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The Impact of Nutritional Therapy in the Management of Overweight/Obese PCOS Patient Candidates for IVF.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder, and it has two main pathological aspects: reproductive and metabolic. Overweight/obesity is a risk factor in terms of adverse effects during hormone stimulation, a reduced response to ovulation induction regimens, reduced success of IVF, and an increased risk of obstetric complications. To resolve this vicious cycle of pathological events, weight loss and lifestyle modifications are promising strategies. Among these possible approaches, the consumption of a very-low-calorie ketogenic diet (VLCKD) or Mediterranean diet (MD) represents a valid option. In our study, 84 obese/overweight PCOS patients were recruited to evaluate the effects induced by the VLCKD and MD on weight, hormonal, and metabolic parameters. BMI decreased significantly among the VLKCD patients compared to the MD patients (both presenting p values < 0.0001 at 90 and 120 days), and a significant reduction in body circumference was observed. At the same time, HOMA index values statistically decreased for the VLCKD patients compared to those on the MD (p value < 0.001 at 90 days and p value < 0.05 at 120 days), and this phenomenon was also observed for AFC at 90 and 120 days (both p values < 0.001) and AMH at 90 days (p value < 0.05). Interestingly, the ovarian hyperstimulation syndrome (OHSS) incidence was statistically lower in the VLKCD patients compared to the MD patients (p < 0.001). We state that these dietary regimes may improve anthropometric parameters (such as BMI) and women's reproductive health, restore menstrual regularity, and reduce the risk of OHSS. Regarding the different nutritional therapies, the results suggest that the VLCKD is an optimal choice for entry into IVF, especially in terms of the time range in which these results are achieved.

A practical approach to the management of thyroid dysfunction during pregnancy.

Pregnancy has an important impact on the thyroid gland and its function. Thyroid activity changes as a consequence of the novel physiological state of pregnancy and requires a complex hormonal and metabolic adaptation, which is possible only in the presence of a perfectly functioning thyroid gland. In fact, thyroid function is crucial for the success of the implantation and the progression of pregnancy. Abnormal thyroid function is very common among childbearing age women, explaining the high incidence of thyroid diseases that occur during pregnancy. Aim of this work is to analyze the adaptive events that characterize the thyroid function during pregnancy, exploring their hormonal, metabolic and molecular mechanisms. Moreover, the interpretation of the laboratory data necessary to monitor the thyroid functioning during normal pregnancy or in the presence of thyroid abnormalities will be discussed.

Management of women with uterine fibroids in reproductive center: retrospective analysis of clinical and reproductive outcomes.

BACKGROUND: Uterine fibroids are the most common benign tumor in women. According to literature, submucosal myomas have a negative effect on reproductive outcomes in women undergoing assisted reproductive techniques (ART) but there are fewer data concerning intramural fibroids. During last years, ulipristal acetate (UPA) 5 mg was widely used as medical option of fibroid's treatment, but from 2020, the Pharmacovigilance Risk Assessment Committee (PRAC) has revoked the marketing authorization after some cases of liver toxicity. METHODS: In this observational, retrospective study we collected data from a sample of 23 women affected by symptomatic uterine fibroids (from type 1 to type 7 according FIGO classification) followed in our center for assisted reproduction from 2016-2019. All patients received 5 mg/day UPA for three months, followed by two months of wash-out therapy. A group of 13 women treated with UPA, with intramural fibroid not distorting the uterine cavity, after wash-out therapy, affected by tubal or idiopathic factors of infertility too, underwent ART. We also evaluated a control group of women, not affected by fibroids, randomly selected from a general group of our ART patients, similar by age, BMI, and cause of infertility only idiopathic or tubal factors. We evaluated the impact of UPA on reduction of fibroid volume, symptomatology and distortion of the cavity in all the women treated, and the IVF (in-vitro fertilization) outcome between the fibroid group of women affected by intramural fibroids who underwent ART, and the control group. RESULTS: In all the women treated with UPA the overall median fibroid volume pretreatment was 45.168±35.360 mm3, that decreased to a mean value of 22.592±22.116 mm3 post one cycle of UPA, with an overall mean decrease of -22.586 mm3 (of 49%) statistically significant (P=0.00001). After treatment, the distortion of the uterine cavity reduced in high percentage of cases: 85,71% (type 1-2), χ2 difference in respect to the value pretreatment of 0.3941, and 86.96% of patients subjectively referred an improvement in the symptomatology. In the group of 13 women that undergone ART, after one IVF cycle for each patient, we obtained 61% of positivity of dosage of beta human chorionic gonadotropin (hCG) after UPA treatment, and we obtained a similar value in the control group. CONCLUSIONS: In our little sample we have observed that UPA represented a valid non-invasive medical treatment strategy for fibroids in women candidate for (IVF, not only in women affected by sub-mucosal, but also by intramural fibroids not distorting uterine cavity. After a single, three months course of treatment, we obtained good results in terms of reduction of fibroid's volume and improvement of symptomatology, without side effects, preparing a more favorable environment for ART.

