Cytoreductive surgery (CRS) with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) versus standard of care (SoC) in people with peritoneal metastases from colorectal, ovarian or gastric origin: protocol for a systematic review and individual participant data (IPD) meta-analyses of effectiveness and cost-effectiveness.

INTRODUCTION: There is uncertainty about whether cytoreductive surgery (CRS)+hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improves survival and/or quality of life compared with standard of care (SoC) in people with peritoneal metastases who can withstand major surgery. PRIMARY OBJECTIVES: To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis. SECONDARY OBJECTIVES: To compare the cost-effectiveness of CRS+HIPEC versus SoC from a National Health Service (NHS) and personal social services perspective using a model-based cost-utility analysis. METHODS AND ANALYSIS: We will perform a systematic review of literature by updating the searches from MEDLINE, Embase, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify randomised controlled trials comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of intervention and control, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications and resource utilisation data. Using IPD, we will perform a two-step IPD, that is, calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses, meta-regression and sensitivity analyses. We will also perform a model-based cost-utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting. ETHICS AND DISSEMINATION: This project was approved by the UCL Research Ethics Committee (Ethics number: 16023/001). We aim to present the findings at appropriate international meetings and publish the review, irrespective of the findings, in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019130504.

Infantile ovariectomy potentiates the stimulatory effect of oestrogen/progesterone on LH secretion in the rat.

Ovariectomy of prepubertal rats (9 days of age) eliminates the ability of the opiate peptide FK 33-824 to inhibit LH secretion when tested 19 days later. We have investigated whether this removal of opiate inhibition would modify the LH/FSH response to stimulation with oestradiol benzoate/progesterone priming. Ovariectomy of rats during infancy (9 days after birth) amplifies the stimulatory effects of these steroids on LH/FSH secretion when tested 19 days later. This amplification was not seen in rats ovariectomized before (day 24) or after puberty (day 43) and tested 19 days later. The pituitary content of LH/FSH does not appear to contribute to this phenomenon, though increased responsiveness to injected gonadotrophin-releasing hormone (GnRH) is clearly involved; ovariectomy at day 9 is considerably more effective than ovariectomy at day 24 of life in enhancing the response to GnRH. We conclude that infantile ovariectomy either removes, or prevents the development of, a hypothalamic inhibitory mechanism which normally modulates the responsiveness of the pituitary to stimulation with GnRH.

Short-day exposure eliminates the LH response to naloxone in golden hamsters.

Short-day-induced testicular regression in golden hamsters is accompanied by changes in opiatergic control of LH release. Serum LH in long-day-exposed hamsters is elevated by subcutaneous injections of naloxone. By day 42 of short-day exposure, naloxone is unable to stimulate LH secretion; responsiveness to naloxone is restored after reexposure to long days. The change in response to naloxone may reflect a loss of opiate regulation of LH release; an alternative, but not mutually exclusive, hypothesis is that additional opiate-independent mechanisms inhibit LH despite the blockade of opiate LH inhibition by naloxone.

The inhibitory effect of opiates on gonadotrophin secretion is dependent upon gonadal steroids.

We have attempted to clarify the physiological involvement of endogenous opiates in the steroid-mediated control of gonadotrophin release. Our studies showed that there was an acute reduction in the inhibitory effects of endogenous opiates on LH and FSH release following gonadectomy in the rat. This was indicated by a significant reduction in the ability of naloxone to stimulate serum LH/FSH levels (sampled at 15 min) in 26-day-old female rats 48 h after ovariectomy. Luteinizing hormone was highly sensitive to the inhibitory effects of the synthetic met-enkephalin analogue, FK 33-824, at this time (sampled at 90 min). An unexpected observation was that long-term absence of gonadal steroids also disrupted the ability of exogenous opiates, FK 33-824 and morphine, to influence LH release. This was seen as an inability of FK 33-824 (1.0 or 3.0 mg/kg) to inhibit LH secretion. The effects of gonadectomy on opiate control of LH occurred at all developmental stages and were not due to a disruption of sexual maturation. Opiate involvement in prolactin secretion did not appear to be adversely affected by an absence of gonadal steroids. Another novel aspect of this work was that the opiatergic component in the control of gonadotrophin secretion could be reinstated in long-term gonadectomized rats by treatment with oestradiol benzoate or testosterone propionate. Similarly, priming with increasing dosages of oestradiol benzoate which resulted in progressively lower LH levels gave larger naloxone in progressively lower LH levels gave larger naloxone responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged elevation of hypothalamic opioid peptide activity in women taking oral contraceptives.

To examine the hypothesis that endogenous opioid peptide activity is chronically elevated by oral contraceptives, we infused either naloxone or saline into 10 women during the use of, or 5-6 and 9-10 days after stopping, combination birth control pills. A paradoxical increase in prolactin occurred with naloxone infusion during and 5-6 days after stopping the pills. Serum LH levels were not significantly elevated by naloxone until 9-10 days after cessation of pill use. These results suggest that hypothalamic opioid peptide activity is continuously elevated in women taking oral contraceptives.

