Low Gonadotropin Research Articles

Proportion and predictors of Hypogonadism Recovery in Men with Macroprolactinomas treated with dopamine agonists.

Hypogonadism is the most common form of hypopituitarism in men with macroprolactinoma. However, evidence on factors related to hypogonadism recovery is limited. We estimated the proportion of hypogonadism in men with macroprolactinoma exclusively treated with dopamine agonists, and we assessed the factors predicting hypogonadism recovery. This was a multicenter retrospective study of men with macroprolactinoma identified using ICD 9 and 10 codes and treated between 2009 and 2019 in five centers in the United Arab Emirates and Saudi Arabia. We evaluated hypogonadism, defined as low total testosterone (TT) level with normal or low gonadotropins on presentation and during the last clinic visit. A total of 79 patients (median age 32 years) were included in the study. The most common symptoms at presentation were headache (73.7%), erectile dysfunction (55.4%), and low libido (54.3%). The median tumor size was 2.9cm (1.0-9.7) at diagnosis. Sixty-three patients (79.7%) had hypogonadism at baseline. Growth hormone deficiency (GHD) and hypothyroidism were present in 34.4% and 32.9% of patients, respectively. The median serum prolactin (PRL) level was 20,175 (min-max 2254 - 500,000) mIU/l with a median serum TT of 4.5 (min-max 0.4-28.2) nmol/l. Most patients were treated with cabergoline (n = 77, 97.5%) with a median of 6 (min-max 0.6-22) years. At follow-up, 65% of patients recovered their pituitary-testicular axis. Patients with recovered hypogonadism had smaller median tumor size (2.4 [1-5.4] vs. 4.3 [1.6-9.7], p = 0.003), lower PRL level (18, 277 [2254 - 274, 250] vs. 63,703 [ 3,365-500,000], p = 0.008 ), higher TT level (4.6 [0.6-9.2] vs. 2.3 [0.5-7.3], p = 0.008), lower PRL normalization time on medical therapy (8 months (0.7-72) vs. 24 (3-120), p = 0.009) as well as lower frequency of GHD (17.1% vs. 60%, p = 0.006) and secondary hypothyroidism (17.9% vs. 57.1%, p = 0.003) compared with those with persistent hypogonadism respectively. Age at diagnosis, presenting symptoms and duration of medical therapy did not predict hypogonadism recovery. About two-thirds of men with macroprolactinoma recover from hypogonadism, mostly with 24 months of therapy. Smaller adenoma size, lower prolactin level, earlier prolactin normalization, and higher testosterone patients were related to testosterone normalization.

P-694 Dosage of exogenous gonadotropins is not related to blastocyst aneuploidy or cumulative live-birth rates in PGT-A cycles

Abstract Study question Does dosage of gonadotropins affect aneuploidy rate rates or cumulative live birth rates (CLBRs) after the transfer of euploid embryos? Summary answer We did not find evidence that dosage gonadotropin influenced significantly the rate of aneuploidy and CLBRs after transfer of euploid embryos. What is known already Aneuploidy rates increase steadily with age, reaching >80% in women >42 years old. The goal of controlled ovarian stimulation obtaining more embryos to biopsy through the recruitment of several follicles, reaching more euploid embryos. However, several studies have suggested that a high response to stimulation might be embryotoxic and/or increase aneuploidy rates by enhancing the abnormal segregation of chromosomes during meiosis. Furthermore, a study on young donors showed differences in the euploidy rates, suggesting an iatrogenic etiology resulting from different stimulation methods. Study design, size, duration A multicenter retrospective study, with the preimplantation genetic test for aneuploidy (PGT-A) between January 2013 and January 2020 collected from clinics IVIRMA in Europe. 6832 cycles of in vitro fertilization (IVF) with PGT-A were included in the study Participants/materials, setting, methods A total of 62131 embryos were analyzed for ploidy status. Embryos that were subjected to chromosomal analysis were performed blastomere by aCGH (array Comparative Genomic Hybridization) or NGS (Next-Generation Sequencing) analysis. The embryos were biopsied on days 5 and 6. Women were divided into two age groups (<37 and ≥37 years old). Outcomes were compared between different total gonadotropin dosages (<3000 and ≥3000 IU), the dosage of hMG, and numbers of oocytes retrieved. Main results and the role of chance The total number of aneuploid embryos was 28336 of the 62131 embryos genetically screened using PGT-A. The embryonic aneuploidy rate was 59.4% (95%CI 58.5-60.3). In the group of women with gonadotropins dosage <3000 IU the embryonic aneuploidy rate was 59.7% (95%CI 58.7-60.8) and in the group with gonadotropins dosage ≥3000 IU was 58.7% (95%CI 57.1-60.3) with no significant difference between them (P = 0.279). In the group of younger patients (<37 y.o) the aneuploidy rate demonstrated no significant differences between patients who received low gonadotropin dosages and patients with high gonadotropin dosages (P = 0.06). Aneuploidy rates in the group of older patients (≥37 y.o) were similar regardless of gonadotropin dosing (P = 0.21). Dividing the according to the number of oocytes retrieved (10, 11-15, >15), the analysis of aneuploidy rate revealed no association between the gonadotropin dosages administrated depending on the total number of retrieved oocytes and age. The aneuploidy rate was also analyzed considering the administration of hMG, there was no statistical difference in the aneuploidy rate with low or high hMG dosages also when it was stratified by age. The cumulative live-birth rate in the groups of different gonadotropins dosage and different ages of patients was similar across the group. Limitations, reasons for caution The retrospective nature is the major limitation of this study, also patients included in the study received PGT-A using NGS and CGH arrays technology. The aCGH analysis used is less sensitive than more recent NGS technology. Wider implications of the findings Our study demonstrated that gonadotropin dosage did not affect aneuploidy rate or cumulative live-birth rates suggesting that the high doses of gonadotropins used in ART cycles may be safe. Trial registration number not applicable

Follicular fluid PlGF and IVF/ICSI outcomes among PCOS and normo-ovulatory women using different controlled hyperstimulation protocols: A prospective case-control study

BackgroundGonadotropin-releasing hormone (GnRH) analogues are used to prevent premature luteinizing hormone (LH) surge during In-Vitro Fertilization. However, the follicular fluid levels of the Placental growth factor (FF PlGF), the novel angiogenic factor, differ significantly between GnRH-agonist and GnRH-antagonist protocols. Thus, we compared the IVF/ICSI outcomes and their correlations with FF PlGF levels in polycystic ovary syndrome (PCOS) and normo-ovulatory women during different hyperstimulation protocols. MethodsThis case-control study is a re-analysis of two prospective trials that were conducted on women who were referred to Orient Hospital, Damascus, Syria, from December 2019 to August 2021. A total of 75 PCOS-women (PCOS-Agonist, n = 53; PCOS-Antagonist, n = 22) and 83 normo-ovulatory women (Control-Agonist, n = 50; Control-Antagonist, n = 33) were included. Follicular fluid samples were collected on retrieval day. ResultsAlthough PCOS-women were stimulated using lower gonadotropin doses, the Ovarian-sensitivity-indexes were higher in PCOS-groups (PCOS-Agonist vs Control-Agonist; P-value <0.001), (PCOS-Antagonist vs Control-Antagonist; P-value = 0.042). However, FF PlGF levels, maturation rate, fertilization rate, and oocytes morphology were comparable between PCOS and controls independently of the protocol used. Interestingly, FF PlGF levels were positively correlated with Ovarian-sensitivity-indexes in the PCOS-Antagonist, Control-Agonist, and Control-Anta groups, but not in the PCOS-Agonist group. Nevertheless, FF PlGF levels were comparable between pregnant and non-pregnant women in all studied groups. ConclusionsAlthough PCOS exaggerates ovarian response to stimulation irrespective of the protocol used, it does not have a detrimental impact on oocytes morphology or competence. Moreover, FF PlGF levels could be a marker of the ovarian response other than a predictor of pregnancy achievement.

Estropause, Sex Hormones and Metal Homeostasis in the Mouse Brain.

Alterations in brain metal ion homeostasis have been reported with aging and are implicated in the pathogenesis of neurodegenerative diseases. To assess whether age-related changes in hypothalamic-pituitary-gonadal (HPG) hormones might be involved in modulating brain metal ion homeostasis, we treated 7.5-month intact, sham-ovariecomized and ovariectomized C57B6SJL mice with vehicle or leuprolide acetate (for 9-months) to differentiate between whether sex steroids or gonadotropins might modulate brain metal ion concentrations. Unlike other aging mammals, there was no increase in plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations following estropause in mice, suggesting there was sufficient residual production by the follicle depleted ovary, of sex steroids like estrogens and protein hormones like the inhibins, in order to suppress pituitary LH/FSH production. Castration on the other hand induced significant increases in circulating LH and FSH. Modulation of plasma sex steroid and gonadotropin levels did not significantly alter the concentrations of brain metals tested (Fe, Zn, Cu, Mn, Co, Ni, Al, Li), although there was a tendency for a decrease in all brain metals following ovariectomy (low estrogens and progesterone, high gonadotropins), a response that was reversed with leuprolide acetate treatment (low sex steroids, low gonadotropins). Brain Cu concentration was the only metal correlated with plasma LH (−0.37, n = 30, p < 0.05) and FSH (−0.42, n = 29, p < 0.01). This study demonstrates that sex hormones do not markedly alter brain metal ion homeostasis, unlike previously reported studies of circulating metal ion homeostasis. The role of gonadotropins in regulating metal ion homeostasis does however warrant further study.

