What is the likely diagnosis for a female in her 40s with hyperandrogenism (elevated androgen levels) and a testosterone level of 360?

Polycystic Ovary Syndrome (PCOS)

A female in her 40s with a testosterone level of 360 ng/dL most likely has polycystic ovary syndrome (PCOS), which accounts for approximately 95% of hyperandrogenism cases in women of reproductive age. 1

Understanding the Testosterone Level

The testosterone value of 360 requires clarification of units, as this dramatically affects interpretation:

• If 360 ng/dL (3.6 ng/mL): This represents moderate elevation consistent with PCOS, which typically presents with total testosterone levels elevated but generally below twice the upper limit of normal for females (normal range approximately 15-70 ng/dL). 2

• If 360 ng/mL: This would represent severe hyperandrogenism requiring immediate evaluation for androgen-secreting tumors of ovarian or adrenal origin, as PCOS rarely causes testosterone levels this dramatically elevated. 3, 2

Assuming the more common scenario of 360 ng/dL, PCOS is the overwhelmingly likely diagnosis. 1

Diagnostic Confirmation Required

To definitively diagnose PCOS using the Rotterdam criteria, the patient needs at least two of three findings: 4

• Biochemical or clinical hyperandrogenism (already present with elevated testosterone)
• Ovulatory dysfunction (oligomenorrhea, amenorrhea, or anovulation)
• Polycystic ovary morphology on transvaginal ultrasound

Essential Laboratory Testing

First-line testing should confirm the testosterone elevation using liquid chromatography-tandem mass spectrometry (LC-MS/MS), which has superior accuracy compared to immunoassay methods. 5, 1 Measure:

• Total testosterone by LC-MS/MS (sensitivity 74%, specificity 86%) 4
• Free testosterone by equilibrium dialysis or calculated free androgen index (FAI = total testosterone/SHBG ratio) (sensitivity 89%, specificity 83% for calculated free testosterone) 1, 4
• SHBG to calculate FAI if direct free testosterone measurement unavailable 1

Second-line testing if total and free testosterone are equivocal: 1

• Androstenedione (A4) (sensitivity 75%, specificity 71%) 4
• DHEAS (sensitivity 75%, specificity 67%) 4

Critical Exclusions

Before confirming PCOS, you must exclude other causes of hyperandrogenism: 3

• Androgen-secreting tumors: If DHEAS >600 μg/dL, suspect adrenal tumor; if testosterone is twice the upper limit of normal with normal DHEAS, suspect ovarian tumor or hyperthecosis. 2 These typically present with rapid-onset virilization (deepening voice, clitoromegaly, severe acne). 1, 3

• Non-classic congenital adrenal hyperplasia (NCCAH): Measure morning 17-hydroxyprogesterone; if >200 ng/dL, perform ACTH stimulation test. 3

• Cushing's syndrome: Screen with overnight 1 mg dexamethasone suppression test or 24-hour urinary free cortisol if clinical features present (central obesity, striae, moon facies). 3, 2

• Hyperprolactinemia: Measure prolactin to exclude prolactinoma. 1, 3

• Thyroid disease: Measure TSH. 1

• Exogenous androgen use: Obtain medication and supplement history. 1

Clinical Context and Associated Features

PCOS in women in their 40s typically presents with: 6

• Menstrual irregularity (oligomenorrhea or amenorrhea) 1
• Hirsutism (excessive terminal hair in male-pattern distribution) 1
• Acne (persistent or treatment-resistant) 1
• Androgenic alopecia (male-pattern hair loss) 1
• Metabolic complications: insulin resistance, obesity, acanthosis nigricans 1

The hormonal mechanism involves accelerated GnRH pulsatility driving excessive LH secretion, with LH/FSH ratio typically >2:1, stimulating ovarian theca cells to overproduce androgens. 6 Hyperinsulinemia amplifies this by directly stimulating androgen production and suppressing SHBG, increasing free testosterone. 6

Important Caveats

• Age considerations: While PCOS is most commonly diagnosed in younger women, it persists into the 40s, though symptoms may evolve as women approach perimenopause. 7

• SHBG fluctuations: Obesity, metabolic syndrome, and certain medications (oral contraceptives) significantly affect SHBG levels, which in turn affects total testosterone and FAI interpretation. 1, 2

• Timing matters: Testosterone should be measured in the morning due to diurnal variation. 1

• Avoid ultrasound pitfalls: Polycystic ovaries on ultrasound alone do not equal PCOS; biochemical hyperandrogenism and ovulatory dysfunction must also be present. 1

Management Approach

Combined oral contraceptives (COCs) are first-line treatment for PCOS-related hyperandrogenism, effectively regulating menstrual cycles and reducing androgen levels by suppressing gonadotropins and increasing SHBG. 1, 8 Screen for and manage metabolic complications, particularly insulin resistance, with lifestyle modifications including diet and exercise for overweight/obese patients. 1