Nomegestrol acetate contraceptive implant use by women with sickle cell disease.

OBJECTIVE: To assess the contraceptive effectiveness, safety, and potential health benefits of nomegestrol acetate contraceptive implant use by women with homozygous sickle cell disease (hemoglobin SS). METHODS: This was a prospective observation before and after insertion of nomegestrol acetate of 20 women with sickle cell disease (test group) compared with 10 women with similar sociodemographic backgrounds. Changes in hematologic and biochemical parameters and symptoms of sickle cell crisis were measured during 12 months of observation. RESULTS: After use of nomegestrol acetate for 1 to 9 months, the women in the test group had symptomatic improvement, with no crisis that required hospitalization and no deaths. Sickle cell symptoms persisted in the women in the control group, with 1 recorded death. Increases in F-cell and fetal hemoglobin parallel the observed clinical improvement in the treated women. There were no adverse hematologic or biochemical changes associated with the use of nomegestrol acetate implants. CONCLUSION: Nomegestrol acetate appears to be a safe and appropriate contraceptive for women with sickle cell disease, showing evidence of being a "stimulant" for F-cell reactivation, independent of F hemoglobin total production increase.

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

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.

PIP: Efficacy and acceptability of 2 combined oral contraceptive pills administered vaginally are summarized. This is the 1st collaborative trial published by the South to South Cooperation in Reproductive Health. 1055 women participated in 12,630 cycles, in 9 countries, from June 1988 to May 1991. The pills were commercially available tablets containing 50 mcg ethinyl estradiol and 250 mg levonorgestrel (Schering AG, Sao Paulo, Brazil), or 30 mcg ethinyl estradiol and 15 mcg desogestrel (Organon, Sao Paulo, Brazil). Subjects were aged 17-39 younger and of lower parity from Mexico and Dominican Republic and older from Egypt and China. All had at least 1 pregnancy. 675 participated for 6 months, 470 for 1 year, 364 for 18 months, and 210 for 2 years. The 1-year discontinuation rate averaged 47.01% for the levonorgestrel group and 56.33% for the desogestrel group (p = 0.0061); 2-year discontinuation rates were 48.01% and 69.36, respectively, explained in part by higher involuntary pregnancy rates and prolonged bleeding rates in the desogestrel group. The most common medical reasons for stopping contraception were unplanned pregnancy, vaginal or vulval irritation, nausea, vaginal discharge and headache. Vaginal irritation was reported by 1%, 9 in each group. There were 32 pregnancies, 14 in the levonorgestrel and 18 in the desogestrel group. 17 were in missed pill cycles and the rest were method failures, 6 in the levonorgestrel group and 9 in the desogestrel group. The Pearl index varied from 0 in Nigeria to 12.24 in Mexico, and was 2.45 for levonorgestrel vs. 3.74 for desogestrel. There was a wide variation in discontinuation rates by center: Brazil and China had few, while many women from Dominican Republic, Mexico and Zambia left the study. Bleeding problems were common complaints, more so in the desogestrel group. There were 363 women with intermenstrual bleeding (only once in 80%), 148 with spotting (only twice in 65%). Bleeding duration was significantly less in pill cycles than baseline, pressure. Women gained an average of 1 kg over 2 years, more in the desogestrel group. The pregnancy rate of 2.78 is within the range reported for levonorgestrel rings.

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.

The objective of this multicenter randomized clinical trial was to compare the efficacy, acceptability, and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. Eight hundred nineteen healthy, parous women of reproductive age were recruited at family planning clinics and research centers, members of the South to South Cooperation in Reproductive Health, in seven countries of the developing world. These women were randomly assigned to use either oral or vaginal administration of the same contraceptive pill, which contained 250 micrograms levonorgestrel and 50 micrograms ethinyl estradiol. No statistically significant differences were found in discontinuation rates between the two groups after 1 year. Involuntary pregnancy rates after 1 year were not statistically significantly different between the two groups. The vaginal route of administration appears to be as acceptable and efficacious as the oral route.

PIP: 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.

Latin America's contributions to contraceptive development.

