Suppression Of Luteinizing Hormone Research Articles

The Role of Nutrition in the Regulation of Luteinizing Hormone Secretion by the Opioidergic, Dopaminergic, and Serotonergic Systems in Female Mediterranean Goats1

This study examined which neural mechanism (opioid, dopaminergic, or serotonergic system) is involved in the regulation of luteinizing hormone (LH) secretion, with and without nutritional modulation, at different times of the photoperiodic cycle. Goats were randomly distributed into two experimental groups that received either 1.1 (high group; n = 18) or 0.7 (low group; n = 18) times the nutritional maintenance requirements. The goats were exposed to alternations of 3 mo of long days and 3 mo of short days. Plasma LH concentrations were measured twice a week. The effects of intravenous injections of naloxone (endogenous opioid receptor antagonist), pimozide (dopaminergic(2) receptor antagonist), and cyproheptadine (serotonin 5-hydroxytryptamine(2) receptor antagonist) on LH secretion were assessed during challenges in three different photoperiodic situations: the onset of LH stimulation by short days (OnsetSD), the onset of LH inhibition by long days (OnsetLD), and during the LH inhibition by long days (LateLD). The role of the different neural systems was clearly modified by the level of nutrition. In the low-nutrition group, only naloxone increased LH concentrations during onsetLD (P < 0.05). However, in the high-nutrition group, naloxone increased the concentration and pulsatility of LH (P < 0.05) in onsetSD and onsetLD. Pimozide increased LH concentration and pulsatility (P < 0.05) in onsetLD and LH concentration in lateLD (P < 0.001). Finally, cyproheptadine significantly increased LH concentration at all three times (P < 0.001). These results provide evidence that all three systems are involved in the inhibition of LH release in onsetLD, and that the opioid and serotonin mechanisms are involved during the onsetSD that were enhanced by a high plane of nutrition.

The role of gonadotropins in the follicular phase

Folliculogenesis in humans is a lengthy process that involves several regulators. Pituitary gonadotropins play crucial roles in the late stages, particularly in the last 15 days of follicle maturation. During the intercycle rise of follicle-stimulating hormone (FSH), selection of the dominant follicle takes place. This is a complex process that also involves locally produced substances. At the same time, luteinizing hormone (LH) stimulates the synthesis of androgens, which serve as the substrate for the production of estrogens. During the second half of the follicular phase, the follicle becomes dependent on LH. Induction of multiple follicular development by exogenous FSH results in a marked suppression of endogenous LH. For normal follicle maturation, both an LH threshold and an LH ceiling have been considered. In the context of an in vitro fertilization program, application of protocols for ovarian stimulation that will prevent the marked suppression of endogenous LH secretion might provide a better approach to treatment optimization.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol

Objective To compare the effects on ovarian activity of two oral contraceptives containing nomegestrol acetate (NOMAC)/17β-oestradiol (E2) or drospirenone (DRSP)/ethinylestradiol (EE).Methods In this open-label, randomised, six-cycle study, 32 subjects using NOMAC/E2 (2.5–1.5 mg; 24/4-day regimen) were compared to 16 subjects using DRSP/EE (3 mg–30 μg; 21/7-day regimen). Measurements included serum oestradiol, progesterone, follicle stimulating hormone (FSH) and luteinising hormone (LH), and ultrasonography of follicular diameter.Results No ovulations occurred during treatment. Progesterone was fully suppressed, with mean maximum values <2 nmol/l in both groups over all cycles. For NOMAC/E2, mean maximum follicular diameter decreased from 19.3 mm before treatment to between 6.9 and 8.2 mm during treatment, with no subject having a follicular diameter ≥15 mm. For DRSP/EE, a decrease from 19.6 to between 7.4 and 10.8 mm was observed, with two subjects (12.5%) having a maximum follicle diameter ≥15 mm. These findings were consistent with observed FSH reductions; full suppression of LH surges was observed in both groups. Post-treatment return of ovulation in both groups occurred on average 21 days after the last active tablet intake.Conclusions NOMAC/E2 achieves consistent ovulation inhibition, with suppressive effects on the ovaries at least similar to those of DRSP/EE.

