Memory after menopause: preliminary considerations of hormone influence on cognitive functioning.

Oestrogen has been shown to have a wide variety of organisational and activating effects on brain structure and function. Despite the significant amount of research investigating the relation and effects of oestrogen to cognitive performance in menopausal women over the past two decades, studies have failed to produce consistent findings. This paper reports on evaluations of eighty-one community-based postmenopausal Australian women comparing current, past and never users of hormone therapy (HT) on a wide range of cognitive measures of general, verbal and visual memory, delayed recall, attention, concentration and verbal comprehension. Few significant differences were found among the three groups in the demographic profile, health status or psychological functioning. Although never users had significantly lower scores on verbal memory than past users, the differences were not statistically significant when adjustments were made controlling for age, education level, verbal comprehension, attention and concentration. These findings challenge long-held beliefs regarding the usefulness of oestrogen supplements as a protective factor against cognitive decline in older women's later years.

Parents' coping in the neonatal intensive care unit: a theoretical framework.

The conceptual framework that has been widely used to study the coping strategies of parents of preterm infants in neonatal intensive care units (NICU) has been the transactional model of stress and coping proposed by Lazarus and colleagues. This model supports the cognitive system as the key factor in stress transactions. The cognitive system produces an interpretation of events that leads to making sense of numerous sensations and perceptions from both external and social sources as well as from the internal physiological environment. The individual cognitive system appraises stimuli in two ways: primary appraisal and secondary appraisal. Another factor that may influence the individual's coping effort is gender difference. Mothers and fathers of preterm infants have been found to use different coping strategies to deal with the preterm birth. Other factors such as personality traits and the perceived and actual availability of social support may also influence the parents' coping effort. Implications for clinical practice by the NICU interdisciplinary team are considered.

Keeping it in the family: caregiving in Australian-Greek families.

Family-based caregiving refers to the daily provision of help to a co-resident family relative with the usual activities of daily living, custody and protection of a dependent relative at risk of self-injury, and support of a person with physical, developmental and/or mental disability or frailty due to ageing. Many reports from western studies refer to the caregiving burdens, stress and strains. A common view of migrant peoples is that they 'look after their own' to a greater extent than do English-speaking groups and that their closer connections with ethno-specific community organisations and with their extended family networks provides more opportunities for assistance and support so that caregiving is shared and the burdens are reduced. A study was carried out with 300 Australian-Greek families in Melbourne where 150 were providing family-based caregiving, and these were age and gender matched with friends or acquaintances who had no such duties. Most care was provided by women, although almost 20% of carers were men. A wide range of disabilities and illnesses were receiving help and care in the caregiving families among care recipients aged from childhood to advanced old age. Distinct evidence of caregiving burden was found to a significant degree. Gender differences were apparent in the type of disorders managed, in the perceived severity of caregiving duties provided and in the total range of activities engaged in. The ethno-specific community organisations and extended family networks played little part in providing assistance to caregivers which challenges the myths of a close-knit migrant community looking after its own. Qualitative reports of concerns for future caregiving were expressed and the implications for future service needs are discussed.

First-time parenthood: influences on pre- and postnatal adjustment in fathers and mothers.

The objective of the study was to examine moods and adjustment through the transition to parenthood as an issue affecting the couple; to examine not only the postpartum but also the pregnancy experience and to explore how each partner's experiences interact with those of the other. A longitudinal repeated measures design was utilized with 327 healthy couples with a first-time pregnancy who were from Melbourne, Victoria in 1995-98. Each partner was interviewed on four occasions: mid- and late pregnancy, early postpartum and 4 months postnatally. Twenty per cent of mothers and 12% of fathers were significantly distressed at mid-pregnancy (Time 1) and this persisted until the early postpartum (Time 3) phase. Young age (particularly in women), negative mood, poor relationship functioning, gender role stress (particularly performance failure regarding work and sex in males) and low social support predicted distress in mid-pregnancy (Time 1). Negative mood in partner and self, and poor relationship functioning at mid-pregnancy predicted vulnerability to postnatal distress (Time 3 and/or Time 4). The incidence of distress in couples during mid- and late pregnancy is of concern and highlights the importance of considering the total transition to parenthood, not only the onset of postnatal distress. The analyses of predictors of postnatal distress from prenatal variables suggest that a 'contagion of distress' may operate in some couples. The standard management provided for couples experiencing pregnancy may be inadequate for many couples. These findings suggest that it is important to consider the mood and relationship quality of both partners and to offer intervention services as early as possible to offset possible progression into postnatal depression.

