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PubMed2002

The sensor kinase CitA (DpiB) of Escherichia coli functions as a high-affinity citrate receptor.

For the CitA-CitB (DpiB-DpiA) two-component signal transduction system from Escherichia coli, three diverse functions have been reported: induction of the citrate fermentation genes citCDEFXGT, repression of the regulator gene appY, and destabilization of the inheritance of iteron-containing plasmids such as pSC101. This poses the question of the principal biological role of this system. Here it is shown that the periplasmic domain of the E. coli sensor kinase CitA functions as a high-affinity citrate receptor. Two CitA derivatives were purified by affinity chromatography and subjected to binding studies using isothermal titration calorimetry (ITC). One of them, termed CitA215MBP, comprised the N-terminal part of CitA (amino acid residues 1-215), including the two transmembrane helices, and was fused to the amino terminus of the E. coli maltose-binding protein lacking its signal peptide. The second CitA derivative, designated CitAP(Ec), encompassed only the periplasmic domain (amino acid residues 38-177). CitA215MBP bound citrate at 25 degrees C with a K(d) of 0.3 microM and a binding stoichiometry of up to 0.9 in 50 mM sodium phosphate buffer, pH 7. Binding was driven by the enthalpy change (Delta H of -95.7 kJ mol(-1)), whereas the entropy change was not favorable for binding ( T Delta S of -58.6 kJ mol(-1)). ITC experiments with CitAP(Ec) yielded similar K(d) values for citrate (0.15-1.0 microM). Besides citrate, also isocitrate ( K(d) approximately tricarballylate ( K(d) approximately t not malate were bound by CitAP(Ec). The results favor the assumption that the primary biological function of the CitA-CitB system is the regulation of the citrate fermentation genes.

Citric Acid↗
PubMedDate not supplied

The Na+-dependent citrate carrier of Klebsiella pneumoniae: high-level expression and site-directed mutagenesis of asparagine-185 and glutamate-194.

The Na+-dependent citrate carrier of Klebsiella pneumoniae (CitS) is a member of the 2-hydroxycarboxylate transporter family. Within the highly conserved helix Vb region, Asn-185 of CitS was mutated to Val and Glu-194 was mutated to Gln. The wild-type and mutant proteins were synthesised in Escherichia coli DH5alpha or C43(DE3) as biotinylated or His-tagged CitS-fusions, respectively. The synthesis and purification procedure yielded 6.5 mg pure CitS per litre culture. The fusion proteins were characterised with E. coli cell suspensions or after reconstitution of the purified enzymes into proteoliposomes. The E194Q mutation had almost no effect on the kinetics of Na+ or citrate transport. In contrast, aberrant citrate transport kinetics were found for the N185V mutant. The apparent K(m) value for the citrate species H-citrate(2-) was increased about nine-fold, whereas the apparent Vmax value and the effect of Na+ on the transport kinetics were comparable to the wild-type. Asn-185 of CitS appears therefore to participate in the binding of H-citrate(2-).

Amino Acid Sequence↗
PubMed2006

Effect of potential renal acid load of foods on urinary citrate excretion in calcium renal stone formers.

The aim of this study was to investigate the influence of the potential renal acid load (PRAL) of the diet on the urinary risk factors for renal stone formation. The present series comprises 187 consecutive renal calcium stone patients (114 males, 73 females) who were studied in our stone clinic. Each patient was subjected to an investigation including a 24-h dietary record and 24-h urine sample taken over the same period. Nutrients and calories were calculated by means of food composition tables using a computerized procedure. Daily PRAL was calculated considering the mineral and protein composition of foods, the mean intestinal absorption rate for each nutrient and the metabolism of sulfur-containing amino acids. Sodium, potassium, calcium, magnesium, phosphate, oxalate, urate, citrate, and creatinine levels were measured in the urine. The mean daily PRAL was higher in male than in female patients (24.1+/-24.0 vs 16.1+/-20.1 mEq/day, P=0.000). A significantly (P=0.01) negative correlation (R=-0.18) was found between daily PRAL and daily urinary citrate, but no correlation between PRAL and urinary calcium, oxalate, and urate was shown. Daily urinary calcium (R=0.186, P=0.011) and uric acid (R=0.157, P=0.033) were significantly related to the dietary intake of protein. Daily urinary citrate was significantly related to the intakes of copper (R=0.178, P=0.015), riboflavin (R=0.20, P=0.006), piridoxine (R=0.169, P=0.021) and biotin (R=0.196, P=0.007). The regression analysis by stepwise selection confirmed the significant negative correlation between PRAL and urinary citrate (P=0.002) and the significant positive correlation between riboflavin and urinary citrate (P=0.000). Urinary citrate excretion of renal stone formers (RSFs) is highly dependent from dietary acid load. The computation of the renal acid load is advisable to investigate the role of diet in the pathogenesis of calcium stone disease and it is also a useful tool to evaluate the lithogenic potential of the diet of the individual patient.

