The use of a pill containing ethinylestradiol-norgestimate improves female sexuality despite the decrease in circulating androgens: a pilot study.

PURPOSE: To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users. MATERIALS AND METHODS: Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg. RESULTS: The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment (p < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (-4.45%, p < 0.0001) and DHEAS (-19.41%, p < 0.0001) serum levels. CONCLUSIONS: Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels.

EE/NGM treatment has a short term non-deteriorating effect on sexuality despite the evident decrease in androgen serum levels.

The impact of COVID-19 pandemic on women with endometriosis: a retrospective cohort study on referral center population.

BACKGROUND: Patients with endometriosis are thought to have been impacted by the COVID-19 pandemic and estimates suggest that 6.2% of them were infected with SARS-CoV-2. METHODS: This is a retrospective cohort study enrolling 284 women at the Polyclinic of Modena between January 2020 and April 2021. Patients were given specific questionnaires to investigate COVID-19 infection and any changes in gynecological symptoms. All patients were also administered the Hospital Anxiety and Depression Syndrome (HADS) Questionnaire to assess the psychological impact of the COVID-19 pandemic. The primary outcome was to assess the clinical impact and any worsening of gynecological symptoms after COVID-19 infection; the secondary outcome was to evaluate the clinical and psychological impact of the COVID-19 pandemic in patients with endometriosis or chronic pelvic pain. RESULTS: A total of 170 women experienced COVID-19 infection, while 114 were consistently negative and asymptomatic for COVID-19. The two groups showed similar baseline. A total of 122 women with COVID-19 infection and 106 COVID-19 negative patients had already the vaccine administration with two doses of vaccine (72.20% vs. 93%, P=0.001). Among the 170 patients affected by COVID-19, 41 (24%) reported worsening gynecologic endometriosis symptoms, during the infection. According to our results, 196 of 284 reported changes in their gynecological health status during pandemic, and 84 reported symptomatic worsening (42.9%); 24% of patients with infection reported feeling slowed down vs. 15.8% of unaffected patients (P=0.065) and 44% of positive patients reported loss of interest in self-care vs. 31% of negative patients (P=0.055). CONCLUSIONS: Patients with endometriosis seemed to have worsening gynecological and psychological clinical status during the pandemic.

The metrics maze in science: navigating academic evaluation without journalistic pressures.

In recent years a troubling trend has emerged in the medical research field, notably in reproductive medicine, manifesting an increased emphasis on quantity over quality in articles published. The pressure to collect copious publication records risks compromising meticulous expertise and impactful contributions. This tendency is exemplified by the rise of 'hyper-prolific researchers' publishing at an extraordinary rate (i.e. every 5 days), prompting a deeper analysis of the reasons underlying this behaviour. Prioritizing rapid publication over Galileo Galilei's systematic scientific principles may lead to a superficial approach driven by quantitative targets. Thus, the overreliance on metrics to facilitate academic careers has shifted the focus to numerical quantification rather than the real scientific contribution, raising concerns about the effectiveness of the evaluation systems. The Hamletian question is: are we scientist or journalist? Addressing these issues could necessitate a crucial re-evaluation of the assessment criteria, emphasizing a balance between quantity and quality to foster an academic environment that values meaningful contributions and innovation.

Luteal phase support in assisted reproductive technology centers: Italian survey.

BACKGROUND: In assisted reproductive cycles (ART), the fine balance of controlling corpus luteum function is severely disrupted. To challenge this iatrogenic deficiency, clinicians aim to provide exogenous support. Several reviews have investigated progesterone route of administration, dosage and timing. METHODS: A survey about luteal phase support (LPS) after ovarian stimulation was conducted among doctors in charge in Italian II-III level ART centers. RESULTS: With regards to the general approach to LPS, 87.9% doctors declare to diversify the approach; the reasons for diversifying (69.7%) were based on the type of cycle. For all the most important administration routes (vaginal, intramuscular, subcutaneous) it appears that in frozen cycles there is a shift towards higher dosages. The 90.9% of the centers use vaginal progesterone, and when a combined approach is required, in 72.7% of cases vaginal administration is combined with injective route of administration. When Italian doctors were asked about the beginning and duration of LPS, 96% of the centers start the day of the pickup or the day after, while 80% of the centers continue LPS until week 8-12. The rate of participation of the centers confirms the low perceived importance of LPS among Italian ART centers, while may be considered quite surprising the relatively higher percentage of centers that measures P level. Tailorization to women's needs is the new objective of LPS: self-administration, good tolerability are the main aspects for Italian centers. CONCLUSIONS: In conclusion, results of Italian survey are consistent to results of main international surveys about LPS.

