Evaluation of the Effects of the Topiramate on Some Hormonal Changes in the Obesity Patients

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

Evaluation of the effects of the topiramate on some hormonal changes in the obesity patients

Fadil A. AL-Quraishe1

1. College of Dentistry, Al-Muthanna University, Iraq Corresponding: [email protected]

Abstract Topiramate is a sulfamate substitute fructopyranose derivative with unique a pharamacodynamic profile, a weight loss drug used a pharmacotherapeutic agent for obesity. The study was performed to evaluate the effects of the topiramate to melatonin and testosterone hormone concentration level in the plasma of obesity treated with topiramate (81 mg/day) for 6 week. Melatonin and testosterone hormone concentration level estimated in the plasma of the peripheral of the blood from 40 obesity with Body Mass Index (BMI) 35 - 39.9 Kg/m2 before and after treated with topiramate (81 mg/day) for 6 week and compare with 20 health person with BMI 18-24.9 Kg/m2 as control group who had never received topiramate and other drug during the period of the study. Most of the obesity treated with topiramate had improved concentration plasma level of melatonin and testosterone hormones when compare before and after treated with control group. In analysis obesity age groups, were significantly increased melatonin and testosterone hormones after treated with topiramate (81 mg/day) dose with 6 week compare with untreated obesity and control in most age groups. In conclusion, the elevated the concentration level of the melatonin and testosterone in obesity treated with topiramate we conclude the obesity treated with topiramate may be associated with improved the circadian rhythm and regulation of hormone secretion in obesity through the effects on the receptors regulation the appetite and food-intake also by inhibition insulin resistance and reduced glucose intolerance and weight gain with atypical psychotics.

Key Words:Topiramate,Melatonin,Testosterone,Obesity.

DOI: http://doi.org/10.36295/ASRO.2021.24455

Page(s):490-497

Volume/ Issue: Volume: 24/ Issue: 04

Introduction The place of pharmacotherapy in the management of obesity is a long and checkered on (1-2).In these study, we examination the effects of topiramate to physiological parameters, hormonal changes that include melatonin and testosterone in obesity treated with topiramate. Melatonin is a neuropeptide hormone released from the pineal gland, the main function of this hormone was to maintain a natural circadian rhythm within the body (3). The melatonin can be caused a decrease in obesity, without affecting food intake and it was considered a thermogenic regulator (4). Melatonin (N- acetyl -5- metho- xytryptamine) was the hormone controlled by central nervous system via the suprachiasmatic nucleus (SCN) of the hypothalamus (5). When the pineal gland is active only in darkness, the levels of the melatonin in the pineal gland and in the blood are high at night and low during the day (6).Melatonin was produced by the pineal gland especially during the night by stimulating adrenergic beta and alpha receptors (7).

The antiobesogenic effect of melatonin was a result of its regulatory role on the place of energy acting mainly on the regulation of the energy flow to and from the stores and in energy consumption, also it was associated with all physiological processes such as the daily activity, wakefulness, rest- sleep and

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

rhythm many impact body weight (5).The treatment with melatonin can inhibit the differentiation and reducing adipose tissue by inhibition fatty acid formation which caused by the accumulation of triglyceride in cells which exposed to olic acid (8) also that treatment of national complaining from metabolic syndrome for month by 5 mg / day of melatonin reduced BMI, systolic, blood pressure (SBP) and plasma fibrinogen , while after two months of treatment ,there was a further significant improvement of (SBP)and antioxidative as indicated by an elevated catalase activity and decrease in low–density lipoprotein cholesterol ( 9 ).

Testosterone is a hormone made by testes and adrenal gland that has many effect throughout the body (10). Testosterone is important for muscle mass , bone strength ,hair growth, and sexual function (11) low testosterone can causes many symptoms such as low energy, poor concentration, depression, low libido, and erectile dysfunction (12).Testosterone concentration are inversely related to BMI and insulin resistances(13). Obesity is associated with a decrease in both total and free testosterone (4 -14).The men suffering from metabolic syndrome, diabetes type II and obesity have decreased level of total and free testosterone and low level of sex hormone binding globulin (SHBG), also reduction levels of serum testosterone in men with prostate cancer who treated with androgen deprivation therapy can increase body fat mass (15).

