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SYSTEMATIC REVIEW article

Front. Endocrinol., 22 March 2023

Sec. Adrenal Endocrinology

Volume 14 - 2023 | https://doi.org/10.3389/fendo.2023.1138114

Pure androgen-secreting adrenal tumor (PASAT): A rare case report of bilateral PASATs and a systematic review

  • 1. Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

  • 2. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

  • 3. Department of Urology, Hainan General Hospital, Haikou, China

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Abstract

Background:

Adult pure androgen–secreting adrenal tumors (PASATs) are extremely rare, and their characteristics are largely unknown.

Methods:

A rare case of adult bilateral PASATs was reported, and a systematic literature review of adult PASATs was conducted to summarize the characteristics of PASATs.

Results:

In total, 48 studies, including 40 case reports and 8 articles, were identified in this review. Analysis based on data of 42 patients (including current case and 41 patients from 40 case reports) showed that average age was 40.48 ± 15.80 years (range of 18-76). The incidence of adult PASAT peaked at 21-30 years old, while that of malignant PASAT peaked at 41-50 years old. Most PASAT patients were female (40/42, 95.23%), and hirsutism was the most common symptom (37/39, 94.87%). Testosterone (T) was the most commonly elevated androgen (36/42, 85.71%), and 26 of 32 tested patients presented increased dehydroepiandrosterone sulfate (DS) levels. In malignancy cases, disease duration was significantly decreased (1.96 vs. 4.51 years, P=0.025), and tumor diameter was significantly increased (8.9 vs. 4.9 cm, p=0.011). Moreover, the androgen levels, namely, T/upper normal range limit (UNRL) (11.94 vs. 4.943, P=0.770) and DS/UNRL (16.5 vs. 5.28, P=0.625), were higher in patients with malignancy. In total, 5 out of 7 patients showed an increase in DS or T in the human chorionic gonadotropin (HCG) stimulation test. Overall, 41 out of 42 patients (including current case) underwent adrenal surgery, and recurrence, metastasis, or death was reported in 5 out of 11 malignant patients even with adjuvant or rescue mitotane chemotherapy.

Conclusion:

Adult PASAT, which is predominant in women, is characterized by virilism and menstrual dysfunction, especially hirsutism. Elevated T and DS may contribute to the diagnosis of adult PASAT, and HCG stimulation test might also be of help in diagnosis. Patients with malignant PASAT have a shorter disease duration, larger tumor sizes and relatively higher androgen levels. Surgery is recommended for all local PASATs, and Malignancy of PASAT should be fully considered due to the high risk of malignancy, poor prognosis and limited effective approaches.

Introduction

The adrenal gland is a complex structure consisting of an inner adrenal medulla and an outer adrenal cortex. Adrenal steroid hormones are synthesized in the following three zones: aldosterone in the zona glomerulosa (ZG); glucocorticoids (particularly cortisol) in the zona fasciculata (ZF); and androgens and estrogens in the zona reticularis (ZR). Aldosterone production is regulated by the renin–angiotensin–aldosterone system, while the synthesis of cortisol and androgens is modulated by the hypothalamic−pituitary−adrenal (HPA) axis (1). The primary function of adrenocorticotropic hormone (ACTH) is to stimulate cortisol and adrenal androgen secretion by increasing their synthesis. The negative feedback from circulating cortisol suppresses the release of corticotropin-releasing hormone (CRH) and ACTH, but adrenal androgens do not have similar suppressive effects on the HPA axis. Compared to cortisol- and aldosterone-secreting tumors, androgen-secreting adrenocortical tumors are less common. Adrenocortical tumors, including androgen-secreting tumors, in children have been investigated in previous studies (2–4), but androgen-secreting adrenal tumors in adults, especially pure androgen–secreting adrenal tumors (PASATs), which are usually reported as case reports or case series, are rare. In the present study, we report a rare case of adult bilateral PASATs and conduct a systematic review of adult PASATs.

Case presentation

A 28-year-old woman was admitted to our hospital in 2022 due to oligomenorrhea and then amenorrhea. The patient (menarche at 13 years) had regular menstruation with a menstrual cycle of 30-40 days and a menstrual period of 6-7 days. The patient’s menstrual cycle then shortened, and her menstrual bleeding gradually decreased from 2012. At that time, her testosterone (T) level was within the normal range according to her statement. Finally, amenorrhea occurred despite the administration of estrogen and progesterone drugs. In 2015, the T level increased to 0.91 ng/ml (normal: 0.10-0.75) despite dydrogesterone administration, and ultrasound indicated polycystic morphology in bilateral ovaries. Polycystic ovary syndrome (PCOS) was considered by physicians of other hospitals, and contraceptive drugs were prescribed. During 2019-2020, the patient presented with clitoromegaly, mild hirsutism (Ferriman–Gallwey score of 9) and amenorrhea. At the same time, bilateral adrenal tumors were reported incidentally by computed tomography (CT) in a health examination.

