Arch Gynecol Obstet (2015) 291:151157

DOI 10.1007/s00404-014-3417-z

GYNECOLOGIC ONCOLOGY

Efficacies and pregnant outcomes of fertility-sparing treatment

with medroxyprogesterone acetate for endometrioid
adenocarcinoma and complex atypical hyperplasia:
our experience and a review of the literature
Chifumi Ohyagi-Hara Kenjiro Sawada Isobe Aki Seiji Mabuchi
Eiji Kobayashi Yutaka Ueda Kiyoshi Yoshino Masami Fujita
Tateki Tsutsui Tadashi Kimura

Received: 6 June 2014 / Accepted: 7 August 2014 / Published online: 14 August 2014
Springer-Verlag Berlin Heidelberg 2014

Abstract
Purpose We retrospectively analyzed oncologic and
reproductive outcomes of fertility-seeking premenopausal
women with complex atypical hyperplasia (CAH) or Grade
1 endometrial adenocarcinoma (G1EA) who underwent
medical management with high-dose medroxyprogesterone
acetate (MPA) therapy.
Methods Patients were given a dose of 400600 mg of
MPA orally on a daily basis. They had histologically
confirmed CAH or G1EA at presumed stage IA and wished
to preserve fertility. Endometrial tissue sampling was carried out by dilation and curettage before and after the
treatment and the pathologic response to MPA treatment
was assessed.
Results A total of 27 premenopausal patients received
MPA therapy. The median follow-up time was
39.2 months (3.4153.8 months). Complete response was
achieved in 81.8 % (9/11) of CAH cases and 68.8 % (11/
16) of G1EA. Although no recurrences were found in CAH
patients, nine G1EA patients (81.8 %) eventually recurred
and underwent total hysterectomy. Neither therapeutic
death nor irreversible toxicities were observed during the
follow-up periods. Five patients (4 CAH and 1 G1EA)
became pregnant and had nine live births.

C. Ohyagi-Hara
K. Sawada (&)
I. Aki
S. Mabuchi

E. Kobayashi
Y. Ueda
K. Yoshino
M. Fujita
T. Tsutsui

T. Kimura
Department of Obstetrics and Gynecology, Osaka University
Graduate School of Medicine, 2-2, Yamadaoka Suita,
Osaka 5650871, Japan
e-mail: daasawada@gyne.med.osaka-u.ac.jp
C. Ohyagi-Hara
T. Tsutsui
Department of Obstetrics and Gynecology, JCHO Osaka
Hospital, 4-2-78, Fukushima, Osaka 5530003, Japan

Conclusion The high efficacy of fertility-sparing treatment with MPA was shown demonstrated. MPA therapy
can be considered acceptable for the purpose of enabling
patients to preserve their fertility. However, the rate of
recurrence was high in patients with G1EA. Even in
responders, close follow-up is required and a total hysterectomy needs to be considered without delay. Patients
should be aware of the risks and limitations of this conservative treatment.
Keywords Endometrial cancer
Complex atypical
hyperplasia
Fertility-sparing treatment
MPA

Introduction
Endometrial cancer (EC) is the most common type of
gynecologic malignancy. Although it is typically a disease
of postmenopausal women, 2025 % of endometrial cancer
and complex atypical hyperplasia cases occur in premenopausal women, with 510 % occurring in women
under the age of 40 years [1]. In Japan, 10,815 women
were diagnosed with EC and 711 of those were younger
than 40 years (6.6 %) in 2008 [2]. The number of patients
younger than 40 years is on the rise [3], although women
tend to marry late in developed countries such as Japan.
The standard treatment for EC includes a total hysterectomy, bilateral salpingo-oophorectomy (BSO), and pelvic and para-aortic lymph node assessment. However, this
management is often an unacceptable option for young
patients who strongly wish to preserve their fertility.
Hence, fertility-sparing treatment with progestin has been
attempted for younger women with stage IA, well-differentiated (Grade 1) endometrioid adenocarcinoma (G1EA)
and complex atypical hyperplasia (CAH), a known

