Giovanni A. Tommaselli

MATERNAL SERUM AND UMBILICAL CORD BLOOD LEPTIN CONCENTRATIONS WITH FETAL GROWTH RESTRICTION

OBJECTIVE To ascertain whether fetal growth restriction is associated with alterations of leptin concentrations in umbilical cord blood and maternal serum. METHODS Maternal serum and umbilical cord blood leptin concentrations were determined by immunoradiometric assay at term in 43 women with uncomplicated singleton pregnancies (group A) and in 27 women with singleton pregnancies complicated by fetal growth restriction (group B), all with normal pregravid body mass index (BMI). RESULTS Maternal serum leptin concentrations were significantly higher in group B compared with group A (45.0 ng/mL [range 34.2–54.9] versus 29.0 ng/mL [range 24.7–33.3]; P < .01). Umbilical cord blood leptin levels were significantly lower in group B compared with group A (8.4 ng/mL [range 3.6–13.2] versus 13.1 ng/mL [9.7–16.5]; P < .01). Maternal serum leptin levels were not significantly correlated with maternal BMI or with neonatal birth weight in either group. Umbilical cord blood leptin concentrations were significantly correlated with neonatal birth weight in both groups. CONCLUSION Growth restricted fetuses at term show umbilical cord blood leptin concentrations significantly lower than those in normal fetuses, suggesting that fetal adipose tissue is a major source of leptin. Maternal serum leptin concentrations are higher in the presence of a growth restricted fetus. This increase might be due to an intrinsic placental mechanism, by which small placentas produce more leptin as a compensatory mechanism, or to early hypoxia.

Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium

OBJECTIVE To evaluate the expression of vascular endothelial growth factor (VEGF), angiopoietin 1 and 2 (ANGPT1/ANGPT2), and matrix metalloproteinases 1, 2, and 9 (MMP-1, MMP-2, MMP-9) in eutopic and ectopic endometrium. DESIGN Experimental retrospective study. SETTING University hospital. PATIENT(S) Eutopic and ectopic endometrium samples from 30 women with endometriosis and endometrium biopsy samples from 30 healthy women. INTERVENTION(S) Biopsies of ovarian endometriomas and eutopic endometrium. MAIN OUTCOME MEASURE(S) Immunohistochemical staining to evaluate the expression of VEGF, ANGPT1, ANGPT2, MMP-1, MMP-2, and MMP-9, and real-time polymerase chain reaction analysis to quantify mRNA expression. RESULT(S) Patients with endometriosis had higher levels of angiogenic factors and metalloproteinases in endometriotic cysts than in eutopic endometrium. These substances were also overexpressed in eutopic endometrium of patients with endometriosis when compared with normal controls. CONCLUSION(S) Overexpression of angiogenic factors and metalloproteinases may be the characteristic feature of endometrium with greater potential to transform into endometriotic lesions in the peritoneal cavity. Structural and/or functional differences of eutopic endometrium could have a role in the pathogenesis of endometriosis secondary to the backward passage of endometrial cells into the peritoneal cavity. Whether these local factors may induce, promote, and/or regulate this transformation remains to be determined.

Effects of hormone replacement therapy on ocular function in postmenopause.

ObjectiveTo evaluate the effect of hormone replacement therapy on climacteric ocular complaints, lacrimal secretion, intraocular pressure (IOP), and corneal thickness. DesignA prospective, controlled, randomized study on 50 healthy women (mean age 53.4 ± 3.8 years) at least 1 year after spontaneous menopause. Twenty-five women (group A) were treated with transdermal 17&bgr;-estradiol (50 &mgr;g/day) and medroxyprogesterone acetate (10 mg/day) for 12 days per cycle. Twenty-five untreated women (group B) were used as a control group. All participants underwent eye examination at the beginning of the study and after 3 and 6 months of therapy to detect ocular diseases and to measure lachrymal secretion, IOP, and corneal thickness. ResultsNo significant differences were observed between the two groups at the beginning of the study. After 3 and 6 months of treatment, we observed a significant reduction in the percentage of women in group A affected by ocular symptoms and in the severity of symptomatology in comparison with baseline and with group B (P < 0.01). A significant increase of both basal and stimulated lachrymal secretion was observed after 3 months of therapy in group A in comparison with baseline (P < 0.01). There was a significant decrease of IOP (P < 0.01) after 3 months of therapy in group A (P < 0.01), and a slight, nonsignificant increase of corneal thickness was observed in group A at 3 and 6 months in comparison with basal values. ConclusionOur data suggest that hormone replacement therapy may exert a beneficial effect on ocular symptomatology, increase lachrymal secretion, reduce IOP, and increase corneal thickness.

Effects of an oral contraceptive containing drospirenone on bone turnover and bone mineral density.

