J. clin. Path. (1967), 20, 731 Synthetic progestogen-oestrogen therapy and uterine changes J. G. AZZOPARDI AND I. ZAYID1 From the Department of Morbid Anatomy, Royal Postgraduate Medical School of London SYNOPSIS Continuous therapy with synthetic progestogen-oestrogen produces marked atrophy of endometrial glands and massive pseudodecidual stromal transformation. Cyclical therapy produces initially a 'frustrated secretory response' with precocious attempts at secretion in poorly developed glands. Pseudodecidua appears about the 20th day. With later cycles there is progressively greater gland atrophy while pseudodecidua is less marked. A possible inductive role of the glands on the stromal response to progestogens is postulated. The effect of different drugs and dosages is discussed. Decidual necrosis may occur with heavy doses. The Arias-Stella reaction, previously regarded as diagnostic of pregnancy, can be produced with ordinary doses of these drugs. Suppression of spiral arterioles is usual. Ballooning of venules is a frequent finding, possibly accounting for breakthrough bleeding. Red degeneration of myomata was present in three of seven hysterectomy specimens containing myomata. The introduction of these drugs is important to the pathologist because they produce endometrial and other uterine changes with which one must be familiar for the interpretation of appearances in endometrial curettings and hysterectomy specimens. The synthetic progestational steroids can be divided into four groups on a chemical basis: GROUP I: ALKYL DERIVATIVES OF TESTOSTERONE GROUP II: 19-NOR-TESTOSTERONE DERIVATIVES (a) Norethynodrel (present in Enavid and Conovid); (b) norethisterone (in orthonovum) and norethisterone acetate (in Anovlar and Gynovlar); (c) ethynodiol diacetate (in Metrulen); (d) lynestrol (in Lyndiol). These drugs are the most potent ovulation inhibitors and are also the drugs of choice in functional uterine bleeding. Many compounds have inherent oestro- genic activity or are metabolized to oestrogen. GROUP III: 1 7ct-HYDROXYPROGESTERONE DERIVATIVES (a) Medroxyprogesterone acetate; (b) megestrol ace- tate; (c) chlormadinone acetate. These drugs are less 'Present address: Department of Pathology, Army Base Hospital, Amman, Jordan. Received for publication 17 March 1967. powerful ovulation-inhibitors than group II drugs. They have no inherent oestrogenic activity and do not metabolize to oestrogen. GROUP IV: PROGESTERONE DERIVATIVES Drugs of groups II and III are used as contracep- tives, in the treatment of endometriosis and of func- tional uterine bleeding. Most proprietary preparations contain oestrogen combined with a synthetic pro- gestogen. Some, like Primolut N, contain progestogen only. MATERIAL Material from 44 patients was originally studied. In two patients histories were unreliable; one patient had an unsuspected endometritis and one was possibly pregnant. Material from the remaining 40 patients constitutes the basis of this study. Seven patients had continuous therapy, 18 had cyclic therapy as a contra- ceptive (17 of these had a normal menstrual history), while 15 had cyclic therapy for menstrual disorders, usually menorrhagia or metrorrhagia. Hysterectomy specimens were examined in 12 patients, endometrial curettings in 28. 731 copyright. on January 12, 2021 by guest. Protected by http://jcp.bmj.com/ J Clin Pathol: first published as 10.1136/jcp.20.5.731 on 1 September 1967. Downloaded from
From the Department of Morbid Anatomy, Royal Postgraduate Medical School ofLondon
SYNOPSIS Continuous therapy with synthetic progestogen-oestrogen produces marked atrophy ofendometrial glands and massive pseudodecidual stromal transformation. Cyclical therapy producesinitially a 'frustrated secretory response' with precocious attempts at secretion in poorly developedglands. Pseudodecidua appears about the 20th day. With later cycles there is progressively greatergland atrophy while pseudodecidua is less marked. A possible inductive role of the glands on thestromal response to progestogens is postulated. The effect of different drugs and dosages is discussed.
Decidual necrosis may occur with heavy doses. The Arias-Stella reaction, previously regarded asdiagnostic of pregnancy, can be produced with ordinary doses of these drugs. Suppression of spiralarterioles is usual. Ballooning of venules is a frequent finding, possibly accounting for breakthroughbleeding.Red degeneration of myomata was present in three of seven hysterectomy specimens containing
myomata.
