The Impact of Aging on Fertility: Similarities and Differences between Ovaries and Testes

The increasing age seems to have a negative impact on reproductive functions not only in women but also in men. Therefore, our aim was to review the data available in the literature regarding the impact of advancing age on fertility and the mechanisms underlying this association in both genders. The available data suggest that the effects of age on ovarian function cause a decrease in fertility starting 13 years before menopause. Statistics show that 10% of women will have a decreased fertility starting with the age of 30. The impact of age on ovary is due to both decreased number and quality of the oocytes, resulting in a high rate of chromosomal aneuploidy in the embryo and mitochondria dysfunction. Assisted reproductive technologies aiming to identify competent embryo were created but for the moment the results are unsatisfactory. On the other hand, in men, the semen quality and testicular function were found to gradually decrease with age and most of the studies also describe a negative impact on fertility. The mechanisms underlying decreased fertility are mainly genetic and epigenetics changes. However, if the effects of age on male fertility in men can be overcome by assisted reproductive technologies is not clear yet as the results of the studies are inconsistent

Hypogonadism in Female Patients with Beta Thalassemia Major

Beta thalassemia is the most frequent hemoglobinopathy worldwide. In patients with beta thalassemia major (BTM), the consequence of long-term life-saving transfusions is iron overload in liver, heart and endocrine glands. Hypogonadotropic hypogonadism is the most frequent endocrine complication. Recent progresses in the treatment of BTM dramatically improved life expectancy and quality of life of these patients, making the concern for fertility and pregnancy to gain importance. Therefore, we performed a review of the available data regarding hypogonadism in female patients with BTM. We found that hypogonadotropic hypogonadism is still frequently found in female patients with BTM. Pituitary iron overload seems to be the main factor contributing to hypogonadism occurrence, although iron-related damage of the ovaries and the genital tract cannot be excluded. The increased oxidative stress observed in BTM patients was hypothesized as a contributor to pituitary-gonadal dysfunction. Hypogonadism has significant consequences on quality of life, final height, bone health and fertility of the patients. Estro-progestative administration is essential in order to minimize consequences, although the best treatment regimen should be carefully weighted in each patient. Although spontaneous fertility is reduced by the presence of hypogonadism, it seems that ovulation-induction treatment with gonadotropins is effective in achieving pregnancies in majority of patients

The Relationship Between the Body Mass Index and the Controlled Ovarian Stimulation Outcomes

When assessing the impact of body mass index (BMI) values on controlled ovarian outcomes, high BMI tips the balance regarding negative impact. Although not all studies agree, it seems that both intermediary and definite endpoints are offset, and the effect is progressively more significant with increasing BMI. In addition, evidence suggests that oocyte quality and endometrial receptivity are lower in overweight and obese patients. Perfecting how increased weight is quantified and unifying definitions of parameters assessed emerge as ways in which a more concise view of the impact of BMI on in vitro fertilization (IVF) procedures could be achieved. The unifying viewpoint is that weight interventions could improve natural and assisted conception results and assure a safer pregnancy for both mother and child. Still, how weight loss could be achieved, especially in these women to whom time pressure is added, remain to be refined

Androgens and Controlled Ovarian Stimulation Outcomes

 Androgens play are an integral part in normal follicular development and in the pathogenesis of conditions such as polycystic ovary syndrome (PCOS), decreased ovarian reserve and poor ovarian response. Besides indirectly mediating the growth of early phases of follicular development, through their actions on FSH (follicle-stimulating hormone) and IGF1(insulin-like growth factor 1), androgens are also the source of estrogens. Hyperandrogenism in PCOS leads to excessive growth of preantral follicles and follicular arrest. Low levels of androgens are responsible for abnormal folliculogenesis and rapid depletion of the ovarian pool. The poor ovarian response is encountered in up to a third of patients undergoing controlled ovarian stimulation, and androgens have been used as a prediction tool and as a treatment intervention. Although the results are not unanimous, serum DHEAS (dehydroepiandrosterone sulfate) appears to anticipate the type of response encountered in controlled ovarian stimulation and the possibility of achieving a live birth after ART (assisted reproduction technique) treatment. Similarly, testosterone could help in the optimization of stimulation protocols. Whether systemically administered androgens could influence the intra-follicular environment is not certain. Still, treatment with both testosterone and DHEA appears to have beneficial effects on both surrogate endpoints, such as embryos quantity and quality, as well as definitive endpoints such as clinical pregnancy rate and live birth rate

In Vitro Fertilization(IVF) for Gilbert Syndrome Associated with ßeta-Thalassemia, A Case Report

