Dose Of Luteinizing Hormone-releasing Hormone Research Articles

A pure microcytic bladder carcinoma synchronous to prostatic adenocarcinoma

Small cell carcinoma (SCC) or microcytic carcinoma of the urinary bladder is a rare entity comprising approximately 0.5% of all bladder tumors. Due to its rarity, no prospective studies evaluating the most effective treatment have been published in the medical literature. Several cases of bladder SCC have been presented so far. We describe our case report and we revise the recent literature. Our patient was diagnosed with pure bladder SCC and prostatic adenocarcinoma. After the initial and complete transurethral resection of the bladder tumour (TUR-BT), he underwent a thorax and mediastinum computer tomography (CT) examination to exclude primary pulmonary small cell carcinoma and a bone scan scintigraphy for staging purposes. He received a three 14-day cycles of Cisplatin-containing chemotherapeutic schema and a single dose of Luteinizing-Hormone Releasing hormone (LHRH) analogue injection after 14 days of bicalutamide administration. The patient is followed for 24 months without any signs of bladder SCC recurrence or biochemical or local relapse from prostatic adenocarcinoma.

Effects of luteinizing hormone-releasing hormone and arginine-vasotocin on the sperm-release response of Günther's Toadlet, Pseudophryne guentheri

BackgroundLuteinizing hormone-releasing hormone (LHRH) is an exogenous hormone commonly used to induce spermiation in anuran amphibians. Over the past few decades, the LHRH dose administered to individuals and the frequency of injection has been highly variable. The sperm-release responses reported have been correspondingly diverse, highlighting a need to quantify dose-response relationships on a species-specific basis. This study on the Australian anuran Pseudophryne guentheri first evaluated the spermiation response of males administered one of five LHRHa doses, and second, determined whether AVT administered in combination with the optimal LHRHa dose improved sperm-release.MethodsMale toadlets were administered a single dose of 0, 1, 2, 4 or 8 micrograms/g body weight of LHRHa. A 4 micrograms/g dose of AVT was administered alone or in combination with 2 micrograms/g LHRHa. Spermiation responses were evaluated at 3, 7 and 12 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy.ResultsLHRHa administration was highly effective at inducing spermiation in P. guentheri, with 100% of hormone-treated males producing sperm during the experimental period. The number of sperm released in response to 2 micrograms/g LHRHa was greater than all other doses administered and sperm viability was highest in the 1 microgram/g treatment. The administration of AVT alone or in combination with LHRHa resulted in the release of significantly lower sperm numbers.ConclusionOverall, results from this study suggest that in P. guentheri, LHRHa is effective at inducing spermiation, but that AVT inhibits sperm-release.

Chronology of Advances in Neuroendocrine Immunomodulationa

This review documents the remarkable progress over the last 50 years of our knowledge of the control of anterior pituitary hormone release and synthesis by a family of peptidic releasing and inhibiting hormones, synthesized in hypothalamic neurons and released into the hypophysial portal vessels. These vessels transport them to the anterior pituitary, where they stimulate release and synthesis of pituitary hormones or inhibit these processes. In general, there are at least two hypothalamic hormones for each pituitary hormone-vasopressin and corticotrophin-releasing hormone (CRH) for adrenocorticotropin hormone (ACTH) and growth hormone-releasing hormone (GHRH) and growth hormone-inhibiting hormone (GIH) for growth hormone (GH). Some of these hormones have extrapituitary action: for example, luteinizing hormone-releasing hormone (LHRH) stimulates mating behavior. High doses of LHRH have an inhibitory action on the growth of prostate cancer. Proinflammatory and anti-inflammatory cytokines act not only in the brain, but also on the pituitary and peripheral tissues. All of these transmitters are controlled by neuronal transmitters. We anticipate further rapid progress and clinical application of these transmitters and the discovery of new ones.

