Testicular torsion and subsequent testicular function in young men from the general population.

STUDY QUESTION: Is prior testicular torsion associated with testicular function (semen quality and reproductive hormones) in young men from the general population? SUMMARY ANSWER: In young men from the general population, no differences in semen parameters were observed in those who had experienced testicular torsion compared to controls and observations of higher FSH and lower inhibin B were subtle. WHAT IS KNOWN ALREADY: Testicular function may be impaired after testicular torsion, but knowledge is sparse and based on studies with small sample sizes and no control group or a less than ideal control group. STUDY DESIGN, SIZE, DURATION: A cross-sectional population-based study was carried out including 7876 young Danish men with unknown fertility potential, examined from 1996 to 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: All men (median age 19.0 years) had a physical examination, provided a blood and semen sample, and filled in a questionnaire including information about prior testicular torsion, birth, lifestyle and current and previous diseases. Markers of testicular function, including testis volume, semen parameters and reproductive hormones, were compared between men operated for testicular torsion and controls, using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The average participation rate was 24% for the entire study period. In total, 57 men (0.72%) were previously operated for testicular torsion (median age at surgery 13.4 years) of which five had only one remaining testicle. Men with prior testicular torsion were more often born preterm (25% versus 9.5% among controls), and they had significantly higher FSH and lower inhibin B levels, and a lower inhibin B/FSH ratio than controls in crude and adjusted models. The association was mainly driven by the subgroup of men who had undergone unilateral orchiectomy. No differences in semen parameters were observed. LIMITATIONS, REASONS FOR CAUTION: A limitation is the retrospective self-reported information on testicular torsion. Also, results should be interpreted with caution owing to the high uncertainty of the observed differences. WIDER IMPLICATIONS OF THE FINDINGS: Overall, the results of our study are reassuring for men who have experienced testicular torsion, especially when treated with orchiopexy, for whom reproductive hormone alterations were subtle and without obvious clinical relevance. Our study found no differences in semen parameters, but follow-up studies are needed to assess any long-term consequences for fertility. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received from the Danish Ministry of Health; the Danish Environmental Protection Agency; the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); A.P. Møller and wife Chastine Mckinney Møllers Foundation; Svend Andersens Foundation; the Research Fund of the Capital Region of Denmark; and ReproUnion (EU/Interreg). The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

The relationship between testicular tumour characteristics and azoospermia: a systematic review.

Subfertility is a risk factor for testicular cancers (TT), and conversely, TT may induce subfertility due to local and regional toxic effects. We aimed to identify the association between TT characteristics and pre-orchidectomy azoospermia. A systematic review of the literature was performed according to the PRISMA checklist. Overall, eight non-randomised studies involving 469 men with TT (azoospermia, n = 57; no azoospermia n = 412) were included in the qualitative analysis. Bilateral TT (12.3% vs 2.9% in non-azoospermia), non-seminoma germ cell tumours (6.4% vs 1.9%), germ cell neoplasia in-situ (GCNIS) (11.1% vs 1.2%), stage 2-3 disease (22.2% vs 0%), Sertoli Cell only (SCO) on biopsy (60% vs 37.5%) and a history of undescended testis (UDT) (66.7% vs 50%) were more common in azoospermic men. FSH levels are higher (18.7-23.2 mIU/L vs <0.1-8 mIU/L in non-azoospermia), testosterone is lower, and testis size are smaller (lower range 1 mL vs 10 mL) in men with azoospermia. Leydig cell tumours and hyperplasia were only detected in men with azoospermia. In summary, bilateral TT, GCNIS, higher tumour stage, smaller testes, SCO and history of UDT may have direct effects on spermatogenesis. Small testis, raised FSH and low testosterone may reflect reduced testicular function in azoospermic men. Performing a pre-orchidectomy semen analysis is important to identify those with azoospermia or severe oligospermia in order to plan for cryopreservation or onco-TESE in young men who wish to conceive.

Evaluation of fertility and embryo implantation in rats after the oral administration of Salvia officinalis (sage) extract / Evaluación de la fertilidad y la implantación de embriones en ratas después de la administración oral de extracto de Salvia officinalis (salvia)

