Clinical studies on testicular growth and descent

Recent population-based cohort studies indicate that semen quality is declining and simultaneously the incidence of testicular germ-cell cancer is increasing globally. A failure of testicular descent i.e. cryptorchidism and reduced testicular volume are risk factors both for testicular germ-cell cancer and reduced semen quality. Epidemiological and experimental studies suggest that these disorders may originate from testicular dysgenesis and reduced intratesticular androgen action during fetal period, which may be caused by genetic factors or exposure to antiandrogen endocrine disrupters. In this study, we explored postnatal testicular descent and the physiological significance of the so-called ‘minipuberty’, the transient activation of the hypothalamic-pituitary-gonadal axis after birth for postnatal testicular position. In addition, we assessed whether the levels of persistent organic pollutants such as polychlorinated biphenyl (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs, or ‘dioxins’) and polybrominated diphenyl ethers (PBDEs) are associated with congenital cryptorchidism. Finally, we assessed the testicular development during puberty among boys with a history of congenital cryptorchidism. We observed that testicular descent continued until the age of three months, and was followed by a ‘physiological’ testicular ascent, which coincided with the decline in circulating reproductive hormones. We also discovered that the circulating concentration of insulin-like growth factor 1 and hormonal indices reflecting Sertoli and Leydig cell function correlated with testicular position. Our results also suggest that the exposure to dioxins may increase the risk of congenital cryptorchidism. Furthermore, we showed that boys who had a history of congenital cryptorchidism display poor testicular growth during puberty in comparison to controls, which may predispose them to reduced semen quality and subfertility.Kliinisiä tutkimuksia kivesten kasvusta ja laskeutumisesta Viimeaikaisten tutkimusten mukaan siemennesteen laatu on heikentynyt ja kivessyövän esiintyvyys lisääntynyt ympäri maailmaa. Laskeutumaton kives eli piilokives ja kivesten pieni koko altistavat sekä kivessyövälle että heikentyneelle siemennesteen laadulle. Epidemiologisten tutkimusten sekä eläinmallien tulosten perusteella nämä häiriöt saattavat johtua kiveksen kehityshäiriöstä ja vähentyneestä sikiökautisesta kiveksensisäisestä androgeenivaikutuksesta. Tämä puolestaan saattaa johtua perintötekijöiden lisäksi altistuksesta ympäristön antiandrogeenisille hormonaalisille haitta-aineille. Tässä väitöskirjassa selvitimme syntymän jälkeisen ohimenevän hypotalamus-aivolisäke-kives –akselin aktivoitumisen eli niin sanotun minipuberteetin merkitystä kivesten laskeutumiselle syntymän jälkeen. Väitöskirjassani myös selvitettiin altistavatko ympäristön pysyvät hormonaaliset haitta-aineet kuten polyklooratut bifenyylit (PCB), dioksiinit (PCDD/F) tai polybromatut difenyylieetterit (PBDE) piilokiveksisyydelle. Lisäksi tutkimme piilokiveksisten ja verrokkien kiveskasvua murrosiässä. Tutkimustulostemme mukaan kivekset laskeutuvat kolmen kuukauden ikään asti, minkä jälkeen kivekset nousevat samaan aikaan kun sukupuolihormonien pitoisuus verenkierrossa vähenee. Väitöskirjani mukaan insuliinin kaltaisen kasvutekijä 1:n pitoisuus sekä Leydigin ja Sertolin solujen toimintaa kuvaavat sukupuolihormoni- indeksit olivat yhteydessä kiveksen laskeutumiseen syntymän jälkeen. Lisäksi altistuminen pysyville hormonaalisille haitta-aineille, erityisesti dioksiineille, näyttää olevan yhteydessä synnynnäiseen piilokiveksisyyteen. Lisäksi synnynnäinen piilokives kasvaa verrokkien kiveksiä heikommin murrosiän aikana, mikä ennustaa heikompaa siemennesteen laatua ja hedelmällisyyttä

Clinical studies on testicular growth and descent

Recent population-based cohort studies indicate that semen quality is declining and simultaneously the incidence of testicular germ-cell cancer is increasing globally. A failure of testicular descent i.e. cryptorchidism and reduced testicular volume are risk factors both for testicular germ-cell cancer and reduced semen quality. Epidemiological and experimental studies suggest that these disorders may originate from testicular dysgenesis and reduced intratesticular androgen action during fetal period, which may be caused by genetic factors or exposure to antiandrogen endocrine disrupters. In this study, we explored postnatal testicular descent and the physiological significance of the so-called ‘minipuberty’, the transient activation of the hypothalamic-pituitary-gonadal axis after birth for postnatal testicular position. In addition, we assessed whether the levels of persistent organic pollutants such as polychlorinated biphenyl (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs, or ‘dioxins’) and polybrominated diphenyl ethers (PBDEs) are associated with congenital cryptorchidism. Finally, we assessed the testicular development during puberty among boys with a history of congenital cryptorchidism. We observed that testicular descent continued until the age of three months, and was followed by a ‘physiological’ testicular ascent, which coincided with the decline in circulating reproductive hormones. We also discovered that the circulating concentration of insulin-like growth factor 1 and hormonal indices reflecting Sertoli and Leydig cell function correlated with testicular position. Our results also suggest that the exposure to dioxins may increase the risk of congenital cryptorchidism. Furthermore, we showed that boys who had a history of congenital cryptorchidism display poor testicular growth during puberty in comparison to controls, which may predispose them to reduced semen quality and subfertility.</p

