Autoimmune adrenalitis and an adrenal tumor: a rare cause of elevated 17-hydroxyprogesterone and secondary amenorrhea

Abstract

Primary adrenal insufficiency (AI) is characterized by insufficient adrenal cortisol production, even with very high adrenocorticotrophic hormone (ACTH) stimulation. Despite massive stimulation of the adrenal cortex in primary AI, there is scarce data describing an association between autoimmune AI and adrenal tumors. This report describes a 17-year-old female presenting with secondary amenorrhea, elevated 17-hydroxyprogesterone (17-OHP) and a lipid-poor adrenal tumor. She was subsequently found to have very low morning cortisol, markedly high ACTH, and positive anti-adrenal antibodies. The diagnosis of autoimmune adrenalitis causing primary AI was made. Fluorodeoxyglucose positron emission tomography (FDG-PET) scan demonstrated intense uptake (standardized uptake value (SUV) of 19.4) in the adrenal lesion. Laparoscopic adrenalectomy revealed a benign adrenal cortical adenoma. Her 17-OHP normalized postoperatively, and her menses resumed with treatment of adrenal insufficiency. This case highlights an interesting coincidence of an adrenal adenoma and primary autoimmune adrenalitis, resulting in elevated 17-OHP and amenorrhea. Low expression of 21-hydroxylase in adrenal adenomas has been previously documented and is suspected in this patient, unmasked by chronic ACTH stimulation.

Introduction

Primary adrenal insufficiency (AI) is a rare disease that has an incidence of approximately 4 in every 1 million people [1]. When diagnosed in the pediatric population, congenital adrenal hyperplasia (CAH) is the most likely cause [1]. In older children and adult patients in developed countries, an autoimmune cause for primary adrenal insufficiency is the more likely etiology [1]. On the other hand, adrenal tumors are a frequent incidental finding with an incidence that increases with age. Co-occurrence of autoimmune primary adrenal insufficiency and unilateral adrenal tumors is very rare and is associated with specific diagnostic and therapeutic challenges. We report here a young patient with autoimmune adrenal insufficiency, who presented with secondary amenorrhea, significantly elevated 17-hydroxyprogesterone (17-OHP), and an incidental adrenal tumor. We hypothesize the underlying pathogenesis for this constellation of findings.

Case presentation

A previously healthy 17-year-old female presented to her primary care physician with a 1-year history of secondary amenorrhea after discontinuing oral contraceptives, which she had taken since age 15 years old for dysmenorrhea. She was otherwise well, took no regular medications, and her family history was unremarkable. Her treating physician prescribed a progesterone challenge, which did not invoke menstruation. An abdominal pelvic ultrasound revealed a 2.7 cm right adrenal tumor. She was referred to endocrinology for further assessment.

Diagnostic assessment

Upon presentation to the pediatric endocrinology clinic, she reported low energy but was otherwise well. On examination, her blood pressure was 102/71 mmHg, her heart rate was 89 beats per minute, and her body mass index was 19.6 kg/m². She was Tanner V and had no evidence of dysmorphic traits, virilization, or cushingoid features. Baseline laboratory results showed negative pregnancy test, low estradiol at <11.7 pg/mL (SI: <43 pmol/L) (ref. 18-227 pg/mL [SI: 67-833 pmol/L]) with luteinizing hormone (LH) at 0.9 mIU/mL (international units) (SI: 0.9 ius/L) (ref. 0.4-17.3 mIU/mL [SI: 0.4-17.3 ius/L]) and follicle stimulating hormone (FSH) at 5 mIU/mL (SI: 5 ius/L) (ref. 1.9-11.2 mIU/mL [SI: 1.9-11.2 ius/L]). Her thyroid function tests, prolactin levels, and testosterone levels were all within normal range. Her 17-OHP was very high at 3860 ng/dL (SI: 117 nmol/L) (ref. 20-264 ng/dL [SI: 0.6-8.0 nmol/L]) tested by enzyme-linked immunosorbent assay (ELISA) and dehydroepiandrosterone sulfate (DHEAS) was low at 5.5 μg/dL (SI: 0.15 μmol/L) (ref. 66-430 μg/dL [SI: 1.75-11.4 μmol/L]) (Table 1). A 1-mg overnight dexamethasone test showed a suppressed cortisol at 0.4 μg/dL (SI: 11 nmol/L)(ref. <1.8 μg/dL [SI: <50 nmol/L]) but a nonsuppressed ACTH at 44 pg/mL (SI: 9.6 pmol/L) (ref. 7-63 pg/mL [SI: 1.6-13.9 pmol/L]). Plasma metanephrines were normal. Genetic analysis showed no mutation in a 12-gene CAH panel.