Changes in serum luteinizing hormone (LH) concentrations in response to luteinizing hormone releasing hormone (LHRH) in bull calves that attained puberty early or late

The objectives of this study were to determine if the response to luteinizing hormone releasing hormone (LHRH) could be used to select bull calves capable of early sexual maturation and to establish the optimum route and dose of LHRH. In Trial 1, at 4, 10 and 20 week of age, 20 calves were treated iv with 2μg/kg body weight of LHRH 1 and 5h after commencing a 9-h period of blood sampling. Bulls were separated into early and late maturing (n=10), based on age at puberty (scrotal circumference (SC) of ≥28cm). At 4 and 20 week of age, peak serum LH concentrations and area under the LH response curve in response to LHRH were lower (P<0.05) in early- versus late-maturing bulls. In Trial 2, calves at 20 week of age were given LHRH as follows: 2μg/kg body weight iv (n=6), im (n=6) or sc (n=6); 5μg/kg im (n=6), or ischio-rectally (ir, n=6) or sc (n=6); and 10μg/kg im (n=6) or sc (n=6). Serum LH concentrations were at a plateau from 30 to 165min after treatment with 5μg/kg of LHRH (im or ir; P>0.05). We concluded that the LH responses to LHRH in calves at 4 and 20 week of age could facilitate the development of a simple test (one blood sample prior to treatment with LHRH and a second during the period of sustained response to LHRH) to select early-maturing bulls.

Patient self-injection: a new approach to administering luteinizing hormone-releasing hormone analogues.

To investigate the feasibility and advantages of self-injection of a depot dose of luteinizing hormone-releasing hormone (LHRH) analogue in patients with prostate cancer. Twenty patients (mean age 70.9 years, range 53-85) with locally advanced or metastatic prostate cancer were recruited from urology clinics and, using a defined protocol, were taught to perform self-injection of a depot LHRH analogue (Prostap SR or Prostap 3, leuprorelin acetate, Wyeth Laboratories, Berks, UK). Patients were then followed for 1 year. Of the 20 patients, 11 successfully learned to use self-injection and administered injections for the duration of the study. Ten of the patients chose self-injection and continued to self-inject after the end of this study. This pilot study of 20 patients showed that it is feasible for a selected group of patients to be taught self-injection of an LHRH analogue, and that some patients prefer this mode of drug administration.

Synergistic activation of androgen receptor by androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells.

We investigated modulation of androgen receptor (AR) activity in prostatic tumor cells by luteinizing hormone-releasing hormone (LHRH)-induced increase of the intracellular cyclic adenosine monophosphate (cAMP) level. AR transactivation activity was assessed in transiently transfected DU-145 and in LNCaP cells. LHRH and cAMP derivative, respectively, induced reporter gene activity to about 15% of the maximal level in DU-145 cells transfected with an AR expression vector and an androgen-inducible reporter gene. LHRH or the cAMP analogue acted synergistically in combination with low concentrations of androgen thus lowering the androgen concentration required for maximal AR activation by a factor of 100. A similar activation of the AR by cAMP analogue was observed in LNCaP cells when enhancement of androgen-induced secretion of prostate-specific antigen was determined. The two nonsteroidal antiandrogens hydroxyflutamide and Casodex(R) inhibited reporter gene activity. The AR is synergistically activated by low doses of androgen and LHRH or the second messenger cAMP. This may have implications for the treatment of advanced prostate cancer.

Co-polymerised peptide particles II: Oral uptake of a novel co-polymeric nanoparticulate delivery system for peptides

