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Effect of Long-Term Combined Oral Contraceptive Pill Use on Endometrial Thickness
Abstract
To estimate whether there is any association of long-term use of combined oral contraceptive pills (OCP) with adverse endometrial growth.
We reviewed the charts of 137 patients with history of OCP use undergoing endometrial preparation with estrogen for frozen embryo transfer. Endometrial thickness was measured by transvaginal ultrasonography on day 10 after menses and patients were divided into two groups (less than 7 mm and 7 mm or more).
Thirty patients had endometrial thickness less than 7 mm and 107 had thickness of 7 mm or more. Mean years of combined OCP use in each group were 9.8±4.54 and 5.8±4.52, respectively (P<.001). With 10 years of combined OCP use as the threshold, the difference between the two groups (63.35% users in less than 7 mm group compared with 28.04% in the 7 mm or more thickness group) was highly significant (P<.001 by Fisher exact test), with an odds ratio of 4.43 (95% confidence interval 1.89-10.41). Past use of 5 years of OCPs was also associated with a significant (P=.002) difference in endometrial thickness. The mean endometrial thicknesses on cycle day 10 in patients using combined OCP for less than 10 years and 10 years or more were 9.54±1.88 mm and 8.48±2.33 mm, respectively, with P=.007. The mean endometrial thickness was 9.72±1.69 mm in less than 5 years and 8.81±2.23 mm in 5 or more years of use, respectively (P=.008). Cycle cancellation rates in the less than 7 mm group and 7 mm or greater endometrial thickness group were 23% and 4%, respectively (P=.002), but there was no difference in the clinical pregnancy rates between the two groups (13% compared with 27%, respectively; P=.15).
Long-term combined OCP use (5 years or more) can potentially affect optimal endometrial growth, leading to a higher cancellation rate and longer stimulation in frozen embryo transfer cycles. These findings suggest a previously unidentified adverse effect of long-term combined OCP use in women who are anticipating future fertility.
II.
... However, Mina [18,19] and others have studied the factors related to the blood flow and the growth of the inner membrane of the thin uterus and found the common characteristics of the thin inner membrane: the increase of the blood flow resistance of the inner membrane and the decrease of the blood supply lead to the damage of the development of glandular epithelial cells and the growth of the inner membrane of the blood tube, (VEGF) expression decreased, which resulted in poor vascular growth in the endometrium, which in turn affected the blood flow in the endometrium. The process was repeated repeatedly, and the most end-result was that the growth of the inner membrane was limited by thin endometrium [20]. ...
The purpose of this experiment is to establish a rat model of thin endometrium and to explore the effect of ligustrazine on the thin endometrium of rats. The thin endometrium model was made by using infusing absolute ethyl alcohol into the uterine cavity. The thickness of endometrium was measured. Hematoxylin-Eosin (HE) staining was used to observe the histopathological changes of endometrium. The mRNA levels of VEGF, VEGFR-2, PI3K, and AKT were detected by RT-PCR. Western blotting was used to detect the levels of VEGF, VEGFR-2, PI3K, and AKT in endometrial tissue. The thickness of endometrium in the model group was significantly thinner than that in the control group. Compared with the model group, the thickness of endometrium in ligustrazine group was increased. HE staining shown that ligustrazine restored the histopathological changes of endometrium. RT-PCR and Western Blotting results showed that the mRNA and protein levels of VEGF, VEGFR-2, PI3K, and AKT in the model group were significantly decreased compared with the control group, while ligustrazine restored the changes. Ligustrazine can improve the morphology of endometrium, can promote the growth of endometrium, and has obvious therapeutic effect. Its mechanism is related to the activation of PI3K/Akt signaling pathway through upregulation of VEGF and VEGFR-2 expression to induce the repair of thin endometrium in rats.
... Moreover, the long-term use of OCPs for several years may result in endometrial thinning that is nonresponsive to estrogen. 3 This adverse effect of long-term use may be crucial for women with endometriosis who want to conceive. ...
Endometriosis is a chronic inflammatory disorder associated with pelvic pain and infertility. Because surgical and medical therapies control symptoms, but it is hard to cure completely endometriosis, long term of pharmacologic management is necessary. Norethisterone (NET), one of progestins, has safety profile and advantage that allow long-term use. In this preliminary report, we showed the efficacy of NET in 6 patients with endometriosis. The size of ovarian endometrioma was decreased after treatment with NET for 6 months, and all patients were relieved from dysmenorrhea pain within 6 months, suggesting that NET would be a suitable medication to treat endometriosis. © 2017, Tottori University Faculty of Medicine. All rights reserved.
... While the use of medical therapeutics including contraceptive steroids, progestins, aromatase inhibitors, agonists of gonadotropin-releasing hormone and non-steroidal anti-inflammatory agents are helpful to relieve pain, the use or ceasing use of these agents rarely improves fertility [18][19][20]. Additionally, the side effects of long term use can be detrimental; for example, the use of oral contraceptives has been show to affect endometrial thickness and growth [21]. Due to Oncotarget 2 www.impactjournals.com/oncotarget ...
Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure.
