Site of negative feedback action of estrogen on gonadotropin secretion in normal women

We have reported that iv administration of conjugated estrogens results in no significant change in the plasma LH-RH level during the negative feedback phase of LH, suggesting that estrogen does not suppress LH by decreasing hypothalamic LH-RH. To determine the site of estrogen action during the negative feedback phase, we studied the pituitary response to a small amount of LH-RH after estrogen administration in normal cyclic women in the mid-follicular phase. The pituitary responses to an iv bolus of 2.5 micrograms of synthetic LH-RH were evaluated by measuring serum LH and FSH 2 h before and 8 h after administration of 20 mg of conjugated estrogens (Premarin). The mean levels of serum LH and FSH were significantly (p less than 0.05) decreased 8 h after the injection. The peak responses of LH and FSH to LH-RH were also significantly (p less than 0.05) reduced after Premarin administration. These findings suggest that the negative feedback effect of estrogen on gonadotropin secretion is caused by its direct suppression on the pituitary response to LH-RH.     

Self-priming effect of LH-RH on pituitary gonadotropins in hyperprolactinemic women

To investigate how various concentrations of serum prolactin (PRL) influence the priming effect of luteinizing hormone releasing hormone (LH-RH) on the pituitary gland, 24 women with various blood PRL concentrations received intravenous injections of 100 micrograms of synthetic LH-RH twice at an interval of 60 minutes and their serum LH and follicle-stimulating hormone (FSH) were measured and analysed. In the follicular phase with a normal PRL concentration (PRL less than 20 ng/ml, n = 6), marked first peaks of the two hormones following the first LH-RH stimulation and enhanced second peaks after the second LH-RH administration were observed, indicating a typical priming effect of LH-RH on gonadotropins, though the second response of FSH was more moderate than that of LH. In hyperprolactinemia, in which the serum PRL concentration was higher than 70 ng/ml (n = 13), the basal concentration of gonadotropins was not significantly changed but the priming effect of LH-RH on LH and FSH was significantly decreased (p less than 0.01). No marked second peaks of LH and FSH were observed, suggesting an inhibitory effect of hyperprolactinemia on the second release of LH and FSH. In contrast, this effect was restored in a group of women whose serum PRL concentration was between 30 and 50 ng/ml (n = 5). Furthermore, enhanced second peaks of both LH and FSH were noted after successful bromocriptine therapy reduced hyperprolactinemia (PRL greater than 70 ng/ml) to less than 25 ng/ml (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of estrogens on renal responsiveness to parathyroid hormone in elderly female subjects

The effect of estrogens on the renal responsiveness to parathyroid hormone (PTH) was examined by PTH loading tests with synthetic human-PTH (1-34) in 8 normal elderly females (mean +/- SD age, 81.0 +/- 7.1 yr) before and after administration of estrogen (Premarin 1.25 mg/day for 4 weeks). Basal urinary adenosine cyclic 3', 5'-monophosphate (cAMP) excretion showed a tendency to increase after estrogen administration (5.47 +/- 1.68 vs 6.60 +/- 2.67 nmol/100 ml GFR) and the theoretical renal phosphorous threshold showed a tendency to decrease from 3.22 +/- 0.98 to 2.73 +/- 0.56 mg/dl. The blood ionized calcium concentration did not change after estrogen administration (4.44 +/- 0.16 vs 4.32 +/- 0.20 mg/dl) and serum phosphorous (P) decreased significantly (3.65 +/- 0.47 vs 3.01 +/- 0.42 mg/dl, p less than 0.05). There was no increase in mean serum immunoreactive PTH (0.34 +/- 0.10 vs 0.34 +/- 0.05 ngeq/ml). The urinary excretions of cAMP in response to PTH loading [100 U of human-PTH (1-34), intravenously] significantly (p less than 0.05) increased (94.8 +/- 57.0 vs 196.7 +/- 118.3 nmol/100 ml GFR/h) after estrogen administration. Moreover the changes in urinary excretion of cAMP (r = 0.698, p less than 0.01) and P (r = 0.555, p less than 0.05) induced by the PTH loading were positively correlated with serum estradiol in elderly females, assessed as groups before and after estrogen administration. These results suggest that estrogens may enhance the renal responsiveness to exogenous PTH administration.     

