Effects of estrogenic therapy upon ovarian function

EFFECTS II.

OF ESTROGENIC THERAPY FUNCTION’: When Employed

During

UPON

Anovulatory

OVARIAN Cycles

E. C. HAMBLEN, M.D., D. V. HIRST, M.D., AND W. KENNETH PH. D., DURHAM,N. C. (From the Endocrine Division of the Department of Obstetrics and Duke

University

School

of Medicine

and Duke

CUYLER, Gynecology,

Hospital)

T

HE ability of adequate estrogenie therapy to transform normal progestational cycles of women to estrogenic (and presumably anovulatory) ones has been verified in the preceding communication.l It would appear most unlikely that therapy of this kind and order is capable of restoring normal progestational cycles in women with ovarian failure of anovulatory type. An investigation, however, of the end results of estrogenic therapy in association with anovulatory failure seemed advisable for several reasons : (1) to confirm or to deny the dictum that, regardless of our ability to substitute for the endocrine deficienry of ovaries with intrinsic ovarian principles no salvage of physiologic functions, i.e., return of the fertile state, results; and (2) to confirm or to deny the theory that the salvage of ovarian function which has been described as following cyclic estrogenprogesterone therapy in a large group of women with prolonged or excessive estrogenic bleeding results solely from t,he estrogenic fraction of the therapeutic schedule. The commercial availability of a cheap, potent,, and orally active nonhormonal est,rogen (diethylstilbestrol) requires a clear definition of the role of estrogens in the treatment of ovarian failure. Methods Sixteen patients whose ages ranged from 15 to 35 years (average age 21.6 years) were selected for this investigation. These patients had presumed anovulatory ovarian failure predicated upon the occurrence of episodes of estrogenic bleeding. The bleeding cycles were comEach patient selected monly irregular and often of prolonged duration. had received from one to three endometrial biopsies prior to initiation of therapy. Two hormonal estrogens, estriol glucuronidet and estradiol in the form of its benzoatet and dipropionate,§ and an nonhormonal estro*Part I of this article was included in the February issue. ?Estriol glucuronide Montreal, Canada. :Estradiol benzoate N. J. $Estradiol dipropionate Inc., Summit. N. J.

(emmenin) (progynon-23)

(di-ovocylin)

supplied supplied supplied 513

by by

Ayerst, Schering by

Ciba

McKenna Corporation. Pharmaceutical

and

Harrison. Bloomfield, Products,

Estradiol

henmate

:

/---

-i 111

treal.

*Uiethylstilbestr.ul Canada.

(cstmbene)

supvliccl

by

Ayrrst,

Mclirnna,

and

Harrison,

Mon-

HAMBLEN

ET

AI,.

:

ERTROGENIC

THERAPY

AXD

OVARIAN

FTJKCTIOK

515

2. Eftxts TIpon the Enrlonlc!t~iul)l.-l~ndometrial studies were made during 26 of the 39 cycles of treatment. of 12 patients. These findings are detailed in Table II. Twenty-t,wo (84.6 per cent) of the 26 endometrial responses remained estrogenic. The 4 progestational endometriurns encountered were in the cases of 2 patients, 3 in one instance and 1 in t,he other. One of these patients had progestational responses during the sixth, seventh, and eighth cycles of therapy (Fig. 1). All of her previously studied endometriums had been estrogenic. She had received previously estriol glucuronide, but at the time of her positive responses she was receiving diethylstilbestrol. The other patient had a progestational response after the fourth consecutive cycle of therapy with estriol glucuronid@. Her 3 precedin, 0’ cvcles . had been characterizrcl by estrogenie endomctriums. I -,f 2

AVERAGE RIOL GLUCURONIDE,

2

; ESTRIOL

4

2400

GLUCURONIDE, ILY

3 5 0 %6 i5 0 7

IO th.-

, 4

I6 20

24

L-Effects of therapy bteeding cycles cycle at the left of TABLE

15 16

1 I2

6

= I

SERIES OF PHERAPY

II.

= I --

1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 1 1

1 . I 26 32 36 40

edb-0 edb-E edb-E edb-E stb-E &b-O stb-0 &b-O stb-0 stb-E stb-E stb-E edb-0 edd-E &b-O edb-0 es-E

--

I 52 56

ILB,

RERI~ONSES

-

2 edb-E ORx-0 edb-E edb-E &b-O

,

stb-E ORx-0

3 edb-0 ORx-0 ORx-0 ORx-0

_-

UWING

days.

5lh

-24lh.deys.

I.0 MG. DAILY, 5th-241hdays. 2.0 MG DAILY,

with estriol glucuronide of Patient 15. Episodes S’tilb., signifies the graph.

ENDOJIETRIAT,

1

I 44 46

24 th days

19 th. days.

