CONTRACEPTION
HIRSUTISM: METABOLIC EFFECTS OF TWO COMMONL USED ORAL CONTRACEPIIVES AND SPIRONOIACTONE ‘k Robert A Wild M D *#+ Lawrence M. Dkmkrs; Ph.D.#k Deborah Applebaum-Bowden, Ph.D.T Rosanna Lenker, CNMW+ #Supported in whole or in part by rants from Meade-Johnson and Parke-Davis Pharmaceuticals as well as Penney ‘ivania American Heart Association and BRSG grant S07-RR 05680-19 awarded by the Biomedical Research Su port grant program, Division of Research Resources, National Institutes of Health, and r:resbyterian Health Foundation, Oklahoma City, OK *Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK #Address correspondence and reprint requests: Robert A. Wild, M.D., OUHSC, Dept. of OB/GYN, P.O. Box 26901 4SP717, Oklahoma City, OK 73190; Phone: (405) 271-8700 +Department of Pathology, Hershey Medical Center, Hershey, PA j:Department
of Medicine, Hershey Medical Center, Hershey, PA
+Department of Obstetrics and Gynecology, Hershey Medical Center, Hershey, PA T;partment
of Internal Medicine, Bowman Gray School of Medicine, Winston-Salem,
ABSTRACT
Fifty-one hirsute women were randomly treated for nine months with ethinyl estradio135 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with s ironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin 1p evels were higher as opposed to either lowdose oral contraceptive preparation. Ethinyl estradiol30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradio135 ug plus norethindrone 0.4 mg and sptronolactone were more effective in lowering Ferriman Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy. Submitted Accepted
for publication for publication
January 25, 1991 June 3, 1991
AUGUST 1991 VOL. 44 NO. 2
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CONTRACEPTION
INTRODUCTION The clinical management of hirsutism continues to pose a significant challenge to clinicians in terms of diagnosis and treatment. As currently viewed in the United States, the choice of therapy is somewhat restrictive and has been limited to either combination oral contraceptive therapy or the use of anti-androgens such as spironolactone. Oral contraceptive therapy was initially developed for antif t’ ‘ty purposes, although its use is now widespread for managing hyperandrogenic states.Y&3 Spironolactone, on the other hand,was initially developed as a potassium-sparing diuretic, however it w shown to be effective in treating patients with mild to moderate hirsutism. i”J-@bzz;:;zo forms of therapy are moderately effective but are not well understood in terms of their systemic metabolic effects. The purpose of this study was to compare the metabolic effects of two commonly used oral contraceptives and spironolactone while comparing efficacy in women whose chief complaint was hlrsutism. METHODS Fifty-one Caucasian women, initially referred to our clinic for the treatment of clinically s@ificant hirsutism, were recruited into the study from several of our outpatient clinics. Patients were referred from the Reproductive Endocrinology Clinic, the practices of physicians in the Department of Obstetrics and Gynecology, and the Medical Endocrinology Clinic, Hershey Medical Center, as well as from clinical faculty practicing in neighboring affiliated hospitals. This study was approved by the Institutional Review Boards of the Milton S. Hershey Medical Center of the Pennsylvania State University and the University of Oklahoma Health Sciences Center. Patients with Gushing’s syndrome, androgen-secreting tumors, or prolactinomas were excluded. All women were in excellent general health. For three months before the study, none had taken any medication known to affect pituitary-gonadal function, carbohydrate or lipid metabolism, or blood pressure. None consumed excessive amounts of alcohol, and none were vegetarians or eating any other special diet. Dietary history, exercise frequency, and family history of rdiovascular disease were recorded and scored previously described. (Y Hirsutismw? gradedr repp{Tdii I?;;;?:;~;~;?$s Acne was graded as reported by Plelwlg and IQ man. women had documented hyperandrogenism, defined as increased ree and albumin-bound testosterone (UT) and/or increased dehydroepiandrosterone sulfate (DHEAS) and/or androstenedione (A). None of the women had a clinical history suggestive of congenital adrenal hyperplasia, i.e. signs of virilization, early onse hyperandrogen-related symptoms, short stature, or appropriate family history. Cl% Patients were selected for treatment on the basis of contraceptive need. They were randomly treated with low-dose combination sex steroids containing 35 ug ethinyl estradiol plus norethindrone 0.4 mg (Ovcon 35; Meade-Johnson) or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate (Loestrin; Parke-Davis) if they needed birth control. If they had no need for birth control, they were treated with spironolactone 100 mg po BID. Patients were evaluated at baseline, after 3 months and subsequently at the completion of 9 months of therapy. Blood was sampled between 0800 and 1000 hours from subjects who had fasted 12 h or more. None had consumed alcohol for at least 48 h before sampling. The samples were coded, centrifuged, and stored frozen until assay (-20°C).