Stress and the timing of breeding: Glucocorticoid-luteinizing hormones relationships in an arctic seabird

In birds, stressful environmental conditions delay the timing of breeding but the underlying mechanisms are poorly understood. The stress hormone corticosterone appears to be a good candidate for mediating the decision to breed and when to start egg-laying, via a possible inhibition of luteinizing hormone (LH) and sex-steroids production. We used luteinizing hormone releasing hormone (LHRH) challenge in pre-laying male and female Black-legged kittiwakes ( Rissa tridactyla) to test whether LH and testosterone secretion were depressed by elevated corticosterone levels. Females bearing high baseline corticosterone levels showed reduced baseline LH levels and a low ability to release LH, following LHRH challenge. Further, females bearing low baseline LH levels and elevated baseline corticosterone levels were more likely to skip breeding. However, non-breeding females were physiologically primed for breeding, since they mounted high LHRH-induced LH release. Egg-laying date was advanced in good body condition females but was unaffected by hormones secretion. In males, corticosterone levels had no effect on LH and/or testosterone secretion and did not affect their decision to breed. Interestingly, males with high LHRH-induced testosterone release bred early. Our study highlights clear sex-differences in the HPG sensitivity to stress hormones in pre-laying kittiwakes. Because females have to store body reserves and to build up the clutch, they would be more sensitive to stress than males. Moreover, intrasexual competition could force male kittiwakes to acquire reproductive readiness earlier in the season than females and to better resist environmental perturbations. We suggest that high testosterone releasing ability would mediate behavioural adjustments such as courtship feeding, which would stimulate early egg-laying in females.

Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats

We have previously shown that urocortin 2 (Ucn 2), a member of the corticotropin-releasing factor (CRF) peptide family that binds to CRF type 2 receptor, is expressed in proopiomelanocortin (POMC) cells of rat pituitary and that its secretion and expression are increased by CRF in both the anterior and intermediate lobes and suppressed by glucocorticoids in the anterior lobe. We have also shown that Ucn 2 secreted by POMC cells acts on gonadotrophs expressing CRF type 2 receptors and inhibits the expression and secretion of gonadotropins. In the present study, we examined whether pituitary Ucn 2 is involved in stress-induced inhibition of gonadotropin secretion. A 90-min period of immobilization stress increased POMC mRNA expression without influencing Ucn 2 mRNA expression and suppressed luteinizing hormone (LH) β-subunit mRNA expression in the anterior lobe and plasma LH levels, while it increased both POMC and Ucn 2 mRNA expression in the intermediate lobe of the pituitary. Pretreatment with anti-CRF IgG blocked immobilization-induced increases in plasma ACTH and corticosterone and in POMC mRNA expression in both pituitary lobes and Ucn 2 mRNA expression in the intermediate pituitary. It also blocked immobilization-induced suppression of plasma LH and LH β-subunit mRNA expression. Pretreatment with anti-Ucn 2 IgG blocked immobilization-induced suppression of plasma LH and LH β-subunit expression without affecting immobilization-induced ACTH and corticosterone release and POMC or Ucn 2 mRNA expression. These results suggest that CRF suppresses the secretion and expression of LH probably through pituitary Ucn 2 in stress.

The effects of dexamethasone and prednisolone on pituitary and ovarian function in the mare

