Hormone therapy and breast cancer: risk communication and the 'perfect storm'.

Many factors are considered when a woman estimates her personal risk of breast cancer. Common to most decisions are four separate influences that have convinced the public and many health-care providers that breast cancer is the greatest concern for menopausal women and that menopausal hormone therapy (MHT) is generally responsible. Historically there have been well-documented situations in which big pharma and doctors have not put patient interests first. Conflicting reports about the safety of MHT and the media imperative to always increase readership by presenting a compelling scary story have created an underlying distrust of science, doctors, and MHT. Numerical and statistical illiteracy in the general population creates a situation where lotteries succeed despite astronomical odds and the risks of medical interventions are exaggerated by their description using relative, rather than absolute, risks. Finally, mammographic overdiagnosis contributing to improved breast cancer survival has contributed to the 'popularity paradox' (more screening - more enthusiasm) especially among survivors and advocacy groups. As a result, worry about breast cancer has overshadowed concern about cardiovascular diseases as the major cause of death and disability in the later years. The ongoing challenge for clinicians dealing with menopausal women is to bridge the gap in risk perception with evidence-based common-sense advice.

Randomized clinical trial of a handheld cooling device (Menopod®) for relief of menopausal vasomotor symptoms.

OBJECTIVE: Anecdotal reports suggest that application of a cool device to the back of the neck at the onset of a hot flush can afford symptomatic relief. The effects of a novel handheld mechanical cooling device in a population of perimenopausal women with moderate-to-severe vasomotor symptoms were evaluated. METHODS: In this randomized, double-blind, sham-controlled pilot study, 40 perimenopausal women experiencing ≥ 7 moderate-to-severe hot flushes per day were recruited at a single university site. Women were randomized to the active (n = 20) or sham (n = 20) device, which was applied to the back of the neck with each hot flush over the 4-week treatment period. Hot flush scores were calculated based on frequency and severity of symptoms. The Carpenter Hot Flash Related Daily Interference Scale and Zung Anxiety Scale were used to evaluate impact on quality of life. At study end, participants completed an open-ended questionnaire to assess the degree of unblinding and overall subjective improvement in symptoms with use of the device. RESULTS: No statistically significant differences were observed between the effects of the active and sham device. However, thematic analysis of the open-ended questionnaire revealed that 12/17 women (70.6%) in the active group, compared to 4/18 (22.2%) women in the sham group felt the device provided some symptomatic relief. CONCLUSIONS: Although the majority of women using the active device acknowledged that its cooling effect afforded a degree of symptomatic relief, the symptom scores chosen for this pilot study did not reflect a beneficial effect.

Stabilization of wild-type p53 in human T-lymphocytes transformed by HTLV-I.

Adult T-cell leukemia/lymphoma is an aggressive malignancy associated with infection by the human T-lymphotropic virus type-I (HTLV-I). We now demonstrate that p53 expression is elevated in the HTLV-I-transformed T-lymphocyte lines C81, MT-2, MT-4 and HUT 102. In pulse-chase experiments, the p53 protein demonstrated a prolonged half-life of 2 to 8 h in HTLV-I-transformed cells compared with 0.5 to 1.0 h for wild-type p53 in primary human and murine fibroblasts, or human peripheral blood lymphocytes. In cell lines C81 and HUT 102, which exhibited the longest p53 protein half-life, the wild-type-related PAb1620 epitope was detected at reduced levels. The PAb240 mutant-related p53 epitope was not detected in any of the transformed cell lines. By direct sequence analysis of RT-PCR products, the entire p53 cDNA coding sequence was determined to be wild-type in all four cell lines. Stabilization of wild-type p53 may represent its functional inactivation and contribute to lymphocyte transformation by HTLV-I.

Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic virus type-I Tax1 binding protein.

Tax1 is essential for human T-cell lymphotropic virus type I (HTLV-I) virus replication and transformation. We have identified and characterized a Tax1 binding protein, TRX, by cDNA screening of a Jurkat T-cell cDNA library. TRX mRNA is ubiquitously expressed in human tissues tested and cell lines analyzed.

