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Effect of Orchidectomy and of Testosterone Administration upon Duodenal

Ulceration Induced by Cysteamine

Article · September 2012

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August-October, 2012, Vol. 2, No. 4, 1897-1912. e- ISSN: 2249 –1929

Journal of Chemical, Biological and Physical Sciences An International Peer Review E-3 Journal of Sciences

Available online at www.jcbsc.org

Section B: Biological Science

CODEN (USA): JCBPAT

Research Article

1897 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

Effect of Orchidectomy and of Testosterone Administration upon Duodenal Ulceration

Induced by Cysteamine

Ashokan Kannarath Valappil,

Department of Zoology, P.V.P.Colleeg, Kavathe Mahankal,Sangli,

Maharashtra, India-416405

Received: 16 August 2012; Revised: 11 September 2012; Accepted: 15 September 2012

ABSTRACT

Duodenal ulcers were induced in adult and old male mice using cysteamine hydrochloride under various

experimental conditions. Under these experimental conditions, orchidectomized adult and normal old

male mice strikingly decreased sensitivity to ulcer induction while testosterone propionate administration

to orchidectomized adult mice showed an increased sensitivity to ulcer induction. This change in ulcer

sensitivity reflected from histological, histochemical and biochemical studies. The histological study was

performed by using haematoxylene-eosin staining technique. The histochemistry of the duodenal region

was studied by using periodic acid Schiff reaction (PAS) for glycoprotein. The biochemical study was

performed to study various constituents of glycoprotein like hexose, fucose, sialic acid and the protein

from Brunner’s gland. The result showed that ulcer severity was more in orchidectomized- cysteamine

treated mice and old mice treated with cysteamine. The histological studies showed that orchidectomy

decreased or did not show any change in the ulcer sensitivity considering Cryptus Lieburkuhn and

Brunner’s glands. The same result reflected by differential intensity in the staining property of the

Brunner’s gland. The biochemical study showed that the glycoprotein contents were reduced many times

in orchidectomized-cysteamine treated-testosterone administered adult and old male mice. These

findings prove that testosterone of booth exogenous and endogenous augment the ulcer pathogenesis in

cysteamine induced ulcer in male mice.

Keywords: Duodenal ulcer, orchidectomy, Cysteamine, Testosterone propionate, Ulcer index, and Brunner’s gland.

Effect… Ashokan Kannarath Valappil.

1898 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

INTRODUCTION

Gastric ulcer and peptic duodenal ulcer is one of the serious health problems worlds over. Available evidence

suggests that duodenal ulcer is due to multiple causes, including infection of Helicobacter pylori, gastric

acid, pepsin, and “defensive” factors such as duodenal mucosal bicarbonate secretion and sex hormones1-4

Peptic ulcer occurs more frequently in men than in women5. The sex differences are less marked after 45

years of age probably because the incidence of ulcer increases in post menopausal women6,7. The general

assumption is that ulcer differences between sexes are related in some way to sex hormone, estrogen, protect

against ulceration6,7.

Aggressive role of androgens and estradiol and their precursors and metabolites in the pathogenesis of

duodenal ulcer was reported3. The mucosal injury in duodenal ulcer was prevented by orchidectomy and by

the treatment with the antiandrogens, cyprotetrone acetate4. Treatment of testosterone in oophrectomized rat

shows enhanced peptic ulcer within 24 hours, but HCl and pepsin output were not affected by androgen

treatment8 . The same study 8 showed that even though androgen enhances the susceptibility of gastric

mucosa to the peptic action of gastric juice, the ulcerogenic effect of male sex hormone is not confirmed.

Bilateral castration of the male rats showed significant reduction in acid gastric secretary responses to

carbachol but not to histamine9.

When castrated rats were given short-term-treatment with 17β-estradiol, there was reduction in acid gastric

secretion9 . The enhancement of ulcer by female sex hormone also reported10,11. The effect of testosterone in

duodenal ulcer is not uniformly confirmed. To substantiate the controversial effect of testosterone on

duodenal ulcer we performed a study on the effect of testosterone propionate on duodenal ulcer induced by

cysteamine in adult female mice, orchidectomized mice, old male mice and old orchidectomized mice.