Persistent mating induced endometritis is among the most common causes of infertility in the mare. Recently, improved pregnancy rates have been reported when corticosteroids were administered to 'problem mares' specifically, to modulate the post mating inflammatory response; however, the effect of treatment on pituitary and ovarian function requires further study. To evaluate the effects of prolonged treatment with glucocorticoids on pituitary and ovarian function. Eighteen cycling Quarter Horse mares in early oestrus were assigned randomly to one of 3 treatment groups: dexamethasone 0.05 mg/kg bwt i.v. twice a day, prednisolone 0.5 mg/kg per os twice a day, or placebo for 5 days. Mares were examined by ultrasound daily to evaluate reproductive function. Blood samples were collected daily to measure luteinising hormone (LH), progesterone and cortisol levels. Dexamethasone treatment caused greater (P<0.05) suppression of endogenous cortisol concentration (9.4 +/- 1.1 ng/ml) compared to prednisolone- (41.9 +/- 4.0 ng/ml) or placebo-treated mares (32.4 +/- 3.8 ng/ml). After 24 h, mares treated with dexamethasone exhibited lower uterine oedema scores than prednisolone- or placebo-treated mares. An ovulation rate of 40% was observed in dexamethasone-treated mares (2/5) compared to 83% for prednisolone (5/6) and 100% for placebo-treated (6/6) mares. An absence of a LH surge was noted in 3 of 5 dexamethasone-treated mares and one of 6 prednisolone-treated mares. Repeated administration of dexamethasone to mares in oestrus is associated with decreased uterine oedema, suppression of LH and a high rate of ovulation failure. It is recommended that dexamethasone treatment is limited to only 1 or 2 days and that a lower dose is considered in the management of persistent mating induced endometritis to avoid potential adverse affects on reproductive function.

Gonadotropin-Regulated Lymphangiogenesis in Ovarian Cancer Is Mediated by LEDGF-Induced Expression of VEGF-C

The risk and severity of ovarian carcinoma, the leading cause of gynecologic malignancy death, are significantly elevated in postmenopausal women. Ovarian failure at menopause, associated with a reduction in estrogen secretion, results in an increase of the gonadotropic luteinizing hormone (LH) and follicle-stimulating hormone (FSH), suggesting a role for these hormones in facilitating the progression of ovarian carcinoma. The current study examined the influence of hormonal stimulation on lymphangiogenesis in ovarian cancer cells. In vitro stimulation of ES2 ovarian carcinoma cells with LH and FSH induced expression of vascular endothelial growth factor (VEGF)-C. In vivo, ovariectomy of mice resulted in activation of the VEGF-C promoter in ovarian carcinoma xenografts, increased VEGF-C mRNA level, and enhanced tumor lymphangiogenesis and angiogenesis. Seeking the molecular mechanism, we examined the role of lens epithelium-derived growth factor (LEDGF/p75) and the possible contribution of its putative target, a conserved stress-response element identified in silico in the VEGF-C promoter. Using chromatin immunoprecipitation, we showed that LEDGF/p75 indeed binds the VEGF-C promoter, and binding is augmented by FSH. A corresponding hormonally regulated increase in the LEDGF/p75 mRNA and protein levels was observed. Suppression of LEDGF/p75 expression using small interfering RNA, suppression of LH and FSH production using the gonadotropin-releasing hormone antagonist cetrorelix, or mutation of the conserved stress-response element suppressed the hormonally induced expression of VEGF-C. Overall, our data suggest a possible role for elevated gonadotropins in augmenting ovarian tumor lymphangiogenesis in postmenopausal women.

The efficiency of progesterone vaginal gel versus intramuscular progesterone for luteal phase supplementation in gonadotropin-releasing hormone antagonist cycles: a prospective clinical trial

We compared the efficiency of progesterone vaginal gel (PVG) with intramuscular progesterone (IMP) supplementation for luteal phase support after in vitro fertilization and embryo transfer in gonadotropin-releasing hormone (GnRH) antagonist cycles. The treatment outcomes were similar for PVG and IMP for luteal support in GnRH-antagonist protocols. With its ease of use, high tolerability by patients, and fewer side effects, PVG can be a successful alternative to IMP.

