Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women.

Daily administration of estrogen antagonists to premenopausal women has been incorporated into the adjuvant treatment of breast cancer. We have studied the changes in reproductive hormones, pituitary responses to hypothalamic-releasing hormones, and endometrial histology during treatment with the antiestrogen tamoxifen in five healthy, premenopausal women. These studies were carried out during one menstrual cycle before and during two cycles of antiestrogen treatment. All subjects continued to have regular menses with biphasic basal body temperature records. During treatment, estradiol (E2) levels were increased but followed the usual pattern reflecting follicular maturation and corpus luteum formation. The mean E2 concentration at the midcycle peak and during the luteal phase was twice that observed during the non-treatment cycle. By contrast, the concentrations and secretory patterns of luteinizing hormone and follicle-stimulating hormone were not greatly changed, and the gonadotropin responses to gonadotropin-releasing hormone were not suppressed. Endometrial biopsies obtained during the follicular phase of control and tamoxifen treatment cycles showed no differences whereas biopsies obtained during the luteal phase of tamoxifen cycles uniformly showed a lack of changes attributed to progesterone action with no progression of histologic changes beyond those expected on day 7-8 of the luteal phase. These observations are consistent with maturation of multiple ovarian follicles, a surprising finding considering the normal gonadotropin concentrations. The retarded development of the endometrium in the presence of supranormal serum E2 and progesterone concentrations is a morphologic demonstration of the antiprogestational effect of antiestrogens. The lack of gonadotropin suppression in the presence of hyperestrogenemia suggests a major antiestrogen action on the hypothalmus and pituitary gland.

PIP: Administration of antiestrogen has recently been incorporated into the management of breast cancer. To explore the endocrine consequences of this therapy 5 healthy premenopausal volunteers were observed and treated with daily administration of the antiestrogen Tamoxifen. During the treatment period all subjects continued to have regular menses and basal body temperature; estradiol (E2) levels increased but followed a regular pattern, and its concentration at midcycle and during the luteal phase were twice as high as during nontreatment. On the other hand, concentrations of LH and of ESH were not greatly changed. In the presence of higher concentrations of E2 and of progesterone the endometrium showed a retarded development, thus demonstrating the antiprogestational effect of Tamoxifen. The lack of gonadotropin suppression also suggests a major antiestrogen action on the hypotalamus and pituitary glands.

French abortion drug RU 486: U.S. research battles heat up.

PIP: With increasing evidence that the controversial French-made abortifacient RU-486 may serve as a treatment to some diseases, Congress and researchers have stopped up the pressure on the Food and Drug Administration to make the drug more available for clinical trials. The FDA has banned the import of RU-486 for personal use, and has placed strict restrictions on importations for clinical studies, having approved only 10 Investigational New Drug applications as of December 1990. Legislators and researchers say that RU-486's maker, Roussel-UCLAF, has also kept tight control of the drug because its parent company, Hoechst, fears reprisals from anti-abortion groups. Nonetheless, preliminary clinical results have shown the drug to have positive results in the treatment of unresectable meningioma, breast cancer. Cushing's syndrome, and endometriosis. A clinical trial conducted at the University of Southern California showed that a daily dose of RU-486 led to minor tumor regressions in 6 of 24 patients with the normally untreatable unresectable meningioma. These results have not gone unnoticed by Congress; the House Small Business Subcommittee on Regulation held a meeting to discuss the issue. The Subcommittee heard from researchers who say that their studies have been affected by the FDA's actions. An FDA representative explained the tight control over the drug by saying the possibility exists that a black market for the drug might arise. Nonetheless, he said that the FDA is not trying to prevent legitimate research. But Subcommittee Chairman Ron Wyden, who favors abortion rights, criticized the FDA's ban as politically motivated.^ieng

Anovulation and increased androgenic activity as breast cancer risk in women with fibrocystic disease of the breast.

The urine of 26 otherwise healthy women with fibrocystic disease of the breast was assayed by gas chromatography for testosterone and androstanediol (5alpha-androstane-3alpha, 17beta-diol), the major metabolite of dihydrotestosterone. The mean values for both androgens were significantly higher than in 18 normal women in the same age range. Sixteen of the 26 fibrocystic disease patients also had endometrial hyperplasia. Since the endometrial specimen was obtained in the premenstrual period, the presence of hyperplasia proved that the menstrual cycle in over two-thirds of the fibrocystic disease patients was nonovulatory.