2. MATERIALS AND METHODS

2.1. Experimental animals: There were 70 male mice (Swiss albino mice (Mus musculus) in the present

study. All the mice were housed in a standard animal care room with a 12-h light, 12-h dark cycle, and were

allowed free access to food and water. The mice were divided into two groups- 2 months old males (40

members) n=10 (Control animals), n=10(mice treated with cysteamine-HCl), n=5(orchidectomized

mice),n=5(orchidectomized mice treated with cysteamine-HCl),n=5 (orchidectomized treated with

testosterone propionate ), n=5 (orchidectomized mice treated with cysteamine-HCl and testosterone

propionate) and 3 years old male males (30 members) n=10 (control animal), n=5(male mice treated with

cysteamine-HCl), n=5 (male mice treated with cysteamine-HCl and testosterone propionate), n=5 (Old mice

treated with cysteamine and testosterone propionate) and n=5 (Old mice orchidectomized-cysteamine and

testosterone treated)

2.3. Castration and administration of testosterone: The bilateral orchidectomy was done under mild ether

anesthesia. The orchidectomized mice were maintained for 15 days in separate cages with optimum care of

light, temperature, humidity, food and water. On the 16th day of orchidectomy 10 orchidectomized mice were

treated with cysteamine (40mg/100g body weight) (i.p) and five mice were treated with testosterone

propionate (4 mg/100g body weight dissolved in olive oil) (Sigma, Batch no. T.1875) (i.p) consecutively for

3 days. The five orchidectomized cysteamine treated mice were injected testosterone in olive oil. On the 4th

day of the 1st injection, cysteamine treated castrated and cysteamine treated orchidectomized testosterone

Administered mice and the orchidectomized mice were used for duodenal ulcer index calculation12. Ten 3

years old mice were used for administration of cysteamine (40mg/100 body weight) (i.p) consecutively for 3

Effect… Ashokan Kannarath Valappil.

1899 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

days. Out of ten, cysteamine treated 3 years old mice, five mice were received testosterone (2 mg/100g body

weight dissolved in olive oil) and five mice were received cysteamine and testosterone as previous.. After

three days, cysteamine treated, cysteamine treated –testosterone administered and control, three years old

mice were subjected for ulcer index calculation.

2.4. Duodenal ulcer index: The duodenal ulcer index were critically evaluated with respect to percentage

incidence, number of ulcers per mice and severity of ulcers were graded according to scale from 0 to 3 based

on microscopic observations and later confirmed by sectioning and staining of the ulcer regions. Zero for no

ulcers, one for superficial mucosal ulcers, two for deep ulcers and three for perforating ulcers. The ulcer

index was calculated by the formula:-

Ulcer index = Mean severity + Incidence (i.e. positive/ total) × 2

2.5. Histology: The tissues were fixed in 10% neutral buffered formalin, washed and routinely processed for

histological technique. The sections were stained with haematoxylene-eosine13 . Histology of pyloric glands,

duodenal villi, Crypts of Lieberkuhn and Brunner’s glands in all groups was studied.

2.6. Histochemistry:To study the changes in the duodenal mucosa glycoprotein of crypts of Lieberkuhn,

goblet cells, pyloric gland cells and Brunner’s glands in all groups, PAS techniques14 was used.

2.7. Biochemistry:The glycoprotein from Brunner’s gland was isolated by the method of Satakopan and

Kurup15.To study various constituents of glycoproteins biochemical estimations of fructose16, hexose17, sialic

acid 18 and protein19 were used.

2.8. Data analysis: Statistical analyses were performed using the Statistical Package for Social Science

(version 13.0, SPSS, Inc) software. Results were expressed as means + SE (standard Error). All reported p-

values were made on the basis of 2-sided tests and compared to a significance level of 5%, differences were

considered statistically significant at p< 0.05.

