The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization.

PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

Predicting the total number of retrieved oocytes following double ovarian stimulation (DuoStim).

STUDY QUESTION: Can anti-Müllerian hormone (AMH) help predict how many oocytes will be retrieved following double stimulation (DuoStim)? SUMMARY ANSWER: A simple clinical tool can use serum AMH values to predict ovarian response following DuoStim in IVF cycles. WHAT IS ALREADY KNOWN: The knowledge that multiple follicular waves arise during a single ovarian cycle has led to the introduction of unconventional ovarian stimulation protocols. The DuoStim protocol involves two successive ovarian stimulations performed during a single ovarian cycle and has been proposed as an approach for patients with poor ovarian response and for medical fertility preservation. As AMH has been used as a marker of ovarian reserve and stimulation response, the current study aimed to investigate the diagnostic performance of AMH in predicting the number of retrieved oocytes following DuoStim. STUDY DESIGN, SIZE, DURATION: This is a retrospective observational study involving 116 patients who received IVF treatment from January 2021 to September 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a private IVF centre. Only patients who had their AMH measured prior to treatment and had complete patient records regarding their clinical and IVF/ICSI cycle characteristics were included. The primary outcome was the correlation between AMH values and the number of oocytes retrieved following DuoStim. Parametric and non-parametric tests were used to compare baseline characteristics and outcomes. Spearman's R was used to analyse correlations between variables, while the C statistic was used to calculate the diagnostic performance of AMH. MAIN RESULTS AND THE ROLE OF CHANCE: AMH levels were significantly correlated with the total number of oocytes retrieved after the DuoStim (R 0.61; CI 0.44-0.70; P < 0.0001). The difference in the total number of oocytes retrieved between the first (median 4 oocytes, interquartile range (IQR) 2-6) and second (median 6 oocytes, IQR 3.2-8) stimulation was statistically significant (P < 0.0001). However, there was no significant difference in the number of mature oocytes that were retrieved (median of 3 and 4 in the first and second stimulations, respectively). After the first stimulation, 68% of patients had at least one blastocyst available, while after the second stimulation, 74% did (NS). Based on linear regression, each 0.25 ng/ml increase in basal AMH corresponds to one additional oocyte recovered at the end of both stimulations (R2: 0.32, P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: The results are limited owing to the observational nature of the study and the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: Counselling infertile couples regarding the intermediate outcome of IVF (i.e. number of retrieved oocytes) is one of the most demanding tasks that clinicians face. To our knowledge, this is the first study that provides an easy-to-use clinical tool that enables the quantitative prediction of ovarian response following DuoStim, based on serum AMH values. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization.

PURPOSE: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? METHODS: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. RESULTS: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response. CONCLUSION: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

Sperm donation: an alternative to improve post-ICSI live birth rates in advanced maternal age patients.

STUDY QUESTION: Can sperm donation increase live birth rates following ICSI in advanced maternal age (AMA) patients? SUMMARY ANSWER: Sperm donation increases the live birth rate in AMA ICSI cycles. WHAT IS KNOWN ALREADY: In ICSI practice, sperm donation has been predominantly applied to overcome male infertility. The involvement of paternal age and lower sperm quality in the severe reduction in fertility observed in AMA patients remains to be clarified. STUDY DESIGN, SIZE, DURATION: Retrospective multicenter cohort study including data generated between 2015 and 2019 from 755 ICSI cycles achieving a fresh embryo transfer, of which 337 were first homologous cycles (normozoospermic partner sperm and homologous oocytes) and 418 were first sperm donation cycles (donor sperm and homologous oocytes). The association of sperm origin (partner vs donor) with live birth was assessed by multivariate analysis in non-AMA (<37 years, n = 278) and AMA (≥37 years, n = 477) patients, separately, including in the model all variables previously found to be associated with live birth in a univariate analysis (number of MII oocytes recovered, number of embryos transferred, and maternal age). ICSI outcomes were compared between sperm donation and homologous cycles in overall, non-AMA and AMA patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in three fertility clinics and included 755 Caucasian patients aged 24-42 years undergoing their first homologous or sperm donation ICSI cycle achieving a fresh embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: The multivariate analysis revealed that sperm donation was positively associated with the likelihood of a live birth independently of all other variables tested in AMA (P = 0.02), but not in non-AMA patients. Live birth, delivery, and miscarriage rates differed substantially between sperm donation and homologous AMA cycles; live birth and delivery rates were 70-75% higher (25.4% vs 14.5% and 22.5% vs 13.5%, respectively; P < 0.01), while miscarriage occurrence was less than half (18.0% vs 39.5%; P < 0.01) in sperm donation compared to homologous AMA cycles. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective nature, differences in patients profiles between sperm donation and homologous-control groups and varying proportion of donor cycles between fertility centers, although these variations have been controlled for in the statistical analysis. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that sperm donation increases live birth rates while reducing miscarriage occurrence in AMA patients, and thus may be a valid strategy to improve ICSI outcomes in this growing and challenging patient group. STUDY FUNDING/COMPETING INTEREST(S): N/A. TRIAL REGISTRATION NUMBER: N/A.

