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We previously reported that a blockade of GnRH receptor activation inhibited the already-initiated C-kinase pathway(s). We tried to investigate whether this finding is a general phenomenon or not. In this study, we employed three GnRH antagonists, [D-Phe2,Pro3,D-Phe6]-GnRH, [Ac-D-Nal-Ala1,D-pCl-Phe2,D-Ser(Rha)6]-GnRH, and [Ac-D-p-Cl-Phe1,2,D-Trp3,D-Lys6,D-Ala10]-GnRH (referred to as #1-, #2-, #3-GnRH antag., respectively). Each antagonist was examined for its potency against GnRH by analyzing its inhibitory effect on LH release from pituitary gonadotrophs as well as on the increase in the cytosolic Ca2+ concentration. As a result, the #1-GnRH antag. was found to be weaker than the other two compounds. Consistent with a previous study, the #3-GnRH antag. inhibited the action of TPA on LH release. However, independently of their potency as GnRH-antagonists, the two other antagonists had no inhibitory effect on TPA-induced LH release. While it is generally accepted that the C kinase pathway plays a major role in the GnRH-induced LH release, not all GnRH antagonists can inhibit LH release by blocking the already-activated C kinase system.

1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

The experiments on 715 adult non-inbred female rats and 111 Wistar male rats have established that the estrogen 11-nitrate of 3-acetoxy-9 alpha,11 beta-dioxyestra-1,3,5(10)-trien-17-one (11-nitrate of dioxyestron (NDE-As) has an oral contraceptive activity which is equal to ethynylestradiol (EE). A combined 14-day administration of NDE-As with various gestagens produces a higher contraceptive effect that does EE used in combination with the same gestagens. A 30-day use of NDE-As with combined acetomepregenol (AMP) results in a more significant and prolonged secretion of luteinizing hormone than does the EE-AMP combination. Unlike ethynylestradiol, NDE-As has no hypertriglyceridemic effect when given in oral doses of 0.25 and 1.25 mg/kg body weight.

Women suffering from premenstrual mastodynia often respond to stimuli of prolactin (Prl) release with a hypersecretion of this hormone. Pharmacological reduction of Prl release by dopamine agonists or treatment with extracts of Agnus castus (AC) improve the clinical situation of patients with such premenstrual symptoms. Extracts of AC contain compounds which inhibit in vivo Prl release in women as well as in vitro from dispersed rat pituitary cells. It is yet unknown whether this inhibitory action of AC is only exerted on Prl release or whether release of other pituitary hormones like LH and FSH is also affected. The effects of AC on LH and FSH release were examined in vitro using rat pituitary cell cultures. To rule out that the Prl-inhibiting properties of AC are at least in part due to a cytotoxic component, pituitary cell cultures were subjected to the MTT test. To assess whether the Prl inhibitory effect of AC preparations is due to compounds acting as dopamine (DA) agonists, we used the corpus striatum membrane DA receptor binding assay. Our results demonstrate for the first time that AC extract contains an active principle that binds to the D2 receptor. Thus, it is very likely that it is this dopaminergic principle which inhibits Prl release in vitro from rat pituitary cells. Furthermore we give evidence for the specificity of action of AC on hormone release, since gonadotropin secretion remained unaffected. The findings of the present study support the therapeutical usefulness of AC extracts for treatment of premenstrual mastodynia which is associated with hypersecretion of Prl. Furthermore, the beneficial effects of AC appear to be due to the inhibition of pituitary Prl release.

Infertility is common in patients with a history of bilateral cryptorchidism, even after successful prepubertal orchidopexy. Recent data suggest that this defect may be partially due to the existence of hormonal abnormalities in some forms of cryptorchidism. To analyze any potential benefit of hormonal therapy, we have evaluated the immediate and long-term effects of chronic hormonal therapy administered following surgical correction of cryptorchidism. First, using young male rats, we examined the effects of chronic human chorionic gonadotropin (HCG) and a luteinizing hormone-releasing hormone agonist (LHRH-A), alone or combined, on acute pituitary-gonadal axis responsiveness to LHRH administration. High doses of HCG and/or LHRH-A induced deleterious effects on the pituitary-testicular axis in terms of suppression of response to LHRH. Therefore, treatment with a low dose of HCG (50 U/kg/day) for 14 days was used, since it produced a significant increase in intratesticular testosterone (ITT). Second, we tested this hormonal regimen in a cryptorchid rat model. Bilateral cryptorchidism was produced by gubernaculum resection at 14 days of age. Early orchidopexy was performed at age 30 days, and HCG therapy was given from 31 to 44 days of age. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) levels were determined before and immediately after hormonal therapy, and at sacrifice. Animals were sacrificed at 61 days of age for determination of serum and testicular hormone levels, accessory sex organ weights and testis histology. Five or six animals from each group were retained for breeding studies at the age of 90 days. Hormonal alterations noted immediately following treatment of cryptorchid animals with HCG are not lasting. The data reveal that the fertility defect in bilateral cryptorchidism is partially prevented by early orchidopexy and that adjunctive hormonal therapy is probably of little additional benefit.

A luteolytic dose (500 micrograms) of cloprostenol was given four days before expected estrus to five mature cyclic cows of native Taiwan Yellow cattle. Blood samples were collected at hourly intervals for 60 hours and then twice daily (0800 h and 1600 h) until onset of the following estrus or Day 29 after prostaglandin (PG) injection. Plasma progesterone levels were quite low in the follicular phase and elevated over an 11-13 day period during the luteal phase for every animal. Two cows showed peak luteinizing hormone (LH) levels of 19.97 and 23.77 ng/ml of plasma at 120 and 127 h after PG injection. One cow did not show peak LH level during the 60-h sampling period, but had its highest concentration of 18.02 ng/ml at 0800 h on Day 8. Two cows showed no detectable peak LH during the 60-h sampling period or on subsequent days. But these two cows had increased concentrations of progesterone beginning on Day 6 and Day 12. All animals came back into estrus 23-28 days after PG treatment.

