Inhibition Of Pituitary Gonadotropin Secretion Research Articles

Clinical practice guidance for the use of clomiphene citrate in Male Hormone Replacement Therapy (HRT)

Introduction: Inhibition of pituitary gonadotropin secretion in men by testosterone (T) is principally mediated by aromatization to estrogen (E), which inhibits hypothalamic secretion of gonadotropin-releasing hormone (GnRH). Material and Methods: Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade. Initial monotherapy with 50 mg of clomiphene citrate (CC) daily for a period of 9 months, with diurnal morning peak testosterone and luteinizing hormone (LH) levels evaluated at three-month intervals thereafter. The patient then resumed hormone replacement therapy (HRT) using T cream with adjuvant CC therapy. Main Outcome Measures were Baseline and stimulated T and LH levels; effect on sexual function. Result(S): CC therapy resulted in complete normalization of pulsatile gonadotropin secretion, serum T level, and sexual function. Conclusion(S): Isolated hypogonadotropic hypogonadism (IHH) may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback. Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. Reversal of gonadotropin deficiency with CC was found to have a similar biological effect.

Variations in pituitary-gonadal suppression during intranasal buserelin and intramuscular depot-triptorelin therapy for central precocious puberty. Belgian Study Group for Pediatric Endocrinology.

This study evaluated pubertal development, growth and pituitary-gonadal suppression in 21 patients with central precocious puberty treated with buserelin intranasally and switched after a mean of 2.1 yr to depot-triptorelin given im for 1 year. Arrest or regression of puberty was observed in 12 patients while progression of puberty during therapy was seen in 9 patients (6 on buserelin, 2 on triptorelin and 1 on both therapies). The increment in serum LH and FSH concentrations after sc injection of short-acting triptorelin was greater on buserelin than on triptorelin therapy, particularly in patients with evidence of progression of puberty. Height velocity during therapy showed a reduction which paralleled the decelerating phase of the normal pubertal growth spurt. The rate of bone maturation during therapy was inversely related to pretreatment bone age. Predicted final height showed marked individual variations which were inversely related to predicted adult height before therapy. These data indicate that differences in the nature and route of administration of Gn-RH agonist therapy for central precocious puberty can be of importance for inhibition of pituitary gonadotropin secretion and development of secondary sex characteristics. Height velocity and bone maturation are age-related and the change in predicted adult height depends on pretreatment level.

Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate

Inhibition of pituitary gonadotropin secretion in men by T is principally mediated by aromatization to estrogen (E), which inhibits hypothalamic secretion of GnRH. We hypothesized that adult-onset isolated hypogonadotropic hypogonadism (IHH) might result from an altered central set-point for E-mediated negative feedback. Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade. A 31-year-old man presenting with an 18-month history of sexual dysfunction resulting from severe adult-onset IHH (LH 1.7 U/L, FSH 2.0 U/L, T 3.5 nmol/L). Initial therapy with 50 mg of clomiphene citrate (CC) three times a day for 7 days, with overnight LH pulse profiling and 9 am T levels evaluated at baseline and on completion. A 2-month washout period, followed by low-dose maintenance therapy (25-50 mg/d) for 4 months. Baseline and stimulated T levels and LH pulsatility; effect on sexual function. Clomiphene therapy resulted in complete normalization of pulsatile gonadotropin secretion, serum T level, and sexual function. Isolated hypogonadotropic hypogonadism may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback. Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. On theoretical grounds, reversal of gonadotropin deficiency with CC might be expected to have a similar biological effect.

