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Fulltext Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Ting YW, Kong AS, Zain SM, Chan WK, Tan HL, Mohamed Z, et al.

Clin Mol Hepatol, 2021 Jul;27(3):486-498.
PMID: 33618508 DOI: 10.3350/cmh.2020.0162

BACKGROUND/AIMS: 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients.
METHODS: Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded.
RESULTS: HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00-0.64; P=0.033 and HR, 0.01; 95% CI, 0.00-0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese.
CONCLUSION: HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

Matched MeSH terms: 17-Hydroxysteroid Dehydrogenases/genetics*
11Beta-hydroxysteroid dehydrogenase bioactivity is increased in the colon but not kidneys of rats given supplementary thyroxine

Ruszymah BH, Zaiton Z, Aminuddin S, Khalid BA

Exp. Clin. Endocrinol. Diabetes, 2001;109(4):227-30.
PMID: 11453035

The aim of this study was to investigate the effect of altered thyroid status on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD type 1) and type 2 (11beta-HSD type 2) bioactivity in rat kidney and colon. Male Sprague-Dawley rats (250 g) were treated with either L-thyroxine (T4) or propylthiouracil (PTU) for 4 weeks. Blood were then analysed for serum thyroxine, sodium (Na+) and potassium (K+). The kidneys and colon were assayed for 11beta-HSD type 1 and 11beta-HSD type 2 bioactivity. In T4 treated rats the serum thyroxine was significantly elevated (p<0.05) whilst PTU decreased serum thyroxine significantly (p<0.001) compared to controls. Serum Na+ and K+ were within normal limits. There were no significant changes in 11beta-HSD type 1 bioactivity in both treatment groups compared to controls. However, the 11beta-HSD type 2 bioactivity in rats given thyroxine was significantly higher in the colon (p<0.003) compared to controls. We conclude that altered thyroid status had no effect on 11beta-HSD type 1 bioactivity but 11beta-HSD type 2 bioactivity was elevated in the colon of rats given supplementary thyroxine.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/metabolism*; 11-beta-Hydroxysteroid Dehydrogenases
Novel effects of deoxycorticosterone on testicular 11beta-hydroxysteroid dehydrogenase activity and plasma testosterone levels in normal and adrenalectomized rats

Nwe KH, Morat PB, Hamid A, Fadzilah S, Khalid BA

Exp. Clin. Endocrinol. Diabetes, 1999;107(5):288-94.
PMID: 10482040

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) protects the testis from the inhibitory effects of corticosterone on testosterone (T) production. The objectives of the present studies were to determine the effects of deoxycorticosterone (DOC) and its mechanism of actions on testicular 11beta-HSD activity and plasma T levels after 7 days of treatment. The results revealed that at the end of 7 days treatment, DOC significantly increased testicular 11beta-HSD activity and plasma T levels in normal rats. However, the time course showed that high plasma T levels lowered 11beta-HSD activity on day 14 and by 21 days both the levels normalized. In adrenalectomized (ADX) rats, only the enzyme activity increased significantly but not plasma T levels. Spironolactone, a competitive inhibitor of mineralocorticoid receptor (MR), did not change testicular 11beta-HSD activity in both normal and DOC treated rats suggesting that DOC did not act through MR in increasing 11beta-HSD activity. On the other hand, spironolactone significantly decreased plasma T levels in DOC treated rats. Progesterone (P), a competitive inhibitor of glucocorticoid receptors (GR) or corticosterone significantly suppressed testicular enzyme activity and plasma T levels in DOC treated normal rats. Carbenoxolone which is an inhibitor of 11beta-HSD activity significantly depressed testicular 11beta-HSD activity and plasma T levels in DOC treated normal rats. This paper suggests that DOC increased testicular 11beta-HSD activity through GR; whilst increase in plasma T levels required functioning adrenal glands. The testicular 11beta-HSD is one of the regulators of T levels and vice versa.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/metabolism*; 11-beta-Hydroxysteroid Dehydrogenases
In vivo effects of stress, ACTH and corticosterone on testicular 11beta-hydroxysteroid dehydrogenase oxidative activity in rats and the possible mechanism of actions

