Unmasked Testicular Seminoma During Use of Hormonal Transgender Woman Therapy: A Hidden hCG-Secreting Tumor

Abstract

Management of gender-affirming hormone therapy (HT) in transgender women includes surveillance of testosterone (T) levels. Failure of T to suppress, despite adherence to therapy, warrants additional investigations for unexpected sources of T or factors stimulating T secretion. Possible causes include T or gonadotropin production by an occult neoplasm. Testicular cancer is the most common malignancy affecting biological men aged between 15 and 35 years. Patients may be asymptomatic until tumor burden is high and/or metastatic. Hormone-producing tumors have rarely been reported in treated transgender women. Routine screening tests are recommended in a gender-incongruent person as per the 2017 Endocrine Society guidelines with measurement of T levels every 3 months initially to reach a goal of less than 50 ng/dL. Expectations should be discussed in detail with the transgender person since anticipated physical changes may not be notable for 6 to 18 months. We herein describe a case of a transgender woman who underwent standard HT including gonadotropin suppression with a gonadotropin-releasing hormone agonist, whose total T level failed to suppress. Testing revealed an elevated serum level of the beta subunit of human chorionic gonadotropin (β‐hCG), diagnostic of an hCG-secreting testicular seminoma, as the underlying cause of unexpected T production. This case illustrates how easily a testicular cancer can remain unnoticed because it can be asymptomatic and the necessity to be alert to, and act on, anomalous laboratory results during treatment of a transgender person.

The number of people reporting gender incongruence and requesting gender-affirming hormone therapy (HT) aimed at harmonizing phenotype with perceived gender has increased tremendously over the past 10 years [1]. This has posed a challenge for clinicians and created a whole new field of transgender medicine. Physicians treating transgender people should be aware that such treatment may occasionally unmask unsuspected disease such as breast cancer [2], pituitary disease (eg, prolactinoma) [3], congenital adrenal hyperplasia [4], among others. To our knowledge, only 3 cases of testicular carcinoma in transgender women have been reported in the literature [5-7]. Neither of them was secreting the beta subunit of human chorionic gonadotrophin (β‐hCG). We report a case of a transgender woman whose treatment with female hormones and a gonadotropin-releasing hormone (GnRH) analogue unmasked an occult hCG-secreting seminoma of the testis.

1. Case Report

A 31-year-old transgender woman, who had been started on HT several years previously by a community endocrinologist, presented to our Veterans Affairs endocrinology clinic for a second opinion. Her response to treatment had been unsatisfactory. She was prescribed 0.25 mg estradiol valerate subcutaneous (SQ) injection once weekly and leuprolide (Lupron) 3.75 mg SQ injection once monthly in 2017 initially, and then spironolactone 100 mg orally twice per day was added to her regimen with no significant physical feminization (regimen A). Despite having serum estradiol levels at goal (146 pg/mL [536 pmol/L]), her testosterone (T) level was higher than expected (131 ng/dL [454 nmol/L]). She reported that her beard growth remained luxuriant, her habitus and muscle distribution were persistently masculine, and breast enlargement was minimal. Due to the above problems, she came to us expressing dissatisfaction, despite adherence to her regimen. Our physical examination revealed masculine features with a man’s voice, light beard growth, and a mature masculine habitus. Breast development was Tanner stage 2. The penis was full adult size and testicles were 20 cc bilaterally with no scrotal masses palpable on careful examination.

We decided to increase estradiol valerate to 0.5 mg SQ once weekly and keep the rest of her regimen the same. One month later, her laboratory results were as shown in Table 1. Given failure of T to suppress, despite use of a potent GnRH analogue and the presence of elevated serum estradiol with suppressed follicle-stimulating hormone and luteinizing hormone levels, we concluded that further investigations were warranted.

Table 1.

