| 1. Title: Early oral contraceptive history: norethynodrel is not a prohormone [letter] Author: Edgren RA Source: STEROIDS. 1994 Jan;59(1):58. Abstract: A reproductive endocrinologist questions Professor Carl Djerassi's long-held claim that norethynodrel is changed in the body to norethindrone. This conversion circumvents Djerassi's patent. Yet, biological facts do not support Djerassi's claim. The biological properties of both progestagens are different. Norethindrone has weak unusual progestational effects and some androgenic activity. In rats, it converts to an estrogen within several days after being ingested orally. Norethynodrel has even weaker and more unusual progestational effects and some estrogenic activity. Neither norethindrone nor norethynodrel carry out much progestational activity when administered locally in the McGinty assay. Neither support pregnancy in spayed female rats. In the Clauberg test, both operate like mixtures of estrogen and progesterone. A series of experiments examining the possibility of gastrointestinal conversion of norethynodrel to norethindrone conducted by the reproductive endocrinologist did not support the claim that norethynodrel converts to norethindrone in the body. In fact, he is not aware of any evidence that norethindrone is a key metabolite of norethynodrel. Yet, over 40 years of study of oral contraceptives (OCs), the scientific community knows little about the metabolism of these progestagens or others that are now components of OCs. A recent review suggests that norethindrone and ethynodiol diacetate are prohormones that hinge on conversion to norethindrone for their effects. The literature does not support such a conversion of norethynodrel, however. The reproductive endocrinologist also questions why contraception is not part of the norethindrone patent, since the goal of early synthetic programs was OCs. The norethynodrel patent also does not make a contraception claim. In 1952, one of Searle's chief scientists called for colleagues to find an orally active progestogen for therapeutic purposes. Later, contraception became another goal. How ironic that the weak progestational properties of the first two progestational components of OCs were the basis for their patents. Language: English Keywords: CRITIQUE | NORETHYNODREL | NORETHINDRONE | METABOLIC EFFECTS | ORAL CONTRACEPTIVES | LABORATORY ANIMALS | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Physiology | Biology | Contraceptive Methods | Clinical Research | Research Methodology Document Number: 095682 |
| 2. Title: The estrogenic activity of synthetic progestins used in oral contraceptives. Author: Jordan VC; Jeng MH; Catherino WH; Parker CJ Source: CANCER. 1993 Feb 15;71(4 Suppl):1501-5. Abstract: Various studies show that use of synthetic progestins is associated with a rise in breast cancer incidence. The Department of Human Oncology at the University of Wisconsin in Madison has conducted laboratory research to determine a mechanism of action for the proliferative potential of the synthetic progestins and to formulate a hypothesis that might be tested in target populations. Its researchers used several assay systems in vitro to compare the actions of 19-nortestosterone derivatives used in oral contraceptives (OCs) (norgestrel [levonorgestrel], norethynodrel, gestodene, and norethindrone) with those of medroxyprogesterone acetate (MPA). They also tested 2 antiestrogens (4-hydroxytamoxifen and ICI 164,384) and the antiprogestin mifepristone (RU-486). They transfected MCF-7 breast cancer cells in vitro with a chloramphenicol acetyl transferase (CAT) reporter gene which has an estrogen response element only triggered by an estrogen receptor (ER). All of the 19-nortestosterone derivatives prompted the growth of ER-positive cells, but not ER-negative cells. The antiestrogens curbed progestin stimulated cell proliferation. Neither RU-486 nor MPA activated cell proliferation. All the synthetic progestins boosting cell replication also stimulated CAT. Antiestrogens prevented CAT activation. RU-486 did not stimulate CAT. MPA caused no effect on CAT activation. These findings suggested that some synthetic progestin use estrogenic actions via the ER. They also showed that synthetic progestins can either stimulate or differentiate cells. They may produce some beneficial estrogen-like effects (e.g. on circulating lipids and bone preservation). The researchers called for studies of the total estrogen content of different OCs which may help identify combinations of synthetic hormones more likely to harm women. A large epidemiologic survey of breast cancer risk related to estrogenicity may explain the inconsistent connection between OCs and breast cancer incidence. Language: English Keywords: UNITED STATES OF AMERICA | WISCONSIN | RESEARCH REPORT | IN VITRO | BREAST CANCER | NORETHYNODREL | NORGESTREL | GESTODENE | MEDROXYPROGESTERONE ACETATE | RU-486 | HORMONE ANTAGONISTS | HORMONE RECEPTORS | ORAL CONTRACEPTIVES, COMBINED | Developed Countries | North America | Americas | Clinical Research | Research Methodology | Cancer | Neoplasms | Diseases | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Hormones | Endocrine System | Physiology | Biology | Membrane Proteins | Oral Contraceptives | Contraceptive Methods Document Number: 092051 |
| 3. Title: Steroids and "the Pill": early steroid research at Searle. Author: Colton FB Source: STEROIDS. 1992 Dec;57(12):624-30. Abstract: The announcement from the Mayo Clinic in 1949 of the dramatic effectiveness of cortisone in the treatment of rheumatoid arthritis stimulated tremendous interest in steroid chemistry, endocrinology, and related areas of medicine. Shortly thereafter, G.D. Searle and Co. initiated a major effort in steroid research, the objective of which was to discover better steroid drugs than those available. This effort was remarkably successful and resulted in the introduction of several important pioneering drugs. These included norethandrolone, marketed in 1956 as Nilevar, the first anabolic agent with a favorable separation between protein building and virilization, and sprionolactone, introduced in 1959 as Aldactone, the first steroid antialdosterone antihypertensive agent. Of special importance was the research that culminated in the discover of Enovid. This substance, a combination of the progestin norethynodrel and the estrogen mestranol was first approved in 1957 for the treatment of a variety of disorders associated with the menstrual cycle. This era of oral contraception began in May 1960, when Enovid was approved by the FDA for ovulation inhibition, and was immediately thereafter introduced for such use. (author's) Language: English Keywords: CONTRACEPTIVE HISTORY | ORAL CONTRACEPTIVES | NORETHYNODREL | NORETHINDRONE | CONTRACEPTION RESEARCH | Contraceptive Usage | Contraception | Family Planning | Contraceptive Methods | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents Document Number: 081235 |
| 4. Title: Steroid research at Syntex: "the pill" and cortisone. Author: Djerassi C Source: STEROIDS. 1992 Dec;57(12):631-41. Abstract: The pharmaceutical industry contributed more to the published record of steroid research during the 1950s than any industry has ever contributed before to any chemical subdiscipline. Syntex, a research-oriented company in Mexico city, contributed much of the publication of industrial research of steroids. Dr. Djerassi arrived at Syntex in 1949 as associate director of chemical research. He conducted partial aromatization studies leading him to the 1st synthesis of an oral contraceptive (OC) on October 15, 1951. This steroid was 19-nor-17 alpha-ethynyltestosterone, later called norethistrone or norethindrone. Syntex submitted the product to a commercial laboratory in Madison, Wisconsin, for biological evaluation. It was indeed the most active, orally effective progestational hormone at the time. Syntex applied for a patent in November 1951. In November 1954, clinical results of norethindrone used to treat various menstrual disorders and fertility problems was presented. G.D. Searle & Co. filed for a patent for the synthesis of the double bond isomer 13 of norethindrone called norethynodrel in August 1953. Acid or human gastric juice converts norethynodrel into norethindrone. Had it not been for Searle using norethindrone in its antimotion sickness drug, Dramamine, Syntex would have filed suit against Searle. Syntex sponsored contraceptive trials with norethindrone. Various incidents prevented Syntex from obtaining US Food and Drug Administration approval to use norethindrone for contraceptive indications before Searle obtained approval to use norethynodrel. By 1964, 3 companies including Syntex were marketing 2 mg doses of Syntex's norethindrone, the most widely used active ingredient in OCs. Dr. Djerassi also played a key role in the synthesis of cortisone from diosgenin, a chemical derived from Mexican yams. This synthesis was a more economical industrial route to cortisone than previous routes. Language: English Keywords: MEXICO | UNITED STATES OF AMERICA | WISCONSIN | HISTORICAL REVIEW | CONTRACEPTION RESEARCH | NORETHINDRONE | NORETHYNODREL | ADRENAL CORTEX HORMONES | ORAL CONTRACEPTIVES | INDUSTRY | LITIGATION | INGREDIENTS AND CHEMICALS | North America | Latin America | Americas | Developing Countries | Developed Countries | North America | Contraception | Family Planning | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Hormones | Endocrine System | Physiology | Biology | Contraceptive Methods | Macroeconomic Factors | Economic Factors Document Number: 081201 |