Testosterone treatment can lead to decreased central obesity and total fat content because testosterone cause to stimulate the B- adrenergic receptor this receptor contribute in the lipolysis processes, while progesterone and estrogen cause to stimulate preferentially α 2- adrenoreceptors which inhibition lipolysis , lipolysis processes play important role in fat accumulation (16).Most of the studies indicated that obese male show decreased in sexual quality of life , lower fertility , and sex hormonal changes which include decreased in the testosterone level (both free and total), increased es tradiol levels compared with general population also suggested that obesity associated with hypogonadism in males are related to the central inhibition of gonadotropin secretion , but the mechanisms are yet unknown (17).Testosterone therapy seems an effective method to improve weight loss in obese hypogonadal men regardless of severity of obesity (18).

Material and Methods This study was conducted between Jun 2019 continued through September 2019 in A l-Diwaniah Teaching Hospital, the study included 60 individuals, subjects with history of chronic medication use, history of chronic and inherited disease , diabetes , drug use ,and other disorder were excluded from this study. The total samples 60 blood samples were taken from men in this study , which divided according BMI into control group (20 sample) which BMI 18-24.9 kg/m2 and obesity group ( 40 sample ) which BMI 35-39.9 kg/m2 and according to age divided into four age groups ,( 20-25 year) , (26-30 year) , (31-35 year) and (36-40 year) .Obesity male groups started examined without treated with body weight loss drug and compared with control groups and obesity were being treated with topiramate (81 mg/day Qsymian®) at time of the study, obesity being treated extended for 6week .

The hospital ethical committee approved the human study, control and obesity were told about the importance, and other details of research and explain the aim of this study and the protocol of ethics. Many of subjects refused to give the blood samples. The blood samples were collected by venipuncture at 8 -10 AM after overnight fast put 3ml in EDTA treated tube for plasma, the plasma were frozen at - 20 co in two replicate until thawed for assay. The intra and inter assay variation for measurement of melatonin and testosterone plasma level was determined by using (ELISA) techniques. (ELISA) instrument was used (Reader and washer, Biotek, U.S.A.). The competitive enzyme technique was used (ELISA) kit (Elabscienc, China) for melatonin pg/ml from the equation in the kit. The quantitative sandwich enzyme technique was used (ELISA) kit (Accu- Bind), (Monobind Company, U.S.A.). Statistical analysis carried out by SPSS version 15, comparison by one way (ANOVA-LSD).

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

Results The melatonin plasma level analysis comparison mean ± SD showed significant increase differences (P<0.05 ) in control group compared with obesity non treated in age groups ( 20 - 25 year ) , ( 26-30 year ) , and (36-40 year) .While no significant differences (P>0.05) between the control and obese group in age group (31-35 year) as in the (Table 1) .

parameter Subject Mean ±SD(Age Groups) L.S.D

Obesity 20 - 25 Year 26 - 20 Year 31- 35 Year 36 - 40 Year BMI N=10 N=10 N=10 N=10 35_39.9

k/m2

N=40 192.12±54.882 174.65±29.836 260.87±14.077 173.28±75.940 Melatonin

Pg/ml Control 20-25 Year 26-20 Year 31-35 Year 36-40 Year BMI N=5 N=5 N=5 N=5 18_24.9

k/m2 * * * N=20 244.24±29.379 295.34±243.191 268.30±222.261 238.79±209.089

*Significant (p>0.05)

Table1: Comparison mean± SD melatonin level in obesity and control in different age groups

As shown in results (Tabl 2) no significant differences (P>0.05) in melatonin levels between the control and obesity treated with topiramate dose (81mg/day) over 6 week in all age group.Correlation between melatonin level in obese, ,obesity treated and control group with age showed significant decreased melatonin(p>0.05) with increased age groups (Figure 1).

