Francisco Alvarez-Sanchez

A four-year clinical study of NORPLANT implants.

A total of 324 women aged 18-35 began use of NORPLANT subdermal implants in Finland Chile and the Dominican Republic in 1978-79. Through 4 years of 1st segment use the average annual continuation rate was 84/100 women and the 4 year cumulative rate was 49/100. There were no pregnancies in the 1st 2.5 years of use and a total of 2 by the end of 4 years. Single decrement (gross) pregnancy rate cumulated to 1.2/100 users at the end of month 48 and the Pearl index through 4 years was .2/100 woman years. Placement and removal of implants subject women to the risk of infection at the implant site. The use of implants as a practical method of family planning rests in part on the question of whether these relatively simple clinical procedures can be performed with a low infection rate under field conditions. Marked bleeding patterns were a concern. Some women experienced very long bleeding runs. With adequate training and supervision delivery and removal of implants can be done quickly and safely as indicated by the low infection rates (0.3/100 women). The training of personnel in the required skills is apparently no more difficult than was the training for the IUD 2 decades ago. Infection should it occur would tend to have less serious consequences for the woman than does pelvic infection. Perforation of the uterus in delivery of a copper IUD requires abdominal surgery to remove the device. No equally serious sequelae have been associated with improper placement or removal of implants.

Hormonal treatment for bleeding irregularities in Norplant implant users

OBJECTIVE Our purpose was to evaluate whether prolonged or irregular bleeding during Norplant implant use could be alleviated with the use of oral hormonal medication. STUDY DESIGN One hundred fifty users of the Norplant levonorgestrel contraceptive implant with prolonged or frequent bleeding were enrolled in this prospective, randomized, comparative study and assigned to one of three treatment groups for 20 days: ethinyl estradiol 50 microg, an oral contraceptive (50 microg ethinyl estradiol and 250 microg levonogestrel), and placebo. Total days of bleeding during treatment and length of the bleeding-free interval were analyzed. RESULTS Women treated with the levonorgestrel-ethinyl estradiol pill bled an average of 2.6 days during treatment compared with 5.4 and 12.3 days in the ethinyl estradiol and placebo groups, respectively. Differences between both hormonal groups and placebo were significant (p <0.00001); moreover, the combined pill was more effective than ethinyl estradiol along (p <0.0001). CONCLUSION The combined pill proved to be an excellent palliative treatment and is a more practical approach because of availability at all clinic sites.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. I-Use effectiveness. An international comparative trial.

Contraceptive vaginal rings (CVRs), with approximate daily release rates of 250-290 mcg of levonorgestrel and 150-180 mcg of estradiol and manufactured in a shell design, were studied for effectiveness and acceptability in multicentered trials involving 1103 ring users in Brazil, Chile, Dominican Republic, Sweden, U.S., Denmark/Finland, and Nigeria. A comparison group of 533 women used the oral contraceptive Nordette. Both 1st and all segment 1 year gross pregnancy rates among CVR users were less than 3/100, rates similar to Nordette users. Continuation at 1 year was 50/100 users of the ring (all segments) and 38/100 among Nordette users, more of whom were lost to follow-up. Gross 1 year rates of termination for medical reasons ranged from 25-29/100. Ring users were more likely to terminate for vaginal problems and pill users for headache, nausea, and associated reasons. These trials indicate that CVRs of this design are as effective and have continuation rates equal to and possibly superior to Nordette under the same study conditions.

Attainment and maintenance of azoospermia with combined monthly injections of depot medroxyprogesterone acetate and testosterone enanthate