Postnatal Testicular Activity in Healthy Boys and Boys With Cryptorchidism

Cryptorchidism, or undescended testis, is a well-known risk factor for testicular cancer and impaired semen quality in adulthood, conditions which have their origins in early fetal and postnatal life. In human pregnancy, the interplay of testicular and placental hormones as well as local regulatory factors and control by the hypothalamic-pituitary (HP) axis, lead to testicular descent by term. The normal masculine development may be disrupted by environmental factors or genetic defects and result in undescended testes. Minipuberty refers to the postnatal re-activation of the HP-testicular (T) axis after birth. During the first weeks of life, gonadotropin levels increase, followed by activation and proliferation of testicular Leydig, Sertoli and germ cells. Consequent rise in testosterone levels results in penile growth during the first months of life. Testicular size increases and testicular descent continues until three to five months of age. Insufficient HPT axis activation (e.g., hypogonadotropic hypogonadism) is often associated with undescended testis and therefore minipuberty is considered an important phase in the normal male reproductive development. Minipuberty provides a unique window of opportunity for the early evaluation of HPT axis function during early infancy. For cryptorchid boys, hormonal evaluation during minipuberty may give a hint of the underlying etiology and aid in the evaluation of the later risk of HPT axis dysfunction and impaired fertility. The aim of this review is to summarize the current knowledge of the role of minipuberty in testicular development and descent

INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants: A protocol for three parallel double-blind, randomised controlled trials (INVESTDIA)

Aims beta-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP - 1) analogue liraglutide in three early stages of type 1 diabetes.Methods We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10-14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed.Conclusions Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic beta-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate.Trial registration NCT02611232 (stage 1 trial), NCT02898506 (stage 2 trial), NCT02908087 (stage 3 trial).</p

Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study: TEFA

AimThe aim of the present study was to assess beta cell function based on an oral glucose tolerance test (OGTT) in participants with single islet autoantibody or an intravenous glucose tolerance test (IvGTT) in participants with multiple islet autoantibodies.Materials and methodsHealthy participants in Sweden and Finland, between 2 and 49.99 years of age previously identified as positive for a single (n = 30) autoantibody to either insulin, glutamic acid decarboxylase, islet antigen-2, zinc transporter 8 or islet cell antibodies or multiple autoantibodies (n = 46), were included. Participants positive for a single autoantibody underwent a 6-point OGTT while participants positive for multiple autoantibodies underwent an IvGTT. Glucose, insulin and C-peptide were measured from OGTT and IvGTT samples.ResultsAll participants positive for a single autoantibody had a normal glucose tolerance test with 120 minutes glucose below 7.70 mmol/L and HbA1c values within the normal range (ConclusionParticipants positive for a single autoantibody appeared to have a normal beta cell function. Participants positive for three or more autoantibodies had a lower FPIR as compared to participants with two autoantibodies, supporting the view that their beta cell function had deteriorated.</p

Rasvakudoksen pysyvien ympäristökemikaalien pitoisuuksien yhteys synnynnäiseen piilokiveksisyyteen

Siirretty Doriast

AQUA naturalis - Hulevesien luonnonmukainen käsittely Lambrobäckenin purolaakson länsiosassa

