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Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation.

Telomerase activity is observed in most malignant tumors and germ cells, whereas normal somatic cells usually do not express it. Human endometrium is composed of glandular and stromal components and exhibits dramatic changes in proliferative activity during the menstrual cycle, which is exquisitely regulated by estrogen function. We previously reported that normal human endometrium expresses telomerase activity. However, it remains unclear which of the above components are the major sources of telomerase activity and how levels of telomerase activity are regulated over the menstrual cycle. Quantitative analysis of telomerase activity revealed that it changes dramatically over the course of the menstrual cycle and is strictly regulated in a menstrual-phase-dependent manner. Maximal activity equivalent to that in endometrial cancer was present in late proliferative phase, and minimal activity in late secretory phase. Postmenopausal endometrium and endometrium treated with anti-estrogen drugs exhibited decreased telomerase activity. Testing isolated epithelial glandular cells and stromal cells, we found that telomerase activity was localized to epithelial glandular cells. In situ RNA hybridization analysis also revealed epithelial-specific expression of human telomerase RNA. In vitro analysis of cultured epithelial cells demonstrated that telomerase activity is correlated with epithelial proliferation but not affected by estrogen treatment. These findings suggest that expression of telomerase activity is specific to epithelial cells and linked to cell proliferative status. The involvement of estrogen in telomerase regulation remains to be elucidated.

Cell Division↗

[Hormonal regulation of the menstrual cycle (author's transl)].

The menstrual cycle is regulated by a complex hormonal system with positive and negative feedback mechanisms and changes in sensitivity of peripheral tissues. Four concepts appear to be fundamental: -- regular, pulsatile secretion of LHR is necessary to the functioning of the system; -- regulation is to a great extent effected by the pituitary gland in response to changes in ovarian steroid levels; -- changes in ovarian steroid levels are due to regulatory changes in receptivity to pituitary hormones, as well as to variations in enzyme activities; -- at the periphery, changes in hormonal impacts are accompanied by modifications of receptivity to steroid hormones.

Estrogens↗

Use of a radioreceptor test for HCG in women practicing contraception.

The importance of a simple, rapid and highly sensitive test for the diagnosis of early pregnancy cannot be overemphasized. In the present times when newer delivery systems of contraceptive agents and menstrual regulation procedures are increasingly used for fertility regulation, it is inevitable that confirmation of early pregnancy poses a severe problem. This radioreceptor test has been found to be very reliable even in early cases. A positive test was 100% accurate for pregnancy whereas the accuracy of a negative test was found to be 94.4%. Confirmation of these results was done by various other parameters like clinical, histological, radioimmunoassay for HCG and biological test for pregnancy.

Abortion, Induced↗

Cutaneous melanoma in women. III. Reproductive factors and oral contraceptive use.

Oral contraceptive use and reproductive factors were investigated in a population-based case-control study of 452 women aged 25-59 years who were diagnosed with cutaneous malignant melanoma during the period 1981-1986 and 930 controls. Ever use of oral contraceptives was reported by 72 percent of melanoma patients and 79 percent of control subjects in this San Francisco Bay Area study, although duration of use was slightly longer for women with superficial spreading melanoma (5.5 years) than for controls (4.3 years). While some subgroups had elevated or reduced odds ratios, no consistent association was observed between cutaneous melanoma risk and oral contraceptive use when use was examined by duration, latency, age at diagnosis, age at first use, and time period of first use. Neither number of live births nor age at birth of the first child was associated with risk for cutaneous melanoma; nor was a history of miscarriage, induced abortion, or endometriosis. No association was observed with regularity of menstrual periods or with use of fertility drugs or hormones to regulate menstrual periods. Women who reported experiencing hyperpigmentation of facial skin during a prior pregnancy had a lowered risk for all cutaneous melanoma (odds ratio (OR) = 0.64, 95% confidence interval (CI) 0.44-0.93) and superficial spreading melanoma (OR = 0.54, 95% CI 0.36-0.83). This effect was more pronounced for light-complexioned women (for superficial spreading melanoma, OR = 0.37, 95% CI 0.20-0.70) than for women with a dark or medium complexion (for superficial spreading melanoma, OR = 0.84, 95% CI 0.48-1.5). Women who reported use of acne medication also had a reduced risk of superficial spreading melanoma (OR = 0.55, 95% CI 0.35-0.84). These results indicate an overall lack of effect of oral contraceptives on cutaneous melanoma risk in this population of women. The reduced melanoma risks associated with hyperpigmentation during a prior pregnancy and use of acne medication (or related hormonal indications for its use) should be studied further.

