Gynecol Endocrinol 2008, 24: 562-570

P Villa, F Sagnella, C Perri, R Suriano, B Costantini, F Macrì, L Ricciardi, A Lanzone

Low- and standard-estrogen dosage in oral therapy: dose-dependent effects on insulin and lipid metabolism in healthy postmenopausal women

Climateric 2008, 11: 498-508

To evaluate the influences of different doses of daily oral unopposed 17ß-estradiol compared with placebo, both on glucose tolerance and lipid metabolism in healthy postmenopausal women.

The low-dose estradiol treatment determined an improvement of the peripheral insulin sensitivity, made evident by a significant increase both in the metabolic index and oral glucose insulin sensitivity index (p < 0.01 and p < 0.05, respectively) as well as a decrease in the homeostasis model assessment-estimated insulin resistance (p < 0.01). Conversely, in the standard-dose group, the metabolic index significantly decreased (p < 0.05), showing a slight deterioration in insulin sensitivity. For lipid metabolism, the 1 mg dose showed a neutral effect, while 2 mg had a beneficial effect on low density lipoprotein cholesterol, but caused an increase in triglycerides (p < 0.01 and p < 0.05, respectively).

The oral low dose of unopposed estradiol therapy had a favorable effect on glycoinsulinemic metabolism in healthy postmenopausal women; however, the standard dose caused a slight but significant deterioration in insulin sensitivity.

VR Mesch, NO Siseles, PN Maidana, LE Boero, F Sayegh, M Prada, M Royer, L Schreier, HJ Benencia, GA Berg

Androgens in relationship to cardiovascular risk factors in the menopausal transition

Climateric 2008, 11: 509-517

To establish the relationship between androgens and cardiovascular disease (CVD) risk factors in the menopausal transition.

A total of 124 women were divided into four groups: 29 premenopausal (PreM), 35 women in the menopausal transition still menstruating (MTM), 29 women in the menopausal transition with 3-6 months amenorrhea (MTA), and 31 postmenopausal women (PostM). Levels of triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, glucose and insulin were assayed in all samples and waist circumference was measured. In a subgroup of 83 women (19 PreM, 21 MTM, 28 MTA and 15 PostM), levels of total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and estradiol were determined. The free androgen index, Homeostasis Model Assessment (HOMA) index, Quantitative Insulin Sensitivity Check Index (QUICKI) and McAuley index, estradiol/total testosterone and triglyceride/HDL cholesterol ratios were calculated.

Androstenedione was higher in MTA vs. PostM women (p < 0.05); DHEAS was higher in PreM women vs. the other three groups (p < 0.05). Sex hormone binding globulin (SHBG) in MTM women was higher than in MTA women (p < 0.05); the free androgen index was lower in MTM women than in MTA and PostM women. SHBG and the free androgen index showed negative and positive correlations, respectively with waist circumference, insulin resistance and lipids. In a multiple regression analysis, considering waist circumference, neither free androgen index nor SHBG showed significant differences between groups. The waist circumference correlated only with SHBG (p = 0.022) and correlations between SHBG and insulin resistance markers continued to be significant, but relationships between SHBG and lipoproteins and all correlations found with free androgen index were lost.

A Tinelli, D Vergara, R Martignago, G Leo, A Malvasi, R Tinelli

Hormonal carcinogenesis and socio-biological development factors in endometrial cancer: A clinical review

Acta Obstet Gynecol Scand 2008, 11: 1101-1113

An extensive literature review, from 1990 to 2007 was performed on modifiable risk factors for type I endometrial cancer. Additionally, carcinogenesis mechanisms, biomarker and hormonal and biomolecular approaches to cancer detection, progression and monitoring and socio-biological factors were reviewed.

Several socio-biological and lifestyle characteristics, such as hormone replacement therapy, glycemic index, obesity, alcohol use, antipsychotic medication, melatonin, physical activity and variants in hormone metabolism genes have been identified as risk factors for developing endometrial cancer of type I, the majority of which are associated with excess estrogens causing continued stimulation of the endometrium. There is a genetic link to non-polyposis colorectal cancer syndrome, but association of endometrial cancer risk to other genetic polymorphisms has yielded conflicting results.

Many factors linked to hormonal imbalance, such as obesity, weight change, body size, alcohol, hyper-androgenic states, glycemic index and antidepressant agents, influence the endometrial cancer risk, central to which are endogenous and exogenous estrogen hyperstimulation of the endometrium. Conversely, smoking cigarettes, diet, physical activity and melatonin production seem to reduce the risk of cancer development. Other external factors fit well with the unopposed estrogen theory, but more studies are needed to investigate modifiable and added risk factors for endometrial cancer.

M Wiksten-Almstr mer, A L Hirschberg, K Hagenfeldt

Prospective follow-up of menstrual disorders in adolescence and prognostic factors

Acta Obstet Gynecol Scand 2008, 11: 1162-1168

Clinical follow-up of menstrual status and eating behavior in grown-up women diagnosed with menstrual disturbance in adolescence. Design. Prospective follow-up study six years after the initial study. Setting. A youth clinic that is part of the school health system in Stockholm.

Eighty-seven women diagnosed with secondary amenorrhea or oligomenorrhea in adolescence.

