Predictive value of serum follicle-stimulating hormone levels in the differentiation between hypogonadotropic hypogonadism and constitutional delay of puberty.

OBJECTIVE: Gonadotropin secretion was evaluated to predict hypogonadotropic hypogonadism (HH) in 36 children suspected of having HH. METHODS: LH was measured for 24 h at 10-min intervals, and FSH and estradiol or testosterone at 1-hour intervals. Twenty boys (age 15.7, range 13.2-19.3 years) and 16 girls (age 16.1, range 13.0-20.6 years) were studied. RESULTS: LH pulses were detected in 9 boys and 5 girls. HH was confirmed in all 11 LH apulsatile boys and in 8 of 11 LH apulsatile girls. Random FSH values of < or =1.11 and < or =2.86 IU/l in boys and girls, respectively, discriminated patients with LH pulses from patients without (sensitivity for lack of LH pulses 97 and 100%, respectively). In boys testicular volume was not discriminatory. In 1 girl LH pulses were observed without estradiol production, suggesting LH neurosecretory dysfunction. CONCLUSIONS: Low FSH levels in adolescence are strongly related to a lack of LH pulses. Lack of LH pulses is highly suspect for HH. FSH may be a tool in the differentiation between HH and delayed puberty.

Increased levels and pulsatility of follicle-stimulating hormone in mothers of hereditary dizygotic twins.

According to the endocrine model of hereditary dizygotic twinning, high FSH is responsible for multiple ovulation and pregnancy. Our study explored the underlying neuroendocrine causes. In a prospective clinical study, we compared the third day of menses parameters of episodic secretion of LH and FSH, the pituitary response to LHRH, plasma estradiol, and dimeric inhibin A and B in 16 regularly menstruating and 9 postmenopausal mothers of dizygotic twins with a family history of twinning and 14 premenopausal and 9 postmenopausal controls. Seven of 16 premenopausal mothers of twins had abnormally high FSH levels of more than 10 IU/L compared with 1/14 in controls (P = 0.024). In the premenopausal mothers of twins, mean FSH concentrations (P = 0.025) and FSH pulse frequency (P = 0.003) were significantly elevated, whereas FSH pulse amplitude and FSH response to LHRH were unaltered. For LH, neither the secretory parameters nor the response to LHRH was different. There were no differences between estradiol and inhibin A and B levels. Postmenopausal mothers of twin and controls did not differ with respect to the secretory pattern of LH and FSH. We conclude that under equal ovarian feedback conditions, premenopausal mothers of a dizygotic twin have hyper stimulation by endogenous FSH caused by neuroendocrine, hypothalamic, or pituitary mechanisms. This is the result of altered responsiveness to ovarian feedback and/or pituitary or suprapituitary, non-LHRH-like mechanisms that stimulate pulsatile FSH.

An artificially induced follicle stimulating hormone surge at the time of human chorionic gonadotrophin administration in controlled ovarian stimulation cycles has no effect on cumulus expansion, fertilization rate, embryo quality and implantation rate.

In the spontaneous menstrual cycle, the mid-cycle gonadotrophin surge causes maturation of the cumulus-oocyte complex, mucification of cumulus cells and expansion of the cumulus oophorus, resumption of meiosis and maturation of the cytoplasm of the oocyte. Whether this is an effect purely of luteinizing hormone (LH) or whether follicle stimulating hormone (FSH) also plays a role is unknown. The effect of an artificially induced FSH surge at the time of human chorionic gonadotrophin (HCG) injection on maturation of the cumulus-oocyte complex was investigated in a prospective randomized double-blind trial. Twelve patients underwent controlled ovarian hyperstimulation [long gonadotrophin-releasing hormone agonist (GnRHa)/human menopausal gonadotrophin (HMG) protocol] for in-vitro fertilization (IVF) treatment. At the time of HCG administration, six patients received a bolus injection of FSH (450 IU i.m.); the other six patients received a placebo. The peak plasma concentrations of FSH of the experimental group were compared with the peak values of FSH obtained at the mid-cycle gonadotrophin surge of the natural cycle of a group of 12 volunteers to validate the bolus injection of FSH. Maturation of the cumulus-oocyte complex was quantified by measuring the expansion of the cumulus, by the fertilization rate and the implantation rate. The quality of the embryos was scored according the average morphology score. The bolus injection of FSH mimicked the mid-cycle gonadotrophin surge. The mean peak value of FSH (12.9 IU/l) in the experimental group was fully comparable with the mean peak value of FSH (10.0 IU/l) of the mid-cycle gonadotrophin surge in the natural cycle. No effect of a bolus injection of FSH on the maturation of the cumulus-oocyte complex or any other outcome variable was found. It is not advantageous to combine the final HCG injection with a bolus injection of FSH in GnRHa/HMG stimulated cycles.

