Compounds interfering with ovum implantation and development – The role of estrogens

Though this study was not statistically significant, it represented the first time that prevention of implantation was demonstrated – with DES usage – in humans

Abstracts

“It has been known for many years that estrogens interfere with early pregnancy in the rabbit and other specics.”…

…”In spite of evidence that success in the macaque should be paralleled by success in man, initial human experimentation was undertaken with some trepidation.

The first cases were rape cases. All of the subjects received 50 mg. of stilbestrol for 4 to 6 days after exposure. The chance of pregnancy following rape is uncertain for many obvious reasons. Sometimes no sperm could be found in the cervix or vagina. In a few instances, temperature charts were started; if no rise occurred, no drug was given. In most of the cases accepted for treatment, exposure occurred near midcycle and fern crystallization of cervical mucus as well as presence of sperm were demonstrated. In this small series of patients, none has become pregnant so far. The subsequent menstruation was generally unremarkable, although in some instances it was either scantier or more profuse or prolonged than usual. Side effects, when they occurred, were those usually associated with administration of estrogen; they consisted of nausea and breast soreness, which ceased shortly after medication was stopped.

A limited number of courageous volunteers furnished an opportunity for further and more adequate observation. Coitus took place at midcycle near the time of the temperature rise. Fern crystallization and Huhner tests with motile sperm were obtained
in most instances.

The apparent effect of 5 to 50 mg. of stilbestrol or 0.5 mg. of ethinyl estradiol on the biphasic temperature curve chart is to counteract the thermogenic effect of progesterone or to shorten the luteal phase.

From these charts it was anticipated that the secretory changes in the endometrium might be altered. However, instead of a proliferative or hyperplastic endometrium, endometrial biopsies taken on postovulation days 5 to 7 and 10 to 12 showed a progestational effect with secretion in some instances on both sides of the nucleus, occasionally almost suggestive of an Arias-Stella reaction. The stroma was dense in some areas, markedly edematous in others. Basal vacuolization often persisted up to menstruation, sometirnes giving an early secretory appearance late in the cycle.

In these preliminary trials there have been no pregnancies. While of interest, these clinical studies are incomplete and have as yet no statistical significance.” …

Sources

  • Compounds interfering with ovum implantation and development. 3. The role of estrogens, American journal of obstetrics and gynecology, NCBI PubMed PMID: 4959099, 1966 Nov.
  • Image credit thinglink.
DES DIETHYLSTILBESTROL RESOURCES

Expanding access to emergency contraception in developing countries

Emergency contraception has been called the best-kept contraceptive secret

1995 Abstract

Previous research shows that several regimens of postcoital contraception offer safe and effective ways for women to avoid pregnancy. Yet the methods are typically unavailable to women in developing countries. In this article, the authors review the main methods of emergency contraception and describe experience with them to date. The prevalence and urgency of the need for making these methods available to women in developing countries are assessed. The necessary elements for creating such access are described. In several developing countries, conditions for introducing the methods may be more favorable than in industrialized countries. These advantages are reviewed. Finally, the authors describe the challenges anticipated for broadening the availability of postcoital methods in the developing world. They conclude with a brief series of recommendations for policymakers.

PIP

In the order of the amount of research available on each, five regimens of emergency contraception are reviewed:

  1. the estrogen/progestin combination of ethinyl estradiol and levonorgestrel, known as the Yuzpe regimen;
  2. the copper IUD;
  3. levonorgestrel-only regimens;
  4. danazol, a synthetic steroid;
  5. and mifepristone, also known as RU-486, a progesterone antagonist that appears to work well as a postcoital contraceptive.

The Yuzpe regimen was discovered more than 20 years ago, and it consists of 200 mcg of ethinyl estradiol and 1.0 mg of levonorgestrel taken 12 hours apart and initiated within 72 hours of unprotected intercourse.

In the late 1970s, Lippes discovered that copper-bearing IUDs could prevent pregnancy when inserted within 5 days after intercourse. This method may even be effective for up to 7 or 10 days postcoitally. Studies have confirmed that the IUD method had a failure rate of less than 0.1%.

The levonorgestrel regimen requires the taking of 1.5 mg levonorgestrel divided into two doses 12 hours apart and initiated within 48 hours of unprotected intercourse. Tablets containing 0.75 mg of levonorgestrel are marketed for infrequent intercourse to be taken immediately after intercourse. Postinor, marketed by Gedeon Richter of Hungary, is registered in eastern European countries and some developing countries.