Menstrual disturbances were still present in 62% of the subjects not using hormonal contraception, 59% of which fulfilled the criteria for polycystic ovary syndrome (PCOS). The frequency of persistent menstrual disturbance was significantly more common in women with previous oligomenorrhea than secondary amenorrhea. The occurrence of eating disorders was decreased by half to 31% in women diagnosed with secondary amenorrhea at the initial study, whereas it was unchanged (40%) in women with previous oligomenorrhea. Recovery from anorectic behavior, primarily in the group of secondary amenorrhea, significantly predicted resumption with menses.

Menstrual disturbances and eating disorders were still frequent after six years in a follow-up of women who had menstrual disturbance in adolescence. PCOS was the main cause explaining persistent menstrual disorder, whereas recovery of anorectic eating disorders predicted resumption of menses. The findings call for a continued follow-up of women diagnosed with menstrual disturbance in their teens.

M Prentki, SR Murthy Madiraju

Glycerolipid Metabolism and Signaling in Health and Disease

Endocrine Reviews 2008, 6: 647-676

Maintenance of body temperature is achieved partly by modulating lipolysis by a network of complex regulatory mechanisms. Lipolysis is an integral part of the glycerolipid/free fatty acid (GL/FFA) cycle, which is the focus of this review, and we discuss the significance of this pathway in the regulation of many physiological processes besides thermogenesis.GL/FFA cycle is referred to as a “futile” cycle because it involves continuous formation and hydrolysis of GL with the release of heat, at the expense of ATP. However, we present evidence underscoring the “vital” cellular signaling roles of the GL/FFA cycle for many biological processes. Probably because of its importance in many cellular functions, GL/FFA cycling is under stringent control and is organized as several composite short substrate/product cycles where forward and backward reactions are catalyzed by separate enzymes. We believe that the renaissance of the GL/FFA cycle is timely, considering the emerging view that many of the neutral lipids are in fact key signaling molecules whose production is closely linked to GL/FFA cycling processes.The evidence supporting the view that alterations in GL/FFA cycling are involved in the pathogenesis of “fatal” conditions such as obesity, type 2 diabetes, and cancer is discussed. We also review the different enzymatic and transport steps that encompass the GL/FFA cycle leading to the generation of several metabolic signals possibly implicated in the regulation of biological processes ranging from energy homeostasis, insulin secretion and appetite control to aging and longevity. Finally, we present a perspective of the possible therapeutic implications of targeting this cycling.

GD Braunstein, BD Johnson, FZ Stanczyk, V Bittner, SL Berga, L Shaw, TK Hodgson, M Paul-Labrador, R Azziz, CN Bairey Merz

Relations between Endogenous Androgens and Estrogens in Postmenopausal Women with Suspected Ischemic Heart Disease

J Clin Endocrinol Metab 2008: 93: 4268– 4275

The objective of the studywasto examine the interrelationshipsamongtestosterone (T), androstenedione, estradiol (E2), estrone, and SHBG in postmenopausal women.

The study was conducted at four academic medical centers.

A total of 284 postmenopausal women with chest pain symptoms or suspected myocardial ischemia.

Post hoc analysis of the relationships among sex steroid hormones with insulin resistance, body mass index (BMI), and presence or absence of coronary artery disease as determined by coronary angiography.

Serum levels of androgens and estrogens track closely in postmenopausal women referred for coronary angiography for suspected myocardial ischemia. Epidemiological studies that relate sex steroid hormones to physiological or pathological processes need to control for the independent effect of both estrogens and androgens.

The Impact of Metformin, Oral Contraceptives, and Lifestyle Modification on Polycystic Ovary Syndrome in Obese Adolescent Women in Two Randomized, Placebo-Controlled Clinical Trials

J Clin Endocrinol Metab 2008, 93: 4299– 4306

Polycystic ovary syndrome (PCOS) presents in adolescence, and obesity is a common
finding. The benefits and risks of alternate approaches to the management of PCOS in obese
adolescent women are not clear.

We investigated the effects of metformin, oral contraceptives (OCs), and/or lifestyle modification in obese adolescent women with PCOS.

Two small, randomized, placebo-controlled clinical trials were performed.

A total of 79 obese adolescent women with PCOS participated.

In the single treatment trial, subjects were randomized to metformin, placebo, a
lifestyle modification program, or OC. In the combined treatment trial, all subjects received lifestyle modification and OC and were randomized to metformin or placebo.

Lifestyle modification alone resulted in a 59% reduction in free androgen index with a
122% increase in SHBG. OC resulted in a significant decrease in total testosterone (44%) and free androgen index (86%) but also resulted in an increase in C-reactive protein (39.7%) and cholesterol (14%). The combination of lifestyle modification, OC, and metformin resulted in a 55% decrease in total testosterone, as compared to 33% with combined treatment and placebo, a 4% reduction in waist circumference, and a significant increase in HDL (46%).

P Wiklund, F Toss, L Weinehall, G Hallmans, P W. Franks, A Nordstrom, P Nordstrom

Abdominal and Gynoid Fat Mass Are Associated with Cardiovascular Risk Factors in Men and Women

Abdominal obesity is an established risk factor for cardiovascular disease (CVD). However, the correlation of dual-energy x-ray absorptiometry (DEXA) measurements of regional fat mass with CVD risk factors has not been completely investigated.

The aim of this study was to investigate the association of estimated regional fat mass, measured with DEXA and CVD risk factors.

This was a cross-sectional study of 175 men and 417 women. DEXA measurements of regional fat mass were performed on all subjects, who subsequently participated in a community intervention program.

Outcome measures included impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, and hypertension.

