Mean PRL Research Articles

Identification of somatotrophs, mammosomatotrophs, and mammotrophs by sandwich cell immunoblot assay in GH-secreting adenomas and prolactinomas: correlations between the proportions of hormone secreting cells and tumor size.

Sandwich cell immunoblot assay(sandwich CIBA) was used to identify somatotrophs (GH cells), mammosomatotrophs, and mammotrophs (PRL cells) in pituitary tumors obtained from patients with GH-secreting adenomas and prolactinomas. The mean serum GH level was 177.6 ng/ml in 19 patients with GH-secreting adenomas and the mean PRL level was 2,129 ng/ml in 9 patients with prolactinomas. GH-secreting adenomas could be divided into 3 groups according to the proportions of the cell types. The GH cell dominant type had more than 70% GH cells. The mammosomatotroph cell dominant type had more than 80% mammosomatotrophs. The non-dominant type had no dominant cell type. There was a good correlation (r2=0.804) between serum GH levels and tumor size in patients with the GH cell dominant type (n=10). The nondominant type (n=8) had a low serum level of GH except for one tumor. The mammosomatotroph cell dominant type (n=1) showed high serum levels of both GH and PRL. All prolactinomas had a predominance of PRL cells. Sandwich CIBA is a simple method for detecting GH cells, mammosomatotrophs, and PRL cells, and useful for classification for GH-secreting adenomas.

Leptin116–130 Stimulates Prolactin and Luteinizing Hormone Secretion in Fasted Adult Male Rats

Leptin is a hormone secreted by adipocytes with an important role in the control of feeding behavior and neuroendocrine function. Leptin stimulates in vivo LH secretion in fasted female rats and in vitro PRL secretion. Recent data indicate that leptin_116–130, an active fragment of the native molecule, exerts effects similar to those of the native peptide on body weight and food intake. The present study was carried out to determine whether this fragment is also able to stimulate LH and PRL secretion. Adult male rats fasted for 5 days were injected with saline or leptin_116–130 (15 µg i.c.v.) and LH and PRL concentrations were measured thereafter at 15-min intervals during a 150-min period. Administration of leptin_116–130 increased the frequency of LH pulses (2.0 ± 0.26 vs. 1.20 ± 0.37/150 min; p ≤ 0.05), mean LH levels (0.24 ± 0.06 vs. 0.07 ± 0.03 ng/ml; p ≤ 0.05), LH pulse amplitude (0.33 ± 0.10 vs. 0.10 ± 0.05 ng/ml; p ≤ 0.05) and the net LH secretion estimated by area under curve (AUC: 36 ± 8.5 vs. 9 ± 3.9 ng/ml/150 min; p ≤ 0.01). In addition leptin_116–130 increased the frequency of PRL pulses (2.83 ± 0.48 vs. 1.33 ± 0.21/150 min; p ≤ 0.05), trough PRL levels (5.71 ± 0.99 vs. 2.72 ± 0.32 ng/ml; p ≤ 0.01), mean PRL levels (13.02 ± 0.92 vs. 5.89 ± 0.51 ng/ml; p ≤ 0.01) and net PRL secretion (AUC: 1,625 ± 171 vs. 658 ± 46 ng/ml/150 min; p ≤ 0.05). In conclusion, these data show that leptin_116–130 stimulates LH and PRL secretion in fasted adult male rats.

Pituitary adenomas in acromegaly: Comparison of different adenoma types with clinical data.

Adenoma tissues from 309 patients with active acromegaly was examined by routine light microscopy and immunohistochemistry, and selectively by electron microscopy. All adenomas were immunoreactive for growth hormone. Eighty-seven adenomas were monohormonal (28%), 58 were bihormonal (immunoreactive for growth hormone and prolactin) (19%), and 157 adenomas were plurihormonal (51%), with positivity for glyco-proteins and/or their α-subunit as well. The mean tumor size was significantly greater in monohormonal adenomas than in other adenoma types. There was no difference in invasiveness among the various adenoma types. Younger patients showed invasive tumor growth more often. Patients with densely granulated GH cell adenomas had a significantly longer duration of symptoms compared to patients with other adenoma types. More than half of the patients with sparsely granulated GH cell adenomas had a duration of less than 5 yr. There was no correlation between duration of symptoms and tumor size. The preoperative mean GH level was significantly higher in patients with sparsely granulated GH cell adenomas than in those with mixed GH/PRL cell adenomas. The preoperative mean PRL level was significantly higher in patients with bihormonal adenomas than in those with plurihormonal adenomas. There was an inverse correlation between age and preoperative GH and PRL levels. No linear correlation was found between preoperative basal GH and PRL levels. Monohormonal adenomas presented more often with suprasellar and/or parasellar extension than other adenoma types. Our data suggest a positive correlation between tumor extension and preoperative GH and PRL levels. Patients with plurihormonal adenomas were significantly older than patients with sparsely granulated GH cell adenomas and mixed GH/PRL cell adenomas. No significant difference was found between the various adenoma types and the extent of surgical removal, which depends on the degree of invasiveness, tumor size, and extrasellar tumor extension.