The synthetic steroid danazol produces fewer side effects than the Yuzpe regimen. 600 mg of danazol has to be taken within 72 hours after unprotected intercourse and another 600 mg taken 12 hours later.

The RU-486 regimen consists of a single 600 mg dose postcoitally within 72 hours of unprotected intercourse.

A variety of other regimens, including ethinyl estradiol, conjugated estrogens, diethylstilbestrol, and quingestanol acetate have also been studied for use as postcoital contraceptives.

The prevalence of need in developing countries depends on conditions for use and potential users. The urgency of need (unintended pregnancies, social conditions, age, and cost), expanding access, challenges to expansion, and some recommendations are also discussed.

Sources

  • Expanding access to emergency contraception in developing countries, Studies in family planning, NCBI PubMed PMID: 8571440, 1995 Sep-Oct;.
  • Image credit becominghuman.
DES DIETHYLSTILBESTROL RESOURCES

The future of hormonal contraception

International journal of fertility, 1991

Abstract

Well over 100,000,000 women have used the combined oral contraceptive (OC) pill. As a result of the population explosion in the 1970s and 1980s, there will be almost one third more women in fertile age in the year 2000 than in 1991. In the developing world outside China, the total number of contraceptive users could double in roughly 10 years. China, the total number of contraceptive users could double in roughly 10 years. The pill has a low failure rate, but one study in Egypt found that 90% of women made errors in moving from one packet to the next. Similarly, a 60% error rate was found among users in Colombia.

The vaginal ring delivers combined progestogen and estrogen through a silastic wall. The device can be left in place for 21 days out of 28, and such delivery would virtually eliminate the low risk of hepatocellular carcinoma among OC users. A vaginal progestogen ring is being tested. Over 700,000 women have used Norplant, the subdermal implant method with an effectiveness rate of 99%.

Depo-provera and norethindrone enanthate injections last 2 to 3 months. The Progestasert IUD, containing 38 mg progesterone released at a rate of 65 mcg per day, is effective.

Progesterone-releasing IUDs lasting from 3 to 5 years could complement subdermal implants.

Ethinyl estradiol (205 mg) and diethylstilbestrol (25-50 mg) have both been used as postcoital agents taken within 36 hours for 5 consecutive days after unprotected intercourse. In more than 3000 cases there were 17 pregnancies (.05%). These regimens are replaced by giving combined oral contraceptive tables (e.g., .25 mg d-norgestrel and 50 mg ethinyl estradiol), taken 2 at a time and repeated 12 hours later, within 72 hours of unprotected intercourse. Epidemiological studies have confirmed that the use of the combined oral contraceptive for 3 to 5 years halves a woman’s risk of ovarian or endometrial cancer, and the protection persists for 10 to 18 years after cessation of use.

Sources

  • The future of hormonal contraception, International journal of fertility, NCBI PubMed PMID: 1687405, 1991.
  • Image credit Alec Favale.
DES DIETHYLSTILBESTROL RESOURCES

Post-ovulatory contraception

High-dose Diethylstilbestrol DES usage as a post-ovulatory pill

1990 Abstract

It has been known since the 1920s that high-dose oestrogens will prevent implantation and interrupt pregnancy in lower mammals. Following successful use in monkeys, Morris began conducting clinical trials in Yale in the 1960s. The first 100 cases were reported in 1967 (Morris and van Wagenen, 1967)] In these trials 25-50 mg stilboestrol (diethylstilbestrol USP) or 0.5-2.0 mg ethinyloestradiol were administered for five days to a group of carefully observed women with mid-cycle exposure to intercourse and both the presence of sperm in the vagina and a rise in basal body temperature confirmed; no pregnancies occurred.

To be effective, oestrogens must be administered within 72 hours of coitus since they work mainly by interfering with implantation. The exact mechanism remains to be established, but Haspels (1976) reported retarded hyperplasia in endometrial biopsies taken from women given high-dose oestrogens post-coitally, while Board (1970) reported a fall in endometrial carbonic anhydrase concentrations after post-coital oestrogens. There is also some evidence that ovum transport may be affected by high-dose oestrogens in some animal species (Smythe and Underwood, 1975), although there is no evidence for such an effect in humans. These findings have been used to explain the increased incidence of ectopic pregnancy apparent in some studies. Stilboestrol 25-50 mg, ethinyloestradiol 2-5 mg (normally 5 rag) and conjugated oestrogens 30 mg have all been used. All are administered for five days and must be given within 72 hours of intercourse.