An endocrine investigation in 2021 showed that the patient’s T levels continued to increase to 1.61 ng/ml (Table 1). In addition, androstenedione (AND), dehydroepiandrosterone sulfate (DS) and 17α-hydroxypregnenolone (17OHP) also increased to 25.67 ng/mL (normal: 0.30-2.00 ng/mL), 12,260 ng/mL (normal: 830-3,770 ng/mL) and 2.49 ng/ml (normal: 0.10-2.30 ng/ml), respectively, in the patient. The ACTH level (8 am) of this patient was 28.9 pg/ml (normal: 7.2-63.3). Both the cortisol level (10.0 µg/dl, normal: 4-22) and 24-h urinary free cortisol level (52.0 µg/24 hr, normal: 12.3-103) were normal. The cortisol level was suppressed (<1.8 µg/dl) by the 48-h low-dose dexamethasone-suppression test (0.5 mg orally every 6 hours for a total of eight doses). In addition, the levels of plasma aldosterone, catecholamine and sexual hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH) and oestradiol, were normal. The patient underwent ACTH stimulation test, and the 17OHP level was 3.89 ng/ml at 60 minutes after administering cosyntropin (0.25 mg), which basically excluded classic and nonclassic congenital adrenal hyperplasia (CAH) according to the endocrine society clinical practice guidelines (17OHP <10 ng/ml) (5, 6). The patient’s bilateral adrenal tumors were gradually enlarged (Figure 1A) and were considered to be responsible for hyperandrogenism. The patient’s right adrenal tumor was removed by laparoscopic partial adrenalectomy at another hospital, and adrenocortical adenoma was identified according to pathological findings.

Table 1

T
(ng/mL)		 AND
(ng/mL)		 DHEA
(ng/mL)		 DS
(ng/mL)
Before surgery 1.61 25.67 ND 12260
After right adrenal tumorectomy 1.01 6.44 23.8 11802
After left adrenalectomy 0.09 0.42 2.4 124
Reference range 0.08-0.60 0.30-2.00 <13 830-3770

Changes of androgens before and after two surgeries.

T, testosterone; AND, androstenedione; DHEA, dehydroepiandrosterone; DS, dehydroepiandrosterone sulfate; ND, not detected.

Figure 1

Figure 1

(A) CT image of bilateral adrenal tumors. (B) CT image of the left adrenal tumor after right adrenal tumorectomy. (C) Surgical specimen of the left adrenal tumor. (D) Haematoxylin and eosin staining of the left adrenal tumor (magnification×20).

Because the patient’s amenorrhea was not relieved, she was admitted to our hospital and underwent further endocrine and imageological examination (Figure 1B). The patient’s testosterone (T), androstenedione (ADN) and dehydroepiandrosterone sulfate (DS) levels were partly decreased but still above the normal range (Table 1). Adrenal steroid hormone tests indicated that pregnenolone and dehydroepiandrosterone (DHEA) were also elevated in addition to T, DS, AND and 17OHP, while the levels of steroids located in the cortisol and aldosterone synthesis pathways were normal (Figure 2). Bilateral ovarian venous sampling (OVS) and left adrenal venous sampling (AVS) were conducted (Figure 3). The left selectivity index (SI, defined as the ratio of cortisol concentration for each adrenal vein and infra-adrenal inferior vena cava or a peripheral vein) was 5.02, which indicated successful catheterization (more than 2:1 without stimulation cosyntropin use) (7). The levels of androgens, including T, ADN, DS and DHEA, in the left adrenal vein were higher (Figure 3), which indicated that excessive androgens were produced by the left adrenal gland rather than the ovaries. The patient underwent left laparoscopic adrenalectomy in our hospital, and the surgical specimen was showed in Figure 1C. The histopathologic examination confirmed the diagnosis of adrenocortical adenoma (Figure 1D). Two weeks after surgery, the levels of T, ADN and DHEA decreased to within the normal range, and the DS level decreased to below the normal level (Table 1). Then DS level returned to the normal range within 3 months. The patient’s menstruation recovered to normal in 2 months after surgery, and no recurrence or metastasis was detected nearly one year after surgery.

Figure 2

Figure 2

Exclusively increased steroid hormones in the androgen-producing pathway in the patient. DHEA, dehydroepiandrosterone; DS, dehydroepiandrosterone sulfate.

Figure 3

Figure 3

Bilateral ovarian venous sampling (OVS) and left adrenal venous sampling (AVS).