114
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1991 VOL. 44 NO. 2
CONTRACEPTION Plasma glucose and insulin concentrations (fasting and 2 hours after a meal), sex hormone binding globulin (SHBG), plasma testosterone (T), free and albumin-bound testosterone (UT), androstenedione (A), and dehydroepiandrosterone sulphate (DHEAS), free and albumimbound estradiol (u&), estradiol (E2), follicle stimulating hormone u ‘nizin hormone (LH) were measured by previously reported ;~$)$.~W’i\ g Measurements of 3-alpha androstanediol glucuronide levels (3-alphadiol glucironide) were performed by radioimmunoassay of unconjugated 3-alpha androstanediol following B-glucuronidase enzyme hydrolysis of the glucuronide conjugate and partia rification of 3-alpha-diol over celite chromatography as previously described.trr3 All assays were performed in the Core Endocrine Laboratory of one of the co-authors (L.M.D.). The mean inter-assay coefficients of variation for the individual assays at the concentrations mea d were 15% or less. Lipids and lipoproteins were determined as previously describe 3Efj . Paired t-test was used to measure differences in lipids, lipoproteins, androgens, estrogens, SHBG, glycoprotein hormones, glucose and insulin concentrations at baseline and at 3 and 9 months of therapy. ANOVA F-test was used to compare differences in the mean concentrations of parameters of interest between treatment modalities and at baseline, 3 months and 9 months of therapy. Only those results where data was available at both baseline and 3 months and baseline and 9 months were used in the analysis. Log transformations of triglycerides and insulin values were made before analysis because of significant skewing towards high values in a hirsute population. To investigate whether changes in the lipoprotein lipids which occurred differentially in the treatment groups could be explained by differential changes in other covariates rather than by the treatment, we correlated the changes. Changes in weight, percent ideal body weight, waist/hip ratio, and insulin were correlated with changes in triglycerides, HDL-cholesterol, and blood pressure. All computations were made using SAS Institute (Cary, NC) procedures, 1985 edition. Level of significance was set at < .05. RESULTS The average Ferriman-Gallwey score was 23.5. The women averaged 140% of ideal body weight. The mean characteristics of the women in each treatment group did not differ statistically when tested by ANOVA with the exception of those women treated with norethindrone acetate 1.5 mg t ethinyl estradiol30 ug. This group had marginally less hirsutism by the Ferrimaffiallwey score (mean = 19.8) prior to therapy (normal < 9). The mean glycoprotein, estrogen, metabolic and clinical profiles of the hirsute women in each treatment group at baseline, 3 months, and 9 months are shown in Tables I-III. All the parameters in Tables I-III show no significant differences between ‘ne, 3 months, and 9 months. They reflect the characteristic profiles of hirsute wome I$W .I Each patient had documented hyperandrogenism and the entire group had lower HDLcholesterol and higher triglyceride concentrations than normal. The groups did not differ with respect to alcohol use, menstrual regularity, exercise history, family history of coronary vascular disease, or distribution of acne. The group treated with .spironolactone had more women with regular menses than the other two groups (9 of 12 versus 2 of 16 and 3 of 17). The mean androgen levels after 3 and 9 months of therapy are shown in Figure 1. It should be noted in Figure 1 that baseline androgen values for the 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate group were higher than in the other groups but not statistically different. All groups had higher androgen concentrations than reference values. Note that both oral contraceptive preparations lowered all of the androgen parameters, however the 35 ug ethinyl estradiol preparation\ was most effective where suppression reached statistical SlgnifiCance at 3 months for T, UT, and A and at 9 months for DHEAS.
AUGUST 1991VOL. 44 NO. 2
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CONTRACEPTION
Table I. The effects of spironolactone on selected hormonal, metabolic, and clinical parameters in hirsute women at baseline, 3 months, and 9 months of treatment Baseline
Variable
3 months
9 months
Reference Range
Luteinizing Hormone (mIU/mL)
16.3 k 2.4 (n= 16)
19.7 f 4.3 (n= 14)
20.7 2 3.5 (n=13)
< 40
Follicle Stimulating Hormone (mRJ/mL)
13.5 ? 1.7 (n= 18)
12.4 f 1.7 (n= 16)
12.1 k 2.3 (n=14)
< 40
Estradiol (pg/mL)
74.4 f 11.7 (n= 17)
57.1 f 9.2 (n = 14)
58.4 + 8.6 (n=13)
Estrone (pg/mL)
54.3 + 7.6 (n= 16)
53.6 it 9.4 (n = 14)
21.1 + 7.8 (n=13)
Sex Hormone Binding Globulin @oL/L)
22.4 5 2.2 (n= 16)
19.4 + 3.0 (n = 14)
20.7 + 3.5 (n=13)
199.2 + 7.6 (n= 17)
194.1 + 8.4 (n= 14)
Cholesterol (mg/dL)
20-120
191.4 f 7.0 138-211 (n=14)
HDL-Cholesterol
(mg/dL)
42.3 f 3.2 (n= 16)
40.3 2 2.5 (n=14)
42.2 k 3.2 (n=14)
40-71
LDL-Cholesterol
(mg/dL)
129.0 + 8.7 (n= 16)
121.0 + 8.2 (n= 14)
123.0 + 6.2 (n= 14)
76-142
105.4 k 21.0 102.3 2 18.0 110.6 2 28.6 (n= 18) (n=16) (n=14)
20-70
Two-hour Insulin (uU/mL) Fasting Glucose (mg/dL) Two-hour Glucose (mg/dL) Diastolic Blood Pressure (mmHg) Waist/hip Ratio FerrimanGallwey
116
94.6 -c 5.3 (n= 18)
92.2 -c 4.7 (n= 13)
70-120
124.2 + 16.2 118.5 + 13.6 110.1 + 15.3 loo-165 (n=18) (n=16) (n=13) 79.7 + 2.1 (n= 18) .85 k -02 (n= 18)