Nwe KH, Norhazlina AW, Hamid A, Morat PB, Khalid BA

Exp. Clin. Endocrinol. Diabetes, 2000;108(5):369-77.
PMID: 10989957

The effects of stress and corticosterone on testicular 11beta-hydroxysteroid dehydrogenase (11beta-HSD) oxidative activity have been controversial, whilst that of adrenocorticotrophic hormone (ACTH) have not been investigated before. Hence, the aim of the present study was to determine the in vivo effects of stress due to injection and sham operation, ACTH and corticosterone on testicular and hepatic 11beta-HSD oxidative activity and plasma testosterone levels in normal and adrenalectomized (ADX) rats and their possible mechanism of actions. Adrenalectomy reduced both testicular 11beta-HSD oxidative activity and plasma testosterone levels. The effects of injection and sham operation significantly increased plasma corticosterone levels with decreased testicular 11beta-HSD oxidative activity and plasma testosterone levels in normal but not in ADX rats. Likewise. ACTH or corticosterone treatment for 7 days decreased both testicular 11beta-HSD oxidative activity in a dose dependent manner and plasma testosterone levels in normal rats; but the values in ADX rats remained unchanged. However, none of the above values were significantly lower than that of the ADX levels. Corticosterone seems to maintain testicular 11beta-HSD oxidative activity within the range between normal and ADX rats. These changes are not attributable to diurnal rhythms, as the time of sacrifice has been fixed between 8:30 and 10:30 am. In the liver, no significant change in 11beta-HSD oxidative activity was observed with sham operation, ACTH or corticosterone treatment; but adrenalectomy significantly decreased it. In conclusion, in the intact normal rats, stress, ACTH or corticosterone modulates testicular (but not hepatic) 11beta-HSD oxidative activity indirectly through the adrenal glands and the physiological level of corticosterone is ideal for normal reproductive functions.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/metabolism*; 11-beta-Hydroxysteroid Dehydrogenases
Differential regulation of the oxidative 11beta-hydroxysteroid dehydrogenase activity in testis and liver

Nwe KH, Hamid A, Morat PB, Khalid BA

Steroids, 2000 Jan;65(1):40-5.
PMID: 10624835

11Beta-hydroxysteroid dehydrogenase (11beta-HSD) Type I enzyme is found in testis and liver. In Leydig cell cultures, 11beta-HSD activity is reported to be primarily oxidative while another report concluded that is primarily reductive. Hepatic 11beta-HSD preferentially catalyzes reduction and the reaction direction is unaffected by the external factors. Recent analysis of testicular 11beta-HSD revealed two kinetically distinct components. In the present study, various steroid hormones or glycyrrhizic acid (GCA), given for 1 week, or thyroxine given for 5 weeks to normal intact rats had different effects on the 11beta-HSD oxidative activity in testis and liver. Deoxycorticosterone, dexamethasone, progesterone, thyroxine, and clomiphene citrate increased testicular 11beta-HSD oxidative activity, but decreased hepatic enzyme activity except for deoxycorticosterone (unchanged). Corticosterone and testosterone decreased 11beta-HSD oxidative activity in testis but not that of liver (which was unchanged). Estradiol, GCA and adrenalectomy lowered oxidative activity of 11beta-HSD in testis and liver, but the degrees of reduction were different. The in vivo effects of glucocorticoids too were different, even in the same organ. Dexamethasone, a pure glucocorticoid, has greater affinity for glucocorticoid receptors (GR) than corticosterone. The direct effects of dexamethasone via GR in increasing testicular 11beta-HSD oxidative activity may override its indirect effects. Possibly, the reverse occurs with corticosterone treatment, as it has both glucocorticoid and mineralocorticoid effects. Because both organs have Type I isoenzyme, the difference in 11beta-HSD oxidative activities of these two organs could be attributable to the presence of an additional isozyme in testis or differences in tissue-specific regulatory mechanisms.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/metabolism*; 11-beta-Hydroxysteroid Dehydrogenases
Opposite effects of sex steroids on 11 beta-hydroxysteroid dehydrogenase activity in the normal and adrenalectomized rat testis