Effects of the menstrual cycle on medical disorders.

Exacerbation of certain medical conditions at specific phases of the menstrual cycle is a well-recognized phenomenon. We review the effects of the menstrual cycle on medical conditions, including menstrual migraine, epilepsy, asthma, rheumatoid arthritis, irritable bowel syndrome, and diabetes. We discuss the role of medical suppression of ovulation using gonadotropin-releasing hormone agonists in the evaluation and treatment of these disorders. Peer-reviewed publications from English-language literature were located via MEDLINE or from bibliographies of relevant articles. We reviewed all review articles, case reports and series, and therapeutic trials. Emphasis was placed on diagnosis and therapy of menstrual cycle-related exacerbations of disease processes. Abrupt changes in the concentrations of circulating ovarian steroids at ovulation and premenstrually may account for menstrual cycle-related changes in these chronic conditions. Accurate documentation of symptoms on a menstrual calendar allows identification of women with cyclic alterations in disease activity. Medical suppression of ovulation using gonadotropin-releasing hormone agonists can be useful for both diagnosis and treatment of any severe, recurrent menstrual cycle-related disease exacerbations.

The effects of estrogen and progesterone on corticotropin-releasing hormone and arginine vasopressin messenger ribonucleic acid levels in the paraventricular nucleus and supraoptic nucleus of the rhesus monkey.

Ovarian steroids increase hypothalamic-pituitary-adrenal (HPA) axis activity and sensitize the hypothalamic-pituitary-ovarian (HPO) axis to stress-induced inhibition. The present study investigated the effect of ovarian steroids on CRH and arginine vasopressin (AVP) messenger RNA (mRNA) levels in the rhesus monkey hypothalamus, as both neuropeptides have been shown to stimulate the HPA axis and inhibit the HPO axis in this species. This was accomplished by measuring CRH and AVP mRNA in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) by in situ hybridization histochemistry. Menstrual cycles were simulated in ovariectomized (OVX) rhesus monkeys by sequential addition and removal of SILASTIC brand (Dow Corning Corp.) tubing containing either 17beta-estradiol (E2) or progesterone (P4). On the morning of day 11 of the simulated follicular phase (E2 alone) or day 21 of the luteal phase (E2 + P4), animals were anesthetized, and the brains were perfused with paraformaldehyde via the carotid artery. Coronal sections (30 microm) were cut, and mRNA for CRH and AVP in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were semiquantified by in situ hybridization. CRH mRNA in the PVN of E2-replaced OVX animals (n = 7) was 2-fold greater than that in untreated OVX controls (n = 4), whereas CRH mRNA after E2 + P4 (n = 4) was no different from that in controls (optical density + SEM, 0.38 +/- 0.06, 0.13 +/- 0.08, and 0.14 +/- 0.09 for OVX + E2, OVX + E2 + P4, and OVX, respectively; P = 0.02). CRH in the SON was undetectable. In contrast to CRH, AVP mRNA in the PVN and the SON was similar in the three treatment groups. We conclude that E2 and E2 + P4 replacement to OVX monkeys exert different effects on CRH and AVP gene expression, as estrogen stimulation of CRH mRNA in the PVN was abrogated by progesterone, whereas no effect of ovarian steroids on AVP mRNA in either the PVN or SON was observed. We postulate that ovarian steroid regulation of CRH synthesis and release may in part explain the central nervous system mechanisms by which ovarian steroids affect the HPA and HPO axes during basal and stress conditions.

Luteinizing hormone secretion and corticotropin-releasing factor gene expression in the paraventricular nucleus of rhesus monkeys following cortisol synthesis inhibition.

