CASE REPORT
Open Access
☒ CrossMark
A rare case of pure testosterone-secreting adrenal adenoma in a postmenopausal elderly woman
Wei-bin Zhou1, Nan Chent and Cheng-jiang Li”ID
Abstract
Background: Hyperandrogenemia is more common in puberty and reproductive age, but relatively rare in postmenopausal women. Postmenopausal virilization may result from androgen-producing tumors. Androgen- secreting adrenal tumors are rare in clinical practice and are diagnosed as adrenocortical carcinoma, most of which can co-secrete androgen and cortisol. Highly elevated serum testosterone level with normal adrenal androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione is usually regarded as ovary origin. Here we describe an unusual case of a postmenopausal woman with markedly elevated serum testosterone level, while DHEAS, androstenedione, 17-hydroxyprogesterone and cortisol were within the normal range.
Case presentation: A 67-year-old postmenopausal woman with hirsutism in the upper lip and armpit, accompanied by clitoromegaly for 5 months. Hormonal evaluation showed markedly elevated serum testosterone level (714.8 ng/ml), whereas DHEAS, androstenedione, 17-hydroxyprogesterone, and cortisol were within the normal range. Imaging examination showed a mass of 1.5 cm in diameter in the left adrenal gland and normal appearance of both ovaries. PET-CT indicated that it was a case of benign adrenal adenoma and excluded ovarian abnormalities and other ectopic tumors. Thus, a pure testosterone-secreting adrenal tumor was suspected and then adrenalectomy was performed. Histology and immunohistochemistry furtherly confirmed the benign adrenocortical adenoma with immunohistochemistry positive for inhibin a, melan A, ß-captenin, SYN (focal), Ki-67(< 3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. After surgery, the level of testosterone returned to normal range and the clinical symptoms also subsided.
Conclusions: Pure testosterone-secreting adrenal adenomas are extremely rare, but it can induce severe hyperandrogenism and virilization. The source identification of hyperandrogenemia only based on the levels of testosterone, DHEAS and androstenedione is limited. It is important to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.
Keywords: Hyperandrogenism, Postmenopause, Adrenal tumors, Testosterone, Immunohistochemistry
* Correspondence: hzcjli03@zju.edu.cn
+Wei-bin Zhou and Nan Chen contributed equally to this work.
Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang 310003, Hangzhou, China
☒ BMC
Background
Hyperandrogenemia is more common in adolescence and childbearing age, but relatively rare in postmenopausal women. Due to the lack of clinical and epidemiological data of postmenopausal women with hyperandrogenemia, the clinical diagnosis and treatment are often difficult. A highly elevated testosterone level and manifestations of hyperandrogenism such as hirsutism and virilization in a postmenopausal woman strongly suggest the potential androgen-producing tumor [1]. Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione are mainly produced in the adrenal glands. The increased DHEAS was used as a marker of in- creased adrenal activity, so the circulating DHEAS level has been used to screen androgen from ovary or adrenal gland [2]. Functional adrenal tumors mainly include those secreting aldosterone or cortisol, and a few secreting both cortisol and androgen, but pure androgen-secreting ad- renal tumors (PASATs) are rare, most of which are re- ported as case studies, and this kind of PASATs that only secrete testosterone with normal adrenal androgens (DHEA, DHEAS and androstenedione) are more rare [3]. Herein, we report a case of benign androgen-secreting ad- renal tumor in a postmenopausal elderly woman, with markedly elevated testosterone levels while DHEAS and androstenedione were within normal range.
Case presentation
A 67-year-old postmenopausal woman with hirsutism of increased hair around the upper lip and armpit and clitor- omegaly for five months was referred to the endocrinology clinic of our hospital. She had normal physiological devel- opment during her infancy and childhood, and also has a normal sexual life with no other medical history. Her me- narche was at 18 years old, and her menopause at age of 56. She had a normal menstrual history before menopause and had no postmenopausal bleeding. She had two healthy children and no miscarriages. She denied taking estrogen, progesterone or health care products. There are no similar patients in her family.
On physical examination, she was 153 cm tall and weighed 53 kg with body mass index of 22.6 kg/m2. In- creased hair was observed in her upper lip and armpit (Ferriman- Gallwey score of 8), and a physical examin- ation of genital revealed clitoromegaly. There was no acne, deepening of the voice or other virilization signs. Findings on examination of the head and neck, breasts and abdo- men were unremarkable. She had no signs of Cushing syndrome, or acanthosis nigricans syndrome.