Estrogen modulates the action of nitric oxide in the medial preoptic area on luteinizing hormone and prolactin secretion

Several substances work as neuromediators of the estrogen direct and indirect (through glial cells or interneurons) action on luteinizing hormone- releasing hormone (LH-RH) neurons in medial basal hypothalamus and medial preoptic area (MPOA).Angiotensin II (AII) in the MPOA stimulates the LH and it inhibits PRL secretion in some situations. On the other hand, the effect of excitatory amino acids on LH and PRL surges during proestrus as well LH surge induced by steroids depend on nitric oxide (NO). In the present study we investigated the participation of MPOA endogenous NO on gonadotropin and PRL secretion mediated by estrogen and AII. Plasma LH, FSH and PRL was determinated in estrogen primed and unprimed ovariectomized Wistar rats that received microinjection of AII or saline into the MPOA, associated or not with a previous microinjection of an inhibitor for NOS. Our results show the following: 1 - there was no change in plasma FSH in estrogen- primed or unprimed ovarictomized related with microinjections of AII or NO antagonist in the MPOA; 2- the increase in LH secretion after ovariectomy depends on, at least in part, NO activity in the MPOA; 3- estrogen may have an indirect negative feedback action on LH-RH neurons in the MPOA through NO; 4- the stimulatory action of AII in the MPOA on LH secretion in ovariectomized rats treated with estrogen depends on NO; 5 - NO in the MPOA stimulates or inhibits PRL secretion depending on the absence or presence of estrogen, respectively; 6- the inhibitory action of AII into the MPOA on PRL secretion does not seem to depend on NO.     

Effects of in vivo pretreatment with D-Trp-6-LH-RH on prolactin and LH secretion by pituitary glands in vitro

In order to study a possible direct action of LH-RH analogs on the pituitary lactotrophs, we investigated the effect of long-term in vivo pretreatment with D-Trp-6-LH-RH on in vitro secretion of PRL and luteinizing hormone (LH) by the pituitary glands from male and female rats. In vivo pretreatment with D-Trp-6-LH-RH (50 micrograms/day, SC) for 15 days greatly reduced basal in vitro PRL release (p less than 0.01) in female, but not in male pituitary glands. TRH-stimulated PRL secretion was not affected by pretreatment with D-Trp-6-LH-RH in female rats, but was impaired in male pituitaries. Acute in vitro exposure to D-Trp-6-LH-RH did not modify PRL secretion by female pituitary glands pretreated in vivo with the analog. However, this same in vivo pretreatment greatly decreased PRL release from male pituitaries (p less than 0.01). Basal in vitro LH release by male pituitary glands was partially lowered by in vivo pretreatment with D-Trp-6-LH-RH, as compared to controls (p less than 0.01), while basal LH release in female pituitaries remained at control levels. Finally, D-Trp-6-LH-RH-induced stimulation of in vitro LH release was severely impaired in female pituitaries (p less than 0.01) but only slightly reduced in the males.     

An acute increase in serum prolactin does not modify gonadotropin release in female rats

Attempts were made to find out whether hyperprolactinemia has an effect on the hypothalamo-pituitary response to estrogen feedback and LHRH stimulation. Adult female rats of Wistar strain were ovariectomized and received subcutaneous injection of 20 micrograms estradiol benzoate (EB) 3-4 weeks later (day-0). A second injection of 20 micrograms EB, when administered at noon on day-3, induced a highly significant increase in serum LH (p less than 0.001 vs. basal values), but not FSH, estimated at 1800 h on the same day. This EB-promoted LH release was not altered by pretreatment with rat PRL (5 micrograms/day), which was administered subcutaneously daily in the morning (1100 h) between day-1 and day-3. No statistical difference in the serum LH concentration was found when compared with the values for the control animals pretreated with 0.9% saline alone. Serum gonadotropins 15 min after LHRH administration (100 ng/100 g BW) in 32-day-old female rats were not statistically different between the animals pretreated with 5 micrograms PRL, which was given subcutaneously daily (at 0800 h) for 3 days, and the controls pretreated with 0.9% saline. These results suggest that an acute increase in serum PRL may not exert a negative effect on the gonadotropin release induced by estrogen feedback and LHRH stimulation.     