Antiovulatory action of chlormadinone acetate (5 mg twice daily from day 7 to day 25) has been assessed in 6 healthy volunteers by daily determination of plasma FSH, LH, estradiol and progesterone. Hormonal profiles during the second treated cycle show that preovulatory gonadotropin surge is blunted and that no significant progesterone secretion occurs. Estradiol production is variable up to the middle of the cycle, and then homogeneously low normal. Menstrual cyclicity is respected and ovarian function is restored during the first cycle after treatment disruption.

Recent evidence has implicated the central nervous system as a target organ for canatoxin, a toxic protein present in Canavalia ensiformis seeds. This toxin activates the lipoxygenase pathway of arachidonic acid metabolism and can thus induce the release of substances mediated by lipoxygenase products. In the present study, the circulating levels of luteinizing hormone (LH) were measured by RIA in male Wistar rats (200-240 g) after the administration of canatoxin into the lateral cerebral ventricle. Canatoxin (0.5-2 micrograms in 2 microliters daily for 3 days) caused a dose- and time-dependent increase in the plasma levels of LH. The total dose of canatoxin used is subconvulsive. At 2, 4 and 24 h after 2 micrograms of canatoxin LH levels were increased by 10%, 43% and 61%, respectively, compared to vehicle-injected animals (0.18 +/- 0.03 ng/ml). This response to 2 micrograms of canatoxin was not attenuated by pretreatment with two different lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA, 125 mg/kg) or esculetin (ECLT, 125 mg/kg), ip, 1 h before each canatoxin (CNTX) injection; % increase in LH with CNTX alone: 61%; CNTX+NDGA: 54%; CNTX+ECLT:76%; N = 5/group. These data show that intracerebral injection of CNTX in rats increases circulating levels of LH via a mechanism that is independent of the lipoxygenase pathway.

Polycystic ovarian syndrome (PCO) occurs frequently in hirsute patients. A dissociated explosive response of LH to LHRH administration has been associated with the diagnosis of PCO. Twenty-four of 58 women seen because of hirsutism were found to have ovarian dysfunction based on clinical signs such as anovulation and irregular menstrual cycles. Plasma androgen levels were elevated in the patient group. The LHRH test (200 micrograms, iv) was applied to the 24 patients and compared with 13 normal ovulatory controls. Serum FSH levels before and after the LHRH test were normal in all patients. Two patterns of LH response to LHRH stimulation were observed: an explosive response in 17 patients (delta LH: 39.4 +/- 21.8 IU/l, control group: 7.35 +/- 4.4 IU/l, P < 0.01) and a normal response in 7 patients (delta LH: 7.53 +/- 2.41 IU/l). There was a significant correlation (r = 0.63, P < 0.05) between basal LH levels and LH response to LHRH. Sensitivity and specificity calculated for basal LH levels higher than 6.0 IU/l, considering the LHRH test as reference, were 58% and 85%, respectively. The positive predictive value measuring the possibility of LH higher than 6.0 IU/l to be from a patient with PCO (explosive response to LHRH) was 92%. These data suggest that, in hirsute anovulatory patients, basal LH levels may be a good predictor in the diagnosis of polycystic ovarian syndrome.

A slow-release gonadotropin-releasing hormone (Gn-RH) analogue was administered to 30 males suffering from chronic cluster headache (CH) in a placebo-controlled study with the aim of enhancing neurotransmission in the pain-suppressing systems of the hypothalamus through a feedback action involving neuroendocrine functions too. A significant improvement in the severity of the pain occurred together with the expected lowering of the libido and serum levels of testosterone and luteinizing hormone. We postulate that the benefit of the Gn-RH analogue relates to an impairment of neuronal modulation in cluster headache.

The formamidine pesticide chlordimeform (CDF) has been found to interfere with the hormonal control of ovulation in the rat by a presumptive disruption in the catecholaminergic regulation of the midcycle surge of luteinizing hormone (LH). While the brain hypothalamic mechanisms underlying generation of the hamster surge have not been as well-defined, there is evidence for an adrenergic component. The present experiments were designed to investigate the effects of CDF on ovulation in the golden hamster and whether any observed alterations are associated with differences in the appearance of the surge. Intraperitoneal CDF injections (0, 75, 150, or 200 mg/kg) at 1400 hr on proestrus caused a dose-related reduction in oocytes retrieved at 0700 hr on the day of estrus. Additional experiments demonstrated that this effect was due to a delay in ovulation and not a decrease in the complement of oocytes released. Doses of 150 or 200 mg/kg at 1100 hr or 200 mg/kg at 1600 hr were without a comparable ovulatory effect. Characterization of the LH surge indicated that there was a dose-related delay, but that this effect was not sufficient to account for the delay in ovulation. Animals dosed at 1100 hr (150 or 200 mg/kg) exhibited shifts in the surge identical to those animals injected at 1400 hr, but did not show any such detectable effects on the time of oocyte release. CDF administered at 1100 or 1400 hr also caused alterations in serum estradiol and progesterone, even at a relatively low dose of 37.5 mg/kg. The results indicate that CDF given at a time just prior to the preovulatory rise in LH is able to impede ovulation in the hamster by possibly influencing some ovulatory event(s) triggered by the surge. Also, the ability of CDF to alter the timing of LH release is consistent with catecholaminergic participation in the generation of the gonadotropin signal stimulating the final events leading to ovulation. Under the present conditions, this perturbation can be characterized as a delay in the LH trigger, rather than a blockade.