Summary of the Laboratory Workup on Different Regimens

	Medical Management (HT)
Laboratory Results	Regimen A (Estradiol valerate 0.25 mg SQ weekly + spironolactone 100 mg PO BID + Lupron 3.75 mg SQ monthly)	Regimen B (Estradiol valerate 0.5 mg SQ weekly + spironolactone 100 mg PO BID + Lupron 3.75 mg SQ monthly)	Regimen B (Prior to surgery + DST)	Regimen B (1 month after right orchiectomy)	Regimen A (2 months after right orchiectomy)	Reference Levels
Estradiol (pg/mL)	146	186		449	133	10-40 pg/ml; 36.7-146.8 pmol/L (men)
(pmol/L)	536	682		1648	488	15-350 pg/mL; 55.1-1284.8 pmol/L* (women) (*levels vary widely through menstrual cycle)
LH (mIU/ mL)	<0.007	<0.007		<0.007		1-9 (men)
(IU/L)						1.0-18.0 (follicular); 20.0-80.0 (midcycle); 0.5- 18.0 mIU/mL (luteal) (women)
FSH (mIU/ mL)	<0.10	<0.10		<0.10		1-13 (men)
(IU/L)						2.0-12.0 (follicular); 4.0-36.0 (midcycle); 1.0-9.0 (luteal) (women)
Total T (ng/ dL)	131	163	232	24.77	8	300-1200 ng/dL; 10.4-41.6 nmol/L (men)
(nmol/L)	4.55	5.66	8.05	0.86	0.28	8-60 ng/dL; 0.3-2.1 nmol/L) (women)
Free T (ng/ dL)	3.08	2.72	4.28		0.14	9.0-30.0 ng/dL; 0.31-1.04 nmol/L) (men)
(nmol/L)	0.106	0.09	0.14		0.004	0.3-1.9 ng/dL; 0.01-0.07 nmol/L (women)
Bioavailable T (ng/dL)	64.6	53.6	89.9		2.7	72.0-235.0 ng/dL; 2.50-8.15 nmol/L (men: aged 30-39 years)
(nmol/L)	2.238	1.854	3.117		0.09	0.8-4.0 ng/dL; 0.03-0.14 nmol/L) (aged 20-50 years, women on oral estrogen); 0.8-10.0 ng/dL; 0.03-0.35 nmol/L (aged 20-50 years, women not on oral estrogen) 10-60 (men)
SHBG (nmol/L)	12	22	19		18	20-130 (women)
17-OH progesterone (ng/dL)		109	79			<220 ng/dL; <6.67 nmol/L (men)
(nmol/L)		3.77	2.7			<80 ng/dL; <2.42 nmol/L (follicular); <285 ng/dL; <8.64 nmol/L (luteal) (women)
DHEAS (µg/ dL)		649	457			65-334 µg/dL; 1.76-9.05 µmol/L (men: aged 30-39 years)
(µmol/L)		17.52	12.34			31-228 µg/dL; 0.84-6.78 µmol/L (women: aged 30-39 years)
Androstenedione (ng/ dL)		34	18			65-210 ng/dL; 2.27-7.33 nmol/L) (men)
(nmol/L)		1.1	0.62			80-240 ng/dL; 2.79-8.38 nmol/L (women)
Morning cortisol (ug/dL)			1.1			5-25 μg/dL; 137.9-689.7 nmol/L
(nmol/L)			30.35
β‐hCG (IU/L)		12		<1		0-3
LDH (U/L)		164		189		125-243
AFP (ng/mL)		<2		<2		2-15

The first 2 columns show hormone levels during the presurgery regimen before (regimen A) and after (regimen B) increasing the dose of estradiol valerate. The third column shows hormone levels after 48 hours of dexamethasone suppression (cortisol was appropriately suppressed). Column 4 shows values after surgery while still on regimen B. Column 5 demonstrates hormone levels after retuning the HT to the lower dose of estrogen (regimen A).

Abbreviations: 17-OH, 17-hydroxyprogesterone; AFP, α‐fetoprotein; β-hCG, BID, twice per day; DHEAS, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; FSH, follicle-stimulating hormone; LDH, lactate dehydrogenase; LH, luteinizing hormone; PO, orally; SBG, SQ, subcutaneous; T, testosterone.

Adrenal testing revealed an elevated dehydroepiandrosterone sulfate (DHEAS) level at 649 µg/dL (1761 µmol/L) with normal 17-hydroxyprogesterone and androstenedione levels. Since the DHEAS was elevated, she underwent a 48-hour 2-mg dexamethasone suppression test, which showed appropriate suppression of both cortisol and DHEAS with a dexamethasone level of 231 ng/dL. Computerized tomography (CT) of the abdomen with adrenal protocol revealed no adrenal nodules. Our search for ectopic gonadotropin secretion revealed an elevated concentration of β‐hCG, a well-known tumor marker, at 12 IU/L (reference range: 0-3 IU/L). Other tumor markers including lactate dehydrogenase and α‐fetoprotein (AFP) were not elevated. Subsequently, scrotal ultrasound revealed a 3.2-cm right testicular mass (Fig. 1A and 1B). Positron emission tomography/CT was reported as showing focal increased activity in the region of the right testicular mass described on ultrasound, with an elevated maximum standardized uptake value at 6.26 (Fig. 2).