IVF Lite: a smart IVF programme based on mild ovarian stimulation for good prognosis patients

Research questionThe IVF Lite programme is based on mild ovarian stimulation including up to three fresh/frozen embryo transfers within 12 months. Is it effective and safe in good prognosis patients? DesignSingle-centre prospective study on infertile patients at their first IVF attempt (female age ≤38 years, anti-Müllerian hormone concentrations >1.5 ng/ml and/or FSH ≤10 mIU/ml). Induction of multiple follicular growth was based on a fixed protocol consisting of clomiphene citrate (100 mg/day) from day 3 to 7 of the menstrual cycle and 150 IU of recombinant FSH on days 5, 7 and 9. In case of low follicular recruitment (fewer than four follicles), the cycle was cancelled. The IVF Lite programme was considered complete after a live birth delivery or up to three embryo transfers within 12 months. The primary outcome was the cumulative live birth rate (cLBR) per couples that completed the programme. ResultsA total of 369 patients completed the IVF Lite programme, with 239 live births; 132 patients delivered after one embryo transfer (35.8%), 70 after a second embryo transfer (cLBR 54.7%), and 37 after a third attempt (cLBR 64.8%). No cases of ovarian hyperstimulation syndrome or clinical complications occurred. Spontaneous dropout rate from the programme was 4.5%. The cLBR per intention to treat was 46.8%. ConclusionsThe IVF Lite programme proved to be effective and safe in good prognosis patients with a good response to clomiphene citrate stimulation. It was well tolerated and implied low gonadotrophin consumption. Two-thirds of the patients achieved a live birth at the completion of the programme.

Prohibitin-1 plays a regulatory role in Leydig cell steroidogenesis

SummaryMitochondria are essential for steroidogenesis. In steroidogenic cells, the initiation of steroidogenesis from cholesterol occurs on the matrix side of the inner mitochondrial membrane by the enzyme P450scc. This requires cholesterol import from the cytoplasm through the outer mitochondrial membrane, facilitated by the StAR protein. The subsequent steps leading to P450scc remain elusive. Here we report that the male transgenic mice that expressed a mutant form of a mitochondrial protein prohibitin-1 (PHB1Tyr114Phe) from the Fabp-4 gene promoter displayed smaller testes, higher testosterone, and lower gonadotropin levels compared with PHB1-expressing and wild-type mice. A subsequent analysis of the testis and Leydig cells from the mice revealed that PHB1 played a previously unknown regulatory role in Leydig cell steroidogenesis. This includes a role in coordinating cell signaling, cholesterol homeostasis, and mitochondrial biology pertaining to steroidogenesis. The implications of our finding are broad as the initial stages of steroidogenesis are indistinguishable across steroidogenic cells.

Homozygosity for a novel INHA mutation in two male siblings with hypospadias, primary hypogonadism, and high-normal testicular volume.

BackgroundThe human INHA gene encodes the inhibin subunit alpha protein, which is common to both inhibin A and B. The functional importance of inhibins in male sex development, sexual function, and reproduction remain largely unknown.ObjectiveWe report for the first time two male siblings with homozygous INHAmutations.MethodsThe medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods.ResultsTwo brothers complained of gynecomastia, testicular pain, and had a history of hypospadias. Biochemistry revealed low serum testosterone, high gonadotropin and anti-Mullerian hormone, and very low/undetectable inhibin concentrations, where available. Both patients had azoospermia in the spermiogram. We have identified a homozygous 2 bp deletion (c.208_209delAG, R70Gfs*3) variant, which leads to a truncated INHA protein in both patients, and confirmed heterozygosity in the parents. The external genital development, pubertal onset and progression, reproductive functions, serum gonadotropins, and sex hormones of mother and father, who were heterozygous carriers of the identified mutation, were normal.ConclusionHomozygosity for INHA mutations causes decreased prenatal and postnatal testosterone production and infertility in males, while the heterozygous female and male carriers of INHA mutations do not have any abnormality in sex development and reproduction.

Initial gonadotropin levels and sperm parameters differentiate the response to clomiphene citrate in subfertile men.

BackgroundEfficacy of clomiphene citrate (CC) in the treatment of male subfertility remains unclear, with inconsistent results in the literature and limited guidance from professional organizations. We sought to stratify the response to clomiphene in men based on their initial gonadotropins and semen parameters.MethodsWe conducted a retrospective analysis of 234 patients from an academic center who took CC for subfertility. Patients with pre-treatment and 3 months follow-up total testosterone (TT) and semen analyses were included. Patients with previous hormone therapy, genitourinary surgery, prior success in conceiving pregnancy, or only one semen analysis were excluded. Primary outcomes were magnitudes of improvement in TT and semen parameters at 3 months. Student’s t-test (alpha =0.05) was used for univariate analyses; multivariable linear regression was used for multivariate analysis.ResultsOne hundred and thirty-seven patients met inclusion criteria. Thirty-four percent of patients experienced improvement in sperm concentration after 3 months of CC treatment, 13% decreased, and 53% showed no change. Using a pre-treatment TT cutoff of 300 ng/dL and gonadotropin thresholds of 7 miU/mL, initial TT did not affect magnitude of improvement in semen parameters, while lower initial gonadotropins showed statistical improvement across all outcomes. Multivariate analysis showed pre-treatment follicle stimulating hormone (FSH) was inversely correlated with improvement in TT [odds ratio (OR): 2.64e-05, 95% confidence interval (CI): 1.32e-09 to 5.28e-01, P=0.04] and sperm concentration (OR: 0.22, 95% CI: 5.70e-02 to 8.48e-01, P=0.03). We also provide initial gonadotropin cutoffs that suggest statistical benefit from CC use.ConclusionsMen with lower gonadotropin levels may expect greater degree of improvement in both hormone and semen parameters with use of CC. Men with azoospermia do not benefit based on semen analyses alone. Degree of non-azoospermia does not affect magnitude of improvement. CC had decreasing efficacy at higher initial gonadotropin levels. These data may provide guidance in stratifying and counseling men for CC treatment.

Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome.

Gordon Holmes syndrome (GHS) is a rare disease characterized by hypogonadotropic hypogonadism (HH), progressive cognitive decline and variable movement disorders. Mutations in RNF216 have been found to be associated with GHS. Here, we identify a novel homozygous RNF216 p.E650X mutation causing GHS. The proband presented with onset dysarthria and developed cerebellar ataxia and cognitive impairment, with a history of azoospermia at the age of 28 years. Cerebellar atrophy and white matter lesions were found in the cerebral hemispheres and brainstem. Low gonadotropin serum levels were also observed. Whole-exome sequencing (WES) revealed a novel homozygous nonsense variant in RNF216, c.1948G>T; p.E650X. Our finding furthers the genetic knowledge of GHS and extends the ethnic distribution of RNF216 mutations.

Dominant follicle and gonadotropin dynamics before ovulation in postpartum lactating mares.

The aim of this study was to compare the dominant follicle (DF) and gonadotropin dynamics for 9 days before ovulation in postpartum lactating (PP Lactating) versus non-postpartum cycling (N-PP Cycling) mares. Every PP Lactating mare on the day of parturition was paired with a N-PP Cycling mare, and the data analyses considered the partum-ovulation interval (POI) and the postpartum interovulatory interval (PPIOI) in PP Lactating mares and two interovulatory intervals in N-PP Cycling mares. The results of the present study revealed several novel and unique aspects of DF development and FSH and LH dynamics before ovulation in PP Lactating mares when compared with N-PP Cycling mares. The most remarkable differences between both groups of mares were the following: (1) a shorter interval to ovulation in PP Lactating mares during the foal heat (POI ≤22 days) compared with all other intervals; (2) a larger DF in PP Lactating mares, and an earlier day of DF at maximum diameter during the foal heat; and (3) lower gonadotropin levels in PP Lactating mares. Regarding the particularities, PP Lactating mares had lower LH levels during the POI than the PPIOI, demonstrating a strong partum effect; spring-foaled mares had longer POIs, larger DF diameters, and lower LH levels; and lower body condition scores and higher body-weight loss led to longer POIs and smaller DF diameters in PP Lactating mares. This study contributes to a broad understanding of ovarian function in the postpartum mare.

Caesarean scar ectopic pregnancy masquerading as gestational trophoblastic disease.

Cesarean scar ectopic pregnancy (CSEP) is a very rare form of ectopic pregnancy in which implantation occurs at the site of the previous cesarean scar with low or absent beta-human chorionic gonadotropin (hCG) levels. It has various differential diagnoses on gross and microscopic examination. A delay in the identification and management of this condition may lead to life-threatening complications. Here, we discuss the incidence and clinicopathological features of chronic CSEP, its types, and differential diagnoses.

Testicular ultrasound in a patient with Kallmann syndrome: A case report

Introduction. Kallmann syndrome is a genetic disorder marked by hypogonadotropic hypogonadism and anosmia. Patients with Kallmann syndrome have low circulating testosterone levels and low gonadotropin levels, whereas other pituitary hormones are normal. The treatment is based on sex steroid replacement with the aim to restore normal pubertal development and includes attempts to restore fertility by using gonadotropin-releasing hormones. Ultrasound examination of the testicles is a very useful complement to determine and monitor the precise testicular volume, which is an important prognostic factor for future fertility. Case Report. At the age of 18, the patient was suspected of having Kallmann syndrome and was referred to an endocrinologist. After three months of testosterone therapy, the patient was sent for an ultrasound of the testicles. The right testicle measured 16 x 6 mm, the left testicle 10 x 5 mm, both with a discrete marginal circular dichroism signal. One year after the first testicular ultrasound, the patient came for a checkup. The right testicle measured 14 x 5 mm, the left testicle 11 x 5 mm, stationary structure. Conclusion. The diagnosis of Kallmann syndrome is often delayed, because hypogonadotropic hypogonadism is usually not apparent until puberty, and individuals with anosmia are often unaware of this sensory deficit. In this case, late recognition of the syndrome, as well as late initiation of therapy, did not give satisfactory results.

Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.

