[Endometrial effects of estro-progestative contraceptives at different dosages].
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Atrophy↗
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Pituitary, ovarian and endometrial effects of progesterone released prematurely during the proliferative phase.
The pituitary, ovarian and endometrial effects of premature exposure to progesterone during the proliferative phase were investigated in 18 normally menstruating women. Daily blood samples were drawn during a control cycle and an endometrial biopsy was obtained on cycle day 6 (in 9 subjects) and on cycle day 11 (in 9 subjects), respectively. Daily blood samples were drawn again throughout a treatment cycle, in which a vaginal delivery system releasing progesterone at a constant rate of 1.4 mg/24 h was inserted and left in situ for 96 hours during cycle days 2-6 (9 subjects) and cycle days 7-11 (9 subjects), respectively. On the 6th and 11th cycle day, respectively, the devices were removed and another biopsy specimen was obtained. In all blood samples the levels of immunoreactive lutropin (LH), estradiol (E2), 17-hydroxyprogesterone (17-HO-P), progesterone (P) and 20 alpha-dihydroprogesterone (20 alpha-HO-P) were estimated by radioimmunoassay. Insertion of the devices resulted in a rapid, approximately six-fold increase (from 0.5 to 3.0 nmol/l) in P levels and an approximately three-fold (from 0.5-0.6 to 1.5-2.0 nmol/l) increase in 20 alpha-HO-P levels. A high degree of correlation was found between P and 20 alpha-HO-P levels. No major changes were observed in the profiles and levels of the other hormonal indices studied. However, premature exposure to small amounts of P during cycle days 2-6 resulted in a significant decrease in the ratio of the E2 to LH peaks and exposure during cycle days 7-11 gave rise to a significant increase in the ratio of the length of follicular to luteal phases. Progesterone released during the early proliferative phase (days 2-6) exerted little, if any, effect on the appearance of the endometrium. However, the same dose of P released during the late proliferative phase (days 7-11) significantly diminished the number of glandular mitoses, the height of the glandular epithelium, reduced pseudostratification and the number of plasmolemmal vesicles, but did not induce any subnuclear vacuolation, predecidual reaction or leucocytic infiltration. It is suggested that systematic studies involving the exposure to progestogens in normally menstruating women during cycle days 7 to 11 will provide a reliable and practical method for the comparative assessment of the potency profile of individual progestogens in women.
17-alpha-Hydroxyprogesterone↗
Endometrial effect of transdermal estradiol and progestin ST-1435 in postmenopausal women.
OBJECTIVE: To study the endometrial effect of the transdermal synthetic progestin ST-1435. DESIGN: Prospective. SETTING: City Maternity Hospital, Helsinki, Finland. PATIENTS: Eleven postmenopausal women used transdermal estradiol (E2) patches for 6 weeks immediately before a vaginal operation for prolapse. For the last 10 days, 1 mg of ST-1435 transdermally in a gel was combined to the treatment. MAIN OUTCOME MEASURES: Blood samples were taken to follow serum concentrations of E2, follicle-stimulating hormone, and ST-1435. Endometrial samples for histologic examination were collected during the operation to evaluate the effect of the progestin. RESULTS: Transdermal absorption of ST-1435 resulted in reasonably constant serum concentrations of ST-1435 in each subject. A progestin effect on the endometrium was seen in 9 of 10 samples obtained. One sample did not show any progestin effect in spite of adequate ST-1435 levels, but this patient's E2 concentrations were low. CONCLUSIONS: When the estrogen stimulation was adequate, the transdermal ST-1435 induced a progestin effect on the endometrium, i.e., it had an end-organ effect.
Administration, Cutaneous↗
Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women.
OBJECTIVE: Our purpose was to assess the endometrial effects of two doses of natural progesterone administered by a bioadhesive vaginal gel in estrogen-treated postmenopausal women. STUDY DESIGN: This was a double-blind, randomized, dose-ranging study of 31 postmenopausal women attending a specialist menopause clinic. Endometrial histologic features, sex steroid hormone concentrations, and vaginal bleeding patterns were assessed during three 28-day cycles of continuous oral conjugated estrogens (0.625 mg/day) and two doses of sequential vaginally administered natural progesterone (45 or 90 mg every 48 hours). Histologic results are presented descriptively. Between-group comparisons of other parameters were made with the use of the Mann-Whitney U and Student t tests. RESULTS: Secretory endometrium was found in 35 of 41 histologic samples that yielded adequate tissue for diagnosis. There was one case of proliferative endometrium in the 45 mg progesterone group and none in the 90 mg group and no cases of hyperplasia. Mean plasma progesterone concentrations of 4.6 ng/ml and 6.8 ng/ml were achieved in the 45 and 90 mg groups, respectively. CONCLUSIONS: Very low doses of natural progesterone, when administered vaginally in a bioadhesive gel, cause secretory endometrial transformation in estrogen-treated postmenopausal women.
