Frank Alvarez

New insights on the mode of action of intrauterine contraceptive devices in women

To gain a better understanding of the mechanism of action of intrauterine devices (IUDs), a search was made for ova in the genital tracts of 115 women using no contraception and of 56 women using IUDs, all of whom volunteered for study in conjunction with surgical sterilization. Ova were recovered from tubal flushings between 48 and 120 hours after the midcycle peak of luteinizing hormone in 39% of the IUD users compared with 56% of women in the control group (0.05 less than P less than 0.10). This suggests an action of the IUD before the ovum reaches the uterus. Eggs with a microscopic appearance consistent with fertilization were recovered from the fallopian tubes of half of the women using no contraception who had intercourse within the fertile period of the reproductive cycle and from whom ova were recovered. In contrast (P less than 0.01), no eggs with this appearance were recovered in IUD users who had intercourse within the fertile period. No ova were recovered from the body of the uterus of any of the IUD users. Fertilized ova are less likely to reach the uterine cavity containing an IUD. Thus, the principal mode of IUDs is by a method other than destruction of live embryos.

Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials

Contraceptive methods, including implants, do not prevent common symptoms and adverse health events that most people experience. It is difficult, therefore, to decide whether or not the occurrence of symptoms or adverse events that are common can be attributed to use of a contraceptive method or to determine if a given method changes the likelihood of their occurrence. Based on the review of the literature, no apparent differences in the frequency of adverse events are evident between the six-implant or two-rod levonorgestrel systems and the single implant etonogestrel and nomegestrol acetate systems. The most frequent adverse events reported in clinical trials that are probably related to implant use are headaches and acne. Weight gain, dizziness, and mood changes are also frequently mentioned adverse events and are possibly steroid-related. Other possibly related adverse events, although much less frequently reported, are loss of libido, fatigue, hair loss, and other skin conditions. Persistent ovarian follicles that spontaneously disappear are a common event during use of progestin-only contraceptives, and providers should be aware of this condition to avoid unnecessary interventions. Overall, the vast experience reported in the clinical studies reviewed here show that all existing implantable contraceptives are equally safe. This can probably be attributed to the low-hormonal dose delivered by progestin-implant systems.

Effects of the Yuzpe regimen, given during the follicular phase, on ovarian function

This study was conducted to assess to what extent the Yuzpe regimen, or half the dose, given in the follicular phase, prevents ovulation during the ensuing 5 days. Sixty women were divided into six groups. All groups received placebo in one cycle and drug in another, in a randomized order. Groups differed by the dose and size of the leading follicle at the time of treatment (12-14, 15-17, or 18-20 mm). Ovulation was absent during the ensuing 5 days in 13 of 20 participants (65%) and in 8 of 20 participants (40%) who received the full and the half dose, respectively, when follicles were 12-17 mm. No ovulation occurred, within the critical period, in 7 of 39 placebo cycles (18%). When follicles were 18-20 mm, treatment did not prevent ovulation. In most drug-treated cycles, plasma gonadotropin and sex steroid levels were significantly depressed within the 5-day period, even when follicular rupture occurred within that period. In conclusion, the Yuzpe regimen can suppress or postpone ovulation to an extent that exceeds the fertile life of spermatozoa. Lack of ovulation within the critical period and dysfunction of the ovulatory process probably account for the contraceptive effect of this method in most cases. The present data do not warrant the use of half the dose of the Yuzpe regimen.

Prospective study of the pituitary-ovarian function after tubal sterilization by the Pomeroy or Uchida techniques

Surgical sterilization has become one of the most widely used methods of fertility regulation in the world. A common concern is the not yet clarified possible disturbance of the ovarian function resulting from the surgical procedure. A prospective study was carried out to contribute toward answering this question. Twenty subjects were enrolled in a longitudinal study of ovarian endocrine function before, and 2 and 6 months after, tubal ligation. The Pomeroy technique, which may compromise ovarian circulation, and the Uchida technique, which is free of this risk, were used randomly. Eight women who underwent to the Pomeroy technique and 9 who underwent the Uchida technique completed the protocol. Luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone were measured daily from days 10 through 18 of the cycle and every other day until the onset of the next menses. No change in any of the hormones studied was observed, with the exception of a significant increase in progesterone 2 months after tubal ligation by the Uchida technique.

Blood levels of levonorgestrel in women following vaginal placement of contraceptive pills

6 healthy women aged 25-38 years, attending a family planning clinic in the Dominican Republic, participated in an experiment to determine blood levels of levonorgestrel (1Ng) resulting from daily vaginal placement of contraceptive pills containing .5 mg dl-norgestrel and .05 mg ethinyl estradiol and to evaluate the effect on ovulation. Subjects were observed for 3 cycles. Blood samples were taken on days 14, 18, 23 and 27 following the 1st day of menses on a pretreatment cycle. In 1 cycle the pill was taken daily for 21 days by the oral route, and in another it was placed in the vagina on the same schedule. Blood samples were taken frequently during the 1st 24 hours and subsequently on days 5, 8, 12, 15, 18, and 21 of experimental cycles. Plasma levels of 1Ng reached a peak of 3-4 ng/ml 1-4 hours after oral administation of dl-norgestrel and fell slowly thereafter to a level slightly over 1 ng at 24 hours after ingestion. Plasma concentrations of 1Ng rose at a slower rate and reached a lower peak value after vaginal placement. After 4 hours the 2 curves were approximately parallel. The mean 1Ng plasma concentration 24 hours after vaginal insertion was less than 1/2 the value after oral administration. The differences in plasma levels were statistically significant for each of the times studied. Differences were most pronounced in the 1st 2 weeks. In each pretreatment cycle, progesterone levels reached a peak above 4 ng/ml, indicating ovulation. All but 1 treatment cycle by either route had progesterone values suggesting anovulation; the exception was a vaginal administration cycle. 4 of the 6 women maintained low estradiol levels, mostly between 20-40 pg/ml, during treatment cycles by either route. The lower plasma levels of 1Ng after vaginal insertion of pills may reflect inefficient absorption of steroids within the vagina, or a difference in metabolic degradation when the drug is administered parenterally via the vaginal blood supply. It was still possible to suppress ovulation in 5 of the 6 vaginal cycles without attempting to adjust the dose.