PIP: The contributions of Latin Americans to contraceptive research began in 1951 when the Mexican chemist, Miramontes, invented norethisterone (norethindrone). Early studies on the use of this drug with ethinyl estradiol in an oral contraceptive (OC) pill were conducted in Puerto Rico. Publication of these studies was the second milestone in contraceptive development. While the leaders of this work, Pincus and Rock, were widely acknowledged, the many doctors who carried out the trials and reported their observations have been forgotten. The next milestone was the introduction of the estrogen-free OC by Martinez-Manautou and his collaborators in 1966. That same year Coutinho, de Souza, and Csapo reported on the contraceptive effect of medroxyprogesterone acetate (MPA) based on work done in Brazil. Also from Brazil came the proposal to use MPA in combination with estrogen in a monthly contraceptive injectable. The development of Depo-Provera and other injectables also took place mostly in Latin America. The first norgestrel-containing pill was also developed in Brazil, and successful efforts to reduce the dosage to a half tablet prefigured the development of low-dose OCs. Norplant was developed in Brazil, with the first clinical trails taking place in Chile. Other proposals followed during the late 1970s, including efforts to develop a male contraceptive. The first clinical trials with gossypol outside of China took place in Brazil. A Latino, Zipper, also proposed the use of copper in IUDs which increased the acceptability of this method. In addition to the researchers cited here, many others have contributed decisively to contraceptive development. The fact that they are not receiving the recognition they deserve is disappointing since the only real reward for their dedicated work would be recognition of their results.^ieng

Physiologic and pharmacologic studies of the human oviduct.

PIP: Tubal motility during the menstrual cycle was measured in women by means of an indwelling polyvinyl catheter. During all phases of the cycle, there were episodes of tubal motility at regular intervals. These episodes were more frequent during menstruation but the intensity and duration were greater during the proliferative phase. During the luteal phase the intensity and duration of the outburst were depressed. The episodes of motor activity were asynchronous between the 2 tubes and between different portions of the same tube. Activity in the rabbit was similar to that of the human and was found in the isthmic and ampullar portions of the tube but not in the infundibulum. Intravenous administration of epinephrine or norepinephrine increased motility. Alpha-adrenergic blockade with phentolamine mesylate and phenoxybenzamine suppressed spontaneous outbursts in the rabbit. The tubes were sensitive to oxytocin but almost insensitive to vasopressin. Suction of the breast increased tubal motility.^ieng

Treatment of endometriosis by vaginal administration of gestrinone.

The effectiveness and acceptability of gestrinone administered by vaginal route was evaluated in a group of 110 patients with endometriosis. Patients were divided into four groups. The first three groups were treated by vaginal route. Group I (n = 17) received two 2.5-mg tablets weekly; group II (n = 31) received three 2.5-mg tablets weekly; group III (n = 35) received two 5.0-mg tablets weekly. Group IV consisted of 27 patients who received 2.5 mg of gestrinone orally twice weekly. Ninety-eight women completed the 6- to 8-month treatment period. Amenorrhea developed in all treatment groups, including group I (34%). The disappearance of both dyspareunia and dysmenorrhea occurred in most patients in all treatment groups soon after the second month of therapy. Patients treated by vaginal route had significantly less seborrhea and acne than those treated by oral route. Weight gain was also significantly less in vaginally treated women than in those treated orally. Pregnancy rate following discontinuation was not significantly different for the various groups.

Long-term treatment of leiomyomas with gestrinone.

A prospective randomized study was conducted in 100 women with leiomyomas in order to evaluate the effect of gestrinone, a synthetic derivative of ethynil-nor-testosterone. Patients in group A received capsules containing 2.5 mg of gestrinone three times weekly orally. Those in group B received capsules containing 5.0 mg twice weekly, also orally. In group C, patients used by vaginal route tablets containing 5 mg of gestrinone three times weekly. Reduction in uterine volume occurred in all three groups of patients. Of patients who discontinued treatment at 6 months, uterine volume remained lower than pretreatment values in 89%, 18 months after discontinuation. Of those patients who discontinued at 1 year, uterine volume remained below pretreatment levels in 76% 1 year after discontinuation. In patients treated continuously for 24 months, mean uterine volume decreased from a mean 339 cm3 to 273 cm3, a statistically significant difference. The vaginal route showed statistically more significant volume decreases than the oral route for all treatment intervals.

The contractile response of the human uterus, fallopian tubes, and ovary to prostaglandins in vivo.

PIP: In vivo studies were carried out in 8 women to ascertain the effects of prostaglandins (PGs) E2 and F2alpha on the human fallopian tubes and ovaries. Recording devices were surgically implanted into the tubal lumen through catheters. 100 mcg. of either PGE2 or PGF2alpha or a mixture of equal amounts of the 2 totaling 100 mcg. were administered intravenously and the effects recorded. Graphs of the effects are presented. The 2 pure substances and the mixture all had a stimulatory effect on the uterus at all phases of the menstrual cycle. There were, however, qualitative and potency differences between PGE2 and PGF2alpha. On a weight basis, PGE2 had more powerful effects on the myometrium. The 2 PGs had opposing effects on the fallopian tubes, with PGF2alpha stimulating while PGE2 inhibited tubal motility. A contractile response of the ovary following intravenous administration of PGF2alpha was noted; no change in intraovarian pressure was recorded following injection of up to 100 mcg. PGE2. The compound was mildly stimulatory. The ability of PGE2 to induce relaxation of the tubes while stimulating uterine activity provides a clue as to why it is more effective in inducing abortion than PGF2alpha. It is suggested that relaxation of the tubal isthmus induced by seminal PGE2 facilitates sperm penetration into the tube.^ieng

Inhibition of ovulation in marmoset monkeys by indomethacin.

