Sex Steroid Deficiency Research Articles

Orchiectomy upregulates free soluble RANKL in bone marrow of aged rats

The osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis is thought to be involved in the upregulation of bone turnover following sex steroid deficiency. Here, we investigated the effects of orchiectomy (ORX) on bone turnover and free soluble RANKL (sRANKL) in aged rats. Free, bioactive sRANKL is a critical determinant and key mediator for survival and activity of mature osteoclasts. Thirty-three 9-month-old male Fischer-344 rats were either ORX or sham-operated (SHAM). Following in vivo fluorochrome labeling, vehicle (ricinus oil/benzyl benzoate)-treated SHAM and vehicle- or testosterone undecanoate (T, 6 mg/kg s.c. once weekly)-treated ORX rats ( n = 8–9 each) were killed 2 months after surgery. Vehicle-treated ORX rats showed lower seminal vesicle weight, loss of proximal tibial trabecular bone mineral density, and reduced cortical thickness at the tibial shaft as measured by peripheral quantitative computed tomography relative to SHAM controls. Bone loss in vehicle-treated ORX rats was associated with enhanced bone turnover as evidenced by increases in tibial cancellous bone formation rate, osteoclast numbers, urinary excretion of calcium and deoxypyridinoline, and serum osteocalcin. T treatment of ORX rats restored seminal vesicle weight to SHAM control levels, and completely protected against post-ORX bone loss by suppressing bone turnover. Free sRANKL concentrations in bone marrow supernatants harvested from the proximal femur were about 3-fold higher in vehicle-treated ORX relative to SHAM rats, and returned to SHAM control levels in T-treated ORX rats. mRNA abundance of matrix metalloproteinase-14 (MMP-14) in bone marrow was 4-fold higher in vehicle-treated ORX rats relative to SHAM rats. T treatment of ORX rats suppressed MMP-14 mRNA expression to SHAM control levels. We conclude that orchiectomy increases the concentration of free sRANKL in bone marrow of aged rats. In addition, increased shedding of membrane-bound RANKL by MMP-14 may be a pivotal mechanism resulting in augmented free sRANKL concentrations in the bone marrow environment after androgen withdrawal.

The Brain, the Penis and Steroid Hormones: Clinical Correlates with Endothelial Dysfunction

Erectile function is a complex neurovascular process that depends on the health of the central and peripheral nervous systems and the vasculature. Thus, signaling from the central nervous system (brain) to the peripheral nervous system (penis) is critical and is modulated by a set of complex interactions that depend on cerebral and vascular circulation. The cerebral and peripheral vasculatures are target tissues for sex steroid hormones. Gonadal, adrenal and neurosteroids regulate the function and physiology of the endothelium and modulate vascular and cerebral circulation by genomic and non-genomic dependent mechanisms. Recent advances in cell and molecular biology have defined a critical role of endothelium in vascular function. A host of biochemical and clinical markers of endothelium function and dysfunction have been identified to assess vascular pathology. Emerging evidence suggests that sex steroid hormones play an important role in maintaining endothelial health and sex steroid deficiency is associated with endothelial dysfunction, vascular disease and erectile dysfunction. Such information has important clinical implications in patient management with sex steroid hormone insufficiency, diabetes, metabolic syndrome, vascular disease and erectile dysfunction. In this review, we discuss the role of sex steroid hormones in modulation of the biochemical and clinical markers associated with endothelial dysfunction. Specifically the regulation of endothelial nitric oxide synthase, asymmetric dimethylarginine, reactive oxygen species, endothelin-1, inflammatory cytokines, tumor necrosis factor-alpha, markers of cell adhesion, dysregulation of fibrinolytic factors and the inability to regenerate from endothelial progenitor cells concomitant with increased endothelial apoptosis, increased cellular permeability and increased vascular tone.

Mécanismes généraux de l’insuffisance ovarienne prématurée et bilan clinique

Premature ovarian failure (POF) is defined as the cessation of ovarian function under the age of 40 years. It is characterized by primary or secondary amenorrhea for at least four months, sex steroid deficiency and elevated serum gonadotropin concentrations. The diagnosis is confirmed by the detection of menopausal FSH levels on at least two occasions a few weeks apart in a woman before the age of 40. It occurs in 1/10,000 in women below the age of 20, 1/1,000 below 30 and 1% in women before the age of 40. Tthe classic etiologies are Turner syndrome, pelvic surgery, radiotherapy or chemotherapy. Although new genetic etiologies have been found in the past 10 years, the cause of POF is unknown in more than 75% of cases. Hormone replacement therapy should be administered in order to avoid vascular diseases and osteoporosis. For infertility, the most successful treatment remains assisted conception with donated oocytes.

Regulation of Bone Turnover by Sex Steroids in Men

The mechanism(s) by which sex steroids regulate bone turnover in humans are unclear, and recent studies have suggested that follicle-stimulating hormone (FSH) may play an important role in regulating bone resorption. Fifty-nine men (median age, 69 yr) underwent suppression of sex steroids using a gonadotropin-releasing hormone (GnRH) agonist and aromatase blocker and were replaced with testosterone (T; 5 mg/d) and estradiol (E; 37.5 microg/d). After assessment of bone resorption markers (serum C-terminal telopeptide of type I collagen [CTX] and TRACP5b), they were randomized to sex steroid deficiency (-T, -E), E alone (-T, +E), T alone (+T, -E), or both (+T, +E) and restudied 3 wk later. Bone marrow aspirates were obtained to isolate osteoblastic, T, and monocytic cells using magnetic-activated cell sorting. Serum CTX and TRACP5b increased significantly (by 71% and 15%, p < 0.01 and < 0.001, respectively) in the -T, -E group, and these increases occurred despite a 60% suppression of serum FSH levels (p < 0.001) caused by the GnRH agonist. There were significant E (but not T) effects on preventing increases in serum CTx and TRACP levels. There was a nonsignificant trend (p = 0.122) for E to suppress RANKL mRNA levels in bone marrow osteoblastic cells. Changes in mRNA levels for other cytokines (TNF-alpha, interleukin (IL)-1alpha, IL-1beta, IL-1ra, IFN-gamma) in bone marrow cells were not significant. E has greater suppressive effects on bone resorption than T, and increased bone resorption after sex steroid deficiency can occur independently of changes in FSH secretion. E effects on bone resorption may be mediated by regulation of RANKL production by osteoblastic cells, although further studies using more highly purified cells may reduce the variability of the mRNA measurements and allow for clearer definition of the mediators of sex steroid action in vivo.

A Population-Based Assessment of Rates of Bone Loss at Multiple Skeletal Sites: Evidence for Substantial Trabecular Bone Loss in Young Adult Women and Men

Using QCT, we made a longitudinal, population-based assessment of rates of bone loss over life at the distal radius, distal tibia, and lumbar spine. Cortical bone loss began in perimenopause in women and later in life in men. In contrast, trabecular bone loss began in young adulthood in both sexes. Although conventional wisdom holds that bone loss begins at menopause in women and later in life in men, this has not been examined longitudinally in population-based studies using precise technology capable of distinguishing cortical and trabecular bone. In an age- and sex-stratified population sample (n = 553), we measured volumetric BMD (vBMD) of trabecular and cortical bone by QCT annually for up to 3 yr at the distal radius (DR) and distal tibia (DT) (n = 552) and trabecular vBMD at baseline and 3 yr at the lumbar spine (LS) (n = 474). Substantial cortical bone loss began in middle life in women but began mainly after age 75 in men. In contrast, substantial trabecular bone loss began in young adult women and men at all three skeletal sites and continued throughout life with acceleration during perimenopause in women. Women experienced 37% and men experienced 42% of their total lifetime trabecular bone loss before age 50 compared with 6% and 15%, respectively, for cortical bone. Median rates of change in trabecular bone (%/yr) were -0.40, -0.24, and -1.61 in young adult women and -0.38, -0.40, and -0.84 in young adult men at the DR, DT, and LS, respectively (all p < 0.001). The early trabecular bone loss did not consistently correlate with putative causal factors, except for a trend with IGF-related variables at DT in women. However, in postmenopausal women and, to a lesser extent, in older men, higher rates of cortical and trabecular bone loss were associated with lower levels of biologically-active sex steroids and with higher levels of follicle-stimulating hormone and bone turnover markers. The late onset of cortical bone loss is temporally associated with sex steroid deficiency. However, the early-onset, substantial trabecular bone loss in both sexes during sex steroid sufficiency is unexplained and indicates that current paradigms on the pathogenesis of osteoporosis are incomplete.

