Download Allylestrenol: Three Years of Experience with Gestanon

CLINICAL THERAPEUTICS/VOL. 3, NO. 3, 1980
Allylestrenol: Three Years of Experience with
Gestanon in Threatened Abortion and Premature
Labor
Joaquín Cortes-Priéto, Alberto Oriol Bosch, and José
Arendbia Rocha
School of Medicine, Complutensis University, Madrid, Spain
ABSTRACT
Allylestrenol* was used to treat 375
women with threatened pregnancies.
Results show that this drug is capable of
maintaining pregnancy in a large series of
ambulant patients and is safe for both
mother and child. Allylestrenol does not
maintain
pregnancy
if
placental dysfunction is present, however.
Newborns whose mothers are treated
with allylestrenol have slightly higher
birth weights than controls. The possible role of allylestrenol in this process is
discussed. At high doses, allylestrenol
effectively stops premature labor, suggesting a selective action on the myometrium.
INTRODUCTION
In normal fertile women the ovary performs a dual function: providing an
ovum for fertilization and preparing the
endometrium for the nidation of the fertilized ovum. Once pregnancy is initiated the ovary must supply the principal substances required to maintain it.
*Trademark: Gestanon® (Organon International, Oss, Holland).
200
By the end of the first trimester ovarian
function gradually subsides and its task
is taken over by the placenta. Both
ovary and placenta may be the source of
many disturbances associated with failures to carry a pregnancy to term.
Many women suffer from a deficiency in the pre gnancy-maintaining
system. These deficiencies can either be
fetal — e.g., in severe malformations —
or maternal in origin. In the latter case
progesterone is thought to play a major
role. Hormonal deficiencies resulting
from corpus luteum graviditatis insufficiency or an impaired trophoblastic
function have been postulated as principal causes of threatened and habitual
abortion.
How progesterone protects pregnancy has not yet been fully elucidated.
The protection of the myometrium
against contractions is one of the most
accepted possibilities. It has been
known for a long time that progesterone reduces the sensitivity of the
myometrium to oxytocin. 1 This progesterone blockade during pregnancy
may be due to the fact that the placenta
releases its progesterone directly into
the adjacent tissue. This theory may explain many of the phenomena ob-
J. CORTÉS-PRIETO ET AL.
served.2 For this reason investigators
have looked for methods and drugs to
stimulate placental progesterone production. Allylestrenol is thought to be
such a substance.3 Observations in this
direction demonstrate that allylestre nol stimulates the enzymatic activity of
the existing syncytiotrophoblast. 4 Earlier investigations indicated an increase in
placental
3β-hydroxy-steroid
dehydrogenase activity. 5 Judged from HPL
levels in serum Spona et al. 6 suggested
that the pregnancy-maintaining effect
of allylestrenol is at least partly due to a
stimulation of the placental function.
The demonstration of alpha- and
beta-receptors in the uterus has led to a
better understanding of the uterine
mechanism. 7 Moreover, it has been
demonstrated that stimulation of the
alpha-receptors increased uterine contractility. Conversely, stimulation of
beta-receptors inhibited such effect.
There is also a difference between the
beta-receptors in the various tissues.
Beta 2-receptors are present in the
uterus 8 whereas the cardiac muscle appears to contain beta1-receptors. 9 Allylestrenol has a strong prevalence for
predominance of beta-receptors. 10
In earlier studies on allylestrenol the
relatively quick onset of its clinical effect was often questioned as it could not
be explained on the basis of hormonal
action. An alternative explanation is
that allylestrenol has some form of
neural-mediated action resulting in
uterine relaxation by stimulating the
myometrial beta2-receptors. A combination of actions of allylestrenol—improvement of the trophoblastic function, which promotes the production of
progesterone, and the beta2-adrenergic
action—could account for the results of
this drug in the treatment of myometrial spasmodic conditions that may
interrupt pregnancy. Other factors,
such as the influence on AMP, may also
play a role in allylestrenol's highly complex mechanism of action.3,11
MATERIALS AND METHODS
Objectives of the Study
Allylestrenol was evaluated for its efficacy in the management of threatened abortion and premature labor. For
ethical reasons a double-blind study was
considered not to be acceptable.