Folliculo-stellate Cells in Pituitary Adenomas of Patients with Acromegaly

Pituitary adenoma tissue from patients with acromegaly (n = 286) was obtained by surgery and examined for folliculo-stellate cells by immunostaining for S100 protein. The number of immunostained cells varied from one adenoma to another. A hundred and ninety-eight pituitary adenomas (69%) contained S100 protein positive cells corresponding to folliculo-stellate cells (FSC): in 100 cases (35%), only few sparse FSC were found, in 43 cases (15%) FSC were scattered throughout the adenoma, and in 55 cases (19%) there was an abundance of FSC. There were no significant differences regarding sex or age of the patients. The relative amount of FSC vaired among different adenoma types. Plurihormonal adenomas showed the highest FSC density, whereas the majority of monohormonal adenomas contained only few or no FSC. Patients with pituitary adenomas containing scattered FSC had a significantly higher preoperative mean GH level than patients with pituitary adenomas not having FSC. There was a negative correlation between the FSC density in adenoma tissue and the preoperative mean PRL level. There was no correlation between the tumour size and the amount of FSC. Our data indicate no effect of the duration of symptoms on the FSC density and do not suggest a correlation between FSC density and the percentage of a certain hormone-secreting cell type.

Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up.

In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma (15 macro- and 11 micro-adenomas) diagnosed at the age of 7-17 yr. All patients were first treated with bromocriptine (BRC) at doses ranging from 2.5-20 mg/day orally. BRC was discontinued for intolerance and/or resistance to the drug and was replaced by quinagolide (CV) at doses ranging from 0.075-0.6 mg/day or by cabergoline at doses ranging from 0.5-3.5 mg/week orally. Two patients received external conventional radiotherapy after surgery. In 7 prepubertal males and 6 females with macroprolactinoma, headache and/or visual defects were the first symptoms. All females presented with primary or secondary amenorrhea. Growth arrest was observed in a male patient with microadenoma, whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 12 patients (3 males and 9 females) and gynecomastia in 4 males. Mean serum PRL concentration (+/-SE) at the time of diagnosis was 1080 +/- 267 microg/L in patients with macroadenoma and 155 +/- 38 microg/L in patients with microadenoma. In 10 patients, BRC normalized PRL levels and caused variable, but significant, tumor shrinkage. CV normalized PRL concentrations and reduced tumor size in 5 patients. Cabergoline normalized PRL concentrations in 7 of 10 patients resistant to CV. Pregnancy occurred in 2 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Only 4 patients are still moderately hyperprolactinemic. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in 7 patients, 5 of whom underwent surgery. Four patients became GH deficient in adult age. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

Enhanced slow wave sleep in patients with prolactinoma.

Bidirectional interactions between nocturnal hormone secretion and sleep regulation are well established. In particular, a link between PRL and rapid eye movement (REM) sleep has been hypothesized. Short-term administration of PRL and even long-term hyperprolactinemia in animals increases REM sleep. Furthermore, sleep disorders are frequent symptoms in patients with endocrine diseases. We compared the sleep electroencephalogram of seven drug-free patients with prolactinoma (mean PRL levels 1450 +/- 1810 ng/mL; range between 146 and 5106 ng/mL) with that of matched controls. The patients had secondary hypogonadism but no other endocrine abnormalities. They spent more time in slow wave sleep than the controls (79.4 +/- 54.4 min in patients vs. 36.6 +/- 23.5 min in controls, P < 0.05). REM sleep variables did not differ between the samples. Our data suggest that chronic excessive enhancement of PRL levels exerts influences on the sleep electroencephalogram in humans. Our result, which seems to be in contrast to the enhanced REM sleep under hyperprolactinemia in rats, leads to the hypothesis that both slow wave sleep and REM sleep can be stimulated by PRL. These findings are in accordance with reports of good sleep quality in patients with prolactinoma, which is in contrast to that of patients with other endocrine diseases.

