What could be causing menstrual irregularities in a patient with a history of regular menstrual cycles for the past year, recent weight loss, and taking levothyroxine (T4) and myo-inositol D-chiro?

Evaluation of New-Onset Menstrual Irregularities in a Patient on Levothyroxine and Myo-Inositol D-Chiro

The most likely causes of menstrual irregularities in this patient are thyroid dysfunction (either over- or under-replacement with levothyroxine), weight loss-induced hypothalamic amenorrhea, or underlying PCOS that was previously masked by regular cycles. 1, 2

Immediate Diagnostic Workup

Mandatory First-Line Laboratory Tests

The following tests must be obtained to identify reversible causes:

• Pregnancy test (urine or serum β-hCG) - This is mandatory regardless of contraceptive use or sexual activity history, as pregnancy remains the most common cause of menstrual irregularity 1

• TSH and free T4 - Levothyroxine overdosage or underdosage can directly cause menstrual irregularities; both hyperthyroidism and hypothyroidism disrupt normal ovarian function 2

• FSH, LH, and estradiol - Draw these between cycle days 3-6 if any bleeding occurs, or at any time if amenorrheic 1

  • LH/FSH ratio >2 suggests PCOS (though less likely with recent weight loss) 1
  • LH/FSH ratio <1 suggests functional hypothalamic amenorrhea in approximately 82% of cases 1
  • Elevated FSH >40 mIU/mL indicates primary ovarian insufficiency and requires repeat testing 4 weeks later 1

• Prolactin - Elevated levels >20 μg/L suggest hyperprolactinemia from pituitary adenoma or medication effect 1

• Total testosterone and androstenedione - Testosterone >2.5 nmol/L suggests hyperandrogenism from PCOS or other causes 1

Physical Examination Priorities

• Calculate BMI and document recent weight changes - Low BMI or significant weight loss suggests hypothalamic amenorrhea, while obesity is associated with PCOS 1

• Assess for signs of hyperandrogenism - Document Ferriman-Gallwey score for hirsutism and evaluate clitoral size (width >10 mm indicates elevated androgens) 1

Interpretation Algorithm Based on Laboratory Results

If TSH is Abnormal

Thyroid dysfunction is the primary culprit and must be corrected first. 3, 2

• Levothyroxine can cause menstrual irregularities through both overdosage (causing hyperthyroidism) and underdosage (causing hypothyroidism) 2

• The FDA label explicitly lists "menstrual irregularities" as an adverse reaction of levothyroxine therapy, primarily from therapeutic overdosage 2

• Adjust levothyroxine dose appropriately and recheck TSH in 4-6 weeks, as peak therapeutic effect may not be attained for 4 to 6 weeks 2

• SHBG levels will normalize once thyroid hormone levels are corrected 3

• Refer to endocrinology if thyroid dysfunction is confirmed for specialized management 3

If LH/FSH Ratio <1 with Low Estradiol

This pattern indicates functional hypothalamic amenorrhea (FHA), likely triggered by recent weight loss. 1

• FHA is characterized by low LH, low estradiol, thin endometrium (<5 mm on ultrasound), and disturbed secretion of pituitary gonadotropins 4, 1

• Weight loss is a well-established trigger for FHA development 4

• Critical pitfall: Do not misdiagnose FHA with polycystic ovarian morphology (FHA-PCOM) as PCOS, as FHA patients have distinctly different hormonal profiles despite similar ovarian appearance on ultrasound 1

• Management focuses on addressing energy deficiency: document eating patterns, exercise habits, and consider bone mineral density testing via DXA if amenorrhea persists 1

If LH/FSH Ratio >2 with Elevated Testosterone

This pattern suggests PCOS, which affects 4-6% of women in the general population. 4

• PCOS is characterized by ovulatory dysfunction (oligomenorrhea or amenorrhea), hyperandrogenism, insulin resistance, and polycystic ovaries on ultrasound 4

• Perform pelvic ultrasound (transvaginal preferred) to evaluate for >10 peripheral cysts of 2-8 mm diameter in one ultrasound plane, with thickening of ovarian stroma 4, 1

• The myo-inositol and D-chiro-inositol combination this patient is taking is appropriate for PCOS management, as both improve menstrual cycle regularity, insulin resistance, and metabolic parameters 5, 6, 7, 8

• D-chiro-inositol specifically improves menstrual cycle regularity in 24% of women at 6 months and 51.6% at 15 months of treatment 6

• The combination of myo-inositol 1.1g + D-chiro-inositol 27.6mg daily restores menstrual regularity in all patients when combined with diet 8

Symptomatic Management of Irregular Bleeding

For Irregular Spotting or Light Bleeding

Use NSAIDs as first-line treatment: 3

• Mefenamic acid 500 mg three times daily for 5 days during bleeding episodes, OR
• Celecoxib 200 mg daily for 5 days during bleeding episodes

For Heavy or Prolonged Bleeding

Use low-dose combined oral contraceptives as short-term treatment for 10-20 days (if medically eligible and no contraindications exist) 3

• Monitor response to symptomatic bleeding management within 1-2 cycles 3

Critical Pitfalls to Avoid

• Do not assume a delayed period is "normal variation" - Evaluate cycles >35 days apart as abnormal 9

• Do not skip endometrial evaluation in women >35 years - Endometrial biopsy should be performed before treatment initiation to exclude hyperplasia or malignancy 1

• Do not continue current management without investigating thyroid function - Levothyroxine dosing must be optimized before attributing irregularities to other causes 3, 2

• Do not forget to document all medications - Antiepileptic drugs can affect reproductive hormones and SHBG levels, though this is less relevant for this specific patient 4, 1

Referral Indications

Refer to endocrinology and/or gynecology if: 3

• Thyroid dysfunction is confirmed (for specialized management)
• Hormonal workup reveals complex endocrine abnormalities
• Infertility is a concern (inability to conceive after 12 months of unprotected intercourse)