What is the approach to hormone replacement therapy (HRT) in patients with hormonal deficiencies?

Approach to Hormone Replacement Therapy (HRT) in Patients with Hormonal Deficiencies

Hormone replacement therapy should be tailored to the specific hormonal deficiency, with careful consideration of patient-specific risk factors, while prioritizing the transdermal route for estrogen administration whenever possible due to its superior safety profile.

General Principles of Hormone Replacement

Adrenal Insufficiency

1. First priority in multiple deficiencies: Always start corticosteroid replacement before other hormone replacements to avoid precipitating adrenal crisis 1
2. Recommended regimen: Hydrocortisone 15-20 mg in divided doses for maintenance therapy 1
3. Education requirements: All patients need instruction on:
   • Stress dosing for sick days
   • Use of emergency injectable steroids
   • When to seek medical attention for impending adrenal crisis
   • Medical alert bracelet/necklace 1

Thyroid Deficiency

• For primary hypothyroidism: Thyroid hormone replacement with goal of normal TSH
• For central hypothyroidism: Target free T4 in upper half of reference range (TSH is not accurate) 1

Sex Hormone Deficiency

Estrogen Replacement

• Preferred formulation: Transdermal 17β-estradiol (50-100 μg daily) 1

  • Advantages over oral formulations:
    • Mimics physiological serum estradiol concentrations
    • Avoids hepatic first-pass effect
    • Minimizes impact on hemostatic factors
    • Better profile on lipids, inflammation markers, and blood pressure
    • More effective for bone mineral density 1

• Alternative options:

  • Oral 17β-estradiol: 1-2 mg daily
  • Conjugated equine estrogens: 0.625-1.25 mg daily 1

Progestin (for women with intact uterus)

• First choice: Micronized progesterone (100-200 mg daily for 12-14 days every 28 days) 1

  • Advantages:
    • Minimizes cardiovascular risks
    • Neutral/beneficial effect on blood pressure
    • Better safety profile for thrombotic risk 1

• Alternatives when micronized progesterone is contraindicated:

  • Medroxyprogesterone acetate: 5-10 mg daily
  • Norethisterone: 5 mg daily 1

Testosterone Replacement (for men)

• Indications:

  • Primary hypogonadism (testicular failure)
  • Hypogonadotropic hypogonadism
  • Delayed puberty in carefully selected males 2

• Important note: Safety and efficacy in age-related hypogonadism have not been established 2

Special Populations

Cancer Survivors

1. Gynecological cancers:

   • No contraindication for HRT in cervical, vaginal, or vulvar cancers (not hormone-dependent)
   • Favorable risk/benefit for most ovarian cancers (high-grade, clear cell, mucinous) and early-stage endometrial cancer 1
   • Contraindicated in:
     • Low-grade serous epithelial ovarian cancer
     • Granulosa cell tumors
     • Certain sarcomas (leiomyosarcoma, stromal sarcoma)
     • Advanced endometrioid uterine adenocarcinoma 1

2. Endometrial cancer:

   • Estrogen replacement therapy is reasonable for patients at low risk for tumor recurrence
   • Consider 6-12 month waiting period after adjuvant treatment 1
   • Several studies show no increase in tumor recurrence or cancer-related deaths 1

3. Premature ovarian insufficiency due to cancer treatment:

   • HRT strongly recommended until at least the average age of natural menopause (age 52) for women without contraindications 3
   • Benefits include improved quality of life, delayed onset of cardiovascular issues, reduced fracture risk, enhanced cognitive function 3

Immune Checkpoint Inhibitor-Related Endocrinopathies

• For hypophysitis with hormonal deficiencies:
  1. Start corticosteroid replacement first
  2. Add thyroid hormone if needed (target free T4 in upper half of reference range)
  3. Add sex hormone replacement if needed and no contraindications exist 1

Monitoring and Follow-up

Initial Assessment

• Evaluate baseline hormone levels appropriate to the deficiency
• For pituitary disorders: ACTH, cortisol, TSH, free T4, LH, FSH, testosterone/estradiol 1
• Consider MRI of pituitary for new hormonal deficiencies or multiple endocrine abnormalities 1

Ongoing Monitoring

• Regular assessment of hormone levels to ensure adequate replacement
• For adrenal insufficiency: Consider testing for recovery of HPA axis after 3 months of maintenance therapy 1
• For osteoporosis risk: Monitor bone density, supplement vitamin D and calcium as needed 1

Risks and Benefits

Benefits

• Relief of menopausal symptoms (vasomotor symptoms, genitourinary syndrome) 4
• Prevention of osteoporotic fractures 4
• Possible cardiovascular risk reduction when started soon after menopause 4
• Reduction in colorectal cancer risk with estrogen-progestin therapy 4

Risks

• Small increased risk of stroke that persists over years 4
• Increased breast cancer risk with long-term estrogen-progestin use 4
• Potential for fluid retention (caution in cardiac or renal dysfunction) 5
• May exacerbate certain conditions: asthma, epilepsy, migraine, SLE, hepatic hemangiomas 5

Common Pitfalls to Avoid

1. Starting other hormones before corticosteroids in multiple deficiencies, which can precipitate adrenal crisis 1
2. Relying on TSH alone in central hypothyroidism (target free T4 instead) 1
3. Using oral estrogen in patients with increased cardiovascular or thrombotic risk (use transdermal) 1
4. Overlooking the need for progestin in women with intact uterus (increases endometrial cancer risk) 5
5. Failing to provide stress-dosing education for patients on corticosteroid replacement 1

By following these evidence-based guidelines and considering individual patient factors, hormone replacement therapy can effectively address hormonal deficiencies while minimizing risks and improving quality of life.