Nwe KH, Morat PB, Khalid BA

Gen. Pharmacol., 1997 May;28(5):661-4.
PMID: 9184798

1. Sex steroids have been shown to regulate the biosynthesis of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 2. In vitro studies showed that oestradiol (E2) or testosterone (T) can interfere with the bioassay of enzyme activity, but not progesterone (P4). 3. For in vivo studies, the activity of 11 beta-HSD in the testis of normal and adrenalectomized (ADX) adult male Wistar rats was determined following a daily IM injection of sex steroids for 7 days. 4. The 11 beta-HSD activity was significantly reduced (P < 0.01) either by E2 or T in normal and ADX rats. The enzyme activity in normal rats given both T and E2 was even lower (P < 0.001) than when E2 was given alone. 5. P4 given to normal and ADX rats increased the enzyme activity higher than normal (P < 0.001). 6. The presence of corticosteroids influenced the effects of E2, but not of T and P4, on 11 beta-HSD activity. 7. E2 and T downregulate 11 beta-HSD activity, whereas P4 increased it. E2 did not act through lowering T level.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/metabolism*; 11-beta-Hydroxysteroid Dehydrogenases
Short- and long-term effects of glycyrrhizic acid in repetitive stress

Ainsah O, Nabishah BM, Osman CB, Khalid BA

Clin Exp Pharmacol Physiol, 1999 7 1;26(5-6):444-8.
PMID: 10386236

1. This study was carried out to determine the effect of short-term and long-term ingestion of glycyrrhizic acid on the response to 2 h of restraint stress by measuring locomotor activity and plasma corticosterone levels. 2. Male Sprague-Dawley rats were randomly assigned into four groups, each group having eight rats. Group 1 (control) was given ordinary tap water, while groups 2 (short term), 3 and 4 (both long term) were given tap water containing 1 mg/mL glycyrrhizic acid to drink for 10 days, 4 weeks and 9 weeks, respectively. All the rats were subjected to 2 h of restraint stress and the locomotor activity assessed using an activity test in an open field arena followed by blood sampling to determine the plasma corticosterone level. These procedures were repeated daily for 14 days. 3. The basal locomotor activity scores for rats given glycyrrhizic acid for 10 days or 4 weeks were similar to those of controls; however, that of the rats treated long term with glycyrrhizic acid was significantly lower (21.0 +/- 3.0 squares crossed; P < 0.0005). Following the first period of restraint stress there was a highly significant decrease in locomotor activity, which remained significantly lower until the seventh and subsequent periods, indicating an adaptation to the repeated stress had occurred. Although the decrease in locomotor activity was partially blocked and adaptation to repetitive stress was enhanced in the rats given glycyrrhizic acid for 10 days, this was not seen in rats treated with glycyrrhizic acid for 4 or 9 weeks. The corticosterone levels in control rats were significantly elevated for 4-5 days following the exposure to repetitive stress but decreased gradually from day 7 onwards. However, both short- and long-term glycyrrhizic acid-treated rats had higher plasma corticosterone levels than the controls (P < 0.05). 4. In conclusion, repetitive restraint stress caused decreased locomotor activity associated with increased plasma corticosterone levels, both of which, in normal rats, decreased with adaptation to stress. The stress response was partially blocked and adaptation enhanced in rats given glycyrrhizic acid for 10 days, but not in rats given glycyrrhizic acid for 4 and 9 weeks. Glycyrrhizic acid ingestion caused high plasma corticosterone.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenases
Differential effect of adrenocorticosteroids on 11 beta-hydroxysteroid dehydrogenase bioactivity at the anterior pituitary and hypothalamus in rats