Among the low dose oral contraceptives that is to say less than 50 mcg of ethinylestradiol per pill one must single out the pills made of a third generation progestagen (desogestrel, gestodene, norgestimate) from the others. The contraceptive efficacy (tested on the Pearl index) according to the files of government authorities visa (AMM) is equivalent for all the oral contraceptives whatever their composition (between 0 to 0.07 women year). The clinical tolerance of the low dose pills of the 3rd generation is comparable to that of the other low dose pills. Is there any advantage then in prescribing them? The most important advantage is the decrease of metabolic and vascular effects. The use of so-called third generation progestive, besides the beneficial effects an lipidic and glucidic metabolisms, has mainly enabled the decrease of the estrogen doses of progestagens. The ethinylestradiol is directly implicated in the risk of venous thrombosis: hemostasis the modifications are less important with 30 mcg than with 50, 20 than 30 mcg. Relying on theoretical arguments one could have estimated that minipills would lead to an insufficient ovarian slow down. These hypothesis are contradicted by recent studies from Falsetti and Benagiano who studied the rates of FSH and LH under minipills. This does not include the variability and the individual sensitiveness of the patients and as well the reason following which minipills would favor functional ovarian cysts, lies on the confusion made between a cyst and a 20 mm diameter follicule.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To assess the efficacy and safety of a long-acting gonadotropin-releasing hormone analogue (GnRHa), leuprolide acetate for depot suspension (Lupron Depot), in the treatment of central precocious puberty in children, and to determine the reversibility of GnRHa therapy after it has been discontinued., Research Design: Children with documented central precocious puberty were treated with Lupron Depot for 1.6 to 3.5 years. Their course of pubertal development, growth rate, skeletal maturation, and response to gonadorelin hydrochloride testing were compared before and during treatment. For those girls who finished treatment, an assessment of the reversibility of the GnRHa was performed by documenting a return to pubertal responses to gonadorelin testing, and by documenting menarche at an appropriately mature bone age., Setting: Community teaching hospital., Patients: Ten girls with central precocious puberty defined as pubertal maturation statistically advanced for age combined with a pubertal gonadotropin response to gonadorelin testing. Children who had been treated for less than 1.5 years were excluded, as were those with congenital adrenal hyperplasia. Patients who finished treatment have been followed up for up to 5 years, and will continue in follow-up throughout their reproductive life. SELECTION SAMPLE: A consecutive group of children with documented central precocious puberty was studied., Interventions: Lupron Depot was administered as a single monthly subcutaneous injection to each patient. Treatment was usually discontinued by 10 to 11 years of age, at which time pubertal progression was allowed to resume., Measurement and Results: Mean peak serum concentrations of follicle-stimulating and luteinizing hormone responses to gonadorelin testing decreased significantly after the initial dose (from 21.8 +/- 4.5 [+/- SEM] to 2.4 +/- 0.2 IU/L for follicle-stimulating hormone and from 50.1 +/- 11.2 to 5.0 +/- 0.8 IU/L for luteinizing hormone) and remained suppressed for the duration of treatment. The progression of puberty slowed or reversed in all patients. Mean growth rate for chronologic age was significantly increased initially by 3.9 SDs and decreased to 0.9 SDs during treatment. The mean rates of skeletal maturation divided by the change in chronologic and height age changes over time were advanced (1.4 +/- 0.1 and 1.1 +/- 0.15, respectively) at the onset of therapy and decreased significantly to 0.7 +/- 0.1 and 0.8 +/- 0.1, respectively, on treatment. There was an increase in mean predicted height of 3.4 cm for all patients, and this was statistically significant. Thus, treatment with Lupron Depot at least maintained the predicted height at the onset of therapy. Girls who completed their course of treatment had pubertal gonadotropin responses to gonadorelin testing within 2 to 6 months, and menarche within the first year if skeletal maturation reached 13.0 to 13.5 years. No significant side effects of therapy were noted., Conclusions: Treatment of central precocious puberty in children using Lupron Depot is safe and efficacious. Its effects are readily reversible after treatment is discontinued, and menarche occurs at a normal bone age. Measurement of serum luteinizing hormone concentrations using an assay that is specific for the beta-subunit is necessary to monitor chemical suppression of luteinizing hormone during treatment. Longer-term studies, including reproductive history, will be needed before the potential effects of treatment on fertility can be assessed.

The use of purified FSH versus classical hMG for normo-ovulatory women superovulation in an IVF programme could reduce the spontaneous LH surges incidence and/or increase the numbers of retrieved oocytes and transfers. In poor responders the advantage of high FSH doses is very discussed. Because of possible adverse effects of LH excess, high responders remain theoretically the best indication. Nevertheless only few prospective studies showed a significant reduction of multiple pregnancies and hyperstimulations by pure FSH. Most effective seems to be using low gonadotropins doses.

The effects were studied of in vivo administration of the new opioid antagonist-estrogen hybrid, naltrexone-estrone azine (EH-NX), on subsequent luteinizing hormone-releasing hormone (LHRH)-stimulated luteinizing hormone (LH) release by the pituitary gland in vitro. It is well known that administration of estrogen exerts negative and positive effects on the pituitary LH response to LHRH, respectively after short-term and long-term treatment. Rats were injected subcutaneously with either 17 beta-estradiol-3-benzoate (EB), EH-NX or oil on days 18 and 19 (long-term treatment), and on day 21 (short-term treatment) following ovariectomy. Twenty minutes later the animals were killed and the pituitary glands were incubated in the presence of LHRH (1000 ng/ml) for 4 h. Whereas short-term treatment with EB on day 21 did not affect LH release in vitro, EH-NX significantly decreased the pituitary LH response to LHRH in oil pretreated rats. This inhibitory effect was partially blocked by the opioid antagonist naltrexone. After long-term EB or EH-NX, followed by short-term oil treatment, the pituitary LH response to LHRH was increased considerably, compared to the long-term oil controls. These observations demonstrate that the opioid antagonist estrogen hybrid EH-NX has estrogenic activity at the level of the pituitary gland. This hybridized drug is more effective in time than EB and an equimolar amount of EH (estrone hydrazone) to induce the negative estrogenic effect.