... Some studies have suggested that administration of exogenous E 2 may lead to lower expression of endometrial receptivity markers in regularly menstruating patients [Ma et al. 2003]. It has also been noted in a recent study that oral contraceptive pills, in which the main effective substance is E 2 , can potentially affect optimal endometrium growth [Talukdar et al. 2012]. Therefore, artificial cycles in which exogenous estrogen and progesterone were administrated may interfere with endometrium readiness. ...
There is no consensus regimen for the optimal endometrial preparation for cryopreservation and vitrified-thawed embryo transfer cycles. This is largely caused by the lack of sufficient investigation and analyses on the respective pregnancy and perinatal outcomes by different regimens. This study aimed to compare both pregnancy and perinatal outcomes between the modified natural and artificial cycles in vitrified-thawed day three embryo transfer for women with regular menstruation. A total of 1,482 vitrified-thawed day three embryo transfer cycles were reviewed including 427 modified natural cycles (NC), 132 ovulation induction cycles (OC), 794 artificial cycles (AC), and 129 GnRH agonist artificial cycles (GAC). The primary outcome that was evaluated was live birth rate. The NC regimen demonstrated a higher rate of ongoing pregnancy (43.8% vs. 30.2%, P = 0.002) and a lower rate of late abortion (2.8% vs. 14.0%, P = 0.003) than the GAC regimen as well as a higher implantation rate (31.9% vs. 27.1%, P = 0.008) and live birth rate (43.1% vs. 34.1%, P = 0.002) than the AC regimen. A significantly higher peak endometrial thickness before transfer was observed in patients using the NC and GAC regimens (10.0 ± 1.7, 9.9 ± 2.4) compared to the AC regimens (9.2 ± 1.5, P = 0.000). Multivariate logistic regression showed that the NC protocol was associated with a higher live birth rate. There were no significant differences in rates of pregnancy complications, neonatal mortality, birth defects, mean birth weight, and other perinatal outcomes among the regimens. Modified natural cycle endometrial preparation regimen for vitrified-thawed day three embryo transfer is associated with superior live birth pregnancy outcomes compared to artificial cycles. Future studies are warranted to investigate the underlying biologic mechanisms of these findings. Abbreviations ART: assisted reproductive technology; BMI: body mass index; FET: frozen-thawed embryo transfer; HCG: human chorionic gonadotropin; IVF: in-vitro fertilization; IVF-ET: in-vitro fertilization and embryo transfer; OHSS: ovarian hyperstimulation syndrome; RCTs: randomized controlled trials.
... 17 Bone health with medically induced amenorrhea The constant inhibition by oral synthetic estrogen and progesterone during continuous COC use leads to suppression of hypothalamic and pituitary release of follicle-stimulating hormone and luteinizing hormone. 18 This in turn impacts bioavailable levels of estrogen and progesterone. Estrogen inhibits bone resorption through its actions on osteoclastic activity and has anabolic effects on osteoblasts. ...
Medically induced amenorrhea can be achieved through alterations in the normal regulatory hormones via the adoption of a therapeutic agent, which prevents menstrual flow. Spaceflight-related advantages for medically induced amenorrhea differ according to the time point in the astronaut’s training schedule. Pregnancy is contraindicated for many pre-flight training activities as well as spaceflight, therefore effective contraception is essential. In addition, the practicalities of menstruating during pre-flight training or spaceflight can be challenging. During long-duration missions, female astronauts have often continuously taken the combined oral contraceptive pill to induce amenorrhea. Long-acting reversible contraceptives (LARCs) are safe and reliable methods used to medically induce amenorrhea terrestrially but as of yet, not extensively used by female astronauts. If LARCs were used, daily compliance with an oral pill is not required and no upmass or trash would need disposal. Military studies have shown that high proportions of female personnel desire amenorrhea during deployment; better education has been recommended at recruitment to improve uptake and autonomous decision-making. Astronauts are exposed to similar austere conditions as military personnel and parallels can be drawn with these results. Offering female astronauts up-to-date, evidence-based, comprehensive education, in view of the environment in which they work, would empower them to make informed decisions regarding menstrual suppression while respecting their autonomy.
... Dilatation and curettage is notorious for its associated risk of permanently thin endometrium and intra-cavitary adhesions, especially if done post-partum [29]. Abnormal response to estrogen as a cause of a persistently thin endometrium is well documented, and might be a result of several different mechanisms; the anti-estrogenic effect of clomiphene citrate [30], prolonged exposure to combined birth control pills [31] and progesterone contraception. The continuous exposure to the progestin in the oral contraceptives leads to down regulation of estrogen receptors and as a result induces atrophy of the glandular epithelium and form a distinct morphological pattern of atrophic glandular epithelium against a background of secretory glands [32]. ...
Introduction: Steroid hormones are responsible for specific changes in the endometrium during the menstrual cycle, when they are sequentially secreted and, because of this, in the early days sequential combined oral contraceptive regimens were utilized. The same basic concept has been utilized with multi-phasic regimens, in order to produce endometrial pictures mimicking the normal cycle.