PIP: Urine of 26 otherwise healthy women with fibrocystic breast disease (FCD) was assayed by gas chromatography for testosterone (Tes) and androstanediol (Ans), the major metabolite of dihydrotestosterone. The 26 patients under study had been subjected 3-5 months previously to biopsies of breast lumps, diagnosed as FCD. The histological features varied from simple cystic formations with moderate epithelial proliferation in 11 women (Group 1) to pronounced intraductal epithelial hyperplasia accompanied by epithelial cell atypia in 15 women (Group 2). The urinary Tes and Ans difference in FCD patients and controls (18 normal women) was significant at the level of p .01 for both androgens. In controls the mean excretion levels of Tes and Ans were 6.5 and 35 mcg/24 hours, respectively. In FCD patients, the mean Tes and Ans values were 17.4 and 68.5 mcg/24 hours, respectively. Group 2 presented a higher urinary Tes level than patients in Group 1, but the difference was not significant. The Ans level of Group 1 patients was significantly above normal (p .01) and near significantly higher (p .08) than that of the Group 2 patients; whereas the Ans level of Group 2 patients did not differ significantly from the normal value. Endometrial specimens showed that 16/26 FCD patients had endometrial hyperplasia. Since the endometrial specimen was obtained in the premenstrual period (Days 20-22), the presence of hyperplasia proved that the menstrual cycle in over two-thirds of the FCD patients was nonovulatory.

Effect of estrogen and progestin treatments on endometria from postmenopausal women.

PIP: This report describes experiments designed to answer several important questions about the biochemistry of estrogen-stimulated postmenopausal endometrium; in particular; how much estrogen enters the endometrium and the biological effectiveness of that estrogen in women receiving different forms of postmenopausal estrogenic therapy. To this end, nuclear and cytoplasmic estradiol receptor (ER) and cytoplasmic progesterone receptor (PR) were measured in curettage samples of endometria from women receiving, either sequentially or cyclically, Premarin, Harmogen, Progynova, or mestranol at either low or high doses. Cyclical treatment with estrogen alone was compared with sequential therapy with 3 weeks of estrogen plus 1 week of estrogen plus 1 week of estrogen plus northisterone. No difference in any of the receptor levels was found in samples obtained during the 3rd week of any of the 4-week treatment cycles. For 2-3 weeks of a treatment cycle, the receptor levels were similar to those seen in premenopausal, proliferative-phase endometrium, suggesting that postmenopausal endometrial cells are subjected to a very potent estrogenic stimulus for a considerable period. Norethisterone ingestion for 1 week decreased both the amount of nuclear ER and the percentage of total cellular ER that were in the nuclear fraction. Estradiol dehydrogenase was also induced by the progestin. The presence of this enzyme could result in lowered nuclear ER levels which were seen during the progestogenic phase of the treatment schedule. Nuclear ER was lower during Week 3 than Week 2 of estrogen treatment. In addition, PR was negatively correlated with nuclear ER in postmenopausal tissues obtained in Week 3 in contrast to positive correlations seen in premenopausal samples. Possibly a 3-week treatment with estrogen leads to a refractory condition. When receptor levels of normal, cystic hyperplastic, typical hyperplastic, and atypical hyperplastic tissues were compared, the endometria that had been returned to normal histology suggested that cells in atypical hyperplastic endometrial cells may be more estrogen sensitive than other types of endometrial tissues.^ieng

Cyclic changes in the fine structure of the epithelial cells of human endometrium.

PIP: Endometrial biopsies from the corpus uteri of women of reproductive age with normal 28-day cycles were processed for electron microscopy in order to examine the refinements of ultrastructure which occur as part of the cyclic hormonal input. The description of the structure of epithelial cells includes: 1) the endoplasmic reticulum and ribosomes, 2) mitochondria, 3) the nucleus, 4) the golgi complex and secretory bodies, 5) lysosomes, 6) annulate lamellae, 7) luminal surface, 8) basal surface, 9) lateral surface, and 10) the nucleolar channel system. The variations in glycogen synthesis during the cycle are presented, as well as uterine secretions. The effects of estrogen and progesterone on the epithelial cells are described.^ieng

Unoccupied nuclear receptors for estrogen in human endometrial tissue.

