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Autonomous Ovarian Cysts in Prepubertal Girls. How Aggressive Should We Be? A Review of the Literature
Accepted Manuscript Autonomous ovarian cysts in prepubertal girls. How aggressive should we be? A review of the literature Athanasios Papanikolaou, MSc, Lina Michala, MRCOG, PhD PII:
S1083-3188(15)00206-5
DOI:
10.1016/j.jpag.2015.05.004
Reference:
PEDADO 1857
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 1 November 2014 Revised Date:
9 April 2015
Accepted Date: 12 May 2015
Please cite this article as: Papanikolaou A, Michala L, Autonomous ovarian cysts in prepubertal girls. How aggressive should we be? A review of the literature, Journal of Pediatric and Adolescent Gynecology (2015), doi: 10.1016/j.jpag.2015.05.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title Page
Autonomous ovarian cysts in prepubertal girls. How aggressive should we be?
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A review of the literature.
Athanasios Papanikolaou, MSc Lina Michala, MRCOG, PhD
SC
1st Department of Obstetrics and Gynaecology, University of Athens,
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Alexandra Hospital
Corresponding author:
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Lina Michala
Lecturer in Paediatric and Adolescent Gynaecology, 1st Department of Obstetrics and Gynaecology, University of Athens
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Alexandra Hospital
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80 Vas Sofias Avenue, 115 28, Athens, Greece
Tel: 210 3381100, Fax: 213 216 2898 Email: [email protected]
ACCEPTED MANUSCRIPT Abstract
Current management for autonomous ovarian cysts in prepubertal girls is either conservative or surgical, with no clear evidence as to the superiority of one treatment option
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against the other.
We performed a literature search to assess available information and identified 9 articles referring to 26 cases of autonomous ovarian cysts. Median age of patients was 5 years
SC
(range 2.2-8) and size of cyst was 41.5mm (9-60). Ten patients underwent cystectomy or
oophorectomy, three were given cyproterone acetate and 13 were managed conservatively.
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Nine of 13 patients that were managed conservatively and two of those that had a cystectomy had a recurrence. There were three cases that progressed to central precocious puberty (CPP) and one case that was then identified to have McCune Albright (MCA) syndrome. One further case with multiple recurrences was given long term treatment with
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letrozole.
We conclude that although a conservative approach should always be proposed in the first instance, one should be aware of the risk of recurrence and progression to CPP or MCA.
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Antiestrogen treatment appears promising; however data comparing it with surgical options and particularly long term consequences with regards to future reproductive outcomes are
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not available.
ACCEPTED MANUSCRIPT Introduction
Precocious puberty is a rare entity. It can be classified into central (or true) preococious puberty (CPP), which is gonadotropin dependent and in peripheral (or pseudopuberty)
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precocious puberty (PPP), which is gonadotropin-independent. CPP is estimated about 1:5000 – 1:10000 in the general population (1). An exact estimate of PPP is not available. It usually occurs as a result of peripheral estrogen production, either due to an autonomous
ovarian cyst, a germ cell tumour or McCune Albright (MCA) syndrome. Millar et al. reported
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that ovarian cysts are prevalent in 2% to 5% of prepubertal girls, and of those, 5% are found
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to produce estrogens, giving an estimated risk of PPP of one in 400 (0,25%) (2).
Symptomatology can range from breast budding, external genitalia changes, pubic hair development, vaginal discharge to overt vaginal bleeding (2,3,4,5,6). Autonomous ovarian cysts can develop at any age and may regress after a few weeks or months (2,5,6). A
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percentage that will regress spontaneously or after treatment may recur either as an isolated event or as a precursor of McCune Albright syndrome(5,6,7). A number of girls may enter in central precocious puberty (5,6). The natural history of autonomous ovarian cyst,
subject.
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however, is not clear and the aim of this study was to review the available literature on the
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Methods
We conducted a search on Pubmed using the keywords peripheral precocious puberty, autonomous ovarian cysts and pseudopuberty in the title or abstract. The search was performed in October 2014 by AP and all collected articles were reviewed by AP and LM. We restricted our search to human studies, written in English after 1980. The date was chosen slightly arbitrarily but was primarily based on the fact that ultrasonographic diagnosis
ACCEPTED MANUSCRIPT became more widespread in the 1980s. We excluded studies on males, relating to tumours, McCune Albright syndrome (MCA) and central precocious puberty (CPP).
The search yielded 32 articles. We further excluded 25 studies, which were relating to
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Congenital Adrenal Hyperplasia (CAH), hypothyroidism, CPP, other endocrine disorders, exogenous hormone exposure. We enriched our study through hand searching relevant articles and reviews to identify other cases or case series in the list of citations.
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As the goal of the study was to identify cases that clearly would cause precocious puberty
we excluded patients over 8 year old, the cut off for normal pubertal development (3) and
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under 2, as this is considered the upper limit for maternal estrogen effect and/or increased levels of gonadotropins after birth due to immaturity of the hypothalamic-pituitary-ovarian axis (4). We only included cases where a suppressed LHRH test result was available as proof of peripheral precocious puberty. A proforma was used to collate information acquired from
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articles.
Through these exclusions we derived 14 articles. Of those, two were editorials or reviews with no data on patients included (5, 6). We then excluded the article by Chao et al (7), as
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we were unable to tease out cases of peripheral puberty out of the total number of patients with precocious puberty, the paper of Sinnecker et al (8) as it referred to a patient with low
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plasma estradiol concentrations, and the article of Baran et al (9) as there was no information about LHRH testing.
We included in the study 9 papers (2, 10-17) and looked for information regarding age at presentation, size of ovarian cyst, management - surgical, conservative or pharmaceutical, recurrences and progression to McCune Albright or CPP.
