A Journey Through Two Lumens!

RJ Levin1*

1Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, Yorkshire, UK

This account describes studies from the Institute of Medical Physiology in the University of Copenhagen, starting in the mid 1970’s, which included some of the earliest European laboratory investigations on human female genital function. The measurements involved vaginal pH, pO2, blood flow, motility, fluid and its ionic concentrations, amino-acid concentrations and electrical activity (transvaginal potential difference) usually in both the basal and sexual aroused states. The blood flow monitoring pioneered the use of the heated oxygen electrode. Other studies examined the effects of arousal to orgasm on cervical secretion, on the heart rate as an objective indicator of orgasmic excitement and investigated the actions of TRH and the cholinergic antagonist atropine on a number of vaginal parameters. The work was part of the scientific watershed that divided the previous descriptive era of human genital mechanisms from the now prevalent quantitative assessments. International Journal of Impotence Research (2003) 15, 2–9. doi:10.1038/sj.ijir.3900977

Three apothegms that influenced my research training commenced at Liverpool University, where philosophy I read for Bachelor of Science degrees in general science and then in Honours Physiology in the 1. The devil is in the detail. laboratory that Sherrington used. The Head of the 2. To see what everyone else has seen but to think Physiology Department, Professor Rod Gregory FRS, what no one else has thought. who was isolating and purifying gastrin (the major 3. A lawyer’s brief is simply to gather all the gastric hormone that activates acid secretion), evidence supporting his case, while a scientist’s invited me in 1957 to accept a University research brief is to gather all the evidence for and against fellowship to isolate and purify secretin (discovered his case and come to a conclusion. by Bayliss and Starling, the first blood-borne agent to be named a ‘hormone’ and controls fluid and ion 1 There was a book published in 1997 titled ‘How I secretion by the exocrine pancreas).This embarked got into sex’ with a subtitle of ‘Personal stories of me on my life-long career as an experimental leading researchers, sex therapists, educators, pros- gastroenterologist. Unfortunately, the purification titutes, sex toy designers, sex surrogates, transsex- turned out to be too mammoth a task to undertake uals, criminologists, clergy and morey.’ I certainly with the techniques then available. Later, in Uvnas’s wasn’t asked to contribute, and if my memory serves laboratory in Sweden, even with the newer separa- me right no other European was either, but perhaps tion techniques available, thousands of hog small it was not too bad an omission looking at the intestines had to be processed to obtain finally but categories in the subtitle! The editor invited me to 1 mg of the substance, a highly basic polypeptide. write an account of my early involvement in the However, the experimental grounding that I ob- now burgeoning study of the physiology of human tained undertaking this research for an MSc led me sexuality, especially that of the female. to my first academic position as a research assistant in 1959 in the Department of Physiology at the University of Sheffield, then under the Headship of First encounters with academic sex Professor David Smyth, FRS. Little did I realise that I would stay there for over 40 years. This was probably the first, and only, time that sex looked The very first involvement with academic sex began kindly on my career development as the position with having to teach medical students reproduction, became vacant only because a pregnancy caused one but let us start at the true beginning. My scientific of the female staff members to leave! My new field of research was investigating the control of intestinal absorption (and later secretion) by hormones and F *Correspondence: RJ Levin, Department of Biomedical diet. It was my first encounter with a lumen the Science, University of Sheffield, Western Bank, Sheffield, intestinal one. The department had an international Yorkshire, S10 2TN, UK reputation for experimental studies on small intest- E-mail: [email protected] inal function and was the birthplace of the everted A journey through two lumens! RJ Levin 3 small intestinal sac, a remarkably simple prepara- whether the epithelium lining the vagina and the tion where the isolated small intestine was everted uterus (endometrium) also transferred ions and fluid and could be tied off into small sacs that actively and by the former, generated electrical activity that transferred solutes and fluid from outside the sac could be used as a simple, objective measure of one into its serosal compartment. The eversion allowed aspect of the organ’s function. Since the vaginal the tissue to be kept oxygenated and alive by being epithelium was a multicell thick tissue, it would incubated in oxygen-gassed buffer and this made need to be dissected out from a rat as an intact tube, possible the discovery of the absorption by active and turned inside out to make a sac. Its ability to transport of ions, amino acids, sugars, fatty acids, transfer in vitro ions