Gender-affirming hormone therapy associated with multiple meningiomas and atypical histology in a transgender woman

Abstract

We present a 69-year-old transgender woman who underwent gender-affirming surgery in 1998 and gender-affirming hormone therapy (cyproterone acetate (CPA) and estradiol) since this time. Following an MRI scan to investigate tremor in 2013, an incidental left anterior clinoid and right petrous meningioma were identified. Subtotal surgical resection was achieved for the anterior clinoid meningioma (WHO grade 1, meningothelial subtype). At follow-up in 2016, an olfactory groove meningioma and left greater wing of sphenoid meningioma were identified. By 2017, both tumours, along with the petrous meningioma, demonstrated significant growth. In 2018, clinical decline was evident and MRI demonstrated further tumour growth. Surgery was scheduled and the olfactory groove meningioma was completely resected (WHO grade 2, chordoid subtype). Hormones were stopped, after which regression of the petrous meningioma was observed. This case demonstrates an association between high-dose CPA and estradiol and the development, growth and regression of meningiomas in a transgender woman.

Background

Cyproterone acetate (CPA) is a synthetic, progesterone-like compound, which displays antiandrogenic properties through competitive inhibition of testosterone binding sites and blockade of testosterone production in the gonads.¹ It is widely prescribed in Europe in combination with estradiol as a common pharmaceutical regimen used by transgender women,² but has other uses, including advanced prostate cancer, acne, hirsutism, alopecia, for intersex conditions, endometriosis (not UK) and paraphilias (off-label).³

Meningioma is the most common primary brain tumour and demonstrates a female preponderance (1.16 times more common in women).⁴ The aetiology of meningioma is largely unknown. There are well-established risk factors, including ionising radiation and the coexistence with certain rare genetic conditions, most notably neurofibromatosis type 2, but these account for a small proportion of the disease incidence.⁵ It is well known that meningiomas express hormone receptors and causal associations are postulated, but the significance and mechanisms of this still remains unclear in the context of hormone exposure and meningioma growth.⁶ For instance, the link between pregnancy and meningioma growth is well documented, but not yet fully understood.⁷ Transgender women are often prescribed CPA at much higher doses, and a recent cohort study described a strong dose–effect relationship between CPA and the risk of intracranial meningioma and subsequent risk reduction after discontinuation of treatment.⁸

Here, we present a case of a transgender woman receiving gender-affirming hormone therapy (a very high dose of CPA in combination with a modest dose of estradiol), associated with the development and growth of multiple meningiomas, necessitating surgical intervention on two occasions.

Case presentation

Our patient is a 69-year-old, right-handed, transgender woman, known to our neurosurgical department since 2013. She underwent gender-affirming surgery in 1998. She had been consistently taking prescribed gender-affirming hormone therapy since 1998, with records of the use of conjugated oestrogens 2.5 mg two times a day (5 mg/day), and CPA 100 mg two times a day (200 mg/day) since at least 2012. In 2005, she was involved in a road traffic collision, after which she reported reduced vision in her left eye and left orbital pain. Ophthalmological review demonstrated visual acuity of 6/60 on the left, with a relative afferent pupillary defect, and barely detectable visually evoked potentials. Subsequent review demonstrated a reduction of visual acuity to light detection only. A CT head, which is no longer available, was reported to show a swollen optic nerve on the left, presumed to be in keeping with a traumatic optic nerve lesion.

In 2013, at the age of 61 years, the patient underwent an MRI scan to investigate a presentation of tremor, which demonstrated a left anterior clinoid meningioma, extending into the planum sphenoidale, along with a small right petrous meningioma (figure 1). Of note, there was no history of ionising radiation or familial genetic conditions known to be associated with meningioma development. The decision was made for surgical resection of the anterior clinoid meningioma, which was performed without complication. Histology confirmed WHO grade 1 meningioma (meningothelial subtype). Follow-up MRI performed 6 weeks later demonstrated a small residuum on the left carotid artery in relation to the ipsilateral cavernous sinus. Radiotherapy was declined by the patient, and annual scanning was commenced. In 2016, two new small meningiomas were observed on MRI scan; an olfactory groove meningioma and a left greater wing of sphenoid meningioma. By 2017, there had been a mild increase in the size of the residual meningioma, but a significant increase in the right petrous meningioma, olfactory groove meningioma and left greater wing of sphenoid meningioma (figure 2).

