Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting.

Objectives Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m(2), or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weight, immune markers and perception of treatment were the main outcome measures. Results Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusions Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

Estrogen receptor 1 haplotype does not regulate oral contraceptive-induced changes in haemostasis and inflammation risk factors for venous and arterial thrombosis.

BACKGROUND: Administration of oral contraceptives (OCs) has profound effects on the plasma levels of haemostasis and inflammation variables, resulting in an increased thrombosis risk. Individuals show large differences in the response of these variables to OCs. Polymorphism in the estrogen receptor-1 (ER1) gene may explain part of this inter-individual response. METHODS: We investigated the relationship between variants (c.454-397T>C and c.454-351A>G polymorphisms and the combined haplotype) in the ER1 gene in relation to changes in haemostasis and inflammation variables that are known risk factors for thrombosis in 507 healthy, nonsmoking, nulliparous women receiving six cycles of monophasic OCs with 20, 30 or 50 microg/day estrogen. RESULTS: A significant relationship was observed between the ER1 haplotype and changes in tissue-type plasminogen activator activity (P = 0.006), but no clear interaction pattern between the genotypes or between the estrogen doses was seen. No relationships were observed for the other variables, neither in the haplotype nor in the single polymorphism analysis. CONCLUSION: The ER1 haplotype does not have a strong effect on the estrogen-induced changes in haemostasis and inflammation risk markers for arterial and venous thrombosis.

Criteria for evaluating evidence that laboratory abnormalities are associated with the development of venous thromboembolism.

The identification of conditions associated with an increased risk of venous thromboembolism may indicate the need for aggressive prophylaxis during periods of high risk, prolonged anticoagulant therapy after an initial venous thromboembolic episode, the investigation of asymptomatic family members and the avoidance of oral contraceptives. Advances in laboratory medicine have led to the identification and assessment of many proteins responsible for normal hemostasis, and associations between abnormalities in a number of these proteins and venous thromboembolism have been reported. Without the ability to appraise this information critically, physicians may be unable to determine whether or how they should modify their clinical practice. Criteria for determining whether specific laboratory abnormalities have a relationship with venous thromboembolism are proposed here, and one example of the application of these guidelines is provided.

Third- and second-generation oral contraceptives are associated with similar risk estimates for venous thromboembolism.

A scientific discussion between 1995 and 1999 addressed the question whether second- and third-generation oral contraceptives (OCs) were associated with different risks of venous thromboembolism (VTE). Results from three epidemiological studies became available in the course of 1995, in which such differences were observed. Although it was unclear at that time whether these observations reflected causality or were induced by bias and/or confounding, some regulatory bodies in Europe restricted the indication for use of third-generation oral contraceptives. Immediate media attention generated a pill scare in those, but also other, countries. Indications for the influence of bias were observed in the initial studies of 1995 and further substantiated in subsequent utilization and prescribing surveys. The most important bias seemed to be related to differences in age and duration of use between third- and second-generation OC users. A number of new studies as well as new analyses in two of the 1995 databases included measures to limit the effect of the identified biases/confounders. These studies observed similar risks of venous thromboembolism with second- and third-generation oral contraceptives. Two other recently published studies did not or could not include the same level of control for confounding and reported similar results as the 1995 studies, thus reconfirming the relevance of the identified confounders. Population data show that the massive switch in the UK from third-generation OCs to second-generation OCs in 1995 has not resulted in a reduction of the incidence of VTE in OC users after 1995, illustrating that the risk of VTE is not determined by the type of low-dose pill used. In addition, data from trend analyses, spontaneous reporting and studies addressing hemostatic mechanisms in pill-users also do not support a potential difference in risk of VTE between users of second- and third-generation OCs.

Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins.

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.

Oral contraceptive use and venous thromboembolism: a consideration of the impact of bias and confounding factors on epidemiological studies.

