Abstract
Objective: To assess the clinical and endocrinological
efficacy of a combination of spironolactone and oral contraceptive pills in the
treatment of hirsutism.
Methods: Thirty-six hirsute women were involved in our
study; all patients were evaluated clinically and by laboratory investigation
before and after six months of treatment with spironolactone (100 mg/day) and
Microgynon 30 tables (levonorgestrel 0.15 mg and ethinylestradiol 0.03) from
day 5 to day 26 of the cycle. Each patient recorded her subjective assessment
of hair growth and any side effects. The
results for the group were expressed as means + standard deviation.
Results: Out of the 36 patients, 32 completed 6 months
of treatment; while 4 patients withdrew from the study due to persistent
nausea. Of the 32 patients, 25 had both
subjective and objective improvement. Serum level of (testosterone,
androstenedione and 17 hydroxyprogesterone) were significantly reduced and sex
hormone binding globulin (SHBG) levels were significantly higher after
treatment. LH, FSH levels were suppressed in all patients to levels of less
than 0.9 i.u/l and less than 0.5 i.u/l after treatment.
Conclusion: Spironolactone in
combination with oral contraceptive is effective and well tolerated for the
treatment of hirsutism.
Key
words: Hirsutism,
Spironolactone, Contraceptive pills.
JRMS
Dec 2004; 11(2): 27-29
Introduction
Hirsutism is a troublesome cosmetic problem, may also be a sign of
serious systemic disease, most patients with functional hirsutism have elevated
production rates of testosterone, elevated metabolic clearance rates of
testosterone, depressed levels of sex hormone binding globulin, and elevated
levels of serum free testosterone and hair follicle sensitivity (1). Pharmacological therapy consists of anti -
androgens and includes the androgen receptor blockers, spironolactone and
cyproterone acetate (2).
Other drugs reducing androgen expression include oral contraceptives and
corticosteroids. A new follicular
5-alpha reductase inhibitor (finasteride) is currently under evaluation as an
anti – androgen. Flutamide (2-4) gonadotrophin, by releasing
hormone agonists suppresses the pituitary, decreases androgen and estradiol
secretion, improves severe hirsutism and shows early promise in the treatment
of hirsute (2,4,5).
A major action of spironolactone is to inhibit androgen-binding
receptor molecules in the cytosol or of the nucleus of target tissues, such as
the skin; it inhibits steroidogenesis by interfering with ovarian enzymatic
activity and inhibits 5-α reductase activities in pilo sebaceous unit (6).
Cyproterone acetate in combination with estrogen has been widely advocated (7,8)
but it is associated with a
number of side
effects. The diuretic
spironolactone, has been
demonstrated to be useful
(9,10,11) but when given alone it is not as effective as the
cyproterone acetate/estrogen combination (12) or in
combination with oral contraceptive (13,14).
Furthermore, nearly 56% of women experienced the problem of
polymenorrhea and other side effects such as urticaria, and scalp hair loss (15,16). To overcome this problem and to produce an
elevation of sex hormone binding globulin (SHBG) (17) we have
assessed the effect of adding estrogen in the form of oral contraceptive to the
spironolactone (100 mg daily).
Methods
Thirty-six premenopausal hirsute women were involved in our study
between 1997 and 2000 at Queen - Alia Military hospital. None of these patients used any medications
in the previous six months. The patients
were advised to avoid pregnancy during the study period. A complete medical and
gynecological examination was performed for each patient. A 20 ml sample of
blood was obtained in the follicular phase in patients with regular menses.
Seven patients had irregular cycles more prolonged than 35 days. Luteinizing hormone (LH),
follicle-stimulating hormone (FSH), testosterone, androstenedione, dehydroepi
and rosterone one sulphate (DHA-S) and sex hormone binding globulin (SHBG) were
measured.
After 6 months of treatment with spironolactone (100mg)
and microgynon 30 from day 5 to 26 of the cycle, all the above mentioned
investigations were repeated. Patients
with hyperprolactinemia, ovarian or adrenal neoplasm, drug - induced hirsutism,
cushing disease, and thyroid disease were excluded. Distributions of patients
according to age, and weight were shown in Table I and II.
Ferriman - Gallwey (F-G) scoring system (16) was
used to assess hair growth before and after treatment, the hair score was
assessed on all occasions by the same observer.
