A New Treatment for Hirsutism ROGERIO F. CORREA de OLIVEIRA, M.D., LEONIDAS P. NOVAES, M.D., MAURICIO B. LIMA, M.D., JAYME RODRIGUES, M.D., SERGIO FRANCO, M.D., AFAF I. KHENAIFES, M.D., and CLEA P. FRANCALANCI, Pharm.C, Rio de Janeiro, Brazil
Twenty-four hirsute female patients were treated with 100 mg of depo-medroxyprogesterone acetate intramuscularly every 15 days. Twenty-three showed definite improvement from their abnormal hair growth. All patients with initially elevated 17-ketosteroids in 24-hour urine collections showed a decrease of these metabolites with treatment. In eleven patients the initial plasma testosterone level was elevated and returned to normal values with treatment. The first patient who was submitted to this therapy stopped the treatment for 5 months and started having abnormal hair growth again. With other patients, after initial treatment with depo-medroxyprogesterone acetate intramuscularly, we started using contraception pills containing medroxyprogesterone; this maintained the reduced ectopic hair growth. The most important side effect was amenorrhea.
MEDROXYPROGESTERONE appears to be the most potent agent for blocking of luteinizing hormone (LH) ( 1 ) . As this synthetic progestogen has been used with success in delaying progression of precocious puberty, we believed it was valid for us to try the use of this agent for treatment of hirsute patients. Just after the beginning of our therapeutic trial, Gordon and colleagues (1) showed that medroxyprogesterone reduced the plasma levels of testosterone in both normal men and women. We present here the results obtained in 24 patients. Materials and Methods Twenty-four patients were studied, the first 12 at the Hospital da Lagoa and the last 12 at the State Institute of Diabetes and Endocrinology. Their ages ranged from 16 to 33 years. The most important clinical features are shown in Table 1. The degree of hirsutism was evaluated as follows. 1. 0 = normal. Only axillary, pubic, and arm and leg hair that required shaving at a frequency of 7 or more days. 2 . 4 - = discrete. Hair at the alba line and peri-areolae, and thicker hair on the arms and legs. 3. + + = moderate. Hair growing on the chin, face, over the lips, and between breasts. 4. + + + =serious. Hair growing on the above mentioned areas and on the back and hips. • From the Section of Endocrinology, Department of Medicine, Hospital da Lagoa, Institute Nacional de Previdencia Social (INPS); the Institute of Diabetes and Endocrinology, Superintendencia de Serviqos Medicos (SUSEME); and the Third Chair of Medicine, Universidade Federal do Rio de Janeiro (UFRJ); Rio de Janeiro, Brasil.
Acne and oily skin have been found in our hirsute patients in categories -f + to + + +. In these patients the hair was harder, thicker, and longer. Table 1 shows the degree of hirsutism and the interval between shaving or depilation before treatment; increase of the interval was one of the measures to evaluate the evolution of the cases. As in the treatment for true precocious puberty, we adopted the dosage of medroxyprogesterone acetate 100 mg intramuscularly every 15 days. This dosage was continued for whatever period of time was needed to obtain the decrease of hirsutism acceptable to the patient and the doctor. Because the aim of this investigation was to ascertain whether or not hirsute women using this therapeutic scheme would respond with clinical improvement of their hirsutism, we describe here only the results of the determinations of the 17-ketosteroids in 24-hour urine and the plasma testosterone, before and after treatment. Therefore, no reference is made to the Jayle tests (2), chromatography of 17-ketosteroids, pelvic pneumography, measurements of serum LH, and other studies. The hormone methods used and the respective normal values for women in our laboratory are as follows: urinary 17-ketosteroids, (Drekter and associates [3]), 5.0 to 9.0 mg/24-h urine; plasma testosterone, isotopic competition with a specific protein (4), 30 to 150 ng/dl of plasma. Having obtained satisfactory results for our patients over various spans of time (ranging from 110 to 405 treatment days), we kept the hirsutism blocked by using anovulatory medication containing medroxyprogesterone. This medication is maintained permanently, being suspended only when the patient wants to have a child. Only two of our patients stopped treatment, wanting pregnancy, and are still being seen in our outpatient clinic. Their menses returned 5 months after discontinuing medication. It is too early at this time (8 months after discontinuing medication) to evaluate whether or not these two patients will become pregnant. Results The results were excellent in 3 cases, good in 20, and showed no improvement in only 1 case. Excellent results are those in which hirsutism decreased from + + + or + + to 0, and good results are those in which it decreased to + . Table 1 shows the grading of the results obtained, the first determination of the urinary 17-ketosteroids in which there was unequivocal decline of the values, and the results of the plasma testosterone determinations. It must be emphasized that the decrease of the urinary 17-ketosteroids and the plasma testosterone usually preceded the clinical results. Figure 1 shows photographically the change in one of our patients (Patient 7 ) .