3. RESULTS

The orchidectomized mice showed little ulceration (Ulcer index2.02) or no ulceration. The orchidectomized

+ testosterone propionate injected mice showed ulceration higher than orchidectomized mice (ulcer index

2.50) (Table.1) The orchidectomized + Cysteamine administered mice showed higher ulceration (Ulcer index

5.2 (Table.1).The administration of testosterone to cysteamine injected orchidectomized mice showed

ulceration (Ulcer index 5.9) higher than cysteamine treated orchidectomized male mice (UI 5.2).The old male

mice administered with cysteamine showed ulceration lower than adult mice administrated with cysteamine

(UI 4.1) (Table 2). The orchidectomized old mice administered with cysteamine showed ulcer index less than

old mice treated with cysteamine (UI 2.51). While the orchidectomized old mice treated with cysteamine and

testosterone showed ulcer index higher (UI 5.71).

The histology of normal, cysteamine treated and orchidectomized mice shown in (Fig 1-3). In

orchidectomized mice the pyloric glands was simple branched, tubular glands situated deep in the sub

mucosa. The pyloric pit occupies greater part of the sub mucosa. The gland cells were normal. The villi were

tall and uniform. The epithelial covers showed columnar cells and goblet cells arranged on basement

membrane.

The Crypts of Leiberkuhn stained more intensely with Haematoxylene-Eosin. The Brunner’s glands showed parenchyma of gland, divided into lobules. The acinar cells and tubules acini were made up of pyramid shaped cells. The nuclei were basally situated and lumen was very narrow. On cysteamine administration to orchidectomized mice showed disturbed pyloric pit (Fig 4).

Effect… Ashokan Kannarath Valappil.

1900 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

Table 1: Ulcer severity in adult male mice with and without Administration of Testosterone

Group Experimental mice Ulcer (In %) Percentage incidence

Superficial Deep Perforating

Mean severity

Ulcer index

Two months old female mice

orchidectomized 100

60 - - 02.05+0.14

2.06

orchidectomized + Testosterone

100

70

20

05

3.01+ 1.2

2.50

orchidectomized + cysteamine

100

10

60

30

3.10+ 0.05

5.2

Orchidectomized + Cysteamine + Testosterone

100

30

60

10

2.40+ 0.13

5.9

Table-2: Ulcer severity in old male mice with and without cysteamine and Testosterones administration

Group Experimental mice

Ulcer (In %) Percentage incidence

Superficial Deep Perforating Mean severity

Ulcer index

Three years old male mice

Old mice + Cysteamine

100

15

55

30

3.12 +1.20

5.1

Old mice + Cysteamine + Testosterone

100 25 55 5 2.31+ 0.15

5.4

Orchidectomized Old mice + Cysteamine

100 68 22 5 2.9+ 1.11 2.51

Orchidectomized Old mice + Cysteamine + Testosterone

100

21

68

10

2.85+0.11

5.71

Old mice (Control)

00 00 00 00 00 00

Effect… Ashokan Kannarath Valappil.

1901 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

PP-pyloric pit, PG-Pyloric gland BG- Brunner’s gland

Fig. 1: Micrograph of duodenum of Normal male mice

G-Goblet celli, E-Epithelium CL-Crypts of Leiberkuhn

Fig. 2: Micrograph of duodenum of cysteamine Treated male mice

Effect… Ashokan Kannarath Valappil.

1902 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

G-Goblet cell, E-Epithelium Brunner’sBG-Brunner’s gland, CL-Crypts of Leiberkuhn

Fig. 3: Micrograph of duodenum of Orchidectomized male mice

PP-Pyloric Pit, PG-Pyloric Gland, BG- Gland, U-Ulcer, CL-Crypts of Leiberkuhn

Fig. 4: Micrograph of duodenum of orchidectomized -cysteamine Injected mal Mice

Effect… Ashokan Kannarath Valappil.

