Baseline Gonadotropin Levels and Testosterone Response in Hypogonadal Men Treated With Clomiphene Citrate.
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ABSTRACT: Objective
To investigate the role of baseline gonadotropins in predicting the biochemical response to clomiphene citrate (CC) treatment.Methods
We conducted a retrospective review of data from hypogonadal men treated with CC in 2 high-volume fertility centers between 2013 and 2018. Patient age, body mass index, and baseline hormones (follicle stimulating hormone [FSH], luteinizing hormone [LH], and total testosterone [TT]) were obtained. Response to treatment was measured as changes in TT levels within 6 months of initiating CC treatment. Linear regression models adjusted for age, body mass index, and time on CC therapy were fitted to assess the associations between baseline LH and FSH levels with treatment response.Results
A total of 332 men with mean ± standard deviation age of 36.2 ± 8.2 years were included. Median time to initial follow-up was 6 weeks (25th-75th interquartile range [IQR]: 4-9 weeks). TT levels increased significantly on CC treatment (mean change: 329.2 ng/dL, 95% CI: 307.4-351.0) with 73% of men having at least 200 ng/dL increase over baseline TT levels. In univariable linear regression models, only age was significantly associated with TT response. Neither the baseline LH nor FSH significantly predicted TT response in linear regression models.Conclusion
CC treatment results in significant increases in testosterone levels in most men. Baseline gonadotropins are not strong predictors for treatment response to CC. Adequate biochemical response with CC trial can be expected in most patients with normal or slightly elevated baseline gonadotropin levels.
SUBMITTER: Keihani S
PROVIDER: S-EPMC7749702 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeTo assess the conversion rate from clomiphene citrate (CC) monotherapy to combination CC+anastrozole (AZ) therapy in hypogonadal men and the predictors associated with the initiation of AZ.Materials and methodsA retrospective review of records from hypogonadal men treated with CC in a single fertility center was performed from 2013 to 2018. Patient age, body mass index (BMI), blood pressure, and reproductive hormones were obtained at baseline. Obesity was defined as BMI≥30 kg/m². Cox proportional hazards models were used to identify predictors of switching to combination CC+AZ therapy.ResultsA total of 318 men on CC were included. Median (interquartile range) age was 34 years (30-39 years) and patients were followed for a median of 9 months (4-17 months). Of these, 97 (30.5%) were started on CC+AZ therapy. These patients had higher baseline BMI and estradiol, which in multivariable regression were significant predictors for switching to CC+AZ therapy. A threshold of 18.5 pg/mL for baseline estradiol provided the highest accuracy for predicting the addition of AZ after adjusting for baseline BMI and total testosterone levels.ConclusionsIn our practice, following CC monotherapy, 30% of men were initiated on CC+AZ. Obesity (BMI≥30 kg/m²) and baseline estradiol ≥18.5 pg/mL can predict the conversion to combination therapy with addition of AZ. This information can be used to counsel patients and also help to identify patients who can be started on combination therapy upfront.
| S-EPMC7502320 | biostudies-literature
Project description:BackgroundClomiphene citrate (CC) is a selective estrogen receptor modulator (SERM) used to stimulate ovulation in women. CC is used off-label in men to increase levels of endogenous testosterone (T) while potentially improving semen parameters by downregulating the inhibitory feedback of estradiol (E) on the male hypothalamus. Our objective was to determine whether pre-treatment E level is associated with greater total testosterone (TT) response to treatment with CC in men with low T.MethodsFollowing IRB approval (The University of Miami IRB No. 20170849), retrospective chart review was performed for all men prescribed CC (25 mg every other day) between January 1, 2015 and December 31, 2018. Age, body mass index (BMI), and prescription date were recorded for all patients. Pre- and post-treatment E, total T (TT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were recorded for all patients as well. Only men with pretreatment TT <300 ng/dL were included in the analysis in order to focus our study on men with low TT. Univariate linear regression analysis was performed to determinate the percent change in TT following CC treatment (dependent variable) and pre-treatment E and other variables including age, BMI, FSH, and LH (independent variables).ResultsA total of 69 men with TT <300 ng/dL received CC 25 mg every other day. Mean age and BMI were 33.3±7.31 years and 35.4±5 kg/m2 respectively. Median pre-treatment E, TT, FSH, and LH were 18 [11.35-24.6] pg/mL, 226 [156-262] ng/dL, 5.1 [2.98-8.05] mIU/mL, and 4.5 [2.6-6.8] mIU/mL respectively. Post-treatment TT was 389 [263-592] ng/dL and TT% change was 102 [45.51-176.75]. Univariate linear regression showed that pre-treatment E (B=-0.595; R2=0.001; P=0.757) did not significantly predict TT% change. TT% change could be significantly predicted by age in years (B=-7.428; R2=0.057; P=0.048), pre-treatment FSH (B=-8.362; R2=0.068; P=0.041), and pre-treatment LH (B=-20.67; R2=0.096; P=0.027).ConclusionsPre-treatment E level does not appear to predict treatment response with CC in men with low T.