SUMMARY: In Saudi Arabia, it is widely believed that women with reproductive problems can use the extract of the sage plant as a tea drink. This study was conducted to investigate the effects of this herb on the fertility of female rats and embryo implantation. Forty-eight Wistar virgin female rats were divided into four groups at random, with 12 rats in each group. The control group received distilled water orally. The three treatment groups received different concentrations of sage extract: 15, 60, or 100 mg/kg for 14 days before mating, then mated with a male and sacrificed on the 7th day of gestation, the uterine horns removed, and photographed. The total body weight of mothers, weight of uteri and ovaries and number of fetuses were determined. Ovarian and uteri tissues were cut into 5 µ sections and stained with hematoxylin and eosin. Serum FSH, LH were determined by the ELISA method. The present study showed that low dose of sage (15 mg/kg) have no effects on serum concentration levels of FSH and LH hormones, also has no effect on the number of growing follicles. The present study showed a significant differences (P≤0.05) in body weight, ovary and uterus weight in the groups treated with high doses of Salvia officinalis as compared to control group. Also a significant differences (P≤0.05) found in FSH, LH hormones. Histological study showed overall histomorphological structural configurations including growing and matured graafian follicular countable changes, besides a number of corpora lutea and regressed follicles in the treated groups with high doses of Salvia officinalis as compared to control group. The researchers concluded that the extract of the sage plant with high doses can stimulate the growth graafian follicles and improve fertility in female rats.

RESUMEN: En Arabia Saudita, se cree ampliamente que las mujeres con problemas reproductivos pueden usar el extracto de la planta de salvia como bebida de té. Este estudio se realizó para investigar los efectos de esta hierba sobre la fertilidad de las ratas hembra y la implantación del embrión. Se dividieron cuarenta y ocho ratas hembra vírgenes Wistar en cuatro grupos al azar, con 12 ratas en cada grupo. El grupo control recibió agua destilada por vía oral. Los tres grupos de tratamiento recibieron diferentes concentraciones de extracto de salvia: 15, 60 o 100 mg/kg durante 14 días antes del apareamiento, luego se aparearon con un macho y se sacrificaron el día 7 de gestación, se extrajeron los cuernos uterinos y se fotografiaron. Se determinó el peso corporal total de las madres, el peso del útero y los ovarios y el número de fetos. Los tejidos ováricos y uterinos se cortaron en secciones de 5 µ y se tiñeron con hematoxilina y eosina. FSH sérica, LH se determinaron por el método ELISA. El presente estudio mostró que dosis bajas de salvia (15 mg/kg) no tienen efectos sobre los niveles de concentración sérica de las hormonas FSH y LH, tampoco tienen efecto sobre el número de folículos en crecimiento. El presente estudio mostró diferencias significativas (P≤0,05) en el peso corporal, peso de ovario y útero en los grupos tratados con altas dosis de Salvia officinalis en comparación con el grupo control. También se encontraron diferencias significativas (P≤0,05) en las hormonas FSH, LH. El estudio histológico mostró configuraciones estructurales histomorfológicas generales que incluyen cambios contables en los folículos maduros (de Graaf) y en crecimiento, además de una cantidad de cuerpos lúteos y folículos en regresión en los grupos tratados con altas dosis de Salvia officinalis en comparación con el grupo de control. Los investigadores concluyeron que el extracto de la planta de salvia en altas dosis puede estimular el crecimiento de los folículos maduros y mejorar la fertilidad en ratas hembra.

Effect of turmeric on adiponectin, sexual function and sexual hormones in stressed mice.

Sexual function is essential for species survival. Melanocortin, progesterone, and estrogen can improve sexual function and they are modulated by adiponectin hormone which can be increased by Turmeric. In various studies shows Turmeric ability that is easily accessible to increase serum adiponectin levels. Therefore, the researchers decided to conduct a study to determine the effect of turmeric on serum adiponectin levels, sexual behavior, and profile of steroid hormones in stressed mice. Thirty female mice, six in each group (1. control group, 2. mice that received stress, 3. stress mice received 100 mg/kg turmeric (extract daily) for 4 weeks, 4. stress mice received turmeric (extract daily) for 4 weeks and also received adiponectin antagonist, and 5. stress groups received adiponectin antagonist), were used in the current study. The mice first underwent blood sampling. Then all mice were subjected to stress testing before the intervention except one group, which considered as a control group. The intervention in this study was done as a 100 mg/kg turmeric extract that was gavaged daily for each mouse. After the intervention, all mice were tested for sexual behavior, and then blood samples were taken to check serum levels of adiponectin, estradiol, progesterone and prolactin. So, the results showed before the intervention there were no significant difference among 5 group in levels of adiponectin (p = 0.145), estradiol (p = 0.148), progesterone (p = 0.166) and prolactin (p = 0.206) but after intervention there were significant difference between 5 group in levels of adiponectin, estradiol and progesterone (p < 0.001). Also there was significant difference among 5 groups in sexual behavior (p < 0.001). Therefore, consumption of turmeric, which increases serum adiponectin in the stressed mice, can improve sexual function and estradiol hormones profiling.

Biochemical predictors of structural hypothalamus-pituitary abnormalities detected by magnetic resonance imaging in men with secondary hypogonadism.

PURPOSE: Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic-pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. METHODS: A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. RESULTS: In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62-0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. CONCLUSION: In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.