Adult↗
Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles.
Previous studies of raloxifene conducted in animal models and postmenopausal women have demonstrated antiestrogenic action on the endometrium. The purpose of this first study of raloxifene in women with normal menstrual cycles was to determine its reproductive endocrine and endometrial effects. In part I, raloxifene (400 mg) was administered for 5 days in the follicular, periovulatory, or luteal phase of the menstrual cycle (n = 12). In part II, women were randomized to receive raloxifene (100 or 200 mg) for 28 days beginning on day 3 of the cycle (n = 19). All women ovulated in both parts of the study. Raloxifene did not alter the length of the menstrual cycle or the day of the LH surge. A 5-day course of raloxifene administered in any phase of the cycle elevated FSH area under the curve (AUC) for the entire cycle and estradiol AUC for the second half of the cycle compared with those in control cycles. In part II, raloxifene also appeared to increase the FSH AUC and estradiol AUC. Raloxifene decreased the number of gland mitoses in follicular phase endometrial biopsies. Subtle effects suggestive of gland-stromal dysynchrony were noted in a limited number of the secretory phase endometrial biopsies. This study has demonstrated that 1) raloxifene does not prevent ovulation in women with normal menstrual cycles; 2) ovarian estrogen production will continue, and in some cases increase, in response to raloxifene; and 3) antiestrogenic effects of raloxifene on the endometrium are subtle in the endocrine milieu of normal to high circulating estradiol concentrations.
Adult↗
Endometrial effects of three doses of trimegestone, a new orally active progestogen, on the postmenopausal endometrium.
OBJECTIVE: To study the effects of oral trimegestone on endometrial histology and vaginal bleeding when given in combination with oral 17-beta-oestradiol. METHODS: This was a prospective, randomised, double-blind, parallel groups, pilot comparative study. Thirty-eight healthy postmenopausal women with normal endometrial histology were given oral 17-beta-oestradiol, 2 mg/day for three continuous cycles of 28 days, plus oral trimegestone, 0.10, 0.25 or 0.50 mg/day from day 15 to day 28 of each cycle. A Vabra biopsy was performed late in the oestradiol/trimegestone phase of cycle 3 and examined for histological evidence of secretory transformation of the endometrium. Characteristics of vaginal bleeding were recorded on a daily basis. RESULTS: Thirty-seven women completed the study, of whom 31 yielded adequate tissue for histological assessment. All showed secretory transformation of the endometrium. Bleeding was of earlier onset and longer duration with the lowest dose of trimegestone. CONCLUSIONS: Trimegestone is a highly effective oral progestogen for endometrial protection, all doses inducing secretory endometrial transformation. Although bleeding patterns suggest a weaker effect of the lowest dose used, the minimum effective dose for endometrial protection has still to be determined and may be lower than those used in this study.
Administration, Oral↗
Pharmacokinetics and endometrial effects of the vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women.
OBJECTIVE: To study the pharmacokinetics of the transvaginal absorption of 100 mg micronized P from an oil-based solution in postmenopausal women before and after the estrogenization of the vaginal mucosa and to evaluate the endometrial effects of 10 days of once daily P vaginal administration. DESIGN: Prospective clinical trial. SETTING: University Medical School. PATIENTS: Nine postmenopausal women undergoing hormone replacement therapy. INTERVENTIONS: A micronized P (100 mg) oil-based solution currently available on the market for IM use was administered vaginally by means of a Teflon cannula without the aid of a speculum. Subsequently, the women received 4 weeks 0.1 mg/d transdermal E2 treatment combined on the last 10 days with the once daily vaginal administration of P in the same way as before. MAIN OUTCOME MEASURES: At the first (before estrogen) and second (during estrogen therapy) P administrations, P serum levels were measured at time 0, and then after 15, 30, 45, 60, 120, 240, 480, and 1440 minutes. Endometrial samples were collected at the end of treatment. RESULTS: After the first administration, a mean Cmax of 5.40 +/- 0.92 ng/mL (mean +/- SD) was reached at a Tmax of 45 minutes (range 30 to 480 minutes). The serum concentrations returned to their initial values after 24 hours. The second P administration reached a mean Cmax of 5.30 +/- 1.04 ng/mL at a Tmax of 60 minutes (range 30 to 240 minutes); after 24 hours, the serum P levels still were significantly higher than at baseline and at the same time after the first administration. None of the women complained of significant vaginal losses. No signs of vaginal phlogosis or irritation were observed. In all subjects, histologic evaluation showed clear endometrial secretory changes. CONCLUSIONS: The daily vaginal administration of one vial of micronized P for 10 days allowed useful serum P levels to be reached, especially after estrogen therapy, and induced clear secretory changes in the endometrium.