Score
95.2 + 6.1 (n= 16)
25.4 + 2.2 (n= 18)
77.6 k 1.3 (n=16)
72.6 2 1.7 (n=13)
.84 + .02 (n=16)
.86 f .03 (n=13)
24.9 + 2.2 (n= 16)
20.0 r 2.0 (n= 12)
< 90
AUGUST1991VOL.44NO.2
< 9
CONTRACEPTION
Table II. The effects of 35 ug ethinyl estradiol plus norethindrone 0.4 mg on selected hormonal, metabolic, and chnical parameters in hirsute women at baseline, 3 months, and 9 months of treatment Variable
Baseline
Reference Range
3 months
9 months
11.3 2 2.1 (n= 14)
12.8 k 2.0 (n=14)
10.7 k 1.6 (n=9)
< 40
9.3 f 0.9 (n=14)
9.2 k 0.9 (n= 14)
10.5 f 1.3 (n=9)
c 40
Estradiol (pg/mL)
62.1 2 9.6 (n= 17)
56.6 f 17.5 (n=14)
38.8 f 11.2 (n= 13)
Estrone (pg/mL)
48.5 k 9.3 (n= 17)
33.1 2 9.4 (n= 14)
21.1 k 7.8 (n= 13)
Sex Hormone Binding Globulin (nmoL/L)
21.0 f 2.3 (n= 13)
74.7 + 10.7 (n= 14)
51.0 t 5.6 (n= 13)
Luteinizing Hormone (mIU/mL) Follicle Stimulating Hormone (dU/mL)
Cholesterol (mg/dL)
209.1 2 7.6 215.4 2 15.4 210.0 + 15.6 138-211 (n=17) (n= 13) (n=8)
HDL-Cholesterol
(mg/dL)
49.3 r 4.3 (n= 14)
LDGCholesterol
(mg/dL)
139.1 + 9.1 (n=14)
Two-hour Insulin (uU/mL) Fasting Glucose (mg/dL) Two-hour Glucose (mg/dL) Diastolic Blood Pressure (mmHg) Waist/hip Ratio Ferriman-Gallwey
Score
AUGUST 1991 VOL. 44 NO. 2
20-120
50.1 f 4.8 (n= 13)
104.1 r 8.5 (n= 16)
40-71
133.0 + 14.1 135.0 + 14.5 76-142 (n= 13) (n=B)
103.6 + 29.4 117.8 f 25.4 (n=16) (n= 13) 91.4 f 3.2 (n= 16)
44.6 f 4.8 (n=8)
88.5 k 2.3 (n=14)
76.3 f 17.2 20-70 (n=8) 87.3 + 1.8 70-120 (n=S)
108.3 + 12.4 116.0 f 11.8 loo-165 (n= 14) (n=9)
73.4 f 1.9 (n= 14)
70.6 f 1.6 (n= 14)
74.0 + 2.1 (n=ll)
.80 ? .Ol (n= 16)
.80 + .Ol (n = 14)
.80 I? .Ol (n=lO)
25.4 + 2.2 (n= 16)
24.9 t 2.2 (n = 13)
20.0 f 2.0 (n=7)
< 90
< 9
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CONTRACEPTION
Table III. The effects of ethinyl estradiol30 ug plus norethindrone acetate 1.5 mg on selected hormonal, metabolic, and clinical parameters in hirsute women at baseline, 3 months, and 9 months of treatment Reference Range
Variable
Baseline
3 months
9 months
Luteinizing Hormone (mIU/mL)
15.8 + 2.8 (n= 16)
6.3 f 1.1 (n=15)
9.4 f 4.3 (n= 13)
< 40
Follicle Stimulating Hormone (mBJ/mL)
11.1 k 0.8 (n= 16)
11.8 r 3.2 (n=15)
8.5 t 1.1 (n= 13)
< 40
Estradiol (pg/mL)
84.1 k 15.1 (n= 16)
40.3 t 5.8 (n=15)
73.1 ? 23.3 (n= 13)
Estrone (pg/mL)
69.3 t 13.1 (n= 15)
19.3 f 4.1 (n=14)
36.1 ? 10.4 (n= 12)
Sex Hormone Binding Globulin (mnoL/L)
18.7 + 2.4 (n= 16)
50.4 2 4.1 (n=15)
51.7 + 5.6 (n= 13)
190.4 2 6.0 (n=16)
195.3 + 3.5 (n=13)
Cholesterol (mg/dL)
20-120
201.5 + 9.2 138-211 (n= 13)
HDL-Cholesterol
(mg/dL)
41.8 ? 2.9 (n= 16)
46.3 r 2.5 (n=13)
43.8 k 2.8 (n= 12)
40-71
LDL-Cholesterol
(mg/dL)
115.0 k 7.0 (n=16)
117.0 t 4.8 (n=13)
125.4 2 9.6 (n= 12)
76-142
155.8 2 65.8 192.1 + 67.3 103.4 + 29.3 (n=17) (n=15) (n=8)
20-70
Two-hour Insulin (uU/mL) Fasting Glucose (mg/dL) Two-hour Glucose (mg/dL) Diastolic Blood Pressure (mmHg) Waist/hip Ratio FerrimanGallwey
118
Score
89.8 + 3.4 (n=15)
93.2 k 2.4 (n=15)
102.4 5 10.7 70-120 (n= 13)
117.5 k 11.2 139.7 r 14.2 173.5 +: 28.6 loo-165 (n=lS) (n=l5) (n= 13) 73.6 ? 2.0 (n= 17)
73.9 + 1.8 (n= 15)
.84 t .02 (n=17)
.82 k .02 (n=14)
19.8 c 1.5 (n=17)
20.8 +- 1.6 (n= 15)
72.8 f 2.6 (n= 12)
< 90
.83 + .03 (n= 12) 20.6 + 2.2 (n= 13)
< 9
AUGUST 1991 VOL. 44 NO. 2
150
200
250
300
350
400
0
0
eline
eline
9
Mos.
3
Mos. UT w'dL
0
Mos. A v/dL
3
1
0
Mos.
9
35 ug + norethindrone 30 ug + norethindrone
I
Mos. DHEAS w/dL
3
acetate 1.5 rng
I
Mos.
9
0.4
The effect of spironolactone (n = 14 at 9 months), ethinyl estradio135 ug plus 0.4 m norethindrone (n = 9 at 9 months), and ethinyl estradiol30 ug plus noret g*mdrone acetate 1.5 mg (n = 13 at 9 months) on mean serum androgens at 3 and 9 months of treatment in hirsute women. Values are means + SEM.
Mos.
Mos. T w/dL
Figure 1.
9
ba
b:
3
**p ( .05 from
*p ( .Ol from
_I
-• spironolactone m---m ethinyl estradiol A---A ethinyl estradiol
l
CONTRACEPTION
Testosterone was suppressed from 92 ng/dL to 41 mg/dL (n = 9)9 < .05) and UT was suppressed from 42 ng/dL to 10 ng/dL (n = 9)@ < .05)with 35 u ethinyl estradiol plus 0.4 mg norethindrone and testosterone was suppressed from 117 ug BdL to 90 n /dL (n = 13) and UT (n = 13) was suppressed from 62.6 ng/dL to 27.8 ng/dL with ethiny Bestradiol30 ug plus norethindrone acetate 1.5 mg over 9 months. For statistical analysis, only those patients seen at both baseline and 3 months and baseline and 9 months are included. The only metabolic parameters which showed significant alterations were increased triglycerides by the oral contraceptive preparations and an increase in fasting insulin concentrations by spironolactone as shown in Figure 2. Average body weights were not statistically different in any of the groups at 3 months and 9 months of therapy. Spironolactone, unlike the two OC preparations, caused a lowering of the systolic blood pressure (Fig. 2). However, both spironolactone and the ethinyl estradio135 ug plus norethindrone 0.4 mg were effective in reducing the Ferriman-Gallwey scores (Fig. 3). By the second visit, changes in the waist/hip ratio correlated with changes in diastolic blood pressure. However, none of the roups had si nificant changes in etther waist/hip ratio or diastolic blood pressure. By the f ourth visit, ci?anges in weight correlated with changes in HDGcholesterol, however, no si nficant differences in HDL-cholesterol concentrations were seen during the 9 months oBtherapy.