PIP: The nuclear content of estrogen-binding sites in normal and pathological endometrial tissue was studied. Extracts of cell nuclei from normal, nonmalignant, and cancerous human endometrial tissues were used, and at 0 degrees centigrade were found to contain material capable of binding estradiol in vitro. Only binding sites unoccupied by endogenous estrogen were determined. Estrogenic receptor (ER) character of this binding was demonstrated by 3 findings: 1) high affinity of binding to estradiol; 2) specificity of binding, competition by diethylstilbestrol and estriol for estradiol binding, and absence of competition by cortisol, progesterone, and 5 alpha-dihydrotestosterone; and 3) sedimentation constant at about 4S in sucrose density gradient. Next, occupied receptors were determined at 30 degrees centigrade. Both occupied and unoccupied receptors were measured by a single saturating dose of 7.5 nM tritiated estradiol with or without a 100-fold excess of diethylstilbestrol to estimate the amount of nonspecific binding. All specimens assayed had unoccupied nuclear receptors. This unoccupied receptor comprised from 9-37% of the total estradiol receptors (cytoplasmic plus nuclear). Such a large percentage of unoccupied nuclear receptors in both normal and pathological endometrial material may indicate that the unoccupied receptor is a necessary product in the normal mechanism of estradiol action.^ieng

Alterations in endometrial stromal cell tissue factor protein and messenger ribonucleic acid expression in patients experiencing abnormal uterine bleeding while using Norplant-2 contraception.

A high incidence of irregular uterine bleeding is the primary patient complaint limiting the utility of long term, progestin-only contraceptive agents such as Norplant. The onset of hemorrhage requires both inadequate hemostasis and impaired vascular integrity. Thus, we first tested whether Norplant-associated endometrial bleeding was accompanied by altered expression of perivascular stromal cell tissue factor (TF), the primary initiator of hemostasis. Norplant effects on TF messenger ribonucleic acid (mRNA) and protein expression by endometrial stromal cells were assessed by in situ hybridization and immunohistochemical examination of endometrial biopsies obtained from normally cycling control women (n = 14) and from patients experiencing Norplant-induced abnormal uterine bleeding (n = 24). TF mRNA and protein expression was increased 150% in secretory vs. proliferative phase endometrial specimens. By contrast, endometrial TF mRNA and protein levels were reduced during 1-6 months of Norplant treatment by about 2-fold (P < 0.05 for protein) compared to the values for control secretory phase specimens. These changes were consistent with observations that patients on Norplant begin to bleed during this interval. Further reductions of TF mRNA and protein levels to 2- and 3-fold of those in secretory phase control specimens were observed in endometria obtained after 6-12 months of Norplant therapy (P < 0.05 and P < 0.01, respectively). A modest rebound in TF mRNA and protein expression was observed after 12 months of Norplant therapy, which occurred commensurate with reduced patient complaints of abnormal uterine bleeding. Pathologically enlarged venous sinusoids were ubiquitous in endometrial specimens obtained after Norplant therapy. The combination of fragile blood vessels and reduced TF expression may account for bleeding in patients receiving Norplant therapy.

Effects of the antiprogesterone steroid RU 486 during midluteal phase in normal women.

UNLABELLED: The antiprogesterone steroid RU 486 (17 beta-hydroxy-11 beta-4-dimethyl-aminophenyl)17 alpha(1-propynyl)estra-4,9-dien-3-one) was given orally to 32 normally cycling women for 4 days, starting on the fourth day of the luteal phase. Uterine bleeding occurred on the third day of RU 486 administration in all 14 women treated with 100 mg/day, in 7 of the 8 women treated with 50 mg, and in 8 of 10 women receiving 25 mg/day. Premature luteal regression induced by RU 486 occurred in 8 women treated with 100 mg/day, in 3 treated with 50 mg, and in 2 receiving 25 mg/day. Plasma LH was measured every 15 min from 0800-1200 h for 5 days in 17 women. Mean LH levels decreased and pulsatile release disappeared in 7 of the 8 women treated with 100 mg, in 2 of 4 receiving 50 mg, and in 1 of 5 treated with 25 mg. RU 486 had no effect when given to 5 women with anovulatory cycles for 4 days starting on day 18 of the cycle. IN CONCLUSION: 1) RU 486, given to normally cycling women at midluteal phase, provokes uterine bleeding. 2) This effect occurs whether or not luteal regression is induced by the compound, indicating that RU 486 acts directly upon the endometrial tissue, very likely at the progesterone receptor level. 3) The drug may impair simultaneously or separately luteal function and gonadotropin secretion in a dose-dependent manner. 4) The lack of antiglucocorticosteroid activity, at the dosage of 100 mg/day, suggests that RU 486 may be useful for fertility control.

