Recombinant FSH versus urinary gonadotrophins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome.

BACKGROUND: Over the last four decades, various urinary FSH (uFSH) products of different purity have been developed. In 1988 recombinant FSH (rFSH ) was prepared by transfecting Chinese hamster ovary cell lines with both FSH subunit genes. Both rFSH and uFSH are known to be effective in inducing ovulation in women with clomiphene-resistant polycystic ovary syndrome. Ovulation induction with FSH bears the risk of multiple follicle development, multiple pregnancies and ovarian hyperstimulation syndrome. The dose regimen used can affect the incidence of these complications. OBJECTIVES: To compare in women with clomiphene-resistant polycystic ovary syndrome (PCOS) the safety and effectiveness in terms of ovulation, pregnancy, miscarriage, multiple pregnancy rate and ovarian hyperstimulation syndrome (OHSS) of 1) rFSH with uFSH and 2) different dose regimens of rFSH. SEARCH STRATEGY: The search strategy of the Menstrual Disorders and Subfertility review group was used to identify all relevant trials. Please see Review Group details. SELECTION CRITERIA: All relevant published RCT's were selected. Randomised controlled trials were eligible for inclusion if treatment consisted of recombinant FSH versus urinary FSH or recombinant FSH in different dose regimens, to induce ovulation in subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: A computerised MEDLINE and EMBASE search was used to identify randomised and non randomised controlled trials. The reference lists of all studies found were checked for relevant articles. Handsearching of bibliographies of relevant publications and reviews and abstracts of scientific meetings was performed. Serono Benelux BV and NV Organon, the manufacturers of follitropin alpha (Gonal F(R)) and follitropin beta (Puregon(R)) respectively, were asked for unpublished data and ongoing studies. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomisation, completeness of follow-up, presence or absence of cross-over and co-intervention. All trials were screened and analysed according to predetermined quality criteria. DATA SYNTHESIS: 2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. MAIN RESULTS: Four randomised trials comparing rFSH versus uFSH were identified. No significant differences were demonstrated for the relevant outcomes. The odds ratio for ovulation rate was 1.19 (95% CI 0.78,1.80), for pregnancy rate 0.95 (95% CI 0.64,1.41), for miscarriage rate 1.26 (95% CI 0.59,2.70), for multiple pregnancy rate 0.44 (95% CI 0.16,1.21) and for OHSS 1.55 (95% CI 0.50,4.84). Similarly, in the only randomised trial that compared chronic low dose versus conventional regimen with rFSH no significant differences were found. REVIEWER'S CONCLUSIONS: At this moment there are not sufficient data to determine which of rFSH or uFSH is preferable for ovulation induction in women with PCOS.

Tolerability of an extract of European mistletoe among immunocompromised and healthy individuals.

CONTEXT: European mistletoe (Viscum album L) has been used parenterally for more than 80 years as an anticancer medication with significant immunomodulating action. Since 1984, clinical experience with a Viscum album extract (Viscum album Quercus Frischsaft [Qu FrF]) among HIV-positive patients has suggested that it inhibits HIV disease progression. OBJECTIVE: To determine the toxicity profile and biochemical effects of a Viscum album extract. DESIGN: A dose-escalating phase I/II study. PATIENTS: 32 HIV-positive and 9 healthy participants. INTERVENTION: Standardized for its lectin and viscotoxin content, the extract was administered subcutaneously twice weekly in gradually increasing doses for 2 to 17 weeks per dose increase. Doses of 0.01 mg to 10.0 mg were administered. MAIN OUTCOME MEASURES: Adverse events, hematology, and biochemistry. RESULTS: No severe side effects were found. During gradual dose escalation, more adverse events occurred at the lower dose range. The hazard rate of systemic adverse events was highest among HIV-positive patients. Drug-related adverse events were flu-like symptoms and transient exacerbations of gingivitis, fever, and eosinophilia. An increase of serum urea nitrogen and serum creatinine levels occurred, as did a slight decrease in total protein caused by a minor fall in albumin concentrations. Dose dependence was apparent for inflammation and fever, which may or may not have been side effects of the preparation. CONCLUSIONS: Viscum album Qu FrF can be administered safely to HIV-positive patients. It induces immunomodulation in HIV-positive and healthy individuals and may inhibit the progression of HIV disease.