Corticotropin-releasing Factor (CRF) is an important inhibitory neuromodulator of GnRH/LH secretion, and mediates in part the inhibitory effects of stress on the hypothalamic-pituitary-gonadal axis. The purpose of the present study was to further investigate CRF's role in regulating LH secretion in primates. This was accomplished by examining LH secretion in ovariectomized rhesus monkeys (n = 7) following cortisol synthesis inhibition with metyrapone. Infusion of metyrapone (5 mg/kg per h) for 4 h decreased cortisol levels to less than 20% of controls while increasing ACTH approximately 10-fold. LH concentrations were not affected by this acute activation of the hypothalamic-corticotroph axis. In a second experiment, metyrapone was infused for 10 h before collecting serial blood samples every 15 min for 6 h. Although this protocol produced a sustained increase in ACTH, no apparent effect on pulsatile LH secretion compared with saline controls was observed. Mean LH (+/- SEM) levels calculated for consecutive 2-h increments were 87.6 +/- 9.2 (0-2 h) 82.1 +/- 5.5 (2-4 h), and 80.7 +/- 4.8 (4-6 h) ng/ml in saline pretreated animals compared with 83.6 +/- 4.9, 79.8 +/- 5.8, and 72.5 +/- 6.2 ng/ml, respectively, in metyrapone pretreated monkeys. The same regimen of metyrapone infusion increased CRF messenger RNA levels in the paraventricular nucleus by approximately 33% (P < 0.0002). In a final experiment designed to examine the potential synergy between CRF and cortisol, the LH response to insulin-induced hypoglycemia was contrasted in saline and metyrapone pretreated monkeys. LH concentrations were reduced to approximately 40% of basal levels following insulin in both metyrapone and saline pretreated monkeys. Therefore, even though inhibition of cortisol synthesis leads to an increase in CRF messenger RNA in the paraventricular nucleus and a robust increase in ACTH secretion in rhesus monkeys, presumably due in part to increased neuroendocrine CRF secretion, LH secretion was not inhibited during either the acute or more chronic phase of corticotroph activation. Absence of LH inhibition was not due to low cortisol concentrations resulting from metyrapone because metyrapone did not prevent hypoglycemia-induced suppression of LH secretion. We conclude that increased neuroendocrine CRF secretion following metyrapone does not inhibit LH secretion under these conditions. Several explanations for this result are discussed.

beta-Endorphin stimulates the secretion of insulin and glucagon in humans.

Administration of beta-endorphin as an iv bolus elicited an acute and simultaneous rise in insulin and glucagon levels within 5 min in fasting normal male and female subjects. This was followed by an increase in the concentration of plasma glucose. The elevation of plasma insulin, glucagon and glucose levels lasted for up to 120 min. These observations suggest a possible role for beta-endorphin in the regulation of alpha and beta cell function within the pancreatic islets.

Gonadotropin-releasing activity of alpha-melanocyte-stimulating hormone in normal subjects and in subjects with hypothalamic-pituitary dysfunction.

The gonadotropin-releasing activity of synthetic alpha MSH, previously found in normal men, was evaluated in women with different hormonal environments and in patients with acyclic gonadotropin release due to hypothalamic-pituitary dysfunction. alpha MSH (2.5 mg, iv) administered as either a single or two repeated pulses (at 2-h intervals) elicited unequivocal pituitary release of LH in normal women during the luteal phase and midcycle surge and in patients with functional hypothalamic amenorrhea, hyperprolactinemic amenorrhea, and polycystic ovary syndrome. Concomitant release of LH and FSH occurred only in polycystic ovarian syndrome patients and normal men. alpha MSH had no discernible effect on gonadotropin release in women during the early and late follicular phases of the cycle, in postmenopausal women, and in patients with isolated gonadotropin deficiency, even after pulsatile GnRH priming. The present observations confirm and extend our earlier finding that alpha MSH possesses gonadotropin-releasing activity in men and indicate that alpha MSH has similar properties in women with progesterone- and androgen-dominated environments or with specific types of hypothalamic-pituitary dysfunction marked by attenuated GnRH-LH release.

Alpha-melanocyte stimulating hormone induces gonadotropin release.

The present study demonstrates that synthetic alpha-MSH given as a 2.5 mg intravenous bolus induces an unequivocal rise in LH and FSH in male subjects but not in female subjects during the low estrogen phase of the cycle.