Annals of Internal Medicine 83:817-819, 1975
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
817
Table 1 . Main Clinical and Laboratory Data of 24 Hirsute Patients*
Patient Age
Menses
Hirsutism Degree
yrs
Depilation Interval f
Clinical Data Results Dayst
Laboratory Results, Before Treatment
Laboratory Results, After Treatment
I V v j Li A LO
17-Ketosteroids§
Plasma Testosterone||
17-Ketosteroids
Plasma Testosterone
ng/dl
mg/24 h urine 4.58
ng/dl
Side Effects
Days**
1
18
O
+++
3
E
110
mg/24 h urine 5.35
2 3
20 22
R O
4 2
G G
141 405
8.80 22.50
189 210
4 5
16 21
O O
5 2
G G
120 139
7.69 6.00
231 241
5.73 13.20 6.45 4.55 6.50
6 7 8 9 10
17 18 18 18 20
O O O O O
3 4 5 5 5
G G G G G
180 160 160 360 135
7.85 2.79 6.60 12.38 11.60
144 283 194 230 210
1.77 1.19 5.00 6.52 8.18
90 136
110 120 90 90 130
11 12 13 14 15
33 23 18 19 32
R R O R A
6 4 4 5 4
G G G E G
195 130 130 330 360
6.33 11.85 4.00 5.06 15.17
178 136 178 192 240
5.45 4.32
157 165
115 100
16 17 18 19 20 21 22
21 26 18 20 21 20 18
R O A O O O O
5 6 5 2 3 3 3
G G G E G G G
160 300 210 180 360 360 310
5.74 3.18 7.55 6.06 3.80 13.40 11.50
23 24
19 21
A O
+++ +++ ++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ +++ ++ + ++ +++ +++ +++ ++ +++ +++ +++
5 4
B G
. • •
8.81 14.40
days
90
273
3.71 8.95
32
53
73
119 60 120 90 60
. .. 155* 135 115 160
. ..
. .. 73 95
4.87
5.40 6.50
. .. . .. Uterine hemorrhage
. . . .
. . . .
. . . .
Uterine hemorrhage
. .. . .. Galactorrhea Uterine hemorrhage
80
. ..
5.00 4.90 4.76 7.15 8.50 84 241
. ..
150 140
Uterine hemorrhage
130 110 115 170 145
. .. 145
170 60
Uterine hemorrhage
. ..
* R = regular; O = oligomenorrhea; A = amenorrhea; E = excellent; G = good; B = bad; + + = moderate; + + + = serious. t Interval between depilation or shaving before treatment. % Number of days from the beginning of the treatment to the first signs of clinical improvement. § Normal = 5.0 to 9.0 mg/24 h urine. || Normal = 30 to 150 ng/dl of plasma. ** Number of days from the beginning of the treatment at which the laboratory results given were determined.
Figure 1 . Abdominal and pubic hair (Patient 7) before (left) and after (right) 9 months of the treatment with depo-medroxyprogesterone acetate.