A novel co-polymeric nanoparticulate drug delivery system (the co-polymerised peptide particle, CPP) has been developed [1], in which a derivative of the peptide luteinizing hormone releasing hormone (LHRH) was co-polymerised with n-butylcyanoacrylate ( n-BCA) and a radiolabel, the co-polymer being formulated as nanoparticles. These particles thus contain covalently bound LHRH molecules as constituents of the oligomeric chains. The CPP system was orally dosed to male Wistar rats. A double antibody radioimmunoassay (RIA) demonstrated that LHRH was present in the plasma over a 12 h period, whereas the free peptide did not show detectable absorption. Maximum plasma uptake, amounting to 1.6% of the administered dose of LHRH, was detected 3 h after dosing, but the total cumulative uptake of LHRH was significantly higher, as demonstrated by the plasma area under the curve (AUC) determined over a 12 h post-dosing period. Non-encapsulated LHRH, i.e., LHRH dissolved in the continuous phase of a suspension of n-BCA particles, but not entrapped within the particulate matrix, was not absorbed after oral dosing, confirming the protective effect of CPP encapsulation. RIA may have under-estimated the extent of oral uptake of LHRH due to ‘shielding effects’ of the CPP particulate matrix as, in vitro, only 10% of the peptide in the particles could be detected by RIA. Multiple (2 or 5 days) dosing led to higher LHRH uptake. The particles were broken down in the blood, as shown by gel filtration chromatography. The results demonstrated that chemical conjugation of a peptide within a protective particulate matrix was a viable approach for enhancing oral peptide delivery, presumably utilising the gut-associated lymphoid tissue as a route delivery.

Oramucosal delivery of LHRH: pharmacokinetic studies of controlled and enhanced transmucosal permeation.

Several transmucosal therapeutic systems (TmTs) were developed to study the enhanced/controlled delivery of luteinizing hormone-releasing hormone (LHRH) through oral mucosae for prolonged periods. TmTs is a track field-shaped bilayer mucoadhesive device consisting of fast-release and sustained-release layers. In vivo evaluations were performed in beagle dogs, and pharmacokinetic profiles were monitored to characterize the transmucosal permeation kinetics of LHRH delivered by the various TmTs formulations containing a stabilizer, cetylpyridinium chloride, and a permeation enhancer, such as bile salts, to enhance the stability and permeability of LHRH. The plasma LHRH concentrations were observed to reach the plateau level within 30 min and were maintained for 2 hr following application of TmTs, in contrast to a rapid elimination profile observed after IV administration. Addition of 5% bile salt into the fast-release layer was observed to produce an enhancement in the absorption rate, higher plateau plasma levels, and greater systemic bioavailability. Addition of pH modifiers was noted to affect the bile salt enhanced transmucosal delivery of LHRH. To prolong the plasma LHRH level, several loading doses of LHRH were incorporated into the sustained-release layer. The plasma levels were sustained and the area under the curve (AUC) values were found to be linearly dependent upon the combined loading doses of LHRH in the fast-release and sustained-release layers. Mucosal irritation was also measured, using buccal mucosa, and results were observed to be low and reversible for the single application. The results indicated that TmTs is relatively safe and capable of achieving enhanced and controlled transmucosal delivery of peptide drugs.

Neuropeptide Y and luteinizing hormone releasing hormone synergize to stimulate the development of cellular follicle-stimulating hormone in the hamster adenohypophysis.

Luteinizing hormone releasing hormone (LHRH) stimulates the development of cellular FSH immunoreactivity in the perinatal hamster adenohypophysis. Because neuropeptide Y (NPY) can act directly on rat adenohypophysial cells to stimulate FSH and LH release and potentiate the stimulatory effect of LHRH on FSH and LH release, we investigated the effects of NPY alone and in combination with a low, ineffective dose of LHRH on inducing cellular FSH immunoreactivity in the neonatal hamster adenohypophysis. Neonatal female pituitary glands were grafted beneath the right renal capsules of hypophysectomized-ovariectomized adult hamster hosts with a catheter implanted in the external jugular vein. After treatment, hosts were decapitated and graft tissue was stained for FSH and LH immunoreactivity. The mean percentage of adenohypophysial cells that stained for FSH was low (2.8%) in grafts in hosts infused continuously with heparinized saline vehicle for 7 days. In other hosts, peptides were pulsed through the catheter every 12 h for 7 days. The mean percentage of FSH cells also was low after pulsing 6 ng LHRH or 2 micrograms NPY but increased substantially when the two peptides were pulsed simultaneously. No differences in the mean percentage of LH cells existed between any of the groups. The results demonstrate that NPY and LHRH can synergize to induce cellular FSH immunoreactivity in the neonatal female hamster.

