radioimmunoassay technique (10): sensitivity (lower limit of detection p = 0.99) for this method being 5 microunits per ml and reproducibility as assessed by inter- and coefficient of intra-assay variation (expressed as a percentage variation over the linear range of the standard curve) were 4.9% and 3.6%,respectively. Insulin responses were calculated as areas under the curve above basal values, using a method of least squares from time 0 to 120 minutes after oral glucose. Statistics Results have been expressed as the mean and standard deviation (SD) of the mean. Changes were compared using both two-tailed Student's T The tests for unpaired observations and 95% confidence intervals. significant variables approximated normal distribution in that 66% of Results were considered the values fell within one SD of their mean. significant at ~(0.05.
RESULTS Fasting
Concentrations
The 24 subjects and 18 controls had similar mean plasma glucose concentrations (4.9 (0.4) v 4.8 (0.6) mmol/l). Mean serum insulin concentrations, however, were significantly increased in the subjects (164.5 (39.9) v 120.3 (34.3) pmol/l, ~(0.01; mean difference 44.2; 95% confidence interval 19.9 to 68.3), as were the mean insulin: glucose ratios (34.3 (8.5) v 24.6 (6.7), p
to Oral Glucose
Basally the 13 subjects and 10 controls had similar mean plasma glucose concentrations (4.8 (0.8) v 4.9 (0.5) mmol/l). Mean serum insulin concentrations, although higher in the subjects, were not significantly
JANUARY 1988 VOL. 37 NO. 1
55
CONTRACEPTION
different from control values (166.2 01.6) v 139.9 (29.9) pmol/l). However, the insulin:glucose ratios were significantly increased mean difference 6.3; 95% confidence (35.0 (7.‘7) v a.7 (5.6), p
Ar. acceptable contraccptivc method :;h~~)u;J carry a low risk of clinically significant metaboiic 'change:;. This study has shown that long-term use of Met-En is not associated with any evidence of oral glucose intolerance, but is associated with relative hyperinsulinaemia, cnnsistent with a decrease in peripheral insulin sensitivity. These findings are in agreement with dither reports on the metabolic effects of Jet-En. Giwa-Osagie and Newton (111 showed that short-term us -5 of Net-En (:‘!I weeks) bar! :10 effort on glucose tolerance; while in a similar study of Thai women, Virutamaser, et al. (12) in spite of 3 rise i:. plasma glucoses ,at 30 minute:; showeti I.o
56
JANUARY
1988 VOL. 37 NO. 1
Y
FIGUBE,
1 and
(-
users
oral
to
120
controls
glucose
90
(mins)
Responses
Time
--- 1.---.-7-r--r--r 0 30 60
(~----.a).
tolerance
0
.
h -
Bars
test
O-
700
310
are
SD.
in Net-En
d
Time
r 60
90 (mins)
---I 120
CONTRACEPTION
Similar decreases in peripheral insulin sensitivity have been reported for medroxyprogesterone acetate (9) and the triphasic, low dose oral contraceptive pill (17). Whether loss of normal insulin sensitivity in target tissues could precipitale the development of impaired glucose tolerance and possibly diabetes, is at present unclear. Some reports have suggested that long-term hyperinsulinaemia may be harmful, while in general non-insulin-dependent diabetics, whether obese or not, are insensitive to insulin (18). However, It remains uncertain whether the decreased insulin sensitivity found in such diabetics precedes the onset of hyperglycaemia or is a result of it. Regarding the use of hormonal contraception, a number of recent stludies have reported that decreased insulin sensitivity was not associated with any evidence of a deterioration in oral glucose tolerance (7, 9, 191, suggesting that decreased insulin sensitivity per se does not precipitate the development of impaired glucose tolerance. In summary, long-term use of norethisterone oenanthate injection as a method of contraception is associated with a decrease in peripheral insulin sensitivity. However, these changes are not associated with any evidence of glucose intolerance. We conclude that glucose tolerance is not adversely affected by long-term use of this progestogen-only contraceptive.
ACKNOWLEDGEMENTS The authors wish to thank Dr David Leslie for his advice and Schering Chemicals for the supply of norethisterone oenanthate over many years.
REFERENCES Spellacy, W.N. contraceptives.
2.