The introduction of these drugs is important to thepathologist because they produce endometrial andother uterine changes with which one must be familiarfor the interpretation of appearances in endometrialcurettings and hysterectomy specimens. The syntheticprogestational steroids can be divided into four groupson a chemical basis:
GROUP I: ALKYL DERIVATIVES OF TESTOSTERONE
GROUP II: 19-NOR-TESTOSTERONE DERIVATIVES (a)Norethynodrel (present in Enavid and Conovid); (b)norethisterone (in orthonovum) and norethisteroneacetate (in Anovlar and Gynovlar); (c) ethynodioldiacetate (in Metrulen); (d) lynestrol (in Lyndiol).These drugs are the most potent ovulation inhibitorsand are also the drugs of choice in functional uterinebleeding. Many compounds have inherent oestro-genic activity or are metabolized to oestrogen.
GROUP III: 1 7ct-HYDROXYPROGESTERONE DERIVATIVES(a) Medroxyprogesterone acetate; (b) megestrol ace-tate; (c) chlormadinone acetate. These drugs are less
'Present address: Department of Pathology, Army Base Hospital,Amman, Jordan.
Received for publication 17 March 1967.
powerful ovulation-inhibitors than group II drugs.They have no inherent oestrogenic activity and do notmetabolize to oestrogen.
GROUP IV: PROGESTERONE DERIVATIVES
Drugs of groups II and III are used as contracep-tives, in the treatment of endometriosis and of func-tional uterine bleeding. Most proprietary preparationscontain oestrogen combined with a synthetic pro-gestogen. Some, like Primolut N, contain progestogenonly.
MATERIAL
Material from 44 patients was originally studied. Intwo patients histories were unreliable; one patient hadan unsuspected endometritis and one was possiblypregnant. Material from the remaining 40 patientsconstitutes the basis of this study. Seven patients hadcontinuous therapy, 18 had cyclic therapy as a contra-ceptive (17 of these had a normal menstrual history),while 15 had cyclic therapy for menstrual disorders,usually menorrhagia or metrorrhagia. Hysterectomyspecimens were examined in 12 patients, endometrialcurettings in 28.
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CONTINUOUS THERAPY Of seven patients on continu-ous therapy, one was in the recovery phase. Theremaining six were treated for periods varying betweenone and six months. One had proven endometriosis,five had heavy or irregular periods. Five of the sixpatients showed similar responses; four were givencombined treatment; one had Primolut N alone. Dosevaried between 10 mg. Conovid and 30 mg. Enaviddaily. The interval between the last drug administra-tion and operation was only one day. The glands aremostly small, inactive and devoid of mitoses (Figs.1-3). A few glands show slight secretory activity in apatient treated for 40 days with 10 mg. Conovid daily.The stroma comprises the bulk of the endometriumand shows striking changes. There is marked pseudo-decidual change with conversion of most stromalcells into large, bloated, polygonal cells (Table I); thischange affects the superficial stroma more markedlythan the deeper part (Figs. 1, 3). Moderate to markedoedema is present. Pseudopolymorphs (kornchen-zellen) are present in varying numbers (Fig. 2). Thereis no unusual concentration of mononuclear cells.Occasional plasma cells in one case are probablyrelated to an endocervicitis. The pseudodecidua maybe as striking as the decidua of early pregnancy butthe discrepancy between glandular and stromal ap-pearances clearly distinguishes the iatrogenic changesfrom early pregnancy decidua. Striking vascularchanges are present with suppression of spiral arteri-oles and development of numerous thin-walled ves-sels. In two of the five patients, irregular uterinebleeding persisted up to the time of hysterectomy orcurettage and yet florid pseudodecidua was found.
In two cases portions of frankly necrotic deciduaare present. Pregnancy could be ruled out because ofatrophic glands and other findings. One patient hadhad a tubal sterilization 10 years previously. Thesepatients received 15 mg. Primolut N daily for sixmonths and 20 to 30 mg. Enavid daily for four weeksrespectively.
One of the six specimens did not show the charac-teristic picture. Cystic endometrial hyperplasia wasfound before treatment. Primolut N was given for sixweeks. The last menstrual period was three weeksbefore hysterectomy. Microscopy shows a mid-secretory endometrium without dissociation betweenglandular and stromal changes. Interpretation isreserved until later.
