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ObjectiveGynaecomastia is a benign proliferation of glandular tissue of the breast; however, it is an important clinical observation because it can be the first symptom of an underlying disease. Some controversy exists concerning the clinical importance of an in-depth investigation of men who develop gynaecomastia. We hypothesise that a thorough work-up is required in adult men with gynaecomastia.DesignAll adult men (n = 818) referred to a secondary level andrological department at Rigshospitalet in Copenhagen, Denmark during a four-year period (2008–2011) under the diagnosis of gynaecomastia (ICD-10: N62) were included.MethodsThirty-two men who did not have gynaecomastia when examined were excluded; leaving 786 men for final analyses. They underwent an andrological examination, ultrasound of the testicles and analysis of endogenous serum hormones levels.ResultsIn 43% of men with adult onset of gynaecomastia (≥18 years) an underlying, and often treatable, cause could be detected. In men younger at onset an underlying cause for gynaecomastia could be detected in merely 7.7%. The study is limited by the fact that we did not have access to investigate men who were referred directly by their GP to private clinics for plastic surgery or who sought cosmetic correction without consulting their GP first.ConclusionsOur study demonstrates the importance of a thorough examination and provides a comprehensible examination strategy to disclose the underlying pathology leading to the development of gynaecomastia in adulthood.

Background: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. Objectives: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. Methods: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). Results: The free androgen index was 15% lower [95% confidence interval (CI): –23, –8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: –16, –1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E2. %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality Conclusion: Our data suggest that both testosterone production and pituitary–hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.

Background The vitamin D receptor (VDR), CYP27B1 and CYP24A1 are expressed in the human kidney, but the segmental expression of the 25-hydroxylases is unknown. A comprehensive analysis of CYP2R1, CYP27A1, CYP27B1, VDR and CYP24A1 expression in normal kidney and renal clear cell cancer (CCc) would reveal the segmental location of expression, and clarify whether the reported loss of VDR in CCc is coincident with alterations of vitamin D metabolism. Materials and methods Tissue was obtained from nine patients (eight CCc and one atrophic kidney), mRNAs were detected with RT-PCR and in situ hybridisation (ISH), and expression of proteins determined by immunohistochemistry and western blotting. Results We detected expression of VDR and the vitamin D metabolising enzymes in normal kidney. VDR and CYP27B1 were strongly expressed in proximal tubules, while CYP2R1 and CYP27A1 had a marked expression in distal tubules. In CCc expression was lost for VDR and all the enzymes, except for very few cells expressing all the investigated proteins. Conclusion This study shows that VDR and all the vitamin D metabolising enzymes are expressed in the normal kidney. During the malignant transformation to CCc, expression of VDR and the metabolising enzymes is lost, however the implications of this loss are unknown.

Few data exist on the diagnostic criteria, and on the effects of puberty induction, in boys with constitutional delay in growth and puberty (CDGP).To develop puberty nomograms based on Danish boys with normal pubertal development. To evaluate the different diagnostic criteria and the effect of oral testosterone undecanoate (TU) in boys with CDGP.A cross-sectional and longitudinal study of Danish boys with normal pubertal development (COPENHAGEN puberty study). A retrospective observational study of 451 boys evaluated for delayed puberty between 1990 and 2013.Tertiary referral center for pediatric endocrinology.One hundred and sixty-four (36%) boys evaluated for CDGP were excluded due to missing data, reclassification, or associated comorbidities, yielding 287 (64%) eligible for analysis.The number of patients with CDGP classified by the puberty nomogram (genital stage-2 SD for age) versus the classical criteria (genital stage 1 at ≥ 14 years). The effect of one year of oral TU treatment on pubertal progression, circulating hormones, height, and predicted adult height (PAH).Seventy-eight (27%) of the 287 boys had delayed pubertal onset according to the classical criteria, whereas 173 (60%) of the 287 boys had impaired pubertal progression according to the puberty nomogram. Ninety-six (56%) of these 173 boys were treated with oral TU for 0.8 years (0.5; 1.3) [median (25th; 75th percentiles)], which resulted in beneficial effects on pubertal progression. Height increased from -1.9 SD (-2.5; -1.2) to -1.5 SD (-2.1; -0.7) (P.001), and PAH increased from 172.3 cm (170.3; 182.8) to 178.1 cm (171.4; 191.7) (P = .001) following one year of treatment.The puberty nomogram evaluates both delayed pubertal onset as well as delayed pubertal progression and allows separation of normal versus abnormal pubertal development. Oral TU treatment was followed by pubertal induction and progression and short-term growth without compromising final height.