GnRH antagonist, cetrorelix, for pituitary suppression in modern, patient-friendly assisted reproductive technology

Background: Gonadotropin-releasing hormone (GnRH) analogues are used routinely to prevent a premature luteinizing hormone (LH) surge in women undergoing assisted reproductive technology (ART) treatments. In contrast to GnRH agonists, antagonists produce rapid and reversible suppression of LH with no initial flare effect. Objective: To review the role of cetrorelix, the first GnRH antagonist approved for the prevention of premature LH surges during controlled ovarian stimulation in modern ART. Method: A review of published literature on cetrorelix. Results: Both multiple- and single-dose cetrorelix protocols were shown to be at least as effective as long GnRH agonist regimens for pituitary suppression in Phase II/III clinical trials. Furthermore, cetrorelix co-treatment resulted in similar live birth rates but a shorter duration of gonadotropin stimulation, a lower total gonadotropin dose requirement and lower incidence of ovarian hyperstimulation syndrome compared with long agonist regimens. A single-dose cetrorelix protocol further decreased the number of injections required. Preliminary studies have also produced promising data on the use of cetrorelix in modified ART protocols, such as frozen embryo transfer and donor oocyte recipient cycles. Conclusion: Cetrorelix offers a potential therapeutic alternative to GnRH agonists during controlled ovarian stimulation and has become an integral part of modern, patient-friendly reproductive medicine.

GPR30 Differentially Regulates Short Latency Responses of Luteinising Hormone and Prolactin Secretion to Oestradiol

Rapid, nongenomic actions of 17beta-oestradiol (E(2)) on hypothalamic neurones that may be relevant to reproductive function were described decades ago. The orphan G protein-coupled receptor, GPR30, was recently shown to bind oestrogens and to trigger rapid signalling in vitro, and is expressed in several rat and human brain regions, including the hypothalamus. We used two complementary approaches to investigate the role of GPR30 in hypothalamic responses to E(2) that are relevant to reproductive physiology. Serial blood sampling after the acute administration of the selective GPR30 agonist G1 was used to assess the role of GPR30 in short latency negative-feedback inhibition of luteinising hormone (LH) secretion and facilitation of prolactin secretion in ovariohysterectomised female rats. In vivo RNA interference (RNAi), mediated by adeno-associated virus-expressing small hairpin RNA (shRNA) infused into the mediobasal hypothalamus, was used to study the effects of GPR30 knockdown on these rapid responses to E(2). Longer-term actions of E(2) on female sexual behaviour (lordosis) were also examined in female rats subjected to in vivo RNAi. Administration of E(2) or G1 triggered a short latency surge of prolactin secretion, and animals subjected to GPR30 RNAi showed significantly less E(2)-dependent prolactin release than animals receiving control virus. G1 did not mimic E(2) negative-feedback inhibition of LH secretion, and GPR30 RNAi did not interfere with E(2) suppression of LH or facilitation of lordosis behaviour. These findings suggest that activation of GPR30 promotes short latency prolactin secretion but does not mediate E(2) negative-feedback inhibition of LH secretion or E(2) facilitation of female reproductive behaviour.

Arrest of pulsatile luteinizing hormone (LH) secretion during insulin-induced hypoglycemia (IIH): improvement by intrahypothalamic perfusion with glucose.

Insulin-induced hypoglycemia (IIH), as with many other acute stressors, restrains the activity of the reproductive axis, reducing luteinizing hormone (LH) release. In adult ovariectomized, steroid-primed rats, we investigated the effect of IIH and of mediobasal intrahypothalamic perfusion with glucose (200 mg/dl) on pulsatile LH secretion. IIH led to a significant decrease in all pulsatility parameters studied using PC-Pulsar analysis, e.g. pulse amplitude and frequency, maximum and baseline LH levels (p < 0.05 versus control), and LH overall mean release (p < 0.01 versus control). Intrahypothalamic perfusion with glucose normalized LH pulse frequency, improved maximum and baseline levels, and partially ameliorated LH pulse amplitude and overall mean release. Thus, our results show that the glucoprivic cessation of LH release is restored, at least partially, by an adequate glucose supply to the hypothalamus; it is proposed, in view of these and previous results, that different mechanisms in the CNS may be involved in LH suppression observed during IIH.