The hormonal test showed high total testosterone levels (714.8 ng/dL, reference value 14-56). Serum DHEAS (145.8 ng/ml, reference value 25.9-460.2), androstene- dione (2.4 ng/ml, reference value 0.3-3.3) and 17-hy- droxyprogesterone (1.7 nmol/l, reference value 0-11.5)
levels were within normal range. The serum values of follicle-stimulating hormone, luteinizing hormone, and prolactin were also within the normal range for the meno- pause. The levels of anti-mullerian hormone, human chorionic gonadotropin (hCG), thyroid- stimulating hor- mone (TSH), plasma renin activity and aldosterone, adre- nocorticotropic hormone (ACTH), serum cortisol, 24-h urinary free cortisol, and 1 mg dexamethasone suppres- sion test were in normal range. The ovarian tumor markers (Ca 125, CEA, Ca 199) were in normal reference range. The repeated samples confirmed that her high tes- tosterone levels were within the tumor range. We ex- cluded overt Cushing Syndrome on the basis of normal cortisol suppression after 1 mg dexamethasone and nor- mal urinary free cortisol levels, as recently proposed by Ceccato F [4]. Then a middle dosage dexamethasone test (0.75 mg, 4 times a day for 5 consecutive days) without testosterone inhibition strongly suggested the potential androgen-producing tumor, further examinations were needed to distinguish ovarian or adrenal origin of hyperandrogenemia.
Initially, the lack of co-secretion of DHEAS and andro- stenedione indicated that her elevated testosterone might be of ovarian origin. However, pelvic ultrasound disclosed that there was no ovarian mass, while adrenal ultrasound showed a hypoechoic nodule in the left adrenal gland. Fur- ther pelvic magnetic resonance image (MRI) showed sub- mucous myoma of uterus, but no abnormal of ovarian, and adrenal CT scan was also performed and a left adrenal mass of about 1.5 cm in diameter was revealed (Fig. 1 a and b). PET-CT confirmed a round nodule in the external branch of the left adrenal gland with slight increase in FDG metabolism (the SUV max of the nodule was 2.56), considering the possibility of benign adenoma. No ovarian abnormalities or other ectopic tumors were found by PET-CT.
Based on the clinical characteristics, hormone detection and imaging appearances of the case, pure testosterone- secreting adrenal tumor was suspected. Subsequently, the patient underwent a laparoscopic resection of left adrenal tumor. Histological examination (Fig. 2 a) and immuno- histochemistry also confirmed the diagnosis of benign ad- renocortical adenoma with immunohistochemistry po sitive for inhibin a, melan A, ß-captenin (Fig. 2 b-d), SYN (focal), Ki-67 (<3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. The level of testoster- one decreased to 15.8 ng/dl on the 3rd day after operation, and the symptoms of virilization were alleviated during the follow-up, which further confirms the adrenal etiology of the testosterone production.
Discussion and conclusions
The postmenopausal female with elevated androgens may present with symptoms of hirsutism and virilization.
A
B
Fig. 1 Adrenal CT (a) and enhanced CT (b) identified a left adrenal mass, 1.5 cm in diameter (Arrow). CT = computed tomography
Hirsutism is defined as excessive terminal hair that ap- pears in a male pattern. Virilization includes balding, deepening of the voice, cystic acne and clitoromegaly. The main androgens in women are testosterone, di- hydrotestosterone, DHEA, DHEAS and androstene- dione. Among them, testosterone is the most active and also plays an important physiological role. One fourth of testosterone is synthetized in the adrenal gland, one fourth in the ovaries and a half produced from the per- ipheral conversion of their precursors (androstenedione, DHEAS, DHEA) [2]. The major androgens secreted by adrenal cortex are DHEA and its sulfate (DHEAS), and androstenedione while only a small amount of testoster- one was directly synthesized by adrenal cortex [5]. Therefore, the increase of serum DHEA, DHEAS, andro- stenedione is generally regarded as adrenal origin, and isolated elevated testosterone is usually thought to
originate from the ovary in women with hyperandrogen- emia [6]. The main differential diagnosis of hyperandro- genemia is either tumoral causes, namely androgen -secreting ovarian or adrenal tumors, or non-tumoral causes, such as polycystic ovarian syndrome, Cushing’s syndrome, congenital adrenal hyperplasia, and iatrogen- esis. The postmenopausal woman with rapid progression of clinical symptoms or highly elevated testosterone levels should be suspected of androgen-producing tu- mors [1, 7]. In postmenopausal woman, ovarian causes of hirsutism and virilization are more common than ad- renal origin, while the adrenal etiology of androgen pro- duction was confirmed in our case. Androgen-secreting adrenal tumors, most of which co-secrete androgen and cortisol, are rare in clinical practice and often diagnosed as adrenocortical carcinoma, while pure androgen-se- creting adrenal tumors (PASATs) are more rarely.