Prolactin pulsatile characteristics in postmenopausal women.

Pulsatile PRL secretion undergoes diurnal variation, with maximal PRL release in the evening during sleep in both women and men. However, the impact of the menopause on PRL pulsatile dynamics are largely unknown. To characterize diurnal PRL pulsatile secretion in postmenopausal women, we performed frequent venous sampling over 24 h every 10 min for serum PRL in 7 postmenopausal women (age, 56 +/- 4 yr) and in 2 control groups, 8 men (age, 25 +/- 8 yr) and 22 cycling women (age, 28 +/- 5 yr), at 3 phases of the menstrual cycle. Standard TRH tests (200 microg, i.v.) were administered at 0900 h after completion of the 24-h sampling, and PRL levels were then obtained at 0, 10, 20, 30, and 60 min in all subjects. PRL pulse characteristics were similar between the postmenopausal women and men. Mean serum PRL levels and PRL pulse frequency were significantly higher in the cycling women than in either postmenopausal women or men over 24 h and during either the day or night periods. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to those during the day in all groups. Pulse amplitude was higher during the night vs. the day in all groups and was highest in the cycling women. PRL responses to TRH administration were greatest in cycling women. These data demonstrate that PRL pulse dynamics are significantly different between postmenopausal women and cycling women, and endogenous estrogen levels may have an important role in this difference. Pulsatile PRL secretion is similar between postmenopausal women and men, suggesting that estrogen levels modulate PRL dynamics across genders.

A novel method of ovarian stimulation for in vitro fertilization: bromocriptine-rebound method

To examine whether a new method of ovarian stimulation, bromocriptine-rebound method, improves IVF outcomes compared with the conventional long protocol of GnRH agonist and hMG regimen. A prospective clinical trial. In vitro fertilization program at a university hospital. Endocrine-normal ovulatory women less than 40 years of age, with normal male partners and previous failed IVF-ET using long protocol. Patients were assigned to either bromocriptine-rebound method (group 1) or long protocol (group 2). The bromocriptine-rebound method was the same as the long protocol, except that bromocriptine was administered daily from day 4 of the preceding cycle until 7 days before hMG stimulation. The number of cleaved and morphologically superior embryos, pregnancy rate per oocyte pick-up, and serum PRL concentrations during administrations of hMG. Significantly more embryos were cleaved and had superior morphology in group 1 than group 2. Clinical and ongoing pregnancy rates per oocyte pick-up were significantly higher in group 1 (42% and 38%, respectively) than group 2 (24% and 21%, respectively). The mean PRL concentration was significantly higher in the group 1 than group 2. A significant correlation between the number of superior embryos and PRL concentrations was observed in group 1, but not in group 2. The bromocriptine-rebound method enhanced embryonic development, resulting in an increased pregnancy rate compared with the long protocol.

The Effect of Routine Breast Examination on Serum Prolactin Levels

Objective To evaluate the effect of a routine breast examination on serum PRL levels. Design Prospective clinical study. Setting University-based reproductive endocrinology unit. Patients Eleven nonlactating, euprolactinemic women of reproductive age with a history of regular menstrual cycles and currently taking no medications. Interventions Breast examination using standard technique. Main Outcome Measure Changes in serum PRL levels after breast examination. Results Baseline PRL levels ranged from 3.64 to 19.23 ng/mL (mean 7.17 ng/mL; conversion factor to SI unit, 1.00). There were no significant increases in PRL levels after breast examination, with mean PRL levels after 15, 30, and 45 minutes of 6.59, 6.84, and 6.45 ng/mL, respectively. Conclusion Routine breast examination does not alter acutely serum PRL levels in normal women.

The effect of routine breast examination on serum prolactin levels

To evaluate the effect of a routine breast examination on serum PRL levels. Prospective clinical study. University-based reproductive endocrinology unit. Eleven nonlactating, euprolactinemic women of reproductive age with a history of regular menstrual cycles and currently taking no medications. Breast examination using standard technique. Changes in serum PRL levels after breast examination. Baseline PRL levels ranged from 3.64 to 19.23 ng/mL (mean 7.17 ng/mL; conversion factor to SI unit, 1.00). There were no significant increases in PRL levels after breast examination, with mean PRL levels after 15, 30, and 45 minutes of 6.59, 6.84, and 6.45 ng/mL, respectively. Routine breast examination does not alter acutely serum PRL levels in normal women.