Results
ACCEPTED MANUSCRIPT In these nine articles we found 26 girls who fulfilled our criteria. Their median age at presentation was 5 years old with a range from 2,2 to 8.
The main clinic symptom of these girls was breast development, reaching a Tanner stage 2
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to 3. Twenty-one out of 26 (80,7%) presented with vaginal bleeding or vaginal discharge. Six of these girls (23%) also presented with pubic hair at Tanner stage 2-3.
The laboratory findings were elevated estrogen levels with low gonadotropins. Estradiol
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levels was available in all patients, of which median value was 155,4pg/ml, with a range from 5 to 918.
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All girls had a simple ovarian cyst, which was identified by transabdominal ultrasound in the majority of patients or was diagnosed at laparotomy or laparoscopy.
All 26 patients presented with unilateral ovarian cysts, whose exact size was documented in 24. In the study by Lyon et al two of the cysts were described as large. The larger diameter of
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the 24 measured cysts was 60mm, with median larger diameter around 41,5mm. We had information about the location of the cysts in 14 cases. Nine were left sided and 5 were on
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the right. All cysts were described ultrasonographically or macroscopically as simple cysts.
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Age, clinical symptoms, laboratory and imaging findings are shown in table 1.
Management is illustrated in table 2. In summary, ten patients underwent surgical treatment, either cystectomy(6) or oopherctomy(4), 13 cases were managed conservatively and three underwent treatment with cyproterone acetate. Follow up was reported in 20 cases and ranged from 7 months to 8 years with a median of around 3 years. Out of the patients followed conservatively, we could deduce information about the time of regression in 11 cases and estimated this to be six weeks.
ACCEPTED MANUSCRIPT Eleven out of 26 cases (42%) presented with recurrences, ranging from 1 to 4 episodes. Recurrences were more likely to occur in those managed conservatively, occurring in 9 of the 13 girls that did not undergo surgery. In total there were 20 episodes of recurrences in 11 patients. Time at recurrence was mentioned in 19 episodes and ranged from 1 month to
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24 months, with a median time of 13,5 months.
Three patients (11.5%) were eventually given GnRHa, presumably for progression to CPP. One further patient was given GnRHa -probably inappropriately- as treatment of the
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autonomous cyst. This particular case eventually underwent an oophorectomy after two cystectomy operations failed to control her symptoms(2). One patient was identified as
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having MCA (13) and one further patient was given anastrozole treatment after persistent symptomatology for six months, despite not having other signs of MCA. Under treatment, the cyst regressed after three months, however treatment with the aromatase inhibitor was
Discussion
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continued for 3 years (15).
In this paper we present a review of all published cases of autonomous ovarian cysts since
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1980 in an attempt to describe and understand associated risks and suggest management plans. As seen, the majority of cysts had an average diameter of 20mm and usual clinical
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presentation was with premature breast development and, in descending frequency vaginal discharge or bleeding. In normal pubertal development uterine bleeding usually starts at breast Tanner stage 3-4. In this series, the majority of patients with vaginal bleeding had attained a breast Tanner stage of 2 to 3, reflecting rapid progression due to acute exposure to estrogen.
Vaginal bleeding in most cases occurred as a result of estradiol withdrawal after cyst resolution. It is interesting to note that breast development was the slowest to regress.
ACCEPTED MANUSCRIPT Stated reasons for proceeding to surgical management were persistence of clinical symptoms, increase of ovarian cyst dimensions or recurrence. Reasons for proceeding to surgery were not always clear with a tendency to more cystectomies being performed in the early eighties and less so in the later years. We could not identify a correlation between size
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of ovarian cyst, level of estradiol and time of regression so as to provide a guidance to practice. Interestingly, surgical treatment did not always protect from recurrence, as
demonstrated by one of the cases in this review. Four patients in this series underwent an
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oophorectomy, a practice that in our opinion is not justifiable, unless malignancy is suspected.
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Regression in those treated conservatively occurred in weeks to months, during which time symptoms of pubertal maturation were likely to persist. This may lead to psychological distress to the patient and her family. More importantly, some of the effects of estrogen exposure, such as bone age maturation and final height suppression may be non-reversible.
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There is also a concern that a proportion of patients may progress into CPP, this being more likely when exposure to estradiol is prolonged. In keeping with this, progression to CPP in this series occurred in those that had at least two episodes of autonomous cyst formation.
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With this in mind, it may well be useful to provide medical treatment to patients as indeed
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was the case in a proportion of patients in this series.
Insight in the management of young girls with autonomous cyst formation may be gathered from McCune Albright (MCA) syndrome, where surgical treatment is only performed in case of ovarian torsion or haemorrhage. In MCA cysts tend to recur and an operation would not provide a viable solution to premature pubertal development.
McCune-Albright Syndrome is a sporadic disease, characterized by polyostotic fibrous dysplasia, café’-au-lait skin pigmentation and endocrine dysfunction with individuals exhibiting peripheral precocious puberty (PPP)(18). It is due to post zygotic activating
ACCEPTED MANUSCRIPT recurrent mutations in the guanine nucleotide binding protein (G protein) α subunit (18). The molecular basis of MCA syndrome is a mutation in the α subunit of the G protein, which couples cell surface receptors to the stimulation of adenyl cyclase, Gsα. These mutation lead to the constitutive activation of adenyl cyclase in various tissues, including the ovary (19).
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Gonadal hyperfunction is the most frequent endocrine dysfunction in females with MCA syndrome, and precocious pseudopuberty is usually the first manifestation of MCA
syndrome in children (20). Diagnosis of MCA syndrome requires a prolonged clinical follow
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up with repeated skeletal radiographs (21). As clinical evidence for MCA can appear later in the course of recurrent autonomous cysts (13), a careful clinical observation of these
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patients and molecular studies may be necessary in such cases. In our series one patient progressed to overt MCA and it is possible that patients with a recurring autonomous cyst, particularly those following cystectomy have a variant of the disease.