123

152

precursor of EC [4]. Several studies at various institutions

have reported the results of fertility-sparing treatment with
progestins [59]. In these reports, although recurrences
were often seen in patients with G1EA after progestin
therapy, the diseases were mostly confined to the endometrium or myometrium, and could be successfully salvaged by surgical management. Therefore, fertility-sparing
treatment with progestin has been thought not to increase
the risk of disease progression or death and can be an
effective and safe alternative treatment option for younger
patients who wish to preserve their fertility until after
childbearing [8, 10]. However, since the number of cases
has been low and various attempts were reported from
various institutions, the efficacy or a standard protocol
including the treatment periods of progestin therapy have
yet to be established. In addition, the pregnancy outcomes
have not been adequately reported because most previous
studies focused on the oncologic outcomes of progestin
therapies and the follow-up periods were relatively short.
With these points in mind, we retrospectively analyzed
not only oncologic but also reproductive outcomes of
patients with G1EA and CAH who underwent medical
management in our institute and conducted a systematic
review of observational studies evaluating the regression,
relapse and live birth rates for the fertility-sparing treatment with MPA in young women who wanted to preserve
their fertility.

Materials and methods

Eligible patients were between 20 and 45 years, had histologically confirmed G1EA or CAH at presumed stage IA
(according to the 1998 International Federation of Obstetrics and Gynecology staging system), and desired to preserve their fertility in spite of an oncologic risk. A total of
27 patients who received progestin therapy to maintain
their fertility at Osaka University Hospital between 2000
and 2012 were retrospectively analyzed. Endometrial tissue
sampling for diagnosis was carried out by dilation and
curettage (D&C). All patients who were diagnosed with
G1EA underwent pelvic magnetic resonance imaging
(MRI) for staging, and myometrial invasion or any extra
uterine lesions were ruled out by institutional radiologists.
If these were strongly suspected by MRI, patients were
excluded from progestin therapy and underwent surgery.
Patients were scheduled to receive 400600 mg of
medroxyprogesterone acetate (MPA) orally on a daily basis
for 12 weeks. After the treatment, endometrial biopsy was
performed by D&C to assess the efficacy of MPA therapy.
The pathologic response to MPA treatment was categorized as complete response (CR), partial response (PR), no
change (NC) or progressive disease (PD) based on the

123

Arch Gynecol Obstet (2015) 291:151157

previous report by Ushijima et al. [9] CR was defined as the

absence of any hyperplastic or cancerous lesion. PR was
defined as residual lesion with degeneration and atrophy of
endometrial glands. NC was defined as residual lesion
without degeneration or atrophy of endometrial glands. PD
was defined as the appearance of grade 2 or 3 endometrioid
adenocarcinoma or when myometrial invasion or any
extrauterine lesions were recognized. If the lesion persisted, a total hysterectomy plus BSO was strongly recommended. If a patient refused surgery, MPA therapy was
further continued for 12 weeks. If the lesion completely
disappeared histologically, the patients were carefully
monitored and allowed to become pregnant. In the first
2 years, patients underwent D&C to obtain endometrial
biopsy every 3 months. If CR was achieved for more than
2 years, endometrial biopsy was obtained by aspiration
using pipelle every 3 months, since it has been reported
that pipelle biopsy and D&C show almost equal success
rate in the diagnosis of endometrial pathologies [11] and
pipelle biopsy is cheaper and less invasive to patients.
Transvaginal sonography was routinely performed at each
time when endometrial biopsy was done and not only
endometrial thickness but the presence of extrauterine
diseases (i.e. ascites, adnexal mass) were assessed. Hysteroscopy was not used in our treatment regimen. If
patients had conceptions, D&C was performed 3 months
after their deliveries. If CR was confirmed, endometrial
biopsy was obtained by aspiration every 3 months. When
recurrent lesions were found, a total hysterectomy plus
BSO was generally recommended. However, if the patient
strongly preferred to preserve fertility, MPA was continued
and the efficacy was evaluated 12 weeks after the treatment. The primary endpoints of this study were the pathologic CR rate, recurrence rate and obstetric outcomes.
Secondary endpoints were adverse events and cancerrelated deaths during the study periods. Adverse effects
were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [12].

