Micronized Estradiol and Progesterone Therapy inPrimary, Preinvasive Endometrial Cancer (1A/G1) inYoung Women With Polycystic Ovarian Syndrome

Stanisław Stanosz, Jarosław von Mach-Szczypinski, Krzysztof Sieja, andJakub Koœciuszkiewicz

Department of Menopause and Andropause (S.S., J.v.M.-S., J.K.), Pomeranian Medical University,70-204 Szczecin, Poland; and Department of Health Education (K.S.), Faculty of Health Culture andHealth Promotion, University of Szczecin, 71-065 Szczecin, Poland

Context: This report presents original, combined mode of treatment of preinvasive endometrialcancer (IA/G1) in young women with polycystic ovarian syndrome.

Objectives: The objective of the study was the assessment of treatment with natural female sexualhormones in combination with antidiabetic, antioxidative, antidopaminergic, and antiserotonintherapy on the concentrations of hormones and serotonin in blood serum in young women withpolycystic ovary syndrome and preinvasive endometrial cancer.

Design: This study was performed within 12 months.

Setting: The study was conducted in the Department of Menopause and Andropause of the Po-meranian Medical University in Szczecin, Poland.

Participants and Study Design: Participants were 57 young PCOS women with concomitant pre-invasive endometrial cancer (1A/G1). These women were 18–29 years old. They were treated withmodified transdermal hormonal replacement therapy. Moreover, in permanent combined treat-ment, metformax 850 mg/d, bromcriptine mesylate 2.5 mg/d, and melatonin 5 mg/d were applied.

Interventions: Interventions in the study included blood sampling and dilation and curettage.

Main Outcome Measures: The concentrations of gonadotropins, estrogens (estrone, 17�-estra-diol), progesterone, total/free T, and prolactin in basic conditions and after a metoclopramide-stimulating test, dehydroepiandrosterone sulfate, and serotonin in blood serum were measured.

Results: A significant increase in the concentrations of gonadotropins, estrogens, and progester-one was found. Moreover, the concentrations of androgens, prolactin, and serotonin were sig-nificantly decreased.

Conclusion: Micronized estradiol and progesterone in primary, preinvasive endometrial cancer(IA/G1) in young women, with polycystic ovarian syndrome with concomitant antidiabetic, anti-oxidative, antidopaminergic, and antiserotonin therapy, favorably influenced on the concentra-tions of female sexual hormones and lipid metabolism and caused the restoration of normalendometrium. (J Clin Endocrinol Metab 99: E2472–E2476, 2014)

Endometrial cancer (EC) is the most common femalegenital tract of malignancy in most countries, affect-

ing 2%–3% of women (mostly postmenopausal) (1). Poly-

cystic ovarian syndrome (PCOS) is the most common en-docrinological disease, affecting women of reproductiveage, 5%–10% of whom have the syndrome (1, 2). There

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2014 by the Endocrine SocietyReceived March 11, 2014. Accepted August 19, 2014.First Published Online August 26, 2014

Abbreviations: BMI, body mass index; D&C, dilation and curettage; DHEA-S, dehydroepi-androsterone sulfate E1, estrone; E2, 17�-estradiol; EC, endometrial cancer; EEC, endo-metrioid cancer; PCOS, polycystic ovarian syndrome.

J C E M O N L I N E

H o t T o p i c s i n T r a n s l a t i o n a l E n d o c r i n o l o g y — E n d o c r i n e C a r e

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are two major histological types of EC: type I or endometri-oid cancer (EEC), accounting for greater than 75% of ECcases, and type 2, non-EEC (2). Type 1 develops from endo-metrial hyperplasia and type 2 from atrophic endometrii (2).EECs are estrogen-dependent tumors with associated distur-bances in lipid, carbohydrate metabolism, and infertility.Sexual hormones regulate proliferation, differentiation, andapoptosis in the endometrium (3). Women with PCOS maybe at increased risk of developing EC (4–9).

Materials and Methods

ObjectivesThe assessment of the treatment with micronized trans-

dermal estradiol and intravaginal progesterone was appliedin 22-day therapeutic cycles and combined with permanenttreatment with metformin, bromergon, melatonin, and de-seril on the level of gonadotropins, estrogens, progesterone,total/free T, dehydroepiandrosterone sulfate (DHEA-S), andserotonin in blood serum in women with PCOS with con-comitant preinvasive endometrial cancer. Moreover, thecourse of menstrual cycles and regression of preinvasive en-dometrial cancer in histopathological examinations wasstudied.