PPP in girls with MCA is usually treated with aromatase inhibitors, drugs initially developed
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for the management of estrogen receptor positive breast cancer. Testolactone and ferdrozole, a first and second generation aromatase inhibitor respectively were initially used
duration.
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for treatment of PPP, with disappointing results and declining efficacy through treatment
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Third generation aromatase inhibitors such as anastrozole and letrozole appear to be more beneficial in suppressing ovarian function and have the added benefit of a once daily formulation, which improves compliance. Long term results are nevertheless awaited, particularly with regards to bone health, since boys treated for idiopathic short stature with letrozole were at increased risk of having vertebral body deformities. Whether this is true for girls with MCA is not yet determined (22).
ACCEPTED MANUSCRIPT Other preparations used in MCA to slow pubertal growth are estrogen receptor agonists such as tamoxifen (23) and cyproterone acetate (24), an antiandrogen that was used in three patients in these series.
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Similar treatment options may be the indicated course of action in patients with autonomous ovarian cysts persisting for longer than 4 to 6 weeks. Through this case series however we were not able to identify a cut off of cyst size or estradiol level above which
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treatment should be introduced.
In conclusion, more than half of the patients in this series were successfully managed
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conservatively. Patients were more likely to have been treated surgically in the 1980s and it is possible that some cystectomies may have been unnecessary, had follow up been longer. We could not formulate a guidance as to when to proceed to ovarian cystectomy, other than in cases of ovarian torsion or hemorrhage or in cases where malignancy cannot be excluded.
was small.
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This was a limitation to this study, as the number of patients that were available for review
Treatment with antiestrogens or aromatase inhibitors appears a likely less invasive
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alternative for those with a persistent or recurrent autonomous cyst. At present however there is no consensus as to the superiority of surgical versus pharmaceutical management.
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In particular, we are lacking data with regards to future pubertal development and reproductive outcomes. Ideally, this would be answered through an RCT, allocating patients to either surgical or conservative management, with or without pharmaceutical back up.
Finally girls having presented with an autonomous ovarian cyst once have a 40% chance of recurrence, which may be an early presentation of MCA. Careful clinical and radiographic examination and monitoring should be undertaken to identify this. Also, a proportion of girls may proceed to CPP and monitoring of pubertal growth should be undertaken at regular
ACCEPTED MANUSCRIPT intervals (4-6 months) and LHRH testing performed if signs of puberty become obvious. Figure 1
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Acknowledgment
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Authors have no conflicts of interest to declare and have received no funding for this study.
References
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1. Partsch CJ, Heger S, Sippel WG. Management and outcome of central precocious puberty. Clin Endocrinol. 2002;56(2):129. 2. Millar DM, Blake JM, Stringer DA, Hara H, Babiak C. Prepubertal ovarian cyst formation: 5 years experience. Obstet Gynecol. 1993;81(3):434-438. 3. Kosloske AM, Goldthorn JF, Kaufman E, Hayek A. Treatment of precocious pseudopuberty associated with follicular cysts of the ovary. Am J Dis Child. 1984;138(2):147-9. 4. Fakhry J, Khoury A, Kotval PS, Noto RA. Sonography of autonomous follicular ovarian cysts in precocious pseudopuberty. J Ultrasound Med. 1988;7(11):597-603. 5. Rodriguez-Macias KA, Thibaud E, Houang M, Duflos C, Beldjord C, Rappaport R. Follow up of precocious pseudopuberty associated with isolated ovarian follicular cysts. Arch Dis Child. 1999;81(1):53-6. 6. de Sousa G, Wunsch R, Andler W. Precocious pseudopuberty due to autonomous ovarian cysts: a report of ten cases and long-term follow-up. Hormones (Athens). 2008;7(2):170-4. 7. Brauner R, Bashamboo A, Rouget S, et al; Clinical, biological and genetic analysis of prepubertal isolated ovarian cyst in 11 girls. PLoS One. 2010;25;5(6). 8. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age 8 benign? Pediatrics. 2003;111(1):47-51. 9. Dolgin SE. Ovarian masses in the newborn. Review. Semin Pediatr Surg. 2000;9(3):121-7. 10. Lightner ES, Kelch RP. Treatment of precocious pseudopuberty associated with ovarian cysts. Am J Dis Child. 1984;138(2):126-8. 11. Stanhope R, Traggiai C. Precocious puberty (complete, partial). Endocr Dev. 2004;7:57-65. 12. Zou CC, Liang L, Dong GP, Zhao ZY. Peripheral precocious puberty: a retrospective study for six years in Hangzhou, China. J Paediatr Child Health. 2008;44(7-8):415-8. 13. Sinnecker G, Willig RP, Stahnke N, Braendle W. Precocious pseudopuberty associated with multiple ovarian follicular cysts and low plasma oestradiol concentrations. Eur J Pediatr. 1989;148(7):600-2. 14. Baran GW, Alkema RC, Barkett GK, Frisch KM. Autonomous ovarian cyst in isosexual precocious pseudopuberty. J Clin Ultrasound. 1988;16(1):58-60. 15. Lyon AJ, De Bruyn R, Grant DB. Transient sexual precocity and ovarian cysts. Arch Dis Child.1985;60(9):819-22. 16. Engiz O, Berberoglu M, Siklar Z, Bilir P, Ocal G. Treatment of autonomous ovarian follicular cyst with longterm anastrozole therapy. Indian J Pediatr. 2009;76(9):950-1. 17. Chae HS, Rheu CH. Precocious pseudopuberty due to an autonomous ovarian follicular cyst: case report with a review of literatures. BMC Res Notes. 2013;12;6:319. 18. Lumbroso S, Paris F, Sultan C. Activating Gsα mutations: analysis of 113 patients with signs of McCune – Albright Syndrome-A European collaborative study. J Clin Endocrinol Metab, 2004;89(5):2107-2113. 19. Schwindinger WF, Levine MA. McCune-Albright syndrome.Trends Endocrinol Metab. 1993;4(7):238-42. 20. Matarazzo P, Lala R, Andreo M, et al; McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age. J Pediatr Endocrinol Metab. 2006;19 Suppl 2:607-17. 21. Frisch LS, Copeland KC, Boepple PA. Recurrent ovarian cysts in childhood: diagnosis of McCune-Albright syndrome by bone scan.Pediatrics. 1992;90(1 Pt 1):102-4. 22. Wit JM, Hero M, Nunez SB. Aromatase inhibitors in pediatrics. Nat Rev Endocrinol. 2011;8(3):135-47. 23. Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr. 2003;143(1):60-6.