Ultrasound-guided fine needle aspiration biopsy (FNAB) demonstrating upper distal extremity metastasis of lung adenocarcinoma: a case report and review of the literature.

Due to early metastasis and delayed diagnosis, lung cancer is the leading cause of cancer-related deaths. Although the most common metastasis sites are brain, bone, lung, adrenal glands, liver, and extra-thoracic lymph node, soft tissues, such as skeletal muscles, skin, and subcutaneous tissues, can also be undermined. This article aims to report the first case of an asymptomatic radial extensor muscle metastasis generating from a lung adenocarcinoma that was diagnosed by ultrasound-guided fine-needle aspiration biopsy (FNAB).

Venous thromboembolism during mycoplasma pneumoniae infection: case report and review of the literature.

Mycoplasma pneumoniae infection is frequent but generally mild or self-limiting. Approximately 10% of cases develop clinical signs of pneumonia with "atypical" radiographic pattern. However, mycoplasma pneumoniae can be responsible for a variety of extrapulmonary manifestations, potentially involving all systems and apparatuses. Although exact pathophysiological mechanisms are not completely known, these could be secondary to direct invasion of the target organ, immunological damage due to molecular mimicry or vascular obstruction. A 45-year-old man was admitted to Internal Medicine Unit because of fever, dry cough and fatigue lasting 15 days. Fever disappeared after starting clarithromycin. About 72 h after admission the patient complained of right calf pain and tachypnea. The presence of anti-mycoplasma antibodies suggested mycoplasma pneumoniae infection. Moreover, a diagnosis of venous thrombo-embolism was performed. Given the absence of classical risk factors for thrombosis, patient was investigated for inherited and acquired thrombophilia and tested positive for antiphospholipid antibodies. A review of the English literature on the association between m. pneumoniae and pulmonary embolism will be provided in order to underline the possible pathogenetic role of antiphospholipid antibodies in this setting. Clinicians should outweigh risk and benefits for LMWH prophylaxis case by case considering these adjunctive pro-thrombotic mechanisms in patients m. pneumoniae infection.

Exploring the pros and cons of new approaches for gamete cross-border donation based on fresh and vitrified oocytes.

As highlighted by European statistics, the employment of donor oocytes is a growing option for women who cannot make use of their own gametes. As the potential recipients are continuously increasing in number, a donor programme which satisfies this demand is mandatory. Improvements in cryopreservation techniques, like oocyte and embryo vitrification, have led to the overcoming of the sequence of stimulation-retrieval-transfer both from a spatial and a temporal point of view, with the development of cryobanks of oocytes permitting crossborder donation. However, while some studies report comparable success when using vitrified and fresh oocytes we still need to investigate whether the use of fresh oocytes give higher live birth rate than cryopreserved ones, when the same number of oocytes are given. The performance of embryo cryopreservation, conversely, seems to be more reliable. A novel approach based on the shipment of frozen sperm from the recipient's country to the oocyte donor's one, where fresh oocytes are inseminated and the resulting embryos frozen and transported back to the referring IVF centre to perform a frozen embryo transfer may be a good strategy. We believe that the use of frozen embryos from fresh oocytes could be associated with a higher cumulative live birth rate per cycle, while favouring personalised oocyte recipient care with a flexible number of oocytes assigned and limiting the burden of travelling abroad.

DNA extraction from soil by EZ1 advanced XL (Qiagen).