New trends in combined use of gonadotropin-releasing hormone antagonists with gonadotropins or pulsatile gonadotropin-releasing hormone in ovulation induction and assisted reproductive technologies

The use of gonadotropin-releasing hormone agonists as adjunctive therapy with gonadotropins for ovulation induction in in vitro fertilization and other assisted reproductive technologies has become common clinical practice. With the recent advent of potent gonadotropin-releasing hormone antagonists free from the marked histamine-release effects that stymied earlier compounds, an attractive alternative method may be available. We have established the feasibility of combining gonadotropin-releasing hormone antagonist-induced inhibition of endogenous gonadotropins with exogenous gonadotropin therapy for ovulation induction in a nonhuman primate model. Here, the principal benefits to be gained from using the gonadotropin-releasing hormone antagonist rather than the gonadotropin-releasing hormone agonist are the immediate inhibition of pituitary gonadotropin secretion without the "flare effect," which brings greater safety and convenience for patients and the medical team and saves time and money. We have also recently demonstrated the feasibility of combining gonadotropin-releasing hormone antagonist with pulsatile gonadotropin-releasing hormone therapy for the controlled restoration of gonadotropin secretion and gonadal steroidogenesis culminating in apparently normal (singleton) ovulatory cycles. This is feasible only with gonadotropin-releasing hormone antagonists because, unlike gonadotropin-releasing hormone agonists, they achieve control of the pituitary-ovarian axis without down regulation of the gonadotropin-releasing hormone receptor system. This capacity to override gonadotropin-releasing hormone antagonist-induced suppression of pituitary-ovarian function may allow new treatment modalities to be employed for women who suffer from chronic hyperandrogenemia with polycystic ovarian disease.

Reversible, long-term inhibition of ovulation with a gonadotropin-releasing hormone antagonist in the marmoset monkey (Callithrix jacchus).

The effects of weekly injections of a gonadotropin-releasing hormone (GnRH) antagonist (GnRHa) ([N-acetyl-DβNal1-D-pCl-Phe2-D-Phe3-D-Arg6-Phe7-Arg8D-Ala10] NH2 GnRH) on pituitary and ovarian function were examined in the marmoset monkey, Callithrix jacchus. In experiment 1, five cyclic females were given weekly injections of vehicle (50% propylene glycol in saline) for 6 weeks followed by GnRHa for 20 weeks, animals receiving either 200 μg GnRHa/injection (n = 2) or 67 μg GnRHa/injection (n = 3) for 10 weeks, after which the treatment was reversed. Bioactive luteinizing hormone (LH) and progesterone (Po) were measured in blood samples (0.2-0.4 ml) collected twice weekly until at least 8 weeks after the last GnRHa injection. GnRHa treatment, timed to begin in the midluteal phase, caused a rapid decline in LH and Po and luteal regression after a single injection (both doses). Po levels were consistently low (<10 ng/ml), and ovulation was inhibited throughout 200 μg treatment in all animals. Short periods of elevated Po (>10 ng/ml) were, however, occasionally seen during 67 μg treatment, indicating incomplete ovarian suppression. Mean LH levels were significantly lower during GnRHa treatment compared with the period of vehicle injection (all animals 200 μg; three animals 67 μg), and there were significant differences in LH levels between GnRHa treatments (200 μg vs. 67 μg) in four animals. Four animals resumed normal ovarian cycles after the end of GnRHa treatment (15/16 days, three animals; 59 days, one animal); the fifth animal died of unknown causes 32 days after the last GnRHa injection. In a second experiment, pituitary responsiveness to exogenous GnRH was tested 1 day after a single injection of vehicle or antagonist (200 or 67 μg). Measurement of bioactive LH indicated that pituitary response to 200 ng native GnRH was significantly suppressed in animals receiving the antagonist, the degree of suppression being dose related. A third experiment examined the effect of four weekly injections of 200 μg GnRHa on follicular size and granulosa cell responsiveness to human follicle-stimulating hormone (hFSH) in vitro. Follicular development beyond 1 mm was inhibited by GnRHa treatment (preovulatory follicles normally 2-4 mm) although granulosa cell responsiveness to FSH during 48 hr of culture was not impaired. These results suggest that the GnRHa-induced suppression of follicular development and ovulation was mediated primarily by an inhibition of pituitary gonadotropin secretion and not by a direct action at the level of the ovary.