We began by assessing the associations of the adipose measures with the cardiovascular outcomes. After adjustment for confounders, a SD unit increase in abdominal fat mass was the strongest predictor of most cardiovascular variables in men [odds ratio (OR) = 2.63–3.37; P<0.05], whereas the ratio of abdominal to gynoid fat mass was the strongest predictor in women (OR = 1.48–2.19; P < 0.05). Gynoid fat mass was positively associated with impaired glucose tolerance, hypertriglyceridemia, and hypertension in men (OR = 2.07–2.15; P < 0.05), whereas the ratio of gynoid to total fat mass showed a negative association with hypertriglyceridemia and hypertension (OR = 0.42–0.62; P < 0.005).

Abdominal fat mass is strongly independently associated with CVD risk factors in the present study. In contrast, gynoid fat mass was positively associated, whereas the ratio of gynoid to total fat mass was negatively associated with risk factors for CVD.

M L’Hermite, T Simoncini, S Fuller, AR Genazzani

Could transdermal estradiol+progesterone be a safer postmenopausal HRT? A review

Maturitas 2008, 60: 185-201

Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. The different types of HRT offer to many extent comparable efficacies on symptoms control; however, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. This paper reviews the role of the non-oral route of administration of sex steroids in the clinical management of postmenopausalwomen.Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens. In addition, recent indications suggest potential advantages for blood pressure control with non-oral estrogens. To the same extent, a growing literature suggests that the progestins used in association with estrogens may not be equivalent. Recent evidence indeed shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for some synthetic progestins. Compelling indications also exist that differences might also be present for the risk of developing breast cancer, with recent trials indicating that the association of natural progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins. In conclusion, while all types of hormone replacement therapies are safe and effective and confer significant benefits in the long-term when initiated in young postmenopausalwomen, in specific clinical settings the choice of the transdermal route of administration of estrogens and the use of natural progesterone might offer significant benefits and added safety.

Maturitas 2008, 60: 230-234

To analyze the effect of estrogen on the cognitive function of postmenopausal women through psychometric tests.

Seventy-four postmenopausal women were divided into two groups: (G1) estrogen group (n = 34), treated with 2mg 17 beta-estradiol; (G2) placebo group (n = 31), treated with inactive substance. All the participants were submitted, before and after treatment, to psychometric tests, Greene’s Scale of Climacteric Symptoms and the Hamilton Scale for depression. Statistical analysis was performed using the Mann–Whitney test and Student’s t-test. In order to evaluate the degree of improvement of symptoms or depression after estrogen treatment, Spearman’s correlation coefficient was calculated.

A few psychometric tests (immediate and late recall of story, Trailmaking A and B, FAS, Stroop, Bells tests) showed post-intervention improvement, but these were not significant when compared to the placebo group’s data. The estrogen group’s climacteric symptoms were mitigated in comparison to placebo’s, but there was no significant difference between the two groups on the Hamilton Scale. Reduction in climacteric symptoms was associated with improvement in executive function performance as evaluated by the Stroop test.

Our results suggest estrogen improves the cognitive function, possibly due to a decrease in vasomotor symptoms.

Fertil Steril_ 2008, 90:1559–1570

To review the malignant potential of endometriosis based on epidemiologic, histopathologic, and molecular data.

The pathogenesis of endometriosis remains unclear. The histopathologic development of endometriosis has undergone long-term investigation. Studies have confirmed histologic transition from benign endometriosis to ovarian malignancy, including malignant transformation of extraovarian endometriosis. The prevalence of endometriosis in patients with epithelial ovarian cancer, especially in endometrioid and clear cell types, has been confirmed to
be higher than in the general population. Ovarian cancers and adjacent endometriotic lesions have shown common genetic alterations, such as PTEN, p53, and bcl gene mutations, suggesting a possible malignant genetic transition spectrum. Furthermore, endometriosis has been associated with a chronic inflammatory state leading to cytokine release. These cytokines act in a complex system in which they induce or repress their own synthesis and can cause
unregulated mitotic division, growth and differentiation, and migration or apoptosis similar tomalignant mechanisms.

The malignant potential of endometriosis holds serious implications for management, such as the need for earlier and more meticulous surgical intervention for complete disease treatment.

CLIMACTERIC 2008;11:181–191

A MEDLINE search was performed, with a priority for well-designed studies (randomized, controlled trials, meta-analysis), for published data related to the efficacy and safety of testosterone therapy in postmenopausal women.

Randomized trials have demonstrated an improvement in sexual function with testosterone in postmenopausal women with hypoactive sexual desire disorder, particularly after oophorectomies. Side-effects have been well tolerated and reversible upon discontinuation.

Exogenous testosterone treatment provides a rational therapeutic alternative to consider in women whose hypoactive sexual desire disorder negatively affects their quality of life and who have no biologic or psychosocial causes not related to decreased androgen levels for their sexual disorder. Women receiving testosterone should be monitored for clinical improvement and for adverse reactions. Transdermal patches and topical gels avoid the hepatic first-pass metabolism and are the preferred formulations. Testosterone therapy is usually administered concomitantly with estrogen therapy due to a lack of adequate safety and efficacy data on testosterone alone.

M Caprio, MC Zennaro, B Feve, C Mammi, A Fabbri, G Rosano

Potential role of progestogens in the control of adipose tissue and salt sensitivity via interaction with the mineralocorticoid receptor

CLIMACTERIC 2008;11:258–264

Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome.
Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects.
Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders.