OBJECTIVE: To compare the effects of a new 21-day combined oral contraceptive containing 30 μg ethinyl/estradiol plus 3 mg drospirenone with a 21-day preparation containing 30 μg ethinyl/estradiol plus 75 μg gestodene on bone turnover and bone mineral density in young fertile women. METHODS: A randomized, controlled trial was conducted with healthy fertile women treated with 30 μg ethinyl/estradiol plus 3 mg drospirenone (group A; n = 24), 30 μg ethinyl/estradiol plus 75 μg gestodene (group B; n = 24) and healthy controls (group C, n = 23). At 3, 6, 9, and 12 months of the study, serum and urinary calcium, osteocalcin, urinary pyridinoline, and deoxypyridinoline were measured. At baseline and after 12 months, lumbar bone mineral density was determined by dual-energy X-ray absorptiometry. RESULTS: In groups A and B, urinary pyridinoline and deoxypyridinoline at 6, 9, and 12 months were significantly reduced in comparison with basal values and group C (P < .05). Pyridinoline and deoxypyridinoline levels were lower in group A than in group B throughout the study, but not significantly. In group A serum calcium levels were significantly increased after 6 months. At 12 months, no significant difference was detected in lumbar bone mineral density values among the 3 groups and in comparison with basal values. CONCLUSION: Both combined oral contraceptives exert a similar positive influence on bone turnover and bone-sparing effect in young postadolescent women. LEVEL OF EVIDENCE: II-1

Hormonal contraception and bone metabolism: a systematic review

BACKGROUND Although a large amount of studies in the literature evaluated the effects of hormonal contraception on bone, many questions remained still unclear, such as the effect of these therapies on fracture risk. STUDY DESIGN We performed a systematic search of the published studies from January 1975 through January 2012 on the effects of hormonal contraceptives on bone metabolism. We analyzed the overall effect on bone mineral density (BMD) and on fracture risk of combined oral contraceptives (COCs), progestogen-only contraceptives, transdermal contraceptives and vaginal ring. RESULTS COC therapy does not seem to exert any significant effect on BMD in the general population. In adolescents, the effects of COCs on BMD seem to be mainly determined by estrogen dose. The use of COCs in perimenopausal women seems to reduce bone demineralization and may significantly increase BMD even at a 20-mcg dose. Use of depot medroxyprogesterone acetate is associated with a decrease in BMD, although this decrease seems to be partially reversible after discontinuation. Data on other progestogen-only contraceptives, transdermal patch and vaginal ring are still limited, although it seems that these contraceptive methods do not exert any influence on BMD. CONCLUSIONS Hormonal contraceptives do not seem to exert any significant effect on bone in the general population. However, other randomized controlled trials are needed to evaluate the effects on fracture risk since the data available are derived from studies having the effects on BMD as the primary end point, and BMD may not accurately reflect the real fracture risk.

Use of leuprolide acetate plus tibolone in the treatment of severe premenstrual syndrome

OBJECTIVE To evaluate the effectiveness of GnRH agonist (GnRH-a) plus tibolone in the treatment of severe premenstrual syndrome (PMS). DESIGN Prospective, double-blind, placebo-controlled clinical trial. SETTING Department of Obstetrics and Gynecology, University of Naples Federico II, Naples, Italy. PATIENT(S); Thirty patients affected by severe PMS, aged 23-29 years (mean age +/- SD, 25.3 +/- 2.9 years). INTERVENTION(S) Treatment for two cycles with leuprolide acetate depot (3.75 mg IM for 28 days) in association with tibolone (2.5 mg/d orally) or placebo (1 tablet per day orally). MAIN OUTCOME MEASURE(S) The mean severity of each symptom and sign of PMS was evaluated using a visual analog scale during the last 7 days of each treatment cycle in comparison with the last 7 days of the cycle before treatment. RESULT(S) Mean scores for each of the adverse psychological/physical and positive psychological symptoms were significantly improved during treatment. No statistically significant difference was detected between patients treated with tibolone and placebo. A significantly lower number of hot flushes per day was observed in groups treated with GnRH-a and tibolone in comparison with GnRH-a and placebo. CONCLUSION(S) Tibolone administered in association with GnRH-a does not reduce the therapeutic effect of GnRH-a in women affected by PMS. Tibolone used in association with GnRH-a may provide long-term medical treatment for women with PMS.

Serum leptin levels in postmenopausal women: effects of transdermal hormone replacement therapy.

Objective: To evaluate serum leptin levels in postmenopausal women who are receiving hormone replacement therapy (HRT) and postmenopausal women who are not receiving HRT with similar body mass index (BMI) to determine whether estrogens exert effects on leptin secretion. Design: Cross‐sectional, prospective study comparing serum leptin levels in premenopausal women, postmenopausal women who were not receiving HRT (group A), and postmenopausal women who were receiving HRT (group B). Results: Serum leptin levels were significantly higher in group A in comparison to group B and control women (15.82 ± 6.6 ng/ml, 8.14 ± 4.17 ng/ml, and 10.12 ± 5.48 ng/ml, respectively; p < 0.05). Total fat mass (FM) was found to be significantly higher in untreated postmenopausal women in comparison to the other two groups (22.66 ± 2.79 kg vs. 19.14 ± 3.39 kg vs. 18.98 ± 3.82 kg; p < 0.05). No significant difference was observed in weight, height, BMI, blood pressure, or glucose levels among the three groups. A linear correlation between BMI and serum leptin levels as well as between total FM and serum leptin levels was observed in all groups. No correlation was found between serum leptin levels and months from menopause and months of HRT. Conclusions: Our results show that serum leptin is increased in untreated postmenopausal women, possibly as a consequence of the increase in FM, and that HRT reduces serum leptin levels to premenopausal values. These data need further investigation by a broader longitudinal study. (Menopause 2000;7:36‐41.

