Gossypol blood levels and inhibition of spermatogenesis in men taking gossypol as a contraceptive. A multicenter, international, dose-finding study.

The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only one man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects on the 7.5 mg/day dose group, 12 recovered sperm counts >20 million/mL within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. Eight of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

PIP: The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only 1 man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects in the 7.5 mg/day dose group, 12 recovered sperm counts higher than 20 million/ml within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. 8 of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

Low dose gossypol for male contraception.

AIM: To ascertain whether the side effects of gossypol, hypokalemia and irreversibility, could be avoided on dose reduction. METHODS: Seventy-seven male volunteers were divided into 3 groups: control (22 cases), 10 mg gossypol (29 cases) and 12.5 mg (26 cases). Serum levels of testosterone, FSH and LH were measured by RIA and potassium by flame photometry. Sperm counts and motility were examined before and regularly after treatment for the evaluation of contraceptive efficacy. RESULTS: The average sperm density and motility started to decrease significantly by the end of month 2 of medication and gradually reached the infertility levels (< 4 million/mL) in both treated groups. After that the 10 mg group was asked to take the same dose every other day for up to a total observation period of 16-18 months for the maintenance of infertility. Subjects in the 12.5 mg group did not take gossypol any more so as to observe the length of the loading dose required, but in a few, a maintenance dose of 12.5 mg every other day was instituted for a few more months. In both treated groups, none of the spouses was pregnant during the maintenance dose period. Serum levels of potassium, FSH, LH and testosterone were not significantly changed and not a single volunteer complained of myoasthenia. After cessation of drug administration, the semen data returned to pretreatment levels. CONCLUSION: A regimen with 10 or 12.5 mg of gossypol as the daily loading dose and 35 or 43.75 mg as the weekly maintenance dose could induce infertility in male volunteers without developing hypokalemia or irreversibility.

Gregory Pincus, father of the pill.

PIP: This paper presents the profiles of Gregory Pincus, popularly known as the "Father of the Pill". Pincus was considered a brilliant scientist who developed an oral contraceptive in 1950. He had already achieved in vitro fertilization of rabbit eggs, foreshadowing later successes in assisted human reproduction that have enabled tens of thousands of couples to overcome infertility. His discovery, however, generated controversy, which cost him tenure at Harvard, prompting his move to Clark University in Worcester, Massachusetts. At Clark, he continued his work, which led to the creation of the Worcester Foundation for Experimental Biology in 1944, teaming up with several other scientists. With his qualities as scientist, Pincus was among the few whose distinction and recognition encourage young scientists to enter the field.^ieng

Liability concerns in contraceptive research and development.

The history of liability claims in the US against contraceptive products is among the issues that discourage manufacturers from investing in discovery and development in this field. Other factors are the high cost of new drug development, elevated insurance rates for contraceptives, and the desire to avoid controversy that can disturb corporate tranquility. General features of the American legal system influence the large number and cost of product liability claims in the US compared to Europe. These differences pertain to issues such as the role of judges, how lawyers receive their compensation, and the use of expert scientific testimony. The history of litigation in the US against pharmaceutical products and devices pertaining to women's health suggests that interventions that involve the reproductive system are held to different standards or elicit different emotional responses than other pharmaceutical products or devices.

Contraceptive development and better family planning.

