Context Clomiphene is a performance-enhancing drug commonly abused by males in sport, but the extent to which testosterone increases in healthy males following its use is unknown. In addition, evidence suggests that clomiphene, a mixture of cis- and trans-isomers zuclomiphene and enclomiphene, is detectable in urine for months following use; the isomer-specific urinary detection window has yet to be characterized in a controlled study. Objective To determine the effect of once-daily, 30-day clomiphene treatment on serum testosterone and gonadotropin levels in the subject population studied and the urinary clearance and detection window of clomiphene isomers following administration for antidoping purposes. Participants and Design Twelve healthy males aged 25 to 38 years, representing a recreational athlete population, participated in this open-label, single-arm study. Intervention Oral clomiphene citrate (50 mg) was self-administered once daily for 30 days. Serum and urine samples were collected at baseline and at days 7, 14, 21, 28, 30, 32, 35, 37, 44, 51, and 58; urine collections continued periodically up to day 261. Results Mean testosterone, LH, and FSH levels increased 146% (SEM, ±23%), 177% (±34%), and 170% (±33%), respectively, during treatment compared with baseline. Serum drug concentrations and urinary excretion were nonuniform among individuals as isomeric concentrations varied. The zuclomiphene urinary detection window ranged from 121 to >261 days. Conclusions Clomiphene significantly raised serum testosterone and gonadotropin levels in healthy men and thus can be abused as a performance-enhancing drug. Such abuse is detectable in urine for ≥4 months following short-term use.
Background Human chorionic gonadotropin (hCG) detection is indicative of pregnancy and can be indicative of some forms of cancerous tumors. The hCG drug itself, however, is a performance enhancing substance used by male athletes to increase testosterone production. Antidoping testing for hCG is conducted in urine, often on immunoanalyzer platforms, many of which utilize biotin-streptavidin dependent immunoassays in which the presence of biotin in samples is a known confounding factor. While biotin interference in serum has been well-studied, the extent of biotin interference in urine has not. Methods Ten active male individuals underwent a 2-week hCG administration protocol concurrent with supplementation with biotin (20 mg/day) or placebo. Urine and serum samples were collected throughout the study and analyzed for hCG and biotin concentrations. Results Urinary biotin levels in the hCG + biotin group increased 500-fold over baseline and 29-fold over corresponding serum biotin levels after biotin supplementation. When using a biotin-dependent immunoassay, the hCG + placebo group produced hCG-positive results (hCG ≥ 5 mIU/mL) in 71% of urine samples, while the hCG + biotin group produced positive results in only 19% of samples. Both groups had elevated hCG values in serum measurements by a biotin-dependent immunoassay and in urine when using a biotin-independent immunoassay. Urinary hCG measurements and biotin levels from the hCG + biotin group showed a negative correlation (Spearman r = −0.46, P < 0.0001) when measured using a biotin-dependent immunoassay. Conclusions Biotin supplementation can severely suppress urinary hCG values in assays utilizing biotin-streptavidin binding methods and therefore these types of assays are not recommended for use in urine samples containing high levels of biotin. Clinicaltrials.gov Registration Number: NCT05450900
Follicle development occurs in two or three waves during the bovine oestrous cycle. Artificially extending the duration of ovulatory follicle dominance influences pregnancy rates in cattle, as does the interval from emergence to oestrus in dairy cows undergoing spontaneous oestrous cycles. The objectives of the presented study were to determine whether the interval from ovulatory follicle emergence to oestrus might be altered by diet and/or gonadotropin-releasing hormone (GnRH) treatment. Lactating primiparous Holstein/Friesian cows (n=21) were randomly allocated to one of two diets at calving (Diet 1, n=ll, DM 480 g/kg, metabolisable energy 12.0 MJ/kg DM crude protein 178 g/kg DM, oil B 48 g/kg DM, neutral detergent fibre 318 g/kg DM and diet 2, n=10, DM 440 g/kg, metabolisable energy 12.1 MJ/kg DM, crude protein 172 g/kg DM, oil B 40 g/kg DM, neutral detergent fibre 300 g/kg DM). From 10 days after observed oestrus (oestrus 1), ovarian follicular and luteal development was monitored by daily transrectal ultrasonography until the subsequent oestrus and ovulation. A GnRH analogue was injected (i.m.; 10 μg) 12 days after oestrus 1 in 6 cows fed diet 1 and 5 cows fed diet 2. Oestrous cycle length was longer (p<0.05) in control cows fed diet 1 than those fed diet 2. Treatment with GnRH increased (p<0.005) cycle length in cows fed diet 2 but not those fed diet 1. Increases in cycle length observed were associated with longer luteal phase length. Follicular phase length was reduced (p<0.05) by GnRH treatment in cows fed diet 1. Ovulatory follicles emerged later (p<0.05) in control cows fed diet 1 than those fed diet 2. GnRH treatment delayed (p<0.01) the emergence of the ovulatory follicle in cows fed diet 2, this delay was associated with an increase (p<0.05) in the incidence of 3 follicle waves in oestrous cycles following GnRH treatment. The interval from emergence of the ovulatory follicle to the subsequent oestrus was similar among the treatment groups. We conclude that treatment with GnRH during the mid-luteal phase may delay the emergence of the ovulatory follicle. However, the response is dependent on diet fed. Where ovulatory follicle emergence is delayed, the interval from emergence to the subsequent oestrus was unaffected since oestrous cycle length is extended.
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