Post-menopausal and chronological age have divergent effects on pituitary and hypothalamic function in episodic gonadotrophin secretion.

OBJECTIVE: Ageing is known to reduce gonadotrophin secretion in post-menopausal women. To what extent the hypothalamus and pituitary are involved in this process is not clear. The aim of this study was to compare pulse characteristics of FSH and LH in relation to chronological and post-menopausal age. Base on the gonadotrophin to GnRH, we assessed the extent to which pituitary and/or hypothalamic ageing is responsible for the observed changes. DESIGN: Blood samples were obtained from post-menopausal women every 10 minutes for 6 hours. Subsequently, 100 micrograms GnRH was administered intravenously and blood samples taken after 30, 60 and 90 minutes. PATIENTS: Twenty healthy women aged 47-72 years and between 1 and 30 years after the menopause. MEASUREMENTS: Plasma LH and FSH were measured by immunoradiometric assay. Pulses were identified by a computerized pulse detection program. End points were the mean number and amplitude of pulses, the mean LH and FSH concentrations during the 6-hour study period and the maximal LH and FSH increments following GnRH. RESULTS: Mean LH and FSH levels did not change with chronological age but the LH pulse frequency declined significantly and the response to GnRH increased. Mean LH levels declined with post-menopausal age without alteration in LH pulse frequency but with a significant decrease in pituitary LH response to GnRH. FSH levels remained unchanged. CONCLUSIONS: Post-menopausal ageing seems to have a major suppressive effect on pituitary gonadotroph function, while chronological ageing mainly affects the hypothalamic regulation of LH secretion.

Serum procollagen I carboxyterminal propeptide (PICP) levels through puberty: relation to height velocity and serum hormone levels.

The synthesis of type I collagen, the major component of the organic bone matrix, is reflected by procollagen I carboxyterminal propeptide (PICP) levels. Conflicting reports have been made about the relationship between PICP levels and puberty. We have studied PICP levels in serum in relation to pubertal stage, height velocity, oestradiol, testosterone, androstenedione, dehydroepiandrosterone sulphate, insulin-like growth factor I and growth hormone levels in 32 healthy boys aged 7.2-15.8 years and 32 healthy girls aged 7.2-14.8 years. The PICP levels in girls tended to be higher during midpuberty: in boys the levels were higher at the end of puberty. The PICP levels correlated strongly with height velocity in boys and girls. In conclusion, PICP correlates especially with height velocity. The variation of PICP between subjects during puberty is considerable. The PICP levels may predict growth at a certain moment, especially in cases where only one height measurement is available.

Androstenedione, dehydroepiandrosterone sulfate, and estradiol levels throughout female puberty: relation to height velocity.

Sex steroids are important contributors to the pubertal growth spurt. Both androgens and estrogens have been related to this moment of rapid growth, but the role of estrogens is thought to be the most important one. Since exogenous estrogens are not capable to induce an appropriate growth spurt in girls, there might be an additional contributing factor involved. In a recent pilot study of 32 healthy pubertal girls, we found that the peak height velocity (HV) is preceded by relatively high levels of dehydroepiandrosterone sulfate and androstenedione (delta4A) as compared with the end-pubertal level. In the present study we evaluated HV in relation to dehydroepiandrosterone sulfate and delta4A levels in 149 healthy girls of various Tanner stages. HV was correlated with delta4A and estradiol levels in Tanner stages I-III. These results suggest that, like estrogens, delta4A might be an important stimulator of the female growth spurt.

The importance of endogenous feedback for monofollicular growth in low-dose step-up ovulation induction with follicle-stimulating hormone in polycystic ovary syndrome: a randomized study.

