Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome.

BACKGROUND AND OBJECTIVES: The emerging association of assisted reproductive techniques (ART) with imprinting disorders represents a major issue in the scientific debate on infertility treatment and human procreation. We studied the prevalence of Beckwith-Wiedemann syndrome (BWS) in children conceived through ART to define the specific associated relative risk. METHODS: Patients with BWS born in Piemonte, Italy, were identified and matched with the general demographic data and corresponding regional ART registry. RESULTS: Between 2005 and 2014, live births in Piemonte were 379 872, including 7884 from ART. Thirty-eight patients with BWS were born, 7 from ART and 31 naturally conceived. BWS birth prevalence in the ART group was significantly higher than that of the naturally conceived group (1:1126 vs 1:12 254, P < .001). The absolute live birth risk in the ART group was 887.9 per 1 000 000 vs 83.3 per 1 000 000 in the naturally conceived group, providing a relative risk of 10.7 (95% confidence interval 4.7-24.2). During the 1997-2014 period, 67 patients were diagnosed with BWS out of 663 834 newborns (1:9908 live births). Nine out of the 67 BWS patients were conceived through ART (13.4%), and 8 were molecularly tested, with 4 having an imprinting center 2 loss of methylation, 2 with 11p15.5 paternal uniparental disomy, and 2 negative results. CONCLUSIONS: ART entails a 10-fold increased risk of BWS and could be implicated in the pathogenesis of genomic events besides methylation anomalies. These data highlight the need for awareness of ART-associated health risk.

ß-thalassemia patients and gynecological approach: review and clinical experience.

Significant improvements in therapy and life expectancy of ß-thalassemia patients in last decades result in the need of commitment for gynecologists and obstetricians as the complexity of organ impairment needs a specific multidisciplinary approach. After a review of clinical manifestations of ß-thalassemia from a gynecologic point of view, we present the experience of a gynecologic center in treating ß-thalassemia patients from more than 20 years.

Progestogen use in women approaching the menopause and breast cancer risk.

OBJECTIVE: Progestogens, particularly synthetic progestins, are widely used to contrast the clinical consequences of the relative hyperestrogenism that characterizes the years preceding the menopause. As a large body of data on postmenopausal hormone therapy (HT) demonstrates that the addition of synthetic progestins to estrogen increases the breast cancer risk compared to estrogen alone, it is important to evaluate if the use of progestogens in premenopausal years is associated with the risk of breast cancer. METHODS: Main literature data on the association with breast cancer risk of progestogens, either used alone in premenopausal years or added to estrogen in postmenopausal HT, were reviewed. RESULTS: Available data suggest that long-term current use of progestogens in premenopausal women after the age of 40 years can increase the risk of breast cancer. Consistently with the data on postmenopausal HT, the risk increase is higher for lobular cancer than for ductal cancer. CONCLUSIONS: The most important and widely accepted indications to the use of progestogens in the years preceding the menopause are anovulatory menstrual disorders, for which a limited period of treatment is generally sufficient. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of increased breast cancer risk and clinical benefits have to be weighed. Anyway, as micronized progesterone and dydrogesterone, at least when they were used in postmenopausal HT, seem to have, according to a large observational study, a safer risk profile on the breast, the preferential use of these preparations could be suggested.

Differential effects of various progestogens on metabolic risk factors for breast cancer.

Biological and epidemiological findings suggest that metabolic factors - insulin, insulin-like growth factor-I (IGF-I) and sex hormone-binding globulin (SHBG) - are involved in the development and promotion of breast cancer. Estrogens, particularly if administered orally, counteract metabolic factors that increase breast cancer risk, i.e. they reduce insulin and IGF-I and increase SHBG. This could contribute toward explaining epidemiological data showing that unopposed oral estrogens do not increase breast cancer risk, or do so only modestly. In contrast to natural progesterone and progesterone-derived progestins, progestins endowed with androgenic (or glucocorticoid) activity negatively influence these metabolic factors, counteracting the favorable effects of estrogens. While most biological and epidemiological findings suggest that natural progesterone does not augment breast cancer risk, available data show an increased risk with synthetic progestins - with the possible exception of progesterone-derived dydrogesterone. Different mechanisms for different progestins could possibly be involved. Differences from progesterone with regard to pharmacokinetics and pharmacodynamics, potency, interaction with the two isoforms of the progesterone receptor, and binding to other steroid receptors could all be relevant. These remain theoretical speculations for the time being, but the possibility that some progestins increase breast cancer risk through their negative influence on metabolic factors cannot be rejected.