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24. Messina MF, Arrigo T, Wasniewska M, et al; Combined treatment with ketoconazole and cyproterone acetate in a boy with McCune-Albright syndrome and peripheral precocious puberty. J Endocrinol Invest. 2008;31(9):83940.
ACCEPTED MANUSCRIPT Table 1. Age, clinical symptoms, laboratory and imaging findings Paper
No
Age
Breast
Vaginal
Pubic Hair
FSH(mIU/mL)
LH(mIU/mL)
E2(pg/ml)
Cyst
1
Kosloke 1984
1
3,7
Y
Y
N
<2
<2
24
9mm L
2
6
Y
N
N
<1
<1
30
11mm R
1
2,8
Y(B3)
Y
Y
3,8
<1
17,4
38mm L
2
4,6
Y(B3)
Y
N
3,9
9,5
25,3
large R
3
4,2
Y(B3)
Y
N
12,7
4
5
Y
Y
N
1
5
Y
Y
N
3,4
2
6,4
Y
Y
N
2,9
1
3
Y
Y
2
4
Y
3
4,5
12
4
8
Y
13
1
6,9
Y(B3)
Y
2
5,9
Y(B3)
Y
3
2,2
Y(B2)
N
16
4
5,4
Y(B2)
Y
17
5
2,6
Y(B2)
Y
18
1
5,3
Y(B2)
Y
2
4,7
Y(B2)
Y
3
6,3
Y(B2)
4
4,7
1
6 7 8
Fakhry 1988
9 10 11
14 15
19 20
DM Millar 1993
Rodriguez 1999
de Sousa G 2008
21 22 23 24
Engiz 2009 Brauner 2010
25
Y
27mm L large R
5,4
129
33mm L
3,8
85
55mm R 27mm 55mm 45mm 50mm
<0,2
<0,2
43
65mm
N
<0,2
0,2
270
30mm
Y(P2)
0,2
0,2
30
25mm
N
0,5
0,3
5
50mm
Y(P3)
0,2
0,2
125
46mm
N
59
40mm L
N
172
60mm
Y
N
242
30mm
Y(B2)
Y
N
310
35mm
8
Y(B2-3)
N
Y(P2)
105
50mm L
1
3,3
Y(B3)
Y
N
<0,1
<0,1
66
50mm L
2
5,6
Y(B3)
Y
Y(P2)
0,4
<0,4
918
60mm L
6,6
Y(B3)
Y
N
<0,4
<0,4
576
41mm L
5,9
Y
Y
N
0,3
0,07
19,8
54mm R
1
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26
13,6
Y(P2)
3 Hee Suk 2013
6
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5
A J Lyon 1985
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4
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3
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2
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No of p.
ACCEPTED MANUSCRIPT Table 2. Management and Recurrence Time of recurrence N/A
laparotomy-cystectomy
1
N/A
1
laparotomy-cystectomy
1
N/A
2
laparoscopy-conservative
4w, 2w, 4m
3
1.9y, 1.9y
3
conservative
2w, 2w
4
laparotomy-oophorectomy
1
laparotomy-cystectomy
2
conservative
1
conservative
2
conservative
3
cystectomy
12
4
cystectomy
13
1
oophorectomy
2
conservative
3
conservative
16
4
conservative
17
5
conservative
18
1
conservative
2
ovariectomy
3
conservative
4
5
A J Lyon 1985
6 7 8
Fakhry 1988
9 10 11
DM Millar 1993
14 15
19 20
Rodriguez 1999
de Sousa G 2008
21 22
Engiz 2009
23 24
Brauner R 2010
25 Hee Suk 2013
24m
1
N/A
1
N/A
1
N/A
1
N/A
1
N/A
2
6m
1
N/A
1
N/A
2-4w
2
11m
2-4w
1
N/A
2-4w
2
1m
2-4w
5
1m,18m,22m,26m
2-3m
5
7m, 12m, 7m
1
N/A
2-3m
3
24m, 18m
conservative
2-3m
3
4m,1m
1
conservative
3m
2
6m
1
cyproterone acetate
5m
1
N/A
2
cyproterone acetate
7m
2
23m
3
cyproterone acetate
3m
1
N/A
1
laparoscopy-cystectomy
1
N/A
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26
2
6w
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4
2
Time of Cyst Regression
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3
Management oophorectomy
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Kosloke 1984
No 1
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No of episodes 1
2
Paper
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Patients 1
ACCEPTED MANUSCRIPT
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Ovarian cyst- premature puberty
Simple cyst
Yes
GnRHa
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CNS imaging
Resolution
Yes
Monitoring for recurrence every 4-6 months
+/- surgery
CPP
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Monitoring 4-6 weeks
Imaging- Tumour markers
No
PPP Exclude MCA
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LH ↓, E2↑
Complex cyst
No
Medical treatment
?
