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�: HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/18057351" Presentation of a meningioma in a transwoman after nine years of cyproterone acetate and estradiol intake: case report and literature review

Running Head: A new case of meningioma in a transwoman treated with cyproterone acetate.

Mancini I�, Rotilio A�, Coati I�, Seracchioli R�, Martelli V� and Meriggiola MC�


� Clinic of Gynecology and Physiopathology of Reproduction, Department of Medicine and Surgery, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
�Department of Surgery, Operative Unit of Neurosurgery, Hospital of Padua, Padua, Italy.
�Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy.


Corresponding Author
Maria Cristina Meriggiola, MD, PhD
Gynecology and Physiopathology of Human Reproduction,
S.Orsola-Malpighi University Hospital
Alma Mater Studiorum University of Bologna
Via Massarenti, 9 - 40138 � Bologna, Italy
Tel: +39 0512143716
Fax: +39 0512143716
Email:  HYPERLINK "mailto:cristina.meriggiola@unibo.it" cristina.meriggiola@unibo.it
ABSTRACT
Background. The combined administration of cyproterone acetate and estradiol is a common regimen used by male-to-female transsexuals (transwoman) to adjust their body to their gender identity. Major adverse events are uncommon in these subjects in spite of long-term, high dose cross-sex steroid treatments. This report aims to establish a possible link between meningiomas and cyproterone acetate (CPA).
Case presentation. We describe the occurrence of a meningioma in a transwoman treated with estrogens and cyproterone acetate over a period of nine years. The meningioma was revealed during a contrast-enhanced magnetic resonance imaging (MRI) scan performed as follow-up of a previous surgery for ganglioglioma. 
CPA intake was discontinued and a tumor resection was performed. Histological diagnosis confirmed a strong progesterone receptor-positive and slight estrogen positive meningioma. After surgery, the patient continued her treatment with leuprorelina acetate and estradiol. At one-year follow-up, the MRI scan reveals no recurrence of the tumor.
Conclusion. This is the ninth case reported in literature of a meningioma occurring in a transwoman treated with estrogens and CPA thus confirming a possible association between female sex steroids and meningioma. Although there isn�t still strong evidence of an association between meningioma and CPA, this report may suggests use of alternative treatment for transwomen who wish to suppress phenotypic characteristics of their biological sex. On the other end, this report highlights the importance to record all the cases of meningiomas in high dose CPA-users, in order to improve data about this association.

KEYWORDS
Meningioma, transsexual, transwomen, cyproterone acetate, cross-sex steroid treatmentBACKGROUND
Transsexual persons have an urgent need to be recognized and live as members of the gender in which they identify [1]. Hormone treatment is an important tool for many transsexuals who wish to modify their phenotypic characteristics according to the gender in which they identify. In Male-to-Female persons (transwomen), the Endocrine Society guidelines recommend the association of estradiol with progestational compounds with anti-androgen properties [2]. The goal of this treatment is to suppress endogenous hormonal secretion and the development of feminine secondary sexual characteristics. In Europe the most widely used anti-androgenic compound is cyproterone acetate (CPA) [3]. Available literature shows that in spite of the long-term intake and sometimes highly uncontrolled doses of cross-sex hormone, overall safety of these regimens is high [4]. In hormone-treated transwomen, the increased mortality is mainly due to non-hormone-related causes [4].

Meningioma is an unusual hormone-related tumor. Eight cases of symptomatic meningioma in male-to-female transsexuals have been reported in literature, seven  after combined CPA and estrogen treatment and the one after estrogen treatment alone [5-9]. Our report describes a further case of this tumor in a transwoman undergoing cross-sex hormone therapy.