Results
A total of 27 patients with CAH or G1EA received MPA
therapy at Osaka University Hospital between 2000 and
2012. The characteristics of the patients at initial diagnosis
are shown in Table 1. Eleven (41 %) cases were CAH and
the remaining 16 cases (59 %) were G1EA. The mean age
was 34.2 4.5 years (2243 years old) and the mean body
mass index was 24.0 7.1 kg/m2 (16.047.3). Four
patients were over 30 kg/m2. The median follow-up period
was 39.2 months (3.4153.8 months). Twenty-four of 27
patients (92.3 %) were nulliparous and 3 had experienced
live births. Transvaginal-ultrasonography showed that 5 of

Arch Gynecol Obstet (2015) 291:151157

Table 1 Characteristics of
patients

153

Characteristic

Patients
no. (%)

Histology
CAH

11 (40.7)

G1EA

16 (59.3)

Age (years)
Median

34.2

Range

22.243.9

Follow-up time (months)

Median

39.2

Range

3.4153.8

BMI
Mean
Range

24.0
16.047.3

Parity

CAH complex atypical

hyperplasia, G1EA welldifferentiated (Grade 1)
adenocarcinoma, BMI body
mass index

Nullipara

24 (92.3)

Multipara

3 (7.7)

Infertility
Yes

12 (44.4)

No

3 (11.1)

Unknown

12 (44.4)

Table 2 Efficacy of MPA therapy

Response

CAH

G1EA

Total

No.

No.

No.

CR

81.8

11

68.8

20

74.1

NC

18.2

25

22.2

PD

6.3

3.7

Recurrence

81.8

45.0

CR complete response, NC no change, PD progressive disease

Table 3 Pregnancy rates after MPA therapy

Achieving pregnancy

Live births

No.

No.

CAH

36.4

7a

G1EA

6.3

Total

18.5

CAH complex atypical hyperplasia, G1EA well-differentiated (Grade

1) adenocarcinoma
a

Including two twin deliveries

27 (18.5 %) patients had polycystic ovaries. Twelve

patients (44 %) had not been able to conceive for more
than 12 months in spite of their wish for fertility. No
remarkable complications related to MPA therapy were
found. The response rate of fertility-sparing MPA therapy
is summarized in Table 2. After 12 weeks MPA therapy,

CR was achieved in 81.8 % (9/11) of CAH patients and

68.8 % (11/16) of G1EA patients. NC was found in 2 of 11
(18.2 %) CAH cases. One underwent a total abdominal
hysterectomy. The other strongly wished to be pregnant
and underwent ART immediately. Fortunately, she could
conceive by the first in vitro fertilization and embryo
transfer (IVF-ET). After her delivery, endometrial tissue
sampling was carried out by D&C and her CAH lesion was
confirmed to have disappeared histologically. NC was
found in 4 of 16 (25.0 %) and PD was found in 1 of 16
(6.3 %) patients with G1EA. One patient with NC was lost
for follow-up due to a move. The other three patients
underwent total abdominal hysterectomy and BSO. In one
case diagnosed as PD, myometrial invasion was strongly
suspected by pelvic MRI and she underwent a total hysterectomy, BSO and pelvic lymphadenectomy. Among the
patients who achieved CR, no recurrences were found in
CAH cases, while 9 of 11 (81.8 %) G1EA cases eventually
recurred during the follow-up period. Three of nine patients
with recurrent diseases strongly desired to maintain fertility
and refused surgery. Accordingly, they received second
MPA therapies for 12 weeks. However, recurrent disease
did not disappear in any of these patients. Eventually, all
nine recurrent patients underwent total hysterectomy and
BSO and four further underwent pelvic lymphadenectomy
because two patients were diagnosed as having myometrial
invasion by an operative rapid pathological diagnosis and
the other two were diagnosed as having G2 endometrioid
adenocarcinoma. In total, 13 of 16 patients with G1EA
underwent surgeries. After surgical treatment, in one case
(7.7 %), recurrence was found at the vaginal stamp 4 years
later and she underwent radiation therapy. Furthermore,
1 year after radiation therapy, lung metastases were found
and she underwent laparoscopic lung tumor resection.
Thereafter, no further recurrence has been found during
5 years. Neither therapeutic deaths nor irreversible toxicities were observed during the follow-up periods. The
pregnancy rate in this study is summarized in Table 3.
Twelve of 20 (60 %) patients who achieved CR and one
patient with NC desired to conceive soon after CR. Eight
patients did not desire to conceive soon. Ten of 13 who
desired to conceive received some kind of fertility treatment. Finally, 5 patients (41 %, 4 CAH and 1 G1EA)
became pregnant and had a total of nine live births. The
obstetrical outcomes of these five patients are shown in
Table 4. There were seven normal full-term deliveries
including two twin pregnancies. Only two patients conceived by timed intercourse. Two required clomiphene
citrate therapy to conceive and one could conceive twice
by receiving IVF-ET. As for case 3, she experienced two
deliveries during the follow-up period. She underwent
D&C to obtain endometrial biopsy every 3 months before
the first conception. Three months after delivery, she re-