Inhibition of Pituitary Gonadotropin Secretion by the Gonadotropin-Releasing Hormone Antagonist Antide. I. In Vitro Studies on Mechanism of Action*

The GnRH antagonist antide is among the most promising "third generation" compounds available for clinical evaluation. In primates, antide manifests prolonged (several weeks) and reversible inhibition of pituitary gonadotropin secretion after a single high dose injection. In the present study, we have examined the effects of antide on pituitary gonadotropin secretion in vitro. Dispersed anterior pituitary cells from adult female rats were plated (48 h; 5 x 10(5) cells/well), washed, and exposed to increasing concentrations of antide for up to 48 h. Media were removed, and cells were washed twice and then incubated with GnRH (1 x 10(-8) M) plus antide for 4 h. Media and cell lysates were assayed for LH/FSH by RIA. Antide had no effect on basal LH/FSH secretion at any dose tested (10(-6)-10(-12) M). In contrast, GnRH-stimulated LH/FSH secretion was inhibited by this GnRH antagonist in a dose- and time-dependent manner. When incubated simultaneously, antide blocked GnRH-stimulated gonadotropin secretion, with a maximal effect at 10(-6) M (ED50, 10(-7) M). Preincubation of pituitary cells with antide for 6-48 h before GnRH exposure shifted the dose-response curve to the left; the maximally effective dose was 10(-8) M; the ED50 was 10(-10) M antide after 48-h preincubation. Intracellular LH/FSH levels increased concomitant with the decrease in secreted gonadotropins. Total LH/FSH levels (secreted plus cell content) remained unchanged. The inhibition of LH secretion by antide was specific for GnRH-stimulated gonadotropin secretion; antide had no effect on K(+)-stimulated LH secretion. Moreover, antide had little or no residual effect on LH secretion; full recovery of GnRH responsiveness in vitro occurred within 4 h after removal of antide. Lineweaver-Burke analysis of antide inhibition of GnRH-stimulated LH secretion indicated that antide is a direct competitor of GnRH at the level of the pituitary GnRH receptor. In summary, antide is a pure antagonist of GnRH stimulation of gonadotropin secretion; no agonistic actions of antide were manifest in vitro. Moreover, antide has no apparent noxious or toxic effect on pituitary cells in culture; the actions of antide are immediately reversible upon removal of antide from pituitary gonadotropes. We conclude that the long term inhibition of gonadotropin secretion by antide in vivo is not due to deleterious effects of this compound at the level of the pituitary gonadotrope.

Inhibition of Pituitary Gonadotropin Secretion by the Gonadotropin-Releasing Hormone Antagonist Antide. II. Development of an in Vitro Bioassay for Characterization of Pharmacokinetics and Pharmacodynamics of Antide in Circulation*

Previous data from this laboratory revealed a rapid and unexpectedly long inhibition of pituitary gonadotropin secretion in ovariectomized monkeys after a single high dose injection of the GnRH antagonist antide. This extended action of antide may correlate with an extended presence of antide in the peripheral circulation. We have reported on use of a RRA for antide in serum; however, during such a prolonged presence in the body, the possibility of catabolic loss of biological activity remained to be analyzed. In the present study, we have developed an in vitro pituitary cell bioassay for antide to investigate the pharmacokinetics and possible mechanism(s) contributory to its long action. Dispersed anterior pituitary cells from adult female rats were plated (48 h; 5 x 10(5) cells/well), washed, and incubated with 0.024-6 ng antide for 24 h. Media were removed, and cells were washed twice and then incubated with GnRH (1 x 10(-8) M) plus antide standards or serum samples for 4 h. Before antide injection into long term ovariectomized monkeys, peripheral GnRH antagonist levels were undetectable. One day after a single injection (3.0 mg/kg, sc, in 50% propylene glycol-water), the level of antide was 31 +/- 13 ng/ml (n = 3). Thereafter, antide levels declined slowly and were still detectable (greater than 1.4 ng/ml) in two of three monkeys 31 days after injection. After iv administration (3.0 mg/kg; n = 2), peripheral antide levels followed a similar pharmacokinetic profile and declined slowly. Detectable antide concentrations were still present 36 days after single iv injection in both monkeys. The circulating half-lives of antide were 1.7 and 14.5 days for the first and second phases, respectively. Peripheral LH levels were suppressed to the limits of detectability within 1 day and slowly recovered to pretreatment levels within 30 +/- 5 days after sc or iv antide treatment. The ratio of bioactive antide to antide levels measured by RRA was similar throughout the study (chi = 1.24 +/- 0.09; range, 0.40-2.22), although there was a trend toward an increased B/R ratio at the end of the study. In summary, we have developed an in vitro bioassay using cultured rat pituitary cells to measure biologically active antide concentrations in peripheral circulation after sc and iv treatments. The prolonged action of antide on pituitary gonadotropin secretion in vivo is apparently due to the continued presence of biologically active antide in circulation after a single injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of Hypothalamic Gonadotropin-Releasing Hormone Secretion in Experimental Uremia: In vitro Studies

