C. Di Carlo

Effects of a low-dose and ultra-low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study

In this prospective, controlled, randomized study, we compared the effect of a low-dose 21-day combined oral contraceptive (COC) containing 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GTD) (Group A; n = 19) with an ultra-low-dose 24-day COC containing 15 microg EE and 60 microg GTD (Group B; n = 18) on bone turnover and bone mineral density (BMD) in young, fertile women. Nineteen healthy fertile women were used as untreated controls (Group C). At 3, 6, 9 and 12 months of the study serum osteocalcin (BGP), urinary pyridinoline (PYD) and deoxypyridinoline (D-PYD) were measured in all subjects. At baseline and after 12 months BMD was determined at lumbar spine by dual-energy X-ray absorptiometry in all patients. In both Groups A and B, urinary levels of PYD and D-PYD at 6, 9 and 12 months, were significantly reduced in comparison with basal values and with control subjects (p < 0.05). No significant differences in urinary PYD and D-PYD levels were observed between Groups A and B during the entire period of treatment. At 12 months, no statistically significant difference in spinal BMD values was detected between the three groups and in comparison with basal values. The present study suggests that the two COCs could exert a similar positive effect on bone turnover in young postadolescent women, without any significant and appreciable modification of BMD.

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.

Effects of genistein on the endometrium: ultrasonographic evaluation.

The aim of our study was to evaluate the effects of isoflavones on climacteric-related symptoms and on the endometrium in postmenopausal women ,in a prospective ,open ,randomized ,clinical trial performed at the Menopause Clinic of our Department. Seventy postmenopausal women were randomly assigned to two treatment groups receiving 12 cycles of treatment with genistein (group A) or calcium (group B). In all patients ultrasonographic endometrial thickness and Kupperman Index (KI) were evaluated at baseline and after 6 and 12 cycles of treatment. At baseline no significant difference was detected in endometrial thickness and in KI between groups A and B. After 6 and 12 cycles of treatment ,no significant difference was observed in endometrial thickness between or within groups. Endometrial thickness was lower than 5 mm in all cases before and during treatment except in two cases in group B and in one case in group A after 12 months. At 6 and 12 months ,the KI was significantly (p < 0.05) lower in group A in comparison with baseline values and group B. We conclude that genistein administration reduces climacteric symptoms in postmenopausal women and does not increase endometrial thickness.

Reduced fertility and neuroendocrine dysfunction in women with epilepsy.

A reduction of fertility in women with epilepsy has been reported since 1950 and is confirmed in recent epidemiological studies. This phenomenon has usually been attributed to the increase of medical and socioeconomic problems in these patients or to hyposexuality, which has been consistently observed in epileptic subjects. Recently, a higher occurrence of reproductive endocrine diseases has been reported in epileptic women and proposed as an important cause of reduced fertility. In particular, polycystic ovary syndrome and hypothalamic ovarian failure have been reported in epileptic women with increased frequency compared to the general population. Moreover, an abnormal pattern of luteinizing hormone (LH) pulsatility has been observed in normally cycling, drug-free epileptic women. We suggest that epilepsy may interfere with the functional activity of the gonadotropin releasing hormone (GnRH) pulse generator. It is possible that paroxysmal discharges spreading within the hypothalamus might affect the regularity of the GnRH pulse generator; alternatively, a neurotransmitter dysfunction might at the same time be responsible both for the lowering of the seizure threshold and for the dysfunction of GnRH secretion. The consequent alteration of LH pulsatility might in the long run, under the effect of additional factors, give rise to a clinical reproductive endocrine disorder.

Effects of alendronate on bone loss in pre- and postmenopausal hyperthyroid women treated with methimazole.

High levels of thyroid hormones accelerate bone turnover. The aim of the present study was to evaluate the effects of treatment with alendronate in patients affected by hyperthyroidism and osteoporosis. We studied 40 hyperthyroid patients with bone loss, divided into two groups according to menopausal state. Before treatment and after 6 and 12 months, serum thyroid hormones levels, serum osteocalcin level and bone mineral density were evaluated. In all patients we observed an increase in bone mineral density after treatment with alendronate, and a corresponding decrease in serum osteocalcin level.

Relationship between cerebrospinal fluid β-endorphin and plasma pituitary-gonadal hormone levels in women

Brain β-endorphin (β-EP) plays an important role in regulating the hypothalamus-pituitary-gonadal axis activity. Cerebrospinal fluid (CSF) β-EP levels seem to reflect the central rather than pituitary secretion. With the aim to correlate the changes of plasma estradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone with brain β-EP, CSF levels of β-EP were measured in 15 normally cycling and 15 postmenopausal women. CSF β-EP levels in post-menopausal women were lower than in fertile women. A positive correlation between plasma E2 and CSF β-EP level was found in all women. In fertile women CSF β-EP levels were inversely correlated to plasma gonadotropin levels. These results showed that CSF β-EP levels differ between fertile and postmenopausal women and are correlated with plasma LH and E2, suggesting a strong linkage between central β-EP levels and pituitary-gonadal axis hormones.

Ultrasonographic prediction of the efficacy of GnRH agonist therapy before laparoscopic myomectomy.

STUDY OBJECTIVE To assess ultrasonographic prediction of the efficacy of administration of a gonadotropin-releasing hormone (GnRH) analog before laparoscopic myomectomy. DESIGN Prospective, randomized study of women treated consecutively from September 1994 to July 1996 (Canadian Task Force classification I). SETTING Endogyn Service, Private Endoscopic Associates, Naples, and Department of Gynecologic and Pediatric Sciences, Reggio Calabria University, Catanzaro, Italy. PATIENTS Sixty-seven infertile women with symptomatic uterine myomata, mainly intramural, undergoing laparoscopic myomectomy. INTERVENTIONS Patients were prospectively randomized in two groups. Group A received preoperative administration of two injections of a depot formulation of leuprolide acetate 28 days apart, and group B underwent direct surgery. In each group we studied the number, diameter, and echogenicity of larger fibroids; resistance index of uterine arteries and myoma vessels; operating time; and blood loss. MEASUREMENTS AND MAIN RESULTS The two groups did not significantly differ in baseline ultrasonographic parameters. Both blood loss (p <0.01) and operating time (p <0.05) were significantly lower in group A. However, operating time was significantly longer when the main myoma was markedly hypoechoic. CONCLUSION Our data confirm the therapeutic efficacy of administration of a GnRH analog before laparoscopic myomectomy in reducing blood loss and decreasing operating time in all cases except those with markedly hypoechoic fibroids.

Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease

The clinical effectiveness and safety of vaginal micronized progesterone treatment in mastodynia were evaluated in a double-blind placebo controlled study. Eighty regularly menstruating worn-’ en affected by severe cyclical mastodynia were randomly assigned to two groups of 40 patients. One group was treated for 6 cycles from the 19th to the 25th day of the cycle with 4 g of vaginal cream containing 2.5% natural progesterone. The other group was similarly treated with placebo. The treatment was preceded by a control cycle. All patients reported every day their breast pain on a 100 mm visual linear analogue scale (VAS). The response of breast tenderness and nodularity to treatment was assessed by clinical examination. Vaginal progesterone resulted significantly more efficacious than placebo in reducing mean ratings of breast pain on VAS and mean scores of breast tenderness to touch. Success of treatment, defined as reduction greater than 50% of basal mean score of breast pain on VAS, was achieved in the 64.9% of patients treated with progesterone and in the 22.2% of patients receiving placebo (p<0.01). Conversely, at the end of treatment, the improvement in breast nodularity showed a not statistically significant difference between the two groups. No major side-effects were detected.

Palmitoylethanolamide Prevents Metabolic Alterations and Restores Leptin Sensitivity in Ovariectomized Rats

It has been suggested a role of fatty acid ethanolamides in control of feeding behavior. Among these, palmitoylethanolamide (PEA) has not been directly implicated in appetite regulation and weight gain. The aim of this study was to investigate the effect of PEA on food intake and body weight and the interaction between PEA and hypothalamic leptin signaling in ovariectomized rats. Ovariectomy produced hyperphagia and increased weight gain, making it an useful model of mild obesity. Ovariectomized rats were treated with PEA (30 mg/kg sc) for 5 weeks. Then, blood was collected, and hypothalamus and adipose tissue were removed for histological, cellular, and molecular measurements. We showed that PEA caused a reduction of food intake, body weight, and fat mass. The mechanisms underlying PEA effects involved an improvement in hypothalamic leptin signaling, through a raise in signal transducer and activator of transcription 3 phosphorylation. We also reported that PEA reduced AMP-activated protein kinase-α phosphorylation and modulated transcription of anorectic and orexigenic neuropeptides in the hypothalamus. Moreover, PEA increased AMP-activated protein kinase-α phosphorylation and carnitine palmitoyltransferase 1 transcription in adipose tissue, suggesting an increase in ATP-producing catabolic pathway. PEA also polarized adipose tissue macrophages to M2 lean phenotype, associated to a reduction of inflammatory cytokines/adipokines. To demonstrate the direct effect of PEA on leptin sensitivity without interference of adiposity loss, we obtained consistent data in PEA-treated sham-operated animals and in vitro in SH-SY5Y neuroblastoma cell line. Therefore, our data provide a rationale for the therapeutic use of PEA in obese postmenopausal woman.

Gonadotropin-releasing hormone agonists administration in polycystic ovary syndrome. Effects on bone mass.

Women with amenorrhea and polycystic ovaries (PCO) seem to present a relative degree of protection against bone loss caused by hypoestrogenism. We treated 20 patients affected by polycystic ovary syndrome (PCOS) with a gonadotropin-releasing hormone agonist (GnRH-a) for 6 months. After treatment mean bone mineral density (BMD) significantly decreased. We concluded that patients with PCOS have to be considered at risk of developing osteopenia when treated with GnRH-a. The relative protection against osteoporosis, that is present in amenorrheic patients with PCO, might be attributed to the characteristics of amenorrhea in these patients.