Search

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.

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.

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.

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.

A series of 407 infertile patients underwent luteal phase laparoscopy and endometrial biopsy as a part of their infertility workup. In 91% of the patients, a good correlation between the results of endometrial biopsy and those of laparoscopy was found. In 8% of the patients a secretory endometrium was found, but the laparoscopy did not show any luteal structures on the ovaries. Seventy-one percent of the patients had corpora lutea, but the stigma was only present in 17.5% of the series with secretory endometrium. Because of the stigma findings, only 325 patients with secretory endometrium were evaluated. The stigma was more frequently seen when laparoscopy was performed between day 17 and day 19 of the cycle. On the other hand, the stigma was also more frequently seen when laparoscopy was performed between 10 and 12 days before the actual onset of the next period. We conclude that the frequency of stigmata at the corpus luteum is a matter of the time in the cycle when laparoscopy is performed, and the particular cycle length of the patient should be considered.

We have shown that the rate of release of PGF2 alpha by monolayer cultures of epithelial cells from proliferative endometrium is markedly elevated by addition of estradiol to the medium. In cultures maintained in HAM F-10 medium containing charcoal stripped calf serum, estradiol (10(-8) M) increased the levels of PGF2 alpha several fold during the second and third days in culture. Similar responses were obtained with estradiol at 10(-10) M concentration. When this system was used to compare the effects of estradiol and estriol at equal concentrations (10(-8) M), similar elevation (10-16-fold) of PGF2 alpha levels were noted during 3 consecutive days in culture. When cultures of epithelial cells derived from secretory endometrium were used for these tests, estriol was as effective as than estradiol in elevating PGF2 alpha levels in the medium. When the effects of estradiol and estriol were compared using fragments of secretory endometrium in organ culture, the increases in PGF2 alpha levels noted in the medium were about equal (2- to 10-fold) for the two estrogens at the same concentration (10(9)-10(8) M). Exposure of the tissue to either estradiol or estriol for only 1 h resulted in increases in PGF2 alpha output for the following 3 days. These results clearly show that estriol is as effective as estradiol in stimulating PGF2 alpha output by human endometrial tissue.

The effect of dydrogesterone, a retro-progesterone on the spontaneous mid-cycle surge of gonadotrophin in regularly cycling women, was investigated. Blood samples were collected through two complete cycles in six subjects. The first untreated cycle acted as a control for the second cycle during which dydrogesterone (10 mg twice daily) was administered. The start of treatment ranged from day 1 (one subject), mid follicular phase (three subjects) to post-ovulation (two subjects). In all subjects where dydrogesterone was given before ovulation, the mid-cycle gonadotrophin surge was either abolished or markedly diminished. Despite this follicular growth occurred in all four subjects and subsequently luteinisation was observed in three. Dydrogesterone given after ovulation did not produce any alteration in endocrine profiles but menses was postponed in both subjects. Thus dydrogesterone can mimic the known blocking actions of progesterone on the mid-cycle gonadotrophin surge and can support a secretory endometrium for a limited period in the absence of endogenous progesterone.

2OO consecutive cases of couples referred for A.I.D. are reviewed. The reasons for referral are given and the technique and donors are discussed. It is estimated that about 85% of women who receive donor insemination will achieve pregnancy if they presevere. Infertility factors are common in women who present for donor insemination and this usually takes the form of ovarian follicular deficiency, probably with non-ovulation. It is suggested that a biphasic basal temperature record or a secretory endometrium in the luteal phase are unreliable tests for ovulation.

The syndrome of the trapped ovum or luteinization of the unruptured follicle has been recognized for some time but has only recently begun to receive attention in the clinical context1,2.

Uteri from four patients with endometrial adenocarcinoma and concomitant “functioning” endometrium were examined by a whole-organ sectioning technique. All showed one or several “progesterone-refractory” mucosal areas or polyps, mainly in the tubal recesses. In one patient the adenocarcinoma obviously originated in a fundal polyp, and in the others the tumors could have arisen in mucosal areas not adequately responding to progesterone. These findings do not in fact contradict the “unopposed estrogen” theory of the genesis of endometrial carcinoma.

