This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term goal is to develop a number of methods of delivering androgen plus progestogen male contraceptive agents for men. This proposal will test whether addition of Nestorone to testosterone (T) gel both applied transdermally will be more efficient in suppressing gonadotropins (Study 1) and sperm concentration (Study 2) to near zero levels (azoospermia) in most normal men when compared to T gel alone. It will also study whether Nestorone (a synthetic progestogen) gel alone will suppress gonadotropins . Recent studies from our center and others demonstrated that testosterone gel, when applied to the skin, achieved dose-dependent, steady state levels of serum T. When 10 g gel was applied to men with partial androgen deficiency, serum LH and FSH dropped to more than 90% of baseline values, rendering some of the values undetectable. In addition, transdermal T gel was found to be more user friendly and the preferred method for many androgen deficient men since its introduction in the United States in 2000. Our group was the lead center for the T gel studies and is familiar with the pharmacokinetics and pharmacodynamics of this transdermal preparation. Lastly, Nestorone is a synthetic progestin that is not expected to have any androgenic and estrogenic activity and may not have some of the undesirable side effects of levonorgestrel or desogestrel. It has undergone clinical trials as an implant and vaginal ring in women and is being developed by the Population Council as a vaginal ring and transdermal gel. This study will be divided into two phases.
The specific aims are: Study 1 is a dose finding study which will estimate the suppression of gonadotropin secretion by T gel alone (10 g/day), Nestorone gel alone at two doses (2 or 4 mg/day), and the combinations of T and Nestorone gel for 14 days each with a 14-21 day washout period between dosing. Each dose of medication will be administered to 24 healthy men. 24 healthy men will be randomized for the study after screening examinations, which include clinical evaluation of general and reproductive history, a detailed physical examination, analyses of blood and semen. Subjects who do not complete the study will be replaced in Study 1. Subjects should have normal baseline blood and semen tests. We anticipate that 24 subjects will complete Study 1. Subjects will be required to use another method of contraception throughout the study. The end point will be the efficacy of suppression of serum gonadotropins. Only 12 subjects well be enrolled at Harbor-UCLA. Study 2 will be done only if Study 1 showed significant and profound suppression of gonadotropins by the combination of T and Nestorone Gel. This study will assess the efficacy of spermatogenic suppression in two groups of 22 subjects each (n=44), receiving the lowest dose combinations that showed the most suppression of gonadotropins based on the results of Study 1 or the same T fel dose alone. This will be a 24-week study with suppression of sperm counts to severe oligozoospermia (< 1 million/mL) as the primary endpoint). Only 22 men will be enrolled at Harbor-UCLA. There is no direct benefit to the subjects. The study will help to develop a male contraceptive for men utilizing transdermal delivery systems producing sustained, constant levels of an androgen and a progestogen. None of the risks are likely to cause any clinical problem because of the physiological dose of testosterone administered, the known safety of Nestorone, the short duration of drug exposure in study 1 and 24 weeks for study 2, the strict inclusion and exclusion criteria, the experience of the investigators and their staff, and the careful monitoring of all possible adverse effects. The consent form will be given and explained to each subject. Only the investigators or their designated medically qualified associates will obtain informed consent. The information provided by the investigator to the subject will include: identification of the investigators and funding source, description of the research study and the patient's involvement, the purpose of the study, the benefit of the research to the patient, the risks and possible side effects of testosterone and Nesterone gels and the possibility of withdrawal at any time without penalty. This information will be clearly detailed in a Consent Form, which will be reviewed and approved by the IRB at both centers and the Population Council. The subjects will also sign a HIPAA consent form to allow the investigators access the protected health information according to HIPAA regulations and those of the Institution's IRB. The subjects will be given the opportunity to ask questions and the investigators to respond to the subject's questions. The subject will then be asked to sign the Consent Form in the presence of a witness. The subjects will also be given a copy of the Experimental Subject's Bill of Rights. The subjects in Los Angeles and Seattle will be recruited via advertisement in bulletin boards, newspapers, radio, and television. They will be asked to contact either one of the study sites by telephone. The nurse coordinator will screen potential subjects over the telephone by inquiring about their age and medical history. Potential subjects who qualify by phone screen will be scheduled for an appointment to consult with the investigator about further eligibility requirements for the study.
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