ORIGINAL ARTICLE
Lynestrenol induced therapeutic amenorrhea: Effects of dose reduction on serum sex-hormones and lipids KARIJ. L. HUOVINEN’, PEKKA
LAHTEENMAKI’,
JOMAKARKKAINEN3 AND MATTIJ. TIKKANEN4
From the Rinnekoti Institute for the Mentally Retarded’, Steroid Research Laboratory and Department of Medical Chemistry, University of Helsinki, Helsinki, Finland2,Pediatric Department3 and First Department of Medicine4, University Central Hospital of Meilahti, Helsinki, Finland.
Actu Ohstet Gynecol Scand 1992; 71: 175-180
The effect of reducing the dose of peroral lynestrenol by half on serum sex-hormone, lipid and lipoprotein status was studied in 21 mentally retarded women with therapeutic amenorrhea (TA). They had previously received 5 o r 10 mg peroral lynestrenol daily for periods ranging from 32 to 196 months. Dose halving of lynestrenol rcsulted in an increase in seriim total testosterone (T) by 16% (p < 0.05). sex-hormone binding globulin (SHBG) by 39% (p < 0.01) and highdensity lipoprotein cholesterol (HDL.-C) by 28% (p < 0.001). Both the mean serum total and free concentrations of norethisterone (NET and tNET) decreased by 60% (p < 0,001). The serum concentrations of 17-beta-estradiol (E?), its free fractions (fEz) and free T (ff) were not significantly altered. Significant correlations were observed between the change in HDL-C and the change in T (r = 0.45, p < 0.05), between the change in SHBG and the change in T (r = 0.62, p < 0.01), ff (r = 0.43. p < 0.05) and Ez (r = 0.51, p < 0.05). The elevation of HDL-C was probably caused by the reduced serum NET concentrations. This also resulted in an increase in serum SHBG concentration, which is regarded as an indicator of the overall estrogen/androgen ratio. Key words: therapeutic amenorrhea; lynestrenol; norethisterone; estradiol; testosterone; SHBG; serum lipids and lipoproteins Submitted September 13, I991 Accepted October 26, I 9 Y l
Therapeutic doses of androgenic progestins reduce the serum concentration of high-density lipoprotein cholesterol (HDL-C), whereas the estrogens used in oral contraception or in hormonal replacement therapy have the opposite effect (1,2). In both types of treatment the progestin is necessary for preventing excessive endometrial proliferation, when the uterus is intact. The effect on the HDL-C level is determined by the estrogen - progestin dose ratio as well as by the androgenicity of the progestin component. Due to avoidance of menstruation related prob-
lems in severely mentally retarded women therapeutic amenorrhea (TA) with peroral lynestrenol became popular in Finland (3,4). Mentally retarded women usually receive lynestrenol 5-10 mg/day for years. At present the incidence of lynestrenol induced TA among Finnish institutionalized mentally retarded women is about 50% (4). In a previous study (5) we reported that the reduction of the lynestrenol dose resulted in significantly increased HDL-C concentration. In this study we sought to elucidate the factors contributing to this change by measuring the total and free sex-hormone Actu Ohstet Gynecol S c a d 71 (IYYZ)
176
Huovinen et al.
Table I. Clinical characteristics of patients (mean f SD) Initial lynestrenol dose 5 mg 10 mg Duration (months) on initial dose on half dose Age (years) Height (cm) Weight (kg) BMI (kg/cm') Blood pressure (mmHg) systolic diastolic
N=15 N=6 82 It: 48 3 . 8 f 1.3 28.8f 6.7 153 k 12 47.4 k 11.5 23.7f 2.5 121 k 17 7 6 5 10
levels, sex-hormone binding_ globulin (SHBG), se_ rum lipids, lipoproteins, and the serum concentration of total and free norethisterone (NET), which is the active metabolite of lynestrenol (6,7):
Material and methods The patient population consisted of 21 mentally retarded women. They all had been receiving lynestrenol (Orgametril', Organon, Netherlands) therapy for 32-196 months (Table I). Diabetics and pa-
tients receiving anticonvukant or antihypertensive drug therapy were excluded. The results of the initial analyses were taken as baseline levels, reflecting the situation which had lasted on average for several years (Table I). The lynestrenol dose was reduced by half (from 10 mg to 5 mg, or from 5 to 2.5 mg per day). Approximately four months later new venous blood samples were obtained after overnight fasting and kept frozen (-20°C) until analyzed. During the study 10 of the 21 patients also received peroral estriol succinate (12 mg/day) (5). As the addition of estriol had no effect on any of the lipid or lipoprotein variables (9,the results of all lynestrenol-receiving patients were pooled and analyzed together. Assessment of blood lipid and lipoprotein status
Serum concentrations of triglyceride (TG), cholesterol, HDL-C, apolipoprotein A, (Apo A,) and apolipoprotein B (Apo B) were measured as described before (5). Serum concentration of low-density lipoprotein cholesterol (LDL-C) was calculated according the equation of Friedewald et al. (8). This method is valid when the TG concentration is less than 4.0 mmolA (9). The present range was 0.3-1.15 mmoVL.