Transcription factor immunohistochemistry in the diagnosis of pituitary tumours.

OBJECTIVE: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours. METHODS: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent's Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the 'histological cohort'. Patients with at least 12 months of post-surgical follow-up were included in the subgroup 'clinical cohort'. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying 'higher-risk' histological subtypes was assessed. RESULTS: There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher-risk histological subtype tumours. These were associated with tumour invasiveness (P = 0.050), early recurrence (12-24 months, P = 0.013), shorter median time to recurrence (49 (IQR: 22.5-73.0) vs 15 (IQR: 12.0-25.0) months, P = 0.005) and reduced recurrence-free survival (P = 0.031). CONCLUSIONS: Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

Insuficiencia ovárica primaria en adolescentes: revisión de la literatura a propósito de un caso clínico / Primary ovarian insufficiency in adolescents: review of the literature regarding a clinical case

El objetivo de este manuscrito es realizar una revisión y actualización de la literatura de la insuficiencia ovárica primaria (IOP) en población adolescente, a partir del diagnóstico, manejo y seguimiento de un caso clínico. La insuficiencia ovárica primaria se define como la menopausia en una mujer antes de los 40 años, acompañada de amenorrea, hipogonadismo hipergonadotrópico e infertilidad. Su prevalencia varía entre 1 a 2%, y en mujeres menores de 20 años su prevalencia es un caso de cada 10,000. Aunque se sabe que muchas afecciones pueden llevar a una IOP, la más común es la causa idiopática. La presentación clínica es diversa, y varios trastornos diferentes pueden también, llevar a esta condición. CASO CLÍNICO: Se presenta el caso de una adolescente de 17 años, previamente sana, con historia de amenorrea secundaria, no embarazada, con examen físico general y ginecológico normal. Se solicita estudio analítico complementario resultando con niveles de hormona folículo estimulante (FHS), estradiol (E2) y hormona antimülleriana (AMH) compatibles con una insuficiencia ovárica como la observada en la posmenopausia. Se inicia terapia hormonal (TH) clásica con estradiol y progesterona, siendo posteriormente reemplazada por anticoncepción hormonal combinada (AHC) oral, coincidente con el inicio de vida sexual, con respuesta favorable y sangrados regulares. La IOP tiene graves consecuencias para la salud incluyendo trastornos psicológicos como angustia, síntomas depresivos o depresión, infertilidad, osteoporosis, trastornos autoinmunes, cardiopatía isquémica, y un mayor riesgo de mortalidad. La enfermedad de Hashimoto es el trastorno autoinmune más frecuente asociado a la IOP. Su tratamiento y diagnóstico deben establecerse de forma precoz para evitar consecuencias a largo plazo. La terapia con estrógenos es la base del tratamiento para eliminar los síntomas de la deficiencia de estrógenos, además de evitar las consecuencias futuras del hipogonadismo no tratado. También el manejo debe incluir los siguientes dominios: fertilidad y anticoncepción, salud ósea, problemas cardiovasculares, función psicosexual, psicológica y neurológica, informando a los familiares y a la paciente sobre la dimensión real de la IOP y la necesidad de tratamiento multidisciplinario en muchos casos. CONCLUSIÓN: El caso presentado, pese a ser infrecuente, permite abordar de manera sistematizada el diagnostico de IOP y evaluar alternativas de manejo plausibles para evitar graves consecuencias en la salud, así como conocer respuesta clínica y de satisfacción de la adolescente.

The objective of this manuscript is to review and update the literature on primary ovarian insufficiency (POI) in an adolescent population, based on the diagnosis, management and follow-up of a clinical case. Primary ovarian insufficiency is defined as menopause in a woman before the age of 40, accompanied by amenorrhea, hypergonadotropic hypogonadism, and infertility. Its prevalence varies between 1 to 2%, and in women under 20 years of age its prevalence is one case in every 10,000. Although it is known that many conditions can lead to POI, the most common is the idiopathic cause. The clinical presentation is diverse, and several different disorders can also lead to this condition. CLINICAL CASE: The case of a 17-year-old adolescent, previously healthy, with a history of secondary amenorrhea, not pregnant, with a normal general physical and gynecological examination is presented. A complementary analytical study is requested, resulting in levels of follicle stimulating hormone (FHS), estradiol (E2) and anti-müllerian hormone (AMH) compatible with ovarian insufficiency such as that observed in postmenopause. Classic hormonal therapy (HT) with estradiol and progesterone was started, later being replaced by combined hormonal contraception (CHC), coinciding with the beginning of sexual life, with a favorable response and regular bleeding. POI has serious health consequences including psychological disorders such as distress, depressive symptoms or depression, infertility, osteoporosis, autoimmune disorders, ischemic heart disease, and an increased risk of mortality. Hashimoto's disease is the most common autoimmune disorder associated with POI. Its treatment and diagnosis must be established early to avoid long-term consequences. Estrogen therapy is the mainstay of treatment to eliminate the symptoms of estrogen deficiency, in addition to avoiding the future consequences of untreated hypogonadism. Management should also include the following domains: fertility and contraception, bone health, cardiovascular problems, psychosexual, psychological and neurological function, informing family members and the patient about the real dimension of POI and the need for multidisciplinary treatment in many cases. CONCLUSION: The case, although infrequent, allows a systematic approach to the diagnosis of POI and evaluate plausible management alternatives to avoid serious health consequences, as well as to know the clinical response and satisfaction of the adolescent.