Administration, Cutaneous↗
Contraceptive and endometrial effects of medroxyprogesterone acetate.
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Adult↗
Pituitary, ovarian and endometrial effects of 300 micrograms norethisterone and 30 micrograms levonorgestrel administered on cycle days 7 to 10.
The ovarian, endometrial and pituitary effects of 300 micrograms norethisterone (NET) and 30 micrograms levonorgestrel (L-NOG) administered orally on cycle days 7-10 were investigated in two groups of 10 women each, by daily analysis of plasma estradiol (E2), progesterone (PROG), immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a pretreatment control cycle and during NET or L-NOG administration. Endometrial biopsies were obtained for morphometric analysis on cycle day 11 in the control and treatment cycles. Treatment with 300 micrograms NET resulted in an increase in the area under the E2 peak (p less than 0.05), reduction in the number of subjects with normal progesterone profile (p less than 0.05) and a decrease in the area under the progesterone curve (p less than 0.05). The treatment suppressed the LH peak in 4 subjects and progesterone in 4 subjects. The follicular phase was prolonged in one subject. Norethisterone induced marked subnuclear vacuolation in the endometrium, while the glandular mitoses were decreased during NET treatment. Treatment with 30 micrograms L-NOG resulted in a decrease in subjects with normal progesterone profiles (p less than 0.05) and in the area under the progesterone curve (p less than 0.05). The treatment suppressed the LH peak in 3 subjects and progesterone in 4 women. The follicular phase was prolonged in one subject. L-NOG did not significantly increase the diameter of glands or induce subnuclear vacuolation in the endometrial glands.
Adult↗
Endometrial effects of long-term low-dose administration of RU486.
OBJECTIVE: To examine endometrial response to long-term low-does RU486 administration. DESIGN: Retrospective controlled study of women with endometriosis treated for 6 months with 50 mg RU486 daily for 6 months. Controls consisted of women in the follicular phase of a spontaneous cycle undergoing endometrial biopsy. SETTING: Patients from the clinical practice of the authors at the University of California, San Diego Medical Center. PATIENTS AND INTERVENTIONS: Nine patients treated with long-term low-dose RU486 and nine normal cycling controls undergoing hysterectomy or endometrial biopsy for benign disease. MAIN OUTCOME MEASURES: Changes in endometrial morphology and immunohistochemical analysis for estrogen receptor (ER) and progesterone receptor (PR) protein. RESULTS: All patients treated with RU486 exhibited abnormal endometrial morphology. The endometrial glands were irregular in size and shape. The stroma was varied but consisted predominantly of dense cellular stroma with frequent mitotic figures. The glands were lined by a combination of epithelial types some of which were secretory. No cytologic atypia was seen. Levels of ER immunoreactivity, as determined by image analysis, were greater in the stroma with no difference in PR immunoreactivity compared with controls. No difference in ER and PR immunoreactivity were seen in the glands compared with normal controls. CONCLUSION: The generalized cystic changes demonstrated are consistent with a chronic unopposed estrogen effect and are concordant with hormonal data showing early to midfollicular phase levels of estrogens. They also are consistent with our findings of increased ER immunoreactivity in the stroma. Evidence of minimal P agonist effect was noted.
Adolescent↗
Endometrial effects of transdermal estradiol/norethisterone acetate.
The efficacy of transdermal norethisterone acetate in sequence with transdermal estradiol has been investigated in a multicenter study of 136 post-menopausal women to determine the incidence of endometrial hyperplasia, the effects on the vaginal cytology and the control of bleeding. Treatment consisted of 12 cycles of 4 weeks each (2 weeks estradiol 50 micrograms/day followed by 2 weeks of a new combined patch delivering norethisterone acetate 0.25 mg/day and estradiol 50 micrograms/day). Endometrial histology was assessed by two pathologists. Of the 136 pre-treatment biopsies 89% provided no material, an inadequate sample or an inactive (atrophic or non-secretory) endometrium. Of the post-treatment biopsies from 110 women who completed the study: 65% showed secretory, 3% proliferative and 24% inadequate material or inactive endometrium. Hyperplasia was found in two biopsies (2%); in one of these focal atypical hyperplasia was agreed by both pathologists, in another a hyperplastic endometrial polyp was diagnosed by one pathologist. The bleeding was regular in 80% of the 1195 cycles and irregular in 11%. No bleeding occurred in 9% of the cycles. Vaginal cytology showed a significant shift towards increased maturation during treatment.