| 5. Title: [Development of Hungarian oral contraceptives] A magyar fogamzasgatlo tablettak korszerusodese. Author: Seregely G Source: ACTA PHARMACEUTICA HUNGARICA. 1992 Nov;62(6):278-83. Abstract: The Hungarian pharmaceutical company Gedeon Richter has been in the front-line of manufacturing hormonal preparations in Europe in its 91 years of history, because between the 2 world wars it distributed several organotherapeutic drugs. 10 years after Enovid, the first American oral contraceptive (OC), was introduced, the Hungarian Infecundin was introduced containing 2.5 mg of norethynodrel and .1 mg of mestranol. When studies indicated that high estrogen levels resulted in liver damage and produced thromboembolic sequelae, no more than .075 mg of estrogen was mandated by the World Health Organization. In 1970 the Hungarian product Bisecurin, containing 1 mg of ethynodiol diacetate and .05 mg of ethinyl estradiol (EE), was developed. Another OC, Continuin, was developed for women susceptible to thrombosis and for lactating mothers in 1974; it had only gestagen: .5 mg of ethynodiol diacetate. The next OC, Ovidon, contained .25 mg of levonorgestrel (LNG) and .05 mg of EE. Low-dose pills followed: Rigevidon with .15 mg of LNG and .03 mg of EE, which became very popular among young nulliparous women. Postinor, a post-coital OC with .75 mg of LNG, was developed for women who had occasional sex. Phasic OCs prevent endometrial and uterine atrophy: the 2-phase Anteovin (11+10 days) and the 3-phase Tri-Regol (6+5+10 days). Rigevidon and Anteovin are the most popular. In 1991 a total of 2,043,846 Anteovin packets (or cycles) were used in addition to 1,558,785 Rigevidon packets and 521,220 Tri-Regol packets. Results of a multicenter clinical trial with 1891 women taking Tri-Regol during 9596 menstrual cycles indicated only 1 pregnancy, and 34 (1.8%) women discontinued because of side effects. Spotting occurred only in 5%, and subjective side effects included headache, mammary tension, and nausea. Language: Hungarian Keywords: HUNGARY | HISTORICAL REVIEW | ORAL CONTRACEPTIVES, COMBINED | ORAL CONTRACEPTIVES, LOW-DOSE | ORAL CONTRACEPTIVES, PHASIC | NORETHYNODREL | MESTRANOL | THROMBOEMBOLISM | ETHYNODIOL DIACETATE | ETHINYL ESTRADIOL | LEVONORGESTREL | CONTRACEPTIVE EFFECTIVENESS | Developing Countries | Europe, Central | Europe | Oral Contraceptives | Contraceptive Methods | Contraception | Family Planning | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraceptive Agents, Estrogen | Embolism | Vascular Diseases | Diseases Document Number: 090424 |
| 6. Title: Introduction -- thirty years of the pill. Author: Roland M Source: INTERNATIONAL JOURNAL OF FERTILITY. 1991;36 Suppl 3:8-9. Abstract: The editor of the International Journal of Fertility, gave a historical survey of research and development of oral contraceptives (OCs) at the Pan American Conference on Fertility and Sterility. G.D. Searle and Co. hosted the first symposium on 19-nor progestational steroids in January 1957. 2 other steroids concurrently developed were norethynodrel also called Enovid (G.D. Searle) and norethindrone (Parke-Davis and Syntex). As part of the pilot studies, the editor, who was a medical researcher, examined sequential endometrial biopsies (5-day intervals) in the same cycle from women with normal ovulatory cycles and from those with anovulatory cycles. 1 22-year-old woman had a bilateral oophorectomy at age 19. The various steroids caused morphologic changes in the endometrium. Some researchers found that Enovid caused estrogenic effects on the endometrium and later learned that synthesis of norethynodrel resulted in traces of mestranol. It would have been too costly to remove it. Researchers decided to keep the mestranol component in Enovid since it prevents breakthrough bleeding and prepares the endometrium for the progestogen. They even added 0.1 mg more mestranol to the formulation of Enovid. Eventually, researchers studied other combinations of progestogens and estrogens, e.g., norgestrel and ethinyl estradiol. This early research laid the ground work for development of the long-acting contraceptive implant, Norplant, which contains levonorgestrel. Increased use of such longer acting hormonal contraceptives should result in a considerable fall in use of induced abortion as a birth control method. Language: English Keywords: CONFERENCES AND CONGRESSES | HISTORICAL REVIEW | ORAL CONTRACEPTIVES | RESEARCH AND DEVELOPMENT | PROGESTERONE | NORETHYNODREL | NORETHINDRONE | NORGESTREL | MESTRANOL | ETHINYL ESTRADIOL | ORAL CONTRACEPTIVES, COMBINED | ENDOMETRIAL EFFECTS | HISTOLOGY | CONTRACEPTIVE IMPLANTS | LEVONORGESTREL | Contraceptive Methods | Contraception | Family Planning | Technology | Economic Factors | Progestational Hormones | Hormones | Endocrine System | Physiology | Biology | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraceptive Agents, Estrogen | Endometrium | Uterus | Genitalia, Female | Genitalia | Urogenital System Document Number: 080120 |
| 7. Title: A comparative study of Norinyl 1/35 versus Lo-Ovral in Ile-Ife Nigeria. Author: Ayangade O; Akinyemi A Source: INTERNATIONAL JOURNAL OF GYNAECOLOGY AND OBSTETRICS. 1989 Oct;30(2):165-70. Abstract: A comparative study of 2 combined oral contraceptives was conducted on 100 women in Ile-Ife, Nigeria. Women were randomly allocated to receive either Lo-Ovral or Norinyl 1/35. Lo-Ovral and Norinyl 1/35 have similar low dose estrogen content, but different progestogen formulations and dosages. The women in the Lo-Ovral group were significantly younger than the Norinyl 1/35 group, with mean ages of 28.3 and 30.6 years respectively. There was no significant statistical difference between the education levels of the 2 groups. The mean parity of the groups was not statistically different, either. Only 3 women had serious complaints at the onset. 15 women, (31.9%) in Norinyl 1/35 and 9 (18.8%) in the Lo-Ovral group reported at least 1 menstrual complaint. However, the difference between the groups was not significant. 28 women (59.6%) in the Norinyl group, and 23 women (47%) in the Lo-Ovral group reported at least 1 complaint. All the women who had initial serious complaints chose to continue the method, and did not report the problems again at follow-up visits. Most of the other complaints decreased in most users with use. 10 women (21.2%) in the Norinyl group and 12 women (25.0%) in the Lo-Ovral group discontinued the method during the study. The difference was not statistically significant. Travel/movement was the primary reason for not continuing in both groups. The loss to follow-up rate was 33.3% and 27.1% for Norinyl and Lo-Ovral, respectively. No pregnancies were reported during the study. The dosages of estrogen used appear very effective and the progesterone component well tolerated. Gastrointestinal symptoms were minimal. Side effects did not contribute to the high rate of discontinuation. Language: English Keywords: COMPARATIVE STUDIES | CONTRACEPTIVE AGENTS, FEMALE | NORETHYNODREL | MESTRANOL | NIGERIA | ORAL CONTRACEPTIVES, LOW-DOSE | ORAL CONTRACEPTIVES, COMBINED | CONTRACEPTIVE AGENTS, PROGESTIN | ETHINYL ESTRADIOL | CONTRACEPTION CONTINUATION | AGE FACTORS | CLINICAL RESEARCH | FAMILY PLANNING ACCEPTOR CHARACTERISTICS | RESEARCH REPORT | SIDE EFFECTS | ORAL CONTRACEPTIVES, SIDE EFFECTS | CONTRACEPTIVE AGENTS, SIDE EFFECTS | Studies | Research Methodology | Contraceptive Agents | Contraception | Family Planning | Contraceptive Agents, Estrogen | Africa, Western | Africa, Sub Saharan | Africa | Developing Countries | Oral Contraceptives | Contraceptive Methods | Contraceptive Usage | Population Characteristics | Demographic Factors | Population | Family Planning Acceptors | Family Planning Programs | Treatment | Contraceptive Safety | Safety | Public Health | Health Document Number: 059058 |