CYCLIC THERAPY Thirty-three patients were treatedfrom day 5 to day 25 of the menstrual cycle. Com-bined treatment with progestogen and oestrogen wasused. Ten patients were in the recovery phase. Of theremaining 23, 13 were normal women treated for fer-tility control and 10 were on treatment for irregularor heavy bleeding. All patients were treated with 19-nor-testosterone derivatives.
It is difficult to generalize about the effect of cyclictherapy because differences are found, depending ondrug dosage, the number of cycles of therapy, andother factors. The following applies to patients taking5 to 10 mg. norethynodrel or 3 to 5 or even 10 mg.norethisterone acetate.
In the first few cycles glandular proliferation,gauged by size and mitoses, is diminished and thenabolished. Subnuclear vacuolation occurs early andis prominent at about nine to 12 days; supranuclearvacuoles may also be found. Subnuclear vacuoles arepresent in rather small glands, usually distinguishablefrom the larger more tortuous glands ofa normal 17thday endometrium (Fig. 4). As epithelial vacuolationrecedes, luminal secretion appears about the 12thday, reaches a peak about the 14th or 15th day anddisappears slowly thereafter. Secretion is scanty andon cursory examination the glands may appear non-secretory. The glands become smaller later in thecycle (Figs. 5 and 6) but a few tortuous glands mayremain. Stromal proliferation is also suppressed butpseudodecidual change usually takes place about the20th day of the cycle, i.e., after 15 days of treatment,becoming progressively more pronounced and some-times as conspicuous as that of the normal menstrual
TABLE ISUMMARY OF MAIN FINDINGS IN 29 PATIENTS ON TREATMENT
No. of Glands Well Developed Vacuolation PseudodeciduaCases Mostly Secretory Glands in Atrophic
Atrophic Glands Slight Moderate Marked
Continuous therapy
Cyclical therapyA Short term (I to 5 cycles) 11
B Long term (6 or more cycles) 12
6 5 11 0
8 of 92 1 of 9 (+1 focal 3 of 8included in previouscoiumn)
12 0 1
0 1 4
2 3 3
3 1 0
"For explanation of exceptional cases in this column see text."Two patients with metrorrhagia and glandular epithelial changes unlike anything seen in gynaecologically normal women on these drugs areexcluded from the table except for the stromal changes.
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Synthetic progestogen-oestrogen therapy and uterine changes
FIG. 1. Forty days' continuous therapy with Conovid FIG. 2. Same case as in Figure 1. Periglandular halo of10 mg./day. Gland atrophy, pseudodecidua in superficial pseudodecidua. The small dark cells are pseudopolymorphs.endometrium, dilated vessels. Haemalum and eosin x 38. Haemalum and eosin x 100.
.7y-, /
:.>
FIG. 3. Five months' continuoustherapy with Enavid 10 mg./day.Gross pseudodecidual responsewith solitary atrophic gland at thetop. Haemalum and eosin x 400.
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J. G. Azzopardi and L Zayid*G: 'iefl I-"SAXt.t'#i.:sf~ :,% -:I-q o:-:--x:W N..0 91 X M
FIG. 4. Ten months' cyclical Conovid E 2-5 mg./day. FIG. 5. Three months' cyclical Orthonovum 2 mg./day.Twelfth cyclical day. Subnuclear vacuolation in straight Twenty-third cyclical day. Small inactive glands. A littleglands. The glands are considerably smaller on a 5 or 10 mg. periglandular and perivascular pseudodecidua in otherdaily dose. Haemalum and eosin x 100. fields. Haemalum and eosin x 100.
FiG. 6. Four months' cyclicalGynovlar 3 mg./day. Nine-teenth cyclical day. Severegland atrophy with periglandularpseudodecidua around a largergland. Haemalum and eosinx 100.
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Synthetic progestogen-oestrogen therapy and uterine changes
FIG. 7. Same case as in Figure 6. Arias-Stella-like FIG. 8. Same case as in Figure 7. Arias-Stella-likereaction in upper gland. Haemalum and eosin x 400. reaction with nuclear anisochromasia, epithelial tufting, loss
of polarity, etc. Haemalum and eosin x 400.
