Effect of hormone replacement therapy on intervertebral disc height.

OBJECTIVE: Intervertebral discs act as shock absorbers, thereby helping to reduce the risk of vertebral body fractures. Previous studies have shown that estrogen loss following menopause is associated with disc height reduction whereas treatment with hormone replacement therapy (HRT) helps to maintain disc height. This study reports the effect of HRT on disc height from a post hoc analysis of a prospective randomized clinical trial of the effect of HRT on bone density. METHODS: A total of 355 healthy postmenopausal women aged (mean ± standard deviation) 55.4 ± 4.8 years were randomized to HRT with oral 1 mg or 2 mg estradiol plus dydrogesterone or placebo. Dual-energy X-ray absorptiometry measurements (Lunar DPX) were obtained at baseline and following 2 years of treatment. Intervertebral disc height was measured in discs between T12 and L3 using the bone densitometer ruler. RESULTS: Compared with baseline, treatment with HRT resulted in a significant increase in total disc height with 1 mg estradiol (0.16 ± 0.65 cm, p = 0.015) and with 2 mg estradiol (0.21 ± 0.86 cm, p = 0.006) whilst there was no significant increase with placebo (0.13 ± 0.65 cm, p = 0.096). Between-group differences were not statistically significant. CONCLUSIONS: These results are consistent with previous findings of a beneficial effect of estrogen on discs. This may be in part responsible for the anti-fracture efficacy of HRT on vertebral fractures.

The urogenital system and the menopause.

The major cause of urogenital atrophy in menopausal women is estrogen loss. The symptoms are usually progressive in nature and deteriorate with time from the menopausal transition. The most prevalent urogenital symptoms are vaginal dryness, vaginal irritation and itching. The genitourinary syndrome of menopause includes vulvovaginal atrophy and the postmenopausal modifications of the lower urinary tract. Dyspareunia and vaginal bleeding from fragile atrophic skin are common problems. Other urogenital complaints include frequency, nocturia, urgency, stress urinary incontinence and urinary tract infections. Atrophic changes of the vulva, vagina and lower urinary tract can have a large impact on the quality of life of the menopausal woman. However, hormonal and non-hormonal treatments can provide patients with the solution to regain the previous level of function. Therefore, clinicians should sensitively question and examine menopausal women, in order to correctly identify the pattern of changes in urogenital atrophy and manage them appropriately.

Chemoprevention of breast cancer among women at elevated risk as defined by Gail Score.

The risk of an individual woman to develop breast cancer over a 5-year period can be estimated using the Gail Model. The risk factors included in this model effectively classify patients into two different subgroups. One subgroup comprises patients at increased risk because of increased exposure to estrogen. These women are more likely to benefit from endocrine chemopreventive therapies, namely selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The second subgroup comprises women who have inherited genetic mutations that predispose them to breast cancer. Chemoprevention in these patients is more likely to be achieved by novel agents, such as lapatinib, gefitinib, fenretinide, rexinoids and poly(ADP-ribose) polymerase (PARP)-inhibitors.

The role of cytokines in skin aging.

Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance. It may contribute to some maladies that occur in aging which, despite not being life-threatening, affect the well-being, psychological state and quality of life of aged women. Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors. Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age. Deranged levels of several interleukins and interferons also affect the aging process. The high level of CCN1 protein in aged skin gives dermal fibroblasts an 'age-associated secretory phenotype' that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin. Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging.

The role of cytokines in cardiovascular disease in menopause.

Various studies suggest that increased levels of pro-inflammatory cytokines play a key role in the declining ovarian function and the resulting complications associated with menopause. In this review article, the authors outline the role of pro- and anti-inflammatory cytokines in cardiovascular disease during menopause.

The effect of menopause on the skin and other connective tissues.

Cutaneous ageing manifests itself as a progressive reduction in function and reserve capacity of skin tissue. Collagen atrophy is a major factor in skin ageing. There is a strong correlation between skin collagen loss and oestrogen deficiency due to the menopause. Skin ageing is associated with a progressive increase in extensibility and a reduction in elasticity. With increasing age, the skin also becomes more fragile and susceptible to trauma, leading to more lacerations and bruising. Furthermore, wound healing is impaired in older women. Oestrogen use after the menopause increases collagen content, dermal thickness and elasticity, and it decreases the likelihood of senile dry skin. Large-scale clinical trials are necessary to help make informed recommendations regarding postmenopausal oestrogen use and its role in the prevention of skin ageing. Oestrogen has profound effects on connective tissue turnover, no matter the site. It has been shown that menopause has similar effects on the connective tissue of the carotid artery media, intervertebral discs and bones.

Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

Estrogens and the intervertebral disc.

Intervertebral discs are an integral part of the vertebral column. It has been shown that menopause has a negative effect on bone and on intervertebral discs. Estrogen has a beneficial effect of preserving the health of collagen-containing tissues, including the intervertebral disc. The intervertebral disc allows for mobility of the spine, and maintains a uniform stress distribution of the area of the vertebral endplates. Also, the disc influences spinal height. The disc tissue is adapted for this biomechanical function. The function of the spine is impaired if there is a loss of disc tissue. Narrowing of the disc space due to degeneration of intervertebral discs is associated with a significantly increased risk of vertebral fractures. Estrogen should be seen as the first-choice therapy for bones and other collagen-rich tissues, such as intervertebral discs, because it maintains homeostasis of the bone-remodelling unit. Unlike bisphosphonates, estrogen is unique in its ability to regenerate bone collagen after its disintegration, apart from suppressing osteoclastic activity. Besides, there is insufficient data on deterioration in bone qualities and micro-cracks in patients on long-term bisphosphonates.

Intervertebral disc height correlates with vertebral body T-scores in premenopausal and postmenopausal women.

OBJECTIVE: To assess the correlation between vertebral body T-score and intervertebral disc height in premenopausal and postmenopausal women. METHODS: A total of 203 women were recruited from a large bone densitometer directory. The disc heights measured were those between the 12th thoracic and third lumbar vertebra. The discs were assigned the symbols D, whereby D1 applies for the disc between the 12th thoracic and first lumbar vertebra. The disc height of the group of women (n=38) with osteoporotic vertebral fractures was compared with the disc heights of hormone-treated women (n=47), untreated postmenopausal women (n=77) and another group of premenopausal women (n=41). Bone density measurements were taken by a Norland Bone Densitometer (DEXA 586). RESULTS: The lowest disc heights were found in the fracture group. The total disc height in the fracture group was 1.42+/-0.25 cm, significantly lower (P<0.0001) than the untreated group (1.82+/-0.3 cm), which in turn was significantly (P<0.0001) lower than the hormone-treated group (2.2+/-0.26 cm) and the premenopausal group (2.11+/-0.21 cm). The lowest T-scores were also noted in the vertebral fracture group (T-score=-3.1+/-0.3) (P<0.0001). The highest T-score recorded for the premenopausal group was -0.38+/-45, higher than that of the untreated menopausal -1.4+/-0.32 and hormone treated women -0.65+/-0.3, all three significantly higher than the fracture group (P<0.0001). The lowest T-scores were also noted in the vertebral fracture group (T-score=-3.1+/-0.3) (P<0.0001). The highest T-score recorded for the premenopausal group was -0.38+/-45, higher than that of the untreated menopausal -1.4+/-0.32 and hormone treated women -0.65+/-0.3, all three significantly higher than the fracture group (P<0.0001). Bone density across all groups revealed a correlation with disc height (R=0.29) (P<0.05). The group with vertebral osteoporotic fractures was the only group to show a negative correlation (-0.21) between disc height and vertebral bone density. Conversely, a significant correlation (R=0.47) (P<0.001) between the T-score and the total lumbar intervertebral disc height was noted in the premenopausal group of women. The menopausal group of untreated women also showed a significant correlation between the T-score and disc height (R=0.25 P<0.05); however, an insignificant positive correlation was found in the hormone-treated group. CONCLUSION: The fracture group was noted to have the lowest intervertebral disc height and lowest T-scores compared with the other three groups. The hormone-treated and the premenopausal women had the highest disc heights and T-scores recorded. Positive correlations between T-score and disc height were noted for all the groups except for the fracture group. These results suggest a coupling between the vertebral body and intervertebral disc, which if disrupted may lead to increased risk for fracture. The combination of both T-score and disc height may improve the screening sensitivity for vertebral body fracture risk.

Urogenital atrophy.

The major cause of urogenital atrophy in menopausal women is estrogen loss. The symptoms are usually progressive in nature and deteriorate with time from the menopausal transition. The most prevalent urogenital symptoms are vaginal dryness, vaginal irritation and itching. The classical changes in an atrophic vulva include loss of labial and vulvar fullness, with narrowing of the introitus and inflamed mucosal surfaces. Dyspareunia and vaginal bleeding from fragile atrophic skin are common problems. Other urogenital complaints include frequency, nocturia, urgency, incontinence and urinary tract infections. Atrophic changes of the vulva, vagina and lower urinary tract can have a large impact on the quality of life of the menopausal woman. However, hormonal and non-hormonal treatments can provide patients with the solution to regain previous level of function. Therefore, clinicians should sensitively question and examine menopausal women, in order to correctly identify the pattern of changes in urogenital atrophy and manage them appropriately.