Relationships between premenstrual complaints and perimenopausal experiences.

This study evaluates whether a history of menstrually-related problems, termed premenstrual complaints (PMCs), is a significant predictive marker for a more symptomatic perimenopausal experience. Two hundred and ninety-one randomly selected urban women, aged between 45 and 55 years were interviewed yearly for three consecutive years to record their individual experiences and changes as they progressed through the menopause transition. Repeated measures were obtained on a range of physical, psychological and social indicators. The experiences of women who reported a self-defined history of premenstrual complaints (n = 104) were compared with those women with no prior premenstrual problems (n = 187) and predictors of perimenopausal symptoms were assessed. Relationships were found between a prior history of both physical and psychological premenstrual complaints and a more symptomatic perimenopause characterised by dysphoria, skeletal, digestive and respiratory symptoms (all ps < 0.05). The more symptomatic women also reported pronounced interpersonal stress (p < 0.001), significant 'hassles', current smoking and low exercise (ps < 0.05). The findings support predictive relationships between a prior history of premenstrual problems and a more problematic menopause transition. The issues of vulnerability and help-seeking behaviors are discussed.

Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase.

Six new diphenyl sulfoxide and five new diphenyl sulfones were designed, synthesized, and tested for their inhibition of human and Escherichia coli thymidylate synthase (TS) and of the growth of cells in tissue culture. The best sulfoxide inhibitor of human TS was 3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4- (phenylsulfinyl)-N-(prop-2-ynyl)-aniline (7c) that had a Ki of 27 nM. No sulfone improved on TS inhibition by the previously reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2- ynylamino)phenyl phenyl sulfone (Ki = 12 nM). Nevertheless, one sulfone, 4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)-N-(prop-2-ynyl)aniline, was selected, on the basis of its inhibition of both TS and cell growth, for antitumor testing; it gave a 61% increase in life span to mice bearing the thymidino kinase-deficient L5178Y (TK-) lymphoma. A crystal structure of N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-((2- methylphenyl)sulfinyl)-N-(prop-2-ynyl)aniline complexed with E. coli TS was solved and revealed selective binding of one sulfoxide enantiomer. AMBER calculations showed that the enantioselection was due to asymmetric electrostatic effects at the mouth of the active site. In contrast, a similar crystal structure of the sulfoxide 7c, along with AMBER calculations, indicated that both enantiomers bound, but with different affinities. The side chain of Phe176 shifted in order to structurally accommodate the chlorine of the more weakly bound enantiomer.

Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase.

To develop novel lipophilic thymidylate synthase (TS) inhibitors, the X-ray structure of Escherichia coli TS in ternary complex with FdUMP and the inhibitor 10-propargyl-5,8-dideazafolic acid (CB3717) was used as a basis for structure-based design. A total of 31 novel lipophilic TS inhibitors, lacking a glutamate residue, were synthesized; 26 of them had in common a N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline+ ++ structure in which the aniline was appropriately substituted with simple lipophilic substituents either in position 3 or 4, or in both. Compounds were tested for their inhibition of E. coli TS and human TS and also for their inhibition of the growth in tissue culture of a murine leukemia, a human leukemia, and a thymidine kinase-deficient human adenocarcinoma. The crystal structures of five inhibitors complexed with E. coli TS were determined. Five main conclusions are drawn from this study. (i) A 3-substituent such as CF(3), iodo, or ethynyl enhances binding by up to 1 order of magnitude and in the case of CF(3) was proven to fill a nearby pocket in the enzyme. (ii) A simple strongly electron-withdrawing substituent such as NO(2) or CF(3)SO(2) in the 4-position enhances binding by 2 orders of magnitude; it is hypothesized that the transannular dipole so induced interacts favorably with the protein. (iii) Attempts to combine the enhancements of i and ii in the same molecule were generally unsuccessful (iv) A 4-C(6)H(5)SO(2) substituent provided both electron withdrawal and a van der Waal's interaction of the phenyl group with a hydrophobic surface at the mouth of the active site. The inhibition (K(is) = 12 nM) of human TS by this compound, 7n, showed that C(6)H(5)SO(2) provided virtually as much binding affinity as the CO-glutamate which it had replaced. (v) The series of compounds were poorly water soluble, and also the potent TS inhibition shown by several of them did not translate into good cytotoxicity. Compounds with large cyclic groups linked to position 4 by an SO or SO(2) group did, however, have IC(50)'s in the range 1-5 microM. Of these, 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylamino )phenyl phenyl sulfone, 7n, had IC(50)'s of about 1 microM and was chosen for further elaboration.

AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies.

3,4-Dihydro-2-amino-6 methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (AG337) is a water-soluble, lipophilic inhibitor of thymidylate synthase (TS) designed using X-ray structure - based methodologies to interact at the folate cofactor binding site of the enzyme. The aim of the design program was to identify TS inhibitors with different pharmacological characteristics from classical folate analogs and, most notably, to develop non-glutamate-containing molecules which would not require facilitated transport for uptake and would not undergo intracellular polyglutamylation. One molecule which resulted from this program, AG337, inhibits purified recombinant human TS with a Ki of 11 nM, and displays non-competitive inhibition kinetics. It was further shown to inhibit cell growth in a panel of cell lines of murine and human origin, displaying an IC50 of between 0.39 microM 6.6 microM. TS was suggested as the locus of action of AG337 by the ability of thymidine to antagonize cell growth inhibition and the direct demonstration of TS inhibition in whole cells using a tritium release assay. The demonstration, by flow cytometry, that AG337-treated L1210 cells were arrested in the S phase of the cell cycle was also consistent with a blockage of TS, as was the pattern of ribonucleotide and deoxyribonucleotide pool modulation in AG337-treated cells, which showed significant reduction in TTP levels. The effects of AG337 were quickly reversed on removal of the drug, suggesting, as would be expected for a lipophilic agent, that there is rapid influx and efflux from cells and no intracellular metabolism to derivatives with enhanced retention. In vivo, AG337 was highly active against the thymidine kinase-deficient murine L5178Y/TK-lymphoma implanted either i.p. or i.m. following i.p. or oral delivery. Prolonged dosing periods of 5 or 10 days were required for activity, and efficacy was improved with twice-daily dose administration. Dose levels of 25 mg/kg delivered i.p. twice daily for 10 days, 50 mg/kg once daily for 10 days, or 100 mg/kg once daily for 5 days elicited 100% cures against the i.p. tumor. Doses required for activity against the i.m. tumor were higher (100 mg/kg i.p. twice daily for 5 or 10 days) but demonstrated the ability of AG337 to penetrate solid tissue barriers. Oral delivery required doses of > or = 150 mg/kg twice daily for periods of 5-10 days to produce 100% cure rates against both i.m. and i.p. implanted tumors. These results were consistent with the pharmacokinetics parameters determined in rats, for which oral bioavailability of 30-50% was determined, together with a relatively short elimination half life of 2h. Clinical studies with AG337 are currently in progress.

Synthesis and biological evaluation of novel 2,6-diaminobenz[cd]indole inhibitors of thymidylate synthase using the protein structure as a guide.

The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.

Premenstrual complaints: an idiosyncratic syndrome.

The two issues of premenstrual syndrome (PMS) symptom heterogeneity and symptom severity are addressed in an examination of the idiosyncratic nature of premenstrual complaints. Analyses of PMS symptoms reported during the first assessment month by a group of treatment-seeking women revealed that when presented with a prepared list of symptoms (Menstrual Distress Questionnaire), they select many more symptoms than when self-reporting their complaints in ranked order of severity. In this study of a sample of 98 women, most of the women reported only four rank-ordered symptoms. Symptom profiles from five symptom categories were constructed for each of the women and from a possible 86 different profiles 84 were discovered. Of these, psychological profiles dominated the total reports. These findings, together with results of previous research, lead to two conclusions. First, that PMS, though multidimensional, may be defined for each woman by a limited number of symptoms; and second, that PMS is highly idiosyncratic in nature.

Sexuality and the menopause.