The hypothesis that endogenous opioids might have a role in mediating the suppressive effects of nicotine on serum LH concentrations in rats was investigated. Naltrexone treatment prevented the inhibitory effect of high doses of nicotine on serum LH concentrations. Nicotine treatment also prevented the stimulatory effect of naltrexone on serum LH concentrations. These results suggest that the inhibitory effects of nicotine on serum LH concentrations involve an opioidergic component.

Administration of n-methyl-d, l-aspartate (NMA) to pigs in vivo increased GH and suppressed LH secretion. Cultures of anterior pituitary cells from pigs in the follicular phase (FOL; n = 3) and luteal phase (LUT; n = 3) of the estrous cycle, and ovariectomized (OVX; n = 10) pigs were treated with NMA (10(-4), 10(-6) or 10(-8) M) or the NMA antagonist, 2-amino-5-phosphonopentanoic acid (AP5; 10(-4), 10(-6) or 10(-8) M), to determine if NMA affects the pituitary directly. Secreted LH and GH were measured at 4 h after treatment. Basal LH and GH secretion (control; C) were 1.1 +/- 0.6, 4.4 +/- 2.1 and 5.6 +/- 1.3 ng/well and 5.2 +/- 1.2, 7.5 +/- 1.2 and 5.2 +/- 1.7 ng/well for FOL, LUT and OVX, respectively. Relative to C, 10(-4) M NMA increased (P < 0.001) LH secretion 2.4-, 2.2- and 5.1-fold in FOL, LUT and OVX cultures, respectively. The effect of 10(-4) M NMA was inhibited by 10(-4) M AP5 (P < 0.05) in FOL cultures, but not in OVX cultures. GnRH increased (P < 0.001) LH levels 3.1-, 2.3- and 3.8-fold in FOL, LUT and OVX cultures, respectively. Relative to C, 10(-4), 10(-6) and 10(-8) M NMA increased (P < 0.03) GH secretion 1.5-, 1.5- and 2.3-fold in LUT and 1.7-, 2.3- 2.0-fold in OVX cultures, respectively. AP5 alone or in combination with NMA failed to alter basal GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

The sheep exhibits a marked sex difference in the timing of the pubertal increase in luteinizing hormone (LH). Male lambs undergo a reduction in sensitivity to inhibitory steroid feedback, leading to an increase in LH by 10 weeks of age, but females remain hypersensitive until 30 weeks of age. Endogenous opioids suppress LH secretion in the female lamb prepubertally and in adult male and female sheep. It has been suggested that a reduction in opioid inhibition of LH secretion is the signal to time puberty. Therefore, if a decrease in opioid tone occurs during sexual maturation, it should begin earlier in the male lamb than in the female. The objective of this study was to compare opioid inhibition of LH secretion in male and female lambs in relation to the timing of puberty. Our approach was to examine the response to the opioid antagonist naloxone at various ages in both sexes. To determine the timing of the pubertal LH rise in the presence of constant inhibitory steroid feedback, male and female lambs (n = 5 each) were gonadectomized at 3 weeks of age and implanted with a Silastic capsule of estradiol. They were then challenged with naloxone at 5, 11, and 23 weeks of age; blood samples were collected every 12 min for 8 hours, and lambs received naloxone (1 mg/kg i.v.) at hours 4, 5, 6, and 7. Mean LH before and during naloxone treatment was compared at each age.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the role of neuropeptide Y (NPY) in the regulation of puberty, the effects of various doses of NPY or saline injected into the 3rd ventricle of peripubertal female rats were determined. A single injection of NPY at a dose range of 10-20 micrograms into the 3rd ventricle of 30-day-old female rats advanced the time of vaginal opening (VO) and first ovulation by 4 days, as compared to saline-treated controls. Ova number and ovarian, adrenal and uterine weights at first estrous were similar in all animals regardless of treatment. The NPY-treated precocious animals showed lower body weight than did the VO-matched controls, but showed similar body weight as that of age-matched controls. Determination of plasma luteinizing hormone (LH) levels in the peripubertal female rats revealed that plasma LH was increased transiently immediately after NPY administration. Also, NPY-treated rats which had precocious puberty showed elevated pituitary and plasma LH levels on the day of VO. These results suggest that NPY can activate the hypothalamic-pituitary-gonadal axis to precociously initiate puberty.

The effect of endogenous opioid peptides (EOP) on LH secretion is variable during different physiological states. A series of experiments concerning the role of EOP on LH secretion in cyclic gilts was performed. They were comprised of (1) an administration of an opioid antagonist or agonist in gilts during the estrous cycle and in ovariectomized (OVX) gilts in which the LH surge was induced with estradiol benzoate (EB) and (2) in vitro studies on GnRH release from the stalk median eminence (SME) of cyclic gilts and OVX estrogen and progesterone primed gilts in response to naloxone (NAL). Naloxone and met-enkephalin analogue (FK 33-824) administration as a single independent injections did not affect LH secretion during the early (Day 16) or late (Day 19 or 20) follicular phase. However, continuous infusion of FK 33-824 for 4 h decreased LH secretion during the infusion period on Day 19 of the estrous cycle. Morphine also exerts an inhibitory effect on the EB-induced LH surge during the positive feedback phase (60-64 h after EB administration) in OVX gilts. On the contrary, NAL infusion in OVX gilts during the negative feedback phase (30-34 h after EB administration) did not alter LH secretion. A single injection of FK 33-824 in luteal phase gilts decreased the number of LH pulses for a 3 h period. This allows to hypothesize that EOP participates in the regulation of pulsatile LH secretion in pigs during the luteal phase. In vitro studies indicate that influence of EOP on LH secretion also takes place at the SME level. GnRH efflux from the SME of gilts during the luteal and late follicular phases was augmented in the presence of NAL. Unexpectedly, the priming of OVX gilts with estrogens caused the highest increase in GnRH release from the SME in vitro in response to NAL. These results confirm the variety of functional links between the opioid system and LH secretion in gilts during different stages of the estrous cycle.