Abortion, Induced↗

Human endometrial matrix metalloproteinase-2, a putative menstrual proteinase. Hormonal regulation in cultured stromal cells and messenger RNA expression during the menstrual cycle.

Proteinases are likely effectors of endometrial menstrual breakdown. We have investigated proteinase production by human endometrial stromal cells subjected in vitro to progesterone (P) withdrawal, the physiologic stimulus for menstruation. Culture media of cells exposed to estradiol, P, or estradiol plus P had low levels of proteolytic activity similar to cultures maintained in the absence of steroids. P withdrawal, or addition of RU486 to P-treated cultures, stimulated proteinase secretion. The stromal cell proteinase was characterized by gelatin zymography, inhibitor profile, and organomercurial activation, as a metalloproteinase present mostly as a 66-kD proenzyme with lower levels of a 62-kD active form. The P withdrawal-induced metalloproteinase was identified as matrix metalloproteinase-2 (MMP-2) by Western blotting. The increase of MMP-2 induced by P withdrawal was associated with the metalloproteinase-dependent breakdown of stromal cultures, involving dissolution of extracellular matrix and dissociation of stromal cells. Northern analysis showed the differential expression of MMP-2 mRNA in late secretory phase endometrium. These findings are consistent with the involvement of stromal cell-derived MMP-2 in the proteolysis of extracellular matrix promoting cyclic endometrial breakdown and the onset of menstrual bleeding.

Blotting, Western↗

Supraphysiological cyclic dosing of sustained release T3 in order to reset low basal body temperature.

The use of sustained release tri-iodothyronine (SR-T3) in clinical practice, has gained popularity in the complementary and alternative medical community in the treatment of chronic fatigue with a protocol (WT3) pioneered by Dr. Denis Wilson. The WT3 protocol involves the use of SR-T3 taken orally by the patient every 12 hours according to a cyclic dose schedule determined by patient response. The patient is then weaned once a body temperature of 98.6 degrees F has been maintained for 3 consecutive weeks. The symptoms associated with this protocol have been given the name Wilson's Temperature Syndrome (WTS). There have been clinical studies using T3 in patients who are euthyroid based on normal TSH values. However, this treatment has created a controversy in the conventional medical community, especially with the American Thyroid Association, because it is not based on a measured deficiency of thyroid hormone. However, just as estrogen and progesterone are prescribed to regulate menstrual cycles in patients who have normal serum hormone levels, the WT3 therapy can be used to regulate metabolism despite normal serum thyroid hormone levels. SR-T3 prescription is based exclusively on low body temperature and presentation of symptoms. Decreased T3 function exerts widespread effects throughout the body. It can decrease serotonin and growth hormone levels and increase the number of adrenal hormone receptor sites. These effects may explain some of the symptoms observed in WTS. The dysregulation of neuroendocrine function may begin to explain such symptoms as alpha intrusion into slow wave sleep, decrease in blood flow to the brain, alterations in carbohydrate metabolism, fatigue, myalgia and arthralgia, depression and cognitive dysfunction. Despite all thermoregulatory control mechanisms of the body and the complex metabolic processes involved, WT3 therapy seems a valuable tool to re-establish normal body functions. We report the results of 11 patients who underwent the WT3 protocol for the treatment of CFS. All the patients improved in the five symptoms measured. All patients increased their basal temperature. The recovery time varied from 3 weeks to 12 months.

Body Temperature↗

Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity.