Buchholzia coriacea (wonderful kola) seeds induce male reproductive toxicity by suppressing the pituitary-gonadal axis in Wistar rats

The methanolic extract of Buchholzia coriacea seeds (MEBC) has been reported to induce male reproductive toxicity by decreasing sperm parameters and fertility index. To elucidate the possible mechanism(s), the effects of graded doses of MEBC on sex hormones and sperm profile were investigated in this study. The MEBC (e.g., 50, 200, 400, and 600 mg/kg) was administered daily (p.o.) to male Wistar rats for 6 weeks, while a concurrent control group received distilled water (vehicle). Then, the animals were sacrificed under sodium pentobarbital anaesthesia. Weights of organs were recorded, and the sperm profile was determined microscopically. Testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were assayed from the obtained serum using the ELISA technique. Sperm motility was significantly reduced by MEBC (i.e., 50 and 200 mg/kg), and sperm count reduced in all treated groups in a dose-dependent manner compared with that of the control. Serum testosterone, LH, and FSH decreased in treated rats. A histopathological examination of testes showed a considerable depletion and necrosis of the epithelium of seminiferous tubules. The result suggests that Buchholzia coriacea seeds induce male reproductive toxicity by suppressing the pituitary-gonadal axis.

High follicle-stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF-κB pathway.

Osteoarthritis is the main cause of pain and disability in the elderly, with the most commonly affected joint being the knee. The prevalence of knee osteoarthritis (KOA) is significantly increased in postmenopausal women, although the mechanisms underlying KOA remain unclear. The present study aimed to investigate the association between follicle-stimulating hormone (FSH) and postmenopausal women with KOA aged between 50 and > 70 years, as well as explore its underlying molecular mechanisms. Here, we report that the 50-60 years age group had the highest level of serum FSH. Compared to the low FSH group (< 40 mIU·mL-1 ) in the same age group, the high FSH group (> 40 mIU·mL-1 ) showed more severe cartilage damage. Furthermore, phosphorylated (p)-phosphoinositide 3-kinase (PI3K)/PI3K, p-AKT/AKT and p-nuclear factor kappa B (NF-κB)/NF-κB levels were significantly higher in the high FSH group compared to the low FSH group. Immunofluorescence experiments showed that FSH stimulation promoted the translocation of NF-κB p65 into the nucleus, and decreased type II collagen and aggrecan in ATDC5 cells. Moreover, we used western blotting in ATDC5 cells to demonstrate that FSH decreased type II collagen and increased p-PI3K/PI3K, p-AKT/AKT, p-NF-κB/NF-κB and p-IKB/IKB in a concentration-dependent manner. Our results suggest that increased FSH levels are associated with KOA for postmenopausal women aged 50-60 years and that high FSH levels might damage the cartilage tissues through the PI3K/AKT/NF-κB pathway.

Identification and semi-relative quantification of intact glycoforms by nano-LC-(Orbitrap)MS: application to the α-subunit of human chorionic gonadotropin and follicle-stimulating hormone.

Human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH) belong to the family of glycoprotein polypeptide hormones called gonadotropins. They are heterodimers sharing the α-subunit structure that has 2 N-glycosylation sites. A method based on nano-reversed-phase liquid chromatography coupled to high-resolution mass spectrometry with an Orbitrap analyzer was developed for the first time to characterize the glycosylation state of the α-subunit at the intact level. A recombinant hCG-based drug, Ovitrelle®, was analyzed. This method combined with an appropriate data treatment allowed the detection of not only the major isoforms but also the minority ones with a high mass accuracy. More than 30 hCGα glycoforms were detected without overlapping of the isotopic patterns. The figures of merit of the method were assessed. The relative standard deviations (RSDs) of the retention time ranged between 0.1 and 6.08% (n = 3), with an average of 0.4%. The RSDs of the peak area measured on the extracted ion chromatogram of each glycoform are below 38% (n = 3), with an average of 16%, thus allowing semi-relative quantification. The ability to accurately profile glycosylated variants of hCGα was next demonstrated by comparing qualitatively and semi-quantitatively 3 batches of Ovitrelle®. The method was also used to analyze 3 batches of a recombinant FSH-based drug, Puregon®, and 30 FSHα glycoforms were detected and semi-quantified. This demonstrates the high potential of this method for fast quality control or comparison of the glycosylation of glycoprotein-based pharmaceutical preparations. Graphical abstract.