OBJECTIVE: To evaluate the role of endogenous feedback in monofollicular growth during low-dose gonadotrophin therapy in polycystic ovary syndrome (PCOS) by measuring FSH levels in a group of patients cotreated with a GnRH agonist (GnRH-a) (group B) compared with patients not cotreated with an agonist (group A). DESIGN: Prospective randomized study. SETTING: University tertiary care Reproductive Endocrinology Unit. PATIENTS: Women with clomiphene citrate-resistant PCOS. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, E2, and inhibin levels, follicular growth. RESULTS: In group A, FSH levels decreased significantly from 7.3 mIU/mL (conversion factor to SI unit, 1.00) at day -5 to 5.9 mIU/mL at day 0 (day that hCG was administered) despite a constant dose, whereas they remained at a level of 7.4 mIU/mL in group B. The rate of monofollicular growth was significantly higher in group A (80%) than in group B (22%). No significant differences in E2 levels or inhibin levels were found between the groups. CONCLUSIONS: The absence of a decrease of FSH during GnRH-a treatment in association with a lower rate of monofollicular growth suggests that endogenous feedback during low-dose step-up ovulation induction in PCOS plays an important role. The absence of this feedback mechanism in the presence of normal inhibin levels suggests that negative feedback control by inhibin during follicular stimulation is minimal.

The GnRH challenge test: a quantitative measure of pituitary desensitization during GnRH agonist administration.

OBJECTIVE: The use of GnRH agonists for desensitization of the pituitary is widespread in gynaecological practice. For indications such as contraception and treatment of uterine leiomyomata partial desensitization may suffice. With respect to partial desensitization of the pituitary we have addressed three basic questions: (1) Is the degree of pituitary desensitization dependent on the dose of agonist used? (2) What is the optimal way to measure the degree of pituitary desensitization? (3) Is it possible to create a standard to express the degree of pituitary desensitization? DESIGN AND PATIENTS: Twenty-four women were randomized into 4 groups of 6 women. To achieve pituitary desensitization, the groups received 0.1, 0.25, 0.5 and 1.0 microgram/min GnRH respectively, for 6 weeks. MEASUREMENTS: Pituitary desensitization was measured by gonadotrophin levels and responses to a 100-micrograms bolus of GnRH and an oestradiol benzoate challenge-test. RESULTS: The level of LH and the responses of LH and FSH to the GnRH challenge showed significant dose-dependent suppression. Multiple regression indicated the LH response to the GnRH challenge was the best way to measure pituitary desensitization. From the LH responses to the GnRH-challenge a 'standard curve' was established for the assessment of the degree of pituitary desensitization. CONCLUSION: The LH response to the GnRH challenge test is the best available measure of pituitary desensitization during GnRH agonist treatment.

Short term pituitary desensitization: effects of different doses of the gonadotrophin-releasing hormone agonist triptorelin.

Gonadotrophin-releasing hormone agonists (GnRHa) are used to prevent inadequate luteinizing hormone (LH) surges during ovarian stimulation in in-vitro fertilization (IVF). Dose studies for optimal dose assessment are lacking and unfavourable effects of the agonist on granulosa function and oocyte quality have been suggested. This double-blind randomized study was undertaken to assess the effect of four different doses to triptorelin on the degree of desensitization of the pituitary, and the recovery time of pituitary function after withdrawal of the agonist. Sixty-six regularly cycling women were allocated to a treatment group (n = 32) and a control group (n = 34). To assess the degree of pituitary desensitization and restoration in the treatment group, gonadotrophin releasing hormone (GnRH) challenges (100 microg, i.v.) were performed during treatment (day 17), and 2, 4 and 6 days after discontinuation of treatment. At the same time blood samples for oestradiol and triptorelin concentrations were drawn. In the control group a GnRH test was performed on day 2 of the menstrual cycle. Both pituitary desensitization during and pituitary recovery after agonist treatment, expressed as the LH response to exogenous GnRH, appeared to be dose dependent. As the use of reduced dosages still offers a considerable degree of pituitary suppression, studies on dose adjustments in the use of triptorelin, in ovarian stimulation in IVF are warranted.

Quantitative MRI of uterine leiomyomas during triptorelin treatment: reproducibility of volume assessment and predictability of treatment response.