318
December 2975 • Annals of Internal Medicine • Volume 83 • Number 6
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
Discussion
Different methods have been applied to the treatment of hirsutism. Mashesh and co-workers ( 5 ) , among others, have suggested the constant and combined use of ovary suppressors (contraception pills) and adrenal cortex suppressors (dexamethasone) with variable results. Kirschner and associates (6) showed that high doses of estrogens administered to 11 hirsute patients to eliminate the L H secretion and, indirectly, the androgens produced by the ovaries yielded positive results in only 2 of these patients. In 23 of our 24 cases there was obvious diminution of the ectopic hair with depo-medroxyprogesterone acetate, which was very encouraging. As Gordon and colleagues (1) have shown, this drug seems to be a powerful inhibitor of LH secretion, in addition to increasing the degradation of the plasma testosterone through stimulation of the hepatic reductase that acts on the A ring of testosterone. ACKNOWLEDGMENTS: Received 9 December 1974; revision accepted 27 January 1975.
de Oliveira, M.D., Centro de Estudos do Hospital da Lagoa, Rua Jardim Botanico 501, ZC-20000 Rio de Janeiro, GB, Brasil. References 1. GORDON
GG, SOUTHREN
AL, TOCHIMOTO S, et al: Effect of
medroxyprogesterone acetate (Provera) on the metabolism and biological activity of testosterone. / Clin Endocrinol 30:449-456, 1970 2. JAYLE MF, SCHOLLER R, MAUVAIS-JARVIS P, et al: Excretion des
steroides chez des femmes presentant un virilisme pilaire associe a des troubles du cycle menstruel. Acta Endocrinol 36:375-392, 1961 3. DREKTER
I, PEARSON S, BARTCZAK E, et al: Determination of
urinary steroids. I. Preparation of pigment-free extracts and simplified procedure for estimation of total 17 ketosteroids. / Clin Endocrinol 7:795-800, 1947 4. MURPHY BEP: Measurement of plasma testosterone by competitive protein binding radio assay. Nature (Lond) 201:679-685, 1964 5. MASHESH VB, GRENBLATT RB, AYDAR CK, et al: Urinary steroid
excretion patterns in hirsutism. I. Use of ovarian and adrenal suppression tests in the study of hirsutism. / Clin Endocrinol 24:1238-1249, 1964 6. KIRSCHNER
MA, BARDIN CW, HEMBREE
WC, et al: Effect of
estrogen administration on androgen production and plasma luteinizing hormone in hirsute women. J Clin Endocrinol 30:727732, 1970
• Requests for reprints should be addressed to Rogerio F. Correa
Correa de Oliveira et al. • Medroxyprogesterone for Hirsutism
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
819
Twenty-four hirsute female patients were treated with 100 mg of depo-medroxyprogesterone acetate intramuscularly every 15 days. Twenty-three showed definite improvement from their abnormal hair growth. All patients with initially elevated 17-ketosteroids in 24-hour urine collections showed a decrease of these metabolites with treatment. In eleven patients the initial plasma testosterone level was elevated and returned to normal values with treatment. The first patient who was submitted to this therapy stopped the treatment for 5 months and started having abnormal hair growth again. With other patients, after initial treatment with depo-medroxyprogesterone acetate intramuscularly, we started using contraception pills containing medroxyprogesterone; this maintained the reduced ectopic hair growth. The most important side effect was amenorrhea.
MEDROXYPROGESTERONE appears to be the most potent agent for blocking of luteinizing hormone (LH) ( 1 ) . As this synthetic progestogen has been used with success in delaying progression of precocious puberty, we believed it was valid for us to try the use of this agent for treatment of hirsute patients. Just after the beginning of our therapeutic trial, Gordon and colleagues (1) showed that medroxyprogesterone reduced the plasma levels of testosterone in both normal men and women. We present here the results obtained in 24 patients. Materials and Methods Twenty-four patients were studied, the first 12 at the Hospital da Lagoa and the last 12 at the State Institute of Diabetes and Endocrinology. Their ages ranged from 16 to 33 years. The most important clinical features are shown in Table 1. The degree of hirsutism was evaluated as follows. 1. 0 = normal. Only axillary, pubic, and arm and leg hair that required shaving at a frequency of 7 or more days. 2 . 4 - = discrete. Hair at the alba line and peri-areolae, and thicker hair on the arms and legs. 3. + + = moderate. Hair growing on the chin, face, over the lips, and between breasts. 4. + + + =serious. Hair growing on the above mentioned areas and on the back and hips. • From the Section of Endocrinology, Department of Medicine, Hospital da Lagoa, Institute Nacional de Previdencia Social (INPS); the Institute of Diabetes and Endocrinology, Superintendencia de Serviqos Medicos (SUSEME); and the Third Chair of Medicine, Universidade Federal do Rio de Janeiro (UFRJ); Rio de Janeiro, Brasil.