Defective regulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion is the primary defect leading to the inhibition of pituitary gonadotropin secretion and its consequences such as androgen deficiency and infertility in experimental uremia. Previous studies using indirect methods to study presumptive GnRH release and the function of GnRH-secreting neurons have suggested functional disturbances of GnRH neurosecretion; however, the precise biochemical mechanisms involved were not defined. Therefore, in order to clarify the mechanisms of aberrant regulation of hypothalamic GnRH secretion in experimental uremia, we examined basal secretion of GnRH from mediobasal hypothalamus (MBH) in vitro and the GnRH-secretory responses to naloxone, an opiate receptor antagonist in experimental uremia. Using a static incubation system, adult male rats, either intact or castrate, with subtotal nephrectomy demonstrated a significant reduction of GnRH secretion by 25% in intact and by 40% in castrate uremic male rats compared with their nonuremic controls. In contrast, hypothalamic GnRH content of uremic animals was increased significantly (6% in intact and 14% in castrate uremic rats). Despite the fall in basal GnRH release from MBH, the MBH GnRH release response to in vitro stimulation by an opioid blocker (naloxone) and a membrane-depolarizing agent (veratrine) were not diminished in uremic male rats. These findings suggest that the inhibition of pituitary gonadotropin secretion in experimental uremia is likely to be due to a functional defect in suprahypothalamic regulation of GnRH secretion rather than an intrinsic defect in the GnRH-secreting neurons. Further studies are required to clarify the nature of the neuromodulator interactions involved.

EXTENDED PRESENCE OF ANTIDE (NAL-LYS GnRH ANTAGONIST) IN CIRCULATION: PROLONGED DURATION OF GONADOTROPIN INHIBITION MAY DERIVE FROM ANTIDE BINDING TO SERUM PROTEINS*

Previous data from this laboratory revealed a rapid (-12h) and unexpectedly long (-30 days) inhibition of pituitary gonadotropin secretion after a single injection of Antide (Nal-Lys GnRH antagonist) in ovariectomized (OVX) monkeys. Although the apparent mechanism of action of Antide is competitive occupancy of GnRH receptors, the etiology of the prolonged action is unknown. Here, we report development of a radioreceptor assay to measure circulating Antide levels to determine the mechanism(s) of its long duration of action. Five long-term OVX monkeys were injected with Antide (3.0 mg/kg). Blood samples were collected daily for 30 days, and thereafter on alternate days until day 60. Following sc or iv Antide injection, peripheral luteinizing hormone (LH) levels declined from 281 +/- 19 ng/ml to 29 +/- 3 ng/ml within one day (P less than 0.05). LH levels slowly recovered to pretreatment levels within 35 +/- 7 days. Peripheral Antide levels were 16,531 +/- 4,432 ng/ml within 15 minutes following iv injection, and 52 +/- 21 ng/ml at 1 day after sc Antide injection. Interestingly, thereafter clearance of Antide-from the peripheral circulation was very slow, with an apparent t1/2 (second phase) of 6.5 days following iv administration. Detectable Antide levels were present in the peripheral circulation for more than one month in all five monkeys. In a second experiment, incubation of 125I-Tyro Antide with OVX monkey serum resulted in binding of the labelled peptide to serum proteins and reduction of 125I-Tyro Antide binding to pituitary receptors. Following gel permeation chromatography, greater than 70% of the radioactivity was associated with a 66 kDa protein(s). In conclusion, the prolonged duration of gonadotropin inhibition by Antide seems to derive from the long circulatory half-life of this molecule. In turn, this extended action of Antide may be manifest, at least in part, by binding to serum protein(s) that serves as a built-in peripheral depot release mechanism.

