Virginia Gargano

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.

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.

Effects of the contraceptive patch and the vaginal ring on bone metabolism and bone mineral density: a prospective, controlled, randomized study

BACKGROUND This study was conducted to compare the effects of the combined contraceptive vaginal ring releasing 15 mcg of ethinylestradiol (EE) and 120 mcg of etonorgestrel daily with the effects of the contraceptive patch, a transdermal system that delivers a daily dose of 20 mcg of EE and 150 mcg of norelgestromin on bone turnover and bone mineral density (BMD) in young fertile women. STUDY DESIGN On the basis of a randomized, computer-generated list, 40 women desiring contraception were assigned to a 12-month treatment with a patch delivering a daily dose of 20 mcg of EE and 150 mcg of norelgestromin (Evra, Janssen-Cilag, Italy) (Group A, n=20) or to a 12-month treatment with a vaginal ring releasing a daily dose of 15 mcg of EE and 120 mcg of etonorgestrel (NuvaRing, Organon, Italy) (Group B, n=20). Twenty patients underwent no treatment and were used as healthy controls (Group C, n=20). At 3, 6, 9 and 12 months, serum and urinary calcium, osteocalcin and urinary pyridinoline (PYD) and deoxypyridinoline (D-PYD) levels were measured. At baseline and after 12 months, lumbar BMD was determined by dual-energy X-ray absorptiometry. RESULTS In Groups A and B, urinary PYD and D-PYD at 6, 9 and 12 months were significantly reduced in comparison with basal values and Group C values (p<.05). In Groups A and B, serum calcium levels were significantly increased after 6 months. No significant difference was detected between Group A and Group B in urinary levels of PYD and D-PYD, in calcium levels and in osteocalcin levels. At 12 months, no significant difference was detected in spinal BMD values between the three groups and in comparison with basal values. CONCLUSION Both contraceptive systems exert a similar positive influence on bone turnover in young postadolescent women.

Short-term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on climacteric-related symptoms in postmenopausal women: A double-blind, randomized, placebo-controlled trial

The present study aimed to evaluate the short-term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on acute climacteric-related symptoms in postmenopausal women in a double-blind, randomized, placebo-controlled trial performed at the menopause clinic of our department. Eighty healthy postmenopausal women were randomly assigned to two treatment groups – one receiving the combination (group A, n = 40), the other receiving calcium supplements (group B, n = 40) – for three cycles of 28 days. Climacteric-related symptoms were evaluated by the Kupperman index (KI) at baseline and after the three cycles of treatment. At baseline no significant difference was detected in KI between groups A and B; however, after three cycles of treatment, KI was significantly (p < 0.05) lower in group A compared with baseline and with group B. We conclude that the administration of a combination of isoflavones, lignans and C. racemosa already reduces acute climacteric symptoms in postmenopausal women after 3 months of treatment. This prompt effect is probably due to the different pharmacokinetic properties of isoflavones and lignans; isoflavones are absorbed faster than lignans, while lignans are removed later. The combination of these molecules can guarantee a better reduction of postmenopausal symptoms over a 24-h period.

Effects of two low-dose combined oral contraceptives containing drospirenone on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study☆

BACKGROUND The effects of a 21-day combined oral contraceptive containing 30 mcg ethinyl estradiol plus 3 mg drospirenone with a 21-day preparation containing 20 mcg ethinyl estradiol plus 3 mg drospirenone on bone turnover and bone mineral density (BMD) in young fertile women were compared. METHODS A randomized, controlled trial was conducted on healthy fertile women treated with 30 mcg ethinyl estradiol plus 3 mg drospirenone (Group A; n=21), 20 mcg ethinyl estradiol plus 3 mg drospirenone (Group B; n=23) and healthy controls (Group C; n=21). At 3, 6, 9 and 12 months, serum and urinary calcium, osteocalcin (BGP), 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). In Groups A and B, serum calcium levels were significantly increased after 6 months. No significant difference was detected between Groups A and B in urinary levels of pyridinoline and deoxypyridinoline, in calcium levels and in BGP levels. At 12 months, no significant difference was detected in spinal BMD values between the three groups and in comparison with basal values. CONCLUSION Both combined oral contraceptives exert a similar positive influence on bone turnover in young postadolescent women.

Longitudinal evaluation of serum leptin and bone mineral density in early postmenopausal women.

Objective:To evaluate total and site-specific bone mineral density (BMD) and serum leptin levels in postmenopausal women treated with a calcium supplement and in postmenopausal women receiving estrogen plus progestin therapy. Design:Forty-four women were randomized to receive either calcium supplementation (group A, n = 22) or transdermal 17&bgr;-estradiol at a dose of 50 &mgr;g/day in a continuous regimen and nomegestrol at a dose of 5 mg/day for 12 days per month in a sequential regimen (group B, n = 22). All women underwent dual-energy x-ray absorptiometry determination of BMD and blood sampling in the morning at the beginning of the study and after 12 months. Leptin was determined by radioimmunoassay in all samples. Results:After 12 months, serum leptin levels were significantly higher in group A (control) in comparison with group B and baseline values, whereas both total and pelvic BMDs were significantly lower in group A in comparison with group B and baseline values. At baseline, a significant correlation was found between leptin levels, body mass index, and total-body BMD. After 12 months, leptin was still correlated to body mass index in both groups, but the association with BMD was lost. Conclusions:This study confirms previous evidence of a significant correlation between serum leptin and BMD in early postmenopausal women. Furthermore, this correlation is lost over time during the progression of the postmenopausal period, independently from the administration of estrogen-progestin therapy. Further studies and longer follow-up periods are needed to better understand theses issues.