Toxicity of a standardized mistletoe extract in immunocompromised and healthy individuals.

Iscador is being used by many patients as unconventional anticancer and immunomodulating therapy. To determine the toxicity profile and biochemical effects of Iscador Qu Spezial (Weleda AG Schwäbisch Gmünd, Germany) in human immunodeficiency virus (HIV)-positive patients and healthy controls, we performed a phase I/II study. Escalating doses of Iscador Qu Spezial, standardized for its lectin and viscotoxin content, were administered to 16 HIV-positive patients and 8 healthy subjects during a period of 6 to 8 months. Iscador Qu Spezial preparations were administered twice per week subcutaneously in increasing doses (ie, 0.01 mg, 0.1 mg, 1.0 mg, 2.0 mg, 5.0 mg, and 0.1 mg/kg for 2-6 weeks per dose). Drug-related adverse effects were flulike symptoms, gingivitis, fever, local erythema, and eosinophilia. These side effects were never severe. The incidence of systemic adverse events was highest in HIV-positive patients. Furthermore, increased urea levels and slightly decreased total protein caused by a minor decrease in albumin were observed. None of the HIV-positive patients progressed in disease stage. Iscador Qu Spezial can be administered safely to immunocompromised patients.

Study on local inflammatory reactions and other parameters during subcutaneous mistletoe application in HIV-positive patients and HIV-negative subjects over a period of 18 weeks.

Subcutaneous injections of fermented and unfermented aqueous extracts of Viscum album L. result in a local inflammatory reaction at the injection site. In this trial, the symptoms associated with this local reaction were investigated. Furthermore the occurrence of local reactions was tried to correlate with an increase in CD3/25- and CD8/38-positive lymphocyte counts, with eosinophilic granulocyte numbers, and with the formation of mistletoe lectin antibodies. Included in the trial were 30 HIV-antibody-positive patients and 17 healthy non-smokers, aged 24-51 years. The CD4 cell count in the HIV-negative subjects was > 800/microliter, compared with 200-600/microliter in the HIV-positive patients. All study participants had a Karnofsky score > or = 70. The trial subjects were observed over a period of 18 weeks. With escalation of the dose of a fermented and unfermented extract of Viscum album L. (Iscador Qu Spezial and Viscum album QuFrF), there was an increase in local reactions. Erythema at the injection site was the most frequently reported symptom. Between the doses and the symptoms induration, swelling and pruritus were marked correlations. Effects of the application of mistletoe extracts on the immune system were demonstrated by an increase in CD3/25-positive lymphocyte counts and antibodies against mistletoe-lectins. There were no changes in eosinophilic granulocytes or CD8/38-positive lymphocyte populations. For evaluation of the therapeutic applications of mistletoe extracts in HIV-positive patients it is advisable to assess primarily activation of CD3-positive lymphocytes and the patient response on the basis of the local reaction. The local inflammatory reaction at the injection site is desirable and well tolerated if the reaction is smaller than 5 cm in diameter.

Subcutaneous infiltrates induced by injection of mistletoe extracts (Iscador).

Iscador, an aqueous extract of Viscum album L., has been widely used as an anti-cancer drug for several decades. Mistletoe lectins have the capacity to activate nonspecific defense mechanisms, and lectin-carbohydrate interactions may be involved in clinically applicable immunomodulation. During treatment with whole-plant mistletoe extract, an inflammatory reaction usually occurs at the site of the injection, early in therapy. These injection sites were examined histologically. Seven subjects received three subcutaneous injections of Iscador QuFrF or Iscador Qu Spezial (twice 0.1 mg and once 2.5 mg) during 9 days. In all subjects, examination of skin biopsies showed a normal epidermis. The dermal and subcutaneous regions contained a dense perivascular lymphocyte infiltrate and increased monocytes. We could not document any increase of plasma cells, eosinophils, mast cells, neutrophils, or granulocytes, as would be the case for a granulomatous infiltrate. In the blood, we observed a significant increase in neutrophils and monocytes 24 hours after administration of 2.5 mg of Iscador.