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Introduction. Endometrial hyperplasia is a commonproblem among premenopausal women. There are nonatypical (EH) and atypical (AH) morphotypes according tocytological atypia. Despite a mostly favorable prognosisof EH, risk of progression to atypia is nearly 2% per year.The next problem is absence of clear criteria on which casewill have an unfavorable prognosis and EH will progress toAH and endometrial cancer. Markers of response of EH andAH to the first line therapy such as progestin are not wellinvestigated either. Investigation of ER and PGR expressionin normal (NE) and hyperplastic endometrium can be usefulfor future development of treatment algorithms in differentendometrial hyperplasia morphotypes and forecastingresponses to progestin therapy.Objective: To investigate the expression of estradiol andprogesterone receptors in the glandular and stromal cells ofnormal endometrium and in the different morphotypes ofendometrial hyperplasia.Material and Methods: Endometrial samples taken from137 women were investigated: 40 – with normal proliferativeand secretory endometrium (NE), 61 – endometrialhyperplasia without atypia (ЕH), 36 – endometrialhyperplasia with atypia (AH). Routine histopathologicaland immunohistochemical (IHC) examination of nuclearantigens in the endometrium samples was conducted. Then,IHC examination was carried out on the paraffin blocksusing monoclonal and polyclonal antibodies and systems ofvisualization. Expression of estradiol (ER) and progesterone(PGR) receptors was investigated. Taking into account thatcells with positive reaction to ER and PGR have significantdifferences in the intensity of IHC coloring, we used theaverage value or H-index according to the number of cellswith positive reaction and reaction intensity. Values from0 to 50 on the H-index were considered for the absence ofER and PGR expression, from 50 to 100 - expression ofantigens to receptors was considered as weakly positive;100 points or more - as positive. Statistical processing ofresults was done using licensed program Statistics (V 6.1;Statsoft, USA).Results: ER expression of EH both in glandular cells (180±8.3) and stromal cells (170.5±4.1) was close to resultsof proliferative NE (193.1±12.2 in the glandular and 166±9.7in the stromal cells), but 1,43 times exceeded indicators inthe glandular (180±8.3 vs 125.4±5.7; p, Вступление. Гиперпластические про-цессы эндометрия являются одной из наиболее распространенныхпатологий у женщин пременопаузального возраста и взависимости от наличия цитологической атипии подразделяются на неатипичные формы (НГЭ) и атипичные(АГЭ). Несмотря на достаточно благополучный прогнозНГЭ, риск развития атипии составляет около 2% в год.Еще одна проблема обусловлена тем, что клиницисты досих пор не имеют четких критериев – в каком случае реализуется неблагоприятный сценарий развития событийи НГЭ прогрессирует до АГЭ и рака эндометрия. Также недостаточно изучены показатели чувствительностиили нечувствительности НГЭ и АГЭ к лечебным препаратам первой линии, а именно – прогестинов. Изучениеэкспрессии рецепторов к эстрадиолу (ER) и прогестерону (PGR) в нормальном (НЭ) и гиперплазированномэндометрии может быть полезным для дальнейшей разработки алгоритмов лечения при различных морфотипах гиперплазий и прогнозированию ответа на лечениепрогестинами.Цель исследования: определение особенностейэкспрессии рецепторов к эстрадиолу и прогестеронув клетках желез и стромы эндометрия в норме и приразличных морфотипах его гиперплазии.