ART and the forgotten siblings: a call for research.

A broader definition of infertility is the incapacity to have the intended number of children. However, most literature on ART exclusively focuses on live birth as an outcome, rather than on the capacity to fully realize the reproductive wishes of the couples. This issue has probably received scant attention because the total fertility rate is below replacement levels in affluent countries, and one may simplistically assume that only a minority of couples may be interested in more than one child. This assumption, however, is unproven and presumably erroneous. Unfortunately, evidence on the rate of return in couples who conceived their first child with ART is scant and information on the intended number of children in infertile couples is lacking. In general, we plea for more research on this subject. The documentation of an intended number of children above two and a high return rate in infertile couples may lead to changes in clinical practice, such as the storage of oocytes or embryos prior to initiating embryo transfers. This could improve the chance of conceiving the second child when the couple comes back some years later. In addition, the identification of the determinants for non-return as well as those explaining the gap between the intended and the realized number of children may reveal specific barriers and possibly how to tackle them. However, at present, available evidence is insufficient to advocate any intervention. Thorough research is warranted.

Prevalence and clinical effect of caesarean scar defects in women undergoing IVF.

RESEARCH QUESTION: How common are caesarean scar defects (isthmocele) among patients who have had previous caesarean delivery undergoing IVF for secondary infertility? Does the presence of isthmocele affect the chances of success of IVF? DESIGN: In this cohort study, women referred to an Italian public assisted reproduction centre between January 2016 and April 2021 were retrospectively reviewed. Women with a history of caesarean delivery and an indication for IVF were selected. On the basis of the local policy, all patients with a history of caesarean section underwent saline contrast sonography (SCS). Sonographic evaluation was standardized. RESULTS: One hundred and forty-four women were eligible, of whom 22 declined SCS and eight decided to delay pregnancy seeking. Overall, 114 women were available for data analysis. Seventy-six women were diagnosed with caesarean scar defects, corresponding to a prevalence of 67% (95% CI 58 to 75%). Baseline characteristics of women with and without isthmocele were similar. Conversely, the clinical pregnancy rate (adjusted OR 0.31, 95% CI 0.13 to 0.72) and live birth rate (adjusted OR 038, 95% CI 0.17 to 0.86) were significantly lower among affected women. No associations between specific sonographic defect characteristics and IVF outcome could be identified. CONCLUSIONS: Caesarean scar defects are common among women with a history of caesarean section requiring IVF. The presence of these lesions may reduce the chance of success of the procedure.

The neglected role of preimplantation genetic testing for Lynch syndrome.

Preimplantation genetic testing for monogenic/single-gene disorders (PGT-M) is a procedure employed in the field of assisted reproductive technology to avoid the transmission of genetic diseases to the offspring. Hereditary cancer syndromes represent a diffuse and accepted indication for PGT-M, but take-up differs among the different disorders. Its use is markedly lower for the genes causing Lynch syndrome compared with the breast cancer type 1 or 2 susceptibility genes (BRCA1/2), despite the similar prevalence and severity of the two conditions. Reasons to explain this difference have not been explored. First, Lynch syndrome may be more frequently undiagnosed compared with hereditary breast and ovarian cancer syndrome. In addition, the different take-up may be due to different patient perceptions of the conditions and of the management options. Finally, this distinct attitude may depend on the awareness and sensibility of the professionals caring for affected patients. The authors' considerations are, however, speculative, and specific studies aimed at disentangling the causes of the different receptions of PGT-M are warranted to understand how to tackle this gap. In the meantime, we believe that empowerment regarding PGT-M of all individuals with hereditary cancer syndromes, including Lynch syndrome, is ethically due, and plead for a more active involvement of caregivers.

Fertility specialists' views, behavior, and attitudes towards the use of endometrial scratching in Italy.

