Approach to androgen excess in women: Clinical and biochemical insights

Abstract

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

Keywords: adrenocortical carcinoma; androgen excess; androstenedione; ovarian hyperthecosis; polycystic ovary syndrome; testosterone.

Figure 1

Adrenal, ovarian and peripheral androgen metabolism. Both classic and 11‐oxygenated androgen pathways are demonstrated. Androgenic precursors are secreted predominantly by the adrenal glands and activated to potent androgens in the ovaries and peripheral tissues. 5αR 1/2, 5α‐reductase type 1 and 2; 11OHA4, 11β‐hydroxyandrostenedione; 11OHT, 11β‐hydroxytestosterone; 11OHDHT, 11‐hydroxydihydrotestosterone; 11KA4, 11‐ketoandrostenedione; 11KT, 11‐ketotestosterone; 11KDHT, 11‐ketodihydrotestosterone; 17OHP, 17‐hydroxyprogesterone; A4, androstenedione; AKR1C3, aldoketoreductase type 1C3; CYP11B1, 11β‐hydroxylase type 1; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; T, testosterone [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Clinical approach to the patient with androgen excess. A typical peripubertal and indolent presentation is in keeping with PCOS. Severe biochemical disturbances, rapid onset symptoms and other red flag clinical features such as virilization should prompt investigation for non‐PCOS adrenal or ovarian pathology. *Baseline biochemical workup: FSH, LH, estradiol, 17‐hydroxyprogesterone (17OHP), testosterone (T), dehydroepiandrosterone sulphate (DHEAS), androstenedione (A4), sex hormone‐binding globulin (SHBG) and prolactin. FSH, follicle‐stimulating hormone; LH, luteinizing hormone; OGTT, oral glucose tolerance test; ONDST, overnight dexamethasone suppression test; PCOS, polycystic ovary syndrome; PET, positron emission tomography

Figure 3

Severity of androgen excess according to diagnosis and androgen measured in premenopausal women on a single assay. Arbitrary stratification of elevated serum androgen levels into mild (M), intermediate (I), and severe (S) was applied, with grouping of values according to underlying diagnosis. Median values for each diagnosis are denoted by a solid black line. ACC, adrenocortical carcinoma; CAH, congenital adrenal hyperplasia; OHT, ovarian hyperthecosis; PCOS, polycystic ovary syndrome (reference J Clin Endocrinol Metab 2018;103(3):1214–1223. doi:10.1210/jc.2017-02426)

Figure 4

Severity of androgen excess according to diagnosis and androgen measured in postmenopausal women on a single assay. Arbitrary stratification of elevated serum androgen levels into mild (M), intermediate (I) and severe (S) was applied, with grouping of values according to the underlying diagnosis. Median values for each diagnosis are denoted by a solid black line. PCOS, polycystic ovary syndrome; CAH, congenital adrenal hyperplasia; ACC, adrenocortical carcinoma; OHT, ovarian hyperthecosis (reference J Clin Endocrinol Metab 2018;103(3):1214–1223. doi:10.1210/jc.2017-02426)