123

154

Arch Gynecol Obstet (2015) 291:151157

Table 4 Obstetric outcomes

Case

Histology

Age

Method for
pregnancy

Outcome

Complications

CAH

32

Clomid-timing

NSVD

DD twins

CAH

34

Timed
intercourse

NSVD

DD twins
TPD

CAH

33

IVF-ET

NSVD

Atonic
hemorrhage

36

IVF-ET

NSVD

CAH

37

Clomid-timing

D&C

Molar
pregnancy

38

Timed
intercourse
Timed
intercourse

NSVD
NSVD

Vacuum
extraction

Timed
intercourse

NSVD

G1EA

29
31

CAH complex atypical hyperplasia, G1EA well-differentiated (Grade

1) adenocarcinoma, IVF-ET in vitro fertilization and embryo transfer,
NSVD normal spontaneous vaginal delivery, D&C dilatation and
curettage, DD twins Dichorionic-Diamnioticctwins, TPD threatened
preterm delivery

visited to our hospital and endometrial biopsy was obtained

by aspiration every 3 months until she had the second
conception. Three months after the second delivery, she revisited our hospital and follow-up was continued. During
over 3-year follow-up period, no recurrence was found.

Discussion
In this study, we used 400600 mg MPA as progestin and
reported that CR was achieved in 68.8 % (11/16) of
patients with G1EA and 81.8 % (9/11) of patients with
CAH. While no recurrences were found in patients with
CAH after achieving CR, 9 of 11 (%) cases of G1EA
eventually recurred during the follow-up periods and
underwent subsequent surgical therapies. Finally, 4 of 11
patients (36.4 %) with CAH conceived and only 1 of 16
patients (6.3 %) with G1EA conceived. Thus, we have
demonstrated both the efficacy and the limitations of highdose MPA therapy for young women who strongly wish to
preserve their fertility.
Several previous studies have reported that progestin
therapy can preserve fertility in a subgroup of young
women with G1EA or CAH. The clinical outcomes of
fertility-sparing therapy with MPA are summarized in
Table 5 [9, 13, 14] and Table 6 [9, 1321]. Table 5 shows
the data of a total of 46 patients with CAH from 3 different
studies. 100600 mg MPA was used in these reports and
84.8(95 % CI, 69.1100) % of patients achieved CR. The
recurrences were found in 23.2 (95 % CI, 053.5) %, and