Areas covered: The Endometrial effects of: progestins and estrogens; combined monophasic high- (50μg), medium- (30μg), low- (20μg), ultralow- (15μg) estrogen content; sequential regimens; multiphasic combinations; treatment schedules.
Cervical effects of combined high-dose and sequential combinations, including evidence for an increase in malignant lesions.
Expert commentary: Overall, combined oral contraceptives (COCs) inhibit normal proliferative changes and the endometrium becomes thin, narrow, with widely spaced glands and pre-decidual changes in the stroma. During the first few cycles the progestin induces a coexistence of proliferative and secretory features; with time, the picture changes because the progestin induces a down-regulation of estrogen receptors, resulting in tortuous glands similar to those in the secretory phase, but characterized by a quiescent, atrophic glandular epithelium.
In the cervical epithelium, under the influence of high-dose COCs, endocervical glands became hypersecretory and in some instances, distinctive type of atypical polypoid endocervical hyperplasia, is found.
Many of the effects of estrogens on the uterus are mediated by ERα, the predominant ER in the mature organ. Because of the
poor reproductive capacity of ERβ knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of
uterine ERβ was explored. In the immature uterus, ERα and ERβ are expressed at comparable levels in the epithelium and stroma,
and 17β-estradiol (E2) treatment decreases ERβ in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone
receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E2, as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the
luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1β, and induction of vascular endothelial
growth factor and insulin-like growth factor 1 but not its receptor. As expected, E2 increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E2 induced PR in the stroma but did not down-regulate it in the epithelium. Increased cell proliferation and exaggerated response
to E2 in BERKO suggest that ERβ plays a role in modulation of the effects of ERα and in addition (or as a consequence of this)
has an antiproliferative function in the immature uterus.
We examined the molecular mechanisms of the antiestrogenic effects of clomiphene citrate (CC) in the endometrium using two types of cell lines, Ishikawa and EM-E6/E7/hTERT cells. CC or ICI182780 inhibited 17beta-estradiol (E2)-induced endometrial cell proliferation and transcriptional activation of the estrogen response element (ERE) gene. We directly visualized the ligand-estrogen receptor (ER)alpha interaction using green fluorescent protein (GFP)-tagged ER alpha in a single living cell. Whereas E2 changed the nuclear localization of GFP-ER alpha to a punctate distribution within 5 min, CC or ICI182780 changed the slower and less mobilization of GFP-ER alpha compared with E2. Pretreatment with CC or ICI182780 partly prevented the E2-induced nuclear redistribution of GFP-ER alpha. Fluorescence recovery after photobleaching revealed that GFP-ER alpha mobility treated with E2 was more rapid than that treated by CC or ICI182780. As coactivator recruitment to the ER is essential for ER-dependent transcription, we examined the interaction between ER alpha and steroid receptor coactivator-1 (SRC-1). The complex formation between ER alpha and SRC-1 was significantly increased by E2 but was prevented in the presence of CC or ICI182780 by coimmunoprecipitation. Moreover, the E2-induced colocalization of GFP-ER alpha and SRC-1 was prevented in the presence of CC or ICI182780 according to an immunofluorescence assay. We also observed that the reduction of SRC-1 using small interfering RNA for SRC-1 resulted in the inhibition of E2-induced cell proliferation and transcriptional activation of the ERE gene. Collectively, these results suggest that CC may inhibit E2-induced endometrial epithelial cell proliferation and ERE transactivation by inhibiting the recruitment of SRC-1 to ER alpha.
We set out to estimate the value of ultrasonographic parameters as prognostic indicators of implantation following in-vitro fertilization (IVF) and embryo transfer. Our survey included 414 natural cycles, 3558 cycles following ovarian stimulation for IVF and embryo transfer, and 411 cycles with hormone replacement therapy for oocyte donation, reviewing 27 reports identified in a computerized literature research. The ultrasonographic prognostic indicators for implantation evaluated included peri-ovulatory endometrial thickness and pattern and Doppler measurements of uterine artery blood flow. Topics include: definitions of the ultrasonographic parameters proposed to evaluate uterine receptivity; the clinical context in which they were used; the proposed optimal timing for sonographic evaluation; and, finally, their actual correlation with pregnancy rate following assisted reproductive technologies. For various sonographic parameters, negative predictive value, positive predictive value, sensitivity and specificity were calculated, based on published data. Sonographic parameters had a high negative predictive value and sensitivity, but a limited positive predictive value and low specificity. Several confounding factors may influence the interpretation of reports, and the statistical evaluation sometimes lacks calculation of the positive and negative predictive values of the parameters examined. Although ultrasonographic parameters of endometrial receptivity have a strong negative value in setting some minimum criteria, their value as prognostic indicators for implantation following embryo transfer has yet to be proved.