from lumen to serosa and vice vitamins, etc. by the enterocytes.2 Studying the versa was recorded by measuring the electrical physiology of sex was very far from my thoughts potential difference across the preparation when during this period. However, when a senior aca- incubated in an oxygen-gassed buffer. Luckily, it demic left to take up a chair in physiology someone worked the very first time I tried it.6 Academic staff had to take up the teaching of reproduction to the members were assigned science students reading for medical and science undergraduates and I volun- a physiology degree who worked with them on a teered. I was given a free reign, so decided that the research project. With Janet Camfield, my under- medical course would have at least one lecture on graduate for 1966 who I trained in the dissection, we the physiology of human sexual arousal and coitusF obtained enough data to publish the first paper on a near unheard of feature in UK medical schools at the first viable in vitro vaginal preparation cheekily that time. No physiology textbook of the period even entitled ‘The isolated everted vaginaFa preparation mentioned the mechanisms of penile erection, for studying vaginal bioelectric activity in vitro’.7 ejaculation or vaginal lubrication. There was little My second encounter with a lumenFthat of the scientific literature available. Dickinson’s3 Atlas of reproductive tractFhad begun. Creating an in vitro Human Sex Anatomy (2nd edn) published in 1949 uterine endometrial preparation was a little more and the descriptive Chapters 14 and 15 (Anatomy tricky as the tissue was much more fragile.8 It was and Physiology of Sexual Response and Orgasm, around this time that I realised that my background respectively) in Kinsey et als’ 4 Sexual Behaviour in and research experience gave me an advantage over the Human Female (1953) were useful, but the nonphysiologists in the sexual/reproductive field publication by Masters and Johnson5 of the Human who were unaware of, or misinterpreted, basic Sexual Response in 1966 heralded a new dawn. The biological mechanisms.9 To my surprise even the previous years of repression can hardly be believed hallowed Masters and Johnson5 could go astray: in today’s world: Chapter 1 of Dickinson’s atlas of they stated, ‘The fact that the vaginal mucosa is a explicit drawings of human genitals and coitus has a permeable two-way membrane emphasises the dif- paragraph (p. 5) about the size of the volume that ficulty in establishing and maintaining a stable was kept to 8.5 Â 11 in because, I quote, the environment’ (p 89). My involvement with the ins ‘controlling reason y is that the book may be and outs of ions and fluid across the intestine conveniently locked up in the stock vertical file made it obvious that a ‘stable (vaginal) lumenal until such time as everyday medical data like these environment’ could actually only be achieved are commonplace and as clear of reproach and as if there was a permeable two-way flux! Any change clean of reproach as any other anatomical figures’! I in the lumen would quickly be equilibrated remember my first reading of the fascinating but by passive movements into or out of the bulk turgidly written Human Sexual Response by phase fluid especially in relation to the electrical Masters and Johnson5 and thinking –‘Oh! dear, it’s potential across the vaginal wall in the case of a real pity that they didn’t have an experimental charged ions. Years later, I returned to the study of physiologist as a team member, look at all the the electrical activity generated across the vagina/ measurements they could have done’. While pre- cervix/uterus using both in vivo and in vitro paring and giving the lectures I realised the obvious preparations of the human female10 and from rats. lack of basic information about human genital I was dissatisfied with the subjective, pseudoquan- function and coitus. Statements in Masters and titative scoring of classical toxicology that was Johnson’s book like ‘vaginal physiology has been, used to assess gross histological damage to the and still remains, an essentially unexplored field’ vagina caused by the insertion of known and (p 80) highlighted our ignorance. putative spermicides/virucides. I thought that measuring the activity of the vaginal epithelial cells to transfer ions across the wall to create an The early vaginal/endometrial studies electrical potential difference and current would give an objective quantitative measure of their function, and any agents that caused membrane As I was studying the transfer of fluid, ions and or cellular damage would be easily and rapidly solutes across the everted intestines by chemical identified and assessed. These studies culminated and electrical measurements, I began to wonder in a number of publications on this theme.11–14

