Gonadotropins and Their Analogs: Current and Potential Clinical Applications.

The gonadotropin receptors LH receptor and FSH receptor play a central role in governing reproductive competency/fertility. Gonadotropin hormone analogs have been used clinically for decades in assisted reproductive therapies and in the treatment of various infertility disorders. Though these treatments are effective, the clinical protocols demand multiple injections, and the hormone preparations can lack uniformity and stability. The past two decades have seen a drive to develop chimeric and modified peptide analogs with more desirable pharmacokinetic profiles, with some displaying clinical efficacy, such as corifollitropin alfa, which is now in clinical use. More recently, low-molecular-weight, orally active molecules with activity at gonadotropin receptors have been developed. Some have excellent characteristics in animals and in human studies but have not reached the market-largely as a result of acquisitions by large pharma. Nonetheless, such molecules have the potential to mitigate risks currently associated with gonadotropin-based fertility treatments, such as ovarian hyperstimulation syndrome and the demands of injection-based therapies. There is also scope for novel use beyond the current remit of gonadotropin analogs in fertility treatments, including application as novel contraceptives; in the treatment of polycystic ovary syndrome; in the restoration of function to inactivating mutations of gonadotropin receptors; in the treatment of ovarian and prostate cancers; and in the prevention of bone loss and weight gain in postmenopausal women. Here we review the properties and clinical application of current gonadotropin preparations and their analogs, as well as the development of novel orally active, small-molecule nonpeptide analogs.

Modeling follicle stimulating hormone levels in serum for controlled ovarian hyperstimulation III: improved gonadotropin administration.

BACKGROUND: A numerical model with two pharmacokinetic parameters (the rate of diffusion into the blood (τin) and the rate of disappearance from the blood (τout)) mimicks the slow changes of follicle stimulating hormone (FSH) seen in serum. It is often desired to change serum FSH levels more rapidly. Since the pharmacokinetic parameters cannot be changed in patients, we used the model to investigate changing the amount and timing of gonadotropin administration to change FSH levels in serum more rapidly. METHODS: Parameters defining the model were obtained as described previously [1]. The doses administered, and the timing of administration were individually specified. RESULTS: The rise of serum FSH was made more rapid by administering an initial injection larger than the subsequent injections. When a rapid decrease of serum FSH was desired, administration of the new, lower dose was delayed. CONCLUSION: Use of a model that simulates the serum levels of FSH during gonadotropin administration provided a framework for learning how to achieve the desired serum FSH levels more rapidly in patients. With knowledge of a particular patient's τin and τout, optimal FSH administration for that patient can be determined through modeling.

Modeling Follicle Stimulating Hormone (FSH) levels in serum for controlled ovarian hyperstimulation II: the underlying mechanisms.

BACKGROUND: Serum levels of follicle stimulating hormone (FSH) in patients change slowly during repeated daily injections of gonadotropin, requiring several days to achieve stable values. Using a numerical (computer) model we mimicked the serum levels of FSH using two kinetic constants that describe biological phenomena: diffusion of FSH from the injection site into the blood (τin) and disappearance of FSH from the blood by excretion/degradation (τout). We investigated the effects of these two parameters on the FSH profiles seen in the model. METHODS: The parameters, τin and τout, were systematically changed to determine their effects on the delay from injection to the peak following a single injection (Tmax). Other values were investigated systematically during repeated daily injections. RESULTS: The model's parameters τin and tout affected Tmax and several features of FSH level during daily injections of gonadotropin. These included the maximum level of FSH in the serum (relative to the level attained following the first injection), the rate of rise of peaks following injections after the first, and the shortening of the delay from injection to peak. CONCLUSION: Knowledge of τin and τout permits us to predict serum FSH levels and time course during daily injections of gonadotropin.

Modeling follicle stimulating hormone levels in serum for controlled ovarian hyperstimulation I: comparing gonadotropin products.

