Ceiling effect of clomiphene citrate on the testosterone to estradiol ratio in eugonadal infertile men
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ABSTRACT: Introduction
The testosterone to estradiol ratio (T/E2 ratio) reportedly exerts a stronger effect on semen quality and sexual desire than does testosterone alone. Clomiphene citrate is a selective estrogen receptor modulator that has long been used as an empirical treatment option in the management of idiopathic oligozoospermia. Clomiphene may change the hypothalamus–pituitary–gonad axis and result in the alteration of the T/E2 ratio. No reliable data are available regarding the change in the T/E2 ratio after clomiphene use in eugonadism. Methods
This study included 24 male patients who were diagnosed with idiopathic infertility with eugonadism. They all received clomiphene citrate (25 mg/day) as empirical treatment. Blood tests for serum testosterone, estradiol, prolactin, luteinizing hormone, and follicle stimulating hormone were performed before and after 4 weeks of clomiphene use. Paired t-tests were used to evaluate the significance of the hormone level change. Results
Overall, the patients’ T/E2 ratio did not increase significantly after clomiphene use. In the subgroup analysis, the T/E2 ratio of patients with a baseline ratio of <200 increased significantly after clomiphene use. Conclusions
Clomiphene citrate may significantly increase the T/E2 ratio in eugonadal men under the premise of its ceiling effect (T/E2 ratio < 200), providing practitioners with guidance on the use of clomiphene in this demographic.
SUBMITTER: Liao Y
PROVIDER: S-EPMC8803167 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:Clomiphene 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. Methods:Following 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). Results:A 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). Conclusions:Pre-treatment E level does not appear to predict treatment response with CC in men with low T.
| S-EPMC7215015 | biostudies-literature
Project description:ObjectiveTo investigate the role of baseline gonadotropins in predicting the biochemical response to clomiphene citrate (CC) treatment.MethodsWe 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.ResultsA 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.ConclusionCC 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.
| S-EPMC7749702 | biostudies-literature
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:Low 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.To 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).Cross-over, randomized, double-blind, placebo-controlled study.24 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.Of 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 ?U/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.A low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters.EudraCT 2011-000439-10.
| S-EPMC5590732 | biostudies-literature
Project description:We aimed to investigate the effect of adding sildenafil vaginal gel to clomiphene citrate (CC) in infertile women with prior CC failure. METHODS:This is a self- controlled clinical trial. Women with CC failure (in prior 5 cycles) and thin endometrium were recruited (N = 42). In their 6th (CC only) cycle, women continued on CC 100 mg/ day for 5 days, and had measurement of endometrial thickness and Doppler assessment of uterine arteries on day of HCG administration. In the 7th cycle, women (N = 36) were given usual dose of CC supplemented with sildenafil vaginal gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 to day of HCG administration. Endometrial thickness and uterine artery Doppler were measured on the day of HCG injection. RESULTS:In the 7th (CC + sildenafil vaginal gel) cycle, endometrial thickness was significantly higher than in the 6th (CC only) cycle (9.3 mm +/- 3.1mm versus 6.6 mm +/- 1.4 mm, respectively, P = < 0.001). Uterine artery pulsatility index dropped from 2.4 +/- 0.8 in 6th cycle to 1.6 +/- 1.3 in 7th cycle (P = 0.002). Clinical pregnancy rate increased but numbers were too small (only 3 pregnancies). CONCLUSION:Sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow, and may improve pregnancy rate in patients with CC failure due to thin endometrium. Mucoadhesive vaginal gel formulation allowed shorter duration of sildenafil application, and less frequent daily dosing.
| S-EPMC5506766 | biostudies-literature
Project description:Purpose:The aim of the study was to evaluate the effect of clomiphene citrate on uterine artery blood flow using pulsed Doppler and endometrial and subendometrial micro vascularization using 3D power Doppler in unexplained infertility. Patients and methods:In a prospective observational study at a university teaching hospital, the mid-luteal (peri-implantation) endometrial thickness and volume, uterine artery pulsatility index (PI) and resistance index (RI), endometrial and subendometrial vascularization index (VI), flow index (FI), and vascularization flow index (VFI), and serum estradiol and progesterone levels were compared between natural and clomiphene citrate stimulated cycles in the same group of 50 patients with unexplained infertility. Statistical analysis was done using paired t-test to compare different study variables. Results:The primary outcome, which was the endometrial flow index, was significantly lower in the stimulated cycles (mean ± SD: 23.89±7.96 vs 27.49±8.73, mean difference (95% CI): -3.6 (-2, -5.9); P=0.03). The mean ± SD of endometrial thickness (10.92±3.04 vs 12.46±3.08 mm; P=0.01), volume (4.57±1.28 vs 5.26±1.32 cm3; P=0.009), endometrial VI (0.86±0.15 vs 0.95%±0.21%; P=0.02), VFI (0.25±0.08 vs 0.31±0.12; P=0.004), subendometrial VI (1.93±0.68 vs 2.26%±0.75%; P=0.02), FI (26.81±9.16 vs 30.73±9.87; P=0.04), and VFI (0.68±0.18 vs 0.79±0.21; P=0.006) were significantly lower in the stimulated cycles. However, there were no significant differences in the uterine artery PI (P=0.12) and RI (P=0.08) or serum estradiol (P=0.54) and progesterone (P=0.37) levels between natural and stimulated cycles. Conclusion:Peri-implantation endometrial perfusion is significantly lower in clomiphene citrate stimulated cycles when compared to natural ones in patients with unexplained infertility.