Acne and oily skin have been found in our hirsute patients in categories -f + to + + +. In these patients the hair was harder, thicker, and longer. Table 1 shows the degree of hirsutism and the interval between shaving or depilation before treatment; increase of the interval was one of the measures to evaluate the evolution of the cases. As in the treatment for true precocious puberty, we adopted the dosage of medroxyprogesterone acetate 100 mg intramuscularly every 15 days. This dosage was continued for whatever period of time was needed to obtain the decrease of hirsutism acceptable to the patient and the doctor. Because the aim of this investigation was to ascertain whether or not hirsute women using this therapeutic scheme would respond with clinical improvement of their hirsutism, we describe here only the results of the determinations of the 17-ketosteroids in 24-hour urine and the plasma testosterone, before and after treatment. Therefore, no reference is made to the Jayle tests (2), chromatography of 17-ketosteroids, pelvic pneumography, measurements of serum LH, and other studies. The hormone methods used and the respective normal values for women in our laboratory are as follows: urinary 17-ketosteroids, (Drekter and associates [3]), 5.0 to 9.0 mg/24-h urine; plasma testosterone, isotopic competition with a specific protein (4), 30 to 150 ng/dl of plasma. Having obtained satisfactory results for our patients over various spans of time (ranging from 110 to 405 treatment days), we kept the hirsutism blocked by using anovulatory medication containing medroxyprogesterone. This medication is maintained permanently, being suspended only when the patient wants to have a child. Only two of our patients stopped treatment, wanting pregnancy, and are still being seen in our outpatient clinic. Their menses returned 5 months after discontinuing medication. It is too early at this time (8 months after discontinuing medication) to evaluate whether or not these two patients will become pregnant. Results The results were excellent in 3 cases, good in 20, and showed no improvement in only 1 case. Excellent results are those in which hirsutism decreased from + + + or + + to 0, and good results are those in which it decreased to + . Table 1 shows the grading of the results obtained, the first determination of the urinary 17-ketosteroids in which there was unequivocal decline of the values, and the results of the plasma testosterone determinations. It must be emphasized that the decrease of the urinary 17-ketosteroids and the plasma testosterone usually preceded the clinical results. Figure 1 shows photographically the change in one of our patients (Patient 7 ) .
Annals of Internal Medicine 83:817-819, 1975
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
817
Table 1 . Main Clinical and Laboratory Data of 24 Hirsute Patients*
Patient Age
Menses
Hirsutism Degree
yrs
Depilation Interval f
Clinical Data Results Dayst
Laboratory Results, Before Treatment
Laboratory Results, After Treatment
I V v j Li A LO
17-Ketosteroids§
Plasma Testosterone||
17-Ketosteroids
Plasma Testosterone
ng/dl
mg/24 h urine 4.58
ng/dl
Side Effects
Days**
1
18
O
+++
3
E
110
mg/24 h urine 5.35
2 3
20 22
R O
4 2
G G
141 405
8.80 22.50
189 210
4 5
16 21
O O
5 2
G G
120 139
7.69 6.00
231 241
5.73 13.20 6.45 4.55 6.50
6 7 8 9 10
17 18 18 18 20
O O O O O
3 4 5 5 5
G G G G G
180 160 160 360 135
7.85 2.79 6.60 12.38 11.60
144 283 194 230 210
1.77 1.19 5.00 6.52 8.18
90 136
110 120 90 90 130
11 12 13 14 15
33 23 18 19 32
R R O R A
6 4 4 5 4
G G G E G
195 130 130 330 360
6.33 11.85 4.00 5.06 15.17
178 136 178 192 240
5.45 4.32
157 165
115 100
16 17 18 19 20 21 22
21 26 18 20 21 20 18
R O A O O O O
5 6 5 2 3 3 3
G G G E G G G
160 300 210 180 360 360 310
5.74 3.18 7.55 6.06 3.80 13.40 11.50
23 24
19 21
A O
+++ +++ ++ +++ +++ +++ +++ +++ +++ +++ ++ +++ +++ +++ ++ + ++ +++ +++ +++ ++ +++ +++ +++
5 4
B G
. • •
8.81 14.40
days
90
273
3.71 8.95
32
53
73
119 60 120 90 60
. .. 155* 135 115 160
. ..