Acids↗
PubMed2005

Citrate and vitamin E blunt the shock wave-induced free radical surge in an in vitro cell culture model.

Free radical formation plays a major role in shock wave lithotripsy induced renal damage. Moreover, previous studies suggest that free radicals may also promote de novo calcium oxalate crystallization of previously damaged urothelium. Citrate is a known inhibitor of renal stone formation and has also been used as a free radical scavenger. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of two free radical scavengers, citrate and vitamin E, on the prevention of the shock wave-induced free radical surge. Suspensions of MDCK cells were placed in containers for shock wave exposure. Six groups of six containers each were examined: (a) no scavengers 0 shocks, (b) no scavengers 100 shocks, (c) citrate 0 shocks, (d) citrate 100 shocks, (e) vitamin E 0 shocks, (f) vitamin E 100 shocks. An unmodified HM3 was used to deliver 100 shocks at 24 kV. The cell groups that were not shocked acted as the control group and were handled identically, except for the lack of shock wave exposure. After shock wave administration, the containers were emptied and cell suspensions were immediately centrifuged. The supernatant was examined for lactate dehydrogenase (LDH) and 8-isoprostane (8-IP), markers of cellular injury and free radical formation, respectively. Intracellular LDH uniformly increased in all groups exposed to shock wave energy. Similarly, 8-IP increased in all shocked groups. However, the 8-IP increase was significantly reduced when the free radical scavengers were employed. As citrate is a well-known inhibitor of calcium nephrolithiasis, its mechanism of action may be further enhanced, based on its ability to reduce free radical formation, by a protective effect on the urothelium. These data further support the use of citrate based medications during the peri-operative period of shock wave lithotripsy, not only to inhibit stone formation and facilitate fragment passage, but also to reduce the incidence of shock wave induced renal damage. Further studies are warranted to clinically test this hypothesis.

Animals↗
PubMed2005

Citrate catabolism and production of acetate and succinate by Lactobacillus helveticus ATCC 15807.

The citrate metabolism of Lactobacillus helveticus ATCC 15807 was studied under controlled-pH fermentations at pH 4.5 and pH 6.2. The micro-organism was able to co-metabolize citrate and lactose at both pH from the beginning of growth, which enhanced the rate of lactose consumption and lactic acid production, compared with cultures without citrate. The effect of citrate on cell growth was dependent on the balance between the ratio of dissociated to non-dissociated forms of the acetic acid produced and the extra ATP gained by the cells, both facts related to the citrate metabolism. The citrate catabolism determined a change in the fermentation pattern of L. helveticus ATCC 15807 from homolactic to a mixed-acid profile, regardless of the external pH. Within this new fermentation pattern, acetate was the major product formed (13-20 mM), followed by succinate (2.4-3.7 mM), while acetoine, dyacetile or butanediol were not detected. The mixed-acid profile displayed by L. helveticus ATCC 15807 was linked to NADH(2) oxidase activity rather than the acetate kinase enzyme.

Acetic Acid↗
PubMed2006

Expression of citrate permease gene of plasmid pCM1 isolated from Lactococcus lactis subsp. lactis biovar diacetylactis NIAI N-7 in Lactobacillus casei L-49-4.

Recombinant vector pJLECit (8,232 bp) was constructed using citrate permease gene contained in the 3,919-bp fragment of plasmid pCM1 (8,280 bp) isolated from Lactococcus lactis subsp. lactis biovar diacetylactis NIAI N-7, repA and ori from pLU1, and pMB1 ori and the erythromycin resistance gene from pJIR418. Lactobacillus casei L-49-4 (plasmid-free mutant of strain L-49) harboring the constructed pJLECit converted citrate into diacetyl/acetoin. Citrate uptake rate of resting cells was the highest at pH 5.5 and 10 mM citrate concentration. Diacetyl formation activity by the cell-free extracts of Lb. casei L-49-4 (pJLECit) grown in de Man-Rogosa-Sharpe (MRS) broth was higher than that of cells grown in MRS broth without citrate. On the other hand, diacetyl reductase activity of cells grown in MRS broth was lower than that of cells grown in MRS broth without citrate.