LH-RH AND ITS ANTAGONIST CETRORELIX INHIBIT GROWTH OF JAR HUMAN CHORIOCARCINOMA CELLS IN-VITRO

The effects of luteinizing hormone-releasing hormone (LH-RH), and LH-RH antagonist Cetrorelix, (SB-75, [Ac-D-Nal(2)(1),D-Phe(4-Cl)(2),D-Pal(3)(3),D-Cit(6),D-Ala(10)]LH-RH) on cell growth and the production of hCG and cAMP in JAR human choriocarcinoma cells were examined in vitro. Both LH-RH and its antagonist SE-75, at 1 mu g concentration, inhibited the growth of JAR cells in cultures. When SE-75 (1 mu M) was given in combination with different doses (0.1 nM to 1 mu M) of LH-RH, it was found that 0.1 nM LH-RH nullified the inhibitory effect of SE-75 on cell growth, however, the 100 nM and 1 mu M doses of LH-RH caused a greater inhibition of cell proliferation than SE-75 alone. Incubation with LH-RH slightly increased the hCG production and the cAMP release in the cultured tumor cells. SE-75 alone or in combination with LH-RH reduced the hCG as well as the cAMP release from JAR human choriocarcinoma cells; however, the magnitude of the decrease was smaller for hCG than for cAMP. The effect of different doses of LH-RH, administered simultaneously with 1 mu M SE-75, on the cAMP production, was similar to that on cell growth: 0.1 nM LH-RH in combination with 1 mu M SE-75 caused a smaller inhibition of cAMP than SE-75 alone. However, when LH-RH was given at concentrations from 1 nM to 1 mu M together with 1 mu M SE-75, we observed a greater inhibition of cAMP than after SE-75 alone. The presence of low affinity LH-RH receptors on JAR cells was also demonstrated and competitive binding studies showed that agonist D-Trp(6)-LH-RH and antagonist SE-75 could bind to these receptors. Our findings provide new information on the effect of LH-RH and antagonist SE-75 on the proliferation of JAR human choriocarcinoma cells and may offer a new insight on their mechanisms of action in the suppression of tumor cell growth and their influence on intracellular signal transduction pathways. Hormonal therapy based on Cetrorelix could be considered for the development of new approaches to treatment of patients with choriocarcinomas.

Neurohypophysial response to haemorrhage or dehydration: interactions of vasopressin and luliberin

Abstract Rats, euhydrated, dehydrated for two days or haemorrhaged, were given intracerebroventricularly (i.c.v.) luteinizing hormone releasing hormone (LH-RH) in a daily dose of 100 ng dissolved in 10 μl of 0.9% sodium chloride. In euhydrated rats, a single dose of LH-RH as well as the daily i.c.v. treatment with LH-RH over two days did not significantly affect either the plasma vasopressin concentrations or hypothalamo-neurohypophysial vasopressin content. On haemorrhage (1 ml per 100 g), the increase in plasma vasopressin was almost inhibited and the depletion of neurohypophysial hormone content significantly diminished in animals previously treated with LH-RH. Similarly, LH-RH attenuated markedly the enhanced vasopressin release from the hypothalamo-neurohypophysial system brought about by two-day dehydration. We suggest that LH-RH may have a regulatory role in the hypothalamo-neurohypophysial system especially under conditions of haemorrhage or hyperosmotic dehydration.

Stimulation of prolactin secretion from rat pituitary by luteinizing hormone-releasing hormone: evidence against mediation by angiotensin II acting through a (Sar1-Ala8)-angiotensin II-sensitive receptor.