| 8. Title: Preparation of deuterium and tritium labelled norethynodrel, norethindrone, and 6-methyleneandrostenedione. Author: Holland HL; Brown FM; Tan L Source: JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS. 1989 Jun;27(6):629-33. Abstract: Tritium labelling is crucial to the investigation of the metabolic effects of norethynodrel and norethindrone--2 widely used progestogen components of oral contraceptives. However, preparation of labelled samples of these progestins is generally a complex chemical process involving numerous steps. The authors report a 1-step method for the preparation of deuterium or tritium-labelled norethynodrel, norethindrone, and 6-methyleneandrostenedione that uses a modified phase transfer catalyzed exchange procedure. The exchange agent (deuterium oxide and lithium or sodium hydroxide) is crucial to this process. Norethynodrel is efficiently exchanged by either sodium or lithium hydroxide, while norethindrone is poorly exchanged by either sodium or lithium hydroxide, while norethindrone is poorly exchanged under these conditions. Tritium-labelled specimens of all 3 hormones can be obtained through use of tritium-labelled water. In addition to providing a simple means for the preparation of tritium-labelled keto steroids whose chemical reactivity rules out the use of normal enolic exchange procedures, this method can be used to label other compounds that contain carbonyl. Language: English Keywords: LABORATORY PROCEDURES | METABOLIC EFFECTS | MEASUREMENT | NORETHYNODREL | NORETHINDRONE | Laboratory Examinations and Diagnoses | Examinations and Diagnoses | Physiology | Biology | Research Methodology | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning Document Number: 062124 |
| 9. Title: Oral contraceptives: significance of their effects in man and relationship to findings in animal models. Author: Pasquale SA Source: TOXICOLOGIC PATHOLOGY. 1989;17(2):396-400. Abstract: A historical review of the 28-year history of oral contraceptives from the viewpoint of correlation or lack thereof between drug toxic and pathologic effects seen in laboratory animals and those seen clinically is presented. Early high dose pills were expected to cause growth of uterine fibroids, but instead they had the unexpected effect of an estrogen dose-related venous thrombosis risk. Work on rats predicted that pills would cause liver cancers, but instead to slightly increase the incidence of being liver adenomas in women. Similarly, rat research predicted pituitary microadenomas. Pituitary effects in women, while rare, are thought to be due to prescription of pills to women with irregular cycles of pituitary origin. Progestins of the 17-acetoxy series were considered likely to produce breast cancers, as they had in beagle dogs. They apparently have not done so in women. They were reports in the mid-1970s that sequential pills containing 100 mcg ethinyl estradiol cause endometrial carcinoma. These pills have been discontinued. Recent evidence has been accumulating that low-dose pills containing levonorgestrel increase blood pressure and possible LDL-cholesterol. Risk of death from vascular disease, however, seems to be concentrated in women who smoke, especially those over 35. Language: English Keywords: UNITED STATES OF AMERICA | LITERATURE REVIEW | HISTORICAL REVIEW | ORAL CONTRACEPTIVES | ORAL CONTRACEPTIVES, COMBINED | ORAL CONTRACEPTIVES, PHASIC | CHLORMADINONE ACETATE | MESTRANOL | LEVONORGESTREL | CONTRACEPTIVE AGENTS, FEMALE | NORETHYNODREL | NORETHINDRONE | CARDIOVASCULAR EFFECTS | HYPERTENSION | THROMBOEMBOLISM | LIVER NEOPLASMS | LIPID METABOLIC EFFECTS | BREAST CANCER | FIBROIDS | PITUITARY GLAND | LABORATORY ANIMALS | COMPARATIVE STUDIES | Developed Countries | North America | Americas | Contraceptive Methods | Contraception | Family Planning | Contraceptive Agents, Progestin | Contraceptive Agents | Contraceptive Agents, Estrogen | Physiology | Biology | Vascular Diseases | Diseases | Embolism | Neoplasms | Lipids | Cancer | Neoplasms, Benign | Endocrine System | Clinical Research | Research Methodology | Studies Document Number: 060515 |
| 10. Title: Manufacturers phase out high-dose oral contraceptives. Source: FDA DRUG BULLETIN. 1988 Aug;18(2):19. Abstract: The 3 manufacturers of high-dose oral contraceptives (OCs) have notified prescribers that they are discontinuing the production and distribution of these products. These "Dear Doctor" letters follow recommendations of FDA's Fertility and Maternal Health Drug Advisory Committee that OCs containing more than 50 mcg of estrogen no longer be marketed because these formulations are no more effective than the lower-dose formulations. In a presentation before the advisory committee, a spokesman for the American College of Obstetricians and Gynecologists opposed continued use of the high-dose formulations. The formulations being phased out contain 75-100 mcg of estrogen. The manufacturers and products are: Ortho Pharmaceutical--Ortho-Novum 1/80 and Ortho-Novum 2 mg; Syntex--Norinyl 2 and Norinyl 2+80; G.D. Searle--Enovid E-21 and Ovulen. The manufacturers notified physicians at the end of March that these products would be discontinued in 6 months, and advised clinicians to transfer patients using the high-dose products to lower-dose formulations containing 30-50 mcg of estrogen. FDA has estimated that 3% of patients taking OCs--or about 400,000 women--were taking the high-dose products before the manufacturers announced their withdrawal. FDA has recommended, since January 1970, that physicians prescribe the lowest possible effective dose OC (see April 1970 Drug Bulletin). (full text) Language: English Keywords: ORAL CONTRACEPTIVES | CONTRACEPTIVE AGENTS, FEMALE | CONTRACEPTION | PRODUCTION | ECONOMIC DEVELOPMENT | NORETHINDRONE | MESTRANOL | HORMONES | REPRODUCTIVE CONTROL AGENTS | NORETHYNODREL | CHANGES | Contraceptive Methods | Family Planning | Contraceptive Agents | Macroeconomic Factors | Economic Factors | Contraceptive Agents, Progestin | Contraceptive Agents, Estrogen | Endocrine System | Physiology | Biology | Social Change Document Number: 056412 |
| 11. Title: Oral contraceptives and breast cancer: what has 20 years of research shown? Author: Buehring GC Source: BIOMEDICINE AND PHARMACOTHERAPY. 1988;42(8):525-30. Abstract: Animal model, histologic, and epidemiologic studies over a 20 year period do not support an increased risk of breast cancer with oral contraceptive (OC) use. Even though the US Food and Drug Administration required using the dog, the monkey, and the rodent as animal models for OC testing at the end of the 1970s, research showed that theses models do not adequately match humans. For example, primates rarely get breast cancer yet the incidence for humans ranges from 7%-10%. The beagle experiences 1-2 estrus cycles/year while humans have 12 menstrual cycles/year. Although rodents have a breast cancer incidence similar to humans, study results varied widely depending on strains, doses, and/or administration routes. As of 1988, no case control or cohort studies had demonstrated a statistically significant overall increase in breast cancer incidence in OC users vs. never users. Yet at least 18 studies in which the investigator corrected for major confounding variables showed an insignificant increased risk of breast cancer among certain subsets of women associated with OC use. Various studies supported the theory that OCs may augment multiplication of already altered cells. For example, OCs induced an increased incidence of mammary cancer only in animal models and strains which had an incidence of mammary cancer at least as high as humans. Further, mammographic studies of breast dysplasia revealed that OC users have >18 times the risk of developing breast cancer than do nonusers. Additionally, in breast tissue culture studies, combination OCs containing norethynodrel-mestranol and norgestrel-ethinyl estradiol triggered cancerous cells to multiply faster than normal cells. Research must continue so as to know how to alter OCs to reduce any tumor promotion capabilities without foregoing contraceptive efficiency. Language: English Keywords: UNITED STATES OF AMERICA | LITERATURE REVIEW | CONTRACEPTIVE AGENTS, PROGESTIN | ETHINYL ESTRADIOL | NORETHYNODREL | NORGESTREL | PROGESTERONE | BREAST CANCER | HISTOLOGY | LABORATORY ANIMALS | IN VITRO | EPIDEMIOLOGIC METHODS | ORAL CONTRACEPTIVES | MESTRANOL | Developed Countries | North America | Americas | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Contraceptive Agents, Estrogen | Progestational Hormones | Hormones | Endocrine System | Physiology | Biology | Cancer | Neoplasms | Diseases | Clinical Research | Research Methodology | Contraceptive Methods Document Number: 058709 |