Table 11. Sex-hormone, lipid, lipoprotein and apoprotein concentrations in women receiving 5 or 10 mg lynestrenol for therapeutic amenorrhea (mean f SD): serum concentrations of 17-beta-estradiol (EJ, testosterone (T), norethisterone (NET), sex hormone binding globulin (SHBG), and the free fractions of E, (fE2),T (ff) and NET (fNET), triglyceride (TG). total cholesterol (tot-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (Apo B) and apolipoprotein A, (Apo A,) Lynestrenol Initial dose
Half dose
Change (%)
0.148 1.51 17.1 12.2
0.177 1.73 6.94 16.9
20 16 -60 39
f0.073 k0.45 k9.94 f4.07
f0.134 +0.53* f4.15*** k8.29**
E, T NET SHBG
(nmol/L) (nmol/L) (nmol/L) (nmollL)
fE,
(nmol/L) (nmol/L) (nmol/L)
0.0031 f 0.0015 0.0343 k 0.0105 1.089 f 0.659
0.0038 f 0.0022 0.0358 f 0.0114 0.433 k0.273***
(mmol/L)
0.63 4.66 3.50 0.87
k0.22 k 1.18 _+ 1.10 f0.16
0.65 4.76 3.37 1.11
k0.22 f 1.07 f0.96 f0.19***
1.19 0.94
k0.21 k0.27
1.22 0.89
f0.14 f0.26
ff
MET TG tot-C LDL-C HDL-C
(mmol/L)
(mmol/L) (mmollL)
APo A, (g/L) Apo B (dL) Number of patients in amenorrhea with menopausal Ez (
Lynestrenol induced therapeutic amenorrhea: Effects of dose reduction on serum sex-hormones and lipids KARIJ. L. HUOVINEN’, PEKKA
LAHTEENMAKI’,
JOMAKARKKAINEN3 AND MATTIJ. TIKKANEN4
From the Rinnekoti Institute for the Mentally Retarded’, Steroid Research Laboratory and Department of Medical Chemistry, University of Helsinki, Helsinki, Finland2,Pediatric Department3 and First Department of Medicine4, University Central Hospital of Meilahti, Helsinki, Finland.
Actu Ohstet Gynecol Scand 1992; 71: 175-180
The effect of reducing the dose of peroral lynestrenol by half on serum sex-hormone, lipid and lipoprotein status was studied in 21 mentally retarded women with therapeutic amenorrhea (TA). They had previously received 5 o r 10 mg peroral lynestrenol daily for periods ranging from 32 to 196 months. Dose halving of lynestrenol rcsulted in an increase in seriim total testosterone (T) by 16% (p < 0.05). sex-hormone binding globulin (SHBG) by 39% (p < 0.01) and highdensity lipoprotein cholesterol (HDL.-C) by 28% (p < 0.001). Both the mean serum total and free concentrations of norethisterone (NET and tNET) decreased by 60% (p < 0,001). The serum concentrations of 17-beta-estradiol (E?), its free fractions (fEz) and free T (ff) were not significantly altered. Significant correlations were observed between the change in HDL-C and the change in T (r = 0.45, p < 0.05), between the change in SHBG and the change in T (r = 0.62, p < 0.01), ff (r = 0.43. p < 0.05) and Ez (r = 0.51, p < 0.05). The elevation of HDL-C was probably caused by the reduced serum NET concentrations. This also resulted in an increase in serum SHBG concentration, which is regarded as an indicator of the overall estrogen/androgen ratio. Key words: therapeutic amenorrhea; lynestrenol; norethisterone; estradiol; testosterone; SHBG; serum lipids and lipoproteins Submitted September 13, I991 Accepted October 26, I 9 Y l
Therapeutic doses of androgenic progestins reduce the serum concentration of high-density lipoprotein cholesterol (HDL-C), whereas the estrogens used in oral contraception or in hormonal replacement therapy have the opposite effect (1,2). In both types of treatment the progestin is necessary for preventing excessive endometrial proliferation, when the uterus is intact. The effect on the HDL-C level is determined by the estrogen - progestin dose ratio as well as by the androgenicity of the progestin component. Due to avoidance of menstruation related prob-
lems in severely mentally retarded women therapeutic amenorrhea (TA) with peroral lynestrenol became popular in Finland (3,4). Mentally retarded women usually receive lynestrenol 5-10 mg/day for years. At present the incidence of lynestrenol induced TA among Finnish institutionalized mentally retarded women is about 50% (4). In a previous study (5) we reported that the reduction of the lynestrenol dose resulted in significantly increased HDL-C concentration. In this study we sought to elucidate the factors contributing to this change by measuring the total and free sex-hormone Actu Ohstet Gynecol S c a d 71 (IYYZ)
176
Huovinen et al.