Naloxone evokes a nutritionally dependent LH response in post partum beef cows but not in mid-luteal phase maiden heifers

AbstractData from two experiments are reported which test the hypothesis that nutrient and/or dry-matter intake and body condition may interact to modify hypothalamic opioidergic activity and thus influence the pulsatile release of LH during the early post-partum period and during the oestrous cycle. Experiment 1 involved 16 multiparous, twin-suckling beef cows, and was a 2 × 2 × 2 factorial design in which the factors were level of post-partum energy intake (80 v. 130 M) metabolizable energy (ME) per day), the digestible undegradable protein (DUP) content of the post-partum diet (14 v. 31 g/kg dry matter), and treatment with either 200 mg or 400 mg naloxone hydrochloride. Blood samples were collected at 15-min intervals for 4h at weeks 4 and 7 post partum. Naloxone was administered intravenously after the eighth sample. Experiment 2 involved 16 cyclic maiden heifers and was also arranged in a factorial manner, with two levels of body condition at the start of the experimental period (2·50 and 3·16 units) and two levels of energy intake thereafter (40 and 80 MJ ME per day). Seven blood samples were collected at 15-min intervals on 4 days consecutively during the mid-luteal phase of the oestrous cycle. On the first 2 of these 4 days naloxone was administered, whilst on the last 2 days a gonadotropin-releasing hormone agonist (buserelin; GnRH) was administered, both after the fourth sample. Plasma from both experiments was assayed for LH and prolactin (Prl).In experiment 1, cows on 130 MJ ME per day returned to oestrus and ovulated earlier than cows on 80 MJ ME per day (44·5 v. 55·0 days; s.e.d. = 3·93; P &lt; 0·05). At week 4 post partum the proportional increase in plasma LH following naloxone challenge was greater for cows on 130 MJ ME per day than cows on 80 MJ ME per day (1·38 v. 1·12; P &lt; 0·05), but the converse was true at week 7 (1·15 v. 1·68; P &lt; 0·05). Cows on the high DUP diet required a higher dose of naloxone to elicit an LH response. Few heifers in experiment 2 exhibited an LH response to naloxone. In contrast, there were significant dietary treatment effects on the LH response to GnRH (P &lt; 0·01). Relatively thin heifers on 40 MJ ME per day exhibited the lowest proportional increases in plasma LH to GnRH challenge, whereas heifers on 80 MJ ME per day and given the higher dose of GnRH produced the greatest plasma LH responses. Mean Prl concentrations before and after feeding in experiment 2 were respectively 13·2 and 10·2 ng/l (P &lt; 0·01).Suckled cows given a high energy diet during the early post-partum period can overcome the opioid mediated block on LH release and resume oestrous cycles earlier than cows given a low energy diet. LH would appear to be inhibited by a non-opioid mechanism in mid-luteal phase heifers. Total pituitary reserves ofLH may be influenced by the animals nutritional status.

Acromegaly

This prospective study defines the clinical and biochemical features of acromegaly in a large cohort of patients. There was no difference in sex distribution, and for men and women the mean ages at diagnosis (40 +/- 12 and 40 +/- 14 yr, respectively) were similar. Nearly three-quarters of patients were overweight and some 12% severely overweight; the frequency and severity of obesity also was not different between the sexes. Half of patients were hypertensive or were taking anti-hypertensive drugs. Neither GH nor insulin levels were significantly different between normotensive and hypertensive patients. Acral growth and facial coarsening, soft tissue swelling, and excessive perspiration were present in the majority (98%) of patients. Mean serum GH, Sm-C, and PRL levels did not differ between the sexes. Sm-C levels correlated with mean GH concentration (r = 0.31, p < 0.001), both variables inversely related to age. With each decade of life, mean GH and Sm-C levels declined by 7.6 +/- 0.2 ng/mL and 0.5 +/- 0.2 U/mL, respectively. Impaired glucose tolerance was diagnosed in 36% and frank diabetes mellitus in 30% of patients. Hyperprolactinemia was noted in 18% of patients. Galactorrhea was noted in 43 (9%) patients, most of whom were female; the mean GH levels of patients with galactorrhea (60.1 +/- 13 ng/mL) were higher than those of patients without (35.4 +/- 2.6 ng/mL, p = 0.02). Acromegaly appears to afflict men and women equally with a preponderance of presentation in the fourth decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Amplitude suppression of the pulsatile mode of immunoradiometric luteinizing hormone release in fasting-induced hypoandrogenemia in normal men.