Sexual problems are often reported to clinicians by women in the midlife years. Yet few of the epidemiological studies of women in midlife have investigated the relationship of the menopause to sexual functioning. This paper reports the results of a cross-sectional telephone survey of 2001 randomly selected Australian-born women aged between 45 and 55 years. The major outcome variables were questions relating to changes in sexual interest over the prior 12 months, reasons for any changes, occurrence of sexual intercourse, and of unusual pain on intercourse. Logistic regression was used to identify explanatory variables for change in sexual interest. The majority of women (62%) reported no change in sexual interest, although 31% reported a decrease. Decline in sexual interest was significantly and adversely associated with natural menopause (p < 0.01) rather than age, decreased well-being (p < 0.001), decreasing employment (p < 0.01) and symptomatology (vasomotor p < 0.05, cardiopulmonary p < 0.001 and skeletal p < 0.01). Eleven to twelve years of education was associated with a lowered risk of decreased sexual functioning (p < 0.01). Heterogeneous results were reported by users of hormone replacement therapies. Longitudinal studies of large and representative samples are needed to determine the etiology of adverse sexual changes with the menopause and the role of hormone replacement therapies.

The treatment-seeking woman at menopause.

Recent studies suggest that health care utilisation by women during menopause transition in general is highly idiosyncratic, despite the widespread advocation of prophylactic hormone therapy and increased health vigilance. The Melbourne Women's Midlife Health Study, a community-based cross-sectional study of 2001 urban Australian-born women aged 45-55 years, evaluated women's physical and emotional experiences, past and present health status, attitudes and beliefs about menopause, health behaviours and current menopausal status in a 30-min telephone interview. This paper reports on those factors related to help-seeking and health care utilisation. Findings show that treatment utilisers, in contrast to non-utilisers, reported a wider range of general symptoms, but reports on vasomotor symptoms did not contribute to the regression analysis. Treatment utilisers were further identified as problem-related or prevention-related utilisers. In three-way analyses, the past and present social and physical health of the problem-related treatment user was reportedly worse than either the prevention-related utiliser or non-utiliser. These findings suggest that medical and societal views about the health of middle-aged women during menopausal transition are likely to be based on the experiences of a particular segment of the population only. It is proposed that biased views of menopause as a time of considerable distress and ill-health are being perpetuated and over-generalised. This perspective appears to have little relevance for the majority of middle-aged women.

The relationship between the menstrual cycle and female sexual interest in women with PMS complaints and volunteers.

This study assesses the influence of menstrual cycle phases and hormones on female sexual interest in both a nonclinical sample of volunteers (n = 18) and women who complained of premenstrual tension (n = 150). Women were assessed prospectively for two menstrual cycles with daily symptom charts. In addition mental status was assessed clinically and the Moos Menstrual Distress Questionnaire completed in the follicular and premenstrual phases. On the basis of these assessments women were assigned to subject groups. During the second cycle, daily 24-h urinary estrogens and urinary pregnanediol were determined. Sexual interest and feelings of well-being were recorded on a daily symptom rating chart. Sexual interest was found to be significantly higher in the follicular and ovulatory phases, than in the luteal, premenstrual, or menstrual phases. Sexual interest and feelings of well-being were correlated (R = 0.29). Sexual interest and feelings of well-being were not correlated with urinary estrogen or pregnanediol levels.

Menstrual cycle hormonal profiles of women with and without premenstrual syndrome.

This paper compares the urinary hormone profiles of estrogen and pregnanediol in women with documented premenstrual syndrome (PMS) (n = 65) and asymptomatic volunteers (n = 18). Daily 24-h urine samples were collected for an entire menstrual cycle. Subject groups did not differ significantly in menses length or in the day of the preovulatory estrogen peak. Cycle length was significantly shorter for the volunteers (p < 0.05). The day of the pregnanediol peak occurred significantly later for the PMS patient group than for the asymptomatic volunteers (p < 0.05). Split plot analysis of variance showed no significant differences overall between subject groups for levels of urinary estrogen or pregnanediol. This study did not find evidence of progesterone deficiency amongst sufferers of the premenstrual syndrome.

Psychosocial influences in postnatal depression.