PIP: The antiprogesterone steroid RU 486 (17beta-hydroxy-11beta-4-dimethyl-aminophenyl)17alpha(1-propynyl)estra-4,9-dien-3-one) was given orally to 32 normally cycling women for 4 days, starting on the 4th day of the luteal phase. Uterine bleeding occurred on the 3rd day of RU 486 administration in all 14 women treated with 100 mg/day, in 7 of the 8 women treated with 50 mg and in 8 of 10 women receiving 25 mg/day. Premature luteal regression induced by RU 486 occurred in 8 women treated with 100 mg/day, in 3 treated with 50 mg, and in 2 receiving 25 mg/day. Plasma LH was measured every 15 minutes from 0800-1200 hours for 5 days in 17 women. Mean LH levels decreased and pulsatile release disappeared in 7 of 8 women treated with 100 mg, in 2 of 4 women receiving 50 mg, and in 1 of 5 treated with 25 mg. RU 486 had no effect when given to 5 women with anovulatory cycles for 4 days starting on day 18 of the cycle. The following were conclusions drawn. 1) RU 486, given to normally cycling women at midluteal phase, provokes uterine bleeding. 2) This effect occurs whether or not luteal regression is induced by the compound, indicating that RU 486 acts directly on the endometrial tissue, very likely at the progesterone receptor level. 3) The drug may impair simultaneously or separately luteal function and gonadotropin secretion in a dose-dependent manner. 4) The lack of antiglucocorticosteroid activity, at a dosage of 100 mg/day, suggests that RU 486 may be useful for fertility control.

Megestrol acetate: clinical experience.

PIP: The use of megestrol acetate in treatment of malignancy (endometrial carcinoma, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, malignant melanoma), endometrial hyperplasia, benign prostatic hypertrophy, contraception, anorexia, cachexia and weight loss is reviewed, concluding with a toxicity profile. Megestrol acetate was introduced in 1971 for treatment of endometrial carcinoma. Megestrol acetate is probably effective in proportion to the number of cytoplasmic progesterone receptors, but it has not been tested in a Phase III trial. For ovarian cancer it has been reported to be effective in 1 trail at doses of 800 mg/day. Prostate cancer, although difficult to assess, responds to megestrol acetate at doses of 120 mg/day because of its suppression of gonadotropins, its inhibition of 5alpha-reductase and its binding to the dihydrotestosterone receptor. Megestrol acetate permits a lower dose of diethylstilbestrol, and thus lower toxicity. There is apparently a dose-response between megestrol acetate and breast cancer, along with a response dependent on the number and type of estrogen and progestin receptors. Responses are better in postmenopausal women, and additive with other agents such as tamoxifen and mitomycin C. The medium duration of effect is 6-8 months. It has no effect on renal cancer or malignant melanoma. Megestrol acetate can be considered as an effective medical alternative to surgery for endometrial hyperplasia or benign prostatic hypertrophy. As a contraceptive in inhibits sperm transport rather than ovulation, but also causes irregular bleeding. Megestrol acetate has few side effects, and has the advantage of stimulating appetite and weight gain, a benefit in cancer patients.^ieng

Mifegyne (mifepristone), a new antiprogestagen with potential therapeutic use in human fertility control.