The effect of indomethacin on human menopausal gonadotropin/human chorionic gonadotropin-induced ovulation was studied in marmoset monkeys. Indomethacin was effective in preventing follicular rupture and ovum extrusion when administered simultaneously with gonadotropin. The production of progesterone and luteinization of the granulosa cells were not affected by indomethacin treatment. Histologic examination of corpora lutea from indomethacin-treated animals revealed the presence of entrapped oocytes surrounded by luteal cells. These results suggest that prostaglandin synthesis is required for ovulation in this species, but not for luteinization and progesterone production.

The inhibitory effect of Ritodrine on human tubal activity in vivo.

PIP: The effect of Ritodrine (4-hydroxy alpha-1-2-4-hydroxyphenyl ethylamino acetylbenzyl alcohol hydrochloride) on fallopian tubal activity was studied in 26 women of reproductive age who underwent abdominal surgery for tuboplasty (8 women), tubal ligation (6 women), or ovarian or uterine pathology (12 women). Tubal mobility was recorded by the intratubal microballoon method. Ritodrine was given intravenously at infusion rates of 50-600 mcg/minute or orally. At infusion rates of 200-300 mcg/minute, Ritodrine suppressed the spontaneous outbursts of increased activity, but tubal quiescence was achieved only at infusion rates of 400 mcg/minute or higher. Oral administration of 5-10 mg of Ritodrine was insufficient to depress motility, however 15-20 mg achieved quiescence lasting longer than 1 hour. It was suggested that it is conceivable that the administration of a beta-adrenergic activator such as Ritodrine at appropriate times of the menstrual cycle would interfere with conception through inhibition of the ovum retention mechanism in the tube.^ieng

Detection of human chorionic gonadotropin in blood of regularly bleeding women using copper intrauterine contraceptive devices.

Highly sensitive and specific radioreceptorassay and radioimmunoassay of human chorionic gonadtropin (hCG) have been used in the detection of hCG in random serum samples during the luteal phase of the menstrual cycles of 200 women and in daily serum samples obtained a few days prior to expected ovulation through the luteal phase in 3 women with regular bleeding patterns and using a copper intrauterine device (IUD). Twelve to nineteen per cent of IUD users showed hCG in serum during the luteal phase, indicating that the presence of the IUD, while permitting fertilization, probably causes interference through degeneration of the blastocyst and consequent lack of implantation.

Antispermatogenic action of gossypol in men.

Twelve Brazilian men were treated with gossypol for 1 year. The treatment schedule consisted of oral administration of 20 mg gossypol daily for 4 months, followed by a maintenance dose of 20 mg on alternate days (3 days a week), totaling 60 mg weekly for 8 months. Ten men became azoospermic at the end of the fourth month of treatment, and the two others developed marked oligospermia with necrospermia. Except for one man who complained of transient listlessness and fatigue, the subjects reported no side effects during treatment. No changes in libido or potency were reported, and plasma testosterone remained unchanged. Blood chemistry values, which included complete blood cell count, cholesterol, glucose, triglycerides, acid phosphatase, urea, transaminases, sodium, and potassium, were not changed significantly during treatment. The response of the pituitary to gonadotropin-releasing hormone stimulation and the response of the testis to gonadotropin stimulation appeared normal in men treated with gossypol. After treatment, the sperm counts reverted to essentially normal levels in 8 of 12 men. In four men, azoospermia continued 1 year after discontinuation of gossypol treatment. Retrograde phlebography carried out in three of the four men who remained azoospermic after discontinuation of therapy revealed subclinical varicocele.