Acetoin↗
PubMed2003

Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of cis-diamminedichloroplatinum.

Attenuation of the renal toxicity of cis-diamminedichloroplatinum (CDDP) is important in the use of this effective but cytotoxic anticancer agent. We have previously shown that the renal toxicity of CDDP can be efficiently reduced by the induction of metallothionein (MT) by preadministration of bismuth compounds in mice. Bismuth subnitrate (BSN) is used as an antigastric ulcer agent and as an antidiarrheic agent, and is suitable for inducing MT in the kidney in cancer patients. However, due to the low absorption rate of Bi from the gastrointestinal tract, the efficacy of BSN in inducing renal MT is low. In the present study, we examined the effects of citrate as a vehicle for oral administration of BSN on the tissue distribution of Bi and induction of MT in the kidneys and tumors in mice inoculated with Meth-A fibrosarcoma. Renal levels of MT and Bi were markedly increased in the mice given BSN dissolved in citrate solution compared with those given BSN suspended in saline. On the other hand, the use of citrate increased Bi accumulation in the tumor only slightly and did not increase tumor MT levels. Administration of BSN with citrate efficiently depressed the renal toxicity of CDDP, but did not affect its antitumor activity. Since both BSN and citrate are used clinically as pharmaceuticals, the combination regimen of BSN and citrate may be readily applicable as a countermeasure against the adverse side effects of CDDP without affecting its antitumor activity.

Administration, Oral↗
PubMed2006

Magnetic resonance spectroscopy in patients with locally confined prostate cancer: association of prostatic citrate and metabolic atrophy with time on hormone deprivation therapy, PSA level, and biopsy Gleason score.

This study was undertaken to determine respective associations between prostatic citrate or metabolic atrophy (no detectable citrate, choline, and creatine) at magnetic resonance spectroscopy (MRS) and time on hormone-deprivation therapy, serum PSA, and biopsy Gleason score. Clinical data, histopathology reports and PSA levels of 36 patients on hormone-deprivation therapy (age, 64+/-9 years, pre-therapeutic biopsy Gleason sum, median 6, range 3-8, antiandrogens only, n=3, LHRH-analogues only, n=4, combined hormone-deprivation therapy, n=29, duration, 27+/-19 weeks) for locally confined prostate cancer (PCA) were retrospectively correlated with findings in the peripheral zone of the prostate at 3D-MRS (endorectal coil, PRESS, TR 1,000 ms, TE 130 ms). The results show that citrate was usually detected after 13 weeks or less of hormone-deprivation therapy (10/12 vs. 6/24 patients, chi-square-test, p=0.002). All patients with PSA levels exceeding 0.20 ng/ml had detectable metabolites (citrate, n=12, choline without citrate, n=6), while 9/18 patients with PSA 0.20 ng/ml or less showed metabolic atrophy (Fisher-exact-test, p=0.001). There were no significant associations between citrate, metabolic atrophy, pre-therapeutic PSA, and biopsy Gleason sum, respectively. It has been concluded that hormone-deprivation therapy for locally confined PCA has not reached its full deprivation potential after 13 weeks. MRS detects prostate metabolism in patients with PSA exceeding 0.20 ng/ml after hormone-deprivation therapy.

Aged↗
PubMed2006

Conditions required for citrate utilization during growth of Lactobacillus casei ATCC334 in chemically defined medium and cheddar cheese extract.

Conditions required for citrate utilization by Lactobacillus casei ATCC334 were identified. Citrate was utilized by this microorganism in modified Chemically Defined Media (mCDM) as an energy source, solely in the presence of limiting concentrations of galactose. The presence of glucose inhibited citrate utilization by this microorganism even when added in limiting concentrations. Utilization of citrate occurred at pH 6.0 +/- 0.2 and 5.1 +/- 0.2. Together these observations suggest that citrate is an energy source for L. casei in ripening cheese only when the residual levels of carbohydrate post-fermentation are limiting (<2.5 mM), and lactose or glucose are absent. However, citrate utilization by this organism was observed in Cheddar cheese extract (CCE), which naturally contains both lactose and galactose, at the beginning of late-logarithmic phase and regardless of the galactose concentration present in the media.