Abstract Depot medroxyprogesterone acetate (DMPA) and testosterone enanthate (TE) were administered as a monthly treatment to 20 normal male volunteers. Two regimens were employed: 1) 1000 mg DMPA and 250 mg TE initially and repeated after 1 month, followed by 150 mg DMPA and 250 mg TE at each sucessive month; 2) 1000 mg DMPA and 250 mg TE initially, followed by 300 mg DMPA and 250 mg TE at each successive month. Sperm production was severely inhibited in the 19 subjects who were followed beyond 2 months: azoospermia in 14 subjects; less than 1 million sperm/ml in 2 subjects; 1–2 million sperm/ml in 2 subjects; and 3 million sperm/ml in 1 subject. The lowest sperm count attained (azoospermia or severe oligozoospermia) was usually maintained for at least several months; then, despite continued treatment, most subjects eventually showed at least slight increases in sperm concentration. However, since only 1 sperm count rose above 20 million/ml, and since sperm motility remained poor, the subjects may actually have been infertile. Gonadotropins and testosterone decreased initially, then tended to recover somewhat in later months of treatment. The only side effects observed were moderate weight gain and some slight increases in serum transaminases. There were no changes in other blood values, in blood pressure, in the size, consistency or sensitivity of testicles, prostate or breasts, or in libido/sexual behavior. The few differences in the effects of the 2 different regimens were not striking.

Absence of chorionic gonadotropin in sera of women who use intrauterine devices

A controlled study was undertaken to determine whether unnoticed pregnancies routinely occur in users of the intrauterine contraceptive device (IUD). Starting on day 10 of the menstrual cycle and continuing through the onset of menstruation or until the diagnosis of pregnancy, we collected daily blood samples from three groups of normally menstruating young women. The study groups were (A) IUD users (n = 30), (B) women with tubal ligation (n = 30), and (C) women trying to become pregnant (n = 15). The sequential serum samples were analyzed by radioimmunoassay for progesterone (P), human luteinizing hormone (hLH), and human chorionic gonadotropin (hCG). No positive hCG assays in luteal phase blood sera of IUD users were observed. The only positive hCG determinations of IUD users coincided with the preovulatory surge of hLH. Two subjects who became pregnant, as judged by progressive increases in hCG and P levels in the luteal phase, belonged to the group planning pregnancy. The finding of two pregnancies in 15 months of exposure is consistent with the assumption of natural fertility. The probability of no pregnancies in 30 months at risk, as observed among the IUD users, is between 1 in 200 and 1 in 100,000, depending on the assumption made for natural fertility. The study demonstrates that IUD users do not retain their natural fertility, and that IUDs do not exert their antifertility effect as abortifacient agents. If a confirmed pregnancy is detected in an IUD user, it may be assumed to represent an isolated case of contraceptive failure.

Evaluation of four different contraceptive vaginal rings: Steroid serum levels, luteal activity. bleeding control and lipid profiles

Four different models of contraceptive vaginal rings were tested during three cycles for luteal activity, bleeding control, plasma lipoproteins and serum levels of the contraceptive steroids. Two progestins, levonorgestrel acetate (LNGA) and ST 1435, alone or in combination with ethynyl-estradiol (EE) were tested. The rings released 100 ug/day of the progestins and 30 ug/day of EE. Luteal activity was detected among users of the progestin-only rings: 4 of 8 cycles with ST 1435 and 2 of 10 with LNGA. Only one of the 18 cycles studied with the two combined rings showed luteal activity, but the measurement of contraceptive steroid in plasma suggested that this subject delayed reinsertion of the ring for about one week in that particular cycle. Breakthrough bleeding was observed in 12 of 30 cycles of use of the progestin-only rings, and in only 2 of 27 cycles with the combined models. No significant changes in total cholesterol or its HDL-fraction were observed. However, the only reduction observed in HDL-cholesterol was among users of the LNGA-only ring. It is concluded that the two combined CVR models offer good possibilities of high effectiveness and bleeding control and merit further development.

A multicenter study of levonorgestrel—Estradiol contraceptive vaginal rings II — Subjective and objective measures of effects: An international comparative trial

Comparative clinical trials of 2 sizes of contraceptive vaginal rings and of an oral contraceptive were undertaken at 8 investigational sites (9 clinics). More than 500 women enrolled on each of the 3 study regimens. Side effects of the rings and of Nordette, the oral contraceptive, were evaluated by noting spontaneous complaints, by recording medications taken and by physical examination. Inquiries about changes in the frequency of specific conditions were made at the end of the subjects participation in the first year of the study. The incidence of spontaneous complaints was similar among users of the 2 different-sized rings and of the pill.