Adding Low Dose hCG to rFSH in GnRH Antagonist ICSI Cycles: A Randomized Controlled Trial

Inhibition of luteinizing hormone (LH) by gonadotropin releasing hormone (GnRH) antagonist may lead to suboptimal response during ovarian stimulation. In addition, several studies suggest that low level of LH is associated with lowered fertilization and implantation rate and increased early pregnancy loss rate. The aim of this study is to study the effect of adding low dose human chorionic gonadotropin (hCG - 200 IU), as an LH supplement, to recombinant follicle stimulating hormone (rFSH) in a GnRH antagonist cycles in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Sixty-three infertile women undergoing IVF were randomly divided into two groups. One group was stimulated with the conventional stimulation protocol (rFSH alone), while the second group received 200 IU hCG in addition to rFSH in the late follicular phase (hCG + rFSH). Both groups' results including pregnancy rate, total dose of rFSH required, duration of stimulation, endometrial thickness, oocytes and embryos characteristic, serum hormone levels (Testosterone, Estradiol, Progesterone, and LH) and level of epidermal growth factor (EGF) were compared. The results show that pregnancy rate among the group of women who received the low dose hCG was higher than those who did not receive hCG. However, this difference did not reach statistical significance. Furthermore, other cycle outcomes and hormonal values were comparable between the two stimulation protocols.

DOES DUAL TRIGGER WITH COMBINATION OF GONADOTROPIN-RELEASING HORMONE AGONIST AND LOW DOSE HUMAN CHORIONIC GONADOTROPIN IMPROVES CLINICAL OUTCOMES IN NORMAL RESPONDERS IN GnRH ANTAGONIST IVF-ICSI CYCLES

Clinical outcomes of dual trigger containing gonadotropin-releasing hormone agonist (GnRHa) and low dose human chorionic gonadotropin (hCG) compared with the standard dose of human chorionic gonadotropin (hCG) trigger for final oocyte maturation in normal responder patients in GnRH Antagonist IVF-ICSI Cycles. A single centre prospective randomized comparative study conducted at a tertiary care infertility centre , Akanksha IVF centre, Janakpuri, New Delhi from 1st March 2020 to 28th February 2021. 80 normal responder patients defined as women in age group 21 to 37 year, with serum AMH level >1.2 ng/ml to < 4ng/ml , with AFC (3- 8) per ovary who were to undergo controlled ovarian hyperstimulation (COH) for IVF-ICSI cycles, were randomized by a computer based program into 2 groups of 40 each. All the patients underwent ovarian stimulation with a starting dose of recombinant FSH with dosage 150-225 IU on D2 and the dosage were adjusted according to follicular monitoring After at least one follicle reached a size of 14mm , antagonist Inj Cetrorelix 0.25 mg started subcutaneously daily. When > 2 follicles reached the size of 18 mm final oocyte maturation was triggered by either dual trigger of Inj Leuprolide acetate 2 mg and low dose 2000 IU highly purified Inj. hCG subcutaneously in Group 1 or by standard trigger dose 10000 IU of highly purified inj hCG in Group2. Oocyte retrievals were performed 35 to 36 hours after the trigger. IVF-ICSI was performed in all cases. Day 3 fresh embryo transfers were performed for all cases (2 x 8cell embryos).The luteal phase support was with vaginal supplementation of 800 mg micronized progesterone. Serum beta hCG was performed after14 days of embryo transfer . Primary outcome measured was clinical pregnancy rate and secondary outcomes measured were: implantation rate, miscarriage rate, number of MII oocytes picked up, number of embryos formed, and risk of OHSS. In dual trigger , group 1 the clinical pregnancy rate (52.50% vs 47.50% ) and implantation rate (29.67% vs 26.08% ) were higher than in Group 2 , and but the difference was not statistically significant. Miscarriage rate was lesser in group 1 (14.28%) than in group 2 (15.78%) and it was also not statistically significant . There were higher number of MII oocytes picked up and higher number of embryos formed in group1/ dual trigger group (10.63+5.46 and 8.2+3.4 respectively ) than in group 2 (8.10+5.74 and 6.8+3.6 respectively) and this difference was statistically significant . No OHSS was reported in group 1/ dual trigger group. Though there was increased clinical pregnancy rate, implantation rate and a lesser miscarriage rate in dual trigger group1 for but it was statistically not significant .There was significant increase in MII oocytes and number of embryos formed (p value .0064 and .0 156 respectively) in the dual trigger group. There was also no risk of OHSS in dual trigger group.

MP31-17 PRE-TREATMENT SEX HORMONE LEVELS AND SPERM CONCENTRATION INFLUENCE MAGNITUDE OF RESPONSE TO CLOMIPHENE IN SUBFERTILE MEN

