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Some structural and functional features of rabbit's uteri following prolonged oestrin administration.

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SOME STRUCTURAL AND FUNCTIONAL FEATURES
O F RABBIT'S UTERI FOLLOWING PROLONGED
OESTRIN ADMINISTRATIOh
SAMUEL R. M. REYNOLDS
Department of PhysioZogy, Long Island College of Y e d i c i n e , Brooklyn, New York
ONE TEXT FIGURE AND OWE PLATE (FOUB FIGURES)
The purpose of this paper is to describe certain results
which have been observed in the uteri of castrated rabbits
following GO to 108 days of daily oestrin administration in
dosages ranging from GOO0 r.u. to 8350 r.u. This work was
undertaken at the suggestion of Doctor Engle and parallels
the recent work of Engle and Smith ('35) in the monkey.
Among the observations made by these investigators was the
finding of uterine bleeding during continued and increasing
oestrin therapy. This observation led Doctor Engle to the
belief that suggestive results might be obtained if one were
to correlate the structural changes of a regressive nature
found to take place with prolonged oestrin administration
with the degree of uterine motility as determined by means
of the uterine fistula method. The following report describes
such observations.
PROCEDURES AND RESULTS
Of ten mature, castrated female rabbits started in the injection series, six terminated successfully with records of
uterine motility after 60, 84, 102, 102, 103 and 108 days,
respectively, of oestrin administration (Amniotin furnished
through the kindness of Dr. 6. A. Morrell of E. R. Squibb
&. Son). The total dosage of Amniotin in each case is indicated in table 1. Except for rabbit A-10, 50 r.u. per day
269
THE ANATOMICAL BECORD, VOL.
62,
?SO.
3
A-9
I
I
I
1
I
102
102
lo3
60
A-control
A-3
84
--
A-1
--
A-6
I
_
-,-
A-10
RABBIT
NUMBEI
OF DAY1
OESTRII
ADMIN.
LSTBREI
6850
7400
7400
8350
8100
6000
r.u.
TOTAL
OESTRIN
DOSAQE
:AMNIOTIN:
Marked
Pitocin
response
0
0
+
b-+t
__-
Few, mostly shallow but
active; tall columnar
epithelium
Active; many deep glands
Qlands
I
Thick
Thick
Stroma
Poorly vaseularized
Poorly vascularized
'Poorly vasculariecd erCopt for
one fold
Moderately
vascularized
jvery vascular
Very vascular
Vascularity
+++(l
Eb.U.1
++(1.5 Rb.U.)
++ (1.5 Rb.U.)
Response to progestin, after
terminating
oestrin
therapy
ENDOYETRIUY FPOM MID-PORTIONO F UTERINE TUBE
Few, shallow; some active, Thin
tall columnar epithelium ;
as many inactive, small,
with little cytoplasm
Marked
some active, but mostly
1 Fairly thick
response inactive glands; very
sparse and shallow
Thin, nearly
Feeble
Fern, nearly all inactive;
nuclei fill cells
absent in
some places
Moderate Few, very shallow and
Thin
nearly all inactive
Moderate
-I-+++Moderate
t+++
ous
Bpontane-
MOTILITY OF THE
UTERINE FISTULA
ON LAST DAY OF
OESTRIN
TABLE 1
Thin, with
eompact
cells
Small, thin
very compact cells
Very thin,
with compact cells
~
_
Thick, cells
large
Thick, eells
large
Thick, cells
large
HYOMETBIUM
_
STRUCTURE AND FUNCTION OF UTERI
271
subcutaneously were given for half the period, after which
the dosage was increased to 100 r.u. per day for the remainder
of the injection period. Rabbit A-10 received 100 r.u. per day
throughout the 60-day injection period.
