The effects of GnRH antagonist on the endometrium of normally menstruating women

Purpose

To study the effects of GnRH antagonist (ganirelix-Orgalutran®) on the endometrium of regularly menstruating women.

Materials and methods

Prospective, self-controlled study. The thirty-five volunteers were studied for two cycles: one as a control and the other, GnRH antagonist-treated cycles in which ganirelix 0.25 mg/d was given daily for 3 days, starting when the largest follicle reached 15 mm. In both cycles, serum estradiol, LH and endometrial thickness were measured when the largest follicle was ≥18 mm. Endometrial biopsy was performed on day 6 after ovulation for histological dating and morphometric study.

Results

No statistical differences between histological dating and the endometrial thickness in the control and GnRH antagonist-treated cycles. All morphometric parameters were also not different. Serum estradiol and LH levels were significantly lower in GnRH antagonist-treated cycles.

Conclusion

GnRH antagonist has no effect on the endometrium of regularly menstruating women as assessed by either histological dating or morphometric analysis.

     

HOXA10 protein expression in the endometrium of normally menstruating women after receiving GnRH antagonist

Objective(s)

To compare HOXA10 protein expression in the endometrium between natural control cycles and GnRH antagonist-treated cycles obtained during the window of implantation of normally menstruating women.

Study design

This study was conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Thirty-five volunteers were recruited into this prospective, self-controlled study, which was divided into two cycles, the first a natural control cycle and the second a GnRH antagonist-treated cycle. The two cycles were separated by one resting cycle. In the GnRH antagonist-treated cycle, when the leading follicle was 15 mm, ganirelix (Orgalutran^®) 0.25 mg was administered daily. In both cycles, ovulation was induced when the largest follicle reached 18 mm in diameter. Finally, endometrial biopsy was performed on day 6 after documented ovulation, which corresponds to the window of implantation. Endometrial HOXA10 protein expression, a marker of endometrial receptivity, was analyzed by immunohistochemistry. The protein expression was compared between the two cycles regarding their percentage of immunostained cells and IHC-scores (percentage of stained cells × intensity of nuclear staining).

Results

HOXA10 protein was exclusively localized in the stromal compartment of the endometrium. The percentage of HOXA10 nuclear staining in the endometrium collected from GnRH antagonist-treated cycles was higher than that of the natural cycles, whereas the IHC-scores showed no difference between the two cycles.

Conclusion(s)

GnRH antagonists may have no effect on HOXA10 protein expression in the endometrium obtained during the implantation window of normally menstruating women.     

Urinary unconjugated cortisol in normally menstruating women and during estrogen-gestagen treatment

Changes in 24-hour excretion of unconjugated urinary cortisol and creatinine clearance were determined in 9 normally menstruating women and in 9 women undergoing estrogen-gestagen treatment on 3 consecutive days. A correlation between the cortisol excretion and the creatinine clearance was found only in the luteal phase of the menstrual cycle. The cortisol excretion increased neither during the menstrual cycle nor during the estrogen-gestagen treatment. A marked intra-individual variation in the excretion of unconjugated urinary cortisol was demonstrated in both groups.     

Changes in soluble proteins in cervical mucus during midcycle in normally menstruating women

Albumin, IgG and complement C3c were analyzed by immunonephelometry in cervical mucus collected daily at midcycle. There was a statistically significant difference in the amount of mucus recovered on the day of the luteinizing hormone (LH) surge and on the following day. Several nadirs in protein concentration could be visualized in 8 out of 14 subjects, whereas in 6 subjects, no such changes in concentration were found. In terms of soluble protein concentrations and amounts there were no differences between cycle days. For changes in soluble protein concentrations and amounts, no systematic time relation to the LH peak could be found.     

Intraepithelial epidermoid carcinoma of the cervix, endometrium, and a fallopian tube

A patient with intraepithelial epidermoid carcinoma of the uterine cervix, endometrium, and a fallopian tube is presented. This abnormality is discussed with particular attention to the association with chronic inflammation. This rare lesion might represent a superficial spread of atypical cervical epithelium to include the endometrium and fallopian tube or could reflect a field change. The effect of this finding upon the prognosis of intraepithelial carcinoma of the cervix is unknown.     

Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervix

An immunoradiometric assay with the use of a monoclonal antibody can detect an antigenic determinant (CA125) in peripheral blood from more than 80% of patients with epithelial ovarian cancer. In this report elevated levels of CA125 were detected in serum from patients with adenocarcinomas of the fallopian tube, endometrium, and endocervix. Among patients with endometrial cancer, CA125 levels were elevated in recurrent or disseminated disease but not with tumors confined to the uterus.     

Induction of multiple follicular growth in normally menstruating women with endogenous gonadotropin suppression

Patients with normal menstrual rhythm and normal luteinizing hormone were treated with exogenous gonadotropins to induce multiple follicular development. This was effected in the absence (34 cycles in 12 patients) or with concurrent suppression of endogenous gonadotropin levels with a gonadotropin-releasing hormone analog (84 cycles in 18 patients). In the absence of the analog, "premature" luteinization occurred in 51% of cycles before the ultrasonic visualization of a follicle with a diameter of 20 mm. In the analog-treated cycles, premature luteinization was almost totally eliminated and progesterone elevations were delayed until after administration of human chorionic gonadotropin. Follicular estrogen production was unaffected by the analog treatment, compared with hypogonadal patients treated with exogenous gonadotropins. The characteristics of follicular development showed that two to three follicles of mature size were induced with this technique, and the capacity for the induction of a larger number of follicles was evident.     

Current understanding of the corpus luteum in women and nonhuman primates

Despite the important advances detailed in this review, our understanding of the factors and mechanisms controlling the function of the corpus luteum in the menstrual cycle is rudimentary. Luteolysis remains a mystery. As the activities and interactions between different cell types in the corpus luteum are defined and the role(s) of endocrine, paracrine, and autocrine factors are elucidated, however, we should begin to understand the "self-destruct" process at the end of the cycle. As cellular and molecular approaches combine with physiologic techniques, new information will be available to address the clinical issues of luteal dysfunction which perplex us all.     

Histology of midluteal corpus luteum and endometrium from clomiphene citrate-induced cycles.

OBJECTIVE: To determine the histologic development of midluteal corpus luteum (CL) and endometrium in normal fertile women after induction of ovulation with clomiphene citrate (CC). DESIGN, PATIENTS, INTERVENTIONS: Twelve normally cycling women planning to undergo an elective tubal ligation were treated with 50 to 150 mg of CC daily on days 5 through 9 of the cycle. Luteectomy and endometrial biopsy were performed simultaneously 7 days after the urinary luteinizing hormone surge. RESULTS: Because polyovulation occurred in 10 of the 12 women, 22 CL and 12 endometrial biopsies were studied. Ten women had luteal and endometrial histology that were within 2 days of the ovulation to biopsy interval. The 2 remaining women had endometrial histology that lagged 3 days behind the chronological postovulatory date. In these women, out-of-phase endometrium occurred despite polyovulatory cycles in which two and three histologically normal CL lutea were present and associated with elevated progesterone concentrations. CONCLUSIONS: In CC-induced ovulatory cycles: (1) midluteal CL histology is normal and (2) apparently out-of-phase preimplantation endometrium occurs in midluteal phase.     

Serum luteinizing hormone during ovulation induction with human menopausal gonadotropin for in vitro fertilization in normally menstruating women

Sixteen cycles in 14 normally menstruating women, stimulated with human menopausal gonadotropin in order to recruit more than one follicle for a successful in vitro fertilization process, were adequately monitored to identify the appearance of the spontaneous luteinizing hormone (LH) surge. Daily serum LH determinations, increased to every 4 hours in the presumptive preovulatory period, showed that in these women the endogenous estrogen-triggered LH midcycle peak did not occur at the expected time. It is hypothesized that the mechanism responsible for this suppression is a negative feedback mediated by an increased circulating protein with an inhibin-like action.     