| S-EPMC5894743 | biostudies-literature
Project description:Introduction: Which is optimal to treat clomiphene citrate-resistant polycystic ovary syndrome (CCR-PCOS) with LOD or metformin remains a problem. There are three inconsistent or even contradictory views. Objectives: The present meta-analysis aimed to evaluate the effectiveness and safety of Metformin with or without CC and to compare them with LOD with or without CC (Met/Met-CC vs. LOD/LOD-CC) in women with CCR-PCOS who also have anovulation. Data source: The PubMed, Cochrane, and Embase databases were searched to identify relevant studies reported between 1 Jan 1966 and 31 Aug 2019; the search was updated on 17 May 2022. Study eligibility criteria: We included randomized controlled trials (RCTs) of CCR-PCOS that had considered Met/Met-CC and LOD/LOD-CC as the exposure variables and fertility as the main outcome variable. Study appraisal and synthesis methods: We assessed study quality using the Cochrane risk-of-bias tool. The primary effectiveness outcome was live birth/ongoing pregnancy rate and the primary safety outcome was miscarriage rate. A fixed-effect meta-analysis was performed. The robustness of the results was assessed using sensitivity analyses. Meta-regression and subgroup analysis were performed to examine the reasons for heterogeneity. Publication bias was examined using the funnel plot, Egger linear regression, and Begg rank correlation tests. The quality of this meta-analysis was estimated according to the GRADE approach. This meta-analysis has been registered in PROSPERO (CRD42021240156). Results: Among 71 potentially relevant studies, we included five RCTs in our meta-analysis. We found no difference in effectiveness between Met-CC and LOD in terms of live birth/ongoing pregnancy (RR = 1.02, 95% CI: 0.87-1.21, z = 0.28; p = 0.780), and miscarriage rates (RR = 0.79, 95% CI: 0.46-1.36, z = 0.86; p = 0.390). I2 tests results revealed moderate or no heterogeneity (I2 = 51.4%, p = 0.083; I2= 0.0%; p = 0.952). Sensitivity analysis confirmed the robustness of the results. Funnel plot, Egger linear regression, and Begg rank correlation tests implied no publication bias (p > 0.05). LOD was more expensive than Met (€1050 vs. €50.16). The evidence quality was moderate. Conclusion: There is no evidence on the difference in the outcomes between the two interventions regarding ovulation, pregnancy, and live birth. As LOD is an invasive procedure and carries inherent risks, the use of Met/Met-CC should be the second-line treatment for women with CCR-PCOS. Systematic Review Registration: identifier CRD42021240156.
| S-EPMC9256960 | biostudies-literature
Project description:Infertility is a widespread health problem, with rising incidence worldwide. Whether the infertility is caused by genetic or environmental factors, the reason for inability to reproduce can be the too low number of sperm or morphological or functional abnormality of the sperm. Therefore there can be a certain possibility that divergent causes would converge in common mechanisms impairing sperm functionality. A key step in the control of the cell phenotype is the regulation of gene expression. Therefore, the sperm transcriptome can reflect the impairment of proper regulatory networks acting during spermatogenesis and later, during sperm maturation. Also, it can be speculated that some sperm RNAs can influence the fitness of the early embryo, despite the small amount of sperm RNA. Although the changes in transcriptome are not always reflected by similar changes in the proteome, a relative ease of transcriptome interrogation makes it an excellent tool for hypothesis generation about infertility mechanisms and for a search for potential infertility biomarkers.
2021-11-03 | GSE160749 | GEO
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.
| S-EPMC5010571 | biostudies-literature
Project description:PurposeTo determine age-adjusted overall success rates for patients undergoing clomiphene citrate only minimal stimulation cycle (mini) in vitro fertilization (IVF) without any gonadotropin administration.MethodsEight hundred thirty-nine women (mean age: 38.4?±?0.1 years; 2488 cycles) underwent clomiphene citrate only mini-IVF. Their first oocyte retrieval was between January 2009 and December 2009, with follow-up until December 2014. The cumulative live birth rate (CLBR) per oocyte retrieval cycle started and live birth rate per oocyte was retrospectively analyzed. The basic CLBR was calculated as the number of women who achieved a live birth divided by the total number of women who started oocyte retrieval.ResultsThe mean number of oocytes retrieved was 1.5. The basic CLBRs for all ages after the first and third cycles were 22.6% and 39.2%, respectively. For ??34 years, 35-37 years, 38-40 years, 41-42 years, and ??43 years, CLBRs after the first and third cycles were 42.5% and 70.1%, 32.9% and 49.1%, 20.0% and 38.6%, 12.6% and 25.2%, and 4.4% and 8.8%, respectively. These rates had a significant relationship with age (P?<?0.01). The LBR per oocyte for all ages was 9.6%.ConclusionAcceptable overall IVF success rates can be achieved in clomiphene citrate only mini-IVF, as well as acceptable LBR. The CLBRs and LBRs per oocyte are evidently influenced by women's age.
| S-EPMC7056817 | biostudies-literature