Altered expression of matrix metalloproteinases within mineralizing bone cells in vitro in the presence of fluoride.

Fluoride is known to alter mineralization within bone, although the mechanism for its action is unclear. An important stage in the formation of mineralized tissues is the remodeling of the osteoid, facilitating mineral deposition. Using a bone mineralizing culture system derived from rat femur washes, this study investigated the influence of fluoride on MMP expression at a developmental stage relating to the onset of mineralization. Bone cells cultured in the absence of fluoride synthesized an active form of a 45-kD MMP, which was immunoreactive with an antibody to human MMP-1 (although full characterization of this MMP was not achieved), trace levels of an MMP immunoreactive with anti-MMP-3, and a 66-kD proteolytic species. Incubation in 10(-7) and 10(-5) M fluoride resulted in a decrease in expression of the 45-kD MMP, sharp increases in the expression of MMP-3, and the appearance of a band at 110 kD, which showed immunoreactivity for MMP-9. The influence of fluoride on MMP expression is likely to influence the composition of the remodeling matrix and subsequent mineralization and offers a potential mechanism by which fluoride alters mineralization.

The isolation and detection of non-collagenous proteins from the compact bone of the dinosaur Iguanodon.

This report describes the isolation of guanidinium chloride extractable protein from demineralised bone extracts obtained from the 125-130 mya dinosaur Iguanodon. Protein products were isolated in the Mr. range 5,000-66,000 using SDS-PAGE and represent the first electrophoretically defined proteins isolated from dinosaur tissues. The levels of glycine, aspartate and serine tentatively suggest the presence of phosphoproteins. Hydroxylysine and hydroxyproline were not detected, confirming the presence of non-collagenous material. In addition the absence of ornithine confirmed lack of bacterial contamination. The relatively high level of leucine in the 2MNaCl NaCl fractions together with the abolition of alcian blue reactivity following protease-free chondroitinase digestion suggests the presence of proteoglycans. The study is of interest in describing the early proteins laid down in mineralised tissues for epitactic crystal growth and may provide evidence on evolutionary aspects of bone proteins.

Structural analysis of proteoglycans synthesized by mineralizing bone cells in vitro in the presence of fluoride.

This study investigated the biochemical structure of proteoglycans synthesized during matrix maturation by mineralizing bone cells in vitro, in the presence and absence of fluoride. Bone cells were obtained from rat femur washes and cultured in alpha MEM media supplemented with fetal calf serum, ascorbic acid, beta-glycerophosphate and dexamethasone. Cells were characterized as osteoblast-like by the expression of alkaline phosphatase activity and the synthesis of collagen type I and osteocalcin. Fluoride, present in the culture media at concentrations of 10(-5) M or 10(-7) M, had negligible effect on cell viability. However, calcium deposition was increased in cell cultures incubated in the presence of fluoride. Proteoglycans were extracted from the extracellular matrix with 4 M guanidinium chloride and purified by anion exchange chromatography. Biochemical analysis identified the presence of the small leucine rich proteoglycan, decorin and biglycan, in addition to degradation products relating to the larger chondroitin sulphate protoeglycan, versican. Fluoride had little effect on the size or amino acid composition of the protein core, but resulted in significant alterations to the GAG chains, including a dramatic reduction in chain length, reduction in sulphation and decrease in the proportion of dermatan sulphate compared to chondroitin sulphate. The influence of fluoride on proteoglycan structure synthesized by mineralizing bone cells provides valuable information, indicating specific roles for dermatan sulphate and chondroitin sulphate proteoglycans. The results suggested that fluoride affected the post-translational assembly of the GAG chains which may be an influential factor in the mineralization process.

Glycosaminoglycan biosynthesis during 5-fluoro-2-deoxyuridine-induced palatal clefts in the rat.

The biosynthesis and hydration of glycosaminoglycans (GAG) has been implicated in the generation of palatal shelf-elevating force(s) in mammals, although the nature of the palatal shelf extracellular matrices during cleft palate formation remains poorly understood. This study quantifies the GAG composition in the palatal shelves of Wistar rat fetuses at various periods of palatogenesis where clefts were induced experimentally using 5-fluoro-2-deoxyuridine (FUDR). For both normal and cleft palatal shelves, hyaluronan, heparan sulphate and chondroitin-4-sulphate were detected but not dermatan sulphate or chondroitin-6-sulphate. Throughout the period of cleft development studied, the total amount of GAG was significantly decreased (by approx. 30%) compared with normal development, this decrease being particularly marked at a time equivalent to post-elevation during normal development (approx. 75%). Furthermore, and unlike normal palatogenesis, no significant differences were recorded between the anterior and posterior parts of the palatal shelves during cleft formation. As for normal palatogenesis, however, the percentages of each GAG were not altered at any stage. The findings are consistent with the view that suppression of GAG biosynthesis is related to the development of cleft palate in FUDR-treated rat fetuses and can therefore be interpreted as providing evidence of a role for the mesenchymal glycoconjugates in shelf elevation during normal palatogenesis.