BACKGROUND: Endometrial scratching (ES) or injury is intentional damage to the endometrium performed to improve reproductive outcomes for infertile women desiring pregnancy. Moreover, recent systematic reviews with meta-analyses and randomized controlled trials demonstrated that ES is not effective, data on the safety are limited, and it should not be recommended in clinical practice. The aim of the current study was to assess the view and behavior towards ES among fertility specialists throughout infertility centers in Italy, and the relationship between these views and the attitudes towards the use of ES as an add-on in their commercial setting. METHODS: Online survey among infertility centers, affiliated to Italian Society of Human Reproduction (SIRU), was performed using a detailed questionnaire including 45 questions with the possibility to give "closed" multi-choice answers for 41 items and "open" answers for 4 items. Online data from the websites of the infertility centers resulting in affiliation with the specialists were also recorded and analyzed. The quality of information about ES given on infertility centers websites was assessed using a scoring matrix including 10 specific questions (scored from 0 to 2 points), and the possible scores ranged from 0 to 13 points ('excellent' if the score was 9 points or more, 'moderate' if the score was between 5 and 8, and 'poor' if it was 4 points or less). RESULTS: The response rate was of 60.6% (43 questionnaires / 71 infertility SIRU-affiliated centers). All included questionnaires were completed in their entirety. Most physicians (~ 70%) reported to offer ES to less than 10% of their patients. The procedure is mainly performed in the secretory phase (69.2%) using pipelle (61.5%), and usually in medical ambulatory (56.4%) before IVF cycles to improve implantation (71.8%) without drugs administration (e.g., pain drugs, antibiotics, anti-hemorrhagics, or others) before (76.8%) or after (64.1%) the procedure. Only a little proportion of infertility centers included in the analysis proposes formally the ES as an add-on procedure (9.3%), even if, when proposed, the full description of the indications, efficacy, safety, and costs is never addressed. However, the overall information quality of the websites was generally "poor" ranging from 3 to 8 and having a low total score (4.7 ± 1.6; mean ± standard deviation). CONCLUSIONS: In Italy, ES is a procedure still performed among fertility specialists for improving the implantation rate in IVF patients. Moreover, they have a poor attitude in proposing ES as an add-on in the commercial setting.

Follicular steroidogenesis in random start protocols for oocyte cryopreservation.

PURPOSE: Random start protocols are commonly used for oocyte cryopreservation in women with cancer. However, albeit generally reassuring, available evidence is still insufficient to rule out a sub-optimal cycle outcome. This study aimed to compare follicular steroidogenesis between women initiating the random start protocol in the luteal phase and those initiating in the follicular phase. METHODS: Consecutive women with cancer scheduled for oocyte cryostorage were prospectively recruited. We excluded those requiring a concomitant letrozole assumption. All women received a standardized protocol with recombinant FSH and GnRH antagonists. At the time of oocyte retrieval, follicular fluids were pooled, and a sample was collected and frozen at -80 °C. All samples were assayed concomitantly after thawing by liquid chromatography-tandem mass spectrometry. The concentration of 15 different steroid hormones was determined. RESULTS: Seventy-one women were recruited. Thirty-three initiated the ovarian stimulation in the luteal phase, while the remaining 38 initiated in the follicular phase. Baseline characteristics were generally similar. Cycle outcome did also not differ; the median (interquartile range) number of frozen mature oocytes was 9 (5-14) and 10 (5-21), respectively (p = 0.42). None of the 15 tested steroid hormones differed. CONCLUSIONS: The endocrine microenvironment surrounding oocytes is not markedly influenced by the phase of the menstrual cycle at the initiation of ovarian stimulation. This result further supports the validity of random start protocols.

2:1 ketogenic diet and low-glycemic-index diet for the treatment of chronic and episodic migraine: a single-center real-life retrospective study.

AIMS: The evidence supporting the efficacy of dietary preventive therapy in migraine is rising, particularly regarding the ketogenic diet. However, less evidence exists for the Low-Glycemic Index Diet and the 2:1 KD. This retrospective single-center real-life study aims to evaluate the efficacy of a 2:1 ketogenic diet and a Low-Glycemic-index Diet in chronic and high-frequency episodic migraine. METHODS: Sixty patients with high-frequency episodic and chronic migraine were treated with either a Low-Glycemic-index diet (39 patients) or a 2:1 (21 patients) ketogenic diet for three months. We collected data on the migraine frequency and intensity and the MIDAS and HIT-6 scores through the headache diary. Anthropometric measurements (BMI, fat mass, free fat mass, and weight) were also collected and analyzed similarly. Data obtained at the baseline and after three months of each diet were compared. RESULTS: Migraine intensity, frequency, MIDAS and HIT-6 scores, fat mass, weight, and BMI improved in both diet groups. CONCLUSIONS: Both diets are effective in reducing migraine symptoms and migraine-related disability.

