In a 22‑year‑old woman with hirsutism, elevated free testosterone, normal total testosterone and low sex hormone‑binding globulin, a day‑14 progesterone of 0.2 ng/mL is reported; what does this indicate about ovulation and how should she be managed for polycystic ovary syndrome if she desires pregnancy versus if she does not?

Day 14 Progesterone of 0.2 ng/mL Indicates Anovulation in This Patient with PCOS

A mid-cycle progesterone of 0.2 ng/mL (approximately 0.6 nmol/L) confirms anovulation, as levels below 6 nmol/L indicate failure to ovulate. 1 This finding, combined with hirsutism, elevated free testosterone, and low sex hormone-binding globulin (SHBG), establishes the diagnosis of polycystic ovary syndrome (PCOS) with chronic anovulation. 1

Understanding the Laboratory Profile

The hormonal pattern—elevated free testosterone with normal total testosterone and low SHBG—is characteristic of PCOS. 2, 3

• Low SHBG levels (which this patient has) increase the bioavailable fraction of testosterone, resulting in elevated free testosterone even when total testosterone remains normal 2, 3
• Total testosterone is abnormal in only 70% of women with PCOS, meaning 30% have normal levels despite confirmed disease 4
• The combination of low SHBG and calculated free testosterone provides superior diagnostic accuracy compared to total testosterone alone 4, 3
• Low SHBG is a biomarker of insulin resistance and metabolic dysfunction in PCOS 2

The anovulatory progesterone level (<6 nmol/L or <2 ng/mL) confirms that this patient is not ovulating regularly. 1 Mid-luteal progesterone should be measured 7 days before expected menses (day 21 in a 28-day cycle, or day 14 in this patient's likely irregular cycle), and levels this low indicate follicular arrest without corpus luteum formation. 1

Management Strategy: Fertility Desired

If this patient desires pregnancy, first-line management is lifestyle modification targeting weight loss, followed by letrozole or clomiphene citrate for ovulation induction. 1, 4

Step 1: Metabolic Optimization

• Calculate BMI and assess for obesity; weight loss of 5-10% significantly improves ovulation rates in overweight/obese PCOS patients 1, 4
• Screen for glucose intolerance with 2-hour oral glucose tolerance test (75g glucose load) 1, 4
• Measure fasting lipid panel (total cholesterol, LDL, HDL, triglycerides) 1, 4
• Interventions to improve insulin sensitivity (weight loss, metformin) are beneficial in improving ovulation frequency 1

Step 2: Ovulation Induction

• Letrozole or clomiphene citrate are first-line ovulation induction agents for PCOS-related anovulatory infertility 1, 4
• Metformin can be added as an adjunct to improve insulin sensitivity and enhance ovulation rates 1
• The FDA has not labeled insulin-sensitizing agents specifically for PCOS treatment, but they improve ovulation frequency 1

Critical Pitfall to Avoid

• Do not use clomiphene citrate in functional hypothalamic amenorrhea (FHA), as it is ineffective and not recommended 1
• This patient's hyperandrogenism (elevated free testosterone, hirsutism) distinguishes PCOS from FHA, which presents with low gonadotropins and no hyperandrogenism 1

Management Strategy: Fertility NOT Desired

If pregnancy is not desired, combined oral contraceptive pills (OCPs) are first-line therapy to suppress ovarian androgen production, increase SHBG, and provide endometrial protection. 1, 4

Hormonal Management

• OCPs suppress ovarian androgen secretion and increase SHBG levels, reducing free testosterone and improving hirsutism 1, 5
• OCPs reduce the risk of endometrial cancer from unopposed estrogen exposure in chronic anovulation 1
• Alternative: Medroxyprogesterone acetate (depot or intermittent oral) suppresses androgens and provides endometrial protection, though optimal dosing frequency is unclear 1

Metabolic Management

• All women with PCOS require metabolic screening regardless of fertility goals 1, 4
• Screen for type 2 diabetes with fasting glucose followed by 2-hour glucose tolerance test 1
• Screen for dyslipidemia with fasting lipid panel; PCOS patients frequently have elevated LDL, low HDL, and elevated triglycerides 1
• Calculate BMI and waist-hip ratio; central obesity (WHR >0.9) exacerbates metabolic and reproductive features 4
• Before initiating lipid-lowering drugs, attempt lifestyle modification with regular exercise and weight control 1

Insulin-Sensitizing Agents

• Metformin improves insulin sensitivity, decreases circulating androgens, and improves metabolic outcomes 1
• Metformin tends to decrease weight, unlike thiazolidinediones which increase weight 1
• These agents are not FDA-labeled for PCOS but have demonstrated benefit 1

Additional Diagnostic Considerations

Complete the PCOS workup by excluding other causes of hyperandrogenism and anovulation: 1, 4

• Measure TSH to exclude thyroid disease (hypothyroidism can mimic or worsen PCOS) 4, 6
• Measure morning resting prolactin to exclude hyperprolactinemia (levels >20 μg/L are abnormal) 1, 4
• If rapid symptom onset, severe hirsutism, or very high androgens, consider androgen-secreting tumor 4
• If DHEAS elevated (>3800 ng/mL age 20-29), evaluate for non-classical congenital adrenal hyperplasia 1, 4
• Screen for Cushing's syndrome only if clinical features present (buffalo hump, moon facies, striae, proximal myopathy) 1, 4

Long-Term Monitoring

Regardless of fertility goals, this patient requires ongoing cardiovascular and metabolic surveillance: 1, 4

• Monitor lipid panel, blood pressure, and weight every 6-12 months 4
• PCOS patients have increased risk for type 2 diabetes, dyslipidemia, and cardiovascular disease 1
• Low SHBG levels predict insulin resistance and metabolic complications 2