CASE REPORT
A 41-year-old transwoman, treated with estradiol gel  (1 mg and thereafter 2 mg and up to 3 mg per day) and CPA (50 mg per day) for the previous nine years, presented with partial inability to read and some prosopagnosia episodes for one year. Neurological examination revealed no abnormalities. No sex reassignment surgery had been performed. Four years earlier the patient had presented some neurological symptoms including episodes of paraesthesia on half of the right side of the body associated with hyposthenia. A magnetic resonance imaging (MRI) scan revealed an expansive mass in left insula. A partial tumor resection was performed after diagnosis without complications. The mass was not completely removed because of its proximity to insular arteries. Immuno-histochemical and morphological tests revealed a ganglioglioma (World Health Organization [WHO], grade I), negative for progesterone and estrogen receptors. Annual follow-up using contrast-enhanced MRI scan were performed thereafter. No abnormal cerebral enhancements were recorded for the first three years. In the fourth year, the MRI scan showed a 3 cm left occipital mass (Figure 1, Panel A). CPA was discontinued and was substituted with leuprorelina acetate (3.75 mg/monthly) administered in combination with transdermal estradiol (1 mg/day).
The patient underwent a second surgery for radical tumor resection. Histological diagnosis indicated a meningothelial meningioma (WHO, grade I), which was strongly progesterone receptor-positive (90%) and slightly estrogen receptor-positive (20%), with MIB-1 index of 1% (Figure 2). At one year MRI follow-up the patient, who had continued the feminizing regimen based on leuprorelina acetate 3.75 mg/month and estradiol (1 mg/day), showed no recurrence of the tumor (Figure 1, Panel B). 

DISCUSSION
We report the ninth known case of growth of intracranial meningioma in a transwoman who had been taking feminizing hormones consisting of estradiol and CPA for the previous nine years. At histological examination the meningioma resulted high positive (90%) for progestin receptors with low positivity for estrogen receptors (20%) thereby confirming the hypothesis of a link between meningioma and sex steroids.  At two years follow-up the patient presents no recurrence of the lesion despite still taking estradiol. 
In our outpatient clinic, over 200 male-to-female transgenders have been treated from 2000 to 2016 and this single case of meningioma has been reported.
Meningioma is a hormone-related intracranial benign tumor, usually arising from the aracnoid cap cells or meningothelial cells. Its occurrence is twice as common in women as men, especially during the reproductive years [10,11]. Increased growth of meningiomas is seen in particular conditions such as in pregnancy or in the luteal phase of the menstrual cycle [12], while spontaneous regression has been reported after delivery [13]. Risk of meningioma seems to be higher in women who have used long-acting contraceptives and in post-menopausal patients with a history of menopausal hormone therapy [14]. This evidence supports the hypothesis that sex hormones may somehow be related to the growth of meningiomas. These intracranial tumors often express functional progesterone receptors (around 90% of cases), while estrogen receptors have been identified in a smaller number of cases (approximately 10%) [15]. Other suggestions of an association between progesterone/progestins and meningioma come from patients on long-term progesterone treatments for different medical reasons, such as lymphangioleiomyomatosis, benign prostatic hypertrophy or females treated for hirsutism [16-18]. In 2006, Pozzati et al. published a case of a rapid growth of multiple intracranial meningiomas in a post-menopausal woman treated with medroxyprogesterone acetate for lymphangioleiomyomatosis. The lesions regressed spontaneously after hormonal withdrawal [19]. Confirming this association, a few papers have reported meningioma regression or reduction in size after progestin withdrawal [5,17,20] and with the use of anti-progestins [21]. This is the reason why, in case of meningioma in patient treated with progestin and without significant symptoms, a conservative strategy, including discontinuation of the progestational compound, should be considered. 
Cyproterone acetate is a progestational compound with anti-androgen properties used in different medical conditions. High dose formulations (e"25 mg) are used in inoperable prostate cancer, severe hypersexuality, severe female hirsutism or male-to-female cross sex hormonal therapy. Lower dosage of CPA are used in combination with estrogen compound with labelled indication to treat female acne, hirsutism or androgenetic alopecia [22].
An epidemiological study performed in the UK reported a significantly increased risk of meningiomas in high dose (50 mg) long-term CPA users for prostate cancer (OR: 6.30; CI: 1.37-28.94) compared with non-users [23], and a recent epidemiological Spanish study reported a rate ratio of 11.4 (95% CI: 4,3-30,8) in the high dose CPA-users cohort (with variable indication) compared with non-users cohort [24]. 
Male-to-female transsexuals are usually treated with the association of estradiol and a progestational compound, usually CPA  (50-100 mg per day) in Europe [25,26]. CPA presents progestogenic and antiandrogenic activities, working on suppression of gonadotropins and thereby testosterone testicular secretion and in competition with androgens for binding to their receptors. CPA may lead to weight gain due to a weak glucocorticoid activity. Cases of hepatotoxicity, dose-dependent sedative effects and increased incidence of depression have also been reported in association with CPA [26]. 
As of now, the literature reported other eight cases of symptomatic meningiomas in Male-to-Female patients. Seven of these have been treated with combination of CPA and estrogen compound [5, 6, 8, 9], while one case has been reported in a patient treated with estrogen therapy without progestin [7]. 
A conservative approach was taken in one case [5], while a partial or total resection was performed in the other cases [6-9], according to the symptomatology referred by the patients and the tumor localization.
Neurological symptoms described at the onset are extremely various: headache, seizures, visual impairment, signs of depression, partial inability to read or prosopagnosia episodes.
Few other cases of meningiomas in high dose CPA-users, excluding MtF transgenders, are reported in the literature. A summary of the cases reported in the literature is in Table 1, focusing on dose and time from CPA prescription to tumor diagnosis.