Progestin-only contraceptive rings

Several progestin-only long acting contraceptives are currently available in the form of implants or injectables. Vaginal rings are another contraceptive option in the final stages of development. These steroid-containing polymer rings are placed in the vagina, providing relatively constant drug release, thus allowing for lower effective doses. Vaginal rings have the advantage of being user-controlled and non-provider dependent, and their use is non-coital related. The first clinical study with medroxyprogesterone acetate vaginal rings was published in 1970. Since then numerous clinical trials testing different steroids and doses have followed. A large Phase III multicenter clinical trial with a levonorgestrel ring, releasing 20 microg/day, was coordinated and sponsored by WHO. The cumulative one-year pregnancy rate was 4. 5%. The principal reasons for discontinuation were menstrual disturbances (17.2%), followed by frequent expulsion of the ring (7. 1%), and vaginal symptoms (6.0%). The finding of erythematous lesions in the vagina in some women has led to the development of a more flexible device. Collaboration with industry should facilitate the manufacture of a redesigned levonorgestrel ring with a higher release rate. The Population Council is also developing a vaginal ring containing Nestorone for 6 months of continuous use. Ovulation inhibition was achieved in over 97% of the segments studied, with rings releasing either 50, 75, or 100 microg/day. No pregnancies occurred in women using the low-dose ring, while one pregnancy each occurred in the intermediate- and high-dose ring groups for a 6-month cumulative pregnancy rate of 0.0, 1.9, and 2.1%. Bleeding irregularities were common. Nestorone is orally inactive; therefore this ring is also excellent for use in lactating women.

The Menstrual Cycle in Women Using an Intrauterine Device

The duration and hormonal characteristics of the menstrual cycles of women using Copper T intrauterine devices (IUDs) were studied. Daily load samples were obtained during both the pre- and postovulatory phases of 30 IUD-associated cycles and the hormone values were compared with those of 15 normally menstruating women not using contraception. The ovulation rate and peak levels of 17 beta-estradiol and luteinizing hormone (LH) were not significantly different between the two groups. The average number of days from the 1st day of menstrual bleeding to the LH peak (the proliferative phase) was longer in the IUD users. The number of days from the LH peak to the onset of menstrual bleeding (the luteal phase) was shorter in the IUD users. Because of the compensating nature of these statistically significant differences, the total cycle length appeared to be unchanged. At the time of menstruation, the plasma levels of both progesterone and 17 beta-estradiol were significantly higher among IUD users. It is concluded that the presence of an IUD does not influence ovarian function, but that ovarian steroid production and endometrial events become asynchronous.

Estradiol delivery by vaginal rings: potential for hormone replacement therapy'

OBJECTIVES To determine if delivery of estradiol from elastomeric vaginal rings gives estradiol blood levels in the range associated with effective estrogen replacement therapy and to determine the relation between in vitro estradiol release from the rings and blood levels in vivo. Secondary objectives related to changes in lipoprotein cholesterol, changes in climacteric symptoms, and evaluation of acceptability to users. METHODS Three ring variants releasing approximately 100, 150 and 200 micrograms/day of estradiol in vitro were used through 22 days in 21 postmenopausal women, 7 on each dose levels. Blood samples for measurement of estradiol were taken at 3-4 day intervals. Lipoprotein cholesterol was measured before and at the end of treatment. Women were questioned about climacteric symptoms and about their satisfaction with the ring. RESULTS Mean serum estradiol levels for the three groups of rings were 63 +/- 6, 94 +/- 5 and 136 +/- 13 pg/ml for the 100, 150 and 200 micrograms/day rings, respectively. FSH levels declined during ring use and the maturation values of cells collected on vaginal swabs markedly increased. Total and LDL cholesterol were significantly reduced and HDL cholesterol was not significantly changed. All women reported relief of postmenopausal symptoms. Vaginal discomfort during the first 3 days of use was reported by 12 women but overall satisfaction with the method was high. CONCLUSIONS Women using the vaginal rings attained estradiol blood levels compatible with control of climacteric symptoms and bone loss. The relation between in vitro estradiol release and blood levels in vivo was essentially identical for all 3 doses. The use of vaginal rings to deliver estradiol for hormone replacement therapy is judged to merit further evaluation.