EZ1 Advanced XL (Qiagen) is an instrument designed to purify automatically nucleic acids from a wide variety of samples: different protocols for DNA extraction from forensic samples are pre-loaded into special EZ1 Advanced XL DNA Investigator Cards. The present study focuses on DNA extraction from biological samples (blood, saliva, sperm) mixed with 3 different types of soils (loam, silt, sandy), using a modified version of the Manufacturer standard protocol. In order to create several traces in the soil, we used biological samples (blood, saliva, sperm) from known donors. Quantification data, reliability and trends in STRs typing success rates using two different commercial multiplexes were evaluated. EZ1 modified DNA extraction protocol allows to recover DNA free of inhibitors and in good quantity for downstream applications.

A novel transnational fresh oocyte donation (TOD) program based on transport of frozen sperm and embryos.

STUDY QUESTION: What is the clinical efficacy of an oocyte donation program based on the transportation of frozen semen and embryos between two countries? SUMMARY ANSWER: The transnational oocyte donation program is efficient and reliable and it could provide a first-line strategy to overcome the lack of donors in some countries. WHAT IS KNOWN ALREADY: While there is increasing need for donated oocytes, in many countries the availability of donors is still insufficient to cover the therapeutic demands, and patients are referred abroad for treatment. Since embryo cryopreservation is reliable and efficient, we propose a strategy based on frozen embryos instead of frozen oocytes to satisfy the increasing demand for cross border oocyte donation. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study including 630 patients treated from December 2015 to July 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women were treated with elective vitrified-thawed embryo shipping and embryo transfer (ET) between two IVF clinics, one in Spain and one in Italy. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2617 embryos were created for the 630 patients and the survival rate after warming was 98.5%. After the first ET the live birth rate (LBR) was 30.6%. In 476 patients (75.5%), embryos were transferred at the cleavage stage (Day 2 or 3) and the LBR was 29.2%. Vitrified blastocysts were available for 154 patients (24.5%) and the LBR was 35%. Among patients who did not achieve a pregnancy after the first frozen ET (FET), 92.5% had at least one frozen embryo for successive procedures. 213 patients underwent a second FET. The LBR at the second FET was 30%. The cumulative LBR at the end of the observation period was 39.3%. LIMITATIONS, REASONS FOR CAUTION: The study design was retrospective. A direct comparison with vitrified oocyte donors cycle and subsequent fresh ET would have permitted to compare this strategy versus the current standard based on vitrified gametes. WIDER IMPLICATIONS OF THE FINDINGS: The LBR found in our study is more than acceptable and seems to be higher than what reported with vitrified oocytes. The transnational fresh oocyte donation program may have several advantages over the shipment of vitrified oocytes: similarly to the fresh oocyte donation program it allows for personalized care in oocyte recipient, which is provided by assigning a flexible number of oocytes, and at the same time it maintains the benefit of a frozen ART program permitting scheduling flexibility. The TOD program is efficient and may be proposed as a first-line strategy for distance and inter-countries oocyte donation programs. STUDY FUNDING, COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NA.

Last-male sperm precedence in Rhynchophorus ferrugineus (Olivier): observations in laboratory mating experiments with irradiated males.

The Red Palm Weevil (RPW) Rhynchophorus ferrugineus (Olivier 1790) is an invasive pest from southeastern Asia and Melanesia that in the last 30 years has spread widely in the Middle East and Mediterranean Basin. Its stem-boring larvae cause great damage to several palm species of the Arecaceae family, many of which are economically important for agricultural and ornamental purposes. Therefore, great attention has recently been focused in studying this species to identify sustainable and effective eradication strategies, such as sterile insect technique (SIT). The rapid spread of RPW is associated with its high reproductive success. To evaluate the suitability of a SIT strategy, particular physiological and behavioral aspects of RPW reproduction, such as the presence of polyandry and post-copulatory sperm selection mechanisms, were investigated. To determine paternity of progeny from multiply mated females, double-crossing experiments were carried out confining individual females with either a wild-type male or a γ-irradiated male (Co-60). Fecundity and fertility of females were scored to evaluate post-copulatory sperm selection. Results showed that progeny were almost exclusively produced by the sperm of the second male, suggesting that a last-male sperm precedence is expressed at high levels in this species, and providing interesting insights for an area-wide RPW management strategy such as the SIT.