Idrus RB, Mohamad NB, Morat PB, Saim A, Abdul Kadir KB

Steroids, 1996 Aug;61(8):448-52.
PMID: 8870163

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) is a microsomal enzyme that catalyzes the dehydrogenation of cortisol (F) to cortisone (E) in man and corticosterone (B) to 11-dehydrocorticosterone (A) in rats. 11 beta-OHSD has been identified in a wide variety of tissues. The differential distribution of 11 beta-OHSD suggests that this enzyme has locally defined functions that vary from region to region. The aim of this study was to investigate the effects of the glucocorticoids B and dexamethasone (DM), the mineralocorticoid deoxycorticosterone (DOC), and the inhibitors of 11 beta-OHSD glycyrrhizic acid (Gl) and glycyrrhetinic acid (GE) on 11 beta-OHSD bioactivity at the hypothalamus (HT) and anterior pituitary (AP). Male Wistar rats were treated with GI or were adrenalectomized (ADX) and treated with either B, DM, or DOC for 7 days. All treatments were in vivo except GE, which was used in vitro. At the end of treatment, homogenates of HT and AP were assayed for 11 beta-OHSD bioactivity, expressed as the percentage conversion of B to A in the presence of NADP, 11 beta-OHSD bioactivity is significantly higher (P < 0.0001) in the AP compared with the HT. Adrenalectomy significantly increased the enzyme activity in the AP (P < 0.05), an effect reversed by B or DM. ADX rats treated with DOC showed decreased enzyme activity in the AP (P < 0.001) but increased the activity in the HT (P < 0.0001). Gl increased activity in both HT and AP, whereas GE decreased activity significantly. We conclude that the modulation of 11 beta-OHSD is both steroid specific and tissue specific.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/drug effects; Hydroxysteroid Dehydrogenases/metabolism*; 11-beta-Hydroxysteroid Dehydrogenases
Effects of naloxone, glycyrrhizic acid, dexamethasone and deoxycorticosterone in repetitive stress

Ainsah O, Nabishah BM, Osman CB, Khalid BA

Clin Exp Pharmacol Physiol, 1999 7 1;26(5-6):433-7.
PMID: 10386234

1. The present study examined the effect of naloxone (NAL), glycyrrhizic acid (GCA), deoxycorticosterone (DOC) and dexamethasone (DEX) on daily repeated 2 h chronic restrained stress (RS) on the locomotor activity (LA) of rats tested in the open field arena to elucidate the possible roles of opioids, glucocorticoids and mineralocorticoids in response to stress. 2. Intact and adrenalectomized (ADX) rats were either injected with 0.1 mL of NAL (0.32 microgram/100 g BW), 2.4 mg/kg DOC or 120 micrograms/kg DEX or had 1.0 mg/mL GCA dissolved in their drinking water or normal saline (for the ADX group) dissolved in their drinking water. 3. In intact groups, treatment with NAL completely blocked the stress response and treatment with GCA, DOC and DEX partially prevented the stress response. Adaptation occurred on either days 4, 5, 6 or 7 for intact rats treated with DEX, DOC, GCA or control rats, respectively. All ADX control rats died following the first 2 h RS. Adrenalectomized rats treated with DEX or DOC adapted later compared with intact rats, while rats given either GCA or NAL were unable to block or adapt to chronic RS. 4. These findings demonstrate that the stress response is primarily mediated by endogenous opioids, in that it is blocked by NAL. Both mineralocorticoids and glucocorticoids, which can act centrally to inhibit endorphins, partially blocked the stress response. The effect of GCA in intact rats was similar to that of both DEX and DOC in intact rats. Adrenalectomized rats treated with GCA (despite their lack of endogenous corticosterone) showed a stress response that was significantly different from the other ADX groups, implying that GCA had effects independent of endogenous corticosterone.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenases
Glycyrrhizic acid (GCA) as 11β-hydroxysteroid dehydrogenase inhibitor exerts protective effect against glucocorticoid-induced osteoporosis

Ramli ES, Suhaimi F, Asri SF, Ahmad F, Soelaiman IN

J. Bone Miner. Metab., 2013 May;31(3):262-73.
PMID: 23274351 DOI: 10.1007/s00774-012-0413-x

Rapid onset of bone loss is a frequent complication of systemic glucocorticoid therapy which may lead to fragility fractures. Glucocorticoid action in bone depends upon the activity of 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). Regulations of 11β-HSD1 activity may protect the bone against bone loss due to excess glucocorticoids. Glycyrrhizic acid (GCA) is a potent inhibitor of 11β-HSD. Treatment with GCA led to significant reduction in bone resorption markers. In this study we determined the effect of GCA on 11β-HSD1 activity in bones of glucocorticoid-induced osteoporotic rats. Thirty-six male Sprague-Dawley rats (aged 3 months and weighing 250-300 g) were divided randomly into groups of ten. (1) G1, sham operated group; (2) G2, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral vehicle normal saline vehicle; and (3) G3, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral GCA 120 mg/kg/day The results showed that GCA reduced plasma corticosterone concentration. GCA also reduced serum concentration of the bone resorption marker, pyridinoline and induced 11β-HSD1 dehydrogenase activity in the bone. GCA improved bone structure, which contributed to stronger bone. Therefore, GCA has the potential to be used as an agent to protect the bone against glucocorticoid induced osteoporosis.