Материал и методы исследования. Обследовано137 женщин: 40 – с нормальным состоянием эндометрия,61 – с НГЭ, 36 – с АГЭ. Проводилось стандартное гистологическое исследование и иммуногистохимическоеисследование (ИГХ) в образцах эндометрия. ИГХ исследования выполняли в парафиновых срезах с использованием моноклональных или поликлональных антител и системы визуализации. Исследовали экспрессиюER и PGR в железах и стромальных клетках с подсчетом усредненного ее значения или Н-индекса, которыйрассчитывался в зависимости от интенсивности реакции и количества клеток с позитивной реакцией. Значения от 0 до 50 баллов по H-индексу считали как отсутствие экспрессии ER и PGR, от 50 до 100 – экспрессиюантигенов рецепторов считали слабо положительной;100 баллов и больше – положительной. Статистическуюобработку результатов проводили с использованием лицензионной статистической программы Statistica (версія 6.1; Statsoft, США).Результаты исследования. При НГЭ активностьэкспрессии ER как в эпителии желез (180±8,3), так и встроме (170,5±4,1) практически не отличалась от нормального эндометрия пролиферативной фазы цикла(193,1±12,2 в железах и 166±9,7 в строме), но превышалауказанные показатели секреторной фазы в 1,43 раза вжелезах (180±8,3 и 125,4±5,7; p, Вступ. Гіперпластичні процеси ендометрію є однією з найпоширеніших патологій у жінок пременопаузального віку та в залежності від наявності цитологічної атипії поділяються на неатипові форми (НГЕ) таатипові (АГЕ). Незважаючи на досить сприятливий прогноз НГЕ, тим не менше ризик розвитку атипії складає близько 2% на рік, ще одна проблема зумовлена тим, що клініцисти й досі не мають чітких критеріїв – уякому ж випадку реалізується несприятливий сценарій розвитку подій та НГЕ прогресує до АГЕ та раку ендометрію. Також недостатньо визначені показники чутливості або нечутливості НГЕ та АГЕ до лікувальнихзаходів першої лінії, а саме – прогестинів. Визначення експресії рецепторів до естрадіолу (ER) та прогестерону (PGR) нормального (НЕ) та гіперплазованого ендометрію може бути корисним для подальшої розробкиалгоритмів лікування при різних морфотипах гіперплазії та прогнозу відповіді на лікування прогестинами.Мета дослідження. Визначення особливостей експресії рецепторів до естрадіолу та прогестерону в клітинах залоз та строми ендометрію в нормі та при різних морфотипах його гіперплазії.Матеріал та методи дослідження. Обстежено 137 жінок: 40 – з НЕ, 61 – з НГЕ, 36 – АГЕ. Проводилосьстандартне гістологічне дослідження та імуногістохімічне дослідження (ІГХ) в зразках ендометрію. ІГХ дослідження виконували в парафінових зрізах з використанням моноклональних або поліклональних антитіл тасистеми візуалізації. Досліджували експресію ER та PGR в залозах та стромальних клітинах з підрахуваннямусередненого його значення або Н-індексу, який розраховували в залежності від інтенсивності забарвлення такількості позитивних клітин. Значення від 0 до 50 балів за H-індексом сприймали за відсутність експресії ERта PGR, від 50 до 100 – експресію антигенів до рецепторів вважали слабко позитивною; 100 балів та більше– позитивною. Статистичну обробку результатів проводили з використанням ліцензійної статистичної програми Statistica (версія 6.1; Statsoft, США).Результати дослідження. Клітини залоз і строми в НЕ мали високі показники експресії ER в проліферативну фазу циклу (відповідно 193,1±12,2 і 166±9,7 балів), але в секреторній фазі циклу активність експресіїER суттєво знижувалася (залози 125,4±5,7, строма – 122,4±4,8 бали). Активність експресії PGR зберігаласьна високому рівні в обидві фази циклу (в залозах 193,2±8,5 та 178,7±6,3, в стромі 140,2±4,4 та 116,6±3,1балів відповідно). При НГЕ активність експресії ER як в епітелії залоз (180±8,3), так і в стромі (170,5±4,1)майже не відрізнялася від нормального ендометрію проліферативної фази циклу, але перевищувала показникисекреторної фази. Експресія PGR в залозистому епітелії при НГЕ була практично на рівні цього показникав НЕ. Експресія PGR в клітинах строми НГЕ склала 197,5±9,3 бали та достовірно перевищувала показникиНЕ. Навпаки, при АГЕ експресія ER і PGR значно зменшувалася. У залозах Н-індекс ER (74,6±3,9) був в 2,6рази нижчім, ніж в проліферативному ендометрії здорових жінок (p