Methods

A systematic review of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 4). The following search strategy was used in the PubMed online database until December 2022: (“androgen”[Title/Abstract] OR “hyperandrogenism”[Title/Abstract] OR “virilism”[Title/Abstract]) AND (“adrenocortical”[Title/Abstract] OR “adrenal”[Title/Abstract]) AND (“tumor”[Title/Abstract] OR “carcinoma”[Title/Abstract] OR “adenoma”[Title/Abstract]) NOT (“children”[Title/Abstract] OR “child”[Title/Abstract] “childhood”[Title/Abstract] OR “paediatric”[Title/Abstract] OR “peripubertal”[Title/Abstract]). Only confirmed cases of adrenal tumors exclusively secreting androgens were included in this review. The exclusion criteria for studies were as follows: (1) age < 18 years; (2) excessive secretion of cortisol, aldosterone and catecholamine, especially cortisol, because cortisol and androgen are usually produced simultaneously in certain adrenal carcinomas or adenomas (only studies with evidence to show normal cortisol in the blood or urine were included); (3) hyperandrogenic status partly or completely caused by nonadrenal factors, including polycystic ovary syndrome (PCOS), idiopathic hyperandrogenism, hyperandrogenic insulin-resistant acanthosis nigricans syndrome (HAIRAN) and ovarian androgen-secreting neoplasms; (4) congenital adrenal hyperplasia (CAH); (5) basic science or animal experiments; (6) editorials, letters and consensus reports; (7) unavailable full text article; or (8) non-English studies.

Figure 4

Figure 4

PRISMA flow diagram.

The clinical data from the included studies were analyzed using GraphPad Prism (version 9; GraphPad Software, San Diego, California, USA).

Continuous data are presented as the mean ± standard deviation (SD), and Student’s t-test or the Mann−Whitney U test was utilized to compare the differences between the malignant and benign groups. A value of P<0.05 was considered statistically significant.

Results

In total, 48 studies met the inclusion criteria, including 40 case reports (8–47) and 8 articles (48–55). Forty case reports including 41 adult PASAT cases are summarized in Table 2, and 8 articles containing adult PASAT patients are summarized in Table 3. Statistical analysis was conducted on the data of 42 PASAT adult patients (including the present case) (Figures 5, 6).