Matched MeSH terms: 11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors*; 11-beta-Hydroxysteroid Dehydrogenases/metabolism
Androgen receptor, androgen-producing enzymes and their transcription factors in extramammary Paget disease

Azmahani A, Nakamura Y, Ozawa Y, McNamara KM, Fujimura T, Haga T, et al.

Hum Pathol, 2015 Nov;46(11):1662-9.
PMID: 26359540 DOI: 10.1016/j.humpath.2015.07.007

Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17β-HSD5, and β-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17β-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.

Matched MeSH terms: 17-Hydroxysteroid Dehydrogenases/metabolism
Effects of glycyrrhizic acid on 11 β-hydroxysteroid dehydrogenase (11 βHSD1 and 2) activities and HOMA-IR in rats at different treatment periods

Chia YY, Yin YY, Ton SH, Kadir KB

Exp. Clin. Endocrinol. Diabetes, 2010 Oct;118(9):617-24.
PMID: 19998240 DOI: 10.1055/s-0029-1237703

Glycyrrhizic acid (GA) has been reported to inhibit postprandial blood glucose rise and 11 β-hydroxysteroid dehydrogenase 1 (11 βHSD1) activity. As not much work has been done on GA effects on 11 βHSD1 and 2 and HOMA-IR at different treatment periods, this work was conducted. 60 male Sprague Dawley rats fed AD LIBITUM were assigned into six groups of control and treated that were given GA at different duration namely 12, 24 and 48 h. Treated and control groups were intraperitoneally administered with GA (50 mgkg (-1)) and saline respectively. Blood and subcutaneous (ATS) and visceral adipose tissue (ATV), abdominal (MA) and quadriceps femoris muscle (MT), liver (L) and kidney (K) were examined. HOMA-IR in GA-treated rats decreased in all groups (P<0.05). In the 12-h and 24-h treated rats, 11 βHSD1 activities decreased in all tissues (P<0.05) except MA and MT (P>0.05) in the former and ATV (P>0.05) in the latter. However, 11 βHSD1 activities decreased significantly in all tissues ( P<0.05) in the 48-h treated rats. Significant decrease in 11 βHSD2 (P>0.05) activities were observed in the L of all treatment groups and K in the 24-h and 48-h treated rats (P<0.05). Histological analysis on ATS showed increase in the number of small-size adipocytes while ATV adipocytes showed shrinkage after GA administration. Increased glycogen deposition in the L was observed in the GA-administered rats in all the treatment periods. In conclusion, GA treatment showed a decrease in the HOMA-IR and both 11 βHSD1 and 2 activities in all tissues, with more profound decrease in the 48-h treated rats.

Matched MeSH terms: 11-beta-Hydroxysteroid Dehydrogenases/metabolism*
Fulltext Down-regulation of steroidogenesis-related genes and its accompanying fertility decline in streptozotocin-induced diabetic male rats: ameliorative effect of metformin

