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Reduced FSH and LH action: implications for medically assisted reproduction.

ABSTRACT: Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play complementary roles in follicle development and ovulation via a complex interaction in the hypothalamus, anterior pituitary gland, reproductive organs, and oocytes. Impairment of the production or action of gonadotropins causes relative or absolute LH and FSH deficiency that compromises gametogenesis and gonadal steroid production, thereby reducing fertility. In women, LH and FSH deficiency is a spectrum of conditions with different functional or organic causes that are characterized by low or normal gonadotropin levels and low oestradiol levels. While the causes and effects of reduced LH and FSH production are very well known, the notion of reduced action has received less attention by researchers. Recent evidence shows that molecular characteristics, signalling as well as ageing, and some polymorphisms negatively affect gonadotropin action. These findings have important clinical implications, in particular for medically assisted reproduction in which diminished action determined by the afore-mentioned factors, combined with reduced endogenous gonadotropin production caused by GnRH analogue protocols, may lead to resistance to gonadotropins and, thus, to an unexpected hypo-response to ovarian stimulation. Indeed, the importance of LH and FSH action has been highlighted by the International Committee for Monitoring Assisted Reproduction Technologies (ICMART) in their definition of hypogonadotropic hypogonadism as gonadal failure associated with reduced gametogenesis and gonadal steroid production due to reduced gonadotropin production or action. The aim of this review is to provide an overview of determinants of reduced FSH and LH action that are associated with a reduced response to ovarian stimulation.

SUBMITTER: Bosch E

PROVIDER: S-EPMC8129594 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIndividualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials.MethodsWe evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in < 10% of patients; otherwise, a normal approximation method was used.ResultsInitially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively.ConclusionsThis systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%.

Project description:Study questionHow did coronavirus disease 2019 (COVID-19) impact on medically assisted reproduction (MAR) services in Europe during the COVID-19 pandemic (March to May 2020)?Summary answerMAR services, and hence treatments for infertile couples, were stopped in most European countries for a mean of 7 weeks.What is known alreadyWith the outbreak of COVID-19 in Europe, non-urgent medical care was reduced by local authorities to preserve health resources and maintain social distancing. Furthermore, ESHRE and other societies recommended to postpone ART pregnancies as of 14 March 2020.Study design size durationA structured questionnaire was distributed in April among the ESHRE Committee of National Representatives, followed by further information collection through email.Participants/materials setting methodsThe information was collected through the questionnaire and afterwards summarised and aligned with data from the European Centre for Disease Control on the number of COVID-19 cases per country.Main results and the role of chanceBy aligning the data for each country with respective epidemiological data, we show a large variation in the time and the phase in the epidemic in the curve when MAR/ART treatments were suspended and restarted. Similarly, the duration of interruption varied. Fertility preservation treatments and patient supportive care for patients remained available during the pandemic.Large scale dataN/A.Limitations reasons for cautionData collection was prone to misinterpretation of the questions and replies, and required further follow-up to check the accuracy. Some representatives reported that they, themselves, were not always aware of the situation throughout the country or reported difficulties with providing single generalised replies, for instance when there were regional differences within their country.Wider implications of the findingsThe current article provides a basis for further research of the different strategies developed in response to the COVID-19 crisis. Such conclusions will be invaluable for health authorities and healthcare professionals with respect to future similar situations.Study funding/competing interestsThere was no funding for the study, apart from technical support from ESHRE. The authors had no COI to disclose.

Project description:Study questionDoes parental fertility, measured by time to pregnancy (TTP), or use of medically assisted reproduction (MAR) affect pubertal development in the offspring?Summary answerNeither TTP nor type of MAR treatment had clinically relevant implications for mean age at achieving individual pubertal milestones or overall timing of puberty in boys and girls.What is known alreadyParental TTP and MAR have been associated with impaired semen quality in adult sons. Timing of puberty reflects earlier signals of reproductive health, but it remains unclear whether parental fertility or MAR affects pubertal development, especially in the growing generation of children conceived by IVF or ICSI.Study design, size, durationIn this study, 15 819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate = 70%). Parental TTP and use of MAR were reported by mothers in early pregnancy and children's pubertal development data was self-recorded in web-based questionnaires from 11 years of age and 6 monthly throughout puberty (2012-2018).Participants/materials, setting, methodsPubertal development in children (of planned pregnancies, n = 13 285) born by untreated subfecund (TTP: 6-12 months) (n =2038), untreated severely subfeund (TTP: >12 months) (n = 1242), treated subfecund (n = 230) and treated severely subfecund (n = 1234) parents were compared to children born to more fertile parents (TTP: ≤5 months). We estimated mean monthly differences in mean age at achieving individual pubertal milestones (i.e. age at menarche, voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for breast or genital development and pubic hair growth) and a combined indicator of timing of puberty. Further, we compared mean age at achieving the individual pubertal milestones in children born by use of IVF or ICSI (n = 480) with children born by controlled ovarian stimulation or ovulation induction with or without intrauterine insemination (n = 902).Main results and the role of chanceWe found tendencies towards slightly later mean age at male pubertal timing and slightly earlier mean age at female pubertal timing among children born by untreated subfecund, treated subfecund, untreated severely subfecund and treated severely subfecund parents. There were no specific patterns with increasing TTP, use of MAR nor type of MAR treatment, and the magnitude of the mean differences for individual milestones and overall timing of puberty were small, i.e. 0.9 months (95% CI: -1.0; 2.8) for first ejaculation and -0.5 months (95% CI: -2.0; 1.0) months for age at menarche in boys and girls, respectively, born by treated severely subfecund parents when compared with children born by more fertile parents.Limitations, reasons for cautionNon-differential misclassification of the self-reported information on parental TTP and pubertal development in the offspring may serve as an alternative explanation of the findings, possibly biasing the estimates towards the null. The information on pubertal development was collected from around 11 years of age and onwards.Wider implications of the findingsThis study adds to the growing body of literature suggesting only limited harmful effects of parental subfecundity and MAR on offspring's long-term growth and development.Study funding/competing interest(s)This work was supported by the Danish Council for Independent Research [DFF 4183-00152]; and the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.

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Reduced FSH and LH action: implications for medically assisted reproduction.

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