BACKGROUND: Despite the dangers of gonadotropin administration, our understanding of serum levels of gonadotropins in our patients is poor. We created a mathematical model of gonadotropin administration in order to learn about the temporal profiles of Follicle Stimulating Hormone (FSH) levels in patients related to the doses of different gonadotropin products administered. METHODS: Model parameters for each product were determined from published pharmacokinetic information available from the manufacturers. RESULTS: For each product, serum levels of FSH rose then fell following a single injection of FSH. When a gonadotropin dose was injected repeatedly (daily), each injection resulted in a peak level of FSH that was higher than the level attained from the previous injection. Daily FSH peaks rose asymptotically, requiring 3-10 days to approach the maximum. The maximum averaged 3.5 times the peak of the first injection. Decline of FSH following the final injection required 3-10 days to approach the baseline. Time courses and peak values of FSH using different gonadotropin preparations varied widely. CONCLUSION: Knowledge of the slow changes of FSH that occur during modeled FSH administration will provide a framework for understanding the gonadotropin profiles that occur in patients during controlled ovarian hyperstimulation.

Kisspeptinas y pubertad / No disponible

Las kisspeptinas fueron inicialmente identificadas como un grupo de péptidos estructuralmente relacionados, codificados por el gen KiSS-1, con capacidad de inhibir la metástasis de ciertos tumores mediante la activación del receptor acoplado a proteínas G, GPR54. No obstante, a finales de 2003, sendas publicaciones demostraron que mutaciones inactivantes del gen GPR54 se asocian a ausencia de pubertad e hipogonadismo hipogonadotropico, tanto en humanos como en roedores, lo que puso de manifiesto el papel clave del sistema ligando-receptor KiSS-1/GPR54 en el control del eje reproductor en general, y de los mecanismos de activación de la pubertad en particular. Estas observaciones iniciales se han visto sustanciadas en los últimos 3 años a través de numerosos estudios experimentales en diversas especies (desde roedores hasta humanos), que han permitido establecer el papel absolutamente crucial de las kisspeptinas y su receptor en la regulación de diversas facetas de la función reproductora. En este trabajo revisaremos los aspectos más sobresalientes del papel del sistema KiSS-1/GPR54 en el control del eje gonadotrópico, con especial atención a la descripción de la implicación de las kisspeptinas en la activación puberal del sistema reproductor y su modulación por factores relevantes, tales como el estado energético y metabólico del organismo (AU)

Kisspeptins were first identified as a family of structurally-related peptides, encoded by the KiSS-1 gene, with ability to inhibit tumor metastasis through binding to the G protein-coupled receptor GPR54. However, in late 2003, two independent publications demonstrated the presence of inactivating mutations of GPR54 gene in patients suffering lack of puberty onset and hypogonadotropic hypogonadism; a phenotype which was also observed in mice with genetic inactivation of GPR54. These observations disclosed the essential roles of the ligand/receptor system KiSS-1/ GPR54 in the control of reproductive function in general, and in the regulation of puberty onset in particular. These contentions have been fully substantiated during the last three years, by a number of experimental studies in different species (from Mouse and rats to humans), which have defined the indispensable role of kisspeptins and their receptor in the regulation of different aspects of reproduction. In the present article, we will review the most salient facets of the KiSS-1/GPR54 system in the control of the gonadotropic axis, with special emphasis on the potential involvement of kisspeptins in the pubertal activation of the reproductive system and its modulation by key regulatory factors, such as energy balance and the metabolic status of the organism (AU)

Indirect evidence of hormone abuse. Proof of doping?