SubjectsBased on clinical, ultrasound, biochemical, and histopatho-

logical examination, samples from the endometrium of 57 youngwomen with PCOS and with concomitant, primary, preinvasiveEC (IA/G1) were examined. We tested the efficiency of our treat-ment for treating women aged younger than 29 years with In-ternational Federation of Gynecology and Obstetrics stage IAlimited to the endometrium, well-differentiated G1 endometri-oid EC who want to preserve their fertility.

These women in the age of 18–29 (average age 25 � 0.9 y)were born from pregnancies with disturbances during the preg-nancies and deliveries. In 70.1% of the women, the pregnancieswere ended with premature delivery, with mean birth weight of2400 � 120.1 g with the Apgar index of 6–8 points. In 29.8%of the women, the cesarean section was performed because of theimminent asphyxia of the fetus. In these women, the averagebirth weight was 2100.1 � 115.1 g with an Apgar score of 3–6points. In this group, the mean time of delivery was 31.7 weeksof gestation. Among 57 of women (100%), 25 (43.9%) were slimwith an average body mass index (BMI) index of 23.1 � 1.7kg/m2, with normal blood pressure (BP) values, irregular men-strual cycles, and infertility in anamnesis. However, 32 (56.1%of the women showed average BMI of 26.9 � 2.8 kg/m2, andborderline hypertension (145 � 6.1/95 � 2.7 mm Hg) with men-strual disturbances and infertility in anamnesis.

The women were treated with modified transdermal hor-monal replacement therapy: 17�-estradiol in the form of trans-dermal patches (Estraderm MX; Novartis Pharm) with subse-quently increasing and decreasing doses (25, 50, 50, 25 �g perdose), imitating the physiological serum concentrations of es-trogens throughout the physiological cycle. In addition, the

women were administered concomitant, intravaginal, intermit-tent micronized progesterone (Lutein; Adamet Medical Co), inthe second phase of the therapeutic cycle at doses of 50 mg dailyfor 6 days and, subsequently, 100 mg daily for the next 6 days (9).Moreover, in permanent combined treatment, we also appliedmetformax 850 mg/d (Teva Pharmaceuticals), bromcriptine me-sylate 2.5 mg/d (Bromergon; Sandoz), melatonin 5 mg/d (LEK-AM) (10). In women with elevated levels of serotonin methyser-gide maleate 3 mg/d (Deseril Sandoz) was applied.

Laboratory analysisSamples of venous blood for biochemical tests were taken.

The samples were used to prepare the following biochemicalstudies: the concentration of gonadotropins, estrogens [estrone(E1), 17�-estradiol (E2)], progesterone, total/free T, and prolac-tin in basic conditions and after the metoclopramide-stimulatingtest, DHEA-S, and serotonin. Moreover, the concentration oftotal cholesterol, low-density lipoprotein-cholesterol, high-den-sity lipoprotein-cholesterol, and triglycerides was assessed. Theconcentration of hormones in blood serum was determined usingimmunoenzymatic methods and ready sets from the IBL Firm.Lipidogram was assessed by means of enzymatic sets by Roche.The histopathological examinations scrapings from dilation andcurettage (D&C) endometrium were performed at the beginningof bleeding before treatment and in therapeutic cycles after 3 and6 months of treatment before expected withdrawal bleeding. Thehistopathological examination was performed in the Pathomor-phology and Genetics Department of the Pomeranian MedicalAcademy (Szczecin, Poland).

Statistical analysisStatistical calculations were performed using the Statistica

6.188 PL package made by StatSoft. The significance of changesin the examined parameters during this study we assessed usingthe proper paired-measure Student’s t test. A value of P � .05 wasconsidered statistically significant. We calculated the power toget P value. This power test value was P � .90. Results arepresented as average values � SD.

Forcarryingout thepresentstudy, theconsentofwomenandtheapproval of the Bioethical Commission of Pomeranian MedicalUniversity (Szczecin, Poland) (No BN-001/127/05) were obtained.