123

39.1 (95 % CI, 30.647.6) % of the patients successfully

conceived. Our present data were similar with these findings. Table 6 shows the data of a total of 201 patients with
E1GA from 10 different studies. In patients with G1EA,
74.0 (95 % CI, 62.385.7) % of patients achieved CR.
Recurrences were found in 49.5 (95 % CI, 32.466.7) %,
and 23.9 (95 % CI, 10.937.0) % of the patients conceived.
A lower success rate was reported compared with those
with CAH. The data presented here have important clinical
implications and will allow clinicians to tailor their counseling of young women with endometrial neoplasia.
In this study, we performed endometrial biopsy and
transvaginal sonography every 3 months for a routine follow-up. Since the clinical stage of the patients was
assumed to be 1A and they had regular menstrual cycles,
endometrial biopsy appears to be the only option to detect
recurrences. Besides, it is noteworthy that 11 % of patients
aged 45 years or younger have been reported to have
synchronous ovarian malignancies, compared with only
2 % of those older than 45 years [22]. Therefore, we
believe transvaginal sonography every 3 months is also
indispensable in order to verify the absence of extrauterine
diseases. Morice et al. [23] commented that a laparoscopic
procedure including adnexal exploration and peritoneal
cytology can be proposed for patients who desire conservative management. Such a procedure might be considered
if extrauterine diseases are suspected.
Since the high recurrence rates were reported especially
in patients with G1EA, it appears reasonable that infertility
treatment should be commenced immediately after
achieving CR by those who wish to conceive. Indeed, we
strongly recommended subsequent fertility treatments to all
patients if they were married, and 10 of 13 patients
received some fertility treatments. If patients do not wish to
conceive immediately, maintenance therapy such as combined estrogenprogestin therapy should be considered. A
levonorgestrel-releasing intrauterine system (LNG-IUS) is
an alternative option for those patients, since it has been
reported to induce an initial CR effectively in patients with
G1EA and to suppress recurrence in patients with CAH
[20, 24]. No definitive consensus exists as for age-dependent therapy-options. Klipstein et al. [25] reviewed birth
outcomes among 1,263 women over the age of 40 undergoing ART and reported that by age 43 the corresponding
birth rate was around 10 % and by 44 it was 1.6 %, while
birth rates for women 40 years old were 25 %. Thus, we
excluded patients older than 45 years even though they
wished to preserve uterus, since the pregnancy rate of this
population is extremely low even if they undergo ART. We
explained to patients older than 40 years that birth rates
drastically decrease year by year. Therefore, we strongly
recommended to those that they should choose surgical
treatment unless they have a strong will to undergo ART

Arch Gynecol Obstet (2015) 291:151157

155

Table 5 Outcomes of MPA therapy in women with complex atypical hyperplasia

Reference

Number of
cases

Complete
response (%)

Recurrence
(%)

Achieving
pregnancy (%)

Getting live
birth (%)

Median follow-up
time (months)

MPA dose
(mg/day)

Ushijima et al. [9]

17

94.1

37.5

41.2

23.5

47.9

600

Minaguchi et al. [13]

11

90.9

40.0

45.5

18.2

42

400600

Kaku et al. [14]

18

72

15.4

33.3

22.2

45.0

100600

Present study

11

81.8

36.4

36.4

38.2

400600

MPA medroxyprogesterone acetate

Table 6 Outcomes of MPA therapy in women with endometrioid (G1) adenocarcinoma

Reference

Number of
cases

Complete
response (%)

Recurrence
(%)

Achieving
pregnancy (%)

Getting live
birth (%)

Median follow-up
time (months)

MPA dose
(mg/day)

Hahn et al. [15]

20

55

45.4

39

201,500

Ushijima et al. [9]

22

63.6

57.1

18.2

13.6

47.9

600

Yamazawa et al. [16]

88.9

22.2

44.4

33.3

35.0

400

Minaguchi et al. [13]

19

78.9

33.3

15.8

5.3

35.7

400600

87.5

100

37.5

25

84.0

600

Ota et al. [18]

12

41.7

40

33.3

16.7

43.5

600

Kaku et al. [14]

Park et al. [19]

12
12

66.7
91.7

25
18.2

16.7
25

8.3
25

24
32.5

200800
30500

12

100b

66.7

58.3

41.7

49

400600

Fujiwara et al. [21]

59

71.2

52.4

30.5

66

400600

Present study

16

68.8

81.8

6.3

6.3

45.5

400600

Yahata et al. [17]