| 12. Title: Pharmaceutical effect of contraceptive pills on the skin. Author: Foldes EG Source: INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY, THERAPY, AND TOXICOLOGY. 1988 Jul;26(7):356-9. Abstract: Hormonal contraceptives, most of which contain norethindrone and norethynodrel combined with estrogen, maintain the body in a state of "artificial pregnancy" and can cause hormonal, vascular, metabolic, and neurolgic side effects similar to the effects seen in pregnancy. Many of these involve the skin. Herpes gestationis is a herpetiform dermatitis with vesicular and bullous eruptions which is triggered by high levels of progesterone and prolactin. Melasma, a dark brown hyperpigmentation, is frequently seen in women taking oral contraceptives. Progesterone activity changes the biochemistry and pH of the skin and sebacious glands, thereby contributing to eruptions of acne vulgaris. Contraceptive pills have been found to increase the incidence of genital candidiasis. Withdrawal from contraceptive pills is often associated with alopecia. Estrogenic substances increase the sensitivity of the skin to light and induce telangiectasia. Oral contraceptives, as well as many other drugs, have been associated with erythema nodosum. Creams, foams, jellies, diaphragms, pessaries and Nonoxynol-9 cause a phenomenon similar to contact dermatitis but with deeper ulcerations due to the acidity of the iritant chemicals. Language: English Keywords: ORAL CONTRACEPTIVES, SIDE EFFECTS | SPERMICIDAL CONTRACEPTIVE AGENTS | NONOXYNOL | PROGESTERONE | NORETHYNODREL | ESTROGENS | DERMATOLOGICAL EFFECTS | ACNE | ERYTHEMA NODOSUM | ALOPECIA | MELASMA | PHOTODERMATITIS | DERMATITIS | TELANGIECTASIA | SIDE EFFECTS | CONTRACEPTIVE METHODS | CONTRACEPTIVE AGENTS, SIDE EFFECTS | Contraceptive Safety | Safety | Public Health | Health | Contraceptive Agents | Contraception | Family Planning | Alcohols | Organic Chemicals | Ingredients and Chemicals | Progestational Hormones | Hormones | Endocrine System | Physiology | Biology | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Diseases | Hair Diseases | Cerebrovascular Effects | Treatment Document Number: 057633 |
| 13. Title: The influence of oral contraceptives on hormonal and metabolic homeostasis in young adolescents. Author: Smith KW; Howard CP; Allphin BJ; Grunt JA Source: JOURNAL OF ADOLESCENT HEALTH CARE. 1988 Nov;9(6):488-90. Abstract: In order to evaluate the effects of oral contraceptives on metabolic and endocrine function in teenagers, Norinyl 1/50 was begun in 46 12-17-year-old girls after a 16-hour-fasting flood sample was obtained for glucose, insulin, glucagon, growth hormone, lutenizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, gluconeogenic substrates, total lipids, and cholesterol. Sampling was repeated at 6 and 12 months of therapy. Of the 46 patients enrolled in the study, 23 returned for follow-up after 6 months, and 13 completed the study. Blood sampling after 6 and 12 months of therapy demonstrated no significant changes (p 0.05). Our results suggest that there were no changes in the metabolic or endocrine functions studied at 6 and 12 months on a medium-dose contraceptive agent. Study participants had requested an oral contraceptive and informed consent was obtained from all participants and their parents or guardians. The 36 black and 10 white patients ranged in age from 12.17 to 17.08 years with a mean of 15.0 years. Sexual development was Tanner stage 4 or 5. Mean gynecologic age was 2.83 years. (author's modified) Language: English Keywords: UNITED STATES OF AMERICA | MISSOURI | NORTH AMERICA | ADOLESCENTS, FEMALE | CONTRACEPTION | ORAL CONTRACEPTIVES | CONTRACEPTIVE AGENTS, FEMALE | METABOLIC EFFECTS | ENDOCRINE EFFECTS | FOLLOW-UP STUDIES | NORETHYNODREL | MESTRANOL | HORMONES | Developed Countries | Americas | Adolescents | Youth | Age Factors | Population Characteristics | Demographic Factors | Population | Family Planning | Contraceptive Methods | Contraceptive Agents | Physiology | Biology | Endocrine System | Studies | Research Methodology | Contraceptive Agents, Progestin | Contraceptive Agents, Estrogen Document Number: 056019 |
| 14. Title: Oral contraception in Japan: past, present, future. Author: Tamaya T Source: In: Human reproduction: current status / future prospect. Proceedings of the VIth World Congress on Human Reproduction, held in Tokyo, Japan, 25-30 October 1987, edited by R. Iizuka, K. Semm, T. Ohno, L. Mettler, T. Tominaga, S. Suzuki. Amsterdam, Netherlands, Excerpta Medica, 1988. :265-6. Abstract: A brief history of market share of oral contraceptives in Japan by dose, compared to those used in the U.S. covers 1960-1985. In 1960 an oral contraceptive containing 10 mg norethynodrel and 150 mcg mestranol was licensed in Japan, but 33% of women had to abandon it because of side effects. Doses were decreased. The Japan Society of Obstetrics and Gynecology recommended strict medical supervision of oral contraceptive use. In 1964 The Japanese Welfare Ministry permitted use of a pill containing norethindrone acetate 4 mg and ethinyl estradiol 50 mcg for regulation of the menstrual cycle. This pill had the largest market share until 1970. Subsequently pills with 0.5-2.5 mg progestin and over 50 mcg estrogen were popular. Currently the most popular formulation has 0.5 mg norgestrel and 0.5 mcg ethinyl estradiol, with 60% of the market. Only 16.2% of Japanese pills contain <50 mcg estrogen. In Japan pill users only account for 3% of contraceptors; the highest proportion of pill users occurred in 1974, with 240,000 users. Higher side effect frequencies in Japan may have been due to the small size of Japanese women. Language: English Keywords: UNITED STATES OF AMERICA | JAPAN | CONTRACEPTIVE METHODS CHOSEN | PRODUCT APPROVAL | LICENSING | SALES | NORGESTREL | ETHINYL ESTRADIOL | GASTROINTESTINAL EFFECTS | CONTRACEPTIVE AVAILABILITY | MARKETING | ORAL CONTRACEPTIVES, LOW-DOSE | ORAL CONTRACEPTIVES, COMBINED | NORETHYNODREL | CONTRACEPTIVE AGENTS, ESTROGEN | LONGITUDINAL STUDIES | CONTRACEPTIVE AGENTS, PROGESTIN | ADMINISTRATION AND DOSAGE | Developed Countries | North America | Americas | Asia, Eastern | Asia | Contraceptive Usage | Contraception | Family Planning | Legislation | Economic Factors | Contraceptive Agents, Female | Contraceptive Agents | Physiology | Biology | Oral Contraceptives | Contraceptive Methods | Studies | Research Methodology | Drugs | Treatment Document Number: 059234 |
| 15. Peer Reviewed Title: A comparative study of norinyl 1/35 versus norinyl 1/50 in Belgrade, Yugoslavia. Author: Behilovic B; Rowan AJ Source: CONTRACEPTION. 1987 Nov;36(5):515-26. Abstract: A comparative study of Norinyl 1/35 and Norinyl 1/50 was conducted at the Dom Zdravlja Stari Grad in Belgrade, Yugoslavia. The study sought to evaluate the differences in continuation rates as well as the frequency of selected side effects which might contribute to method discontinuation. The trial included 299 women who were randomly allocated to 1 of the 2 oral contraceptives. In the Norinyl 1/35 group, significantly more women (p.05) reported a complaint of vaginal discharge as well as an increase in the occurrence of vaginal discharge compared to the Norinyl 1/50 group. There was no significant difference in continuation rates or for particular discontinuation reasons for the Norinyl 1/35 and Norinyl 1/50 groups. No accidental pregnancies were reported during this study. Both oral contraceptives appear to be safe and effective; there appears to be no difference in the acceptability of 1 oral contraceptive over the other among this group of Yugoslavian women. (author's) Language: English Keywords: YUGOSLAVIA | EUROPE, SOUTHERN | EUROPE | ORAL CONTRACEPTIVES | EVALUATION | CONTRACEPTIVE AGENTS, FEMALE | CONTRACEPTION FAILURE | CONTRACEPTION CONTINUATION | CONTRACEPTION | COMPARATIVE STUDIES | VAGINITIS | VAGINAL ABNORMALITIES | GENITAL EFFECTS, FEMALE | UROGENITAL EFFECTS | DISEASES | NORETHYNODREL | MESTRANOL | HORMONES | RESEARCH REPORT | Europe, Southeastern | Developing Countries | Developed Countries | Contraceptive Methods | Family Planning | Contraceptive Agents | Contraceptive Usage | Studies | Research Methodology | Genitalia, Female | Genitalia | Urogenital System | Physiology | Biology | Contraceptive Agents, Progestin | Contraceptive Agents, Estrogen | Endocrine System Document Number: 046506 |