Changes in the composition of glycosaminoglycans during normal palatogenesis in the rat.

The synthesis and hydration of glycosaminoglycans (GAG) has been implicated in the generation of a palatal shelf-elevating force in mammals. This study quantifies the GAG composition in the palatal shelves of Wistar rat fetuses at various stages of palatogenesis. Hyaluronan, heparin sulphate and chondroitin-4-sulphate were detected but not dermatan sulphate or chondroitin-6-sulphate. The distribution of the GAG differed in the anterior and posterior regions (i.e. the presumptive hard and soft palates) and with the stage of development. At the time of palatal-shelf reorientation, there were no significant differences for either the total amount of GAG or for the percentages of specific GAG types between anterior and posterior regions. Indeed, the most marked differences were detected at the stages of histogenesis after shelf elevation. Nevertheless, the results support the view that hyaluronan is involved in palatal-shelf reorientation, its percentage being initially high and decreasing after shelf elevation. No changes were detected for the other (sulphated) GAG during the time of elevation. The findings point to the need to correlate the events during histogenesis with changes in the ground substance of palatal-shelf mesenchyme and indicate that there are different developmental mechanisms within the presumptive hard and soft palates.

Levels of glycosaminoglycans in peri-implant sulcus fluid as a means of monitoring bone response to endosseous dental implants.

The presence of certain glycosaminoglycans in peri-implant sulcus fluid may be an effective means of monitoring changes in bone metabolic activity following initial loading of implant abutments. This study has investigated levels of chondroitin 4 sulphate and hyaluronan in peri-implant sulcus fluid from titanium osseointegrated implants following initial abutment placement and exposure to masticatory stresses. Abutments were placed after a 3-month osseointegration period post-initial surgical placement of the interosseous stage. 10 edentulous patients, each with 5 mandibular implants were reviewed at 2, 4, 6 and 8 days after abutment placement. Clinical details were assessed and recorded and sulcus fluid collected in microcapillary tubes for a 5-min period for each abutment. Levels of glycosaminoglycans were assessed using cellulose acetate electrophoresis and densitometric scanning of alcian blue stained strips against known glycosaminoglycan standards. Maximum levels of sulcus fluid (0.3-1.25 microliters/5 min) were evident at 4 days with a decrease towards 8 days. Levels of sulphated glycosaminoglycans were also maximal at 2-4 days (range 0.03 - 0.126 micrograms/5 min) and decreased at 6-8 days. Hyaluronan was detected within a similar range of values reaching maximal levels at 4 days and decreasing by 8 days. The results indicate that glycosaminoglycan levels of peri-implant sulcus fluid is an effective means of measuring and maintaining changes in bone metabolism. The absence of proteodermatan sulphate precludes soft tissues being a source of these markers.

Intravenous streptokinase. A reappraisal of its therapeutic use in acute myocardial infarction.