Figure 1.

T1-weighted, gadolinium-enhanced MRI demonstrating newly-identified meningioma (August 2013). The larger of the two, a left anterior clinoid (AC) meningioma, invading the planum sphenoidale and optic sheath shown in the coronal (A), sagittal (B) and axial (C) planes. The second, smaller meningioma lies on the right petrous bone (PB) shown in the coronal (D), sagittal (E) and axial (F) planes.

Figure 2.

T1-weighted, gadolinium-enhanced MRI (April 2017) demonstrating olfactory groove (OG) meningioma (images A, C), growth of right petrous bone (PB) meningioma (images B, C), residual left anterior clinoid (AC) meningioma and left greater wing of sphenoid (WS) meningioma (C).

In 2018, at the age of 66 years, the patient was admitted as an emergency following a period of significant deterioration in cognition, memory and balance. A further MRI demonstrated extensive growth of the olfactory groove, greater wing of sphenoid and petrous bone meningiomas (figure 3). A decision was made to proceed to surgical resection of the olfactory groove meningioma to prevent further clinical deterioration and reduce intracranial pressure. Complete macroscopic resection was achieved. The small residual tumour at the left orbital apex was seen to be separate from the olfactory groove meningioma. A biopsy of this residuum was obtained for repeat histology.

Figure 3.

T1-weighted, gadolinium-enhanced MRI (July 2018) demonstrating rapid growth of the olfactory groove (OG) meningioma (A, B), petrous bone (PB) meningioma (C, D) and greater wing of sphenoid (WS) meningioma (D).

Histology confirmed that the olfactory groove meningioma was WHO grade 2 (chordoid subtype), but with a mixed growth pattern, including meningothelial parts. Ninety per cent of cells demonstrated progesterone receptor positivity, while oestrogen receptor positivity was variable at 15%–60%. A sample of the residual anterior clinoid meningioma obtained at the time of second surgery still proved to be WHO grade 1. Receptor status from this sample also demonstrated 90% progesterone receptor positivity, but did not demonstrate oestrogen receptor positivity. In conjunction with the patient’s next of kin, owing to a lack of capacity, the clinical team took the decision to stop all hormone therapy postoperatively in the patient’s best interests. This decision was made on the assumption that the extensive and rapid growth of the meningiomas could be attributable to these medications, and in particular, CPA, based on a review of the available literature.

Outcome and follow-up

Rehabilitation is ongoing and significant cognitive difficulties persist. MRI scan at most recent follow-up in 2020 has shown a reduction in the size of the petrous meningioma, and the other tumours are stable.

Discussion

The true prevalence of gender dysphoria is hard to assess. Estimates of the transgender population in the UK range from 0.2% to 0.6% in adults,⁹ and are thought to be increasing at a rate of approximately 14% every year in the UK.¹⁰ Gender-affirming surgery and gender-affirming hormonal therapy are critical components for the successful treatment of this patient cohort and are increasingly in demand.¹¹

Hormonal regimens for transgender women are complex because treatment with oestrogen alone is insufficient to suppress testosterone levels into the normal range for a woman.² Therefore, adjuvant treatment is needed. Multiple options are available, such as goserelin acetate or leuprolide, which are GnRH agonists that effectively reduce testosterone levels,² spironolactone, which directly blocks androgens during their interaction with the androgen receptor,¹² and may also have estrogenic activity,¹³ and CPA among other progestins, such as nomegestrol acetate and chlormadinone acetate.² The clinical use of CPA is based on its progesterone-like activity, and antiandrogenic action, with resultant antigonadotropic activity, which produces rapid suppression of serum testosterone.¹⁴ When used as a solitary agent, it causes a total androgen blockade, and hence, is usually supplemented with adjuvant therapies to provide optimal results (eg, luteinising hormone-releasing hormone agonists or orchidectomy).¹⁴