PIP: 12 Brazilian men were treated with gossypol for 1 year. The treatment schedule consisted of oral administration of 20 mg gossypol daily for 4 months, followed by a maintenance dose of 20 mg on alternate days (o days/week), totaling 60 mg weekly for 8 months. 10 men became azoospermic at the end of the 4th month of treatment, and the other 2 developed marked oligospermia with necrospermia. Except for 1 man who complained of transient listlessness and fatigue, the subjects reported no side effects during treatment. No changes in libido or potency were reported, and plasma testosterone remained unchanged. Blood chemistry values, which included complete blood cell count, cholesterol, glucose, triglycerides, acid phosphatase, urea, transaminases, sodium, and potassium, were not changed significantly during treatment. The response of the pituitary to gonadotropin-releasing hormone stimulation and the response of the testis to gonadotropin stimulation appeared normal in men treated with gossypol. After treatment, sperm counts reverted to essentially normal levels in 8 of 12 men. In 4 men, azoospermia continued 1 year after gossypol treatment discontinuation. Retrograde phlebography carried out in 3 of 4 men who remained azoospermic after therapy discontinuation revealed subclinical varicocele.

Effect of prostaglandin F2 alpha on oviduct contractility in marmoset monkeys.

Prostaglandin F2 alpha (PGF2 alpha) increased oviductal contractility under different hormonal conditions. Changes in the response of the oviduct to PGF2 alpha were observed during the reproductive cycle. The response to PGF2 alpha was reduced during the follicular phase, but it increased markedly following both spontaneous and human chorionic gonadotropin-induced ovulation. During the luteal phase the effect of PGF2 alpha on the oviduct was significantly greater than during the follicular phase. The spontaneous motility of the oviduct also increased significantly following ovulation. This increase in motility occurred when progesterone blood levels reached values higher than 1.5 ng/ml, and it was not suppressed by indomethacin, a potent inhibitor of prostaglandin synthesis.

Conception control by vaginal administration of pills containing ethinyl estradiol and dl-norgestrel.

One hundred twenty-four women of reproductive age have used vaginal pills containing 50 micrograms dl-norgestrel and 35 micrograms ethinyl estradiol to prevent conception for periods ranging from 6 to 20 months. One thousand four hundred thirty-eight woman-months were recorded. No pregnancies occurred. Cycle control was good. Bleeding usually lasted 3 to 5 days, and the interval between withdrawal bleeding events was 26 to 30 days in 86% of the cycles. Amenorrhea, breakthrough bleeding, and spotting occurred rarely. The continuation rate at 1 year was 64%.

PIP: This paper reports the results of a clinical trial of124 women of reproductive age who relied on daily administration of a vaginal pill containing 50 mg dl-norgestrel in combination with 35 mcg ethinyl estradiol fro contraceptive purposes for 6-20 months. No pregnancies occurred in 1438 woman-months of abservation. Bleeding generally developed 3-5 days after insertion of the last pill and lasted an average of 3-5 days. The interval between withdrawal bleeding events was 26-30 days in 86% of cycles. Incidence of intermenstrual bleeding, spotting, and amenorrhea was minimal. No siginificant alterations in blood pressure or blood cell counts and hematocrit were noted. Vaginal discharge requiring treatment developed in 20.9% od subjects; however, this incidence is comparable to that found in oral contraceptive (OC) and IUD users and may thus be unrelated to the vaginal pill. After 1 year of use, 64% of the subjects opted to continue the vaginal pill. This contrasts favorably with continuation rates recorded at the same clinic for vaginal ring users (48%) and OC users (47%). Only 7 of the 44 vaginal pill discontinuers cited medical reasons; the majority gave trivial reasons, and several reapplied for inclusion in the vaginal pill trial a few months after discontinuation. These findings suggest that the vaginal pill avoids the undesirable side affects of the vaginal ring (e.g., expulsion, interference with coitus, odor) as well as those associated with the gastric absorption os steroids, demonstrates a low incidence of complications, and is highly effective in preventing pregnancy.

Long-term contraception with a single implant of the progestin ST-1435.

Silastic capsules containing the synthetic progestin ST-1435 was inserted in 282 women of reproductive age who desired long-term contraception. Each woman received a single implant for 6 months' use. After evaluating the experience of the first 45 subjects, replacement capsules were offered to women desirous of continuing the method after the initial 6 months of use. In the first 6-month segment one pregnancy and 1720 woman-months of use were recorded. The total experience, through as many as six segments of use was 3373 woman-months of use and one pregnancy. The Pearl Index is 0.36 per 100 woman-years. The single pregnancy, recorded in the 1st month of the first segment, may represent a conception prior to implant placement. Amenorrhea was the most common side effect reported, with 83% of the women having at least one nonbleeding interval longer than 60 days during the first segment of use.

Ovulation suppression in women following vaginal administration of oral contraceptive tablets.

