الفهرس 
Hepatic MorphologyOnly 14 pages are availabe for public view
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Abstract
The rapid increase in birth rate has encouraged the adoption of birth control programmes on a wide scale. Soon after oral hormonal contraceptives were introduced by Dr. Rock and his associates in Puerto -Rico in 1954 , this method of conception control was quickly accepted and incorporated into family planning services all over the world , with the oral contraceptive pill being the most popular method followed by a synthetic
progestogen , injectable depot medroxyprogesterone acetate ,
[The effect of contraceptive steroids on carbohydrate metabolism
and liver function has beer) under investigation for more than 25 years.
A number of excellent reviews reflect the diversity of openion which has
resulted from a wealth of profoundly contradictory data. The factors
responsible for this situation have only partially been resolved. As in all pc.studies of carbohydrate metabolism , population characteristics, dietary
and socioeconomic factors , and genetic individuality play a confounding
role. In addition , the type and dosage of oestrogen and progestogen and
their interactions at various biologic levels add to the complexity of the problem . The situation is complex even in animal experiments .
The combined oestrogen - progestogen oral contraceptive pill (OC) is known to produce deterioration in carbohydrate tolerance ranging from mild impairment to overt diabetes mellitus in predisposed individuals. Exactly how individual contraceptive steroids exert their effect on carbohydrate metabolism las proved difficult to investigate .
FL________ The concern about these metabolic alterations was hightened when clinical studies suggested’ women who were using OC were at. an
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increased risk for accelerated atherogenesis and premature myocardial infarction Since most pharmacologic effects are related to dosage, it seemed reasonable to expect a lessened metabolic effect from the lower -
dose drugs
Many authors have commented on alterations in liver function in women taking steroidal contraceptives Some have attempted to elucidate whether such changes are due to oestrogen or the progestogen in any combination tablet. This is not an easy task, because most of the progestogens used may to a small extent be metabolized to oestrogens. Further difficulty arises because conventional liver function tests are relatively insensitive and may not be significantly altered by the Functional changes induced by these drugs
.4,3- in our work , thirty women were selected to study the effects of one
c_fil.
rV of the common conventional combined (>C on carbohydrate metabolism and
.Acto
liver function. Ten subjects who never received any steroidal rrcl contraceptives served as controls (group 1). Ten women were using this pill
trm
for less than 2 years (group 11) and ten women were using the same pill
for more than 2 years (group Ill)
1,, •
fasting and postprandial 30 , 60 and 120 minutes values , compared to the
%is. ir-t0v.■ ,..Z
control group nt- - - , • 1: . ..- • or o f a
1114eua tif A.0 a pw,,,
/significant decrease in/ serum alkaline phosphatase level fila—r6-4)-1,),
(4...1 (Ph f ” a ) ) --A
between groups I At Wand, between
A 0 < 0 , 0 i 1 1”-tA,,,,,4-4.0 A. p•-trA
groups II 1 111. $ significant decrease inidtrect serum bilirubin WU 4,4
notion , between groups 1 it II (P z-c • .$)
-VOW t je( she pill - users revealed no significant changes in Ybke-”
166
The metabolic effects of CC and the injectable DMPA were furtherly w cc
studied *the experimentakgroup of manners , in which we studied also the
histopathological and hisjochemical changes induced by these steroidal
Asa- k
contraceptives. FoF-this-purpose416 control group that consists of 10 rats-
6) A- /U-k-
aitd—a study group witieh consisted of 90 rats W.eiren0estee■ffintrer
0:4
subdiviaum of-the-study-nts into 3 groups iiewcimeaach gfoup-eoastst. ed
of 30 rats . Group I rats received a type of low dose oestrogen combined pills, and group II rats received a type of conventional combined pills The pills were administered to-group-14L-1-1-cats daily/bylaslom’ach.ltib#6 for three out of 4 weeks monthly for a total period of 6 months . Group III rats received DMPA by intramuscular injection at the beginning of the study and was repeated later after 3 months . The dose given to rats was calculated to equal that dose received by an average woman / Kg body weight daily oralty or by injection Five rats from each
ct- were chasm monthly .
totheireilecapiration .01
changes of the
medium showed a significant decrease in glucose production in the 3
4^4
groups of the study,compared to the control rats. In group I .9 II,the
decrease showed a steady and progressive course with the advance of therapy. The same pattern of decrease was not observed in group III owing to the fluctuation of serum MPA through the period of the study .