Physiological responses that involve adrenergic mechanisms, such as stress-induced changes in cardiovascular indices, were reported to fluctuate along the menstrual cycle. Metastatic development following surgery was also reported to vary according to the menstrual phase during which a primary breast tumour was removed. Natural killer (NK) cells are believed to play an important role in controlling metastases. Our recent studies in rats demonstrated that adrenergic suppression of NK activity and of resistance to metastasis is more profound during oestrous phases characterized by high levels of oestradiol. In the current study in humans, we examined the in vitro impact of a beta-adrenergic agonist, metaproterenol (MP), on NK activity, comparing blood drawn from (a) women tested at 3-4 different phases of their menstrual cycle (n = 10), (b) women using oral contraceptives (OC) (n = 10), and (c) men (n = 7). NK activity in each blood sample was assessed in the presence of 5 different concentrations of MP (10(-8)M to 10(-6)M), and in its absence (baseline). The results indicated marked group differences in the magnitude of NK suppression by MP: EC(50)was 2. 6-fold lower in the luteal phase compared to the follicular phase, and 1.8-fold lower in OC users compared to men, who were least susceptible to the effects of MP. No significant group differences or menstrual effects in baseline levels of NK activity were evident. These findings provide the first empirical evidence for menstrual regulation of adrenergic impact on cellular immune competence. Relevance of these findings to the relation between the timing of breast cancer excision within the menstrual cycle and survival rates is discussed.

Adrenergic beta-Agonists↗

Oral contraceptive use and the occurrence of pituitary prolactinoma.

To determine whether prior oral contraceptive (OC) use is a risk factor for pituitary prolactinoma, we attempted to identify all women (n = 72) with a prolactinoma diagnosed between 1976 and 1980 in three counties in western Washington. A control group of 303 women was selected by dialing random telephone numbers from the same counties. Prior OC use, according to OC indication, was ascertained during a standardized telephone interview. Relative to the risk for women who had never used an OC, the risk of prolactinoma for women who had used OCs for birth control was 1.3 (95% confidence interval, 0.7 to 2.6). This risk was 7.7 for women who used OCs for menstrual regulation (95% confidence interval, 3.7 to 17.0). Previous findings of an association between OC use and prolactinoma may have resulted from OC treatment of menstrual irregularity in women with an undiagnosed prolactinoma.

Adolescent↗

Metformin treatment is effective in obese teenage girls with PCOS.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of menstrual disorders in teenage girls. Little information is available about the effects of metformin in adolescent girls with PCOS and its dose and its efficacy in regulating menstrual cyclicity and hyperandrogenic symptoms. We evaluated the effects of metformin treatment on ovulatory function, hirsutism, acne, hormonal patterns and body weight in adolescent girls with PCOS. METHODS: Eighteen girls, ranging in age from 15 to 18 years, were enrolled in the study. Clinical diagnosis of PCOS was based on the consensus criteria for PCOS accepted in May 2003 at Rotterdam. All subjects received 1700 mg/day metformin as tablets continuously for 6 months. They were then followed up for 6 months. RESULTS: Two patients complained of side effects for >2 weeks and interrupted treatment; they were not evaluated. All the others showed an improvement in menstrual cyclicity. Menstrual periods were ovulatory, with progesterone levels up to 6 ng/ml in luteal phase and a significant reduction in testosterone, androstenedione and free testosterone. BMI was restored within normal limits in all girls between 21 and 24 kg/m(2). Six months after the end of metformin treatment, menstrual cycles continued to be regular and ovulatory with normal BMI. Side effects were slight. CONCLUSIONS: The present results confirm the positive effects of metformin on menstrual periods and show that the drug can be administered to young women to improve ovulation and hyperandrogenic symptoms such as hirsutism, acne and weight gain.

Adolescent↗

Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium.