In the male rodent and primate, fasting or severe caloric restriction significantly decreases serum testosterone concentrations, putatively via inducing secondary hypogonadotrophism. To clarify this presumptive pathophysiology, we have used: 1) a high sensitivity immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay of LH; 2) blood sampling every 5 min for 24 h basally and every 10 min for 3 h after GnRH injection before and after a 5-day (water only) fast in eight healthy young men; and 3) deconvolution analysis to evaluate in vivo LH secretory burst frequency, amplitude, duration, and mass, and LH half-life simultaneously. We documented a 50% fall in serum total and free testosterone concentrations, and a 30% decrease in 24-h mean serum LH concentrations (viz., fed 3.0 +/- 0.47 vs. fasted 2.1 +/- 0.39 U/L, P = 0.043). Deconvolution analysis revealed preservation of LH secretory pulse frequency (fed 12.9 +/- 0.48 vs. fasted 12.6 +/- 0.78 secretory bursts/day, P = NS) during fasting-induced hypogonadotropism. The duration of computer-resolved LH secretory bursts, the interburst interval, and the calculated endogenous half-life of LH also did not change, whereas LH secretory burst mass declined significantly; viz. from 28 +/- 5 in the fed to 14 +/- 3.2 U/L of distribution volume/day in the fasted state (P = 0.034). In contrast, LH release after a 10 micrograms pulse of GnRH iv was enhanced during fasting in seven of the eight men. Fasting also decreased mean (24 h) serum TSH and PRL, increased cortisol, dehydroepiandrosterone sulfate and GH, and did not affect FSH concentrations or the radioiodinated albumen distribution space. In summary, in young men 5 days of nutrient deprivation selectively attenuates the mass of LH secreted per burst without altering LH secretory event frequency or LH half-life. We infer that decreased LH release per burst is due to decreased hypothalamic GnRH impulse strength, since LH release induced by a submaximally effective pulse of exogenous GnRH is amplified rather than attenuated.

Preclinical hypogonadism in genetic hemochromatosis in the early stage of the disease: evidence of hypothalamic dysfunction

We studied endocrine functions at baseline and after TRH and LHRH stimulation in a group of 7 young male patients with genetic hemochromatosis (HE) without liver damage (i.e. fibrosis and cirrhosis). In five patients endocrine re-evaluations after complete iron depletion was also performed. Mean basal testosterone (T), FSH, LH and PRL were significantly lower than in controls. Serum T increased normally after HCG stimulation. The normal or high increments of LH after LHRH stimulation suggest that secretion capacity of LH was intact and that hypothalamic dysfunction could be responsible for the preclinical gonadal deficiency found in our patients. The response of PRL to TRH indicates that secretion capacity of lactotrophs although present, was decreased and did not improve after phlebotomy therapy. After iron depletion the two patients with the lowest basal T levels showed the highest increments indicating that in the early stages of hypothalamic-pituitary damage gonadal dysfunction is still reversible in HE patients.

Robustness of the male lactotropic axis to the hyperprolactinemic stimulus of primary thyroidal failure.