PIP: Animal and human volunteer research involving the hormone antagonist Mifegyne (mifepristone) is reviewed. Studies in animals and humans show that the potent antiprogesterone, Mifegyne, causes pregnancy interruption by acting directly at the level of the endometrium. Pharmacokinetic studies indicate that gastrointestinal absorption is low (25%), but subcutaneous and intramuscular routes do not fare better than does oral administration. Experimental studies in women testing for antiprogesterone effects indicate that mifegyne does not affect menstrual cycle length in women with regular ovulatory cycles, except when using the highest doses (600 mg). Mifegyne inhibits gonadotrophin secretion in a dose-dependent way. In humans, mifegyne has some progestomimetic activity in the endometrium in the absence of progesterone. Researchers know that larger doses of mifegyne than those sufficient to induce uterine bleeding are required to cause antiglucocorticosteroid effects. Studies demonstrate that in 18% of patients studied the only significant side effect is prolonged uterine bleeding. In addition, mifegyne fails to cause an abortion in 15% of the cases. The success rate is 85% when mifegyne is given prior to the 5th week of amenorrhea. Due to the occurrence of failed abortions and prolonged uterine bleeding in some women, researchers advise close medical supervision. An added effect of mifegyne is that in both animal and human studies it is effective in inducing labor. Preliminary studies suggest that mifegyne taken once a month only on the expected date of individual menses could be used as a safe and effective form of fertility control.^ieng

Buserelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical profile.

The gonadotrophin releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); gonadorelin] agonist buserelin is a promising new agent in the treatment of a variety of disorders in gynaecology and andrology, paediatrics and oncology. While a single dose of buserelin stimulates the release of pituitary gonadotrophins, multiple doses produce reversible pituitary desensitisation, and this specific blockade of gonadotrophin support to the gonads provides the basis for the drug's efficacy in conditions dependent on sex hormone secretion. Thus, buserelin provides comparable efficacy to orchidectomy or high dose estrogens in the treatment of hormone-sensitive prostate cancer and exhibits a lower incidence of adverse effects. During the early phase of treatment it may be particularly useful in combination with antiandrogens. Buserelin also appears promising in hormone-sensitive premenopausal breast cancer. Extensive studies have proven the value of buserelin in endometriosis, where it produces a transient remission with gradual recurrence of the disease on cessation of treatment. Surgical intervention is necessary in severe disease after buserelin-induced involution of the lesions. In patients with uterine leiomyoma, preliminary data suggest that buserelin may be beneficial in rendering surgery more conservative by reducing fibroid size, although it appears unlikely to preclude surgical intervention. The use of buserelin to induce a state of reversible hypogonadotrophism before administration of exogenous gonadotrophins is a promising strategy in the treatment of infertility associated with polycystic ovary syndrome and other conditions of infertility with underlying ovarian dysfunction; such a strategy also clearly enhances the efficiency of in vitro fertilisation programmes. Initial studies suggest its potential usefulness as a female contraceptive when administered intermittently in conjunction with a progestogen. Buserelin represents a first-line treatment of central precocious puberty. In endometriosis the adverse effect profile of buserelin is generally favourable, with hypoestrogenic effects such as hot flushes and vaginal dryness, and decreased libido, predominating. There is no apparent detrimental effect on lipid metabolism. The potential for adverse hypoestrogenic effects on bone mineral content with long term administration remains to be clarified. Thus, the GnRH agonist buserelin represents an advance in the treatment of a variety of gynaecological and andrological as well as paediatric and oncological conditions, infertility and other sex-hormone dependent conditions, with a low incidence of adverse treatment effects.

Scanning electron microscopy, x-ray diffraction, and electron microprobe analysis of calcific deposits on intrauterine contraceptive devices.

Deposits found intrauterine contraceptive devices (IUDs) were studied by scanning electron microscopy, x-ray diffraction, and energy dispersive x-ray microanalysis. All seven devices, including five plastic and two copper IUDs, were coated with a crust containing cellular, acellular, and fibrillar material. The cellular material was composed of erythrocytes, leukocytes, cells of epithelial origin, sperm, and bacteria. Some of the bacteria were filamentous, with acute-angle branching. The fibrillar material appeared to be fibrin. Most of the acellular material was amorphous; calcite was identified by x-ray diffraction, and x-ray microanalysis showed only calcium. Some of the acellular material, particularly that on the IUD side of the crust, was organized in spherulitic crystals and was identified as calcium phosphate by x-ray microanalysis. The crust was joined to the IUD surface by a layer of fibrillar and amorphous material. It is suggested that the initial event in the formation of calcific deposits on IUD surfaces is the deposition of an amorphous and fibrillar layer. Various types of cells present in the endometrial environment adhere to this layer and then calcify. Thus, the deposition of calcific material on the IUDs is a calcification phenomenon, not unlike the formation of plaque on teeth. Hum Pathol 16:732-738, 1985.