Gonadotropins in the Management of Couple Infertility: Toward the Rational Use of an Empirical Therapy.

Although epidemiology shows that both men and woman can experience infertility, the female partner usually experiences most of the diagnostic and therapeutic burden. Thus, management of couple infertility is a unique example of gender inequality. The use of exogenous gonadotropins in assisted reproductive technology (ART) to induce multifollicular growth is well consolidated in women, but the same is not done with the same level of confidence and purpose in infertile men. Indeed, the treatment of idiopathic male infertility is based on an empirical approach that involves administration of the follicle-stimulating hormone (FSH) in dosages within the replacement therapy range. This treatment has so far been attempted when the endogenous FSH serum levels are within the reference ranges. According to the most recent evidence, a "substitutive" FSH administration may not be effective enough, while a stimulatory approach could boost spermatogenesis over its basal levels without adverse extragonadal effects. This article aims to describe the rationale behind the empirical application of gonadotropins in couple infertility, highlighting the need for a change in the therapeutic approach, especially for the male partner.

Oral hormonal therapy as treatment option for abnormal uterine bleeding.

BACKGROUND: abnormal uterine bleeding is a very frequent reason for referral to gynaecologists and can deeply influence the quality of life. Once organic causes requiring surgical treatment are ruled out, clinicians should be able to manage these patients conservatively in the most effective way. MATERIALS AND METHODS: a search in PubMed/MEDLINE database was conducted in order to find relevant and recent meaningful sources for this narrative review. RESULTS: LNG-IUS 52 mg is the first-line treatment for non-organic causes. Nevertheless, it could be contraindicated or declined by the patient. Combined oral contraceptives (COC) and progestin-only pills inhibit the hypothalamic-pituitary-ovarian axis, preventing ovulation, and induce endometrial atrophy. Consequently, they are effective in treating AUB. Moreover, brand new pills containing a combination of oestrogens, progestins and GnRH antagonists are now available for the management of AUB related to uterine fibroids. CONCLUSIONS: In daily clinical practice, oral hormonal therapies are convenient and reversible tools to manage AUB when LNG-IUS 52 mg is contraindicated or turn down by the patient. Many oral hormonal therapies are prescribed to treat AUB, but only a few have been approved with this specific indication, therefore further large well-designed studies are necessary in order to compare the efficacy of different pills for treating AUB.

Even though LNG-IUS 52 mg is the first-line treatment for abnormal uterine bleeding, oral hormonal therapies should be effectively managed by gynaecologists in case of contraindications or patient's decline. Contraceptive pills are practical, but further studies are necessary to compare their efficacy and to approve them with the specific AUB indication.

New insights into the role of LH in early ovarian follicular growth: a possible tool to optimize follicular recruitment.

Evidence shows that LH participates in enhancing transition from the early stage to the antral stage of folliculogenesis. It has been demonstrated that functional LH receptors are expressed, albeit at a very low level and even in smaller follicles, during the phase that was traditionally considered to be gonadotrophin independent, suggesting a role for LH in accelerating the rate of progression of non-growing and primary follicles to the preantral/antral stage. Hypogonadotropic hypogonadism, together with other clinical conditions of pituitary suppression, has been associated with reduced functional ovarian reserve. The reduction in LH serum concentration is associated with a low concentration of anti-Müllerian hormone. This is the case in hypothalamic amenorrhoea, pregnancy, long-term GnRH-analogue therapy and hormonal contraception. The effect seems to be reversible, such that after pregnancy and after discontinuation of drugs, the functional ovarian reserve returns to the baseline level. Evidence suggests that women with similar primordial follicle reserves could present with different numbers of antral follicles, and that gonadotrophins may play a fundamental role in permitting a normal rate of progression of follicles through non-cyclic folliculogenesis. The precise role of gonadotrophins in early folliculogenesis, as well as their use to modify the functional ovarian reserve, must be investigated.

