John Guillebaud

The incidence of chronic scrotal pain after vasectomy : a prospective audit

To assess the extent of scrotal pain in men before and after vasectomy, to produce accurate data for the benefit of men considering this procedure, and hence improved informed consent about the outcomes, as chronic scrotal pain after vasectomy is a poorly quantified clinical problem.

Two hundred out-patient laparoscopic clip sterilizations using local anaesthesia

Female sterilization using clips applied laparoscopically under local anaesthesia was used in 200 women. Apart from two patients in whom there were technical difficulties, the operation was completed without complication and without immediate or delayed morbidity. The technique, which avoids the risks of general anaesthesia, is commended as a safe, simple method of sterilization suitable for, and acceptable to, the majority of women.

Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens.

The effects of irreversible α1‐adrenoceptor antagonists, SZL‐49 (an alkylating analogue of prazosin), dibenamine and benextramine on contractions to noradrenaline (NA) in longitudinal and circular muscle of human epididymal vas deferens were investigated. Competitive α1‐adrenoceptor antagonists were also used to further characterize the α1‐adrenoceptor subtype stimulated by NA in longitudinal and circular muscle. NA evoked concentration‐dependent contractions of both muscle types (pD2; 5.4 and 5.2 respectively). The contraction of circular muscle was comparatively more sensitive than that of longitudinal muscle to pretreatment with SZL‐49. In contrast, dibenamine or benextramine produced comparable effects in both muscle types. The relationship between receptor occupancy and contraction in either longitudinal or circular muscle was nonlinear, with half‐maximal response requiring similar receptor occupancy (longitudinal muscle 14%, circular muscle 16%). Maximal response in both muscle types occurred with little or no receptor reserve (<10%). The competitive α1‐adrenoceptor antagonists produced dextral shifts of the dose‐response curves to NA in longitudinal and circular muscle. The inhibitory potencies, estimated from the apparent pKB values were significantly different in longitudinal and circular muscle respectively for either WB 4101 (pKB, 8.6 and 9.5) or RS‐17053 (pKB, 7.1 and 9.0) but not for Rec 15/2739 (pKB, 9.2 and 9.8) or HV 723 (pKB, 8.3 and 8.4). In conclusion, the potency profile of the competitive α1‐adrenoceptor antagonists and the lack of different receptor reserves for NA in the muscle types suggest that the discriminatory effects of SZL‐49 is primarily due to a predominance of the α1L‐adrenoceptor subtype in longitudinal muscle and α1A‐subtype in circular muscle.

Functional characterization of α1-adrenoceptor subtypes in longitudinal and circular muscle of human vas deferens

The alpha1-adrenoceptor subtype(s) mediating contraction to noradrenaline in longitudinal and circular muscle of human epididymal vas deferens was studied using competitive antagonists. The effects of the alkylating agents, phenoxybenzamine and chloroethylclonidine were also investigated. Noradrenaline evoked concentration-dependent contractions of longitudinal and circular muscle with comparable potencies (pD2; 5.6 and 5.5 respectively). The contractions in longitudinal and circular muscle respectively were inhibited by prazosin (pA2, 8.6 and pKB, 9.2), 5-methylurapidil (pKB, 8.7 and 9.1) and less potently by spiperone (pA2, 7.1) or BMY 7378 (pKB, 6.3 and 6.6). Contractions of the circular but not longitudinal muscle was comparatively insensitive to pretreatment with phenoxybenzamine. In contrast pretreatment with chloroethylclonidine reduced the contractions in both muscle types and also enhanced phenoxybenzamine-sensitivity in longitudinal but not circular muscle. The results suggest that contractions evoked by noradrenaline in both muscle types of human vas deferens is mediated via activation of alpha1-adrenoceptors with pharmacological profile of the alpha1A-subtype. However the involvement of alpha1A-adrenoceptor variants, such as the hypothesised alpha1L-subtype may underlie the differential effects of phenoxybenzamine in longitudinal and circular muscle. Factors contributing to chloroethylclonidine-sensitivity are discussed.

Perspective on the role of P2X-purinoceptor activation in human vas deferens contractility.