A total of 150 patients were submitted to in-vitro fertilization (IVF) and endometrial pattern and thickness were assessed
on the day of administration of human chorionic gonadotrophin (HCG). Ovarian stimulation was performed with gonadotrophins
[human menopausal (HMG) or follicle stimulating hormone (FSH)] after down-regulation with leuprolide acetate. The endometrium
was evaluated by vaginal ultrasound and classified into two groups: pattern I (a ‘triple line’ multilayer) and pattern II
(fully homogeneous and hyperechogenic in relation to myometrial tissue). Pattern I was detected in 129 cycles (86%) and pattern
II in 21 cycles (14%). The clinical pregnancy rates per cycle were similar (P = 0.79) for pattern I (29.4%) and pattern II (33.3%). There was no significant difference (P = 0.40) in the number of miscarriages between patients with pattern I and those with pattern II. Endometrial thicknesses
were similar (10.3 ± 2.0 mm and 11.2 ± 3.1 mm) (P = 0.25). The thicknesses were similar (P = 0.14) for pregnant (10.8 ± 2.1 mm) and non-pregnant (10.2 ± 2.2 mm) women, but no pregnancies occurred when thickness was
< 7.0 mm. However, there was a significant difference (P = 0.04) between pregnant (10.8 ± 1.9 mm) and non-pregnant (10.0 ± 1.9 mm) women who showed pattern I. The conclusions from
these data are that endometrial ultrasound in terms of pattern and thickness is of no prognostic value in IVF cycles on the
day of administration of HCG. However, a minimum thickness has to be achieved for pregnancy to occur (7.0 mm). The presence
of pattern I appears more likely to favour pregnancy.
The endometrial tissue is a sensitive target for steroid sex hormones and is able to modify its structural characteristics with promptness and versatility. This article discusses briefly endogenous hormonal effects (cyclic changes, luteal phase defect, unopposed estrogen effect) and describes the histologic patterns encountered in the most commonly used hormone therapies: oral contraceptives, ovulation stimulation, hormone replacement therapy, and antitumoral hormone therapy. Oral contraceptives exert a predominant progestational effect on the endometrium, inducing an arrest of glandular proliferation, pseudosecretion, and stromal edema followed by decidualized stroma with granulocytes and thin sinusoidal blood vessels. Prolonged use results in progressive endometrial atrophy. Ovulation induction therapy accelerates the maturation of the stroma and is often associated with a discrepancy between early secretory glands and an edematous or decidualized stroma with spiral arterioles. Hormone replacement therapy with estrogen alone may result in continuous endometrial proliferation, hyperplasia, and neoplasia. The use of both estrogen and progesterone elicits a wide range of histologic patterns, seen in various combinations: proliferative and secretory changes, often mixed in the same tissue sample; glandular hyperplasia (in polyps or diffuse) ranging from simple to complex atypical; stromal hyperplasia and/or decidual transformation; epithelial metaplasia (eosinophilic, ciliated, mucinous); and inactive and atrophic endometrium. Progesterone therapy for endometrial hyperplasia and neoplasia induces glandular secretory changes, decidual reaction, and spiral arterioles. Glandular proliferation is usually arrested, but neoplastic changes may persist and coexist with secretory changes. Lupron therapy produces a shrinking of uterine leiomyomas by accelerating their hyaline degeneration, similar to that in postmenopausal involution. It generally produces endometrial atrophy. Tamoxifen for breast carcinoma has an estrogen agonist effect on the uterus in approximately 20% of patients, who develop endometrial polyps, glandular hyperplasia, adenomyosis, and/or leiomyomata. Both endometrioid and nonendometrioid carcinomas are seen, often in polyps. Their causal relationship to tamoxifen therapy is debatable.
The aim of this study was to investigate the association of total duration of oral contraceptive usage with time to conception.
This was a prospective study of 8497 planned pregnancies drawn from a population that recruited 85% of eligible couples in South-West England who were expecting a baby in a 21 month period. Self-completion questionnaires were administered at 18 weeks gestation to ascertain parity, paternity, co-habitation, use of the contraceptive pill, smoking and alcohol status, educational achievement, height, weight and time taken to conceive. Logistic regression was used to identify factors independently related to conception in < or =12 months.
Of the participants, 74% conceived in < or =6 months, 14% in 6-12 months and 12% after 1 year. Previous prolonged oral contraceptive usage was statistically significantly associated with a decreased risk of delayed conception. Prolonged use of oral contraception was also associated with improved fecundity independent of other factors. Selection bias due to particularly fertile women using oral contraceptives is unlikely because similar odds ratios were calculated for nulligravid women.
Women who have prolonged use of oral contraceptives might be reassured that they will not be disadvantaged in terms of time taken to achieve conception.
Many of the effects of estrogens on the uterus are mediated by ER alpha, the predominant ER in the mature organ. Because of the poor reproductive capacity of ER beta knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of uterine ER beta was explored. In the immature uterus, ER alpha and ER beta are expressed at comparable levels in the epithelium and stroma, and 17 beta-estradiol (E-2) treatment decreases ER beta in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E-2, as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1 beta, and induction of vascular endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E-2 increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E-2 induced PR in the stroma but did not down-regulate it in the epithelium, Increased cell proliferation and exaggerated response to E-2 in BERKO suggest that ER beta plays a role in modulation of the effects of ER alpha and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.