The overall mean failure rate of all types of high-dose oestrogen is 0.7% (Fasoli et al, 1989). In 1973, Morris and van Wagenen reported 29 pregnancies in over 9000 mid-cycle exposures, only three of which were attributed to a true method failure. Van Santen and Haspels (1985) reported two pregnancies in 226 women in whom they calculated an expected rate of 11.9 pregnancies.

One case of acute pulmonary oedema during stilboestrol administration (Morris and van Wagenen, 1973) has been reported. Because of the possible association between the thromboembolic disorders and high-dose oestrogens, women with a history of thromboembolism are advised to avoid this form of PCC; however, no directly related incidents have been reported.

It is known that stilboestrol use during pregnancy is associated with an increased risk of vaginal adenosis and clear-cell carcinoma of the vagina and cervix in female offspring. There is no evidence that post-coital use of stilboestrol is associated with such an increased risk. Nevertheless, most clinicians now avoid using stilboestrol under any circumstances.

The common side-effects are those commonly associated with oestrogens. Most studies report nausea in around 50% of patients, mainly on day 1 of administration, and vomiting in up to 25%. These symptoms limit compliance and, if vomiting occurs, reduce efficacy. Up to 23% of women complain of breast tenderness and 11% of both menorrhagia and alteration in the timing of the next menstrual period. Vaginal spotting may occur during or shortly after treatment.

Morris and van Wagenen (1973) reported an increased incidence of ectopic pregnancy following high-dose oestrogens administered postcoitally. Three out of the 29 pregnancies that occurred were ectopic, a highly significant increase in the expected rate. For this reason a previous history of ectopic pregnancy is generally regarded as a contraindication to oestrogen-containing PCCs.

Sources

DES DIETHYLSTILBESTROL RESOURCES

1989 DES Case: Brownfield v. Daniel Freeman Memorial Hospital

Must a Catholic hospital inform a rape victim of the availability of the “morning-after pill” ?

Abstract

The California Court of Appeals discussed in Brownfield v. Daniel Freeman Memorial Hospital, 256 Cal. Rptr. (1989), whether a health-care giver must inform a patient of medical options that the care-giver morally opposes.

In this case, workers in a Catholic hospital refused to inform a rape victim about the “morning-after pill” (diethylstilbestrol) despite the victim’s mother requesting the information, the possibility of a pregnancy, and the need for treatment within 72 hours, because such information conflicted with the institutions’ religious beliefs.

The plaintiff did not become pregnant, and the court dismissed the case because there was no compensable injury; the plaintiff did not appeal the dismissal. The court agreed with the plaintiff that the “morning-after pill” is postcoital contraception (like the IUD), not an abortifacient, since the fertilized ovum has not yet become implanted in the uterine mucosa (nidation).

In reviewing the California Therapeutic Abortion Act the court said that while religious facilities need not perform abortions, the statute does not apply to medical emergencies or spontaneous abortions. The court stated that a patient has the right to self-determination in his or her treatment, superseding the moral and religious convictions of the hospital, and that medical malpractice would exist in cases where “damages have proximately resulted from the failure to provide [a patient] with information concerning…treatment option[s],” when “a skilled practitioner of good standing would have provided her with information…under similar circumstances,” and “that if such information had been provided to her, she would have elected such treatment.”

The court found no duty to provide non emergency treatment, only a duty to inform the patient about treatment options.

Sources

  • Must a Catholic hospital inform a rape victim of the availability of the “morning-after pill”?, American journal of hospital pharmacy, NCBI PubMed PMID: 2309736, 1990 Feb.
  • Image credit Online Archive of California.
DES DIETHYLSTILBESTROL RESOURCES

Pharmacist’s refusal to dispense diethylstilbestrol for contraceptive use

American journal of hospital pharmacy, Ethics, 1989

Abstracts

…”One Sunday afternoon. Attendant Jones from the facility arrives at Lakeside Hospital with an order for a dose of diethylstilbestrol (DES) that clearly is intended for postcoital contraception. Pharmacist Smith, the only pharmacist on duty, informs Attendant Jones that he will not fill the prescription…

… When Dr. Doe, the prescribing physician, learns of Pharmacist Smith’s response, she telephones Pharmacist Smith and explains that the drug must be administered that afternoon; the patient for whom the prescription is intended had sexual intercourse approximately two days ago, and the drug most likely will not be effective if it is administered on Monday. Pharmacist Smith remains adamant in his refusal to fill the prescription.