L. Parameter Subjects Mean ± S.D (Age Groups) S. D Obesity 20 25 Year 26 30 Year 31 35 Year 36 40 Year – – – – Topiramate N = 10 N = 10 N = 10 N = 10 Treated

(81mg/day)

BMI 35-39.9 263.76±45.326 329.50±218.204 263.41±228.268 218.23 ±83.007 2 K/m

N = 40

20 – 25 Year 26 – 30 Year 31 – 35 Year 36 – 40 Year

N = 10 N = 10 N = 10 N = 10 Obesity Melatonin BMI 35-39.9 pg/ml K/ m2 192.12±154.882 174.65±89.836 260.78±14.077 173.28±75.940 N =40

20 – 25 Year 26 – 30 Year 31 – 35 Year 36 – 40 Year

N = 5 N = 5 N = 5 N = 5 Control BMI 18-24.9 2 K/m * * * N = 20 244.24±29.379 295.34±243.191 286.30±222.261 238.79±209.089 *Significant <0.005 Table2: Comparison mean ± SD melatonin level between obese, obesity treated, and control in different age groups

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

Melaton in Pg/ml

Age groups Figure 2: Correlation between melatonin level in obese, obesity treated, and control with age groups

Also results revealed no significant differences (P> 0.05) in the testosterone levels in control and obesity no treated in age groups ( 20 -25 year ) and ( 26-30 year) .While a significant differences increase ( P <0.05) in the testosterone level in control group compared with obesity in age groups (31- 35 year) and ( 36- 40 year ) as in the ( Table 3).

Parameter Subject Mean ± SD (Age Groups) L.S. D 20 - 25 Year 26 - 20 Year 31- 35 Year 36 - 40 Year

Obesity N=10 N=10 N=10 N=10 BMI 35-39.9

k/m2

N=40 11.420 ± 5.130 9.945 ± 4.675 8.720 ± 3.403 6.953± 6.340 Testosterone ng/ml 20-25 Year 26-20 Year 31-35 Year 36-40 Year Control N=5 N=5 N=5 N=5 BMI 18-24.9

k/m2 12.281 ± 1. 751 10.855 ± 3.943 * * N=20 13.552 ± 3.536 11.667 ± 5.134 * Significant (P > 0.05)

Table 3: Comparison mean± SD testosterone level in obesity and control group in different age groups

Our study demonstrated no significant differences ( P>0.05) in the testosterone level between obesity treated with topiramate dose (81mg/day) for 6 week and control groups in all age groups as in the (Table 4 ), also showed significant differences (P<0.05) in the testosterone level where L.S.D. =90.646 between obesity non treated group in age group ( 36 – 40 year)compare with other age groups in obesity that is revealed correlation between decreased with age groups.

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

L. Parameter Subjects Mean ± S.D (Age Groups) S. D

Obesity 20 – 25 Year 26 – 30 Year 31 – 35 Year 36 – 40 Year

Topiramate N = 10 N = 10 N = 10 N = 10 Treated (81mg/day)

BMI 35-39.9

K/m2 13.578± 1.578 12.353 ± 1.796 12.958 ± 1.127 10.575 ± 4.750

N = 40

20 – 25 Year 26 – 30 Year 31 – 35 Year 36 – 40 Year

Obesity N = 10 N = 10 N = 10 N = 10 BMI 35-39.9 2 Testosterone K/ m

ng/ ml N =40 11.420 ± 5.130 9.945 ± 4.675 8.720 ± 3.403 6.953± 6.340

Control BMI 18-24.9 20 25 Year 26 30 Year 31 35 Year 36 40 Year K/m2 – – – – N = 5 N = 5 N = 5 N = 5 N = 20

* * * * 12.281 ± 1. 751 10.855 ± 3.943 13.552 ± 3.536 11.667 ± 5.134

Significant (P > 0.05)*

Table4: Comparison mean± SD testosterone level between obese, obesity treated, and control in different age groups.