FSH Levels Are Related to E-cadherin Expression and Subcellular Location in Nonfunctioning Pituitary Tumors.

CONTEXT: Gonadotroph pituitary neuroendocrine tumors (PitNETs) can express follicle-stimulating hormone (FSH) and luteinizing hormone (LH) or be hormone negative, but they rarely secrete hormones. During tumor development, epithelial cells develop a mesenchymal phenotype. This process is characterized by decreased membranous E-cadherin and translocation of E-cadherin to the nucleus. Estrogen receptors (ERs) regulate both E-cadherin and FSH expression and secretion. Whether the hormone status of patients with gonadotroph PitNETs is regulated by epithelial-to-mesenchymal transition (EMT) and ERs is unknown. OBJECTIVES: To study the effect of EMT on hormone expression in gonadotroph nonfunctioning (NF)-PitNETs. DESIGN: Molecular and clinical analyses of 105 gonadotroph PitNETs. Immunohistochemical studies and real-time quantitative polymerase chain reaction were performed for FSH, LH, E-cadherin, and ERα. Further analyses included blood samples, clinical data, and radiological images. SETTING: All patients were operated on in the same tertiary referral center. RESULTS: NF-PitNET with high FSH expression had decreased immunohistochemical staining for membranous E-cadherin (P < .0001) and increased staining for nuclear E-cadherin (P < .0001). Furthermore, high FSH expression was associated with increased ERα staining (P = .0002) and ERα mRNA (P = .0039). Circulating levels of plasma-FSH (P-FSH) correlated with FSH staining in gonadotroph NF-PitNET (P = .0025). Tumor size and invasiveness was not related to FSH staining, E-cadherin, or ERα. LH expression was not associated with E-cadherin or ERα. CONCLUSION: In gonadotroph PitNETs, FSH staining is related to E-cadherin, ERα expression, and circulating levels of P-FSH. There was no association between FSH staining and invasiveness. The clinical significance of these findings will be investigated in ongoing prospective studies.

Age-related presence of spermatogonia in patients with Klinefelter syndrome: a systematic review and meta-analysis.

BACKGROUND: Klinefelter syndrome (KS) has been defined by sex chromosome aneuploidies (classically 47, XXY) in the male patient. The peripubertal timeframe in KS patients has been associated with the initiation of progressive testicular fibrosis, loss of spermatogonial stem cells (SSC), hypogonadism and impaired fertility. Less than half of KS patients are positive for spermatozoa in the ejaculate or testis via semen analysis or testicular sperm extraction, respectively. However, the chance of finding spermatogonia including a sub-population of SSCs in KS testes has not been well defined. Given the recent demonstration of successful cell culture for mouse and human SSCs, it could be feasible to isolate and propagate SSCs and transplant the cells back to the patient or to differentiate them in vitro to haploid cells. OBJECTIVE AND RATIONALE: The main objective of this study was to meta-analyse the currently available data from KS patients to identify the prevalence of KS patients with spermatogonia on testicular biopsy across four age groups (year): fetal/infantile (age ≤ 1), prepubertal (age 1 ≤ x ≤ 10), peripubertal/adolescent (age 10 < x < 18) and adult (age ≥ 18) ages. Additionally, the association of endocrine parameters with presence or absence of spermatogonia was tested to obtain a more powered analysis of whether FSH, LH, testosterone and inhibin B can serve as predictive markers for successful spermatogonia retrieval. SEARCH METHODS: A thorough Medline/PubMed search was conducted using the following search terms: 'Klinefelter, germ cells, spermatogenesis and spermatogonia', yielding results from 1 October 1965 to 3 February 2019. Relevant articles were added from the bibliographies of selected articles. Exclusion criteria included non-English language, abstracts only, non-human data and review papers. OUTCOMES: A total of 751 papers were identified with independent review returning 36 papers with relevant information for meta-analysis on 386 patients. For the most part, articles were case reports, case-controlled series and cohort studies (level IV-VI evidence). Spermatogonial cells were present in all of the fetal/infantile and 83% of the prepubertal patients' testes, and in 42.7% and 48.5% of the peripubertal and adult groups, respectively were positive for spermatogonia. Additionally, 26 of the 56 (46.4%) peripubertal/adolescent and 37 of the 152 (24.3%) adult patients negative for spermatozoa were positive for spermatogonia (P < 0.05). In peripubertal/adolescent patients, the mean ± SEM level for FSH was 12.88 ± 3.13 IU/L for spermatogonia positive patients and 30.42 ± 4.05 IU/L for spermatogonia negative patients (P = 0.001); the mean ± SEM level LH levels were 4.36 ± 1.31 and 11.43 ± 1.68 IU/L for spermatogonia positive and negative, respectively (P < 0.01); the mean ± SEM level for testosterone levels were 5.04 ± 1.37 and 9.05 ± 0.94 nmol/L (equal to 145 ± 40 and 261 ± 27 and ng/dl) for the spermatogonia positive and negative groups, respectively (P < 0.05), while the difference in means for inhibin B was not statistically significant (P > 0.05). A similar analysis in the adult group showed the FSH levels in spermatogonia positive and negative patients to be 25.77 ± 2.78 and 36.12 ± 2.90 IU/L, respectively (mean ± SEM level, P < 0.05). All other hormone measurements were not statistically significantly different between groups. WIDER IMPLICATIONS: While azoospermia is a common finding in the KS patient population, many patients are positive for spermatogonia. Recent advances in SSC in vitro propagation, transplantation and differentiation open new avenues for these patients for fertility preservation. This would offer a new subset of KS patients a chance of biological paternity. Data surrounding the hormonal profiles of KS patients and their relation to fertility should be interpreted with caution as a paucity of adequately powered data exists. Future work is needed to clarify the utility of FSH, LH, testosterone and inhibin B as biomarkers for successful retrieval of spermatogonia.