A
B
C
D
Moreno et al. [8] reviewed 801 adrenalectomies from 1970 to 2003, only 21 cases were due to PASATs, while all these PASATs had elevated testosterone and DHEAS.
It can be seen from above that PASATs are rare and usually accompanied by a concomitant increase in com- mon adrenal androgens such as DHEA, DHEAS, and androstenedione. Our case is unusual, for that testoster- one levels were within tumor range, while the serum DHEAS, androstenedione levels were normal. The im- aging results, postoperative pathology and postoperative normal testosterone levels confirm the adrenal etiology of the androgen production. As to our knowledge, very few cases of PASATs that only secrete testosterone had been reported [9-12]. From these cases, we find that ad- renal tumors secreting testosterone often have low ma- lignant potential and misdiagnosed as ovarian disease due to its normal DHEAS levels. Surgical resection has a good effect on treatment of these tumors, but none of them did immunohistochemistry to confirm the nature of these tumors. In our case, immunohistochemistry showed that the tumor was positive for inhibin a, melan A, SYN (focal +), Ki-67 (<3%), negative for CK, CgA, S-100, which supported benign adrenocortical adenoma.
The exact pathogenesis of these testosterone-secreting adrenal tumors is unclear. In healthy individuals, circu- lating DHEAS levels are known to reach a peak in the early 20s, and decrease linearly thereafter [13]. Carlos Morán et al. [14] found that such an age-related de- crease of DHEAS levels also exists in hyperandrogen- emia patients. Therefore, we speculate that DHEAS levels may tend to be not high in elder women with PASATs. Aguirre [15] suggested that testosterone-only adrenal tumors may actually originate from translocated gonadal cells. From 1981 to the present, to our know- ledge, a total of 4 cases of adrenal adenoma secreting an- drogen were reported to have been found the specific Reinke crystallization of Leydig cells, suggesting the pos- sibility of differentiation into Leydig cells during the process of tumorigenesis and development of tumor cells [11, 16-18]. In this case, we didn’t find Reinke crystallization. However, the absence of these inclusions does not exclude a Leydig cell character, because those inclusions are present in only 40% of Leydig cell tumors and the immunohistochemistry of our patient revealed that the tumor was positive for inhibin a. Inhibin a was a commonly used immunohistochemical index for diag- nosis of Leydig’s cell tumor, even the specificity of in- hibin a is limited since it is also expressed in adrenal cortical tumors. Besides, it was revealed that ß-catenin over-expression might be also involved in the tumori- genesis of these pure testosterone-secreting adrenal adenomas.
When hirsutism accompanied by virilization signs such as severe balding and clitoromegaly appear in
postmenopausal women, an underlying androgen-secre ting tumor should be suspected. Adrenal tumors secret- ing only testosterone with no concomitant increase of common adrenal androgens such as DHEA, DHEAS, and androstenedione are extremely rare. This case re- ports an unusual case of a postmenopausal woman with a pure testosterone-secreting adrenal adenoma and shows that in the daily clinic, the source identification of hyperandrogenemia only based on the levels of testoster- one, DHEAS and androstenedione is limited. The suspi- cious patients are recommended to receive a thorough pelvic examination and adrenal imaging examinations. The testosterone secreting tumors are able to induce se- vere hyperandrogenism and virilization, and laparoscopic resection provides a very effective treatment. PET-CT is helpful in differentiating benign or malignant testostero- ne-secreting adrenal tumors and excluding ectopic tumors.
In conclusion, our case indicates the importance to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.
Abbreviations
ACTH: Adrenocorticotropic hormone; CgA: Chromogranin; CK: Cytokeratin; DHEA: Dehydroepiandrosterone; DHEAS: Dehydroepiandrosterone sulfate; hCG: Human chorionic gonadotropin; MRI: Magnetic resonance image; PASATs: Pure androgen-secreting adrenal tumors; SUV: Standard uptake values; TSH: Thyroid- stimulating hormone
Acknowledgements
Research project of Zhejiang Provincial Education Department (Y201737212 to WZ), Zhejiang medical science and technology projects (2018KY056 to WZ).
Funding
No funding was required for the reporting of this work.
Availability of data and materials
The datasets supporting the conclusions of this article is included within the article and in figures.
Authors’ contributions
WZ and NC were involved in acquisition of data and drafting the manuscript. LJ is corresponding author and organized the study. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was carried out in accordance with the Helsinki Declaration and approved by the the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. Written informed consent was obtained from all participants.
Consent for publication
Written informed consent to publish has been obtained from the person described in this case report and study participants.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Received: 15 November 2018 Accepted: 14 January 2019 Published online: 23 January 2019
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