Objective Increasing age at first childbirth has been suggested to increase the risk for infertility. Our objective is to determine whether women above thirty years of age historically have been able to sustain fertility rates above replacement level. Design A descriptive nationwide Danish study using birth registries from 1901–2014. Setting Information on women’s age at childbirth was obtained by using records from primary, secondary and tertiary institutions. Participants Mothers to 8,024,969 live births. Main outcome measures Mothers were stratified according to age at childbirth to determine total and age specific fertility rates. Results Total fertility rate (TFR) decreased from 4.1 to 1.8 children per woman and age specific fertility also decreased from 1901 to 2014. Women aged 30–34, 35–39 or 40–44 years in the first decade of the 20th century had higher fertility rates than the corresponding five year younger age groups (25–29, 30–34 and 35–39, respectively) have had for the last 65 years. On average, women gave birth to two children after the age of 30 and one or more child after 35 years of age in the beginning of the 1900s. Furthermore, women more than 40 years of age accounted for 10% of TFR in 1901 compared with 4% in 2014 despite usage of assisted reproduction. Conclusion This nationwide study shows that women above 30 years of age historically have been able to sustain fertility rates above replacement level. This implies that other factors besides age are strong determinants of fertility in women above 30 years of age.

background: The vitamin D receptor (VDR) is expressed in human spermatozoa, and VDR-knockout mice and vitamin D (VD) deficiency in rodents results in impaired fertility, low sperm counts and a low number of motile spermatozoa. We investigated the role of activated VD (1,25(OH)2D3) in human spermatozoa and whether VD serum levels are associated with semen quality. methods: Cross-sectional association study of semen quality and VD serum level in 300 men from the general population, and in vitro studies on spermatozoa from 40 men to investigate the effects of VD on intracellular calcium, sperm motility and acrosome reaction. All men delivered samples for routine semen analysis and blood for measurements of follicle stimulating hormone, Inhibin B, 25-hydroxy-VD, albumin, alkaline phosphatase, calcium and parathyroid hormone (PTH). results: In the association study, 44% were VD insufficient (,50 nM), and VD was inversely correlated with PTH (P , 0.0005). VD serum levels correlated positively with sperm motility and progressive motility (P , 0.05), and men with VD deficiency (,25 nM) had a lower proportion of motile (P ¼ 0.027), progressive motile (P ¼ 0.035) and morphologically normal spermatozoa (P ¼ 0.044) compared with men with high VD levels (.75 nM). 1,25(OH)2D3 increased intracellular calcium concentration in human spermatozoa through VDR-mediated calcium release from an intracellular calcium storage, increased sperm motility and induced the acrosome reaction in vitro. conclusions: 1,25(OH)2D3 increased intracellular calcium concentration, sperm motility and induced the acrosome reaction in mature spermatozoa, and VD serum levels were positively associated with sperm motility, suggesting a role for VD in human sperm function.

Vitamin D is a key factor for calcium and bone homeostasis, but signalling through the vitamin D receptor (VDR) seems also to be important for testicular function. To test the functional role of vitamin D signalling we examined the male reproductive system of the Leuven Vdr-ablated (Vdr(-/-)) mice, previously established as a model for hereditary vitamin D-resistant rickets. We investigated reproductive hormones, changes in gene expression and histological phenotype of eleven Vdr(-/-), eight Vdr(+/-) and nine Vdr(+/+) mice. Testicular and epididymal histology were grossly normal in Vdr(-/-) mice. Accordingly, no differences were found in serum concentrations of testosterone, estradiol, LH, and FSH or testicular expression of Cyp19a1, Ersα, Cyp17a1, Star, Insl3, Inhbb, and Amh. However, a significantly lower ERβ expression was found in testis of Vdr(+/-) and Vdr(-/-) mice, conversely epididymal expressions of ERα and the estrogen-target gene Aqp9 were higher. In conclusion, vitamin D seems dispensable for murine spermatogenesis and sex hormone production, but aberrant estrogen-signalling may elicit some of the VDR-mediated effects on male reproduction.

