Luteinizing hormone (LH) formed a complex with an immunoglobulin G caused abnormally high levels of LH: A case report.

We encountered a 30-year-old woman with remarkably elevated luteinizing hormone (LH) levels, as measured by electrochemiluminescent immunoassay (ECLIA), and no specific symptoms. We performed the following investigations: dilution linearity test, polyethylene glycol (PEG) precipitation test, immunoprecipitation test, protein G addition test, and high-performance liquid chromatography (HPLC) analysis. The linearity of patient's serum was similar to that of a standard LH preparation, and non-specific reactions were not observed. The recovery rate of LH shown by the PEG precipitation test, immunoprecipitation test, and protein G addition test was low. Moreover, an abnormal peak in HPLC was located at a slightly larger molecular weight position than that of IgG. These results showed the presence of macro-LH, LH, and anti-LH-IgG autoantibody complex and suggested that the clearance of LH from the blood was delayed due to IgG binding, and therefore, the LH value was falsely high. We should keep the possibility of macro-LH in mind in cases of unexpectedly high LH values.

Dynamic Interactions Between LH and Testosterone in Healthy Community-Dwelling Men: Impact of Age and Body Composition.

BACKGROUND: Aging is associated with diminished testosterone (Te) secretion, which may be attributed to Leydig cell dysfunction, decreased pituitary stimulation, and altered Te feedback. OBJECTIVE: To study all regulatory nodes-gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and Leydig cell-in the same cohort of healthy men. STUDY DESIGN: This was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age range 19 to 73 years, and body mass index (BMI) range 20 to 34.3 kg/m2. A submaximal dose of the GnRH antagonist ganirelix was used to assess outflow of GnRH, by calculating the difference between LH output during the control arm and ganirelix arm. Ketoconazole (a steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during the ketoconazole and control arm. High-dose ganirelix and repeated LH infusions were used to measure testicular responsivity. Blood sampling was performed at 10-minute intervals. RESULTS: There were age-related, but not body composition-related decreases in estimated GnRH secretion, the feedback strength of Te on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and computed tomography (CT)-estimated abdominal visceral mass (AVF), without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF. CONCLUSION: Advancing age is associated with (1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, (2) diminished testicular responsivity to infused LH pulses, and (3) partial compensation by diminished Te feedback on central gonadotropic regulation.

Effects of AY9944 A-7 on gonadotropin-induced meiotic resumption of oocytes and development of parthenogenetic embryos in sheep.

Follicular fluid meiosis-activating sterol (FF-MAS), an intermediate in the cholesterol biosynthetic pathway, has been identified as a compound that induces the resumption of meiosis in mammalian oocyte. Follicular fluid meiosis-activating sterol is converted to testis meiosis-activating sterol by a sterol Δ14-reductase. An inhibitor of Δ14-reductase and Δ7-reductase, AY9944 A-7, causes accumulation of FF-MAS by inhibiting its metabolism. The objective of this research was to investigate the specific contribution of AY9944 A-7 on gonadotropin-induced meiotic resumption and its interactive effects with FSH or LH on meiotic maturation of oocytes and preimplantation development of parthenogenetic embryo in sheep by addition of AY9944 A-7 during IVM to cause accumulation of FF-MAS. First, ovine cumulus-oocyte complexes (COCs) were cultured in the presence of FSH (10 µg/mL), LH (10 µg/mL), AY9944 A-7 (20 µmol/L), FSH (10 µg/mL)+AY9944 A-7 (20 µmol/L), or LH (10 µg/ml) + AY9944 A-7 (20 µmol/L) with an inhibitor hypoxanthine (Hx) to prevent spontaneous meiosis of oocytes. The resumption of meiosis was assessed by the frequency of germinal vesicle breakdown and the first polar body (PBI) extrusion. The kinetics of gonadotropin and AY9944 A-7-induced meiotic resumption in vitro was also evaluated in the study. The numbers of oocytes resuming meiosis and undergoing germinal vesicle breakdown were counted after the COCs were cultured for 2, 4, 8, 12, 16, 20, and 24 hours. Matured oocytes extruding PBI were selected for parthenogenetic activation, and the percentages developing to the two-cell stage and blastocyst stage were recorded as indicators of parthenogenetic embryo developmental competence. It was observed that FSH could induce the resumption of meiosis of ovine COCs cultured in the presence of Hx, but LH could not. AY9944 A-7 had a synergistic effect with FSH on nuclear maturation and developmental competence of embryos produced by parthenogenetic activation, whereas it had no added advantage on LH action. However, the kinetics of meiotic resumption after AY9944 A-7 stimulation was remarkably delayed when compared with FSH-induced maturation. In conclusion, the current study suggested that AY9944 A-7 supplementation in IVM medium optimized the beneficial effects of FSH on meiotic maturation of ovine oocytes and subsequent developmental competence of embryos produced by parthenogenetic activation. This work had important potential for developing a novel technique in IVM of ovine oocytes.

Pharmacodynamics of aqueous leuprolide acetate stimulation testing in girls: correlation between clinical diagnosis and time of peak luteinizing hormone level.

We assessed the pharmacodynamics of a 3-hour leuprolide stimulation test in 11 girls with precocious puberty to determine an optimal single sampling time. Luteinizing hormone level following leuprolide stimulation was near maximum by 30 minutes in girls with central precocious puberty, whereas it continued to rise slowly in girls with nonprogressive puberty.

Current opinion on use of luteinizing hormone supplementation in assisted reproduction therapy: an Asian perspective.

LH and FSH have complementary functions in ensuring optimal oocyte maturation and ovulation. In women undergoing assisted reproduction technology protocols with gonadotrophin-releasing hormone analogues, LH and FSH concentrations are reduced. While FSH use in assisted reproduction technology is well established, there is no published consensus on the need for exogenous LH in Asian patients. Having reviewed the concept of the LH therapeutic window and differences between recombinant human LH (r-HLH) and human menopausal gonadotrophin, a consensus was reached on which patient subgroups may benefit from LH supplementation. Adjuvant r-HLH gives clinicians precise control over the dose of LH bioactivity administered to target the therapeutic window. The use of r-HLH is recommended in women with poor response in a previous cycle or suboptimal follicular progression in a current cycle by day 6-8 of stimulation. r-HLH should also be considered in women at risk of suboptimal response, specifically age > 35 years. Other risk markers that suggest the need for LH supplementation, which include baseline/day-6 serum LH and anti-Müllerian hormone concentrations, antral follicle count and LH polymorphisms require further research and verification. For measurement of LH response adequacy, the monitoring of follicular progression, oestradiol concentrations and endometrial thickness is recommended.

Recombinant human follicular stimulating hormone and recombinant human luteinizing hormone in a 2:1 ratio combination. Pharmacological characteristics and clinical applications.

IMPORTANCE OF THE FIELD: A new fixed combination of recombinant human follicle stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) at a 2:1 ratio has been recently developed to induce ovulation in patients with hypogonadotrophic hypogonadism. Whether or not this compound is useful for controlled ovarian stimulation for in vitro fertilization is still a matter of debate. AREAS COVERED IN THIS REVIEW: Description of pharmacological and clinical aspects of this new product, through the analysis of the Phase I, II and II trials and post-marketing clinical randomized trials, performed since the initial assays in 1998 to nowadays. WHAT THE READER WILL GAIN: After reading this review the reader will understand the pharmacological aspects of this new compound, in terms of efficacy and safety, and will have an update of the potential role of r-LH administration in controlled ovarian stimulation for in vitro fertilization. TAKE HOME MESSAGE: The 2:1 combination of r-hFSH and r-hLH has been seen as an optimum preparation in terms of safety and clinical efficacy in hypogonatrophic hypogonadism patients. Its use in ovarian stimulation for IVF remains controversial, as the target population that may receive a benefit of it is not well defined.

The influence of porosity changes in human epidermal membrane during iontophoresis on the permeability enhancement of a model peptide.

PURPOSE: We tested the hypothesis that the increases in the porosity of the skin during iontophoresis would not significantly increase the transport of peptides due to the small size of electrically induced pores. To investigate this mechanistically, we used human epidermal membrane under constant voltage conditions, applying the Nernst-Planck equation to the transport of a small ionic solute, tetraethylammonium bromide (TEAB), and a model peptide, luteinizing hormone releasing hormone. METHODS: Steady-state flux of the drugs was determined under passive conditions and also during iontophoresis using constant DC voltages applied across side-by-side diffusion cells. Electrical conductance measurements were used to monitor the porosity changes that occur during electrical field application. RESULTS: Porosity increases observed in the membrane substantially increased the permeability enhancement of the small ionic solute TEAB. The permeability enhancement was well described by Nernst-Planck model predictions after porosity changes in the membrane were taken into account. Enhancement of luteinizing hormone releasing hormone under identical conditions was much less than TEAB. The porosity increases induced by iontophoresis had little or no effect on the permeability enhancement of the larger molecule. CONCLUSIONS: These findings closely parallel those reports that have found electrically induced pores to be significantly smaller than preexisting pores in the human epidermal membrane. The data obtained also support the view that iontophoresis-induced pores, alone, may provide limited benefit for macromolecule transport across the skin.

Bioequivalence of recombinant human FSH and recombinant human LH in a fixed 2:1 combination: two phase I, randomised, crossover studies.

OBJECTIVES: To assess bioequivalence of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) and recombinant human luteinising hormone (r-hLH, lutropin alfa) in a fixed 2:1 combination (Pergoveris) compared with injection of each of the hormones separately. RESEARCH DESIGN AND METHODS: Two, two-way crossover, phase I studies in healthy female volunteers after gonadotrophin-releasing hormone agonist down-regulation. Volunteers were randomised to the order in which they received subcutaneous injections. In the r-hFSH study, volunteers received one injection of r-hFSH (300 IU) and one of r-hFSH (300 IU)/r-hLH (150 IU) > or = 7 days apart; in the r-hLH study they received r-hLH (450 IU) and r-hFSH (900 IU)/r-hLH (450 IU) > 21 days apart. MAIN OUTCOME MEASURES: The serum concentration-time profiles of FSH in the r-hFSH study and LH in the r-hLH study from zero to the last measurable concentration (AUC(0-last)) and the peak FSH/LH serum concentrations (C(max)) were assessed by non-compartmental analysis. The pre-defined range for bioequivalence was 0.8-1.25 for 90% confidence intervals (CI) of the ratio (fixed combination/single gonadotrophin) of the mean for each pharmacokinetic parameter. RESULTS: Bioequivalence criteria were met for the r-hFSH study (n = 34) for C(max) (ratio of means 1.0024, 90% confidence interval (CI) 0.9611-1.0454) and AUC(0-last) (ratio of means 1.0167, 90% CI 0.9933-1.0407), and for the r-hLH study (n = 63) for C(max) (ratio of means 0.9687, 90% CI 0.9194-1.0207) and AUC(0-last) (ratio of means 0.9753, 90% CI 0.8990-1.0581). In the r-hFSH study, 20 adverse events (AEs) were reported after injection of r-hFSH and 20 after r-hLH/r-hFSH. In the r-hLH study, 179 AEs were reported after injection of r-hLH and 193 after the fixed-dose combination. Across both studies, headache was the most commonly reported AE. No serious AEs occurred. CONCLUSIONS: These studies demonstrated bioequivalence between r-hFSH and r-hLH administered alone or in fixed 2:1 combination. The 2:1 combination of follitropin alfa and lutropin alfa allows administration of both recombinant gonadotrophins in a single injection.

Molecular pharmacology of gonadotropins.

Gonadotropins have been studied in biological systems for decades and many of their properties are well defined. These include pharmacological properties such as affinity, stability, and pharmacokinetics also used to characterize drugs. Technologies applied to research on gonadotropins have led to the creation of hormone analogs with alterations to one or more of these proper-ties. Some of these analogs have potential therapeutic applications. A challenge to realizing this potential is the accurate prediction of how these compounds will perform in humans. This could be facilitated by advances in biological models and the understanding of specific effects of the hormones on their receptors.

Fast renal trapping of porcine luteinizing hormone (pLH) shown by 123I-scintigraphic imaging in rats explains its short circulatory half-life.

BACKGROUND: Sugar moieties of gonadotropins play no primary role in receptor binding but they strongly affect their circulatory half-life and consequently their in vivo biopotencies. In order to relate more precisely hepatic trapping of these glycoproteic hormones with their circulatory half-life, we undertook a comparative study of the distribution and elimination of porcine LH (pLH) and equine CG (eCG) which exhibit respectively a short and a long half-life. This was done first by following half-lives of pLH in piglets with hepatic portal circulation shunted or not. It was expected that such a shunt would enhance the short half-life of pLH. Subsequently, scintigraphic imaging of both 123I-pLH and 123I-eCG was performed in intact rats to compare their routes and rates of distribution and elimination. METHODS: Native pLH or eCG was injected to normal piglets and pLH was tested in liver-shunted anaesthetized piglet. Blood samples were recovered sequentially over one hour time and the hormone concentrations were determined by a specific ELISA method. Scintigraphic imaging of 123I-pLH and 123I-eCG was performed in rats using a OPTI-CGR gamma camera. RESULTS: In liver-shunted piglets, the half-life of pLH was found to be as short as in intact piglets (5 min). In the rat, the half-life of pLH was also found to be very short (3-6 min) and 123I-pLH was found to accumulate in high quantity in less than 10 min post injection at the level of kidneys but not in the liver. 123I-eCG didn't accumulate in any organ in the rats during the first hour, plasma concentrations of this gonadotropin being still elevated (80%) at this time. CONCLUSION: In both the porcine and rat species, the liver is not responsible for the rapid elimination of pLH from the circulation compared to eCG. Our scintigraphic experiments suggest that the very short circulatory half-life of LH is due to rapid renal trapping.

Lifestyle and nutritional determinants of bioavailable androgens and related hormones in British men.

OBJECTIVE: To investigate the lifestyle and nutritional determinants of serum bioavailable androgens and their related hormones in men. METHODS: This study is based on a sample of 696 men with a wide range of nutrient intakes, whose diet and lifestyle characteristics were assessed with a questionnaire and serum sex hormones measured using immunoassays. RESULTS: Men aged 70 years or older had 12% lower testosterone and 40% lower free-testosterone (FT) and androstanediol glucuronide (A-diol-g) concentrations than men who were 20-29 years of age. Conversely, sex hormone-binding globulin (SHBG) and luteinizing hormone (LH) concentrations were 90% and 49% higher in the oldest age group compared with the lowest, respectively. Men who had a body mass index (BMI) of 30+ kg/m2 had 30% lower testosterone, 45% lower SHBG, 22% lower LH and 5% lower FT concentrations compared with men with a BMI of <20 kg/m2. Conversely, A-diol-g concentration was 15% higher in the highest BMI category compared with the lowest. A high waist circumference was further associated with a 12% lower testosterone and SHBG concentration, after adjusting for BMI. Compared with never-smokers, smoking 10+ cigarettes/day was associated with 15% higher testosterone, 22% higher SHBG and 17% higher LH concentrations; FT and A-diol-g were not associated with smoking. Compared with no exercise, vigorous exercise of 3+ hours/week was associated with 11% higher testosterone and 16% higher SHBG concentrations, whilst LH, FT, and A-diol-g were not associated with vigorous exercise. Dietary factors were not strongly associated with hormones, although saturated fat intake was negatively associated with SHBG (r = -0.10; p = 0.01) and alcohol intake was positively associated with A-diol-g (r = 0.11; p = 0.004). No dietary factors were associated with testosterone, FT, or LH. CONCLUSIONS: Age is the strongest determinant of serum bioavailable androgens. BMI and some lifestyle and dietary factors influence SHBG and testosterone concentrations, but have no strong association with FT, suggesting that homeostasis is effective. A-diol-g shows broadly similar associations to FT, with the exception of the effect of BMI and alcohol.

Immobilization of hormones for drug targeting.

Biological active compounds such as insulin, heparin, progesterone and labeled-LH were entrapped in glutaraldehyde cross-linked bovine serum albumin (BSA) and human serum albumin (HAS) microspheres. Studies were carried out for their binding capacity and biodegradability using new proteolytic enzymes. Effects of proteolytic enzymes such as trypsin, chymotrypsin, papain and pronase-E on microspheres were studied in order to understand the biodegradability of the cross-linked proteins. It has been observed that labeled-LG was entrapped 60% in BSA and HAS microspheres. Labelled-LH-BSA, Labelled-LH-HAS and insulin microspheres were injected into mice and rabbits. It was observed that these cross-linked microspheres were biodegradable and the process appeared to be slow one, useful for sustained release of hormones. It was also observed that these albumin microspheres exhibit fluorescence at 495 nm.

The influence of glycoprotein hormones selected properties of selected properties of glycoprotein hormones on their absorption after intranasal administration in foxes.

The absorption of glycoprotein hormones, i.e. folitropin and lutropin, whose approximate molecular weight is 30,000 D, were estimated for the intranasal administration. The maximal hormone concentrations were observed 30 minutes after their administration. The maximal concentration of folitropin was 32% higher than the maximal concentration of lutropin. Bioavailability level for foliotropin was 138.58% compared to lutropin bioavailability level, which was considered the pattern bioavailability level (100%) in our experiments. It was established that the absorption of hormones from nasal mucous membrane depended not only on their molecular mass but also on the isoelectric point, content of carbohydrates and sialic acids. Hormonal substances of acid character, containing a greater content of carbohydrates and sialic acids (as in the case of folitropin) were absorbed from the nasal mucosa more rapidly.

The role of nitric oxide in reproduction.

Nitric oxide (NO) plays a crucial role in reproduction at every level in the organism. In the brain, it activates the release of luteinizing hormone-releasing hormone (LHRH). The axons of the LHRH neurons project to the mating centers in the brain stem and by afferent pathways evoke the lordosis reflex in female rats. In males, there is activation of NOergic terminals that release NO in the corpora cavernosa penis to induce erection by generation of cyclic guanosine monophosphate (cGMP). NO also activates the release of LHRH which reaches the pituitary and activates the release of gonadotropins by activating neural NO synthase (nNOS) in the pituitary gland. In the gonad, NO plays an important role in inducing ovulation and in causing luteolysis, whereas in the reproductive tract, it relaxes uterine muscle via cGMP and constricts it via prostaglandins (PG).

The role of nitric oxide in reproduction

Nitric oxide (NO) plays a crucial role in reproduction at every level in the organism. In the brain, it activates the release of luteinizing hormone-releasing hormone (LHRH). The axons of the LHRH neurons project to the mating centers in the brain stem and by afferent pathways evoke the lordosis reflex in female rats. In males, there is activation of NOergic terminals that release NO in the corpora cavernosa penis to induce erection by generation of cyclic guanosine monophosphate (cGMP). NO also activates the release of LHRH which reaches the pituitary and activates the release of gonadotropins by activating neural NO synthase (nNOS) in the pituitary gland. In the gonad, NO plays an important role in inducing ovulation and in causing luteolysis, whereas in the reproductive tract, it relaxes uterine muscle via cGMP and constricts it via prostaglandins (PG).

Recombinant forms of rat and human luteinizing hormone and follicle-stimulating hormone; comparison of functions in vitro and in vivo.

We have previously described the preparation, purification and partial characterization of recombinant (rec) forms of rat luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the present study, the special functional features of these hormones were studied further, in vitro and in vivo, and compared with human recLH and recFSH, as well as with human urinary choriongonadotropin (hCG) and rat pituitary LH (NIDDK-RP3). In radioreceptor assay, the affinity of hCG binding to rat testis membranes was 5-fold higher than that of human recLH and 100-fold higher than that of rat recLH. In in vitro bioassay, using dispersed adult mouse interstitial cells or a mouse Leydig tumor cell line (BLT-1), hCG and human recLH were 10- to 20-fold more potent than rat recLH. Correspondingly, rat pituitary LH was about 10-fold less potent than rat recLH, and evoked a maximum testosterone response that was about half of that elicited by the other LH/CG preparations. Rat recFSH was about 10-fold less potent than human recFSH in stimulating cAMP production of a mouse Sertoli cell line (MSC-1) expressing the recombinant rat FSH receptor. The circulating half-times (T1/2) of rat and human rec hormones were assessed after i.v. injections into adult male rats rendered gonadotropin-deficient by treatment with a gonadotropin-releasing hormone antagonist. A novel immunometric assay was used for the rat FSH measurements. In the one-component model the T1/2 values of rat and human recLH were 18.2 +/- 1.9 min (n = 7) and 44.6 +/- 3.1 min (n = 7) respectively and those of rat and human recFSH were 88.4 +/- 10.7 min (n = 6) and 55.0 +/- 4.2 min (n = 6) respectively; the two-component models revealed similar differences between the rec hormone preparations. Collectively, rat recLH was eliminated significantly faster from the circulation than human recLH (P < 0.0001). In contrast, the elimination of rat recFSH was significantly slower than that of human recFSH (P = 0.02). In conclusion, rat recFSH and rat recLH display lower biopotencies per unit mass than the respective human hormones in vitro, and also in vivo for LH. This is paralleled by shorter T1/2 of rat recLH than the respective human hormone in the circulation, whereas human recFSH has a shorter T1/2 than human FSH. The special functional features of the rat rec gonadotropins emphasize the use of these preparations on studies of gonadotropin function in the rat, an important animal model for reproductive physiology.

Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone.

OBJECTIVE: To assess the pharmacokinetics after i.v. administration of a recombinant human LH and to compare them to those of a reference hMG preparation containing urinary human LH. DESIGN: Prospective, dose-escalating, cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received single i.v. doses of 300, 10,000, and 40,000 IU of recombinant human LH, followed by a single i.v. dose of 300 IU of hMG, all separated by 1 week. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULTS: For both preparations, LH serum levels were well described by similar biexponential models. The pharmacokinetics of recombinant human LH were linear over the 300 to 40,000 IU range. After a rapid distribution phase with an initial half-life of 1 hour, both recombinant human LH and urinary human LH were eliminated with a terminal half-life of 10-12 hours. Total serum clearance was 1.7 L/h with < 4% and 30% of the dose being eliminated in the urine for recombinant human LH and urinary human LH, respectively. The volume of distribution at steady-state was approximately 10 L. Irrespective of the dose, recombinant human LH was well tolerated. CONCLUSION(S): The pharmacokinetics of recombinant human LH are linear with dose and similar to those of urinary human LH.

Clinical pharmacology of recombinant human luteinizing hormone: Part II. Bioavailability of recombinant human luteinizing hormone assessed with an immunoassay and an in vitro bioassay.

OBJECTIVE: To assess the single-dose pharmacokinetics of a recombinant human LH preparation administered by the i.v., i.m., and s.c. route. DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received single i.v., i.m., and s.c. doses of 10,000 IU of recombinant human LH, each separated by 1 week. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULT(S): After single i.v. administration, the pharmacokinetics were described by a two-compartment model, after i.m. or s.c. administration, by a one-compartment model with zero order absorption and a lag time. Using the immunoassay, after i.v. administration initial half-life was 1 hour and terminal half-life was 10 hours (half-life was prolonged after extravascular administration, suggesting rate-limiting absorption). Total serum clearance was 2.6 L/h, and steady, state volume of distribution was 14 L. Observed Cmax, after i.m. and s.c. administration, was 43 IU/L with median tmax of 9 hours (i.m.) and 5 hours (s.c.). Bioavailability was 0.54 (i.m.) and 0.56 (s.c.). The pharmacokinetics of LH are comparable using an in vitro bioassay. CONCLUSION(S): The terminal half-life of recombinant human LH is around 12 hours and is slightly prolonged after extravascular administration. The pharmacokinetics are similar after i.m. and s.c. injection, and one-half the administered dose is available systemically.

Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone.

OBJECTIVE: To assess the pharmacokinetics of a recombinant human LH preparation and its pharmacokinetic and pharmacodynamic interactions with recombinant human follicle-stimulating hormone (FSH). DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received 150 IU of s.c. recombinant human LH and FSH, either alone or in combination, followed by recombinant human LH and FSH once daily for 7 days. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters, ovarian follicle development. RESULT(S): No pharmacokinetic interaction between recombinant human LH and FSH was observed, with no significant difference in baseline-corrected maximal observed concentration over baseline, area under the concentration-time curve from t = 0 to t = 24 hours, or time to maximal concentration after single doses alone or in combination. After daily administration, the mean accumulation ratio was 1.6 for LH and 2.9 for FSH, with absorption and terminal phase half-life estimates of 4 and 11 hours for LH and 8 and 16 hours for FSH, respectively. Combined administration of FSH and LH for 7 days was effective in stimulating ovarian follicular development and steroidogenesis, with large interindividual variability related to ovarian sensitivity. CONCLUSION(S): A new recombinant human LH preparation has a low accumulation ratio at steady-state and no pharmacokinetic or pharmacodynamic interactions with recombinant human FSH.