Preventive effect of oral estetrol in a menopausal hot flush model.

OBJECTIVE: To evaluate the efficacy of estetrol (E(4)) in alleviating hot flushes in an experimental animal model considered representative for menopausal vasomotor symptoms. METHODS: Recording of the thermal responses in the tail skin of morphine-dependent ovariectomized rats after morphine withdrawal by administration of naloxone. Six groups of rats were treated orally for 8 days as follows: vehicle (negative) control; E(4): 0.1, 0.3, 1.0 and 3.0 mg/kg/day; and, as active (positive) control, ethinylestradiol 0.3 mg/kg/day. On day 8, tail skin temperature was recorded at baseline and for 60 min at 5-min intervals following naloxone administration. Results In control animals, tail skin temperature increased sharply by about 4.5 degrees C after naloxone treatment and reverted to baseline by 60 min. Estetrol suppressed the tail skin temperature increase in a dose-dependent fashion. The highest dose of E(4) tested (3 mg/kg/day) was equipotent to a 10-fold lower dose of ethinylestradiol. Both fully suppressed tail skin temperature changes. CONCLUSION: Estetrol is effective in alleviating hot flushes in an experimental animal model considered representative for studying menopausal hot flushes (vasomotor symptoms). In this model, the potency of estetrol is 10-fold lower compared to ethinylestradiol.

The skin, carotid and intervertebral disc: making the connection!

A fairly consistent finding in work on the menopause and hormone replacement therapy is the positive effect of estrogen on connective tissue and its turnover. The menopause has been shown repeatedly to have a negative effect on the connective tissue in the dermis of the skin. Such an effect is prevented and in some cases reversed with estrogen therapy. This is similar to what happens in bone matrix. Similarly, the media in the carotid has been shown to undergo the same change with the menopause and with estrogen therapy as the dermis. The carotid artery media is increased in menopausal women on estrogen therapy and is thinner in untreated women. Recently, new information has revealed that the menopause, i.e. estrogen deprivation, has similar effects on the connective tissue of intervertebral discs. In aged intervertebral discs, the predominant collagen is type III, not type I, which is the predominant collagen in skin and bone, although skin has additional type III. These negative changes are once again prevented or reversed with estrogen therapy. This effect probably also extends to the extracellular non-collagenous matrix in all these systems, i.e. skin, carotid and intervertebral discs. The common thread is that estrogen has profound effects on connective tissue turnover, no matter the site. This has far-reaching implications not only in maintaining the structure and aesthetic appearance of tissue, but also the strength and stiffness of various tissues and the functioning of neighboring and surrounding organs.

Low intervertebral disc height in postmenopausal women with osteoporotic vertebral fractures compared to hormone-treated and untreated postmenopausal women and premenopausal women without fractures.

OBJECTIVE: To assess the intervertebral disc height in postmenopausal women with osteoporotic vertebral fractures. METHODS: A total of 203 women were recruited from a bone densitometer directory. The disc heights measured were those between the 12th thoracic and 3rd lumbar vertebrae. The discs were assigned the symbols D, whereby D(1) refers to the disc between the 12th thoracic and 1st lumbar vertebrae. The disc height of the group of women (n = 38) with osteoporotic vertebral fractures was compared to the disc heights of hormone-treated women (n = 47), untreated postmenopausal women (n = 77) and another group of premenopausal women (n = 41). RESULTS: The total disc height (D(1) - D(3)) (mean +/- standard deviation) in the fracture group was 1.58 +/- 0.1 cm, significantly lower (p < 0.0001) than in the untreated group (1.82 +/- 0.06 cm), which in turn was significantly (p < 0.0001) lower than in the hormone-treated group (2.15 +/- 0.08 cm) and in the premenopausal group (2.01 +/- 0.09 cm). CONCLUSION: The fracture group was noted to have the lowest intervertebral disc height compared to the other three groups. The hormone-treated and the premenopausal women had the highest disc heights recorded. These results may be due to the effect that the menopause and senescence have on the discal connective tissue components. This may lead to loss of the shock-absorbing properties of the intervertebral disc and an altered discoid shape, influencing the occurrence of osteoporotic vertebral body fractures.