Spontaneous premature ovarian failure: Management challenges

Premature ovarian failure (POF) generally describes a syndrome consisting of amenorrhea, sex steroid deficiency, and elevated/menopausal levels of ganadotropins in a woman aged more than two standard deviations below the mean age at menopause estimated for the reference population. Numerous questions relating to this condition remain unanswered, and several important management issues are yet to be addressed. The challenges posed by this important condition range from difficulties with nomenclature to the absence of standardized diagnostic criteria and management guidelines. In the present paper we discuss the management of spontaneous premature ovarian failure, highlight the challenging issues, review the current literature and propose a practical management outline based on our local practice. Women with POF have unique needs that require special attention. There is an urgent need for a more suitable terminology and evidence-based guidelines on which to establish the diagnosis and manage this difficult condition.

Circulating Sex Steroids, Sex Hormone-Binding Globulin, and Longitudinal Changes in Forearm Bone Mineral Density in Postmenopausal Women and Men: The Tromsø Study

Bone loss during advancing age in women and men is partly the result of sex steroid deficiency. As the contribution of circulating sex steroids and sex hormone-binding globulin (SHBG) to bone loss remains uncertain, we sought to determine whether levels of sex steroids or SHBG predict change in bone mineral density (BMD) in women and men. A population-based study in the city of Tromsø of 6.5 years' duration (range 5.4-7.4) included 927 postmenopausal women aged 37-80 years and 894 men aged 25-80 years. Total estradiol and testosterone, calculated free levels, and SHBG were measured at baseline, and BMD change at the distal forearm was determined using BMD measurements in 1994-1995 and 2001. Bone loss was detected in postmenopausal women and men. Free estradiol and SHBG predicted age-adjusted bone loss in postmenopausal women, but only free estradiol was associated after further adjustment for body mass index and smoking in mixed models (P < 0.05). After same adjustment, only SHBG persisted as a significant independent predictor of bone loss in men (P < 0.001). However, only 1% of the variance in bone loss was accounted for by these measurements. We therefore conclude that the relations between sex steroids and bone loss are weak and measurements of sex steroids are unlikely to assist in clinical decision making.

Screening for FOXL2 gene mutations in women with premature ovarian failure: an Indian experience

Premature ovarian failure (POF) occurs in 1% of the general population and affects approximately 10% of non-ovulating women, resulting in infertility and sex steroid deficiency. The forkhead domain transcription factor ( FOXL2) gene is one of the candidate genes associated with POF. This case–control study was designed for mutational analysis of the coding region of the FOXL2 gene in 80 cases of POF patients, 50 controls and 17 family members of 11 index cases using restriction fragment length polymorphism, single-stranded conformational polymorphism, heteroduplex analysis and direct DNA sequencing. A 738C→T transition and a 773C→G transversion were detected in two of the 80 patients and a family member of one index case, but in none of the 50 controls screened. No other alterations in the coding region of FOXL2 gene were detected. These data suggest that FOXL2 gene mutations are a rare occurrence in isolated POF cases and may not be involved in the pathogenesis of POF.

Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.

