Dental Panoramic Radiographic Indices as a Predictor of Osteoporosis in Postmenopausal Saudi Women.

BACKGROUND: Many oral presentations of osteoporosis-a bone metabolic disease-were recorded. Thus, we aimed to assess panoramic radiomorphometric indices with bone mineral density (BMD) values among Saudi postmenopausal women and its importance in the prediction of osteoporosis. METHODS: A total of 431 Saudi women were enrolled in this study. Panoramic radiographs were obtained at the time of BMD measurement. Subjects were fatherly classified into; normal BMD, osteopenia, and osteoporosis groups. Serum follicle-stimulating hormone, luteinizing hormone (LH), estradiol (E2), 25-hydroxy-vitamin D (25[OH]D) and intact-parathyroid hormone were measured. Moreover, serum creatinine, calcium, and phosphate, together with serum osteocalcin (s-OC), procollagen type I N-terminal propeptide (s-PINP) and cross-linked C-terminal telopeptide of type 1 collagen (s-CTX) were measured. Receiver-operator curve (ROC) curve analysis for use of mandibular cortical width (MCW), panoramic mandibular index (PMI), and maxillary-mandibular ratio (M/M ratio) to differentiate women with osteoporosis or osteopenia from normal subjects was calculated. Cut off values of 4.6 at T score <-1 and 4.1 at T score ≤-2.5 were used. RESULTS: Body mass index is significantly low in the osteoporotic group. There is no significant difference in serum levels of LH, E2, calcium, phosphate, and 25(OH)D between the studied groups. Moreover, s-OC, C-terminal propeptide of procollagen type I, s-PINP, s-CTX, and urinary-CTX are significantly higher in osteoporosis than normal and osteopenia groups. ROC curve analysis revealed that MCW and PMI showed significant data while M/M ratio is non-significant. CONCLUSIONS: It could be concluded that MCW as an important panoramic radiographic parameter can be used for prediction and diagnosis of osteoporosis in postmenopausal Saudi women with low BMD.

High Plasma Sphingosine 1-phosphate Levels Predict Osteoporotic Fractures in Postmenopausal Women: The Center of Excellence for Osteoporosis Research Study.

BACKGROUND: Higher sphingosine 1-phosphate (S1P) plasma levels are associated with decreased bone mineral density (BMD), and increased risk of prevalent vertebral fracture. So, we hypothesized that postmenopausal women with increased baseline plasma S1P levels have a greater risk for future incident fracture (osteoporosis-related fractures [ORFs]). METHODS: This study was conducted in a prospective longitudinal cohort of 707 women recruited in 2004 and followed up annually for a mean period of 5.2±1.3 years. They were postmenopausal (aged ≥50 years). The primary outcome measure was the time to the first confirmed ORF event using radiographs and/or a surgical report. RESULTS: The plasma S1P levels (µmol/L) were significantly higher in the women with incident fracture (7.23±0.79) than in those without ORFs (5.02±0.51; P<0.001). High S1P levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the hazard ratio (HR) was 6.12 (95% confidence interval [CI], 4.92-7.66) for each 1-standard deviation increase in plasma S1P levels. The women in the highest quartile of S1P levels had a significant increase in fracture risk (HR, 9.89; 95% CI, 2.83-34.44). Results were similar when we compared plasma S1P levels at the 1-year visit. CONCLUSIONS: The associations between plasma S1P levels and fracture risk were independent of BMD and other confounders. These findings demonstrate that high plasma S1P level at baseline and at years 1 to 5 is a strong and independent risk factor for future [ORFs] among postmenopausal women and could be a useful biomarker for fracture risk assessment in this population.

Genomic answers for recurrent spontaneous abortion in Saudi Arabia: An array comparative genomic hybridization approach.

To study the genomics/genetic factors associated with recurrent spontaneous abortion (RSA), as ∼50% of RSA are unexplained. However, chromosome abnormalities have been reported to play major role in RSA. We performed whole genome array-CGH based genomic analysis of forty four Saudi RSA patients to identify potential molecular and chromosomal abnormalities. We identified a total of 845 alterations, usually not detected by classic cytogenetic methods, in different genomic regions using a cut off value of -0.25 and 0.25 for structural loss and gain, whereas -1.0 and 0.58 were used for single copy number deletion and duplication respectively. We identified frequent (present at least in 10% of patients) alterations including three macro-alteration at 8p23.1, 10q11.21-q11.22 and 15q11.2 as well as large numbers of micro-deletions/amplifications with affected genes including 22q11.23 (GSTT1), 3p22.2 (CTDSPL), 6p21.32 (HLA), and 8p22 (MSR1). Pathway analysis of genes located in detected CNVs regions revealed the allograft rejection signaling, IL-4 signaling, and autoimmune thyroid disease signaling as the most significant canonical pathways associated with RSA. Whole genome array CGH technique can be used to identify potential genes, biofunctions and chromosomal abnormalities associated with RSA which is supported by our findings of a number of novel CNVs/genes (22q11.23/GSTT1, 3p22.2/CTDSPL, 6p21.32/HLA, 8p22/MSR1, and 14q32.33/AKT1) and pathways in patients affected with RSA. To improve diagnosis and treatment of RSA, a comprehensive procedure is needed for identification and validation of causative genes.