Besides anabolic steroids, the most common performance-enhancing hormones are erythropoietin (EPO), insulin, GH, and gonadotropins, mostly indistinguishable from endogenous hormones and with very short half-life. This makes virtually impossible to demonstrate their use by measuring their concentration in the blood or urine. A possible approach to the problem may lie in in-direct demonstration through detection of the biological effects of these substances. The finding of an increased hematocrit level is suspicious but not clearly demonstrative of EPO abuse. Very high levels of circulating EPO could be associated with a strong suspicion of doping, when associated to other abnormal parameters, such as Ht, sTFRr, EPO, RDW. The presence of antibodies against the polysaccharide fraction of lateral chains of EPO has been observed only in patients treated with rhEPO. Owing to the pulsatile pattern of GH, particularly during physical exercise, pathologically high values may be found in normal subjects. Therefore, as in the case of EPO, evidence of GH abuse can be gathered only indirectly by detecting the biological effects of its administration. In training subjects GH treatment increased GH, IGF-I, IGFBP-3 and ALS, and decreased IGBP-2. After cessation of treatment IGF-I, IGFBP-3 and ALS approached basal values between 49 and 96 h. Also the bone parameters PICP ICIP, PIUP and osteocalcin increased significantly. Four days after cessation of treatment, levels of PIIIP and ICTP were still abnormally elevated. In conclusion, increases in IGF-I, IGFBP-3, ALS, PIIIP and ICTP are all indicative of recent GH abuse or of acromegaly.

Gonadotrophin heterogeneity and biopotency: implications for assisted reproduction.

The extensive heterogeneity of the gonadotrophin hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), is due primarily to the heterogeneous nature of their carbohydrate side-chains, in particular sialic acid residues. In this review, we discuss the role of carbohydrate chains in receptor binding and activation, biological activity, and metabolic half-life. The synthesis and secretion of the various glycoforms of both FSH and LH appear to be under endocrine control with gonadotrophin-releasing hormone (GnRH), oestradiol and testosterone playing important roles. Evidence for different glycoforms having variable biopotency or different encoded functions is increasing, and the production and secretion of more or less acidic gonadotrophin species in different physiological states may represent an important mechanism whereby the pituitary regulates gonadal cell and organ function. This has potential importance for the development of new pharmaceutical reagents and new therapeutic regimens in assisted reproduction. It is envisaged that the use of existing and new forms of FSH/LH will allow patients to be treated in a more controlled and physiological manner, with treatment regimens individualized to the needs of the patient.

Pharmacokinetics and ovarian-stimulatory effects of equine and human chorionic gonadotropins administered singly and in combination in the domestic cat.

Pregnancy success and embryo survival are low with the use of assisted reproduction in felids treated with exogenous gonadotropins. In this study, the pharmacokinetics and ovarian-stimulatory effects of eCG and hCG were evaluated in the domestic cat. Catheterized anestrual queens (n = 4 per treatment [Trt] group) were given 100 IU eCG i.v. (Trt 1), 100 IU eCG i.m. (Trt 2), 75 IU hCG i.v. (Trt 3), 75 IU hCG i.m. (Trt 4), or 100 IU eCG i.m. followed 80 h later by 75 IU hCG i.m. (Trt 5). Blood samples were collected at 0, 5, 30, and 60 min and 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 h postinjection, and serum samples were analyzed for estradiol-17beta, progesterone, eCG, and hCG. Pharmacokinetic traits (volume of distribution, Vd; elimination half-life, t1/2beta; clearance rate, Clr) were calculated for eCG and hCG. When i.v. and i.m. administration were compared, no differences (p > 0.05) were observed in follicle or corpus luteum (CL) number or hormone concentrations for queens receiving eCG or hCG alone. Number of mature ovarian follicles (> or = 2 mm diameter) observed at 168 h postinjection did not differ (p > 0.05) for eCG (mean +/- SEM, 10.5 +/- 2.0) vs. hCG (11.1 +/- 3.0), indicating that these were equally effective in inducing follicular growth. In most queens (> 90%) given single gonadotropins (i.m. or i.v.), eCG and hCG persisted in circulation for at least 120 h and 96 h after injection, respectively, reflecting similar (p > 0.05) pharmacokinetic (i.v.) values for Vd (eCG, 91.4 +/- 24.8 ml/kg; hCG, 59.1 +/- 7.9 ml/kg), t1/2beta (eCG, 23.0 +/- 2.4 h; hCG, 22.9 +/- 4.1 h), and Clr (eCG, 2.7 +/- 0.5 ml/h per kg; hCG, 1.8 +/- 0.1 ml/h per kg). Sequential treatment with eCG+hCG did not affect (p > 0.05) the t1/2beta of individual gonadotropins. In summary, eCG and hCG have comparable pharmacokinetics and ovarian-stimulatory activity when administered alone to the domestic cat. These findings suggest that hCG promotes the ancillary follicle formation that is frequently observed after ovulation in cats treated with eCG+hCG regimens, possibly disrupting the maternal environment and decreasing fecundity following assisted reproductive procedures.

Pharmacodynamics and pharmacokinetics after repeated subcutaneous administration of three gonadotrophin preparations.

Recently, several new urinary gonadotrophin preparations have been developed, containing less luteinizing hormone (LH) activity than human menopausal gonadotrophin. Normegon is a gonadotrophin preparation with a follicle stimulating hormone (FSH)/LH ratio of 3:1; Follegon and Metrodin-HP are purified FSH preparations. The aim of the present randomized study was to compare pharmaco-dynamics, -kinetics and local tolerance of these preparations after repeated s.c. administration. Thirty-six healthy female subjects were treated with Lyndiol contraceptive pills for 5 weeks to suppress endogenous gonadotrophin concentrations. After 3 weeks of Lyndiol treatment, 150 IU of Normegon, Follegon or Metrodin HP were administered once daily, s.c. for 7 days. Blood samples were collected once daily during the fourth and fifth weeks of the study and assayed for FSH and oestradiol. After the last gonadotrophin injection, blood samples were collected more frequently to determine pharmacokinetic parameters of FSH. During the fourth and fifth study weeks, daily ultrasound measurements of follicular growth were performed. Endogenous FSH and LH values were extremely suppressed during Lyndiol treatment. Serum FSH values showed similar patterns in the three groups. The maximum FSH concentration was reached 9-11 h post-injection, the terminal half-life was 43-47 h. The preparations were bioequivalent with respect to FSH immunoreactivity. The number of follicles tended to be larger after Normegon than after Follegon and Metrodin HP treatment, though this was not statistically significant. Serum oestradiol concentrations were significantly higher after Normegon treatment. In general, s.c injections were well tolerated. In conclusion, the three preparations were bioequivalent with respect to FSH immunoreactivity. Nevertheless, the biological activity of Normegon tended to be higher than that of Follegon and Metrodin HP in Lyndiol-suppressed women.

Evaluación neuroendocrinológica e histopatológica de pacientes azoospérmicos normogonadotrópicos: utilidad de la prueba de estimulación con GnRH / Neuroendocrinologic and histopathologic evaluation of azoospermic, normogonadotropic patientes: usefulness of GnRH challenge test

Se valoró el efecto de la administración de hormona liberadora de gonadotropinas (GnRH) sobre las concentraciones séricas de FSH y LH, Se correlacionaron estos resultados con los hallazgos histopatológicos de biopsias testiculares obtenidas de pacientes azoospérmicos normogonadotrópicos. Se trató de un estudio prospectivo, con grupo testigo. Tuvo lugar en Clínica de Biología de la Reproducción, Centro Hospitalario " 20 de Noviembre" ISSSTE. Quince varones azoospérmicos normogonadotrópicos, sin atrofia testicular. Así como un grupo testigo de diez pacientes sanos. Se realizó una prueba de estimulación con GnRH en ambos grupos y dos días después se efectuó biopsia testicular a los pacientes azoospérmicos. Determinación de las concentraciones séricas de FSH y LH. Además, examen anatomopatológico de las biopsias de testículo. No hubo diferencia significativa en los valores de LH de los dos grupos antes ni después de aplicar la GnRH. Se encontró diferencia significativa en los niveles de FSH, siendo ésto más elevados en los pacientes azoospérmicos. Entre mayor fue el daño testicular, hubo tendencia a que los pacientes presentaran hiperrespuesta de la FSH a la GnRH. La prueba de estimulación con GnRH en pacientes azoospérmicos normogonadotrópicos es útil para detectar casos de lesión gonadal. Entre mayor se la respuesta de la FSH, es más probable que haya alteración histológica del testículo