PIP: Contraception helps many people achieve their desired fertility. Pharmacological or mechanical contraceptive methods by themselves do not lead to successful contraception. Once empowered through education or improved socioeconomic status to realize their ability to limit their family size, women's options are abstinence (including delaying the marriage age), contraception (including surgical sterilization and natural family planning methods), or abortion. Most people in the US trying to avoid pregnancy use surgical sterilization. The reversible methods most used, in order of frequency, are the pill, the condom, and the diaphragm. The 10% of couples who use no method make up slightly more than 50% of unplanned pregnancies, while the 90% of those who use contraception make up the remaining 50% (i.e., contraceptive failures). If used properly, modern contraceptives are very effective. Methods with low failure rates (IUDs, implants, and injectables) are used by only 2% or fewer of US contraceptive users but are more widely used elsewhere. More than 50% of pregnancies in the US are unplanned. Most adolescent pregnancies are unplanned. Contraceptive users account for about 50% of induced abortions. Reducing unwanted pregnancies has helped people achieve their desired fertility and greatly reduces the induced abortion rate. The US has the highest adolescent pregnancy rate in the Western world, partly due to the time lag between initiating sexual activity and initiating contraceptive use. Reasons for unplanned pregnancies among youth include lack of counseling and contraceptive failure. Contraceptive development should focus on improving use-effectiveness. The implant is the newest contraceptive method. A variety of male and female contraceptive methods are currently under study (e.g., immunological methods, postcoital pills, skin methods [patches, creams, and gels], improved IUDs, and improved male condoms). Leaders should consider unplanned pregnancy as a serious public health problem and take steps to reduce unplanned pregnancies.^ieng

Contraceptive revolution.

PIP: Global population will increase by almost 1 billion people in the 1990s, the largest 10-year increase ever recorded. In 1994 alone, population will surpass 5.7 billion. The prospect of double-digit billions of people is worrisome, especially since these numbers may affect global warming, supplies of fresh water, destruction of rain forests, industrial pollution, and sustainable development. Yet, many indicators of quality of life show that people enjoy a better quality of life today than they did 100 years ago. Between India's independence and now, life expectancy increased by 20 years, infant mortality decreased 2-fold, literacy increased, and the food supply stabilized. Even though India's population has almost tripled since 1947, its economy increased rapidly and is 1 of the world's top 10 economies. University enrollment stands at 4.5 million. Agricultural production has exceeded demand. India represents the potential for human achievement through technological advancement and social organization. If the world's first national family planning program had been more successful when it began in 1952 in an India of 350 million people, India's population would be around 500 million instead of the expected 1 billion in 2000. All countries need to achieve a sustainable balance between human numbers and needs and natural resources. Family planning is an essential, cost-effective part of any development strategy. Family planning use has reduced fertility from 6 to 3.6 in developing countries. In 1965, only 8% used contraception, while more than 50% use it now. The most remarkable family planning/fertility reduction successes are Bangladesh, Brazil, Colombia, Indonesia, Mexico, and Thailand. Sufficient investment in family planning is needed if significant declines in fertility are to occur. More than 90% of the developing world's people are in countries with official family planning programs. Cost-effective assistance by donors and developing countries implementing their own sustainable development policies should curb population growth.^ieng

Regulation of serotonin-induced calcium uptake in Spisula oocytes by tricyclic antidepressants.

The effect of tricyclic antidepressants on 5-hydroxytryptamine (serotonin or 5-HT)-induced maturation and Ca2+ uptake in Spisula oocytes was determined. The drugs at a concentration of 20 microM completely blocked germinal vesicle breakdown and 45Ca2+ uptake by Spisula oocytes. The order of effectiveness of the antidepressants were imipramine > desipramine > clomipramine. The present findings suggest that the action of tricyclic antidepressants is to regulate Ca2+ uptake into 5-HT-responsive cells.

Trends in population and contraception.

There has been an explosion in contraceptive use in the past 30 years. In 1960-65, the level of contraceptive use in the developing countries of Asia, Latin America and Africa represented about 9% of married couples of reproductive age. In the 1990s use of contraception in developing countries comprises over 50% of couples and contraceptive prevalence is increasing each year. Total fertility rates for the developing world have already fallen from over 6, where they were in 1960 to about 4, halfway toward the replacement level of 2.1. The United Nations projects that during this decade, over 90 million people will be added each year to world population. If this projection is not to be exceeded, prodigious supplies of contraceptives will have to be available at affordable cost to the people of developing countries, where 94% of this population increase will occur. New technology alone will not guarantee this success, but it would help ensure that people are able to meet their fertility objectives.