Magnetic resonance (MR) imaging is increasingly applied for the quantitative evaluation of uterine leiomyomas. MR is thought to be more accurate in comparison to ultrasound (US) techniques. MR signal intensity (SI) may prove to be predictive of myoma response to GnRH agonist treatment. This study aimed to evaluate the precision of uterine volume assessment by a parallel planimetric MR method and the accuracy of the ellipsoid formula based calculations from MR and US images. It was also attempted to analyze the precision of MR leiomyoma volume measurements and examine the relation between pretreatment myoma SI patterns and the response to agonist therapy. Twenty-seven women with a myomatous uterus were scanned three times during GnRH agonist treatment for 6 months. T1- and T2-weighted, as well as T1 contrast-enhanced sequences of the uterus were obtained in the transverse and sagittal plane. Abdominal US of the uterus was performed with a conventional sector scanner. By the use of a software system for analysis of three-dimensional images obtained by MR, uterine volume was measured by a parallel planimetric method (MR-ROI) as well as the use of the ellipsoid formula (MR-ELL). Myoma volume was assessed by the MR-ROI method. SI of the myomas was estimated from selected tissue samples as well as from the integral myoma region of interest. By abdominal US, volume was assessed by the ellipsoid equation (US-ELL). Within- and between-observer and method reliability (Rw/Rb) was calculated from mean squares obtained by analysis of variance. For uterine volume assessment, reliability between observers and between methods when the MR-ROI and MR-ELL methods were analyzed was excellent. For the US-ELL measurements, the between-observer reliability was limited. Moreover, the reliability of the US-ELL was low when the MR-ROI method was used as the standard. Myoma volume assessment with the MR-ROI method showed high between-observer and between-method agreement. The myoma/fat SI ratio and the mean SI coefficient of variation failed to show a correlation with the degree of response to triptorelin treatment of individual myomas. In MR uterine volume assessment the MR-ELL method is very accurate compared with the more complicated MR-ROI method. The agreement between MR and US is limited. Therefore, the ellipsoid method on MR images is to be regarded as the method of choice for quantitative assessment of uterine volume response to hormonal treatment. Myoma SI patterns were shown to be of no value in the response prediction of myomas to treatment with GnRH agonists.

The probability of pregnancy after embryo transfer is affected by the age of the patient, cause of infertility, number of embryos transferred and the average morphology score, as revealed by multiple logistic regression analysis.

Because the process of conception is affected by many variables, a multiple logistic regression analysis was performed to assess (i) the impact and relative weight of both patient and embryo variables and (ii) their possible effects on the probability of a vital pregnancy after embryo transfer. A statistical model was constructed predicting the probability of pregnancy after embryo transfer. The variables that contributed significantly to the predictive value of the model were the age of the patient, the cause of infertility, the number of embryos transferred and the average morphology score of the transferred embryos. Embryo variables appeared to have a significant but modest value in predicting the probability of pregnancy after embryo transfer. Other variables, such as the thickness of the endometrium, were found to have no prognostic value. Moreover, we found that their effect could be explained by the variables already included in the model.

Exploring the recovery phase after treatment with a gonadotrophin-releasing hormone-agonist for ovulation induction in polycystic ovary syndrome: three pilot trials.

OBJECTIVE: Guided by the favorable results of pulsatile gonadotrophin-releasing hormone (GnRH) in the recovery phase after GnRH agonist (GnRH-a) in PCOS, two hypotheses concerning the recovery phase were tested: (1) The resistance to clomiphene citrate will be broken in the recovery phase. (2) Stimulation with (i) a fixed dose of follicle stimulating hormone (FSH) or (ii) with the GnRH-a itself is equally effective in inducing ovulation as pulsatile GnRH. DESIGN: After discontinuation of a 17-21 days GnRH-a treatment, ovulation induction was attempted with clomiphene citrate (CC) or with a fixed dose of FSH or with GnRH-a itself in three separate pilot trials. A previously reported group of 12 patients, treated with pulsatile GnRH in the recovery phase served as control. PATIENTS: Three groups of six patients having PCOS. The group treated with CC was a selected CC-resistant group. RESULTS: No CC-treated patient ovulated. After FSH stimulation two patients ovulated, and one patient ovulated on stimulation with a low dose of the GnRH-a. Endocrine observations in the recovery phase showed an early rise of FSH as compared to the rise of LH and androgens. CONCLUSION: This study could not demonstrate any effect of the recovery phase with respect to facilitation of follicular growth in PCOS. Both tested hypotheses were rejected: (1) The resistance to CC appeared not to be broken by the GnRH-a treatment and (2) subsequent stimulation with FSH or with the GnRH-a itself were not as effective as stimulation with pulsatile GnRH. An extensive further study of the mentioned modalities did not seem feasible.

Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients.