eRegarding the glycogen content in the liver our results showed that it
oat
increased significantly in group I it 11.compared to the control group . Both groups showed the same pattern of increase , that was steady , gradual and pogressive. The glycogen content reached its maximum level after the sixth
of the 3 groups
je e in y
=1/4 liaminpalicaas_studie(N4L s tOGIUCOSe
N
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month of therapy Group 111 rats showed also a significant increase in liver glycogen content in comparison to control rats in the first , second , fourth and fifth months of therapy , but no significant difference was noted in the third and sixth months of treatment .
atic he
&lactate content of the medium v)getfousul a significant increase in lactate production in group I et 11,c;ompared to the control Lactate production was maximum in the first month of pill ingestion , then it began to decrease till the end of the study . Group III rats showed no significant change in lactate production throughout the 6 months of the study .
Increased glycogen deposition in the liver is simply due to the glycogenic effects of steroid hormones. This effect can also explain the decrease in glucose production observed in the three study groups. Increased lactate production has different explantions . Changes in enzyme activity secondary to changes in the rate of protein synthesis may be responsible for increased lactate production . Increased amount of glucose passing down the glywlytie pathway to pyruvate and lactate rather than impaired emoval of theAe metabolites may be another explanation
je,” tbAt
he istopathological changes that occurred in the liver of the
experimental groups were manifested by albuminous degeneration and reactionary increased number of binucleated cells with vascular changes and sinusoidal narrowing . The timing of occurrance of these changes , the degree to which they progressed , and the attempts of the liver at healing denotes that the conventional pills have more hepatotoxic effect than the low dose oestrogen pills and the injectable I)MPA The latter proved to be the least
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9 e (s) 1 The histopathological result, are supported by the histochemical study
that proved the development /of adaptive mechanisms in the liver in
response to the mild injurio9t effect of low dose oestrogen pills and DivIPA.
These adaptive mechanisms checked the moderate injurious effect of the
conventional pills and prevented the marked increase in alkaline
phosphatase and Marked decrease in ATP-ase activity that reached
maximum after he fourth month of therapy, but stopped and even regressed let
At the end we can come to the conclusion that we mustiook critically at. (X.: formulation yet again , realizing that excessive oestrogenic activity is undesirable because of its thromboembolic and hepatotoxic effect and that excessive progestogen p uces changes in biochemical parameters thought to be impl ed as cardiovascular risk factors.The ideal OC must be a compromiseClt seems unnecessary in most women to use more than 30 to 35 lig of oestrogen. [For the majority of women , a less potent progestogen than levonorgestrel would appear to be preferable j
Contraceptive steroids appear not to affect significantly the structure and function of the liver cell , and their action is transient . Only in women whose livers have not the full reserve capacity to deal with the increased amount of circulating oestrogens and progestogens will jaundice occur. This will be fleeting in most cases , and will disappear despite continued administration of the contraceptive agent , when the liver becomes adapted to an increased amount of circulating contraceptive steroids . Only in exceptional cases will the liver not be able to adapt itself , because of some genetic defect . it is ofcourse , not always easy to recognize the occasional women with this genetic tendency . In most cases a small dose of the
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contraceptive steroids and careful check in the first few days of administration for possible increase in serum bilirubin and perhaps transaminase and alkaline phosphatase levels , should reveal whether the woman is at risk in taking contraceptive steroids .
icIP from the evidence at hand , there see s to be a presumptive triad in women using steroidal contraceptives , sisting of pain , a palpable upper right quadrant mass , and signs of im ending shock This triad should alert any practitioner to the probabilit of a liver neoplasm
ci-D3 G leAtier-51=MqUaings Depot-Provera may have an advantage over oral contraceptive pills on a short-term basis as there are less alterations in carbohydrate metabolism and 4.0/0/eSit”).6 /pathological liver changes. Since this method of contraception is convenient and easy to administer , it can be used more widely as an alternative to oral pill for family spacing when the changes in metabolism and liver function are not significant. However , the drug should be administered with care especially in long-term use with careful obsrvation and follow up at least every six months .
Even though5these studies are only short- term and on small numbers of women and experimental animals they are encouraging. They suggested that at least some of the important adverse metabolic and liver pathological effects may be reduced or eliminated7with some of the new OC and injectable contraceptive preparations Longer follow - up studies with larger groups of women are now needed with injectable contraceptives and low dose oestrogen (C preparation in order to confirm or refuse these
findings.
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