Genetic and morphological studies of Trichosirocalus species introduced to North America, Australia and New Zealand for the biological control of thistles.

Trichosirocalus horridus sensu lato has been used as a biological control agent of several invasive thistles (Carduus spp., Cirsium spp. and Onopordum spp.) since 1974. It has been recognized as a single species until 2002, when it was split into three species based on morphological characters: T. horridus, Trichosirocalus briesei and Trichosirocalus mortadelo, each purported to have different host plants. Because of this taxonomic change, uncertainty exists as to which species were released in various countries; furthermore, there appears to be some exceptions to the purported host plants of some of these species. To resolve these questions, we conducted an integrative taxonomic study of the T. horridus species complex using molecular genetic and morphological analyses of specimens from three continents. Both mitochondrial cytochrome c oxidase subunit I and nuclear elongation factor 1α markers clearly indicate that there are only two distinct species, T. horridus and T. briesei. Molecular evidence, morphological analysis and host plant associations support the synonymy of T. horridus (Panzer, 1801) and T. mortadelo Alonso-Zarazaga & Sánchez-Ruiz, 2002. We determine that T. horridus has been established in Canada, USA, New Zealand and Australia and that T. briesei is established in Australia. The former species was collected from Carduus, Cirsium and Onopordum spp. in the field, whereas the latter appears to be specific to Onopordum.

The ovarian response to controlled stimulation in IVF cycles may be predictive of the age at menopause.

STUDY QUESTION: Can the number of oocytes retrieved in IVF cycles be predictive of the age at menopause? SUMMARY ANSWER: The number of retrieved oocytes can be used as an indirect assessment of the extent of ovarian reserve to provide information on the duration of the reproductive life span in women of different ages. WHAT IS KNOWN ALREADY: Menopause is determined by the exhaustion of the ovarian follicular pool. Ovarian reserve is the main factor influencing ovarian response in IVF cycles. As a consequence the response to ovarian stimulation with the administration of gonadotrophins in IVF treatment may be informative about the age at menopause. STUDY DESIGN, SIZE, DURATION: In the present cross-sectional study, participants were 1585 infertile women from an IVF clinic and 2635 menopausal women from a more general population. PARTICIPANTS/MATERIALS, SETTING, METHODS: For all infertile women, the response to ovarian stimulation with gonadotrophins was recorded. For menopausal women, relevant demographic characteristics were available for the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: A cubic function described the relationship between mean numbers of oocytes and age, with all terms being statistically significant. From the estimated residual distribution of the actual number of oocytes about this mean, a distribution of the age when there would be no oocytes retrieved following ovarian stimulation was derived. This was compared with the distribution of the age at menopause from the menopausal women, showing that menopause occurred about a year later. LIMITATIONS, REASONS FOR CAUTION: The retrieved oocyte data were from infertile women, while the menopausal ages were from a more general population. WIDER IMPLICATIONS OF THE FINDINGS: In the present study, we have shown some similarity between the distributions of the age when no retrieved oocytes can be expected after ovarian stimulation and the age at menopause. For a given age, the lower the ovarian reserve, the lower the number of retrieved oocytes would be and the earlier the age that menopause would occur. STUDY FUNDING/COMPETING INTERESTS: This work was supported by a grant from the Italian Ministry of Health (GR-2009-1580036). There are no conflicts of interest.

Protein modification as oxidative stress marker in follicular fluid from women with polycystic ovary syndrome: the effect of inositol and metformin.

PURPOSE: The purpose of this study was to evaluate the oxidative stress status (OS) of follicular fluid (FF) and the oocyte quality in women with polycystic ovary syndrome (PCOS) undergoing different ovarian stimulation protocols. METHODS: FF samples were collected after gonadotropin administration in association or not with metformin or D-chiro-inositol (DCI). OS status was then evaluated by checking the follicular fluid protein oxidation profile after specific labeling of aminoacidic free-SH groups, and two-dimensional electrophoresis followed by qualitative and semiquantitative analysis. Oocyte quality was assessed by international morphological criteria. RESULTS: Our data indicated that both treatments, even if to different extent, recovered a significantly high level of free-SH groups in FF proteins of PCOS women clearly indicating a decrease of OS level with respect to that found in FF samples from gonadotropins alone treated women. A higher number of good quality MII oocytes was also observed in DCI (P < 0.05) or metformin (P < 0.05) study groups in comparison to untreated control group. CONCLUSION: A natural supplement and a drug both showed a statistically significant positive effect on follicular milieu by decreasing the oxidative damage on FF proteins, as well as in recovering good quality oocytes.