Streptokinase, the first of the thrombolytic agents to be used in acute myocardial infarction, has now been administered to many thousands of patients with this condition. Since early intervention and accessibility of care is paramount in these patients, intravenous infusion of streptokinase has largely replaced intracoronary use. Results of major trials (GISSI, ISIS-2 and ISAM) comparing streptokinase with standard treatment in more than 30,000 patients prove convincingly that intravenous streptokinase increases patient survival after myocardial infarction. The largest trial, ISIS-2, demonstrated a 23% reduction in 5-week vascular mortality after streptokinase use. The greatest benefits occur where streptokinase infusion is initiated early after symptom onset, although late benefit has been observed in patients treated up to 24 hours after pain onset. Importantly, mortality is further decreased by combining streptokinase with aspirin, as shown by a 53% reduction in mortality using the combination in the ISIS-2 trial. Mortality has also been reduced in trials investigating the use of the thrombolytic agents rt-PA and anistreplase. Streptokinase and rt-PA produced similar reductions in mortality in the recent GISSI-2 and International t-PA/Streptokinase Mortality trials, findings which may be further clarified by ongoing comparative trials such as ISIS-3. Reperfusion of about 50 to 60% of occluded coronary arteries occurs with intravenous streptokinase, and left ventricular function is improved. Direct comparisons with rt-PA show a superior effect for the newer agent on early reperfusion, but a similar ability to salvage myocardial function. The complexities of the relationship between reperfusion, left ventricular function and mortality constitute an area of considerable clinical interest requiring further study to clearly differentiate between the drugs available to the physician. The most common adverse events observed during intravenous streptokinase infusion are bleeding complications. An incidence of 3.6% for minor bleeding and 0.4% for major haemorrhage (requiring transfusion) is derived from the combined results of the GISSI and ISIS-2 studies. Bleeding does not appear to be more frequent or severe with intravenous streptokinase than with the more fibrin-selective agent, rt-PA. While the risk to benefit ratio of sequential heparin following streptokinase therapy remains equivocal, the adjuvant use of aspirin confers a clinical advantage over streptokinase alone. In conclusion, streptokinase has now been proven to reduce mortality in patients with acute myocardial infarction, with an acceptable risk of bleeding complications. Given the substantial data that have now accumulated with extensive clinical experience, intravenous streptokinase should be considered a first-line agent in suitable patients.

Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease.

Nimodipine is a dihydropyridine calcium antagonist which has been shown to dilate cerebral arterioles and increase cerebral blood flow in animals and humans. It has potential in the treatment of a range of cerebrovascular disorders. Major interest to date, however, has focused on its use in the prevention and treatment of the delayed ischaemic neurological deficits that frequently occur in patients with subarachnoid haemorrhages as a result of sustained cerebral vasospasm. Initial studies in which patients were treated with an intravenous infusion of nimodipine for up to 2 weeks, followed by oral treatment for 7 days, indicated that a higher proportion of patients than would normally be expected recovered with little or no permanent neurological damage. In a number of controlled studies oral nimodipine treatment for 3 weeks significantly decreased mortality rates and increased the number of patients who had a 'good' neurological outcome as compared with placebo treatment. In some of these trials fewer of the nimodipine-treated patients developed neurological deficits during the treatment period, but in none was there a significant effect on the incidence of angiographic vasospasm. It would seem that other pharmacological actions, such as increasing collateral blood flow to underperfused regions or a direct anti-ischaemic effect at the cellular level, may contribute to the clinical benefits obtained with nimodipine treatment. Preliminary results suggest that nimodipine is potentially useful in other cerebrovascular disorders, particularly ischaemic stroke. To date, nimodipine has been well-tolerated, the only adverse effects of any significance being reductions in the blood pressure of some patients and reversible increases in liver enzymes during intravenous therapy. Thus, nimodipine has significant potential in the treatment of patients with subarachnoid haemorrhage. Wider clinical use should confirm its value as a significant addition to the very limited range of therapeutic choices currently available for patients with this disorder.

Felodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension.

Felodipine is a dihydropyridine calcium antagonist which selectively relaxes vascular smooth muscle. By acting at peripheral arterioles, it lowers systemic vascular resistance and thereby produces substantial decreases in blood pressure and increases in cardiac output. Felodipine is indicated for the management of hypertension, and in patients with mild to moderate disease felodipine monotherapy markedly lowers blood pressure. It proved as effective as atenolol, and equivalent to hydrochlorothiazide, either with or without amiloride, in terms of antihypertensive activity. Comparative studies also demonstrated that once daily administration with an extended-release formulation provides equivalent antihypertensive efficacy to the same amount of drug administered twice daily as the standard tablets. As a second- or third-line treatment for patients with moderate to severe hypertension refractory to standard drug combinations, felodipine produced considerable reductions in blood pressure when added to beta-blockers and diuretics, either alone or in combination, in studies lasting up to 48 weeks. In comparative studies of multiple-drug treatments felodipine was found to have superior efficacy to hydralazine and prazosin, and was at least as effective as nifedipine, minoxidil and propranolol, when used with diuretics and/or beta-blockers. As an alternative to hydrochlorothiazide, in combination with beta-blockers, felodipine consistently controlled blood pressure in a greater percentage of patients and usually provided greater decreases in blood pressure. The main side effects with felodipine are ankle oedema, headache and flushing. Although the overall incidence of effects is quite high, they are usually mild in nature. Nevertheless, withdrawal due to side effects has been necessary in about 7% of patients overall. Thus, the efficacy of felodipine has been demonstrated in mild, moderate and severe hypertension. At the present time it seems particularly suitable as a second- or third-line treatment in refractory hypertension, but it also can be used as monotherapy for mild to moderate disease.