Pregnancy, progesterone and progestins in relation to breast cancer risk.

In the last two decades the prevailing opinion, supported by the "estrogen augmented by progesterone" hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likelihood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.

Polyunsaturated fatty acids (PUFAs) might reduce hot flushes: an indication from two controlled trials on soy isoflavones alone and with a PUFA supplement.

OBJECTIVES: To investigate the effect on hot flushes of a soy isoflavone extract alone (Study A) and with the addition of a supplement of polyunsaturated fatty acids, PUFAs (Study B). METHODS: Subjects were postmenopausal women (29 in Study A, 28 in Study B) with more than five troublesome hot flushes per day. Both studies were double-blind randomized placebo-controlled trials with cross-over design, of 24-week duration. After a 2-week observation period, they were randomized to receive two capsules per day providing 60mg of isoflavones or placebo for 12 weeks; thereafter, women who had taken isoflavones were given placebo for a second 12-week period, and vice-versa. Women in the Study B were given also two capsules per day containing a PUFA supplement for the entire 24-week test period. RESULTS: Both studies showed the isoflavone extract to have no greater efficacy on hot flushes than the placebo. During the 24 weeks of the Study B there was a progressive and highly significant reduction in the number of hot flushes, independent of whether the women had begun with isoflavones or with placebo. CONCLUSION: In these two trials the isoflavone extract did not show greater efficacy on the hot flushes than the placebo. The reduction of hot flushes observed in the Study B might be due to the PUFA supplement. PUFAs, particularly Omega (Omega) 3-fatty acids, could reduce hot flushes through their influence on neuronal membranes and/or the modulation of the neurotransmitter function and the serotoninergic system. Studies specifically designed to document the action of PUFAs on hot flushes would be welcome.

Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.

Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used. Continuous-combined regimen inhibits the sloughing of mammary epithelium that occurs after progesterone withdrawal in a cyclic regimen. More importantly, the progestins used (medroxyprogesterone acetate and 19-Nortestosterone-derivatives) are endowed with some non-progesterone-like effects, which can potentiate the proliferative action of estrogens. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of insulin-like growth factor-I, and decreased levels of SHBG), which contrast the opposite effects induced by oral estrogen.

Differential effects of progestins on the circulating IGF-I system.

OBJECTIVE: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins. METHOD: All available reports on the effects of different forms of HRT have been taken into account. RESULTS: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects--the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)--tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent. CONCLUSION: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.

Temperament and character in couples with fertility disorders: a double-blind, controlled study.

OBJECTIVE: To evaluate the personality features of infertile patients. DESIGN: A double-blind, controlled study. SETTING: An outpatient facility for diagnosis and care of infertility. PATIENT(S): We assessed 142 infertile couples with obstetric-gynecologic clinical and instrumental examinations. The couples were divided into three groups: organic infertility, functional infertility, and infertility of uncertain origin. The third group was excluded. INTERVENTION(S): Organic infertility and functional infertility were ascertained with gynecologic and andrologic clinical examinations, seminal liquid examination, postcoital testing, progesterone assay, hysterosalpingography, biopsy of endometrium, and laparoscopy. Personality traits were assessed with the Temperament and Character Inventory (TCI). MAIN OUTCOME MEASURE(S): Results of the Temperament and Character Inventory. RESULT(S): Infertile women showed lower Cooperativeness than control women. Women with functional infertility had lower scores in Cooperativeness and Self-Directedness than women with organic infertility. Men belonging to the functional infertility group had a lower Novelty Seeking score than did those of the organic infertility group. Men and women in the functional infertility group showed higher Harm Avoidance than those in the organic infertility and control groups. CONCLUSION(S): The results emphasize that the study of personality in the diagnostic and therapeutic assessment of infertility might provide useful predictive elements for functional infertility.