Oral Antioxidant Treatment of Men Significantly Improves the Reproductive Outcome of IVF Cycles.

Some 30% to 80% of male sub-fertility may be associated with oxidative stress that damages spermatozoa and can decrease success of in vitro fertilization (IVF) techniques. This multicenter, longitudinal, prospective study aimed to investigate whether oral antioxidant supplementation improved the reproductive competence of men who had had low fertilization rates in their previous intracytoplasmic sperm injection (ICSI) cycles without azoospermia or severe oligozoospermia or any identifiable andrological disease. Seventy-seven men from couples who had an ICSI attempt with unexplained <60% fertilization rate took an antioxidant mix of myo-inositol, alpha-lipoic acid, folic acid, coenzyme Q10, zinc, selenium, and vitamins B2, B6, and B12. Semen parameters were analyzed before (T0) and after 90 days (T90) of treatment, and outcomes of the paired T0 and T90 cycles were compared. After the treatment there was an increase in sperm concentration (p = 0.027), total motile sperm count (p = 0.003), progressive motility (p < 0.0001), and a decreasing trend of DNA-fragmented spermatozoa. Embryological outcomes (fertilization, embryo quality, blastocyst development) were significantly higher in T90 than T0 cycles. No T0 cycle resulted in an evolutive pregnancy. Conversely, in T90 cycles 29 singleton clinical pregnancies were obtained. No negative neonatal outcomes were recorded in newborns after antioxidant treatment. Diet supplementation of men who have had low fertilization rates in their previous ICSI cycles with a combination of myo-inositol, alpha-lipoic acid, folic acid, coenzyme Q10, zinc, selenium, betaine, and vitamins may improve semen reproductive potential and ICSI clinical outcome.

Positive Impact of Levothyroxine Treatment on Pregnancy Outcome in Euthyroid Women with Thyroid Autoimmunity Affected by Recurrent Miscarriage.

Impaired thyroid hormone availability during early pregnancy is associated with recurrent miscarriage (RM) and adverse pregnancy outcomes. The main cause of thyroid dysfunction is thyroid-related autoimmunity (TAI), characterized by a significantly higher serum level of thyroid-stimulating hormone (TSH) compared to that of women without thyroid autoimmunity. TAI is associated with a significantly increased risk of miscarriage, and the incidence of TAI in women experiencing RM is higher compared to normal fertile women. In the present study, we have performed a retrospective analysis comparing the ability to conceive, the number of miscarriages and full-term pregnancies between 227 euthyroid women with autoimmune thyroid disease affected by RM and treated with levothyroxine (LT4) as adjuvant therapy, and a control group of 230 untreated women. We have observed a significant improvement of full-term pregnancies in treated women (59%) compared to untreated women (13%, p < 0.0001). Compared to the control group, treated women had a lower percentage of miscarriages (12% vs. 30%) and improved capacity to conceive (57% vs. 29%). Using age as a variable, the outcome in women younger than 35 years was not influenced by the LT4 therapy. Whereas, in women over 35 years, supplementation with LT4 significantly reduced the miscarriage rate (p < 0.05). We can conclude that a transient impairment of TH availability, not easily detectable before pregnancy, could be an important cause of RM in a subset of euthyroid women with autoimmune thyroid disease. This transient impairment may be reverted using adjuvant treatment with low doses of LT4.

Use of Biosimilar Follicle-Stimulating Hormone in Asthenozoospermic Infertile Patients: A Multicentric Study.

