Endometrial expression of glycodelin in women with levonorgestrel-releasing subdermal implants.

OBJECTIVE: To determine whether subdermal levonorgestrel implants induce endometrial expression of glycodelin. DESIGN: Cross-sectional, blinded study. SETTING: University clinic. PATIENT(S): One hundred and eight women with subdermal implants and 19 postmenopausal women. INTERVENTION(S): Endometrial biopsies, curettages, and hysterectomies. MAIN OUTCOME MEASURE(S): Endometrial glycodelin expression was examined through immunohistochemistry, in situ hybridization, and morphologic endometrial dating. RESULT(S): Overall, 80% of the endometrial specimens obtained from women with subdermal levonorgestrel implants stained positive for glycodelin. Endometrial morphology of these women showed proliferative (71%), inactive/weakly proliferative (19%), menstrual or regenerating (6.5%), and other patterns (2.8%). Of these, 79%, 71%, 100%, and 100% were glycodelin positive, respectively. Nineteen specimens were obtained during the midcycle when glycodelin is not normally expressed: of these, 89% stained positive for glycodelin. Implant-related amenorrhea was associated with endometrial glycodelin expression in 58% of the women, whereas the endometrium specimens obtained from women with postmenopausal hypoestrogenic amenorrhea contained no detectable glycodelin. CONCLUSION(S): Subdermal levonorgestrel implant use is often associated with endometrial expression of glycodelin. Because glycodelin has been shown to inhibit sperm-egg binding, the induction of glycodelin may contribute to the contraceptive activity of the implant.

Endometrial markers of uterine receptivity utilizing the donor oocyte model.

BACKGROUND: Ethical constraints limit the ability to study peri-implantation phase human endometrium. In this study, the donor oocyte model was used to study candidate endometrial markers of uterine receptivity. METHODS: Archived, paraffin-embedded tissue obtained by endometrial biopsy during cycle days 21-23 of patients undergoing 'mock' hormonal treatment cycles were evaluated by standard histological criteria and immunohistochemical staining for alpha v beta 3 integrin and glycodelin. All of these patients (n = 101) had undergone a donor oocyte embryo transfer cycle utilizing the exact same hormonal protocol. RESULTS: Histological evaluation revealed 62 (61.3%) in-phase, 34 (33.7%) dyssynchronous, 2 (2.0%) immature and 3 (3.0%) advanced endometria. The clinical outcomes of patients with either in-phase or dyssynchronous endometria were similar. Very strong correlations were noted between endometrial glandular dating and either alpha v beta 3 integrin or glycodelin immunostaining intensity (P < 0.001 for both). Glycodelin and alpha v beta 3 integrin immunostaining intensities were also highly correlated with each other (P < 0.001). CONCLUSIONS: Throughout the time period corresponding to the putative window of maximal endometrial receptivity (cycle days 21-23) a dynamic process was observed in exogenous hormonal replacement cycles characterized by a rapid histological advancement of endometrial glandular elements as well as progressive alpha v beta 3 integrin and glycodelin expression.

Histochemical localization of endometrial insulin-like growth factor binding protein-1 and -3 during the luteal phase in controlled ovarian hyperstimulation cycles: a controlled study.

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of IGFBP-1 and IGFBP-3. DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Eighteen oocyte donors undergoing COH cycles and 17 natural cycle controls. INTERVENTION(S): Controlled ovarian hyperstimulation, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial IGFBP-1 and -3 expression, morphological endometrial dating, and serum estradiol (E(2)), LH, and progesterone (P(4)) concentrations. RESULT(S): No statistically significant difference was observed between natural and stimulated cycles in change in IGFBP-1 or -3 over standardized cycle days throughout the window of embryo implantation (days 17-24). The IGFBP-1 and -3 expression was zero or near zero for both the natural and COH cycles until day 12-13. Both IGFBPs showed increased production throughout the secretory phase. Advanced endometrial histology (>/=1 day) in glands and stroma was noted in COH cycles. Significant positive correlations of E(2) and P(4) were noted with IGFBP-1 and -3 but not with advanced endometrial morphology in the COH cycles. CONCLUSION(S): The COH cycles have no significantly increased endometrial IGFBP-1 or -3 expression throughout the implantation phase of the luteal cycle compared with normal menstrual cycles. Both IGFBPs were absent in the proliferative phase and increased throughout the secretory portion of the embryo implantation window.

Endometrial glycodelin-A expression in the luteal phase of stimulated ovarian cycles.

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of glycodelin-A (GdA). DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Fifteen oocyte donors undergoing COH cycles and 19 natural-cycle control patients. INTERVENTION(S): COH, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial GdA expression, morphologic endometrial dating, and serum E2, LH, and P4 concentrations. RESULT(S): GdA was detected in all subjects throughout the implantation window period. Immunolocalization was demonstrated in the endometrial glands and not in the stroma or on the surface. A significantly increased proportion of GdA-staining endometrial cells were noted in COH cycle patients as compared with natural-cycling control patients throughout the window of embryo implantation. Both cycle types demonstrated increasing GdA expression throughout the late luteal phase. A significant positive correlation was noted between GdA expression and serum E2 levels (r = 0.5, P<.001) in natural cycles and advanced histology in COH cycles (r = 0.63, P=.01). Neither LH nor P4 were correlated with endometrial GdA expression. CONCLUSION(S): COH cycles have a significantly increased endometrial GdA expression throughout the implantation phase of the luteal cycle when compared with normal menstrual cycles. The increased expression may affect implantation during COH cycles.

Glycodelins: role in regulation of reproduction, potential for contraceptive development and diagnosis of male infertility.