Nna VU, Bakar ABA, Ahmad A, Mohamed M

Andrology, 2019 01;7(1):110-123.
PMID: 30515996 DOI: 10.1111/andr.12567

BACKGROUND: Metformin has long been used for glycemic control in diabetic state. Recently, other benefits of metformin beyond blood glucose regulation have emerged.
OBJECTIVES: To investigate the effect of metformin on the expression of testicular steroidogenesis-related genes, spermatogenesis, and fertility of male diabetic rats.
MATERIALS AND METHODS: Eighteen adult male Sprague Dawley rats were divided into three groups, namely normal control (NC), diabetic control (DC), and metformin-treated (300 mg/kg body weight/day) diabetic rats (D+Met). Diabetes was induced using a single intraperitoneal injection of streptozotocin (60 mg/kg b.w.), followed by oral treatment with metformin for four weeks.
RESULTS: Diabetes decreased serum and intratesticular testosterone levels and increased serum but not intratesticular levels of luteinizing hormone. Sperm count, motility, viability, and normal morphology were decreased, while sperm nuclear DNA fragmentation was increased in DC group, relative to NC group. Testicular mRNA levels of androgen receptor, luteinizing hormone receptor, cytochrome P450 enzyme (CYP11A1), steroidogenic acute regulatory (StAR) protein, 3β-hydroxysteroid dehydrogenase (HSD), and 17β-HSD, as well as the level of StAR protein and activities of CYP11A1, 3β-HSD, and 17β-HSD, were decreased in DC group. Similarly, decreased activities of epididymal antioxidant enzymes and increased lipid peroxidation were observed in DC group. Consequently, decreased litter size, fetal weight, mating and fertility indices, and increased pre- and post-implantation losses were recorded in DC group. Following intervention with metformin, we observed increases in serum and intratesticular testosterone levels, Leydig cell count, improved sperm parameters, and decreased sperm nuclear DNA fragmentation. Furthermore, mRNA levels and activities of steroidogenesis-related enzymes were increased, with improved fertility outcome.
DISCUSSION AND CONCLUSION: Diabetes mellitus is associated with dysregulation of steroidogenesis, abnormal spermatogenesis, and fertility decline. Controlling hyperglycemia is therefore crucial in preserving male reproductive function. Metformin not only regulates blood glucose level, but also preserves male fertility in diabetic state.

Matched MeSH terms: Hydroxysteroid Dehydrogenases/genetics
Pre- and postnatal toxicity of diazinon induces disruption of spermatogenetic cell line evidenced by increased testicular marker enzymes activities in rat offspring

Jayachandra S, D'Souza UJ

J Environ Pathol Toxicol Oncol, 2013;32(1):73-90.
PMID: 23758154

The objective of this study was to study the possible reproductive adverse effects of the diazinon on rat offspring exposed in utero and during lactation. Dams were gavaged daily (10, 15, and 30 mg/kg) before mating, during mating, and during pregnancy and lactation in separate groups. Reproductive outcome data of dams were examined. Body weight, testis weight, testicular marker enzyme activities (alkaline phosphatase, acid phosphatase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase), qualitative and quantitative testicular and epididymal histology, and immunohistochemisty for 3-β-hydroxysteroid dehydrogenase (HSD) were examined in male offspring at puberty and adulthood. The 30-mg/kg dose induced significant adverse effects at both puberty and adulthood in offspring. At puberty the male offspring showed a decrease in testicular weight, degenerative changes, and 3-β-HSD. Moreover, an increase in activity of alkaline and acid phosphatase also was observed. At adulthood, there was a decrease in testicular weight and 3-β-HSD with an increase in the levels of testicular marker enzyme. There was evidence of some adverse reproductive effects in male offspring at the 15-mg/kg dose. Most of the adverse effects were irreversible and were evident at both puberty and adulthood in offspring, although a few parameters reverted back to the normal growth pattern. Hence, diazinon is a reproductive toxicant in male offspring, which caused significant damage to the testes when exposed during prenatal and postnatal life.

Matched MeSH terms: 3-Hydroxysteroid Dehydrogenases/metabolism
Fulltext Lipoprotein lipase expression, serum lipid and tissue lipid deposition in orally-administered glycyrrhizic acid-treated rats

Lim WY, Chia YY, Liong SY, Ton SH, Kadir KA, Husain SN

Lipids Health Dis, 2009;8:31.
PMID: 19638239 DOI: 10.1186/1476-511X-8-31

The metabolic syndrome (MetS) is a cluster of metabolic abnormalities comprising visceral obesity, dyslipidaemia and insulin resistance (IR). With the onset of IR, the expression of lipoprotein lipase (LPL), a key regulator of lipoprotein metabolism, is reduced. Increased activation of glucocorticoid receptors results in MetS symptoms and is thus speculated to have a role in the pathophysiology of the MetS. Glycyrrhizic acid (GA), the bioactive constituent of licorice roots (Glycyrrhiza glabra) inhibits 11beta-hydroxysteroid dehydrogenase type 1 that catalyzes the activation of glucocorticoids. Thus, oral administration of GA is postulated to ameliorate the MetS.

Matched MeSH terms: 11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors

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