OBJECTIVE: To study the associations between self-reported psychological stress, semen quality, and serum reproductive hormones among young Danish men.DESIGN: Cross-sectional study.SETTING: University hospital-based research center.PARTICIPANT(S): Danish men (median age 19 years) from the general population were investigated from 2008 to 2012.INTERVENTION(S): Participants completed a questionnaire on health and lifestyle, including a four-item questionnaire about self-rated stress, had a physical examination performed, delivered a semen sample, and had a blood sample drawn.MAIN OUTCOME MEASURE(S): Semen parameters (semen volume, sperm concentration, and percentages of motile and morphologically normal spermatozoa) and serum levels of reproductive hormones (LH, FSH, T, calculated free T, sex hormone-binding globulin, and inhibin B).RESULT(S): Poorer semen quality was detected among men with self-reported stress scores above an intermediate stress level, in a dose-response manner. For example, men with the highest stress levels had 38% (95% confidence interval [CI] 3%; 61%) lower sperm concentration, 34% (95% CI 59%; 106%) lower total sperm count, and 15% (95% CI 1%; 27%) lower semen volume than men with intermediate stress levels. No significant associations between self-reported stress and levels of reproductive hormones were detected.CONCLUSION(S): A negative association between self-reported stress and semen quality was detected. If causal, stress may be a contributing factor for suboptimal semen quality among otherwise healthy men.

The mitosis-meiosis switch is a key event in the differentiation of germ cells. In humans, meiosis is initiated in fetal ovaries, whereas in testes meiotic entry is inhibited until puberty. The purpose of this study was to examine the expression pattern of meiosis reg- ulators in human gonads and to investigate a possible role of DMRT1 in the regulation of meiotic entry. The expression pattern of DMRT1, STRA8, SCP3, DMC1, NANOS3, CYP26B1 and NANOS2 was investigated by RT -PCR and immunohistochemistry in a series of human testis samples from fetal life to adulthood, and in fetal ovaries. DMRT1 was expressed in testes throughout development but with marked spatio-temporal changes. At the early fetal period of 8-20 gestational weeks (GW) and at infantile mini-puberty, DMRT1 was predominantly expressed in Sertoli cells, whereas at later stages of gestation (22 -40 GW), during childhood and in post-pubertal testes, DMRT1 was most abundant in spermatogonia, except in the A-dark type. In fetal ovaries, DMRT1 was detected in oogonia and oocytes until 20 GW, but was completely down-regulated following meiotic entry. STRA8, SCP3 and DMC1 were expressed mainly in oocytes and spermatogonia in ac- cordance with their role in initiation and progression of meiosis. The putative meiosis inhibitors, CYP26B1 and NANOS2, were primarily expressed in Leydig cells and spermatocytes, respectively. In conclusion, the expression pattern of the investigated meiotic regulators is largely conserved in the human gonads compared with rodents, but with some minor differences, such as a stable expression of CYP26B1 in human fetal ovaries. The sexually dimorphic expression pattern of DMRT1 indicates a similar role in the mitosis-meiosis switch in human gonads as previously demonstrated in mice. The biological importance of the changes in expression of DMRT1 in Sertoli cells remains to be established, but it is consistent with DMRT1 reinforcing the inhibition of meiosis in the testis.

The spectrum of vitamin D (VD)-mediated effects has expanded in recent years, and VD is now recognized as a versatile signaling molecule rather than being solely a regulator of bone health and calcium homeostasis. One of the recently identified target areas of VD is male reproductive function. The VD receptor (VDR) and the VD metabolizing enzyme expression studies documented the presence of this system in the testes, mature spermatozoa, and ejaculatory tract, suggesting that both systemic and local VD metabolism may influence male reproductive function. However, it is still debated which cell is the main VD target in the testis and to what extent VD is important for sex hormone production and function of spermatozoa. This review summarizes descriptive studies on testicular VD metabolism and spatial distribution of VDR and the VD metabolizing enzymes in the mammalian testes and discusses mechanistic and association studies conducted in animals and humans. The reviewed evidence suggests some effects of VD on estrogen and testosterone biosynthesis and implicates involvement of both systemic and local VD metabolism in the regulation of male fertility potential.