Progesterone and LH variations after LH-RH administration in the luteal phase of the menstrual cycle

We have investigated the pituitary and luteal responses to LH-RH and their related changes. 11 normal women were studied during the luteal phase (day +4/+11). Blood samples were collected every 15 min for a basal period of 180 and 120 min after the intravenous administration of 25 micrograms of LH-RH. Progesterone (P) and LH were assayed by radioimmunoassay. Data were analyzed as maximum peak and its percent increase (delta max), integrated secretory area (ISA) and percent increase of ISA (delta A) in respect to basal values for both P and LH. LH-RH elicited a secretory response of both hormones in all cases. ISA of LH was significantly greater after LH-RH administration in respect to basal values (p less than 0.001) and delta max accounted to 475 +/- (SE) 36% of the basal concentration. Luteal responsiveness varied from about 115-130% to more marked increments. ISA of P differed from basal to stimulated conditions (p less than 0.05) and delta max was 166 +/- (SE) 14%. The analysis of temporal relationship between P and LH secretion showed that LH promptly rose after LH-RH, while the enhancement of P plasma levels occurred within 31 +/- 19 min after LH rise. Then P levels reached a plateau, values of which were statistically different from those observed before LH-RH administration. In two cases where luteal function was blunted or absent, in spite of marked increments of LH, P secretion did not occur. These data are consistent with the presence of close relationships between hypothalamic, pituitary and luteal functions and strengthen the contention about the usefulness of LH-RH during luteal phase for the lifespan and maintenance of corpus luteum.     

Influence of postmenopausal hormone replacement therapy on an estrogen metabolite biomarker of risk for breast cancer.

Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer. We studied 34 healthy postmenopausal women not on HRT and 19 women on HRT (Premarin 0.625 mg daily plus Provera, 2.5 mg daily, in women with a uterus and Premarin alone in women without a uterus); treatment duration ranged from 3 months to 15 years. We also studied four women with recently diagnosed, untreated breast cancer. The women with breast cancer showed a significantly lower 2-hydroxyestrone to 16 alpha-hydroxyestrone ratio than control women on HRT (1.35 +/- 0.13 vs. 2.71 +/- 0.84; p < 0.0001). There was no significant difference in the metabolite ratio between healthy women on HRT and women not on HRT (2.82 +/- 0.92 vs. 2.71 +/- 0.84). There was no significant difference between women receiving Premarin alone and women receiving Premarin plus Provera (2.46 +/- 0.84 vs. 3.13 +/- 0.90), and neither differed significantly from women not on HRT (2.71 +/- 0.84). The finding that the ratio of women on HRT was not decreased to or toward the ratio in women with breast cancer can be interpreted, we believe, as a suggestive item of biochemical evidence that HRT is not a risk for breast cancer.     

The renotropic effect of ovine luteinizing hormone on subtotally nephrectomized rats.

Some of luteinizing hormone (LH) isoforms can stimulate renal growth. The objective of this study is to determine whether the administration of LH modifies subtotal nephrectomy-induced chronic renal failure. Castrated 3/4-nephrectomized male rats were divided into four groups of seven each and fed a low-protein (6%) diet. Ovine LH with renotropic activity (40 micrograms/day) or vehicle only (control) was given for three weeks or six weeks. Compared with controls, remnant kidney weights (% body weight) in LH-treated rats had increased significantly at three weeks (0.385 +/- 0.019 vs 0.443 +/- 0.052, P less than 0.02), but not at six weeks (0.281 +/- 0.004 vs 0.272 +/- 0.013). 24 h creatinine clearance (ml/day/100 g body weight) increased significantly both by three weeks (242 +/- 58 vs 301 +/- 36, P less than 0.05), and six weeks (323 +/- 55 vs 395 +/- 10, P less than 0.01). Urinary thromboxane B2 excretion increased in LH-treated rats, suggesting that hemodynamic changes may play a role in increasing creatinine clearance. Our results suggest that renotropically active oLH stimulated the glomerular function in castrated rats with reduced renal mass. Further study may clarify its clinical usefulness.     