Table 2

case year 1st author Sex Age(y) Duration (y) Hirsutism Clitoromegaly acne voice deepening alopecia Menstruation T/UNRL DHEA/UNRL DS/UNRL
1 1975 Blichert-Toft M F 27 2 yes – yes – yes normal 1.15 – –
2 1976 Larson BA F 76 3 yes yes – – yes menopause (GS) 11.41 – –
3 1977 Nogeire C M 23 – – – – – – – 0.44 10.50 5.20
4 1978 Smith HC F 50 5 yes yes yes yes yes menopause (aged) 4.35 – –
5 1980 Stephen W F 62 3 yes – – – yes menopause (aged) 5.49 – –
6 1981 Trost BN F 60 3 yes – yes yes – menopause (aged) 11.54 – –
7 1983 Vancouver F 29 3 yes yes yes yes – amenorrhea 2.47 – 1.95
8 1983 Fuller PJ F 33 7 yes yes – yes – normal 1.06 1.36 4.58
9 1983 Aguirre P F 58 10 yes yes yes yes yes menopause (aged) 3.35 – –
10 1984 Faggiano M F 20 – yes yes yes – – normal 1.39 – 2.54
11 1985 Vasiloff J F 49 7 yes – – yes yes menopause (GS) 14.08 0.15 –
12 1986 O'leary TJ F 30 – yes yes – – yes normal 2.23 – 4.29
13 1986 Pollock WJ F 60 4 yes – – yes – menopause (GS) 8.13 0.21 –
14 1987 Guillausseau PJ F 41 15 yes – – – – amenorrhea normal increased increased
15 1989 Clouston WM F 45 7 yes yes – – yes menopause (GS) 2.18 – 3.57
16 1991 Jeffrey A F 64 8 yes yes – – yes menopause (aged) 2.21 – 7.54
17-L 1992 Micić D F 22 5 yes – – – – amenorrhea 4.11 – 1.43
17-R
18 1992 Ruutiainen K-patient 1 F 30 1 yes yes – yes – normal 2.76 – 3.51
19 1992 Ruutiainen K-patient 2 F 41 1 yes – – yes yes oligomenorrhea 2.28 – 0.49
20 1995 Coonrod DV F 24 2 yes yes yes – – normal increased – normal
21 2000 Bozbora A F 23 0.25 yes – – – – amenorrhea 42.86 – 125.71
22 2007 Mavroudis K F 45 2 yes yes – yes yes – 1.78 – 0.66
23 2011 Amano T F 31 0.16 virilism (no details provided) amenorrhea increased – –
24 2012 Surrey LF F 55 – yes – – – yes – 14.11 – 1.58
25 2013 Rodríguez-Gutiérrez R F 18 10 yes yes – yes – amenorrhea 5.28 – 2.33
26 2013 Varma T F 42 7 yes yes – – yes amenorrhea 5.28 – 2.94
27 2013 Galketiya KP F 47 – yes – – – yes irregular 3.40 – 1.90
28 2015 Tetsi Nomigni M F 34 3 yes – – – – irregular 2.70 – 0.17
29 2015 Uruc F F 48 – – – – – yes – 1.19 – 5.30
30 2016 Ghorayeb NE M 50 – – – – – – – – – 1.80
31 2016 Carré J F 50 – yes yes – – – menopause (GS) 2.35 – 0.38
32 2018 LaVoie M F 26 0.75 yes – yes yes – amenorrhea 6.12 – 1.33
33 2019 Karimi F F 26 1.5 yes – – – – – – – 3.29
34 2019 Zhou WB F 28 3 yes yes – yes – amenorrhea 0.35 – 23.06
35 2019 Dotto RS F 67 0.42 yes yes – – – menopause (aged) 12.76 – 0.32
36 2020 Sailo SL F 20 5 yes yes – yes – amenorrhea increased – –
37 2020 Pinge SR F 57 – – – – – yes menopause (aged) 0.61 0.42 3.53
38 2021 Prachi F 29 3 yes – – – – irregular, amenorrhea 8.85 – 37.39
39 2021 Correia DN F 41 0.83 yes yes – yes – irregular 28.05 – 2.44
40 2022 Bao ZZ F 23 2 yes – yes – – irregular, oligomenorrhea 7.28 – 1.79
41 2022 Gopinath C F 68 1.50 yes – – – yes menopause (GS) 3.44 – 5.62
42-L current case F 28 7 yes yes – – – amenorrhea 2.21 – 3.14
42-R current case
case year 1st author AND/
UNRL		 location Side Tumor size(cm) surgery Pathology biobehavioral Outcome Follow-up time
1 1975 Blichert-Toft M – US, angiography R 8 tumor resection adenoma benign well 3m
2 1976 Larson BA normal AVS, OVS R 4 adrenalectomy adenoma benign well 2m
3 1977 Nogeire C – abdominal exploration R – tumor resection carcinoma malignant recurrence, metastasis, dead –
4 1978 Smith HC – – R 3.5 adrenalectomy adenoma benign – –
5 1980 Stephen W – – R 1 adrenalectomy adenoma benign – –
6 1981 Trost BN – AVS R 3 adrenalectomy adenoma benign well 2y
7 1983 Vancouver 0.88 CT L 3 adrenalectomy adenoma benign well 17m
8 1983 Fuller PJ 1.66 CT R 5 tumor resection adenoma benign – –
9 1983 Aguirre P – abdominal exploration R 3 adrenalectomy ganglioneuroma benign – –
10 1984 Faggiano M 0.86 X-ray, angiography L 4 adrenalectomy adenoma benign – –
11 1985 Vasiloff J 0.46 CT R 3 adrenalectomy adenoma benign – –
12 1986 O'leary TJ – CT R 7.8 tumor resection adenoma benign – –
13 1986 Pollock WJ – CT R 1.2 adrenalectomy adenoma benign well 2y
14 1987 Guillausseau PJ – CT, AVS L 10 adrenalectomy adenoma benign well 6y
15 1989 Clouston WM 6.00 CT L 6 tumor resection adenoma benign well 3y
16 1991 Jeffrey A – CT L 6 adrenalectomy adenoma benign – –
17-L 1992 Micić D 3.47 MRI, AVS, OVS L 5.5 adrenalectomy adenoma benign well 6m
17-R – R 5.4 adrenalectomy adenoma
18 1992 Ruutiainen – angiography R 10.5 adrenalectomy adenoma benign well 10m
19 1992 Ruutiainen – angiography R 3.5 adrenalectomy adenoma benign well 2.5y
20 1995 Coonrod DV – CT R 6.4 adrenalectomy carcinoma malignant well 8y
21 2000 Bozbora A 2.29 CT R 9 adrenalectomy carcinoma malignant metastasis, dead 8m
22 2007 Mavroudis K 1.21 MRI L 2.5 tumor resection adenoma benign – –
23 2011 Amano T – CT, SPE-CT, PET-CT L 5.8 adrenalectomy carcinoma malignant well 1y
24 2012 Surrey LF – CT, MRI L 7 tumor resection oncocytoma, myelolipoma benign – –
25 2013 Rodríguez-Gutiérrez R 3.70 CT L 9.5 adrenalectomy adenoma benign well 2m
26 2013 Varma T – CT L 9.6 tumor resection carcinoma malignant well 3m
27 2013 Galketiya KP – CT, PET-CT R 10 adrenalectomy carcinoma malignant well 1y
28 2015 Tetsi Nomigni M 3.47 CT, AVS, OVS R 2.6 Laparoscopic adrenalectomy oncocytoma benign well 3y
29 2015 Uruc F – US, MRI, PET-CT L 1.7 tumor resection carcinoma malignant mitotane ongoing. –
30 2016 Ghorayeb NE – MRI L 14.9 tumor resection carcinoma malignant metastasis, dead 3y
31 2016 Carré J 5.84 CT L 3.5 adrenalectomy oncocytic carcinoma malignant well 4y
32 2018 LaVoie M 2.17 MRI L 2.5 laparoscopic adrenalectomy adenoma benign well 1y
33 2019 Karimi F – CT L 15 non-resectable carcinoma malignant metastasis, dead –
34 2019 Zhou WB – CT L 7.1 tumor resection myelolipoma benign well 1.5m
35 2019 Dotto RS 0.73 ultrasound, CT, PET-CT L 1.5 laparoscopic tumor resection adenoma benign – –
36 2020 Sailo SL – CT R 7.1 adrenalectomy adenoma uncertain well 2m
37 2020 Pinge SR 0.65 CT R 3.8 adrenalectomy adenoma benign well 11m
38 2021 Prachi – US, CT, PET-CT R 8.1 laparoscopic adrenalectomy oncocytoma benign – –
39 2021 Correia DN – CT, PET-CT L 13.2 extensive surgery oncocytic carcinoma malignant metastasis, progressing 1m
40 2022 Bao ZZ 2.86 CT L 10 adrenalectomy oncocytic neoplasm uncertain well 4y
41 2022 Gopinath C – CT, PET-CT L 7.3 laparoscopic adrenalectomy adenoma benign well 7y
42-L current case 7.78 CT, AVS, OVS L 3.1 adrenalectomy adenoma benign well 1y
42-R current case R 2.5 tumor resection adenoma benign

