Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda (1993)

A

Abortion, 2, 72, 92, 106

animal studies, 58-59, 265-266

cervical ripening for, 32, 96-97, 175, 177-179

dosages, 26-27, 28, 31, 94, 166, 168-170, 185-186

enzymatic inhibitor use, 73, 258

first trimester, 6-7, 26-29, 92-96, 149, 164-172, 174

protocols, 27, 29-30, 166

research needs, 6, 7, 29, 30, 31-32

second trimester, 7, 30-32, 97, 175, 186-187

service delivery and access, 6, 29-30, 95-96, 106, 168, 183-185

side effects, 27-28, 78, 94, 167, 175, 186

success rates, 27, 28, 94, 165, 166, 167

Acceptability (to patients), 6-7, 30

Adenocorticotropic hormone (ACTH), 38, 43, 45, 52-54, 102, 104, 192 -193, 229-231, 234-235, 244

Adjuvant therapy, for breast cancer, 11, 45-46

Adrenal insufficiency, 53, 55

AIDs, 105

Alzheimer's disease, 105

Amenorrhea, 4, 21

Animal models and studies, 15, 57-61, 262-266

abortifacient use, 58-59, 265-266

antiestrogenic effects, 247-249

breast cancer, 11, 43-44, 47, 60, 217-219

endometriosis therapy, 37-39

and labor induction, 8, 33, 34, 59-60

Antiandrogen effects, 235, 239, 240

Antiestrogenic effects, 9, 10, 153-154, 244-245, 247-249, 269-270

Antiglucocorticoid effects, 1, 13, 16, 52, 55, 76, 78, 104-105, 140 -141, 234-239, 244

of cancer therapy, 10, 21, 40, 41, 236

of endometriosis therapy, 9, 38, 39

of low dosages, 4, 9, 21

research needs, 13, 55, 239-240

therapeutic, 13, 53-55, 170, 234-235, 239-240, 271

Antihormone antibodies, 73

Antitumor effects, 11, 43-44, 47, 103-104, 106, 217-219, 235-236

Apoptosis, and breast cancer therapy, 12, 43, 103

Arthritis, 55, 236

Azastene, 258

B

Biosynthesis inhibition, 73, 257-259

Bone retention and loss, 4, 10, 21, 22, 38, 40

Brain, see Meningiomas;

Mood effects

Breast cancer, 11, 41-47, 91, 103-104, 105, 210, 271

animal studies, 11, 43-44, 47, 60, 217-219

dosages, 12, 46, 48

and oral contraceptives, 20

progesterone receptors, 11, 12, 42-43, 48, 123-124, 133, 213-217, 220-222

research needs, 11-12, 47-48, 222-224

and side effects, 12, 45

C

Cancer and tumors, see Antitumor effects;

Breast cancer;

Meningiomas;

Uterine leiomyomas

Cardiovascular effects, of prostaglandin, 27-28, 94, 167

Cataracts, 55, 236

Cervical mucus, 139-140, 141

Cervical ripening, 7-8, 32-33, 96-97, 165, 270

for abortion, 32, 96-97, 175, 177-179, 270

dosages, 32, 177-178

side effects, 32

Cesarean section, 34

Chemoprevention, for breast cancer, 11, 45-46

China, abortifacient use and licensing, 149, 271

trials, 265

Cholesterol, 140

Chromatin modification, 88

Clinical trials, 2-3, 18

abortifacient use, 6, 7, 29, 31-32, 165, 166-167, 168-170, 176

breast cancer therapy, 11-12, 44-45, 47-48, 60, 103, 219-220, 223

cervical ripening, 177-179

contraceptive use, 4, 22, 160

endometriosis therapy, 10, 38-39, 189, 190, 192-197

leiomyoma therapy, 10, 189-190, 198-207

meningioma therapy, 13, 49, 50

post-coital contraception, 5, 23, 160

Complications, see Antiglucocorticoid effects;

Side effects and toxicity

Conception, 19

Contraception, definition, 72, 98.