The 310 cases of abnormal uterine bleeding in which secretory endometrium was found are reviewed by age group, presenting symptoms, duration of symptoms, severity of bleeding, continued ovulation, medical treatment, parity, and results. Two unusual endometrial histologic patterns were identified: (1) abnormal stromal and/or glandular response to progesterone and (2) secretory hyperplasia. Twenty-eight per cent of all patients with an adequate follow-up eventually received a hysterectomy—14.8 per cent for bleeding alone. Hypermenorrhea was most likely to result in a hysterectomy, with metrorrhea least likely. Dating the endometrium placed approximately 50 per cent of the problems at the time of ovulation and 50 per cent at the time of menses. Those patients with an abnormal response to progesterone were most likely to have a hysterectomy.

A ligand-specific progesterone-binding protein which migrated in sucrose gradients, as a 4–5S complex, has been identified in endometrial cytosol. The association constant (Ka) for progesterone binding to cytosol protein was estimated at 1.2–3.4 i 109 M

Summary: A series of 50 patients whose pregnancy was complicated by incomplete abortion is reported. The average time which elapsed before the return of ovulation, as diagnosed by the demonstration of secretory endometrium histologically, was 50 days (range 10 to 104 days), and there was no difference between patients who aborted in the first and second trimesters. Twenty per cent of first menstruations were anovular and 6% of patients had 2 anovular menstruations prior to the return of ovulation.

Studies on the normal human endometrium using Bertalanffy's fluorescent microscopic technique were made. Our results revealed that DNA and RNA exist in rather constant amount in nonovulatory, proliferative, and secretory endometrium.

Sclerocystic ovarian disease is primarily a clinical diagnosis, since there is no pathognomonic physical finding or laboratory study. The purpose of this study was to evaluate in a planned manner consecutive patients suspected of having sclerocystic ovarian disease. Fifty-five consecutive clinic and private cases diagnosed by this plan were carefully studied in relation to menstrual history, physical findings, laboratory studies, and clinical follow-up. Criteria for operation were outlined. In this group of patients, 54 patients had secretory endometrium on first postoperative period, 44 continued regular ovulatory period for one year, and 63 per cent of patients with patent tubes became pregnant in the first 2 years postoperatively.

1. 1. An additional case of bilateral ovarian dermoids in pregnancy is reported, bringing the total number of reported cases up to 66. 2. 2. Of the total number of cases reported only 10 cases were treated with conservative ovarian surgery. 3. 3. The present patient treated conservatively has continued to menstruate normally and endometrial biopsy done 6 months post operation revealed secretory endometrium and thereby gives presumptive evidence of ovulation. 4. 4. A plea is made for conservative ovarian surgery and reasons are advanced to support this plea.

The earliest time at which ovulation may occur postpartum was investigated in this study of histological specimens of the endometrium. 128 endometrial biopsies were obtained, but only 92 had adequate material for study. Of the remaining 92 cases, decidual tissue was found in 11 cases, proliferative endometrium was found in 65 cases, and secretory endometrium was found in 16 cases. 12 of these 16 showed unequivocal secretory endometrium on or before the 43rd day postpartum; one was found as early as Day 33. The other 4 cases were found to be secretory between Days 44 and 93. 2 patients had menstruated once before biopsy. Those 16 cases with secretory endometrium ranged in age from 19-30 years; 12 of these women had had their pregnancy terminated between Weeks 38 and 41 and 3 women were terminated at Week 36, while 1 was terminated at Week of gestation. All women studied were nonlactating. Based on these data, contraceptive counseling postpartum should commence between Weeks 3 and 4 postpartum.

A method is presented for the study of the pH of the human uterine fluids and/or mucosa in situ. The hydrogen-ion concentration of the uterine cavity varies during the normal menstrual cycle. A decrease in the alkalinity of the uterine fluids and/or mucosa is associated with a corresponding secretory endometrium. The occurrence of ovulation appears to be accompanied by a period of relative acidity of the uterine fluids and/or mucosa.