Table 1.

Initial secondary amenorrhea workup results

Test	Result	Test	Result
FSH (ref. 1.9-11.2 mIU/mL [SI: 1.9-11.2 ius/L])	5 mIU/mL (SI: 5 iμs/L)	Prolactin (ref. 10.5 ng/mL [SI: 3-29 μg/L])	10.5 ng/mL (SI: 10.5 μg/L)
LH (ref. 0.4-17.3 mIU/mL [SI: 0.4-17.3 ius/L])	0.9 mIU/mL (SI: 0.9 ius/L)	TSH (ref. 0.35-5.5 μ IU/mL [SI: 0.35-5.5 mU/L])	3.43 mIU/L (SI: 3.43 mU/L)
Estradiol (ref. 18-227 pg/mL [SI: 67-833 pmol/L])	<11.7 pg/mL (SI: < 43 pmol/L)	T4 Free (ref. 0.62-1.40 ng/dL [SI: 8-18 pmol/L])	1.08 ng/dL (SI: 13.9 pmol/L)
Progesterone	0.27 ng/mL (SI: 0.86 nmol/L)	T3 Free (ref. 3.06-4.69 pg/mL [SI: 4.7-7.2 pmol/L])	4.1 pg/mL (SI: 6.3 pmol/L)
17-OHP (ref. 20-264 ng/dL [SI: 0.6-8 nmol/L])	3860 ng/dL (SI: 117 nmol/L)	Beta HCG (ref. <5 mIU/mL [SI: <5 U/L])	<2 mIU/mL (SI: <2 U/L)

On a subsequent visit to review workup and transition to adult endocrinology care, she remained amenorrheic, admitted to salt craving, morning nausea, fatigue, and darkening of the skin compared to her twin sister. The next morning, urgent baseline cortisol was obtained at 2.7 μg/dL (SI: 76 nmol/L) (ref. 4.35-19.4 μg/dL [SI: 120-535 nmol/L]) and ACTH was over 1997 pg/mL (SI: >440 pmol/L). Adrenal autoantibodies, tested with an indirect immunofluorescence assay on patient serum incubated with primate tissue, were positive. Her renin was also high at 464 pg/mL (SI: 464 ng/L) (ref. 3.3-61 pg/mL [SI: 3.3-61 ng/L]). She was diagnosed with autoimmune primary AI.

An abdominal magnetic resonance image (MRI) demonstrated a 2.5 × 1.4 × 1.8-cm right adrenal, well-circumscribed tumor, isointense in T2, hypointense in T1, with no loss of signal on the out-of-phase T1 sequences, in keeping with a lipid-poor lesion (Fig. 1). A fluorodeoxyglucose (FDG) positron emission tomography (PET) scan demonstrated the mass to be FDG avid at 19.4 standardized uptake value (SUV) (Fig. 2).

Figure 1.

MRI images of adrenal lesion.

Figure 2.

Positron emission tomography scan images of the adrenal lesion.

Treatment

The patient was immediately started on hydrocortisone and fludrocortisone replacement at time of adrenal insufficiency diagnosis. She later underwent an uneventful laparoscopic right adrenalectomy. Histologic examination revealed a well-circumscribed adrenocortical adenoma measuring 1.3 × 1.5 cm, composed predominantly of compact eosinophilic (oncocytic) cells with abundant granular cytoplasm, prominent nucleoli, and scattered fine lipofuscin granules. Lymphoplasmacytic infiltrates were present both within the tumor and at its periphery, involving the adjacent adrenal parenchyma. The tumor almost completely replaced the adrenal cortex, whereas the medulla appeared unremarkable. There was no necrosis, mitotic activity, or capsular or vascular invasion, and the overall architecture and reticulin framework were preserved, supporting a benign adrenocortical adenoma. (Figure 3). Immunohistochemistry for adrenal cortical markers (calretinin and inhibin-α) was positive.