Endometrial preparation does not affect the risk of hypertensive disorders of pregnancy in low-risk women undergoing frozen embryo transfer.

OBJECTIVE: Frozen embryo transfer (FET) is associated with a higher risk of hypertensive disorders in pregnancy. The objective of the present study is to evaluate the effect of different protocols of endometrial preparation on the risk of these disorders. METHODS: We conducted a retrospective cohort study on 594 singleton pregnancies achieved by embryo transfer of single frozen-thawed blastocysts. Women with preexisting risk factors for hypertensive disorders were excluded. Women were divided into two groups according to the endometrial preparation protocol: either natural cycle (n = 495) or programming cycle with hormonal replacement therapy (n = 97). The primary outcome was the frequency of hypertensive disorders in pregnancy: specifically, gestational hypertension and preeclampsia. RESULTS: No differences emerged between women following the natural cycle and those following the programming cycle in the frequency of gestational hypertension (5 vs. 4%) and preeclampsia (1.1 vs. 1.2%). No impact emerged also after multivariate analyses. CONCLUSIONS: Women receiving hormonal replacement therapy have the same risk of gestational hypertension and preeclampsia as women following natural cycles when considering low-risk singleton pregnancies.

Effect of letrozole on follicular fluid steroids concentrations in cancer patients undergoing oocyte cryopreservation.

PURPOSE: To investigate the impact of letrozole administration on follicular steroid hormones during controlled ovarian hyperstimulation for fertility preservation. METHODS: One hundred and nineteen women with cancer undergoing oocytes retrieval for fertility preservation were recruited. All women underwent ovarian hyperstimulation according to a random start protocol. Those with hormone-sensitive tumors also received letrozole, an aromatase inhibitor aimed at keeping peripheral estrogen levels low. At the time of oocytes retrieval, a sample of follicular fluid was collected and frozen. All samples were assayed concomitantly after thawing, by liquid chromatography tandem mass spectrometry. The concentration of 15 steroid hormones was determined and results were compared between women who did and did not receive letrozole. RESULTS: Fifty-two women were treated with letrozole, while 67 were not. Statistically significant differences emerged for 12 of the 15 tested steroids. They were the following: cortisol, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), estradiol, androstenedione, testosterone, dihydrotestosterone (DHT), 17-hydroxyprogesterone, progesterone and corticosterone. The most striking differences were observed for testosterone that showed a more than 200-time increase in women receiving letrozole. Estradiol was conversely reduced to a third. CONCLUSIONS: The endocrine microenvironment surrounding oocytes is markedly perturbed by the concomitant assumption of letrozole. Robust clinical evaluation is pressingly needed to rule out any detrimental effect on the chance of live birth with the use of these oocytes.

Conization and lymph node evaluation as a fertility-sparing treatment for early stage cervical cancer.

INTRODUCTION: To evaluate oncological and obstetrical outcomes of early stage cervical cancer patients who underwent conservative management to retain childbearing potential. METHODS: Data of women (aged <40 years) who underwent fertility sparing treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with lymphovascular invasion (LVSI) and IB1 cervical cancer were prospectively collected. All patients underwent cervical conization/s and laparoscopic nodal evaluation (pelvic lymphadenectomy/sentinel node mapping). Oncological and obstetrical outcomes were assessed. RESULTS: Overall, 39 patients met inclusion criteria; 36 (92.3%) women were nulliparous. There were: 3 (7.7%) IA1-LVSI+; 11 (28.2%) IA2; and 25 (64.1%) IB1 cervical cancers, according to 2018 FIGO stage classification. Histological types were 22 (56.4%) squamous carcinoma and 17 (43.6%) adenocarcinoma. Pelvic lymphadenectomy was performed in 29 (74.4%) patients, while 10 (25.6%) patients had only sentinel node mapping. In 4 (10.3%) patients conservative treatment was discontinued due to nodal involvement and 2 (5.1%) patients requested definitive treatment (hysterectomy) after a negative lymph node evaluation. Among 33 (84.6%) patients who retained their childbearing potential, 17 (51.5%) had a second conization. 2 (6.1%) patients relapsed and underwent definitive treatment. After a median follow-up of 51 months (range 1-184) no deaths were reported. 22 (70.9%) patients attempted to conceive. There were 13 natural pregnancies among 12 (54.5%) women who got pregnant. Live birth rate was 76.9%: 9 (69.2%) term and 1 (7.7%) preterm (at 32 weeks) deliveries. 2 (15.4%) miscarriages (first and second trimester) and 1 (7.7%) termination of pregnancy for medical reasons were recorded. CONCLUSION: Conization plus laparoscopic nodal evaluation may be a safe and feasible conservative option in the setting of fertility-sparing treatment for early-stage cervical cancer patients.