DISCUSSION Whereas combination oral contraceptive steroid therapy and spironolactone are widely utilized in the United States and throughout the world to treat hirsutism, they are routinely prescribed for this purpose without regard for their potential adverse metabolic effects. Although each modality of therapy has been reported to be effective in patients with mild to moderate hirsutism, no study has yet been reported which compares these treatment strategies with respect to both efficacy and their metabolic consequences in a population of clinically documented hirsute women. While both preparations cause considerable suppression of androgen levels, only suppression of testosterone with the 35 ug ethinyl estradtol plus 0.4 mg norethindrone preparation reached statistical significance at 9 months. This might have occurred because this group had lower baseline testosterone concentrations and possibly a more pure ovarian source of their androgen excess. The decrease in 3-alpha-diol glucuronide may relate to the androgenic potency difference between the two preparations and negative feedback suppression leading to decreased precursor androgen substrate availabtlity. As p viously reported, spironolactone did not lower 3-alpha-diol glucuronide concentrations. 6 The significant reduction in FerrimanGallwey scores with 35 ug ethinyl estradiol plus 0.4 mg norethindrone but not the 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate was unexpected. This may relate to the fact that the 35 ug ethinyl estradiol preparation is metabolically slightly more estrogenic or alternatively this may relate to limitations of the Ferriman-Gallwey scoring system for hirsutism. We found that both the higher estrogenic OC preparation and spironolactone were also effective in reducing or eliminating unwanted hair growth. The two commonly prescribed combination oral contraceptives used in this study showed little difference with respect to observed metabolic alterations in response to therapy. Both preparations elevated triglyceride concentrations. While markedly elevated, triglyceride levels are a known risk factor for coronary artery disease in women, and while hirsute women are more likely to have higher triglyceride concentrat’ to regularly menstruating non-hirsute, non-hyperandrogenic women, lBP:;t;_;:rd consequences of sex steroid-induced hypertrrgl ceridemia remain to be studied. In this study, we did not find that measuring 3-alpha- c?to1 glucuronide levels was a useful tool in momtorin the clinical efficacy of these therapies. Recent reports su l@jt ;;:; ,3fall;;elpl glucurom .d”e may be a useful marker of adrenal androgen production.
AUGUST 1991 VOL. 44 NO. 2
CONTRACEPTION
F
loo-
0 90 . . EJ BB
spironolactone ethinyl estradial etbinyl estradiol
80 ..
35 ug + norelhemdrane 30 ug + norethindrone
0.4 mg acetate 1.5 mg I
I
70 60 50 40 30 20 10 n
9 mos.
3 mos.
lp (.Ol
from
baseline
El 0 El =
3o__
s ironolactone e Phinyl e&radial ethinyl estradiol
35 ug + norclhindrone 30 ug + norclhindrone
0.4 mg acetate
1.5 mg
a0 --
-40
I
’ l
9 mos.
3 mos.
p ( .05
from
baseline
0 spironolactone m ethinyl estradiol WJ ethinyl lrtradml
10
__ t
35 ug + norethindrons 30 ug + ncrethindrone
3 mos. p ( .05
from
0.4 mg scetstc
1.5 mg
9 mos.
baseline
The effect of spironola$one, ethinyl estradio135 ug plus 0.4 mg norethmdrone and ethmyl estradiol30 ug plus 1.5 mg norethindrone acetate on mean 2 SEM triglyceride, fasting insuhn concentrations and systolic blood pressure at 3 months and 9 months of treatment in hirsute women. AUGUST 1991 VOL. 44 NO. 2
121
CONTRACEPTION
%
Flon
A _I
_I-
0 m ES
400
spironolactone ethinyl estradiol ethinyl estradiol
35 ug + norethindrone 30 ug + norethindrone
0.4 mg acetate
1.5 mg
300 i
200 t
100 t
M
0
I
NJ9
1?
-100 -200 -300
-500
’ *
9 mos.
3 mos.
p ( .05 from
baseline
B 0 spironolactone LSS ethinyl estradiol 10 -- EiTJ ethinyl estradiol
3 mos. *p ( .05 from
Figure 3.
122
35 ug + norethindrone 30 ug + norethindrone
0.4 mg acetate
1 5 mg
9 mos.
baseline
The effect of s ironolactone, ethinyl estradio135 ug plus norethindrone 0.4 m and ethiny Pestradiol30 II? plus norethindrone acetate 1.5 mg on mean f SB M 3-alpha-diol concentrations and Ferrirnan-Gallwey scores at 3 months and 9 months of treatment in hirsute women.
AUGUST 1991 VOL. 44 NO. 2
CONTRACEPTION
that the slightly more progestational preparation ethhiyl estradiol30 ug t norethindrone acetate 1.5 mg inhibited 3-alpha-diol glucuronide concentrations, yet was not as clinically effective as judged by the Ferriman-Gallwey score response or by a suppression of DHEAS concentrations. Although combination steroid therapy has been adrenal component of androgen excess in women with hirsutism, tpl”d”, %ZLc~et&nse in adrenal androgen pathway suppression according to the relative estrogen and progestin content of the combination sex steroid preparations used has yet to be documented. Only spironolactone raised fastin insulin levels and lowered systolic blood pressure. The two OC preparations did not alter either the fasting insulins or the blood pressure in the subjects placed on this medication. Ret evidence suggests that lowering blood pressure without lowering insulin resistance @) may not be as cardioprotective as was irsute women are more likely to display an array of ::$::%::;:;~:~VV these data introduce a note of caution when systemic therapy for hirsutism is p&scribed. Attention to altering the lifestyles of these women in the form of dietary therapy to reduce saturated fats and an increase in exercise regimens to improve insulin resistance as well as to reduce weight are important factors for these subjects to consider. The diagnosis and therapy of hirsutism continues to be an important and significant challenge to the clinician. When oral contraceptives are used singly or in combination with spironolactone, evaluation of metabolic status (de ree of insulin resistance) would appear * take into account potential to be prudent. Treatment strategies are needed wf Ich metabolic consequences as well as the need to improve efficacy. As cosmetic concerns are addresseq, frequently using a combination of systemic therapy and electrolysis, the health care provider must focus on recommendations for lifestyle alterations.
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CONTRACEPTION 9.
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Rittmaster RS. Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist Leurolide. J Clin Endocrinol Metab 1988;67:651-57.
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Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:159599.
21.
Wild RA, Grubb B, Hartz A, Van Nort JJ, Bachman W, Bartholomew M. Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 1990;54:255-59.