There is increasing data in favour of follicle-stimulating hormone (FSH) therapy in patients with oligo-asthenozoospermia and normal-range gonadotropins in order to increase sperm count and above all sperm motility. Some studies showed an improvement in DNA fragmentation and spontaneous pregnancy. Recently, biosimilar FSH has been marketed with the same indications. We performed a retrospective multicentric case-control study involving 147 asthenozoospermic patients between 18 and 45 years of age. A total of 97 patients were treated with biosimilar FSH 150 UI three times a week for 3 months, while 50 control subjects received no treatment. Patients were evaluated at baseline and after 3 months with semen analysis including DNA fragmentation, testicular colour Doppler ultrasound, and blood tests. Spontaneous pregnancies were recorded during a further follow-up period of 6 months. Treated patients showed after treatment a statistically significant increase in sperm concentration, total sperm count, and total motile sperm, as well as improved progressive motility and non-progressive motility. DNA fragmentation showed a significant reduction. Conversely, in the control group, no significant change was found. Pregnancy rate was significantly higher in treated patients. These data suggest comparable efficacy of biosimilar FSH in the treatment of male infertility; however, larger studies are needed to confirm our results.

Use of follicle-stimulating hormone for the male partner of idiopathic infertile couples in Italy: Results from a multicentre, observational, clinical practice survey.

BACKGROUND: The management of male idiopathic infertility is heterogeneous. Although meta-analyses reported the effectiveness on pregnancy rate, the real clinical impact of follicle-stimulating hormone (FSH) was not evaluated so far. In Italy, FSH is approved by the National Medicines Agency (AIFA) for idiopathic infertile patients with FSH < 8 IU/L, independently of semen parameters. AIM: Primary endpoint was to record the therapeutic approach to the male partner of infertile couples. Secondary aim was to assess changes of semen parameters during FSH treatment. METHODS: A multicentre, prospective, observational, clinical practice survey was carried out, enrolling the male partner of infertile couples attending ten Italian participating centres. Inclusion criteria were as follows: couple infertility, age >18 years and FSH serum levels <8 IU/L. Thus, all men in which AIFA allowed the FSH prescription were enrolled. Primary endpoint was the number of infertile patients treated with FSH. Secondary outcomes were semen parameters. The treating physician decided whether to offer FSH therapy and whether to re-evaluate the male partner. RESULTS: A total of 718 infertile couples were enrolled, and 241 patients were re-evaluated (median follow-up: 4.5 months). In 64.9% (466 patients), a treatment was prescribed. FSH was prescribed in 397 patients (85.2% of treated men). Sperm concentration (P = .002) and normal form percentage (P < .001) significantly improved during FSH administration. No correlation was found between these parameters and FSH duration (P = .545 and P = .627, respectively) or dosage (P = .455 and P = .533, respectively). Among patients treated with FSH, the incidence of oligozoospermia decreased from 73.0% to 56.0% (P < .001) and teratozoospermia from 43.6% to 27.7% (P < .001). DISCUSSION: This first nation-wide survey reveals a FSH prescription rate of 55% in patients qualifying for treatment according to AIFA. Although the study was not designed to highlight FSH efficacy in male infertility, a slight increase in semen parameters was demonstrated in about half of the treated men without adverse events.

Impact of Paternal Age on Seminal Parameters and Reproductive Outcome of Intracytoplasmatic Sperm Injection in Infertile Italian Women.

Background: We conducted a retrospective study on a cohort of couples attending the Department of Andrology and Reproductive Physiopathology at Sandro Pertini Hospital in Rome for Intracytoplasmatic Sperm Injection (ICSI)-assisted reproduction programs. Some of the couples included in the study underwent more than one ICSI cycle. Between January 2015 and April 2017. Objective: To evaluate whether the advancing of the paternal age may have effect on the seminal parameters, thus negatively affecting the embryo formation, development and quality, as well as the pregnancy rate. Materials and Methods: Five hundred and forty three ICSI cycles were performed on 439 couples undergoing Assisted Reproductive Technologies (ART). Patients were subdivided into three male and three female age groups having similar size: Men: ≤38 years (MI), 39-43 years (MII), ≥44 years (MIII). Women: ≤35 years (FI), 36-40 years (FII),≥41 years (FIII). Discussion and Conclusion: Male age groups did not reveal any statistical significant differences in any age-related semen parameters. We also confirmed a statistical significant increase in the pregnancy rate of couples with older partner age difference and younger female. We found that the advanced male age increases the probability of obtaining one or no type A embryo (NA≤1), which was almost doubled in the MIII group in comparison with MI, suggesting a negative effect of male age on the efficacy of the reproductive outcome in terms of a reduced number of type A embryos. Such an effect does not seem related to semen parameters and may deserve further investigations.