International Journal of Impotence Research A journey through two lumens! RJ Levin 4 The most recent with human vaginal (ectocervical) instant friends. At the weekend, we undertook a few tissue incubated in vitro as a sheet15 showed pilot experiments in Gorm’s laboratory in the old that the cells could actively transfer Na+ ions Rockefeller physiology building, collecting vaginal from the lumen back into the blood, and it was fluid on weighed strips of filter paper during mainly this that generated the potential difference control, basal conditions and during sexual arousal, across the human vagina making the lumen sometimes to orgasm. The results were so promising negative to the blood by up to 30–40 mV.10 It is that we decided to cooperate on a regular basis, with also obvious that this reabsorption of Na+ by the me coming over to Copenhagen in the academic vaginal cells is the osmotic cause of the reabsorp- holidays and staying in a guest room in the roof of tion in the resolution phase of the increased the Rockefeller building (in fact, we are still working vaginal ‘lubricating’ fluid, created during sexual together on a research project in 2002!). In the long excitement, restoring the vagina to the ‘just moist’ summer vacations, my wife and our two young sons resting condition. A recent paper16 using a near- came over and all of us stayed in a University flat identical preparation of the human vagina con- provided for foreign research workers. Later, the firmed the viability of the tissue in vitro by University converted an old nurse’s home into a monitoring its electrical activity, but made no use guesthouse for visiting foreign research workers. of it as a preparation to further the study of vaginal To this day, I applaud the academic authorities of function. the University of Copenhagen for their great fore- sight in creating and funding highly subsidised accommodation for foreign research workers to The first Danish visit stay and work with the faculty at their University. It allowed studies to be undertaken for low accommodation costs and fostered international academic I had been publishing my experimental studies on cooperation. It is a feature that is still in operation the influence of dietary intake and hormones on today. intestinal function (for which I obtained my PhD as a staff candidate in 1964) concomitant with my few early papers on vaginal and uterine endometrial function. I began to attend and read papers at The Danish research period international conferences. At one of these in 1975, I met Eric Skadhauge, a Danish research academic but also involved in teaching physiology to medical The research was very productive. Over the years students. He invited me to Copenhagen to lecture from 1976, we published a number of papers with the Danish Biological Society on diet and intestinal the help of our respective laboratory technicians transport function. We talked about teaching repro- Birdie Knudsen (Copenhagen University) and Andy duction. At that time the medical school in Parker (Sheffield University). There were only a Copenhagen, in the then new Panum building, had handful of personnel and laboratories undertak- a pioneering course on human sexuality for their ing research and publishing on human female medical students organised by Gorm Wagner. Be- sexual arousal in the late 1970s; most were males cause of my own teaching commitment to the in the United StatesFJim Geer,17 Peter Hoon,18 medical students, Eric suggested that I write to Henson and Rubin19 and Julia Heiman20Fthe lone Gorm to audit the course during my planned lecture woman performing such studies in the USA. Only visit. I wrote and duly got a reply from Gorm two groups were active in the UK, Cyril Fox with his accepting me on the course and, enclosed with the unique ‘family bedroom’ studies21 and the single week’s timetable, a synopsis of his film ‘Sexual photoplethysmographic study by Gillan and Brind- arousal of the human female in the laboratory’. It ley.22 Later, other women entered the fieldFEllen bowled me over. Here was somebody in Europe Laan in Amsterdam, and Cindy Meston and Eileen undertaking observations like Masters and Johnson Palace in the States. who apparently had access to subjects who sexually The academic world of physiology in the UK was aroused themselves for scientific study. I immedi- hugely uninterested in the work; some were outright ately wrote back (no e-mails in those days!) with antagonistic. Looking back, my decision to research details of the studies I had published on the vagina human sexual arousal is what academics now call a and uterus and wondered if it would be possible to career-limiting move (CLM)! There was little doubt undertake a few simple experiments measuring that the laboratory studies on sexual arousal and vaginal potential difference, fluid production and especially orgasm were looked on by some senior its ionic concentration in human subjects during members of the UK academic community (even sexual arousal to characterise possible mechanisms physiologists) with some disapproval, and I was of its production. The reply came back ‘Sure, let’s even told that such studies did not collect many have a try.’ The visit in January 1976 was a great ‘brownie points’ when it came to the evaluation of success. Gorm met me at the airport and we became one’s research output. The unique course of explicit