Niwa et al. [20]

a

MPA medroxyprogesterone acetate

a

Includes G2 endometrioid adenocarcinoma

Only picked up patients who achieve complete response

immediately after the temporary success of MPA

treatment.
Several studies have reported predictive markers for
achieving CR in patients with G1EA. Minaguchi et al.
reported that phosphorylated-Akt expression was significantly decreased by MPA administration and weak Akt
phosphorylation or PTEN-null expression was significantly
associated with receiving hysterectomy. In contrast, they
further showed that the strong expression of both estrogen
receptor (ER) and progesterone receptor (PgR) were significantly correlated with successful pregnancy after MPA
therapies [13]. Yamazawa et al. [16] reported that the positive expression of PgR was significantly related to the CR
rate by MPA therapies. Thus, it appears that PgR positive
expression in cancer cells may predict the response rate of
progestin therapies. However, it is also known that receptornegative tumors can also respond to the agent, suggesting
that there might be another direct anti-tumor action of progestin without mediation by ER or PgR [13]. Since MPA also
exerts via glucocorticoid receptor [26] or androgen receptor
[27], MPA might induce anti-tumor effects through these
receptors. Since there have not been any effective treatment

options other than progestin therapy so far, we assume that

progestins such as MPA should continue to be the first-line
therapeutic option for fertility-sparing treatment at present.
Further elucidation will be needed to identify factors that
predict the response to progestins and to allow treatment
protocols to be optimized for individual patients.
The standard treatment with CAH or G1EA remains a
total hysterectomy plus BSO. Since endometrial carcinoma
in premenopausal women has an excellent prognosis after
surgery [28], there is a therapeutic dilemma regarding
conservative management in young women who strongly
wish to preserve their fertility. The results of progestin
therapy reported so far are unsatisfactory, especially
compared with the high cure rate ([93 %) of surgical
treatments [29]. The establishment of more effective
treatment protocols continues to be a challenge and several
new attempts have been reported. Gallos et al. [30]
reported in a systematic review that LNG-IUS achieved a
higher pooled regression rate compared with oral progestins for atypical hyperplasia (90 vs 69 %, P = 0.03).
However, unsatisfying results have also been reported as
for LNG-IUS applications for early-stage endometrial

123

156

carcinoma [31, 32]. Kim et al. [33] recently evaluated the

efficacy of combined oral MPA/LNG-IUS treatment in
young women with early-stage endometrial cancer who
wish to preserve their fertility and reported that CR was
achieved in 87.5 % (14/16) of patients and the recurrence
rate was 14.3 % (2/14), suggesting that combined oral
MPA/LUG-IUS treatment may be more effective and
favorable as a conservative treatment. Further elucidation
is needed to clarify the efficacy of this combination therapy, considering that the study comprised relatively small
numbers and a short observational follow-up period.
In the present study, 10 of 13 women who desired to
conceive received some kind of fertility treatments. Of
these 13 patients, 5 patients became pregnant and 3 of them
received fertility treatments as summarized in Table 4. In a
recent meta-analysis, while 142 of 451 women who
underwent fertility sparing treatments for CAH or G1EA
received assisted reproduction treatment (ART) and 56 of
them achieved at least 1 live birth (39.4 % live birth rate),
the remaining 309 women were presumed to have tried to
spontaneously conceive and 46 of them had at least 1 live
birth, with a live birth rate of 14.9 % [34]. Since it appears
that ovulation-induction drugs do not seem to increase the
recurrence rate of patients as Ichicnose et al. [35] reported,
we consider that patients should be encouraged to undertake fertility treatments including ART to maximize their
chances of a live birth and minimize the time before a
hysterectomy, which could prevent them from relapse.
In summary, we reported our 13 years experiences of
fertility sparing treatments using MPA. Although MPA
therapy is an effective and favorable method for young
patients with CAH or G1EA who want to preserve their
fertility, the risks of disease relapse and worsening during
follow-up periods are considerable, especially for patients
with G1EA. Even in patients who achieve CR, close follow-up is required and total hysterectomy needs to be
appropriately considered without delay. Patients should be
informed of the risks and the limitations of this conservative treatment, which remains less effective when compared to surgery, the standard therapy for endometrial
carcinoma. Fertility treatment including ART may minimize the risk of disease regression and should be considered soon after a patient achieves CR. At present, the
standard treatment methods, including daily dose and
administration period, have yet to be established and further prospective studies will be required for the establishment of an optimal treatment protocol.
Acknowledgments We thank Yuko Nishimura for her secretarial
assistance and Yuri Matsumoto for her statistical advices.
Conflict of interest The authors declare that they have no conflicts
of interest in the research.