The Gilbert syndrome is a familial tip of a benign condition characterized by a high level of unconjugated bilirubin without hemolysis or liver disease. In this syndrome, there is a mutation of the UGT1A1 gene on the long arm (q) of chromosome 2, which synthesize the enzyme uridine diphosphate-glucuronosyltransferase-1A1 (UGT1A1), that conjugate bilirubin. Hepatic glucuronidation activity is diminished by 30%. The association between Gilbert syndrome and in vitro fertilization (IVF) is not yet presented in the literature. A 34-year-old nulliparous woman presented to our clinic for primary infertility. Antimullerian hormone level was normal: 3.5 ng/ml. Her partner sperm analysis showed severe oligoasthenoteratozoospermia: 5milion/ml concentration, 25 % progressive motility, 3% standard form. She was known for Gilbert syndrome and ßeta thalassemia. She decided to go for in vitro fertilization (IVF) with ICSI (intracytoplasmic sperm injection). We used a short antagonist protocol with letrozole 2.5mg twice a day and 150 UI menotropins to avoid estradiol rising, which could determine, in her case, the level of serum bilirubin to increase. We collected fourteen oocytes; twelve of them were in metaphase II, nine fertilized by ICSI, and we obtained three good blastocyst 4aa, 4ab, and 4ba (according to Gardner-Schoolcraft criteria). We transferred one blastocyst, and ß HCG was negative on day eleven after embryo transfer. Next month, we transferred on a natural cycle one blastocyst: 4ab after thawing. Ultrasound confirmed a single pregnancy with a heartbeat. In this Gilbert syndrome, to avoid estradiol rising, we used aromatase inhibitors in conjunction with gonadotropins for IVF ovarian stimulation

The Antimullerian Hormone (AMH) and the Thyroid Autoimmunity

Infertility affects nowadays10-15% of the reproductive population which led to the rapid development of therapeutical methods such as ART (assisted reproduction techniques). Ovarian reserve plays a key role in evaluating these patients and their prognosis. The best tool that we have for appreciating ovarian reserve is AMH (antimullerian hormone). On the other hand, maintaining thyroid function in normal parameters is essential for reproduction. We review in our paper the liaison between these two factors: AMH and thyroid autoimmunity. It appears that thyroid autoimmunity may affect controlled ovarian stimulation in ART

The Impact of Endometriosis on Controlled Ovarian Stimulation Outcome

Endometriosis, a frequent condition in reproductive age women, is also associated with infertility by mechanisms incompletely clarified. The effectiveness of endometriosis treatment for infertility is debated, being possible that in vitro fertilization (IVF) offers a better alternative. The response to controlled ovarian stimulation (COS) is an important predictor of live birth, but it might be affected in endometriosis possibly through a decrease of ovarian reserve. Moreover, the predictive value of anti-mullerian hormone (AMH) for the response to COS could be altered by factors disrupting the AMH production in endometriosis. Therefore, we aim to review the literature regarding the response to COS and the AMH production and their predictive value for COS response in patients with endometriosis

Endometrial Receptivity in Patients with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a frequent disorder affecting women of reproductive age characterized by infertility. Affected endometrial receptivity seems to contribute to decreased fertility of these patients as suggested by several studies. Understanding the mechanism behind this reduced endometrial receptivity could contribute to discovery of new therapeutic targets for infertility of PCOS. The aim of the paper is to review the current data regarding endometrial receptivity in PCOS patients, the potential mechanisms involved with particular focus on recent findings as the impact of gut microbiota on endometrium, the relationship between vitamin D and endometrial receptivity and the different impact of letrozole and clomiphene citrate on endometrial receptivity in infertile PCOS women

The Connections Between Androgens and Adipose Tissue Function in Polycystic Ovary Syndrome Patients

Few studies reported that androgens levels could be among the regulators of adipose tissue hormones. Polycystic ovary syndrome (PCOS) is characterized by both increased adiposity and hyperandrogenism, but the relationship between androgens levels and adipokines in PCOS has not been well characterized. Our aim was to study the relationship between leptin, adiponectin, total testosterone, sex hormone binding globulin (SHBG) and free androgen index (FAI) in PCOS patients. We conducted a cross-sectional study on 131 PCOS patients (mean age 24 [6] yrs, mean body mass index (BMI) 25.8 [10.44] kg/m2) diagnosed based on Rotterdam Consensus criteria. All the patients were evaluated by clinical, paraclinical and hormonal exam. HOMA-IR was calculated for all the patients. Leptin was positively associated with age (p<0.05), BMI (p<0,0001), waist-hip ratio (WHR) (p<0.0001), waist circumference (WC) (p<0,0001), HOMA-IR (p<0,0001), insulinemia (p<0.0001) and FAI (p<0,0001) and negatively with SHBG (p<0.0001). Adiponectin was negatively associated with age (p<0.05), BMI (p<0,0001), WC (p<0,0001), WHR (p<0,0001), HOMA-IR (p<0,0001), insulinemia (p<0.0001) and FAI (p<0,005) and positively associated with SHBG (p<0,0001). Both adipokines were not correlated with total testosterone. The association between serum leptin and FAI/SHBG was lost after adjustment for age and body mass index. In turn the relationship between leptin and FAI, but not SHBG was independent of HOMA-IR. Circulating adiponectin was associated with SHBG independently of adiposity and HOMA-IR, but the association with FAI was lost after adjustment for HOMA-IR. In conlusion, circulating adipokines are correlated with FAI and SHBG serum levels. This association seems to be mediated by adiposity for leptin. Although the link between adiponectin and FAI is probably due to insulin resistance, SHBG seems to directly modulate adiponectin production

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality