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Objective: To compare the endocrine and cardiometabolic cord blood characteristics of offspring of mothers with polycystic ovary syndrome (PCOS) with those of healthy controls., Design: Cross-sectional case control study., Setting: University medical centers., Patient(s): Offspring from mothers with PCOS (n = 61) and healthy controls (n = 82)., Intervention(s): Cord blood withdrawal from neonates., Main Outcome Measure(s): Cord blood estradiol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone-binding globulin, free androgen index (FAI), insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, c-reactive protein, adiponectin, and leptin., Result(s): Androstenedione and leptin concentrations were increased in the offspring of women with PCOS compared with the controls: androstenedione median 2.9 (interquartile range [IQR] 2.3-3.9) nmol/L vs. 2.2 [IQR 1.6-2.7] nmol/L; and leptin median 13.6 [IQR 8.3-22.9] μg/L vs. 9.8 [IQR 6.0-16.5] μg/L. After adjusting for maternal and pregnancy-related confounders (such as maternal age, gestational age, birth weight), androstenedione appeared associated with PCOS in both male (relative change 1.36 [1.04; 1.78]) and female offspring (relative change 1.40 [1.08; 1.82]). Similarly, in male offspring the leptin concentrations appeared associated with PCOS after correction for confounders (relative change 1.55 [1.12; 2.14]). After correction for multiple testing, these associations attenuated., Conclusion(s): Observed results suggest that androstenedione concentrations are increased in the cord blood of male and female offspring of women with PCOS, although this requires confirmation. This finding would support the hypothesis that a maternal hyperandrogenic environment during pregnancy in women with PCOS may predispose their offspring to fetal hyperandrogenism. The potential associations between fetal hyperandrogenism and long-term health effects remain to be elucidated., Clinical Trial Registration Number: NCT00821379., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether women pregnant after a poor response in IVF have pregnancy-induced hypertension and preeclampsia more frequently than women with pregnancies after a normal response in IVF. Poor response to ovarian stimulation for IVF reflects advanced ovarian aging, which may be associated with early vascular aging. This may become apparent in an increased incidence of hypertensive pregnancy complications in pregnancies achieved after poor response in IVF., Design: Patient-control study., Setting: Tertiary Fertility Center., Patient(s): One hundred fifty poor (three oocytes or fewer) and 150 normal responders (8-12 oocytes) pregnant after IVF-intracytoplasmic sperm injection (ICSI), matched for age, type of infertility, dose of recombinant FSH, singleton or twin pregnancy, and IVF or ICSI treatment., Intervention(s): None., Main Outcome Measure(s): Primary end points were birth weight of the neonate and the incidence of pregnancy-related hypertensive disorders. Secondary end points were duration of pregnancy, type of delivery, and live birth of the neonate., Result(s): Poor and normal responders did not have significantly different incidences in pregnancy-related hypertensive disorders, nor did their neonates differ significantly in birth weight. Moreover, duration of pregnancy, type of delivery, and live birth ratios were similar in both poor and normal responders., Conclusion(s): From this matched control study we were unable to confirm our hypothesis, that women pregnant after a poor response in IVF have pregnancy-induced hypertension and preeclampsia more frequently than women with pregnancies after a normal response in IVF. These results do not support a vascular etiology of poor response., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To report an in vitro fertilization (IVF) pregnancy in a patient with histologically confirmed chronic endometritis before the IVF treatment without prior antibiotherapy., Design: Case report., Setting: Academic reproductive medicine unit., Patient(s): A 30-year-old woman with primary infertility due to mild oligoasthenoteratospermia of the male partner., Intervention(s): Diagnostic hysteroscopy and endometrial biopsy., Main Outcome Measure(s): Delivery after the first IVF., Result(s): Histologic examination of the endometrium revealed chronic endometritis. The patient delivered a healthy boy at 40 weeks' gestation after the first IVF treatment., Conclusion(s): Our findings suggest that the impact of chronic endometritis on infertility and IVF outcome should be further investigated in prospective randomized studies.

Objective: To investigate relations between dose of GnRH antagonist and follicular phase characteristics., Design: Randomized controlled multicenter trial., Setting: Tertiary referral fertility centers., Patient(s): Three hundred and twenty-nine IVF patients., Intervention(s): Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist., Main Outcome Measure(s): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations., Result(s): In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E(2) levels showed a GnRH antagonist dose-related decrease (P<0.05). Late follicular phase E(2) levels correlated with total follicular surface area, AD, LH, and FSH (all P<0.001). Increasing GnRH antagonist doses exhibited additional suppressive action on E(2) levels., Conclusion(s): Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E(2) levels could not be exclusively attributed to suppression of LH.

Objective: To study whether minimal interference in the process of selection of the single dominant follicle may serve as the basis for a simplified ovarian stimulation regimen for IVF., Design: Single-center randomized pilot study., Setting: Tertiary referral fertility center., Patient(s): Fifteen normo-ovulatory patients with a regular indication for IVF., Intervention(s): Ovarian stimulation for IVF was begun with 100 or 150 IU/d recombinant FSH starting on cycle day 5. From cycle day 8 or later, cotreatment was begun with 0.25 mg/d GnRH antagonist. No luteal support was provided., Main Outcome Measure(s): Total number of dominant follicles and characteristics of the endocrine cycle., Result(s): Multiple follicle development occurred in five of eight patients in the 100-IU group and in all seven women in the 150-IU group. Follicular phase and luteal phase lengths were normal, but the endocrine profile was abnormal., Conclusion(s): A fixed daily dose of 150 IU recombinant FSH starting in the midfollicular phase resulted in ongoing growth of a restricted number of dominant follicles and sufficient oocytes retrieved to lead to ET. A marked reduction in the total amount of gonadotropins administered compared with standard treatment was achieved. Withholding luteal support did not exclude pregnancies.

Objective: To evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of two embryos that had been cultured for 3-5 days., Design: Prospective study., Setting: An IVF laboratory at a tertiary referral university hospital., Patient(s): One thousand seven hundred eighty-seven couples who underwent their first IVF cycle between January 1995 and December 1997., Intervention(s): In vitro fertilization and transfer of embryos after 3, 4, or 5 days of culture using a single medium without coculture., Main Outcome Measure(s): Implantation and pregnancy rates., Result(s): Overall implantation and pregnancy rates were not significantly different with different culture periods. Forty-one percent of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, whereas the implantation rate of eight-cell embryos on day 3 was 18%. Implantation rates for retarded, normal, and advanced embryos were not significantly different with an extended culture period., Conclusion(s): Under the study conditions, the transfer of embryos after 5 days rather than 3 days of embryo culture did not change the overall implantation and pregnancy rates. The implantation potential of embryos available for transfer can be assessed better after an extended culture period. Five days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.

Objective: To compare the safety and efficacy of recombinant FSH (follitropin beta, Puregon; NV Organon, Oss, the Netherlands) and urinary FSH (urofollitropin, Metrodin; Ares-Serono, Geneva, Switzerland)., Design: A prospective, multicenter, assessor-blind, randomized, clinical trial., Setting: Twelve European infertility clinics., Patient(s): One hundred seventy-two women (recombinant FSH: n = 105; urinary FSH: n = 67) with clomiphene citrate-resistant normogonadotropic chronic anovulation (World Health Organization group II)., Intervention(s): Eligible subjects were randomized (ratio of recombinant to urinary FSH, 3:2) and treated for a maximum of three cycles. A low-dose step-up regimen was used, with 75 IU of FSH given IM daily for a maximum of 14 days and, if needed, weekly increments of half an ampule given thereafter until the threshold dose for follicular development was achieved., Main Outcome Measure(s): Cumulative ovulation rate after three cycles, total FSH dose, and treatment period needed to achieve ovulation., Result(s): The cumulative ovulation rates after three treatment cycles were 95% and 96% for the recombinant and urinary FSH groups, respectively. Overall, ovulation was seen in 155 of 223 treatment cycles (69.5%) in the recombinant FSH group, compared with 92 of 138 treatment cycles (66.7%) in the urinary FSH group. In the first cycle, a statistically significantly lower total dose (750 versus 1,035 IU) and a shorter treatment period (10 versus 13 days) were needed in the recombinant FSH group to reach ovulation. Only one case of ovarian hyperstimulation syndrome led to hospitalization. Two sets of twins (one in each treatment group) and one set of triplets (in the recombinant FSH group) were born., Conclusion(s): Recombinant FSH (Puregon) is more efficient than urinary FSH (Metrodin) in inducing follicular development.