Cheese↗
PubMed1995

Interference with uterine blood flow by clomiphene citrate in women with unexplained infertility.

OBJECTIVE: To investigate the effect of clomiphene citrate on the uterine blood flow in women with unexplained infertility. METHODS: Twenty-one women who had normal uterine blood flow (pulsatility index [PI] less than 3 from the LH peak to the middle luteal phase of a natural ovulatory cycle) were enrolled in this study. Patients were given clomiphene citrate (100 mg/day) from days 5-9 of the next ovulatory cycle. The PI values measured in the natural and clomiphene citrate-treated cycles were compared using repeated measures analysis of variance. Their correlations with the estradiol (E2) and progesterone concentrations in the treatment cycle were calculated using the Pearson correlation coefficient. RESULT: In the natural cycles of those with normal uterine blood flow, the highest impedance of uterine blood flow was detected at the late follicular phase, then blood flow increased during the luteal phase. In the clomiphene citrate-treated cycles, a statistically significant decrease in uterine blood flow also occurred during the early luteal phase (P < .05). No significant correlation of E2 or progesterone serum concentrations with PI values of the uterine artery could be found in either natural or clomiphene citrate-treated cycles. CONCLUSION: The use of clomiphene citrate decreases the uterine blood flow during the early luteal phase, a periimplantation stage.

Adult↗
PubMed2005

Effect of a neutral citrate solution on the fluoride release of conventional restorative glass ionomer cements.

OBJECTIVES: This study investigates the effect of a neutral citrate solution on the fluoride release of 10 acid-base setting glass ionomer cements during 140 days at 37 degrees C. METHODS: Five disks of 10 acid-base setting restorative glass ionomers were prepared according to the manufacturer's instructions. These specimens were immersed individually in 25 ml of a 0.01 mol/l citrate solution with pH = 7. Over 140 days, the solutions were regularly renewed and the fluoride concentration eluted during each period was determined with a combined fluoride ion selective electrode. RESULTS: The cumulative fluoride release was the result of an initial high release that ceased after some time and a long-term of low fluoride release. The long-term fluoride release was higher in neutral citrate solution than in water. For some formulations the short-term fluoride release also was higher in neutral citrate solution than in water suggesting that the polysalt matrix composition could be important in this respect. SIGNIFICANCE: The fluoride release process is due not only to a loss of relatively loosely bound fluoride in the cement matrix, but also to the release of strongly bounded fluoride inducing a long-term fluoride release. The effect of citrate on the fluoride release process may increase depending on the acid (polyacrylic acid versus copolymers of polyacrylic acid) used for the polysalt formation in the hardening cement. Depending on the competition between the polyacrylate anion and the citrate anion for the metal cation extraction the fluoride release process may be retarded.

Cariostatic Agents↗
PubMed1986

The primary treatment of luteal phase inadequacy: progesterone versus clomiphene citrate.

This study was undertaken in order to evaluate the superiority, if any, of progesterone or clomiphene citrate in treatment of infertile women with luteal phase inadequacy. Eighty-two patients were randomly treated with progesterone or clomiphene citrate. Some patients with failure of progesterone were changed to clomiphene citrate treatment; some patients with failure of clomiphene citrate were changed to progesterone treatment. A life-table analysis was used for evaluation of the results. No statistical difference was noticed between the two treatments. Seventeen of 57 patients treated with progesterone and 13 of 62 patients treated with clomiphene citrate conceived. It is recommended that: patients with luteal phase inadequacy can be treated primarily with progesterone; an endometrial biopsy should be performed if the patients fail to conceive; if endometrial biopsy continues to be abnormal the patients can be treated again with clomiphene citrate. Some alternative treatments for luteal phase inadequacy are needed.

Biopsy↗
PubMed1998

Citrate and isocitrate in plant metabolism.

The relevance of citrate and isocitrate metabolism in plants is discussed in connection with the different pathways for their conversions. The routes for citrate and isocitrate conversions are incorporated into the system of cross-linked metabolic processes and may provide carbon skeletons for nitrogen assimilation and reducing equivalents for biosynthetic reactions, support the functioning of the glyoxylate cycle and play an important role in the TCA and energy metabolism as a whole. The possibility of the coupling of citrate and isocitrate metabolism with various electron transport systems is discussed from the point of view of the efficiency of the balancing cellular NAD(P)H/NAD(P)+ and ATP/ADP ratios. The role of citrate and isocitrate and their derivations as potent effectors of some enzymes is considered. Special attention is paid to the enzymes associated with citrate and isocitrate metabolism and to the mechanisms which regulate their activity. The possibilities of the coordination of the main processes of energy and biosynthetic metabolism at the level of citrate and isocitrate distribution are discussed.