D Rachon, H Teede

Postmenopausal hormone therapy and the risk of venous thromboembolism

CLIMACTERIC 2008;11:273–279

Venous thromboembolism (VTE) is an important determinant of the benefit-to-risk profile of postmenopausal hormone replacement therapy (HRT). Women’s health practitioners who prescribe HRT to their patients are often more concerned about the thromboembolic complications than the risk of breast malignancy. This is in contrast to their patients who are eligible and considering commencing hormonal treatment where breast cancer is often the primary concern. This review summarizes the data on the actual HRT-related VTE risk and factors influencing it. It also provides practical guidelines which should support the health professional in ensuring informed choice on HRT for women.

C Antoine, J Vandromme, M Fastrez, B Carly, F Liebens and S Rozenberg

A survey among breast cancer survivors: treatment of the climacteric after breast cancer

CLIMACTERIC 2008;11:322–328

A questionnaire assessing quality of life was sent to 325 breast cancer patients. A 66% valid response rate was obtained. Among these responses, 169 women were postmenopausal. The following results concern these patients only.

Forty-five women were using some treatment to alleviate certain menopausal symptoms (26.6%). More than half of the patients used no therapy to alleviate menopausal symptoms, either because they had no symptoms (n¼43; 25.4%), they feared breast cancer recurrence (n¼24; 14.2%), they were advised not to use a treatment (n¼27; 16%), it had been shown to be inefficient (n¼5; 3%), or because of contraindication (n¼3; 1.8%). In this survey, 62.3% of postmenopausal women affected by breast cancer suffered from hot flushes (n¼94), of which half were severe (n¼46). Among women suffering from hot flushes, a third used various products to alleviate their symptoms (n¼30). Younger women suffered more often from vasomotor symptoms than did older women (p50.000). Current users of aromatase inhibitors suffered more from sexual disorders than did non-users (p50.001). They had more
often an unsatisfactory sexual life (p50.01), more vaginal dryness (p¼0.01) and a decreased libido (p50.02) compared to non-users.

More than 50% of postmenopausal women suffered from climacteric symptoms such as hot flushes, but few were taking a treatment to alleviate these symptoms.

S Franks, LJ Webber, M Goh, A Valentine, DM. White, GS. Conway, S Wiltshire, MI McCarthy

Ovarian Morphology Is a Marker of Heritable Biochemical Traits in Sisters with Polycystic Ovaries

J Clin Endocrinol Metab 93: 3396–3402, 2008

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of uncertain etiology but with strong evidence for a genetic contribution.

The objective of the study was to test the hypothesis that the typical polycystic ovarian morphology is a marker of inherited biochemical features in families of women with PCOS.

Patients included 125 probands and 214 sisters. All probands had PCOS, defined by symptoms of anovulation and/or hyperandrogenism with polycystic ovaries on ultrasound. Affected sisters were defined by polycystic ovaries, regardless of symptoms, and unaffected sisters defined by normal ovarian morphology.

This was a clinic-based study.

Clinical, endocrine, and metabolic features in the various groups were compared, and estimates of broad-sense heritability were obtained using the quantitative transmission disequilibrium test.

Although affected sisters had fewer symptoms than probands (30% had no symptoms of PCOS), serum testosterone, androstenedione, LH, and fasting insulin and insulin sensitivity were similar in thetwogroups with polycystic ovaries but significantly different from those in unaffected sisters or controls.We observed moderateto high heritabilities for all traits studied in affected sister pairs, whereas heritabilities calculated from discordant siblings were substantially lower.

These data provide further evidence for a genetic basis of PCOS. The high heritability of biochemical features in probands and affected sisters, despite wide variation in symptoms, shows that not only are these biochemical traits strongly influenced by genetic factors but also, importantly, that polycystic ovarian morphology is an index of inherited traits in families with PCOS.

MR Sowers, AD Eyvazzadeh, D McConnell, M Yosef, ML. Jannausch, D Zhang, S Harlow, JF Randolph, Jr.

Anti-Mullerian Hormone and Inhibin B in the Definition of Ovarian Aging and the Menopause Transition

J Clin Endocrinol Metab 93: 3478–3483, 2008

The objective of the study was to determine whether anti-Mullerian hormone (AMH) and inhibin B are viable endocrine biomarkers for framing the menopause transition from initiation to the final menstrual period (FMP).

We assayed AMH, inhibin B, and FSH in 300 archival follicular phase specimens from 50 women with six consecutive annual visits commencing in 1993 when all women were in the preand perimenopausal menopause stages. Subsequently each woman had a documented FMP. The assay results were fitted as individual-woman profiles and then related to time to FMP and age at FMP as outcomes.

Based on annual values from six time points prior to the FMP, logAMHlongitudinal profiles declined and were highly associated with a time point 5 yr prior to FMP [including both observed and values below detection (P<0.0001 and P<0.0001, respectively)]. BaselineAMHprofiles were also associated with age atFMP(P<0.035). Models of declining loginhibinBprofiles (including both observed and values below detection) were associated with time toFMP(P<0.0001 and P<0.0003, respectively). There was no significant association of loginhibin B profiles with age at FMP.

AMH, an endocrine marker that reflects the transition of resting primordial follicles to growing follicles, declined to a time point 5 yr prior to the FMP; this may represent a critical biological juncture inthemenopausetransition.Lowandnondetectablelevels inhibinBlevels alsowereobserved 4–5 yr prior to the FMP but were less predictive of time to FMP or age at FMP.