15 Control 10 Obesity 5

retsotseT Obesity Topiramate 0 one Treated2 Ng/ml 20-25 26-30 31-35 36- 40 Year Year year Year

Age Groups Figure 2: Correlation between testosterone level in obese, obesity treated, and control with age groups.

Discussion Topiramate (sulfamate - substituted monosaccharide) a weight loss drug used a pharmacotherapeutic agent for obesity (19 -20), a study was performed to evaluate the effects of topiramate on the plasma levels of the melatonin and testosterone in obesity treated with weight loss drug topiramate dose (81 mg/day) for 6 week, compare with obesity non treated and control groups in different of age groups.

Our investigation confirm with new study where the present result showed there are no significant differences between control and obese person in age groups (20 -25 year ) and (26 -30 year) in the melatonin hormone while significant increased (P < 0.05) in control group compare with obesity non

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

treated groups in (31-35 year) and ( 36-40 year). As it is well known melatonin it was contributed in several physiological processes such as regulation body weight, energy balance and reproduction (21). Also melatonin play protective role against obesity, it was modulated food consumption, serum lipid profile and blood glucose level (22).

Topiramate, the first agent in more than 10 year to achieve regulatory approval chronic management weight in obese patients (23), topiramate marketed since 1996 , and initially approved by Food and Drug Administration (FDA) for management of seizure disorders , it was first investigated as an anti- diabetic medication ; as fructose -1-6- diphosphateanalog(sulfamatesubstituted monosaccharide) that inhibit 1-6-bisphosphatase and thus inhibit gluconeogenesis (24 -25).We are think according our result and the previous study the support the topiramate may be effect to the increased melatonin level in obesity as in control group according to effect the topiramate to inhi-bition gluconeogenesis and prevent fast insulin resistance and reduced glucose intolerance that lead to increased melatonin secretion by pineal gland. Finding showed the differences in age group may be related with stress and the type of stress , especially in ( 26-30 year ) old where many study show continues exposure to stress can causes the development of the obesity via the activation sleep disturbance and metabolic circadian disruption the result confirmed with Cipolla- Neto et al., 2014 . The absence or decreased melatonin production in obese group during aging, or illuminated environment during the night , induces insulin resistance , glucose intolerance , sleep disturb-ance and metabolic circadian disruption characterizing a state of chronic disruption and metabolic disease that form a vicious cycle aggravating over ill is health and leading to obesity (5).

The data revealed significant differences ( P>0.05) in testosterone level in control group compare with obese untreated in some age groups, but no significant differences in the testosterone level in obesity treated with topiramate and control group. Result showed the level of testosterone was decreased with increasing both the age and obesity as in the age group (36-40 year). Low level of testosterone hormone are related with increasing of the body fat mass and aging (26). Many study revealed obesity treated with topiramate reduction weight among obese men with obstructive sleep apnea can cause increasing level of testosterone (27 -28 -29).

Our suggestion, the testosterone when decreased may be improved the development of obesity, diabetes type II, cardiovascular disease and when obesity patients treated with topiramate elevated testosterone , these result are conventional with other work indicated testosterone may be enhance reduced the fat in the abdominal region according to effect the topiramate on the treatment the diabetes during reduced insulin resistance and glucose intolerance participate to reduced obesity and improved the testosterone hormone increased(28-29).

Topiramate mechanism of action specifically in appetite suppression is lacking and thus the potential for topiramate contributionto the increase in dopamine specifically in the prefrontal cortex versus various area of the brain (30). Topiramate (Qsymi®) specifically the phentermine component, functions by blocking the dopamine and norepinephrine transporter (31).Many studies have shown that weight loss increase totaltestosterone (33), on average, 5%weight loss increase total testosterone concentration by 50 ng/dl (13). Testosterone concentration are inversely related to BMI and insulin resistance (34), obesity is associated with decrease in both total and free testosterone (14-34-35).

Conclusions The elevated plasma levels of the melatonin and testosterone in obesity treated with topiramate may be association with improved the circadian rhythm and regulation of hormones in obesity.

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Al-Quraishe (2021): The effects of the topiramate on some hormonal changes © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24455

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