The functionality of the oestrogen-positive feedback mechanism is the basis for the preovulatory LH surge and thus for regular cyclic activity in the sow. The LH surge mechanism (LH SM) gradually matures as a function of age, immature gilts display delayed, low amplitude LH surges in response to oestradiol benzoate (OB). The maturation of the LH SM apparently is ovarian oestrogen-dependent. Continuous ovarian secretions, probably oestrogens, also appear to be necessary for the final peripubertal maturation of the LH SM and to maintain the functionality of this mechanism in the sexually mature gilt. Superphysiological levels of oestrogens are, however, detrimental to the development of the LH SM. Failure of various infusions of the opioid antagonist naloxone during the surge period to enhance the magnitude of OB-induced LH surges in immature gilts does not support the idea, that central opioidergic systems are of major importance in preventing mature LH surge response at this age. However, opioids could be involved in the termination of the LH surge. Experiments using the opioid agonist morphine and the antagonist naloxone to demonstrate that opioids are involved in the generation of the LH surge in the mature gilt have so far provided equivocal data. Studies using pulsatile infusions of LHRH or of a potent LHRH-agonist during the surge period in OB-treated immature gilts, in which endogenous LHRH release was blocked by methallibure, suggest that oestradiol fails to generate mature LH surges because the gonadotrophs of the immature gilt are unable to respond to enhanced LHRH secretion during the surge period in an adult-like manner. During early lactation the LH SM cannot be activated by OB, while during late lactation a partial recovery of the LH SM occurs. Minor breed differences exist in the functionality of the LH SM during lactation between LW sows and highly fertile Chinese Meishan sows, in which lactational anoestrus is not obligatory.

We recently demonstrated that pulsatile LH secretion is associated with pulsatile gonadotropin releasing hormone (GnRH) in the pig. Endogenous opioid peptide (EOP) inhibition of pulsatile LH and prolactin (PRL) secretion is dependent on reproductive status and development of this EOP system is a brain maturational process independent of the ovary. Once sexual maturation has occurred, EOP then become part of a progesterone dependent system and EOP inhibit a noradrenergic component of this system. During lactation, EOP also inhibit pulsatile LH, but stimulate PRL secretion. N-methyl-d,l-aspartate (NMA), an agonist of the excitatory amino acids (EAA), aspartate and glutamate, suppressed LH secretion in gilts pretreated with progesterone or vehicle. Both the EOP agonist, morphine (MOR), and the EOP antagonist, naloxone (NAL), delayed emergence and time to maximum serum LH concentration of the estradiol-induced LH surge in prepuberal and mature gilts, respectively. Therefore, EOP may normally have both a permissive as well as an inhibitory role in the LH surge mechanism. Although a norepinephrine synthesis inhibitor failed to alter basal PRL secretion, the PRL increase after NAL was suppressed in progesterone-treated ovariectomized (OVX) gilts. NAL suppressed the PRL response to NMA in OVX gilts pretreated with oil vehicle or progesterone, indicating that NMA stimulation of PRL secretion is mediated through the EOP system.

The effects of bombesin receptor antagonist RC-3095 and gastrin-releasing peptide [GRP (14-27)] on basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels, as well as on the release of LH and FSH in response to LH-releasing hormone, were studied in normal and castrated male rats. We also examined the release of LH and FSH after intracerebroventricular injection of RC-3095 under different types of anesthesia (urethane, sodium pentobarbital, Metofane). Following injection of 10 micrograms RC-3095 into the lateral brain ventricle, serum LH levels were rapidly and significantly (p < 0.001) lowered. This effect lasted for at least 60 min and was not affected by the type of anesthetic used. Serum FSH levels were not affected by intracerebroventricular administration of RC-3095 or GRP (14-27), indicating different central control mechanisms between LH and FSH release. The suppressive effect of RC-3095 on LH release could be completely prevented by prior intracerebroventricular administration of GRP (14-27) at a dose of 1 micrograms, but intravenous administration of either peptide RC-3095 or GRP (14-27) did not change the basal levels of LH, FSH, and testosterone. The pituitary LH response to LH-releasing hormone was also not modified by intravenous administration of RC-3095. These results indicate that bombesin-like peptides might be involved in control of LH release from the pituitary by an action on the CNS which is mediated by specific bombesin receptors.

The purpose of the work was to answer the question whether time of haemodialysis treatment affects the secretion of lutropin (LH) in patients with chronic renal failure. The study was carried out in 41 men with chronic renal failure and 15 healthy controls. There were three groups of hemodialyzed patients. The first one comprised 17 patients dialyzed up to 50 months, the second one 14 patients treated during 51-100 months and the third one 10 patients hemodialyzed for more than 100 months. In all these subjects the test of stimulation with luliberin (LH-RH) was done. Significantly higher serum levels of LH were found in patients as compared to controls. No significant alterations in LH levels were observed in the groups of patients. After administration of LH-RH the reactivity of LH secretion was significantly lower in patients dialyzed longer than 50 months then in men dialyzed shorter and in controls. These facts suggest an influence of long-term dialysis treatment on the secretion of LH in men with chronic renal failure.