Patients
The study group comprised 415 pregnant women without anatomical
anomalies of the genital tract. Of these,
40 women who did not use drugs during
pregnancy serve as controls for hormonal determinations. The remaining
375 patients were treated with allylestrenol because of difficulties during current or previous pregnancies (Table I).
Treatment
In 297 patients treatment was instituted because of threatened abortion
201
CLINICAL THERAPEUTICS
in the first trimester, in 37 women because of threatened abortion in the second trimester, and in 41 because of premature labor (Table II). Allylestrenol
was the only drug given. This was combined with bedrest until vaginal bleeding subsided. The daily dosage of allylestrenol ranged from 10 to 40 mg per
day. As prophylaxis in women who had
aborted previously, treatment was
started directly after pregnancy had
been diagnosed. In patients with premature labor complete bedrest and 10
mg of allylestrenol orally every four
hours was prescribed. When uterine
contractility had ceased the dose was
gradually lowered to 10 to 15 mg per
day. This was continued until one to
two weeks before term.
Hormonal Assays
For hormonal determinations we
selected 77 women. Forty were normal
pregnant women who served as controls, and 37 were from the allylestrenol group who had difficulties in the
first trimester of their pregnancy. Assays were carried out for total estrogens and for pregnanediol. Urine was
202
collected every 24 hours whenever possible. Once the patient's condition
remained stable there was less necessity
for daily delivery of urine and subsequent analysis. In such cases determinations were made every fortnight.
Hormonal determinations for total
estrogens were performed according to
Brown's method and expressed in
micrograms per 24 hours. Pregnanediol was determined by gas chromatography using a semi-automated
method.
At all births the placenta was carefully inspected. For most of the patients
subjected to hormonal assays a histologic examination of placental tissue
was carried out as well.
RESULTS
Allylestrenol was administered in 375
pregnancies for the reasons mentioned.
In total, each of 281 women gave birth
to one baby, and one woman gave birth
to twin girls (Table II). Each of the 40
normal women serving as controls gave
birth to one baby.
Figure 1 shows the excretion patterns
J. CORTÉS-PRIETO ET AL.
of total estrogens of the normal women
and of the 37 patients treated with allylestrenol. In the latter group some initial
low values are noteworthy. In the
course of the treatment, however, all
values were well within our normal
limits. The pregnanediol excretion patterns are set out in Figure 2. The same
pattern as described for estrogens is
found here.
We carefully determined the weight
of the babies born to mo thers for
whom hormonal levels were known.
The difference in mean birth weights between the babies originating from 40
normal mothers and from 25 allylestrenol-treated patients is striking: 3,186
grams versus 3,455, respectively.
Apart from one baby with tetralogy
of Fallot, no other easily detectable
malformation was evident in children
from mothers treated with allylestrenol. The perinatal mortality was well
within the limits of our experience.
DISCUSSION Threatened
Abortion
The prognosis for the continuation of
pregnancies in our patients was poor as
nearly all patients had already had one or
more abortions. The fact that in such
patients allylestrenol normalized the excretion patterns of urinary hormones
confirms earlier findings that the drug
promotes placental hormonal production. A number of failures also oc-
203
CLINICAL THERAPEUTICS
curred. According to the literature,
however, in 50% of abortions the cause
is unknown. In the other half trophoblastic changes are reported. 12
Macroscopic and microscopic inspection of the placentas from the allylestrenoi group revealed no deviations
from normal. In 12 of 90 women who
aborted despite treatment in the first
trimester, placental changes could be
demonstrated microscopically. Inspection revealed such placental deficiencies
that significant aberrations of the fetus
had to be feared if they had been carried
to term. To our knowledge, however,
none of the changes found are attributable to the influence of allyiestrenol.
Our findings suggest that allyiestrenol is
not capable of maintaining pregnancy
204
in the presence of serious placental
aberrations. It is this selective capacity
that makes the product safe in the treatment of habitual abortion.
All newborns were examined systematically for the presence of any obvious anomalies. As the mothers were
treated with hormones during pregnancy we were particularly alert for
signs of masculinization. None such
signs could be found in any of the babies
whose mothers had been treated.