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Project description:Estradiol (E2), mainly produced from Testosterone (T) in men, promotes visceral lipolysis. However, high visceral fat and hyperestrogenemia are features of obese hypogonadal (HG) men. Our study objectives are to evaluate relationships between circulating E2 and: (1) fat mass; (2) Estrogen Receptor ? (ESR1) expression in subcutaneous adipose tissue; (3) changes in body fat after 6 months (M) of T therapy in HG men. HYPOTHESES:(1) existence of a range of circulating E2 associated with better body composition; (2) serum E2 determines tissue E2 sensitivity which affects response to T therapy. Men 40?74 years old, T < 300 (ng/dL), given T-cypionate for 6 months. Subjects were divided into 4-E2 categories: (1) <10.0; (2) 10.0?15.9; (3) 16.0?19.9; (4) ?20.0 (pg/mL). Body composition (DXA), fat biopsies (liposuction), gene expression (qPCR), serum E2 and T (LC/MS), at baseline and 6 months. We enrolled 105 men; 90 completed the study. Group 2 had lower total and truncal fat mass (p < 0.01) but higher % lean mass (p < 0.001). ESR1 mRNA was the highest in group 1 (p = 0.01). At 6 months, group 1 had higher reduction in total (p = 0.03) and truncal (p = 0.01) fat. In conclusion, serum E2 = 10?15.9 (pg/mL) is associated with the best body composition profile in HG men; however, those with E2 < 10 (pg/mL) had the best response (greater fat loss) to T replacement possibly because of greater E2 sensitivity.
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Project description:BackgroundSeveral recent journal articles report that D-chiro-inositol (DCI), primarily known as insulin second messenger, influences steroidogenesis. In particular, new evidence is arising on DCI ability to regulate aromatase expression and testosterone biosynthesis. In this regard, DCI administration could represent a good therapeutic opportunity in case of reduced levels of testosterone. Older men generally have lower testosterone concentrations than younger men, and recent randomized controlled trials have examined whether testosterone treatment might improve health outcomes in this age group. There is limited information about the safety of testosterone replacement therapy in these men, hence DCI could represent an interesting alternative for future trials. Therefore, this study aims to evaluate the effect of DCI treatment on testosterone levels in older male patient.ResultsTen older men with basal low testosterone levels were enrolled in this study. Patients took 600 mg of DCI, two-times per day, for 30 days. We evaluated hormonal and glycaemic parameters, weight, waist circumference, and Body-Mass Index at baseline (T0) and after 30 days (T1). Finally, all patients also filled in the standardized International Index of Erectile Function questionnaire and performed the Handgrip test at T0 and T1. Men receiving DCI showed increased androgen and reduced oestrogen concentrations, and improved glycaemic profiles. DCI was also associated with reduced weight, Body-Mass Index, waist circumference, and improved grip strength and self-reported sexual function. All these effects led to the improvement of sexual function and physical strength.ConclusionsIn this pilot study, DCI treatment improved the levels of testosterone and androstenedione at the expense of oestrogens in elder men with low basal levels of these hormones without adverse effects.Trial registrationClinicaltrials.gov: D-chiroinositol Administration in Hypogonadal Males, NCT04708249.
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Project description:ContextLow testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate.ObjectiveTo evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET).DesignCross-over, randomized, double-blind, placebo-controlled study.Methods24 obese men, aged 47.3 ±. 6.3 (range 35-55 years), with low T level (≤3 ng/mL) and naïve diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment.ResultsOf 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03±0.80 to 5.99±1.67 ng/mL P<0.001) but not after the Plac treatment (2.87±0.78 to 3.09±0.84 ng/mL P<0.001 between the treatments). T changes were similar in IGT and T2DM subjects. Gonadotropins as well raised significantly after CC treatment (LH 3.83±1.45 to 8.53±6.40 mU/mL; FSH 4.84±1.67 to 10.15±5.08 mU/mL P<0.001 respectively), whereas no changes for LH (3.51±1.59 to 3.63±1.39 mU/mL) but a smooth increased for FSH (4.61±2.49 to 5.39±2.65 mU/mL; P = 0.004) were shown after Plac treatment (LH P = 0.001 and FSH P = 0.002 between treatments). Furthermore, fasting glucose (106.8±23.2 to 101.1±25.7 mg/dL; P = 0.004), insulin (19.3±12.1 to 15.6±10.1 μU/mL; P = 0.010) and HOMA-IR (4.94±2.89 to 3.69±2.12; P = 0.001) decreased significantly during the CC treatment period, whereas no significant changes were observed in any of these parameters in the Plac treatment.ConclusionsA low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters.Trial registrationEudraCT 2011-000439-10.