M Misra, DK Katzman, J Cord, SJ Manning, N Mendes, DB. Herzog, KK Miller, A Klibanski

Bone Metabolism in Adolescent Boys with Anorexia Nervosa

J Clin Endocrinol Metab 93: 3029–3036, 2008

We hypothesized that BMD would be low in adolescent boys with AN compared with controls associated with a decrease in bone turnover markers, and that the gonadal steroids, testosterone and estradiol, and levels of IGF-Iandthe appetite regulatory hormones leptin, ghrelin, and peptide YY would predict BMD and bone turnover markers.

Boys with AN had lower BMD and corresponding Z-scores at the spine, hip, femoral neck, trochanter, intertrochanteric region, and whole body, compared with controls. Height-adjusted measures (lumbar bone mineral apparent density and whole body bone mineral content/height) were also lower. Bone formation and resorption markers were reduced in AN, indicating decreased bone turnover. Testosterone and lean mass predicted BMD. IGF-I was an important predictor of bone turnover markers.

AN boys have low BMD at multiple sites associated with decreased bone turnover
markers at a time when bone mass accrual is critical for attainment of peak bone mass.

Update in Female Reproduction: A Life-Cycle Approach

J Clin Endocrinol Metab 93: 2439–2446, 2008

Female reproduction spans a developmental life arc from fetal life and childhood,
through puberty to the reproductive years, and, finally, ovarian follicle depletion and the onset of menopause.

This invited review highlights a selection of reports from leading journals over the past 2 yr that have significantly advanced our understanding of female reproduction from conception to menopause.

During fetal life, in utero exposures may be important determinants of later pubertal and adult endocrine physiology. Epigenetic mechanisms are likely involved in the fetal programming of adult endocrine function. With regards to the polycystic ovary syndrome, recent clinical trials have confirmed the central role of clomiphene for ovulation induction in women with this disease. In addition, an expert panel has recommended that all women with polycystic ovary syndrome have a glucose tolerance test because of the high prevalence of impaired glucose tolerance in this population. In menopausal women the precise impact of estrogen therapy on cardiovascular biology remains to be delineated fully. Evolving data indicate that when initiated near the onset of menopause, estrogen therapy has fewer cardiovascular risks than when it is administered decades after the menopause.

The essence of reproduction is the successful transmission of germ-line DNA to a succeeding generation. Advances in genetics and endocrinology are converging to advance significantly our understanding of the biology of reproduction and our ability to influence reproductive processes. These advances will translate into new treatments for the prevalent medical problems of reproduction.

S Kayemba-Kay’s, MPP Geary, J Pringle, CH Rodeck, JCP Kingdom, PC Hindmarsh

Gender, smoking during pregnancy and gestational age influence cord leptin concentrations in newborn infants

Low birth weight (BW), small head circumference, reduced length, increased preterm births and neuro-endocrine dysfunctions are among known consequences of smoking during pregnancy. Few studies have linked leptin to clinical features of growth restriction associated with maternal smoking and explored interaction with other determinants of size at birth, such as gender.

Cord serum leptin concentrations were measured in 1215 term infants born to Caucasian mothers at completion of uneventful pregnancy. Serum concentrations were related to BW, gestational length, gender and maternal smoking and interaction with other determinants of size at birth evaluated.

Smoking was more frequent in younger (P!0.001) and shorter mothers (P=0.03) from lower socio-economic groups (SEGPs) (P<0.001). Infants born to smokers were lighter (190 g less), shorter and with smaller head circumference. Cord serum leptin concentrations were higher in girls (9.8 S.D. 7.6 ng/ml) than in boys (7.05 S.D. 5.8 ng/ml) (P<0.001). Boys were heavier (BW 3.52 S.D. 0.49 kg) than girls (3.39 S.D. 0.44 kg) (P<0.001), but girls had greater skinfold thickness measurements (subscapular and quadriceps skinfold thicknesses 5.5 S.D. 1.6 mm and 7.6 S.D. 1.9 mm respectively; boys 5.3 S.D. 1.6 vs 7.24G1.90 mm, P!0.001 respectively). Multivariate analyses showed gender (P<0.001), BW SDS (P<0.001), gestational length (P!0.001) and maternal smoking (P<0.042) as factors that influenced umbilical cord serum leptin concentrations in newborns.

Maternal smoking restrains foetal growth through placental vascular effects, and likely also via associated effects on leptin metabolism. More studies are needed to determine the influence that maternal smoking may have on placental syncytiotrophoblast and foetal adipose tissue.

FR Perez-Lopez

Clinical experiences with drospirenone: From reproductive to postmenopausal years

Maturitas 60 (2008) 78–91

To review the scientific publications concerning the clinical use of drospirenone (DRSP) as the progestin in combined oral contraceptives (OCs), and as hormone treatment for menopause.

This is a retrospective study of published information concerning DRSP retrieved from both a PubMed and a personal search.

DRSP is a progestin with antimineralocorticoid and antiandrogenic activities that confer special clinical relevance. The OC containing ethinyl estradiol (either 30 or 20 _g/day) and DRSP (3 mg) has been shown to be highly efficacious and to provide safety equivalent to that of other OC formulations. These OCs appear to improve many of the symptoms associated with premenstrual complaints and dysphoric disorders, including negative mood, water retention and increased appetite. The comparative safety and efficacy of newer OC formulations is difficult to establish since only a few randomized controlled trials have compared newer OCs in a head-to-head manner, and because pregnancy rates with today’s OCs are so low that demonstrating a significant difference in efficacy would require very large sample sizes. The combined daily administration of DRSP and estradiol valerate has been reported to reduce most of the frequent climacteric symptoms and to provide a slight
reduction in blood pressure, preventing fluid retention and hypertension. The unwanted effects related with DRSP are minor and not medically serious. Therefore, the follow-up rate is high in both OC and menopause treatments.