Differential effects of flurothyl- and electro-convulsive shock on sexual maturation and prolactin release in the rat.

The effects of single and repeated seizures on luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin secretion and on the onset of sexual maturation in rats are described. In addition, the influence of convulsions generated electrically (electroconvulsive shock, ECS) and chemically (using flurothyl) are compared. Repeated flurothyl convulsions and ECS (one daily convulsion from age 24 days) significantly delay vaginal opening in female rats. The incidence of first ovulation at maturation is reduced to 20% compared with 70-100% for untreated groups. Body and adrenal weights in immature rats are not modified by flurothyl convulsions. Repeated ECS does not influence adrenal weight although somatic growth is inhibited. In an effort to clarify the mechanism of action of convulsions on puberty onset, we examined acute changes in LH, FSH and prolactin secretion and the surge response of LH/FSH to gonadal steroid priming. A single flurothyl convulsion potently inhibits prolactin secretion. In contrast, an ECS acutely stimulates prolactin release in male and female rats. Convulsive seizures do not consistently alter tonic gonadotropin output. However, both flurothyl convulsions and ECS attenuate estradiol benzoate/progesterone-induced LH and FSH surges in ovariectomized rats though this is apparently not mediated by dopamine/prolactin since bromocriptine treatment delays sexual maturation without preventing ovulation at first estrus. Similarly, bromocriptine does not disrupt LH/FSH surges induced by gonadal steroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged estrogen treatment induces changes in opiate, benzodiazepine and beta-adrenergic binding sites in female rat hypothalamus.

Exposure of the rat brain to estradiol is known to modify certain neurotransmitter binding sites. We have now examined the influence of long-term (3 months) treatment with this steroid. Opiate and benzodiazepine receptors are both elevated in hypothalamus but not in amygdala or cerebral cortex. In contrast, the affinity, but not maximum binding, of hypothalamic beta-adrenergic sites is reduced 5-fold. Our results confirm and extend previous reports that hypothalamic neurotransmitter binding sites are particularly sensitive to estrogen feedback.

Opiatergic control of gonadotropin secretion during puberty in the rat: a neurochemical basis for the hypothalamic 'gonadostat'?

We have examined (1) the effects of naloxone and an opiate peptide, FK 33-824, on LH and FSH secretion in immature male and female rats and (2) the influence of sexual maturation on the ability of this peptide to inhibit LH secretion. FK 33-824 potently inhibits LH secretion in the 48-h-gonadectomized rat. This effect could be blocked by coinjection of naloxone, suggesting that the peptide exerts its influence through opiate receptors. An endogenous opiate component in the control of LH secretion was demonstrated by examining the effect of naloxone injection alone. Naloxone rapidly stimulated LH secretion in the intact or the acutely gonadectomized rat. Naloxone or FK 33-824 did not modify LHRH-stimulated release of gonadotropins from organ cultures of anterior pituitary obtained from immature rats. This suggests, in agreement with other reports, that naloxone or FK 33-824 controls LH secretion via a central, possibly hypothalamic site. We further observed a clear age-related reduction in LH sensitivity to FK 33-824 in the acutely (48-h) gonadectomized rat. Dose-response studies indicated a 4-fold reduction in opiate responsiveness in the 10 days preceding the first ovulation. Thus, the doses required to reduce serum LH levels by 50% are 0.03, 0.04, 0.16, and 0.17 mg/kg, respectively, for the groups 12, 23, 29, and 33 days of age. In the male, a similar change was noted when responsiveness was compared in pre- and postpubertal rats; 50% inhibition was achieved at 0.25, 0.89, and 0.88 mg/kg FK 33-824 for rats aged 26, 70, and 90 days, respectively. The shift in sensitivity to FK 33-824 is probably not due to a change in clearance rates, but this cannot be completely ruled out. Thus, our demonstration of a maturation-related reduction in opiate inhibition of LH suggests a critical role for endogenous (hypothalamic?) opiate peptides and opiate receptors in the onset of sexual maturation. Our results may also provide a neurochemical basis for the well described shift in hypothalamic sensitivity to gonadal steroids that occurs with the approach of puberty.

Photoperiodic modification of opiate but not beta-adrenergic or benzodiazepine binding sites in hamster brain.

Exposure to short photoperiods induces gonadal regression in the golden hamster. This is accompanied by a fall in serum gonadotropins and changes in hypothalamic neurotransmitter turnover. We have attempted to correlate these changes with alterations in neurotransmitter receptor binding parameters. Compared to hamsters held in long photoperiods, opiate ([3H] naloxone) binding in hamsters exposed to short photoperiods is elevated in whole brain and in cerebral cortex but not in hypothalamus. However, beta-adrenergic ([3H] dihydroalprenolol) and benzodiazepine ([3H] flunitrazepam) binding are unaffected in whole brain, cerebral cortex or hypothalamus. Thus, changes in hypothalamic noradrenaline turnover rate previously reported may not be correlated with changes in beta-adrenergic binding.