FIG. 9. Cyclical Enavid 10 to20 mg./day for 12 days. Moderategland atrophy, gross stromal oedemaand ballooning of superficial vessels.Other areas show pseudodecidua.Haenmalum and eosin x 100.
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cycle (Table I). Pseudodecidua, often more marked inthe superficial endometrium, shows also a tendencyto localize around glands and vessels (Fig. 6). A vari-able degree of stromal oedema is found at any time ofthe cycle. With the second to fifth cycles glands tendto remain progressively smaller, attaining a lesserdegree of development early in the cycle. Pseudo-decidua is less marked; by the fourth or fifth cycle itmay be very patchy and inconspicuous. From thesixth to the 60th cycles endometrial glands are usuallyuniformly small, with inactive epithelium virtuallydevoid of mitoses, with dense eosinophilic cytoplasmand a sharp luminal edge. Luminal secretion is nowminimal or absent but subnuclear vacuolation maystill be seen, especially with small doses (Fig. 4). Thestroma is mostly dense and inactive, individual cellshave little cytoplasm, the overall appearance resem-bling the stroma of postmenopausal endometrium.Stromal mitoses are rarely found. The endometriumis very thin, possibly accounting for the reduced with-drawal bleeding that patients may experience. Pseudo-decidua may be altogether absent or, if present, takesthe form of very small superficial patches, or haloesaround glands.Two of the 23 cases contain foci of decidual necro-
sis. They were treated with larger doses than are usedfor contraception, one receiving 5 to 10 mg. Enavidinitially and 20 mg. for the five days before curettage,the other receiving 20 mg. Enavid daily for eight days.
Glandular changes indistinguishable from theArias-Stella reaction are present in two of the 13gynaecologically normal women taking drugs as acontraceptive. Only some glands show Arias-Stellachange; these are rather larger than the majority ofthe glands which are small and tubular (Figs. 7 and 8).The epithelium in affected glands varies betweencolumnar with sharp luminal edges and cells withbulbous luminal margins; the nuclei are relativelylarge, variable in size and staining intensity, andsometimes situated in the bulbous portion. In bothcases small foci of periglandular pseudodecidua arepresent; these periglandular haloes are strikinglyassociated with the slightly larger glands showingArias-Stella change.
Vascular changes are similar to those seen on con-tinuous therapy. There is partial or complete sup-pression of development of spiral arterioles, withdevelopment of thin-walled sinusoids which some-times appear ectatic (Fig. 9). These sinusoids can bemistaken for dilated glands with flattened epithelium.In one patient with Arias-Stella change, an endo-metrial polyp contains large branched glands and anabundance of muscular arterioles, i.e. looks verydifferent from the remainder of the endometrium.Two patients with abnormal gynaecological histor-
ies merit separate mention. In one, curettage for met-
rorrhagia showed cystic endometrial hyperplasia.Following Primolut N for two cycles, curettagerevealed secretory glands and a pseudodecidual re-action. Curettage in a second patient with metrorrhag-ia showed focal hyperplasia. After one cycle ofEnavidtherapy, curettage on the 26th day showed a fewsecretory glands among a majority of small non-secretory ones.
RECOVERY PHASE This covers curettings from patientswho have discontinued treatment for seven days ormore, except for one patient with a gap of only fourdays. Eleven patients were in the recovery phase, oneafter continuous therapy for four months, 10 aftercyclical therapy for periods varying between two and48 months. In the patient on continuous treatmentcurettage revealed, four days after stopping therapy,an early proliferative endometrium with epithelial,but very rare stromal, mitoses. This appears to indi-cate that partial recovery can take place in only fourdays. In the 10 patients on cyclical therapy, treatmenthad been discontinued for between four months andonly seven days. Curettage showed normal prolifera-tive or secretory endometrium in all. As examples ofthe endometrial capacity to recover, two instancesare cited. A patient on 2-5 mg. Conovid E for fouryears as a contraceptive and another treated for almostone year with massive Enavid therapy of up to 80 mg.daily for uncontrollable metrorrhagia both had nor-mal proliferative endometria after stopping treatment.While no abnormalities were seen in these 11 patients,in a patient still on continuous therapy a small,circum-scribed stromal nodule of fibroblast-like cells ispresent.