Objective: To investigate the predictive value of polycystic ovaries for endocrine signs of polycystic ovary syndrome (PCOS)., Design: Controlled descriptive study., Setting: Academic tertiary care fertility clinic., Patient(s): Normogonadotropic (FSH levels between 1 and 10 mIU/mL conversion factor to SI unit, 1.0) oligomenorrheic or amenorrheic women visiting our fertility clinic and a control group of regularly cycling, healthy, normal weight volunteers recruited by advertisement., Intervention(s): Single blood samples and transvaginal sonography were performed., Main Outcome Measure(s): Serum levels of FSH, LH, androstenedione (A), and T and ovarian volume, ovarian stroma density, and follicle number., Result(s): In control women, the 95th percentile was calculated for ovarian volume, follicle number, and stroma count as well as endocrine parameters. The use of these upper limits of normal in the study group resulted in 217 (66%) patients with polycystic ovaries on ultrasound (defined as increased mean ovarian volume and/or mean follicle number per ovary), whereas only 120 (36%) patients exhibited elevated serum androgens (increased A and/or T concentrations) and 155 (47%) showed elevated LH levels. Sensitivity and specificity of single or combined sonographic parameters for prediction of elevated serum LH or androgen concentrations were limited., Conclusion(s): In the study group of normogonadotropic oligomenorrhea or amenorrheic infertile women, we set strict cutoff levels for various criteria used in the literature for defining PCOS. Groups defined by sonographic or endocrine PCOS criteria did overlap, but sonographic parameters had limited predictive value for abnormal hormone serum levels.

Objective: To study increases of serum FSH and gonadal response in gonadotropin-deficient men treated with recombinant FSH (Puregon; NV Organon, Oss, The Netherlands)., Design: An open, prospective, multiple rising dose study in which volunteers received single daily IM doses of recombinant FSH for 3 weeks. The dose administered was increased at weekly intervals: the first 7 days, 75 IU/d; the subsequent 7 days, 150 IU/d; and the last 7 days, 225 IU/d., Participants: Nine men suffering from isolated gonadotropin deficiency or panhypopituitarism., Main Outcome Measurements: Immunoreactive FSH, LH, inhibin, T, and androstenedione., Results: Serum immunoreactive FSH (median) rose in accordance with the recombinant FSH doses administered from 0.5 mIU/mL (range < 0.05 to 1.9 mIU/mL) at baseline to 4.3 mIU/mL (range 2.0 to 8.5 mIU/mL), 8.4 mIU/mL (range 4.9 to 17.8 mIU/mL), and 13.6 mIU/mL (5.6 to 28.4 mIU/mL) after 1, 2, and 3 weeks of medication, respectively. The elimination half-life of recombinant FSH was 48 +/- 5 hours (mean +/- SD), which was slightly longer than that reported after single dose administration of recombinant FSH (32 +/- 12 hours). The bioactivity of recombinant FSH was reflected by serum inhibin levels, which rose from 116 U/L (range 34 to 356 U/L) at baseline to 350 U/L (range 63 to 1,109 U/L) at day 22. However, serum FSH and inhibin levels did not correlate when compared after 1, 2, and 3 weeks of recombinant FSH administration. Serum immunoreactive LH, T, androstenedione, and E2 were 0.2 mIU/mL (range < 0.05 to 0.7 mIU/mL [conversion factor to SI unit, 1.0]), 58 ng/dL (range < 12 to 222 ng/dL [conversion factor to SI unit, 0.0347]), 14 ng/dL (range 6 to 115 ng/dL [conversion factor to SI unit, 0.0349]), and 14 pg/mL (range < 14 to 16 pg/mL [conversion factor to SI unit, 3.67]), respectively, at baseline and remained unchanged during the entire treatment period., Conclusion: These data indicate that recombinant FSH treatment increases serum FSH in a dose-proportional fashion, increases inhibin secretion, and lacks intrinsic LH activity.