Results

The biochemical results are shown in Tables 1 and 2. InTable 1 the concentrations of gonadotropins, estrogens,progesterone, and prolactin in basal conditions and afterthe metoclopramide test, total/free T, DHEA-S, and sero-tonin in serum are shown.

In Table 1 before treatment the concentrations of go-nadotropins, estrogens, and progesterone were decreased,but prolactin, total/free T, DHEA-S, and serotonin wereincreased compared with reference norms.

After 3 months of treatment, the concentrations of go-nadotropins (P � .05), estrogens ( E1 P � .01; E2 P � .05),and progesterone (P � .001) were significantly increasedcompared with initial values before treatment, but the

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concentration of prolactin in the basic condition (P �.001), prolactin after the metoclopramide test (P � .01),total T (P � .05), free T (P � .01), and DHEA-S (P � .01)were significantly lower compared with the initial values.Moreover, the concentration of serotonin was signifi-cantly decreased (P � .001).

After 6 months of treatment, the concentration of go-nadotropin (FSH, P � .001; LH, P � .001), estrogens (E1,P � .01; E2, P � .001), and progesterone (P � .001) weresignificantly increased. The concentration of prolactin inthe basic condition (P � .001), prolactin after the meto-clopramide test (P � .001), total T (P � .05), free T (P �.001), DHEA-S (P � .001), and serotonin (P � .001) weresignificantly decreased compared with values beforetreatment.

In this statistical analysis, after 12 months of treatment,all concentrations of the examined hormones and sero-

tonin were significantly unchanged compared with the re-sults after 6 months.

Table 2 shows the concentration of the lipid fractionsin women with PCOS and concomitant preinvasive endo-metrial cancer, depending on the BMI before and after 6months of treatment.

Moreover, it must be underlined that in women withnormal BMI, hyperinsulinemia was not found. But among23 women (100%) with PCOS with concomitant prein-vasive endometrial cancer with elevated BMI in eight(25%) women, hyperinsulinemia was revealed.

Ultrasound examinations were performed before theD&C procedure. Transvaginal ultrasound in PCOSwomen with concomitant endometrial cancer revealed theincreased length of the uterus with an average diameter8.1 � 1.3 cm and increased thickness of the endometriumin 50 of the women and irregularities of the endometrium

Table 2. Lipidogram in Women With PCOS With Concomitant Preinvasive EC, Depending on BMI (n � 57)

Lipid Fraction,mg/dL

Women With Mean BMI 23 � 1.6 kg/m2

(n � 25)Women With Mean BMI 26.9 � 1.9 kg/m2

(n � 32)

BeforeTreatment

After 6 Monthsof Treatment

BeforeTreatment

After 6 Monthsof Treatment

Total cholesterol 221 � 25.2 205 � 11.1a 253 � 7.0 209 � 6.1b

HDL-cholesterol 61.4 � 9.3 65.9 � 5.2c 52.9 � 8.0 62.3 � 4.7a

LDL-cholesterol 127.2 � 16.1 110.7 � 9.1a 155.6 � 17.1 119 � 97.0a

Triglycerides 225.2 � 15.1 205.5 � 7.1a 235.7 � 14.1 211.7 � 2.1b

Abbreviations: HDL, high-density lipoprotein-cholesterol; LDL, low-density lipoprotein.a P � .01.b P � .001.c P � .05.

Table 1. Concentrations of gonadotropins, estrogens, prolactin (in basic condition and after metoclopramide test),total/free T, DHEA-S, and 5-HT in blood serum in women before and after 3, 6, and 12 months of treatment withmicronized estradiol and progesterone with concomitant antidiabetic, antioxidative, antidopaminergic, andantiserotonin therapy in preinvasive endometrial cancer in young women with PCOS (n � 57)