Table I. Clinical characteristics of patients (mean f SD) Initial lynestrenol dose 5 mg 10 mg Duration (months) on initial dose on half dose Age (years) Height (cm) Weight (kg) BMI (kg/cm') Blood pressure (mmHg) systolic diastolic
N=15 N=6 82 It: 48 3 . 8 f 1.3 28.8f 6.7 153 k 12 47.4 k 11.5 23.7f 2.5 121 k 17 7 6 5 10
levels, sex-hormone binding_ globulin (SHBG), se_ rum lipids, lipoproteins, and the serum concentration of total and free norethisterone (NET), which is the active metabolite of lynestrenol (6,7):
Material and methods The patient population consisted of 21 mentally retarded women. They all had been receiving lynestrenol (Orgametril', Organon, Netherlands) therapy for 32-196 months (Table I). Diabetics and pa-
tients receiving anticonvukant or antihypertensive drug therapy were excluded. The results of the initial analyses were taken as baseline levels, reflecting the situation which had lasted on average for several years (Table I). The lynestrenol dose was reduced by half (from 10 mg to 5 mg, or from 5 to 2.5 mg per day). Approximately four months later new venous blood samples were obtained after overnight fasting and kept frozen (-20°C) until analyzed. During the study 10 of the 21 patients also received peroral estriol succinate (12 mg/day) (5). As the addition of estriol had no effect on any of the lipid or lipoprotein variables (9,the results of all lynestrenol-receiving patients were pooled and analyzed together. Assessment of blood lipid and lipoprotein status
Serum concentrations of triglyceride (TG), cholesterol, HDL-C, apolipoprotein A, (Apo A,) and apolipoprotein B (Apo B) were measured as described before (5). Serum concentration of low-density lipoprotein cholesterol (LDL-C) was calculated according the equation of Friedewald et al. (8). This method is valid when the TG concentration is less than 4.0 mmolA (9). The present range was 0.3-1.15 mmoVL.
Table 11. Sex-hormone, lipid, lipoprotein and apoprotein concentrations in women receiving 5 or 10 mg lynestrenol for therapeutic amenorrhea (mean f SD): serum concentrations of 17-beta-estradiol (EJ, testosterone (T), norethisterone (NET), sex hormone binding globulin (SHBG), and the free fractions of E, (fE2),T (ff) and NET (fNET), triglyceride (TG). total cholesterol (tot-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (Apo B) and apolipoprotein A, (Apo A,) Lynestrenol Initial dose
Half dose
Change (%)
0.148 1.51 17.1 12.2
0.177 1.73 6.94 16.9
20 16 -60 39
f0.073 k0.45 k9.94 f4.07
f0.134 +0.53* f4.15*** k8.29**
E, T NET SHBG
(nmol/L) (nmol/L) (nmol/L) (nmollL)
fE,
(nmol/L) (nmol/L) (nmol/L)
0.0031 f 0.0015 0.0343 k 0.0105 1.089 f 0.659
0.0038 f 0.0022 0.0358 f 0.0114 0.433 k0.273***
(mmol/L)
0.63 4.66 3.50 0.87
k0.22 k 1.18 _+ 1.10 f0.16
0.65 4.76 3.37 1.11
k0.22 f 1.07 f0.96 f0.19***
1.19 0.94
k0.21 k0.27
1.22 0.89
f0.14 f0.26
ff
MET TG tot-C LDL-C HDL-C
(mmol/L)
(mmol/L) (mmollL)
APo A, (g/L) Apo B (dL) Number of patients in amenorrhea with menopausal Ez (