Oral glucose tolerance during the menstrual cycle in normal women and women with alleged premenstrual "hypoglycemic" attacks: effects of naloxone.

To resolve existing controversies about the impact of the menstrual cycle on oral glucose tolerance, we examined the glucose, insulin, and glucagon responses to an oral glucose challenge at different phases of the menstrual cycle in five normal women (NW) and six women with premenstrual syndrome and alleged premenstrual hypoglycemic attacks (PMHA). Responses to oral glucose did not differ significantly between follicular and luteal phase studies in either group, nor were significant differences found between the responses of NW and women reporting PMHA. In parallel studies, the possible glucoregulatory effects of endogenous opiates were assessed. Concomitant infusion of naloxone altered neither the basal concentrations of glucose, insulin, and glucagon nor the responses of these measures to the glucose challenge. We conclude that NW and women with premenstrual syndrome and alleged PMHA have no menstrual cycle-related changes in glucose, insulin, or glucagon responses to an oral glucose load. The fact that four of six PMHA subjects had symptoms typical of hypoglycemia at glucose nadirs above 50 mg/dl suggests that an explanation other than hypoglycemia must be sought for such symptomatic episodes. Endogenous opiate peptides appear to exert no glucoregulatory effects at naloxone-sensitive receptor sites.

The disappearance of opioidergic regulation of gonadotropin secretion in postmenopausal women.

In postmenopausal women, the administration of beta-endorphin in repeated pulses (1-2.5 mg) at 1- to 2-h intervals or constant infusion (1 mg/h) for 3-6 h elicited the prompt release of PRL without concomitant change in LH levels. Infusion of an opiate receptor antagonist, naloxone (1.6 mg/h), for 6-7 h also had no effect on LH levels. Since substantial evidence indicates that endogneous opioid peptides exert an inhibitory role on GnRH-LH secretion and that the functional activity of opiate receptors appears to be ovarian steroid dependent, the present observation suggests that the hypersecretion of gonadotropin in the absence of ovarian steroid feedback may, in part, be causally related to a reduced opioid inhibition of GnRH-LH release.

Naloxone antagonism of corticotropin-releasing hormone stimulation of prolactin secretion in rhesus monkeys.

The effect of opiate receptor blockade on human CRH-induced PRL secretion was examined in ovariectomized and normal female rhesus monkeys. A bolus iv dose of 100 micrograms CRH acutely stimulated PRL secretion in both normal and ovariectomized animals. The magnitude of the PRL response was greater in ovariectomized monkeys (212% increase; n = 5) than in normal monkeys (56% increase; n = 5). Naloxone pretreatment inhibited CRH-induced PRL release in a dose-dependent fashion, whereas nalmefene did not, in both normal and ovariectomized monkeys. Administration of nalmefene alone significantly stimulated PRL secretion in normal monkeys (57% increase; n = 10), but not in ovariectomized monkeys (10% increase; n = 10). Naloxone alone had no effect. Since nalmefene has a high affinity for both the kappa- and mu-receptors whereas naloxone binds primarily to the mu-receptor, these results suggest that CRH-induced PRL secretion in monkeys is mediated by an endogenous opiate which binds to an opiate receptor other than or in addition to the mu- and kappa-receptors.

Progesterone inhibits the estrogen-induced gonadotropin surge in the rhesus monkey independent of endogenous opiates.