Three to 5 days before the termination of oestrin therapy,
uterine fistulae were prepared (technic, Reynolds, '30 ; Reynolds and Friedman, '30). On the day following the last
injection, records of uterine motility in the unanesthetized
animal were obtained, and the response to 0.1 to 0.4 cc. of
pitocin was determined. Portions of these records are shown
in figure 1, while the type of motility and pitocin responses
Fig. 1 Records of uterine motility in unanesthetized rabbits after prolonged
oostrin administration; A-10, 60 days; A-9, 103 days; A-8, 108 days; A-6, 102
days; A-3, 84 days; A-1, 102 days.
are indicated in table 1. With the two exceptions noted below,
the rabbits were sacrificed immediately and a section of the
mid-portion of a uterine cornu fixed in Bouin's fluid. The
tissues were prepared for the writer through the kindness
of Doctor Engle.
I n addition to oestrin, progestin, prepared according to the
Corner-Allen method, was administered to two rabbits (A-1,
A-6) following termination of oestrin therapy. A total of
1.5 Rb.U. was administered for 5 days after obtaining a
section of uterus at biopsy, immediately following the motility
records. As shown in table 1 and in figure 2, proliferation
of the endometrium resulted. It also resulted in a control
272
SAMUEL R. M. REYNOLDS
rabbit (A-C) which received 1.0 Rb.U. in 5 days, following
3 days of preliminary oestrin injections.
The results are briefly discussed below.
Elzdoinetrial condition at termimation of injection period.
A full description of these tissues will not be given. Rather,
brief attention will be directed to four structural characteristics that are of chief interest in the correlation that is to
be made with the type of motility the uteri showed at the time
the tissues were taken. These features are: 1) the character
of the endometrial glands, 2) the thickness of the stroma,
3) the degree of vascularity, and 4) the general character
of the myometrium.
I n agreement with the findings of Engle and Smith in the
monkey, involution of the endometrium eventually takes place
(see A-1 and A-3 especially). This is reflected in the thinness of the stroma, the great proportion of inactive glands
in which many or even all the cells are low and the nuclei
centrally placed. Moreover, sections from these rabbits show
that the endometrium is poorly vascularixed. I n the two
instances in which motility was nil (A-1, A-3) the myometrium
is also thin, with compact cells. I n accordance with the results of Engle and Smith, not all the treated rabbits show
such marked regressive changes for rabbits A-9 and A-10
have thick endometria with active glands, deeper than those
in the other rabbits. The endometria of these two rabbits
are also richly .vascular and the myornetria are thick, with
large cells having a high proportion of cytoplasmic to nuclear
material.
Two rabbits (A-6, A-8) are somewhat intermediate between
the extremes just described: the glands are few in number and
shallow, but have a large proportion of tall columnar cells;
the stroma is thin in isolated places, and in general is poorly
vascularized.
Uterine motility at termination of the imjectioit period. A
glance at figure 1 is sufficient to show that marked oestral
motility did not occur in four out of six cases. The surprising
thing, based on a priori reasoning, is not that two of the six
STRUCTURE AND FUNCTION O F UTERI
273
rabbits showed marked motility, but rather that four did not
show it, inasmuch as oestrin is specific for the initiation
of rhythmic uterine contractions in the uterine fistula (Reynolds, ’31).
These results show, therefore, that under the prolonged
oestrin treatment of these experiments the myometrium becomes refractory to the normal, adequate stimulus for that
tissue.
Relatioa o f inuolutionary chamges to motility of the uterus.
As strikingly shown in table 1,the best developed endometria
are in the two rabbits showing the most marked motility,
whereas in the two showing no motility whatever, the endometria underwent profound atrophy. The two rabbits that
are intermediate with respect to motility are likewise intermediate as regards the state of the endometria. One hesitates
to say on the basis of these few data whether the coincidence
of these findings is the result of chance, or whether one feature (structure) docs not bcar a secondary relationship to
the other (function). It is a physiological probability that
the vascularity of the endometrium is to a certain extent
sustained by the activity of the myometrium. Some of the
reasons f o r believing that this may be so will be described
short1y.