Administration, Cutaneous↗
GnRH agonist for postpartum contraception: biochemical, hormonal and endometrial effects.
OBJECTIVE: To determine whether GnRH agonist administration induces changes in biochemical, hormonal and endometrial parameters in breastfeeding women. DESIGN AND PATIENTS: Starting at 6 weeks postpartum, fully breastfeeding mothers began treatment with GnRH agonist, receiving 300 micrograms and 600 micrograms per day by nasal spray for 6 months. A third group of breastfeeding women who were users of IUDs served as controls. Eighteen biochemical analyses were quantified in serum. Blood samples were collected at 0, 3 and 6 months after treatment and endometrial biopsies were obtained at 0 and 6 months. No other method of contraception was employed. RESULTS: Interindividual and intergroup differences were observed in clinical chemistry. According to the hormonal levels and the histopathologic analysis, various grades of follicular activity were found in the treated groups. No pregnancies occurred. CONCLUSION: Because GnRH agonist treatment had no significant deleterious effects on the parameters studied, this treatment could represent a feasible and safe approach to postpartum contraception.
Administration, Intranasal↗
Endometrial effects of levonorgestrel and estradiol: A Scanning electron microscopic study of the luminal epithelium.
Fertile women in the follicular phase possessed an uterine luminal surface with many ciliated cells and with non-ciliated cells, which carried numerous, fairly long microvilli. A moderate number of the non-ciliated cells had an irregular surface with small apical protrusions. Postmenopausal women had an endometrial surface containing rather flat cells. Ciliated cells were seldon encountered, and the non-ciliated cells possessed mostly only few short microvilli. When menopausal women had been wearing estradiol-containing intravaginal rings for three weeks, the uterine surface had developed many ciliated cells, and the non-ciliated cells now possessed many long microvilli. This appearance resembles that appearing during the follicular phase. Fertile women with levonorgestrel-containing subdermal implants or intravaginal rings showed a surface epithelium with few ciliated cells and with non-ciliated cells possessing short and irregular microvilli; that is, an epithelium less developed than that from a cyclic women. Adding estradiol to the levonorgestrel-containing intravaginal rings resulted in an estrogen response with an increase in number and length of the microvilli and an appearance of a few small apical protrusions.
Endometrium↗
Endometrial effect of oral estriol treatment in postmenopausal women.
Estriol is a weak estrogen with a claimed specific action on the epithelium in cervix uteri and vagina and with no or limited ability to induce endometrial proliferation. In a previous pharmacokinetic study we have shown elevated estriol levels for only 2-3 hours after oral administration of the drug. The present study was performed to test if estriol, when given orally in daily divided doses to postmenopausal women, has any effect on the endometrium. Twenty postmenopausal women who had no vaginal bleeding in response to lynestrenol (Orgametil 5 mgX2XV) were treated with 6 mg estriol a day (Ovesterin 2 mgX3), divided into three doses, for 2 up to 3.5 months. When lynestrenol (5 mgX2XV) was given following the estriol treatment periods, 12 women out of 20 experienced a vaginal bleeding and one reported spotting. Endometrial biopsies in ten of these women who had a bleeding were examined histologically. The endometrium was atrophic in four women, proliferative in two, slightly hyperplastic in one and showed signs of weak hormonal activity in one. Two women had secretory endometrium. It is concluded that estriol, administered in a way that gives prolonged elevation of the blood levels, is able to produce the same effect on the endometrium as other estrogens.
Administration, Oral↗
Review of the endometrial effects of estrogens and progestins.