You have accessJournal of UrologyInfertility: Therapy (MP31)1 Sep 2021MP31-17 PRE-TREATMENT SEX HORMONE LEVELS AND SPERM CONCENTRATION INFLUENCE MAGNITUDE OF RESPONSE TO CLOMIPHENE IN SUBFERTILE MEN Tommy Jiang, Alvaro Santamaria, Neilufar Modiri, Michael Zheng, Vadim Osadchiy, John Sigalos, Jesse Mills, and Sriram Eleswarapu Tommy JiangTommy Jiang More articles by this author , Alvaro SantamariaAlvaro Santamaria More articles by this author , Neilufar ModiriNeilufar Modiri More articles by this author , Michael ZhengMichael Zheng More articles by this author , Vadim OsadchiyVadim Osadchiy More articles by this author , John SigalosJohn Sigalos More articles by this author , Jesse MillsJesse Mills More articles by this author , and Sriram EleswarapuSriram Eleswarapu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002035.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Selective estrogen receptor modulators (SERMs) are known to improve sperm counts. Men with low testosterone and gonadotropins are thought to benefit most from SERMs like clomiphene, though predictors of efficacy have not been robustly characterized. We sought to identify changes in sperm counts with clomiphene, stratifying by pre-treatment sex hormones and sperm parameters. METHODS: With IRB approval, we retrospectively analyzed sex hormone levels and sperm parameters in subfertile men before and after 3 months of clomiphene (25 mg qd or 50 mg qod) during 10/2015-6/2020. Men were stratified by initial hormone levels (T≥300 vs T<300, LH≥7 vs LH<7, FSH≥7 vs FSH<7) and separately by initial sperm concentration (azoospermia, oligozoospermia, and normospermia). Men who previously underwent hormone therapy, genital surgery, or conceived a pregnancy were excluded. Student t-test was conducted with α=0.05. RESULTS: Out of 137 patients, 34% improved, 13% worsened, and 53% had no change in sperm concentration categorization (Fig. 1). 77% of azoospermic men had no change in sperm concentration. Table 1 summarizes changes in T and semen analyses stratified by initial parameters. No significant difference was found in magnitude of changes in semen parameters stratified by testosterone. Men with lower LH had greater improvements in total sperm count (TSC) and total motile sperm count (TMSC). Men with lower FSH had greater improvements in T, sperm concentration, and TSC. Azoospermic men showed least improvement across all semen parameters. No significant differences in magnitude of improvement were observed between oligozoospermia sub-categorizations (mild, moderate, severe) and normospermia. CONCLUSIONS: Not all patients experience the same benefit from clomiphene. Our data suggest that men with azoospermia do not significantly benefit. Degree of non-azoospermia did not affect magnitude of improvement. Men with lower gonadotropin levels may expect greater degree of improvement in both hormone and semen parameters. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e561-e562 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tommy Jiang More articles by this author Alvaro Santamaria More articles by this author Neilufar Modiri More articles by this author Michael Zheng More articles by this author Vadim Osadchiy More articles by this author John Sigalos More articles by this author Jesse Mills More articles by this author Sriram Eleswarapu More articles by this author Expand All Advertisement Loading ...

EFFICACY OF CLOMIPHENE CITRATE IN SUBFERTILE MEN STRATIFIED BY PRE-TREATMENT SEX HORMONE LEVELS AND SPERM CONCENTRATION

Selective estrogen receptor modulators (SERMs) are known to improve sperm count. Men with low testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) are thought to benefit most from SERMs like clomiphene citrate (CC), though predictors of efficacy have not been robustly characterized. We sought to identify changes in sperm counts with CC, stratifying by pre-treatment sex hormones and semen parameters. With IRB approval, we retrospectively reviewed sex hormone levels and semen parameters in subfertile men before and after 3 months of CC use (25 mg qd or 50 mg qod) during 10/2015-6/2020. Men were stratified by initial hormone levels (T≥300 vs T<300, LH≥7 vs LH<7, FSH≥7 vs FSH<7) and separately by initial sperm concentration (azoospermia, oligozoospermia, and normospermia). Men who previously underwent hormone therapy, genital surgery, or had previously conceived were excluded. Men with or without varicoceles were included. Student t-test was conducted with alpha=0.05. Out of 137 patients, 34% improved, 13% worsened, and 53% had no change in sperm concentration with CC use. 77% of azoospermic men had no change in sperm concentration. Table 1 summarizes changes in T and sperm concentration stratified by initial parameters. No significant difference was found in magnitude of changes in semen parameters stratified by testosterone. Men with lower LH had greater improvements in total sperm count (TSC) and total motile sperm count. Men with lower FSH had greater improvements in T, sperm concentration, and TSC. Azoospermic men showed least improvement across all semen parameters. No significant differences in magnitude of improvement were observed between oligozoospermia sub-categorizations (mild, moderate, severe) and normospermia. Not all patients experience the same benefit from CC. Our data suggest that men with nonobstructive azoospermia do not significantly benefit from CC use. Degree of oligospermia did not affect magnitude of improvement. Men with lower gonadotropin levels may expect greater degree of improvement in both hormone and semen parameters.