Lipoprotein patterns in women in Santo Domingo using a levonorgestrel/estradiol contraceptive ring.

Ten healthy, normally menstruating women attending a family planning clinic in Santo Domingo Participated in a study to determine the effects on plasma lipid levels of levonorgestrel and estradiol released from a contraceptive ring. A schedule of 21 days of use followed by 7 days of non-use was followed for 6 cycles. During the first two cycles of use, concentrations of cholesterol, HDL cholesterol, triglycerides and LDL cholesterol declined significantly from control levels, up to 25% for cholesterol, 28% for HDL cholesterol, 45% for friglycerides and 24% for LDL cholesterol. There were no subsequent changes with continued use. These declines are similar in direction but of lesser magnitude than those reported from clinics in other countries where pretreatment plasma levels of the same lipids are considerably higher. There was no significant change in the total cholesterol to HDL cholesterol ratio during treatment.

First year clinical experience with six levonorgestrel rods as subdermal contraception.

Previous clinical experience with six levonorgestrel subdermal capsules showed a very good contraceptive effectiveness and continuation rate, but with a high proportion of bleeding disturbances, particularly of increased bleeding. It was hypothesized that bleeding could be reduced by higher plasma levels of the steroid, using subdermal rods instead of capsules, as rods have been shown to have a release rate 3 or 4 times that of the capsules. Fifty volunteers were enrolled in a study of the clinical performance of 6 subdermal levonorgestrel rods. Results were compared with a previous experience with 100 volunteers who wore 6 levonorgestrel capsules for a year in the same clinic. Requirement for volunteers to enter the study were the same for capsules and rods. The proportion of women wearing 6 subdermal rods who had increased bleeding was about one half as for the women using 6 levonorgestrel capsules. On the other hand, women using rods had about twice the incidence of amenhorrea, and about four times more hypomenorrhea (4 days or less of bleeding in a 90-day period). There were no pregnancies among the rod users and the discontinuation rate for medical reasons was not higher than for capsule users in the same clinic.

Pros and cons of vaginal rings for contraceptive hormone delivery

The capacity of the vaginal epithelium to absorb hormonal steroids and the ability of silicone elastomers to release these hormones at an almost constant rate form the basis for the use of synthetic rubber vaginal rings for therapeutic purposes. The first prototypes were made for contraception purposes but were later used for hormone replacement therapy (HRT) and, more recently, for the release of antiviral drugs. We have limited this article to contraceptive vaginal rings (CVRs), as their use in HRT was recently extensively reviewed and there are no publications on microbicide-delivering vaginal rings, available to date. Numerous models of CVRs have been studied, but only two have reached the market: NuvaRing® that releases ethinylestradiol and etonogestrel; and Progering® that releases progesterone, for use in lactating women. The main advantages of CVRs are: their effectiveness (similar or slightly better than the pill); ease of use, negating the need to remember a daily routine; the user’s ability to control initiation and discontinuation; the nearly constant release rate allowing for lower doses; and, the good cycle control with the combined ring. It was expected that the CVRs would also allow avoidance of the first-pass effect on liver metabolism, but that hypothesis has not yet been confirmed. The main disadvantages are related to the mode of delivery: vaginal insertion may be unpleasant for some women; ring expulsion is not uncommon; the ring may be felt during coitus and be unpleasant for some partners; and, it may cause vaginal discharge and complaints. Although one ring model was associated with disruption of the vaginal mucosa, other studies with different models have not shown conclusive evidence that the ring causes vaginal lesions. CVRs are new methods of hormonal contraception that are likely to be used by many women, particularly in countries where there is greater cultural acceptance of women touching their own genitals.

Local side effects observed among long-term users of norplant contraceptive implants

The prevalence of local signs and symptoms related to the site of insertion of implants, and the association of these signs and symptoms with time of use, skin color and body mass index (BMI) was evaluated among users of the Norplant implant system. Three hundred and three Norplant users attending at the reproductive health clinic of PROFAMILIA in Santo Domingo, Dominican Republic, were asked if they had ever had any discomfort at the site/arm of implant insertion and the implant insertion area was examined and hyperpigmentation and hollowing of the surface was recorded. Half of the subjects reported either pain or paresthesia or both, in almost equal numbers, some time since insertion. Hyperpigmentation was observed in 35.6% and hollowing in 22.4% of the subjects. Report of pain and paresthesia was inversely associated to time of use and to BMI. Hyperpigmentation was directly associated to time of use and darker skin, and hollowing of the arm surface in the implants area with time of use and BMI. Local signs and symptoms were more frequent than previously reported, although they were of mild nature and appeared not to worry most of the users.