In a reproductive‑age woman taking standard‑dose tofacitinib (5 mg twice daily for rheumatoid arthritis or 10 mg twice daily for ulcerative colitis) who reports missed periods or changes in menstrual flow, could the drug be causing the irregularities and what evaluation and management steps are recommended?

Tofacitinib and Irregular Periods

Tofacitinib does not directly cause menstrual irregularities based on available evidence, but a thorough reproductive endocrine evaluation is warranted to identify the actual cause, which is most commonly polycystic ovary syndrome (PCOS), hypothalamic dysfunction, or other hormonal disorders unrelated to the medication.

Direct Evidence on Tofacitinib and Menstrual Effects

• Pharmacokinetic studies demonstrate no clinically relevant interaction between tofacitinib and reproductive hormones. A controlled trial showed tofacitinib 30 mg twice daily (three times the standard RA dose) caused only a 6.6% increase in ethinylestradiol AUC and 0.9% increase in levonorgestrel AUC, with 90% confidence intervals falling within the 80-125% bioequivalence range 1
• No reproductive endocrine adverse effects are documented in tofacitinib clinical trials or safety monitoring guidelines. The comprehensive ACR/CHEST guideline monitoring protocol for tofacitinib includes CBC, CMP, and lipids but does not require hormonal assessment or list menstrual irregularities as a recognized adverse effect 2
• Tofacitinib is not listed among medications known to cause reproductive dysfunction. The 2020 ACR reproductive health guideline provides no specific recommendations regarding tofacitinib and menstrual irregularities due to lack of data, contrasting with clear guidance for drugs with known reproductive effects like cyclophosphamide, methotrexate, and NSAIDs 2

Recommended Evaluation Algorithm

Initial Assessment

• Obtain detailed menstrual history: cycle length, flow duration, pattern of irregularity, age at menarche, previous menstrual patterns before tofacitinib 2
• Document body mass index and waist-hip ratio: weight gain is a common trigger for PCOS manifestation in predisposed women 2
• Review all concurrent medications: corticosteroids (commonly used with tofacitinib) can affect menstrual cycles; NSAIDs may interfere with conception 2
• Assess for symptoms of hyperandrogenism: hirsutism, acne, male-pattern hair loss 2

Laboratory Workup (Day 3-6 of Cycle)

• LH and FSH levels (average of three measurements 20 minutes apart): LH/FSH ratio >2 suggests PCOS; FSH >35 IU/L indicates ovarian failure; LH <7 IU/ml suggests hypothalamic dysfunction 2
• Prolactin (morning resting level, not post-stress): >20 μg/L warrants evaluation for hypothyroidism or pituitary adenoma 2
• Testosterone and androstenedione: testosterone >2.5 nmol/L or androstenedione >10.0 nmol/L suggests PCOS or adrenal pathology 2
• Mid-luteal progesterone (day 21 of 28-day cycle): <6 nmol/L indicates anovulation 2
• Fasting glucose and insulin: glucose >7.8 mmol/L or glucose/insulin ratio >4 suggests insulin resistance associated with PCOS 2
• TSH and free T4: to exclude thyroid dysfunction as a cause 2

Imaging

• Transvaginal or transabdominal pelvic ultrasound (day 3-9 of cycle): >10 peripheral cysts 2-8 mm diameter with thickened ovarian stroma confirms polycystic ovaries 2

Common Pitfalls to Avoid

• Do not attribute menstrual irregularities to tofacitinib without proper evaluation. PCOS affects 4-6% of the general population and is the most common cause of irregular periods in reproductive-age women 2
• Do not overlook weight changes as a trigger. Tofacitinib itself does not cause weight gain, but concurrent corticosteroid use is common in rheumatologic and gastroenterologic conditions; weight gain reduces insulin sensitivity and can trigger PCOS in predisposed women 2
• Do not measure prolactin immediately after stress or seizure activity, as this causes transient elevation unrelated to true hyperprolactinemia 2
• Do not confuse isolated polycystic ovaries (17-22% of normal women) with PCOS syndrome, which requires both ovarian morphology and clinical/biochemical hyperandrogenism 2

Management Based on Findings

If PCOS is Diagnosed

• Address insulin resistance: metformin for patients with elevated glucose/insulin ratio or BMI >25 2
• Manage hyperandrogenism: combined oral contraceptives (if not contraindicated by thrombotic risk) or anti-androgens 2
• Weight reduction: even 5-10% weight loss can restore ovulatory cycles in obese women with PCOS 2

If Hypothalamic Amenorrhea is Diagnosed

• Evaluate for excessive exercise, stress, or eating disorders 2
• Consider reducing immunosuppressive burden if disease activity permits, as chronic inflammation and high-dose corticosteroids can affect the hypothalamic-pituitary axis 2

If Hyperprolactinemia is Confirmed

• Rule out hypothyroidism and pituitary adenoma with TSH and MRI if prolactin persistently >20 μg/L 2
• Review all medications: while tofacitinib does not affect prolactin, concurrent medications may 2

Regarding Tofacitinib Continuation

• Continue tofacitinib if controlling underlying disease (rheumatoid arthritis or ulcerative colitis), as there is no evidence linking it to menstrual dysfunction 1
• Ensure appropriate contraception if sexually active: tofacitinib has no pregnancy safety data and should be avoided in pregnancy; highly effective contraception (IUD or implant) is recommended 2
• Maintain standard tofacitinib monitoring: CBC, CMP, and lipids at 4-8 weeks then every 3 months, but hormonal monitoring is not required unless abnormalities are identified 2