The relationship between vascular endothelial growth factor (VEGF) expression and the pattern of vascular proliferation in the rhesus macaque endometrium has not been studied. In this report, we used in situ hybridization to evaluate VEGF, VEGF receptor type 1 and VEGF receptor type 2 mRNA expression during hormonally regulated menstrual cycles in ovariectomized macaques. Proliferating endothelial cells were identified by a double immunocytochemistry procedure that detected Ki-67 antigen and von Willebrand factor in the same endothelial cells. One and 2 d after progesterone withdrawal (premenstrual), VEGF mRNA was up-regulated in the glands and stroma of the superficial endometrial zones, a finding that supports our previous suggestion that VEGF may play a role in the menstrual induction cascade. During the postmenstrual repair phase, the healing surface epithelium showed a further, dramatic increase in expression of VEGF mRNA, accompanied by strong increases in signals for VEGF receptor types 1 and 2 in multiple profiles of small blood vessels immediately below the surface epithelium. This finding implicates VEGF in the early angiogenic processes associated with endometrial healing and regeneration. Vascular endothelial proliferation persisted throughout the cycle in the upper endometrial zones and showed a dramatic estrogen- dependent peak during the midproliferative phase. This proliferative peak coincided with a peak in VEGF expression in the endometrial stroma. Endothelial proliferation was also significantly correlated with the degree of stromal VEGF expression during the proliferative and secretory stages of the cycle. These results implicate VEGF of stromal origin in endometrial vascular proliferation.

Animals↗

Clinical investigation of the menstrual cycle. II. Neuroendocrine investigation and therapy of the inadequate luteal phase.

Nonhormonal drugs--diphenylhydantoin and nialamide, which act on the central nervous system and have no known endocrine activity--were given to two groups of women with distinct types of electroencephalographic patterns in an effort to regulate menstrual disorders. Equalization of the lengths of both the follicular phase and the luteal phase to the normal range was observed during the drug therapy. Forty-five per cent of the pregnancy rate was achieved in 36 of the 80 infecund patients within 4 months of treatment. The mode of action of these drugs is still unknown.

Adult↗

Abortion traditions in rural Jamaica.

Abortion is not condoned in Jamaica. Its meaning is linked to the meanings of kinship and parenthood, which are expressed through procreation and involve altruism and the assumption of responsibility for the well-being of others. Abortion subverts these ideals but indigenous methods for it are known and are secretly used. The inconsistencies between abortion talk and abortion practice are examined, and the structural functions of abortion (and of its culturally constructed, ideological meaning) are discussed. The distinction--and the overlap--between abortion as such and menstrual regulation is explored. The use of the culturally constructed 'witchcraft baby' syndrome to justify abortion is also investigated. Traditional abortion techniques follow from (and can illuminate) general health practices, which focus on inducing the ejection of 'blockages' and toxins, and from ethnophysiological beliefs about procreation and reproductive health, which easily allow for menstrual delays not caused by conception. The latter understanding and the similarity between abortifacients, emmenagogues and general purgatives allows women flexibility in interpreting the meanings of their missed periods and the physical effects of the remedy.

Abortion, Illegal↗

Insulin-like growth factor binding protein-1: recent findings and new directions.