Fertility in female cancer survivors: a systematic review and meta-analysis.

Data on the effects of cancer treatments on fertility are conflicting. The aim of the present systematic review and meta-analysis was to determine the chances of childbirth in women survivors of different types of cancer. PubMed, MEDLINE, Embase and Scopus were searched from database inception to 17 July 2019 for published cohort, case-control and cross-sectional studies that investigated the reproductive chances in women survivors of different cancer types. Random-effects models were used to pool childbirth hazard ratios, relative risks, rate ratios and odds ratios, and 95% confidence intervals were estimated; 18 eligible studies were identified. Childbirth chances were significantly reduced in women with a history of bone cancer (HR 0.86, 95% CI 0.77 to 0.97; I2 = 0%; P = 0.02 (two studies); RaR 0.76, 95% CI 0.61 to 0.95; I2 = 69%; P = 0.01 (two studies); breast cancer (HR 0.74, 95% CI 0.61 to 0.90 (one study); RaR 0.51, 95% CI 0.47 to 0.57; I2 = 0%; P < 0.00001 (two studies); brain cancer (HR 0.61, 95% CI 0.51 to 0.72; I2 = 14%; P < 0.00001 (three studies); RR 0.62, 95% CI 0.42 to 0.91 (one study); RaR 0.44, 95% CI 0.33 to 0.60; I2 = 95%; P < 0.00001 (four studies); OR 0.49, 95% CI 0.40 to 0.60 (one study); and kidney cancer (RR 0.66, 95% CI 0.43 to 0.98 (one study); RaR 0.69, 95% CI 0.61 to 0.78 (one study). Reproductive chances in women survivors of non-Hodgkin's lymphoma, melanoma and thyroid cancer were unaffected. Women with a history of bone, breast, brain or kidney cancer have reduced chances of childbirth. Thyroid cancer, melanoma and non-Hodgkin's lymphoma survivors can be reassured.

Oocyte cryopreservation in two women with borderline ovarian tumor recurrence.

Borderline ovarian tumors (BOTs) commonly occur during reproductive years. Given the good prognosis, fertility-sparing surgery can be considered in young women wishing to preserve their fertility. However, conservative management exposes patients to the risk of recurrence. In these cases, the new surgery may be radical (completing the removal of both adnexa) or, when conservative, it may be associated with relevant damage to the ovarian reserve. In this study, we report on two women who decided to perform ovarian hyper-stimulation and oocyte cryostorage at the time of the diagnosis of recurrence, but before undergoing the new surgery. They both obtained a satisfactory number of oocytes, the retrieval was unremarkable, and no main detrimental effects on the ovarian lesions were noticed. These two cases suggest that ovarian hyper-stimulation and oocyte retrieval before planned surgery for BOT recurrence is a feasible option.

Long-term results of fertility-sparing treatment for early-stage cervical cancer.