Progestogens such as micronized progesterone and the synthetic progestins are defined by their ability to transform the estrogen-primed proliferative endometrium into secretory endometrium. More than 200 progestogens have been synthesized, but only a few are used clinically in hormone therapy. Clinicians caring for menopausal women should be familiar with the clinical properties and characteristics of the three most-used progestogens for hormone therapy: micronized progesterone, medroxyprogesterone acetate, and norethindrone acetate.

Luteal phase defect (LPD) is a condition with insufficient endogenous progesterone for maintenance of functional secretory endometrium, normal embryo implantation, and growth. In today’s era, there is a lot of complex research with wide diversity with respect to LPD and its treatment. With such diversity and complexity of research data, we hereby did this review to address the pathophysiology of LPD and the role of luteal phase support in assisted reproductive cycles based on available scientific evidence in a simplified manner. An electronic search of Pubmed, Scopus, Embase, and Google Scholar was performed for LPD, luteal phase support, and assisted reproductive technologies. There is no valid diagnostic test for LPD. Prompt identification and treatment of underlying factors is the preferred approach. In assisted reproductive cycles, the luteal phase is usually abnormal and luteal phase support in form of exogenous progesterone with or without estrogen or hCG and GnRH agonists, which enhance endogenous progesterone release have a significant effect on successful reproductive outcomes. The choice of drug is dependent upon the patient’s characteristics and type of ongoing treatment. It should be started on the day of oocyte retrieval or till the day 3 postretrieval and to be continued till a positive pregnancy test at least.

Endometrial intraepithelial neoplasia (EIN) with secretory differentiation and ordinary EIN occurring in a secretory context are rare but recognized findings. We determined how often secretory differentiation in EIN was associated with evidence of circulating progestins in the background endometrium, and studied clinical characteristics and clinical outcomes of affected patients. We selected 41 patients with secretory differentiation in either the EIN itself (n=31) and/or background endometrium (n=38). Most (90%, 28/31) secretory EINs were associated with circulating progestins. Rare exceptions were observed, suggesting that secretory EIN may occur as a hormone-independent phenomenon. Circulating progestins are not sufficient, however, to induce EIN secretory differentiation, as 26% (10/38) of EIN within a secretory background were of the ordinary (non-secretory) type. EIN patients with secretory endometrium in the background are younger (averaging 45 years) than the aggregate group of all patients with EIN (53 years in previously published studies) and are often premenopausal with a cyclical source of endogenous progestins. Involution of EIN during follow-up was more frequent (81%, 17/21) for those with a secretory background at the time of initial EIN diagnosis compared with historical averages (25%, 36/142). These results suggest a potential role for endogenous progesterone, as well as therapeutic progestins, in modulating EIN outcomes.

AimTo investigate the expression of Wilms' tumor 1 (WT1) protein in endometrial adenocarcinoma (EC) and endometrial intra-epithelial neoplasia (EIN). MethodsWT1 protein expression was determined on immunohistochemistry in 30 EC patients and in 20 EIN patients. WT1 protein expression in proliferative (n = 7), secretory (n = 9) and atrophic endometrium (n = 9) and benign endometrial polyps (n = 28) was used as the control group. Cellular and vascular WT1 staining was scored semiquantitatively. ResultsCellular WT1 staining was 67% and vascular positivity was 73% in the EC group. In the EIN group the cellular staining was 100% and vascular staining was 85%. Although all EIN samples were positive for cellular WT1 staining, median cellular staining score was similar to that of EC (median, 2; range, 1-3; IQR, 1.75 vs 2, 0-3, 0.75, respectively). Increasing EC grade and stage were not associated with cellular or vascular WT1 staining score. ConclusionWT1 is expressed in EIN.

Progesterone receptor modulators (PRMs) have been used for contraceptive research, as well as for treatment of fibroids, endometriosis and heavy or irregular menstrual bleeding. Long-term treatment with these compounds results in changes to the endometrium resulting in potential confusion in trying to characterize endometrial biopsies. A meeting was held to discuss the properties of PRMs, the effects of perturbed hormonal control of the endometrium and the need for further understanding of the biology of progesterone receptor action to facilitate the development of new PRMs. A panel of pathologists was convened to evaluate endometrial changes associated with a minimum of three months of chronic treatment with PRMs. Four different agents were used in the treatment regimens but the pathologists were blinded to treatment regimen or agent. The panel agreed that the endometrial biopsies did not fit into a classification of either proliferative or secretory endometrium but exhibited an unusual architecture that could be characterized as glandular dilatation. There was little evidence of mitosis, consistent with a proposed anti-proliferative effect of PRMs. The panel concluded that the biopsies did not reveal evidence of safety concern and that pathologists and investigators familiar with endometrial effects of chronic PRM exposure should consider working with pharmaceutical companies and regulatory agencies to develop standard descriptions of PRM-associated endometrial changes as well as the types of histologic changes that would signal a need for intervention.