Association of Testosterone and Estradiol Deficiency with Osteoporosis and Rapid Bone Loss in Older Men

The clinical value of measuring testosterone and estradiol in older men with osteoporosis and of measuring bone mineral density (BMD) in older men with testosterone or estradiol deficiency is uncertain. The objective of the study was to examine the association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. This study was a cross-sectional and longitudinal analysis. The study was conducted at six U.S. centers of the Osteoporotic Fractures in Men study. The study population consisted of 2447 community-dwelling men aged 65 yr or older. Total testosterone deficiency was defined as less than 200 ng/dl. Total estradiol deficiency was defined as less than 10 pg/ml. Osteoporosis was defined as femoral neck or total hip BMD T-score of -2.5 or less. Rapid bone loss was defined as 3%/yr or more. Prevalence of osteoporosis in men with deficient and normal total testosterone was 12.3 and 6.0% (P = 0.003) and 15.4 and 2.8% (P < 0.0001) in those with deficient and normal total estradiol. Among osteoporotic men and those with normal BMD, prevalence of total testosterone deficiency was 6.9 and 3.2% (P = 0.01), and prevalence of total estradiol deficiency was 9.2 and 2.4% (P = 0.0001). Incidence of rapid hip bone loss in men with deficient and normal total testosterone was 22.5 and 8.6% (p = 0.007) and in those with deficient and normal total estradiol was 14.3 and 6.3% (p = 0.08). Older men with total testosterone or estradiol deficiency were more likely to be osteoporotic. Those with osteoporosis were more likely to be total testosterone or estradiol deficient. Rapid hip bone loss was more likely in men with total testosterone deficiency. BMD testing of older men with sex steroid deficiency may be clinically warranted.

Periosteal Remodeling at the Femoral Neck in Nonhuman Primates

Periosteal bone turnover is poorly understood. We documented intramembranous periosteal bone turnover in the femoral neck in intact nonhuman primates and an increase in osteoclast numbers at the periosteal surface in sex steroid-deficient animals. Our studies are the first to systematically document periosteal turnover at the femoral neck. Bone size is an important determinant of bone strength, and cellular events at the periosteal surface could alter bone dimensions. We characterized periosteal cellular activity with dynamic histomorphometric studies of nonhuman primate femoral neck and shaft. Femur specimens from 16 intact adult male and female nonhuman primates (Rhesus [Macaca mulatta, n = 9] and Japanese Macaque [Macaca fuscata, n = 7]) were analyzed. Animals were double-labeled with tetracycline, and necropsy was performed 2-7 days after the last dose. We characterized periosteal resorptive activity in an additional group of five intact and four castrate female animals. Multiple group comparisons in intact animals were performed by one-way ANOVA followed by a Fisher PLSD posthoc test. In gonadectomized animals, Fisher's exact test was used for dichotomous and Mann-Whitney U-test for continuous variables. Bone turnover in the periosteum of the femoral neck in intact animals was more rapid than at the femoral shaft but slower than in femoral neck cancellous bone. Similarly, in these intact animals, the eroded surface of cortical bone at the femoral neck periosteal surface was significantly greater than in the cancellous bone compartment (p < 0.0001) or on the femoral shaft (p < 0.0001). Gonadectomized female animals showed an increase in osteoclast number on the periosteal surface compared with intact controls (p < 0.01). We documented intramembranous periosteal bone turnover in the femoral neck by histomorphometric analyses. The tissue level bone formation rate was sufficient to add substantively to femoral neck size over time. Periosteal osteoclastic activity was not the result of the emergence of intracortical tunneling at the bone surface. Sex steroid deficiency produced an increase in osteoclast numbers at the periosteal surface. This is the first systematic documentation of periosteal turnover at the femoral neck.

Circulating osteoprotegerin is correlated with lipid profile, insulin sensitivity, adiponectin and sex steroids in an ageing male population