See also Contraceptive use;

Menses induction;

Oral

contraceptives

Contraceptive use, 3-4, 20-21, 22, 99-102, 106, 187

dosages, 3, 4, 20-21, 141-142, 159

endometrial, 100-101, 148, 157

follicular phase administration, 3, 20, 141-142, 144, 145, 148, 150, 153, 156

luteal phase administration, 3, 20-21, 99-100, 143, 148, 157-158

for males, 101-102

post-coital, 4-5, 22-23, 98, 99, 143, 148, 157-158, 187

research needs, 4, 22, 106, 144, 160

side effects, 4, 21, 22

Contragestion, 72, 98-99.

See also Menses induction

Contraindications, abortifacient use, 6, 28, 29, 167

Corpus luteum, 3, 14, 19, 21, 150, 253-254

progesterone production, 6, 15, 26, 164

Cortisol antagonism, 54, 76, 104, 141

Cushing's syndrome, 1, 13, 53-54, 105, 234-235, 236, 271

D

Danazol

in endometriosis therapy, 9, 37, 191

as post-coital contraceptive, 22-23

Depression, 238, 270

Developing countries, abortifacient access, 96, 106

Development of antiprogestins, 1, 71-72, 76, 149, 259-260

Dexamethasone, 54, 55

Dilapan, 31, 97, 175, 187

Dilation and evacuation (D&E), 7, 31, 187

Dimerization, 87, 122, 129-130

DNA binding, 87-88, 120-125 passim, 127, 129-130

Dosages, 140

abortifacient use, 26-27, 28, 31, 94, 166, 168-170, 185-186

breast cancer therapy, 12, 46, 48

cervical ripening, 32, 177-178

contraceptive use, 3, 4, 20-21, 141-142, 159

Cushing's syndrome, 54

endometriosis therapy, 9

labor induction, 8, 33-34

leiomyoma therapy, 10, 40-41, 102

menses induction, 5

ovulation inhibition, 154-156

post-coital contraception, 22-23, 156-157

E

Ectopic tissue, see Endometriosis

Endometrial contraception, 100-101, 148, 157

Endometriosis, 8-9, 10, 36-39, 92, 102, 189, 190-197, 271

Endometrium, 3, 19, 21, 90-91, 150, 152-153

effects of contraceptive use, 4, 21, 22

End points, 140-141

Enzymatic inhibitors, 73, 257-259

Epidermal growth factor, 12, 48

Epostane, 73, 258-259

Estradiol, 9, 15, 22, 39, 73-74, 144

Estrogen, 14, 19, 139-140

and breast cancer, 42

and long-term use, 10, 144

and low dosages, 21, 39, 142

see also Antiestrogenic effects

Estrogen receptors, 10, 15, 74-75, 153-154, 268-270

and breast cancer, 11, 42

F

Fertility effects, 10

of mother's use, 8, 34

Fetal demise

and cervical ripening, 7-8, 32, 33

labor induction, 33, 175

Fibroids, see Uterine leiomyomas

Follicle-stimulating hormone (FSH), 14, 91, 102, 150

Follicular phase, 9, 14, 19, 20, 140

contraceptive administration over, 3, 20, 141-142, 144, 145, 148, 150, 153, 156

Food and Drug Administration, 6, 29, 30, 32

France, abortifacient use and licensing, 2, 6, 27, 29, 93, 149, 166

G

Gemeprost, 27, 28, 31, 94, 166, 167, 169

Glaucoma, 92, 105, 236, 238, 271

Glucocorticoids, 1, 13, 52-53, 229-234.