123

Arch Gynecol Obstet (2015) 291:151157

References
1. Gallup DG, Stock RJ (1984) Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol
64(3):417420
2. Center for Cancer Control and Information Services. Cancer
statistics in Japan; Table download. http://ganjoho.jp/profes
sional/statistics/statistics.html. Accessed 23 Feb 2014
3. Matsuda T, Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue
T et al (2011) Cancer incidence and incidence rates in Japan in
2005: based on data from 12 population-based cancer registries in
the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J
Clin Oncol 41(1):139147
4. Gunderson CC, Fader AN, Carson KA, Bristow RE (2012) Oncologic and reproductive outcomes with progestin therapy in
women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol 125(2):477482
5. Chiva L, Lapuente F, Gonzalez-Cortijo L, Carballo N, Garca JF,
Rojo A et al (2008) Sparing fertility in young patients with
endometrial cancer. Gynecol Oncol 111:S101S104
6. Erkanli S, Ayhan A (2010) Fertility-sparing therapy in young
women with endometrial cancer: 2010 update. Int J Gynecol
Cancer 20(7):11701187
7. Ramirez PT, Frumovitz M, Bodurka DC, Sun CC, Levenback C
(2004) Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol
95(1):133138
8. Park JY, Seong SJ, Kim TJ, Kim JW, Kim SM, Bae DS et al
(2013) Pregnancy outcomes after fertility-sparing management in
young women with early endometrial cancer. Obstet Gynecol
121(1):136142
9. Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito
T et al (2007) Multicenter phase II study of fertility-sparing
treatment with medroxyprogesterone acetate for endometrial
carcinoma and atypical hyperplasia in young women. J Clin
Oncol 25(19):27982803
10. Tangjitgamol S, Manusirivithaya S, Hanprasertpong J (2009)
Fertility-sparing in endometrial cancer. Gynecol Obstet Invest
67(4):250268
11. Demirkiran F, Yavuz E, Erenel H, Bese T, Arvas M, Sanioglu C
(2012) Which is the best technique for endometrial sampling?
Aspiration (pipelle) versus dilatation and curettage (D&C). Arch
Gynecol Obstet 286:12771282
12. National Cancer Institute Cancer Therapy Evaluation Program
Common Terminology Criteria for Adverse Events (CTCAE).
http://ctep.cancer.gov/protocolDevelopment/electronic_applica
tions/ctc.htm#ctc_40. Accessed 3 Feb 2014
13. Minaguchi T, Nakagawa S, Takazawa Y, Nei T, Horie K, Fujiwara T et al (2007) Combined phospho-Akt and PTEN
expressions associated with post-treatment hysterectomy after
conservative progestin therapy in complex atypical hyperplasia
and stage Ia, G1 adenocarcinoma of the endometrium. Cancer
Lett 248(1):112122
14. Kaku T, Yoshikawa H, Tsuda H, Sakamoto A, Fukunaga M,
Kuwabara Y et al (2001) Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in
young women: central pathologic review and treatment outcome.
Cancer Lett 167(1):3948
15. Hahn HS, Yoon SG, Hong JS, Hong SR, Park SJ, Lim JY et al
(2009) Conservative treatment with progestin and pregnancy
outcomes in endometrial cancer. Int J Gynecol Cancer
19(6):10681073
16. Yamazawa K, Hirai M, Fujito A, Nishi H, Terauchi F, Ishikura H
et al (2007) Fertility-preserving treatment with progestin, and