Standardized questionnaires assessing quality-of-life (36-item short-form health survey, SF-36), depressiveness (Beck Depression Inventory), emotional distress (Symptom Check List 90, SCL-90-R), sexual satisfaction and self-worth (visual analogue scales), and a questionnaire on the desire for a child (FKW) were administered at the outpatient endocrine clinic to consecutive PCOS patients.

Questionnaires from 115 PCOS patients were analysed. The majority (76.1%) worried about remaining childless in the future, and 51.3% reported a current wish to conceive. 23.9% of patients had scores indicating mild to moderate depression, and 25.2% had scores indicating clinically relevant depression. Furthermore, all quality-of-life scores were significantly lower compared with normative data (P < 0.001). Unexpectedly, comparisons of patients with a current unfulfilled desire to conceive to those with no present wish for a child revealed no discernable impact on depressive symptoms, quality-of-life or emotional distress. Reduced sexual satisfaction and self-worth were largely determined by partnership status and not infertility. However for PCOS patients who wished to conceive, the wish for a child was a significantly greater priority when compared with normative data from infertile patients.

PCOS represents a major risk factor for psychosocial and emotional problems, but at least in this sample of PCOS patients, infertility does not appear to constitute a primary determinant of psychological problems.

Metformin was reported to improve the alterations of endothelial reactivity in normal-weight subjects with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the mechanisms of action of this drug on the vascular function of this population.

Our data confirm the positive effects of metformin on the altered vascular reactivity, a precocious marker of cardiovascular risk, in normoinsulinemic PCOS subjects. This improvement seems to be mediated through hormonal changes, thus highlighting the detrimental role of hyperandrogenemia on the endothelial function, even beyond the metabolic factors. However, a direct effect of metformin on the endothelium should not be excluded.

Mounting evidence has shown that increased body mass index has a significant adverse effect on pregnancy and miscarriage rates in women seeking to conceive naturally. Several studies have sought to determine the effects of obesity on the endometrium by analyzing outcomes in patients receiving ovum donation.

The aim of the present study was to compare the effect of three different progestins with differing androgenicity on carbohydrate and lipid metabolism in overweight-obese younger postmenopausal women. Additionally, the relationship between testosterone and insulin resistance was assessed.

The study included 125 postmenopausal women. Estradiol (E2) 2 mg/day was given to 20 hysterectomized women and the remaining 105 women were randomized into three treatment groups: E2 2 mg/day plus dienogest 2 mg/day (n=35); E2 2 mg/day plus norethisterone acetate (NETA) 1 mg/day (n=35); E2 2 mg/day plus medroxyprogesterone acetate (MPA) 2.5 mg/day (n=35). A 75-g oral glucose tolerance test was performed at the initial and 3-month visit. Serum glucose, insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides were measured before and after treatment.

A significant treatment-related increase was observed only in the E2/MPA group for insulin resistance (p=0.031). When the change in the insulin/glucose ratio was compared, the E2 group was significantly different from the E2/MPA and E2/NETA groups (p=0.008 and 0.02, respectively). Only the E2/dienogest group showed a treatment-related increase in fasting glucose level (p=0.037). A decrease in total cholesterol and LDL-C levels was observed in all groups (p=0.004 and 0.012, respectively). The only significant decrease in HDL-C level was observed in the E2/NETA group (p=0.005).

Women selected for IVF–ICSI cycles who previously underwent bilateral endometriomas cystectomy were matched (1:2) for age and study period with patients who did not undergo prior ovarian surgery.

Sixty-eight cases and 136 controls were recruited. Women operated on for bilateral endometriotic ovarian cysts had a higher withdrawal rate for poor response (P < 0.001). In these patients, despite the use of higher doses of gonadotrophins, the number of follicles (P = 0.006), oocytes retrieved (P = 0.024) and embryos obtained (P = 0.024) were significantly lower. The clinical pregnancy rate per started cycle in cases and controls was 7% and 19% (P = 0.037) and the delivery rate per started cycle was 4% and 17%, respectively (P = 0.013).

IVF outcome is significantly impaired in women operated on for bilateral ovarian endometriomas.

Low pregnancy rate has been reported in women with congenital adrenal hyperplasia (CAH) and little information on pregnancy and children is known.

In a Swedish study, 62 adult women with CAH, aged 18–63 years, and 62 age-matched controls were followed-up. Medical records, including those concerning pregnancies and deliveries, were examined and the 21-hydroxylase genotype of patients was noted. All women answered a questionnaire concerning sexual and reproductive health including health of the children.

Pregnancy and delivery rates were significantly lower in women with CAH (P < 0.001, P < 0.0056, respectively), and the severity of the 21-hydroxylase-mutation correlated with the reduced number of children born. More women with salt-wasting CAH were single and had not attempted pregnancy. Pregnancies were normal except for a significantly increased incidence of gestational diabetes in CAH patients (P < 0.0024). The children had normal birthweight and no malformations were observed. A later follow-up of the children showed a normal intellectual and social development. The sex ratio of the offspring differed significantly, with 25% boys in the CAH group compared with 56% among controls (P < 0.016). CAH women had more gynaecological morbidity during menopause.

In women with polycystic ovarian syndrome (PCOS), the relationship of insulin to LH secretion and responses to GnRH remains unresolved. A rigorous analytical examination of this relationship has not been performed.