Characteristics of adult PASAT: summary of case reports (including current case).

T, testosterone; AND, androstenedione; DHEA, dehydroepiandrosterone; DS, dehydroepiandrosterone sulfate; UNRL: upper normal range limit; GS: gynecological surgery. US, ultrasound; AVS, adrenal venous sampling; OVS, ovarian venous sampling; CT, computed tomography; PET-CT, Positron emissiontomography–computed tomography. R, right; L, left.

Table 3

year 1st author Time span(y) Measured androgens Adult PASAT (total subjects) average age Female (number) average size Bio
behavior		 Outcome
1988 Naganuma H – – 2 (19) 48.5 2 – 2 (B) –
1993 Gaudio AD 1960-1990 T, DS, AND, 17-KS 8 (190) 41.6 – – 6 (M)/2 (B) 4D, 2W (M)/
2W (B)
1998 Filipponi S 1994-1997 – 1 (50) – – – 1 (B) –
2000 Wajchenberg BL 1982-1999 – 4 (47) – – – 4 (M) –
2003 Gordera F 1946-2002 T, DS, AND, 17-KS 7 (11) 24.6(M)/
38.8(B)		 7 10.7 (M)/
4.2(B)		 3 (M)/4 (B) 1D, 2W (M)/
4 W (B)
2004 Moreno S 1970-2003 T, DHEA, DS, AND, 17-KS Unknown*(21) 45(M)/
34.5(B)		 21 14 (M)/
9 (B)		 10 (M)/11 (B) 5D, 3R&MS, 2 W (M)/
11W (B)
2011 Sarfati J 1995-2009 T, DS, AND 1 (22) – – – 1 (M) –
2017 Tong A 2002-2015 T, DS, AND 6 (9) 66(M)/
32.2(B)		 6 15 (M)/
5.3 (B)		 1 (M)/5 (B) 1 MS (M)/
4W(B)

Summary of articles containing adult PASAT.

T, testosterone; AND, androstenedione; DHEA, dehydroepiandrosterone; DS, dehydroepiandrosterone sulfate; 17-KS; 17-ketosteroid; R, reoccurrence, M, malignant group; B benign group; MS, metastasis; W, well (no recurrence or metastasis observed in the following time or till death).

*the adult and preadult patients can’t be distinguished in this article and the youngest age of patient is 15 years old.

Figure 5

Figure 5

Clinical characteristics of PASAT cases. (A) Age distribution. (B) Sex distribution. (C) Virilism symptoms. (D) Menstruation change. (E) Tumor side. (F) Tumor behavior.

Figure 6

Figure 6

Comparison of malignant and benign tumors. (A) Age differences. (B) Duration before diagnosis. (C) Tumor size. (D) Androgen level. T, testosterone; DS, dehydroepiandrosterone sulfate; UNRL, upper normal range limit. ns, not significant; * P<0.05.