Studied Parameter

Time of the Study

BeforeTreatment

After 3Months

After 6Months

After 12Months

FSH, U/L 1.4 � 0.5 1.9 � 0.42a 5.2 � 1.1b 6.2 � 1.9b

LH, U/L 1.8 � 0.4 2.5 � 0.7a 6.4 � 1.4b 5.3 � 1.65b

E1, pg/mL 104 � 12.3 141.3 � 19.2c 114.4 � 12.7c 112 � 29.2c

E2, pg/mL 97 � 8.2 112 � 19.7a 165 � 17.1b 177 � 30.2b

P, ng/mL 1.2 � 0.9 4.5 � 1.3b 14.1 � 2.3b 16.3 � 3.1b

PRL, ng/mL 44.2 � 7.1 24.5 � 2.1b 20.1 � 2.2b 18.1 � 2.1b

PRL MCP, ng/mL 321 � 18.7 257 � 67.1c 251 � 30.3b 197 � 22.1b

Total T, ng/mL 1.49 � 0.9 1.2 � 0.8a 1.1 � 0.4a 1.2 � 0.5a

Free T, pg/mL 1.65 � 0.31 1.4 � 0.15c 1.1 � 0.9b 0.7 � 0.1b

DHEA-S, nmol/L 331 � 41.2 308.2 � 34c 290.1 � 25.6b 195 � 19.1b

5-HT, nmol/L 591 � 81.4 487.1 � 69.2b 385.2 � 30.2b 401 � 25.7b

Abbreviations: 5-HT, serotonin; MCP, monocyte chemotactic protein; P, progesterone; PRL, prolactin.a P � .05.b P � .001.c P � .01.

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in 36 of these. The ultrasound images of the ovaries in all57 women showed typical for PCOS, with multiple fol-licular cysts in different cycles of development.

The typical result of an initial histopathological exam-ination, the biopsy and curettage specimens of the endo-metrium showed screening pictures of the glandular en-dometrial hyperplasia with well-differentiated, stage G1

preinvasive glandular cancer of the endometrium (1A) (ac-cording to Fédération Internationale de Gynécologie etd’Obstétrique). After 3 months of treatment, the controlhistopathological examination pictured only a few glan-dular ducts with stroma of the endometrium. After 6months of therapy, the results of the histopathologicalexamination of the biopsy and curettage specimens of theendometrium revealed normal restoration of the endome-trium. After 6 months of treatment, the histopathologicalexamination of the biopsy and curettage specimens fromthe endometrium revealed a normal picture without neo-plasmatic texture.

From 57 patients treated according to the presentedscheme 1 year after the completion of the treatment(100%), 14 women (25%) were pregnant and deliveredhealthy newborns at term.

Discussion

Although endometrial cancer is primarily a postmeno-pausal disease, 25% of patients are in premenopausal age,with 3%–5% being 40 years old or younger (1). Theyounger groups of women with endometrial carcinomaare frequently nulligravid with a history of infertility andstrong desire to preserve fertility, which may pose a ther-apeutic dilemma for both patients and physicians (4–9).

Hormonal therapy has been proposed for youngwomen with endometrial cancer (grade 1) who want topreserve their fertility (2, 4, 8, 9). However, a detailedevaluation including a physical examination, history tak-ing, performing D&C, examining the specimen by askilled pathologist, and using imaging techniques isnecessary.

In our study, modified hormonal therapy was admin-istered because in these young women with PCOS andpreinvasive EC (stage IA/G1), relative hyperestrogenismand an insufficiency luteal phase were found (Table 1).This was, for us, the inspiration to apply micronized es-tradiol and progesterone in the treatment of PCOS. Higherhyperinsulinemia and hyperglycemia in obese rather thanin lean women were found (10–12). The increased con-centration of IGF-1 in ovaries stimulates ovaries to an-drogen production in theca cells and causes the develop-ment of insulin-dependent hyperandrogenization (5, 11)

(Table 1). Obesity is the key symptom in metabolic syn-drome. It is associated with metabolic syndrome in 30%–70% (5). Obesity is connected with hyperandrogenism,insulin resistance, impaired glucose tolerance, and dyslip-idemia (10–12) (Tables 1 and 2). The pathophysiologicalmechanism of PCOS in still not completely understood.There is the evidence that the main role in the pathogenesisof PCOS plays the ovarian overproduction of androgens,caused by genetic reasons connected with hyperinsulin-emia and hypersecretion of LH (5). As was concluded inTable 1, in young women with preinvasive endometrialcancer (1A/G1), applying combined hormonal (EstradermMX; Luteina), antidiabetic (metformax), antioxidative(melatonin), and antidopaminergic (bromergocriptinemesylate) therapy and in selected cases of hypersero-toninemia, antiserotonin (deseril) therapy leads to favor-able changes in the level of hormones and serotonin inblood. Moreover, this influences the lipidogram positively(Table 2).