Our objective was to determine the relationship of basal LH secretion and responses to GnRH, insulin, and other endocrine variables in normal and PCOS women.

In PCOS and normal women, mean composite 12-h LH secretion was analyzed for correlating factors. LH responses to varying doses of GnRH during a fixed rate of insulin infusion and LH responses to a fixed dose of GnRH during varying doses of insulin infusion were analyzed for contributing factors.

Eighteen PCOS and 21 normal women underwent studies of frequent blood sampling and GnRH stimulation before and during insulin infusion at theGeneral Clinical Research Center, University of California, San Diego.

Group mean composite 12-h LH levels were assessed with respect to other endocrine variables. In addition, LH responses to GnRH with or without insulin infusion were assessed.

In normal women, insulin negatively predicted mean LH. In PCOS, the combined effect of body mass index (negative) and testosterone (positive) predicted LH. The best predictor of LH was body mass index and insulin combined. Basal LH and LH responses to GnRH were unaltered by insulin infusion in normal women. These measures were reduced during insulin infusion in PCOS women.

In PCOS, insulin infusion suppresses pituitary response to GnRH. In normal women, insulin negatively correlates with mean LH and suppresses GnRH response at a high infusion rate.

Serum antimüllerian hormone (AMH) levels are highly correlated with antral follicle counts, while being menstrual cycle independent and easily measurable. However, AMH, unlike antral follicle counts, has not been tested as yet as a predictor of reproductive status. By relating AMH levels to the age distribution of reproductive events like onset of menopause, we tested this hypothesis.

AMH levels were measured in 144 fertile normal volunteers and used to determine an estimate of mean AMH as a function of age. Data on the onset of menopause were obtained from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition [Prospect-EPIC] cohort. Estimation of an AMH threshold to predict menopause was done by maximum likelihood using the observed (Prospect-EPIC) distribution of age at menopause and the predictive distribution from this AMH threshold. Predictions of age at menopause follow from an individual woman’s AMH relative to percentiles of the distribution of AMH for a given age, and the corresponding percentiles of the predictive distribution of age at menopause.

There was good conformity between the observed distribution of age at menopause and that predicted from declining AMH levels.

The similarity between observed and predictive distributions of age at menopause supports the hypothesis that AMH levels are related to onset of menopause. Results of this study suggest that AMH is able to specify a woman’s reproductive age more realistically than chronological age alone.

To describe neonatal outcome including the presence of congenital malformations in infants born to women substituted with thyroid hormones, and the maternal characteristics of these women. Design. Register study based on prospectively collected data in relation to delivery. Setting. Swedish Health Registers. Population. All pregnant women (n=848,468) and all infants born (n=861,989) in Sweden from 1 July 1995 to 31 December 2004.

Neonatal outcome, malformations and maternal characteristics. Data were analyzed with adjustments for identified confounders.

Women using thyroxine had an increased rate of pre-eclampsia, diabetes (pre-existing or gestational), cesarean sections and inductions of labour compared to women in the reference population. The risk for preterm birth was marginally increased (OR 1.13, 95% CI 1.03-1.25). Neonatal thyroid disease was found in eight infants (seven with thyreotoxicosis and one unspecified), the expected number was 0.2. No further anomalies in neonatal diagnoses were found. A small but statistically significant risk for congenital malformations (OR =1.14, 95% CI 1.05-1.26) was found.

Women on thyroid substitution during pregnancy had an increased risk for some pregnancy complications, but their infants were only slightly affected.

There is growing evidence that hypertensive pregnancy complications and other adverse pregnancy outcomes are associated with the presence of inherited or acquired thrombophilias. As hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is one of the most severe forms of pre-eclampsia we aimed to assess the prevalence of the factor V Leiden, the prothrombin 20210G >A mutation and the methylenetetrahydrofolate reductase (MTHFR) 677C >T polymorphism in women with HELLP syndrome and in their fetuses from the same index pregnancy.

The study was performed retrospectively in a case-control design. Seventy-one mother-child pairs with HELLP syndrome and 79 control mother-child pairs with uncomplicated pregnancies were included in the study.

Genotyping of the three thrombophilic mutations was performed using the LightCycler technology. The chi-squared test was used for statistical analysis. Main outcome measures were maternal and fetal genotypes and their correlation with clinical parameters.

Maternal heterozygosity for factor V Leiden was significantly more prevalent in the HELLP group than in controls (OR 4.45, 95% CI 1.31-15.31). No significant association was observed for maternal prothrombin mutation or MTHFR polymorphism (p=0.894, p=0.189, respectively). The fetal genotype was not associated with HELLP syndrome for any of the three mutations investigated. Analysis of gene-gene interactions and genotype-phenotype correlation with respect to clinical parameters and perinatal outcome revealed no further differences.

Our study confirms that women heterozygous for factor V Leiden have an increased risk of developing HELLP syndrome, while the most frequent mutations of the prothrombin and MTHFR gene do not play a major role in the pathogenesis of HELLP syndrome.

Women with polycystic ovarian syndrome (PCOS) are at increased risk for developing glucose intolerance and type 2 diabetes mellitus (DM). Recommendations for the timing and method of screening have varied. The purpose of this statement is to determine the optimal screening method, timing of screening, and treatment modalities for impaired glucose tolerance (IGT) among women with PCOS.

The expert panel was appointed by the Androgen Excess Society (AES) to review the literature and make recommendations based on the available evidence. Meetings were open, and there was no funding for the panel.