In aggregate cell cultures of 15- to 20-day-old rat pituitary maintained in serum-free medium, luteinizing hormone-releasing hormone (LHRH) (10 nM) stimulated prolactin (PRL) release, confirming our previous results and those of others with serum-supplemented medium. Since angiotensin II (AII) stimulates PRL release and a renin-angiotensin system is expressed in gonadotrophs, LHRH stimulation of PRL release might be mediated by AII. To evaluate this hypothesis, the influence of (Sar1,Ala8)AII and (Sar1,Ile8)AII two peptide AII receptor antagonists, of DUP753, a nonpeptide and stable AII receptor antagonist, of a converting enzyme inhibitor, and of angiotensinogen on LHRH-induced PRL release was tested in various in vitro conditions of 15- to 20-day-old female rat pituitary. In aggregates maintained in serum-free medium with or without dexamethasone (DEX) and triiodothyronine (T3), or maintained in serum-supplemented medium, the effect of LHRH on PRL release was not affected by (Sar1Ala8)AII (0.1 microM), (Sar1,Ile8)AII (10 microM) or DUP753 (10 microM). Only a high dose (10 microM) of (Sar1,Ala8)AII attenuated the LHRH-induced PRL release. The latter attenuation was seen only with aggregates cultured in the DEX/T3 medium and not with aggregates cultured in the presence of serum. A dose of 1 or 10 nM (Sar1,Ala8)AII also failed to block the effect of LHRH used at 1 nM. In contrast, (Sar1,Ala8)AII dose dependently as well as DUP753 (10 microM) abolished the AII-induced PRL release. (Sar1,Ala8)AII also failed to affect the LHRH-induced PRL release in pituitary cell aggregates from 6-week-old male rats. However, in aggregates from both immature and 6-week-old rats, (Sar1,Ala8)AII provoked a small and statistically significant attenuation of the LHRH-induced PRL release when a 100 nM dose of LHRH was used. In freshly isolated hemipituitaries from 5-day-old rats, (Sar1,Ala8)AII (1 or 10 microM) did not affect the LHRH- (10 nM) induced PRL release. In single cells obtained by redispersion of aggregates and mounted in a Biogel P2 column, LHRH still stimulated PRL release. Again this effect could not be blocked by DUP753. Treatment of aggregate cell cultures with the angiotensin-converting enzyme inhibitor captopril or with angiotensinogen did not alter the LHRH-induced PRL release. It is concluded that AII is not the paracrine factor mediating the effect of LHRH at low nanomolar doses on PRL release, at least not through the classical AII receptor. The involvement of AII acting on a non-(Sar1,Ala8)AII-sensitive receptor cannot be excluded and warrants further investigation.

Pulsatile Luteinizing Hormone Responses to Intermittent iV-Methyl-D,L- Aspartate Administration in Hamsters Exposed to Long- and Short-Day Photoperiods*

Hamsters exposed to short-day photoperiods (6-h light, 18-h darkness) develop a reversible inhibition of the reproductive axis which includes decreased LH pulse frequency, decreased FSH and testosterone levels, testicular regression, and presumably, decreased luteinizing hormone-releasing hormone (LHRH) release. The decrease in LHRH release could reflect a decrease in the ability of LHRH neurons to release the decapeptide in response to intermittent neuronal excitation. To analyze this possibility, the LHRH secretagogue, N-methyl-D-aspartate (NMA) was used to estimate relative releasability of endogenous LHRH pulses in hamsters exposed to long- and short-day photoperiods. Long-day (LD) or short-day (SD) hamsters were fitted with indwelling atrial catheters 2 days before experimentation. During 5-h sampling sessions (1300-1800 h), blood was withdrawn at 10-min intervals. In initial experiments, a NMA dose-response analysis revealed that 10 and 20 mg/kg NMA but not 2.5 and 5 mg/kg NMA, produced significant, dose-related LH responses in LD hamsters. Treatments with LHRH antagonist 4 h prior to NMA treatment completely blocked LH responses. The 10 mg/kg NMA dose was then used to directly compare LHRH responsiveness in LD and SD hamsters. NMA injections were administered to groups of LD and SD hamsters after hours 1, 2, 3, and 4 of sampling. In LD hamsters, LH responses to the first NMA pulse (2.65 +/- 0.09) were followed by diminishing responses to the second, third, and fourth NMA pulses (1.22 +/- 0.50, 1.22 +/- 0.43, and 1.15 +/- 0.42). By contrast, initial LH responses in SD hamsters (1.61 +/- 0.31) were followed by even more robust LH responses to the second, third, and fourth NMA challenges (2.89 +/- 0.34, 3.08 +/- 0.59, 2.65 +/- 0.32). Although LH responses to the first NMA pulse were slightly less in SD vs. LD animals, responses to all subsequent injections were actually greater in SD hamsters vs. their LD counterparts. Injections of 20 ng/kg LHRH in SD hamsters produced LH responses similar to those evoked by NMA. The same LHRH dose also produced continued, robust LH responses in LD hamsters, indicating that decrements in response to NMA were not due to diminished pituitary responsiveness. These results suggest that 1) the stimulatory actions of NMA are mediated by LHRH, 2) exposure to short days does not decrease the responsiveness of LHRH neurons to NMA, and 3) successive NMA challenges produce diminishing LH responses in LD hamsters, but not in SD hamsters.(ABSTRACT TRUNCATED AT 400 WORDS)