Surgical treatment
S1083-3188(15)00206-5
DOI:
10.1016/j.jpag.2015.05.004
Reference:
PEDADO 1857
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 1 November 2014 Revised Date:
9 April 2015
Accepted Date: 12 May 2015
Please cite this article as: Papanikolaou A, Michala L, Autonomous ovarian cysts in prepubertal girls. How aggressive should we be? A review of the literature, Journal of Pediatric and Adolescent Gynecology (2015), doi: 10.1016/j.jpag.2015.05.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title Page
Autonomous ovarian cysts in prepubertal girls. How aggressive should we be?
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A review of the literature.
Athanasios Papanikolaou, MSc Lina Michala, MRCOG, PhD
SC
1st Department of Obstetrics and Gynaecology, University of Athens,
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Alexandra Hospital
Corresponding author:
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Lina Michala
Lecturer in Paediatric and Adolescent Gynaecology, 1st Department of Obstetrics and Gynaecology, University of Athens
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Alexandra Hospital
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80 Vas Sofias Avenue, 115 28, Athens, Greece
Tel: 210 3381100, Fax: 213 216 2898 Email: [email protected]
ACCEPTED MANUSCRIPT Abstract
Current management for autonomous ovarian cysts in prepubertal girls is either conservative or surgical, with no clear evidence as to the superiority of one treatment option
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against the other.
We performed a literature search to assess available information and identified 9 articles referring to 26 cases of autonomous ovarian cysts. Median age of patients was 5 years
SC
(range 2.2-8) and size of cyst was 41.5mm (9-60). Ten patients underwent cystectomy or
oophorectomy, three were given cyproterone acetate and 13 were managed conservatively.
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Nine of 13 patients that were managed conservatively and two of those that had a cystectomy had a recurrence. There were three cases that progressed to central precocious puberty (CPP) and one case that was then identified to have McCune Albright (MCA) syndrome. One further case with multiple recurrences was given long term treatment with
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letrozole.
We conclude that although a conservative approach should always be proposed in the first instance, one should be aware of the risk of recurrence and progression to CPP or MCA.
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Antiestrogen treatment appears promising; however data comparing it with surgical options and particularly long term consequences with regards to future reproductive outcomes are
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not available.
ACCEPTED MANUSCRIPT Introduction
Precocious puberty is a rare entity. It can be classified into central (or true) preococious puberty (CPP), which is gonadotropin dependent and in peripheral (or pseudopuberty)
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precocious puberty (PPP), which is gonadotropin-independent. CPP is estimated about 1:5000 – 1:10000 in the general population (1). An exact estimate of PPP is not available. It usually occurs as a result of peripheral estrogen production, either due to an autonomous
ovarian cyst, a germ cell tumour or McCune Albright (MCA) syndrome. Millar et al. reported
SC
that ovarian cysts are prevalent in 2% to 5% of prepubertal girls, and of those, 5% are found
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to produce estrogens, giving an estimated risk of PPP of one in 400 (0,25%) (2).
Symptomatology can range from breast budding, external genitalia changes, pubic hair development, vaginal discharge to overt vaginal bleeding (2,3,4,5,6). Autonomous ovarian cysts can develop at any age and may regress after a few weeks or months (2,5,6). A
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percentage that will regress spontaneously or after treatment may recur either as an isolated event or as a precursor of McCune Albright syndrome(5,6,7). A number of girls may enter in central precocious puberty (5,6). The natural history of autonomous ovarian cyst,
subject.
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however, is not clear and the aim of this study was to review the available literature on the
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Methods
We conducted a search on Pubmed using the keywords peripheral precocious puberty, autonomous ovarian cysts and pseudopuberty in the title or abstract. The search was performed in October 2014 by AP and all collected articles were reviewed by AP and LM. We restricted our search to human studies, written in English after 1980. The date was chosen slightly arbitrarily but was primarily based on the fact that ultrasonographic diagnosis
ACCEPTED MANUSCRIPT became more widespread in the 1980s. We excluded studies on males, relating to tumours, McCune Albright syndrome (MCA) and central precocious puberty (CPP).
The search yielded 32 articles. We further excluded 25 studies, which were relating to
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Congenital Adrenal Hyperplasia (CAH), hypothyroidism, CPP, other endocrine disorders, exogenous hormone exposure. We enriched our study through hand searching relevant articles and reviews to identify other cases or case series in the list of citations.
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As the goal of the study was to identify cases that clearly would cause precocious puberty
we excluded patients over 8 year old, the cut off for normal pubertal development (3) and
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under 2, as this is considered the upper limit for maternal estrogen effect and/or increased levels of gonadotropins after birth due to immaturity of the hypothalamic-pituitary-ovarian axis (4). We only included cases where a suppressed LHRH test result was available as proof of peripheral precocious puberty. A proforma was used to collate information acquired from
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articles.
Through these exclusions we derived 14 articles. Of those, two were editorials or reviews with no data on patients included (5, 6). We then excluded the article by Chao et al (7), as
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we were unable to tease out cases of peripheral puberty out of the total number of patients with precocious puberty, the paper of Sinnecker et al (8) as it referred to a patient with low
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plasma estradiol concentrations, and the article of Baran et al (9) as there was no information about LHRH testing.
We included in the study 9 papers (2, 10-17) and looked for information regarding age at presentation, size of ovarian cyst, management - surgical, conservative or pharmaceutical, recurrences and progression to McCune Albright or CPP.
Results
ACCEPTED MANUSCRIPT In these nine articles we found 26 girls who fulfilled our criteria. Their median age at presentation was 5 years old with a range from 2,2 to 8.