Objective: To study ovarian stimulation and response patterns during a gonadotropin step-down dose regimen for induction of ovulation by applying a decremental dose regimen in polycystic ovary syndrome (PCOS) patients., Design: The present prospective study involves 28 infertile clomiphene citrate-resistant PCOS patients during gonadotropin-induced cycles using a modified step-down dose regimen (and adjuvant GnRH agonist medication). Applied gonadotropin doses included initial daily doses of 150 IU IM followed by two reducing steps (37.5 IU each) based on sonographic criteria to a final daily dose of 75 IU IM., Setting: Anovulatory infertile women in an academic referral center., Intervention: Daily blood withdrawal and transvaginal pelvic ultrasound., Main Outcome Measures: Serum FSH and E2 concentration and follicle growth were investigated daily during gonadotropin administration., Results: An initial 2.1-fold increase in serum FSH levels was observed followed by a subsequent decrease of 10% (median) per day for 4 days. Growth of ovarian follicles was sustained and ovulation achieved (midluteal P, 11.7 +/- 1.3 ng/mL; conversion factor to SI unit, 3.180; mean +/- SD) in 22 patients. Major variability in day 3 E2 increase (range, 67 to 866 pg/mL; conversion factor to SI unit, 3.671)--not related to differences in FSH serum concentrations and without changes in follicle number and size--suggests differences in ovarian sensitivity for FSH stimulation. A strong correlation (r = 0.82) was found between day 3 E2 increase and the chance of ovulation. Moreover, E2 levels on the day of gonadotropin dose reduction predict (r = 0.68) chances of late follicular phase E2 levels exceeding 871 pg/mL (conversion factor to SI value, 3.671)., Conclusions: These findings provide the endocrine basis for the concept of gonadotropin induction of ovulation using a step-down dose regimen. Initial E2 increase (before initiation of follicle growth) represent differences in ovarian sensitivity to gonadotropins and predict treatment outcome.

Objective: To study the relationship between decreasing serum FSH levels in the follicular phase of the normal menstrual cycle and follicle development by means of transvaginal sonography and E2 production., Design: Daily blood samples were taken and transvaginal sonography was performed every other day in 16 normal regularly cycling female volunteers., Main Outcome Measure: Serum levels of FSH, LH, E2, and P and follicle diameter by transvaginal sonography., Results: A distinct variability in individual maximal early follicular phase FSH plasma levels was observed (range 4.4 to 11.2 mIU/mL [conversion factor to SI unit, 1.000]). Differences in maximum FSH levels did not correlate with other endocrine or sonographic follicular phase characteristics. The follicular phase FSH decrease (from median 6.6 to 2.9 mIU/mL [conversion factor to SI unit, 1.000]) took place between cycle day 5 and 13 and was linear (0.5 +/- 0.05 mIU/mL per day; mean +/- SD). A significant correlation was found between serum FSH decrease and E2 increase. The day of sonographic appearance of a dominant follicle (median cycle day 8) did correlate with the first rise of the E2 plasma concentration., Conclusions: The present study suggests that even in women exhibiting normal ovarian function a 2.5-fold difference in FSH threshold concentrations for follicle recruitment does occur. Moreover, the magnitude of decrease in serum FSH concentrations during the follicular phase affects dominant follicle E2 production. The sonographic appearance of the dominant follicle is associated with a rise in serum E2 levels.