. .. 73 95
4.87
5.40 6.50
. .. . .. Uterine hemorrhage
. . . .
. . . .
. . . .
Uterine hemorrhage
. .. . .. Galactorrhea Uterine hemorrhage
80
. ..
5.00 4.90 4.76 7.15 8.50 84 241
. ..
150 140
Uterine hemorrhage
130 110 115 170 145
. .. 145
170 60
Uterine hemorrhage
. ..
* R = regular; O = oligomenorrhea; A = amenorrhea; E = excellent; G = good; B = bad; + + = moderate; + + + = serious. t Interval between depilation or shaving before treatment. % Number of days from the beginning of the treatment to the first signs of clinical improvement. § Normal = 5.0 to 9.0 mg/24 h urine. || Normal = 30 to 150 ng/dl of plasma. ** Number of days from the beginning of the treatment at which the laboratory results given were determined.
Figure 1 . Abdominal and pubic hair (Patient 7) before (left) and after (right) 9 months of the treatment with depo-medroxyprogesterone acetate.
318
December 2975 • Annals of Internal Medicine • Volume 83 • Number 6
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
Discussion
Different methods have been applied to the treatment of hirsutism. Mashesh and co-workers ( 5 ) , among others, have suggested the constant and combined use of ovary suppressors (contraception pills) and adrenal cortex suppressors (dexamethasone) with variable results. Kirschner and associates (6) showed that high doses of estrogens administered to 11 hirsute patients to eliminate the L H secretion and, indirectly, the androgens produced by the ovaries yielded positive results in only 2 of these patients. In 23 of our 24 cases there was obvious diminution of the ectopic hair with depo-medroxyprogesterone acetate, which was very encouraging. As Gordon and colleagues (1) have shown, this drug seems to be a powerful inhibitor of LH secretion, in addition to increasing the degradation of the plasma testosterone through stimulation of the hepatic reductase that acts on the A ring of testosterone. ACKNOWLEDGMENTS: Received 9 December 1974; revision accepted 27 January 1975.
de Oliveira, M.D., Centro de Estudos do Hospital da Lagoa, Rua Jardim Botanico 501, ZC-20000 Rio de Janeiro, GB, Brasil. References 1. GORDON
GG, SOUTHREN
AL, TOCHIMOTO S, et al: Effect of
medroxyprogesterone acetate (Provera) on the metabolism and biological activity of testosterone. / Clin Endocrinol 30:449-456, 1970 2. JAYLE MF, SCHOLLER R, MAUVAIS-JARVIS P, et al: Excretion des
steroides chez des femmes presentant un virilisme pilaire associe a des troubles du cycle menstruel. Acta Endocrinol 36:375-392, 1961 3. DREKTER
I, PEARSON S, BARTCZAK E, et al: Determination of
urinary steroids. I. Preparation of pigment-free extracts and simplified procedure for estimation of total 17 ketosteroids. / Clin Endocrinol 7:795-800, 1947 4. MURPHY BEP: Measurement of plasma testosterone by competitive protein binding radio assay. Nature (Lond) 201:679-685, 1964 5. MASHESH VB, GRENBLATT RB, AYDAR CK, et al: Urinary steroid
excretion patterns in hirsutism. I. Use of ovarian and adrenal suppression tests in the study of hirsutism. / Clin Endocrinol 24:1238-1249, 1964 6. KIRSCHNER
MA, BARDIN CW, HEMBREE
WC, et al: Effect of
estrogen administration on androgen production and plasma luteinizing hormone in hirsute women. J Clin Endocrinol 30:727732, 1970
• Requests for reprints should be addressed to Rogerio F. Correa
Correa de Oliveira et al. • Medroxyprogesterone for Hirsutism
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
819
