Changes in steroid enzyme activity in the human endometrium during the menstrual cycle

Sulfokinase, sulfatase, 17 beta-HSD, 20 alpha-HSD, 3 beta-HSD and 5 alpha-reductase activity and steroid concentrations including estradiol, estrone, estrone-sulfate, progesterone, 20 alpha-dihydroprogesterone, DHA and DHA-sulfate in endometrial tissue were examined in order to study the changes in steroid metabolism in relation to the menstrual cycle in the human endometrium. Thirty-one (14) proliferative and 17 secretory) endometrial tissue samples were obtained from women who underwent hysterectomy. Low enzymatic activity of sulfokinase, sulfatase and 17 beta-HSD activity were observed in the proliferative phase (0.25, 8.5, 3.1 nmole/mg protein/h). A pronounced increase in enzymatic activity was observed in the early secretory phase and activity gradually decreased toward the mid and late secretory phase. On the other hand, 20 alpha-HSD and 3 beta-HSD activity did not change during the cycle. 5 alpha-reductase activity was not detectable under the conditions used. The concentration of progesterone in the secretory phase was significantly higher than that in the proliferative phase. The concentration of estradiol in the proliferative phase was significantly higher than that in the secretory phase. There was no significant change in the concentration of estrone, estronesulfate, 20 alpha-dihydroprogesterone, DHA or DHA-sulfate during the cycle. The relationship between the steroid concentration and the enzymatic activity was discussed. The results suggested an active role of the endometrium in controlling the biological effect of steroids.     

Proliferation kinetics of human endometrium during the normal menstrual cycle.

A radioautographic analysis of the number and distribution of labeled nuclei after in vitro incorporation of radiothymidine was carried out in human endometrium during the normal menstrual cycle. The highest rates of proliferation were recorded on cycle days 8 to 10 in the upper one third of the functionalis layer. Coinciding with intraglandular secretory activity on cycle day 19, the rate of proliferation of gland cells decreased near zero levels and remained unchanged thereafter. Midsecretory phase arteriolar coiling and stromal predecidualization were associated with increased isotope incorporation. DNA synthesis in premenstrual endometrium was limited to the surface epithelium, predecidua, and vascular endothelium. The endometrium of the isthmus and cornual regions and of the basalis zone demonstrated relatively constant and comparatively lower rates of proliferation throughout the cycle. Regional and cellular variations in nucleic acid synthesis in cyclic endometrium are likely to reflect differences in physiologic functions in target cells in response to cyclic hormonal stimuli.     

Prolactin production by human endometrium during the normal menstrual cycle.

Prolactin (PRL) synthesis by human decidua from term pregnancies has been reported. The present study examined the tissue content and in vitro production of prolactin by "decidualized" and "nondecidualized" endometrium unassociated with pregnancy. Tissue obtained throughout the menstrual cycle was dated histologically. When proliferative endometrium (N = 16) or secretory endometrium prior to day 22 (N = 6) was examined, no PRL was detected in the tissue or medium after a 24-hour incubation at 37 degrees C in Gey's buffer. Total PRL in tissue and medium measured by radioimmunoassay increased significantly from 1.2 +/- 0.3 ng/100 mg of tissue at cycle days 22 to 24 (N = 4) to 5.3 +/- 2.4 ng/100 mg of tissue at cycle days 25 to 26 (N = 7). The addition of 100 micrograms/ml of cycloheximide to the medium prevented the net increase in PRL content during incubation. It is concluded that PRL is synthesized by endometrium during the normal menstrual cycle and that the appearance and degree of synthesis and decidualization of the stroma correspond.     

Sex steroid hormones influence the cAMP content in human endometrium during the menstrual cycle

The measurement of the tissue concentrations of cyclic adenosine monophosphate (cAMP) in human endometrium shows that the levels of the nucleotide vary during the menstrual cycle, being 11.4 +/- (SE) 2.5 and 37.7 +/- (SE) 10.1 pmol/mg protein in the proliferative and secretory phase, respectively. The individual determinations of cAMP are significantly correlated to the estradiol/progesterone blood concentration ratio: by this means we obtained a superimposable distribution with the results of histologic examination suggesting that the hormones have a direct action in determining the cAMP levels in this tissue. The relevance of these observations for the physiology of the endometrium is discussed.     

Ultrastructure of the microvasculature in the human endometrium throughout the normal menstrual cycle.