Recent epidemiological studies have reported an approximately two-fold, significant, increased odds ratio for venous thromboembolism in users of third-generation oral contraceptives (OCs) compared to users of second-generation OCs. However, in each study, this association is of borderline statistical significance, and the studies do not indicate an increase in the absolute risk of venous thromboembolism for users of third-generation OCs compared with the data from prior studies primarily involving second-generation products. The data derived from these recent studies show a lower reported incidence of venous thromboembolism with the use of second-generation OCs over time compared to the prior studies, while the incidence of venous thromboembolism for use of third-generation OCs is approximately equal to that previously reported for second-generation products. Generally, evidence has shown that the risk of venous thromboembolism and the impact on hemostatic parameters are reduced with declining estrogen dose. In addition, there is no evidence of a clinically significant effect of the OC progestogen doses on hemostatic parameters. These inconsistencies point to factors other than a causal relationship to explain the higher risk of venous thromboembolism in users of third-generation OCs. An examination of factors not included in the recent studies has identified at least three potential biases that should be considered: prescription bias, a 'healthy-user' effect and referral bias. Available data on prescription bias come from marketing research surveys, databases of prescribing patterns, epidemiological databases and the recent studies. These data indicate that the recently introduced third-generation OCs have been more extensively used by younger women, for shorter periods of time, and by women with risk factors for venous thromboembolism that have the second-generation OCs. There is also evidence for a healthy-user effect, whereby women who were most susceptible for venous thromboembolism have left the cohort of users of second-generation OCs as a result of a venous thromboembolism during pregnancy or early OC use, and thus were possibly not included in these recent studies. The women remaining in the cohort, who are included in the recent studies, are less susceptible to venous thromboembolic events than are those making up the cohort of women using third-generation OCs. In addition, there are indications that referral bias has occurred because women with risk factors for venous thromboembolism (who disproportionately receive third-generation OCs) are more likely to be referred to a hospital for investigation of possible symptoms of venous thromboembolism, and thus users of third-generation OCs have the potential to be over-represented among cases. These biases act spuriously to increase the observed odds ratio for the first-time occurrence of venous thromboembolism amongst users of third-generation OCs, when compared to users of second-generation OCs. None of the recent epidemiological studies have been able to adjust for the three major biases. These biases are likely to contribute to, or even totally account, for the small increased risk of venous thromboembolism observed for users of third-generation OCs when compared to that for users of second-generation OCs.

Oestriol in the treatment of postmenopausal urgency: a multicentre study.

UNLABELLED: Oestrogen deficiency in postmenopausal women is thought to be important in the genesis of lower urinary tract symptoms, in particular the 'urge syndrome'. Evidence to support the use of oestrogen therapy in symptomatic postmenopausal women is, however, limited. Oestriol is a weak, naturally occurring oestrogen that may be beneficial to the urogenital tissues without stimulating the endometrium. We have investigated the use of oestriol in the treatment of postmenopausal sensory and motor urge incontinence. MATERIALS AND METHODS: A double-blind, placebo-controlled, randomised, multicentre study of 3 mg oral oestriol/day for 3 months in the treatment of women with urge incontinence was undertaken. RESULTS AND CONCLUSIONS: Sixty-four women were recruited into the study. Although oestriol produced both subjective and objective improvement in lower urinary tract function, it was not significantly better than placebo. Some of the difficulties of running a multicentre study were encountered.

The menopause, urinary incontinence and other symptoms of the genito-urinary tract.

In a study on incontinence and other symptoms of the genito-urinary tract in postmenopausal women covering their prevalence, consequences and predisposing factors, the prevalence of incontinence was found to be 26.4%. Daily incontinence was present in postmenopausal women more than twice as often as before the menopause (P < 0.05). The frequency of medical consultation for such incontinence was low; only 26.1% of the postmenopausal women had ever seen their doctor about it. Urgency, nocturia and dyspareunia were more prevalent in postmenopausal women, while vaginal itching and discharge were more frequent in premenopausal women (P < 0.05). The prevalence of incontinence and the other genito-urinary symptoms was higher after surgical than after natural menopause. Multivariate analysis showed the menopause to be the only factor that contributed significantly to the onset of incontinence (P < 0.001).