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Project description:ContextA novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial.ObjectiveDetermine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy.DesignRandomized, active-controlled, open-label study.Setting and patientsAcademic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old.MethodsPatients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography-mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP).Results87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg.ConclusionA new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.
| S-EPMC7282712 | biostudies-literature
Project description:PurposeExogenous gonadotropins (EGn) have been used occasionally in clomiphene citrate (CC)-based minimal stimulation cycles to compensate insufficient secretion of endogenous gonadotropin; however, the effectiveness of EGn supplementation remains unknown. In the present study, we assessed whether EGn improved pregnancy outcomes in CC-based minimal stimulation cycles.MethodsA total of 223 patients treated with CC and EGn (CC-EGn group) were matched one to one to patients treated with CC only (CC group) by propensity score matching. Embryonic and pregnancy outcomes were retrospectively compared between the groups.ResultsThe numbers of retrieved oocytes, fertilized oocytes, cleaved embryos, and cryopreserved blastocysts were increased in the CC-EGn group compared with the CC group. However, the cumulative live birthrate was comparable between the two groups. Although the increased number of retrieved oocytes was correlated significantly with improvement of the cumulative live birthrate in both groups, the correlation tended to be lower in the CC-EGn group than in the CC group (odds ratio, 1.193 vs 1.553).ConclusionsIn CC-based minimal stimulation cycles, the stimulation should be started with CC only, and EGn administration should be scheduled only if insufficient secretion of endogenous gonadotropin is observed in the late follicular phase.
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Project description:ObjectiveTo assess the relative effects of individual testosterone products among hypogonadal men.DesignSystematic review and network meta-analysis.MethodsWe searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (25 May 2017) for randomised-controlled trials (RCTs) and non-randomised studies (NRS) that involved hypogonadal men given testosterone replacement therapy (TRT) for ≥3 months. Comparators were placebo, another TRT, or the same product at a different dose. Outcomes were quality of life, depression, libido, erectile function, activities of daily living and testosterone levels, as well as cardiovascular death, myocardial infarction, stroke, prostate cancer, heart disease, diabetes, serious adverse events, withdrawals due to adverse events and erythrocytosis. RCT data were pooled via meta-analysis and network meta-analysis. Risk of bias was assessed using Cochrane's risk of bias tool (RCTs) andScottish Intercollegiate Guidelines Network (SIGN)50 (NRS).ResultsEighty-seven RCTs and 51 NRS were included. Most were at high or unclear risk of bias, with short treatment duration and follow-up. When compared as a class against placebo, TRT improved quality of life (standardised mean difference (SMD) -0.26, 95% CI -0.41 to -0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD -0.23, 95% CI -0.44 to -0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs.ConclusionDespite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer-term high-quality trials are needed to fully assess the risk of harm.Prospero registration numberCRD42014009963.
| S-EPMC5701987 | biostudies-literature
Project description:ContextThe hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood.ObjectiveTo determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men.DesignTwo randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately.SettingA single-site academic medical center.ParticipantsHealthy men ages 20-50, with normal serum testosterone levels.InterventionCohort 1 (n = 198, 81% completion) received goserelin acetate every 4 weeks to suppress gonadal steroids and were randomized to placebo or 1.25, 2.5, 5, or 10 g of testosterone gel daily for 16 weeks. Cohort 2 (n = 202, 78% completion) received the same regimen as cohort 1 plus anastrozole to block aromatization of testosterone. Controls (n = 37, 89% completion) received placebos for goserelin acetate and testosterone.Main outcome measuresIncidence of visits with VMS. This was a preplanned secondary analysis.ResultsVMS were reported at 26% of visits in cohort 1, and 35% of visits in cohort 2 (P = .02), demonstrating an effect of estradiol deficiency. When adjacent estradiol level groups in cohort 1 were compared, the largest difference in VMS incidence was observed between the 5-9.9 and 10-14.9 pg/mL groups (38% vs 16%, P < .001). In cohort 2, the 10-g testosterone group differed significantly from placebo (16% vs 43%, P = .048) after adjustment for small differences in estradiol levels, indicating that high testosterone levels may suppress VMS.ConclusionsEstradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect.
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