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The Roles of Estrogen and Testosterone in Diabetic Nephropathy

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Both OBESITY and PCOS are associated with elevated androgen levels and increased ... Castration of diabetic male rats delays the progression and decreases the ... – PowerPoint PPT presentation

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Title: The Roles of Estrogen and Testosterone in Diabetic Nephropathy


1
The Roles of Estrogen and Testosterone in
Diabetic Nephropathy
  • A Clinical Trial
  • Shannon D. Sullivan, MD, PhD
  • Christine Maric, PhD

2
Hypotheses
  • There is an imbalance in the estrogen
    testosterone (ET) in patients with DM2,
  • AND
  • The ET imbalance is associated with increased
    incidence and progression of diabetic nephropathy

3
Hypotheses
  • In diabetic women, the ET ratio is decreased due
    to low E and/or high T
  • Both OBESITY and PCOS are associated with
    elevated androgen levels and increased incidence
    of DM2

4
Clinical data
  • Men have a higher incidence of DM2, and earlier
    and more severe progression of diabetic
    nephropathy, than women
  • Women with PCOS, which is defined by elevated
    androgens, have a higher prevalence of IR and DM2
  • Diabetic women have a higher prevalance of
    menstrual disorders, suggesting altered steroid
    hormone balance

5
Clinical data
  • Diabetic women reach menopause earlier than
    non-diabetics, suggesting lower baseline E levels
  • In postmenopausal women with DM2, estrogen
    replacement therapy decreased testosterone, and
    this was associated with improvement in glucose
    control as indicated by decreased fasting glucose
    and HbA1C levels

6
Laboratory Studies
  • Estrogen
  • In rat models of DM2, females have decreased
    serum estrogen levels compared to non-DM females
  • Decreased E is associated with earlier
    progression and increased severity of diabetic
    nephropathy
  • ER expression in the kidneys of diabetic females
    is altered, further implicating E signaling in
    diabetic nephropathy

7
Laboratory Studies
  • Estrogen
  • Estrogen replacement to female diabetic rats
    attenuates the decline in renal function and
    changes in kidney pathology associated with
    diabetes
  • One mechanism for Es action is altered
    expression of renal Na-K-2Cl co-transporters and
    epithelial Na channels

8
Laboratory Studies
  • Estrogen
  • Raloxifene (a SERM) administered to female
    diabetic rats decreased proteinuria and
    pathologic changes of nephropathy, implicating
    signaling pathways specific to the ER

9
Laboratory Studies
  • Testosterone
  • Castration of diabetic male rats delays the
    progression and decreases the severity of
    diabetic renal disease

10
Laboratory Studies
  • Testosterone
  • Exogenous testosterone treatment to diabetic
    female animals promotes earlier onset and
    increases the severity of diabetic renal damage

11
Unknowns in humans
  • Are hormone levels altered in human diabetics?
  • Do altered hormone levels in diabetic patients
    correlate with the progression of diabetic renal
    disease?
  • Is estrogen protective against, and/or, does
    testosterone contibute to, diabetic renal disease?

12
Study Design
  • Participants
  • Premenopausal women with DM2 with diabetic renal
    disease
  • Premenopausal women with DM2 without renal
    disease
  • Age-matched men with DM2 with diabetic renal
    disease
  • Age-matched men with DM2 without renal disease
  • Premenopausal, non-diabetic women (controls)
  • Age-matched, non-diabetic men (controls)

13
Study Design
  • Initial medical HISTORY, including menstrual hx,
    diabetic hx, and medications
  • DATA COLLECTION
  • PHYSICAL exam, including BP and BMI
  • LABWORK
  • Urine AlbCr
  • Steroid hormone levels E, T and SHBG, FSH and
    LH in women
  • Cr, fasting glc, HbA1C, lipids

14
Statistical Analysis
  • Are hormone levels altered in diabetics compared
    to controls?
  • Do altered hormone levels correlate with renal
    disease?
  • Are altered hormone levels independent of
  • Obesity?
  • Metabolic syndrome?
  • PCOS?
  • ACEI or ARB?

15
Future Investigations . . .
  • Do post-menopausal women taking HRT have a
    decreased incidence of DM and/or complications of
    DM?
  • Do women who are taking or have been treated with
    tamoxifen and/or AIs as adjuvant therapy for
    ER- breast ca have a decreased incidence of DM
    and/or complications of DM?
  • Do African American women, who have a higher
    incidence of DM compared to caucasion women, have
    lower serum ET?

16
  • QUESTIONS?
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