Pubertal Administration of DEHP Delays Puberty, Suppresses Testosterone Production, and Inhibits Reproductive Tract Development in Male Sprague-Dawley and Long-Evans Rats

Although is clear that exposure to high dosage levels of some phthalates delays the onset of puberty in the male rat, it has been hypothesized that low levels of di(2-ethylhexyl) phthalate (DEHP) accelerate puberty by enhancing testicular androgen synthesis. The current study was designed to determine if the dose response to DEHP was nonmonotonic, as hypothesized. Pubertal administration of DEHP delayed the onset of puberty and reduced androgen-dependent tissue weights in both Long-Evans (LE) and Sprague-Dawley (SD) male rats 300 and 900 mg DEHP/kg/day. These effects were generally of greater magnitude in LE than SD rats. By contrast, alterations in testis histopathology (300 and 900 mg/kg/day) were more severe in SD than in LE rats. Taken together, these results suggest that DEHP may be acting on the pubertal male rat testis via two modes of action; one via the Leydig cells and the other via the Sertoli cells. Treatment with DEHP generally reduced serum testosterone and increased serum luteinizing hormone (LH) levels, demonstrating that the reduction in testosterone was due to the effect of DEHP on the testis and not via an inhibition of LH from hypothalamic-pituitary axis. Testosterone production ex vivo (with and without human chorionic gonadotropin stimulation) was consistently reduced in males at the time of puberty and shortly thereafter. DEHP treatment did not accelerate the age at puberty or enhance testosterone levels at 10 or 100 mg/kg/day in either LE or SD rats, as some have hypothesized. Taken together, these results do not provide any evidence of a nonmonotonic dose response to DEHP during puberty.

Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat

The orexigenic gut peptide ghrelin negatively modulates the hypothalamic–pituitary–gonadal (HPG) axis. Hyperghrelinaemia results during negative energy balance, a state often associated with delayed puberty and disrupted fertility, whilst exogenous ghrelin suppresses pulsatile luteinising hormone (LH) secretion. The recent identification of kisspeptin (Kiss1) and its G protein-coupled receptor (GPR)54 (Kiss1r) as an essential component of the HPG axis controlling gonadotrophin secretion raises the possibility that kisspeptin-Kiss1r signalling may play a critical role in the transduction of ghrelin-induced suppression of LH. Ovariectomised oestrogen-replaced rats were implanted with intravenous catheters and blood samples collected for detection of LH pulses prior to and after intravenous administration of ghrelin (3 nM/250 μl) or saline (250 μl) during ad libitum feeding or after overnight fasting. Quantitative RT-PCR was used to determine Kiss1 and Kiss1r mRNA levels in brain punches of the key hypothalamic sites regulating gonadotrophin secretion, the medial preoptic area (mPOA) and arcuate nucleus (ARC), collected 6 h following administration of ghrelin. Ghrelin significantly lowered LH pulse frequency in fed rats, an effect significantly enhanced by food deprivation. Fasting, ghrelin or their combination down-regulated Kiss1, without affecting Kiss1r, expression in the mPOA, and affected the expression of neither in the ARC. Considering the pivotal role for kisspeptin signalling in the activation of the HPG axis, the ability of ghrelin to down-regulate Kiss1 expression in mPOA may be a contributing factor in ghrelin-related suppression of pulsatile LH secretion.

Effect of Mesterolone* on Plasma L.H., F.S.H. and Testosterone

An attempt to determine the effect of mesterolone on plasma luteinizing hormone (LH) follicle stimulating hormone (FSH) and testosterone levels is reported. Subjects were 4 normal 23-45 year old males. Each was given 50 mg mesterolone orally 3 times a day for 4 weeks. The full effect of the drug was obtained in 1 week. To show that gonadotropins could be suppressed in these subjects 17alpha-methyl testosterone was given in doses of 25 mg orally 3 times a day for 1 week. Suppression was shown. Also 2 hypogonadal patients with elevated gonadotropin levels were treated with both 17alpha-methyl testosterone or mesterolone for 5 months. Plasma samples were collected at monthly intervals. In another patient with delayed puberty the same treatment with 17alpha-testosterone was given for 9 months followed by mesterolone 25 mg 3 times a day for the next 9 months. Plasma LH and FSH were measured during treatment and for 10 months afterward. Of the 4 normal subjects 2 who were given mesterolone showed significant suppression of gonadotropins 1 showing suppression of both LH and FSH and the other of FSH only (p less than .01). In the other 2 normal subjects there were significant falls in plasma testosterone but plasma LH and FSH were not suppressed (p less than .05). In the hypogonadal patients only administration of 17alpha-methyl testosterone resulted in a satisfactory clinical response. Serial sampling of blood during therapy showed suppression of plasma LH and FSH. Signs of androgen activity were significantly greater with the 17alpha-methyl testosterone treatment than with mesterolone. It is concluded that mesterolone is a weak androgen.