Primary hypothyroidism is a presumptive proximate basis for increased serum PRL concentrations. However, most studies to date have been performed in females and do not address the possible effect of sex differences. In the present study we investigated the 24-h patterns of pulsatile PRL release in 10 hypothyroid men (24-h mean +/- SEM: total T4, 35 +/- 8 nmol/L; TSH, 55 +/- 10 mU/L) by sampling blood at 10-min intervals for 24 h. The study was repeated in 5 men, 5-7 months and again 14-36 months after treatment with levothyroxine. The control group consisted of 7 normal age-matched euthyroid men. The mean 24-h serum PRL concentration of 4.9 +/- 0.6 micrograms/L in 10 hypothyroid men was not significantly different from the value of 4.9 +/- 0.5 micrograms/L found in the normal group (P greater than 0.5). Pulsatile features of PRL release were evaluated by Cluster analysis, which revealed normal mean PRL peak frequency (12.6 +/- 0.7 vs 13.4 +/- 0.6 pulses/24 h; P greater than 0.5), maximal peak amplitude (6.1 +/- 0.7 vs. 6.7 +/- 0.6 micrograms/L; P greater than 0.5), peak increment (2.2 +/- 0.3 vs. 2.6 +/- 0.3 micrograms/L; P = 0.3), mean valley (4.2 +/- 0.6 vs. 4.4 +/- 0.4 micrograms/L; P greater than 0.5), and prepeak nadir (3.6 +/- 0.5 vs. 3.6 +/- 0.4 micrograms/L; P greater than 0.5) PRL concentrations. Five to 7 months of T4 therapy in 5 hypothyroid men caused significant decreases in the mean 24-h (2.9 +/- 0.5 vs. 6.1 +/- 1.2 micrograms/L; P less than 0.05), interpulse valley (2.5 +/- 0.4 vs. 5.2 +/- 1.1 micrograms/L; P less than 0.05), and prepeak nadir (2.3 +/- 0.3 vs. 4.6 +/- 1.0 micrograms/L; P less than 0.05) PRL concentrations. These values returned to normal after 14-36 months of treatment. Cosinor analysis revealed preserved circadian PRL rhythmicity during hypothyroidism, with a normal circadian mesor (mean), amplitude, and acrophase. In summary, we have demonstrated normal mean 24-h serum PRL concentrations as well as normal pulsatile and circadian patterns of PRL release in men with primary hypothyroidism. These results stand in contrast to previous reports of increased serum PRL concentrations observed predominantly in hypothyroid premenopausal women. The foregoing disparity suggests the possibility of a role for estrogen in enhancing the effect of hypothyroidism on PRL release.(ABSTRACT TRUNCATED AT 400 WORDS)

Preservation of Pulsatile Luteinizing Hormone Release during Postpartum Lactational Amenorrhea*

To evaluate the pulsatile mode of immunoactive LH release during physiological lactational amenorrhea, we withdrew blood samples at 10-min intervals for 24 h from breastfeeding women (n = 9) at both 3 weeks and 3 months postpartum. Nonlactating women (n = 7) were sampled similarly in the early follicular phase of the normal menstrual cycle. Objective LH pulse analysis revealed that the mean frequencies of pulsatile LH release were similar at both times postpartum and in menstruating young women. By 3 months postpartum, mean serum PRL concentrations had declined 50%, and serum LH peak areas doubled. In contrast, LH interpulse interval, peak duration, and maximal, incremental, and fractional LH pulse amplitude did not change significantly. When deconvolution analysis was used to assess pituitary responses to two pulses of exogenous GnRH at 3 months (vs. 3 weeks) postpartum, we found significant increases in maximal LH secretory rates and the total mass of LH secreted. There was no change in the duration or timing of the evoked LH secretory burst and/or the estimated half-life of endogenous LH. In summary, during lactational amenorrhea, pulsatile LH release occurs at a mean frequency no different from that in the normal early follicular phase. As hyperprolactinemia wanes, there is increased pituitary responsiveness to exogenously administered GnRH and a doubling of spontaneous serum LH concentration peak areas. Such amplitude changes are consistent with the hypothesis of increased endogenous GnRH drive (e.g. augmented GnRH secretion per burst and/or increased pituitary responsiveness to available GnRH) during recovery of the postpartum hypothalamopituitary-ovarian axis.

A Physiological Role for Sporadic Interruptions of the Dopaminergic Tone in the Genesis of Big Mass Prolactin Pulses