Figure 3.

Histology of the adrenal tumor shows a well-circumscribed adrenal cortical adenoma composed of cells with abundant eosinophilic cytoplasm and some lymphoplasmacytic infiltrates, suggestive of underlying inflammatory disease. No significant cytologic atypia, mitoses, or capsular/vascular invasion was identified.

Outcome and follow up

Menstruation returned 3 months after initiation of hormonal replacement. Her 17-OHP level decreased to 1450 ng/dL (SI: 44 nmol/L) with hydrocortisone treatment and completely normalized to 17 ng/dL (SI: 0.5 nmol/L) after adrenalectomy (Table 2). The patient will continue to be followed in the endocrinology department for her lifelong adrenal insufficiency.

Table 2.

Evolution of adrenal biochemical results; treatment refers to initiation of hydrocortisone, fludrocortisone, and surgical resection of the lesion

	Pre-treatment	Post-treatment
Morning cortisol (ref. 4.35-19.4 μg/dL [SI: 120-535 nmol/L])	2.7 μg/dL (SI: 76 nmol/L)	N/A
ACTH (ref. 7-63 pg/mL [SI: 1.6-13.9 pmol/L])	>1997 pg/mL (SI: 440 pmol/L)	667 pg/mL (SI: 147 pmol/L)
17-OHP (ref. 20-264 ng/dL [SI: 0.6-8.0 nmol/L])	3860 ng/dL (SI: 117 nmol/L)	17 ng/dL (SI: 0.5 nmol/L)
Renin (ref. 3.3-61 pg/mL [SI: 3.3-61 ng/L])	464 pg/mL (SI: 464 ng/L)	140 pg/mL (SI: 140 ng/L)
Aldosterone (ref. 2.20-35.2 ng/dL [SI: 61-978 pmol/L])	3.93 ng/dL (SI: 109 pmol/L)	N/A
Dexamethasone suppression and normetanephrines	Normal	N/A

Discussion

In this report, we present a 17-year-old female with autoimmune primary adrenal insufficiency who presented with secondary amenorrhea, an adrenal tumor, and elevated 17-OHP, a constellation of findings that do not usually co-occur. This rare clinical entity is suspected to be mediated by the patient's very elevated ACTH and a 21-OHase-deficient incidental adenoma.

In general, patients with autoimmune AI can be at risk for secondary amenorrhea for various reasons. Importantly, it has been reported that 1 in 10 women with autoimmune adrenalitis can have concurrent autoimmune primary ovarian insufficiency [2]. This can be ruled out with non-elevated gonadotropins on blood tests, as in our patient. When gonadotropins are low or normal, functional hypothalamic amenorrhea should be considered. Gonadotropin function is dependent on the body energy available. At least 30 kcal/kg/day are required for LH pulsatility to occur [3]. In severe cortisol deficiency, the energy deficit may surpass this limit. Therefore, although rare, adrenal insufficiency may result in hypogonadotropic hypogonadism as hypothesized in our patient.

Furthermore, in our patient, the very elevated 17-OHP could also cause negative feedback on gonadotropins via the progesterone receptor and interfere with her menstrual cycle [4]. Our patient's ovulatory cycle ultimately returned with treatment of her cortisol deficiency and prior to the complete normalization of her 17-OHP from adrenal tumor resection. This therefore favored hypothalamic amenorrhea from AI as the driving force. Moreover, a significant decline of 17-OHP was seen after initiation of therapy with hydrocortisone due to the subsequent decline in ACTH levels. Although the 17-OHP remained above 990 ng/dL (SI: >30 nmol/L), this was potentially beneficial in allowing ovulation to occur. Last, the fact that the hypothalamic-pituitary-gonadal axis was already suppressed at the onset of her disease while on oral contraceptives may have potentiated the impact of the previously discussed factors.

Although adrenal tumors are frequent in adults (up to 8.7% in autopsy studies) [5], in the pediatric population, they are far less common and, when present, they are more likely to be malignant. In children, they are more commonly neuroblastomas and pheochromocytomas [6]. Adrenal masses associated with adrenal insufficiency are typically non-adrenal lesions that affect both adrenals simultaneously, such as lymphomas, metastatic lesions, or infectious granulomas [7-9]. Lymphomas have been reported to trigger autoimmune adrenal destruction. These lesions are rarely circumscribed but rather infiltrative and invasive. No reports of adrenal tumors in patients with autoimmune adrenalitis were found.