We also weighed all children directly
after birth. When comparing the children's weight of the control group with
the weight of the babies of the allyiestrenol group, the difference was striking. Andelkovic 13 also reported a higher birthweight of ne wborns from
J. CORTÉS-PRIETO ET AL.
patients treated with allylestrenol than
of newborns from normal mothers. In
this investigation the difference ranged
from 250 to 400 grams per child. There
is no adequate explanation for this
weight difference. Possibly the betaadrenergic action of allylestrenol is at
the basis of this difference. This betaadrenergic action reduces the activity of
the uterus (myometrium activity) and
subsequently the permanent hypertonic
state. It is logical to conclude that this
relaxation induces a better blood supply
thus enhancing the action of the fetoplacental unit. Consequently a better
fetal metabolic exchange can exist and
intrauterine hypoxia would be far less
likely to occur. The relaxed atmosphere in which the fetus lives might
also ensure better fetal development
(Figure 3). The extent to which these
slightly higher birth weights are an advantage and will be followed by future
better academic results, as described
elsewhere,14 is beyond the scope of the
present trial.
The real beta-adrenergic drugs used to
maintain pregnancy in patients with
imminent abortion, such as ritodrine,
isoxsuprine, and orciprenaline are
known to cause such high birth weights
that the partus itself becomes more
risky or at least gives rise to heavy
labor. In our opinion this limits the use of
such products. Moreover, we consider the side effects observed with, for
example, ritodrine (tachycardia and
other cardiovascular complaints, dizziness, vomiting)15 hardly acceptable for
pregnant women. We prefer the
smoother, perhaps even more physiologic and selective beta-adrenergic action of allylestrenol. This latter effect
together with the placentotrophic effect
described by others 3-6 and the complete
absence of side effects for both mother
205
CLINICAL THERAPEUTICS
and child, make allylestrenol a safe
drug in the management of situations
that endanger a pregnancy at an early
stage.
Premature Delivery
Birth before term but after week 28
of pregnancy is usually designated as
premature. Uncomplicated spontaneous premature labor occurs frequently.
Prevention seems to be difficult because
patients at risk can only occasionally be
identified. The problem of prematurity
is to find an effective treatment to stop
premature labor. Proposed treatments
have to be substantially better than the
conservative treatment. There are many
known ways to block the process, one of
which is interference with the release of
oxytocin by means of intravenous
ethanol. 16 The initially good results
reported17 were not confirmed by later
data.18
Widely used nowadays are betaadrenergic drugs such as isoxsuprine
and ritodrine. The quantity to be given
is adjusted individually. Treatment is
usually started by intravenous drip infusion. The side effects of these drugs are,
as mentioned, very important in pregnant women. The difference between
the beta-receptors in the uterus and the
cardiac muscle and the less selective action of these substances may well be at
the basis of these side effects. Moreover, a true myometrial action of these
drugs is questionable, as it has been
stated that the efficacy of drugs such as
ritodrine for the treatment of high-risk
pregnancies after week 30 does not differ significantly from that of other infusion therapies using substances such as
Hartmann's solution, aminofusin, or a
206
solution containing 10% dextrose.19
These investigators consider the effects
of the various therapeutic regimens on
metabolic acidosis to be one of the main
factors in this respect.
Our report deals with 37 patients with
threatened abortion in the second trimester and 41 pregnancies with premature labor. In the latter group the
membranes were not yet ruptured. In
the first group in all but one case the
baby was born during week 39 to 41; in
one case labor could be delayed only until week 36. Of the 41 patients with premature labor only three could not be
brought to term. Two were cases of immature unidentical twins (abortion in
week 31 and 34). In one case a cesarian
section was performed.
The fact that despite massive doses of
the drug no subjective or clinical effects
on smooth muscle organs containing
beta-receptors, including the heart,
were reported strongly suggests that allylestrenol has a highly selective influence. Our data support our earlier
theory that allylestrenol has some form
of beta-adrenergic action on the betareceptors of the myometrium. 20 The
rapid arrest of uterine contractions
(usually within the first 24 hours) cannot be explained by bedrest or by a
higher production of progesterone only.