Opiatergic control of LH secretion is eliminated by gonadectomy.

We have studied the stimulatory effects of naloxone and the inhibitory influence of the opiate peptide, FK 33-824, on LH secretion in the gonadectomized rat. Our results indicate that endogenous and exogenous opiate involvement in LH release disappear coincident with the removal of gonadal steroid feedback. At 7 days post-surgery naloxone is no longer able to stimulate LH secretion in male or female rats. Similarly, by 7 days in the male, and 21 days in the female, FK 33-824 is unable to inhibit LH secretion. We conclude that the coupling of hypothalamic opiate receptors to the LH regulatory mechanisms is dependent upon gonadal steroids. The most important of these appear to be estradiol and testosterone, since careful priming of long-term gonadectomized rats with these steroids is able to largely restore the LH responses to naloxone and FK 33-824.

Opiate binding to brain slices and ontogenesis of hypothalamic [(3)H]naloxone binding sites.

We have developed a radioligand binding assay based on the use of hypothalamic slices and have examined the ontogenesis of [(3)H]naloxone binding sites in male and female rats. [(3)H]NAL binding is reversible, saturable, stereospecific, of high affinity, readily displaceable by morphine and is sensitive to phenoxybenzamine. These characteristics suggest that [(3)H]NAL readily binds to opiate receptors in brain slices. With this assay we have demonstrated that: (a) there is an age-related increase in opiate binding sites in rat hypothalamus, (b) there are sex differences in the binding affinity of the sites and (c) the values of Bmax are approximately 2-5-fold higher than the levels previously reported from assays with brain homogenates.

Flurothyl-induced convulsions delay the onset of sexual maturation in the female rat.

We have investigated whether sexual maturation in female rats is affected by repeated flurothyl-induced convulsions. This treatment had no effect on the normal age-related increase in body weight though puberty (vaginal opening) was significantly delayed when compared with non-convulsed control rats. In an attempt to probe the mechanism of this delaying effect we observed that (1) anterior pituitary response to gonadotrophin releasing hormone in vitro was normal in terms of LH release but FSH secretion was impaired and (2) progesterone injection in oestrogen-primed convulsed rats failed to generate an ovulatory-type surge of LH or FSH. Basal serum levels and basal in-vitro secretion of LH and FSH were normal. We conclude that repeated convulsions adversely affect the hypothalamo-pituitary-gonadotrophin system of immature female rats.

Repeated convulsions induce pseudopregnancy in the intact rat and inhibit steroid-mediated gonadotrophin secretion in the ovariectomized rat.

We have investigated the effects of repeated flurothyl-induced seizures on reproductive function in the female rat. This treatment rapidly induced a state of pseudopregnancy in intact cyclic rats. Prolactin is clearly implicated in this response since treatment with bromocriptine readily counteracted the influence of the convulsions. The mechanism of action of repeated seizures was further characterized in experiments on ovariectomized rats. Thus, 11 daily convulsions, but not a single acute seizure, were able to inhibit the positive feedback effect of progesterone on LH and FSH release in oestrogen-primed animals. In this model also the pituitary gland response to gonadotrophin releasing hormone in vitro was significantly reduced. However, the convulsions had no effect on basal serum or basal in-vitro secretion of LH and FSH in ovariectomized or oestrogen-treated ovariectomized rats. Thus, repeated seizures modified the hypothalamo-pituitary axis in such a way as to prevent it from responding to stimulation. Our results indicate that normal reproductive function in the female rat is very sensitive to repeated seizures and suggest that similar effects may be evident in women subjected to electroconvulsive shock therapy. The successful use of bromocriptine in reversing the influence of seizures in the rat suggests its use in man also.

A puberty-related attenuation of opiate peptide-induced inhibition of LH secretion.

The long-acting synthetic enkephalin FK 33-824 (FK) potently inhibits LH secretion in gonadectomized prepubertal male and female rats. The effect is reversible by coinjection of naloxone. We have observed an age-related decrease in the ability of FK to reduce LH secretion in the 48 h post-gonadectomized rat. Thus, the IC50 values (i.e. the dose required to give 50% reduction in LH levels) for 12, 23 and 33-day old female rats were 0.03, 0.04 and 0.17 mg/kg BW, respectively. The figures for pre- and post-pubertal male rats (ages 26 and 70 days) were 0.25 and 0.89 mg/kg BW, respectively. This attenuation of opiate-induced inhibition of LH release may provide a neurochemical basis for the well-described shift in sensitivity of gonadal steroid feedback which occurs with the approach of puberty.