Objective: To determine whether ovarian polycystic changes estimated by transvaginal sonography correlate with clinical and endocrine findings associated with the polycystic ovarian syndrome., Design: Prospective study., Setting: Reproductive Endocrinology Unit in the Department of Obstetrics and Gynecology at a teaching hospital., Participants: Ninety-five consecutive patients suffering from oligoamenorrhea entering an infertility treatment program., Interventions: All women were examined by transvaginal sonography, assessed for body mass index and hirsutism. Blood withdrawal was performed for hormone estimates., Main Outcome Measures: Ovarian follicle number, volume, and stroma echogenicity. Estimates of immunoreactive and bioactive luteinizing hormone (LH), testosterone (T), free T, insulin levels, and insulin resistance index were performed., Results: Hirsutism was present in 63% of the patients and correlated with the number of follicles, ovarian volume, and stroma echogenicity. Follicle number, ovarian volume, and stroma echogenicity values were significantly correlated with immunoreactive LH, bioactive LH, and T levels. Both T and immunoreactive LH were independently correlated with ovarian structure sonography parameters. Insulin and insulin resistance correlated with ovarian volume and stroma echogenicity. Insulin resistance was of significant additional predictive value of ovarian volume and amount of stroma. Evaluating the predictive value of immunoreactive LH and T together in regard to all sonography parameters, only T levels were statistically significant predictors of increase in follicle number, ovarian volume, and stroma amount., Conclusions: Although immunoreactive LH and bioactive LH correlated with all ovarian parameters, the effect of androgens on ovarian changes appeared to be independent from LH. This further substantiates the apparent cardinal role of androgens in the genesis of polycystic ovaries. Besides, transvaginal sonography assessment of ovaries is a valuable additional tool for the diagnosis of PCOS. In this regard, insulin resistance is of additional predictive value for ovarian volume and stroma echogenicity.

Objective: To assess safety, pharmacokinetic, and pharmacodynamic properties of recombinant human follicle-stimulating hormone (FSH; Org 32489, Organon International, Oss, The Netherlands) after a single intramuscular injection in the buttock., Design: In a prospective study, safety variables, serum FSH, luteinizing hormone, inhibin, estradiol (females only), and testosterone (males only) were evaluated up to a maximum of 11 days after injection of 300 IU recombinant FSH., Setting: Four specialist Reproductive Endocrinology and Infertility units., Volunteers: Fifteen men and women exhibiting all pituitary gonadotropin deficiency., Results: A single bolus of 300 IU recombinant FSH was well tolerated, and no drug-related adverse effects were noted. Comparison of before and after treatment safety variables, including serum antirecombinant FSH antibodies, showed no changes of clinical relevance. Analysis of serum FSH levels revealed comparable elimination half-lives of 44 +/- 14 (mean +/- SD) and 32 +/- 12 hours in women and men volunteers, respectively. In contrast, peak FSH concentrations were significantly lower in women than in men volunteers (4.3 +/- 1.7 versus 7.4 +/- 2.8 IU/L), and the time required to reach peak levels of FSH was significantly longer in women than in men (27 +/- 5 versus 14 +/- 8 hours). The area under the serum level versus time curve tended to be smaller in women than in men volunteers (339 +/- 105 versus 452 +/- 183 IU/L x hours), but the difference did not reach statistical significance. Together these data suggest that recombinant FSH is absorbed from its intramuscular depot to a lower rate and extent in women than in men. In both sexes a relationship between serum FSH levels and body weight was apparent. During the experimental period, other hormones remained low at baseline levels or were only slightly increased., Conclusion: Our findings indicate that recombinant FSH is well tolerated and that it is absorbed from its intramuscular depot to a higher rate and extent in men than in women. After intramuscular administration, its half-life is in good agreement with that previously reported for natural FSH.

Data presented in this study indicate that ovulation can be induced in patients with PCOS using a GnRH analogue combined with hMG in a decreasing dose regimen. Based on the observed decline in functional, medium sized follicles in the late follicular phase, it may be speculated that the risk of ovarian hyperstimulation during gonadotropin induction of ovulation in patients with PCOS can be reduced.

