Abstract
The aim of the study was to investigate the hypothesis that women using depogestagens
and low-dose oral contraceptives (Ethinylęstradiol ?20ęg) carry a higher risk of
postmenopausal osteoporosis. The use of these hormonal contraceptives results in marked
decrease of estradiol serum level, which suggest a negative impact on bone metabolism
with long-term effects on peak bone mass and premenopausale bone density.
The present study contributed to clarifying this hypothesis since the influence of progestins
of different partial effects on bone density in adult female rats were investigated.
The first experiment detected for the first time the relationship between 17-? -estradiol
substitution doses, 17-? -estradiol-serum level and the decrease of bone density in adult
ovariectomised rats.
52 three month old female rats were randomised into six groups. Five groups were
ovariectomised and one group SHAM-operated. Four groups received 17-? -estradiol-substitution
over 28 days as follows:
0,5 ęg/ rat * day
0,3 ęg/ rat * day
0,1 ęg/ rat * day
0,05 ęg/ rat * day.
Along with rapid decrease of 17-? -estradiol serum level, the OVX-control rats showed a
30 % reduction of bone density. Osteocalcin was significantly increased. The oestrogen
treatment of the ovariectomised groups influenced the bone density and 17-? -estradiol-serum
levels in a dose-dependent manner. In the substitution groups of 0,5 ęg and 0,3 ęg/
rat*day the bone density was not changed. The 17-? -estradiol -serum concentration
reached nearly constant levels for the first group at 140 pmol/l and for the last at 60 pmol/l.
Contrary to these findings, bone resorption increased in the 0,1 ęg and 0,05 ęg/ rat*day
treated groups at about 10 % and 14 %. The average 17-? -estradiol -serum levels ranged
between 50 and 32 pmol/l.
From this experiment it is suggested that the serum estradiol level of 50 pmol/l is a crucial
threshold value for bone density in female rats. As the 17-? -estradiol -serum levels fell
below this level, negative effects on bone density were observed. On the other hand, serum
estradiol levels above 50 pmol/l suppress bone resorption and work bone protective.
In a second experiment, the minimal ovulation inhibition dose for the applied progestins
(Levonorgestrel, Medroxyprogesteronacetat und Promegeston) were determined.
Three doses for each progestin were tested. According to this experiment and internally
performed trials at the Schering AG the following doses for application in the third
experiment were scheduled:
Levonorgestrel ę 50 ęg/ rat and day
Medroxyyprogesteronactat ę 500 ęg/ rat and day
Promegeston ę 50 ęg/ rat and day
In the third experiment, the influence of progestin treatment in an ovulation inhibiting dose
over a period of seven weeks on bone density was investigated.
47 three-month-old female rats were randomised into five groups. Three groups, each with
eight rats, received the three mentioned progestins in ovulation inhibiting dose. One group
with 16 rats received vehicle and served as an intact control group. One group with seven
rats was ovariectomised.
At the end of the experiment none of the progestin treated groups showed a significant
change of bone density compared to the intact control group. However, the bone density
decreased by 30 % in the ovariectomised group, as had been expected.
The 17-? -estradiol -serum level of the progestin treated groups reached 80 pmol/l. In the
ovariectomised group 30 pmol/l was determined.
These results confirm the findings of the first experiment where a crucial threshold value
for bone density preservation at 50 pmol/l was found.
17-? -estradiol serum levels higher than 50 pmol/l are bone protective. None of the
investigated progestins leads to a decrease of the 17-? -estradiol serum levels below this
limit. These findings suggest that negative effects on the bone density of the investigated
progestins given in an ovulation inhibiting dose to adult rats can be excluded. In this
context, no influence of an androgen partial effect on bone density and bone structure
could be observed. |