Self-assembly of green tea catechin derivatives in nanoparticles for oral lycopene delivery.

Lycopene is a natural anti-oxidant that has attracted much attention due to its varied applications such as protection against loss of bone mass, chronic diseases, skin cancer, prostate cancer, and cardiovascular disease. However, high instability and extremely low oral bioavailability limit its further clinical development. We selected a green tea catechin derivative, oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG) as a carrier for oral lycopene delivery. Lycopene-loaded OEGCG nanoparticles (NPs) were prepared by a nano-precipitation method, followed by coating with chitosan to form a shell. This method not only can easily control the size of the NP to be around 200nm to improve its bioavailability, but also can effectively protect the lycopene against degradation due to EGCG's anti-oxidant property. OEGCG was carefully characterized with nuclear magnetic resonance spectroscopy and mass spectrometry. Lycopene-loaded polylactic-co-glycolic acid (PLGA) NPs were prepared by the same method. Chitosan-coated OEGCG/lycopene NPs had a diameter of 152±32nm and a ζ-potential of 58.3±4.2mv as characterized with transmission electron microscopy and dynamic light scattering. The loading capacity of lycopene was 9% and encapsulation efficiency was 89%. FT-IR spectral analysis revealed electrostatic interaction between OEGCG and chitosan. Freeze drying of the NPs was also evaluated as a means to improve shelf life. Dynamic light scattering data showed that no aggregation occurred, and the size of the NP increased 1.2 times (Sf/Si ratio) in the presence of 10% sucrose after freeze drying. The in vitro release study showed slow release of lycopene in simulated gastric fluid at acidic pH and faster release in simulated intestinal fluid. In an in vivo study in mice, lycopene pharmacokinetic parameters were improved by lycopene/OEGCG/chitosan NPs, but not improved by lycopene/PLGA/chitosan NPs. The self-assembled nanostructure of OEGCG combined with lycopene may be a promising application in oral drug delivery in various indications.

Lycopene treatment against loss of bone mass, microarchitecture and strength in relation to regulatory mechanisms in a postmenopausal osteoporosis model.

Lycopene supplementation decreases oxidative stress and exhibits beneficial effects on bone health, but the mechanisms through which it alters bone metabolism in vivo remain unclear. The present study aims to evaluate the effects of lycopene treatment on postmenopausal osteoporosis. Six-month-old female Wistar rats (n=264) were sham-operated (SHAM) or ovariectomized (OVX). The SHAM group received oral vehicle only and the OVX rats were randomized into five groups receiving oral daily lycopene treatment (mg/kg body weight per day): 0 OVX (control), 15 OVX, 30 OVX, and 45 OVX, and one group receiving alendronate (ALN) (2µg/kg body weight per day), for 12weeks. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Micro computed tomography was also used to evaluate changes in microarchitecture. Lycopene treatment suppressed the OVX-induced increase in bone turnover, as indicated by changes in biomarkers of bone metabolism: serum osteocalcin (s-OC), serum N-terminal propeptide of type 1 collagen (s-PINP), serum crosslinked carboxyterminal telopeptides (s-CTX-1), and urinary deoxypyridinoline (u-DPD). Significant improvement in OVX-induced loss of bone mass, bone strength, and microarchitectural deterioration was observed in lycopene-treated OVX animals. These effects were observed mainly at sites rich in trabecular bone, with less effect in cortical bone. Lycopene treatment down-regulated osteoclast differentiation concurrent with up-regulating osteoblast together with glutathione peroxidase (GPx) catalase (CAT) and superoxide dismutase (SOD) activities. These findings demonstrate that lycopene treatment in OVX rats primarily suppressed bone turnover to restore bone strength and microarchitecture.

Risk factors for falls in a longitudinal cohort study of Saudi postmenopausal women: the Center of Excellence for Osteoporosis Research Study.

OBJECTIVE: This study aims to identify possible risk factors for falls among Saudi postmenopausal women in a population-based study. METHODS: Seven hundred seven postmenopausal women aged 50 years or older were followed in a prospective cohort study. Participant demographic characteristics, medical history, lifestyle factors, past-year history of falls, and physical activity (PA) scores were assessed. We recorded single and multiple falls, anthropometric parameters, five special physical performance tests, hormone levels, and bone mineral density measurements. Data on knee osteoarthritis (OA), lumbar spondylosis, and osteopenia were collected. Knee and lower back pain were assessed by interview, and cognition was assessed with Mini-Mental State Examination. RESULTS: During the mean (SD) follow-up of 5.2 (1.3) years, 164 women (23.2%) reported at least one fall, of whom 73 women (10.3%) reported multiple falls. Six independent predictors of all falls were identified: PA score of 12.61 or lower (lowest quartile; odds ratio [OR], 4.10; 95% CI, 1.82-8.90); past-year history of falls (OR, 2.44; 95% CI, 2.30-2.90); age 65 years or older (OR, 2.16; 95% CI,1.30-3.12); presence of knee OA (OR, 1.56; 95% CI,1.03-2.34); handgrip strength of 13.88 kg or lower (lowest quartile; OR, 1.33; 95% CI,1.09-1.64); and 8-ft walk test of 3.94 s or longer (highest quartile; OR, 1.18; 95% CI, 1.07-1.35). CONCLUSIONS: Poor PA score, past-year history of falls, age 65 years or older, presence of knee OA, poor handgrip strength, and prolonged time on the 8-ft walk test are risk factors for all falls among Saudi postmenopausal women.

Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes.

Insulin-like growth factor 1 (IGF-1) is a determinant of bone mass and is inversely associated with vertebral fractures (VFs). Sclerostin regulates bone formation by inhibiting Wnt/ß-catenin signaling. Currently, there is little information on circulating sclerostin levels among postmenopausal women with type-2 diabetes mellitus (T2DM) with VFs in relation to serum IGF-1 (s-IGF-1). We investigated the relationships between serum sclerostin, s-IGF-1, and VFs in postmenopausal women with T2DM. We assessed cross-sectionally 482 postmenopausal women with T2DM and 482 age-matched postmenopausal women without T2DM who were recruited at diabetic clinics and primary health care centers for inclusion in a bone health survey. The main outcome measures were serum sclerostin, s-IGF-1, bone mineral density (BMD), and bone turnover markers. Lateral X-rays of the thoracic and lumbar spine were taken to diagnose VFs. Serum sclerostin levels were increased, whereas s-IGF-1 levels were decreased when T2DM women were stratified by the number of VFs (P<0.0001). Multiple logistic regression analysis showed that serum sclerostin levels were positively associated with 1 VF (odds ratio [OR]=1.27, (95% CI:1.01-2.03), P=0.016), 2 VFs (OR=1.41, (95% CI:1.03-2.36), P=0.006), and ≥3 VFs (OR=1.54, (95% CI:1.12-2.44) P=0.005). s-IGF-1 levels were inversely associated with 1 VF (OR=0.58, (95% CI:0.39-0.88), P=0.041), 2 VFs (OR=0.42, (95% CI:0.21-0.90), P=0.012), and ≥3 VFs (OR=0.19, (95% CI: 0.14-0.27), P<0.001). Increased serum sclerostin and decreased s-IGF-1 were associated with VFs among postmenopausal women with T2DM, suggesting that sclerostin and/or IGF-1 may be involved in increased bone fragility in T2DM and could be potential markers of VF severity.

Physical activity in relation to serum sclerostin, insulin-like growth factor-1, and bone turnover markers in healthy premenopausal women: a cross-sectional and a longitudinal study.

CONTEXT: There is limited information on the effects of mechanical loading caused by physical activity (PA) on sclerostin, IGF-I, and bone turnover markers (BTM). OBJECTIVE: The objective of the investigation was to study the relationships between serum sclerostin, serum-IGF-I (s-IGF-I), BTM, and the PA level in premenopausal women and to discern how 8 wk of PA training (PAT) affects the serum levels of sclerostin, IGF-I, and BTM. DESIGN: This was a cross-sectional study with a subgroup followed up longitudinally. SETTINGS AND SUBJECTS: A total of 1235 randomly selected premenopausal women were cross-sectionally studied. We also followed up 58 of these women longitudinally during an 8-wk course of PAT (4 d/wk) and compared them with 62 controls. All women were medically examined, and bone mineral density (BMD) and serum levels of sclerostin, s-IGF-I, and BTM were determined. RESULTS: Women with PA of greater than 120 min/wk showed significantly lower serum sclerostin (by 36.8%) but higher s-IGF-I (by 107%) levels than sedentary controls. Bone formation markers were also higher in the PA greater than 120 min/wk group compared with the sedentary controls. In the longitudinal study, the 8-wk PAT program led to a decrease in serum sclerostin (by 33.9%, P<0.0001) but increases in the serum levels of the bone-formation markers and IGF-I (s-IGF-I by 74.2%, P<0.0001). CONCLUSIONS: This study demonstrates that even minor changes in PA are associated with effects on serum levels of sclerostin, IGF-I, and BTM and suggests that sclerostin could be a link between mechanical loading and disuse osteoporosis in humans.