P–712 Ovulation induction in type 1 anovulation: a comparative study using gonadotrophins and the GnRH pump

Abstract Study question Is there a difference in treatment outcome between gonadotrophin releasing hormone (GnRH) pump or hMG for women with Type 1 anovulation undergoing ovulation induction? Summary answer Treatment with GnRH was more efficient compared to hMG, with fewer number of cycles to pregnancy, fewer days of stimulation and fewer cycle cancellations. What is known already Whilst there is a lot of information on ovulation induction in WHO type II anovulation (PCOS), type 1 anovulation is under-represented in research. WHO type 1 anovulation is characterised by low pituitary gonadotrophins and oestradiol. Treatment options used to include induction of ovulation using gonadotrophins (hMG) or the Gonadotrophin hormone releasing hormone (GnRH) pump delivering pulsatile GnRH. Since the withdrawal of GnRH pump, options have become limited. One study reveals that monofollicular cycles are lower and cycle cancellation higher in women with Type 1 anovulation women treated with gonadotrophins. Study design, size, duration: This is a single centre retrospective cohort study. All women with a diagnosis of WHO type 1 anovulation attending the Reproductive Medicine Unit at the University College London Hospital who received ovulation induction treatment using either hMG or GnRH pump between 1993 and 2020 were included in the study Participants/materials, setting, methods 147 women with WHO type 1 anovulation were included in the study. Diagnosis was based on the presence of primary or secondary amenorrhoea in combination with low gonadotrophins and oestradiol. Demographic and clinical data were obtained by reviewing medical records stored within an electronic database. A total of 599 treatment cycles were identified. Statistical analysis between the groups was performed using the independent T test and chi squared test. Main results and the role of chance 147 women with WHO type 1 anovulation underwent ovulation induction. hMG was used in 500 cycles (83.5%) and the GnRH pump in 99 cycles (16.5%). Per cycle started the pregnancy rate in the hMG cycles was 107/500 (21.4%) and in the GnRH pump cycles was 19/99 (19.2%) p = 0.36. Cycle cancellation was significantly greater in hMG than GnRH pump cycles (hMG 137/ 500 27.4% vs GnRH pump 17/99 17.2% p = 0.02). Over response was more common in hMG cycles than GnRH pump cycles (66/130 50.8% vs 3/16 18.8% p = 0.01). A total of 363/500 (72.5%) cycles in the hMG and 82/99 (82.8%) cycles in the GnRH pump group reached ovulation. There was no difference in the pregnancy rate after ovulation (hMG 107/363 29.5% vs GnRH pump 19/82 23.2% p = 0.15). The mean number of treatment cycles to achieve pregnancy was significantly fewer with the GnRH pump compared to hMG (1.8 (min 1 – max 3) vs 2.4 ( min 1 – max 8) p = 0.03).The mean days of stimulation required to reach ovulation was also significantly less with the GnRH pump compared to hMG (16.7 (min 8 – max 34) vs 23.4 (min 7 – max 72) p = &amp;lt;0.001). Limitations, reasons for caution This is a retrospective cohort study and is reliant on the quality and quantity of the data entry at the time of clinical treatment. Wider implications of the findings: Ovulation induction for women with type 1 anovulation is now restricted to a single treatment, namely hMG. hMG is not as effective or optimal as GnRH. Reinstating GnRH in routine clinical practice should be promoted to allow more individualised treatment options and prevent the premature need for in vitro fertilisation.. Trial registration number NA

P–708 Comparison of reproductive outcomes after progestin-primed ovarian stimulation with dydrogesterone versus cetrorelix to inhibit spontaneous ovulation in oocyte donation

Abstract Study question Is dydrogesterone (DYG) equivalent compared to cetrorelix with respect to clinical pregnancy rate, ongoing pregnancy rate and live birth rate in oocyte donation (OD) cycles? Summary answer DYG is comparable to cetrorelix in terms of clinical pregnancy, but higher rates of ongoing pregnancy and live birth were observed in the DYG group What is known already Progestin-primed ovarian stimulation (PPOS) is an ovarian stimulation regimen based on a freeze-all strategy using progestin as an alternative to GnRH analog for suppressing a premature LH surge. DYG is an oral progestin that has been studied in PPOS protocols. Published reports indicate that length of ovarian stimulation, dose of gonadotrophin needed and number of MII retrieved from PPOS cycles are comparable to short protocol of GnRH agonists during OD cycles. However, while some studies noted no differences in terms of live births, worse pregnancy rates have been reported in recipients of oocytes from PPOS cycles compared to GnRH antagonists. Study design, size, duration Prospective controlled study to assess the reproductive outcomes of OD recipients in which the donors were subjected to the DYG protocol (20mg/day) compared with those subjected to the short protocol with cetrorelix (0.25 mg/day) from Day 7 or since a leading follicle reached 14 mm. The OD cycles were triggered with triptoreline acetate and the trigger criterion was ≥3 follicles of diameter &amp;gt;18mm. Participants/materials, setting, methods 202 oocyte donors were included, 92 under DYG and 110 under cetrorelix. The study was performed in a private infertility center between January 2017 and December 2020. The main outcome included the rates of clinical pregnancy, ongoing pregnancy and live births. Secondary outcomes included the number of oocytes retrieved, number of MII, fertilization rate, length of stimulation and total gonadotropin dose. Differences were tested using a Student’s t-test or a Chi2 test, as appropriate. Main results and the role of chance Compared to antagonist cycles, cycles under DYG had fewer days of stimulation (9.9 ± 0.9 vs. 10.8 ± 1.1, p&amp;lt;.001) and a lower total gonadotropin dose (1654 ± 402.4 IU vs. 1844 ± 422 IU, p&amp;lt;.001). The number of MII retrieved was no different: 16.9 (SD 6.2) with DYG and 15.4 (SD 5.8) with cetrorelix (p = 0.072). Recipients and embryo transfer (ET) characteristics were also similar between groups. The mean number of MII assigned to each recipients was 6.7 (SD 1.8) in DYG and 6.6 (SD 1.7) in cetrorelix (P = 0.446). The fertilization rate was 66.2% in DYG versus 67.6% in cetrorelix (P = 0.68). Regarding the reproductive outcomes, the overall clinical pregnancy rate in DYG group (65/87: 74.7%) and cetrorelix group (66/104: 63.4%) (p = 0.118) was similar. Meanwhile, the DYG group compared to cetrorelix group had higher rates of ongoing pregnancy (63.2% vs 45.1%; p = 0.014) and live births (54,9% vs 37.8%; p = 0.040). Limitations, reasons for caution These results should be evaluated with caution. The limitations of this study include the limited number of participants enrolled and the limited data on pregnancy outcomes. A randomized controlled trial is necessary to provide more evidence on the efficacy of the DYG protocol. Wider implications of the findings: The efficacy of PPOS protocol compared to GnRH-antagonist protocol in terms of reproductive outcomes has been little studied. PPOS using DYG yields comparable clinical pregnancy rates compared to cetrorelix in OD cycles. The differences found regarding the rates of ongoing pregnancy and live births should be further investigated. Trial registration number Not applicable