Often, it is necessary to evaluate the mid-secretory endometrium appearance in Gynecology. For this purpose, hysteroscopic videos have been used, and are of fundamental importance nowadays for diagnosis/prognosis of several uterine pathologies. These videos are continuous (non-interrupted) video sequences, usually recorded in full. However, only a few segments of the recorded videos are relevant for diagnosis/prognosis, and need to be evaluated and referenced later. This paper proposes a new technique to identify clinically relevant segments in diagnostic hysteroscopy videos and, consequently, to find images that present the best view of the endometrium details (e.g. glandular openings and vascularization). Our method produce a rich and compact video summary which supports fast video browsing. This method is based on an extension of known properties of the singular value decomposition (SVD), and it is adaptive, in the sense that it minimizes the need of parameter adjustments. Our preliminary experimental results indicate that our method produces compact video summaries containing a selection of clinically relevant video segments. These experimental results were validated by specialists.

The divergent requirement for tolerance to support conception and protective response against sexually transmitted infections defines the unique immunological dynamics in the female reproductive tract (FRT). In part, these requirements are achieved by the cyclic modulation of cytolytic CD8T cell function in the FRT that underlie the respective immunosuppressive and immunocompetent milieus during the secretory and proliferative phases of the menstrual cycle. The CD8T cell function can be dampened by exposure to indoleamine 2,3-dioxygenase and/or arginase enzymes. Indeed, these 2 enzymes are known as primary inducers of immune suppression in tumor microenvironments. This review discusses the intriguing parallel expression of these 2 enzymes in tumor microenvironments and in the secretory endometrium. We surmise that investigating the underlying natural mechanisms that suppress and restore the immunocompetence of CD8T cells in the FRT each month may provide valuable insights into ways to artificially recapitulate these mechanisms and inhibit immune suppression in tumor microenvironments.

The evidence still supports abandoning the histological dating of the endometrium during the routine evaluation of the infertile couple. Once molecular determinants are discovered and validated as markers of endometrial function, then the clinical usefulness of the endometrial biopsy for the evaluation of infertility will need to be re-examined.

Endometrial adenocarcinoma in young women below the age of 45 years and in a functioning endometrium is rare. We present the case of a 41-year-old woman, who without clinical risk factors, was found to have a focal well-differentiated endometrial adenocarcinoma in the background of a histologically secretory endometrium. Endometrial evaluation for abnormal vaginal bleeding in a young ovulating female and thorough examination of the endometrium in its entirety in the hysterectomized uterus are reemphasized.

The mechanism of implantation is perhaps the least well understood aspect of human reproduction, because hitherto there has been a lack of interest in endometrial function. Implantation is a complex process involving the cyclical preparation of a receptive endometrium, the development of a normal embryo, the attachment and penetration of trophoblast, decidualisation and the maternal recognition of pregnancy. Research is inevitably hindered by the physical and ethical difficulty of obtaining suitable human material.

A well controlled double blind prospective trial was undertaken to determine the efficacy of mefenamic acid in the treatment of menorrhagia. Eighty patients who had unexplained cyclical menorrhagia with secretory endometrium received mefenamic acid orally in a dose of 500 mg 8 hourly or a placebo tablet thrice daily starting from day-one of the cycle for 5 days or till cessation of menses. Mefenamic acid administration caused a statistically significant reduction in the number of days of bleeding from 9.7 +/- 3.1 days before treatment to 4.1 +/- 0.6 days after treatment. It also brought about significant reduction in the amount of bleeding in terms of number of pads used per day, that is from 15.2 +/- 3.1 before treatment to 6.5 +/- 0.02 after treatment. Eighty-six percent patients in the treatment group had control of menorrhagia with the drug compared to 20% in the control group without drugs and this difference was statistically significant. Mefenamic acid proved to be a potent and efficacious agent in the control of unexplained menorrhagia.

Two cases of endometrial adenocarcinoma concurrent with secretory endometrium are described. The theory that the side effects of continuous estrogenic exposure can be averted by periodic interruption with progestins is also discussed.

QuergebAnderte filamentAre Assoziate werden im Extrazellularraum des Endometrium, im Bindegewebe eines EDS-Patienten und einer rupturierten Sehne sowie beim Morbus Dupuytren auch intrazellulAr beschrieben. Diese Assoziate werden als Momentaufnahmen auf dem Wege eines kollagenolytischen Prozesses gedeutet und mit der Anwesenheit von Typ III-Kollagen in Zusammenhang gebracht.