Influence of stage of the estrous cycle on endogenous opioid modulation of luteinizing hormone, prolactin, and cortisol secretion in the gilt

Fourteen gilts that had displayed one or more estrous cycles of 18-22 days (onset of estrus = Day 0) and four ovariectomized (OVX) gilts were treated with naloxone (NAL), an opiate antagonist, at 1 mg/kg body weight in saline i.v. Intact gilts were treated during either the luteal phase (L, Day 10-11; n = 7), early follicular phase (EF, Day 15-17; n = 3), or late follicular phase (LF, Day 18-19; n = 4) of the estrous cycle. Blood was collected at 15-min intervals for 2 h before and 4 h after NAL treatment. Serum luteinizing hormone (LH) concentrations for L gilts averaged 0.65 +/- 0.04 ng/ml during the pretreatment period and increased to an average of 1.3 +/- 0.1 ng/ml (p less than 0.05) during the first 60 min after NAL treatment. Serum prolactin (PRL) concentrations for L gilts averaged 4.8 +/- 0.2 ng/ml during the pretreatment period and increased to an average of 6.3 +/- 0.3 ng/ml (p less than 0.05) during the first 60 min after NAL treatment. Serum PRL concentrations averaged 8.6 +/- 0.7 ng/ml and 7.6 +/- 0.6 ng/ml in EF and LF gilts, respectively, prior to NAL treatment, and decreased (p less than 0.05) to an average of 4.1 +/- 0.2 ng/ml and 5.6 +/- 0.4 ng/ml in EF and LF gilts, respectively, during the fourth h after NAL. Naloxone treatment failed to alter serum LH concentrations in EF, LF, or OVX gilts and PRL concentrations in OVX gilts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased circadian prolactin release is blunted after body weight loss in obese premenopausal women

We recently showed that prolactin (PRL) release is considerably enhanced in obese women in proportion to the size of their visceral fat mass. PRL release is inhibited by dopamine 2 receptor (D2R) activation, and dietary restriction/weight loss are associated with increased dopaminergic signaling in animals. Therefore, we hypothesized that enhanced PRL release in obese humans would be reversed by weight loss. To evaluate this postulate, we measured 24-h plasma PRL concentrations at 10-min intervals in 11 obese premenopausal women (BMI 33.3 +/- 0.7 kg/m2) before and after weight loss (50% reduction of overweight/15% absolute weight loss, using a very low-calorie diet) in the follicular phase of their menstrual cycle. The 24-h PRL concentration profiles were analyzed by a peak detection program (Cluster) and a wave form-independent deconvolution technique (Pulse). Spontaneous 24-h PRL secretion was significantly reduced in obese women [mean daily release, before 128 +/- 24 vs. after weight loss 110 +/- 17 microg/liter distribution volume (Vdl)(-1) x 24 h, P = 0.05]. Body weight loss particularly blunted PRL secretory burst mass (Pulse area, before 230 +/- 28 vs. after weight loss 221 +/- 31 microg/Vdl(-1) x 24 h, P = 0.03), whereas burst frequency was unaffected (no. of pulses, before 11 +/- 1 vs. after weight loss 12 +/- 1 n/24 h, P = 0.69). Thus elevated PRL secretion rate in obese women is significantly reduced after loss of 50% of overweight. We speculate that amelioration of deficit D2R-mediated neurotransmission and/or diminutions of circulating leptin/estrogen levels might be involved in the physiology of this phenomenon.     

Serum hormone levels during a post-implantation LH-RH induced luteolysis in the rat.