While there is a limited amount of evidence that conventional doses of CPA may influence the growth of meningioma,³ an increasing body of evidence supports a dose-dependent relationship between CPA exposure and the development and/or growth of intracranial meningioma.⁸ Observations, such as this have not been made to the same extent for oestrogen-based preparations. Transgender women are a potentially at-risk cohort for gender-affirming hormone therapy-associated meningioma as prescribed doses reported in case reports are far higher, especially with respect to CPA, when compared with non-gender-affirming applications of these medications.^{6 15–21} These case reports are highly variable with respect to presentation, drug dose and length of exposure, pathological features and management strategy, but attempt to draw attention to this important observation.

This case adds to the limited number reported in the literature to date and offers new insights into the described association. Our patient demonstrated de novo occurrence of multiple meningiomas at discrete time points while under follow-up. In addition, the growth rates for each meningioma varied substantially. For instance, the anterior clinoid meningioma, which was probably present in 2005, remained relatively stable on surveillance. However, the WHO grade 2 olfactory groove meningioma grew rapidly over a very short period of time, along with the petrous and greater wing of sphenoid meningiomas (although not to the same extent). The observation of growth regression on hormone withdrawal supports the described association, and suggests that the biological response of the tumour tissue to hormone therapy was fundamentally different. The opportunity to biopsy the residual anterior clinoid meningioma at the time of second surgery for the olfactory groove meningioma allowed us to reassess WHO grade and obtain hormone receptor status. The high (90%) progesterone receptor status of both tumours suggests that this is not simply a direct effect of CPA on progesterone receptors. The role of progesterone receptor status in meningioma development generally is not clear, and there is currently no evidence to support progesterone receptor inhibitors in the management of meningioma.²²

Conversely, the oestrogen receptor status was variable at 15%–60% in the olfactory groove WHO grade 2 meningioma, but oestrogen receptor status was negative in the WHO grade 1 anterior clinoid meningioma. Oestrogen receptor positivity was seen in the only other reported case of CPA-related WHO grade 2 meningioma, which, therefore, questions the role of oestrogen receptor status and estradiol in the development of atypical meningioma.¹⁸ To what extent CPA and/or estradiol influenced the development, histological subtype and grade, either independently or synergistically, cannot be elucidated from this case report when considering that our patient received both drugs.

The preferred treatment option for large and/or symptomatic meningioma is usually surgical resection.²³ However, CPA-induced tumour growth is reported to halt and/or reverse on cessation.^{16 17 21} Therefore, total hormone cessation or as a minimum, CPA cessation, may be the optimal first-line management strategy unless one is concerned about critically raised intracranial pressure, risk of clinical deterioration or permanent neurological disability through not operating in the acute phase (as was the scenario in this case).

A drug safety update issued by the UK government in 2020 states that patients with existing meningiomas or a history of meningiomas must not be prescribed CPA, but this does not apply to medication preparations containing low-doses, such as the contraceptive co-cyprindiol (Dianette), typically containing 2 mg.²⁴ Interestingly, de novo or accelerated growth of meningioma is not listed as a medical risk associated with sex hormone therapy by the Endocrine Society clinical practice guideline, which was updated in 2017.² However, these guidelines recommend a dose of CPA in the range of 25–50 mg, combined with monitoring of hormone levels, to avoid overtreatment and treatment-related side effects.² This suggests that the prescribing practice of CPA has changed or will change in the future.

Patient’s perspective.

I think that it is important that my case is published so that clinicians are aware of the risk of cyproterone acetate and how meningioma can be managed in these circumstances.

Learning points.

• There is a dose-dependent association between cyproterone acetate and the development and/or growth of intracranial meningioma.

• This case demonstrates differential growth patterns of multiple intracranial meningiomas (with different histological profiles) in response to gender-affirming hormone therapy in a transgender woman.

• While surgical resection was required in this case, regression following hormone cessation supports a non-surgical solution for appropriately selected patients.

Ethics statements

Patient consent for publication

Obtained.