Sperm DNA fragmentation in Italian couples with recurrent pregnancy loss.

The aetiopathogenesis of recurrent pregnancy loss (RPL) is heterogeneous. The aim of this study was to investigate the male factor in Italian couples experiencing RPL following natural conception. The study investigated 112 men from RPL couples and two control groups: 114 infertile men with one or more impaired semen parameters and 114 fertile men with high-quality semen parameters. Semen parameters were examined according to WHO criteria. Sperm DNA fragmentation (SDF) was evaluated using TdT-mediated dUDP nick-end labelling (TUNEL) assay. With the exception of ejaculate volume, the seminal profile of patients with RPL was similar to that of fertile patients and better than the infertile ones. Despite good spermatogenesis, however, sperm DNA integrity was impaired in the RPL group, with SDF values significantly higher than in fertile controls (18.8 ± 7.0 versus 12.8 ± 5.3, P < 0.001) and similar to those of infertile patients. SDF also showed a positive correlation with the age of patients with RPL and number of miscarriages. The results suggest a correlation between increased SDF and impaired reproductive capacity in terms of both fertilization and pregnancies carried to term, but high SDF cannot yet be considered a predictive factor for the risk of RPL.

Prediction of early pregnancy maternal thyroid impairment in women affected with unexplained recurrent miscarriage.

BACKGROUND: Proper maternal thyroid function is necessary for a successful pregnancy. In order to identify women who may experience miscarriage due to transient impairment of the pituitary-thyroid axis in early pregnancy, we aimed to investigate the ratio between basal and peak thyroid stimulating hormone (TSH) [following stimulus with thyrotrophin-releasing hormone (TRH)] in euthyroid women with unexplained recurrent miscarriage (RM). METHODS: We have established a 'iTSHa index' (TSH increase after TRH adjusted for the levels of basal TSH), determining TSH serum levels at time 0 and 20 min after TRH stimulus in 463 consecutive women attending two antenatal care units for two or more miscarriages occurring within the first 10 weeks of pregnancy. RESULTS: The mean basal TSH serum levels were higher (P < 0.001) in RM women [2.1 µIU/ml; 95% confidence interval (CI): 2.0-2.2] compared with the controls (1.3 µIU/ml; 95% CI: 1.2-1.4). Establishing serum TSH at an individual level, a large overlap was observed and the receiver operating characteristic curves did not allow us to find an optimal cut-off point with an adequate sensitivity/specificity ratio. Therefore, we suggest a novel statistical model, the 'iTSHa index' (available on www.afar.it/tsh-trh-miscarriage), that is capable of identifying women with RM due to transient thyroid function impairment of the early pregnancy, in particular when baseline serum TSH is less than 1.5 µIU/ml, i.e. well below the conventional upper cut-off indicated as 'safe' in those who want to conceive. CONCLUSIONS: A transient impairment of thyroid function in early pregnancy may cause an inadequate adaptation to the increased thyroid requirement and may be implicated in RM. The evaluation of the proposed iTSHa index, if validated in a larger cohort of patients, may provide information useful to identifying a subset of healthy women, without evidence of thyroid dysfunction or autoimmunity and a TSH in the low-normal reference range, who may be at risk of RM.

Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.

PROBLEM: To determine the presence of anti-thyroid antibodies in patients with primary antiphospholipid syndrome (APS) [antiphospholipid antibodies (aPL) + recurrent spontaneous abortion (RSA)], compare APS alone with APS and thyroid autoimmunity for fecundity and for pregnancy outcome. METHOD OF STUDY: A total of 203 non-pregnant women affected with primary APS were evaluated for anti-thyroid antibodies; 162 non-pregnant women affected with RSA and thyroid autoimmunity alone served as controls. RESULTS: Anti-thyroid antibodies were found in 27% of APS patients studied. Patients with aPL alone had higher percentages of spontaneous pregnancies (P < 0.0001) and live births (P = 0.0003), when compared with patients positive for anti-thyroid antibodies alone or with aPL. CONCLUSIONS: Thyroid autoimmunity is frequently present in APS recurrent aborters and is often associated with either reduced fecundity or with poor pregnancy outcome. Thyroid antibodies should always be evaluated in women with RSA including those with aPL.