Daily administration of LH-RH (100 micrograms sc at 0900 and 1500 h) to rats over day 7-12 (D7-12) of pregnancy induced reovulation by D9 and a sustained decrease in uterine:fetal weight and vaginal bleeding by 0600 h on D10 of pregnancy. Serum hormone levels determined at 0600, 1200, and 2000 h over D7-12 of pregnancy revealed that luteinizing hormone (LH) was significantly elevated after each administration of LH-RH, while prolactin (PRL) was not significantly altered in any systematic fashion. An acute decline in serum progesterone at 2000 h on D7-9 following LH-RH administration was not sustained until after 0600 h on D10 when serum 20 alpha-dihydroprogesterone (20 alpha-hydroxy-4-pregnen-3-one, 20 alpha-DHP) in LH-RH treated animals rose significantly above control (2000 h, D10) and remained elevated throughout D11-12. Progesterone and 20 alpha-DHP values were reflected morphologically after D10 as the corpora lutea of LH-RH treated rats underwent luteolysis. A peak in serum estradiol levels in control animals was observed at 0600 h on D9. Serum estradiol-17 beta levels in LH-RH treated animals were similar to control except at 2000 h on D8 and D12 when LH-RH induced a significant increase. These observations suggest that subsequent to implantation in the rat, the temporal sequence of a decrease in progesterone secretion, luteolysis and pregnancy failure in response to LH-RH does not result from an increase in estradiol secretion attendant to reovulation.     

Relationships between insulin and glucose metabolism and pituitary-ovarian functions in fasted heifers

The effects of fasting between Days 8 and 16 of the estrous cycle on plasma concentrations of luteinizing hormone (LH), progesterone, cortisol, glucose and insulin were determined in 4 fasted and 4 control heifers during an estrous cycle of fasting and in the subsequent cycle after fasting. Cortisol levels were unaffected by fasting. Concentrations of insulin and glucose, however, were decreased (p less than 0.05) by 12 and 36 h, respectively, after fasting was begun and did not return to control values until 12 h (insulin) and 4 to 7 days (glucose) after fasting ended. Concentrations of progesterone were greater (p less than 0.05) in fasted than in control heifers from Day 10 to 15 of the estrous cycle during fasting, while LH levels were lower (p less than 0.01) in fasted than in control heifers during the last 24 h of fasting. Concentrations of LH increased (p less than 0.01) abruptly in fasted heifers in the first 4 h after they were refed on Day 16 of the fasted cycle. Concentrations (means +/- SEM) of LH also were greater (p less than 0.05) in fasted (11.2 +/- 2.6 ng/ml) than in control (4.7 +/- 1.2 ng/ml) heifers during estrus of the cycle after fasting; this elevated LH was preceded by a rebound response in insulin levels in the fasted-refed heifers, with insulin increasing from 176 +/- 35 pg/ml to 1302 +/- 280 pg/ml between refeeding and estrus of the cycle after fasting. Concentrations of LH, glucose and insulin were similar in both groups after Day 2 of the postfasting cycle. Concentrations of progesterone in two fasted heifers and controls were similar during the cycle after fasting, whereas concentrations in the other fasted heifers were less than 1 ng/ml until Day 10, indicating delayed ovulation and (or) reduced luteal function. Thus, aberrant pituitary and luteal functions in fasted heifers were associated with concurrent fasting-induced changes in insulin and glucose metabolism.     

The role of protein kinase C in LH release

To investigate the postreceptor mechanism, especially the role of protein kinase C (C-kinase), in luteinizing hormone (LH) release from anterior pituitary cells, dispersed rat anterior pituitary cells were stimulated with luteinizing hormone-releasing hormone (LH-RH), [D-Ser(tBu)]6 des-Gly-NH2(10) ethylamide (Buserelin), 12-0-tetradecanoyl phorbol-13-acetate (TPA) and trifluoperazine (TFP) and the LH released into the medium was determined by radioimmunoassay. LH released by combined stimulation with TPA and either LH-RH or Buserelin was significantly less than that released by LH-RH or Buserelin alone (LH-RH: p less than 0.05; Buserelin: p less than 0.01). It is thought that this paradoxical phenomenon occurred due to desensitization accompanied by down-regulation of LH-RH receptors induced by TPA. This hypothesis was supported by the finding indicating that the binding capacity of LH-RH receptors decreased in a time-course manner during incubation with TPA. The amount of LH released by combined stimulation with TPA and TFP was significantly greater than with TPA alone (P less than 0.01). This suggests that TFP has dual actions, i.e., facilitating and inhibiting LH release.     