See also Antiglucocorticoid effects

Gonadotropin-releasing hormone (GnRH) and agonists, 14, 91

and endometriosis therapy, 37, 39, 191

and leiomyoma therapy, 9, 40, 198

Gynecomastia, 235, 239

H

Half-life, of mifepristone, 77-78, 140

Heat shock protein binding, 86-87, 123, 127, 128

Heterodimerization, 87

Hospitalization, second-trimester abortion, 7, 31, 175, 187

Human chorionic gonadotropin, 91, 93, 99, 100, 150, 158, 170, 247-249

Human papillomavirus, 102-103

Hypercortisolism, 235, 271

Hypertension, 27, 55, 105, 236-237, 239, 270

I

Immune suppression (protection against), 105, 237

infertility, and endometriosis, 8, 9, 36, 37

Inflammation, 55, 236, 237

Insulin-like growth factor, 12, 48

Intrauterine devices, 98

Intraocular pressure, 54, 236

L

Labor induction, 8, 33-34, 97, 179-180, 186-187

animal studies, 8, 33, 34, 59-60

cervical ripening for, 7, 32, 270

Lactation, 8, 33, 34, 139

Lamicel dilator, 97, 187

Laminaria tents, 31, 97, 175, 187

Leiomyomas, see Uterine leiomyomas

Licensing, see Regulatory approval

Ligand binding, 81-82, 84-85, 121, 122

Lilopristone, 16, 77, 78, 260

Lipid profiles, 140

and contraceptive use, 4, 21, 22

Local administration, 54, 236, 238, 239

Long-term administration, 3-4, 18, 21, 105, 195-197

side effects, 3, 18, 143-144, 196

Low-dosage administration, 4, 21, 22

Luteal phase, 6, 15, 19, 38, 140, 150, 152-153

and breast cancer, 42

contraceptive administration over, 3, 20-21, 99-100, 143, 148, 157 -158

and menses induction, 5, 23

and post-coital administration, 156-158

Luteinizing hormone (LH), 14, 40, 91, 102, 140, 141-142, 150

M

Male contraception, 101-102

Mechanisms of action, 2, 18, 76-78

cervical ripening, 175, 177

myometrial gap junctions, 268

ovulation inhibition, 154-156

prostaglandin metabolism, 266-268

receptor mediation, 78-89, 120-130, 268-270

reproductive effects, 89-92, 141, 149-154, 164-165

research needs, 2, 18, 134-135, 144, 159-160

transcription activity, 75, 84, 88-89, 121-123, 127-128, 130-135

Meningiomas, 12-13, 48-50, 104

and side effects, 13, 21, 49

Menses induction, 5, 23-24, 98, 171

Menstrual cycle, 3, 19

contraceptive administration over, 3-4, 141-143

and endometriosis, 8

progesterone production, 3, 4-5, 19, 140

see also Follicular phase;

Luteal phase;

Menses induction

Metabolism, 76-77, 237, 240

of prostaglandin, 266-268

Miscarriage, see Abortion;

Fetal demise

Misoprostol, 28, 30, 94, 95, 99, 100, 169-171

Mood effects

of contraceptive use, 4, 21, 22

of progesterone, 140

Morning-after pill, 4, 22

Muscular deterioration, 54

Myocardial infarction, from abortifacient use, 27-28, 94

Myometrium, 31, 32, 40, 90, 139, 164, 268

Myopathy, 54

N

Neonatal effects, 8

of labor induction, 33, 34, 97, 180

of unsuccessful abortion, 28, 167

New Drug Application, for abortifacient use, 6, 30

Norethisterone, 142

Novel antiprogestins, research needs, 106, 107

O

Obesity, 105

Older women, and abortifacient use, 6, 28, 29, 167

Onapristone, 16, 78, 153, 260

breast cancer therapy, 42, 43, 44, 46

Oral contraceptives, 14, 20, 71, 187

in endometriosis therapy, 37

post-coital use, 4, 5, 22, 23, 156

side effects, 20, 156

Organon, 16-17, 260

Orosomucoid binding, 77, 264-265

Osteoporosis, 4, 10, 21, 22, 38, 40

Ovarian cysts, 4, 21, 36-37

Ovulation, 14, 58

Ovulation inhibition, 3, 16, 91, 148, 154-156

contraceptive application, 4, 21, 101, 142, 156-157

Oxytocin, 8, 34, 97, 179

P

Pain and pain relief

abortion, 94, 169, 170, 171

breast cancer therapy, 44

endometriosis therapy, 38, 102, 193

Phosphorylation, 123-124, 133

Pituitary gland, 14, 16

Placenta, progesterone production, 3, 19, 164

Post-coital contraception, 4-5, 22-23, 98, 99, 143, 148, 157-158, 187

failure rates, 157-158

research needs, 160

side effects, 22-23, 156

Pregnancy, 1, 72

animal models, 58-60

progesterone role, 1, 3, 72, 139, 149, 164

see also Abortion;