MYOMETRIUM Of 12 cases undergoing hysterectomy,seven had uterine myomata and, of these, threeshowed red degeneration. These patients receivedtreatment for periods of nine days, four weeks, andsix weeks respectively. The first received only 1 mg.Metrulen M daily for nine days; the last was oncontinuous therapy for six weeks with Primolut N. Inall three cases multiple myomata were present butonly one in each case showed red degeneration. Intwo this affected the largest myoma present (9 cm. and4 cm.) while in the third, one of the smaller myomata(1 cm.) was affected.
DISCUSSION
CONTINUOUS THERAPY This produces florid pseudo-decidual change but with dissociation between gland-ular and stromal effects. Dockerty, Smith, andSymmonds (1959) drew attention to this change intheir case 3. The development of abnormal thin-walled vessels in theseendometria is probably respons-
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Synthetic progestogen-oestrogen therapy and uterine changes
ible for the breakthrough bleeding that may occur.In two of our cases uterine bleeding persisted up tothe time of hysterectomy or curettage and yet theendometrium was still thick and showed pseudo-decidua. This we believe represents bleeding withoutmenstruation.
Since continuous therapy is used in the treatmentof endometriosis, it is noteworthy that ectopic endo-metrium may respond like the normally placed tissue(Lebherz and Fobes, 1961). This can lead to the patho-logist being confronted with a biopsied or resected'tumour' with very baffling appearances.
CYCLICAL THERAPY Depressed gland proliferationand 'frustrated secretion' epitomize the epithelialchanges. Epithelial vacuoles appear precociously butthe secretory response is incomplete and luminalsecretion diminished. Repressed secretion is probablythe result of and proportionate to failure of glandulardevelopment. Pseudodecidua appears about the 20thday and may become well developed. With subsequentcycles epithelial vacuolation is slighter, perhaps be-cause gland atrophy is more complete, and pseudo-decidual change is less marked. The finding of slightpseudodecidua as early as the seventh day by Ryan,Craig, and Reid (1964) was not confirmed. Thisvariation with the number of cycles was seen also byRice-Wray, Aranda-Rosell, Maqueo, and Goldzieher,(1963). The reason for the lessening of the pseudo-decidual response is far from clear though one poss-ibility is that development ofendometrial glands playsan inductive role in the response of the stroma to pro-gestogen. This is suggested by a few cases with pseudo-decidua around larger glands when there is nonearound completely atrophic ones. An alternativepossibility is that alterations in vascular flow accountfor the diminished stromal response.
EFFECT OF SIZE OF DOSE Flowers (1964) found novariation between successive cycles using low-dosagetherapy. Epithelial vacuolation appeared somewhatlater, while there was no pseudodecidual change. Sub-nuclear vacuolation was consistently present in thesecond year of therapy, perhaps because this low-dosage therapy caused less gland suppression early inthe cycle (Fig. 4) In this context it is believed thatprogestogen allows endometrial glands to secrete byantagonizing oestrogen, which is a secretion inhibitor(Ober, 1966). At the other end of the scale, treatmentwith, say, 20 mg. norethynodrel for eight to 10 dayscan produce pseudodecidua seen onaly after 15 to 20days ofmore moderate dosage. Within limits, a largerdose produces earlier change or more intense wide-spread effect; there is a partial exception in the case ofsecretory change which may be actually less prominent
with the larger dose, where the latter has effectedsevere gland atrophy.
EFFECT OF TYPE OF DRUG The effects produced bydrugs of groups II and III are similar but with quanti-tative differences. Ethynodiol diacetate in the 1 to 2mg. dose usually prescribed causes little or no pseudo-decidual reaction. The 1 7ox-hydroxyprogesteronederivatives produce less intense pseudodecidua thanthe 19-nor-testosterone derivatives (Ober, 1966). Inaddition to group differences, there are minor differ-ences between individual drugs. Maqueo, Perez-Vega,Goldzieher, Martinez-Manautou, and Rudel (1963)found that norethynodrel, compared with norethis-terone, caused more oedema (Fig. 9), earlier and moremarked gland regression, and less pseudodecidualreaction: conversely, with norethisterone, secretorychanges were more marked and pseudodecidua betterdeveloped. These differences are relatively minor.