High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: the Center of Excellence for Osteoporosis Research Study.

Sclerostin regulates bone formation by inhibiting Wnt pathway signaling. Low circulating sclerostin levels cause high bone mass. We hypothesized that postmenopausal women with increased sclerostin levels have a greater risk for osteoporosis-related fractures. We examined the association between circulating sclerostin together with bone turnover markers and osteoporosis-related fracture risk in 707 postmenopausal women, in a population-based study with a mean follow-up period of 5.2 ± 1.3 years. Multivariate Cox proportional hazards regression models were used to analyze fracture risk, adjusted for age, body mass index, and other confounding risk factors. High sclerostin levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the relative fracture risk was more than sevenfold among postmenopausal women for each 1-SD increment increase in sclerostin level. Women in the highest quartile of sclerostin levels had about a 15-fold increase in fracture risk. Results were similar when we compared sclerostin at the 1-year visit to an average of two to three annual measurements. Fracture risk attributable to sclerostin levels was 56.6% in the highest quartile. Only high levels of bone resorption markers (plasma cross-linked C-terminal telopeptide of type 1 collagen [p-CTx], urinary CTx [u-CTx], and urinary N-telopeptide of type 1 collagen [u-NTx]) were predictive of osteoporosis-related fractures but at much lower hazard ratio (HR) values than that of serum sclerostin. Associations between sclerostin levels and fracture risk were independent of bone mineral density and other confounding risk factors. High sclerostin levels are a strong and independent risk factor for osteoporosis-related fractures among postmenopausal women. © 2012 American Society for Bone and Mineral Research.

Independent predictors of all osteoporosis-related fractures among healthy Saudi postmenopausal women: the CEOR Study.

This study was designed to identify independent predictors of all osteoporosis-related fractures (ORFs) among healthy Saudi postmenopausal women. We prospectively followed a cohort of 707 healthy postmenopausal women (mean age, 61.3±7.2 years) for 5.2±1.3 years. Data were collected on demographic characteristics, medical history, personal and family history of fractures, lifestyle factors, daily calcium intake, vitamin D supplementation, and physical activity score. Anthropometric parameters, total fractures (30.01 per 1000 women/year), special physical performance tests, bone turnover markers, hormone levels, and bone mineral density (BMD) measurements were performed. The final model consisted of seven independent predictors of ORFs: [lowest quartile (Q(1)) vs highest quartile (Q(4))] physical activity score (Q(1) vs Q(4): ≤12.61 vs ≥15.38); relative risk estimate [RR], 2.87; (95% confidence interval [CI]: 1.88-4.38); age≥60 years vs age<60 years (RR=2.43; 95% CI: 1.49-3.95); hand grip strength (Q(1) vs Q(4): ≤13.88 vs ≥17.28 kg) (RR=1.88; 95% CI: 1.15-3.05); BMD total hip (Q(1) vs Q(4): ≤0.784 vs 0.973 g/cm(2)) (RR=1.86; 95% CI: 1.26-2.75); dietary calcium intake (Q(1) vs Q(4): ≤391 vs ≥648 mg/day) (RR=1.66; 95% CI: 1.08-2.53); serum 25(OH)D (Q(1) vs Q(4): ≤17.9 vs ≥45.1 nmol/L) (RR=1.63; 95% CI: 1.06-2.51); and past year history of falls (RR=1.61; 95% CI: 1.06-2.48). Compared with having none (41.9% of women), having three or more clinical risk factors (4.8% of women) increased fracture risk by more than 4-fold, independent of BMD. Having three or more risk factors and being in the lowest tertile of T-score of [total hip/lumbar spine (L1-L4)] was associated with a 14.2-fold greater risk than having no risk factors and being in the highest T-score tertile. Several clinical risk factors were independently associated with all ORFs in healthy Saudi postmenopausal women. The combination of multiple clinical risk factors and low BMD is a very powerful indicator of fracture risk.