The average ages of all patients, the malignant group and the benign group were 40.48 ± 15.80, 38.64 ± 10.62 and 43.17 ± 16.73 years, respectively. The incidence of adult PASAT peaked at 21-30 years old, followed by 41-50 years old, while the incidence of malignant PASAT peaked at 41-50 years old (Figure 5A). In addition, PASATs were predominantly found in women (40/42, 95.23%; Figure 5B).

Hirsutism was the most common symptom, and almost all female PASAT patients (37/39, 94.87%) presented with hirsutism (one patient’s virilism was not described in detail), followed by clitoral enlargement, alopecia, voice deepening and acne (Figure 5C). Menstrual dysfunction, including oligomenorrhea, irregularity and even amenorrhea, was reported in 42.5% of female patients, while 15% of female patients showed normal menstruation (Figure 5D). There was no difference in tumor location (left or right side) (Figure 5E), but there were only two bilateral PASATs, including the present case. Tumors showing benign or malignant biological behavior accounted for 71.43% and 26.19%, respectively, with 2 uncertain tumors (Figure 5F).

The age differences between the malignant and benign groups were not significant (Figure 6A). The duration in the malignant group was significantly shorter (Figure 6B) than that in the benign group (1.96 vs. 4.51 years, P=0.025), while the tumor diameter in the malignant group was significantly increased (8.9 vs. 4.9 cm, p=0.011) (Figure 6C). For comparison, the androgen level was demonstrated as androgen concentration/upper normal range limit (UNRL). T was elevated in 36 adult PASAT patients (85.71%). The androgen levels, shown as T/UNRL (11.94 vs. 4.943, P=0.770) and DS/UNRL (16.5 vs. 5.28, P=0.625), in the malignant group were much higher than those in the benign group, but the differences were not significant (Figure 6D).

The responses of T and DS to the endocrine test are shown in Table 4. In the ACTH/synacthen test, the androgen levels increased in two patients but did not change in two patients. In another patient, the level of DS increased, but T was unresponsive. In the current patient, T decreased, but DS increased. The androgen response to the low-dose or high-dose dexamethasone test was not coordinated in different patients, and there were also paradoxical T and DS responses in the same patient. Regarding HCG (human chorionic gonadotropin) stimulation, most patients (5/7) showed an increase in DS or T. Furthermore, T and DS were slightly increased in the gonadotropin-releasing hormone (GnRH) test in two patients.

Table 4

year 1st author Age Androgen(unit) basal line ACTH test DXM test HCG test GnRH
test
1975 Blichert-Toft M 27 T
(ng/ml)		 0.98 unresponsive unresponsive (Low dose) unresponsive (high dose) Increased to 1.53 (5d, under DXM) –
1978 Smith HC 54 T
(ng/ml)		 6.1-8 4.3→5.4(0.25mg over 8h, after DXM) 6.1 (2mgx7d) 4.4 (8mgx7d) Increased to 10 (3000IUx4d) –
1981 Trost BN 60 T
(nmol/l)		 22.2-27.7 – 29.8 (2mgx7d) – – –
1983 Vancouver 29 T
(ng/ml)		 173 – – 108 (8mgx3d) – –
DS
(ng/ml)		 6600 – – 6850 (8mgx3d) – –
1983 Fuller PJ 33 T (nmol/l) – – unresponsive (dose unknown) – 2.64→3.64 (5000IU over 16h) 4.4→5.6 (100mins)
1984 Faggiano M 20 T
(ng/dl)		 – unresponsive (0.25mg) decrease slightly (2mgx4d) – Increase
(3000IUx3d, under DXM)		 –
DS
(ng/ml)		 – unresponsive (0.25mg) unresponsive (2mgx4d) – Increase (3000IUx3d, under DXM) –
1986 O’leary TJ 30 T
(nmol/l)		 4.9 – – 9.8 (8mgx2d) unresponsive (5000IU) –
DS (nmol/l) 39.5 – – 99.5 (8mgx2d) unresponsive (5000IU) –
1987 Guillausseau PJ 41 T
(ng/ml)		 0.56 1.98 (1mgx2d) 0.6 (2mgx2d, after HCG) 0.75 (8mgx2d, after low DXM) 0.9 (5000IUx3d, after ACTH) –
DS
(ng/ml)		 5100 13000 10000 8700 7400(5000IUx3d) –
1989 Clouston WM 45 T
(nmol/l)		 6.6-8.7 – 9.4 14 – –
DS
(μmol/l)		 20-25 – 35 71 – –
1992 Ruutiainen (case 1) 41 T
(nmol/l)		 – – – unresponsive – –
DS (μmol/l) – – – decrease slightly – –
1992 Ruutiainen (case 2) 30 T
(nmol/l)		 – – – unresponsive (10mg injection) – –
DS (μmol/l) – – – decrease slightly (10mg injection) – –
1992 Micić D 22 T (nmol/l) – – 20.2→15.2 (2mgx7d) – 16.0→15.8 (3000IUx3d) –
2007 Mavroudis K 45 T (pmol/l) – Unresponsive (0.25mg) 4.8→7 (0.5mgx7d) – – –
DS (μg/dl) – increased by 44% 2650→2200 (0.5mgx7d) – – –
current case T (nmol/l) – 5.82→4.33 (0.25mg over 1h) – 5.55→6.45 (2mgx2d) – 6.66 (over 24h, after DXM)
DS (μmol/l) – 23.5→36 (0.25mg over 1h) – 36.2→47.7 (2mgx2d) – 66.4 (over 24h, after DXM)

Endocrine test summary of PASAT.