In the early proliferative phase endometrial capillary basal lamina is loosely formed and discontinuous. It becomes more distinct in the late proliferative phase and develops whorled extensions that include pericytes in the early secretory to midsecretory phase. Throughout the cycle both endothelial cells and pericytes possess cytoplasmic processes that extend through discontinuities in the basal lamina and make contact with each other. These contacts may be simple or complex. They become more elaborate as the cycle progresses to the midsecretory phase. Endothelial cells show progressive but heterogeneous differentiation into the midsecretory phase, with individual cell hypertrophy. In the late-secretory phase the endometrial stroma and the basal lamina are characterized by widespread degeneration, and the cell-to-cell contacts sharply decrease. However, endothelial cells remain relatively intact.     

Polymorphonuclear leukocytes in the endometrium during the normal menstrual cycle

We investigated the presence of polymorphonuclear leukocytes (PMNs) in normal endometrium. Hematoxylin and eosin stained slides of 100 endometrial curettage and biopsy specimens were reviewed for dating and presence of PMNs. Polymorphonuclear leukocytes were quantitated by chloroacetate esterase (CAE) stains. Polymorphonuclear leukocytes were present in large numbers in areas of tissue degradation (day 28 and menstrual phase endometrium) and were found only in small numbers in intact tissue throughout the cycle. The CAE and H&E stains showed minimal difference in ability to detect PMNs. Polymorphonuclear leukocytes could be easily discriminated from endometrial granulocytes, which did not stain with CAE.     

Danazol binding to steroid receptors in human uterine endometrium

To understand the mechanism of action of danazol, the binding of danazol to multiple classes of intracellular steroid binding proteins was studied in the human uterine endometrium. Danazol bound to endometrial receptors for estrogen, progesterone, and androgen and seemed to bind to endometrial intracellular corticosteroid-binding globulin and sex-hormone-binding globulin. Danazol occupies almost all binding sites of steroids in the steroid target cells in spite of the presence of endogenous steroids. It is speculated that the binding behavior of danazol may be related to its therapeutic effect on endometriosis.     

Heat shock proteins in human endometrium throughout the menstrual cycle

Human endometrium, in response to steroid hormones, undergoes characteristic cycles of proliferation, secretory changes, and tissue shedding. Human endometrium expresses a molecular repertoire which includes the heat shock proteins (Hsps) Hsp27, Hsp60, Hsp70, Hsp90, and alpha crystallin B chain. The expression of Hsp27, Hsp60, and the constitutive form of Hsp70 (Hsc70) shows a sharp increase in human endometrium after ovulation. The maximal expression of the molecular chaperone, alpha crystallin B chain, occurs during the secretory phase. In view of known functions of the Hsps, it is likely that these proteins are involved in protection of the endometrial proteins against factors with the potential to lead to protein denaturation. Tumor necrosis factor-alpha (TNF-alpha) is a cytotoxic cytokine that is produced in progressive amounts during the secretory phase. The function of the Hsps may be to protect cells against the cytotoxic damage of TNF-alpha, particularly during the critical period of "implantation window."     

Serum gonadotropin and steroid patterns during the normal menstrual cycle

At the University of Southern California School of Medicine, the reproductive hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone, and estradiol were measured in serum samples obtained daily from a group of women throughout a normal menstrual cycle. Competitive binding techniques were used for the analysis of aliquots from the 10 women, aged 20-28, whose hormonal levels were studied. The results were generally in agreement with those of previous investigators, whose separate researches were less extensive than the research described here. FSH showed an early follicular phase rise, a late follicular phase decline, and a midcycle peak occurring on the day of the LH peak or on the day before and followed by a luteal phase decline. LH showed a slight progressive rise in the follicular phase, a midcycle peak, and a slight fall in the luteal phase. Estradiol also reached a midcycle peak. After the midcycle peaks, a rise progesterone. Progesterone and estradiol fell a few days before menstruation.     

Antigen-presenting cells in human endometrium during the menstrual cycle compared to early pregnancy

OBJECTIVE: Human endometrium and early pregnancy decidua harbor a considerable and diverse population of antigen-presenting cells (APC). Changes in the number and distribution of macrophages and dendritic cells (DC) could point to a possible role of these immunocompetent cells in implantation and success of early pregnancy. METHODS: Uterine tissue was obtained from 22 women undergoing hysterectomy for bleeding disorders or dysmenorrhea and from 11 women undergoing legal abortion. Tissue was investigated with antibodies against CD14, CD68, CD83, DC-SIGN, Ki-67, and human leukocyte antigen (HLA)-DR using single and double immunohistochemical staining techniques. RESULTS: The number of CD14(+) cells was stable during all phases of the menstrual cycle and early pregnancy. In comparison to nonpregnant endometrium, DC-SIGN(+) cells showed a higher proliferation rate and were found associated in clusters with CD56(+) natural killer (NK) cells in early pregnancy. In the late secretory phase of the menstrual cycle, numbers of CD83(+) (P <.01) cells were significantly higher than in other endometrial phases and early pregnancy. HLA-DR(+) expression was significantly increased in early pregnancy but remained unchanged throughout the menstrual cycle. CONCLUSION: The presence of DC-SIGN(+) cells during the menstrual cycle and their proliferation in early pregnancy suggests an important role of these cells with regard to the balance between defense against pathogens and tolerance of the fetal allograft. Whether the increase of CD83(+) mature DC and CD68(+) macrophages in the late secretory phase is caused by hormonal stimuli and/or is due to changes of the cytokine/chemokine micromilieu remains to be investigated.     

