Nathan Rojansky

DECREASED BONE MINERAL DENSITY IN MEDICATED PSYCHIATRIC PATIENTS

Osteoporosis is a common problem in postmenopausal women.It has been linked to estrogen deficiency, other neuroendocrine processes such as hypercortisolemia and male hypogonadism, nutritional deficiencies, and other mechanisms. Some of these changes have been also reported in male and female patients with mental disorders, especially those receiving psychotropic medications. Therefore, bone mineral density was measured by dual-photon absorptiometry in the lumbar spine and in the femoral neck of 33 female and 35 male consenting psychiatric inpatients admitted consecutively. Patients were diagnosed as having major depressive disorder (N = 21), schizophrenia (N = 33), schizoaffective disorder (N = 7), mania (N = 2), and adjustment disorder (N = 5). Plasma levels of prolactin, estrogen, cortisol, and testosterone were also measured in a subgroup of these patients. It is reported that female patients, but especially male patients, had a highly significant decrease in bone mineral density when compared with age- and sex-matched normal data. It is suggested that psychiatric patients treated with antidepressants or neuroleptics might have decreased bone mineral density than is normal for their age and sex, and may be at an increased risk for fractures. These results may be related to low levels of gonadal hormones, especially in male subjects. Data should be confirmed with a larger number of patients with and without medications to distinguish between diagnosis-related and treatment-related effects.

Estrogen augments serotonergic activity in postmenopausal women.

To investigate the influence of estrogen replacement on serotonergic activity in postmenopausal women, the serotonin agonist meta-chlorophenylpiperazine (m-CPP) (0.5 mg/kg) was given orally to 18 normal postmenopausal women, 11 of whom were also tested following 30 days treatment with estrogen transdermal patches (estraderm 0.1 mg). Fifteen normal, healthy women of reproductive status served as a control group. Cortisol and prolactin responses to m-CPP were measured. Without estrogen, the prolactin and cortisol responses of postmenopausal women to m-CPP were blunted compared to those of reproductive women. Estrogen replacement increased the hormonal responses. It is suggested that decreased serotonergic activity in postmenopausal women might contribute to their vulnerability to affective disorders. Estrogen replacement therapy might decrease this vulnerability and might add to the efficacy of serotonergic antidepressants when warranted.

How Often Are Endometrial Polyps Malignant

Objective: Endometrial polyps are a frequent pathology encountered during pelvic sonography and diagnostic hysteroscopies. The true incidence of malignant endometrial polyps is unknown. The estimations range from 0.5 to 4.8%. The objective of this study was to investigate the frequency of malignant endometrial polyps, and to characterize the hysteroscopic image of these polyps. Methods: The study included 300 consecutive women with endometrial polyps who underwent hysteroscopic polypectomy. Patients’ characteristics, operative findings, and pathology reports were analyzed. Results: Four of the 300 endometrial polyps removed by operative hysteroscopy were malignant (1.3%). Patients with malignant polyps were symptomatic peri- or postmenopausal women. All asymptomatic polyps in this series were found to be benign. We could not identify any distinct hysteroscopic feature of malignancy. Conclusions: Our study shows that about 1.5% of endometrial polyps may be malignant. This finding reinforces the indication for removal of symptomatic endometrial polyps, preferably by a hysteroscopic procedure. The significance of asymptomatic uterine polyps has still to be determined.

Imipramine Receptor Binding and Serotonin Uptake in Platelets of Women with Premenstrual Changes

Gonadal hormones are believed to be involved in the pathophysiology of premenstrual changes (PMC) possibly through their interaction with neurotransmitter systems in the brain. The serotonergic system, an important central modulator of mood and behavior which is involved in the pathophysiology of affective disorders has been suggested to play a role in the genesis of dysphoric PMC. Blood platelet serotonin (5-HT) uptake and imipramine (IMI) binding have been shown to share similarities with serotonergic mechanisms in the brain thus enabling the study of serotonergic mechanisms. In this study, we report on platelet 5-HT uptake and IMI receptor binding which were simultaneously studied in women with PMC. Subjects with PMC showed a large interindividual variability with no consistent typical pattern or change during the late symptomatic as compared to the early nonsymptomatic luteal phase. Their IMI receptor binding, however, was lower compared to controls already during the early luteal phase before they developed symptoms and was similar during the symptomatic phase. This might suggest a preexistent vulnerability to the development of dysphoric PMC that might be related to impaired gonadal hormone modulation of the serotonergic system.