ACTH, adrenocorticotropic hormone; DXM, dexamethasone; HCG, human chorionic gonadotropin; GnRH, gonadotropin-releasing hormone; T, testosterone; DHEAS, dehydroepiandrosterone sulfate.

The androgen level decreased in 36 patients in a short time after surgery, and virilism symptoms were also partly or completely relieved. However, details regarding androgens after surgery were not reported in six patients. All ten patient with malignancy underwent surgery, except for one patient with nonresectable disease with multiple metastases at diagnosis (Table 2). Mitotane was applied to seven malignant patients (5 post-surgically, 1 with nonresectable disease and 1 after recurrence). Five patients with malignancy (including the one with nonresectable disease) were reported to have experienced recurrence, metastasis, or death.

The articles containing adult PASAT were summarized Table 3. T and DS were the most frequent androgens used for hormone evaluation, and urinary 17-ketosteroid was a significant indicator of hyperandrogenism in the earlier studies. The age distribution of the patients with malignant or benign tumors varied among the different studies. The age of the malignant group was younger than that of the benign group in the study by Gordera F but older in the study by Moreno S. The average size of the malignant tumors was larger than that of the benign tumors. Most malignancy patients (14/20) had a negative outcome (recurrence, metastasis or death), while no patient with benign conditions were reported to have a negative outcome during the follow-up period.

Discussion

Androgen-secreting adrenal tumors are rare. A recent population-based study of 1287 patients diagnosed with adrenal tumors reported only one androgen-excess adrenal tumor (0.1%) (56). In another study of 1205 patients with androgen excess, 20 (1.7%) individuals were identified as having androgen-secreting adrenal tumors (57). Androgen-secreting adrenocortical tumors, especially adult PASATs, remain a challenge in clinical diagnosis and treatment due to their rarity. Here, we report a rare case of adult bilateral PASATs, and to our knowledge, only one other case of bilateral PASATs has been reported since 1970. Furthermore, we conducted a systematic review of adult PASATs to increase the understanding of adult PASATs and provide guidelines for the diagnosis and treatment of adult PASATs.

The incidence peak for adult PASAT occurred at 21-30 years of age, while the incidence peak for malignant PASAT occurred at 41-50 years of age. Hirsutism, as one of the initial complaints, was the most common symptom found in the present review and other PASAT studies (53, 55, 58). Young females might focus more on their appearance, and they may notice hirsutism once it occurs, prompting them to visit doctors and undergo medical screening for virilism-causing adrenal tumors. This may contribute to the peak incidence of adult PASAT at 21-30 years of age. The incidence of malignant PASAT peaked at 41-50 years of age, which is close to the age of incidence peak of adult adrenocortical carcinoma in a previous study (51). Several factors may be responsible for this. Above all, the incidence peak of malignant PASAT may be associated with age because the risk of malignant tumors is higher in older people (59). It may also be associated with menstrual dysfunction. It was indicated that the occurrence of menstrual dysfunction is associated with higher androgen levels in women with hirsutism (60), and our data analysis demonstrated that patients with malignant PASAT presented with higher androgen levels, which indicates that malignant PASAT might lead to more menstrual disorders. It is well known that females aged 41-50 years usually begin to suffer menstrual problems due to perimenopause, prompting them to seek medical advice and hormone evaluation. Therefore, androgen abnormalities that are related to potential virilism-causing malignant adrenal tumors are more likely to be diagnosed in patients aged 41-50 years. However, the potential factors responsible for the age distribution of PASAT need to be identified in further research.

In the present review, PASAT was predominant (40/42) in women. The low incidence of PASAT in men may be associated with clinical ignorance. It is difficult to ascertain the onset of androgen-excess symptoms in males, which are usually clinically ignored until the presence of a consistent peripheral androgen-to-estrogen conversion is determined (61). In addition to hirsutism and menstrual dysfunction, other virilism manifestations, such as clitoral enlargement, alopecia, voice deepening and acne, were found to be important signs for screening and diagnosis.