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic.

Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.

Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic.

Brotizolam is a new thienotriazolodiazepine derivative with a pharmacological profile similar to that of benzodiazepines. It is indicated for use as an hypnotic in the management of insomnia, although it also has anticonvulsant, antianxiety and muscle relaxant properties in animals. In clinical trials brotizolam 0.125 to 0.5mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5mg, flunitrazepam 2mg and triazolam 0.25mg, whilst brotizolam 0.5mg was shown to be superior to flurazepam 30mg in some studies. Brotizolam is an effective hypnotic for hospital patients awaiting surgery, in whom it also reduces anxiety. Brotizolam has an elimination half-life of about 5 hours, which is 'intermediate' compared with the shorter-acting hypnotic, triazolam, and longer-acting benzodiazepines. Consequently, it is able to induce sleep without producing early morning rebound insomnia, and can also maintain sleep throughout the night. Brotizolam at dosages below 0.5mg at night usually produced minimal morning drowsiness; no residual impairment of psychomotor performance occurs following dosages within the recommended range of 0.125 to 0.25 mg/kg. No serious side effects have been reported to date and the most frequently observed adverse experiences are drowsiness, headache and dizziness. Mild rebound insomnia may occur in some patients when treatment is stopped. Thus, brotizolam is a useful hypnotic which can be used in patients who have difficulty in falling asleep and also in patients who are troubled by night-time awakenings. Used in the recommended dosage it may be particularly useful for patients in whom daytime impairment of performance is unacceptable.

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy.

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.

Identification and measurement of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in human saliva.

Sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) were detected by specific immunoassays in mixed-saliva taken from normal men and women. The immunochemical identity of both proteins was demonstrated by parallelism between dose response curves generated by serial dilutions of saliva and standards in the immunoassays. In addition, the specific removal of both proteins by incubation with steroid affinity-chromatography gels demonstrated the integrity of their steroid binding activity. The mean +/- SD concentrations of SHBG (pmol/l) and CBG (microgram/l) in mixed-saliva taken from normal volunteers were as follows: men (n = 6) 19 +/- 10 and 38 +/- 18; women (n = 6) 63 +/- 60 and 72 +/- 71 and women during late pregnancy (n = 6) 282 +/- 168 and 92 +/- 80, respectively. The data indicate that the concentrations of SHBG and CBG in saliva represent approximately 0.1% of plasma concentrations. It is suggested that these proteins pass from the blood to saliva in a non-specific manner, and may influence the steroid content of saliva under certain physiological circumstances.

Serum steroid binding proteins and the bioavailability of estradiol in relation to breast diseases.

Serum concentrations of sex hormone binding globulin (SHBG), corticosteroid binding globulin (CBG), and albumin were found to be normal in women with breast cancer (Ca), with benign breast disease (BBD), or with a family history of breast cancer (FHCa). Comparisons between serum steroid binding capacities and immunoassayable SHBG and CBG concentrations did not reveal abnormal forms of either protein. The serum distribution of estradiol (E2) was also determined, and women with Ca were found to have a significantly (P less than .025) higher mean percentage of non-protein-bound E2 than matched controls, but the difference was very small. In general, women with Ca also had proportionately more (P less than .05) albumin-bound E2 and less (P less than .05) SHBG-bound E2 in their sera than the controls, but the serum distributions of E2 in the BBD and FHCa subjects were the same as in controls. The dissociation rates of 5 alpha-dihydrotestosterone and E2 from SHBG in serum appear to increase with time in frozen serum samples, and this factor may effect measurements of the distribution of these steroids in serum.

A liquid-phase immunoradiometric assay (IRMA) for human sex hormone binding globulin (SHBG).