Anti-Müllerian Hormone promotes human osteoblast differentiation and calcification by modulating osteogenic gene expression.

OBJECTIVE: To investigate whether the Anti-Müllerian Hormone (AMH), an ovarian hormone belonging to the Transforming Growth Factor ß superfamily, may represent a possible candidate for use as a bone anabolic factor. METHODS: We performed in vitro studies on Human Osteoblasts (HOb) to evaluate the expression and the functionality of AMHRII, the AMH receptor type-2, and investigate the effects of exogenous AMH exposure on osteogenic gene expression and osteoblast functions. RESULTS: We reported the first evidence for the expression and functionality of AMHRII in HOb cells, thus suggesting that osteoblasts may represent a specific target for exogenous AMH treatment. Furthermore, the exposure to AMH exerted a stimulatory effect on HOb cells leading to the activation of osteogenic genes, including the upregulation of osteoblastic transcription factors such as RUNX and OSX, along with increased deposition of mineralized nodules. CONCLUSION: Our findings proved interesting clues on the stimulatory effects of AMH on mature osteoblasts expressing its specific receptor, AMHRII. This study may therefore have translation value in opening the perspective that AMH may be an effective candidate to counteract the bone loss in osteoporotic patients by selectively targeting osteoblast with minimal off-target effect.

Free your patients and yourself from day 2-3: start ovarian stimulation any time in freeze-all cycles.

Ovarian stimulation for assisted reproductive technology is traditionally started in the early follicular phase. The essential rationale is to allow timely follicle growth and oocyte retrieval to ensure synchronization of the in-vitro cultured embryos with the receptive period of the endometrium in a fresh transfer cycle. In addition, conventional thought suggested that follicle recruitment happened only once, around menstruation. A deeper understanding of folliculogenesis, advances in cryobiology and an increasing proportion of freeze-all cycles provide a unique opportunity here. Experience from oncofertility patients as well as infertile women and oocyte donors who underwent ovarian stimulation in different phases of the menstrual cycle, dubbed 'random start' cycles, suggests that the number of oocytes collected and their reproductive potential do not depend on the time of starting ovarian stimulation, although the duration of stimulation and gonadotrophin consumption can vary slightly. It may be time to free both patients and clinics from the obsession with starting ovarian stimulation in the early follicular phase in planned freeze-all cycles. The flexibility provided by random start cycles is one aspect of individualizing treatment to patients' needs.

Evidence for the expression of vasorin in the human female reproductive tissues.

Objective: To investigate the expression and localization of Vasorin (Vasn) in human female reproductive system. Methods: The presence of Vasorin was evaluated by RT-PCR and immunoblotting analyses in patient-derived endometrial, myometrial and granulosa cells (GCs) primary cultures. Immunostaining analyses were performed to detect Vasn localization in primary cultures and in ovarian and uterine tissues. Results: Vasn mRNA was detected in patient-derived endometrial, myometrial and GCs primary cultures without significant differences at the transcript level. Otherwise, immunoblotting analysis showed that Vasn protein levels were significantly higher in GCs than proliferative endometrial stromal cells (ESCs) and myometrial cells. Immunohistochemistry performed in ovarian tissues revealed that Vasn was expressed in the GCs of ovarian follicles at different stages of development with a higher immunostaining signal in mature ovarian follicles such as the antral follicle or on the surface of cumulus oophorus cells than in early-stage follicles. The immunostaining of uterine tissues showed that Vasn was expressed in the proliferative stroma endometrium while it was significantly less expressed in the secretory endometrium. Conversely, no protein immunoreactivity was revealed in health myometrial tissue. Conclusions: Our results revealed the presence of Vasn in the ovary and the endometrium. The pattern of Vasn expression and distribution suggests that this protein may have a role in the regulation of processes such as folliculogenesis, oocyte maturation, and endometrial proliferation.