Influence of age, sex and diurnal variability on imipramine receptor binding and serotonin uptake in platelets of normal subjects

Imipramine (IMI) binding and serotonin (5-HT) uptake were determined in platelets of 98 healthy volunteers; and their association with age, sex and circadian rhythm were evaluated. A large interindividual variability was found for both IMI and 5-HT parameters. There was a negative correlation of IMI affinity constant (Kd) and binding (Bmax) with age, but no such correlation of 5-HT affinity constant (Km) or uptake (Vmax). Significant age-related diurnal variability was found for 5-HT Km in the whole group as well as for IMI Kd in males, but not in females. There was no significant correlation between 5-HT Vmax and IMI Bmax. Our results underscore a cautious approach to the interpretation of platelet serotonergic studies. In light of the multiple variables influencing the results, the usefulness of IMI or 5-HT as clinical markers should be re-evaluated.

Elimination of ovulation and menstrual cyclicity (with danazol) improves dysphoric premenstrual syndromes

OBJECTIVEnTo assess whether the therapeutic effect of danazol on premenstrual syndromes (PMS) is associated with suppression of ovulation.nnnDESIGNnAfter 1 month on placebo, we administered 200 mg/d of danazol for 90 days to 24 women with dysphoric PMS. Symptoms during ovulatory cycles were compared with anovulatory periods.nnnSETTINGnOutpatient PMS program in a general hospital.nnnPATIENTSnTwenty-four women who had dysphoric PMS and otherwise were physically and mentally healthy.nnnINTERVENTIONSnNone (except the oral medication).nnnMAIN OUTCOME MEASUREnProspective daily monitoring of symptoms with the Daily Rating Form, before, during, and after treatment.nnnRESULTSnTwenty of 23 anovulatory periods were symptom-free versus 6 of 32 ovulatory periods (chi 2 = 15.63, P = 0.0002).nnnCONCLUSIONnThe beneficial effect of danazol as treatment depends mostly on achieving an an-ovulatory state and elimination of hormonal cyclicity and not on the drug per se.

Increased imidazoline and α2 adrenergic binding in platelets of women with dysphoric premenstrual syndromes

An association between dysphoric premenstrual syndromes (PMS) and a lifetime history of major depressive disorders has previously been documented. Other studies have demonstrated an increase in the binding of radiolabeled imidazoline compounds to platelets of depressed patients. Clonidine and related imidazoline compounds interact with alpha 2 adrenoceptors to inhibit neuronal noradrenergic activity and in higher concentrations, they stimulate noradrenergic activity through their interaction with imidazoline receptors. Here we report increased 3H para-aminoclonidine binding to high affinity alpha 2 adrenoceptor sites as well as to nonadrenergic imidazoline binding sites in platelets of women with dysphoric PMS. This higher binding was most pronounced during the late-luteal-symptomatic phase of the menstrual cycle and, to a lesser degree, during the non-symptomatic mid-follicular phase. Binding to the imidazoline site distinguished women with dysphoric PMS from women with no such symptoms, was highly positively correlated with the severity of symptoms, and was negatively correlated with plasma levels of progesterone. These findings suggest that platelet imidazoline binding sites might be a biological marker for dysphoric states in PMS or for the vulnerability to develop them. These findings also point to a possible biological link between dysphoric PMS and major depressive disorders.

LDL induces Saos2 osteoblasts death via Akt pathways responsive to a neutral sphingomyelinase inhibitor

Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis (OP) presumably by common etiologic factors, reflecting a state of co‐morbidity in aging. Osteoblasts make a significant facet of this co‐morbidity state. Since oxidized low‐density lipoprotein (oxLDL) is a major factor in generation of vascular wall pathology, we examined the ability of native LDL (nLDL) and oxLDL to induce Saos2 osteoblasts growth arrest. OxLDL induced Saos2 cell death with morphological features of apoptosis that was inhibited mainly by caspase‐9 and partially by caspase‐3 but not by caspase‐8 inhibitors. nLDL, like oxLDL, has induced cell death, where 60% (Pu2009=u20090.00033) and 30% (Pu2009=u20090.075, ns) of the cell death, respectively, could be inhibited by scyphostatin (a neutral sphingomyelinase [nSMase] inhibitor). Upon similar condition, nLDL inhibited the phosphorylation of Akt and two of its downstream targets, fork head receptor (FKHR) and glycogen synthase kinase‐3 (GSK3). This is a pathway that stimulates cell survival and proliferation. nLDL has also induced an increase in the proapoptotic Bcl‐Xs and it has diminished the potential antiapoptotic Src kinase activity. At the 4 h time‐point, upon a substantial decrease in nLDL‐induced Akt phosphorylation, scyphostatin has inhibited the reduction in FKHR and GSK3 phosphorylation but inexplicably not that of Akt. Scyphostatin has also corrected the reduction in Src kinase activity. Taken together, the results indicate that nLDL has induced apoptosis in Saos2 osteoblasts by inactivation of the pathway downstream to Akt using nSMase, and by involvement of Src kinase. Inferring that caspase‐9 was the main executioner (rather than caspase‐8 and‐3) in Saos2 cell death, indicates that the nSMase‐induced release of ceramide, directly activated the intrinsic mitochondrial apoptotic pathway. With regard to the Akt inactivation by nLDL, Saos2 osteoblasts responded in an opposite fashion to the response reported by others, in macrophages. J. Cell. Biochem. 98: 661–671, 2006.

Menstrually-related changes in monoaminergic systems and their association with gonadal hormones and symptoms

Activity of several parameters of monoamine neurotransmitters is influenced by gonadal hormones. It has been suggested that the hormones-neurotransmitters interaction is involved in the pathophysiology of menstrually-related symptoms. Women seeking treatment for premenstrual dysphoric changes (PMC) as well as symptom-free women underwent a series of studies of putative indications of activity of the serotonergic system: challenges with m-CPP and tryptophan, as well as imipramine receptor binding and serotonin uptake in platelets. In another study, platelets alpha, adrenoreceptors were determined. Late luteal phase abnormality of the serotonergic system is demonstrated with the three different studies and estradiol dependent defect of post synaptic responsiveness is suggested. The alpha* adrenoreceptor results suggest that at least some women with PMC have increased binding similar to that of patients with MDD. Possible abnormality of NA system and increased vulnerability of these women to develop MDD is discussed in the context of a multi-factorial mechanism.

Preparation of Low Density Lipoprotein from Large Apheresis Cartridges for Induction of Cell Death in Saos2 Osteoblasts

Abstract:u2002 Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis presumably by common etiologic factors, reflecting a state of comorbidity in aging. Osteoblasts make a significant facet of this comorbidity state. The present study shows that LDL (native and oxidized) separated by conventional density ultracentrifugation induces osteoblast cell growth arrest in culture. Since the density unltracentrifugation is a tedious procedure we examined, in the present study, the option of LDL purification by ionic strength elution from LDL‐apheresis cartridges. We tested the ability of LDL and oxidized LDL (oxLDL) from apheresis columns to induce apoptosis in human Saos2 osteoblasts. Isotonic NaCl effluent washed from LDL‐apheresis columns (before starting elution of LDL) induced cell proliferation. In some of the effluent fractions that stimulated Saos2 osteoblasts, up to 15% of the stimulation levels could be significantly inhibited with antilipoprotein A antibodies. After the isotonic washing (150u2003mM NaCl), upon elution with high ionic strength, 0.2–0.3u2003M NaCl, some front‐runner LDL eluate fractions also induced cell growth and others did not inhibit Saos2 cell growth. This indicates that these fractions might have been contaminated with apolipoprotein A or with other mitogenic compounds. In contrast, the late‐to‐elute (last 1/3) LDL portion, with a mean density of 1.042u2003g/mL, killed the cells as expected. This suggests that only the very last one third of LDL eluted by high ionic strength (0.3–0.5u2003M) is free of osteoblast‐mitogenic compounds or lipoprotein‐A containing particles. This approach to LDL purification might serve as a convenient and economic method for studying the composition of individual LDL particles and their interaction with cells in culture.