An experiment was conducted to test the hypothesis that the effect of body fatness on LH pulsatility in post-partum cows is entirely independent of the negative feedback effects of ovarian steroids. Forty beef cows were fed in the last 100 d of gestation so that they achieved either a thin (mean score 1.97) or fat (mean score 2.79) body condition (0 to 5 scale) at calving and were fed after calving to maintain live weight and body condition. At 15 (sd 3.7) d post partum all cows were ovariectomised and half from each body condition score treatment group received a subcutaneous estradiol implant (+EST) while the remainder received no implant (-EST). At weeks 5 and 9 post-partum blood samples were collected via jugular catheter every 20 minutes for 10 hr on two consecutive d and on the third d cows were injected via the jugular vein with 2.5 micrograms GnRH. Blood samples were collected every 15 minutes for 1 hr before and 2 hr after GnRH injection. At 5 and 9 weeks the fatter cows had significantly higher mean LH concentrations, baseline LH concentrations, LH pulse amplitudes and pulse frequencies (P < 0.01). Implantation with estradiol in both fat and thin cows reduced mean LH concentrations, baseline LH concentrations, LH pulse amplitudes and pulse frequencies (P < 0.001). The lack of interaction between body condition and the presence or absence of estradiol implies that the effect of body condition on LH release is independent of ovarian steroid feedback mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Acute (0.5-4 h) treatment of estradiol (E)-primed female rat pituitary cells with progesterone (P) augments gonadotropin-releasing hormone (GnRH)-induced LH release, whereas chronic (48 h) P-treatment reduces pituitary responsiveness to the hypothalamic decapeptide. Dispersed E-primed (48 h, 1 nM) rat pituitary cells were cultured for 4 or 48 h in the presence of 100 nM P to assess the effects of the progestagen on GnRH receptors and on gonadotrope responsiveness to the decapeptide. P-treatment (4 h) significantly augmented GnRH-receptor concentrations (4.44 +/- 0.6 fmol/10(6) cells) as compared to cells treated only with E (2.6 +/- 0.5 fmol/10(6) cells). Parallel significant changes in GnRH-induced LH secretion were observed. The acute increase in GnRH-receptor number was nearly maximal (180% of receptor number in cells treated with E alone) within 30 min of P addition. Chronic P-treatment (48 h) significantly reduced pituitary responsiveness to GnRH as compared to E-treatment. The GnRH-receptor concentrations (3.9 +/- 0.6 fmol/10(6) cells), however, remained elevated above those in E-primed cells. GnRH-receptor affinity was not influenced by any of the different treatments. These results indicate that the acute facilitatory P-effect on GnRH-induced LH release is at least chronologically closely related to an increase in GnRH-receptor concentration. The chronic negative P-effect on pituitary responsiveness to GnRH, however, shows no relation to changes in available GnRH receptors.

The effects of n-methyl-d,l-aspartate (NMA), a neuroexcitatory amino acid agonist, on luteinizing hormone (LH), prolactin (PRL) and growth hormone (GH) secretion in gilts treated with ovarian steroids was studied. Mature gilts which had displayed one or more estrous cycles of 18 to 22 d were ovariectomized and assigned to one of three treatments administered i.m.: corn oil vehicle (V; n = 6); 10 micrograms estradiol-17 b/kg BW given 33 hr before NMA (E; n = 6); .85 mg progesterone/kg BW given twice daily for 6 d prior to NMA (P4; n = 6). Blood was collected via jugular cannulae every 15 min for 6 hr. Pigs received 10 mg NMA/kg BW i.v. 2 hr after blood collection began and a combined synthetic [Ala15]-h GH releasing factor (1-29)-NH2 (GRF; 1 micrograms/kg BW) and gonadotropin releasing hormone (GnRH; .2 micrograms/kg BW) challenge given i.v. 3 hr after NMA. NMA did not alter LH secretion in E gilts. However, NMA decreased (P < .02) serum LH concentrations in V and P4 gilts. Serum LH concentrations increased (P < .01) after GnRH in all gilts. NMA did not alter PRL secretion in P4 pigs, but increased (P < .01) serum PRL concentrations in V and E animals. Treatment with NMA increased (P < .01) GH secretion in all animals while the GRF challenge increased (P < .01) serum GH concentrations in all animals except in V treated pigs. NMA increased (P < .05) cortisol secretion in all treatment groups. These results indicate that NMA inhibits LH secretion and is a secretagogue of PRL, GH and cortisol secretion with ovarian steroids modulating the LH and PRL response to NMA.

To evaluate the possible role of central dopaminergic suppression of gonadotropin secretion in the genesis of amenorrhea associated with anorexia nervosa (A.N.), a central D-2 dopamine receptor blocker was administered to 10 women with A.N. and 10 regularly menstruating age-matched controls. Serum prolactin and luteinizing hormone (LH) levels were measured at -15, 0, 30, 60, 120, and 180 min after administration of metoclopramide (10 mg orally). Mean basal prolactin (p less than 0.001) and estradiol levels (p less than 0.02) were significantly lower in women with A.N. The prolactin response to metoclopramide was significantly impaired in women with anorexia nervosa. No correlation was found between the prolactin response and percentage ideal body weight. Basal and post-stimulation prolactin levels were correlated with estradiol levels. After adjusting for the effects of estradiol, significant differences between patients with A.N. and controls remained in prolactin levels at baseline (p less than 0.01), 120 min (p less than 0.02) and 180 min (p less than 0.05). Metoclopramide did not induce a significant rise in LH levels in either the A.N. or control groups. These data are consistent with central dopaminergic inhibition of prolactin secretion in anorexia nervosa but do not support the hypothesis that central dopaminergic inhibition is related to diminished LH release in this state.