In a Cochrane review the authors suggest that treatment with antioxidant supplementation in subfertile men may improve the outcome of live birth and pregnancy rate for infertile couples undergoing assisted reproductive technology cycles. We disagree as publication bias cannot be excluded and most studies were designed to investigate the effects of antioxidant treatment on semen quality. In addition, the men were treated with many different combinations and doses of antioxidants and it is not possible to recommend infertile men on type and dose of antioxidant. Future studies should be large, randomized placebo-controlled trials.

The spectrum for vitamin D (VD) mediated effects has expanded in recent years. Activated VD (1,25(OH)(2)D(3)) binds to the VD receptor (VDR) and mediates non-genomic effects through the alternative ligand binding-pocket (VDR-ap) or regulates gene transcription through the genomic binding-pocket. VDR and VD-metabolizing enzymes are expressed in human testis, male reproductive tract and mature spermatozoa, and VD is considered important for male reproduction. Expression of the VD-inactivating enzyme CYP24A1 at the annulus of human spermatozoa distinguish normal and infertile men with high specificity, and CYP24A1 expression is positively correlated with all semen variables and suggested as a marker for both semen quality and VD responsiveness. Moreover, spermatozoa are transcriptionally silent and are therefore a unique model to study non-genomic effects. 1,25(OH)(2)D(3) induced a rapid increase in intracellular calcium concentration [Ca(2+)](i) in human spermatozoa. The [Ca(2+)](i) increase was abrogated by the non-genomic VDR antagonist 1β,25(OH)(2)D(3), while the specific agonist for VDR-ap (JN) increased [Ca(2+)](i) with similar kinetics as 1,25(OH)(2)D(3). The rise in [Ca(2+)](i) originated as a Ca(2+)-release from intracellular stores since inhibition of phospholipase-C diminished the 1,25(OH)(2)D(3) mediated Ca(2+) response, while suspending spermatozoa in a nominally Ca(2+)-free medium did not affect the VD mediated Ca(2+) rise. The spatio-temporal kinetics of the VD-response differed from the progesterone-mediated increase in [Ca(2+)](i) as the VD-mediated Ca(2+) rise was not observed in the tail region and was independent of extracellular Ca(2+). A functional role of the VD-mediated Ca(2+) increase was supported by showing that 1,25(OH)(2)D(3) increased sperm motility and induced the acrosome reaction in vitro.

The decline in semen quality has been the subject of an animated debate. A recent prospective study now irrefutably shows a decline in semen quality in men from Finland, a country that previously boasted good semen quality. Semen quality has, in some countries, reached a level where a considerable fraction of young men are at risk of fertility problems. Impaired semen quality, testicular cancer, cryptorchidism and hypospadias are risk factors for each other, and the testicular dysgenesis syndrome (TDS) has been put forward to explain the observations. This syndrome implies that the four disease entities share the same patho-physiological etiology caused by disturbed testicular development in early fetal life. It seems likely that the rapid rise in TDS-associated conditions can, at least partly, be explained by environmental factors. Animal studies provide strong evidence that manmade chemicals can disrupt the hormone dependent pathways responsible for fetal gonadal development, subsequently leading to TDS-like symptoms. In humans, fetal exposure to endocrine disrupting substances may play a role, although genetic factors are probably also involved. Recent studies indicate that exposure to endocrine disrupters also in adulthood may affect semen quality and reproductive hormones. Causal relationships are inherently difficult to establish in humans, and a clear connection between the disorders and specific toxicants has not been established. It seems likely that the cumulative effects of various low-dose exposures to endocrine disrupters in our environment are responsible for the adverse effects in the male reproductive system. Semen quality may be the most sensitive marker of adverse environmental exposures, and we suggest that standardized surveillance studies of semen quality are continued or initiated to monitor the combined effects of various preventive actions.