Background Oral contraceptives were introduced almost 50 years ago, and over 100 million women currently use them. Oral contraceptives can reduce the risk of ovarian cancer, but the eventual public-health effects of this reduction will depend on how long the protection lasts after use ceases. We aimed to assess these effects. Methods Individual data for 23 257 women with ovarian cancer (cases) and 87 303 without ovarian cancer (controls) from 45 epidemiological studies in 21 countries were checked and analysed centrally. The relative risk of ovarian cancer in relation to oral contraceptive use was estimated, stratifying by study, age, parity, and hysterectomy. Findings Overall 7308 (31%) cases and 32 717 (37%) controls had ever used oral contraceptives, for average durations among users of 4 . 4 and 5 . 0 years, respectively. The median year of cancer diagnosis was 1993, when cases were aged an average of 56 years. The longer that women had used oral contraceptives, the greater the reduction in ovarian cancer risk (p<0. 0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat attenuated over time the proportional risk reductions per 5 years of use were 29% (95% CI 23-34%) for use that had ceased less than 10 years previously, 19% (14-24%) for use that had ceased 10-19 years previously, and 15% (9-21%) for use that had ceased 20-29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The incidence of mucinous tumours (12% of the total) seemed little affected by oral contraceptives, but otherwise the proportional risk reduction did not vary much between different histological types. In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1 . 2 to 0 . 8 per 100 users and mortality from 0 . 7 to 0 . 5 per 100; for every 5000 woman-years of use, about two ovarian cancers and one death from the disease before age 75 are prevented. Interpretation Use of oral contraceptives confers long-term protection against ovarian cancer. These findings suggest that oral contraceptives have already prevented some 200000 ovarian cancers and 100000 deaths from the disease, and that over the next few decades the number of cancers prevented will rise to at least 30 000 per year.
Intrauterine pregnancy after superovulation with gonadotrophins and after in-vitro fertilization (IVF) and embryo replacement
has not been reported to occur in cases where the thickness of the pre-ovulatory endometrium was <6 mm. We report a case where
an intrauterine pregnancy was established where the endometrium was no more than 4 mm in thickness at the time of follicular
aspiration. It is suggested that an IVF cycle should not necessarily be abandoned merely because the pre-ovulatory endometrium
is thin, and especially if other parameters, including follicular development and serum oestradiol concentrations, are appropriate.
The human endometrium has remarkable regenerative capacity. It contains rare clonogenic epithelial and stromal cells.¹ The aims of this study were to compare the stem cell properties, self renewal, differentiation and proliferative potential, of endometrial cells initiating large clones (HPP-CFU, high proliferative potential–colony forming units) with those initiating small clones (LPP-CFU, low PP-CFU). Endometrial tissue obtained from 12 ovulating women undergoing hysterectomy was dissociated into single cell suspensions and epithelial and stromal cells were cultured at clonal density (8–20 cells/cm²). Individual clones were harvested and serially recloned to measure self-renewal, serially passaged to assess proliferative potential and cultured in various media to assess differentiation. Secondary stromal clones were characterized for mesenchymal stem cell (MSC) markers by flow cytometry. Epithelial HPP-CFU serially cloned significantly more times than epithelial LPP-CFU (P < 0.005, Table 1) indicating greater self renewal capacity. Similarly, stromal HPP-CFU demonstrated greater self renewal activity compared with stromal LPP-CFU (P < 0.005, Table 1). Serially passaged epithelial HPP-CFU underwent significantly more population doublings (PD) before senescence than epithelial LPP-CFU (P < 0.05, Table 1). Likewise, stromal HPP-CFU underwent a higher number of PD compared with stromal LPP-CFU (P < 0.005, Table 1). Stromal HPP-CFU expressed CD29, CD44, CD73, CD90, CD105 and CD146, and were negative for haemopoietic and endothelial markers, CD45, CD34 and CD31. Stromal HPP-CFU differentiated into adipocytes, smooth muscle cells, osteoblasts and chondrocytes when cultured in appropriate differentiation media. Our studies of human endometrial cells demonstrate that the rare epithelial and stromal HPP-CFU exhibit self-renewal and high proliferative potential. Furthermore stromal HPP-CFU express markers typical of bone marrow MSC and differentiate into four mesenchymal lineages. These data suggest that epithelial and stromal HPP-CFU, but not LPP-CFU, have characteristic properties of adult epithelial stem cells and MSC respectively and are likely responsible for the remarkable cyclical, regenerative capacity of human endometrium.
Inactivation of the PTEN suppressor gene has been shown to occur in the majority of endometrial cancer cases. Somatic PTEN inactivation by deletion and/or mutation, the first detectible change of endometrial carcinogenesis, has been reported to occur at a high frequency in the endometrium of normal premenopausal women, although few of these cases progress to cancer. It was hypothesized that the 50% to 60% reduced cancer risk attributed to oral contraceptives (OCPs) and intrauterine devices (IUDs) occurred in part through their activity as negative selection factors for these subclinical mutated glands.
A total of 71 women with a history of OCP use and 80 with a history of IUD use were age matched with 191 and 119 controls, respectively. Endometrial biopsy specimens were immunostained for PTEN, and each was scored for the presence or absence of PTEN-null glands (latent precancer).