Luteinizing Hormone Responses to N‐Methyl‐D,L‐Aspartate During a Photoperiodically‐lnduced Reproductive Cycle in the Ram

Abstract Aspartate and glutamate represent a major class of excitatory amino-acid neurotransmitters in the vertebrate brain, and stimulation of gtutaminergic receptors by the specific agonist N-methyl-D, L-aspartate (NMDA) induces luteinizing hormone-releasing hormone (LHRH) and LH secretion. In this study, we used NMDA as a probe to investigate the hypothalamic regulation of LH secretion at different stages of a reproductive cycle in Soay rams induced by exposure to alternating 16-week periods of long and short days. NMDA (20 mg/kg) injected intravenously caused an acute increase in blood plasma concentrations of LH, with a significant increase within 2 to 4 min, and peak levels within 20 min. The magnitude of the response changed markedly during the cycle; it was greatest in the sexually inactive phase under long days (with a linear dose-response over the range 1 to 20 mg/kg NMDA) and least in the sexually active phase under short days (only 20 mg/kg NMDA produced a small response). Pituitary responsiveness to a standard dose of LHRH (5.3 ng/kg iv) varied only slightly at the different stages and could not account for the observed changes in the LH response to NMDA. There were the expected changes in the endogenous pattern of LH secretion during the cycle, with high frequency LH pulses occurring during the sexually active phase. There was an inverse relationship between the frequency of LH pulses and the LH response to NMDA. Pretreatment of rams with an LHRH antagonist (36 mug/kg iv; Syntex, RS18286) totally blocked the LH response to both NMDA and LHRH, while in a separate study, treatment with dexamethasone (synthetic glucocorticoid, 133.4 mug/kg iv) partially blocked the LH responses. The overall results indicate that NMDA stimulates LHRH secretion in the ram and the response is independent of the activation of the hypothalamo-pituitary-adrenal axis. The variation in the LH response during the reproductive cycle may reflect changes in the releasable stores of LHRH in the median eminence. These appear to be depleted in the sexually active phase, when LHRH is secreted in pulses at high frequency. The variation in the response to NMDA may also reflect changes in release of endogenous excitatory amino-acids, which act via NMDA receptors to form part of the physiological regulation of the reproductive cycle in the ram.

Porcine Lymphocytes Secrete a Bioactive and Immunoreactive LH-like Factor in Response to LHRH and Concanavalin A