Transdermal estradiol and oral or vaginal natural progesterone: bleeding patterns

Objective To evaluate the effects on bleeding pattern of two different doses of natural progesterone (NP) administered per os or per vagina in association with transdermal estradiol in a continuous, sequential estrogen–progestin therapy. Methods A prospective, randomized trial was conducted on 100 patients randomized into four groups. Each group received transdermal 17β-estradiol treatment at the dose of 50 μg/day. Groups A and B received NP per os at the dose of 100 mg/day and 200 mg/day, respectively. Groups C and D received NP per vagina at the dose of 100 mg/day and 200 mg/day, respectively. Results After 12 cycles of treatment, no significant differences were observed in endometrial thickness between groups, suggesting that all treatments are effective in balancing the effects of estradiol on endometrium. Regarding bleeding control, patients in Groups C and D showed a higher number of episodes of regular bleeding than patients in Groups A and B and fewer episodes of spotting. The better control of bleeding was associated with a higher treatment compliance in patients who received vaginal NP, with a larger percentage of women completing the study. Conclusion Transdermal estrogen replacement therapy combined with 100 mg of micronized NP administered per vagina from the 14th day to the 25th day of each 28-day cycle leads to good cycle control and provides excellent patient satisfaction without serious side-effects. This therapy could be a treatment of first choice in early postmenopausal patients.

Effects of estradiol valerate and dienogest on quality of life and sexual function according to age.

Abstract This is an observational study on 102 women aged 25–45 years to evaluate if the E2V/DNG pill has any impact on quality of life (QoL) and sexual function (FSF). Thirty-nine women were younger than 35 years (group A), and 63 women were 35 years old or older (group B). At baseline and after 6 months, patients received the Italian validated version of the Short Form-36 questionnaire and the Italian validated version of the Female Sexual Function Index questionnaire. Group A showed an overall higher perception in all QoL scores at baseline and after 6-months (p < 0.05). E2V/DNG treatment did not exert any significant effect on QoL perception in group A apart from an increase in the GH domain (general health). In group B we observed a significant improvement both in GH and in VT (vitality) scores. We found a significant reduction in “lubrication” after 6 months both in group A and B (p < 0.01) and a significant improvement in “satisfaction” and “pain” scores in group A and in “desire”, “satisfaction” and “total” score in group B (p < 0.01). The E2V/DNG pill is associated with a significant improvement of GH and VT and with an improvement in FSF with no difference between age groups. Chinese abstract 这是一项关于戊酸雌二醇/地诺孕素是否对年龄在25岁–45岁的102名女性生活质量（QOL）和性功能（FSF）有影响的观察性研究。39名女性小于35岁（A组），63名女性大于35岁或更大（B组）。在未用药和用药6个月后，患者接受意大利版的36个问卷调查和女性性功能指数问卷调查。未用药及用药6个月后（p<0.05），A组显示总体的生活质量评分更高。除了提高GH（一般健康状况）外，戊酸雌二醇/地诺孕素对A组生活质量没有任何明显影响。我们观察到B组GH和VT（体力）评分明显升高。我们发现6个月后A组和B组（p<0.01）“性润滑”作用明显降低，A组“性满意度”和“性交疼痛”评分明显升高；B组“性欲”、“性满意度”和“总”评分（p<0.01）明显升高。戊酸雌二醇/地诺孕素明显改善GH和VT，在不同年龄组中对性功能的改善没有显著差异。

A case of ovarian torsion in a patient carrier of a FSH receptor gene mutation previously affected by spontaneous ovarian hyperstimulation syndrome.

Abstract We here report a case of ovarian torsion in a patient with an history of two previous episodes of spontaneous ovarian hyperstimulation syndrome during her two pregnancies. A mutation of follicle-stimulating hormone receptor (FSHr) gene was identified in this patient and in other members of the family. Two years after her successful second pregnancy, the patient showed signs of severe thyroiditis during administration of oral contraceptive, with suppressed TSH and increased thyreoglobulin, in the absence of any abnormalities of the auto-antibodies. In few days, she developed severe pelvic pain and ultrasonographic evidence of increased ovarian volume. She underwent laparoscopy with unilateral adnexectomy for ovarian ischemic necrosis due to adnexal torsion. Our experience suggests that patients’ carrier of a mutation of FSHr gene are at risk of ovarian pathologies also when non-pregnant and in the presence of low TSH levels. Further investigations are needed for an appropriate knowledge of typical and atypical manifestations of spontaneous ovarian hyperstimulation syndrome.

Successful pregnancy complicated by spontaneous, familial, recurrent ovarian hyperstimulation syndrome: report of two cases.

Abstract We here report two cases of spontaneous, familial, recurrent ovarian hyperstimulation syndrome ended in a successful pregnancy. First case was a 26-year-old woman, gravida 3 para 0 and two previous terminations of pregnancy due to spontaneous ovarian hyperstimulation syndrome (OHSS). During her pregnancy, patient was treated with IV fluid therapy, albumin and thromboembolic prophylaxis and required pleural and peritoneal drainage. She was referred to the hospital twice, at 8 and 28 weeks’. At 32 weeks due to worsening of clinical condition, decision was made for a caesarean section. A live, healthy preterm baby of 1950 g was delivered. Second case was a 27-year-old woman, gravida 2 para 0 with one previous termination of pregnancy due to spontaneous OHSS. During her pregnancy patient was treated with IV fluid therapy, albumin, and thromboembolic prophylaxis. She did not require any pleural or peritoneal drainage. She was referred to the hospital twice, at 8 and 30 weeks. At 37 weeks of gestation, due to worsening of clinical condition decision for a caesarean section was made. A live, healthy term baby of 2700 g was delivered. Our experience seems to confirm that management of spontaneous OHSS during pregnancy should be conservative and treatment tailored to severity of symptoms.