1903 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

The pyloric glands decreased with enlarged lumen. The duodenal villi showed sign of destruction. The lamina propria showed inflammation the Crypts of Leiberkuhn showed irregular and picnotic nuclei and increased eosinophilia. The Brunner’s glands also showed increased eosinophilia. The cells of acini and tubulo acini showed decreased acini and dilated lumen. Testosterone treated orchidectomized male mice showed the histology similar to adult mice with (Fig 5).Upon administration of testosterone propionate in orchidectomized cysteamine treated mice the pyloric pit and pyloric glands showed more disturbances (Fig 6). The pyloric pit showed enlargement and pyloric gland showed increased eosinophilia, a sign of inflammation with more mast cells and mucosa showed erosion. The Crypts of Leiberkuhn also showed increased eosinophilia. The Brunner’s gland, the shape and size of the acinar cells are changed, the height of the cells were reduced. The acini cells were dilated. The lumen of ducts also showed dilation.

In the case of old mice the orchidectomization showed no difference in the overall structure of pyloric glands, pyloric pits and Brunner’s glands comparing to the orchidectomized adult male mice (Fig 7). Up on administration of cysteamine in orchidectomized old mice (Fig 8) the pyloric pit showed dilation, pyloric glands showed more eosinophilia and dilation of the pyloric pit increased. The Brunner’s glands showed increased eosinophilia. The cells of acini and tubulo acini showed decrease acini and dilated lumen. The administration of testosterone in systeamine treated orchidectomized old mice (Fig 9) showed enhanced ulcer induction. The pyloric pit showed dilation and increased eosinophilia than the orchidectomized-cysteamine treated old mice. Pyloric glands decreased more with enlarged lumen. The lamina propria showed increase eosinophilia. The cells of acini and tubulo acini showed decreased acini and dilated lumen.

E-Epithelium, CL-Crypts of Leiberkuhn, gland G-Goblet cell Fig. 5: Micrograph of duodenum orchidectomized - Hormone treated Mice

Effect… Ashokan Kannarath Valappil.

1904 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

PP-Pyloric pit, BG-Brunner’s gland, PG-Pyloric

Fig. 6: Micrograph of duodenum of orchidectomized Hormone injected-Cysteamine treated Injected Mice

G-Goblet cell, E- Epithelium, CL-Crypts of Leiberkuhn

Fig. 7: Micrograph of duodenum of Orchidectomized Old

Effect… Ashokan Kannarath Valappil.

1905 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

CL-Crypts of Leiberkuhn, U-Ulcer, PP-Pyloric pit, PG-Pyloric gland,BG- Brunner’s gland

Fig. 8: Micrograph of duodenum of Orchidectomized Old Mice treatedwith cysteamine

BG-Brunner’s gland, CL-Crypts of Leiberkuhn

Fig. 9: Micrograph of duodenum of Orchidectomized Old male Mice treated with cysteamine and Hormone

Effect… Ashokan Kannarath Valappil.

1906 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

The histochemistry of orchidectomized-testosterone treated mice (Fig 10) showed strong PAS (Periodic Acid Schiff Reaction) reaction in pyloric pit, pyloric gland and goblet cells, Crypts of Leiberkuhn and Brunner’s gland than orchidectomized-cysteamine treated mice (Fig 11).Up on administration of testosterone propionate in orchidectomized- cysteamine treated mice the PAS activity was reduced to bottom (Fig 12). The reaction was observed in pyloric pit cells, but it was not properly localized, indicating destruction of the structure. The goblet cells also showed poor PAS reaction. Crypts of Leiberkuhn showed reduced staining intensity. The PAS activity was diffused in both Crypts of Leiberkuhn and Brunner’s gland. In old mice (Fig 13) the orchidectomized-cysteamine treated- testosterone administered mice showed more ulcer sign in pyloric pit, pyloric glands, goblet cells and Brunner’s gland than orchidectomized- cysteamine treated mice (Fig.14 and 15). In biochemical study, carbohydrates and protein contents of soluble glycoprotein isolated from Brunner’s glands of male mice were evaluated. The values were found to be more in orchidectomized mice comparing to normal. There was maximum loss in orchidectomized-cysteamine treated- testosterone administered mice. The hexose content of normal mice was (78.21+ 0.21) and in orchidectomized mice it is (80.21+ 0.35). In orchidectomized- cysteamine treated- testosterone administered mice it was reduced to (28.96+ 0.15). In old mice the hexose contents was lower than orchidectomized adult mice. Upon administration of cysteamine in old mice the sugars was further lowered (Table 3). Administration cysteamine in orchidectomized old mice the hexose sugar lowered and the reduction was maximum in orchidectomized-testosterone-cysteamine treated old mice (10.99+0.45). The fucose, sialic acid and protein content showed decrease upon administration of cysteamine which was further reduces upon testosterone administration both in adult and old (Table 3). The maximum reduction was observed in orchidectomized-cysteamine treated-testosterone administered mice.