124
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1991 VOL. 44 NO. 2
HIRSUTISM: METABOLIC EFFECTS OF TWO COMMONL USED ORAL CONTRACEPIIVES AND SPIRONOIACTONE ‘k Robert A Wild M D *#+ Lawrence M. Dkmkrs; Ph.D.#k Deborah Applebaum-Bowden, Ph.D.T Rosanna Lenker, CNMW+ #Supported in whole or in part by rants from Meade-Johnson and Parke-Davis Pharmaceuticals as well as Penney ‘ivania American Heart Association and BRSG grant S07-RR 05680-19 awarded by the Biomedical Research Su port grant program, Division of Research Resources, National Institutes of Health, and r:resbyterian Health Foundation, Oklahoma City, OK *Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK #Address correspondence and reprint requests: Robert A. Wild, M.D., OUHSC, Dept. of OB/GYN, P.O. Box 26901 4SP717, Oklahoma City, OK 73190; Phone: (405) 271-8700 +Department of Pathology, Hershey Medical Center, Hershey, PA j:Department
of Medicine, Hershey Medical Center, Hershey, PA
+Department of Obstetrics and Gynecology, Hershey Medical Center, Hershey, PA T;partment
of Internal Medicine, Bowman Gray School of Medicine, Winston-Salem,
ABSTRACT
Fifty-one hirsute women were randomly treated for nine months with ethinyl estradio135 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with s ironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin 1p evels were higher as opposed to either lowdose oral contraceptive preparation. Ethinyl estradiol30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradio135 ug plus norethindrone 0.4 mg and sptronolactone were more effective in lowering Ferriman Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy. Submitted Accepted
for publication for publication
January 25, 1991 June 3, 1991
AUGUST 1991 VOL. 44 NO. 2
113
CONTRACEPTION
INTRODUCTION The clinical management of hirsutism continues to pose a significant challenge to clinicians in terms of diagnosis and treatment. As currently viewed in the United States, the choice of therapy is somewhat restrictive and has been limited to either combination oral contraceptive therapy or the use of anti-androgens such as spironolactone. Oral contraceptive therapy was initially developed for antif t’ ‘ty purposes, although its use is now widespread for managing hyperandrogenic states.Y&3 Spironolactone, on the other hand,was initially developed as a potassium-sparing diuretic, however it w shown to be effective in treating patients with mild to moderate hirsutism. i”J-@bzz;:;zo forms of therapy are moderately effective but are not well understood in terms of their systemic metabolic effects. The purpose of this study was to compare the metabolic effects of two commonly used oral contraceptives and spironolactone while comparing efficacy in women whose chief complaint was hlrsutism. METHODS Fifty-one Caucasian women, initially referred to our clinic for the treatment of clinically s@ificant hirsutism, were recruited into the study from several of our outpatient clinics. Patients were referred from the Reproductive Endocrinology Clinic, the practices of physicians in the Department of Obstetrics and Gynecology, and the Medical Endocrinology Clinic, Hershey Medical Center, as well as from clinical faculty practicing in neighboring affiliated hospitals. This study was approved by the Institutional Review Boards of the Milton S. Hershey Medical Center of the Pennsylvania State University and the University of Oklahoma Health Sciences Center. Patients with Gushing’s syndrome, androgen-secreting tumors, or prolactinomas were excluded. All women were in excellent general health. For three months before the study, none had taken any medication known to affect pituitary-gonadal function, carbohydrate or lipid metabolism, or blood pressure. None consumed excessive amounts of alcohol, and none were vegetarians or eating any other special diet. Dietary history, exercise frequency, and family history of rdiovascular disease were recorded and scored previously described. (Y Hirsutismw? gradedr repp{Tdii I?;;;?:;~;~;?$s Acne was graded as reported by Plelwlg and IQ man. women had documented hyperandrogenism, defined as increased ree and albumin-bound testosterone (UT) and/or increased dehydroepiandrosterone sulfate (DHEAS) and/or androstenedione (A). None of the women had a clinical history suggestive of congenital adrenal hyperplasia, i.e. signs of virilization, early onse hyperandrogen-related symptoms, short stature, or appropriate family history. Cl% Patients were selected for treatment on the basis of contraceptive need. They were randomly treated with low-dose combination sex steroids containing 35 ug ethinyl estradiol plus norethindrone 0.4 mg (Ovcon 35; Meade-Johnson) or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate (Loestrin; Parke-Davis) if they needed birth control. If they had no need for birth control, they were treated with spironolactone 100 mg po BID. Patients were evaluated at baseline, after 3 months and subsequently at the completion of 9 months of therapy. Blood was sampled between 0800 and 1000 hours from subjects who had fasted 12 h or more. None had consumed alcohol for at least 48 h before sampling. The samples were coded, centrifuged, and stored frozen until assay (-20°C).