PIP: A preliminary trial was conducted to test the possibility of using intravaginally a contraceptive tablet manufactured for oral use to achieve ovulation suppression. 12 women who could not continue with oral contraceptives (OCs) because of gastrointestinal complaints and/or nausea volunteered to participate. All subjects discontinued oral use of tablets for at least 2 months prior to the vaginal administration. Condoms were provided for use during the interim period. Patients were instructed to manually place in the vagina either 1 (4 subjects) or 2 tablets (8 subjects) daily for 21 days. Progesterone blood levels remained at preovulatory levels, below 2 ng/ml, throughout the treatment period, indicating that ovulation was suppressed in all subjects. Levels of 17beta-estradiol (32) which showed considerable variation during the control cycle remained low during the treatment cycle. Withdrawal bleeding occurred 2-5 days following the last tablet and lasted 3-5 days, as in normal menstruation. In patients inserting 1 tablet, intermenstrual spotting was common, but in those inserting 2 tablets daily no spotting occurred. 5 of 6 subjects who complained of nausea during OC use reported no nausea during the period of vaginal administration. These patients requested vaginal administration as a regular contraceptive method.^ieng

The use of non-specific immunopotentiators in experimental Trypanosoma cruzi infection.

The effects of levamisole, isoprinosine and Corynebacterium parvum on Trypanosoma cruzi (Y strain) experimental infection of mice were studied. In prophylactic treatment these drugs reduced the peak of parasitaemia, and had no apparent effect on mortality rate or on histopathological and electrocardiographic findings. Levamisole and isoprinosine had no effect when used after infection. Electrocardiograms were obtained from all chronic chagasic mice. The most frequent changes were left atrial overload and first degree atrio-ventricular block. These findings became more frequent the longer the animals survived. The net effect of the non-specific immunopotentiators seems to depend on several factors: host immune state, severity of infection, dose and timing of drug administration. This probably explains the variable published results and the paradoxical findings of different laboratories.

Proliferation profile of endometrial polyps in post-menopausal women.

OBJECTIVE: To determine whether or not the presence of c-erbB2 over-expression in endometrial polyps affects the percentage of cells positive for Ki-67 proliferation marker. METHODS: Thirty-five patients with endometrial polyps were submitted to polypectomy by hysteroscopy. Ki-67 and c-erbB2 over-expression were investigated in the polyps by immunohistochemistry. RESULTS: The presence of c-erbB2 over-expression by immunohistochemistry was observed in 80% of endometrial polyps and was associated with higher proliferation rates as determined by the number of positive Ki-67 cell nuclei. In c-erbB2-negative polyps, the proliferation rates were low. CONCLUSION: Ki-67 and c-erbB2 over-expression are frequent in endometrial polyps in post-menopausal women.

One year contraception with a single subdermal implant containing nomegestrol acetate (Uniplant).

One single silastic capsule containing nomegestrol acetate, Uniplant, was inserted subcutaneously in 100 women of reproductive age who desired to avoid conception. Insertions and removals of the capsules were made in the gluteal region following intracutaneous local anesthesia with 2% procaine. Eighty women completed one year of use. Eleven women bore the implant for 6-11 months. A total of 1,085 women-months were recorded. One pregnancy occurred, resulting in a Pearl Index of 1.1. Bleeding episodes similar to menstruation occurred in all women but the degree of regularity varied from subject to subject. Amenorrhea developed in the range of 14-18% during the first six months of use but declined to less than 10% during the last six months. Menorrhagia likewise was higher in the first six months (18% in the first month) but fell to less than 10% during the last six months. Spotting was 5% or less. Of the twenty women who did not complete one year of use, nine discontinued because they found other methods were either more practical or less revealing. Three discontinued because of bleeding irregularities, three desired to become pregnant, one became pregnant. Other complaints included dizziness, headache, increased blood pressure, loss of libido, painful breasts and nausea. Over half of the women indicated their desire to continue using the single implant as a contraceptive.

Clinical experience with gossypol in non-Chinese men: a follow-up.

Gossypol monoacetic acid was administered to 12 Brazilian volunteers. The initial dose was 20 mg daily for 4 months. The dose was then reduced to 60 mg weekly (20 mg three times weekly). A significant reduction in sperm motility was detected in all subjects. An increase in the number of immature cells in the ejaculate was also detected in all subjects. Severe oligospermia or azoospermia developed in all subjects at the end of the loading phase. Two years following discontinuation, 3 men were still azoospermic. Only 1 man who was azoospermic 2 years after discontinuation had a late (3 years) recovery. Two of the 3 men who were subjected to high spermatic vein ligation because of varicocele remained azoospermic 2 years after the operation. The third patient, who did not have the operation, also remained azoospermic. Of the 9 patients who recovered, 3 had fathered children during the last 2 years.