The aim of this study was to assess the possibility that ovulation might be induced in seven amenorrheic hyperprolactinemic women by treatment with naltrexone (50 mg/day) for 4-5 weeks. None of the patients ovulated. Increases in LH levels, LH area under the curve, FSH levels, and the number of LH pulses per 6 h were observed in all patients, 2-8 h after the beginning of naltrexone administration. However, all of these parameters had returned to the pretreatment range on day 7. The LH area under the curve, LH levels, FSH levels, and the number of LH pulses per 6 h on day 1 were significantly higher compared to the values on either day 0 (basal levels) or day 7. These data show that long term opioid receptor blockade induces desensitization of the hypothalamic-pituitary unit for the effects of opioid receptor blockade. Due to the induced desensitization, naltrexone is not an effective drug for ovulation induction in hyperprolactinemic patients.

Follicle stimulating hormone (FSH) dynamics of low dose step-up ovulation induction with FSH in patients with polycystic ovary syndrome.

Pharmacodynamics of follicle stimulating hormone (FSH) were studied during low dose step-up gonadotrophin therapy in patients with polycystic ovary syndrome (PCOS). To obtain stable levels of FSH, Metrodin was administered i.v. By making daily determinations, the FSH concentration was slowly increased in steps of approximately 1 IU/l. A total of 16 patients were treated for a maximum of three treatment cycles. Out of 38 treatment cycles, in 26 (68%) a single dominant follicle developed. The overall ovulation rate was 78%. FSH concentrations were evaluated with regard to intra- and interindividual variability of the FSH threshold and with regard to the relationship between FSH concentrations, FSH dose and treatment outcome. The high variability of the FSH threshold, ranging from 5.7 to 12 IU/l, appeared to be mainly a function of inter-individual variability. Higher FSH concentrations were associated with multifollicular growth as opposed to monofollicular growth, whereas the increases in concentration from a substimulating to a stimulating level were not. Multifollicular growth might thus be associated with a higher elevation of FSH concentration above the threshold. Different patterns of FSH concentration in the course of the growth phase of the dominant follicle in mono- compared to multifollicular cycles suggested a difference in the effect of endogenous FSH on the plasma concentration. Endogenous feedback on FSH release may therefore still play a role during treatment with exogenous FSH.

Pulsatile gonadotrophin releasing hormone stimulation after medium-term pituitary suppression in polycystic ovary syndrome.

Ovulation induction in the polycystic ovary syndrome with pulsatile gonadotrophin releasing hormone (GnRH) in the recovery phase after treatment with a GnRH agonist (GnRHa) during 6-8 weeks has been reported to improve ovulation and pregnancy rates and to normalize follicular phase luteinizing hormone (LH) levels. We studied the results of stimulation with pulsatile GnRH after a shorter 'medium-term' period of 3 weeks of treatment with a GnRHa by comparing a cycle without GnRHa pre-treatment with a cycle with GnRHa (post-GnRHa) pre-treatment in 12 patients. We could prove no significant clinical improvement in post-GnRHa cycles. Ovulation rates were similar. However, in the post-GnRHa cycles, two ongoing pregnancies were observed versus one spontaneous abortion in the cycles without GnRHa pre-treatment. This observation might be explained by the fact that follicular phase LH levels in post-GnRHa cycles were significantly decreased.

The relationship between follicle-stimulating hormone dose and level and its relevance for ovulation induction with adjuvant gonadotropin-releasing hormone-agonist treatment.

OBJECTIVE: To investigate the effect of a GnRH agonist (GnRH-a) on the FSH threshold level and the relationship between the FSH dose and the FSH level of patients suffering from polycystic ovarian syndrome (PCOS). DESIGN: The stimulation with low-dose FSH in PCOS (group 1) was compared with the subsequently performed stimulation with low-dose FSH combined with GnRH-a in another group of patients suffering from the same syndrome (group 2). SETTING: Specialist Reproductive Endocrine Unit. PATIENTS: Suffering from clomiphene citrate-resistant PCOS. MAIN OUTCOME MEASURES: The FSH threshold level for ongoing follicular growth and the relationship between dose and level of FSH. RESULTS: In 15 patients in group 1 and in 13 patients in group 2, respectively, 39 and 32 stimulation cycles were performed. Below and above threshold values of FSH of group 1 and 2 did not differ significantly. For the equation stable level of FSH (Y mIU/mL) = A X infusion rate of FSH (X IU/24 h) + basal level of FSH (B mIU/mL), the median A of group 1 was 0.027 and A of group 2 was 0.055 (significant difference). CONCLUSIONS: In PCOS, a change of the FSH threshold level for ongoing follicular growth induced by the GnRH-a could neither be proven nor ruled out. The use of a GnRH-a resulted in larger FSH level increases per IU/24 h of FSH administered and might therefore interfere with the effect of low-dose FSH treatment.