The contractile actions of α,β‐methylene ATP (α,β‐meATP) and ATP and the effects of K+ channel blockers in longitudinal and circular muscles of human vas deferens were investigated with a view to clarifying the functional importance of P2X1‐purinoceptor activation and K+ channels in modulating contractility of the tissues. The results provide an experiment‐based perspective for resolving differing reports on purinergic activation of the tissues and uncertain roles of large‐conductance Ca2+‐activated K+ (BKCa) and voltage‐gated delayed rectifier K+ (KV) channels. α,β‐Methylene ATP (3–100 μm) evoked suramin‐sensitive contractions of longitudinal muscle but rarely of circular muscle. ATP (0.1–3 mm) less reliably activated only longitudinal muscle contractions. These were enhanced by ARL 67156 (100 μm), but a different ectonucleotidase inhibitor, POM 1, was ineffective. Both muscle types were unresponsive to ADP‐βS (100 μm), a P2Y‐purinoceptor agonist. Longitudinal muscle contractions in response to α,β‐meATP were enhanced by FPL 64176 (1 μm), an L‐type Ca2+ agonist, TEA (1 mm), a non‐specific K+ channel blocker, 4‐aminopyridine (0.3 mm), a selective blocker of KV channels, and iberiotoxin (0.1 μm), a selective blocker of BKCa channels. Quiescent circular muscles responded to α,β‐meATP reliably in the presence of FPL 64176 or iberiotoxin. Apamin (0.1 μm), a selective blocker of small conductance Ca2+‐activated K+ (SKCa) channels had no effect in both muscle types. Y‐27632 (1–10 μm) reduced longitudinal muscle contractions in response to α,β‐meATP, suggesting involvement of Rho‐kinase‐dependent contractile mechanisms. The results indicate that P2X1‐purinoceptor stimulation elicits excitatory effects that: (a) lead to longitudinal muscle contraction and secondary activation of 4‐aminopyridine‐sensitive (KV) and iberiotoxin‐sensitive (BKCa) K+ channels; and (b) are subcontractile in circular muscle due to ancillary activation of BKCa channels. The novel finding of differential action by P2X1‐purinoceptor agonists in the muscle types has functional implication in terms of the purinergic contribution to overall contractile function of human vas deferens. The modulatory effects of KV and BKCa channels following P2X1‐purinoceptor activation may be pivotal in providing the crucial physiological mechanism that ensures temporal co‐ordination of longitudinal and circular muscle contractility.

Failure and Regret After Laparoscopic Filshie Clip Sterilization Under Local Anesthetic

OBJECTIVE: To estimate the failure, regret, and reversal rates 5 or more years after laparoscopic Filshie clip sterilization using local anesthesia. METHODS: A total of 1,101 women underwent Filshie clip sterilization between 1983 and 2002. They completed follow-up questionnaires that were analyzed for the following outcomes: failed sterilization, regret after the operation, and sterilization reversal. RESULTS: Two hundred thirty-three of 968 (24%) eligible women sent the questionnaire had moved from their last known address. Of the remaining 735 women, 573 (78%) completed the questionnaire: 223 (39%) 5–6 years after the operation, 175 (30%) after 7–9 years, and 175 (30%) after 10–15 years. One pregnancy occurred 10 months after surgery, and one woman had the procedure repeated when unilateral tubal patency was identified by hysterosalpingography 3 weeks after surgery. Twenty-four (4%) women regretted having the operation; 7 (1.2%) women had a reversal operation, and all subsequently conceived. CONCLUSION: Failure after tubal sterilization using Filshie clips is less than 1:500 operations. Patient selection and surgeons’ experience may have influenced these results. Regret occurred in a small proportion. LEVEL OF EVIDENCE: III

Contractile actions of imidazoline α-adrenoceptor agonists and effects of noncompetitive α1-adrenoceptor antagonists in human vas deferens