Improvements in metabolic abnormalities among overweight schizophrenia and bipolar disorder patients.

PURPOSE: As weight-gain and metabolic abnormalities during treatment with psychotropic drugs are of great concern, we evaluated effects of psycho-education and medical monitoring on metabolic changes among severely mentally ill patients. MATERIALS AND METHODS: During repeated, systematic psycho-education about general health among 66 consecutive patients diagnosed with DSM-IV-TR schizophrenia (n=33) or type-I bipolar disorder (n=33), we evaluated (at intake 1, 2, 3, and 6 months) clinical psychiatric status, treatments and doses, recorded physiological parameters, and assessed attitudes about medication. RESULTS: At intake, patients with schizophrenia vs bipolar disorder were receiving 3-7 times more psychotropic medication, with 14% higher initial body-mass index (BMI: 29.1 vs 25.6 kg/m²), 12 times more obesity, and significantly higher serum lipid concentrations. During 6-months follow-up, among bipolar disorder patients, polytherapy and serum lipid concentrations declined more than among schizophrenia patients (e.g., total cholesterol+triglycerides, by 3.21 vs 1.75%/month). BMI remained stable. Declining lipid levels were associated with older age, bipolar disorder, being unemployed, higher antipsychotic doses, and lower initial BPRS scores (all P ≤ 0.001). CONCLUSIONS: Psychotropic treatments were more complex, and metabolic measures more abnormal among bipolar disorder than schizophrenia patients. Intensive psycho-education, clinical monitoring, and encouragement of weight-control for six months were associated with improvements in metabolic measures (but not to BMI), and more realistic attitudes about medication.

The combination of genetic variants of the FSHB and FSHR genes affects serum FSH in women of reproductive age.

STUDY QUESTION: What is the effect of FSHB-211G>T together with the FSHR 2039 A>G on serum FSH in women? SUMMARY ANSWER: Serum FSH levels are affected by the combination of genetic polymorphisms in FSHR and FSHB. WHAT IS KNOWN ALREADY: The relationship between SNPs of the FSHR gene and serum FSH has not been completely clarified. Genetic variants of the FSHB gene have been associated with variation in gene transcription and serum FSH levels in men. No data have been published on the effect of the FSHB-211G>T in women, alone or in combination with the FSHR 2039 A>G. STUDY DESIGN, SIZE, DURATION: This study was a prospective study including 193 healthy women of reproductive age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile and otherwise healthy eumenorrheic women (n = 193) with normal BMI and serum FSH levels were recruited for the study. In all women early follicular phase FSH and AMH were measured by commercial assays, and antral follicle count was measured by transvaginal ultrasound. Genomic DNA was purified from total peripheral blood and genotyping for the two SNPs was performed. MAIN RESULTS AND THE ROLE OF CHANCE: No significant gradients of increasing or decreasing Day 3 FSH across the FSHR 2039 (AA/AG/GG) and FSHB-211 (GG/GT/TT) genotypes, respectively, were observed. When women were stratified according to the FSHR 2039, and FSHB-211 genotypes a statistically significant reduction of d3 FSH was shown in the group of women with the FSHB-211 GT + TT/FSHR2039 AA genotype compared with the FSHB-211 GG/FSHR2039 GG genotype, hence confirming a possible additive effect of the different SNPs in FSHR and FSHB on regulating serum FSH. LIMITATIONS, REASONS FOR CAUTION: This finding requires an independent confirmation. However, it confirms the relationship between serum FSH and FSHB together with FSHR gene polymorphisms already reported in males. WIDER IMPLICATIONS OF THE FINDINGS: The knowledge of the FSHB/FSHR genotype combination is fundamental for the proper interpretation of serum FSH levels in women of reproductive age. STUDY FUNDING/COMPETING INTERESTS: Merck Serono supported the study in the form of a research grant for the laboratory session. None of the authors have any competing interest to declare.