The endometrial approach in contraception.

PIP: Contraceptive techniques that selectively impair endometrium receptivity have the potential to reduce the risk of cardiovascular complications associated with hormonal methods. However, further research is needed to provide better treatment when oral estrogen is contraindicated, to improve tolerance of progestin-only contraceptives, and identify alternative techniques that will not interfere with the endocrine events of the cycle. This article presents an overview of the endometrial approach to contraception. Discussed are endometrium physiology and the mechanisms of hormonal contraception, endometrial modifications following hormonal contraceptive use, emergency contraception, and intrauterine steroid administration. Outstanding research issues include the mechanisms of endometrial bleeding, definition of molecular and cellular targets for an endometrial approach to contraception, progesterone action, integrins, placental protein 14, insulin growth factor binding protein-1, and plasminogen activators. Short-term developments in this area are expected to include the intrauterine administration of steroids and continuous administration of antiprogestins at doses that do not interfere with secretion. Long-term development will focus on defining new targets for a pharmacological approach in a tissue-specific manner.^ieng

A review of the endometrial changes in Norplant users.

PIP: Prolonged exposure to levonorgestrel associated with use of Norplant contraceptive implants leads, in many acceptors, to menstrual irregularities. Endometrial biopsies collected from a group of Norplant acceptors with persistent or prolonged breakthrough bleeding indicated this side effect is associated with proliferative-type endometrium. The number of both proliferative and secretory endometrium was markedly reduced. The stroma showed edema, sloughing, and inflammatory infiltration. Despite chronic levonorgestrel exposure, only 31% of stroma showed poorly developed decidualization. There was no association between endometrial findings and levonorgestrel levels. Hysteroscopy revealed markedly engorged superficial vessels in long-term Norplant users. It is hypothesized that progestin-related bleeding abnormalities may be due to the changes in the vascular system (e.g., damaged vessels) and hemostatic factors. Confirmation of this hypothesis requires detection of the presence of hemostatic plugs in patients with and without abnormal bleeding, study of the perivascular expression of tissue factor, measurement of estrogen and progesterone receptors at bleeding and non-bleeding sites, and identification of factors that increase angiogenesis and the fragility of uterine vessels.^ieng

Pyometra. A complication of cervical cryosurgery.

PIP: In a series of 300 patients at the Duke University Medical Center cryosurgery was performed in cases of abnormal cytology indicative of preinvasis cervical disease. Colposcopy and biopsies were done before freezing. Only minor complications had followed until recently 2 patients developed pyometra within 72 hours after cryosurgery. Both had a previous history of pelvic inflammatory disease. Each had an intrauterine device (IUD) in place. In 20 other patients with IUDs no complications had occurred. An additional 4 patients had an acute exacerbation of pelvic infections during the 1st week after cryosurgery. None were wearing an IUD. Patients with a history of repeated gonococcal infections had residual mixed anaerobic infections are not considered suitable for cryosurgery. Pelvic inflammatory disease may be aggravated by this technique. Pyometra as a side effect may result.^ieng

Role of prostaglandins in IUD-associated uterine bleeding--effect of a prostaglandin synthetase inhibitor (ibuprofen).

Prostaglandins have been shown to be increased in the endometrium of women and experimental animals wearing intrauterine devices (IUDs). As prostaglandins may cause increased vascularity and vascular permeability, and as certain prostaglandins (PgI2) inhibit platelet activity, the local generation of prostaglandins may contribute to endometrial bleeding. Thus, the effect of ibuprofen, a prostaglandin synthetase inhibitor, was tested by quantifying menstrual blood loss in 20 women wearing IUDs in a double-blind, 2-period crossover study. Ibuprofen produced a significant reduction in menstrual blood loss; the percentage reduction was greater in women using a Lippes Loop and who had heavier blood loss (39%) than in women using a copper device and who had lighter blood loss (25%). These findings support the contention that prostaglandin synthesis is important in the genesis of IUD-associated menorrhagia and that prostaglandin inhibitors may be useful in the therapy of this condition.