The main clinic symptom of these girls was breast development, reaching a Tanner stage 2
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to 3. Twenty-one out of 26 (80,7%) presented with vaginal bleeding or vaginal discharge. Six of these girls (23%) also presented with pubic hair at Tanner stage 2-3.
The laboratory findings were elevated estrogen levels with low gonadotropins. Estradiol
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levels was available in all patients, of which median value was 155,4pg/ml, with a range from 5 to 918.
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All girls had a simple ovarian cyst, which was identified by transabdominal ultrasound in the majority of patients or was diagnosed at laparotomy or laparoscopy.
All 26 patients presented with unilateral ovarian cysts, whose exact size was documented in 24. In the study by Lyon et al two of the cysts were described as large. The larger diameter of
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the 24 measured cysts was 60mm, with median larger diameter around 41,5mm. We had information about the location of the cysts in 14 cases. Nine were left sided and 5 were on
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the right. All cysts were described ultrasonographically or macroscopically as simple cysts.
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Age, clinical symptoms, laboratory and imaging findings are shown in table 1.
Management is illustrated in table 2. In summary, ten patients underwent surgical treatment, either cystectomy(6) or oopherctomy(4), 13 cases were managed conservatively and three underwent treatment with cyproterone acetate. Follow up was reported in 20 cases and ranged from 7 months to 8 years with a median of around 3 years. Out of the patients followed conservatively, we could deduce information about the time of regression in 11 cases and estimated this to be six weeks.
ACCEPTED MANUSCRIPT Eleven out of 26 cases (42%) presented with recurrences, ranging from 1 to 4 episodes. Recurrences were more likely to occur in those managed conservatively, occurring in 9 of the 13 girls that did not undergo surgery. In total there were 20 episodes of recurrences in 11 patients. Time at recurrence was mentioned in 19 episodes and ranged from 1 month to
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24 months, with a median time of 13,5 months.
Three patients (11.5%) were eventually given GnRHa, presumably for progression to CPP. One further patient was given GnRHa -probably inappropriately- as treatment of the
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autonomous cyst. This particular case eventually underwent an oophorectomy after two cystectomy operations failed to control her symptoms(2). One patient was identified as
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having MCA (13) and one further patient was given anastrozole treatment after persistent symptomatology for six months, despite not having other signs of MCA. Under treatment, the cyst regressed after three months, however treatment with the aromatase inhibitor was
Discussion
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continued for 3 years (15).
In this paper we present a review of all published cases of autonomous ovarian cysts since
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1980 in an attempt to describe and understand associated risks and suggest management plans. As seen, the majority of cysts had an average diameter of 20mm and usual clinical
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presentation was with premature breast development and, in descending frequency vaginal discharge or bleeding. In normal pubertal development uterine bleeding usually starts at breast Tanner stage 3-4. In this series, the majority of patients with vaginal bleeding had attained a breast Tanner stage of 2 to 3, reflecting rapid progression due to acute exposure to estrogen.
Vaginal bleeding in most cases occurred as a result of estradiol withdrawal after cyst resolution. It is interesting to note that breast development was the slowest to regress.
ACCEPTED MANUSCRIPT Stated reasons for proceeding to surgical management were persistence of clinical symptoms, increase of ovarian cyst dimensions or recurrence. Reasons for proceeding to surgery were not always clear with a tendency to more cystectomies being performed in the early eighties and less so in the later years. We could not identify a correlation between size
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of ovarian cyst, level of estradiol and time of regression so as to provide a guidance to practice. Interestingly, surgical treatment did not always protect from recurrence, as
demonstrated by one of the cases in this review. Four patients in this series underwent an
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oophorectomy, a practice that in our opinion is not justifiable, unless malignancy is suspected.
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Regression in those treated conservatively occurred in weeks to months, during which time symptoms of pubertal maturation were likely to persist. This may lead to psychological distress to the patient and her family. More importantly, some of the effects of estrogen exposure, such as bone age maturation and final height suppression may be non-reversible.
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There is also a concern that a proportion of patients may progress into CPP, this being more likely when exposure to estradiol is prolonged. In keeping with this, progression to CPP in this series occurred in those that had at least two episodes of autonomous cyst formation.
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With this in mind, it may well be useful to provide medical treatment to patients as indeed
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was the case in a proportion of patients in this series.
Insight in the management of young girls with autonomous cyst formation may be gathered from McCune Albright (MCA) syndrome, where surgical treatment is only performed in case of ovarian torsion or haemorrhage. In MCA cysts tend to recur and an operation would not provide a viable solution to premature pubertal development.
McCune-Albright Syndrome is a sporadic disease, characterized by polyostotic fibrous dysplasia, café’-au-lait skin pigmentation and endocrine dysfunction with individuals exhibiting peripheral precocious puberty (PPP)(18). It is due to post zygotic activating
ACCEPTED MANUSCRIPT recurrent mutations in the guanine nucleotide binding protein (G protein) α subunit (18). The molecular basis of MCA syndrome is a mutation in the α subunit of the G protein, which couples cell surface receptors to the stimulation of adenyl cyclase, Gsα. These mutation lead to the constitutive activation of adenyl cyclase in various tissues, including the ovary (19).
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Gonadal hyperfunction is the most frequent endocrine dysfunction in females with MCA syndrome, and precocious pseudopuberty is usually the first manifestation of MCA
syndrome in children (20). Diagnosis of MCA syndrome requires a prolonged clinical follow
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up with repeated skeletal radiographs (21). As clinical evidence for MCA can appear later in the course of recurrent autonomous cysts (13), a careful clinical observation of these
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patients and molecular studies may be necessary in such cases. In our series one patient progressed to overt MCA and it is possible that patients with a recurring autonomous cyst, particularly those following cystectomy have a variant of the disease.