The relationship between osteoprotegerin (OPG) and lipid profile, insulin sensitivity, adipocytokines and sex steroids has been poorly studied and subject to controversy. The purpose of this study was to look at the correlates of OPG in an elderly male population. One hundred and fifty-one nondiabetic, elderly Lebanese men (age range 50-83) were recruited in this cross-sectional study based on voluntary enrolment. In all the subjects, serum OPG levels were measured and related to clinical parameters (age, waist, body mass index (BMI), systolic and diastolic blood pressure), as well as to metabolic and hormonal parameters. The following fasting laboratory measurements were performed: plasma glucose and insulin levels, total cholesterol, triglycerides and HDL cholesterol, adiponectin, leptin, as well as sex steroids (testosterone, SHBG, free androgen index, ooestradiol, DHEAS), GH and IGF-1. QUICKI index was calculated as a measure of insulin sensitivity. OPG levels were significantly correlated with age (r = 0.28, P < 0.0001) but not with BMI, waist, systolic or diastolic blood pressure. There was a trend towards higher OPG levels in subjects without, compared to subjects with the metabolic syndrome (3.58 +/- 1.28 vs. 3.26 +/- 1.04 pmol/l, P = 0.09). OPG was negatively correlated with fasting glucose and triglyceride levels (r = -0.18, P = 0.031 and r = -0.19, P = 0.02, respectively) and positively correlated with the QUICKI index (r = 0.17, P = 0.033), HDL cholesterol (r = 0.21, P = 0.009) and adiponectin levels (r = 0.27, P = 0.001). No significant correlations were reported with total or LDL cholesterol levels and with leptin levels. After adjustment for age, OPG is still correlated with triglycerides (r = -0.19, P = 0.02), glucose (r = -0.21, P = 0.011) and adiponectin (r = 0.19, P = 0.02). Finally, OPG was positively associated with SHBG (r = 0.31, P < 0.001) and negatively associated with free androgen index (r =-0.346, P < 0.001); both correlations persisted after adjustment for age (r = 0.21, P = 0.009 and r = -0.23, P = 0.005, respectively). No significant correlation was found between OPG and oestradiol levels while a weak negative correlation was demonstrated with DHEAS (r = -0.18, P = 0.025). Also, no significant correlation was found between OPG and GH or IGF-1 values. In a multiple regression analysis with a stepwise model, the main determinants of OPG were free androgen index and adiponectin (P < 0.0001 and P = 0.015, respectively). Our results show that circulating OPG levels are favourably associated with some components of the metabolic syndrome. Also, for the first time, an association between OPG and adiponectin is described. Finally, the negative correlation we found between OPG and free androgen index may suggest a potential role of OPG in the increase in cardiovascular disease related to ageing and sex steroid deficiency.

Mandible analysis in sex steroid‐deficient rats

The aim of this study was to evaluate, by morphologic techniques, the effects of sex steroid deficiency on mandible bone remodeling of female rats, in groups of different experimental periods and to compare the results with 90-day orquiectomized males. Female and male Wistar rats, 3 months old, were divided into experimental groups and at the end of each experimental period were killed, and mandibles were extracted. The left mandibles were prepared with rote technique bone and examined by a light microscope. Morphological analyses of the mandibles demonstrated resorption signals in the alveolar bone, after 30 days in ovariectomized females, but it was more intense 90 days after castration. The orquiectomized group exhibited some signals of resorption similar to the ovariectomized group of 60 days. Morphometric analysis of alveolar bone thickness in females after 60 days was in agreement with morphological results. However, the analysis of periodontal ligament thickness did not show any significant difference. There were variations in sexual hormone deficiency in the mandibles of males and females and they seemed to be more precocious in ovariectomized than in orquiectomized rats. It is important for a health professional to have knowledge about bone metabolism to improve the quality of life of postmenopaused and old people.

High Risk of Hypogonadism After Traumatic Brain Injury: Clinical Implications

Several recent studies have convincingly documented a close association between traumatic brain injury (TBI) and pituitary dysfunction. Post-traumatic hypogonadism is very common in the acute post-TBI phase, though most cases recover within six to twelve months following trauma. The functional significance of early hypogonadism, which may reflect adaptation to acute illness, is not known. Hypogonadism persists, however, in 10-17% of long-term survivors. Sex steroid deficiency has implications beyond psychosexual function and fertility for survivors of TBI. Muscle weakness may impair functional recovery from trauma and osteoporosis may be exacerbated by immobility secondary to trauma. Identification and appropriate and timely management of post-traumatic hypogonadism is important in order to optimise patient recovery from head trauma, improve quality of life and avoid the long-term adverse consequences of untreated sex steroid deficiency.

