Doctors and overpopulation 48 years later: a second notice.

Overpopulation exacerbates environmental and health problems, from climate change to biodiversity loss and pandemics. It is the 'upstream' driver of numerous existential threats. Addressing this compassionately - always - should be axiomatic for doctors. Our profession, by dramatically reducing death-rates since the 1800s while birth-rates remained high, sadly bears - unintendedly - some responsibility for the increase: one billion then, eight billion looming. Therefore, as doctors, we must surely be uniquely motivated to: be involved in rights-based policies and services with unbroken supply chains ensuring optimal contraceptive care being available to all couples worldwide, remove well-known tangible (contraceptives unavailable) and intangible (cultural, religious and mis-informational) barriers to women's choice to access family planning everywhere, while achieving full gender equity, especially in education, warn how overpopulation risks all planetary life, through optimal environmental education both for colleagues and the public, and campaign for a maximum of two children (replacement fertility - or less) on principle. Doctors and Overpopulation was established in 1972. Before and since, this issue has become taboo, still affecting many doctors and even people claiming to care passionately about a sustainable future: the environmental NGOs. Their silence implies conservation goals are achievable regardless of human numbers, while many studies show they are not. It is time for an open discussion about this taboo. Therefore we, concerned doctors of 2020, reiterate here the doctors' 48-year long cri de Coeur.

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

The contractile actions of α,ß-methylene ATP (α,ß-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 P2X(1)-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 Ca(2+)-activated K(+) (BK(Ca)) and voltage-gated delayed rectifier K(+) (K(V)) channels. α,ß-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-ßS (100 µm), a P2Y-purinoceptor agonist. Longitudinal muscle contractions in response to α,ß-meATP were enhanced by FPL 64176 (1 µm), an L-type Ca(2+) agonist, TEA (1 mm), a non-specific K(+) channel blocker, 4-aminopyridine (0.3 mm), a selective blocker of K(V) channels, and iberiotoxin (0.1 µm), a selective blocker of BK(Ca) channels. Quiescent circular muscles responded to α,ß-meATP reliably in the presence of FPL 64176 or iberiotoxin. Apamin (0.1 µm), a selective blocker of small conductance Ca(2+)-activated K(+) (SK(Ca)) channels had no effect in both muscle types. Y-27632 (1-10 µm) reduced longitudinal muscle contractions in response to α,ß-meATP, suggesting involvement of Rho-kinase-dependent contractile mechanisms. The results indicate that P2X(1)-purinoceptor stimulation elicits excitatory effects that: (a) lead to longitudinal muscle contraction and secondary activation of 4-aminopyridine-sensitive (K(V)) and iberiotoxin-sensitive (BK(Ca)) K(+) channels; and (b) are subcontractile in circular muscle due to ancillary activation of BK(Ca) channels. The novel finding of differential action by P2X(1)-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 K(V) and BK(Ca) channels following P2X(1)-purinoceptor activation may be pivotal in providing the crucial physiological mechanism that ensures temporal co-ordination of longitudinal and circular muscle contractility.

Comparative effects of T-type and L-type Ca(2+)-antagonists against noradrenaline-induced contractions of human vas deferens.

OBJECTIVE: To investigate the effects of the relatively selective T-type Ca(2+)-antagonists, mibefradil and flunarizine, and the L-type Ca(2+)-antagonist, nifedipine, on the contractions of longitudinal and circular muscles of human vas deferens, to elucidate the possible involvement of T-type voltage-gated Ca(2+) channels (VOCs) in the contractile function of the tissue. MATERIALS AND METHODS: Human vas deferens specimens from elective vasectomies were cut into strips of longitudinal muscle or transversely into rings of circular muscle. These were set up for tension recording and superfused with Krebs' medium (36 degrees C). Contractions were evoked by noradrenaline or high [K(+)](o) (in the presence of the L-type Ca(2+) agonist, FPL 64176) and the effects of Ca(2+) antagonists were determined. RESULTS: Noradrenaline (0.1-100 micromol/L) evoked rhythmic and tonic contractions of longitudinal and circular muscles, which were potently inhibited by nifedipine (

Contraception for women taking antiepileptic drugs.

Antiepileptic drugs (AEDs) that induce hepatic enzyme activity may alter the metabolism of most hormonal methods of contraception, and this may affect their contraceptive efficacy. There is also the potential for the hormonal method to affect the AED. Women may also be prescribed AEDs to treat conditions other than epilepsy, such as chronic pain and migraine. These effects should be considered in the choice of both the treatment of the epilepsy and the choice of contraceptive method. This review considers these interactions and offers advice about their management.

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.

The 7-day contraceptive hormone-free interval should be consigned to history.