114
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1991 VOL. 44 NO. 2
CONTRACEPTION Plasma glucose and insulin concentrations (fasting and 2 hours after a meal), sex hormone binding globulin (SHBG), plasma testosterone (T), free and albumin-bound testosterone (UT), androstenedione (A), and dehydroepiandrosterone sulphate (DHEAS), free and albumimbound estradiol (u&), estradiol (E2), follicle stimulating hormone u ‘nizin hormone (LH) were measured by previously reported ;~$)$.~W’i\ g Measurements of 3-alpha androstanediol glucuronide levels (3-alphadiol glucironide) were performed by radioimmunoassay of unconjugated 3-alpha androstanediol following B-glucuronidase enzyme hydrolysis of the glucuronide conjugate and partia rification of 3-alpha-diol over celite chromatography as previously described.trr3 All assays were performed in the Core Endocrine Laboratory of one of the co-authors (L.M.D.). The mean inter-assay coefficients of variation for the individual assays at the concentrations mea d were 15% or less. Lipids and lipoproteins were determined as previously describe 3Efj . Paired t-test was used to measure differences in lipids, lipoproteins, androgens, estrogens, SHBG, glycoprotein hormones, glucose and insulin concentrations at baseline and at 3 and 9 months of therapy. ANOVA F-test was used to compare differences in the mean concentrations of parameters of interest between treatment modalities and at baseline, 3 months and 9 months of therapy. Only those results where data was available at both baseline and 3 months and baseline and 9 months were used in the analysis. Log transformations of triglycerides and insulin values were made before analysis because of significant skewing towards high values in a hirsute population. To investigate whether changes in the lipoprotein lipids which occurred differentially in the treatment groups could be explained by differential changes in other covariates rather than by the treatment, we correlated the changes. Changes in weight, percent ideal body weight, waist/hip ratio, and insulin were correlated with changes in triglycerides, HDL-cholesterol, and blood pressure. All computations were made using SAS Institute (Cary, NC) procedures, 1985 edition. Level of significance was set at < .05. RESULTS The average Ferriman-Gallwey score was 23.5. The women averaged 140% of ideal body weight. The mean characteristics of the women in each treatment group did not differ statistically when tested by ANOVA with the exception of those women treated with norethindrone acetate 1.5 mg t ethinyl estradiol30 ug. This group had marginally less hirsutism by the Ferrimaffiallwey score (mean = 19.8) prior to therapy (normal < 9). The mean glycoprotein, estrogen, metabolic and clinical profiles of the hirsute women in each treatment group at baseline, 3 months, and 9 months are shown in Tables I-III. All the parameters in Tables I-III show no significant differences between ‘ne, 3 months, and 9 months. They reflect the characteristic profiles of hirsute wome I$W .I Each patient had documented hyperandrogenism and the entire group had lower HDLcholesterol and higher triglyceride concentrations than normal. The groups did not differ with respect to alcohol use, menstrual regularity, exercise history, family history of coronary vascular disease, or distribution of acne. The group treated with .spironolactone had more women with regular menses than the other two groups (9 of 12 versus 2 of 16 and 3 of 17). The mean androgen levels after 3 and 9 months of therapy are shown in Figure 1. It should be noted in Figure 1 that baseline androgen values for the 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate group were higher than in the other groups but not statistically different. All groups had higher androgen concentrations than reference values. Note that both oral contraceptive preparations lowered all of the androgen parameters, however the 35 ug ethinyl estradiol preparation\ was most effective where suppression reached statistical SlgnifiCance at 3 months for T, UT, and A and at 9 months for DHEAS.
AUGUST 1991VOL. 44 NO. 2
115
CONTRACEPTION
Table I. The effects of spironolactone on selected hormonal, metabolic, and clinical parameters in hirsute women at baseline, 3 months, and 9 months of treatment Baseline
Variable
3 months
9 months
Reference Range
Luteinizing Hormone (mIU/mL)
16.3 k 2.4 (n= 16)
19.7 f 4.3 (n= 14)
20.7 2 3.5 (n=13)
< 40
Follicle Stimulating Hormone (mRJ/mL)
13.5 ? 1.7 (n= 18)
12.4 f 1.7 (n= 16)
12.1 k 2.3 (n=14)
< 40
Estradiol (pg/mL)
74.4 f 11.7 (n= 17)
57.1 f 9.2 (n = 14)
58.4 + 8.6 (n=13)
Estrone (pg/mL)
54.3 + 7.6 (n= 16)
53.6 it 9.4 (n = 14)
21.1 + 7.8 (n=13)
Sex Hormone Binding Globulin @oL/L)
22.4 5 2.2 (n= 16)
19.4 + 3.0 (n = 14)
20.7 + 3.5 (n=13)
199.2 + 7.6 (n= 17)
194.1 + 8.4 (n= 14)
Cholesterol (mg/dL)
20-120
191.4 f 7.0 138-211 (n=14)
HDL-Cholesterol
(mg/dL)
42.3 f 3.2 (n= 16)
40.3 2 2.5 (n=14)
42.2 k 3.2 (n=14)
40-71
LDL-Cholesterol
(mg/dL)
129.0 + 8.7 (n= 16)
121.0 + 8.2 (n= 14)
123.0 + 6.2 (n= 14)
76-142
105.4 k 21.0 102.3 2 18.0 110.6 2 28.6 (n= 18) (n=16) (n=14)
20-70
Two-hour Insulin (uU/mL) Fasting Glucose (mg/dL) Two-hour Glucose (mg/dL) Diastolic Blood Pressure (mmHg) Waist/hip Ratio FerrimanGallwey
116
94.6 -c 5.3 (n= 18)
92.2 -c 4.7 (n= 13)
70-120
124.2 + 16.2 118.5 + 13.6 110.1 + 15.3 loo-165 (n=18) (n=16) (n=13) 79.7 + 2.1 (n= 18) .85 k -02 (n= 18)