Nature o f uterine atrophy during proloaged admimistratiola
of oestrin. Two general explanations suggest themselves to
account for the uterine involution which occurred in our experiments, despite injections of oestrin totalling thousands
of rat units. One view, regarding which Engle and Smith
say “Involution of the endometria . . may be due to
exhaustion effects of continued stimulation,’’ is hypothetical
and if it is the basis of the effects observed, the mechanism
involved must be elucidated. The alternative view, suggested
by the recent work of Collip and his associates (Collip, ’34;
Selye, Thompson and Collip, ’35), is that prolonged treatment with hormones may give rise to the production of
anti-hormones. Thus one might suspect that, the ineffectiveness of oestrin in our experiments is due to a tendency toward
.
.
274
SAMUEL R. M. REYNOLDS
an immunity to oestrin developed by the extensive injections.
Our results show conclusively that this is not so, however.
The most marked involution occurred in rabbit A-1, yet this
uterus responded to progestin treatment. Since progestin
action depends in part upon sensitization of the endometrium
by oestrin, it is clear that the involuted endometria of A-1
and A-6 are still sensitized by that hormone. Thus the
alternative view of ‘exhaustion effects’ may be invoked to
account for the changes described above.
This conclusion renders attractive as a working hypothesis
the ,view already anticipated in the previous section above,
namely, that the myometrium becomes passive to thc action
of oestrin, and ensuant upon this passivity it is physiologically likely that a diminution takes place in the functional
state (number open) of the endometrial capillaries. This
concept requires proof by direct experimentation, however.
SUMMARY
Following prolonged oestrin administration (84 to 108
days) the uterus tends to become non-motile and coincident
with this diminished activity, the endometrium undergoes
progressive involution. Since such atrophied uteri are still
responsive to progestin, hence sensitized by oestrin, the involution is not attributable to the de,velopment of an antihormone to oestrin. The probable cause of the regressive
structural and functional changes as well as their relation to
each other, is discussed,
ADDENDUM
Attention has been called to tlie fact elsewhere (Reynolds,
’31, p. 716) that castration during heat “results in a partial
loss at first, and a complete loss eventually, of all uterine
motility. This occurs without exception, and as surely as
atrophy of the uterus follows complete ovariectomy, although
the loss of motility appears to take place far more rapidly
than does atrophy, and not pari passzl with it.”
STRUCTURE AND FUNCTION O F UTERI
275
LITERATURE CITED
COLLIP, J. B. 1934 Some recent advances in the physiology of the anterior
pituitary. J. Mt. Sinai Hosp., vol. 1, pp. 28-71.
ENQLE, E. T., AND P. E. SMITH 1935 Some observations on the effects of
prolonged oestriii administration i n the mookey. Anat. Rec., vol. 61,
pp. 471-484.
REYNOLDS,
S. R. If. 1930 Studies on the uterus. I. A method for reeoraing
uterine activity in chronic experiments on unanesthetized animals.
Am. J. Physiol., vol. 92, pp. 4 2 0 3 2 9 .
1931 Studies on the uterus. V. The influence of the ovary on the
niotility of the non-gravid uterus of the unanesthetized rabbit. Am. J.
Physiol., vol. 97, pp. 706-721.
REYNOLDS,
S. R. M., AND 15. H. FEIEDMAN
1930 Studies on the uterus. IV. The
activity of the uterine fistula in unanesthetized rabbits following coitus
and during pseudopregnancy. Am. J. Physiol., vol. 94, pp. 696-704.
SELYE,
H., D. L. THOXPSON,AND J. B. COLLIP 1935 Metsplasia of uterine
epithelium induced by chronic oestrin administration. Nature, vol. 135,
pp. 65-66.
PLATE 1
EXPLANATION OF FIQURES
2 Section of uterus, rabbit A-9. Oestrin for 103 days. Note marked vascu
larity of stroma. H and E. X 8.
3 Section of uterus, rabbit A-6. Oestrin for 102 days. H and E. X 8.
4 Section of uterus, rabbit A-1. Oestrin for 102 days. Note marked involution and poor vascularization. H and E. X 8.
5 Section of uterus, rabbit A-1, showing moderate proliferation of endometrium, following administration of 1.5 Rb.U. of progestin, given after 102 days
of oestrin. See previous figure. I€ and E. X 8.
276
PLATE 1
STRUCTURE AND FUNCTION OF UTERI
S A M C h L 11. If. 1tEYNOLTIS
277
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