International Journal of Impotence Research A journey through two lumens! RJ Levin 5 lectures that I created in the department at Sheffield of a two-thirds caudal (upper) section lined with for our final year honours physiologists dealing with columnar epithelium (like the cervix) and a one- the mechanisms of human sexual arousal entitled third distal (lower) part with squamous epithelium ‘The physiology of human sexuality’, unsurprisingly similar to that of the human, making it imperative a very popular course, was criticised by one external that the upper section is tied off. Unlike the human, examiner because he thought, mistakenly, that the the vaginas of small rodents (rats, hamsters, guinea study of ‘human sexuality’ was unscientific (despite pigs) undergo enormous histological changes during the fact that I was undertaking basic physiological their normal 4–5 day oestrus cycles, from a 2-cell- measurements of the activity) and that my students’ thick, cuboidal epithelium to a squamous epithe- reading list referred to too many of my own papers! I lieum (with cornification) some 10–20 cells thick. recall giving an oral communication on female The properties of the vagina depend greatly on the sexual arousal at a Physiological Society meeting stage of the oestrus cycle.11,25 The dog is not only a in the UK, where the first question after my delivery very expensive experimental animal in Europe but was not related to the science I presented but simply its vagina is very S-shaped under the pubic sym- ‘How much did you pay the female subjects?’ with physis, making insertion of our large measuring its obvious implication that the subjects of the study devices difficult. We finally settled on the sheep. It were prostitutes. As always funding for travel, was cheap and easily available. While the normal maintenance, consumables, etc. was a problem, but pH of its vagina is about 7, it becomes more like the fortunately there were supportive people and agen- acidified pH 4–5 of the human vagina when heavily cies and we managed to get by with a hand-to-mouth oestrogenised. We used it to assess the vasodilator existence with small grants from a variety of sources properties of intravenous and locally applied VIP (International Planned Parenthood Federation, the and evaluated the effects of TRH on vaginal blood British Council, the Wellcome Foundation, the flow.26 TRH, a simple tripeptide, is fascinating Royal Society, The Foundation for the Scientific because it appears to be the only compound that Study of Sex, the University of Copenhagen and when injected into conscious women creates a Sheffield’s medical research funds, a variety of local feeling of genital warmth probably because of a Danish funds and later a number of pharmaceutical transient increase in genital blood flow and a low company grants). Since Gorm found money to pay level of sexual arousal. It appears to have no action someone to undertake my teaching obligations, I on male genitals. Since our study, no further was able to take a 6-month sabbatical in Copenhagen investigation of this phenomenon has been pub- in 1986, coming back to visit my long-suffering wife lished. We were the first European laboratory to and young family for the odd weekend! It was a little begin to quantitate physiological aspects of vaginal time after the appearance of Toxic Shock Syndrome function in the resting and sexually aroused states. when some 30 women had died in the States We summarised the early studies in a chapter in the because of toxic shock induced probably by the book The Human Vagina published in 1978.27 combination of a new tampon and a bacterial infection that created a deadly toxin. Studies with tampons showed that when they were inserted into Our successes? the vagina, because of the air trapped between the fibres they raised the pO2 of the normally hypoxic lumen quite dramatically to atmospheric levels, (i) We showed that the basal vaginal fluid had a low creating conditions for the growth of Staphylococ- Na+ and a very high K+ compared to plasma, and cus aureus and the production of a protein toxin.23 that this remained so throughout both phases of the Later studies showed that even inserting a solid menstrual cycle and therefore was uninfluenced by rubber Dutch cap (diaphragm) into the vagina oestrogen and progesterone.28 By placing sacs of dramatically elevated its lumenal oxygen.24 Prior visking tubing filled with autologous serum (ob- to these studies, the concept that the insertion of tained from the subject) into the subject’s vagina for vaginal devices could dramatically alter its gaseous a few hours, we showed that the ionic changes in the environment and thus have potential effects on the serum were compatible with vaginal epithelial bacteria was not considered. mechanisms for the secretion of K+ into the vaginal fluid and for an absorption of Na+ and ClÀ out of the fluid.29 During sexual arousal, the ‘fluid’ that moved Animal models for vaginal studies into the vagina had a greatly enhanced NaCl concentration, supporting the hypothesis that it was a (neurogenic) transudate coming from the We were working on the effects of VIP on vaginal plasma.29,30 You have to realise that at the time blood flow and wanted an animal model to under- medical physiology knew the ionic concentrations take invasive experiments. The choice of an animal of practically every human body fluid (even that of vagina to match exactly that of the human is the endolymph inside the cochlea!) but showed difficult. That of the rabbit unfortunately consists complete indifference as to what the concentrations