V-Villus, CL- Crypts of Leiberkuhn BG- Brunner’s g land, G-Goblet cell

Fig. 10: Micrograph of duodenum of Orchidectomized hormone treated Mice Stained with PAS

Effect… Ashokan Kannarath Valappil.

1907 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

V-Villus, CL- Crypts of Leiberkuhn BG- Brunner’ s gland

Fig. 11: Microphotograph of Orchidect- omized mice hormone and cysteamine treated with PAS

BG- Brunner’s gland, PP-Pyloric pit PG-Pyloric gland

Fig. 12: Micrograph of duodenum of Orchidectomized cysteamine treated mice with PAS

Effect… Ashokan Kannarath Valappil.

1908 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

BG- Brunner’s gland, CL- Crypts of Leiberkuhn, V-V illus, G-Goblet cell

Fig. 13: Micrograph of duodenum of old Orchidectomized

V-Villi, PP-Pylopric pit, BG-Brunner’s Gland, PG-Py loric gland

Fig. 14: Micrograph of duodenum of old Orchidectomized -cysteamine treated mice with PAS

BG-Brunner’s gland

Fig. 15: Micrograph of duodenum of old Orchidectomized -cysteamine-hormone

treated mice with PAS

Effect… Ashokan Kannarath Valappil.

1909 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

Table- 3: Carbohydrates and protein contents of soluble glycoprotein isolated from Brunner’s glands of

male mice

Group Hexose Fucose Sialic acid protein P- values

Normal

80.125 +0.72

1

3.85+0.01

12

0.26+0.01

23

20.48+0.14

34

1:2

p<0.005

23:24

P<0.001

Normal

+

Cysteamine

31.36+0.41

2

1.25+0.11

13

0.04+0.01

24

14.89+0.33

35

3:4

p<0.005

25:26

P<0.005

orchidectomized

67.48+0.74

3

2.82+0.04

14

0.11+0.09

25

16.47+0.17

36

5:6

p<0.005

27:28

P<0.001

orchidectomized

+

Cysteamine

15.30+0.23

4

0.49+0.01

15

0.31+0.00

26

13.53+0.18

37

7:8

p< 0.005

29:30

p< 0.001

orchidectomized

+

Testosterone

58.21+0.35

5

2.14+0.01

16

0.02.01

27

14.48+0.18

38

9:10

p<0.005

31:32

P< 0.005

orchidectomized

+

Cysteamine

+

Testosterone

12.96+0.16

6

0.14+0.01

17

0.13+0.00

28

11.44+0.18

39

11:12

p<0.001

33:34

p< 0.005

Old

62.14+0.14

7

2.68+0.0

18

0.20+0.00

29

15.13+0.12

40

13:14

p<0.05

35:36

p< 0.001

Old

+

Cysteamine

12.50+0.31

8

0.40+0.02

19

0.18+0.01

30

11.61+0.20

41

15:16

P<0.005

37:38

P<0.005

Old

+

Cysteamine

+

Testosterone

11.9.23+ 0.25

9

0.14+ 0.1

20

0.07+ 0.01

31

10.80+0.12

42

17:18

P<0.5

39:40

P<0.5

Orchidectomized

Old mice

+

Cysteamine

12.91+ 0.22

10

0.45+ 0.05

21

0.19 + 0.03

32

11.82+ 0.02

43

19:20

P<0.001

41:42

P<0.001

Orchidectomized

Old mice

+

Cysteamine

+

Testosterone

10.99 + 0.45

11

0.38 + 0.15

22

0.11 + 0.44

33

10.28 + 0.29

44

21:22

P<0.001

43:44

P<0.005

4. DISCUSSION

Effect of sex hormone on duodenal ulcer is extensively documented1-4,20-23-27. The role of androgens and estradiol and its precursors and metabolites in the pathogenesis of duodenal ulcer was evaluated3. Estradiol