136 TREATMENT OF PRECOCIOUS PUBERTY BY INIRANASAL D-SER (TBU)6 LHRHI – 9EA10(BUSERELIN

GnRH analogues afford effective, selective, reversible inhibition of pituitary gonadotropin secretion. We administered Buserelin (300 ug × 6/die) to 18 girls affected by precocious puberty, for 6-24 months (onset of first symptoms before 8 years of age). We evaluated Buserelin's effects on pituitary-gonadal, pituitary-thyroid, pituitary-adrenal Function, ultrasonographic pelvic organs and thermographic mammary patterns, clinical and auxological features. Results: significant decreases (paired t test) were observed in: both LH and FSH reserves (LHRH test) and basal FSH since the First month (m) of treatment, E2 (3rd m), Progesterone (6th m); also TSH reserve (TRH test) since the 6th m, T3 (12th m) and fT3 (6th m) decreased significantly, though remaining in control range. 14, fT4, PRL, ACTH and adrenal hormones did not change significantly. Ultrasonography of the pelvis showed significant decreases of uterine (6th m) and ovarian (12th m) volume; the ovarian structure did not progress and follicle diameter uas always 9 mm. Clinical/thermographic evaluation oF the breast showed a generalized arrest or regression of its maturational patterns. Auxological data (slower bone maturation and growth velocity, lower SD scores For chronological and bone age, adult height prediction tending to improve) suggested a good prognosis. We conclude that these results of intranasal Buserelin administration and the absence of serious side effects make it advisable in the treatment of girls with true precocious puberty.

HMG-induced follicular maturation after blocking of endogenous pituitary gonadotropin discharge

Induction of ovulation in patients with functional hypothalamus and pituitary is frequently complicated by unpredictable LH discharge and premature early luteinization. The best response and highest pregnancy rate following hMG-treatment can be achieved in hypogonadotropic patients [1]. Therefore a procedure was developed for selective temporary inhibition of pituitary gonadotropin secretion with the LH/RH-analogue Buserelin [2]. In a clinical study hMG-induced follicular maturation and succeeding fertilization during pharmacologic hypogonadotropism was investigated. In 31 cycles of 26 patients hMG/hCG-stimulation for in-vitro fertilization (IVF) because of a tubal factor was started after pretreatment with Buserelin (1.2 mg/day, nasal spray) had resulted in the absence of endogenous LH-discharge to an estrogen provocation test (group I). The cycles were compared with previous hMG/hCG cycles of the same patients without Buserelin treatment (n = 18, group II) and the total of hMG-treatment cycles for IVF (n = 66, group III).

Treatment of breast cancer with gonadotropin-releasing hormone.