Several controversial areas have been reviewed. It would seem from the evidence at hand that progression from endometrial hyperplasia to endometrial carcinoma does occur in a significant percentage of women and that endometrial hyperplasia, particularly adenomatous hyperplasia and atypical hyperplasia, must be regarded as premalignant changes. Gambrell believes that all stages of hyperplasia should be regarded as premalignant. Previous and retrospective studies provide evidence implicating estrogens in the causation of both endometrial hyperplasia and endometrial carcinoma. Although some of these studies may have design flaws, the amount of data is substantial. Prospective studies have demonstrated an increased risk of hyperplasia in women treated with estrogens. An increased risk of endometrial carcinoma in estrogen users compared with nonusers has been suggested even more recently. Reviewed as a whole, the cumulative evidence provided by these studies clearly supports this association, and it would appear the only issue left to resolve may be the magnitude of the association. Cyclic administration of estrogens may decrease the risk of development of endometrial carcinoma. It would seem, however, that such administration does not totally eliminate risk under any circumstances, and in fact, a dose-related relationship appears to persist. It seems well established that progestogens do decrease the risk of both endometrial hyperplasia and endometrial carcinoma associated with the administration of estrogen to peri- and postmenopausal women. Such reduction in risk is significant and lower relative risks in estrogen/progestogen treated women have been reported compared to untreated women. This reduction in risk has been reported in a variety of studies. Whitehead and co-workers have provided a clear biochemical mechanism for progestogen protection of the endometrium in the antagonism of estrogen at the endometrial cellular level. The evidence at hand in the literature would suggest that progestogens should be administered for at least 10 days per cycle. In summary, there is good evidence that the addition of a progestin to estrogen therapy prescribed for the symptoms of menopause provides protection from endometrial hyperplasia and related carcinoma. The protection conferred is greater than that afforded by cyclical estrogen-alone therapy, and allows for continuous therapy, hereby providing greater symptomatic relief. There is little evidence for adverse effects caused by the added progestins, but further studies of women on combined therapy will undoubtedly be warranted.
Endometrial Neoplasms↗
Endometrial effects of RU486 in primates--antiproliferative action despite signs of estrogen action and increased cyclin-B expression.
Continuous antiprogestin administration to hormone replaced, castrate monkeys inhibits estrogen-induced endometrial proliferation through mechanisms which remains unclear. To elucidate the molecular mechanisms of RU486-induced endometrial suppression, we treated six intact female cynomolgus monkeys on cycle days 2-22 sequentially with placebo, RU486 (1 mg/kg/day) and levonorgestrel (LNG) (2 microg/kg/day) intramuscularly (i.m.), with uterine wedge sections and endometrial biopsies collected on day 22 of each cycle. The uterine sections were evaluated for morphology, mitosis and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Changes in the mRNA levels of ER, PR, cyclin-B and tumour suppressor gene p21 were assessed using co-amplification with beta-actin by reverse transcriptase-polymerase chain reaction (RT-PCR). Administration of RU486 uniformly resulted in characteristic suppression of endometrium with few mitosis, dense stroma and simple glands, whereas the effects of LNG were less uniform. Following RU486 administration, the levels of endometrial ER and PR mRNA were comparable to proliferative phase endometrium, and significantly higher than those seen in the secretory endometrium, indicating that some of the biological actions of E2 were not inhibited during RU486 treatment. Despite scarce mitosis, PCNA was readily detectable in all samples. Curiously, in comparison to secretory phase controls, the levels of cyclin-B, but not p21, mRNA were markedly increased following RU486. The effects of LNG on the levels of these mRNA species varied, with mean levels falling between those of the secretory phase controls, and RU486-treated specimens. The increase in cyclin-B mRNA and lack of mitosis suggests that anti-proliferative actions of RU486 in the primate endometrium might be associated with a cell-cycle block at the G2-M interphase. Whether mechanisms similar to these are associated with the beneficial clinical effects of RU486 seen in the treatment of various hormone dependent maladies remains to be determined.
Animals↗
Endometrial effect of vaginal estriol treatment. A scanning electron microscopic study of the luminal surface.
Estriol, 0.5 mg, was administered intravaginally as ovula once a day for 16 days to 5 menopausal women. Endometrial biopsies were taken before and after the last day of treatment. Before the treatment scanning electron microscopy showed a typical menopausal uterine surface with sparsely occurring ciliated cells among the non-ciliated ones. The non-ciliated cells possessed a small number of short microvilli. After estriol treatment the ciliated cells occurred more frequently. The cells possessed more numerous and longer microvilli and several non-ciliated cells showed apical protrusions. These changes are considered to be signs of an estrogenic influence. It is concluded that the estriol release from the vaginal ovula is sufficient to induce an estrogenic response in the surface of the uterine epithelium.
Aged↗
Endometrial effects of danazol in perimenopausal abnormal bleeding.
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Cells, Cultured↗