Treatment algorithms for high responders: What we can learn from randomized controlled trials, real-world data and models.

A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). According to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles ≥11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Müllerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unexpected high response after starting treatment.

De novo variants and recombination at 4q35: Hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the deletion of an integral number of 3.3 kb units of the polymorphic D4Z4 repeat array at 4q35. The prenatal identification of this defect can be carried out on chorionic villi or amniocytes, whereas preimplantation genetic testing for monogenic disorders (PGT-M) requires molecular markers linked to the D4Z4 allele of reduced size. In this context the reliability of this association is crucial. To test the informativeness of the nearby polymorphic markers we investigated recombination at 4q35 using the polymorphic markers D4S1523, D4S163 and D4S139 positioned at 0.55, 0.5 and 0.21 Mb proximal to the D4Z4 array respectively. We determined the probability of recombination events to occur in the D4Z4-D4S1523 interval considering 86 subjects belonging to 12 FSHD families and found a recombination frequency of 14% between D4Z4 and D4S1523. Our study also revealed the occurrence of de novo variants and germline mosaicism. These findings highlight the recombinogenic nature of the 4q subtelomere and indicate that caution should be taken when interpreting PGT-M results. It is advisable that a woman who underwent a PGT-M cycle undertakes a prenatal DNA analysis to confirm the size of the D4Z4 alleles carried by the fetus.

How adenomyosis changes throughout pregnancy: A retrospective cohort study.

OBJECTIVE: To study how adenomyosis changes during pregnancy and to possibly correlate these changes to maternal and fetal outcomes. METHODS: Retrospective exploratory cohort study including 254 women with a pre-conceptional/first-trimester scan to document adenomyosis and known obstetric outcome. If visible, adenomyosis signs were documented in each trimester and postpartum. Mann-Whitney U tests or χ2 tests were used for continuous and categorical variables, respectively. RESULTS: A globular uterus was reported in 79% (n = 52) of women with adenomyosis in the first trimester, in 38% (n = 20) and 2% (n = 1) of women in the second and third trimesters, respectively, and postpartum in 77% (n = 34) of women. Asymmetrical thickening (n = 20, 30%) and cysts (n = 15, 23%) were only visible in 1st trimester. Adenomyosis was associated with miscarriage (odds ratio [OR] 5.9, 95% confidence interval [CI] 2.4-14.9, P < 0.001) also in normal conception only (OR 5.1, 95% CI 1.8-14.2, P = 0.002) or adjusting for maternal age (adjusted OR 5.9, 95% CI 2.3-15.2, P < 0.001). Gestational age at delivery was lower in adenomyosis (P = 0.004); the cesarean section rate was higher than in controls (OR 2.5, 95% CI 1.3-4.8, P = 0.007) also adjusting for age (adjusted OR 2.07, 95% CI 1.06-4.08, P = 0.035). CONCLUSIONS: Signs of adenomyosis were visible but progressively disappeared in pregnancy; adenomyosis was associated with an increased risk of early miscarriage. Prospective studies are needed to confirm our results.

Extended LH administration as a strategy to increase the pool of recruitable antral follicles in hypothalamic amenorrhea: evidence from a case series.