An immunoradiometric assay (IRMA) for sex hormone binding globulin (SHBG) has been developed in which an 125I-labeled monoclonal antibody [( 125I]S1B5) and a rabbit anti-SHBG antiserum (RAb) are incubated in "liquid-phase" with standards or samples, and RAb-bound complexes are separated using donkey anti-rabbit IgG antibody-coated cellulose. This immunoassay technique is characterized by several advantages; the [125I]S1B5 imparts additional specificity and obviates the requirement for pure SHBG; the use of excess reagents reduces incubation times and also improves assay performance and sensitivity, and incubation in "liquid-phase" conserves and increases the efficiency of the RAb. The assay measures only non-denatured SHBG and is not influenced by the presence of steroid at the binding site. Assay specificity was demonstrated by parallelism between dilutions of pure SHBG and different serum samples. The quantitative recovery of SHBG added to serum, and the agreement between specific activities of SHBG in pure standards and sera, confirm the accuracy of the method. The within and between assay coefficients of variation were less than 7% and less than 11%, respectively, between 12 and 450 nmol/l. The assay sensitivity may be manipulated by altering the concentration of RAb and/or by preincubation with either [125I]S1B5 or RAb, and 0.2 fmol SHBG may be measured on a standard curve. The SHBG assay has been used to measure SHBG concentrations in sera, amniotic fluid, cerebral spinal fluid, seminal plasma and saliva.

A solid-phase radioimmunoassay for human corticosteroid binding globulin.

A radioimmunoassay (RIA) for human corticosteroid binding globulin (CBG) has been developed using 125I-labelled CBG and a monospecific solid-phase CBG-antiserum (CBG-Ab-cellulose). In an RIA of serum CBG concentrations, pure CBG standards (1-100 ng protein) or samples (1:200) were incubated (16 h at 20 degrees C) with 125I-labelled CBG and CBG-Ab-cellulose. After addition of 2 ml 0.9% NaCl, the tubes were centrifuged, supernatants were aspirated and the 125I-labelled CBG bound to the CBG-Ab-cellulose pellet was counted. The specificity of the RIA was confirmed by parallel displacement curves for serial dilutions of male, female and pregnancy sera, as well as pure CBG standards. The mean +/- S.D. recovery (99 +/- 8%) of pure CBG (1.6-25.0 ng) added to a diluted serum sample verified the accuracy of the method, and a good correlation (r = 0.97; n = 43) existed between serum CBG cortisol binding capacity (nmol/l) measurements and CBG concentrations (mg protein/l) measured by RIA. Intra- and interassay precisions (C.V.) at low to high serum CBG concentrations were less than 5% and less than 9% respectively. The mean +/- S.D. serum CBG concentrations (mg protein/l) measured by the RIA were: 21.8 +/- 4.6 in boys (n = 12), 20.0 +/- 4.2 in girls (n = 9), 20.7 +/- 2.7 in men (n = 6), 20.5 +/- 2.9 in women (n = 6) and 47.1 +/- 10.5 in pregnant women (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel.

The oral administration of 150 micrograms desogestrel and 30 micrograms ethinyl estradiol (EE2) increases (P less than 0.001) serum concentrations of sex-hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG), whereas treatment with 150 micrograms levonorgestrel and 30 micrograms EE2 only increases serum CBG concentrations. No changes in serum albumin concentrations occurred during or after treatment with either preparation, and increases in SHBG and CBG returned to the pretreatment values 1 month after treatment ceased. The serum distribution of levonorgestrel was unchanged during treatment, whereas the increase in serum SHBG concentrations after treatment with the preparation containing desogestrel decreased (P less than 0.001) the percentage of non-protein-bound 3-keto- desogestrel and the percentage of albumin-bound 3-keto- desogestrel but increased (P less than 0.001) the SHBG-bound fraction. Oral contraceptives containing either progestogen decrease the mean serum non-protein-bound testosterone concentrations, especially during treatment with desogestrel (P less than 0.001), and desogestrel may therefore by the more appropriate progestogen for the treatment of women prone to androgenic side effects.

PIP: The oral administration of 150 mcg desogestrel and 30 mcg ethinly estradiol (EE2) increases (P0.001) serum concentrations of sex hormone binding globulind (SHBG) and corticosteroid-binding globulin (CBG) whereas treatment with 150 mcg levonorgestrel and 30 mcg EE2 only increases serum CBG concentrations. No changes in serum albumin concentrations occurred during or after treatment with either preparation, and increases in SHBG and CBG returned to the pretreatment values 1 month after treatment ceased. The serum distribution of levonorgestrel was unchanged during treatment, whereas the increase in serum SHBG concentrations after treatment with the preparation containing desogestrel decreased (P0.001) the percentage of nonprotein-bound 3-keto-desogestrel and the precentage of albumin-bound 3-ketodesogestrel but increased (P0.001) the SHBG-bound fraction. Oral contraceptives containing either progestogen decrease the mean serum nonprotein-bound testosterone concentratious, especially during treatment with desogesgtrel (P0.001), and desogestrel may therefore be the more appropriate progestogen for the treatment of women who are prone to androgenic side effects.