Analogs of GnRH, given chronically in a continuous fashion, produce a paradoxic inhibition of pituitary gonadotropin secretion and, consequently, gonadal steroidogenesis. Thus, GnRH analogs are an attractive class of compounds for achieving a medical castration in the treatment of hormone-dependent neoplasms. In a group of 25 premenopausal patients with progressive advanced breast cancer, daily sc administration of 1-10 mg Leuprolide [D-Leu6-Pro9GnRH ethylamide (NEt)] induced objective tumor regression in 44% with a median duration of 9 months. All women treated for at least 10 weeks developed amenorrhea. Profound suppression of gonadotropins, estradiol, and progesterone secretion occurred in all patients on chronic therapy and persisted for the whole treatment period. These effects on tumor growth and ovarian hormone levels are similar to those observed after surgical ovariectomy. Other GnRH analogs such as Buserelin and Zoladex have been found to have similar antitumor and hormonal effects which are also comparable to those produced by surgical ovariectomy. The mode of drug administration is important. Consistent suppression of ovarian function has only been observed with sc injections of the analogs. Chronic intranasal therapy has been found to induce an incomplete suppression of ovarian function in most patients, probably as a result of the poor absorption of these compounds through this route (approximately 2%). Treatment of metastatic breast cancer with GnRH analogs has been associated with remarkable absence of significant toxicity. Despite some evidence in favor of a direct antitumor effect independent of suppression of ovarian function, the use of GnRH analogs in the therapy of advanced breast cancer should be restricted to premenopausal women.

Inhibition of pituitary gonadotropin secretion by 4-aminopyrazolo(3,4-d) pyrimidine.

The reduction of plasma testosterone (T) in male rats treated with 4-aminopyrazolo(3,4-d)pyrimidine (4-APP) has been recently shown to be associated with a fall in plasma LH, and appears to be secondary to this impairment of gonadotropin secretion rather than to the decrease in lipoprotein cholesterol caused by the adenine analog. The effects of 4-APP on pituitary function and the mechanism of the fall in gonadotropin secretion were analyzed in adult male rats treated ip with 5, 10, 25, and 50 mg 4-APP/kg BW for 3 days. Twenty four hours later, serum cholesterol levels were reduced by 68 +/- 5% (mean +/- SE) in animals treated with 5 mg 4-APP/kg BW and by up to 84 +/- 1% after higher doses. Basal levels of serum T were not affected by 5 mg/kg APP but were significantly reduced by higher doses (P less than 0.05). Serum T responses to human CG (100 IU) stimulation in APP-treated rats were reduced in absolute magnitude, but were enhanced in terms of percentage increase above baseline. The three highest doses of 4-APP reduced serum levels of LH (51-79%) and FSH (21-39%). However, serum gonadotropin responses to GnRH stimulation were augmented by 32 +/- 9% for LH and 27 +/- 12% for FSH after 4-APP treatment. Serum levels of TSH were significantly (P less than 0.05) reduced by 25 and 50 mg/kg 4-APP and serum PRL was lowered by only the higher dose. Serum GH was lowered and ACTH increased by 5 mg/kg 4-APP. The pituitary contents of LH, FSH, and TSH were unchanged after 4-APP treatment, but PRL and GH contents were slightly but significantly increased (P less than 0.05). Pituitary receptors for GnRH (88 +/- 14 fmol/mg protein) were reduced by in vivo treatment with 25 and 50 mg/kg 4-APP to 52 +/- 5 and 57 +/- 7 fmol/mg, but not by 10 mg/kg 4-APP. No change in pituitary GnRH receptor content was observed after 48-h exposure to 10(-7) or to 10(-5) M 4-APP in vitro. The medial hypothalamic GnRH content was unchanged by 4-APP treatment. The dissociated effects of 4-APP on serum cholesterol and T levels, and the maintenance of T responses to human CG, provide further evidence that testicular androgen biosynthesis is not solely dependent on circulating cholesterol. The greater sensitivity of pituitary gonadotropins to 4-APP inhibition is evidence for a selective action of this drug on pituitary hormone release in vivo. Although the hypothalamic content of GnRH was unaltered by 4-APP treatment, the decrease in pituitary GnRH receptors observed in vivo, together with the fall in circulating LH and FSH and retention of gonadotropin responses to GnRH stimulation, suggest that the primary effect of 4-APP is to inhibit GnRH synthesis and/or release from the hypothalamus.

Oral contraception: mechanism of action.