OBJECTIVE: To evaluate the long-term outcomes of young early stage cervical cancer patients wishing to preserve their childbearing potential. METHODS: Data of young (aged <40 years) patients with early stage cervical cancer were prospectively collected. All patients with stage IA2, IB1 and IB2 cervical cancer were included; they have cervical conization and pelvic node dissection performed via minimally invasive surgery. Survival outcomes were assessed with the Kaplan-Meier model. RESULTS: Overall, 32 patients met the inclusion criteria. Mean (SD) age of the population included was 33 (±4). According to the FIGO 2018 staging system, the stage of disease was IA2, IB1 and IB2 in 9 (28%), 21 (66%) and 2 (6%) cases, respectively. All patients included had cervical conization and laparoscopic pelvic node assessment, including systematic pelvic lymphadenectomy (N = 30, 94%) and sentinel node mapping (N = 2, 6%). In six (19%) patients the planned conservative treatment was discontinued. Median follow-up was 75 (range, 12-184) months. No recurrent disease was diagnosed among patients undergoing conservative treatment; while 2 out of 6 patients having definitive surgical or radiotherapy treatments developed recurrent disease. Five-year disease free and overall survivals were 94% and 97%, respectively. Considering reproductive outcomes, 11 (69%) out of 16 patients who attempted to conceive got pregnant. CONCLUSIONS: Cervical conization and pelvic nodes assessment could be considered a valid treatment modality for early-stage cervical cancer patients who are wishing to preserve their childbearing potential.

The puzzling issue of silica toxicity: are silanols bridging the gaps between surface states and pathogenicity?

BACKGROUND: Silica continues to represent an intriguing topic of fundamental and applied research across various scientific fields, from geology to physics, chemistry, cell biology, and particle toxicology. The pathogenic activity of silica is variable, depending on the physico-chemical features of the particles. In the last 50 years, crystallinity and capacity to generate free radicals have been recognized as relevant features for silica toxicity. The 'surface' also plays an important role in silica toxicity, but this term has often been used in a very general way, without defining which properties of the surface are actually driving toxicity. How the chemical features (e.g., silanols and siloxanes) and configuration of the silica surface can trigger toxic responses remains incompletely understood. MAIN BODY: Recent developments in surface chemistry, cell biology and toxicology provide new avenues to improve our understanding of the molecular mechanisms of the adverse responses to silica particles. New physico-chemical methods can finely characterize and quantify silanols at the surface of silica particles. Advanced computational modelling and atomic force microscopy offer unique opportunities to explore the intimate interactions between silica surface and membrane models or cells. In recent years, interdisciplinary research, using these tools, has built increasing evidence that surface silanols are critical determinants of the interaction between silica particles and biomolecules, membranes, cell systems, or animal models. It also has become clear that silanol configuration, and eventually biological responses, can be affected by impurities within the crystal structure, or coatings covering the particle surface. The discovery of new molecular targets of crystalline as well as amorphous silica particles in the immune system and in epithelial lung cells represents new possible toxicity pathways. Cellular recognition systems that detect specific features of the surface of silica particles have been identified. CONCLUSIONS: Interdisciplinary research bridging surface chemistry to toxicology is progressively solving the puzzling issue of the variable toxicity of silica. Further interdisciplinary research is ongoing to elucidate the intimate mechanisms of silica pathogenicity, to possibly mitigate or reduce surface reactivity.

Fertility preservation in women with malignancies: the accuracy of antral follicle count collected randomly during the menstrual cycle in predicting the number of oocytes retrieved.

PURPOSE: To evaluate the capacity of random antral follicle count (AFC), i.e., AFC recorded at any time during the menstrual cycle, to predict the number of retrieved mature oocytes in women with malignancies undergoing random start ovarian hyperstimulation METHODS: A consecutive series of 72 women with malignancies who underwent ovarian hyperstimulation aimed at egg freezing between July 2014 and December 2016 was retrospectively reviewed. A standardized random start protocol was used for all women. AFC and serum AMH were systematically assessed prior to initiating ovarian hyperstimulation. The main outcome was the retrieval of ≥ 10 mature oocytes. The accuracy of random AFC was tested with the c-statistics (area under the ROC curve). RESULTS: For the whole cohort, the c-statistics for the prediction of ≥ 10 mature oocytes using AFC and serum AMH were similar. Specifically, the areas under the curve were 0.76 (95%CI 0.66-0.87) and 0.82 (95%CI 0.72-0.92), respectively (p = ns). Moreover, when considering the subgroup of women recruited after day 5 of the cycle (proper random start, n = 52), the areas under the curve did not also differ. Specifically, they resulted in 0.77 (95%CI 0.64-0.89) and 0.83 (95%CI 0.72-0.95), respectively (p = ns). CONCLUSIONS: AFC collected at any time during the menstrual cycle can provide valuable information for the counseling of women with malignancies scheduled for oocyte cryopreservation. Its reliability appears to be non-inferior to that of serum AMH.