Citric Acid↗
PubMed2001

The iron chelator pyridoxal isonicotinoyl hydrazone inhibits mitochondrial lipid peroxidation induced by Fe(II)-citrate.

Pyridoxal isonicotinoyl hydrazone (PIH) is able to prevent iron-mediated hydroxyl radical formation by means of iron chelation and inhibition of redox cycling of the metal. In this study, we investigated the effect of PIH on Fe(II)-citrate-mediated lipid peroxidation and damage to isolated rat liver mitochondria. Lipid peroxidation was quantified by the production of thiobarbituric acid-reactive substances (TBARS) and by antimycin A-insensitive oxygen consumption. PIH at 300 microM induced full protection against 50 microM Fe(II)-citrate-induced loss of mitochondrial transmembrane potential (deltapsi) and mitochondrial swelling. In addition, PIH prevented the Fe(II)-citrate-dependent formation of TBARS and antimycin A-insensitive oxygen consumption. The antioxidant effectiveness of 100 microM PIH (on TBARS formation and mitochondrial swelling) was greater in the presence of 20 or 50 microM Fe(II)-citrate than in the presence of 100 microM Fe(II)-citrate, suggesting that the mechanism of PIH antioxidant action is linked with its Fe(II) chelating property. Finally, PIH increased the rate of Fe(II) autoxidation by sequestering iron from the Fe(II)-citrate complex, forming a Fe(III)-PIH, complex that does not participate in Fenton-type reactions and lipid peroxidation. These results are of pharmacological relevance since PIH is a potential candidate for chelation therapy in diseases related to abnormal intracellular iron distribution and/or iron overload.

Animals↗
PubMed1999

Octreotide is not useful for clomiphene citrate resistance in patients with polycystic ovary syndrome but may reduce the likelihood of ovarian hyperstimulation syndrome.

OBJECTIVE: To determine whether octreotide is effective for ovulation induction in patients with polycystic ovary syndrome (PCOS) and clomiphene citrate resistance or for reduction of the risk of ovarian hyperstimulation syndrome (OHSS) with gonadotropin therapy. DESIGN: Prospective, double-blind, placebo-controlled, crossover trial. SETTING: Private infertility practice. PATIENT(S): Twelve patients with PCOS undergoing therapy for infertility. INTERVENTION(S): The patients were assigned randomly to receive either octreotide or placebo. Those with clomiphene citrate-resistant PCOS received clomiphene citrate, 150 mg. Patients at risk for the development of OHSS received urinary FSH for ovulation induction. MAIN OUTCOME MEASURE(S): Ovulation, pregnancy, the development of OHSS, and levels of fasting insulin, insulin-like growth factor 1, insulin-like growth factor binding proteins 1 and 3, testosterone, androstenedione, DHEAS, E2, LH, and FSH. RESULT(S): Octreotide significantly reduced levels of fasting insulin, insulin-like growth factor 1, and LH in both clomiphene citrate- and urinary FSH-stimulated cycles. Levels of insulin-like growth factor binding protein 3 were increased. Two of six clomiphene citrate-stimulated cycles reached ovulation with the use of either octreotide or placebo. In urinary FSH-stimulated cycles, patients who received octreotide had significantly lower E2 levels at the time of hCG administration and fewer mature follicles. No cases of OHSS occurred in either group. One pregnancy occurred in each group. CONCLUSION(S): Octreotide was no more effective than placebo for clomiphene citrate resistance in patients with PCOS, but it did reduce E2 levels and follicle numbers when combined with urinary FSH. Thus, octreotide may reduce the incidence of OHSS in patients with PCOS.

Adult↗
PubMed1998

Characterisation of non-transferrin-bound iron (ferric citrate) uptake by rat hepatocytes in culture.