O-110 A randomised, controlled, assessor-blind trial assessing clinical outcomes of individualised dosing with follitropin delta in Asian IVF/ICSI patients

Abstract Study question To evaluate the efficacy and safety of individualised dosing with follitropin delta versus conventional dosing with follitropin alfa in an Asian population undergoing ovarian stimulation. Summary answer Individualised dosing with follitropin delta results in significantly higher live birth rate and fewer early OHSS and/or preventive interventions compared to conventional follitropin alfa dosing. What is known already Previous randomised controlled trials conducted in Europe, North- and South America mainly including Caucasian IVF/ICSI patients as well as in Japan have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum AMH level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates. Study design, size, duration Randomised, controlled, assessor-blind trial conducted in 1,009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first IVF/ICSI cycle. Randomisation was stratified by age (&amp;lt;35, 35-37, 38-40 years). The primary endpoint was ongoing pregnancy assessed 10-11 weeks after transfer (non-inferiority limit -10.0%; analysis adjusted for age strata). Patients &amp;lt;35 years underwent single embryo transfer if a good-quality embryo was available, otherwise double embryo transfer. Patients ≥35 years underwent double embryo transfer. Participants/materials, setting, methods Follitropin delta (Rekovelle, Ferring Pharmaceuticals) daily treatment consisted of a fixed dose individualised according to each patient’s initial AMH level (&amp;lt;15 pmol/L: 12 μg; ≥15 pmol/L: 0.19 to 0.10 μg/kg; min-max 6-12 μg) and body weight. Follitropin alfa (Gonal-f, Merck Serono) dose was 150 IU/day for the first five days with subsequent potential dose adjustments according to individual response. A GnRH antagonist protocol was applied. OHSS was classified based on Golan’s system. Main results and the role of chance The ongoing pregnancy rate was 31.3% with follitropin delta and 25.7% with follitropin alfa (adjusted difference 5.4% [95% CI: -0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with follitropin delta compared to 24.7% with follitropin alfa (adjusted difference 6.4% [95% CI: 0.9%; 11.9%]; p &amp;lt; 0.05). Live birth rates per age stratum were as follows for follitropin delta and follitropin alfa; &amp;lt;35 years: 31.0% versus 25.0%, 3537 years: 35.3% versus 26.7%, 38-40 years: 20.0% versus 14.3%. Early OHSS risk, evaluated as the incidence of early OHSS and/or preventive interventions, was significantly (p &amp;lt; 0.01) reduced from 9.6% with follitropin alfa to 5.0% with follitropin delta. The number of oocytes was 10.0±6.1 with follitropin delta and 12.4±7.3 with follitropin alfa. Individualised follitropin delta dosing compared to conventional follitropin alfa dosing resulted in 2 more oocytes (9.6±5.3 versus 7.6±3.5) in potential low responders (AMH &amp;lt;15 pmol/L) and 3 fewer oocytes (10.1±6.3 versus 13.8±7.5) in potential high responders (AMH ≥15 pmol/L). Among patients with AMH ≥15 pmol/L, excessive response occurred less frequently with individualised than conventional dosing (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%). Total gonadotropin dose was reduced from 109.9±32.9 μg with follitropin alfa to 77.5±24.4 μg with follitropin delta. Limitations, reasons for caution The trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers. Wider implications of the findings The present trial implies that in addition to reducing the early OHSS risk, individualised dosing has the potential to improve the take-home baby rate in fresh cycles across all ages and with a lower gonadotropin consumption. The benefits in outcomes appear to be explained by the modulation of ovarian response. Trial registration number NCT03296527