The present studies were designed to evaluate pulsatile PRL secretion after the establishment of either a continuous dopaminergic input or a complete blockade of the dopaminergic inhibitory tone. Adult female rats on estrus and male rats implanted with indwelling jugular cannulae were bled at 3-min intervals for a 3-h period. Bromocriptine (CB-154) and domperidone (DOM) were administered sc and iv, respectively. The administration protocol used for both treatments produced either a continuous dopaminergic input (CB-154 treatment) or a complete dopaminergic blockade (DOM treatment). Pulse analysis was performed on the data series using the algorithm Detect. In both estrous female and male rats, dopaminergic receptor activation by CB-154 reduced peak and trough values, pulse amplitude, area under the pulse, and mean PRL levels. In contrast, a complete dopamine (DA) receptor blockade by DOM increased these parameters. Domperidone treatment increased pulse frequency and reduced pulse interval and duration. Bromocriptine, however, differentially affected some pulsatility parameters depending on the sex of the rats. In females, CB-154 did not alter any of the qualitative parameters (frequency, pulse interval, and duration) of pulsatile PRL secretion. In contrast, in male rats the treatment reduced frequency and duration while increasing pulse interval. CB-154 reduced basal PRL levels in male rats, whereas in estrous females this parameter was not altered. PRL pulses were further evaluated by frequency distribution analysis, using the area under the pulses divided by the baseline to normalize the data due to treatment-induced differences in baselines. This calculation allows the estimation of the amount of hormone released per pulse over the baseline. In both estrous female and male rats, two classes of PRL pulses were identified. One class corresponded to pulses containing a small mass of hormone [small mass pulses (SM)], while the others were characterized by pulses containing a large mass of hormone [big mass pulses (BM)]. Interestingly, both the dopaminergic agonist CB-154 and the dopaminergic antagonist DOM dramatically diminished BM pulse incidence in both estrous female and male rats. In fact, BM pulses were practically absent in both experimental groups. To further substantiate this notion, animals of each experimental group were assigned to one of the following categories: animals depicting BM and SM pulses or rats presenting solely SM pulses.(ABSTRACT TRUNCATED AT 400 WORDS)

Prolactin Secretion and Corpus Luteum Function in Women with Luteal Phase Deficiency

Luteal phase deficiency (LPD) as a clinical infertility problem is considered to have a heterogeneous etiology. Hyperprolactinemia has long been considered a causative factor of LPD. In this context we investigated PRL secretion in 18 women with LPD. All of the subjects were infertile with 2 out of phase (greater than 2 days) endometrial biopsies; 10 of the women also had daily blood samples, this latter subgroup had significantly decreased integrated luteal phase progesterone (P) levels compared to normal women with in-phase biopsies. PRL secretion was investigated as follows: 1) daily blood levels; 2) pulsatile secretion patterns in 3 cycle phase [early follicular (12 h); late follicular (12 h); midluteal (24 h)], 3) LH-PRL coupling, and 4) nocturnal patterns. Results were compared to findings in 36 normal women. The mean daily levels of PRL over the menstrual cycle were not different between the two groups (LPD, 12.1 +/- 1.5; normal, 13.8 +/- 0.8 microgram/L; P = 0.3). There was no correlation between luteal phase integrated P and PRL levels for either group. There was a small difference in the PRL pulse amplitude in the early follicular phase between the LPD and normal women (2.6 +/- 0.3 vs. 5.5 +/- 1.3 micrograms/L; P less than 0.05). There were no significant differences between groups in PRL pulse frequency or mean level during the 12 or 24 h in any cycle phase. There was an equivalent amount of LH-PRL pulse coupling in both groups in all three cycle phases. Diurnal and nocturnal PRL secretion was studied by breaking the 24 h data (midluteal) into day (0700-2300 h) and night (2300-0700) segments. Mean PRL levels were higher at night in both groups (LPD, 15.9 vs. 12.6; normal, 15.4 vs. 9.3 micrograms/L; P less than 0.05), as expected. There were no differences in nocturnal PRL secretory patterns between the two groups. In summary, we have serious reservations whether abnormalities in PRL secretion are a common or integral part of the pathophysiology of LPD. From previous work we know these subtle abnormalities in PRL secretion in LPD are associated with definite abnormalities in gonadotropin secretion. We believe these gonadotropin abnormalities are probably more significant in terms of decreased P secretion.

Dose-Response Effects of Exogenous Pulsatile Human Corticotropin-Releasing Hormone on Adrenocorticotropin, Cortisol, and Gonadotropin Concentrations in Agonadal Women*