In our opinion the beta-adrenergic action of allylestrenol is the main factor
responsible for this rapid onset of action
on the myometrium. Possibly this latter
action combines with the placentotrophic action mentioned by other investigators, but this dual action or
perhaps synergism has not been fully
elucidated. Further studies, including
the effect on other factors that figure in
the initiation of labor, will be necessary
J. CORT ÉS-PRIETO ET AL.
to pinpoint the exact mechanism of allylestrenol. The difficulty, however, will
be that no model other than woman
can be found to test this. Indeed, apart
from the hormonal and obstetrical,
psychological processes may also play a
major role in initiating uterine contractions leading to labor. Moreover, once
this process has started it seems to be
regulated by some autonomous process. This investigation provides
grounds for assuming that allylestrenol
selectively interferes with this process.
ACKNOWLEDGMENT
We want to thank Dr. F. Nogales-Ortiz
for the inspection of the placentas.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
Knaus, H. (1975): In: Pharmacology
of Hormones. By M. Tausk. Georg
Thieme Publishers, Stuttgart.
Csapo, A.I. (1961): In: Progesterone
and the Defence Mechanism of Pregnancy. Editors: G.E. Wolstenholme
and M.P. Cameron, London.
Fanard, A., and Picazo, J.J. (1976):
How to stimulate the placental function. Reproduccion 3, 15-25.
Stavric, V. (1974): Statistical evaluation of hormones and enzymes modifications during treatment of threatened abortion with allylestrenol. Lecture held at 25th Congress of the Federation of the Gynaecological
Societies, Montreal, September 25-28.
Toth, F., and Treit, S. (1964): The development of HCG and pregnanediol
excretion in abortions treated with gestagens and tranquillizers. Z. Geburtshilfe u. Gynaek. 162, 140-152.
Spona, J., Mütiller-Tyl, E., and Leodolter, S. (1976): Influence of allylestrenol on the serum level of human placentotropic lactogen in high risk pregnancies. Z. Geburtshilfe Perinatal.
180, 356-362.
Willems, J.L., and de Schaepdryver,
A.F. (1966): Adrenergic receptors in
the oestradiol and allylestrenol domi -
nated rabbit uterus. Arch. Int.
Pharmacodyn. Ther. 161, 269-274.
8. Lands, A.M., Arnold, A., McAuliff,
J.P., et al. (1967): Differentiation of receptor systems activated by sympathomimetic amines. Nature 214,
597-598.
9. Editorial (1977): Postponing premature labour. Br. Med. J. /, 1118-1119.
10. Willems, J.L. (1965): Gestanon and
beta-receptors. Personal communication.
11. De La Fuente, P. (1972): J. Gynecol.
Obstet. Biol. Reprod. 1, 497-507.
12. Botella-Llusia, J. (1973): Endocrinology of Women. W.B. Saunders Company, Philadelphia.
13. Andelkovic, S. (1978): Effect of gestanon on birth weight. Srp. Arh.
Celok. Lek. 106, 53-55.
14. Dalton, K. ( 1 9 7 6 ) :
Prenatal
progesterone and educational attainments. Br. J. Psychiatry 129, 438-442.
15. Editorial (1974): Delaying premature
labour. Lancet 2, 875-876.
16. Gibbens, G.L.D., and Chard, T.
(1976): Observations of maternal oxytocin release during human labor and
the effect of intravenous alcohol administration. Am. J. Obstet. Gynecol.
126, 243.
207
CLINICAL THERAPEUTICS
17. Zlatnik, F.J., and Fuchs, F. (1972): A
controlled study of ethanol in threatened premature labor. Am. J. Obstet.
Gynecol. 112, 610.
al. (1977): Trial of intravenous therapy in women with low urinary estriol
excretion. Am. J. Obstet. Gynecol
127, 793-797.
18. Castrén, O., Gummerus, M., and
Saarikoski, S. (1975): Treatment of
imminent premature labour. Acta Obstet. Gynecol. Scan. 54, 95-100.
19. Chang, A., Abell, D., Beischer, N., et
20. Cortes-Prieto, J. (1973): Beta-stimulant action of allylestrenol. Lecture
held at the VII World Congress of Obstetrics and Gynecology, Moscow August 12-18.
208