Paired t- test was carried out to detect the significance of
hormonal profile changes, which were expressed as means and standard deviation
values.
Results
Of the 36 patients, 32 completed 6 months of
treatment. Four patients withdrew due to persistent nausea.
Breast tenderness occurred in two patients and intermenstrual
spotting in three. No changes in blood
pressure were demonstrated.
Two reported polyuria in the first few days of treatment. After 6 months of treatment, 25 of the 32
patients showed an improvement on the basis of a reduction of more than 3
points in the score Ferriman and Gallwey hair.
No patient had a higher score after the treatment, and the hair scores
fell from a mean of 17.3 (± 2.8) to 11.1 (± 2.7), (p<0.01). LH and FSH were suppressed in all patients to
levels of <0.7 i.u/L and <0.2 i.u./L after treatment. Serum levels of
testosterone, androstenedione, and 17-OHP were significantly reduced and SHBG
levels were significantly higher after treatment (Table I). Serum levels of
testosterone were suppressed from 3.2 ±
0.3 n mol /
L to
2.3 ± 0.2 n
mol /L (p<0.05), androstenedione
from 8.7 ± 0.3 n mol /L to 4.5 ± 0.4 n
mol /L (p<0.01), 17
hydroxyprogesterone from 7.4 ± 0.7 to
3.1 ± 6.3 (p<0.01), and SHBG raised from 48 ± 3 to 102 ± 8
(p<0.005), no significant change of Dehydroepiandrosterone sulphate before
and after treatment 5.2 ± 0.3 n mol /L
to 4.3 ± 0.3 n mol /L.
Discussion
Spironolactone blocks androgen receptors and its effectiveness in
hirsutism is dosage - dependent, Low dosages are less active than other
antiandrogens, whereas high dosages (200 mg /day) are very effective at the
cost of several adverse effects particularly dysfunctional uterine bleeding (2,15,16).
Spironolactone when given alone is not as effective as in
combination with oral contraceptive (13,14).
The addition of oestrogen increase, therapeutic effectiveness by
suppressing gonadotrophin - mediated ovarian androgen secretion and by
increasing sex hormone binding in plasma, this reduce the free, biologically
androgen in the circulation (2).
GnRH agonist, suppressing the pituitary, decrease
androgen and oestradiol secretion and improve severe hirsutism, to avoid
estrogen deficiency problem, (add back) therapy with estrogen -progestogens or
combined oral contraceptives is advised, this method of treatment is
complicated and expensive limiting its use to severe form of ovarian
hyperandrogenism with hyperinsulinemia (2,5). Cyproterone acetate with ethinyl oestradiol
is effective and better tolerated but much expensive than the combination of
spironolactone and the oral contraceptive pills (19). Bassaw et al (20)
showed no significant change in hirsutism index, and measurement of serum
testosterone, androstenedione, Dehydroepiandrosterone sulphate and sex hormone
binding globulin (binding Capacity).
Although spironolactone has a known diuretic effect, this was not
a long term problem in any of our patients, two reported polyuria in the first
few days of treatment. No changes in blood pressure were demonstrated during
treatment. In our study combination of
spironolactone and microgynon produced an improvement in hirsutism as assessed
by Ferriman and Gallwey score in 78% of the patient who completed treatment
also produced significant change in serum androgen concentration including
serum levels of testosterone, androstenedione, 17-hydroxy progesterone and sex
hormone binding globulin so spironolactone in combination with oral oestrogen
are effective and well tolerated agents for the treatment of hirsutism.
Table I. Distribution of patients according to age
|
Age
(year)
|
Number of patients
|
|
<
20
|
4
|
|
21
– 25
|
12
|
|
26
– 30
|
9
|
|
31
– 35
|
8
|
|
36
– 40
|
3 |
Table II. Distribution of
patients according to weight.
|
Weight
(kg)
|
Number
of patients
|
|
<
50
|
3
|
|
50
– 60
|
7
|
|
61
– 70
|
15
|
|
71
– 80
|
8
|
|
>80
|
3 |
Table III. Serum androgen concentrations before and
after 6 months of treatment with spironolactone 100 mg plus Microgynon 30.
|
|
Pre-treatment
|
Post-treatment
|
Significance of difference (P)
|
|
Testosterone
|
3.2 (± 0.3)
|
2.3 (± 0.2)
|
< 0.05
|
|
Androstenedione
(n mol/L)
|
8.7 (± 0.8)
|
4.5 (± 0.4)
|
< 0.01
|
|
Dehydroepiandrosterone
Sulphate (μ
mol/L)
|
5.2 (± 0.3)
|
4.3 (± 0.3)
|
NS
|
|
17-
hydroxy progesterone (n mol/L)
|
7.4 (± 0.7)
|
3.1 (± 6.3)
|
< 0.01
|
|
Sex
hormone binding globulin (Binding Capacity)
|
48 (±3)
|
102 (± 8)
|
< 0.005 |
Results are
means + SD.
