Mark Brincat

Metformin has direct effects on human ovarian steroidogenesis

OBJECTIVE To investigate the possibility of direct effects of metformin on ovarian steroidogenesis. DESIGN Cultured ovarian cells. SETTING Academic research environment. PATIENT(S) Women undergoing bilateral salpingoophorectomy for benign gynecological disease. MAIN OUTCOME MEASURE(S) Estradiol and P were measured in granulosa cell (GC) conditioned medium and androstenedione (A) and P in theca conditioned medium. RESULT(S) The effect of addition of metformin alone to GCs was variable, but significant inhibition of both P and E2 was seen (range 0%-30%). Metformin dose-dependently inhibited gonadotrophin and insulin-stimulated P and E2 production (range 25%-50%). In theca, metformin inhibited A production (0%-40%) with no effect on P. In the presence of insulin, A was inhibited dose-dependently and P increased by a similar magnitude. CONCLUSION(S) These results demonstrate a direct effect of metformin on ovarian steroidogenesis. The inhibitory effects on androgen production in particular would be beneficial in polycystic ovary syndrome (PCOS).

Skin aging and menopause : implications for treatment.

The skin is one of the largest organs of the body, which is significantly affected by the aging process and menopause. The significant changes sustained by the skin during the menopause are due to the effect sustained on the skin’s individual components.The estrogen receptor has been detected on the cellular components of the skin. Accordingly, dermal cellular metabolism is influenced by the hypoestrogenoemic state of menopause leading to changes in the collagen content, alterations in the concentration of glycoaminoglycans and most importantly the water content. Consequently changes in these basic components leads to an alteration in function compatible with skin aging.Changes in the skin collagen leads to diminished elasticity and skin strength. Collagen content may be measured by various methods such as direct skin biopsy, skin blister assessment for collagen markers and skin thickness measurement. All these variables indicate a reduction in collagen content following menopause. This may be reversed with the administration of estrogen given both topically and systemically.A reduction in hydrophilic glycoaminglycans leads to a direct reduction in water content, which influences the skin turgor. These effects on glycoaminoglycans, due to the hypoestrogenia, have been clearly shown in animal studies and appeared to be rapidly reversed with the application of estrogens. The sum total of these basic effects on the skin leads to wrinkles, the skin condition typifying skin aging.Structures resident in the skin are likewise influenced by menopause. Changes to the cutaneous vascular reactivity are noted following menopause. Capillary blood flow velocity decreases significantly in postmenopausal women. Postmenopausal flushing is due to profound vasodilatation in the dermal papillae. Hair growth is also influenced by the hormonal milieu and consequently hair loss has been associated with the beginning of menopause.Treatments administered for menopause, in particular hormone replacement therapy, appear to alter its effects on the basic components of the skin as well as the more complex structures residing in the skin, consequently retarding the skin aging process.

Urogenital prolapse and atrophy at menopause: a prevalence study.

Abstract: For 285 subjects referred to a menopause clinic data were prospectively collected on the time elapsed since the onset of menopause (menopausal age), sexual activity, dyspareunia, smoking, chronic cough and constipation. Prolapse and atrophy were sought on examination. FSH assay confirmed menopausal status. We found an anterior wall prolapse in 51% of the subjects, of which 6% were protruding beyond the introitus. Posterior wall prolapse was present in 27% and apical prolapse in 20%; none was protruding beyond the introitus. No trend was noted between prolapse and menopausal age. Atrophy was evident in 34% of the women, and this was related to menopausal age (P<0.001). Forty per cent of the sexually active women admitted to dyspareunia, of which 2/3 were superficial. This correlated with advancing menopausal age (P<0.02). In conclusion, genital prolapse was frequent in the population of postmenopausal women, predominantly cystocele, but the prevalence did not correlate with menopausal age.

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 estrogens effects at the cellular level.

Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells

OBJECTIVE To determine that anti-Müllerian hormone (AMH) has been shown to inhibits E(2) production in rodents and in luteinized granulosa cells (GC). We determined whether this occurs in human cells most highly expressing AMH (i.e., from small antral follicles) and whether this is an effect on aromatase promoter activity. We also investigated the effects of AMH on other factors determining FSH sensitivity. DESIGN Granulosa cells were exposed to AMH with and without gonadotropins for 48 hours. SETTING University laboratory. PATIENT(S) Not applicable. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Aromatase and FSH receptor messenger RNA expression measured using real time quantitative polymerase chain reaction (PCR). Aromatase promoter II activity measured using a luciferase assay. Estradiol, inhibin A and B, and vascular endothelial growth factor production were measured in the conditioned medium. RESULT(S) The AMH decreased gonadotropin-stimulated aromatase expression and decreased forskolin-stimulated aromatase in KGN cells and this effect was through a dose-dependent inhibition of promoter II. Surprisingly, AMH also reduced FSH receptor mRNA expression. High AMH doses had no effect on inhibin B, whereas a low dose stimulated production. There was no effect on inhibin A or vascular endothelial growth factor. CONCLUSION(S) The AMH inhibits factors affecting FSH sensitivity. As AMH levels decrease with follicle growth, this inhibition would be removed. The AMH overproduction in anovulatory polycystic ovaries (PCO) may therefore restrict folliculogenesis by an inhibitory effect on FSH sensitivity, thereby contributing to anovulation.

Guidelines for hormone treatment of women in the menopausal transition and beyond

Recent communications regarding estrogen or estrogen + progestin treatment and clinical cardioprotection, breast cancer risk and cerebral aging have produced considerable confusion and concerns among women, care-givers and the media. The actions of the United States’ Food and Drug Administration (FDA) and other National Safety of Medicine Boards, such as the European Medicine Evaluation Agency (EMEA), in response to publication of data from the Women’s Health Initiative (WHI) and the Million Women Study (MWS), have also raised concerns. The Executive Committee of the International Menopause Society (IMS) has considered position statements presented at the Fourth Workshop of the IMS, December 2003 and reviewed all presently available information from observational studies, randomized controlled trials (RCTs) and preclinical research, and wishes to point out the following:

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.

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.

EMAS position statement: Managing the menopause in the context of coronary heart disease

INTRODUCTION Cardiovascular disease (CVD) including coronary heart disease (CHD) and stroke is the most common cause of female death. Premenopausal CHD is very rare but when women enter the menopause the incidence of CHD increases markedly. CHD presents 10 years later in women than in men. The reason is still unclear but the protective effects of estrogens have been suggested. AIMS To formulate a position statement on the management of menopause women in the context of coronary heart disease. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS Based on long term randomized placebo-controlled studies hormone therapy (HT) is not recommended for the primary or secondary prevention of CHD in postmenopausal women. In most countries the only indication for HT is the treatment of menopausal symptoms. Women with known CHD or with many coronary risk factors seeking HT because of troublesome climacteric symptoms should be evaluated for their individual baseline risk of developing breast cancer, venous thromboembolism and CHD recurrence. The same applies to non hormone therapy-based treatments where long term clinical studies are lacking. Risks should be weighed against expected benefit from symptom relief and improved quality of life. The lowest effective estrogen dose should be used during the shortest possible time. Transdermal administration is preferred if risk factors for VTE exist. Different progestogens might differ in their cardiovascular effects. Observational studies suggest that micronized progesterone or dydrogesterone may have a better risk profile than other progestogens with regard to thrombotic risk.

Carotid artery wall thickness in women treated with hormone replacement therapy

OBJECTIVE To measure the thickness of the individual layers (externa, media, intima) of the carotid artery in two groups of postmenopausal women. METHODS A high resolution ultrasound (25-MHz Osteoson DIII Minhorst) was used to assess the distal end of the common carotid artery. Forty-six women were on hormone replacement therapy (Premarin 0.625 mg and Norgestrel 1 mg) for more than 1 year. The measurements of the treated group were compared to those of 51 postmenopausal women who acted as controls. RESULTS No significant difference between the externa and media layers of both groups of women were noted. The media showed a tendency to be thicker in the treated group. The intima of the untreated group was found to be significantly thicker than that of the treated group (P < 0.05). Significant correlations were found between the layers of the carotid artery especially between the externa and media both mainly composed of connective tissue (Collagen Type I and III and elastin). The media/intima ratio of the treated women was significantly higher than that of the untreated group (P< 0.003). CONCLUSION It is postulated that the changes observed may be due to the effect of oestrogen on connective tissue. These arterial changes induced by hormone replacement therapy may partially explain the cardioprotective effect this treatment has on postmenopausal women. The increased intimal thickness in untreated women compared to treated ones on the other hand would represent the reduction in atheromatous plaque formation in women on oestrogen replacement therapy.