New evidence is indicating a growing role of LH in promoting ovarian follicular growth and maturation, even at the early stages. LH seems to enhance the transition of follicles to the antral stage hence leading to an increase in the so-called functional ovarian reserve (recruitable antral follicles). Hypogonadotropic hypogonadism is characterized by low, and sometimes undetectable, serum LH and FSH levels, which may indeed explain the low anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) found in patients affected by this condition. We report here the cases of two young women affected by hypothalamic amenorrhea (HA) that presented for fertility treatment with very low functional ovarian reserve. The two patients were treated with exogenous LH for 1 and 2 months (extended LH administration: ELHA) at the dose of 187.5 IU LH every day and 150 IU LH every other day, respectively. In both the cases there was an increase in serum AMH levels and in the AFC. In one patient, the AMH and AFC increased from a baseline 1.3 ng/ml and 8 to 2.3 ng/ml and 14 at end of treatment, respectively. In the second case, serum AMH and AFC increased from 0.4 ng/ml and 6 to 1.6 ng/ml and 13, respectively. One patient underwent ovarian stimulation before and after ELHA, showing an increase in the number of mature oocytes recruited (3 versus 8 metaphase II (MII) oocytes before and after, respectively). The second patient underwent an IVF cycle after ELHA resulting in the retrieval of six MII oocytes and an ongoing pregnancy following transfer of a single blastocyst. Women with HA are characterized by chronic, low levels of gonadotrophins, which may impact not only on the cyclic recruitment of follicles but also the progression of small growing follicles through the first stages of folliculogenesis. Some women with HA may in fact show very low serum AMH and AFC. Our case series shows that the administration of LH at a dose of at least 150-187.5 IU every day or every other day may contribute to a clinically evident increase in the functional ovarian reserve (AFC), and probably accounts for a positive effect of LH on the progression of follicles throughout the early stages of folliculogenesis.

The number and rate of euploid blastocysts in women undergoing IVF/ICSI cycles are strongly dependent on ovarian reserve and female age.

STUDY QUESTION: Can the possibility of having at least one euploid blastocyst for embryo transfer and the total number of euploid blastocysts be predicted for couples before they enter the IVF programme? SUMMARY ANSWER: Ovarian reserve and female age are the most important predictors of having at least one euploid blastocyst and the total number of euploid blastocysts. WHAT IS KNOWN ALREADY: The blastocyst euploidy rate among women undergoing ART has already been shown to significantly decrease with increasing female age, and the total number of euploid embryos is dependent on the blastocyst cohort size. However, the vast majority of published studies are based on retrospective analysis of data. STUDY DESIGN, SIZE, DURATION: This prospective analysis included 847 consecutively enrolled couples approaching their first preimplantation genetic testing for aneuploidies (PGT-A) cycle between 2017 and 2020. Only couples for whom ejaculated sperm was available and women with a BMI of <35 kg/m2 were included in the study. Only the first cycle was included for each patient. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at an IVF centre where, for all patients, the planned treatment was to obtain embryos at the blastocyst stage for the PGT-A programme. The impact of the following covariates was investigated: a woman's serum AMH level, age, height, weight and BMI and a man's age, height, weight, BMI, sperm volume and sperm motility and morphology. The analysis was performed with a machine learning (ML) approach. Models were fit on the training set (677 patients) and their predictive performance was then evaluated on the test set (170 patients). MAIN RESULTS AND ROLE OF CHANCE: After ovarian stimulation and oocyte insemination, 40.1% of couples had at least one blastocyst available for the PGT-A. Of 1068 blastocysts analysed, 33.6% were euploid. Two distinct ML models were fit: one for the probability of having at least one euploid blastocyst and one for the number of euploid blastocysts obtained. In the training set of patients, the variable importance plots of both models indicated that AMH and the woman's age are by far the most important predictors. Specifically, a positive association between the outcome and AMH and a negative association between the outcome and female age appeared. Gradient-boosted modelling offers a greater predictive performance than generalized additive models (GAMs). LIMITATIONS, REASONS FOR CAUTION: The study was performed based on data from a single centre. While this provides a robust set of data with a constant ART process and laboratory practice, the model might be suitable only for the evaluated population, which may limit the generalization of the model to other populations. WIDER IMPLICATIONS OF THE FINDINGS: ML models indicate that for couples entering the IVF/PGT-A programme, ovarian reserve, which is known to vary with age, is the most important predictor of having at least one euploid embryo. According to the GAM, the probability of a 30-year-old woman having at least one euploid embryo is 28% or 47% if her AMH level is 1 or 3 ng/ml, respectively; if the woman is 40 years old, this probability is 18% with an AMH of 1 ng/ml and 30% with an AMH of 3 ng/ml. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant from Gedeon Richter. The authors declared no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.