PPP in girls with MCA is usually treated with aromatase inhibitors, drugs initially developed
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for the management of estrogen receptor positive breast cancer. Testolactone and ferdrozole, a first and second generation aromatase inhibitor respectively were initially used
duration.
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for treatment of PPP, with disappointing results and declining efficacy through treatment
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Third generation aromatase inhibitors such as anastrozole and letrozole appear to be more beneficial in suppressing ovarian function and have the added benefit of a once daily formulation, which improves compliance. Long term results are nevertheless awaited, particularly with regards to bone health, since boys treated for idiopathic short stature with letrozole were at increased risk of having vertebral body deformities. Whether this is true for girls with MCA is not yet determined (22).
ACCEPTED MANUSCRIPT Other preparations used in MCA to slow pubertal growth are estrogen receptor agonists such as tamoxifen (23) and cyproterone acetate (24), an antiandrogen that was used in three patients in these series.
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Similar treatment options may be the indicated course of action in patients with autonomous ovarian cysts persisting for longer than 4 to 6 weeks. Through this case series however we were not able to identify a cut off of cyst size or estradiol level above which
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treatment should be introduced.
In conclusion, more than half of the patients in this series were successfully managed
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conservatively. Patients were more likely to have been treated surgically in the 1980s and it is possible that some cystectomies may have been unnecessary, had follow up been longer. We could not formulate a guidance as to when to proceed to ovarian cystectomy, other than in cases of ovarian torsion or hemorrhage or in cases where malignancy cannot be excluded.
was small.
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This was a limitation to this study, as the number of patients that were available for review
Treatment with antiestrogens or aromatase inhibitors appears a likely less invasive
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alternative for those with a persistent or recurrent autonomous cyst. At present however there is no consensus as to the superiority of surgical versus pharmaceutical management.
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In particular, we are lacking data with regards to future pubertal development and reproductive outcomes. Ideally, this would be answered through an RCT, allocating patients to either surgical or conservative management, with or without pharmaceutical back up.
Finally girls having presented with an autonomous ovarian cyst once have a 40% chance of recurrence, which may be an early presentation of MCA. Careful clinical and radiographic examination and monitoring should be undertaken to identify this. Also, a proportion of girls may proceed to CPP and monitoring of pubertal growth should be undertaken at regular
ACCEPTED MANUSCRIPT intervals (4-6 months) and LHRH testing performed if signs of puberty become obvious. Figure 1
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Acknowledgment
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Authors have no conflicts of interest to declare and have received no funding for this study.
References
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1. Partsch CJ, Heger S, Sippel WG. Management and outcome of central precocious puberty. Clin Endocrinol. 2002;56(2):129. 2. Millar DM, Blake JM, Stringer DA, Hara H, Babiak C. Prepubertal ovarian cyst formation: 5 years experience. Obstet Gynecol. 1993;81(3):434-438. 3. Kosloske AM, Goldthorn JF, Kaufman E, Hayek A. Treatment of precocious pseudopuberty associated with follicular cysts of the ovary. Am J Dis Child. 1984;138(2):147-9. 4. Fakhry J, Khoury A, Kotval PS, Noto RA. Sonography of autonomous follicular ovarian cysts in precocious pseudopuberty. J Ultrasound Med. 1988;7(11):597-603. 5. Rodriguez-Macias KA, Thibaud E, Houang M, Duflos C, Beldjord C, Rappaport R. Follow up of precocious pseudopuberty associated with isolated ovarian follicular cysts. Arch Dis Child. 1999;81(1):53-6. 6. de Sousa G, Wunsch R, Andler W. Precocious pseudopuberty due to autonomous ovarian cysts: a report of ten cases and long-term follow-up. Hormones (Athens). 2008;7(2):170-4. 7. Brauner R, Bashamboo A, Rouget S, et al; Clinical, biological and genetic analysis of prepubertal isolated ovarian cyst in 11 girls. PLoS One. 2010;25;5(6). 8. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age 8 benign? Pediatrics. 2003;111(1):47-51. 9. Dolgin SE. Ovarian masses in the newborn. Review. Semin Pediatr Surg. 2000;9(3):121-7. 10. Lightner ES, Kelch RP. Treatment of precocious pseudopuberty associated with ovarian cysts. Am J Dis Child. 1984;138(2):126-8. 11. Stanhope R, Traggiai C. Precocious puberty (complete, partial). Endocr Dev. 2004;7:57-65. 12. Zou CC, Liang L, Dong GP, Zhao ZY. Peripheral precocious puberty: a retrospective study for six years in Hangzhou, China. J Paediatr Child Health. 2008;44(7-8):415-8. 13. Sinnecker G, Willig RP, Stahnke N, Braendle W. Precocious pseudopuberty associated with multiple ovarian follicular cysts and low plasma oestradiol concentrations. Eur J Pediatr. 1989;148(7):600-2. 14. Baran GW, Alkema RC, Barkett GK, Frisch KM. Autonomous ovarian cyst in isosexual precocious pseudopuberty. J Clin Ultrasound. 1988;16(1):58-60. 15. Lyon AJ, De Bruyn R, Grant DB. Transient sexual precocity and ovarian cysts. Arch Dis Child.1985;60(9):819-22. 16. Engiz O, Berberoglu M, Siklar Z, Bilir P, Ocal G. Treatment of autonomous ovarian follicular cyst with longterm anastrozole therapy. Indian J Pediatr. 2009;76(9):950-1. 17. Chae HS, Rheu CH. Precocious pseudopuberty due to an autonomous ovarian follicular cyst: case report with a review of literatures. BMC Res Notes. 2013;12;6:319. 18. Lumbroso S, Paris F, Sultan C. Activating Gsα mutations: analysis of 113 patients with signs of McCune – Albright Syndrome-A European collaborative study. J Clin Endocrinol Metab, 2004;89(5):2107-2113. 19. Schwindinger WF, Levine MA. McCune-Albright syndrome.Trends Endocrinol Metab. 1993;4(7):238-42. 20. Matarazzo P, Lala R, Andreo M, et al; McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age. J Pediatr Endocrinol Metab. 2006;19 Suppl 2:607-17. 21. Frisch LS, Copeland KC, Boepple PA. Recurrent ovarian cysts in childhood: diagnosis of McCune-Albright syndrome by bone scan.Pediatrics. 1992;90(1 Pt 1):102-4. 22. Wit JM, Hero M, Nunez SB. Aromatase inhibitors in pediatrics. Nat Rev Endocrinol. 2011;8(3):135-47. 23. Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr. 2003;143(1):60-6.