The most important aim of the treatment applied wasto restore reproductive functions in young women withincomplete procreation. From 57 patients treated accord-ing to presented scheme 1 year after the completion of thetreatment, 14 women (25%) were pregnant and delivereda healthy newborn at term. We know that this result is notfully successful, however essential. We underline that wehave these patients under follow-up observation.

Metformin was used for the endometrial abnormalitiesin treatment (10, 12). Endometrial hyperplasia is a pre-malignant condition that usually heralds EC, and it sharesidentical risk factors with EC. Palomba et al (12) suggestthat measures to improve insulin resistance could play arole in reducing the risk of EC in women with PCOS. It hasbeen clearly shown in both animal and human studies thatmetformin is of value in reversing endometrial hyperplasia(10, 12). Metformin may therefore prevent EC in PCOS.Shafiee et al (10) reviewed the use of metformin in reduc-ing the EC risk in PCOS and makes a case for future re-search on this topic.

Melatonin is the modulator of the hypothalamic-pitu-itary-gonadal axis (13). Women with PCOS were found tohave a significantly higher melatonin level at 8:00 AM and asmaller mean night-day difference in the concentrations ofmelatonin in comparison with those of healthy women (14).The results obtained by Terzieva et al (14) about the changesof melatonin in women with PCOS could help in elucidatingthe complex pathophysiological pattern of this disease.

Melatonin levels have been shown to decrease in pa-tients with cancer, and exogenous melatonin exhibits an-tiproliferative effects against certain cancers.

Melatonin inhibits tumor genesis in a variety of in vivoand in vitro experimental models of neoplasia (15–18).

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Cucina et al (16) have shown that, via activation of itsMT1 receptor, melatonin modulates the transcriptionalactivity of various nuclear receptors and the proliferationof both estrogen receptor-�� and estrogen receptor-��human breast cancer cells. These results demonstrate thatthe MT1 receptor is a major transducer of the action ofmelatonin in the breast, suppressing mammary gland de-velopment and mediating the anticancer actions of mela-tonin through multiple pathways (16).

The pineal hormone melatonin has been shown to haveanticancer therapeutic properties in patients with gastriccancer; the mechanisms, however, remain largely un-known (17). Data reported by Jung-Hynes et al (18) sup-port the suggestion that melatonin should be thoroughlyinvestigated as an agent for the management of prostatecancer and other age-related malignancies.

In the study of Li et al (9), five patients with PCOS andpreinvasive endometrial cancer were cotreated with Di-ane-35 and metformin for 6 months to reverse the endo-metrial carcinoma and preserve their fertility. Li et al (9)concluded that combined treatment with Diane-35 andmetformin has the potential to revert the endometrial car-cinoma into normal endometrial cells in PCOS-insulin re-sistant women.

We concluded that the above-mentioned complex, theoriginal mode of therapy presented in this report, pro-duced positive changes in the neurohormonal state of af-fected women and after 6 months of treatment caused theregression of preinvasive endometrial cancer (1A/G1) (Ta-bles 1 and 2).

ConclusionsSeveral conclusions from this study were reached. First,combined therapy may have a role for safe and effectiveconservative management of early endometrial cancer(stage IA/G1) in selected patients with polycystic ovariansyndrome wanting to preserve their fertility. Second, mi-cronized estradiol and progesterone therapy in primary,preinvasive endometrial cancer (stage IA/G1) in youngwomen with PCOS with concomitant antidiabetic, anti-oxidative, antidopaminergic, and antiserotonin therapyfavorably influenced the concentration of female sexualhormones, lipid metabolism, and caused the restoration ofnormal endometrium. Finally, conservative pharmacolog-ical treatment of young women with well-defined endo-metrial carcinoma stage IA/G1 type I should be monitoredwith follow-up histopathological examinations of mate-rial obtained from D&C of the endometrium and assess-ment of concentrations of sex hormones in the serum.

Acknowledgments

Address all correspondence and requests for reprints to:Krzysztof Sieja, MD, Department of Health Education, Fac-

ulty of Health Culture and Health Promotion, University ofSzczecin, Aleja Piastów 40B, 71-065 Szczecin, Poland. E-mail:siejakrzysztof@wp.pl.

Disclosure Summary: The authors have nothing to disclose.

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