STILE, I

days

0 U, 5th - 24th.

.>I 0 MG. DAILY,

DAYS+0

CASE

5ih - 20th

0 U DAILY, 5th.-

4600

8

Fig. consecutive for each

OVARIAN CYCLE

0 U. DAILY.

ESTRIOL GLUCURONtDE,

g3 ;

2400

5th.-241h.duys.

and diethylstilbestrol of bleeding are diethylstilbestrol.

ASD

AFTER

represented

in

THERAPY"

4

5

ORx-E

ORx-0

ORx-0

ORx-0

ORx-0

6

stb-0 ORx-0

stb-Et

ORx-0

ORx-0

ORx-0

ORx-E-

es-E es-P

stb-E stb-0

stb-P-

8

ORx-0

ORx-0

stb-P-

stb-P

stb-Et stb-E stb-0 ORx-E es-E es-E

-

es-E es-E

*Therapy

edd. Estradiol dipropionate edb, Estradiol’benzoate es, Estriol glucuronide stb, Diethylstilbestrol OHX, No therapy, but data cycle and bleeding obtained

-

of E?LdometvircZ Resjmmes Minimal estrogenic response Moderate estrogenic response Marked or hyperestrogenic response Minimal (immature) regular progestation ivormal progestation No biopsy ClassifLcatio?a

on

Em, E, E+. Pm, -__ P-‘. 0,

7

516

AMERICAN

JOURSAI,

Ol?

OBSTETRICS

ASI)

GYSECOLOGY

Few endometrial studies were maclc f’ollowing cessation o I’ t ~~(~v;I~IJ~ due to the fact that the majorit?- of the patients were transt’(~rrt~ti IO other therapeutic regimen. Three follo~-~~~~ endometrial samplrs, how ever, were taken on two patient.s ; all wcrc etit rogenica. 3. Effects UPOR. tke Iiengths of tlrc C’yc7es.--The characterist iv VTfeet was a reduction in the cycle lengths to within normal limits: Ilte average lengths of cycles prior to trcatrnent, were 49.2 days and d~uGnp therapy 28.7 days. This effect was apparent in the first treatment ~~clcs which averaged 33.1 days in length. In 2 instances, however, c!stradiol therapy was followed by absence of expected episodes of bleeding with sequential doubling in the 1eng;ths of the cyrlcs. Roth of these exceptions occurred during first ircnt,ment, cycles ant1 a t’c in~lndccl in tilt illJ(~~(~ average of 33.1 days.

4. Efects ljfm fhc I)uurliri)c tr~l A~II~~H~/ of lJtt:riw I~kctlirl,q-The average dural ion 01’ I)lrcding dwrrasrd 1’ront 1X.4 days I)rior to treatment to 6.2 days during t 11rral)y. This altc~ration was imiue~liatcl~ apparent in the first episodes 0I’ blecdilr g which occurred tlnring t,hcrapy. Episodes of bleeding followin g ccssat,ioii of therapy averaged 7.2 days. During the cycles studied after therapy only 1 pat,icnt. had a IWWrence of prolonged bleeding. This oc~uri~d at the tein~ination or lllc set*ond cycle which followed the cessation of therapy. This patiunt had received only 1 cycle of diethylstilt~est~rol therapy, 2 mg. dail>-, from the fifth to the twenty-fourth days, inclusive. Prior t,o therapy an average of -26 well saturated sanitary pads were used per episode of blecdin g, during thcraI)y 13, and following c(Jssution of treatment, 15 per episode of bleeding. Tha reduction in the Iota1 number of pads used by these patients clutsing treatment par~allclc~l that decrease in the duration OK bleeding. 5. Effects tipo~ lVit?dwwul !Pimt.. -,h cljisode of bleeding \vas clcfined to be due t,o estrogen withdrawal it’ it. occurred within a few tla,vs after cessation of therapy and consitlrrably j n advance of l.h(l t~sl)t~~~t(l( I 111 6 tt*entmeni. (:yclw of 4 patients Ihe will~dt~awal date OS bleeding. time averaged 4.5 days, t tlr range bran, 0’ front Iwo lo eight days. Thrc~ of these patients had received est radio1 benzoste during fh(x first ha1 f of the cycle while the fourth patient, had received diethr-lstil})~st~ol during the same int.crval.

Discussion There is little evidence from the data presented that the use of moderately small doses of hormonal or nonhormonal estrogens exerts st imudative or restorative effects upon the disturbed ovario-endometrial status Of 26 endometrial rmponses studictl of anovulatory ovarian failure. during therapy 22, or S4.6 per cent, were estrogenic. The 4 progestational responses encountered in the in&ances of 2 Thrl Ihc~raprlltic schedules ol’ 11wsc patients warrant discussion. 2 patients have two l-hings in common : i 1) They wl;cre ol’ greatest length (5 and 8 consecutive cycles) ; and (2) they comprised 3 consecu-

HAMBLES

ET

AL.:

ESTROGESIC

THERAPY

AND

OVARIAS

FUNCTION

517

tivc cycles of estriol glucuronide therapy. The progestational response of one patient followed the third cycle of estriol glucuronide therapy but did not recur in the succeeding cycle of diethylstilbestrol therapy. The 3 progestational responses of the other patient occurred during the second, third, and fourth consecutive cycles of diethylstilbestrol therapy, which were sequential to the treatment with estriol glucuronide. These progestational responses may be regarded as being the results of intercurrent recovery of ovarian function or one may relate their incidence to a specific virtue of prolonged therapy with estriol glucuronide. Therapeutic schedules of this kind and order warrant furt,her study. The estrogenic therapy was observed to regulate quite uniformly the cyclicity and duration of flowing. The majority of the patients studied had lengthened cycles (average 49.2 days) and prolonged flowing (average duration 18.4 days) prior to institution of therapy. During therapy the cycle lengths were reduced to an average of 28.7 days and the durations of bleeding episodes to an average of 6.2 days. From these studies, it seems reasonable to relate chiefly the regulatory effects of cyclic estrogen-progesterone therapy in prolonged or excessive estrogenic bleeding to specific effects of the estrogen fractions on the endometrial vascular system. The ultimate salvage, i.e., return of progestational cycles, which has been relat,ed to this cyclic combined therapy seems dependent upon the one-two sequential use of and the synergism existing between estrogen and progesterone. It is doubtful that any direct stimulative effects upon ovarian function result but rather it is likely that intercurrent recovery is facilitated and progression of ovarian failure prevented by the regulatory actions of this therapy on the functional capacities of the endometrial vascular tree and the pituitary.

Summary

and Conclusions

Moderately small doses of hormonal estrogens (estrone, estradiol benzoate and dipropionate, and estriol glucuronide) and of a nonhormonal estrogen (diethylstilbestrol) were administered cyclically to 16 women who were experiencing anovulatory ovarian failure predicated upon the occurrence of prolonged and excessive cstrogenic bleeding. Twenty-two of the 26 (84.6 per cent) endometrial biopsies studied during therapy continued to be of est,rogenic nature. The 4 progestational responses, which were encountered in 2 patients, were related to prolonged therapy with estriol glucuronide and were judged to be evidence of intercurrent recoveries of function. SaGsfactory regulation of the cyclicity and duration of flowing was credited to the cyclic estrogenic therapy. The following conclusions are judged warranted : 1. The cyclic administration of moderate doses of hormonal and nonhormonal estrogens resulted in no direct stimulational effects upon ovaries in anovulatory failure.

2. Therapy of this kind and order i*c~gulatc~sthe eyclicity and dltratioil of flowing probably by direct alterations in the functional capacities of the endometrial vessclcs. 3. The regula,tory action of cyclie estrogen-progest,erone therapy is due primarily to effects of the estrogen fraction. 4. The salvage of physiologic function which occurs in many 1)atients with cstrogenic flowing following therap>- wit,h the cyclic cstrogenprogesterone schedule is dependent upon the progesterone fraction. 5. The one-two administration of and the synergism between estrogens and progesterone arc important, facets of the combined therapy. 6. Salvage, when it oeeurs, probably is clt~c?to the ability of this eomplemental therap>- IO prevent progress of ovarian failure and to favor spontaneous recovery of normal function. (E. and N.

Part of the expenses of these studies w:~s Ilrfra~ed C. H.) from the Research Council trf I~ulrc University, Harrison, Ltd., Montreal, Canada, and from Schering

by

grants to one of us from Ayrrst, Mckenna Corporation, Bloornfield,

J.

Reference 1. Ha&den, 268,

THE

E. c‘., Hirst,

I). I-.,

ant1 Cu~lert

IV.

Ii. :

i\M.

.T. (h3ST.

& (:YNE(‘.

45:

1!)43.

MANAGEMENT

OF OVAR,IAN WOlvIEW

TUMOR13

IN

ELDERLY

URGERY in elderly- women, csltcc*ially in t.he sevent,h, eighth. and ninth decades of life, is attended with considerable risk. Many such patients present themselves at; a. hospital or a clinic with ovarian tumors, but because of their age or poor physical condition, they a,re denied the benefits of surgery. Alt,hough most gynecologists, agree that the only chance these patients have to 1x1 cured is by operation, frequently they feel that the additional life expectancy does not warrant the procedure. Our espericnec at Kings County Hospital has been at variance with this. \Vc present, Ihercfore, a brief summary of our results in the management of ovarian l.umors in women past the menopause.

S

E’rom Jan. 1, 1935, through July 1, 1942, a period 01’ S~WII and one-half years, 13,010 patients were admitted to the gynecologic service of the Long Island College Division of the Kings County Hospital. Of this number, 344, or 2.6 per cent, had ovarian tumors. Pathologic study revealed practically all varieties (Table I), and 262, or 76.2 per cent, were benign, while 82, or 23.8 per cent, were malignant. Eighty*Read

at a meeting

of the

Brooklyn

Gynecological

Society,

Nov.

6, 3842.