Changes in moods, behaviours and physical states following the birth of a baby are well known and generally accepted as common, expected and short-lived. It is also recognised that a number of women are severely affected postnatally by a psychotic illness that may require lengthy hospitalisation and treatment. Between these two extremes is the profoundly disturbing experience of postnatal depression of non-psychotic origin that may persist for many months, seriously disrupting the mother-baby and marital and family relationships. The extent and characteristics of PND are receiving attention from health care professionals who have been largely unaware of the problem and are poorly prepared to respond. Although many early reports support biological theories of this problematic disorder, recent studies have begun to examine psychosocial sources of strain. This paper, through drawing together evidence from stress research and maternal and infant development, presents a multifactorial model to describe postnatal depression.

Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase.

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benz[cd]indole-containing inhibitors of thymidylate synthase (TS) are described. The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region. Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM. Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells. The inhibitors were synthesized from substituted 6-aminobenz[cd]indol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion. The 2,6-diaminobenz[cd]indoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.

Comparative bioavailability of orally and vaginally administered progesterone.

OBJECTIVE: To study the pharmacokinetics of progesterone (P) in healthy premenopausal female volunteers to compare the bioavailability of orally or vaginally administered hormone. DESIGN: Subjects were randomly allocated to receive either oral P or a vaginal pessary then crossed over to the alternate preparation 1 month later. SETTING: The study was conducted in outpatient setting. SUBJECTS: All subjects were healthy, normal female volunteers who underwent a physical and gynecological examination before the study. None were using oral contraceptives. Ten subjects (mean age 32.6 +/- 7.3 years) entered the study and all completed it. INTERVENTIONS: Progesterone was administered as 200 mg of micronized hormone or as a pessary containing 400 mg. MAIN OUTCOME MEASURE: Plasma levels of P were measured by radioimmunoassay to test the apriori hypothesis of similar bioavailability. RESULTS: Peak plasma P concentrations attained within 4 hours after oral administration ranged from 8.5 to 70.6 ng/mL, whereas after vaginal administration the peak levels were attained within 8 hours and ranged from 4.4 to 181.1 ng/mL. Considerable interindividual variation was noted. Area under the plasma concentration-time curve for the two formulations was not significantly different (F = 1.09; P greater than 0.1; ANOVA). CONCLUSIONS: The two formulations had similar bioavailability.

PIP: This study examined the pharmacokinetics of progesterone (P) in healthy, premenopausal female volunteers in order to compare the bioavailability of orally or vaginally administered hormone. Subjects were randomly allocated to receive either oral P or a vaginal pessary and were then crossed over to the alternate preparation 1 month later. All subjects were healthy, normal female volunteers who underwent a physical and gynecological examination prior to this outpatient study. None used oral contraceptives. There were 10 subjects (mean age 32.6 +or- 7.3 years) who entered the study and all completed it. P was administered as 200 mg of micronized hormone or as a pessary containing 400 mg. Plasma levels of P were measured by radioimmunoassay in order to test the apriori hypothesis of similar bioavailability. Peak plasma P concentrations attained within 4 hours after oral administration ranged from 8.5 to 70.6 ng/mL, whereas after vaginal administration, the peak levels were attained within 8 hours and ranged from 4.4-181.1 ng/mL. Considerable interindividual variation was evident. Area under the plasma concentration-time curve for the 2 formulations was not significantly different (f=1.09; p0.1; ANOVA). The conclusion is that the 2 formulations had similar bioavailability.

A comparison of hormone therapy, coping skills training, and relaxation for the relief of premenstrual syndrome.

Approximately 10% of women are severely affected by premenstrual syndrome (PMS) during their reproductive years. Several biological theories of causation have been proposed and each has provoked treatment attempts through medication to little sustained effect. As many of the reported complaints are psychological, a new treatment approach was considered using cognitive-behavioral therapy. A preliminary study which combined cognitive-behavioral therapy with drug treatment produced considerable symptom reduction. The present study examined the efficacy of cognitive-behavioral therapy alone in direct comparison with hormone treatment. Relaxation instructions were provided to a control group. Initial rapid responses to drug treatment and relaxation diminishes after 2 months, together with marked attrition in the control group. Significant positive benefits from cognitive-behavioral therapy were achieved after the first treatment month that continued throughout and were maintained at follow-up 3 months later. Implications for future management are discussed.