Is postmenopausal hormone replacement therapy suitable after a cardio- or cerebrovascular event?

PURPOSE Vascular disease is the leading cause of death in women. One-third of acute events affect women below age 60, when the prevalence of menopausal symptoms is high. This raises the question if hormone replacement therapy (HRT) may be an appropriate treatment for individual women although vascular disease is generally considered a contraindication. METHODS Selective literature search was used for this study. RESULTS In healthy women, HRT increases risks for venous thromboembolism and ischemic stroke, but for cardiovascular disease apparently only beyond 10 years after menopause or 60 years of age. Limited data in women with cardio or cerebrovascular disease have not demonstrated an increased risk for a vascular recurrent event, but for the first year after initiation. In HRT users affected by a cardiovascular event continuation of HRT has not been found to be associated with adverse outcome. Low dose estradiol--preferentially as transdermal patches, if necessary combined with metabolically neutral progestins--appears to convey lower risk. CONCLUSIONS Safety data on HRT in survivors of cardiovascular events or ischemic stroke are limited, but exceptionally increased risk appears to be excluded. If off-label use of HRT is considered to be initiated or continued in women with cardio- or cerebrovascular disease, extensive counseling on the pros and cons of HRT is mandatory.

Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance

Replacement of growth hormone (GH) in patients suffering from GH deficiency (GHD) offers clinical benefits on body composition, exercise capacity, and skeletal integrity. However, GH replacement therapy (GHRT) is also associated with insulin resistance, but the mechanisms are incompletely understood. We demonstrate that in GH-deficient mice (growth hormone-releasing hormone receptor (Ghrhr)(lit/lit)), insulin resistance after GHRT involves the upregulation of the extracellular matrix (ECM) and the downregulation of microRNA miR-29a in skeletal muscle. Based on RNA deep sequencing of skeletal muscle from GH-treated Ghrhr(lit/lit) mice, we identified several upregulated genes as predicted miR-29a targets that are negative regulators of insulin signaling or profibrotic/proinflammatory components of the ECM. Using gain- and loss-of-function studies, five of these genes were confirmed as endogenous targets of miR-29a in human myotubes (PTEN, COL3A1, FSTL1, SERPINH1, SPARC). In addition, in human myotubes, IGF1, but not GH, downregulated miR-29a expression and upregulated COL3A1. These results were confirmed in a group of GH-deficient patients after 4 months of GHRT. Serum IGF1 increased, skeletal muscle miR-29a decreased, and miR-29a targets were upregulated in patients with a reduced insulin response (homeostatic model assessment of insulin resistance (HOMA-IR)) after GHRT. We conclude that miR-29a could contribute to the metabolic response of muscle tissue to GHRT by regulating ECM components and PTEN. miR-29a and its targets might be valuable biomarkers for muscle metabolism following GH replacement. KEY MESSAGES GHRT most significantly affects the ECM cluster in skeletal muscle from mice. GHRT downregulates miR-29a and upregulates miR-29a targets in skeletal muscle from mice. PTEN, COL3A1, FSTL1, SERPINH1, and SPARC are endogenous miR-29a targets in human myotubes. IGF1 decreases miR-29a levels in human myotubes. miR-29a and its targets are regulated during GHRT in skeletal muscle from humans.

EMAS position statement: Testosterone replacement therapy in the aging male‏.

INTRODUCTION Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. AIMS The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.

Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50-60% of VO2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn't significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

New aspects of estrogen action in the endometrium: Reciprocal interplay with retinoic acid pathway and a novel estrogen-regulated gene

The uterine endometrium is a major target for the estrogen. However, the molecular basis of estrogen action in the endometrium is largely unknown. I have used two approaches to study the effects of estrogen on the endometrium. One approach involved the study of the interaction between estrogen and retinoic acid (RA) pathways in the endometrium. I have demonstrated that estrogen administration to rodents and estrogen replacement therapy (ERT) in postmenopausal women selectively induced the endometrial expression of retinaldehyde dehydrogenase II (RALDH2), a critical enzyme of RA biosynthesis. RALDH2 was expressed exclusively in the stromal cells, especially in the stroma adjacent to the luminal and glandular epithelia. The induction of RALDH2 by estrogen required estrogen receptor and occurred via a direct increase in RALDH2 transcription. Among the three RA receptors, estrogen selectively induced the expression of RARα. In parallel, estrogen also increased the utilization of all-trans retinol (the substrate for RA biosynthesis) and the expression of two RA-regulated marker genes, cellular retinoic acid binding protein II (CRABP2) and tissue transglutaminase (tTG) in the endometrium. Thus estrogen coordinately upregulated both the production and signaling of RA in both the rodent and human endometrium. This coordinate upregulation of RA system appeared to play a role in counterbalancing the stimulatory effects of estrogen on the endometrium, since the depletion of endogenous RA in mice led to an increase in estrogen-stimulated stromal proliferation and endometrial Akt phosphorylation. In addition, I have also used a systematic approach (DNA microarray) to categorize genes and pathways affected by the ERT in the endometrium of postmenopausal women and identified a novel estrogen-regulated gene EIG121. EIG121 was exclusively expressed in the glandular epithelial cells of the endometrium and induced by estrogen in vivo and in cultured cell lines. Compared with the normal endometrium, EIG121 was highly overexpressed in type 1 endometrial cancer, but profoundly suppressed in type 2 endometrial tumors. Taken together, these studies suggested that estrogen regulates the expression of many genes of both the pro-proliferative and anti-proliferative pathways and the abnormality of these pathways may increase the risks for estrogen-dependent endometrial hyperplasia and endometrial cancer. ^

Hormone replacement therapy and risk of hip fracture: population based case-control study

Objective: To determine the relative risk of hip fracture associated with postmenopausal hormone replacement therapy including the effect of duration and recency of treatment, the addition of progestins, route of administration, and dose.

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Estrogen regulates hippocampal dendritic spine density and synapse number in an N-methyl-d-aspartate (NMDA) receptor-dependent manner, and these effects may be of particular importance in the context of age-related changes in endocrine status. We investigated estrogen's effects on axospinous synapse density and the synaptic distribution of the NMDA receptor subunit, NR1, within the context of aging. Although estrogen induced an increase in axospinous synapse density in young animals, it did not alter the synaptic representation of NR1, in that the amount of NR1 per synapse was equivalent across groups. Estrogen replacement in aged female rats failed to increase axospinous synapse density; however, estrogen up-regulated synaptic NR1 compared with aged animals with no estrogen. Therefore, the young and aged hippocampi react differently to estrogen replacement, with the aged animals unable to mount a plasticity response generating additional synapses, yet responsive to estrogen with respect to additional NMDA receptor content per synapse. These findings have important implications for estrogen replacement therapy in the context of aging.

The effect of hormone replacement therapy on mood and everyday memory in younger mid-life women

Research on the effect of hormone replacement therapy (HRT) on both mood and memory indicates that oestrogen may enhance verbal memory in younger mid-aged women. This study examined the effect of HRT on everyday memory, while accounting for mood changes, in women between ages 40 and 60. A within-subjects comparison of 17 women, showed that mood, everyday memory, working memory, and delayed verbal memory improved after 3 months of HRT use. The improvement in memory was not mediated by mood, but changes in mood were moderated by exercise habits. The results suggest that verbal memory in particular may be enhanced by HRT in this age group, and everyday memory is an important construct to consider in future research.