AIM: This review summarises the available data on the disadvantages of the 7-day contraceptive-free interval (CFI) of combined oral contraceptives (COCs), in contrast to shorter CFIs or continuous use - including flexible regimens - and provides recommendations for practice. METHODS: Relevant papers were identified by Medline and PubMed. The final reference list was generated on the basis of relevance to the review, with priority given to systematic reviews and randomised controlled trials. RESULTS: There is considerable inter- and intra-individual variation in the absorption and metabolism of COCs. Even with perfect use, the loss of endocrine suppression during the standard 7-day CFI allows follicular development with the risk of escape ovulation in a vulnerable minority. This risk increases in typical users whenever the CFI is prolonged: late restarts are a common reason for pill omissions. Shortening or eliminating the CFI improves contraceptive efficacy using the lowest doses available, without evidence to date of compromised safety. CONCLUSIONS: There is no scientific evidence to support a 7-day CFI and it should be replaced either by a continuous flexible regimen, or extended regimens with a shortened CFI, prescribed first-line. In women preferring a monthly 'bleed', a 4-day CFI similarly provides a greater safety margin when pills are omitted.

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

OBJECTIVE: 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. PATIENTS AND METHODS: Between November 2004 and January 2006 nine surgeons carried out vasectomies in 625 men (mean age 39.9 years, sd 5.6) under local anaesthesia. A questionnaire was devised to establish the presence of any scrotal or testicular pain, and to characterize this discomfort; 6 months after the procedure a modified version of the same questionnaire was administered. RESULTS: In all, 593 (94.7%) men returned the preoperative questionnaires and were entered into the study; 488 (82.2%) of these completed the follow-up questionnaire, giving a mean (sd) follow-up of 6.8 (1.6) months. In all, 65 men reported new-onset scrotal pain at 7 months (14.7%). The mean visual analogue score for this pain was 3.4/10. Four men (0.9%) in the responding group described pain after vasectomy as 'quite severe and noticeably affecting their quality of life'. CONCLUSION: At 7 months after vasectomy about 15% of previously asymptomatic men have some degree of scrotal discomfort. These early data indicate that chronic scrotal pain after vasectomy is a genuine entity, but a longer-term follow-up in this group will be important to allow further evaluation of how this pain develops with time.

Combined hormonal contraceptive trials: variable data collection and bleeding assessment methodologies influence study outcomes and physician perception.

Initially approved for use in the United States nearly 50 years ago, oral hormonal contraceptives containing both estrogen and progestin have undergone steady improvements in safety and convenience. Concurrent with improvements in safety associated with decreasing doses of both steroids, there has been an increased incidence of unscheduled bleeding and spotting. There exist no standards regarding data collection techniques and methods, and reporting and analysis of bleeding and spotting events during combined hormonal contraceptive (CHC) trials. For the regulatory review of hormonal contraceptives, data regarding the incidence of bleeding and spotting events are not included in either of the traditional categories of efficacy and safety. Standardization of methods for collecting and analyzing data about cycle control in all clinical trials of CHCs is long overdue. Until such standards are developed and implemented, clinicians need to familiarize themselves with the techniques used in each study in order to provide correct information to their patients about the frequency of bleeding and spotting associated with different formulations and delivery systems.

Recommendations for standardization of data collection and analysis of bleeding in combined hormone contraceptive trials.

This is the second of a two-article series describing the outcomes of the Hormonal Contraceptives Trial Methodology Consensus Conference held in Philadelphia, PA, on September 23, 2005. The first manuscript, "Hormonal Contraceptive Trials: Variable Data Collection and Bleeding Assessment Methodologies Influence Study Outcome and Physician Perception," provided a description of methodologies applied in the US Food and Drug Administration medical officer's review of clinical trial data as contained in the Summary Basis of Approvals of New Drug Applications, results of the review and general conclusions. This manuscript provides recommendations regarding best practices in trial design, data collection and analysis regarding bleeding data in combined hormone contraception trials.

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

The effects of irreversible alpha1-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 alpha1-adrenoceptor antagonists were also used to further characterize the alpha1-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 alpha1-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 alpha1-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 alpha1L-adrenoceptor subtype in longitudinal muscle and alpha1A-subtype in circular muscle.

The levonorgestrel intrauterine system: a clinical perspective from the UK.