Score
95.2 + 6.1 (n= 16)
25.4 + 2.2 (n= 18)
77.6 k 1.3 (n=16)
72.6 2 1.7 (n=13)
.84 + .02 (n=16)
.86 f .03 (n=13)
24.9 + 2.2 (n= 16)
20.0 r 2.0 (n= 12)
< 90
AUGUST1991VOL.44NO.2
< 9
CONTRACEPTION
Table II. The effects of 35 ug ethinyl estradiol plus norethindrone 0.4 mg on selected hormonal, metabolic, and chnical parameters in hirsute women at baseline, 3 months, and 9 months of treatment Variable
Baseline
Reference Range
3 months
9 months
11.3 2 2.1 (n= 14)
12.8 k 2.0 (n=14)
10.7 k 1.6 (n=9)
< 40
9.3 f 0.9 (n=14)
9.2 k 0.9 (n= 14)
10.5 f 1.3 (n=9)
c 40
Estradiol (pg/mL)
62.1 2 9.6 (n= 17)
56.6 f 17.5 (n=14)
38.8 f 11.2 (n= 13)
Estrone (pg/mL)
48.5 k 9.3 (n= 17)
33.1 2 9.4 (n= 14)
21.1 k 7.8 (n= 13)
Sex Hormone Binding Globulin (nmoL/L)
21.0 f 2.3 (n= 13)
74.7 + 10.7 (n= 14)
51.0 t 5.6 (n= 13)
Luteinizing Hormone (mIU/mL) Follicle Stimulating Hormone (dU/mL)
Cholesterol (mg/dL)
209.1 2 7.6 215.4 2 15.4 210.0 + 15.6 138-211 (n=17) (n= 13) (n=8)
HDL-Cholesterol
(mg/dL)
49.3 r 4.3 (n= 14)
LDGCholesterol
(mg/dL)
139.1 + 9.1 (n=14)
Two-hour Insulin (uU/mL) Fasting Glucose (mg/dL) Two-hour Glucose (mg/dL) Diastolic Blood Pressure (mmHg) Waist/hip Ratio Ferriman-Gallwey
Score
AUGUST 1991 VOL. 44 NO. 2
20-120
50.1 f 4.8 (n= 13)
104.1 r 8.5 (n= 16)
40-71
133.0 + 14.1 135.0 + 14.5 76-142 (n= 13) (n=B)
103.6 + 29.4 117.8 f 25.4 (n=16) (n= 13) 91.4 f 3.2 (n= 16)
44.6 f 4.8 (n=8)
88.5 k 2.3 (n=14)
76.3 f 17.2 20-70 (n=8) 87.3 + 1.8 70-120 (n=S)
108.3 + 12.4 116.0 f 11.8 loo-165 (n= 14) (n=9)
73.4 f 1.9 (n= 14)
70.6 f 1.6 (n= 14)
74.0 + 2.1 (n=ll)
.80 ? .Ol (n= 16)
.80 + .Ol (n = 14)
.80 I? .Ol (n=lO)
25.4 + 2.2 (n= 16)
24.9 t 2.2 (n = 13)
20.0 f 2.0 (n=7)
< 90
< 9
117
CONTRACEPTION
Table III. The effects of ethinyl estradiol30 ug plus norethindrone acetate 1.5 mg on selected hormonal, metabolic, and clinical parameters in hirsute women at baseline, 3 months, and 9 months of treatment Reference Range
Variable
Baseline
3 months
9 months
Luteinizing Hormone (mIU/mL)
15.8 + 2.8 (n= 16)
6.3 f 1.1 (n=15)
9.4 f 4.3 (n= 13)
< 40
Follicle Stimulating Hormone (mBJ/mL)
11.1 k 0.8 (n= 16)
11.8 r 3.2 (n=15)
8.5 t 1.1 (n= 13)
< 40
Estradiol (pg/mL)
84.1 k 15.1 (n= 16)
40.3 t 5.8 (n=15)
73.1 ? 23.3 (n= 13)
Estrone (pg/mL)
69.3 t 13.1 (n= 15)
19.3 f 4.1 (n=14)
36.1 ? 10.4 (n= 12)
Sex Hormone Binding Globulin (mnoL/L)
18.7 + 2.4 (n= 16)
50.4 2 4.1 (n=15)
51.7 + 5.6 (n= 13)
190.4 2 6.0 (n=16)
195.3 + 3.5 (n=13)
Cholesterol (mg/dL)
20-120
201.5 + 9.2 138-211 (n= 13)
HDL-Cholesterol
(mg/dL)
41.8 ? 2.9 (n= 16)
46.3 r 2.5 (n=13)
43.8 k 2.8 (n= 12)
40-71
LDL-Cholesterol
(mg/dL)
115.0 k 7.0 (n=16)
117.0 t 4.8 (n=13)
125.4 2 9.6 (n= 12)
76-142
155.8 2 65.8 192.1 + 67.3 103.4 + 29.3 (n=17) (n=15) (n=8)
20-70
Two-hour Insulin (uU/mL) Fasting Glucose (mg/dL) Two-hour Glucose (mg/dL) Diastolic Blood Pressure (mmHg) Waist/hip Ratio FerrimanGallwey
118
Score
89.8 + 3.4 (n=15)
93.2 k 2.4 (n=15)
102.4 5 10.7 70-120 (n= 13)
117.5 k 11.2 139.7 r 14.2 173.5 +: 28.6 loo-165 (n=lS) (n=l5) (n= 13) 73.6 ? 2.0 (n= 17)
73.9 + 1.8 (n= 15)
.84 t .02 (n=17)
.82 k .02 (n=14)
19.8 c 1.5 (n=17)
20.8 +- 1.6 (n= 15)
72.8 f 2.6 (n= 12)
< 90
.83 + .03 (n= 12) 20.6 + 2.2 (n= 13)
< 9
AUGUST 1991 VOL. 44 NO. 2
150
200
250
300
350
400
0
0
eline
eline
9
Mos.
3
Mos. UT w'dL
0
Mos. A v/dL
3
1
0
Mos.
9
35 ug + norethindrone 30 ug + norethindrone
I
Mos. DHEAS w/dL
3
acetate 1.5 rng
I
Mos.
9
0.4
The effect of spironolactone (n = 14 at 9 months), ethinyl estradio135 ug plus 0.4 m norethindrone (n = 9 at 9 months), and ethinyl estradiol30 ug plus noret g*mdrone acetate 1.5 mg (n = 13 at 9 months) on mean serum androgens at 3 and 9 months of treatment in hirsute women. Values are means + SEM.
Mos.
Mos. T w/dL
Figure 1.
9
ba
b:
3
**p ( .05 from
*p ( .Ol from
_I
-• spironolactone m---m ethinyl estradiol A---A ethinyl estradiol
l
CONTRACEPTION
Testosterone was suppressed from 92 ng/dL to 41 mg/dL (n = 9)9 < .05) and UT was suppressed from 42 ng/dL to 10 ng/dL (n = 9)@ < .05)with 35 u ethinyl estradiol plus 0.4 mg norethindrone and testosterone was suppressed from 117 ug BdL to 90 n /dL (n = 13) and UT (n = 13) was suppressed from 62.6 ng/dL to 27.8 ng/dL with ethiny Bestradiol30 ug plus norethindrone acetate 1.5 mg over 9 months. For statistical analysis, only those patients seen at both baseline and 3 months and baseline and 9 months are included. The only metabolic parameters which showed significant alterations were increased triglycerides by the oral contraceptive preparations and an increase in fasting insulin concentrations by spironolactone as shown in Figure 2. Average body weights were not statistically different in any of the groups at 3 months and 9 months of therapy. Spironolactone, unlike the two OC preparations, caused a lowering of the systolic blood pressure (Fig. 2). However, both spironolactone and the ethinyl estradio135 ug plus norethindrone 0.4 mg were effective in reducing the Ferriman-Gallwey scores (Fig. 3). By the second visit, changes in the waist/hip ratio correlated with changes in diastolic blood pressure. However, none of the roups had si nificant changes in etther waist/hip ratio or diastolic blood pressure. By the f ourth visit, ci?anges in weight correlated with changes in HDGcholesterol, however, no si nficant differences in HDL-cholesterol concentrations were seen during the 9 months oBtherapy.