Ectopic endometrium in omentum. Uterine perforation by Lippes loop.

A case of ectopic endometrium in the omentum following perforation of the uterus by a Lippes Looptm is reported. Evidence is presented substantiating Sampson's theory of endometrial implantation.

PIP: This is a case report of a patient who had an IUD inserted the year following a spontaneous abortion. The next year she became pregnant and delivered a full-term infant. Another IUD was then inserted. After 2 years lower abdominal pain and vaginal bleeding of 2 months duration caused her to ask to have the IUD removed. The thread broke during the removal attempt so the patient was admitted to the hospital where a hysterogram revealed a Majzlin spring partially embedded in the uterine wall and a Lippes loop outside the uterine cavity. The Majzlin spring was removed through the vagina and curettage done. At laparotomy to remove the other IUD the Lippes loop was found embedded in a large mass of omentum. The loop and adherent omentum were removed. Histologic study revealed an area of well-preserved endometrium, an area of hemorrh agic endometrium with leukocytic infiltration, and dense fibrous tissue surrounding the endometriotic foci. These findings support the theory of endometrial transplantation rather than the theory of metaplasia.

Fertility control by intrauterine release of progesterone.

PIP: The contraceptive effectiveness of small amounts of progesterone released in the uterine cavity via a silastic progesterone T IUD was studied. Over 1600 woman-months of use in 249 women were evaluated. The amount of progesterone remaining in 14 capsules revoved 161-200 days after insertion was variable, indicating a possible effect of individual uterine environment on release rates. No pregnancies occurred while devices releasing adequate amounts of progesterone were in situ. 7.9% of the devices were displaced or expelled. Serial plasma hormonal determinations showed no differences between patients with inert and progesterone IUDs. There was no inhibition of ovulation or change in cervical mucus. The mechanism of action is probably related to the decidual changes induced in the endometrial receptors.^ieng

Conception control by a single monthly injection.

PIP: 73 women of childbearing age and proven fertility were injected with dehydroxy-progesterone acetophenide, 150 mg and estradiol enanthate, 10 mg on Day 7, 8, or 9 of a new cycle and on Days 7-9 in succeeding cycles for a total of 929 cycles (1-24 cycles/patient). Patients missing 1 or more injections because of failure to menstruate were started as new patients and no patient was restarted more than 3 times. 69% received 1 series of injections; 24% received 2 series; and 7% received 3 series. There was a moderate prolongation of monthly bleeding. Cycles averaged 2 days shorter than before therapy. There was absolute pregnancy protection. Discontinuation was 45% for this study, most during the first 5 cycles, 1/2 of drug related discontinuation due to abnormal bleeding. Cytology smears, breast examinations and endometrial biopsies repeated before and during therapy were unremarkable.^ieng

Norgestrel, a low dose, oral progestogen for fertility contro. Supplementary report.

PIP: 264 women (about 50% private patients), all less than 40 years old and none with history contraindicating oral contraception, were started on a regimen with Ovral (.5 mg norgestrel and .05 mg ethinyl estradiol). Medication started on Day 5 of a menstrual cycle. Then therapy followed a 3 weeks on, 7 days off schedule. Patients continued for 1-22 cycles (mean 7 cycles) for a total of 1918 cycles. Despite the omission of 42 doses by 32 patients, no pregnancies occurred. The percentages of cycles with average flow, spotting, breakthrough bleeding, and dysmenorrhea were 74.4, 2.5, .4, and .6, respectively. The incidence of amenorrhea, .2%, was spectacularly low in comparison with findings in other studies. Papanicolaou smears (483) were all normal (Class I or II). Morphologic changes seen at endometrial biopsy (61) were similar to those produced by other available progestogen-estrogen compounds. No significant variation from control findings (1878) were found in 1463 laboratory studies. The studies included leukocyte and differential counts (724), and determinations of hemoglobin and hematocrit (388), fasting blood sugar and blood urea nitrogen (114), bilirubin and liver function (61), and renal function (176). Minor symptoms (nausea, vomiting, headache, etc.) were few and disappeared after the first few cycles. The preparation suppresses ovulation (probably through action of the estrogen), probably alters the cervical mucus to inhibit sperm penetration, possibly interferes with nidation, and may interfere with follicular development.^ieng