The frequency of latent precancers was found to be significantly reduced in OCP‒exposed (13%; odds ratio [OR], 0.19 [P < .001]) and IUD‒exposed (18%; OR, 0.42 [P = .015]) women compared with respective matched controls (43% and 34%). The presence or absence of endometritis did not appear to be significantly correlated with PTEN status within the IUD-exposed group (P = .24).
Normal-appearing PTEN mutated endometrial glands, which are highly prevalent in the normal population, may be targets of endometrial cancer risk‒modulating exposures. Some exposures reported to diminish the incidence of endometrial cancer in epidemiologic outcome studies, including OCP and IUD use, are associated with a proportionate decline in the frequency of latent precancers. Involution of pre-existing endometrial latent precancers, as evaluated by PTEN analysis, may provide an accessible surrogate marker for long-term endometrial cancer risk. Cancer 2009.
The texture and the thickness of the endometrium as assessed by transvaginal sonography were prospectively evaluated in 123 patients undergoing IVF treatment. Three different types of endometrial patterns could be distinguished: (A) an entirely homogeneous, hyperechogenic endometrium; (B) an intermediate type characterized by the same reflectivity of ultrasound as the myometrium, with a nonprominent or absent central echogenic line; and (C) a multilayered endometrium consisting of prominent outer and midline hyperechogenic lines and inner hypoechogenic regions. On the day before oocyte retrieval, endometrial thickness was significantly greater in the group of patients who achieved pregnancy than in the group who did not (8.70.4 vs 7.50.2 mm, respectively; P-6 mm thick was seen, the pregnancy rate per embryo transfer was 39%. When type A or B endometrial pattern was seen, the negative predictive value for the occurrence of pregnancy was 90.5%. Our results suggest that transvaginal sonographic evaluation of endometrial texture and thickness may be an indicator of the likelihood of achieving pregnancy.
Assessment of follicular development and endometrial growth using transvaginal sonography in spontaneous and clomiphene citrate (CC) cycles with a spontaneous luteinizing hormone surge.
Prospective study of a spontaneous cycle followed by a CC cycle to compare paired data.
Institutional tertiary referral infertility clinic.
Eighteen couples with primary unexplained infertility voluntarily recruited from the infertility clinic.
Daily transvaginal sonography and endocrine monitoring. Clomiphene citrate (150 mg) was administered on days 5 to 9 of CC cycle.
Leading follicular diameter and endometrial thickness.
The growth rate of the leading follicle was similar in both study cycles, although in CC cycles the leading follicle diameter was significantly larger. Endometrial thickness was reduced in CC cycles.
Follicular development and endometrial thickness are altered in CC cycles.
The texture and the thickness of the endometrium as assessed by transvaginal sonography were prospectively evaluated in 123 patients undergoing IVF treatment. Three different types of endometrial patterns could be distinguished: (A) an entirely homogenous, hyperechogenic endometrium; (B) an intermediate type characterized by the same reflectivity of ultrasound as the myometrium, with a nonprominent or absent central echogenic line; and (C) a multilayered endometrium consisting of prominent outer and midline hyperechogenic lines and inner hypoechogenic regions. On the day before oocyte retrieval, endometrial thickness was significantly greater in the group of patients who achieved pregnancy than in the group who did not (8.7 +/- 0.4 vs 7.5 +/- 0.2 mm, respectively; P less than 0.01) and significantly more patients had multilayered, pattern C, endometrium (75% in pregnant women vs 42.4% in nonpregnant women; P less than 0.01). No pregnancy occurred when the endometrial thickness was less than 6 mm. When type C endometrium greater than or equal to 6 mm thick was seen, the pregnancy rate per embryo transfer was 39%. When type A or B endometrial pattern was seen, the negative predictive value for the occurrence of pregnancy was 90.5%. Our results suggest that transvaginal sonographic evaluation of endometrial texture and thickness may be an indicator of the likelihood of achieving pregnancy.
To assess the utility of endometrial thickness, echogenic endometrial pattern, and uterine artery impedance measured as pulsativity index in predicting implantation.
Prospective case-controlled study of infertile patients undergoing assisted reproductive technologies (ARTs).
Four hundred five women undergoing ARTs were studied: 100 women after ET of thawed embryos in natural cycles (frozen ET), 107 women after standardized IVF-ET, 99 women receiving donor oocytes after controlled endometrial development with estrogen and P, and 99 women undergoing IUI with various ovarian stimulation regimens (none, 16; GnRH, 7; clomiphene citrate [CC], 29; hMG, 47).
Transvaginal ultrasonographic examination performed on the day of hCG administration during stimulated cycles; on E2 day 15 during controlled endometrial cycles; and on the day of ovulation during natural, CC, and GnRH pump cycles.
The endometrial thickness, echogenic pattern, and pulsativity index results in 170 conception cycles were compared with 235 nonconception cycles.
When conception and nonconception cycles were compared, no difference in mean endometrial thickness and significant differences in the frequency of nonmultilayered pattern and pulsativity index > 3.3 were observed. Forty-seven percent of nonconception and 9% of conception cycles were associated with at least one of these factors.
Ultrasonic measurements of pulsativity index, resistance index, and echogenic pattern are useful in predicting implantation after assisted reproduction.