The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome.

The objective of this study was to investigate whether the incidence of monofollicular growth during stimulation with low dose follicle stimulating hormone (FSH) changes when adjuvant gonadotrophin-releasing hormone agonist (GnRHa) pre-treatment is administered in polycystic ovary syndrome (PCOS). One group of patients (group 1) suffering from clomiphene resistant PCOS was stimulated with low dose FSH. The results were compared with those from another group of similar patients (group 2) subsequently stimulated with low dose FSH combined with GnRHa. In group 1 15 patients had 39 stimulation cycles performed; in group 2 13 patients had 33 stimulation cycles performed. In group 1 44% of cycles were monofollicular, whilst the corresponding figure in group 2 was 14% (P = 0.04). Evidence was found for postponed atresia in group 2. In both groups 1 and 2 inter-individual and intra-individual variability of the FSH dose inducing follicular growth were observed. We concluded that during the use of GnRHa, stimulation with low dose FSH less frequently resulted in monofollicular growth, possibly due to postponed atresia. Furthermore, the use of GnRHa does not abolish the inter- and intra-individual variability of the FSH dose inducing ongoing follicular growth.

The reliability, acceptability and applications of basal body temperature (BBT) records in the diagnosis and treatment of infertility.

The possibilities and limitations of basal body temperature (BBT) records as an adjunct in the management of infertility were re-evaluated. To assess its accuracy as an index of ovulation, 172 charts were analyzed by three different physicians. While the average true positive rate was 90%, the false negative rate was only 2%. The remaining graphs (8%) were classified as non-interpretable, probably reflecting measurement problems. Retrospective assessment of 210 biphasic records showed the thermal nadir to occur within 1 day of the urinary luteinizing hormone (LH) surge in 75% of the cases, and in 90% when 2 days where considered. This confirms BBT as a relatively accurate guide for retrospective identification of the periovulatory period. Moreover, results of a study conducted to investigate how patients experienced daily recording of BBT graphs suggest that the method is well accepted by a high proportion of women. From all these it appears that there are many indications where BBT graphs can still be applied. Development of new electronic devices may further improve the reliability, acceptability and applications of the BBT records in the fertility investigation.

Conventional versus slug CO2 loading and the control of breathing in anaesthetized cats.

1. Conventional inspiratory CO2 loading (CCL) is accomplished by having the subject breathe CO2-enriched air. An alternative method of CO2 loading is to inject a bolus of CO2 at the start of each inspiration into the inspired air: slug CO2 loading (SCL). During SCL PCO2 in the conducting airways declines quickly towards 0 kPa in the course of inspiration, whereas PCO2 remains at a constant value equal to the inspiratory PCO2 during CCL. Therefore, CCL and SCL may stimulate the respiratory controller differently. 2. We compared the ventilatory responses to SCL and CCL in fourteen anaesthetized, spontaneously breathing cats. In each experimental animal we applied, in a fixed randomized order, five CCL experiments (fractional inspiratory CO2, FI,CO2 = 0.01-0.05), six SCL experiments (slugs of 50% CO2 ranging from 0.5 to 6 ml) and three control experiments in which no CO2 was loaded. Partial pressure of CO2 in arterial blood was determined from small blood samples (0.14 ml). In three cats we repeated the experiments after bilateral transection of the cervical vagi to evaluate the contribution of vagal receptors to the responses observed. 3. The average slope of the CO2 response curves for SCL was 2 times steeper than that for CCL (P less than 0.01). The larger minute ventilation for SCL for a particular value of arterial PCO2 (Pa,CO2) could not be attributed exclusively to the increased breathing frequency or the increased tidal volume (P greater than 0.10). Further, mean inspiratory flow (VI) was larger for SCL than for CCL at the same Pa,CO2 (P less than 0.01), also because the ratio TI/TE (inspiratory duration/expiratory duration) was smaller (P less than 0.01). After vagotomy the difference between SCL and CCL response curves was much reduced. 4. It is concluded that SCL and CCL affect the respiratory controller in a different way causing differences in breathing pattern and CO2 sensitivity between the two methods. Evidently, a mechanism based on CO2 sensitivity of pulmonary receptors is involved in the responses observed.