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

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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?

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• QUESTIONS?