To determine if ultrasonographic endometrial pattern or thickness is predictive of histologic endometrial maturation in women undergoing hormone replacement for ovum donation.
Ultrasonographic endometrial thickness and pattern were determined and compared with histologic assessment of endometrial maturation.
Forty-six women underwent 52 preparatory cycles for ovum donation. Transvaginal ultrasound (US) was performed after 14 days of E2 replacement and, after 12 days of P, an endometrial biopsy was performed. In 12 cycles, a continuous dose of 2 mg/d E2 was administered. In cycles with out-of-phase biopsies (dated earlier than day 24) and in the last 34 cycles, all women received an escalating dose of E2 before initiation of P. Additionally, the 46 women underwent 55 ETs with USs performed on cycle day 15.
Six women had abnormal biopsies in their first preparatory cycle on the continuous E2 protocol, which normalized with the escalating protocol. All other women had normal biopsies. Women with abnormal biopsies had significantly thinner endometrium (< or = 6 mm) but similar endometrial patterns compared with women with normal biopsies. In women having US in preparatory and transfer cycles, there were no differences in endometrial thickness or pattern between examinations.
Endometrial thickness > or = 7 mm in hormone replacement cycles predicts in phase endometrial histology and can replace the endometrial biopsy.
Intrauterine pregnancy after superovulation with gonadotrophins and after in-vitro fertilization (IVF) and embryo replacement has not been reported to occur in cases where the thickness of the pre-ovulatory endometrium was <6 mm. We report a case where an intrauterine pregnancy was established where the endometrium was no more than 4 mm in thickness at the time of follicular aspiration. It is suggested that an IVF cycle should not necessarily be abandoned merely because the pre-ovulatory endometrium is thin, and especially if other parameters, including follicular development and serum oestradiol concentrations, are appropriate.
The rapid development of ultrasonographic equipment now permits instantaneous assessment of follicles and endometrium. The sonographic appearance of the endometrium has been discussed in relation to in-vitro fertilization (IVF) cycles. However, a generally agreed view of the relationship of the sonographic appearance to fecundity in IVF cycles has not emerged. We have studied the relationship between steroid receptors and the sonographic appearance of the preovulatory endometrium in natural cycles and ovulation induction cycles. Preovulatory endometrial thickness was not found to be indicative of fecundity, although a preovulatory endometrial thickness of <9 mm related to an elevated miscarriage rate. The preovulatory endometrial echo pattern did not predict fecundity. No relationships were found among endometrial appearance, endometrial steroid receptors and steroid hormone concentrations in serum. Oestrogen or progesterone receptor concentrations were not related to endometrial thickness or to concentrations of serum oestradiol, the only significant correlation being found between the endometrial concentrations of oestrogen and progesterone receptors. The ratio of progesterone:oestrogen receptor concentration was somewhat less in echo pattern B (not triple line) endometrium compared with pattern A (triple line) endometrium. Oestrogen and progesterone receptor concentrations appeared stable on gonadotrophin induction, though fewer numbers were found during clomiphene cycles than in natural cycles. With regard to the distribution of receptor concentration between clomiphene and natural cycles, most women using clomiphene had very low oestrogen receptor populations. Pregnancy rates were low, in spite of high ovulatory rates during clomiphene treatment and were mainly related to low oestrogen receptor concentrations in preovulatory endometrium.
Modern hormonal contraceptives and intrauterine contraceptive devices have multiple biologic effects. Some of them may be the primary mechanism of contraceptive action, whereas others are secondary. For combined oral contraceptives and progestin-only methods, the main mechanisms are ovulation inhibition and changes in the cervical mucus that inhibit sperm penetration. The hormonal methods, particularly the low-dose progestin-only products and emergency contraceptive pills, have effects on the endometrium that, theoretically, could affect implantation. However, no scientific evidence indicates that prevention of implantation actually results from the use of these methods. Once pregnancy begins, none of these methods has an abortifacient action. The precise mechanism of intrauterine contraceptive devices is unclear. Current evidence indicates they exert their primary effect before fertilization, reducing the opportunity of sperm to fertilize an ovum.
To determine whether menstrual cycle stage or activity has an effect on the clonogenic activity of human endometrial epithelial and stromal cells.
Clonal analysis of human endometrial epithelial and stromal cells derived from full-thickness endometrium.
University research laboratory.
Twenty-six women of varying age and race undergoing hysterectomy for nonendometrial pathologies.
Full-thickness human endometrial tissue was dissociated into single cells. Epithelial and stromal cells were separated using magnetic beads, and cloning assays were performed in serum-containing or growth factor-supplemented serum-free medium.
Clonogenic activity of epithelial and stromal cells.
Clonogenicity of epithelial and stromal cells did not vary significantly between proliferative, secretory, and inactive endometrium. However, epithelial and stromal cells did show a trend for greater numbers of clonogenic cells in secretory and proliferative endometrium respectively. A large variation between samples was observed, which may have masked any significant differences.