Skin ageing.

Cutaneous ageing manifests itself as a progressive reduction in maximum function and reserve capacity of skin tissue. It is not a unique and uniform biological event. Skin comprises three layers: epidermis, dermis and subcutaneous tissue. Collagen atrophy is a major factor in skin ageing. There is a strong correlation between skin collagen loss and estrogen deficiency due to the menopause. Skin ageing, especially in the face, is associated with a progressive increase in extensibility and a reduction in elasticity. With increasing age, the skin also becomes more fragile and susceptible to trauma, leading to more lacerations and bruising. Furthermore, wound healing is impaired in older women. Estrogen use after the menopause increases collagen content, dermal thickness and elasticity, and it decreases the likelihood of senile dry skin. Large-scale clinical trials are necessary to help make informed recommendations regarding postmenopausal estrogen use and its role in the prevention of skin ageing.

Endodontics and infective endocarditis--is antimicrobial chemoprophylaxis required?

The purpose of this review is to evaluate the evidence implicating nonsurgical endodontic procedures in inducing infective endocarditis (IE). The literature is reviewed and findings about dental procedures that elicit bacteraemia [in particular root canal treatment (RCT)], sequelae of bacteraemia, relationship between IE and RCT and variation between antibiotic prophylaxis (AP) guidelines are highlighted. At present, there is still significant debate as to which dental procedures require chemoprophylaxis and what antibiotic regimen should be prescribed. Currently, there are insufficient primary data to know whether AP is effective or ineffective against IE. Practitioners are bound by current guidelines and medico-legal considerations. Thus, the profession requires clear, uniform guidelines that are evidence-based.

TNFRSF11B gene variants and bone mineral density in postmenopausal women in Malta.

UNLABELLED: A number of polymorphisms in various genes have been identified and associated with bone mineral density (BMD) and with an increased risk of osteoporosis. OBJECTIVE: In this study, three single nucleotide polymorphisms (SNPs) within the TNFRSF11B gene were studied for association with an increased risk of osteoporosis in postmenopausal Maltese women (n=126). METHODOLOGY: Analysis was performed by PCR restriction fragment length polymorphism (RFLP) while BMD at the lumbar spine, femoral neck, Ward's triangle and trochanter was measured by DEXA. RESULTS: No significant association was observed between genotypes and BMD for all polymorphisms studied within this gene. Homozygotes CC (T(950)-C) were observed to have the highest BMD at all anatomical sites although statistical significance was not reached when comparing the three genotypes. A statistical significant difference was observed in the distribution of genotype frequencies for this polymorphism between normal individuals and those that were either osteopenic or osteoporotic at one or both anatomical sites, with the TT genotype associated more frequently with low BMD. The T(950)-C and G(1181)-C polymorphisms were in strong linkage disequilibrium with each other but not with the A(163)-G polymorphism further upstream in the OPG promoter. Statistical significance was reached when constructing haplotypes, where the A-T-G haplotype was found to be more frequent in individuals with low BMD. CONCLUSIONS: These results indicate the possible role of TNFRSF11B gene variants in postmenopausal bone loss in women in Malta.

Estrogens and the skin.

OBJECTIVE: A review of the medical literature concerning the effect of the menopause and its hormonal treatment on the skin. METHODS: An extensive Medline and Pubmed internet search utilizing the key words: collagen, elastin, estrogen, hormone replacement therapy, skin and aging. RESULTS: The literature review demonstrated a wide array of research ranging from basic science work to clinical implications of the effects of the menopause and its treatment on the skin. CONCLUSION: Estrogen loss at menopause has a profound influence on skin. Estrogen treatment in postmenopausal women has been repeatedly shown to increase collagen content, dermal thickness and elasticity, and data on the effect of estrogen on skin water content are also promising. Further, physiologic studies on estrogen and wound healing suggest that hormone replacement therapy (HRT) may play a beneficial role in cutaneous injury repair. Results on the effect of HRT on other physiologic characteristics of skin, such as elastin content, sebaceous secretions, wrinkling and blood flow, are discordant. Given the responsiveness of skin to estrogen, the effects of HRT on aging skin require further examination, and careful molecular studies will likely clarify estrogen's effects at the cellular level.

Immunomodulatory activity of cucurbitacin E isolated from Ecballium elaterium.

The immunomodulatory effect of cucurbitacin E, extracted from Ecballium elaterium, was tested on peripheral human lymphocytes. These lymphocytes were co-cultured with cancer cells and an interesting lymphocyte-mediated cytotoxicity was observed.