The main contraceptive effects of this valuable product [the levonorgestrel intrauterine system (LNG-IUS)] are by endometrial suppression and changes to the cervical mucus and uterotubal fluid that impair sperm migration. The blood levels of LNG are very low, so progestogenic symptoms are uncommon. Most women still ovulate and in the remainder sufficient estrogen for health is produced from the ovary, even if they become amenorrhoeic, as many do; this is primarily a local end-organ effect and should be seen as a benefit. Although usable by selected nulliparae, it is ideal for the parous woman. It has unsurpassed efficacy, and return of fertility is rapid. Combining the best features of hormonal and intrauterine contraception, its gynecological benefits are impressive: the LNG-IUS user can expect a dramatic reduction in the amount and, after the first few occasionally troublesome months, in the duration of blood loss. Hemoglobin levels rise and dysmenorrhea is usually greatly benefited, unlike with current uterine ablation techniques. In perimenopausal women, it can protect the endometrium from overstimulation when estrogen replacement therapy (ERT) is added, by any chosen route. It thus provides a contraceptive modality of ERT with, usually, no bleeding and few progestogenic side effects-and is applicable before final ovarian failure. In summary, adverse side effects are few and in general they are not in the "hazardous" category. Regarding the admitted inconvenience of the first weeks of light postinsertion bleeding and the early phase low incidence of steroidal side effects: good counseling is paramount, since forewarned is forearmed!

Contractile actions of imidazoline alpha-adrenoceptor agonists and effects of noncompetitive alpha1-adrenoceptor antagonists in human vas deferens.

The contractile actions of imidazoline alpha-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 alpha(1H)- and alpha(1L)-adrenoceptor subtypes. The imidazoline alpha-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 (pD(2); longitudinal muscle 6.9, circular muscle 6.4) and cirazoline a partial agonist (pD(2); 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 (alpha(1H)) compared to longitudinal (alpha(1L)) 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 (pK(d)) 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 (alpha-adrenoceptor agonists with lower efficacies relative to A-61603). The differential inhibitory actions of phenoxybenzamine and SZL-49 are discussed.

Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data.

OBJECTIVE: To present efficacy and cycle control data pooled from three pivotal studies of the contraceptive patch (Ortho Evra/Evra). DESIGN: Three multicenter, open-label, contraceptive studies that included up to 13 treatment cycles. SETTING: 183 centers. PATIENT(S): 3,319 women. INTERVENTION(S): Three consecutive 7-day patches (21 days) with 1 patch-free week per cycle. MAIN OUTCOME MEASURE(S): Contraceptive efficacy and cycle control. RESULT(S): Overall and method failure life-table estimates of contraceptive failure through 13 cycles were 0.8% (95% CI, 0.3%-1.3%) and 0.6% (95% CI, 0.2%-0.9%), respectively. Corresponding Pearl indices were 0.88 (95% CI, 0.44-1.33) and 0.7 (95% CI, 0.31-1.10). Contraceptive failure among women with a body weight < 90 kg (<198 lb) was low and uniformly distributed across the weight range. A subgroup of women with body weight > or = 90 kg (> or = 198 lb) may have increased risk of pregnancy. The incidence of breakthrough bleeding was low and decreased over time. CONCLUSION(S): In contraceptive patch users, the overall annual probability of pregnancy was 0.8% and the method failure probability was 0.6%. The efficacy of the patch was high and similar across age and racial groups. Among women < 90 kg (<198 lb), contraceptive failure was low and uniformly distributed across the range of body weights. In women > or = 90 kg (> or = 198 lb), contraceptive failures may be increased. Efficacy and cycle control have been shown to be comparable to an established oral contraceptive.

Risks and benefits of oral contraceptive pills.

In the more than 40 years since the combined oral contraceptive pill was first marketed, much information has been obtained as to its risks. Considerably less publicity has been given to the balancing benefits that have also emerged. There has been an increasing realization that the risks are focused in those women with recognised risk factors, meaning that the remainder can use the product with increasing reassurance. The doses of both hormones have also been lowered considerably since the early years. Thus, it can be a rational decision by a fully informed woman to use this form of contraception.

Unanswered questions in contraceptive management: what do the experts do?

CONTEXT: Several areas exist in the practice of contraception where evidence for practice is deficient, yet clinical decisions need to be made. OBJECTIVES: The aim of the study was to find the practice habits of lead practitioners in the area of contraception in specific clinical scenarios where the published evidence is inadequate to provide clear guidance to clinicians. Results can provide 'Level V' evidence for practice for the 'nonexpert' practitioner. DESIGN: Descriptive study. PARTICIPANTS: The study was conducted as a postal questionnaire mailed to the 205 lead practitioners whose contact details were known through the Society of Consultants in Reproductive Health (hereafter referred to as 'consultants') working in reproductive health in the National Health Service. RESULTS: A total of 138 consultants returned completed questionnaires (67% response rate). Important results included 100% of respondents being prepared to prescribe progestogen-only emergency contraception more than once in a cycle (contrary to product labelling) and 71% recommending two tablets daily of the progestogen-only pill for women of high body mass. CONCLUSIONS: Some questions had responses that showed clear majorities, providing a clear guide to practice, while other areas remain doubtful. Comments from respondents indicated great interest in all areas covered and a desire for consensus on many of the issues. Certainly the licensing and the advice from pharmaceutical companies is conservative, and in many scenarios a majority of consultants indicated that in order to serve the best interests of their clients they feel constrained to practise outside the Summary of Product Characteristics.

Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzyme-inducing drugs.

CONTEXT: Contraception for women on enzyme-inducing drugs. OBJECTIVE: To gather preliminary information on the contraceptive efficacy of the hormone-releasing intrauterine system (IUS) Mirena, when used concurrently with enzyme-inducers. DESIGN: Observational series. SETTING/PARTICIPANTS: Mirena users on enzyme-inducers were recruited from within the Margaret Pyke Centre and via doctors from throughout the UK. Data were collected systematically on structured questionnaires with particular reference to duration of Mirena use, exposure to pregnancy risk, type of concurrent medication, and reasons for drop-out. MAIN OUTCOME MEASURE: Accidental pregnancies. RESULTS: To date, 56 women have provided follow-up information. Most took enzyme-inducers for epilepsy. They have accumulated 1454 months of use, of which 1075 months represent exposure to pregnancy risk. Only one apparently true Mirena failure has been documented, representing a failure rate of 1.1 per 100 woman-years (95% CI 0.03-6.25). Including a second pregnancy, probably conceived after the Mirena had been removed,would raise the failure rate to 2.2 per 100 woman-years (95% CI 0.27-8.07). Although 9/30 Mirena removals were followed by re-insertion, only the first segment of use is analysed. CONCLUSION: As this is a pilot study, no firm conclusions can be drawn, but our preliminary results suggest that any increased pregnancy risk, if it exists, falls within acceptable bounds.

Comparative trial of the force required for, and pain of, removing GyneFix versus Gyne-T380S following randomised insertion.

OBJECTIVE: To assess the force required for, and pain of, removal of the GyneFix as compared with T-framed intrauterine devices (IUDs). DESIGN: A comparative trial following patient-blinded randomisation in an outpatient clinic setting. METHOD: Women requesting an IUD for emergency contraception were fitted with either a GyneFix or a Gyne-T380S. For those requesting removal of the IUD, visual analogue scores were used to assess their perception of the associated pain, and a Newton dynamometer was used to measure the force required to remove the device. RESULTS: Removal required significantly more force for GyneFix as compared with Gyne-T380S (p = 0.004), but there was no significant difference in pain perceived by women during removal. Interestingly, anticipated pain was worse than actual pain experienced. CONCLUSION: Although more force is needed to remove the GyneFix as compared with the Gyne-T380S, this does not translate into more pain.

Randomised controlled trial assessing the acceptability of GyneFix versus Gyne-T380S for emergency contraception.

OBJECTIVE: To assess insertion-linked pain and the short-term user-acceptability and safety of the GyneFix as compared with T-framed intrauterine devices (IUDs). DESIGN: A randomised controlled trial in an outpatient clinic setting. METHOD: Women requesting an IUD for emergency contraception (EC) were allocated to either the short-term arm (GyneFix versus Nova-T200, or the long-term arm (GyneFix versus Gyne-T380S, and then randomised within each group. Visual analogue scores were used to assess the women's perception of the pain associated with insertion, which was patient-blinded. Follow-up was double-blinded, at 6 weeks, with bleeding and pain recorded over this time. RESULTS: A total of 175 women received an IUD in the long-term arm. The short-term arm was discontinued due to low recruitment (17 women at 20 months) and therefore the results relate to the long-term arm only. Outcome was known in 98% of subjects. The actual insertion procedure was scored as more painful for the GyneFix, both by the women (p = 0.013) and the doctors making their assessment of the women's pain (p = 0.04). The women with GyneFix described less pain in the subsequent 30 days after insertion (p = 0.005). Only 13% of women with GyneFix requested removal as compared with 20% with Gyne-T380S, with the difference being attributed to removal due to pain. The bleeding pattern was similar for those using GyneFix and Gyne-T380S. CONCLUSIONS: Our study suggests that although the actual fitting may be more painful, pain is less during the 6 weeks after insertion of GyneFix and fewer women discontinue its use because of pain, as compared with Gyne-T380S. The high overall continuation rate of all emergency IUDs at 6 weeks and low morbidity seen in this study favours more frequent IUD insertion where unprotected intercourse has occurred, given also its higher efficacy over oral hormonal EC.