A systematic review was conducted of the published, peerreviewed medical literature using MEDLINE to identify studies that addressed the prevalence, risk factors, testing, and treatment for IGT in both adults and adolescents with PCOS. Unpublished data were not considered.

The panel recommends that all patients with PCOS be screened for IGT with a 2-h oral glucose tolerance test.Afew members of the AES board recommend alternatively screening women with PCOS for IGT and type 2DMusing an oral glucose tolerance test only in patients with a body mass index of 30 kg/m2 or greater or in lean patients with additional risk factors. Patients with normal glucose tolerance should be rescreened at least once every 2 yr, or more frequently if additional risk factors are identified. Those with IGT should be screened annually for development of type 2 DM. PCOS patients with IGT should be treated with intensive lifestyle modification and weight loss and considered for treatment with insulinsensitizing agents.

Polycystic ovary syndrome (PCOS) is associated with comorbidities that may contribute to increased risk of cardiovascular disease. PCOS is associated with increased risk of metabolic syndrome, dyslipidemia, and diabetes, but it remains unclear whether traditional cardiovascular (CV) risk factors can help predict coronary artery disease in this population.

This was a prospective case-control study.

The study was conducted at a university hospital.

Twenty-four obese (body mass index ≥ 30 kg/m2) PCOS subjects and 24 obese controls participated.

Fifty-three prepubertal and 22 pubertal (Tanner stages II–V) daughters of PCOS women (PCOSd) and 32 prepubertal and 17 pubertal daughters of control women (Cd) were studied. In both groups, an oral glucose tolerance test was performed with measurement
of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, sex steroids, and lipids were determined in the fasting sample.

D Vitiello, F Naftolin, HS Taylor

Menopause: Developing a rational treatment plan

Gyn Endocrinol 23: 682-691, 2007

In recent years, growing importance has been afforded to assisting women in coping with the menopausal transition. Menopause is a normal stage of development and a woman’s attitude toward this transition embodies biological, psychological and social influences. An enlarging body of conflicting data concerning menopausal hormone therapy (MHT) demands reassessment of established paradigms of disease prevention and menopausal health. Currently, a woman’s decision to participate in or abstain from menopausal HT is personal. It involves not only consideration of risk stratification of potential harm and benefit, but also involves her expectations and attitudes toward perceived physical and emotional changes associated with this change. Through the use of extensive patient history, quality-of-life questionnaires and powerful biological profiling, we may be able to develop a rational approach to menopausal HT that safely guides our patients through this transition.

Abstract:

Chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic–pituitary–adrenal axis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11b-hydroxysteroid dehydrogenase enzymes. These effects influence vascular function, atherogenesis and vascular remodelling following intravascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury.
The conclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease.

Effects of tibolone and raloxifene on health-related quality of life and sexual function

Maturitas 58: 164–173, 2007

Abstract:

Objectives: Study to compare the effects of tibolone and raloxifene on health-related quality of life, sexuality and vaginal atrophy.
Methods: A double-blind, randomized study was conducted in 308 osteopenic, but otherwise healthy, postmenopausal women (mean age 66 years) who received tibolone 1.25 mg/day or raloxifene 60 mg/day for 2 years. Health-related quality of life was assessed by the women’s health questionnaire (WHQ), sexual function by the McCoy female sexuality questionnaire (MFSQ) and vaginal atrophy by assessing the karyopycnotic index (KI) and vaginal maturation (VM).
Results: At week 104, the tibolone group showed a trend towards an improved health-related quality of life (HRQoL) mean score in eight out of nine WHQ domains. HRQoL scores approximated values for premenopausal women, being pre-defined as “clinically relevant”. The raloxifene group showed a trend to a diminished HRQoL mean score from baseline to week 104. No difference could be assessed between the tibolone and raloxifene group in mean total score and separate domains’ scores of the MFSQ, except for the vaginal lubrication domain (p = 0.037). The increase in KI and VM was statistically significantly greater with tibolone than with raloxifene (for both KI and VM p < 0.0001). Tibolone and raloxifene were equally well tolerated.
Conclusions: In older postmenopausal women, tibolone treatment showed a trend towards an improvement in quality of life and sexuality when compared to raloxifene.

BACKGROUND: We evaluated carotid intima-media thickness (CIMT) as an early marker of atherosclerosis, as well as its main determinants among androgen excess, obesity and insulin resistance, in patients with polycystic ovary syndrome (PCOS).
METHODS: We selected 40 PCOS patients and 20 non-hyperandrogenic women who were similar in terms of age and grade of obesity. Complete clinical, metabolic and hormonal profiles and left common CIMT measurements were obtained.
RESULTS: Patients with PCOS presented with increased mean CIMT values when compared with controls (F = 8.575; P = 0.005), and this was independent of obesity. Five PCOS patients but no controls had increased CIMT values. CIMT correlated directly with serum total and free testosterone, androstenedione and dehydroepiandrosterone-sulfate levels and mean 24-h heart rate (HR), and inversely with the insulin sensitivity index (ISI), but no correlation was observed with the body mass index (BMI). Multiple stepwise linear regression models showed that in PCOS patients, the main determinants of CIMT were serum total testosterone or androstenedione concentrations, with no influence of ISI or the mean 24-h HR.
CONCLUSIONS: Compared with control women, PCOS patients present with an increased CIMT, independent of obesity and related directly to androgen excess; this suggests that hyperandrogenism is associated with atherosclerosis and cardiovascular risk in these women.