Administration of an estrogen challenge during the luteal phase, a time when progesterone concentrations are elevated, fails to elicit a gonadotropin-positive feedback response. The purpose of the present study was to determine if endogenous opiates are involved in the mechanism by which progesterone blocks the estrogen-induced gonadotropin surge in monkeys. To this end, rhesus monkeys in the luteal phase were pretreated with either saline or various regimens of nalmefene, a long-acting opiate antagonist, before being given an estrogen challenge. Three groups of animals were given nalmefene (10 mg, iv) every 12 h beginning 24, 48, or 96 h before an estrogen challenge and continued until 48 h after the start of the estrogen challenge. A fourth group received a continuous sc infusion of nalmefene (20 mg/day) via osmotic minipumps beginning 48 h in advance of the estrogen challenge. In a second experiment, monkeys in the follicular phase received progesterone implants at the time of an estrogen challenge and iv injections of nalmefene every 12 h for 48 h. Gonadotropin and steroid levels were monitored in both experiments by collecting blood samples by saphenous venipuncture at intervals of 6-12 h. The majority of luteal phase animals that were pretreated with saline were unresponsive to the estrogen challenge. Only 2 of 16 (12.5%) had an increase in LH concentrations that could be classified as a surge. Animals pretreated with iv nalmefene every 12 h beginning 48 h before the estrogen challenge exhibited a higher incidence of positive feedback responses (8 of 12 or 66.7%). A concomitant FSH surge was observed in 3 of these instances. However, when progesterone concentrations, which declined before the estrogen challenge in the nalmefene-treated group, were supplemented with exogenous progesterone, nalmefene failed to evoke any LH surges. Six of 8 animals that received nalmefene by sc infusion exhibited LH responses. However, the amplitude and duration of these LH responses were diminished, and no FSH responses were observed. Monkeys pretreated with nalmefene for either shorter (24 h) or longer (96 h) periods before the challenge were less responsive (0 responses out of 6 trials and 1 response out of 4 trials, respectively). Nalmefene was equally ineffective in preventing progesterone inhibition of the estradiol-induced LH surge in follicular phase animals (0 of 15 animals had LH surge). These results indicate that nalmefene antagonism of endogenous opiates does not enable estrogen to exert positive feedback effects on LH release when progesterone levels are high, such as during the luteal phase or after progesterone administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoglycemia-induced inhibition of luteinizing hormone secretion in the rhesus monkey is not mediated by endogenous opioid peptides.

A role for endogenous opioid peptides in stress-induced inhibition of LH secretion has been suggested based on the observation in rats, humans, and nonhuman primates that LH inhibition in response to a variety of different stresses could be blocked by the administration of opiate antagonists. In the present study, we have examined in rhesus monkeys whether suppression of LH secretion by insulin-induced hypoglycemia is prevented by administration of the opiate antagonist naloxone. The administration of 1.0 U insulin/kg to chair-restrained ovariectomized monkeys (n = 6) decreased blood glucose levels from 4.98 +/- 0.17 to 2.08 +/- 0.05 mmol/L and increased cortisol levels from 1279 +/- 205 to 2191 +/- 475 nmol/L. LH levels declined to 62% of the levels observed in the pretreatment control period (P < 0.05). Infusion of naloxone (2-mg bolus plus 2 mg/h or 10-mg bolus plus 10 mg/h) did not reverse the effects of insulin-induced hypoglycemia on LH concentrations. The administration of 1.0 U insulin/kg to nonrestrained monkeys produced a similar hypoglycemic state. Blood glucose levels declined from 4.08 +/- 0.11 to 2.45 +/- 0.05 mmol/L, while cortisol concentrations increased from 577 +/- 53 to 1324 +/- 294 mmol/L. However, LH concentrations did not decline in response to hypoglycemia. These data indicate that hypoglycemia-induced inhibition of LH secretion in chair-restrained ovariectomized monkeys is not mediated by endogenous opiates, since naloxone failed to reverse this effect. The observation that hypoglycemia inhibited LH levels only during a period of restraint suggests either an additive or synergistic effect of these two stresses on LH secretion.

Effects of exogenous beta h-endorphin on pituitary hormone secretion and its disappearance rate in normal human subjects.

The disappearance rate of the immunoreactive beta h-endorphin and the effects of beta h-endorphin on pituitary hormone secretion were investigated in normal volunteers. Synthetic human beta h-endorphin was administered as a 2.5-mg iv bolus to five normal women resulting in a 1000-fold increase in concentration of circulating immunoreactive beta h-endorphin within 2.5 min. This was followed by a triple exponential disappearance curve yielding an initial fast component with a half-time (t 1/2; +/-SD) of 4.1 (+/-0.6) min, a midrange component with a t 1/2 of 13.1 (+/-0.6 min, and a slow component with t 1/2 of 46.2 (+/-7.0) min. In both male and female subjects this dose of beta-endorphin induced a significant increase in the levels of PRL and a significant decline in the concentration of LH, without altering basal levels of GH and TSH.