background: The vitamin D receptor (VDR) is expressed in human testis, and vitamin D (VD) has been suggested to affect survival and function of mature spermatozoa. Indeed, VDR knockout mice and VD deficient rats show decreased sperm counts and low fertility. However, the cellular response to VD is complex, since it is not solely dependent on VDR expression, but also on cellular uptake of circulating VD and presence and activity of VD metabolizing enzymes. Expression of VD metabolizing enzymes has not previously been investigated in human testis and male reproductive tract. Therefore, we performed a comprehensive analysis of the expression of VDR, VD activating (CYP2R1, CYP27A1, CYP27B1) and inactivating (CYP24A1) enzymes in the testis, epididymis, seminal vesicle (SV), prostate and spermatozoa. methods: Tissue samples were obtained after orchiectomy (testis n ¼ 13; epididymis n ¼ 7), prostatectomy (prostate n ¼ 5 and SVs n ¼ 3) and semen samples obtained after ejaculation (n ¼ 13). mRNA was detected with RT– PCR and expression of proteins was determined by immunohistochemistry. results: VDR and VD metabolizing enzymes were concomitantly expressed in round and elongated spermatids, vesicles within the caput epididymis, and glandular epithelium of cauda epididymis, SV and prostate. The expression pattern in ejaculated spermatozoa varied, although, concomitant expression of VDR, CYP2R1, CYP27B1 and CYP24A1 was observed in neck and midpiece in a subpopulation of mature spermatozoa. conclusion: On the basis of the marked expression of VDR and the VD metabolizing enzymes in human testis, ejaculatory tract and mature spermatozoa, we suggest that VD is important for spermatogenesis and maturation of human spermatozoa.

Background Male fertility largely depends on the quality of sperm production, which may be affected by environmental and genetic factors. In this study, we explored a possible role of the polymerase gamma (POLG) gene polymorphism, recently reported to be associated with male infertility in some populations. Methods The polymorphic CAG repeat (usually 10 codons long) in the POLG gene was studied in 1298 male subjects: 429 patients with infertility/subfertility, and 869 controls (495 men from the general population with unknown fertility and 374 recent fathers). In all subjects, the POLG polymorphism was assessed in relation to their semen quality, and--in the fertile controls--with biological fecundity measured as waiting time-to-pregnancy (TTP) for the couples. In the patients lacking the common POLG allele, the outcome of the assisted reproductive techniques (ART) for the couples was evaluated. Results The absence of one (10/ not equal to 10) or both common POLG alleles (not equal to 10/not equal to 10) was more frequent among the subfertile patients than among fertile controls (P=0.021 and P=0.04 respectively). The estimated predictive value for infertility in a man homozygous for the POLG polymorphism was 15.5% (95% CI: 4.8-51%). There was a positive association with sperm concentration: 14.3% of the normospermic subfertile patients were homozygous for the absence of the common POLG allele (not equal to 10/not equal to 10), in comparison with 2.3% of unselected controls (P=0.001) and 0.9% of the fertile men (P=0.0001). No association with sperm motility, morphology and TTP was found. Spermatozoa of the three not equal to 10/not equal to 10 patients treated with IVF retained the ability to penetrate the egg, but the fertilization rate was low. Nine homozygous not equal to 10/ not equal to 10 patients were treated with ICSI, resulting in pregnancy in seven couples. Conclusions The POLG gene polymorphism should be considered as a possible contributing factor in patients with unexplained subfertility and normal spermiograms. The oocyte penetration ability of sperm may be partially impaired in the not equal to 10/not equal to 10 patients but most of them can be successfully treated with ICSI.

The International Network for Young Researchers in Male Fertility (INYRMF; http://www.youngresearcher.eu) is committed to establish global networks among young (early stage) scientists in testicular research and to promote collaboration and exchange of methodologies and expertise. We provide a more informal way of communication than many other congresses and meetings and promote online discussions on the homepage and during our annual meetings. Our network evolved at the European Testis Workshop (ETW) in 2006 in Germany1,2 and is continually expanding both in number of members and number of member countries. Participation in our network is open and free for all ‘young' scientists according to their scientific experience in the field of reproductive medicine/biology. Therefore, we welcome all students—PhD students, post-docs, etc., to join our network. The registration is an easy procedure on our homepage http://www.youngresearch.eu. Currently, we have almost 300 members from 37 different countries. Our first meeting was held in Naantali, Finland in 2008 adjacent to the Fifteenth ETW, followed by Munster, Germany in 2009, Elba, Italy in 2010, and Edinburgh, United Kingdom in 2011. Our Fifth meeting was held on 19–20 April this year at Djuronaset in the beautiful archipelago at the outskirts of Stockholm, Sweden. This meeting was held adjacent to the Seventeenth ETW which occurs every other year. Our Fifth Meeting was mainly organized by Dr Aida Wahlgren and Dr Jan-Bernd Stukenborg. The audience comprised 50 participants from 12 European and Asian countries. The program covered a wide range of interests relevant to young researchers in male fertility, from basic to clinical, and to translational science. Similar to former meetings adjacent to the ETW, we organized four invited talks by well-known experts in the field. In addition, all participants had the opportunity to discuss the topics in two open panels. We were pleased about these excellent talks and a very active audience, which brought us particularly fruitful discussions and ultimately a successful meeting for all of us.