International Journal of Impotence Research A journey through two lumens! RJ Levin 6 of Na+,K+,ClÀ, and Ca2+ were in human vaginal on a research project is an essential prophylactic fluid! Indeed, one of my critics said, ‘Why on earth (the devil is in the detail). do you want to know the ion concentrations of the (iii) We utilised the built-in ability of the Radio- vaginal fluids, of what possible purpose can it be meter oxygen electrode to measure indirectly the useful for?’ Apart from the fact that it is the first blood flow underneath it by monitoring the heat loss genital fluid that the spermatozoa are ejaculated of the electrode in terms of the electrical power in into and its ions may well have important repro- milliwatts needed to maintain its original set ductive influences (see Wagner and Levin28 for a temperature, usually a few degrees above blood discussion), two studies have utilised our data to temperature.36 Comparing the AC-signals obtained create an artificial vaginal fluid for use in work by vaginal photoplethysmography with those ob- on bacterial growth in vaginal fluids and the role tained from the heated oxygen electrode showed of the ions on vaginal bacteriocides and spermi- that there were real discrepancies immediately after cides.31,32 We also showed that the basal vaginal orgasm.39 This created doubts about the usual fluid contained remarkably high values of a simple interpretation of the AC signal amplitude number of amino acids.33 The five highest levels as a direct measure of vasodilatation, but the were those of aspartic acid (71 times that of plasma), warning was unheeded and still remains so! The taurine (48 times that of plasma), ethanolamine AC-signal is so easy to obtain and appears so very (29 times that of plasma), glutamic acid (12 times) simple, but in reality the interpretation of it is much and methionine (10 times plasma). The role(s) more complicated. A feature ignored is that changes of these high concentrations have not been in venous tone may well be a factor in affecting the studied, but one possibility is that as taurine is amplitude of the AC signal;40 an enhanced venous known to affect (stabilise) animal sperm mem- tone creating a reduced venous drainage may well branes,34,35 it could have similar actions in the create an artifactually high amplitude giving the human female. appearance of increased arterial blood flow. (ii) We pioneered the use of the heated oxygen (iv) In our laboratory study of orgasm,41 we found electrode in human vaginal studies.36 Unlike the that the increase in vaginal blood flow at orgasm was photoplethysmograph, it could be used to monitor not correlated to the gradings of the orgasm by the vaginal function throughout sexual arousal to and subject, or the orgasm latency (time taken to induce after orgasm. It was originally produced by Radio- the orgasm) or the measured duration of orgasm. The meter, Copenhagen, for hospital intensive-care mean duration of orgasm as measured from the units. The firm was extremely generous in helping subjects’ verbal signals of initiation and end was us in our studies. We held it onto the vaginal wall by 19.9 s (n ¼ 26), but when they were asked to estimate inserting it into a suction capsule (based on the how long the orgasm lasted, this was greatly under- design of the suction capsules used to collect estimated being some 12.2 s. parotid saliva in humans) and measured the oxygen (v) We were the first to show that the subjective tension of the vaginal surface fluid both in the basal intensity of orgasm could be related to an objective and in the sexually aroused to orgasm conditions.37 physical measure, namely the increase in heart In the basal or nonsexually aroused state, the vaginal rate during the period just before orgasm;42 the surface oxygen level was very low, practically greater the increase, the better the grade of orgasm. 7 7 43 anaerobic (pO2 ¼ 9 11 mmHg, mean s.d.). Sexual The finding was later confirmed. arousal caused a rapid increase in the pO2 to (vi) We assessed the secretory function of the 50 mmHg or more while orgasm brought about its cervix during arousal to orgasm by monitoring its 2+ 2+ dissipation. The low basal vaginal pO2 was in surface pH and ionised pCa using pH and pCa keeping with the normal flora of Lactobacilli electrodes held against the ectocervix and showed (Doderlein’s bacillus), a facultative anaerobe pre- that there was little change.44 As far as I know, this sumed to be a major manufacturing source of the is the only study of cervical function during sexual acidity of vaginal fluid. The danger of publishing arousal to orgasm where actual measurements have such early studies way ahead of general academic been made. interest is that later research workers (and the (vii) We showed that the increase in vaginal blood referees who review the work) do not bother to read flow during sexual arousal was unaffected by any literature more than 5 and certainly 10 years atropine, a powerful blocker of cholinergic transmis- back! You then are chagrined to see a publication sion, and it had little or no effect on the induction of measuring the oxygen tension of the vaginal wall orgasm. This was the first experimental evidence claiming it to be a new way to assess sexual arousal indicating that it was highly unlikely that acetylcho- in the human female without any acknowledge- line, previously assumed to be the neurotransmitter ment of the fact that it was repeating work enhancing vaginal blood flow and the lubricating accomplished 24 years back (see Levin and mechanism of the vagina, was involved.45 A few Wagner38 for a comment). As few researchers like years later, Riley and Riley46 showed, as expected, to hear ‘We did that twenty odd years ago’ said about that atropine had no effect on vaginal lubrication. their work, a good literature search before embarking Later studies by Gorm with Bent Ottesen and