Hormonal dynamics during luteal-follicular transition.

To gain insights into the neuroendocrine basis for the initiation of folliculogenesis, the hormonal dynamics during the period from the late luteal to the early follicular phase of the menstrual cycle (the luteal-follicular transition) were examined. Blood samples were obtained at 2-h intervals for 5 consecutive days in seven women and at 15-min intervals for 8 h on each of 4 consecutive days in five women. The results indicate that the luteolytic process, as reflected by an exponential decline of both serum estradiol and progesterone levels, began at least 64 h before the onset of menses. During estradiol and progesterone withdrawal, there was a selective increase in mean serum FSH levels (P less than 0.001) beginning 24 h before and reaching a peak 24 h after the onset of menses. The frequency of LH pulses increased slightly but not significantly during this period, with a significant rise in mean serum LH levels on the day of menses. Thus, an acute rise in FSH concentrations the day before and in LH concentrations the day after the onset of menses occurs during luteal-follicular transition. The dissociation of FSH and LH secretion observed suggests that additional neuroendocrine events other than changes in pulsatile GnRH secretion may be operative during this period. These findings indicate that the initiation of folliculogenesis for the ensuing cycle occurs during the late luteal phase by a process of selective augmentation in FSH secretion independent of hypothalamic GnRH secretion. This event may ultimately prove to be a manifestation of the action of recently characterized ovarian peptides on FSH secretion.

Effect of menstrual cycle phase and oral contraceptive use on serum lithium levels after a loading dose of lithium in normal women.

Serum lithium levels were analyzed in six healthy, normal women during the midfollicular, midluteal, and premenstrual phases of their menstrual cycles after they had received 300 mg of lithium carbonate orally. An identical protocol was followed for seven women with artificial cycles induced by oral contraceptive steroids. Analysis of variance for repeated measures over time showed no significant differences between groups or between cycle phases. Therefore, hormonal effects of ovarian or contraceptive steroids per se do not appear to alter serum lithium concentrations. Other factors may account for changing lithium requirements during the menstrual cycle in some patients with affective illness.

Alterations of fecal steroid composition induced by changes in dietary fiber consumption.

The short-term effects of high carbohydrate diets of normal foods either high or low in dietary fiber on fecal steroids and fiber was assessed in eight healthy young men. Each subject consumed in random order for 4 days a diet containing 59 g (high fiber) or 21 g (low fiber) neutral detergent fiber. After a 9-day rest period he consumed the other diet. Analysis of random fecal samples during their usual diet and after 4 days of each experimental diet showed an increased in primary bile acids from less than 4 to 32% of total bile acids, and a decreases of coprostanol from 76% (control diet) or 64% (low fiber diet) to 45% of total neutral sterol after the high fiber diet. Fecal fiber concentration doubled after the high fiber diet. We conclude that 4 days of high fiber diet is sufficient to cause a large increase in primary and decrease in secondary fecal steroids. Such changes have implications for prevention of arteriosclerosis and cancer of the colon.

Effect of test meals of varying dietary fiber content on plasma insulin and glucose response.

To assess the effect of dietary fiber on glucose tolerance four different meals of varying fiber content but identical protein fat and carbohydrate content were fed to eight healthy men aged 22 to 45. Each meal provided 75 g of carbohydrate as liquid glucose formula, as brown rice, pinto beans, or All Bran. The mean plasma glucose and insulin responses were highest following the formula, and least for All Bran and pinto beans. Rice produced nearly as great a rise in insulin and glucose as did the formula. The rank of each meal by content of neutral detergent fiber was nearly the inverse of the rank by magnitude of the insulin response evoked, fiber content being greatest in All Bran (18 g) and pinto beans (16.2 g), low in rice (2.8 g) and absent from the formula. It was concluded that dietary fiber dampened the insulin response to a high carbohydrate meal.