DECIDUAL NECROSIS This was noted in four of the 29cases. It may make one suspect pregnancy, as hap-pened in one of our cases, until it became clear thatdrugs alone can cause this. High dosage appears to benecessary for this effect; duration of therapy is notimportant. No necrosis was seen in patients on moremoderate dosage as used for contraceptive purposes.
ARIAS-STELLA-LIKE CHANGES These changes werepresent in two women taking moderate drug doses ascontraceptive therapy. It has hitherto been acceptedthat the Arias-Stella reaction only occurs in the pre-sence of trophoblastic tissue and that it is a sign ofpregnancy in uterine and extrauterine sites (Birch andCollins, 1961; Mackles, Wolfe, and Pozner, 1961).However, Arias-Stella (1955) found that this reactioncould be induced by giving oestrogen and progester-one for 18 to 20 days to castrated rats; oestrogen alonefailed to produce this effect.
VASCULAR ALTERATIONS Ober drew attention to theimportance of vascular changes. Inhibition of devel-opment of spiral arterioles is common to all pro-gestogen-oestrogen regimens. Dilated venules areoften present, more frequently in therapy with 19-nor-testosterone than with 17a-hydroxyprogesteronederivatives. With less than 2 mg. of any type of drugvenule ectasia is rare.
EFFECT ON ABNORMAL ENDOMETRIA Treatment con-verted two previously hyperplastic endometria intonear-normal secretory endometria while a third caseof focal endometrial hyperplasia showed, after treat-ment, focal secretory glands among atrophic ones. It
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is tempting to think that the 'overprimed' endo-metrium responds by the development of secretoryglands. Should further data confirm this, it wouldimply that the presence after treatment of full-blownsecretory glands probably indicates a precedinghyperplasia.
RECOVERY PHASE Discontinuation of therapy is be-lieved to lead to a return to a normal endometriumand this is true of our 11 cases. Charles (1964), how-ever, reported abnormalities in three patients afterstopping treatment, viz., squamous metaplasia inendometrial glands, an endometrial myoma, and afibrous stromal nodule; a minute stromal nodulesimilar to the latter was present in one of our cases ontherapy. It is important to document all such changesto establish any relationship to therapy.
MYOMETRIUM Dockerty et al. reported myometrialvascular congestion and red degeneration of uterinemyomata in a postmenopausal woman. No fewerthan three of our seven cases with myomata showedthis change. It can occur with a small dose, after abrief period of therapy, and with progestogen alone.
Myometrial hypertrophy and congestion, red de-generation ofmyomata, florid pseudodecidual change,
and an Arias-Stella reaction are the anatomical com-ponent of an induced pregnancy-like state which hasbiochemical, haematological, and clinical equivalents.The changes produced by synthetic progestogen-oestrogen therapy mimic those of pregnancy, with thedifference that there is no foetus.
We are grateful to Professor J. McClure Browne and hisdepartment for free access to their clinical data. We wishto thank Professors C. V. Harrison and J. Browne, andDr. K. Fotherby for valuable discussion, Miss J. Allenfor help with the pharmaceutical nomenclature, and Mr.B. Chalk and Mrs. V. Chalk for technical and secretarialassistance.
REFERENCES
Arias-Stella, J. (1955). Arch. Path., 60, 49.Birch, H. W., and Collins, C. G. (1961). Amer. J. Obstet. Gynec., 81,
1198.Charles D. (1964). J. clin. Path., 17, 205.Dockerty, M. B., Smith, R. A., and Symmonds, R. E. (1959). Proc.
Mayo Clin., 34, 321.Flowers, C. E., Jr. (1964). J. Amer. med. Ass., 188, 1115.Lebherz, T. B., and Fobes, C. D. (1961). Amer. J. Obstet. Gynec., 81,
102.Mackles, A., Wolfe, S. A., and Pozner, S. N. (1961). Ibid., 81, 1209.Maqueo, M., Perez-Vega, E., Goldzieher, J. W., Martinez-Manautou,
J., and Rudel, H. (1963). Ibid., 85, 427.Ober, W. B. (1966). J. clin. Path., 19, 138.Rice-Wray, E., Aranda-Rosell, A., Maqueo, M., and Goldzieher,
J. W. (1963). Amer. J. Obstet. Gynec., 87, 429.Ryan, G. M., Jr., Craig, J., and Reid, D. E. (1964). Ibid., 90, 715.
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