References
1. Kvedar JC, Gibson M,
Krusinski PA. Hirsutism: Evaluation and treatment. J Am
Acad Dermatol 1985; 12 : 2 (part 1) 215-225.
2. Falsettil L, Gambera A,
Platto C. Management of hirsutism. Am J Clin Dermatol 2000; 1(2): 89-99.
3. Cusan L, Dupont A, Gomez
JL, et al. Comparison of Flutamide and spironolactone in
the treatment of hirsutism; a randomized controlled trial. Fertil Steril 1994; 61(2): 281-287.
4. Cusan L, Dupont A, Belanger
A, et al.
Treatment of hirsutism with the pure antiandrogen flutamide. J Am Acad Dermatol 1990; 23(3):
115-116
5. Young R, Sinelair R.
Hirsute. II: Treatment. J Dermatol 1998, 39(3): 151-157.
6. Tremblay RR.
Treatment of hirsutism with spironolactone. Clin Endocrinol Metab 1986;
15(2): 363-371.
7. Erenus M, Yücelten D,
Gürbüz O, et al. Comparison of
spironolactone - oral contraceptive versus cyproterone acetate - estrogen
regimens in the treatment of hirsutism. Fertil
Steril 1996; 66(2): 216-219.
8. O’Brien RC, Cooper ME,
Murray RM, et al. Comparison of sequential
cyproterone acetate /estrogen versus spironolactone /oral contraceptive in the
treatment of hirsutism. J Clin Endocrinol Metab 1991; 72(5): 1008-1013.
9. Shaw JC. Spironolactone in dermatologic therapy. J Am Acad Dermatol 1991; 24(2): 236-
243.
10. Yistalo P, Heikkinen J, Kauppila A, et al. Low – dose spironolactone in the treatment of
female hirsutism. Int J Fertil
1987; 32(1): 41-45.
11. Vetr M. Hirsutism - a low dose spironolactone
therapy. Acta Univ Palacki Olomuc Fac
Med 1989; 122: 239- 245.
12. Chapman MG, Katz M, Dowsett M, et al. Spironolactone in the treatment of hirsutism. Acta Obstet Gynecol Scand 1986; 65(4): 349-350.
13. Wild RA, Demers LM, Applebaum-Bowden D, et al. Hirsutism:
Metabolic effects of two commonly used oral contraceptives and spironolactone. Contraception
1991; 44(2): 113-124.
14. Pittaway DE, Maxson WS, Wentz AC.
Spironolactone in combination drug therapy for unresponsive hirsutism. Fertil
Steril, 1985; 43(6) 878 - 882.
15. Vetr M, Sobek A. Low dose spironolactone in
the treatment of female hyperandrogenemia and hirsutism. Acta Univ Palacki
Olomuc Fac Med, 1993; 135: 55-57.
16. Helfer EL, Miller JL, Rose LI. Side - effects of spironolactone therapy in
the hirsute woman. J Clin Endocrinol Metab. 1988; 66(1): 208-211.
17. Mckenna KM, Popperell RJ, Evans J. Hirsutismin
a gynecological context. Aust N2 J Obestet Gynaecol. 1990; 30(2): 153
-156.
18. Ferrimen D, Gallway JD. Clinical assessment
of body hair growth in women. J Clin Endocrinol Metab. 1961; 21: 1440 -
1447.
19. Marcondes JA, Minanni SL, Luthold WW. The
effects of spironolactone on testosterone fractions and sex-hormone binding
globulin binding capacity in hirsute women. J Endocrine Invest. 1995; 18(6): 431-435.
20. Bassaw B, Maharaj R, Ali A, et al.
Therapeutic alternatives for the hirsute women. West Indian Med J. 1992;
41(1): 12- 14.