Determinants of serum sclerostin in healthy pre- and postmenopausal women.

Sclerostin is a secreted Wnt antagonist produced almost exclusively by osteocytes that regulates bone mass. However, there is currently limited information on the determinants of sclerostin in a large population-based study. The main objectives of the present study were to: (1) establish reference normative interval values for serum sclerostin in randomly selected healthy premenopausal women; (2) study the changes in serum sclerostin in relation to age in premenopausal and postmenopausal women and the factors that may influence bone turnover; and (3) determine the effect of menopausal status on serum sclerostin. A total of 1803 women were studied (including [n = 1235] premenopausal, and [n = 568] postmenopausal women, respectively, aged 20 to 79 years). A total of 443 healthy premenopausal women (aged 35 to 45 years) were used to establish reference normative intervals for serum sclerostin. All women studied were medically examined and had their bone mineral density values obtained for the lumbar spine (L(1) -L(4) ) and femoral neck according to a detailed inclusion criteria. In all women, values of serum sclerostin increased with increasing age up to the age of 45 years, and remained increased in postmenopausal women. Significant increases were evident in serum sclerostin in postmenopausal women with increasing years since menopause. Using stepwise multiple linear regression analysis, several variables were identified as determinants of serum sclerostin, including age, parathyroid hormone, estradiol (E(2)), and follicle-stimulating hormone (FSH) for premenopausal women; age, FSH, and E(2) for postmenopausal women; and age, serum osteocalcin, FSH, and E(2) in the entire sample studied. Further studies are needed to establish the potential role of this increase in mediating the known age-related impairment in bone formation.

Reference intervals of biochemical bone turnover markers for Saudi Arabian women: a cross-sectional study.

Biochemical bone turnover markers (BTMs) provide important information on the diagnosis, therapy and monitoring of metabolic bone diseases including osteoporosis. One goal of antiresorptive therapy in women is to decrease biochemical BTMs to the lower half of reference intervals for healthy pre-menopausal counterparts, using newly developed automated assays of such markers. The main objectives of the present study were to: (1) establish reference interval values for the following biochemical BTMs: serum osteocalcine (s-OC), bone alkaline phosphatase (s-bone ALP), procollagen type 1 N-terminal propeptide (s-PINP), crosslinked C-terminal telopeptide of Type 1 collagen (s-CTX), tartarate-resistant acid phosphatase isoform 5b (s-TRACP-5b) and urinary: CTX (u-CTX), N-telopeptides of type 1 collagen (u-NTX), pyridinoline (u-PYD) and deoxypyridinoline (u-DPD) in randomly selected Saudi healthy pre-menopausal women; (2) study the changes in biochemical BTMs in relation to age in pre- and post-menopausal women and the factors reported to influence bone turnover and (3) determine the effect of menopausal status on BTMs. A total of 2125 women were studied [including (n=1557) pre-, and (n=568) post-menopausal women, respectively, aged 20-79 years]. A total of 765 healthy pre-menopausal women (aged 35-45 years) were used to establish reference intervals for biochemical BTMs. All women studied were medically examined and had their bone mineral density (BMD) values obtained for the lumbar spine (L(1)-L(4)) and femoral neck according to detailed inclusion criteria. In all women, values of biochemical BTMs, decreased with increasing age up to the age of 45 years, increased steeply among women in their 50s and remained increased in post-menopausal women. Significant increases were evident in all biochemical BTMs in post-menopausal women with >5 years since menopause with the exception of s-OC, u-DPD, and u-PYD. Using stepwise multiple linear regression analysis, several variables were identified (depending on the BTM) as determinants of BTMs including age, BMI, parity, FSH, LH, PTH, s-Ca, s-Mg, s-PO(4) and 25(OH)D. In the reference intervals group, there are no significant correlations between any of the biochemical BTMs and age of menarche, day of menstrual cycle, physical activity, total daily dietary calcium and caffeine intakes and parity. It is recommended that the age range 35-45 years should be used when establishing biochemical BTMs reference intervals in Saudi Arabian pre-menopausal women.

Maternal serum free-beta-chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency thickness at 10-13(+6) weeks in relation to co-variables in pregnant Saudi women.

OBJECTIVE: To establish normative values and distribution parameters of first-trimester screening markers, namely, fetal nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), at 10 to 13(+6) weeks of gestation in Saudi women and to evaluate the effect of co-variables including maternal body weight, gravidity, parity, fetal gender, twin pregnancy, smoking and ethnicity on these markers. METHODS: A cohort of Saudi women (first cohort n = 1616) with singleton pregnancies prospectively participated in the present study, and fetal NT together with maternal serum free beta-hCG and PAPP-A were determined at 10 to 13(+6) weeks of gestation. The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and normative values were established, and correction for maternal body weight was made accordingly. The influence of various co-variables was examined using the data collected from the first and the second (n = 1849) cohorts of women and 62 twin pregnancies, and compared with other studies. RESULTS: All markers exhibited log-normally distributed MoMs. Gestational age-independent normative values were established. Maternal body weight was corrected, particularly for maternal free beta-hCG and PAPP-A using standard methods. Fetal NT showed a negative relationship with increasing gravidity (r = -0.296) or parity (r = -0.311), whereas both free beta-hCG and PAPP-A exhibited a significant positive relationship. There was a significant increase in the MoM of free beta-hCG in female fetuses. Smoking decreased MoM values of free beta-hCG (by 14.6%; P < 0.01) and PAPP-A (by 18.8%; P < 0.001). Twin pregnancy showed significant increases in MoM values of free beta-hCG (by 1.87-fold) and PAPP-A (by 2.24-fold), with no significant changes in fetal NT MoM values. Fetal NT MoM values were lower in Africans and Asians but higher in Orientals, as compared to Saudi women (P < 0.05; in each case). MoM values (body weight-corrected) of free beta-hCG were 25.2% higher in Africans and 19.4% higher in Orientals but 6.8% lower in other Arabian and Asian (by 5.8%) women as compared to Saudi women (P < 0.05; in each case). CONCLUSIONS: The normative values and distribution parameters for fetal NT, maternal serum free beta-hCG and PAPP-A were established in Saudi singleton pregnancies, the maternal body weight together with smoking, twin pregnancy and ethnicity being important first-trimester screening co-variables. Gravidity, parity and fetal gender are also considered to influence one or more of the first-trimester markers examined.

A randomized controlled trial of the efficacy of rosiglitazone and clomiphene citrate versus metformin and clomiphene citrate in women with clomiphene citrate-resistant polycystic ovary syndrome.

OBJECTIVE: To compare the efficacy of rosiglitazone and clomiphene citrate (CC) with metformin and CC in women with CC-resistant polycystic ovary syndrome (PCOS). DESIGN: Randomized controlled trial (RCT). SETTING: A university teaching hospital in Jeddah, Saudi Arabia. PATIENT(S): Twenty-five women with CC-resistant PCOS. INTERVENTION(S): Twelve women were assigned to the rosiglitazone and CC group, and 13 women were assigned to the metformin and CC group for three treatment cycles. The first cycle was started on the first day of the period with either rosiglitazone (4 mg twice daily) or metformin (500 mg three times daily) and continued for three cycles. Clomiphene citrate (100 mg) from the third day for 5 days was added to each cycle. MAIN OUTCOME MEASURE(S): Ovulation rate, number of follicles and estradiol (E2) on day 12 of the cycle, pregnancy rate, and changes in fasting glucose, serum insulin, HbA(1C), total testosterone (T), free T, luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), delta4-androstenedione (delta4-A), sex hormone-binding globulin (SHBG), insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3. RESULT(S): No significant differences were found in the baseline characteristics of both groups. Ovulation rate was significantly higher in the rosiglitazone and CC group (18 out of 28 cycles [[64.3%]]) than the metformin and CC group (12 out of 33 cycles [[36.4%]]) (P=.035). Similarly, statistically significant differences were found in the number of follicles > or =14 mm in the rosiglitazone and CC group (2.2 +/- 1) compared with the metformin and CC group (1.1 +/- 0.9) (P=.02) and E2 on day 12 of the cycle in the rosiglitazone and CC group (1,991 +/- 1,389 pmol/L) compared with the metformin and CC group (548 +/- 327) (P<.001). The pregnancy rate was also higher in the rosiglitazone and CC group (6 out of 12 [[50%]] women) than the metformin and CC group (5 out of 13 [[38.5%]] women), but did not reach statistical significance (P=.58). Both groups showed no significant changes in fasting plasma glucose or HbA(1C) or IGFBP-3 values. However, in both groups, fasting serum insulin, total T, free T, LH, DHEA-S, delta4A, and IGF-1 levels decreased significantly, and SHBG and IGFBP-1 exhibited significant increases. CONCLUSION(S): These findings suggest that short-term use of rosiglitazone and CC is more efficacious than metformin and CC in ovulation induction in women with CC-resistant PCOS.

Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome.

OBJECTIVE: To determine plasma adiponectin concentration in women with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adiponectin to the hormonal and metabolic parameters, including measures of insulin resistance (IR). DESIGN: Case-control study. SETTING: Tertiary-referral university hospital. PATIENT(S): One hundred eighty selected women were classified as follows: 45 obese (body mass index [BMI] >30 kg/m2) with PCOS; 45 lean (BMI <25 kg/m2) with PCOS; 45 obese (BMI >30 kg/m2) without PCOS, and 45 lean (BMI <25 kg/m2) without PCOS. INTERVENTION(S): Blood samples were collected from all women with or without PCOS between 8 and 11 am, after an overnight fast. MAIN OUTCOME MEASURE(S): Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), free T4, testosterone (T), 17-alpha-hydroxyprogesterone, Delta4-androstenedione (Delta4-A), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), insulin, and plasma levels of adiponectin and glucose. Measures of IR included fasting serum insulin, glucose-to-insulin ratio, and homeostasis model assessment (HOMA). RESULT(S): Adiponectin concentrations were found to be significantly decreased in women with PCOS and in obese women without PCOS as compared with lean women without PCOS. Adiponectin concentrations correlated inversely with body weight, BMI, fasting plasma glucose, serum insulin, Delta4-A, DHEA, DHEAS, and HOMA but correlated positively with serum T, SHBG, FAI, and glucose-to-insulin ratio. Multiple regression analysis showed that BMI, HOMA, Delta4-A, and insulin were independent determinants of adiponectin concentrations. CONCLUSION(S): Hypoadiponectinemia is evident in obese and lean women with PCOS with variable degree of IR; and it is suggested that IR per se or other metabolic abnormalities of PCOS are involved in the regulation of adiponectin concentration in women with PCOS.

Influence of age, sex, folate and vitamin B12 status on plasma homocysteine in Saudis.

OBJECTIVE: To evaluate the reference intervals for fasting total plasma homocysteine concentrations in Saudi healthy males and females in relation to age, sex and the nutritional status of folate and vitamin B12. METHODS: A prospective study was conducted on randomly selected Saudi healthy males (n=642) and females (n=784) living in the Jeddah area, Kingdom of Saudi Arabia. Plasma homocysteine together with serum folate and plasma vitamin B12 concentrations were determined. Analysis of variance was used to examine differences among various groups according to age, sex or folate, or both or vitamin B12 status for different variables. Correlations were carried out using multiple linear regression analysis. RESULTS: Reference intervals for plasma homocysteine concentrations in Saudi healthy males and females (age 20 -69 years) was documented. The age-adjusted geometric mean of plasma homocysteine concentration was significantly greater in males (9.91 micromol/L) than in females (8.08 micromol/L) (P<0.0001). In both males and females, values for serum folate and plasma vitamin B12 concentrations significantly and negatively correlated with plasma homocysteine concentrations (P<0.000). Serum total cholesterol showed significant positive correlations with plasma homocysteine in both males (r=0.448, P<0.000) and females (r=0.313; P < 0.000). Diastolic (r= 0.182; P<0.001) and systolic (r=0.309; P < 0.000) blood pressure values showed significant positive correlations with plasma homocysteine concentrations in females only. Stepwise multiple linear regression analysis showed that in both males and females, age, sex, serum folate, and waist-to-hip ratio and plasma vitamin B12 were significant determinants of plasma homocysteine concentrations. CONCLUSION: The first data on plasma homocysteine concentrations in Saudi healthy males and females are reported. Age and sex differences were confirmed and a significant inverse relationship between plasma homocysteine concentrations and that of serum folate and plasma vitamin B12 was observed. Various independent variables including age, sex, serum folate, waist-to-hip ratio and plasma vitamin B12 contributed to the changes in plasma homocysteine. Plasma homocysteine concentrations should be evaluated in patients at risk for cardiovascular and other related diseases in the Saudi population.

Are women at an increased risk of gestational thyrotoxicosis?