Furthermore, adrenal tumors with significant FDG avidity, such as in our patient (19 SUV), are always concerning for malignancy. Metser et al. described more than 150 patients in whom a cut-off SUV of 3.1 resulted in a sensitivity of 98.5% and specificity of 92% for differentiating adenomas from malignant lesions in the adrenal gland [10]. Therefore, an FDG-PET scan result with avidity over 6 times this cutoff, reasonably prompted surgical management. Fortunately, our patient's lesion was benign, leading us to believe that the strong ACTH stimulation was driving the high FDG uptake, contrasting with the surrounding ongoing adrenalitis.

In our patient, the elevated plasma 17-OHP level is unusual in the absence of any genetic defects associated with CAH, particularly the absence of a CYP21A2 pathogenic variant. In the literature, a case report describes a similar relationship; however, in this case, the elevation was only mild, and the underlying diagnosis was primary adrenal lymphoma, rather than autoimmune disease [11]. In another case, a 24-year-old woman known for autoimmune AI since age 18 years, was investigated for secondary amenorrhea. An elevated 17-OHP led to the diagnosis of co-occurring CAH and was responsible for her amenorrhea [12]. The possibility that 17-OHP may rise in certain stages of autoimmune adrenal destruction, although rarely documented, is not supported by several studies that documented a parallel, progressive deficiency of all adrenal steroids (including 17-OHP) from the early stages of autoimmune adrenal inflammation [13, 14].

The suspicion that the rise in 17-OHP in our patient was secondary to overstimulation by ACTH of the 21-OHase-deficient adrenal adenoma tissue seems to be the most plausible explanation. Barzon et al. reviewed the literature and concluded that 30% to 70% of incidental adrenal tumors have 21-OHase deficiency [15]. Furthermore, sporadic adrenocortical carcinomas exhibit decreased CYP21A2 mRNA and enzyme activity. Non-functioning adrenocortical adenomas also have low CYP21A2 mRNA levels compared to normal tissue and display elevated 17-OHP, despite normal aldosterone and cortisol levels. In contrast, functioning tumors display normal CYP21A2 mRNA levels [9]. Such a deficiency goes unnoticed in most patients because the typical workup for adrenal lesions does not include measuring plasma 17-OHP or performing an ACTH stimulation test to measure adrenal steroids. In support of this hypothesis, the 17-OHP in our patient declined as ACTH decreased on glucocorticoid replacement and completely normalized after the adenoma was removed.

Contrary to 21OH-ase deficiency in CAH, we do not expect a strong androgen shunt with high DHEAS along with 17-OHP in a case like the one presented here. This is because most benign non-secreting adenomas have been shown, by genomic analysis to originate from the zona fasciculata, which does not contain significant amounts of 17,20-lyase, the obligated step for adrenal androgen production [14, 16]. Whereas the adjacent and contralateral zona reticularis, responsible for DHEAS production, has been destroyed by the autoimmune process limiting expression of the 17,20-lyase.

In conclusion, this patient's presentation of autoimmune adrenalitis with elevated 17-OHP, secondary amenorrhea, and adrenal tumor is a unique clinical constellation. The co-occurrence of these findings is suspected to be mediated by her very elevated levels of ACTH. Fortunately for our patient, her lesion was benign, and she had a complete clinical recovery.

Learning points

• Nonsecreting adrenal adenomas may show partial 21-hydroxylase deficiency, which may result in isolated 17-OHP elevation.

• Primary adrenal insufficiency may unmask adrenal adenomas that are 21-hydroxylase deficient by causing significant increase in 17-OHP.

• Adrenal lesions coexisting with primary adrenal insufficiency may require surgical management because of the trophic effect of high ACTH on these tumors.

Contributors

All authors made individual contributions to authorship. L.W. contributed to the clinical care of the patient and drafting and revision of the manuscript. L.F. contributed to the clinical care of the patient and revision of the manuscript. O.A. contributed to the clinical care of the patient and revision of the manuscript. J.R. contributed to the clinical care of the patient and drafting and revision of the manuscript.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed patient consent for publication

Signed informed consent obtained directly from patient.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.