Is it within Pharmacist Smith’s rights to refuse to fill this prescription ?“…

Read the full paper (free access) on watermark.silverchair, 1989 Jul.

DES DIETHYLSTILBESTROL RESOURCES

DES “treatment” of a gender-dysphoric transvestite

DES usage as a “gender management”

1985 Study Abstract

A synthetic ovarian hormone, diethylstilbestrol, was used to reduce the desire to cross-dress in a 65-year-old, gender-dysphoric transvestite.

Antiandrogens may be of use in treating patients refractory or inaccessible to other clinical approaches.

Sources

  • Antiandrogenic treatment of a gender-dysphoric transvestite, Journal of sex & marital therapy, NCBI PubMed PMID: 3159907, 1985 Summer.
  • Image credit Serhii Borodin.
DES DIETHYLSTILBESTROL RESOURCES

DES usage as a post-ovulatory pill

The Stilbestrol Story, Albrecht W. Schmitt, M.D., 1974

Abstract

Finally, a few comments should be made concerning DES-related problems. First, the morning-after pill, which should better be called the post-ovulatory pill, needs to be mentioned. As we know, there are a great number of practitioners and clinics who use DES for the prevention of pregnancies in girls who come to the office or clinic after sexual exposure, specifically rape or incest. DES should not do any harm to these patients as the drug is given at a time when the duct systems of the genital organs are not yet being formed. With this fact in mind, there should be no objection to the use of DES in such emergencies. However, considering the potential teratogenic effect of DES, it should be advised against the routine use of DES as a morning-after pill, as expressed in a pamphlet recently distributed by Eli Lilly and Company, the only manufacturer of DES, according to the current PDR.

Another point of importance is the feeding of cattle and sheep with DES. The FDA banned stilbestrol for this purpose in 1972 because small amounts of DES had been found in the livers of DES-fed livestock. This ban is, of course, difficult to enforce but all possible ways should be used to prevent meat from DES-fed or implanted animals from reaching the food markets.

The final point concerns the question of whether a patient with a history of DES-exposure in utero should be permitted to take the birth control pill. The author goes along with Herbst that there is no evidence that the pill has ever changed adenosis into clear cell carcinoma. However, on the basis of our knowledge, that clear cell carcinoma develops mostly after puberty when the ovaries produce an increased amount of endogenous estrogen, patients with DES history should be advised against the pill; and an alternate means of contraception should be used.

Sources

  • Read the full paper (free access) : The Stilbestrol Story, Dept. of Obstetrics & Gynecology. The Medical College of Pennsylvania., doi/pdf/10.1177/019262337400200201, June 1974.
  • Image credit avert.
DES DIETHYLSTILBESTROL RESOURCES

Estrogen Treatment for Victims of Rape, 1985

Correspondence, Eugene F Diamond M.D., Stritch School of Medicine, Loyola University, 1985

Sources

  • Estrogen treatment for victims of rape, The New England journal of medicine, NCBI PubMed, PMID: 3974688, 1985 Apr 11.
  • Image credit headtopics.
DES DIETHYLSTILBESTROL RESOURCES

Use of DES for postcoital contraception, 1979

Physician Advisory: Health Effects of the Pregnancy Use of Diethylstilbestrol

Abstract

Although the doses and duration of DES use for postcoital contraception are less than the doses and duration which were commonly used when DES was prescribed for pregnancy complications, health risks may be similar.

It also is possible that women may take the drug as a postcoital contraceptive when already pregnant from previous intercourse. In such cases the potential offspring of such pregnancy would be exposed to the risks previously described.

Additionally, there is controversy over the efficacy of the drug for postcoital contraception and over the validity of studies showing it to be effective for that purpose. In light of these considerations, the following recommendations are made:

Postcoital contraception with estrogens in any woman should be restricted to situations where no alternative is judged acceptable by a fully informed patient and her physician.

Thorough birth control counseling should accompany or follow any prescription of estrogens for postcoital purposes. A principal objective of such counseling should be to discourage women to whom the drug is administered from considering it as a routine method of contraception upon which to rely in the future.

Sources

DES DIETHYLSTILBESTROL RESOURCES