OBJECTIVE: To evaluate the relative importance of thyroid hormones and human chorionic gonadotropin in relation to the risk of gestational thyrotoxicosis in Saudi women living in Jeddah, Kingdom of Saudi Arabia. METHODS: A prospective study was conducted on Saudi healthy pregnant women (N=406) at 12-15 weeks of gestation and compared with healthy non-pregnant controls (N=200). Maternal serum levels of free thyroxine free triiodothyronine, thyrotropin, human chorionic gonadotropin and free b-human chorionic gonadotropin together with urinary iodine excretion were determined. Analysis of variance was used to examine differences among the groups for different variables and the Bonferroni criterion was used when significance tests were made. RESULTS: Pregnant women were classified into 2 groups according to the lower limit of serum thyrotropin levels in non-pregnant euthyroid controls at >= 0.3 mIU/L (Group one) or < 0.30 mIU/L (Group 2). Suppressed levels of serum thyrotropin (< 0.30 mIU/L) were found in 11.1% of pregnant women which was accompanied by significant increases in free thyroxine (P<0.001), free triiodothyronine (P < 0.05), human chorionic gonadotropin (P<0.001) and b-human chorionic gonadotropin (P<0.001). A significant negative correlation between serum levels of thyrotropin and that of human chorionic gonadotropin (r=-0.381, P<0.001) was observed. The relative risk of having a serum thyrotropin level of < 0.30 mIU/L was 4.89 (P<0.001) for the pregnant women examined as compared with non-pregnant controls. Approximately 5.6% of the women examined exhibited biochemical evidence of thyrotoxicosis. CONCLUSION: The results of the present study show that Saudi pregnant women are at risk of developing biochemical evidence of thyrotoxicosis during early gestation, and thus, are likely to be at greater risk of clinically evident gestational thyrotoxicosis and hyperemesis gravidarum. Genetically determined differences in the synthesis or metabolism of human chorionic gonadotropin isoforms, or both may contribute to this increased risk.

Urinary iodine excretion and maternal thyroid function. During pregnancy and postpartum.

OBJECTIVE: To evaluate urinary iodine excretion during the course of pregnancy and postpartum in relation to maternal and neonatal thyroid function parameters in Saudi women living in Jeddah, Kingdom of Saudi Arabia. METHODS: A prospective longitudinal study was conducted on Saudi normal pregnant women during the course of pregnancy (N=80), at term and 6-10 weeks postpartum (N=65), during the period January 1997 through to December 2000. Maternal urinary iodine excretion was determined together with serum levels of total thyroxine, total tri-iodothyronine, free thyroxine, free tri-iodothyronine, thyrotropin, reverse tri-iodothyronine, thyroxine-binding globulin and thyroglobulin. A group of non-pregnant woman (N=200) were included for comparative purposes. Data were also analyzed for significant trends using ANOVA. Neonatal serum levels of total thyroxine, total tri-iodothyronine, free thyroxine, thyrotropin, thyroxine-binding globulin, and thyroglobulin were also measured. RESULTS: Changes in urinary iodine excretion and in serum thyroid function parameters during the course of pregnancy, at term and postpartum have been demonstrated. Subclinical iodine deficiency was evident in 28.8% of pregnant women at term and 11.5% of women at 6-10 weeks postpartum. Serum total thyroxine and total tri-iodothyronine levels increased in the first trimester (P<0.001) and remained elevated at term (P<0.001). Serum free thyroxine levels showed a significant decrease by the 2nd trimester (P<0.001) and continued to decrease in the 3rd trimester (P<0.001). Serum free tri-iodothyronine showed continuous decrease throughout gestation. Thyrotropin levels were decreased during the first and 2nd trimesters (P<0.001) but then increased to be comparable to non-pregnant values. Serum reverse tri-iodothyronine increased during the first and 2nd trimesters (P<0.001). There was a significant increase in serum thyroxine-binding globulin and thyroglobulin levels during the course of pregnancy. A significant negative correlation between thyrotropin and human chorionic gonadotropin levels was observed throughout pregnancy (r=-0.31, P<0.001). The observed correlation was stronger (r=-0.37; P<0.001) in the first trimester as compared to that in the second (r=-0.164; P<0.001) or the third (r=-0.125; P<0.269) trimester. There was a negative correlation between maternal free thyroxine and neonatal thyrotropin (r=-0.70; P<0.001). Positive correlation was found between neonatal total thyroxine and birth weight (r=0.61; P<0.001) and maternal urinary iodine concentration (P<0.001). CONCLUSION: The changes in urinary iodine excretion during the course of pregnancy were documented. The decrease in free thyroxine and free tri-iodothyronine and the increase in reverse tri-iodothyronine concentrations during pregnancy resemble the changes in thyroid hormones seen in non-thyroidal illness. Moreover, the changes in thyrotropin in relation to that of human chorionic gonadotropin support the view that the thyroid gland is not primarily thyrotropin driven in early pregnancy. The results suggest that a more complex control may finally regulate maternal thyroid activity; the pituitary and the chorionic systems both function in an independent way in response to possible different feedback stimuli. This could be a physiological adaptation enabling energy conservation during the high metabolic demands of pregnancy. Finally, the results of the present study point to the need of an increased iodine supply in Saudi pregnant women living in Jeddah, Kingdom of Saudi Arabia to decrease the potential consequences of low iodine intake on maternal thyroid economy.