Glucose tolerance in Szabo, A.J., Coles, H.S., Grimaldi, R.D. gestational diabetic women during and after treatment with a combination type oral contraceptive. N.Eng. J. Med. 282:
646-50
58
A review of carbohydrate metabolism and the oral Amer. J. Obstet. Gynecol. 104: 448-60 (1969)
1.
(1970)
3.
Comparison of the mechanisms underlying Beck, P., Wells, S.A. carbohydrate intolerance in subclinical diabetic women during pregnancy and during post-partum oral contraceptive steroid J. Clin. Endocrinol. Metab. 29: 807-13 (1969) treatment.
4.
Wynn, V., Adams, P.W., Godsland, I., Melrose, J., Niththyananthan, Comparison of effects of different R., Oakley, N.W., Seed, M. combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1: 1045-9 (1969)
5.
Perlman, J.A., Russell-Briefel, R., Eggati, R., Lieberknecht, G. Oral glucose tolerance and the potency of contraceptive progestins. J. Chronic. Dis. 10: 857-64 (1985)
JANUARY
1988 VOL. 37 NO. 1
CONTRACEPTION
6.
Effect of low dose oral contraceptive administration Wynn, V. on carbohydrate metabolism. Amer. J. Obstet. Gynecol. 142: 739-46 (1982)
7.
Dhall, K., Kumar, M., Rastogi, G.K., Devi, P.K. Short-term effects of norethisterone oenanthate and medroxyprogesterone acetate on glucose, insulin, growth hormone and lipids. Fertil. Steril. 28: 156-8 (1977)
a.
9.
Amatayajul, K., Swassomboon, B., Singkamani, medroxyprogesterone acetate on serum lipids, tolerance and liver function in Thai women. 283-97 (1980)
R. Effects of protein, glucose Contraception 21:
Fraser, I.S., Weisberg, E. A comprehensive review of injectable contraception with special emphasis on depot-medroxyprogesterone acetate. Med. J. Australia 1: 3-19 (1981)
10.
Yalow, R.S., Berson, S.A. Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 1157-1175 (1960)
11.
Giwa-Osagie, O.F., Newton, J.R. Injectable norethisterone oenanthate contraception: Absence of an effect on oral glucose tolerance. Contraceptive Delivery Systems 3: 61-2 (1982)
12.
Virutsmasen, P., Nitichai, Y., Tangkeow, P., Kankeerati, W., Rienprayura, D., Boonsiri, B. A clinical and metabolic study of norethisterone oenanthate in Thai women. Contraception 22: 397-408 (1980)
13.
Howard, G., Blair, M., Trayner, I., Hamawi, A., Elder, M.G. Some metabolic effects on long-term use of the injectable contraceptive norethisterone oenanthate. Lancet 1: 423-5 (1982)
14.
Howard, G., Myatt, L., Elder, M.G. The effects of intramuscular norethisterone oenanthate used as a contraceptive on intravenous glucose tolerance and on blood coagulation factors VII and X. Brit. J. Obstet. Gynaecol. 84: 618-21 (1977)
15.
Bamji, M.S., Safaya, S., Prema, K. Low dose injectable contraceptive norethisterone enanthate 20 mg monthly - II. Metabolic side effects. Contraception 23: 23-36 (1981)
16.
Amatayajul, injectable
J. Gynae.
JANUARY
The effects of long-acting K., Suriyanan, V. Inter. contraceptives on carbohydrate metabolism. Obstet. 23: 361-8 (1985)
1988 VOL. 37 NO. 1
59
CONTRACEPTION
17.
Skouby, S.O., Anderson, O., Saurbrey, N., Kuhl, C. ception and ins;:lin sensitivity: In viva assessment -women and women with previous gestational diabetes. Endo. Metab. 64: 519-23 (1987)
id.
Leslie, R.D.G. Causes of Non-Insulin Dependent Diabetes. Medicine International 1985, vol. 2, No. 13, 533-4
19.
Skouby, S.O., Kuhl, C., Mblsted-I'edersen, L. Triphasic oral contraception: Metabolic effects in normal women and those with previous gestational diabetes. Amer. J. Obstet. Gynecol. 153: 495-500 (1985)
60
JANUARY
Oral contrain normal J. Clin.
1988 VOL.
37 NO. 1