Under conditions of iron overload plasma transferrin can be fully saturated and the plasma can transport non-transferrin-bound Fe which is rapidly cleared by the liver. Much of this Fe is complexed by citrate. The aim of the present work was to characterise the mechanisms by which Fe-citrate is taken up by hepatocytes using a rat hepatocyte cell culture model. The cells, after one day in culture, were incubated with 59Fe-labelled Fe-citrate for varying time periods, then washed and Fe uptake to the membrane and intracellular compartments of the cell was determined by radioactivity measurements. Maximal rates of internalisation of Fe occurred at a Fe:citrate molar ratio of 1:100 or greater, a pH of approximately 7.4 and an extracellular Ca2+ concentration of 1.0 mM. Fe uptake showed Michaelis-Menten kinetics and was a temperature-dependent process. The K(m) and Vmax for Fe internalisation by the cells at 37 degrees C were approximately 7 microM and 2 nmol/mg DNA/min (25 x 10(6) atoms/cell/min), respectively; and the Arrhenius activation energy was 35 kJ/mol. The transition metals, Zn2+, Co2+ and Ni2+, inhibited Fe uptake when used at 10 and 100 times the concentration of Fe. The rate of Fe internalisation from Fe-citrate was found to be approximately 20 times as great as that from Fe-transferrin with Fe concentrations of 1 and 2.5 microM for both forms of Fe. The rate of Fe uptake by iron-loaded hepatocytes obtained from rats which had been fed carbonyl Fe was not significantly different from that by normal hepatocytes. These experiments show that rat hepatocytes in primary culture have a high capacity to take up non-transferrin-bound Fe in the form of Fe-citrate and that uptake occurs by facilitated diffusion. The iron transport process does not appear to be regulated by cellular Fe levels.

Animals↗
PubMed2001

Novel pH-sensitive citrate cross-linked chitosan film for drug controlled release.

Turbidimetric titration revealed that there were electrostatic attractive interactions between citrate and chitosan in the pH region of 4.3-7.6, depending on their degree of ionization. Citrate cross-linked chitosan film was prepared simply by dipping chitosan film into sodium citrate solution. The swelling ratio of citrate/chitosan film was sensitive to pH, ionic strength etc. Under acidic conditions, citrate/chitosan film swelled and even dissociated in the pH less than 3.5, and the model drugs (brilliant blue and riboflavin) incorporated in the film were released quickly (usually within 2 h released completely in simulated gastric fluid at 37 degrees C) while under neutral conditions the swelling ratio of citrate/chitosan film was less significant and the release rate of brilliant blue and riboflavin was low (less than 40% released in simulated intestinal fluid in 24 h). Sodium chloride weakened the electrostatic interaction between citrate and chitosan, and therefore facilitated the film swelling and accelerated drug release. The parameters of film preparation such as citrate concentration, solution pH etc. influencing the film swelling and drug release profiles were examined. The lower concentration and the higher pH of citrate solution resulted in a larger swelling ratio and quicker riboflavin release. To improve the drug controlled release properties of citrate/chitosan film, heparin, pectin and alginate were further coated on the film surface. Among them only the coating of alginate prolonged riboflavin release noticeably (for 80% of drug released the time was extended from 1.5 to 3.5 h with 0.5% w/v alginate used). The results indicated that the citrate/chitosan film was useful in drug delivery such as for the site-specific drug controlled release in stomach.

Chitin↗
PubMed2004

Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy.

This single centre randomized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and low-dose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome (PCOS). Seventy-six infertile patients with PCOS were randomized to receive clomiphene citrate (50-150 mg/day for 5 days) (clomiphene citrate group, n = 38) or recombinant human FSH (FSH group, n = 38) in a chronic, low-dose, step-up protocol (daily starting dose 75 IU) for up to three consecutive cycles. Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin (HCG) was given to trigger ovulation in all cycles with appropriate follicular development. The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles. Secondary outcomes were cycle cancellation rate, ovulation rate per cycle, cumulative ovulation rate, pregnancy rate per cycle, incidence of OHSS, cumulative live birth rate, and multiple birth rate. One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable. The relative risk and its 95% confidence interval were 1.17 (0.97-1.46) for HCG cycles with ovulation, 1.78 (0.92-3.54) for the pregnancy rate per woman, and 1.83 (0.79-4.40) for live births per woman in favour of FSH. The cumulative pregnancy rate after three treatment cycles was 43% with FSH and 24% with clomiphene citrate (P = 0.06). By logistic regression analysis, the factors predicting ovulation included female age, serum androstenedione and use of FSH. Predictors of pregnancy were duration of infertility and use of FSH. This randomized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients. Thus, further studies, possibly multi-centre, in order to avoid problems with patient recruitment, are warranted to confirm these results.

Adult↗