PIP: The trends are identified for population growth, the momentum of growth, contraceptive use, choice of method, and future contraceptive needs. The forecast for the 1990s, based on UN estimates, is for growth of 90 million each year. 94% of growth will occur in developing countries. Sub-Saharan Africa will experience the fastest rate of growth, but the largest numbers will be in Asia. Population is expected to increase by 112% between 190 and 2015 (550 million) in sub-Saharan Africa, by 60% (750 million) in South Asia, and by 76% in the Middle East and North Africa. Even if developing countries have replacement level fertility, the numbers of women of reproductive age are high enough in most developing countries to continue to increase population for 6 decades. Fertility rates in developing countries are halfway to replacement level with fertility rates of around 4. Worldwide there has been a ten-fold increase in contraceptive use over the past 30 years. By 1990 over 50% of married couples of reproductive age used contraception. There is evidence that family planning methods have been found to be acceptable by people of many different cultures and socioeconomic conditions. Sterilization is the most commonly used method worldwide. Most of the sterilized population lives in China (70 million) and in India (36 million), which constitutes 59% of persons of reproductive age. Populations with more than 40% of the reproductive age population sterilized include Puerto Rico, Canada, and South Korea. More than 25% of sterilized couples are found in Brazil, the Dominican Republic, El Salvador, Panama, the US, Sri Lanka, Thailand, Taiwan, and the UK. The second most popular method is the IUD. The country with the highest proportion of people using the IUD is China. 67 million in China use the IUD compared to 26 million in other developing countries and 10 million in developed countries. New methods, which lower logistical and cost factors, need to be developed; greater access to the very poor or those in remote areas is targeted. Potential users might be attracted to methods with improved safety, reduced side effects, and greater convenience. Access to a wide variety of methods is a means of reaching a larger audience of users. New contraceptive technology will be available during the 1990s, i.e., implants, a vaccine to prevent pregnancy, and a pill or injection for men.

The South to South Cooperation in Reproductive Health.

PIP: The South to South Cooperation in Reproductive Health program is a means for university based scientists and clinicians from developing countries to initiate and collaborate on research. It has been funded primarily by the Rockefeller Foundation since 1987; local governments contribute support. The Cooperative is incorporated as a tax-exempt international organization in Salvador, Brazil, where a computer center with biostatistical capability is maintained. Semiannual meetings are held to plan, critique, modify and approve protocols for research projects. Multicenter studies, managed by the project director who initiated the study, are monitored on a rotating basis in participating countries. This organization provides opportunities for investigators from developing countries to take the lead in projects in their own countries.^ieng

Norplant implants: the mechanism of contraceptive action.

OBJECTIVE: To determine if fertilization occurs unnoticed among Norplant users who are ovulatory. DESIGN: Serial blood samples were obtained during 1 month from sexually active Norplant users experiencing regular menstrual bleeding patterns and a control group of noncontracepting women trying to conceive. The sequential blood samples were assayed for the presence of human chorionic gonadotropin (hCG). SETTING: All samples were obtained from women receiving contraceptive service and health care at the Center for Research and Services in Human Reproduction and Contraception, Santo Domingo, The Dominican Republic. Assays for hCG were performed at the Department of Biomedical Sciences, University of Tampere, Finland. PATIENTS, PARTICIPANTS: A total of 32 women using Norplant implants were enrolled in the treatment group, and 20 women of proven fertility who were attempting to conceive served as a control group. INTERVENTIONS: Duration of Norplant use was as follows: 4 in the 2nd year of use, 13 in the 3rd year, 11 in the 4th year, 3 in the 5th year, and 1 in the 7th year. MAIN OUTCOME MEASURE: The determination of pregnancy was based on the presence of hCG in the luteal phase, using a sensitive and specific immunoenzymatic assay that can detect dimeric hCG as early as 7 days after ovulation. RESULTS: Nine pregnancies were detected. All were in the control group trying to conceive. Six of these advanced to clinical pregnancies, and three did not proceed beyond the next expected menses. None of the Norplant users had evidence of hCG production, whether the observed cycles were anovulatory or ovulatory. The probability of finding no pregnancies in the ovulatory months at risk among Norplant users is between 1 in 50 and 1 in 150,000. The null hypothesis that Norplant users conceive at a natural rate can be rejected at the 0.05 level. CONCLUSION: Interruption of early pregnancy (menstrual abortion) does not play a role in the mechanism of action of Norplant contraceptive implants.