Glycodelins are glycoproteins synthesized in various glands, with sequence homology to beta-lactoglobulins, and named according to their unique oligosaccharide structures. We purified, cloned and sequenced endometrium- and seminal plasma-derived glycodelins (GdA and GdS respectively) and found that they are involved in various types of cell-cell communications. These include interactions between the spermatozoon and the egg, and between immune cells and their targets. Endometrial GdA inhibits sperm-egg binding, whereas the differently glycosylated GdS in seminal plasma does not. These observation are of interest for reproductive physiology, detection of causes of infertility, and they also may have potential for contraceptive development.

Levonorgestrel-releasing intrauterine device-wearing women express contraceptive glycodelin A in endometrium during midcycle: another contraceptive mechanism?

Intrauterine devices (IUDs) exert contraceptive action by interfering with sperm transport, ovum development, fertilization and implantation. Glycodelin A (GdA) is a uterine glycoprotein that has local contraceptive activity by inhibiting sperm-egg binding. GdA is normally absent from endometrium during the fertile midcycle and it is not expressed until the fifth postovulatory day. The phase of menstrual cycle addressed in this study covers the phase when conception is most likely to follow an unprotected intercourse and when GdA is normally absent. We present here evidence that levonorgestrel-releasing IUD (LNg-IUD) is accompanied by 'inappropriate' expression of GdA in endometrium between days 7 and 16 of the menstrual cycle (six out of six cases). The same was also found in copper-releasing IUD (Cu-IUD)-wearing women, but less frequently (four out of 11 cases, P < 0.0345, Fisher's exact test). In-situ hybridization localized GdA mRNA into endometrial glands in the midcycle endometrium, confirming the cellular site of synthesis. Based on the potent inhibitory activity of GdA on sperm-egg binding, the presence of GdA in uterine glands of IUD wearers may lead to prior exposure of sperm to contraceptive GdA, thus contributing to the contraceptive activity of the IUD.

PIP: Glycodelin A (GdA), a uterine glycoprotein that exerts local contraceptive activity by inhibiting sperm-egg binding, is generally absent from the endometrium during the fertile midcycle and is not expressed until postovulatory day 5. In this study of endometrial specimens collected from 6 Finnish users of the levonorgestrel-releasing IUD, "inappropriate" expression of GdA between days 7 and 16 of the cycle was observed in every case. Endometrium samples showed epithelial atrophy and stromal decidualization regardless of the duration of IUD use. GdA was localized to endometrial glands, with only sporadic faint patches in the stroma. Unexpected expression of GdA was also detected in 4 of 11 endometria from women with copper-releasing IUDs. Based on the potent inhibitory activity of GdA on sperm-egg binding, the presence of GdA in the uterine glands of hormone-releasing IUD users may lead to prior exposure of sperm to contraceptive GdA, thus contributing to the fertility control activity of the device.

Pharmacokinetics of mifepristone after low oral doses.

Relatively low doses of the antiprogestin mifepristone (RU 486) have recently proven to be efficient for a variety of possible clinical uses of the drug. However, the pharmacokinetics after low single oral doses have not been characterized. We evaluated the pharmacokinetics of mifepristone following single ingestion of 2 and 25 mg in five women as well as repeated ingestion of 8 mg in two women. Maximal serum concentrations were reached rapidly (within 0.5-2 h) with all doses used. Serum mifepristone concentrations were proportional to the oral doses taken. The mean (+/- SD) areas under the concentration curves (AUCs) (0-24 h) were 1134 (+/- 144), 4846 (+/- 64), and 17,015 (+/- 4,421) h x ng/mL following 2, 8, and 25 mg doses, respectively. No cumulative increases in serum concentrations were detected with prolonged daily administration of 8 mg of mifepristone. The study subjects appeared to vary in their ability to metabolize mifepristone, as two different half-lives (t1/2) emerged after both 2 and 25 mg single doses (24.2 +/- 0.6 [SD] h for three subjects; and 44.4 +/- 1.8 [SD] h for two subjects). We conclude that within the dose range of 2-25 mg/day, the pharmacokinetics of mifepristone are linear, unlike those seen following ingestion of higher daily doses. Keeping in mind previously published data on the biological effects of low dose mifepristone administration, these data infer that certain effects of the drug, such as inhibition of ovulation, might be achieved at serum concentrations of approximately 100 ng/mL.

PIP: At the outpatient clinic of Lohja District Hospital in Lohja, Finland, clinical researchers examined the pharmacokinetics of mifepristone in 5 healthy women, 29-37 years old, receiving a single dose of 2 mg mifepristone and of 25 mg mifepristone and in 2 other women receiving 8 mg mifepristone each day for 30 days. Regardless of the dose, serum concentrations of mifepristone peaked within 1.2-1.4 hours. These concentrations were proportional to the oral doses: 104-227 ng/ml after 2 mg dose; 474-561 ng/ml after 8 mg dose; and 1285-4851 ng/ml after 25 mg dose. The areas under the concentration curves (0-24 hours) were also proportional to the oral doses: 1134.4, 4846, and 17,015.2, respectively. Daily doses of 8 mg mifepristone over 30 days did not effect cumulative increases in serum concentrations. The women taking the 2 mg and 25 mg single oral doses exhibited different half-lives (24.2 [3 women] vs. 44.4 [2 women] hours; p = 0.001), suggesting that they varied in their ability to metabolize mifepristone. These findings show that, at daily ingestion of 2-25 mg mifepristone, the pharmacokinetics of mifepristone are linear. Based on these findings, the authors think that inhibition of ovulation might be achieved at serum concentrations of about 100 ng/ml.