Dr.Nihal El Habachi MD Professor of Physiology, Executive Academic & administrative

Director of Alex CRC, Faculty of Medicine-Alexandria University

Certified Trainer of GCP & Clinical Research Coordination, University of Maryland,USA

Nutrition 2015,Chicago,USA

CDSCO

Egypt

The menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity.

It is associated with several disorders including:

IR

E2 has both direct antioxidant effect due to the similarity of its structure with Vit E and indirect effect through upregulation of both enzymatic and non enzymatic scavengers.

The loss of estrogens associated with menopause leads to increase ROS production and OS.

OS is defined as imbalance between ROS and antioxidants in favour of the former with formation of peroxidation products.

Recently, many studies suggested the involvement of OS in several menopausal disorders.

Hormonal replacement therapy

The principal risks

Stroke

Venous thromboembolic events

Breast & endometrial cancer

So it is suggested to use alternative treatments as

Antioxidants

Oxidative stress

Weight gain& visceral obesity

Dyslipidemia

Insulin resistance

Osteoporosis

Vitamin C&A

Estrogen replacement

Group I:Normal,Control

Group II:Oophorectomised (OVX)

Group III:OVX+E2

Group IV: OVX+ Vitamins

10 sham operated rats represented as controls received corn oil daily orally.

10 bilaterally ovariectomized (OVX) female rats received corn oil daily orally.

10 OVX rats received 17β- estradiol (E2) (0.5 mg/kg/day) orally.

Group III OVX+E2

10 OVX rats received daily doses of vitamin C (100mg/kg)dissolved in distilled water and vitamin A (1500 IU/kg) dissolved in corn oil orally.

The doses were decreased gradually over a period of 10 days till a maintenance doses (vit A 500 IU/kg) and (vit C 25mg/kg).

All treatments started from the day following surgery up to 6 weeks (end of the study).

Body weight was assessed before and every week of the experimental period.

Treatment was given

via a gastric tube .

All rats were weighed to assess the weight gain.

The perinephric, mesenteric, and retroperitoneal fat

pads are removed and weighed as an indicator for

visceral obesity.

blood sample:

Markers of oxidative stress: TAO, MDA

Total lipid profile: TC, TG, HDL, LDL

Fasting serum insulin

Fasting blood glucose

HOMA-IR

BALP as a marker for bone formation.

0

0.5

1

1.5

2

2.5

Control OVX OVX + E2 OVX +Vitamins

Me

an

(TAO) [mM/L]

*

Mean serum total antioxidant capacity (TAO)

* : significantly different in comparison to control : significantly different in comparison to OVX group

0

2

4

6

8

10

12

14

Control OVX OVX + E2 OVX +Vitamins

Me

an

(MDA) [nmol/ml]

* *

*

* : significantly different in comparison to control group :significantly different in comparison to OVX group :significantly different in comparison to OVX+ E2 group

Mean serum malondialdehyde (MDA)

Mean weight gain and weight of visceral fat in grams

0

5

10

15

20

25

30

35

Me

an

Weight gain

*

0

1

2

3

4

5

6

Me

an

Weight of visceral fat …

*

*: significantly different in comparison to control sham operated group significantly different in comparison to ovariectomized group

* : significantly different in comparison to control group : significantly different in comparison to OVX group : significantly different in comparison to OVX+ E2 group

*

*

* *

Lipid profile in all studied groups

Increases the No. of hepatic LDL receptors leading to increase LDL clearance.

Increase the rate of production of triglyceride rich VLDL

Increases hepatic expression of apolipoprotein-A1 & decreases HTGL activity that degrades TG portion in HDL leading to a decrease in clearance of HDL.

Estrogen

Activation of 7 α- hydroxylase that enhances the conversion of cholesterol into cholic acid.

Prevents the peroxidation of LDL enhancing its clearance.

Correlation between MDA and LDL

0

20

40

60

80

100

120

140

160

0 2 4 6 8 10 12 14 16 18 20

LDL

Malondialdehyde (MDA)

r= 0.69** P=.000

0

20

40

60

80

100

120

Control OVX OVX + E2 OVX +Vitamins

Me

an

Fasting blood glucose level

* * *

Mean fasting blood glucose (FBG) level (mg/ dl)

* : significantly different in comparison to control group : significantly different in comparison to OVX group

insulin

IR Tyrosine phosphorylation

GLUT-4 vesicle

glucose

GLUT-4

modulate insulin receptors tyrosine phosphorylation.

insulin

IR Tyrosine phosphorylation

GLUT-4 vesicle

glucose

GLUT-4

Induction of Glut-4 expression in skeletal muscle and white adipose tissue

Oxidative stress leads to activation of multiple serine kinases targeting insulin receptors leading to impaired insulin action.

β cells of pancreas are vulnerable to ROS due low antioxidant levels

GLUT4 levels

Estrogen • Activation of estrogen receptors in osteoblasts iduces

anabolic activity and reduces the pathway which osteoblasts can activate osteoclasts.

• Estrogen deficiency leads to activation of several cytokines as TNF-α and RANKL producing bone resorption and increasing bone resorption markers.

• Bone formation also increased to fill in resoptive areas

leading to increase bone formation markers.

• However Bone resortion > bone formation leading to osteoporosis.

Correlation between MDA and urinary hydroxyproline

0

5

10

15

20

25

30

35

0 5 10 15 20

Hyd

roxy

po

rlin

e le

vel

Malondialdehyde (MDA)

r=0.76** P=.000

ROS (+) osteoclastogenesis

(-) osteoblast differentiation

Antioxidants may inhibit OS-induced osteoporosis

Vitamin C is an important micronutrient for bone Health as it is Cofactor for collagen ,hydroxyproline and hydoxylysine.

Low dose of vitamin A could be protective for bone

Similar actions of estrogen and antioxidant vitamins regarding :

- oxidative stress

- weight gain & visceral obesity

- Dyslipidemia

- Insulin resistance

- Osteoporosis

However the main differences

Vitamins didn’t increase plasma triglycerides in OVX rats.

Vitamins were significantly more

potent to decrease the oxidative

stress marker MDA.

A future promising modality in preventing menopausal disorders.

Further studies are needed to demonstrate the efficacy of this combination of vitamins in the clinical setting.

Prof. Hala Maklad