Valuma-alueella tapahtuvan rakentamisen myötä mm. vettä läpäisevän pinnan määrä vähenee ja veden luonnollinen kiertokulku estyy. Imeytymisen vähennyttyä entistä suurempi osa sadevesistä muuttuu pintavalunnaksi, ylivirtaamat kasvavat ja alivirtaamat pienenevät. Virtaamaolosuhteiden äärevöityessä myös veden laatu heikkenee. Rakentamisen negatiivisia vesistövaikutuksia voidaan kuitenkin ehkäistä hyvällä suunnittelulla. Luonnonmukaisilla hulevesien käsittelytoimilla pyritään palauttamaan veden kiertokulku valuma-alueella kohti luonnontilaista. Suunnittelu lähtee liikkeelle valuma-aluetasolta ja luonnon olosuhteiden kartoituksesta. Pohjoisiin olosuhteisiin soveltuvia luonnonmukaisia hulevesien käsittelymenetelmiä on käytettävissä rajallinen valikoima. Ne voidaan jakaa hulevesien imeyttämiseen, viivyttämiseen ja varastointiin sekä johtamiseen tarkoitettuihin ratkaisuihin. Menetelmien valintaan vaikuttavat suunnittelualueen ominaisuudet, kuten maaperän laatu, topografia, kasvillisuus ja maankäyttö sekä siihen kohdistuvat muutokset. Diplomityön osana on laadittu suunnitelma Länsi-Espoossa sijaitsevan Lambrobäckenin purolaakson kehittämiseksi luonnonmukaisen vesirakentamisen keinoin. Suunnitelma havainnollistaa diplomityön teoriaosuutta käytännössä. Lambrobäckenin 568 hehtaarin suuruinen valuma-alue sijaitsee voimakkaasti kehittyvällä Kauklahden kasvualueella, jonka kaavoittaminen on parhaillaan käynnissä. Puro on luonteeltaan loiva ja rakenteeltaan yksipuolinen. Valuma-alueelle suunniteltu rakentaminen äärevöittää alueen virtaamavaihtelua, joka mm. lisää tulvariskiä alueella. Purolaakso on haja-asutettua vanhaa kulttuurimaisemaa, jossa harjoitetaan edelleen maanviljelyä. Puron vedenlaatu ilmentää alueen maankäyttöä. Suunnitelman tavoitteena on mm. tasapainottaa vesistöön kohdistuvia virtaamavaihteluita, parantaa veden laatua ja kohentaa puron ekologista tilaa. Lisäksi tavoitteena on nostaa puro arvoiseensa asemaan maisemassa kunnioittaen alkuperäisen kulttuurimaiseman ja luonnon ominais- ja erityispiirteitä. Purolaakson sijainti suunnitteilla olevan viherverkoston ja kevyen liikenteen reitistön osana on keskeinen. Se mm. liittää Espoon keskuspuiston ja Espoonlahden ranta-alueet toisiinsa. Purolaakso on suunniteltu palvelemaan sekä paikallista että seudullista virkistyskäyttöä. Puron yhteyteen suunnitellut vesirakentamisratkaisut tulevat toimimaan viheralueen uusina vetonauloina. Suunnitelmaan on liitetty purolaaksoon rajautuvien uusien asuinalueiden hulevesien luonnonmukaisen käsittelyn suuntaviivat sekä tarkempi esimerkki uuden Saunaniemen asuinalueen hulevesien luonnonmukaisen käsittelyn sijoittamisesta ja mitoittamisesta

Extremely Early Appearance of Islet Autoantibodies in Genetically Susceptible Children

Objective. We studied the characteristics of children who developed islet autoantibodies by the age of 0.50 years and hypothesized that the appearance of extremely early islet autoimmunity differs between four birth cohorts within 1994-2019 according to the change in the incidence of Type 1 diabetes (T1D) in Finland. Methods. Data from Finnish children participating in the Type 1 Diabetes Prediction and Prevention (DIPP) study, or the Environmental Determinants of Diabetes in the Young (TEDDY) study were analyzed. These studies follow children with increased HLA-conferred risk for T1D with regular measurements of islet autoantibodies. Maternally transferred antibodies were excluded by comparing islet autoantibodies in cord serum, child's first follow-up serum and the maternal serum. Results. Among 20,979 Finnish children at increased risk to T1D, 53 (0.25%) developed at least one islet autoantibody at the age of <= 0.50 years. During a mean follow-up of 8.1 years, 15.1% progressed to T1D (median age at diagnosis 2.0 years), 43.4% developed confirmed islet autoimmunity but no T1D, and 41.5% had only transient islet autoantibodies. IAA was the most common first-appearing autoantibody. Among progressors, age at diagnosis was 1.0-2.4 years in children with IAA-initiated autoimmunity and 4.5-16.1 years in ZnT8A-initiated autoimmunity. When comparing children developing autoantibodies either at the age of <= 0.50 years or 0.51-0.75 years, confirmed positivity during follow-up was more common in the older group (81.7% vs. 58.5%; p=0.002). In four birth cohorts within 1994-2019 appearance of islet autoantibodies at the age of <= 0.50 years decreased towards the most recent birth cohorts (p=0.016). Conclusion. Islet autoimmunity by the age of 0.50 years was rare in genetically susceptible children and was typically initiated with IAA. Confirmed positivity was less common in children with autoantibodies at age <= 0.50 than at slightly older age. The secular decrease of islet autoimmunity before age 0.50 years was observed. This trial is registered with NCT03269084 and NCT00279318.Peer reviewe