Female repro L5: Menopause

Question 1

Physiology of Menopausal Transition

Answer 1

• Best indicator of reduced ovarian reserve is decreased anti-Mullerian hormone (AMH) levels (granulosa cells)
• Increased serum FSH levels result from absence of inhibin B (also from Granulosa cells)
  
  • – Inhibin B levels normally inhibit FSH secretion in early follicular phase
  • – Decrease in levels believed to initiate menopause
  • – Low levels increase follicular recruitment and induce aromatase enzyme activity to maintain E2 at near normal levels
  • – Ultimately leads to follicular depletion
• Later the number of follicles recruited per cycle decreases
  
  • – Ovulation becomes irregular leading to poor corpus luteum development
  • – Reduced progesterone secretion
  • – Lengthening of the menstrual cycle
• The ovaries become unresponsive with near total follicular
• depletion (<1000)
  
  • – Markedly elevated FSH levels (10 – 20-fold)
  • – 3-fold rise in LH levels (shorter half-life)
• Sustained theca cell response to LH stimulation maintains androgens secretion
• Serum estradiol (E2) levels decline making estrone (E1) the predominant estrogen (Peripheral aromatization of ovarian and adrenal androgens)

Question 2

Pathophysiology of Immediate Symptoms: Hot flashse

Answer 2

• Mechanisms are related to
• – Thermal dysregulation resulting from loss of estrogen- induced opioid activity in the hypothalamus; Obese women are relatively protected
• – High endogenous production of estrone and low SHBG levels
• – Estrogenic actions are mediated by noradrenaline and serotonin
  
  • Clonidine (α-adrenergic agonist) used in symptomatic treatment (vasomotor stabilizing effects)
  • Venlafaxine (SSNRI) as an alternative to estrogen replacement
• – Action of interleukin-1 and interleukin-7 on the hypothalamus (relate to thermoregulation)

Question 3

Pathophysiology of Immediate Symptoms: Mood disturbances

Answer 3

• Associated with estrogen deficiency-induced fall in neurotransmitter levels e.g. serotonin
• History of postnatal depression and premenstrual syndrome increases risk

Question 4

Pathophysiology of Intermediate Symptoms

Answer 4

• Estrogen deficiency induces loss of collagen leading to generalized atrophy
• Estrogen improves cutaneous circulation
• Estrogen deficiency leads to reduced blood flow to vaginal epithelium
  
  • – Vaginal atrophy
  • – Decreased glycogen production
  • – Decreased cervical secretion resulting in vaginal dryness
• Estrogen contributes to the integrity of lower urinary tract
  
  • – Internal urethral sphincter, and epithelium of the trigone and urethra are estrogen sensitive
• Effects of estrogen deficiency on the lower urinary tract
  
  • – Reduced tone of internal urethral sphincter
  • – Atrophy of the urethral epithelium
  • – Reduced collagen content of periurethral tissue
  • – Increased incidence of dysuria, urgency and frequency (urethral syndrome)
• Generalized body pain results from loss of collagen in joints and ligaments

Question 5

Osteoporosis

Answer 5

**Risk Factors **

• Genetics (Family history)
• Race (Caucasian/Asian)
• Estrogen deficiency
• Glucocorticoid treatment
• Eating disorder
• Prolonged bed rest/sedentary lifestyle
• Prolonged heparin treatment

Question 6

Osteoporotic fracture & Pathogenesis

Answer 6

• Estrogen exhibits both skeletal and extraskeletal effects on bone homeostasis
• Skeletal actions could be direct or indirect
  
  • – Direct actions mediated through estrogen receptors on osteoblasts
  • – Indirect through estrogen receptors on other cells
• Estrogen deficiency contributes to the pathogenesis of osteoporosis

Extraskeletal effects of estrogen deficiency

• Increased renal calcium excretion and decreased intestinal calcium absorption
• Secondary hyperparathyroidism
• Enhances sensitivity of bone to PTH
• Senile renal changes in vitamin D metabolism
• The immune cells mediate many indirect effects of estrogen deficiency
  
  • – Increased production of cytokines and other inflammatory mediators IL-1, IL-6, TNF-α, PGE2
  • – Estrogen treatment increases production of IGF-1 and TGF-β by osteoblasts
• Increased IL-7 in estrogen deficiency leads to T- cell activation
• Activated T-cells produces more IFN-γ and TNF-α
• IFN-γ upregulates MHC class II molecules on APCs
• (bone marrow macrophages and dendritic cells)
• Upgraded MHC class II further activate T-cells to secrete more RANKL and TNF-α
• Estrogen deficiency creates a progressive inflammatory state
  
  • – Increased systemic IL-1, IL-6 and TNF-α
  • – Expanded CD8+, CD57+ subset
  • – Accumulation of reactive oxygen species in the bone marrow
• Antigen-presenting potential increase many folds following ovariectomy

Question 7

Diagnosis of Osteoporosis

Answer 7

• Biochemical markers of increased bone turnover
  
  • – Osteocalcin
  • – Urinary hydroxylysylpyridinoline & lysylpyridinoline
• Radiographic examinations
• Measurement of bone mineral density (BMD) – Gold standard

Question 8

Prevention and Treatment of Osteoporosis: Pharmacologic measures

Answer 8

• Hormone replacement therapy (HRT): Estrogen
• Bisphosphonates
• Calcitonin
• Selective estrogen receptor modulators (SERMs)
• Sodium fluoride

Question 9

HRT: Contraindications

Answer 9

• Possibility of pregnancy
• Undiagnosed abnormal vaginal bleeding
• Active or recent angina or myocardial infarction (MI)
• Suspected, current or past breast cancer
• Endometrial cancer or other estrogen-
• dependent cancers
• Active liver disease
• Uncontrolled hypertension

Question 10

HRT: Risks

Answer 10

• Venous thromboembolism
• Stroke
• Cardiovascular disease (MI, hypertension)
• Breast cancer– Higher with combined HRT
  
  • Combined trophic effect of estrogen and progesterone
  • Increase breast density and risk of having abnormal mammogram