Chemotherapy-related damage to ovarian reserve in childhood cancer survivors: interpreting the evidence.

Chemotherapy during childhood damages ovarian reserve and can affect future fertility. However, recent large epidemiological studies showed that the detrimental impact on fertility is less severe if women seek for pregnancy at a younger age. To explain this observation, we hypothesize that the detrimental effects of previous chemotherapy on the ovarian reserve may be attenuated in young adults for two main reasons. Firstly, recent evidence showed that the amount of ovarian reserve is not a critical factor for effective natural conceptions. Provided that the residual ovarian reserve allows regular ovulatory cycles, the chances of pregnancy are similar in women with intact or reduced ovarian reserve. Secondly, ovarian reserve depletion appears to be a phenomenon that is inversely related to the residual ovarian reserve rather than to age. From a mathematical perspective, this kind of regulation intrinsically attenuates the effects of an early loss of a significant amount of primordial follicles. In conclusion, the detrimental effects of chemotherapy on natural fertility may be less severe if women with a history of chemotherapy during childhood seek for pregnancy early. This information should be part of the counseling.

Fertility preservation in women harboring deleterious BRCA mutations: ready for prime time?

Fertility issues have become critical in the management and counseling of BRCA mutation carriers. In this setting four points deserve consideration. (1) Women in general lose their ability to conceive at a mean age of 41 years, thus the suggested policy of prophylactic bilateral salpingo-oophorectomy at age 40 for BRCA mutation carriers does not affect the chances of natural pregnancy. Conversely, if the procedure is chosen at 35 years old, oocyte cryopreservation prior to surgery should be considered. (2) Some evidence suggests that ovarian reserve may actually be partly reduced in BRCA mutations carriers and that the mutation may affect ovarian responsiveness to stimulation. However, these findings are still controversial. (3) Breast cancer is not rare before the age of 40 and fertility preservation after diagnosis can be requested in a significant proportion of BRCA mutation carriers. Thus, a policy of oocyte cryopreservation in young healthy carriers deserves consideration. The procedure could be considered at a young age and in an elective setting, when ovarian stimulation may yield more oocytes of better quality. (4) Preimplantation genetic diagnosis (PGD) could be considered in BRCA mutations carriers, particularly when good quality oocytes have been stored at a young age. Based on the current knowledge, a univocal approach cannot be recommended; in depth patient counseling is warranted.

Long-acting recombinant follicle-stimulating hormone in random-start ovarian stimulation protocols for fertility preservation in women with cancer.

INTRODUCTION: The objective of this study was to assess the effectiveness and potential benefits of the use of long-acting recombinant follicle-stimulating hormone (FSH) in a random-start protocol for fertility preservation in women with cancer. MATERIAL AND METHODS: This is a retrospective before-and-after study performed between February 2013 and December 2015 in women who underwent ovarian hyperstimulation for oocyte cryobanking using a random-start approach. In the first part of the study period, the women were treated with daily recombinant FSH whereas in the second part the stimulation was initiated with long-acting recombinant FSH. The primary aim of the study was to compare the number of oocytes stored in the two study periods. In all, 140 women were ultimately selected. RESULTS: Compared with daily recombinant FSH, the use of the long-acting compound was associated with a reduced number of injections (12.5 ± 3.5 vs. 16.4 ± 0.3; p < 0.001) and a longer duration of stimulation (11.4 ± 1.9 vs. 10.6 ± 1.9, p = 0.01). Conversely, the number of oocytes collected (13.7 ± 9.5 vs. 11.3 ± 7.0, p = 0.10) as well as those cryopreserved (11.0 ± 8.0 vs. 9.5 ± 5.8, p = 0.21) did not differ. CONCLUSIONS: The use of long-acting recombinant FSH in random-start protocols for fertility preservation appears to be a valuable option.

Age-related infertility and unexplained infertility: an intricate clinical dilemma.