Transvaginal ultrasound examinations were performed in seven normally cycling women to characterize growth of nondominant follicles in both ovaries. Mean follicle number showed little variation throughout the menstrual cycle with no differences between dominant and nondominant ovaries. Up to 11 follicles (greater than or equal to 2 mm) were observed in any one ovary. From observations of the first appearance of the dominant follicle (mean size 9.9 +/- 3.0 [SD] mm), selection was assumed to take place on cycle day 6.3 +/- 2.3. The diameter of nondominant follicles always remained less than 11 mm. Growth of small follicles was established in both dominant and nondominant ovaries up to the time of selection. The late follicular and luteal phases were characterized by a decrease in mean growth slopes of nondominant follicles in the dominant ovary only. These observations may provide in vivo evidence for the concept of intraovarian paracrine mechanisms and may have implications for the sonographic diagnosis of anovulation and monitoring of ovulation induction.

Basal serum gonadotropin levels in 11 oligospermic men were significantly higher than in 9 euspermic control subjects, although most were still in the normal range. Basal serum testosterone (T), 17-hydroxyprogesterone (17-OHP), and estradiol levels and their ratios did not differ significantly. Continuous luteinizing hormone-releasing hormone (LH-RH) infusion (1 microgram/minute for 180 minutes) during integrated blood sampling evoked similar gonadotropin responses in both groups but had a differential effect on T: in the control subjects T increased (P less than 0.01) within 15 minutes to 1.5 times baseline, whereas in the oligospermic men T decreased (P less than 0.01). From 60 minutes on, however, T also significantly rose in the oligospermic men, but the maximum increment was about half lower (P less than 0.01) than in the euspermic men, despite virtually similar rises in 17-OHP. Only in the oligospermic men did the 17-OHP/T ratio increase (P less than 0.02) during LH-RH, which is compatible with the occurrence of a 17,20-lyase block. Serum estradiol did not increase in either group. In conclusion, continuous LH-RH infusion uncovers an intrinsic difference in acute Leydig cell stimulation between euspermic and oligospermic men.

Aromatase inhibition by delta 1-testolactone (TL), 500 mg twice daily for 4 weeks, in nine patients with idiopathic oligospermia lowered circulating estradiol (E2) levels by about 30%, enhanced the secretion of follicle-stimulating hormone (+ 30%), 17-hydroxyprogesterone (17-OHP) (+ 40%), and testosterone (T) (+ 30%), but did not affect serum luteinizing hormone levels. Despite E2 lowering, there was an accumulation of 17-OHP over T, suggesting 17, 20-lyase inhibition. Unexpectedly, administration of TL almost completely deleted the T response to continuous luteinizing hormone-releasing hormone infusion present before TL therapy, despite similar gonadotropin release. Because the 17-OHP response to the luteinizing hormone-releasing hormone infusion was even higher during therapy, the 17,20-lyase lesion seemed aggravated despite substantial reduction of E2 levels. Although the present data suggest that estrogens play a less dominant role in the origin of the late steroidogenetic lesion than previously assumed, the suggestion also arises that TL per se, in addition to its antiestrogenic action, exerts an inhibiting effect on the 17,20-lyase locus, which may obscure the beneficial effect of reducing E2.

In 22 potentially fertile men, pituitary gonadotropin secretion was investigated by intravenous luteinizing hormone-releasing hormone (LH-RH) administration. LH-RH was administered continuously (1 microgram/minute) and in a pulsatile fashion (20 micrograms at 20-minute intervals, 20 micrograms at 60-minute intervals, and 60 micrograms at 60-minute intervals), for 3 hours, under standardized conditions. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration after any type of pulsatile administration rose significantly more than after continuous LH-RH administration. The mean increase in LH after pulsatile LH-RH administration with a 60-micrograms dose and 60-minute intervals was significantly greater than after pulsatile administration with a 20-micrograms dose and 20- or 60-minute intervals. No differences were observed in follicle-stimulating hormone responses after any type of LH-RH administration. These data confirm the existence of a self-priming effect for LH in the men; and maximum pituitary stimulation, within the dosage range tested, is reached after pulsatile LH-RH stimulation with an interval of 60 minutes.