Effects of sex steroid hormones and menopause on serum leptin concentrations

Leptin is a protein secreted by adipocytes; its circulating levels are correlated to fat mass and it acts on the hypothalamic centers regulating body weight. Leptin may also play an important role in regulating reproductive function. Indeed, ob/ob mice, lacking leptin due to a genetic mutation, are obese and infertile; administration of recombinant leptin to these animals reduces body weight and restores fertility. A sexual dimorphism in serum leptin levels has also been observed, with higher concentrations in women. Studies in vitro seem to indicate that estrogens stimulate leptin secretion, while in vivo studies are extremely discordant. In humans, several studies showed increased, unmodified and decreased leptin levels after the menopause. Furthermore, hormonal replacement therapy (HRT) after the menopause was reported to result in unmodified, increased or decreased leptin levels. It is likely that the effects of postmenopausal hypoestrogenism on leptin levels are masked by the postmenopausal changes in body composition. Indeed, after menopause, there is an increase in body weight, body mass index (BMI) and fat mass with a centralization of fat distribution. Administration of HRT may stop these changes and even restore a premenopausal pattern, leading then to decreased leptin levels.

Menstrual status and serum leptin levels in anorectic and in menstruating women with low body mass indexes.

OBJECTIVE To evaluate serum leptin levels in anorectic women, menstruating women with low body mass indexes (BMI) and normally menstruating women with normal BMI. DESIGN Prospective study. SETTING University clinics. PATIENT(S) Fourteen amenorrheic patients with anorexia nervosa (group A), 11 menstruating women with a BMI <18 kg/m(2) (group B), and 20 normal controls. MAIN OUTCOME MEASURE(S) Determination of BMI, caloric intake, total fat mass, ovarian volume, and serum leptin, insulin-like growth factor I, FSH, LH, E(2), PRL, and TSH levels. INTERVENTION(S) None. RESULT(S) Mean BMI and fat mass were similar in groups A and B and significantly higher in controls. Mean caloric intake was significantly lower in group A than in group B and controls. Median serum leptin levels were significantly lower in group A than in group B and controls, and significantly lower in group B than in controls. Median serum insulin-like growth factor I levels were significantly lower in group A than in group B and controls. Binary segmentation analysis of groups A and B showed that LH was the most relevant variable in differentiating the two groups, followed by leptin. CONCLUSION(S) A threshold of leptin levels exist above which, even in the presence of low body mass indexes, the menstrual function is preserved.

Effects of estrogen-progestin therapy on serum levels of RANKL, osteoprotegerin, osteocalcin, leptin, and ghrelin in postmenopausal women.

Objective: The aim of this study was to evaluate the effects of estrogen-progestin therapy on serum levels of receptor-activating nuclear factor &kgr;&bgr; ligand (RANKL), osteoprotegerin, osteocalcin, leptin, and ghrelin in a cross-sectional study of 99 healthy postmenopausal women conducted at the Menopause Clinic of our department. Design: In this cross-sectional, observational study, 99 participants were divided into two groups. Group A was composed of 77 postmenopausal women who had never received estrogen-progestin therapy, and group B was composed of 22 postmenopausal women who had received transdermal 17&bgr;-estradiol at a dose of 50 &mgr;g/day in a continuous regimen for at least 24 months and nomegestrol at a dose of 5 mg/day for 12 days/month in a sequential regimen. All participants underwent blood sampling in the morning and quantitative ultrasound bone-densitometry measurement of the proximal phalanges of the dominant hand. Results: T score and amplitude-dependent speed of sound were significantly higher in group B than in group A. No significant differences in RANKL, osteoprotegerin, and osteocalcin were observed between the two groups. Serum leptin levels were significantly lower in group B than in group A, whereas ghrelin was significantly higher in group B than in group A. Conclusions: The data gathered in this preliminary study indicate that estrogen-progestin therapy may protect against postmenopausal bone loss, but this protective effect does not seem to be exerted through action on the RANK-RANKL-osteoprotegerin system. Similarly, although several reports suggest that leptin and ghrelin are involved in bone metabolism, we could not detect any important correlation of these two hormones with bone metabolism or bone status in treated and untreated postmenopausal women. Because of the limited number of treated participants and the study design, the results of this preliminary study must be confirmed in larger, prospective, longitudinal studies.