Pituitary hormone replacement

<h2>Abstract</h2> Hormone replacement therapy is available for patients suffering diabetes insipidus and all the anterior pituitary hormone deficiencies, with the exception of prolactin. In patients with adrenocorticotrophic hormone and thyroid-stimulating hormone deficiencies, replacement is with the target-gland hormone products cortisol (hydrocortisone) and thyroxine, respectively. Sex steroid replacement therapy is offered to patients with gonadotrophin deficiency to deal with the sex steroid deficiency, but if fertility is desired gonadotrophin therapy is required. Growth hormone (GH) deficiency requires GH replacement, but only adult patients with severe GH deficiency are considered for replacement and, in the UK, such patients are chosen by virtue of severe impairment of quality of life; strict criteria must be satisfied before the 9-month trial of therapy can be extended to lifelong GH replacement. Desmopressin, a synthetic analogue of arginine vasopressin, is the drug of choice for the treatment of antidiuretic hormone deficiency; it is available in several different preparations.

Endocrinology of Menopausal Transition and Its Brain Implications

The central nervous system is one of the main target tissues for sex steroid hormones, which act on both through genomic mechanisms, modulating synthesis, release, and metabolism of many neuropeptides and neurotransmitters, and through non-genomic mechanisms, influencing electrical excitability, synaptic function, morphological features, and neuron-glia interactions. During the climacteric period, sex steroid deficiency causes many neuroendocrine changes. At the hypothalamic level, estrogen withdrawal gives rise to vasomotor symptoms, to eating behavior disorders, and altered blood pressure control. On the other hand, at the limbic level, the changes in serotoninergic, noradrenergic, and opioidergic tones contribute to the modifications in mood, behavior, and nociception. Hormone replacement therapy (HRT) positively affects climateric depression throughout a direct effect on neural activity and on the modulation of adrenergic and serotoninergic tones and may modulate the decrease in cognitive efficiency observed in climaterium. The identification of the brain as a de novo source of neurosteroids, suggests that the modifications in mood and cognitive performances occurring in postmenopausal women may also be related to a change in the levels of neurosteroids. These findings open new perspectives in the study of the effects of sex steroids on the central nervous system and on the possible use of alternative and/or auxiliary HRT.

Transient Versus Sustained Phosphorylation and Nuclear Accumulation of ERKs Underlie Anti-Versus Pro-apoptotic Effects of Estrogens

Sex steroids exert anti-apoptotic effects on osteoblasts/osteocytes but exert pro-apoptotic effects on osteoclasts, in both cases requiring activation of the extracellular signal-regulated kinases (ERKs). To explain the mechanistic basis of this divergence, we searched for differences in the kinetics of phosphorylation and/or in the subcellular localization of ERKs in response to 17beta-estradiol in the two cell types. In contrast to its transient effect on ERK phosphorylation in osteocytic cells (return to base line by 30 min), 17beta-estradiol-induced ERK phosphorylation in osteoclasts was sustained for at least 24 h following exposure to the hormone. Conversion of sustained ERK phosphorylation to transient, by means of cholera toxin-induced activation of the adenylate cyclase/cAMP/protein kinase A pathway, abrogated the pro-apoptotic effect of 17beta-estradiol on osteoclasts. Conversely, prolongation of ERK activation in osteocytes, by means of leptomycin B-induced inhibition of ERK export from the nucleus or overexpression of a green fluorescent protein-ERK2 mutant that resides permanently in the nucleus, converted the anti-apoptotic effect of 17beta-estradiol to a pro-apoptotic one. These findings indicate that the kinetics of ERK phosphorylation and the length of time that phospho-ERKs are retained in the nucleus are responsible for pro-versus anti-apoptotic effects of estrogen on different cell types of bone and perhaps their many other target tissues.

Bone mineral density in early-onset hypogonadism and the effect of hormonal replacement.