Hormonal Status and Cognitivo-Emotional Profile in Real-Life Patients With Neuropathic Pain: A Case Control Study.

BACKGROUND: The specific impact of neuropathic pain and recommended neuropathic pain treatments on the hormonal and immune status of patients has been so far poorly explored. This study aimed at studying, in real life, the hypothalamic-pituitary-adrenal axis and the cytokine profile of patients with neuropathic pain. It also explored their links with cognition, emotion, quality of life, and drug treatment. METHODS: This prospective study (clinicaltrials.gov NCT01543425) included 60 patients with neuropathic pain and 60 age- and gender-matched healthy volunteers after obtaining signatures of informed consent. A number of parameters were measured: adrenocorticotropic hormone, cortisol, cortisol awakening response, dehydroepiandrosterone sulphate, sex hormone binding globulin, testosterone, 17-ß-estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, cytokines, brain-derived neurotrophic factor, and vitamin D. Psychological parameters were assessed by questionnaires. RESULTS: Patients with neuropathic pain had lower levels of adrenocorticotropic hormone (P = 0.009) and dehydroepiandrosterone sulphate (P < 0.001) than controls, and the cortisol awakening response was impaired. Patients were more depressed and anxious (P < 0.001) and had a diminished quality of life (P < 0.001), which was influenced by cytokines (P = 0.0067) and testosterone (P = 0.028). Antidepressants and antiepileptics appeared to interfere with testosterone and cognitivo-emotional domains. CONCLUSION: An impairment of the hormonal status and of the immune system was observed in patients. It identified testosterone as a potential pivotal mediator between antidepressants/antiepileptics and quality of life. Further studies must address the exact impact of different types of drugs on central effects, of gender differences, and of the immune system of neuropathic pain.

Follicular dynamics of glycerophospholipid and sphingolipid metabolisms in polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) is a common heterogeneous disease, affecting up to 5-10% women at reproductive age. Although PCOS patients could produce morphologically normal metaphase II oocytes undergoing assisted reproductive techniques (ART), oocyte developmental competence and embryo development have been impaired in following in-vitro fertilization (IVF) steps. Follicular fluid (FF) provides a variety of information in oocyte environment when oocytes grow. In the present work, based on ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), the metabolic signatures of PCOS FF have been compared with healthy women using untargeted metabolomics approach. Significant abundance differences of a series of glycerolipid, glycerophospholipids, sphingolipids, and carboxylic acids have been discovered. Among them, reduced levels of phosphatidylglycerolphosphate (PGP) and a triglyceride (TG) were highly related to the lower fertilization rate in PCOS; increased abundance of lysoPE and decreased amount of PC were significantly correlated with LH/FSH (ratio of luteinizing hormone to follicle stimulating hormone). Some metabolites, including decreased sphingolipids, glycerophospholipids, and fluctuated fatty acyls, also performed close relationship with other ART and clinical results. We concluded that dysfunctions in the metabolism of glycerolipid, glycerophospholipid, sphingolipid, and glycosphingolipid biosynthesis in PCOS patients' follicles play a non-ignorable role in declining the 2 pronuclei (PN) fertilization rate during IVF procedure.

Bilateral Endometrioma Excision: Surgery-Related Damage to Ovarian Reserve.