In 1988, insulin-like growth factor-binding protein-1 (IGFBP-1) became the first characterized member of a group of structurally related soluble proteins which specifically bind and modulate the actions of the IGFs. Since then, a wealth of information has accumulated regarding the physiology of this dynamic serum protein. In this review, we update our 1993 summary (Lee PDK et al. Proc Soc Exp Biol Med 204:4-29) of the status of IGFBP-1 research. The IGFBP-1 protein sequence contains 12 N-terminal and 6 C-terminal cysteine residues which are conserved in other mammalian IGFBP-1 sequences and amongst other IGFBPs; both of the cysteine-rich regions are required for optimal IGF binding. The nonconserved IGFBP-1 midregion may act as both a hinge which defines ligand binding characteristics and as a specific target for protease activity. Integrin-binding and phosphorylation sites within the IGFBP-1 sequence have functional significance in vitro, but their physiologic relevance in vivo have not been defined. The human IGFBP-1 and IGFBP-3 genes are contiguous and located in close proximity to the homeobox A (HOXA) gene cluster on chromosome 7. The other IGFBP genes, located on chromosomes 2, 12, and 17, are also associated with HOX clusters, suggesting evolutionary linkage of the IGFBP and HOX gene families. Similarities between the hIGFBP-1 and phosphoenolpyruvate kinase (PEPCK) promoters, including regions conferring insulin, glucocorticoid, and cyclic adenosine-monophosphate responses, are consistent with our previous hypothesis that IGFBP-1 is involved in regulation of glucose metabolism. The tissue-specific patterns of IGFBP-1 gene expression in liver, kidney, decidua, and ovary may be due to stimulation of IGFBP-1 transcription by hepatic nuclear factor 1 (HNF1) proteins. Clinical and basic studies of IGFBP-1 physiology have been aided by several recently developed assay methods. Numerous investigations have confirmed that insulin, via inhibition of IGFBP-1 transcription, is the primary determinant of IGFBP-1 expression both in vitro and in vivo. IGF-I and IGF-II also have specific inhibitory effects on IGFBP-1 expression. Glucocorticoids and cAMP stimulate IGFBP-1 transcription, but these effects are observed only in conditions of low or absent insulin effect. Other stimulants of IGFBP-1 expression include thyroid hormones and epidermal growth factor. Phorbol ester stimulation of IGFBP-1 expression can supersede the effects of insulin in vitro;however, the mechanism and in vivo correlates of this effect have not been determined. Cytokines and, perhaps, growth hormones may affect IGFBP-1 expression, perhaps by altering the regulatory actions of insulin; this effect may have important clinical relevance. IGFBP-1 expression is upregulated in liver and (nonhuman) kidney during postinjury regeneration. The IGF-inhibitory actions of IGFBP-1 has been confirmed by numerous in vitro studies and several in vivo animal investigations, including administration of recombinant IGFBP-1 and IGFBP-1 transgenic models. IGFBP-1 has been shown to inhibit somatic linear growth, weight gain, tissue growth, and glucose metabolism. Moreover, IGFBP-1 appears to be a primary determinant of free IGF-I levels in serum. Excess levels of IGFBP-1 may contribute to growth failure in intrauterine growth restriction and in pediatric chronic renal failure, while low IGFBP-1 levels are associated with obesity and with cardiovascular risk factors in insulin resistance syndromes. Serum IGFBP-1 measurements may be useful biochemical marker in these pathologic conditions. IGFBP-1 is expressed in decidualized stromal cells of the uterine endometrium and in ovarian granulosa cells. IGFBP-1, together with IGFs, insulin, ovarian steroids, cytokines, and other factors, is involved in a complex system which regulates menstrual cycles, ovulation, decidualization, blastocyst implantation, and fetal growth. (ABSTRACT TRUNCATED)

Amino Acid Sequence↗

Treatment of hirsutism in polycystic ovary syndrome with bromocriptine.

The value of bromocriptine in the treatment of hirsutism in polycystic ovary syndrome (PCO) was assessed subjectively and photographically in a double-blind trial in 22 women studied for 1 year. Menstrual frequency was recorded. Circulating concentrations of oestradiol, oestrone, testosterone, androstenedione, and sex hormone binding globulin (SHBG) were determined before treatment and after 6 and 12 months therapy. On the same occasions gonadotrophin concentrations (mean of 24 samples) and their response to 100 micrograms LHRH were determined. No evidence was found to support a therapeutic role for bromocriptine in the treatment of hirsutism or menstrual regulation in PCO. No biochemical changes were seen specific to bromocriptine therapy.

Adolescent↗

Menstrual cycle variability and the perimenopause.

Menopause, the final cessation of menstrual cycling, occurs when the pool of ovarian follicles is depleted. The one to five years just prior to the menopause are usually marked by increasing variability in menstrual cycle length, frequency of ovulation, and levels of reproductive hormones. Little is known about the mechanisms that account for these characteristics of ovarian cycles as the menopause approaches. Some evidence suggests that the dwindling pool of follicles itself is responsible for cycle characteristics during the perimenopausal transition. Another hypothesis is that the increased variability reflects "slippage" of the hypothalamus, which loses the ability to regulate menstrual cycles at older reproductive ages. This paper examines the underlying cause of the increasing variability in menstrual cycle length prior to the menopause. A model of ovarian cycles is developed, based on the process of follicular growth and depletion. Under this model, the follicular phase of each menstrual cycle is preceded by an inactive phase, a period of time when no ovarian follicles have left the resting state and begun secreting steroids in response to gonadotropin stimulation. The model makes predictions about the variability in menstrual cycles across the reproductive life span based on the size of the surviving pool of ovarian follicles. We show that the model can explain several characteristics of the perimenopause in humans and macaques and illustrate how the model can be applied to research on the biological and cultural correlates of the timing of menopause.

Age Factors↗