Luteinizing hormone-releasing hormone in prepubertal and pubertal girls.

Estimations of immunoreactive LH-RH and LH in pooled sera of girls, adult women and postmenopausal women have been carried out. The girls were divided into three groups: I--girls aged 2--4 years, II--girls aged 5--8 years and III--girls 9--12 years of age. The estimated concentrations of LH-RH in particular groups were as following: in group I--1.2 +/- 0.2 pg/ml, in group II--2.2 +/- 0.4 pg/ml, in group III 31.0 +/- 4.4 pg/ml, in adult women 6.3 +/- 1.8 pg/ml. and in postmenopausal women 16.6 +/- 2.4 pg/ml. The concentrations of LH in the same groups were 4.3 +/- 0.7; 4.5 +/- 0.8; 11.0 +/- 1.4, 23.3 +/- 2.4; and 120.0 +/- 14.7 mIU/ml, respectively. The authors suggest that the sexual maturation of girls is initiated by the enhanced hypothalamic activity, reflected in higher concentrations of immunoreactive LH-RH in peripheral serum.     

Preovulatory secretion of progesterone, luteinizing hormone, and prolactin in 4-day and 5-day cycling rats

Timing of ovulation and changes in plasma progesterone, luteinizing hormone (LH), and prolactin (PRL) during periovulatory stages were determined in Holtzman rats exhibiting regular 4- or 5-day cycles under a daily artificial illumination from 0500 to 1900 h. The 5-day cycling rats ovulated between 0130 and 0930 h on estrus, whereas some of the 4-day cycling animals ovulated as early as about 0130 h and others as late as 1130 h on estrus. Onset time of preovulatory LH and progesterone surges was about 1500 h on proestrus in both the 4- and the 5-day cycling rats. Peak levels of plasma LH and progesterone were measured at 1700 to 1900 h on proestrus, while the first rises and peak values of plasma PRL were evident a few hours earlier than those of plasma LH in the rats with two cycle lengths. Plasma LH levels at 1900 h on proestrus as well as plasma progesterone levels at 1600 and 2300 h on proestrus and at 0130 and 0330 h on estrus were significantly lower in the 5-day cycling rats than in the 4-day cycling animals (p less than 0.05). In contrast, PRL levels from 1500 through 2300 h on proestrus remained consistently higher in 5-day cycling rats than in 4-day cycling rats, and significant differences in PRL levels between these rats were apparent at 1500, 1600, and 2100 h (p less than 0.05-0.01). Thus, these results demonstrate that the 5-day cycling rats exhibit the attenuated magnitude of LH surge accompanied by the augmented preovulatory PRL release, and that plasma progesterone levels reflect the magnitude of LH surge. A tentative working hypothesis concerning the etiology of the 5-day cycle has been proposed.     

Gonadotropin, prolactin and thyrotropin pituitary secretion after exogenous dehydroepiandrosterone-sulfate administration in normal women.

The effect of exogenous dehydroepiandrosterone-sulfate (DHAS) on luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL) and thyroid-stimulating hormone (TSH) pituitary secretion was studied in 8 normal women during the early follicular phase. The plasma levels of these hormones were evaluated after gonadotropin-releasing hormone (GnRH)/thyrotropin-releasing hormone (TRH) stimulation performed after placebo or after 30 mg DHAS i.v. administration. The half-life of DHAS was also calculated on two subjects; two main components of decay were detected with half-times of 0.73-1.08 and 23.1-28.8 h. The results show an adequate response of all hormones to GnRH or TRH tests which was not significantly modified, in the case of LH, FSH and PRL, when performed in the presence of high levels of DHAS. However, the TSH response to TRH was significantly less suppressed (p less than 0.05) (39%) after DHAS administration than during repeated TRH stimulation without DHAS (51%). The data support the hypothesis that DHAS does not affect LH, FSH and PRL secretion, while TSH seemed to be partially influenced.     