To study whether unoperated ovarian endometrioma(s) or its surgical excision led to a modified pattern of ovarian decay with increasing female age. A sectional analysis of basal follicle stimulating hormone (FSH) and ovarian response to gonadotropins was conducted on women treated with fresh autologous In Vitro Fertilization/Intracytoplasmic sperm injection (IVF/ICSI) cycles. The study group included patients with unoperated ovarian endometrioma(s) (108 cycles); control groups were women with previous surgery for monolateral ovarian endometrioma (101 cycles), surgery for bilateral ovarian endometriomas (39 cycles), and tubal factor infertility (171 cycles). Simple linear regression analyses and the Pearson correlation were used to analyze the correlation between basal FSH, number of dominant follicles, number of retrieved oocytes, and age of patients. The relationship between the variables was significant in case of patients with nonoperated ovarian endometrioma(s) and patients with previous surgery for monolateral endometrioma and tubal factor infertility group. In patients with a history of surgery for bilateral endometriomas, no relationship was found among the variables (basal FSH 95% confidence interval [CI]: -0.475 to 0.319; P = .688; number of dominant follicles 95% CI: -0.484 to 0.382; P = .808; number of retrieved oocytes 95% CI: -0.478 to 0.370, P = .792). In women with unoperated ovarian endometrioma(s) or with a history of surgery for monolateral endometrioma, the remaining ovarian parenchyma maintains the same pattern of ovarian decay as healthy ovaries. Unoperated ovarian endometriotic lesions did not interfere with ovarian reserve and IVF/ICSI cycles' outcomes and were less injurious than surgery. After surgery for bilateral ovarian endometriomas, a decline in ovarian reserve seems independent from the patient's age.

Evaluation of a Novel General Pituitary Hormone Score to Evaluate the Function of the Residual Anterior Pituitary (Adenohypophysis) in Patients Following Surgery for Pituitary Adenoma.

BACKGROUND The aim was to develop and assess a general pituitary hormone score to evaluate the function of the anterior pituitary (adenohypophysis) in patients following resection of pituitary adenomas. MATERIAL AND METHODS Sixty-six patients with pituitary null cell macroadenoma (1-3 cm diameter) (N=38) and pituitary null cell giant adenoma (≥3 cm diameter) (N=28) had preoperative and postoperative data including magnetic resonance imaging (MRI) and measurement of six pituitary hormones levels, adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The postoperative general pituitary hormone score, for 57 patients who underwent subtotal resection (>60%) and nine patients who underwent partial resection (≤60%), was 1-5 for each hormone level (score range, 6-30). RESULTS ACTH, GH, TSH, PRL, FSH, and LH levels in 38 patients with pituitary null cell macroadenoma were not statistically different from the 28 patients with pituitary null cell giant adenoma; the general pituitary hormone score in the former group was significantly increased compared with the latter group (P<0.05). ACTH, GH, TSH, PRL, FSH, and LH levels in the 57 patients with subtotal tumor resection were not significantly different from the nine patients with partial tumor resection; the general pituitary hormone score in the former group was significantly reduced compared with the latter group (P<0.05). CONCLUSIONS A general pituitary hormone score was developed that might be relevant to the evaluation of pituitary function following surgical resection of pituitary null cell macroadenoma and giant adenoma.

An Evaluation of Reported Follicle-stimulating Hormone, Luteinizing Hormone, Estradiol, and Prolactin Reference Ranges in the United States.

OBJECTIVE: To characterize US clinical laboratory reference range reporting and testing methods of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and prolactin. METHODS: One hundred and seventeen US laboratories were surveyed. Outcomes measured were variation in lower and upper limits of normal male reference ranges for serum FSH, LH, estradiol, and prolactin, method of analysis and source of reference range RESULTS: The upper limit of normal reference ranges for FSH, LH, estradiol, and prolactin varied substantially across laboratories compared to the lower limits. The range of upper limits of FSH, LH, estradiol, and prolactin respectively are 7.9-20.0, 4.9-86.5, 37.7-77.0, and 7.4-25.0. Ninety-four percent of laboratories performed measurements on in-house high throughput analyzer utilizing immunoassays. Seventy percent of reported reference ranges for each hormone were based on validation studies of the analyzer's package insert values. Ten percent of laboratories derived their own reference ranges. Both the validation studies and derivations were based on a limited number of patient samples, ranging from 20 to 200. CONCLUSION: Current reference ranges are based on small population studies of men with unknown medical histories, sexual or reproductive function. Influence of race and age has not been evaluated and could potentially be important in normal variation. The absence of standard information has yielded a spectrum of upper and lower normal values, which could delay an appropriate male infertility evaluation. Our findings highlight the need for a large population study of males with known normal sexual and reproductive function to formulate more accurate clinical reference ranges.