A cross-over study of three oral contraceptives containing ethinyloestradiol and either desogestrel or levonorgestrel.

A randomised cross-over trial was performed to compare the pharmacodynamic actions of three low-dose oral contraceptives (OCs): Marvelon (150 micrograms desogestrel (DSG)+ 30 micrograms ethinyloestradiol (EE)), Mercilon (150 micrograms DSG + 20 micrograms EE) and Microgynon (150 micrograms levonorgestrel (LNG) + 30 micrograms EE). None of the OCs produced any significant changes in serum cholesterol, LDL-C and apoprotein B. Triglycerides were increased by the desogestrel OCs but not by Microgynon. The latter however increased the glucose and insulin responses to a glucose tolerance test whereas Marvelon and Mercilon had no effect. HDL-C increased with Marvelon, was unchanged with Mercilon and was decreased with Microgynon. Apoprotein AII was increased by all three OCs but only the DSG OCs increased apoprotein AI. All OCs produced similar increases in caeruloplasmin but the increase in SHBG was much greater with Marvelon and Mercilon than with Microgynon. Testosterone was reduced more with Microgynon than with the DSG OCs. Many of the changes reflect the strong anti-oestrogenic action of LNG on metabolic parameters compared to DSG. Except for the effect on HDL-C, there was little difference between Marvelon and Mercilon on metabolic parameters and this complements the findings from large-scale clinical trials of the two OCs. Mercilon, therefore provides a very satisfactory alternative to Marvelon.

PIP: 12 healthy volunteers attending the family planning clinic at Shanghai, First Maternity and Infant China, Hospital, enrolled in the study, Oral contraceptives (OCs) were prescribed: Marvelon (150 mcg of desogestrel--DSG), Mercilon (150 mcg of DSG), and Microgynon (150 mcg of levonorgestrel--LNG). The patients were divided into 6 groups of 2 persons each in a randomized cross-over study. OCs were taken on day 6 of the cycle up to day 21, then stopping for 7 days. Each OC was used for 3 months. During the pretreatment cycle between days 6 and 9 of the follicular phase and 21 and 22 of the luteal phase a blood sample was taken after fasting for determination of lipids, sex hormone binding globulin (SHGB), ceruloplasmin, and testosterone. After glucose loading, significant increases of glucose and insulin occurred at 1, 2, and 3 hours during treatment with Microgynon only. The ratio for total areas of insulin to glucose did not change significantly nor did glycosilated hemoglobin A1 levels. Serum triglyceride concentrations increased significantly for both Marvelon (27%-43%) and Mercilon (29-40%). Serum high density lipoprotein (HDL) cholesterol concentrations were significantly elevated with Marvelon but less so with Mercilon, while HDL-C decreased significantly with Microgynon. The serum low density lipoprotein (LDL) cholesterol changes were not significant, but LDL-C concentrations declined with DSG formulations and increased with Microgynon. Apoprotein A1 and A2 increased significantly for both Marvelon and Mercilon. Apoprotein A2 increased with Microgynon. Serum SHBG increased markedly with Marvelon (335-380%). Serum testosterone concentrations decreased significantly (33.2-40.4% with Microgynon) and so did ceruloplasmin values. The antiestrogenic effect of strong LNG in Microgynon produced significant metabolic changes. The effect of 30 mcg EE in Marvelon and 20 mcg EE of Mercilon was equal.

Urinary incontinence in women from 35 to 79 years of age: prevalence and consequences.

We investigated the prevalence and the consequences of urinary incontinence in a group of 1299 women aged 35 to 79. Incontinence was present in 344 women (26.5%), in 5.9% the incontinence occurred at least once daily. The prevalence was highest in the younger age-groups and lowest between 65 and 69 years of age, thereafter it increased again. Almost half of the incontinent women used protective sanitary towels. In contrast to this, only 13.3% considered themselves handicapped by their symptoms, and only 28.2% had ever sought medical help, although the symptoms had been present for as long as 7.5 years on average. The major reason for not seeking medical help was that the symptoms were not considered to be so serious.