The Ventral Premammillary Nucleus Links Fasting-Induced Changes in Leptin Levels and Coordinated Luteinizing Hormone Secretion

Physiological conditions of low leptin levels like those observed during negative energy balance are usually characterized by the suppression of luteinizing hormone (LH) secretion and fertility. Leptin administration restores LH levels and reproductive function. Leptin action on LH secretion is thought to be mediated by the brain. However, the neuronal population that mediates this effect is still undefined. The hypothalamic ventral premammillary nucleus (PMV) neurons express a dense concentration of leptin receptors and project to brain areas related to reproductive control. Therefore, we hypothesized that the PMV is well located to mediate leptin action on LH secretion. To test our hypothesis, we performed bilateral excitotoxic lesions of the PMV in adult female rats. PMV-lesioned animals displayed a clear disruption of the estrous cycle, remaining in anestrus for 15-20 d. After apparent recovery of cyclicity, animals perfused in the afternoon of proestrus showed decreased Fos immunoreactivity in the anteroventral periventricular nucleus and in gonadotropin releasing hormone neurons. PMV-lesioned animals also displayed decreased estrogen and LH secretion on proestrus. Lesions caused no changes in mean food intake and body weight up to 7 weeks after surgery. We further tested the ability of leptin to induce LH secretion in PMV-lesioned fasted animals. We found that complete lesions of the PMV precluded leptin stimulation of LH secretion on fasting. Our findings demonstrate that the PMV is a key site linking changing levels of leptin and coordinated control of reproduction.

Cardiovascular Effects of Physiological and Standard Sex Steroid Replacement Regimens in Premature Ovarian Failure

Current hormone replacement therapy may not optimize cardiovascular health in women with premature ovarian failure. We compared the effects of physiological and standard sex steroid replacement regimens on cardiovascular health in these women. In an open-label, randomized, controlled crossover trial, 34 women with premature ovarian failure were randomly assigned to 4-week cycles of physiological (transdermal estradiol and vaginal progesterone) and standard (oral ethinylestradiol and norethisterone) therapy for 12 months. Cardiovascular health was assessed by 24-hour ambulatory blood pressure, arterial stiffness, and renal and humoral factors. Eighteen women (19 to 39 years of age) completed the 28-month protocol. Both regimens caused similar suppression of luteinizing hormone and follicle-stimulating hormone and provided symptom relief. In comparison with the standard regimen, physiological sex steroid replacement caused lower mean 24-hour systolic and diastolic blood pressures throughout the 12-month treatment period (ANOVA; P<or=0.0001 for both): systolic blood pressure was 7.3 mm Hg (95% CI: 2.5 to 12.0 mm Hg) and diastolic was 7.4 mm Hg (95% CI: 3.9 to 11.0 mm Hg) lower at 12 months. Although there were no differences in arterial stiffness, physiological sex steroid replacement reduced plasma angiotensin II (ANOVA; P=0.007) and serum creatinine (ANOVA; P=0.015) concentrations without altering plasma aldosterone concentrations. In comparison with a standard regimen, physiological sex steroid replacement in women with premature ovarian failure results in lower blood pressure, better renal function, and less activation of the renin-angiotensin system. These findings have major implications for the future cardiovascular health of young women who require long-term sex steroid replacement therapy.