Although endogenous opioids seem to play an important role in the inhibition of luteinizing hormone releasing hormone (LHRH) secretion in women with hypothalamic amenorrhea, opioid antagonism does not always cause an increase of pituitary luteinizing hormone (LH) secretion. The effect of the long-acting oral opiate antagonist naltrexone on pulsatile LH secretion was studied in eight women with weight loss and exercise-related hypothalamic amenorrhea. LH pulse studies and LHRH tests were performed in basal conditions and after 4 days of naltrexone treatment, 50 mg q.d. Naltrexone caused a slight, but significant increase of LH pulse frequency. Six weeks later, a second experiment was performed. The response to naltrexone was studied after enhancement of the pituitary sensitivity. Patients were pretreated with pulsatile LHRH during 4 days, followed by naltrexone 50 mg q.d. during 4 days. An increased LH response to LHRH, but no response to naltrexone, were seen after discontinuation of pulsatile LHRH. It is concluded that the limited pituitary response to opioid antagonism, observed in weight loss-related forms of hypothalamic amenorrhea, is not caused by pituitary insensitivity to LHRH.

In order to test the possible role of estradiol in the response of the LH-adenohypophyseal cells to the administration of met-enkephalin in the albino male rat, an immunocytochemical (peroxidase-antiperoxidase), morphometric (cellular and nuclear areas and numerical density) and radioimmunoassay (LH serum levels at the moment of sacrifice) study was carried out. The intraventricular administration of met-enkephalin (150 micrograms in 25 microliters of distilled water) does not produce any changes in the parameters considered. However, when the animals were pretreated with estradiol (chronically, 15 days), met-enkephalin produced a significant decrease in all the parameters considered.

Sixty-seven patients whose ovulation was stimulated following a protocol of Clomiphene Citrate/HMG in order to carry out in vitro fertilisation were divided randomly in to two groups. In the first group ovulation was provoked by giving 10,000 IU HCG IM, but in the other group ovulation was provoked by releasing endogenous LH after the administration of Triptoreline in a dose of 0.1 mg in a dose subcutaneously three times in one day at 8 hour intervals. The number of oocytes recovered, cleavage and embryo transfer were compared between the two groups over 48 cycles. The number of conceptions was statistically significantly higher in the group that had triptoreline (28%) as compared with 17.4% pregnancies in the other group (p less than 0.01). These figures confirm that the endogenous LH surge provoked by giving an LHRH agonist can cause adequate final oocyte maturation. This property which is associated with a very low risk of hyperstimulation, should make it possible to stimulate ovulation when it is not used for IVF and so replace the usual injection of chorionic gonadotrophins.

During treatment of prostate cancer patients with luteinizing hormone-releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-LHRH should prevent the "flare-up" phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000 micrograms/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6-LHRH agonist (50 micrograms/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000 micrograms/rat 3 days prior to administration of the agonist significantly lowered LH response (P less than 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500 micrograms/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000 micrograms/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D-Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500 micrograms/rat) on LH secretion could be totally suppressed by an injection of 50 micrograms/rat of SB-75 1 hour beforehand.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperandrogenemia in postmenopausal women requires an evaluation to exclude pathologic ovarian or adrenal causes. Our patient exhibited no signs of hypercortisolism, congenital adrenal hyperplasia, or adrenal or ovarian neoplasia based on biochemical testing and pelvic sonography. We hypothesized that unexplained androgen excess in our patient was due to the development of gonadotropin-dependent excess ovarian stromal androgen production. This syndrome may be comparable to gestational hyperreactio luteinalis where elevated gonadotropins stimulate ovarian stromal androgen production. If tumor can confidently be excluded, such women may benefit from gonadotropin suppression with long-acting GnRH-a.

The purpose of the study was to establish the optimal combinations of ethynilestradiol and norethysterone acetate exhibiting a high contraceptive activity. It was shown that the ratio of 1:20 (ethynilestradiol 0.04 mg/kg and norethysterone acetate 0.8 mg/kg) is characterized by a high contraceptive efficacy. The inhibitory effect on the incretion of lutropin and follitropin leading to the change of the process of oogenesis and gravidary reorganization of the endometrium underlies probably the mechanism of action.

In a series of 126 therapeutic cycles in 48 patients with primary infertility and treated with HMG for anovulation or preparation to insemination, ovulation was triggered by endogenous LH instead of HCG when the patient was considered to be at high risk for ovarian hyperstimulation syndrome (OHS), (plasma oestradiol greater than 1200 pg/ml) and/or multiple pregnancy (greater than 3 follicles greater than 17 mm in diameter). The endogenous LH surge was provoked and maintained by intranasal buserelin 200 micrograms three times at 8-hourly intervals. In the 37 cycles with buserelin, no OHS occurred despite high preovulatory levels of oestradiol; a single twin pregnancy was recorded despite the presence of numerous mature preovulatory follicles. Conception results (21.6% pregnancy per therapeutic cycle) compared favourably with HCG administration (16.8%). It is concluded that, when ovulation must be triggered in a hazardous situation, the use of endogenous LH through the administration of a short-acting GnRH analogue prevents the complications of exaggerated follicular stimulation.

To investigate the effects of aging on the secretion of the common alpha-subunit of the glycoprotein hormones, we measured basal levels of luteinizing hormone (LH), testosterone (T) and alpha-subunit in 176 normal men aged 19 to 89 years. In addition, in two groups of young (less than 65 years; n = 25) and old (greater than 65 years; n = 15) subjects, the effects of luteinizing hormone-releasing hormone (LHRH) on LH and alpha-subunit secretion were determined. Age-related increases in serum alpha-subunit and LH were noted only in the oldest men while T levels decreased progressively with advancing age. LHRH stimulation resulted in significantly greater secretion of alpha-subunit in the old subjects while no difference in LH release between young and old men was observed. Moreover, there was a delay to peak LH and alpha-subunit levels after LHRH in the old subjects. These data suggest that the aging process in males involves deficits in both testicular and gonadotroph functions as demonstrated by (1) the relative hypogonadotropic hypogonadism seen until the ninth decade; (2) the hypergonadotropic hypogonadism apparent in men greater than 80 years; (3) the delay in the timing of peak responses of LH and alpha-subunit after LHRH administration; and (4) the disproportionate increase in the secretion of alpha subunit relative to intact LH.