DISCUSSION Whereas combination oral contraceptive steroid therapy and spironolactone are widely utilized in the United States and throughout the world to treat hirsutism, they are routinely prescribed for this purpose without regard for their potential adverse metabolic effects. Although each modality of therapy has been reported to be effective in patients with mild to moderate hirsutism, no study has yet been reported which compares these treatment strategies with respect to both efficacy and their metabolic consequences in a population of clinically documented hirsute women. While both preparations cause considerable suppression of androgen levels, only suppression of testosterone with the 35 ug ethinyl estradtol plus 0.4 mg norethindrone preparation reached statistical significance at 9 months. This might have occurred because this group had lower baseline testosterone concentrations and possibly a more pure ovarian source of their androgen excess. The decrease in 3-alpha-diol glucuronide may relate to the androgenic potency difference between the two preparations and negative feedback suppression leading to decreased precursor androgen substrate availabtlity. As p viously reported, spironolactone did not lower 3-alpha-diol glucuronide concentrations. 6 The significant reduction in FerrimanGallwey scores with 35 ug ethinyl estradiol plus 0.4 mg norethindrone but not the 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate was unexpected. This may relate to the fact that the 35 ug ethinyl estradiol preparation is metabolically slightly more estrogenic or alternatively this may relate to limitations of the Ferriman-Gallwey scoring system for hirsutism. We found that both the higher estrogenic OC preparation and spironolactone were also effective in reducing or eliminating unwanted hair growth. The two commonly prescribed combination oral contraceptives used in this study showed little difference with respect to observed metabolic alterations in response to therapy. Both preparations elevated triglyceride concentrations. While markedly elevated, triglyceride levels are a known risk factor for coronary artery disease in women, and while hirsute women are more likely to have higher triglyceride concentrat’ to regularly menstruating non-hirsute, non-hyperandrogenic women, lBP:;t;_;:rd consequences of sex steroid-induced hypertrrgl ceridemia remain to be studied. In this study, we did not find that measuring 3-alpha- c?to1 glucuronide levels was a useful tool in momtorin the clinical efficacy of these therapies. Recent reports su l@jt ;;:; ,3fall;;elpl glucurom .d”e may be a useful marker of adrenal androgen production.
AUGUST 1991 VOL. 44 NO. 2
CONTRACEPTION
F
loo-
0 90 . . EJ BB
spironolactone ethinyl estradial etbinyl estradiol
80 ..
35 ug + norelhemdrane 30 ug + norethindrone
0.4 mg acetate 1.5 mg I
I
70 60 50 40 30 20 10 n
9 mos.
3 mos.
lp (.Ol
from
baseline
El 0 El =
3o__
s ironolactone e Phinyl e&radial ethinyl estradiol
35 ug + norclhindrone 30 ug + norclhindrone
0.4 mg acetate
1.5 mg
a0 --
-40
I
’ l
9 mos.
3 mos.
p ( .05
from
baseline
0 spironolactone m ethinyl estradiol WJ ethinyl lrtradml
10
__ t
35 ug + norethindrons 30 ug + ncrethindrone
3 mos. p ( .05
from
0.4 mg scetstc
1.5 mg
9 mos.
baseline
The effect of spironola$one, ethinyl estradio135 ug plus 0.4 mg norethmdrone and ethmyl estradiol30 ug plus 1.5 mg norethindrone acetate on mean 2 SEM triglyceride, fasting insuhn concentrations and systolic blood pressure at 3 months and 9 months of treatment in hirsute women. AUGUST 1991 VOL. 44 NO. 2
121
CONTRACEPTION
%
Flon
A _I
_I-
0 m ES
400
spironolactone ethinyl estradiol ethinyl estradiol
35 ug + norethindrone 30 ug + norethindrone
0.4 mg acetate
1.5 mg
300 i
200 t
100 t
M
0
I
NJ9
1?
-100 -200 -300
-500
’ *
9 mos.
3 mos.
p ( .05 from
baseline
B 0 spironolactone LSS ethinyl estradiol 10 -- EiTJ ethinyl estradiol
3 mos. *p ( .05 from
Figure 3.
122
35 ug + norethindrone 30 ug + norethindrone
0.4 mg acetate
1 5 mg
9 mos.
baseline
The effect of s ironolactone, ethinyl estradio135 ug plus norethindrone 0.4 m and ethiny Pestradiol30 II? plus norethindrone acetate 1.5 mg on mean f SB M 3-alpha-diol concentrations and Ferrirnan-Gallwey scores at 3 months and 9 months of treatment in hirsute women.
AUGUST 1991 VOL. 44 NO. 2
CONTRACEPTION
that the slightly more progestational preparation ethhiyl estradiol30 ug t norethindrone acetate 1.5 mg inhibited 3-alpha-diol glucuronide concentrations, yet was not as clinically effective as judged by the Ferriman-Gallwey score response or by a suppression of DHEAS concentrations. Although combination steroid therapy has been adrenal component of androgen excess in women with hirsutism, tpl”d”, %ZLc~et&nse in adrenal androgen pathway suppression according to the relative estrogen and progestin content of the combination sex steroid preparations used has yet to be documented. Only spironolactone raised fastin insulin levels and lowered systolic blood pressure. The two OC preparations did not alter either the fasting insulins or the blood pressure in the subjects placed on this medication. Ret evidence suggests that lowering blood pressure without lowering insulin resistance @) may not be as cardioprotective as was irsute women are more likely to display an array of ::$::%::;:;~:~VV these data introduce a note of caution when systemic therapy for hirsutism is p&scribed. Attention to altering the lifestyles of these women in the form of dietary therapy to reduce saturated fats and an increase in exercise regimens to improve insulin resistance as well as to reduce weight are important factors for these subjects to consider. The diagnosis and therapy of hirsutism continues to be an important and significant challenge to the clinician. When oral contraceptives are used singly or in combination with spironolactone, evaluation of metabolic status (de ree of insulin resistance) would appear * take into account potential to be prudent. Treatment strategies are needed wf Ich metabolic consequences as well as the need to improve efficacy. As cosmetic concerns are addresseq, frequently using a combination of systemic therapy and electrolysis, the health care provider must focus on recommendations for lifestyle alterations.
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Pleiwig G, Kligman J. Acne: morphogenesis and treatment. Springer Verlag, 1964:48-63.
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Santner SJ, Santen RJ, Kahn HE, Demers LM. A model for validation of radioimmunoassay kit reagents and measurement of follitropin and lutroprin in blood and urine. Clin Chem 1981;27:11:1892-95.
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