Objectives Considerable interest and controversy over a possible decline in semen quality during the 20th century raised concern that semen quality could have reached a critically low level where it might affect human reproduction. The authors therefore initiated a study to assess reproductive health in men from the general population and to monitor changes in semen quality over time. Design Cross-sectional study of men from the general Danish population. Inclusion criteria were place of residence in the Copenhagen area, and both the man and his mother being born and raised in Denmark. Men with severe or chronic diseases were not included. Setting Danish one-centre study. Participants 4867 men, median age 19 years, included from 1996 to 2010. Outcome measures Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. Results Only 23% of participants had optimal sperm concentration and sperm morphology. Comparing with historic data of men attending a Copenhagen infertility clinic in the 1940s and men who recently became fathers, these two groups had significantly better semen quality than our study group from the general population. Over the 15 years, median sperm concentration increased from 43 to 48 million/ml (p=0.02) and total sperm count from 132 to 151 million (p=0.001). The median percentage of motile spermatozoa and abnormal spermatozoa were 68% and 93%, and did not change during the study period. Conclusions This large prospective study of semen quality among young men of the general population showed an increasing trend in sperm concentration and total sperm count. However, only one in four men had optimal semen quality. In addition, one in four will most likely face a prolonged waiting time to pregnancy if they in the future want to father a child and another 15% are at risk of the need of fertility treatment. Thus, reduced semen quality seems so frequent that it may impair the fertility rates and further increase the demand for assisted reproduction.

Context Several heterozygous loss-of-function mutations in the calcium-sensing receptor gene (CASR) leading to elevated ionized serum calcium and familial hypocalciuric hypercalcemia 1 (FHH1) have been characterized. Few mutations are not pathogenic, and previous studies suggested that the Q459R mutation does not result in an FHH1 phenotype. Objective We identified a family with a heterozygous CASR Q459R mutation and characterized their calcium homeostasis and the pathophysiological mechanisms of a homozygous and heterozygous Q459R mutation in vitro. Design The index patient and her family had clinical, biochemical, and genetic analyses performed. In vitro functional characterization of homozygous and heterozygous (Q459R) mutations was conducted by determining CaSR cell-surface expression and inositol monophosphate (IP1) signaling in transiently transfected human embryonic kidney 293A (HEK293A) cells. Results All 3 heterozygous carriers had mild asymptomatic hypercalcemia, hypocalciuria, and 2 had elevated serum parathyroid hormone (PTH). In vitro characterization in HEK293A cells revealed that CASR Q459R is a loss-of-function mutation with no impact on cell-surface expression. Cells with the homozygous Q459R genotype had significantly reduced calcium potency of IP1 signaling compared to wild type, whereas the heterozygous Q459R also had lower calcium potency albeit not significantly different from wild type. Conclusion A loss-of-function Q459R mutation in CASR in a family caused FHH1 characterized by elevated ionized calcium and PTH and low calcium excretion. The marked presence of CaSR at the membrane and inhibition of IP1 signaling in vitro suggest that calcimimetics may be functional in patients with this mutation, which seems to be a mild loss-of-function mutation associated with autosomal dominant transmission of FHH1.

In a Cochrane review the authors suggest that treatment with antioxidant supplementation in subfertile men may improve the outcome of live birth and pregnancy rate for infertile couples undergoing assisted reproductive technology cycles. We disagree as publication bias cannot be excluded and most studies were designed to investigate the effects of antioxidant treatment on semen quality. In addition, the men were treated with many different combinations and doses of antioxidants and it is not possible to recommend infertile men on type and dose of antioxidant. Future studies should be large, randomized placebo-controlled trials.