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24. Messina MF, Arrigo T, Wasniewska M, et al; Combined treatment with ketoconazole and cyproterone acetate in a boy with McCune-Albright syndrome and peripheral precocious puberty. J Endocrinol Invest. 2008;31(9):83940.
ACCEPTED MANUSCRIPT Table 1. Age, clinical symptoms, laboratory and imaging findings Paper
No
Age
Breast
Vaginal
Pubic Hair
FSH(mIU/mL)
LH(mIU/mL)
E2(pg/ml)
Cyst
1
Kosloke 1984
1
3,7
Y
Y
N
<2
<2
24
9mm L
2
6
Y
N
N
<1
<1
30
11mm R
1
2,8
Y(B3)
Y
Y
3,8
<1
17,4
38mm L
2
4,6
Y(B3)
Y
N
3,9
9,5
25,3
large R
3
4,2
Y(B3)
Y
N
12,7
4
5
Y
Y
N
1
5
Y
Y
N
3,4
2
6,4
Y
Y
N
2,9
1
3
Y
Y
2
4
Y
3
4,5
12
4
8
Y
13
1
6,9
Y(B3)
Y
2
5,9
Y(B3)
Y
3
2,2
Y(B2)
N
16
4
5,4
Y(B2)
Y
17
5
2,6
Y(B2)
Y
18
1
5,3
Y(B2)
Y
2
4,7
Y(B2)
Y
3
6,3
Y(B2)
4
4,7
1
6 7 8
Fakhry 1988
9 10 11
14 15
19 20
DM Millar 1993
Rodriguez 1999
de Sousa G 2008
21 22 23 24
Engiz 2009 Brauner 2010
25
Y
27mm L large R
5,4
129
33mm L
3,8
85
55mm R 27mm 55mm 45mm 50mm
<0,2
<0,2
43
65mm
N
<0,2
0,2
270
30mm
Y(P2)
0,2
0,2
30
25mm
N
0,5
0,3
5
50mm
Y(P3)
0,2
0,2
125
46mm
N
59
40mm L
N
172
60mm
Y
N
242
30mm
Y(B2)
Y
N
310
35mm
8
Y(B2-3)
N
Y(P2)
105
50mm L
1
3,3
Y(B3)
Y
N
<0,1
<0,1
66
50mm L
2
5,6
Y(B3)
Y
Y(P2)
0,4
<0,4
918
60mm L
6,6
Y(B3)
Y
N
<0,4
<0,4
576
41mm L
5,9
Y
Y
N
0,3
0,07
19,8
54mm R
1
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26
13,6
Y(P2)
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6
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5
A J Lyon 1985
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4
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3
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2
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No of p.
ACCEPTED MANUSCRIPT Table 2. Management and Recurrence Time of recurrence N/A
laparotomy-cystectomy
1
N/A
1
laparotomy-cystectomy
1
N/A
2
laparoscopy-conservative
4w, 2w, 4m
3
1.9y, 1.9y
3
conservative
2w, 2w
4
laparotomy-oophorectomy
1
laparotomy-cystectomy
2
conservative
1
conservative
2
conservative
3
cystectomy
12
4
cystectomy
13
1
oophorectomy
2
conservative
3
conservative
16
4
conservative
17
5
conservative
18
1
conservative
2
ovariectomy
3
conservative
4
5
A J Lyon 1985
6 7 8
Fakhry 1988
9 10 11
DM Millar 1993
14 15
19 20
Rodriguez 1999
de Sousa G 2008
21 22
Engiz 2009
23 24
Brauner R 2010
25 Hee Suk 2013
24m
1
N/A
1
N/A
1
N/A
1
N/A
1
N/A
2
6m
1
N/A
1
N/A
2-4w
2
11m
2-4w
1
N/A
2-4w
2
1m
2-4w
5
1m,18m,22m,26m
2-3m
5
7m, 12m, 7m
1
N/A
2-3m
3
24m, 18m
conservative
2-3m
3
4m,1m
1
conservative
3m
2
6m
1
cyproterone acetate
5m
1
N/A
2
cyproterone acetate
7m
2
23m
3
cyproterone acetate
3m
1
N/A
1
laparoscopy-cystectomy
1
N/A
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26
2
6w
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4
2
Time of Cyst Regression
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3
Management oophorectomy
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Kosloke 1984
No 1
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No of episodes 1
2
Paper
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Patients 1
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Ovarian cyst- premature puberty
Simple cyst
Yes
GnRHa
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CNS imaging
Resolution
Yes
Monitoring for recurrence every 4-6 months
+/- surgery
CPP
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Monitoring 4-6 weeks
Imaging- Tumour markers
No
PPP Exclude MCA
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LH ↓, E2↑
Complex cyst
No
Medical treatment
?
Surgical treatment