Cyclosporine A inhibits the secretion of certain anterior pituitary hormones in patients with nephrotic syndrome.

To clarify the effects of cyclosporine A (CsA) on the secretion of serum thyrotropin (TSH), prolactin (PRL), luteinizing hormone (LH) and follicular stimulating hormone (FSH), we performed TRH and LH-RH testing in 4 patients with the nephrotic syndrome before and after the administration of CsA, 6 mg/kg/day for 4 to 12 weeks. Prior to CsA all patients responded normally to TRH with respect to TSH and PRL secretion. Two patients showed normal response of LH and FSH to LH-RH stimulation while the response in 2 other patients, who were both menopausal, was exaggerated. By the third or fourth week of CsA administration the basal and peak TSH and PRL values declined significantly in all patients in response to TRH stimulation while those of LH and FSH showed only a modest decrease in response to LH-RH stimulation. Two to 4 weeks after the cessation of CsA the response of TSH, PRL and FSH returned to the pretreatment level. These observations suggest that: 1) CsA exerts an inhibitory effect on the secretion of at least TSH and PRL in humans, and 2) the effect of CsA on the pituitary may be partially reversible after the cessation of the therapy.     

The bio/immuno ratio of serum luteinizing hormone increases after orchiectomy in prostatic cancer patients and is associated with decreased molecular weight and appearance of isohormones with alkaline pI values

Serum concentrations of bioactive (B) and immunoreactive (I) luteinizing hormone (LH) were determined in six patients with prostatic cancer before castration and at frequent intervals after the operation up to 6 mo. B-LH increased in 6 mo from 11 +/- 1 to 90 +/- 9 (mean +/- SEM, n = 6) IU/liter (p less than 0.01), and I-LH from 9 +/- 1 to 37 +/- 5 IU/liter (p less than 0.01). Accordingly, a significant increase in the B/I ratio of LH occurred at the same time, from 1.3 +/- 0.1 to 2.4 +/- 0.2 (p less than 0.01). To elucidate the molecular basis of the B/I ratio change, serum samples obtained before and 2-6 mo after orchiectomy were fractionated by gel filtration and chromatofocusing, and the eluted fractions were analyzed for B-LH and I-LH. In gel filtration, the fractions with the highest B-LH and I-LH contents were eluted later in the post-castration samples than in the pretreatment samples (mean Ve/Vo 1.31-1.32 vs. 1.26-1.28; p less than 0.02-0.01), indicating a small reduction in the average Mr of the circulating LH after castration. In chromatofocusing, a single major peak of immunoreactivity with a pI value of 7.4 was identified before castration, but in post-castration samples, a significantly large proportion of the immunoreactivity was eluted in the alkaline pI range 7.4-9 (22.2 +/- 2.4% before, 56.5 +/- 5.2% after castration, p less than 0.05). These findings indicate that after castration, the increased B/I ratio of serum LH is explained by a preferential increase in isohormones with slightly reduced molecular weights and alkaline pI values.     

Evidence of altered dopaminergic modulation of prolactin and thyrotropin secretion in patients with polycystic ovary syndrome

In order to evaluate the functional activity of the tubero-infundibular dopaminergic system in polycystic ovary syndrome (PCOS), we analysed the prolactin (PRL) and thyrotropin (TSH) responses to the dopamine antagonist sulpiride. We studied 8 euthyroid women affected by PCOS and 7 normal women. The mean baseline PRL values were normal in both groups. After sulpiride administration the incremental area under the PRL profile in PCOS was significantly lower than in normal subjects (p less than 0.01). The mean basal plasma TSH levels were significantly higher in the PCOS than in the control group (p less than 0.01). After sulpiride administration the incremental area under the TSH profile was significantly lower in PCOS patients than in normal women (p less than 0.01). The higher basal plasma levels of TSH, the blunted response of PRL and the lack of response of TSH to sulpiride in PCOS suggest a relative decrease of the dopaminergic activity in PCOS patients.