Lymphocyte conditioned medium (CM) was prepared by incubating 0 (cell-free control) or 4 x 10(6) lymphocytes/ml in serum-supplemented RPMI containing 0, 10(-9), 10(-7), and 10(-5) M luteinizing hormone releasing hormone (LHRH), 10(-5) M LHRH antagonist (LHRHA), or 10(-7) M LHRH + 10(-5) M LHRHA. Treatments were applied with and without 10 micrograms/ml concanavalin A (con A), and media were analyzed for LH. Aliquots of the CM from cultures incubated for 48 h were later applied to porcine granulosa cell cultures (suspended to 1.25 x 10(5) cells in 450 mul). Thereafter, 50 mul of CM were added to granulosa cell cultures. Media were collected after 12, 24, and 48 h and progesterone determined. Immunoreactive LH increased with time of incubation in lymphocyte CM but not cell-free CM. LH content of lymphocyte CM increased as LHRH concentration increased. LHRHA significantly reduced the amount of LH measured. The presence of con A in the medium resulted in maximal concentrations of LH, irrespective of dose of LHRH or LHRHA. Cell-free CM containing LHRH, LHRHA, and/or con A did not affect progesterone production by granulosa cells at any of the time periods. Lymphocyte CM containing LHRH caused a dose-dependent increase in progesterone production at 48 h. This stimulation was blocked by lymphocyte CM containing LHRHA. Lymphocyte CM containing con A also stimulated progesterone production at all of the LHRH concentrations studied. This response was not inhibited by lymphocyte CM containing the LHRHA.(ABSTRACT TRUNCATED AT 250 WORDS)

Progesterone alters the pituitary response to luteinizing hormone releasing hormone in postmenopausal women previously treated with estradiol

The effect of luteinizing hormone-releasing hormone (LHRH) on LH release was studied in 5 menopausal women injected with progesterone. Each patient received 2 x 100 micrograms doses of LHRH administered intravenously 120 minutes apart under the following conditions: without any previous treatment (test 1); 16 hours after intramuscular injection of 10 mg progesterone (test 2); after 3-4 weeks of oral treatment with 50 micrograms/day of ethinyl estradiol (EE2) (test 3); 16 hours after intramuscular injection of 10 mg progesterone following treatment with 50 micrograms/day oral EE2 for 3-4 weeks (test 4). The interval between tests was at least 1 month. Progesterone decreased the total plasma hormonal increment (PHIt) of hypogonadal women, with a reduction in plasma hormonal increment both after the 1st stimulus (PHI1) and after the 2nd stimulus (PHI2), whereas estradiol increased PHIt, mainly due to an increase of PHI2. The administration of progesterone to hypogonadal women previously treated with EE2 maintained the increased PHIt caused by the latter, but not owing to a greater increase in PHI1.

Pulsatile luteinizing hormone–releasing hormone therapy in women with polycystic ovary syndrome

Induction of ovulation with pulsatile luteinizing hormone-releasing hormone (LH-RH) therapy was attempted in 48 women with polycystic ovary disease (PCOD) and clomiphene citrate (CC) resistant anovulation. Fourteen women ovulated regularly, 23 ovulated variably, but 11 did not ovulate at all. Fifty-two of the 108 cycles of pulsatile LH-RH therapy alone (15 μ gm per pulse, one pulse every 90 minutes) administered through the subcutaneous route were ovulatory. In patients who did not ovulate on subcutaneous LH-RH, treatment with CC (100 mg per day for 5 days) was added to the LH-RH therapy in an additional 33 cycles, of which 21 were ovulatory. In those who did not respond to the combination of treatments, the same dose of LH-RH was administered intravenously: 14 of 29 cycles of intravenous therapy were ovulatory. The overall cumulative conception rate after 6 months of therapy was 60%. When recalculated for ovulatory cycles alone it was 90%, indicating that failure of ovulation was the only cause of the failure of conception. Analysis of the clinical and endocrine findings indicated that failure to ovulate was associated with obesity and hyperandrogenization. Ten of the 23 conceptions ended in miscarriage, 8 within 4 weeks of ovulation. The authors conclude that infertility in patients with PCOD is not optimally corrected by pulsatile LH-RH therapy.