Effect… Ashokan Kannarath Valappil.

1910 J. Chem. Bio. Phy. Sci. Sec. B, 2012, Vol.2, No.4, 1897-1912.

protects the duodenal mucosa from gastric acid secretion is well known28,29,30. The high circulating testosterone enhances the cysteamine induced gastro duodenal ulceration was reported4. Besides the sex hormone theory of duodenal ulcer pathogenesis gender difference in the Helicobacter pylori infection, gastric acid secretion, basal and acid-stimulated duodenal mucosal bicarbonate secretion (DMBS) are also reported 26,27,31,32,33. When considering the gender related responses, reproductive hormone mainly from the female ovary (estrogen and progesterone) and the male testis (i.e. testosterone) are often first taken into consideration. In the present study we focused on the effect of sex hormone (testosterone) on cysteamine induced duodenal ulceration in male adult mice and male old mice under different experimental conditions. We found that testosterone have augmentation effect on cysteamine induced duodenal ulcer. The ulcer index showed cysteamine induced duodenal ulcer is greater in orchidectomized-cysteamine treated and testosterone administered mice when comparing the ulcer index of adult mice having endogenous testosterone and orchidectomized mice treated with testosterone. Ovariectomized rats treated with 17B-oestradiol (short-term treatment) showed a statistically significant reduction in gastric acid secretion induced with all the secretagogues, but the results when rats were treated with testosterone were inconsistent9. The age factor for the duodenal ulcer is reported 24,30 . In male testosterone continually secreting throughout his life, even though the rate and quantity is varied. Hence we performed experiment in adult and old male mice under different experimental conditions.

In orchidectomized-cysteamine induced ulcer showed same ulcer frequency in both adult and old male mice. Upon administration of testosterone in orchidectomized-cysteamine treated mice the frequency of ulcer increased, which was assessed by the morphological changes in histology of pyloric pit, pyloric glands and Brunner’s glands. Pyloric pit become dilated, pyloric glands become less stained with basal nucleus and having more eosinophilia. Brunner’s glands also shows changes like having more eosinophilia and reduced glycol protein secretion like hexose, fucose, sialic acid and total protein. In orchidectomized old male mice all these histological and biochemical changes are like that of orchidectomized adult male mice. This indicating that testosterone or its precursors or metabolites may enhance the ulcer pathogenesis. These can be proved by treating orchidectomized mice with testosterone and cysteamine. Orchidectomized adult and old mice treated with cysteamine and testosterone showed enhanced ulcer pathogenesis in histology and biochemical analysis.

The result of histological and biochemical and ulcer index prove that adult orchidectomized mice and old orchidectomized mice and their comparison with old mice and adult mice showed that aging decreases the ulcer pathogenesis. The results are consistently reflected in ulcer index calculation, histology and biochemical studies in other experimental conditions. Hence, we conclude that testosterone is an aggressive factor in duodenal ulcer pathogenesis which augments the formation of ulcer when other factors are favorable to ulcer, particularly duodenal ulcer pathogenesis, like increased DMBS, Helicobacter pylori and increased gastric secretion. These findings are supported by decreased frequency of ulcer when rats are administered antiandrogen, cyproton acetate4 . Testosterone realizes its effects in target organs mainly through metabolites formed in those organs in the course of its bioformation.

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*Correspondence Author: Dr.Ashokan.K.V, PVP College Department ofZoology,

Kavathe Mahankal, Sangli, Maharshtra, India-416405; akvsangli@gmail.com

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