Fluctuation of 6Ckine expression in human endometrium during the menstrual cycle

OBJECTIVE: To clarify the expression of 6Ckine, a potential chemoattractant for endometrial natural killer (NK) cells, in the human endometrium. DESIGN: Experimental study. SETTING: Department of obstetrics and gynecology at a medical university. PATIENT(S): Fifty-seven fertile women 25 to 52 years of age who had regular menstrual cycles and normal endometrium and were undergoing hysterectomy. INTERVENTION(S): Endometrium was obtained from operative samples. MAIN OUTCOME MEASURE(S): Tissue was immunostained to determine the localization of 6Ckine in the endometrium throughout the menstrual cycle. The number of NK cells was counted in 10 nonoverlapping stromal areas. The concentration of 6Ckine in homogenized endometrium was determined by enzyme-linked immunosorbent assay. RESULT(S): Endometrial surface, glandular epithelial cells, and perivascular stromal cells were immunoreactive for 6Ckine throughout the menstrual cycle with some fluctuation. In addition, some T cells, NK cells, and macrophages in the stroma were immunoreactive for 6Ckine. The 6Ckine concentration was low in the proliferative phase but elevated in the secretory phase. It showed a moderate positive correlation with the number of endometrial NK cells. CONCLUSION(S): 6Ckine may be a potential chemoattractant for endometrial NK cells.     

Estrogen receptor in human endometrium during the menstrual cycle and early pregnancy

Available estrogen receptor has been estimated in endometrial tissue obtained from 8 women on the eighth and twenty-first days of the same menstrual cycle. Respective concentrations were 3.8 ± 1.1 and 6.0 ± 2.5 femtomoles (fmoles) per milligram of wet tissue during 5 ovulatory cycles and were 8.1 ± 3.7 and 2.9 ± 0.3 fmoles per milligram during 3 anovulatory cycles. The latter cycles appear to be associated with elevated endometrial receptor concentration on Day 8, and a marked drop between Days 8 and 21. In decidual tissue obtained from 4 patients who were 9 to 18 weeks pregnant, receptor concentration is low. The data indicate that available receptor concentration in human endometrium changes with hormonal status.     

Endometrial steroid receptor during normal menstrual cycle and physiopathology of nidation

Human uterine endometrial steroid receptor [estrogen (ER), progestin (PR) and androgen (AR) receptors] in the normal menstrual cycle were determined at the cellular level. Endometria with pathological out-of-phase findings or with hypoplastic uterus were evaluated for the concentration of steroid receptors, for a better understanding of their pathophysiology. ER and PR levels gradually rose toward the early secretory phase, remained at the maximum level during the mid-secretory phase and dropped to the lowest level during the late secretory phase. Especially nuclear PR reached the maximum level during the mid-secretory phase. These results indicate that the endometrial ER and PR, especially the endometrial nuclear PR, is kept in the maximum level at implantation. AR showed only a slight change in a very low level throughout the menstrual cycle. This indicates that androgen may not play so important a role in endometrial physiology. Endometria with out-of-phase or with hypoplastic uterus contained significantly low levels of endometrial ER and PR, while serum hormones levels were normal. This indicates indigenous reduction of ER and PR synthesis in such endometria.     

Variation during the menstrual cycle of immune cell populations in human endometrium.

Morphometric analysis and immunohistology of tissue sections have been used to assess variation, during the normal menstrual cycle, of the bone marrow-derived cell populations in human endometrium. Levels of T cells and macrophages were found to be relatively constant throughout the cycle. In contrast, numbers of large granular lymphocytes, identified as being CD56-positive, were generally low between days 10 and 19, but increased sharply in the latter part of the luteal phase, decreasing again after menstruation. This LGL population is known to be abundant in first trimester pregnancy decidua, and is presumed to play a role in early pregnancy success.