Acute activation of the hypothalamic-pituitary axis with CRH has been reported to suppress gonadotropin secretion in women of reproductive age. In this study we specifically examined the effects of increasing doses of human CRH (hCRH) on circulating concentrations of ACTH, cortisol, and gonadotropins in five agonadal women, aged 46-65 (mean, 51.2) yr. The subjects had undergone either natural menopause or surgical removal of their ovaries at least 1 yr before study. Each woman was studied on four separate occasions and received either saline or hCRH at a dose of 0.5, 1.0, or 2.0 micrograms/kg BW through an indwelling iv catheter in a randomized, single blind fashion. During each experiment, five sequential iv injections of the same dose of hCRH or saline were administered at 90-min intervals over an 8-h period, followed by a 10-micrograms iv bolus of GnRH to test for pituitary gonadotropin responsiveness. Blood samples for measurement of LH, FSH, PRL, ACTH, and cortisol were obtained at 15-min intervals through an indwelling iv in the contralateral arm. Episodic pulses of LH secretion were analyzed using the Cluster computer program. Transverse mean LH, FSH, and PRL levels did not change with increasing hCRH doses. Mean (+/- SEM) LH pulse frequency [saline, 5.2 +/- 0.4/8 h; hCRH, (0.5 micrograms/kg), 4.8 +/- 0.2; hCRH (1 microgram/kg), 5.2 +/- 0.2; hCRH (2 micrograms/kg), 5.4 +/- 0.2] and amplitude [saline, 14.4 +/- 4.2 IU/L; hCRH (0.5 microgram/kg), 14.0 +/- 2.4; hCRH (1 microgram/kg), 15.8 +/- 2.5; hCRH (2 micrograms/kg), 17.2 +/- 2.9] did not differ among groups. Although the transverse mean levels of ACTH [saline, 8.7 +/- 0.2 pmol/L; hCRH (0.5 microgram/kg), 12.4 +/- 0.3; hCRH (1 microgram/kg), 11.5 +/- 0.4; hCRH (2 micrograms/kg), 12.8 +/- 0.4] did not change with increasing doses of hCRH, the duration of cortisol peaks after hCRH was longer and accounted for the increased transverse mean at each dose [saline, 152.8 +/- 4.1 nmol/L; hCRH (0.5 microgram/kg), 265.4 +/- 10.5; hCRH (1 microgram/kg), 329.7 +/- 14.3; hCRH (2 micrograms/kg), 348.2 +/- 12.1]. These findings suggest that ever larger doses of pulsatile hCRH continue to increase adrenal output of cortisol secondary to more sustained ACTH responses. However, hCRH-induced acute hypercortisolism does not alter gonadotropin secretion in agonadal women.

Prolactin Secretion and Corpus Luteum Function in Women with Luteal Phase Deficiency*

Luteal phase deficiency (LPD) as a clinical infertility problem is considered to have a heterogeneous etiology. Hyperprolactinemia has long been considered a causative factor of LPD. In this context we investigated PRL secretion in 18 women with LPD. All of the subjects were infertile with 2 out of phase (greater than 2 days) endometrial biopsies; 10 of the women also had daily blood samples, this latter subgroup had significantly decreased integrated luteal phase progesterone (P) levels compared to normal women with in-phase biopsies. PRL secretion was investigated as follows: 1) daily blood levels; 2) pulsatile secretion patterns in 3 cycle phase [early follicular (12 h); late follicular (12 h); midluteal (24 h)], 3) LH-PRL coupling, and 4) nocturnal patterns. Results were compared to findings in 36 normal women. The mean daily levels of PRL over the menstrual cycle were not different between the two groups (LPD, 12.1 +/- 1.5; normal, 13.8 +/- 0.8 microgram/L; P = 0.3). There was no correlation between luteal phase integrated P and PRL levels for either group. There was a small difference in the PRL pulse amplitude in the early follicular phase between the LPD and normal women (2.6 +/- 0.3 vs. 5.5 +/- 1.3 micrograms/L; P less than 0.05). There were no significant differences between groups in PRL pulse frequency or mean level during the 12 or 24 h in any cycle phase. There was an equivalent amount of LH-PRL pulse coupling in both groups in all three cycle phases. Diurnal and nocturnal PRL secretion was studied by breaking the 24 h data (midluteal) into day (0700-2300 h) and night (2300-0700) segments. Mean PRL levels were higher at night in both groups (LPD, 15.9 vs. 12.6; normal, 15.4 vs. 9.3 micrograms/L; P less than 0.05), as expected. There were no differences in nocturnal PRL secretory patterns between the two groups. In summary, we have serious reservations whether abnormalities in PRL secretion are a common or integral part of the pathophysiology of LPD. From previous work we know these subtle abnormalities in PRL secretion in LPD are associated with definite abnormalities in gonadotropin secretion. We believe these gonadotropin abnormalities are probably more significant in terms of decreased P secretion.