Arch Gynecol Obstet (2015) 291:151157

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

pathological criteria to predict responses, in young women with

endometrial cancer. Hum Reprod 22(7):19531958
Yahata T, Fujita K, Aoki Y, Tanaka K (2006) Long-term conservative therapy for endometrial adenocarcinoma in young
women. Hum Reprod 21(4):10701075
Ota T, Yoshida M, Kimura M, Kinoshita K (2005) Clinicopathologic study of uterine endometrial carcinoma in young women
aged 40 years and younger. Int J Gynecol Cancer 15(4):657662
Park H, Seok JM, Yoon BS, Seong SJ, Kim JY, Shim JY et al
(2012) Effectiveness of high-dose progestin and long-term outcomes in young women with early-stage, well-differentiated
endometrioid adenocarcinoma of uterine endometrium. Arch
Gynecol Obstet 285(2):473478
Niwa K, Tagami K, Lian Z, Onogi K, Mori H, Tamaya T (2005)
Outcome of fertility-preserving treatment in young women with
endometrial carcinomas. BJOG 112(3):317320
Fujiwara H, Jobo T, Takei Y, Saga Y, Imai M, Arai T et al (2012)
Fertility-sparing treatment using medroxyprogesterone acetate for
endometrial carcinoma. Oncol Lett 3(5):10021006
Evans-Metcalf ER, Brooks SE, Reale FR, Baker SP (1998) Profile of women 45 years of age and younger with endometrial
cancer. Obstet Gynecol 91:349354
Morice P, Fourchotte V, Sideris L, Gariel C, Duvillard P, Castaigne D (2005) A need for laparoscopic evaluation of patients
with endometrial carcinoma selected for conservative treatment.
Gynecol Oncol 96:245248
Lee SY, Kim MK, Park H, Yoon BS, Seong SJ, Kang JH et al
(2010) The effectiveness of levonorgestrel releasing intrauterine
system in the treatment of endometrial hyperplasia in Korean
women. J Gynecol Oncol 21(2):10210525
Klipstein S, Regan M, Ryley DA, Goldman MB, Alper MM,
Reindollar RH (2005) One last chance for pregnancy: a review of
2,705 in vitro fertilization cycles initiated in women age 40 years
and above. Fertil Steril 84:435445
Govender Y, Avenant C, Verhoog NJ, Ray RM, Grantham NJ,
Africander D, Hapgood JP (2014) The injectable-only contraceptive medroxyprogesterone acetate, unlike norethisterone acetate and progesterone, regulates inflammatory genes in

157

27.

28.

29.

30.

31.

32.

33.

34.

35.

endocervical cells via the glucocorticoid receptor. PLoS One

9:e96497
Africander DJ, Storbeck KH, Hapgood JP (2014) A comparative
study of the androgenic properties of progesterone and the progestins, medroxyprogesterone acetate (MPA) and norethisterone
acetate (NET-A). J Steroid Biochem Mol Biol 143C:404415
Creasman WT, Soper JT, McCarty KS, Hinshaw W, ClarkePearson DL (1985) Influence of cytoplasmic steroid receptor
content on prognosis of early stage endometrial carcinoma. Am J
Obstet Gynecol 151(7):922932
National Comprehensive Cancer Network. NCCN Practice
guidelines in oncology. http://www.nccn.org/professionals/physi
cian_gls/recently_updated.asp. Accessed 26 Jul 2013
Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK,
Coomarasamy A, Gupta JK (2010) Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet
Gynecol 203(6):547e1547e10
Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ
(2002) Intrauterine progesterone treatment of early endometrial
cancer. Am J Obstet Gynecol 186(4):651657
Dhar KK, NeedhiRajan T, Koslowski M, Woolas RP (2005) Is
levonorgestrel intrauterine system effective for treatment of early
endometrial cancer? report of four cases and review of the literature. Gynecol Oncol 97(3):924927
Kim MK, Seong SJ, Kim YS, Song T, Kim ML, Yoon BS et al
(2013) Combined medroxyprogesterone acetate/levonorgestrelintrauterine system treatment in young women with early-stage
endometrial cancer. Am J Obstet Gynecol 209(4):358e1358e4
Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A,
Gupta JK (2012) Regression, relapse, and live birth rates with
fertility-sparing therapy for endometrial cancer and atypical
complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 207(4):266e1266e12
Ichinose M, Fujimoto A, Osuga Y, Minaguchi T, Kawana K,
Yano T et al (2013) The influence of infertility treatment on the
prognosis of endometrial cancer and atypical complex endometrial hyperplasia. Int J Gynecol Cancer 23(2):288293

123