| 16. Title: Estrogen dose-response relationship [letter] Author: Edgren RA Source: CLINICAL PHARMACOLOGY AND THERAPEUTICS. 1987 May;41(5):587. Abstract: This letter criticizes a report on the increased relative risk of developing gall bladder disease with increasing dose exposure to the estrogens in oral contraceptives. The chief objection is the assumption that the risk is said to apply to mere dose of estrogen, without acknowledging that 2 different estrogens of different potency on various target organs were ingested since 1980. From 1980 to 1980, pills with over 50 mg estrogen contained mestranol, while later pills of lower dose contained ethinyl estradiol (EE). Furthermore, the effect of estrogens is modified by the type and dose of the progestin used in the combination. Five different progestins were used during the period: norethindrone (with mestranol or EE), northynodrel (with mestranol), ethynodiol diacetate (with either estrogen), and norethindrone acetate and norgestrel (with EE). Norethindrone and norgestrel as such, while the others are metabolized to various degrees to norethindrone. Thus, the dose-response relationship between estrogen and gall bladder disease cannot be supported by the data presented. Language: English Keywords: CALIFORNIA | UNITED STATES OF AMERICA | NORTH AMERICA | FAMILY PLANNING | CONTRACEPTION | CONTRACEPTIVE AGENTS, FEMALE | CONTRACEPTIVE AGENTS, ESTROGEN | ORAL CONTRACEPTIVES, SIDE EFFECTS | ORAL CONTRACEPTIVES, COMBINED | REPRODUCTIVE CONTROL AGENTS | HORMONES | ETHINYL ESTRADIOL | MESTRANOL | ETHYNODIOL DIACETATE | NORETHINDRONE | NORETHYNODREL | BILIARY TRACT DISEASES | GALLBLADDER DISEASES | RESEARCH METHODOLOGY | DISEASES | SIDE EFFECTS | Developed Countries | Americas | Contraceptive Agents | Contraceptive Safety | Safety | Public Health | Health | Oral Contraceptives | Contraceptive Methods | Endocrine System | Physiology | Biology | Contraceptive Agents, Progestin | Treatment Document Number: 044584 |
| 17. Title: Oral contraception in perspective. Thirty years of clinical experience with the pill. Author: Gunn AD; Greenblatt RB; Guillebaud J; Potts DM; Riphagen F Source: Carnforth, England, Parthenon Publishing Group, 1987. 152 p. Abstract: This book of contributions on the history, significance, action and future of the oral contraceptive pill, was published on the 30th anniversary of the 1st scientific report of the clinical trial of an oral contraceptive in 1956. The historical chapters, on the events leading to synthesis of progestogens, hormone actions and theory, early contraception and later serendipitous events which resulted in the major oral contraceptive pharmaceuticals, are full of human interest events and photographs not found in ordinary literature reviews. The pill's current image is described based on surveys of women's perceptions of available contraceptives in several European countries. The chapter on risks vs. benefits of the pill puts the pill into the perspective of everything from evolving primate sexual bonding to teen pregnancy, Comstock laws, gynecological cancer, smoking, maternal mortality, sexually transmitted diseases, universal misinformation about the dangers of the pill, and Catholic theology to the risk of dying from being hit by a falling airplane. The final chapters deal with the effects of the latest triphasics on the pertinent physiological systems and potential future contraceptives. Language: English Keywords: LITERATURE REVIEW | PHILOSOPHICAL OVERVIEW | ETHICS | CATHOLICISM | ATTITUDES | PERCEPTION | SEX BEHAVIOR | MODERNIZATION | MESTRANOL | NORETHINDRONE | NORETHYNODREL | RISK FACTORS | CONTRACEPTIVE METHOD ACCEPTABILITY | MISINFORMATION | ORAL CONTRACEPTIVES, PHASIC | ORAL CONTRACEPTIVES | Christianity | Religion | Psychological Factors | Behavior | Social Change | Contraceptive Agents, Estrogen | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Contraceptive Agents, Progestin | Biology | Contraceptive Usage | Communication | Oral Contraceptives, Combined | Contraceptive Methods Document Number: 062415 |
| 18. Title: [Progestagens as contraceptives] Progestagene zur Empfangnisverhutung. Author: Kuhl H Source: WIENER MEDIZINISCHE WOCHENSCHRIFT. 1987;137(18-19):433-40. Abstract: The different spectrum of biological actions of the various synthetic progestogens is compared on the basis of chemical structure, pharmacokinetics, and interaction with the multiple receptors. The mechanism of action of the progesterone derivatives (medroxyprogesterone acetate, chlormadinone acetate, and cyproterone acetate), the norethisterone-related (norethisterone, ethynodiol diacetate, lynestrenol, and norethynodrel), and the norgestrel-related progestogens (levonorgestrel, desogestrel, gestodene, and norgestimate), and a possible influence of some metabolites on the biological profile are discussed. With regard to progestogenic activity, the time course of the serum concentrations of the steroids after the application (pharmacokinetics) which is dependent on absorption, metabolization in the gastrointestinal tract and liver (1st-pass effect), distribution and storage in fat and other tissues, binding to serum proteins, inactivation, and conjugation is of particular importance. The various side effects of the progestogens are based mainly on their influence on hepatic metabolism (lipids, lipoproteins, serum proteins) and upon other organs which influence their estrogenic, antiestrogenic, androgenic, antiandrogenic, glucocorticoid, and antimineralocorticoid actions. (author's modified) (summaries in ENG, GER) Language: German Keywords: HORMONES | REPRODUCTIVE CONTROL AGENTS | STEROID METABOLIC EFFECTS | METABOLIC EFFECTS | LIPID METABOLIC EFFECTS | SIDE EFFECTS | ANALYSIS | MEDROXYPROGESTERONE ACETATE | CHLORMADINONE ACETATE | CYPROTERONE ACETATE | NORETHINDRONE | LYNESTRENOL | ETHYNODIOL DIACETATE | NORETHYNODREL | LEVONORGESTREL | Endocrine System | Physiology | Biology | Family Planning | Lipids | Treatment | Research Methodology | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Hormone Antagonists Document Number: 051407 |
| 19. Title: Oral contraceptives and breast cancer. In vitro effect of contraceptive steroids on human mammary cell growth. Author: Longman SM; Buehring GC Source: CANCER. 1987 Jan 15;59(2):281-7. Abstract: The growth responses were measured of human mammary epithelial cells, from 59 normal, nonmalignant atypical and malignant breast specimens, in tissue culture with oral contraceptive steroids. The steroid levels, 0.1 mcg/ml for estrogens and 1.0 mcg/ml for progestins, were taken from dose response curves so that the lowest steroid doses found to stimulate maximum growth in control cell lines were chosen. These concentrations were 3 times the serum estrogen level and 4 times the progesterone level of late pregnancy. Growth was assessed by daily area measurements of cells attached to culture vessels, known to be proportional to cell numbers, and expressed either as proportion of stimulated cultures or as doubling times. Stimulated growth was highly individual, especially in response to progestins. Growth was generally stimulated by ethinyl estradiol alone and in combination, and by 17B-estradiol, but not by mestranol. Most (75%) of the malignant cultures responded to at least 1 progestin, but nonmalignant cells usually did not. The progestins progesterone, norethindrone, norgestrel and norethinodrel stimulated most of the malignant cultures. Ethynodiol diacetate was less active, and mestranol inhibited growth of 1 specimen. Proliferative response to estrogens was rather well correlated with presence of estrogen receptor, but that to progestins was unrelated to progesterone receptor. Malignant cells grew faster than nonmalignant cells from the same subject in the presence of 2 combinations: ethinyl estradiol/norgestrel and mestranol/norethindrone. This study demonstrated the ability of progestins alone to stimulate neoplastic cell growth, in some cases more rapidly than normal tissue. This opens the possibility that oral contraceptive steroids could act as cancer promoters, selectively stimulating the growth of a few previously transformed cancer cells. The relationship of the highly individualized and heterogeneous responses seen here to actual cells growing in vivo is unknown. Language: English Keywords: FAMILY PLANNING | CONTRACEPTION | CONTRACEPTIVE AGENTS, FEMALE | ORAL CONTRACEPTIVES | ORAL CONTRACEPTIVES, COMBINED | CONTRACEPTIVE AGENTS, ESTROGEN | CONTRACEPTIVE AGENTS, PROGESTIN | HORMONES | ETHINYL ESTRADIOL | MESTRANOL | NORETHINDRONE | NORGESTREL | NORETHYNODREL | ETHYNODIOL DIACETATE | CORPUS LUTEUM HORMONES | PROGESTERONE | ESTROGENS | ESTRADIOL | NEOPLASMS | CANCER | BREAST CANCER | HORMONE RECEPTORS | PHYSIOLOGY | GROWTH | RESEARCH METHODOLOGY | RESEARCH AND DEVELOPMENT | IN VITRO | CALIFORNIA | Contraceptive Agents | Contraceptive Methods | Endocrine System | Biology | Progestational Hormones | Diseases | Membrane Proteins | Child Development | Technology | Economic Factors | Clinical Research | Developed Countries | United States of America | North America | Americas Document Number: 045164 |
| 20. Title: [Principles and evolution of progestin use in contraception] Principes et evolution des methodes de traitement progestatif en contraception. Author: Sitruk-Ware R Source: REVUE DU PRATICIEN. 1987 Sep 21;37(38):2315-21. Abstract: 19-norsteroid compounds with strong progestational properties were 1st synthesized in 1950. Norethynodrel, the 1st orally active progestin, was used as a contraceptive because it produced a hormonal milieu comparable to that observed in women in the luteal phase or during pregnancy. A synthetic estrogen was added to reduce uterine bleeding, thus creating the 1st oral contraceptive. The pharmaceutical industry responded to the potentially vast new market for OCs by synthesizing a variety of progestins of diverse origin and with varying properties. Progestins currently in use not only have luteomimetic properties but also, according to their clinical structure, may have antigonadotropic, antiestrogenic, antimineralocorticoid, or antiandrogenic properties. The 1st trials of progestin-only contraceptives began in 1963 with injectable depot medroxyprogesterone acetate. Another injectable progestin, norethindrone enanthate, was subsequently also used. 3 great advantages account for the popularity of these injectables in some countries: simplicity of administration, long duration of action, and absence of the vascular effects of synthetic estrogens. Nevertheless, modifications of lipid and carbohydrate metabolism were observed and frequent amenorrhea or menstrual irregularities disturbed some users. 80 countries permit these methods, and in 1981 the World Health Organization concluded that they were acceptable. Low dose progestin-only pills were introduced in France in 1978. The persistence of partial follicular maturation with these low dose pills means that basal secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) continues, resulting in a hyperestrogenic climate. Menstrual irregularities are frequent, the pills must be taken at exactly the same time each day, and they are inactivated by some common medications such as barbiturates which act as enzyme inductors. Pregnancy may ensue if these conditions are not respected. The Pearl index is between 1-3/100. Low dose progestins are therefore an appropriate choice only for women at vascular risk for whom IUDs are contraindicated. Low dose progestins should be avoided in women who already show signs of luteal insufficiency. 19-norsteroid derivatives with strong antigonadotropic action can totally block FSH and LH and therefore follicular maturation and ovulation at doses of about 10 mg/day. Use of these high-dose progestins remains controversial. The main concern since 1980 has been over their lowering of the level of high density lipoprotein cholesterol, and they are prescribed only for women who are not obese, diabetic, hypertensive, or hypercholesterolemic. Derivatives of 17 OH progesterone have no metabolic side effects, but are less effective than the norsteroids. Progestin-only methods may be indicated for women over 40 and those with family histories of breast cancer. Research on other routes of administration to avoid hepatic effects of oral 19 norsteroids has led to development of subcutaneous implants and vaginal rings. New molecules devoid of undesirable androgenic effects are also under study. Language: French Keywords: ORAL CONTRACEPTIVES | CONTRACEPTIVE AGENTS, PROGESTIN | LOW-DOSE PROGESTINS | ORAL CONTRACEPTIVES, LOW-DOSE | INJECTABLES | CONTRACEPTIVE AGENTS, FEMALE | CONTRACEPTION | FAMILY PLANNING | HORMONES | REPRODUCTIVE CONTROL AGENTS | ADMINISTRATION AND DOSAGE | CONTRAINDICATIONS | CONTRACEPTIVE IMPLANTS | VAGINAL RING | NORETHYNODREL | MEDROXYPROGESTERONE ACETATE | NORETHINDRONE ENANTHATE | CLINICAL RESEARCH | RESEARCH AND DEVELOPMENT | Contraceptive Methods | Contraceptive Agents | Endocrine System | Physiology | Biology | Drugs | Treatment | Norethindrone | Research Methodology | Technology | Economic Factors Document Number: 048318 |
| 21. Title: Estrogen therapy for bleeding gastrointestinal telangiectasias [letter] Author: Brinberg D; Green PH; Lebwohl O Source: ANNALS OF INTERNAL MEDICINE. 1986 Sep;105(3):462-3. Abstract: Angiodysplasia (or telangiectasia) is a recognized cause of gastrointestinal bleeding seen in up to 23% of patients with chronic renal failure and 6.6% of patients evaluated for rectal bleeding. Treatments for angiodysplastic lesions have included surgery, electrocautery, and laser and angiographic obliteration. We present a case of a patient who received estrogen-progestogen therapy for recurrent gastrointestinal bleeding from angiodysplastic lesions. A 72-year-old woman presented with melena in 1979 had an evaluation which included an upper gastrointestinal series, barium enema, panendoscopy, and colonoscopy. These studies revealed multiple angiodysplasias in her stomach, duodenum, and colon. Her medical history included a hysterectomy in 1953, parathyroidectomy, and cholecystectomy. Physical examination revealed no evidence of buccal or skin telangiectasias. There was no family history for gastrointestinal hemorrhaging or epistaxis. She received 3 units of blood and was discharged. Over the next 7 years, she was hospitalized 30 times for gastrointestinal bleeding. Repeated diagnostic studies showed angiodysplasias. She received 120 units of packed erythrocytes between 1979 and 1986. From January 1985 to January 1986, she required 14 admissions and 63 units of blood. Throughout 1985, she received laser therapy without any obvious benefit. In January 1986, she began therapy with 5 mg of norethynodrel and 75 mcg of mestranol (Enovid 5 mg; Searle and Co., San Juan, Puerto Rico). She has required no transfusions nor has had any recurrent gastrointestinal bleeding since institution of hormonal therapy. Systemic hormonal therapy for reducing bleeding from angiodysplasia was first described by Koch in 1952 in 5 patients with epistaxis and hereditary hemorrhagic telangiectasia. The first report of hormonal treatment for bleeding gastrointestinal telangiectasias was by McGee. He described a patient who ceased bleeding for more than 18 months after administration of estrogen-progestogen therapy. Hormonal therapy for chronic gastrointestinal bleeding from telangiectasias may offer an alternative to repeated treatments with laser, electrocautery, or surgery. Controlled trials are needed to confirm its efficacy. (full text) Language: English Keywords: ESTROGENS | HORMONES | REPRODUCTIVE CONTROL AGENTS | TELANGIECTASIA | CEREBROVASCULAR EFFECTS | VASCULAR DISEASES | DISEASES | GASTROINTESTINAL EFFECTS | TREATMENT | EVALUATION | PROGESTERONE | NORETHYNODREL | MESTRANOL | Endocrine System | Physiology | Biology | Family Planning | Progestational Hormones | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Contraceptive Agents, Estrogen Document Number: 041223 |
| 22. Title: Reminiscences on early pill development. Author: Chang MC Source: NETWORK. 1986 Summer;7(4):6. Abstract: This article, written in a narrative style, describes the author's experience as a member of the team that developed the first oral contraceptives. The author served as a research assistance for Dr. Pincus and Dr. Hoagland. The research was done at the Worcester Foundation for Experimental Biology. The pill was developed in only 9 years, in the period 1951-1960. The earliest pills had only progesterone compounds and only after some human testing was it discovered that estrogen reduced the likelihood of break through bleeding. The earliest human test subjects were in Haiti and Puerto Rico. Language: English Keywords: PUERTO RICO | HAITI | ORAL CONTRACEPTIVES | ESTROGENS | NORETHYNODREL | NORETHINDRONE | CONTRACEPTION RESEARCH | PRODUCT APPROVAL | Developed Countries | Caribbean | Americas | Developing Countries | Contraceptive Methods | Contraception | Family Planning | Hormones | Endocrine System | Physiology | Biology | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Legislation Document Number: 058696 |
| 23. Title: Endocrine effects of systemic, steroidal contraceptives. Author: Edgren RA Source: In: Contraceptive steroids: pharmacology and safety, edited by A.T. Gregoire and Richard P. Blye. New York, New York, Plenum, 1986. :163-78. Abstract: Researchers have been able to predict clinical effects of systemic, steroidal contraceptives based on animal models. They cannot accurately predict, however, what quantities are appropriate for humans. Therefore, scientists should depend on human data to identify the optimum dose. Estrogens bind to cytoplasmic receptors in laboratory animals which cause several effects including prevention of uterine growth, particularly the preovulatory endometrium,; control of cyclic changes in the vagina; and regulation of the menstrual cycle. When estrogens are administered simultaneously with progestagens, however, the estrogenic induced uterine and vaginal effects do not appear. Most progestagens bind to the endometrial progesterone receptor, except those that are derivatives of 19-nortestosterone. Further, some bind to the testosterone receptor and produce androgenic effects. Progestational effects consist of secretory change of the uterus, delay of menstruation, and efficacy as an oral contraceptive when combined with estrogen. The progestogen, medroxyprogesterone acetate, binds to the glucocorticoid receptor. Toxicological tests indicate clinical corticoid action, such as deterioration of the adrenal gland. These effects have not yet appeared in Depo Provera users, however. Recommendations for preclinical criteria include not changing present requirements for endocrine studies and pharmacological and clinical effects, allow field trials after 6 months of toxicity studies in 2 species, narrow toxicity criteria to those established for other classes of drugs, and no longer require the 7 year dog and 10 year monkey studies which test for tumor development. Language: English Keywords: UNITED STATES OF AMERICA | CALIFORNIA | GOVERNMENT AGENCIES | CONTRACEPTIVE AGENTS, PROGESTIN | CHLORMADINONE ACETATE | ETHINYL ESTRADIOL | ETHYNODIOL DIACETATE | LEVONORGESTREL | LYNESTRENOL | DEPO-PROVERA | MESTRANOL | NORETHINDRONE | NORETHINDRONE ACETATE | NORETHYNODREL | NORGESTREL | QUINGESTANOL ACETATE | TESTOSTERONE | PROGESTERONE | ESTRADIOL | ENDOCRINE EFFECTS | LABORATORY ANIMALS | INJECTABLES | ORAL CONTRACEPTIVES, COMBINED | Developed Countries | North America | Americas | Organizations | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Contraceptive Agents, Estrogen | Medroxyprogesterone Acetate | Androgens | Hormones | Endocrine System | Physiology | Biology | Progestational Hormones | Estrogens | Clinical Research | Research Methodology | Contraceptive Methods | Oral Contraceptives Document Number: 058689 |
| 24. Title: Contraceptive steroid effects on serum lipoproteins and lipoprotein subclasses. Author: Krauss RM Source: In: Contraceptive steroids: pharmacology and safety, edited by A.T. Gregoire and Richard P. Blye. New York, New York, Plenum, 1986. :321-38. Abstract: A contraceptive drug study in California revealed that women who took pure estrogens or the sequential ethinyl estradiol dinorethisterone preparations had higher levels of HDL cholesterol than those who took combinations with higher doses of progestin, especially norethindrone acetate and levonorgestrel. Further, the lowest HDL cholesterol levels occurred in women who took norethindrone acetate alone. As a result of this study and other similar studies, researchers at the University of California--Berkeley (UCB) conducted further research to evaluate the effects of estrogenic and progestational agents on serum lipoproteins. For example, they compared HDL levels in 18 oral contraceptive users, mainly norethindrone-estradiol combinations, with 19 nonusers. The major difference between the 2 groups consisted of an increase in HDL3- the most dense and protein enriched of the HDL subspecies. These results and those from other subsequent studies demonstrated that progestin use changes the estrogen mediated increase in HDL form more buoyant to more dense HDL subspecies. UCB researchers also studied the progestin effect on LDL subspecies in women using vaginal rings containing levonorgestrel and estradiol. Levels of LDL at an analytic ultracentrifuge flotation rate of 0-7 increased while levels of IDL, VLDL, and the less dense LDL subspecies with a higher molecular weight decreased. In addition, a decrease in HDL2 (high amount of lipid and cholesterol) also occurred. These changes in LDL levels returned to baseline levels 1 week after removal of the vaginal ring. These studies and cross sectional studies data show that individual progestin may vary in their effects on lipoprotein metabolism, even in the lower dose formulations. Yet norethindrone preparations may improve potentially detrimental changes in HDL2 and LDL/HDL ratios. Language: English Keywords: UNITED STATES OF AMERICA | CALIFORNIA | CONTRACEPTIVE AGENTS, PROGESTIN | VAGINAL RING | DIMETHISTERONE | ETHINYL ESTRADIOL | LEVONORGESTREL | MESTRANOL | NORETHINDRONE | NORETHINDRONE ACETATE | NORETHYNODREL | NORGESTREL | PROGESTERONE | CHOLESTEROL | LONGITUDINAL STUDIES | ORAL CONTRACEPTIVES, COMBINED | ORAL CONTRACEPTIVES, PHASIC | CHANGES | Developed Countries | North America | Americas | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Contraceptive Methods | Contraceptive Agents, Estrogen | Progestational Hormones | Hormones | Endocrine System | Physiology | Biology | Lipids | Studies | Research Methodology | Oral Contraceptives | Social Change Document Number: 058687 |
| 25. Title: Androgen-progestogen combinations. Author: Paulsen CA Source: In: Male contraception: advances and future prospects, edited by Gerald I. Zatuchni, Alfredo Goldsmith, Jeffrey M. Spieler [and] John J. Sciarra. Philadelphia, Pennsylvania, Harper and Row, 1986. :300-3. (PARFR Series on Fertility Regulation) Proceedings of an International Workshop on Male Contraception: Advances and Future Prospects, May 28-31, 1985, Geneva, Switzerland. Sponsored by the Program for Applied Research on Fertility Regulation, Northwestern University, Chicago, Illinois. Abstract: Animal studies and clinical investigations have indicated the potential of synthetic progestational steroids for the development of chemical male contraceptive agents. Administration of 19-norprogestational compounds such as norethindrone and norethynodrel has proven effective in terms of suppressing gonadotropin secretion by the anterior pituitary; however, these compounds also suppressed testosterone levels and caused decreases in libido and sexual potency. This led to consideration of medroxyprogesterone acetate, a less potent gonadotropin inhibitor that does not possess estrogenic properties. Clinical trials have compared the efficacy of both the oral form and the depo preparation of this agent in terms of suppressing spermatogenesis. In addition, testosterone was added to the regimen. Several centers have evaluated the effect of depomedroxyprogesterone acetate (DMPA) plus testosterone enanthate (TE) or cypionate (TC), both administered monthly in doses of 150 mg and 250-500 mg, respectively, and found that oligospermia or azoospermia was induced in the majority of subjects. In another study, over 80% of volunteers achieved oligospermia or azoospermia with monthly doses of 200 mg or 400 mg of DMPA and 200 mg or 400 mg of TC. Full recovery generally occurs within 14-40 weeks, and no decreases in libido or sexual potency have been reported. In addition, no laboratory changes indicated liver or other toxicity. Of concern, however, was a transient drop in mean high density lipoprotein (HDL) levels in a small number of volunteers following drug discontinuation. Another problematic area concerns the presence of oligospermia in some volunteers and its meaning in terms of actual method failure rate. It appears to be impossible to induce azoospermia in 100% of cases in a safe and reversible manner. Carefully designed, well monitored, multicentered clinical trials are needed to determine the actual method failure rate associated with the induction of oligospermia. Language: English Keywords: CLINICAL RESEARCH | RESEARCH AND DEVELOPMENT | CONTRACEPTION RESEARCH | MALE CONTRACEPTION | SPERMATOGENESIS | MEDROXYPROGESTERONE ACETATE | NORETHINDRONE | NORETHYNODREL | TESTOSTERONE | Research Methodology | Technology | Economic Factors | Contraception | Family Planning | Reproduction | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Androgens | Hormones | Endocrine System | Physiology | Biology Document Number: 035526 |
| 26. Title: Effect of oral and injectable contraceptives on low density and high density lipoproteins. Author: Shafique M; Khan IA; Mirza A Source: JPMA. Journal of the Pakistan Medical Association. 1986 Oct;36(10):267-9. Abstract: Low density lipoproteins (LDL), LDL-cholesterol and high-density lipoprotein (HDL)-cholesterol were measured in 50 Pakistani women taking oral contraceptives, 40 taking injectable contraceptives, and 20 age-matched controls. The subjects were further divided into those taking contraceptives for 2-6 months and 6-12 months, and those taking Ovral or Norinyl. Women using orals had significantly higher LDL, 487 vs 440 mg/dl (p<.05); LDL cholesterol, 171 vs 156 (p<.02), and lower HDL cholesterol, 55.4 vs 66.2 (p<.01) than controls. Those receiving injectables had values tending in this direction but not significantly different. Similarly, when subdivided, the results tended to be higher for LDL and lower for HDL for Ovral compared to Norinyl at 6 months or less, and for longer-term users, but not significantly so. This is the first report of serum lipoproteins for Pakistani oral contraceptive users. Language: English Keywords: PAKISTAN | DEVELOPING COUNTRIES | FAMILY PLANNING | CONTRACEPTION | CONTRACEPTIVE AGENTS, FEMALE | ORAL CONTRACEPTIVES | ORAL CONTRACEPTIVES, COMBINED | INJECTABLES | CONTRACEPTIVE AGENTS, PROGESTIN | HORMONES | MEDROXYPROGESTERONE ACETATE | ETHINYL ESTRADIOL | NORETHYNODREL | MESTRANOL | LIPID METABOLIC EFFECTS | LIPIDS | CHOLESTEROL | RESEARCH METHODOLOGY | RESEARCH AND DEVELOPMENT | CLINICAL RESEARCH | HUMAN VOLUNTEERS | Asia, Southern | Asia | Contraceptive Agents | Contraceptive Methods | Endocrine System | Physiology | Biology | Contraceptive Agents, Estrogen | Technology | Economic Factors Document Number: 044939 |
| 27. Title: New steroidal contraceptives, implications for toxicological models. Author: Zbinden G Source: In: Contraceptive steroids: pharmacology and safety, edited by A.T. Gregoire and Richard P. Blye. New York, New York, Plenum, 1986. :203-10. Abstract: Standard toxicological experiments have demonstrated that it is basically the hormonal effects of steroidal contraceptives which induce changes. THese changes vary among animal species since different sex hormones and interactions with peptide hormones regulate the same reproductive functions. Further, they are secreted in different amounts. For example, animal research show that progestogen increase growth hormone secretion in the beagle causing enlargement of the mammary gland. Yet this does not occur in humans. Epidemiological research has identified an association between steroidal contraceptives and metabolic changes in humans, such as lipid and carbohydrate metabolism. Routine animal studies did not report such changes, however. Therefore human experience is the only reliable predictor of metabolic effects of new contraceptive steroids. If a new contraceptive steroid's pharmacological and pharmacokinetic traits differ widely from existing approved steroids, both the toxicological work up and pharmacological evaluation must be done carefully and thoroughly. On the other hand, if a new steroid is similar to existing drugs, researchers should assume that the side effects will be like the existing compounds. Then, using a variety of animal species, the clinical pharmacologist should identify similarities and differences to known and established compounds. After a minimum of a 1-3 month study in a rodent and preferably a primate testing for toxic effects caused by hormonal activity, researchers should begin human pharmacological studies to identify pharmacokinetic characteristics and the basic effects on endocrine functions and hormone levels. Assuming acceptable results, phase II studies to determine clinical efficacy should begin. Language: English Keywords: SWITZERLAND | CYPROTERONE ACETATE | LEVONORGESTREL | NORETHYNODREL | PROGESTERONE | ENDOCRINE EFFECTS | FIBROADENOSIS | STEROID METABOLIC EFFECTS | LABORATORY ANIMALS | HUMAN VOLUNTEERS | Developed Countries | Europe, Central | Europe | Hormone Antagonists | Hormones | Endocrine System | Physiology | Biology | Contraceptive Agents, Progestin | Contraceptive Agents, Female | Contraceptive Agents | Contraception | Family Planning | Progestational Hormones | Diseases | Metabolic Effects | Clinical Research | Research Methodology Document Number: 058691 |
| 28. Peer Reviewed Title: Iron stores in users of oral contraceptive agents. Author: Frassinelli-Gunderson EP; Margen S; Brown JR Source: American Journal of Clinical Nutrition. 1985 Apr;41(4):703-12. Abstract: A comparison of serum ferritin and other parameters of iron status was made between 46 women taking oral contraceptives (OCs) for 2 or more years continuously and 71 women who never took them. The mean serum ferritin level for OC users was 39.5 +or- 21.5 ng/ml and the control group mean level was 25.4 +or- 15.96 ng/ml which is significantly different at P0.001. Serum transferrin, serum iron, TIBC, MCH, and MCHC levels were significantly greater for the group using OCs. Significantly lower RBD and hematocrit levels were found for OC users while other parameters, hemoglobin, MCV, and percent transferrin saturation were not significantly different. No major differences in subject characteristics and dietary traits were in evidence, except for a difference in reported menstrual cycle losses and a higher heme iron content in the diet of OC users. (author's modified) Language: English Keywords: SERUM IRON LEVEL | HEMIC SYSTEM | PHYSIOLOGY | ORAL CONTRACEPTIVES, SIDE EFFECTS | CONTRACEPTIVE AGENTS, FEMALE | CONTRACEPTION | DATA COLLECTION | RESEARCH METHODOLOGY | NUTRITION | LABORATORY PROCEDURES | LABORATORY EXAMINATIONS AND DIAGNOSES | EXAMINATIONS AND DIAGNOSES | MENSTRUAL CYCLE | MENSTRUATION | REPRODUCTION | ANALYSIS | POPULATION CHARACTERISTICS | NORETHYNODREL | MESTRANOL | NORETHINDRONE | ETHINYL ESTRADIOL | ETHYNODIOL DIACETATE | ANTHROPOMETRY | CONTRACEPTIVE METHODS | SIDE EFFECTS | Biology | Contraceptive Safety | Safety | Public Health | Health | Contraceptive Agents | Family Planning | Demographic Factors | Population | Contraceptive Agents, Progestin | Contraceptive Agents, Estrogen | Measurement | Treatment Document Number: 031059 |
| 30. Title: Photosensitized decomposition of contraceptive steroids: a possible explanation for the observed (photo)allergy of the oral contraceptive pill. Author: Sedee A; Beijersbergen van Henegouwen G Source: Archiv Der Pharmazie. 1985 Feb;318(2):111-9. Abstract: The photosensitized decomposition of the main steroids used in oral contraceptives was studied. Under the circumstances applied, ethinyl estradiol and norethynodrel decomposed rapidly (t 1/2 = 11.0 + or - 0.2 minutes for ethinyl estradiol and 5.7 + or - 0.4 minutes for norethynodrel). The decomposition product of ethinyl estradiol has been identified as 17 alpha-ethynyl-10 beta-hydroperoxy-17 beta-hydroxyestra-1,4-dien-3-one. The decomposition products of ethinyl estradiol and norethnodrel were previously found in experiments in which the irreversible binding of these steroids to protein was studied. Photosensitized decomposition of the steroids may be the cause of photoallergic side effects of "the pill." (author's modified) Language: English Keywords: ORAL CONTRACEPTIVES, SIDE EFFECTS | CONTRACEPTIVE AGENTS, SIDE EFFECTS | CONTRACEPTION | ETHINYL ESTRADIOL | NORETHYNODREL | HORMONES | PHOTODERMATITIS | DERMATOLOGICAL EFFECTS | DISEASES | WOMEN | SIDE EFFECTS | CONTRACEPTIVE METHODS | Contraceptive Safety | Safety | Public Health | Health | Contraceptive Agents | Family Planning | Contraceptive Agents, Estrogen | Contraceptive Agents, Female | Contraceptive Agents, Progestin | Endocrine System | Physiology | Biology | Dermatitis | Demographic Factors | Population | Treatment Document Number: 034117 |
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