CONCLUSION
In conclusion we report the ninth case of a meningioma occurring in a transwoman treated with cross-sex hormones. This report further confirms the hypothesis that female sex steroid hormones, in particular the progestin CPA, may play a role in the occurrence of intracranial meningioma. Although strong evidence of an association between meningioma and CPA is still lacking, it is important to record all these cases in order to increase and improve our awareness on this possible link. Find out a possible relationship between CPA-dose and time from prescription to tumor diagnosis could be essential. Futhermore these reports may suggest use of alternative treatment for transwomen who wish to suppress phenotypic characteristics of their biological sex. GnRH analogs may represent a valid option even if the high cost of this treatment may represent a barrier to their use.  Low dose CPA may be effective in the suppression of gonadotrophins due to accumulation in subcutaneous tissue [26] and has been suggested to have a weaker association with meningioma occurrence [24] . Spironolactone is a further option although this itself is not free of adverse effects such as iperkaliemia, upper gastrointestinal bleeding [27] and it is not as effective as CPA or GnRH analogs. 
The occurrence of meningiomas in MtF transgenders is uncommon but asymptomatic tumor cases are not considered leading to an underestimation of the real incidence of this pathology; on the other hand, misunderstanding of symptoms may lead to a delayed or missed diagnosis. Our aim is to promote interest about a rare but possible association between CPA use and meningioma onset, to allow for an early recognition of these brain tumors and possibly hypothesize alternative treatments in MtF transgenders .

CONSENT
Written informed consent was obtained from the patient for publication of this
Case report and any accompanying images. A copy of the written consent is
available for review by the Editor of this journal.

LIST OF ABBREVIATIONS
CPA: cyproterone acetate
MRI: magnetic resonance imaging
WHO: World Health Organization

DISCLAIMER
All authors declare no conflict of interest.
Financial disclosure: nothing to declare.
AUTHORS� CONTRIBUTIONS
IM participated in the conception and design of the report, drafted the manuscript and carried out the acquisition, analysis and interpretation of data. MCM participated in the conception and design of the report, drafted the manuscript and carried out the acquisition, analysis and interpretation of data. AR helped in the acquisition of data. IC helped in the acquisition of data. RS helped to draft the manuscript. VM helped to draft the manuscript. All authors read, revised and approved the final manuscript.




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