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.

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.

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.

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.

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.

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.

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.

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.

Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation.

Polycystic ovary syndrome is the most common cause of anovulatory infertility. Anovulation in polycystic ovary syndrome is characterized by the failure of selection of a dominant follicle with arrest of follicle development at the 5-10 mm stage. In an attempt to elucidate the mechanism of anovulation associated with this disorder we have investigated at what follicle size human granulosa cells from normal and polycystic ovaries respond to LH. Granulosa cells were isolated from individual follicles from unstimulated human ovaries and cultured in vitro in serum-free medium 199 in the presence of LH or FSH. At the end of a 48-h incubation period, estradiol (E2) and progesterone (P) were determined in the granulosa cell-conditioned medium by RIA. In ovulatory subjects (with either normal ovaries or polycystic ovaries), granulosa cells responded to LH once follicles reached 9.5/10 mm. In contrast, granulosa cells from anovulatory women with polycystic ovaries responded to LH in smaller follicles of 4 mm. Granulosa cells from anovulatory women with polycystic ovaries were significantly more responsive to LH than granulosa cells from ovulatory women with normal ovaries or polycystic ovaries (E2, P < 0.0003; P, P < 0.03). The median (and range) fold increase in estradiol and progesterone production in response to LH in granulosa cell cultures from size-matched follicles 8 mm or smaller were E2, 1.0 (0.5-3.9) and P, 1.0 (0.3-2.5) in ovulatory women and E2, 1.4 (0.7-25.4) and P, 1.3 (0.3-7.0) in anovulatory women. Granulosa cells from anovulatory (but not ovulatory) women with polycystic ovaries prematurely respond to LH; this may be important in the mechanism of anovulation in this common endocrinopathy.

How low can you get?

Since the early 1960s the side effects of oral contraceptives have been known to be related to the high doses (50 micro g) of ethinyl estradiol used. Research has focused on reducing the dose of both the estrogen and progestin components to reduce these side effects. While reducing the dose of both components, the contraceptive efficacy has to be maintained so as to retain a satisfactory Pearl index. These requirements appear to have been attained with 24-day regimen of a low-dose pill (15 microg of ethinyl estradiol and 60 microg of gestedone) as one part of an open-label noncomparative multicenter study. This paper reports our unit's results, which indicate that the low-dose pill promises to reduce contraceptive-related side effects, to encourage better compliance, and as corollary, to retain a satisfactory Pearl index.

Carotid artery wall changes in estrogen-treated and -untreated postmenopausal women.

OBJECTIVE: To investigate whether the thickness of the layers of the carotid artery (externa, media, and intima) are affected by menopause and its treatment with hormone replacement therapy (HRT). METHODS: One hundred twenty-nine postmenopausal women were recruited sequentially and classified into three groups. Forty-six were taking oral HRT, 32 had estradiol implants, and 51 had never taken HRT. The three layers of the externa wall of the carotid artery were identified and measured by high-resolution ultrasound. RESULTS: Women with implants had thicker carotid artery wall measurements (0.84 +/- 0.26 mm) than the other groups. The media (0.32 +/- 0.11 mm) was significantly thicker in the implant group. This layer has a high connective tissue component, including collagen type I, collagen type III, and elastin fibers. The intima layer was thinner (0.25 +/- 0.09 mm) in the oral HRT group compared with controls (0.29 +/- 0.1 mm). A statistically significant higher intima-media ratio (1.17 +/- 0.05) was calculated for the control group, compared with both the oral HRT (0.92 +/- 0.04) and implant groups (0.94 +/- 0.03). CONCLUSION: Our findings suggest that HRT given to postmenopausal women influences differentially the layers of the carotid artery. Hormones seem to encourage thickening of the layers with the highest connective tissue component (externa and media) and to delay thickening of the atheromatous intima layer. These effects on the vascular system may be partly responsible for the cardioprotection attributed to HRT.

Amenorrhea and endometrial atrophy with continuous oral estrogen and progestogen therapy in postmenopausal women.

An oral regimen of continuous conjugated equine estrogens (Premarin 0.625 or 1.25 mg daily) and low-dose progestogen (Norethisterone 0.35 to 2.1 mg daily) have been used to treat 95 nonhysterectomized postmenopausal women for up to 2.5 years. This method of hormone replacements was undertaken in an attempt to avoid the withdrawal bleeding and progestogenic side effects associated with conventional cyclical therapy with estrogen and progestogen, while simultaneously protecting the endometrium from estrogenic over-stimulation. With the lower dose of estrogen, amenorrhea was achieved immediately in 30 of 46 patients (65%), and after adjustments to the dose of the progestogen in all ten patients observed for at least one year (maximum 2.5 years). With the higher dose of estrogen, irregular spotting during the first three months resulted in the cessation of treatment by six of the 49 patients (12%), but 23 (47%) women had no bleeding during that time; by 15 months, all 13 patients who had remained in treatment had become amenorrheic (maximum 2.25 years). Endometrial biopsy specimens after six months of combined treatment in 56% of patients revealed atrophic histology regardless of the dose of the estrogen.

A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman.

The skin collagen content, skin thickness, metacarpal index, and forearm bone mineral content in postmenopausal women showed a similar decline of between 1-2% per year after the menopause. All four parameters showed a decline that was significant when compared with the years from the menopause. Significant correlations between all four parameters suggest that a similar pathology causes the decrease in bone mass and skin thickness--a decline in the connective tissue element that is common to both bone and skin.

Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy.

Collagen is a widespread body constituent that is affected by estrogen status in women. Its decrease after menopause can be prevented and/or restored by estrogen treatment. We explored the effect of four different hormonal replacement regimens on total skin collagen content by measuring hydroxyproline in skin biopsy specimens taken from postmenopausal women. All regimens showed increases in skin collagen levels proportionate to the levels at the start of the treatment. Estrogen replacement therapy is shown to be prophylactic in women who have higher skin collagen levels and both prophylactic and therapeutic in women with lower skin collagen levels.

Response of skin thickness and metacarpal index to estradiol therapy in postmenopausal women.

A radiologic method for measuring skin thickness and metacarpal index was used to investigate 41 postmenopausal women treated with estradiol (100-mg) subcutaneous implants (Organon, UK). All the women completed the first six months of the study, and 33 completed one year. Both skin thickness and metacarpal index increased to a statistically significant degree over the one-year period, with most of the increase occurring in the first six months of therapy. Skin thickness showed the largest increases, from a mean of 0.86 mm at the start of the study to 0.97 mm at six months and 1 mm at one year. The metacarpal index increased from a mean of 0.77 at the start of the study to a mean of 0.799 and 0.8 at six months and one year, respectively.

Hormone replacement therapy and the skin.

Estrogens have a profound influence on skin. The hypoestrogenism occurring after the menopause leads to measured deterioration in the skin. Estrogen receptors have been identified in the skin and the concentration of these receptors varies in the different parts of the body. Estrogen improves skin in more than one way, the collagen content and quality is improved, skin thickness is increased, while vascularisation is enhanced. The extracellular matrix responsible for the tone and appearance of the skin is also improved. It is not just the skin that shows an improvement with estrogen therapy but also skin appendages, such as hair. Estrogens have been shown to increase the hair follicle life cycle. Skin aging is not totally estrogen dependent because the ravages of age and the external environment play very important roles. The effects of estrogen on skin need further elucidation and with the emergence of newer techniques it is now possible to study more clearly the changes occurring at the cellular level. Estrogen replacement reverses the deleterious effect of estrogen deprivation on the skin, which is thus yet another organ that benefits from hormone replacement therapy.