Figure 1.

Testicular ultrasound (A = left testicle, B = right testicle) revealed 3.2 × 2.1 × 2.7 cm mass on right testis, described as a heterogeneous echogenicity vascular mass in the mid to inferior right testis. The left testis was normal. The color Doppler showed normal vascularization of the left testicle, while there was an increase in vascularity of the right testicle. Note that the colors on the Doppler images depend on the direction of the blood. If the blood is moving toward the transducer, a red color will be seen. However, a blue color means the blood is streaming away from the transducer (Note: blue and red does not necessarily mean low oxygen and high oxygen in the blood, respectively).

Figure 2.

PET/CT scan (LEFT = transverse view, RIGHT = sagittal view) revealed focal increased activity localized to the inferior aspect of the right testis, corresponding to the 3.2-cm mass demonstrated on previous ultrasound. SUV_max was 6.26 (reference level: average: SUV_max of the testicles 3.42 ± 0.61). CT, computed tomography; PET, positron emission tomography, SUV_max, maximum standardized uptake value.

She was referred to our urology service and underwent right radical orchiectomy. Pathological examination revealed a 3.1 × 3.1 × 2.3 cm seminoma within the right testis, without vascular or capsular invasion and with surgical margins free of tumor. No lymph nodes were removed. Immunohistochemical stains were strongly positive for OCT3/4, SALL4, D2-40, and CD117, which confirmed the diagnosis of seminoma. The seminoma was classified as pT1b, Nx, M0 (Fig. 3A and 3B).

Figure 3.

Pathology of right testicular mass (A = seminoma, B =OCT3/4 stain). Immunohistochemical stains for OCT3/4, SALL4, D2-40, CD117, CD30, and inhibin were performed by integrated oncology of Phoenix, AZ. The tumor was strongly positive for OCT3/4, SALL4, D2-40, and CD117. It was negative for inhibin and showed only focal weak staining for CD30. These results confirm the diagnosis of seminoma.

Results of relevant laboratory testing before and after surgery are shown in Table 1. Subsequently, we reduced her dose of estradiol valerate back to 0.25 mg SQ once weekly and continued both spironolactone and leuprolide, resulting in goal serum T and estradiol levels. Six months later, she reported improved satisfaction with her feminization, which included an increase in breast tissue and a decrease in facial hair, with a softer skin. She also felt that the pitch of her voice was higher, a finding we could not confirm. Spironolactone was discontinued afterward, while HT with estradiol valerate and leuprolide were maintained.

2. Discussion

Testicular carcinoma is the most common malignancy affecting biological men aged between 15 and 35 years. Family history of testicular cancer is associated with higher incidence. However, the exact etiology is still not clearly understood [8, 9]. Environmental factors, high estrogen concentration in utero, and testicular trauma have been suggested as potential risk factors. The majority of testicular cancers present as painless masses so that absence of symptoms can delay diagnosis. Rarely do patients have other clinical manifestations such as gynecomastia [10]. Patients often remain asymptomatic until tumor burden is high and metastasis has occurred. The most common site of metastasis is to the lymph nodes in the abdomen, but metastasis to the lungs, liver, bones and brain can occur [8, 11, 12].

Upon suspicion of a testicular tumor, scrotal ultrasound should be the first diagnostic imaging study [13]. Tumor markers, including AFP, β‐hCG, and lactate dehydrogenase should be ordered for evaluation and differentiation of the type of testicular tumors. Less than 20% of patients with pure seminoma have elevated β‐hCG. Moreover, AFP is usually not elevated in these patients. Other imaging studies such as CT scan of the abdomen, chest, and pelvis are routinely performed to rule out metastasis [8, 9]. Treatment with chemotherapy, radiotherapy, or surgery is prescribed according to the histological subtype and stage. In most cases, pure seminoma is discovered in an early stage, and its prognosis is generally excellent [8, 9, 14].