PIP: This study sought to determine if fertilization can occur unnoticed among Norplant users who are ovulatory. Serial blood samples were obtained during a 1-month period from women receiving contraceptive service and healthcare at the Center for Research and Services in Human Reproduction and Contraception, Santo Domingo, The Dominican Republic. These women were all sexually active Norplant users who experienced regular menstrual bleeding patterns, and their sequential blood samples were assayed for the presence of human chorionic gonadotropin (hCG) at the Department of Biomedical Sciences at the University of Tampere, Finland. There was also a control group of 20 noncontracepting women included who were trying to conceive. Duration of Norplant was as follows: 4 in the 2nd year of use, 13 in the 3rd year, 11 in the 4th, 3 in the 5th year, and 1 in the 7th year. Pregnancy determination was based on the presence of hCG in the luteal phase by use of a sensitive and specific immunoenzymatic assay that can detect dimeric hCG as early as 7 days postovulation. 9 pregnancies were detected, all in the control group who were trying to conceive. 6 of these advanced to clinical pregnancies and 3 terminated spontaneously at the next menstrual period. None of the Norplant users evidenced and hCG production, whether or not the observed cycles were ovulatory. The probability of finding no pregnancies in the ovulatory months at risk among Norplant users is between 1/50 and 1/150,00. The null hypotheses that Norplant users conceive at a natural rate can be rejected at the 0.05 level. Thus, interruption of early pregnancy (menstrual abortion) does not play a role in the mechanism of action of Norplant contraceptive implants.

Inactivation of human immunodeficiency virus in vitro by gossypol.

Gossypol, a polyphenolic aldehyde extracted from cottonseed, is a male anti-fertility agent which has been reported to have anti-viral activity. In this paper we report that gossypol inactivates human immunodeficiency virus (HIV) in an in vitro system. Following exposure of cell-free incubates of HIV to 100 uM gossypol, ultracentrifugation and inoculation of the washed pellet onto H9 cells, there is no evidence of elevated reverse transcriptase activity over 21 days. Treatment with lower concentrations of gossypol reduces the peak and lengthens the time to maximal reverse transcriptase activity compared with control cultures. These observations suggest that gossypol could be used as a vaginal spermicidal/virucidal agent. The mechanism of the in vitro anti-viral action as well as the effect of orally administered gossypol on the infectivity of semen of HIV-seropositive men warrant further study.

PIP: Following research that demonstrated the quality of gossypol, a polyphenolic aldehyde taken from cottonseed, in causing anti-viral activity, testing was done in pursuit of the inactivation of Human Immunodeficiency Virus in vitro. Gossypol is an orally active male anti-fertility agent that has been used in China by more than 10,000 men. Its biological abilities and effects include both anti-viral and anti-parasitic activity. virucidal activity has been observed against many diseases including herpes simplex-2. Thus, the preventative applications for gossypol are evident particularly as a spermicidal/virucidal agent used as a vaginal contraceptive. Gossypol can be absorbed by women vaginally. In the testing of the possibility of the inactivation of HIV, it was found that a concentration of 100uM of gossypol completely inactivates cell-free preparations of HIV. Although the applications for the use of gossypol as a vaginal preparation are apparent, further research and testing is needed of a process that limits or reduces the virus content, especially among seropositive men, and a process that affects the infectivity of semen at the point of ejaculation.