Twelve patients with a normal menstrual rhythm were given 500 R.U. of antuitrin-S daily for four or six weeks. The majority of these patients did not show any significant alteration in rhythm. Five (42 per cent) experienced an amenorrhea of from one to five months following treatment. This induced amenorrhea was accompanied by a progressive atrophy of the endometrium, indicating a suppression of ovarian follicles. Antuitrin-S failed to establish uterine bleeding in patients with amenorrhea. No evidence of ovulation or luteinization, as demonstrated by a secretory endometrium, was found. On the basis of this experiment it appears that the anterior pituitary-like substances are not gonadotropic in the human female and in sufficient dosage may even be gonadotoxic.

SUMMARY Human proliferative endometrial tissue was maintained in organ culture. Glandular cells in the fragments were stimulated to secrete by adding progesterone to the culture medium—but not by insulin, oestradiol or cortisol; insulin enhanced the effect of progesterone. With progesterone, subnuclear vacuolation appeared in the glandular cells after 2–3 days. As the culture continued, these vacuoles disappeared and secretion into the lumen occurred.

1. 1. It has been too widely accepted that functional uterine bleeding is almost invariably associated with endometrial hyperplasia, but in our experience with 83 consecutive cases about 14 per cent are associated with secretory endometrium. 2. 2. Forty-one cases of functional uterine bleeding associated with secretory endometrium are studied in detail. (a) In most cases the complaint was simple menorrhagia. (b) Secretory endometrium was found during bleeding which lasted for as long as thirty-four days, and it was also found after prolonged bleeding associated with corpus luteum cysts, suggesting the possibility that with functional uterine bleeding secretory endometrium may persist for a long period of time.

SummaryThe results presented indicate the necessity for determination of the purity of the P.G. isolated from non-pregnant urine. It has been clearly shown that the modifications reported by Venning1 do not necessarily remove all impurities from the final product. The implications of these findings, for much of the data in the literature, are clear. In the light of our results, the finding (first reported by Hamblen, et al.,2 that P.G. may be present in the absence of a secretory endometrium, particularly warrants critical reexamination.

SummarySingle luteal phase serum progesterone values were determined in 34 infertile Nigerian women with regular menstrual cycles. Endometrial biopsies were obtained simultaneously and histologically dated. Subsequent analysis showed that a serum progesterone value of 4•89 nmol/l (1•63 ng/ml) or above was always associated with a secretory endometrium. Taking a progesterone value of 6 nmol/l (2 ng/ml) as presumptive evidence of ovulation, 82 per cent of the patients were judged to have ovulated by both parameters. Two patients (6 per cent) had anovulatory cycles by both the serum progesterone as well as the endometrial histology.

A case of recent ovulation in a postmenopausal, chronically alcoholic woman taking conjugated estrogens is presented. Bilateral corpora lutea, Graafian follicles, numerous corpora albicantia and secretory endometrium were found. The possible role of the prolonged alcohol and conjugated estrogens intake in modulating the pituitary-gonadal axis is discussed.

Summary1) 6α-methyl-17α-acetoxyprogesterone is a highly active progestin based on its ability to promote a secretory endometrium and to prevent ovulation in rabbits. 2) Subcutaneously, 6α-methyl-17α-acetoxyprogesterone is 6 to 8 times and orally 60 to 75 times as active as 17α-acetoxyprogesterone in the McPhail assay. The ability of the 6-methyl compound to inhibit ovulation in rabbits is at least 20 times as great as that of progesterone subcutaneously, while 17α-acetoxyprogesterone is 7 times as active as progesterone.

Electrophoretic separation of the fractions of lactic dehydrogenase in normal endometrium has been described. Fractions I, II, and III predominate in the proliferative phase of the cycle, while fractions III, IV, and V are most marked in the secretory phase. Endometrium of pregnancy and that from patients using oral progestins is similar to secretory endometrium in this respect. The suggestion that fractions IV and V are those most involved in anaerobic glycolysis has likewise been discussed.

Summary. The expression of Ca antigen in normal, hyperplastic and neoplastic endometria has been studied by an immunoperoxidase technique. Ca antigen was frequently detectable in normal secretory endometrium, was found only rarely in cystic glandular hyperplasia or hyperplasia with architectural atypia, was expressed with moderate frequency in hyperplasia with cytological atypia and was invariably present in endometrial adenocarcinoma. It is concluded that the Ca antigen is of no discriminatory value in differentiating between hyperplastic and neoplastic conditions of the endometrium.