Exogenous luteinizing hormone-releasing hormone (LH-RH) was intravenously administered as a single-bolus injection to 26 healthy normal men. LH-RH doses were selected at 1, 2.5, 5, and 20 micrograms for exploration of the optimum LH-RH dose to obtain adequate pituitary stimulation. Blood samples (for LH-RH and LH determinations) were collected at frequent intervals from 10 minutes before to 60 or 90 minutes after injection. LH-RH peak levels varied, in a dose-dependent way, between 119 +/- 16 and 517 +/- 70 ng/l. Peak values were all reached between 1 and 3 minutes after injection, and elimination occurred rapidly, with half-lives between 2.6 +/- 0.4 and 5.2 +/- 1.0 minutes. The area under the curves increased significantly (P less than 0.01) if the doses of LH-RH had been augmented from 1 to 20 micrograms. Maximum LH values were reached more rapidly in the low-dose (1 and 2.5 micrograms) experiments (between 13.5 and 16.3 minutes), with an obvious decline afterwards. The area under the LH curves increased (P less than 0.01) if the doses of LH-RH had been elevated from 1 to 2.5 micrograms, but no further increase of LH release occurred (P greater than or equal to 0.21) if LH-RH doses were further elevated from 2.5 to 20 micrograms. The current study demonstrates that a 2.5-micrograms intravenous LH-RH dose is best suited for an adequate pituitary stimulation in normal men.

In 14 healthy, potentially fertile men, pituitary gonadotropin responses were studied under standardized conditions. Luteinizing hormone-releasing hormone (LH-RH) was given as a continuous infusion of 1 microgram/minute for 4 hours or in a pulsatile fashion with 20 micrograms as an intravenous bolus at intervals of 20 minutes for 4 hours. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration showed an oscillating pattern around a plateau level reached within 45 minutes during continuous LH-RH administration. During pulsatile infusion, an identical pattern for the first 45 minutes was observed with, thereafter, a continuous increase from 105 minutes until the end of the infusion. The mean increase in the serum LH level during pulsatile administration was significantly higher (P = 0.00001) than the mean increase seen during continuous infusion. The follicle-stimulating hormone concentration revealed a gradual progressive increase after both methods of stimulation, without a significant difference in the mean increase between the two types of administration. This study demonstrates the existence of a self-priming effect of LH after pulsatile LH-RH administration in the man like that in the woman.

Serum levels of luteinizing hormone-releasing hormone (LH-RH), LH, and follicle-stimulating hormone (FSH) were measured for 60 minutes after 5- and 20-micrograms bolus doses of LH-RH given either intravenously or subcutaneously to 20 healthy men, for the study of LH-RH pharmacokinetics and the corresponding pituitary gonadotropin release. Intravenous (5- and 20-micrograms) LH-RH administration revealed much sharper LH-RH pulses, with significantly higher levels between 1 and 5 minutes (P less than 0.001) but lower levels between 30 and 60 minutes (P less than 0.05), compared with the subcutaneous route. No statistically significant differences were observed in the magnitude and time occurrence of maximum LH release or in the area under the LH response curves between intravenous and subcutaneous LH-RH administration, either in the 5-micrograms or in the 20-micrograms group. FSH responses were small and insignificant in all the performed tests. The intravenous route of administration seems preferential in therapeutic regimens that use pulsatile exogenous LH-RH, because the conditions of intermittent pituitary stimulation are more adequately fulfilled and the risk of dose accumulation is reduced. Furthermore, LH-RH doses of 5 micrograms are capable of producing adequate pituitary LH release, whereas increases in the pulse dose up to 20 micrograms seem to have no additional effects.