Hypogonadism is associated with reduction of bone mineral density (BMD), especially if sex steroid deficiency occurs early in life. In this situation, the effect of hormonal replacement therapy on bone mass is controversial. We evaluated the BMD through dual-energy X-ray absorptiometry (DXA) in patients with genetically determined hypogonadism or hypogonadism acquired in adulthood. The results of the BMD of patients never treated (pretreatment) or under treatment were compared with population standards and were submitted to pair analysis. Thirty-three patients were evaluated: group 1: BMD evaluated pretreatment (24); group 2: BMD evaluated under treatment (21); group 3: BMD evaluated pretreatment and under treatment (12). In group 1, there was a significant reduction of bone mass in all regions, with no gender differences. In patients with concomitant growth hormone (GH) deficiency, the total body (-3.60) and lumbar spine (-4.10) BMDs were significantly reduced compared to patients without associated GH deficiency (-2.37 and -2.35, respectively). In group 2, a significant reduction of bone mass was detected in all regions. In group 3, the patients showed statistically significant improvement in BMD with hormonal replacement therapy in all regions in both sexes. We conclude that the early onset of hypogonadism reduces the BMD significantly. This effect is increased when there is associated GH deficiency. Gonadal steroid replacement therapy increases the BMD in all bone regions, and the increase is similar in both sexes. However, although hormone replacement improves bone mass, it still remains significantly lower in comparision with population standards.

Impaired Endothelial Function in Young Women with Premature Ovarian Failure: Normalization with Hormone Therapy

Normal menopause is associated with vascular endothelial dysfunction, an early stage of atherosclerosis. The effect of premature ovarian failure (or premature menopause) on endothelial function in young women is unknown. Endothelial function was assessed in 18 women with premature ovarian failure before and after 6 months of hormone therapy and was compared with the endothelial function of 20 age- and body mass index-matched premenopausal women. Brachial artery diameter was measured both during hyperemia (an index of endothelium-dependent vasodilation) and in response to glyceryl trinitrate (an index of endothelium-independent vaso-dilation). Flow-mediated dilation was significantly lower in women with premature ovarian failure at baseline (increase in brachial artery diameter during hyperemia by 3.06 +/- 4.33%) than in control women (increase by 8.84 +/- 2.15%; P < 0.0005). Glyceryl trinitrate-induced vasodilation did not differ between the groups. After hormone therapy for 6 months, flow-mediated dilation was improved in women with premature ovarian failure, increasing by more than 2-fold (7.41 +/- 3.86%; P < 0.005 compared with pretreatment) and reaching normal values (P not significant compared with control women). Glyceryl trinitrate-induced vasodilation did not change after treatment in women with premature ovarian failure. Young women with premature ovarian failure have significant vascular endothelial dysfunction. Early onset of endothelial dysfunction associated with sex steroid deficiency may contribute to the increased risk of cardiovascular disease and mortality in young women with premature ovarian failure. Hormone therapy restores endothelial function within 6 months of treatment.

Effects of ovariectomy and estrogen replacement on rat oral mucosa

Objective: Although a close relationship between the oral discomfort and the menopause is suggested, it is not clear if the alteration of sex steroids would cause any histological or even pathological change in the oral mucosa. The aim of this study was to investigate the possible effect of sex steroid deficiency on the rat oral mucosa as well as the effect of its replacement. Methods: The oral mucosa of ovariectomized rats was compared to that of sham-operated rats both histologically and immunohistochemically. The same evaluation was also performed after hormone replacement therapy for the ovariectomized rats. Results: The ovariectomized animals presented reduced thickness of the mucosal epithelium with an irregular corneal (keratinised) surface. Partial disappearance of lingual papilla with irregular lete-peg was also noted. The corneal (keratinised) layer in the sublingual region was significantly thinner in ovariectomized animals. The results from immunohistochemistry showed the possibility that the turnover period was prolonged in ovariectomized rats. Estrogen replacement could compensate for the reduction in mucosal thickness in the animal model. Conclusions: The overall results suggest that sex steroids have a specific role in the maintenance of normal oral mucosa, and its deficiency possibly leads to the onset of oral discomfort in postmenopausal women.