We found that clonogenicity does not vary from the proliferative to secretory stage of the menstrual cycle, or between active, cycling and inactive endometrium for both epithelial and stromal cells. We have demonstrated for the first time that inactive endometrium contains clonogenic epithelial and stromal cells.
To show that early follicular-phase administration of an oral contraceptive pill (OC) consistently provides a thin endometrium, as determined by transvaginal ultrasound. This is an ideal condition when performing operative hysteroscopy.
Retrospective chart review of patients who have undergone ultrasound evaluation of the endometrial thickness under different hormonal conditions. Endometrial measurement was obtained during menstruation, in the late follicular phase, and in the luteal phase in 20 patients. In another group of 100 patients, endometrial measurement was made on the 18th day of OC administration, initiated during menses.
A reproductive endocrinology unit in a university-affiliated medical center.
Patients undergoing treatment for subfertility of various etiologies.
Transvaginal ultrasound measurements of the endometrium.
Endometrial thickness by transvaginal ultrasound.
Combination OCs started on menstrual days 1-3 maintain a uniformly thin endometrium, 4.1 +/- 1.6 mm (mean +/- SD), comparable to menstrual endometrium (3.7 +/- 1.5 mm). This was statistically thinner compared with endometrium observed in the late follicular phase (11 +/- 2.0 mm) or late luteal phase (12 +/- 2.3 mm). Transvaginal ultrasound measurements of the endometrium under different conditions were compared by the unpaired t-test.
Oral contraceptives maintain a very thin, flat endometrium, such that lesions might be readily identified and treated during operative hysteroscopy procedures. Prevention of pregnancy and endometrial thinning with administration of OCs facilitates procedural scheduling for patients and surgeons.
Oral contraceptives were introduced almost 50 years ago, and over 100 million women currently use them. Oral contraceptives can reduce the risk of ovarian cancer, but the eventual public-health effects of this reduction will depend on how long the protection lasts after use ceases. We aimed to assess these effects.
Individual data for 23,257 women with ovarian cancer (cases) and 87,303 without ovarian cancer (controls) from 45 epidemiological studies in 21 countries were checked and analysed centrally. The relative risk of ovarian cancer in relation to oral contraceptive use was estimated, stratifying by study, age, parity, and hysterectomy.
Overall 7308 (31%) cases and 32,717 (37%) controls had ever used oral contraceptives, for average durations among users of 4.4 and 5.0 years, respectively. The median year of cancer diagnosis was 1993, when cases were aged an average of 56 years. The longer that women had used oral contraceptives, the greater the reduction in ovarian cancer risk (p<0.0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat attenuated over time-the proportional risk reductions per 5 years of use were 29% (95% CI 23-34%) for use that had ceased less than 10 years previously, 19% (14-24%) for use that had ceased 10-19 years previously, and 15% (9-21%) for use that had ceased 20-29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The incidence of mucinous tumours (12% of the total) seemed little affected by oral contraceptives, but otherwise the proportional risk reduction did not vary much between different histological types. In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; for every 5000 woman-years of use, about two ovarian cancers and one death from the disease before age 75 are prevented.
Use of oral contraceptives confers long-term protection against ovarian cancer. These findings suggest that oral contraceptives have already prevented some 200,000 ovarian cancers and 100,000 deaths from the disease, and that over the next few decades the number of cancers prevented will rise to at least 30,000 per year.
During the menstrual cycle the endometrium undergoes cyclic proliferative and secretory changes in preparation for implantation. If this preparation is not sufficient, then implantation will fail. The impact of endometrial thickness on the day of embryo transfer on IVF outcome was investigated in the present study.
A retrospective analysis was conducted of 1228 IVF/ICSI cycles. Stimulation was with clomiphene citrate (CC) + hMG in one-third of the cycles, and ultrashort GnRH agonist stimulation in two-thirds. Cycle parameters were compared between pregnant and non-pregnant patients. A similar comparison was made between ongoing pregnancies and those that resulted in a loss.
There were more follicles, oocytes and embryos, the endometrium was thicker and the embryo quality was higher among women who became pregnant when compared with non-pregnant women after assisted reproduction. The pregnancy rate improved as endometrial thickness increased. No difference in cycle parameters and endometrial thickness was found between ongoing pregnancies and pregnancies that resulted in a first-trimester loss. CC had no measurable adverse endometrial effect, but the pregnancy rate was lower in CC+hMG cycles.
Increased endometrial thickness is associated with higher pregnancy rates. However, neither attainment of pregnancy nor pregnancy outcome was predicted by endometrial thickness alone.
Involutionoflatentendometrialprecancersbyhormonaland nonhormonal mechanisms
- Mc Lin
- Ka Burkholder
- An Viswanathan
- D Neuberg
- Mutter
Lin MC, Burkholder KA, Viswanathan AN, Neuberg D, Mutter GL.Involutionoflatentendometrialprecancersbyhormonaland nonhormonal mechanisms. Cancer 2009;115:2111–8
Contraceptive efficacy Contraceptive technology. 19th revised ed Ardent-Media
- J Trussel
Trussel J. Contraceptive efficacy. In: Hatcher RA, editor.
Contraceptive technology. 19th revised ed. New York (NY):
Ardent-Media; 2007.