The person described in this report has gender incongruence defined as a self-perceived gender identity that differs from external sexual anatomy at birth. Transgender individuals should have their gender incongruence evaluated by qualified medical providers with expertise in the diagnostic criteria. Prior to initiating HT and/or surgical treatment, clinicians should counsel the transgender person about risks and benefits, including expectations and timing of physical changes [1, 15, 16]. The Endocrine Society Clinical Practice Guidelines published in 2017 recommend transgender women HT consists of anti-androgen treatment (eg, spironolactone, GnRH agonists) and estrogen. Some authors have suggested prescribing oral micronized progesterone therapy to transgender women since premenopausal women experience high levels of both estradiol and progesterone during the normal menstrual cycle. Progesterone is believed to have beneficial effects including improvement of the bone density, suppression of gonadal androgen, optimal breast maturation, and improvement in cardiovascular physiology [12, 17]. The guidelines recommend routine hormone monitoring. For transgender women, serum T and estradiol levels should be measured every 3 months in the first year. The goals are serum T levels less than 50 ng/dL and serum estradiol levels in the range of 100 to 200 pg/mL for the premenopausal age group and 40 to 60 ng/dL for the postmenopausal group. Breast development and feminization of habitus should occur within 6 to 18 months [12, 18, 19]. Persistently elevated T levels despite HT warrant evaluation for ectopic sources, including testicular cancer and adrenal tumors or hyperplasia [4-6].

Meerwijk et al [1] suggested a current transgender US population size of 390 adults per 100 000. Because the overall incidence of testicular germ cell tumors is low, at only 1% to 2% of all malignancies in men, testicular carcinoma/seminoma incidence in the transgender population is expected to be low [1]. Hyperandrogenism is usually easily diagnosed in biological women, given the more obvious clinical features. It is more challenging to diagnose hyperandrogenism in transgender women. Previous published reports similar to ours include one by Wolf-Gould [5] of an in-situ germ cell testicular carcinoma detected 22 months after initiation of gonadotropin suppressive therapy and one by Kobori et al [6] of a mature testicular teratoma discovered 2 years after HT initiation, when she complained of a right 5-cm testicular mass. Additionally, Kvach et al in 2019 [7] reported a 2.1-cm testicular seminoma (non–hCG-secreting), which was incidentally discovered after an inversion vaginoplasty for gender-confirming surgery This transgender woman had been on HT for almost 2 years, however her T level had been elevated (125 ng/dL) despite spironolactone and bicalutamide therapy.

The transgender woman described in this case report failed to evolve the anticipated physical changes and maintained male normal T levels despite adequate dose of HT for 1.5 years. This prompted further investigations, leading to the discovery of elevated β-hCG and a right testicular mass, after which diagnosis of testicular cancer was confirmed. No metastasis was found on positron emission tomography/CT. Surgical right radical orchiectomy was curative and was followed by normalization of T levels with clinical improvement and increase in her feminization.

In summary, this case report documents detection of an hCG-secreting testicular neoplasm due to appreciation of an anomalously elevated T level in a transgender woman treated with a GnRH analogue that clearly suppressed her luteinizing hormone level. Detection of such otherwise asymptomatic tumors may be critical for improved survival of patients with testicular carcinoma. In fact, survival rates after diagnosis of a testicular carcinoma have improved dramatically over the last few years despite an increase in tumor incidence, especially in the northern European population [20, 21].

3. Conclusion

This case emphasizes that HT in transgender women requires regular surveillance as the latest guidelines recommend. The nonsuppressed T level led to additional evaluations that ultimately revealed testicular cancer, highlighting the importance of routine biochemical workup and physical examination in hormone-treated transgender persons.

Glossary

Abbreviations

AFP

α‐fetoprotein

β‐hCG

beta unit of human chorionic gonadotropin

CT

computerized tomography

DHEAS

dehydroepiandrosterone sulfate

GnRH

gonadotropin-releasing hormone

HT

gender-affirming hormone therapy

SQ

subcutaneous injection

T

testosterone

Additional Information

Disclosure Summary: All authors declare no conflict of interest.

We declare that the manuscript is original, has not been published before, and is not currently being considered for publication elsewhere. We know of no conflict of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. As corresponding author, I confirm that the manuscript has been read and approved for submission by all the named authors.

Data Availability: All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.