Malignant adrenal neoplasms were identified in 26% of adult PASAT patients, which was significantly higher than the incidence (8.6%) of malignant adrenal tumors in an adrenal tumor population (56). The average duration before diagnosis in the malignant group was significantly shorter than that in the benign group, which may be related to the rapid progression of the malignant adrenocortical tumor. The malignant adrenal tumor size was significantly larger than that of benign tumors, consistent with various studies on adrenal tumors. Testosterone is the most sensitive marker in the hormone evaluation of PASAT, as it is elevated in almost all PASAT patients and is the only increased androgen in certain patients (41, 62, 63). Some studies (64, 65) have demonstrated that increased DS (produced uniquely by the adrenal zona reticularis) and DHEA (produced mainly by the adrenal zona reticularis) are indicators of adrenal etiology, especially DS. In the current review, however, the DS level was normal in 6/32 patients, and the DHEA levels was normal in 3/6 patients. The levels of T and DS, which are presented as androgen levels/upper normal range limit in Table 2, were much higher in malignant cases, but these differences were not significant and the potential differences in androgens between malignant and benign PASAT need to be identified in future studies due to the limited number of cases in the present review.

The contribution of the ACTH/synacthen test and dexamethasone test (low dose or high dose) to the diagnosis of PASAT may have been limited because the T and DS responses varied among different patients. However, most female patients showed an increased T and DS level in the HCG test, which may potentially contribute to the diagnosis of PASAT. Leydig cells or features related to Leydig cells, which could increase testosterone secretion under the stimulation of HCG, have been reported in the pathological findings of PASAT neoplasm (11, 13, 16, 18), and this may be the possible reason why PASAT responds actively respond to HCG.

A previous study indicated that as many as 45% of female patients with androgen-producing adrenal neoplasms underwent needless ovarian surgical treatment before obtaining the correct diagnosis (66). Polycystic ovarian morphology, a potential factor in hyperandrogenemia, has been reported in several PASAT patients (11, 24, 28, 38, 39) and was present in the current case, but it was identified as an irrelevant factor. Unfortunately, two PASAT patients included in the current review also underwent an unnecessary oophorectomy (11, 28). It is unclear whether polycystic ovarian morphology is caused by hyperandrogenemia itself, but it does lead to difficulties in identifying the source of hyperandrogenism in terms of location. Notably, adrenal venous sampling (AVS) or ovarian venous sampling (OVS) played a significant role in accurately identifying the aetiological location in some PASAT patients (9, 13, 21, 24, 34) and in the current case. Thus, AVS and OVS are recommended for the identification of the location of hyperandrogenemia aetiology, especially when clinical findings are inconclusive.

Conclusion

Adult PASATs are extremely rare, and their characteristics are largely unknown. The diagnosis and treatment of adult PASATs remain a clinical challenge. Adult PASATs are predominant in women and most frequently characterized by hirsutism symptoms and other virilism signs. Serum testosterone is the most sensitive indicator, and elevated DS could contribute to the diagnosis of PASAT specifically. HCG stimulation test might also be of help in diagnosis. Individuals with malignant PASATs have a shorter disease duration before diagnosis, larger tumor sizes and relatively higher androgen levels. AVS and OVS may be important approaches for the location diagnosis. Surgery is recommended for all patients with local PASATs, whether benign or malignant. Tumor malignancy should be fully considered in patients PASATs due to the high risk of malignancy, poor prognosis and limited effective treatment approaches.

Statements

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author contributions

Conceptualization, ZL, YG, and YSZ. Methodology, ZL and YZ. Validation, ZW and XW. Data analysis, ZL, YG, and JZ. Writing—original draft preparation, ZL. Writing—review and editing, YSZ. All authors contributed to the article and approved the submitted version.

Funding

The research was supported by the National Natural Science Foundation of China (81670611).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Summary

Keywords

pure androgen-secreting adrenal tumor (PASAT), clinical characteristics, diagnosis and treatment, adrenal venous sampling (AVS), ovarian venous sampling (OVS)

Citation

Liao Z, Gao Y, Zhao Y, Wang Z, Wang X, Zhou J and Zhang Y (2023) Pure androgen-secreting adrenal tumor (PASAT): A rare case report of bilateral PASATs and a systematic review. Front. Endocrinol. 14:1138114. doi: 10.3389/fendo.2023.1138114

Received

05 January 2023

Accepted

01 March 2023

Published

22 March 2023

Volume

14 - 2023

Edited by

Yuxuan Song, Peking University People’s Hospital, China

Reviewed by

Ruizhi Xue, First Hospital of Shanxi Medical University, China; Andreas G. Moraitis, Corcept, United States; Ana Valea, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania; Xiang Chen, Xiangya Hospital, Central South University, China

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Copyright

© 2023 Liao, Gao, Zhao, Wang, Wang, Zhou and Zhang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yushi Zhang,

This article was submitted to Adrenal Endocrinology, a section of the journal Frontiers in Endocrinology

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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