Abstract The contractile actions of imidazoline α-adrenoceptor agonists were investigated in human vas deferens longitudinal and circular muscle. The effects of phenoxybenzamine were studied in comparison to dibenamine and SZL-49 (4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-bicyclo[2,2,2]octa-2,5-dienylcarbonyl-2-piperazine), an alkylating prazosin analogue that discriminates between α1H- and α1L-adrenoceptor subtypes. The imidazoline α-adrenoceptor agonist, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide), was a potent agonist (pD2; longitudinal muscle 6.9, circular muscle 6.4) and cirazoline a partial agonist (pD2; longitudinal muscle 6.1, circular muscle 5.1). Oxymetazoline was less effective, indanidine and clonidine were ineffective. SZL-49 produced a differential inhibition of contractions evoked by A-61603 in circular (α1H) compared to longitudinal (α1L) muscle and phenoxybenzamine had the opposite effect. Dibenamine inhibited the contractions comparably in both muscle types and analyses of its partial alkylation of receptors yielded identical estimates of equilibrium dissociation constant (pKd) for A-61603 in longitudinal (5.82) and circular (5.84) muscle. Receptor occupancy–response relationships revealed that whilst the muscle types are not different in receptor reserves for A-61603, contraction to the potent imidazoline is more efficiently coupled in longitudinal than in circular muscle. This underlies the markedly different responsiveness of the muscle types to cirazoline or oxymetazoline (α-adrenoceptor agonists with lower efficacies relative to A-61603).The differential inhibitory actions of phenoxybenzamine and SZL-49 are discussed.

A prospective cohort study of menstrual symptoms and morbidity over 15 years following laparoscopic Filshie clip sterilisation

OBJECTIVE To observe the incidence of menstrual symptoms and relevant surgery after sterilisation. STUDY DESIGN 1101 women sterilised with Filshie clips between 1983 and 2002 were assessed prospectively comparing menstrual symptomatology documented immediately before surgery and 5-14 years later by questionnaire. MAIN OUTCOME MEASURES Prevalence of menstrual dysfunction and subsequent surgery related to pre-operative menstrual symptoms and contraception. RESULTS After excluding 232 (24%) of the 968 eligible women sent questionnaires whose address had changed, 573 of the remaining 735 women (78%) completed the questionnaire, 223 5-6 years after sterilisation, 175 after 7-9 years and 175 after 10-15 years; the respondents were demographically representative of the total population. Heavy periods increased from 9% before to 35% (P<0.0001) after sterilisation, painful periods from 2% to 21% (P<0.0001) and 6% had undergone hysterectomy or endometrial ablation. These findings were not influenced by the pre-sterilisation method of contraception but were inversely related to advancing age (P<0.0002). The lowest rates of menstrual symptoms were reported 10-15 years after sterilisation. CONCLUSION Menstrual symptoms increased following Filshie clip sterilisation irrespective of pre-sterilisation symptoms and contraception. Whatever the causative mechanism, the progestogen-loaded intrauterine system (IUS), with similar efficacy but with improved menstrual symptoms, should be considered before sterilisation.

Contractile actions of L-type Ca2+ agonists in human vas deferens and effects of structurally different Ca2+ antagonists

The actions of L-type Ca(2+) agonists, FPL 64176 and Bay K 8644 were investigated in human vas deferens in the presence of structurally different L-type Ca(2+) antagonists. The L-type Ca(2+) agonists (<or=3 microM, approximately 10 min) produced no detectable contractions but higher concentrations evoked intermittent rhythmic contractility of longitudinal and circular muscles. Exposure to the drugs (1 microM, >or=20 min) evoked only rhythmic contractility even in moderately depolarizing ([K(+)](o), 10mM) medium. These findings suggest low basal activity of L-type Ca(2+) channels (VOCs) in both muscle types. In the presence of L-type Ca(2+) agonists (1 microM), high [K(+)](o) (30 or 120 mM) evoked contractions with different profiles. Circular muscle had a predominance of rhythmic activity ([K(+)](o) 30 mM) and slow time to peak and decline ([K(+)](o) 120 mM). Longitudinal muscle was more tonic ([K(+)](o) 30 mM) with a rapid time to peak and decline ([K(+)](o) 120 mM). The contractions in both muscle types were blocked by nifedipine or methoxyverapamil; indicating the involvement of L-type VOCs and suggests that the distinct contractile profiles originate from differences in mechanisms that regulate contractility. In comparison to the conventional L-type Ca(2+) antagonists, fendiline, prenylamine and thioridazine were more effective against longitudinal than circular muscle contractions. Structurally similar diphenylalkylamines (cinnarizine, flunarizine, and pimozide) and phenothiazines (sulphoridazine, chlorpromazine, and trifluoperazine) inhibited the contractions comparably in both muscle types. These findings are discussed in relation to inhibition of muscle type-specific mechanisms that may contribute more to L-type VOC activation and contractility in longitudinal than in circular muscle.