Degarelix: A gonadotropin-releasing hormone antagonist for the management of prostate cancer

Background: Prostate cancer is the most commonly diagnosed cancer among men. Treatment can include surgery, radiation, chemotherapy, or hormonal manipulation. Gonadotropin-releasing hormone (GnRH) analogues are used to manage prostate cancer by desensitizing the stimulus to synthesize and release gonadotropins, such as luteinizing hormone (LH), which stimulate the synthesis and release of androgens, in turn stimulating the growth of prostate cancer cells. Although effective, these agents have limitations, such as a flare-up of cancer symptoms within the first 2 weeks of starting the drug. Objective: This article reviews the pharmacology, pharmacokinetic and pharmacodynamic characteristics, and clinical data available on the newly approved drug degarelix for use in treating prostate cancer. Methods: A search of the medical literature was performed in January 2009 with the databases MEDLINE and EMBASE (1950-present) and International Pharmaceutical Abstracts (1970–November 2008) using the terms degarelix and FE200486; follow-up searches using the same strategy were conducted in May 2009 and August 2009. Additional sources were identified by scanning available references and online journals and textbooks. Results: GnRH antagonists, such as degarelix, offer clinicians another means to reduce the level of circulating androgens and limit this growth stimulus directed at malignant prostate tissue. Degarelix has been shown in animal studies to antagonize GnRH receptors in the pituitary gland, resulting in a significant reduction in circulating LH and a subsequent decrease in the synthesis of testosterone. Pharmacokinetic analysis suggests that upon subcutaneous administration, degarelix forms a gel depot, from which the drug then distributes to the rest of the body in a first-order manner. A Phase II study of the effect of degarelix in 187 men with prostate cancer found a loading dose of 240 mg to be not significantly better than 200 mg in reducing serum testosterone concentrations to ≤=0.5 ng/mL within 3 days of dosing (200 mg, 88%; 240 mg, 92%). This difference in percentage of patients with testosterone suppression became statistically significant when measured again 1 month into the study (200 mg, 86%; 240 mg, 95%; P = 0.048). Evaluation of 80−, 120−, and 160-mg maintenance doses found all doses effective in maintaining suppression of testosterone, LH, and prostate-specific antigen (PSA); only minor differences were observed during the study period. In a Phase III study of 610 patients with prostate cancer, a loading dose of degarelix 240 mg SC followed by monthly maintenance doses of either 80 or 160 mg was compared with monthly doses of leuprolide 7.5 mg IM. Degarelix was found to be at least as effective as leuprolide in the ability to suppress serum testosterone to ≤=0.5 ng/mL for up to 1 year (degarelix response rate, 80 mg, 97.2%; 95% CI, 93.5%–98.8%; degarelix 160 mg, 98.3%; 95% CI, 94.8%–99.4%; leuprolide response rate, 96.4%; 95% CI, 92.5%–98.2%). Other studies investigating various doses and schedules of degarelix have also been conducted. Adverse effects of degarelix in clinical trials were mild and relatively uncommon and included flushing reactions, injection-site pain, weight gain, and increases in serum transaminase levels. Conclusions: Degarelix offers another option for chemical castration to reduce the androgenic growth stimulus on prostate cancer cells. The manufacturer of degarelix recommends a loading dose of 240 mg SC followed by the first monthly maintenance dose of 80 mg 28 days later. Serum testosterone and PSA concentrations must be obtained to monitor the response during treatment with degarelix.