Menstrual cycle irregularity and menopause status influence cognition in women with schizophrenia.

Cognitive impairments are a core feature of schizophrenia and contribute significantly to functional complications. Current pharmacological treatments do not ameliorate cognitive dysfunction and the aetiology of cognitive impairments are poorly understood. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain and have been suggested to also influence cognition. The aim of the current study was to investigate how HPG axis hormones effect cognition, specifically exploring the influence of menopause status and menstrual cycle irregularity on cognitive performance in women with schizophrenia. The data for the present study represents pooled baseline data from three clinical trials. Two hundred and forty female participants with a diagnosis of schizophrenia or schizoaffective disorder were included in the analysis. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Hormone assays for serum sex steroids and pituitary hormones (including estradiol, progesterone, luteinising hormone and follicle-stimulating hormone) were conducted and women were classified as postmenopausal; perimenopausal; premenopausal/reproductive, further classified into regular and irregular menstrual cycles. To model a comparison of cognitive performance for i) perimenopausal; ii) post-menopausal women and iii) reproductive aged women with irregular cycles to reproductive aged women with regular cycles a semiparametric regression model (generalised additive mode) was fitted. The results revealed that in females with schizophrenia, menstrual cycle irregularity predicted significantly poorer cognitive performance in the areas of psychomotor speed, verbal fluency and verbal memory. Perimenopause was not associated with cognitive changes and the post-menopausal period was associated with poorer visuospatial performance. This study provides evidence to associate reproductive hormones with cognitive dysfunction in schizophrenia.

Ovarian Reserve Assessment in Celiac Patients of Reproductive Age.

BACKGROUND This study aimed to investigate ovarian reserve in patients of reproductive age with Celiac disease (CD) using anti-Müllerian hormone (AMH) levels, antral follicle counts (AFCs), and ovarian volume. MATERIAL AND METHODS We included into this study 46 CD female patients and 40 healthy female subjects of reproductive age, ages 18-45 years. Venous blood samples were taken from both groups on days 2-4 of the menstrual cycle, and follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), and AMH levels were measured. On the same day, AFCs and ovarian volumes were determined. Data on body mass index (BMI), gravidity/parity/abortions/alive counts, disease duration, and Marsh histological classification were recorded. RESULTS There were no statistically significant differences between CD and control groups in terms of mean age, BMI, or median gravidity/parity/abortions/alive counts (p>0.05). Also, there were no statistically significant differences between the 2 groups in terms of mean FSH, LH, E2, PRL levels, right and left ovarian volumes, and median right and left ovarian AFCs (p>0.05). However, AMH level was significantly lower in the CD group (p=0.032). No statistically significant correlation was found between AMH levels and age, BMI, FSH, LH, E2, PRL levels, right and left ovarian volumes, right and left ovarian AFCs, or Marsh histological classification using the Spearman correlation test (p>0.05). However, an inverse correlation was detected showing that AMH levels decrease with increasing CD duration (r=-0.054, p=0.001). CONCLUSIONS We found that AMH level and ovarian reserve was decreased in CD patients of reproductive age compared to healthy controls, and that AMH level and ovarian reserve decreased with increasing disease duration in CD patients.

Lowered reference limits for hCG improve follow-up of patients with hCG-producing tumors.

BACKGROUND: Human Chorionic Gonadotropin (hCG) is produced by germ cell tumors, but can also be elevated in benign conditions such as primary hypogonadism, where hCG is produced by the pituitary gland. In our experience, the reference limits for hCG (Elecsys hCG+ß-assay, Roche Diagnostics), were unnecessarily high and did not reflect levels encountered in clinical practice. We wanted to establish new reference limits to increase the clinical utility of the hCG-assay. METHODS: We analysed hCG in serum samples from a healthy adult population and in a cohort of testicular cancer survivors. The gonadotropins LH and FSH were measured in the cohort and in a selection of the reference population to assess gonadal function. RESULTS: We found low hCG levels for all men and women <45years (97.5 percentiles 0.1 and 0.2IU/L, respectively) from the healthy population (n=795) having normal FSH and LH. Due to assay limitations, we suggest a common reference limit of <0.3IU/L. For the age group ≥45, the 97.5 percentiles in the healthy population were 0.5IU/L for men and 6.0IU/L for women. In all subjects from both the reference population and the cohort (n=732), hCG levels exceeding the reference limit could be fully explained by reduced gonadal function indicated by elevated LH and FSH levels. CONCLUSION: The Elecsys hCG+ß-assay should have lower reference limits than recommended by the manufacturer, with important implications for tumor follow-up. Elevated hCG is rare with intact gonadal function, both in a normal population and among survivors of testicular cancer, and should lead to further investigations when encountered in clinical practice.