Hormonal influences and pharmacokinetic aspects of the new antiestrogen droloxifene (3-hydroxytamoxifen) have been studied in a total of 148 postmenopausal patients with breast cancer. A negligible decrease in the gonadotropins LH and FSH was observed in patients treated with 20 mg (34 patients) and 40 mg (43 patients) of droloxifene (once daily). Serum concentrations of the gonadotropins obviously decreased (71 patients) with the highest dose of droloxifene (100 mg, once daily) given in this study. Sex hormone binding globulin rose only marginally in the 20- and 40-mg dose group. However, with 100 mg of droloxifene, a moderate increase was found, indicating some estrogenicity at higher doses. Rapid pharmacokinetic characteristics have been confirmed. The time to peak concentration ranges from 2 to 4 h, and the terminal half life is about 24 h, allowing interesting new schedules in endocrine therapy.

The involvement of specific opiate receptors in the suppression of LH release during acute fasting in ovariectomized estradiol-treated rats was examined by intracerebroventricular (i.c.v.) administration of opiate receptor antagonists that exert a specificity directed mainly, although not absolutely, towards the delta-, kappa- or mu-opiate receptors. Fasting for 48 h significantly decreased mean plasma LH levels in estradiol-treated animals by increasing sensitivity to the negative feedback effect of estradiol. Injecting i.c.v. the mu-opiate receptor antagonist naloxone (10 or 100 nmol in 2 microliters of saline) blocked the inhibitory effect of fasting on pulsatile LH release and reinstated LH pulses. On the other hand, i.c.v. administration of the same dosages of a delta-opiate receptor antagonist ICI 174,864 or a kappa-opiate receptor antagonist WIN 44441-3 did not have any effect. These results suggest that the increased sensitivity of the LH-releasing mechanism to the negative feedback effect of estradiol during fasting involves the endogenous opioids mainly through the selective activation of the mu-opiate receptors.

Experiments were staged on immature (21 days) and mature (3.5 mos.) Wistar male rats to investigate the influence of the aromatase inhibitor 1, 4, 6-androstatriene-3, 17-dione on the activity of the aromatase and 5 alpha-reductase enzymatic complexes of the hypothalamus and the blood levels of LH and testosterone (T). The formation of 5 alpha-dehydrotestosterone against a background of aromatase activity inhibition was increased in mature rats and was unchanged in immature animals. The blood levels of LH and T were increased, the reaction of LH in immature animals being more marked. A conclusion has been made of a role of T aromatic transformations in the hypothalamus in tonic inhibition of LH secretion by endogenous T and a possible involvement of this mechanism in the maturation of male rats.

When fertility is desired, idiopathic hypothalamic hypogonadism is amenable to treatment with pulsatile low dosage GnRH administration or injections of gonadotrophins. Patients with this disorder are hypogonadal and require therapy with androgens or oestrogens/progestagens. This would presumably lower pituitary gonadotrophin production even further. However, fertility occurring spontaneously during testosterone substitution, as proven by paternity testing, has been described twice. The present report adds two more cases. It is unwise to make a definite statement about infertility in male patients with this condition.

The effect of tefestrol on the content of luteinising hormone in blood and hypophysis in female and male rats was studied on the basis of the radioimmunological assays. It was shown that administration of tefestrol to the female rats depending on the preparation dose and the time of administration during the estrous cycle can produce an increase and a decrease of luteinising hormone content in the material under study. In the male rats tefestrol induced a stable elevation of blood gonadotropine level. The results obtained suggest that tefestrol may be used as a stimulant of the reproductive function and also as a contraceptive depending on the dose and the functional state of the reproductive system during the treatment.

The in vivo responsiveness of the ovine fetal and neonatal pituitary was investigated using acute and chronic preparations. Several studies were performed on six fetuses and six lambs from 112 days' gestation through 5 weeks after birth. Ten micrograms of gonadotropin-releasing hormone (GnRH) was injected intravenously into each fetus and lamb, and serial blood samples were collected from the fetus, ewe and lamb. The luteinizing hormone (LH) content of each sample was determined by species-specific radioimmunoassay. Both the fetus and the neonate showed a response to GnRH. A significant elevation of LH was found in all animals by 15 minutes. There was no response in the ewe when GnRH was injected into its fetus. Great variability in response was noted among various age groups and between animals, with the maximum individual LH response reaching 33.7 ng/ml. The maximum LH response of the neonate during the first week of life was significantly depressed (p < 0.05) as compared to that of the fetus and the older neonate.

A review of the features of RHLH, especially of the pulsating secretion, which is very important to the correct function of the reproduction system, is presented. Now it is accepted that this pulsating secretion is the producer of the episodic release of gonadotrophins, the gonadal steroids being the modulator of the frequency and the extent of the LHRH pulses. Several experiences showed that changes in the pulse frequency of GnRH, can dynamically modify the seric concentration of LH and FSH.

Fifteen male paranoid schizophrenics underwent an initial 4-week therapy with haloperidol 7.5 mg/day, and a subsequent 4-week treatment with haloperidol 15 mg/day, p.o. (group I). Another 15 male paranoid schizophrenics received an initial 4-week treatment with haloperidol 30 mg/day, and a subsequent 4-week therapy with haloperidol 60 mg/day, p.o. (group II). In each group of patients, serum prolactin (PRL), luteinizing hormone (LH) and testosterone (T) levels were measured before treatment and at the end of the two consecutive periods of treatment. A dose-related increase in serum PRL levels was found in both groups of medicated patients. Serum LH levels were not significantly affected by haloperidol treatment. A significant decrease in serum T levels was detected only in group II medicated patients, i.e., in the patients who were treated with relatively high daily doses (30 or 60 mg/day) of haloperidol.