Effects of three combined oral contraceptive preparations containing desogestrel plus ethinyl estradiol on lipid metabolism in comparison with two levonorgestrel preparations.

The effects of three different desogestrel-containing combined oral contraceptive preparations on lipid metabolism were compared with those of two levonorgestrel preparations. The following preparations were studied: (1) monophasic desogestrel (150/30), (2) monophasic desogestrel (150/20, containing 20 micrograms of ethinyl estradiol instead of 30 micrograms of ethinyl estradiol, (3) biphasic desogestrel, (4) monophasic levonorgestrel (150/30), and (5) triphasic levonorgestrel. The effects of these preparations were assessed on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol, and the ratio of apolipoprotein A-I to apolipoprotein B after 3 months of treatment, and the percentage changes with regard to pretreatment were calculated. The monophasic desogestrel (150/30) and biphasic desogestrel preparations induced higher high-density lipoprotein cholesterol and apolipoprotein A-I levels than did their levonorgestrel-containing counterparts. Low-density lipoprotein cholesterol levels were increased in monophasic levonorgestrel and clearly decreased in the lowest ethinyl estradiol-containing monophasic desogestrel (150/20) and biphasic desogestrel preparations. Apolipoprotein B increased in all preparations. The antiatherogenic indexes (ratios of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol and apolipoprotein A-I to apolipoprotein B were higher for monophasic desogestrel (150/30) and biphasic desogestrel than for comparable levonorgestrel-containing preparations. The differences seen between the desogestrel and levonorgestrel preparations can best be explained by the lower intrinsic androgenicity of 3-keto-desogestrel (active metabolite of desogestrel) than that of levonorgestrel.

Multicenter trial of a monophasic oral contraceptive containing ethinyl estradiol and desogestrel.

A clinical trial was conducted at 47 centers in 11 countries to assess the efficacy and acceptability of a monophasic oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms desogestrel. 1,613 women took part for a total of 23,258 cycles. One pregnancy occurred in a cycle where two consecutive tablets had been forgotten. Cycle control was excellent, with reported decreases in the duration and amount of withdrawal bleeding during consecutive treatment cycles and a low incidence of irregular bleeding. Blood pressure was not affected during 2 years of use. The incidence of minor side effects was already low in the first treatment cycle and decreased further in the subsequent cycles. The combination (Marvelon) was shown to be a very reliable and acceptable oral contraceptive.

PIP: The efficacy and acceptability of a monophasic oral contraceptive (OC) containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel were evaluated in a clinical trial involving 1613 women at 47 centers in 11 countries. A total of 23,258 menstrual cycles were available for analysis. Although or more tablets were forgotten in 892 cycles (3.8%), there was only 1 pregnancy due to patient failure in this study and no pregnancies attributable to method failure. Cycle control was good and comparable to that reported for other low-dose OCs. In 90% of the cycles, the withdrawal bleed started 1-4 days after intake of the last pill and lasted 5 days or less. The incidence of breakthrough bleeding and spotting decreased with duration of pill use. After 24 cycles, the discontinuation rate because of bleeding problems was only 6%. The discontinuation rate for minor side effects was 4% after 24 cycles; these side effects included nausea, headache, nervousness, and breast tension. After 24 cycles, body weight was not affected in 70% of the participating women, 18% reported a weight increase of greater than 2 kg, and 12% experienced a weight decrease of over 2 kg. Most of the women who reported a weight gain were under 20 years of age. The ethinyl estradiol-desogestrel combination had no effect on average blood pressure. Previous research has shown desogestrel to have unique advantages as the progestogen component of combined OCs in that it does not counteract the ethinyl estradiol-induced increase in high-density lipoprotein. This, together with the good reliability and acceptability recorded in the present study, suggests that the monophasic desogestrel OC should be prescribed on a widespread basis.