Infertility with Hypothyroidism - OB&G Clinical Overview

1. Epidemiology & Etiology of Hypothyroidism in Women of Reproductive Age

• Creasy & Resnik's Maternal-Fetal Medicine, p. 1502

2. How Hypothyroidism Causes Infertility - Pathophysiology

A. Disruption of the HPG Axis

• Hypothyroidism decreases sex hormone levels and increases prolactin (via elevated TRH stimulating pituitary lactotrophs)
• Elevated prolactin produces abnormal GnRH secretion/pulsatility, causing:
  • Oligo/anovulation
  • Menstrual disturbances (oligomenorrhea, amenorrhea, menorrhagia)
  • Up to 25% of hypothyroid women have menstrual irregularities that may respond to thyroxine treatment
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1503
• Berek & Novak's Gynecology, p. 1879

B. Uterine Receptivity Impairment

• Deiodinases, T3 and T4 receptors in the uterine epithelium change expression throughout the menstrual cycle
• Hypothyroidism alters uterine epithelial proliferation and differentiation, impairing fertilization and embryo implantation
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1503

C. Hyperprolactinemia (secondary)

• Elevated TSH stimulates excess prolactin from the pituitary
• Prolactin suppresses the HPG axis, causing additional anovulation and luteal phase defects
• On lab evaluation: elevated TSH with or without elevated prolactin = primary hypothyroidism
• Goldman-Cecil Medicine, p. 1649

3. Clinical Presentation

• Oligomenorrhea or amenorrhea (amenorrhea occurs in only some hypothyroid women)
• Menorrhagia (heavy periods) - also possible
• Galactorrhea (if hyperprolactinemia is co-present)

• Weight gain, constipation, cold intolerance
• Dry skin, coarse brittle hair/nails, periorbital edema
• Fatigue, bradycardia, diastolic hypertension
• Depression, memory deficits, slowing speech
• Anemia (normocytic or megaloblastic)

4. Investigations

All amenorrheic and oligomenorrheic women should have basal FSH, prolactin, and TSH measured to confirm clinical impression. - Goldman-Cecil Medicine, p. 1647

The PCOS diagnosis explicitly excludes patients with significant thyroid dysfunction - thyroid disease must be ruled out before labeling as PCOS. - Berek & Novak's Gynecology, p. 1879

5. Subclinical Hypothyroidism (SCH) and Infertility

• Retrospective and cross-sectional studies in couples undergoing ART show a dose-dependent association between mild TSH elevations above the population median (1.7-2.0 mIU/L) and:
  • Infertility
  • Lower ovarian reserve
  • Decreased pregnancy rates
• LT4 treatment of mild SCH generally shows higher pregnancy and delivery rates in ART patients
• Current evidence most strongly associates infertility with overt hypothyroidism, particularly in the setting of TPO antibody positivity
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1503

6. Management

Step 1: Treat the hypothyroidism with Levothyroxine (LT4)

• T4 is critical for fetal brain development

• 80% of circulating T3 comes from conversion of T4

• Creasy & Resnik's Maternal-Fetal Medicine, p. 1504

Step 2: Optimize LT4 Absorption

• Take LT4 fasting in the morning, 60 min before breakfast, OR at bedtime (3+ hours after last meal)
• Avoid co-ingestion with: ferrous sulfate, iron-containing prenatal vitamins, high-dose calcium, soy products (take 4+ hours apart)
• Conditions like celiac disease, atrophic gastritis, gastroparesis may require higher doses or gel-cap formulation (Tirosint)

Step 3: Monitor and Adjust

• Recheck TSH 4-6 weeks after dose initiation or change
• Increase LT4 dose by ~25-30% as soon as pregnancy is confirmed (metabolic demands increase)
• If prolactin remains elevated despite euthyroid state on LT4, evaluate for pituitary adenoma (MRI pituitary)

Step 4: Induce Ovulation if Needed

• Once euthyroid, many women resume spontaneous ovulation
• If anovulation persists despite normal TSH, consider ovulation induction:
  • First line: Letrozole
  • Second line: Clomiphene citrate
• Harrison's Principles of Internal Medicine, p. 1404

7. Pregnancy Considerations

• LT4 requirements increase by ~30-50% in pregnancy - adjust immediately when pregnancy is confirmed
• Untreated overt hypothyroidism is associated with adverse perinatal outcomes: miscarriage, preeclampsia, preterm birth, fetal growth restriction, and impaired fetal neurologic development
• Screen all pregnant women with risk factors for thyroid disease (personal/family history, symptoms, autoimmune disease)
• Anti-TPO antibody positivity even with normal TSH is associated with increased risk of miscarriage and preterm birth

8. Summary Algorithm

Infertile woman
        |
        ↓
Rule out pregnancy (hCG)
        |
        ↓
Screen: TSH, Prolactin, FSH
        |
    ┌───┴───┐
Elevated TSH    Normal TSH
    |              |
    ↓              ↓
Free T4        Further workup (PCOS, POI,
Anti-TPO        hyperprolactinemia, structural)
    |
    ↓
Overt vs. Subclinical hypothyroidism
    |
    ↓
Start LT4 → Target TSH 0.5-2.5 mIU/L
    |
    ↓
Re-evaluate ovulation
    |
    ↓
If anovulation persists → Ovulation induction (Letrozole)

1. TSH is the single most important first test in a woman with anovulatory infertility
2. Hypothyroidism must be excluded before diagnosing PCOS
3. Even mild TSH elevation above 2.5 mIU/L can impair fertility, especially with anti-TPO positivity
4. LT4 treatment alone may restore fertility in overt/significant subclinical hypothyroidism
5. LT4 dose must be increased immediately upon confirmed pregnancy