Gossypol: a contraceptive for men.

Normal, healthy male volunteers (n = 6) were fed diets [high docosahexaenoic acid-DHA] containing 6 g/d of DHA for 90 d. The stabilization (low-DHA) diet contained less than 50 mg/d of DHA. A control group (n = 4) remained on the low-DHA diet for the duration of the study (120 d). Blood samples were drawn on study days 30 (end of the stabilization period), 75 (midpoint of the intervention period), and 120 (end of the intervention period). Adipose tissue (AT) samples were taken on days 30 and 120. The plasma cholesterol (C), low density lipoprotein (LDL)-C and apolipoproteins (apo) [Al, B, and lipoprotein (a)] were unchanged after 90 d, but the triglycerides (TAG) were reduced from a mean value of 76.67 +/- 24.32 to 63.83 +/- 16.99 mg/dL (n = 6, P < 0.007 using a paired t-test) and the high density lipoprotein (HDL)-C increased from 34.83 +/- 4.38 mg/dL to 37.83 +/- 3.32 mg/dL (n = 6, P < 0.017 using a paired t-test). The control group showed no significant reduction in plasma TAG levels. Apo-E, however, showed a marked increase in the volunteers' plasma after 90 d on the high-DHA diet, from 7.06 +/- 4.47 mg/dL on study day 30 to 12.01 +/- 4.96 mg/dL on study day 120 (P < 0.002 using a paired t-test). The control subjects showed no significant change in the apo-E in their plasma (8.46 +/- 2.90 on day 30 vs. 8.59 +/- 2.97 on day 120). The weight percentage of plasma DHA rose from 1.83 +/- 0.22 to 8.12 +/- 0.76 after 90 d on the high-DHA diet. Although these volunteers were eating a diet free of eicosapentaenoic acid (EPA), plasma EPA levels rose from 0.38 +/- 0.05 to 3.39 +/- 0.52 (wt%) after consuming the high-DHA diet. The fatty acid composition of plasma lipid fractions--cholesterol esters, TAG, and phospholipid--showed marked similarity in the enrichment of DHA, about 10%, after the subjects consumed the high-DHA diet. The DHA content of these plasma lipid fractions varied from less than 1% (TAG) to 3.5% (phospholipids) at baseline, study day 30. EPA also increased in all plasma lipid fractions after the subjects consumed the high-DHA diet. There were no changes in the plasma DHA or EPA levels in the control group. Consumption of DHA also caused an increase in AT levels of DHA, from 0.10 +/- 0.02 to 0.31 +/- 0.07 (wt%) (n = 6, P < 0.001 using a paired t-test), but the amount of EPA in their AT did not change. Thus, dietary DHA will lower plasma TAG without EPA, and DHA is retroconverted to EPA in significant amounts. Dietary DHA appears to enhance apo-E synthesis in the liver. It appears that DHA can be a safe and perhaps beneficial supplement to human diets.

The effect of dietary docosahexaenoic acid on plasma lipoproteins and tissue fatty acid composition in humans

Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.

Gossypol treatment of recurrent adult malignant gliomas.

For centuries, plants and plant-based products have been used as a valuable and safe natural source of medicines for treating various ailments. The therapeutic potential of most of these plants could be ascribed to their anticancer, antidiabetic, hepatoprotective, cardioprotective, antispasmodic, analgesic and various other pharmacological properties. However, several commonly used plants have been reported to adversely affect male reproductive functions in wildlife and humans. The effects observed with most of the plant and plant-based products have been attributed to the antispermatogenic and/or antisteroidogenic properties of one or more active ingredients. This review discusses the detrimental effects of some of the commonly used plants on various target cells in the testis. A deeper insight into the molecular mechanisms of action of these natural compounds could pave the way for developing therapeutic strategies against their toxicity.

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Effects of plants and plant products on the testis.

OBJECTIVES: To estimate the overall balance of harms and benefits from the potential use of oral contraceptives (OCs) for the primary prevention of ovarian cancer DATA SOURCES: We searched PubMed(R) Embase(R) the Cochrane Database of Systematic Reviews and ClinicalTrials.gov for English-language studies published from January 1990 to June 2012 that evaluated the potential benefits (reduction in ovarian colorectal and endometrial cancers) and harms (increase in breast and cervical cancer and vascular complications) of OC use. REVIEW METHODS: Two investigators screened each abstract and full-text article for inclusion; the investigators abstracted data and they performed quality ratings applicability ratings and evidence grading. Random-effects models were used to compute summary estimates of effects. A simulation model was used to estimate the effects of OC use on the overall balance of benefits and harms. RESULTS: We reviewed 55 studies relevant to ovarian cancer outcomes 66 relevant to other cancers and 50 relevant to vascular events. Ovarian cancer incidence was significantly reduced in OC users (OR [odds ratio] 0.73; 95% CI [confidence interval] 0.66 to 0.81) with greater reductions seen with longer duration of use. Breast cancer incidence was slightly but significantly increased in OC users (OR 1.08; 95% CI 1.00 to 1.17) with a significant reduction in risk as time since last use increased. The risk of cervical cancer was significantly increased in women with persistent human papillomavirus infection who used OCs but heterogeneity prevented a formal meta-analysis. Incidences of both colorectal cancer (OR 0.86; 95% CI 0.79 to 0.95) and endometrial cancer (OR 0.57; 95% CI 0.43 to 0.76) were significantly reduced by OC use. The risk of vascular events was increased in current OC users compared with nonusers although the increase in myocardial infarction was not statistically significant. The overall strength of evidence for ovarian cancer prevention was moderate to low primarily because of the lack of randomized trials and inconsistent reporting of important characteristics of use such as duration. The simulation model predicted that the combined increase in risk of breast and cervical cancers and vascular events was likely to be equivalent to or greater than the decreased risk in ovarian cancer although the harm/benefit ratio was much more favorable when protection against endometrial and colorectal cancers was added resulting in net gains in life expectancy of approximately 1 month. CONCLUSIONS: There is insufficient evidence to recommend for or against the use of OCs solely for the primary prevention of ovarian cancer. Although the net effects of the current patterns of OC use likely result in increased life expectancy when other noncontraceptive benefits are included the harm/benefit ratio for ovarian cancer prevention alone is uncertain particularly when the potential quality-of-life impact of breast cancer and vascular events are considered.

Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer

Hypokalemia has been associated with the taking of gossypol, a potential oral antifertility drug for men. Because the frequency of this response differed in different parts of the world, this study was done to learn if "normal" serum [K+] also differed. [K+] was measured by flame photometry in serum from apparently normal men from Austria (n = 30), China (53), Brazil (100), the Dominican Republic (38), and the US (103), and in plasma from Nigerian men (82). The mean (SD) for [K+] in Chinese men, 3.82 (0.27) mmol/L, was lower than that in Brazilians [4.06 (0.29) mmol/L], Austrians [4.14 (0.44) mmol/L], Dominicans [4.37 (0.33) mmol/L], or Americans [4.38 (0.37) mmol/L]. Apparently there are regional differences in average serum [K+], with men in China having lower serum [K+] than men elsewhere. This may predispose them to hypokalemia.

Differences in serum potassium concentrations in normal men in different geographic locations.

The efficacy and acceptability of two widely used oral contraceptive tablets, one containing 250 mg levonorgestrel and 50 micrograms ethinyl estradiol and the other containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, administered by the vaginal route were compared in 1055 women studied over 12,630 woman-months of vaginal contraceptive pill use. This multicenter clinical trial was performed in nine countries of the developing world by the "South to South Cooperation in Reproductive Health," an organization founded by scientists from the Third World working in the area of reproductive health, and the study was developed and coordinated by one of these centers. The findings of this study confirm the efficacy of both these tablets when administered by the vaginal route. Involuntary pregnancy rates at 1 year of 2.78 for subjects in the levonorgestrel group and 4.54 for subjects the desogestrel group showed no statistically significant difference between the two groups. However, total discontinuation rates of 47.01 for subjects in the levonorgestrel group and 56.33 for subjects in the desogestrel group showed a statistically significant difference between the two groups, and discontinuation rates attributable to prolonged bleeding of 0.6 for subjects in the levonorgestrel group and 3.2 for subjects in the desogestrel group were also significantly higher in the group of subjects using the desogestrel vaginal contraceptive pill. Blood pressure remained at admission values throughout treatment. A statistically significant weight increase from admission values occurred in both groups of subjects.

Comparative study on the efficacy and acceptability of two contraceptive pills administered by the vaginal route: an international multicenter clinical trial.

The objective of this multicenter randomized clinical trail was to compare the efficacy acceptability and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. This study started in June 1987 and data collection extended up to April 1992 at family planning clinics and research centers members of the South to South Cooperation in Reproductive Health in seven countries of the developing world. The 819 subjects were from 17 to 39 years of age had already had at least one pregnancy had had regular menstrual cycles for 3 months before were exposed to the risk of pregnancy and were not using any other method of contraception. 424 were randomly assigned to use the pills orally (which contained 250 mcg levonorgestrel and 50 mcg ethinyl estradiol) whereas 395 inserted the pills vaginally. 625 subjects completed at least 6 months of use 326 used the pills orally and 299 used the pills vaginally. 385 subjects completed 1 year of pills use 201 in the oral group and 184 in the vaginal group. The 1-year discontinuation rate per 100 subjects per year for the oral group was 34.71 +or- 2.42 while it was 36.35 +or- 2.53 for the vaginal group. This difference was not statistically significant. The only single reason of statistically significant difference for discontinuation was "desire for pregnancy" (p = 0.444). Paired value analysis of subjects completing 12 months of study showed that women in the oral group had a statistically significant increase in weight from a mean of 55.8 kg at admission to a mean of 56.9 kg at 6 months (p < 0.05) and 57.3 kg at 1 year (p = 0.05). The mean weight of the vaginal group increased from 56.52 kg to 57.22 kg (p = 0.036) at 12 months. Significantly more complaints of vaginal discharge were recorded in women using the pills by the vaginal route (p = 0.001). However only one subject discontinued the pills because of vaginal discharge.

Comparative study on the efficacy acceptability and side effects of a contraceptive pill administered by the oral and the vaginal route: an international multicenter clinical trial.

Zhi-Ping Gu

Papers

Differences in serum potassium concentrations in normal men in different geographic locations.

Comparative study on the efficacy and acceptability of two contraceptive pills administered by the vaginal route: an international multicenter clinical trial.

Comparative study on the efficacy acceptability and side effects of a contraceptive pill administered by the oral and the vaginal route: an international multicenter clinical trial.

Serum potassium: values in normal men in Shanghai vs those in men from Shanghai living abroad.