Four synchronous female genital malignancies: the ovary,cervix, endometrium and fallopian tube

Objective To present a unique case of a 63 year-old woman with coexistent adenocarcinoma of the ovary, endometrium, cervix and fallopian tube. Materials and methods A case report from a tertiary health center. Results A woman presenting with postmenopausal bleeding and abdominal distantion was assessed by endometrial biopsy and explorative surgery. The frozen section of the mass on the right adnex revealed malign mucinous carcinoma of the ovary. As usual, optimal debulking was performed as initial surgical staging procedure of ovarian cancer. The microscopic examination of the right ovary revealed a typical mucinous cystadenocarcinoma. Furthermore, the focal endometrial irregularity at the left uterine cornus turned out to be a well differentiated endometrial carcinoma of the endometrioid type with <1/3 myometrial invasion. The pale infiltrative lesion in the cervix also turned out to be an adenocarcinoma of the endocervical type with deep stromal invasion and areas of diffuse glandular dysplasia and in-situ glandular neoplasia at the periphery. Besides, several sections from the left fallopian tube uncovered diffuse dysplasia in the lining epithelium and a focus of adenocarcinoma with papillary and cribriform pattern. Discussion When compared with patients having metastatic lesions, most synchronous female malignancies are accompanied with early stage and low-grade with a more favorable prognosis. However, there is paucity of data for the exact criterion to distinguish primary tumors from metastatic lesions. In such cases, the validity of immunohistochemical and cloning studies are not clear.     

CA 125 in normal tissues and carcinomas of the uterine cervix,endometrium and fallopian tube

The distribution of cancer antigen 125 (CA 125) has been investigated in normal tissues and carcinomas of the Müllerian duct by immunohistochemical methods using the monoclonal antibody OC 125. Detection of CA 125 was most intense in cryostat sections and decreased in formalin fixed and paraffin embedded tissues according to the duration of fixation. Enzymatic digestion with neuraminidase or alkaline hydrolysis abolished specific staining suggesting the antigen is a sialylsaccharide bound to protein by alkali-labile linkage. Immunohistochemical staining demonstrated the presence of CA 125 in all normal glandular epithelia of the endocervix, endometrium and fallopian tube in different distribution patterns. In normal endometrium the cellular distribution pattern was related to the menstrual cycle. In endocervical, endometrial and tubal adenocarcinomas CA 125 was found in 73% of cases. In glandular structures the antigen was concentrated at the luminal surface of the tumour cells, in solid tumour areas it was spread throughout the cytoplasm or concentrated in large cytoplasmic vacuoles. The expression of CA 125 was considerably lower in solid tumour areas. These data show that CA 125 is not a true "tumour marker", but a product of female genital mucosae and of their cancerous derivates provided their synthesizing ability is not lost in the course of pathologic differentiation.     

CA 125 in normal tissues and carcinomas of the uterine cervix,endometrium and fallopian tube

Summary The study deals with the occurrence of cancer antigen 125 (CA 125) in the normal and neoplastic uterine cervix, endometrium and fallopian tube and its applicability as a tumour marker. CA 125 concentrations were measured in 52 secretion specimens, in cytosol fractions of 97 tissue biopsies and in serum from 47 women with nonmalignant disorders and from 334 patients with carcinomas. High quantities of CA 125 (780-454860 U/ml) were detected in cervical mucus, intra-uterine and tubal fluid, exceeding those in the corresponding serum samples by factors of up to 2000. CA 125 concentrations were 9–53 fold higher in cytosol fractions of normal and neoplastic glandular epithelia of the endocervix and endometrium than in those of cervical squamous epithelia and the cervical wall. Despite similarly high antigen concentrations in normal glandular epithelia and adenocarcinomas serum levels elevated to above 65 U/ml were only found in patients with malignant tumours. The positivity rates in serum increased with tumour extent and were 0–43% for primary and 63–79% for recurrent cervical, endometrial and tubal adenocarcinomas. During long-term follow-up, CA 125 serum concentrations were concordant with the clinical course in 10 out of 11 patients with progressive carcinomas. According to these results, the release of CA 125 into the peripheral blood is apparently dependent on the infiltrative growth and the mass of the tumour rather than on, the local tissue concentrations. The clinical use of CA 125 is limited to the detection of advanced adenocarcinomas of the Müllerian duct.Presented in part at the 46. Tagung der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe, Sept. 1986, Düsseldorf/FRGDedicated to Prof. Dr. A. Bolte, Köln, for his 60th birthday