Seminars in reproductive endocrinology最新文献

Insomnia, disturbed sleep, and fatigue are among the most frequent health complaints of perimenopausal women. Estrogen replacement therapy (ERT) usually improves sleep, most likely by alleviating vasomotor symptoms. However, sleep difficulties are not restricted to the perimenopausal period. Older postmenopausal women typically experience longer latencies to sleep onset, increased nocturnal waking, increased fragmentation of sleep, and less slow wave (deep) sleep. These sleep changes in older women may be partially related to the postmenopausal profile of sex steroid hormones. Estrogen has powerful effects on several biological factors that directly influence sleep, including body temperature regulation, circadian rhythms, and stress reactivity. The link between sleep disturbance in older women and these CNS effects of estrogen is largely speculative at present. This article reviews what is known, what remains to be addressed, and some clinical implications.

During progesterone-induced decidualization of estradiol (E2)-primed human endometrial stromal cells (HESCs), the interstitial-type extracellular matrix (ECM) of the follicular phase endometrium is transformed in the luteal phase to a mixture of residual interstitial- and new basal laminar-type components. This transformation is accelerated by reduced proteolytic activity of HESCs undergoing decidualization (DZ). In cultured HESCs, progestins, but not E2, induce the expression of several DZ markers, and E2 enhances these effects despite the lack of response to E2 alone. Using this well-characterized in vitro DZ model we evaluated the expression of plasminogen activators (PAs), which degrade ECM components that undergo rapid turnover, and matrix metalloproteinases (MMPs), which degrade the bulk of ECM components. Medroxyprogesterone acetate (MPA) inhibited the catalytic activity of urokinase-type PA (uPA) and tissue-type PA (tPA) as well as the expression of such MMPs as interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3). Moreover, E2 + MPA elicited greater inhibitory effects on the expression of all of these proteases. Progestin inhibition of PA activities reflected reciprocal upregulation in the output of the PA inhibitor PAI-1, which produced large molar excesses of PAI-1 compared with the PAs in HESC-conditioned medium. By contrast, the tissue inhibitor of the MMPs, TIMP1, as well as gelatinase A (MMP-2), was constitutively expressed by the HESCs. In the absence of implantation, menstruation-associated degradation of the functional endometrial ECM is triggered by withdrawal of circulating ovarian steroids. This process was evaluated in cultured HESCs that were first decidualized during 10 days of exposure to E2 + MPA, and then withdrawn to steroid-free medium with and without the antiprogestin RU 486. As expected, steroid withdrawal reversed progestin-inhibited PA activity as well as the expression of MMP-1 and MMP-3 and progestin-enhanced PAI-1; much greater reversal was observed in medium supplemented with RU 486. Unlike the changes in PAI-1, neither TIMP1, nor MMP-2 expression was affected by withdrawal to steroid-free or to RU 486-medium. By altering the composition of the ECM of the luteal phase endometrium, progestin-elicited inhibition of the PAs, uPA and tPA, as well as that of the MMPs, MMP-1 and MMP-3, modulates trophoblast adhesion, migration and differentiation. Conversely, steroid withdrawal elicited increases in uPA, MMP-1 and MMP-3 activities would promote endometrial sloughing by degrading the mixture of decidual cell-derived basement membrane-like proteins and interstitial components that comprise the stromal ECM of the perimenstrual endometrium.

Diabetic embryopathy is the leading cause of neonatal death and/or congenital malformations in infants of diabetic mothers. Because the development of the embryo critically depends on the maternal and the embryonic signaling pathways, a defective signaling mechanism between the maternal and the embryonic tissues appears to be involved in the etiology of diabetic embryopathy. Analyses of the recent studies from different laboratories suggest a "multifactorial" basis for diabetic embryopathy. These studies suggest that a wide variety of signal-transducers converge towards the regulation of elcosanoid signaling pathway which appears to be the critical pathway involved in diabetic embryopathy. The characterization of the regulatory components of this pathway is likely to identify the signaling loci susceptible for the therapeutic intervention.