Long-term treatment of central precocious puberty with an intranasal LHRH analogue: control of pituitary function by urinary gonadotropins

Daily subcutaneous doses of luteinizing hormone-releasing hormone (LHRH) analogues are a well-established therapy for gonadotropin-dependent precocious puberty. Reports on intranasally administered analogues, however, are controversial. We studied the effect of intranasal D-Ser(TBU)6-LHRH(BUS) on growth rate, skeletal maturation, and urinary gonadotropins in five girls and one boy with central precocious puberty (CPP) who had been treated for 1.4-2.3 years (mean 1.9). Because of the potential antifertility effects of LHRH analogues, testicular histology was analysed in the boy. In the five children with accelerated growth, the bone age-related velocity of height gain decreased from 10.58 +/- 2.77 to 5.82 +/- 1.8 cm/year (means +/- SD, P less than 0.01), and the ratio of change in bone age to change in chronological age fell below 1. Basal luteinizing hormone (LH), and LHRH-stimulated LH and follicle stimulating-hormone, at pubertal levels before treatment, decreased significantly in all children, normalizing in four (P less than 0.04). During therapy, pituitary function was best controlled by urinary LH, which correlated with clinical data. After 13 months of therapy, testicular histology showed degenerated Sertoli cells, and absence of B- and Ap-spermatogonia and of primary spermatocytes in the boy. We conclude that: (1) Efficient long-term suppression of central precocious puberty--including accelerated growth and skeletal maturation--can be maintained by intranasal dosage of BUS. (2) Urinary LH reflects pituitary function and proves to be a reliable guide to adjustment of the LHRH-analogue dose regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of luteinizing hormone releasing hormone on the copulatory behavior of hyperprolactinemic male rats

The present study was undertaken to test the hypothesis that the deficits in copulatory behavior observed in hyperprolactinemic male rats may be related to a reduction in hypothalamic release of luteinizing hormone releasing hormone (LHRH). Adult male Fischer 344 rats were made hyperprolactinemic by ectopic pituitary grafts or were sham operated and 30 min prior to being tested for copulatory performance received a single subcutaneous injection of 500 ng LHRH, 100 ng LHRH, or saline. On different occasions, testosterone (T) levels were measured in plasma collected 30 min following identical treatments. Plasma prolactin (PRL) levels were determined in samples collected 30 min after injection of 500 ng LHRH. Pituitary grafting produced the expected, significant increase in plasma PRL levels and significant deficits in copulatory behavior. Treatment of hyperprolactinemic subjects with 500 ng LHRH significantly reduced both the time to first intromission and the time to ejaculation to times comparable with those of sham-operated subjects. The 100-ng dose produced a significant reduction in mount frequency. Plasma T levels were significantly elevated following either dose of LHRH. These results demonstrate that exogenous LHRH can restore normal copulatory performance in hyperprolactinemic male rats and support the hypothesis that a reduction in hypothalamic LHRH release is responsible for the behavioral deficits observed in those animals.

Contraceptive Studies with Luteinizing Hormone - Releasing Hormone Agonists

Attempts to produce azoospermia in men with luteinizing hormone-releasing hormone (LHRH) agonists combined with testosterone for short and long-term trials are described. LH is probably more important for FSH in controlling endogenous testosterone production. LHRH agonists given alone will lower testosterone to 2.1 nmol/L after 4 weeks simultaneously reducing libido and potency reversibly. Short-term administration of the LHRH agonist Nafarelin 10 and 100 mcg daily stimulates LH FSH and testosterone levels temporarily followed by a progressive decline. Adding daily testosterone injections did not block the initial increase but lowered LH and FSH even further. Long term experiments (28 days) with the daily sc injections of the LHRH agonist [D-Nal(26)6]LHRH combined with 200 mg testosterone biweekly lowered sperm counts variably. When the trials were repeated with continuous sc infusions of LHRH agonists for 28 days LH FSH and testosterone levels were similar to those seen with intermittent injections. Another long-term trial for 16 weeks using continuous infusion and twice as high a dose of LHRH 400 mcg with 200 mg bimonthly doses of testosterone lowered sperm counts significantly in 7 men to 92% below normal. Basal LH levels did not decline below normal FSH showed a biphasic response and testosterone levels were normal. Libido and potency were not diminished. There are many questions on the mechanism of action of these analogs their safety and whether partial azoospermia is sufficient to prevent pregnancy.