The combination of steroid hormones in oral contraceptives (OCs) acts both centrally and peripherally to alter normal reproductive function. Through the suppression of gonadotropin release, ovulation is inhibited. Follicular maturation is impaired as well. Even if ovulation occurs occasionally, the changes which occur secondary to chronic exposure to the progestin portion of OCs make both fertilization and implantation unlikely. The OC mechanism of contraceptive action on the central nervous system, on the hypothalamus and pituitary, and on peripheral reproductive organs is discussed. Multiple complex reactions occur in the hypothalamus and pituitary as a result of steroid ingestion. The clinical literature now agrees that the inhibition of pituitary gonadotropin secretion is the most important mode of action of OCs. Hormonal contraceptive preparations also affect the ovary, cervical mucus, the oviduct, and the endometrium. Sperm transport into the cervix is impeded by progesterone counteraction of estrogenic stimulation of cervical mucus penetrability. Through continued OC use, the endometrium becomes a hostile environment to implantation and further embryonic growth--due to glandular atrophy and stromal decidualization.

Long-Term Effects of Endocrine Treatment on Serum Pituitary Hormones in Advanced Prostatic Carcinoma Patients

Peripheral serum concentrations of FSH, LH, prolactin and ACTH were measured in 22 patients with advanced prostatic carcinoma treated by castration, polyestradiol phosphate (Estradurin) administration and a combination of castration and Estradurin administration during the first 12 months of treatment. Estradurin treatment alone (80 mg i.m.l once a month) did not result in any significant changes in the circulating concentrations of FSH, LH and prolactin. Therefore, the clear-cut inhibition of testicular steroidogenesis observed under this kind of treatment does not appear to be due to an inhibition of pituitary gonadotropin secretion, and is most likely due to a direct estrogen effect on Leydig cells. Castration led to grossly elevated serum FSH and LH levels. In this group, serum FSH remained at a high level, whereas LH was close to pretreatment levels 9 months after castration, suggesting differences in pituitary capacity to secrete FSH and LH under these conditions. Concentrations of circulating FSH, and to a lesser extent LH, in the combination treatment group were between those found in the castration and estrogen-only treatment groups, suggesting that the secretion of both gonadotropins can be suppressed by estrogen. No changes in serum prolactin and ACTH concentrations were seen in the three treatment groups.

The effect of hepatic interposition on ovary-pituitary interaction.

When the livers of female rats were provided with exclusive first access to all ovarian venous effluents by simultaneous castration and implantation of a portion of one of the ovaries beneath the splenic capsule, systemic venous plasma concentrations of estrone and estradiol were reduced 40%. Paradoxically, progestins in the peripheral plasma increased threefold, most probably because of augmented adrenocortical progestin secretion. Nevertheless, the change in estrogen levels alone was sufficient to abolish trophic effects on the genital organs and to block normal inhibition of pituitary gonadotropin secretion. Plasma gonadotropin concentrations were markedly elevated to levels comparable to those of castrates, and, as a result, the intrasplenic ovarian implants grew excessively and became histologically disorganized. A patent portacaval shunt negated the entire process, providing proof that the measured hormonal alterations and the change in the implant itself were direct consequences of hepatic screening.

Anti-androgenic activity of a series of 17-iminosteroids.

SummaryA series of five 17-iminoste-roids was tested in combination with testosterone propionate in castrated male rats. All of these compounds inhibited the response to testosterone propionate in the seminal vesicles and ventral prostate glands. There was no indication of inhibition of pituitary gonadotropin secretion in spayed female rats treated with several of these compounds. While inhibition of the action of exogenous testosterone propionate was obtained, no effect on endogenous androgen was observed in intact males at the dose used.

Inhibition of pituitary gonadotropin secretion in domestic fowl by enheptin (2-amino,-5-nitrothiazole).

SummaryAdministration of gonadotropic substances simultaneously with Enheptin (2-amino, 5-nitrothiazole) sustained sexual activity in most cases. Failure to restore sexual normality in all cases is probably due to the quality and quantity of administered gonadotropic hormone. The drug Enheptin was not able to suppress thyroidal hypertrophy during thiouracil treatment. Pituitary gonadotropic hormone potency is reduced in intact as well as capons treated with Enheptin.