A Potential Means of Investigating the Role of Luteinizing Hormone in the Pathogenesis of Alzheimer Disease

Editor - I read with great interest the recent review article, “The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis” by Webber et al.1 In this paper and in another article,2 the authors present some intriguing data from various lines of basic, epidemiological and clinical research supporting their hypothesis implicating luteinizing hormone (LH) in the pathogenesis of Alzheimer disease. One might speculate that women who have undergone oophorectomy and men who have undergone orchiectomy might be at increased risk according to this model. Conversely, one would expect that people with lower levels of LH might be less predisposed to Alzheimer disease. If this is true, pharmacological intervention to lower LH levels might potentially decrease this risk. The authors mention Phase II data suggesting stabilization of cognitive function in men with Alzheimer disease from a trial specifically designed to test the potential of leuprolide acetate (leuprolide) (Lupron).3 Leuprolide, along with a similar agent, goserelin acetate (goserelin) (Zoladex), are gonadotropin-releasing hormone (GnRH) agonist analogues that decrease circulating LH levels. GnRH is a hypothalamic hormone that stimulates LH release from the anterior pituitary gonadotrophs when the pituitary is exposed to GnRH in the physiologically normal pulsatile fashion. Although leuprolide and goserelin are agonists at the receptor level, continuous stimulation of the anterior pituitary gonadotrophs by these synthetic analogues paradoxically diminishes LH release. Both agents are commonly used in the treatment of endometriosis, precious puberty and metastatic prostate cancer. Radiation oncologists also frequently use them as adjuvant therapy for locally advanced or high-risk localized prostate cancer. Long-term follow-up has documented improved local control, biochemical control, disease specific survival and overall survival compared to radiotherapy alone for high-risk prostate cancer patients. Given that these studies were prospective, randomized clinical trials, which began in the 1980s, they could perhaps provide additional evidence supporting or refuting the hypothesis. For instance, in the clinical trial RTOG 85–31,4 patients with high-risk prostate cancer were randomized to either indefinite use of goserelin acetate or no treatment following radiation therapy. Thus, a cohort of patients given goserelin (and thus having suppressed LH levels) dating back to 1985 can be compared to a very similar cohort who did not receive such therapy. Definite conclusions, of course, will be limited due to the high percentage of patients who eventually crossed over to the goserelin arm when their disease progressed, the high number of deaths since the trial began, and the possibility that data on Alzheimer disease development over the years was not fully documented. Of note, certain other clinical trials of goserelin or leuprolide and radiation therapy may not be as useful as cohort studies to test the role of LH inAlzheimer disease pathogenesis. A European study5 had an outcome very similar to the RTOG study4 as far as prostate cancer control goes, and many of these men never fully recovered testicular function following withdrawal of the use of adjuvant goserelin for 3 years. Although men in both trials had long-term reductions in testosterone levels and improved prostate cancer control compared to radiotherapy alone, at the completion of the EORTC trial,5 LH levels presumably increased, whereas in the RTOG study4 LH levels remained suppressed. Similarly, although the effect of orchiectomy may be similar to long-term goserelin or leuprolide therapy (i.e. testosterone is decreased to castration levels), the effects on LH will be drastically different with orchiectomy leading to increased LH and “chemical castration” leading to lowered LH. In light of this intriguing hypothesis, it might be interesting and worthwhile to investigate the effects of LH suppression on Alzheimer disease development in these completed, long-term cohorts.

Testosterone Surge: Rationale for Gonadotropin-Releasing Hormone Blockers?

Gonadotropin-releasing hormone (GnRH) agonists currently form the mainstay of management of advanced prostate cancer. They effectively suppress serum testosterone levels, which in turn inhibits tumor growth. However, the initial response to GnRH agonists is a transient increase in the serum testosterone levels. Known as a testosterone surge, this can lead to a worsening of symptoms and can adversely affect survival. Therefore, much interest exists in the development of a new class of drugs-GnRH antagonists-which produce immediate suppression of luteinizing hormone and testosterone without a testosterone surge. The most promising GnRH antagonist to date is degarelix.

Oral contraceptive pretreatment in women undergoing controlled ovarian stimulation in ganirelix acetate cycles may, for a subset of patients, be associated with low serum luteinizing hormone levels, reduced ovarian response to gonadotropins, and early pregnancy loss

Oral contraceptive pretreatment facilitated scheduling of pure FSH/GnRH antagonist cycles but in a small subset of patients was associated with low serum LH levels, reduced ovarian response, and early pregnancy loss. Supplementation with LH could be examined as a possible way to improve cycle outcome.