The perimenopause represents a time of great variability in reproductive hormone dynamics and menstrual cycle characteristics, but age-related changes begin prior to this. These changes include a gradual increase in follicle stimulating hormone (FSH) levels, a gradual shortening of mean cycle length, and a decline in the number of ovarian follicles. The onset of perimenopause is thought to occur with the first break in menstrual cycle regularity. With the onset of cycle irregularities, hormone concentrations exhibit large increases in variability and unpredictability, rather than following a gradual trend with the approach of menopause, the final menstrual period. Abrupt spikes in gonadotropins and considerable fluctuations in estradiol and inhibin levels have been observed. Variability is the norm in the perimenopause, with hormonal fluctuations contributing to the visible signs of menstrual cycle and bleeding irregularities. To date there is no single endocrine indicator to serve as an adequate marker of menopausal status. This paper provides a review of research to date on patterns of reproductive hormones and menstrual bleeding during the menopausal transition. An understanding of such patterns can contribute to a better ability to distinguish "normal" transitional events from more serious pathology.

Synthesis of prolactin (PRL) in human endometrium extends from the late luteal phase of the menstrual cycle throughout the pregnancy. We have studied the hormonal requirements for the sustained production of PRL and its receptor (PRL-R) in a long-term primary cell culture system. Progestin stimulates the production PRL and its receptor when stromal cells transform into decidual cells. The rise in PRL production rate correlates with an increase in steady-state PRL mRNA levels which are caused by increased transcription rate gene. Replacing progestin by the antiprogestin, RU 486, causes a transient superinduction of PRL production followed by reduction to basal level of expression. On the other hand, RU 486 exerts immediate inhibition of PRL-receptor mRNA expression. In addition, relaxin (RLX) enhances PRL synthesis. The transcription of the PRL gene in endometrium is dependent upon the promotor 6-kb upstream of the transcription start site in the pituitary. That biological functions of PRL and its receptor are critical to implantation and the maintenance of pregnancy is suggested by the impaired fertility of PRL and PRL-R knockout mice. PRL enhances endometrial cell growth at low concentrations and inhibits it at high concentrations. This dual action indicates an autocrine action of PRL-R-mediated signaling transduction pathways during reproductive cycles and pregnancy. During gestation, decidual-derived prolactin regulates the volume of amniotic and fetal extracellular fluid and electrolytes.

Uterine endometrial epithelial cells undergo profound changes in structure and function in preparation for blastocyst implantation. The dynamics of this process for human endometrium can be studied only in cell culture. Primary cell cultures started from tissue removed at varying times during the cycle retain some aspects of differentiation as manifest in regulated protein synthesis. Differentiation of endometrial, epithelial cell lines will occur when culture conditions are varied. Domes, gland-like structures, polarized sheets and spheroids can be produced. Studying the process of differentiation in vitro should provide information about differentiation in vivo, particularly about how changing protein synthesis accompanies changing cell structure. Endometrial epithelial cells in culture can also be manipulated to allow study of steroid agonism and antagonism, cancer, menses and regeneration and endometriosis.

Congenital malformations remain the major cause of morbidity and mortality among the offspring of women with diabetes. Animal and human studies indicate that these anomalies occur very early in pregnancy and result from derangements of the maternal metabolic fuels which support embryogenesis. The mechanism for induction of dysmorphogenesis in experimental diabetic pregnancy has been shown to include deficiency states of membrane lipids (myoinositol, arachidonic acid, etc.), alteration in the prostaglandin cascade, and the generation of excess free oxygen radicals. These biochemical alterations result in characteristic morphological and molecular changes which are considered to be the basis of diabetic embryopathy. This article not only discusses the pathomechanism, but also reviews both clinical and experimental strategies to prevent diabetes-associated birth defects.