A diagnosis of unexplained infertility is commonly made when clinical investigations fail to identify any obvious barriers to conception. As a consequence, unexplained infertility includes several heterogeneous conditions, one being women with age-related infertility. However, the latter represent a peculiar and different situation. Women with age-related infertility may have a different prognosis and may benefit from different treatments. Unfortunately, since fecundity declines with age, discerning between unexplained infertility and age-related infertility becomes more and more difficult as the woman's age increases. In this opinion, with the use of a mathematical model we show that the rate of false positive diagnoses of unexplained infertility increases rapidly after 35 years of age. Using a threshold of 2 years of unfruitful, regular unprotected intercourse, this rate exceeds 50% in women starting pregnancy seeking after 37 years. The scenario is much worse using a threshold of 1 year. From a clinical perspective, extrapolating results obtained in a population of young women with unexplained infertility to those with age-related infertility is not justified. It is noteworthy that, if Assisted Reproductive Technologies are unable to overcome age-related infertility, the older women erroneously labeled with unexplained infertility may receive inappropriate therapies. These may expose women to unjustified risks and waste financial resources. Unfortunately, the available literature about older women is scanty and does not provide valid evidence. Randomized controlled trials aimed at identifying the most suitable clinical management of older women with a normal infertility work-up are pressingly needed.

Sperm cryopreservation and reproductive outcome in male cancer patients: a systematic review.

This systematic review of the literature reports on the use and effectiveness of sperm banking programmes for cancer patients. Thirty studies with 11798 patients were included. The aggregated rate of use of cryopreserved semen was 8% (95% CI 8 to 9%). A statistically significant correlation emerged between the mean and median duration of follow-up and the rate of use (R(2) = 0.46; P = 0.03). The rate of patients discarding their frozen sample was reported in 11 studies. The aggregated rate was 16% (95% CI 15 to 17%). The rate of patients who used their frozen semen and achieved parenthood was reported in 19 papers. The aggregated rate was 49% (95% CI 44 to 53%). The rate of patients achieving parenthood with the use of frozen sperm is low and, from an economical perspective, the effectiveness of programmes of sperm banking might therefore be questioned. On the other hand, the low rate of patients discarding their frozen samples and the correlation between rate of use and duration of follow-up suggest that the calculated 8% rate of use may be an under-estimation and that cumulative rate of use may be substantially higher. Specific studies are, however, required to clarify this issue.

THE LONG-TERM IMPACT OF CONTROLLED OVARIAN HYPERSTIMULATION ON THYROID FUNCTION.

OBJECTIVE: Evidence on the long-term impact of controlled ovarian hyperstimulation (COH) on thyroid function is scarce. To investigate this, we report on serum thyroid-stimulating hormone (TSH) modifications in euthyroid and hypothyroid women during COH and 3 months after the end of the stimulation cycle. METHODS: Women who underwent in vitro fertilization (IVF) and who did not become pregnant were eligible. Cases were women with treated hypothyroidism and basal serum TSH <2.5 mIU/L. Controls were euthyroid women matched to cases by age and basal serum TSH. Women could be included if serum TSH was available at 4 time points: prior to initiating COH (time 1); at the time of human chorionic gonadotropin (hCG) administration (time 2); 16 days after hCG administration (time 3); and 3 months after the end of the IVF cycle (time 4). RESULTS: Thirty-seven case-control pairs were included. Serum TSH at times 1, 2, 3, and 4 was 1.7 ± 0.6, 3.1 ± 1.4, 3.1 ± 1.3, and 2.7 ± 1.7 mIU/L, and 1.7 ± 0.6, 2.9 ± 1.0, 2.7 ± 1.0, and 1.9 ± 0.7 mIU/L among cases and controls, respectively. A statistically significant difference emerged at time 4 (P<.001). In both groups, serum TSH was higher at time 4 compared to time 1. Serum TSH exceeded the recommended threshold of 2.5 mIU/L at time 4 in 51% of cases (95% confidence interval [CI], 35 to 68%) and in 16% of controls (95% CI, 4 to 28%) (P = .003). CONCLUSION: COH seems to have a long-term impact on TSH levels. The magnitude of this effect is particularly pronounced in hypothyroid women.