Cervical ripening;

Fetal demise;

Labor induction

Premenstrual syndrome, progesterone effects, 140

Progesterone, 1, 4-5, 14, 16, 72, 254

and breast cancer, 42, 212-213

menstrual cycle production, 3, 4-5, 19, 140

and normal breast function, 211-212

ovarian production of, 3, 6, 15, 26

placental production, 3, 19, 164

pregnancy role, 1, 3, 72, 139, 149, 164

Progesterone receptors, 72, 254, 263-264

animal models, 57-58

of breast tumors, 11, 12, 42-43, 48, 123-124, 133, 213-217, 220-222

of leiomyomas, 9, 40

mechanisms of action, 81-89, 120-135, 149, 268, 269

membrane-bound, 134

of meningiomas, 12, 48-49

Programmed cell death, see Apoptosis

Prostaglandin

abortifacient use, 6, 7, 26-29, 31, 93-96, 165-171 passim, 175, 255, 258

and cervical ripening, 8, 32-33, 165

contraceptive use, 3, 158

and menses induction, 5, 24

metabolism, 266-268

side effects, 27-28, 94, 167, 175, 186

see also Gemeprost, Misoprostol, Sulprostone

Protocols, abortion, 27, 29-30, 166

Psychosis, 105

R

Receptors, see Estrogen receptors;

Progesterone receptors

Regulatory approval, 6, 30

France, 2, 27, 93

Sweden, 2, 27

United Kingdom, 2, 27

Research Triangle Institute, 16-17, 245-246

Resistance to antiprogestins, of tumors, 12, 46, 220-222

Risk assessment, 4, 6, 29

Roussel-Uclaf, 16-17, 75-76, 149, 259

abortion protocol, 29-30, 166

S

Saline injection, 7, 31

Schering AG, 16-17, 78

Septic shock, 105

Sexual behavior effects, 91

Side effects and toxicity

abortifacient use, 27-28, 94, 167, 175, 186

breast cancer therapy, 12, 45

cervical ripening, 32

contraceptive use, 4, 21, 22

endometriosis therapy, 9, 10, 38, 191, 193-194, 196

leiomyoma therapy, 21, 40-41, 201

long-term use, 3, 18, 143-144, 196

meningioma therapy, 13, 21, 49

of oral contraceptives, 20, 156

post-coital contraception, 22-23, 156

of prostaglandin, 27-28, 94, 167, 175, 186

see also Antiglucocorticoid effects

Smoking, and abortifacient use, 6, 28, 29, 167

Southwest Oncology Group, 13, 50

Special Programme of Research, Development and Research Training in Human Reproduction, 254-255, 257

Steroid-induced myopathy, 54

Sulprostone, 27, 28, 93-94, 166, 167

Surgical abortion, 6, 7, 31, 187

after mifepristone failure, 28, 94, 167

cervical ripening for, 175, 177-179

Sweden, abortifacient use and licensing, 2, 6, 27, 94, 149, 166

T

Tamoxifen, 42, 44-45, 46, 74-75, 217-218, 223

Tenascin, 43

Teratogenicity, 28, 167

Testosterone, 37

Topical administration, 54, 236, 238, 239

Toxicity, see Antiglucocorticoid effects;

Side effects and toxicity

Transconformation, 85-86

Transcription activity, 75, 84, 88-89, 121-123, 127-128, 130-135

Transforming growth factor, 12, 48

Triphenylethylene derivatives, 73-74

Tumors, see Antitumor effects;

Breast cancer;

Meningiomas;

Uterine leiomyomas

U

United Kingdom, abortifacient use and licensing, 2, 6, 27, 94, 149, 166

Uterine contractility, 164-165

Uterine leiomyomas, 9-10, 39-41, 92, 102-103, 189-190, 197-207, 271

dosages for, 10, 40-41, 102

research needs, 10

and side effects, 21, 40-41, 201

Uterine perforation, 7, 32

V

Viral disease, 54

W

Wound healing, 55, 92, 105, 236, 270, 271

Y

Yuzpe regimen, 156

Z

ZK 98 299 antiprogestin, 125, 130, 133, 219

ZK 112 993 antiprogestin, 43, 78