International Journal of Impotence Research A journey through two lumens! RJ Levin 7 colleagues infusing VIP in conscious human sub- look at female sexual dysfunction in a new lightFif jects strongly suggested that it could be the a pill could be found for men surely it could also be transmitter for the increase in vaginal blood flow created for women. With this came the realisation at arousal and the enhanced production of vaginal that female sexual physiology had been practically fluid.47 ignored, certainly grossly underfunded and that a (viii) We measured the vaginal pH at six separate concertive effort was needed to stimulate the field. surface sites under direct observation during basal The European Society for the Study of Impotence conditions and after sexual arousal to orgasm, and created a section for women’s sexual function and found that on some sites there could be a large dysfunction and its newsletter now has a regular increase in pH (at least 1 unit) while at others topical section on research themes on female sexual there was very little or even an occasional de- function. I gave the first female-based lecture at their crease.48 Masters49 had previously made similar Second Annual Conference in Madrid in 1997 measures, but he placed the electrode blindly into entitled ‘Sex and the human female reproductive the vagina and did not undertake any statistical tractFwhat really happens during and after coitus’. analysis of his data. A study using a radiotelemetry My opening comment was that they had all come to pH electrode placed high up in the fornix in just one learn how to create an erection and here I was going subject50 did not find any change in pH during to tell them in the next 50 min how to lose itFwith coitus to orgasm. As a result of this, they questioned pleasure! The International Society for Impotence the hypothesis that the lubrication fluid formed on Research has now changed its title to International the surface of the vagina at arousal was a transudate Society for Sexual and Impotence Research in order of plasma as they assumed that the pH should have to cover female studies and its journal title is become neutralised to pH 7. They overlooked two restyled to ‘The International Journal of Impotence factors: (i) that the upper part of the vagina is the ResearchFJournal of Sexual Medicine’ to broaden least responsive to the formation of the transudate its field to include female studies. Irwin Goldstein, and (ii) the pH measuring membrane of the electrode with his inimitable energy and drive, created the may simply have been on a site that showed little Female Sexual Function Forums in Boston, bringing change. This made their challenge of the hypothesis hundreds of workers in the field together to meet very weak, if not invalid. The heterogeneity of the and discuss about female sexual function and pH response to sexual arousal makes the employ- dysfunction. This has finally culminated in the ment of the pH change a poor index of normal creation of a new societyFthe International Society vaginal function. for the Study of Women’s Sexual Health (ISSWSH), whose first highly successful meeting was in Vancouver in October 2002. Zucker54 has described The latter years how the handful of journals that dealt with human sexuality in the 1970s has now grown to some 76 titles. After this burst of activity studying various aspects Now retired from my position after 41 years in the of female sexual arousal in the laboratory by us and joint academic harness of departmental research, other workers in the 1970s and 1980s, research teaching and administration, the restraints on time support funds became increasingly difficult to have gone. I can prosecute research and write obtain, and a lull or quiet period ensued.51,52 The critical reviews on the topics of my choice (see research ticked over and papers were published, but Levin55,56) without worrying about whether they fit there was still very little interest/support shown in a department’s, university’s or government’s mission the study of the physiology of female sexual arousal. statement! Recently, I realised that I could offer an The sea change occurred on the serendipitous explanation for the enigma of vaginal tenting, the discovery of the oral treatment for erectile dysfunc- elevation of the cervix away from the posterior tionFsildenafil and the inhibition of PDE5 creating vaginal wall and the ballooning of the distal vagina vasocongestion. Suddenly a simple oral treatment described by Masters and Johnson5 some 37 years for a major sexual dysfunction appeared that worked ago. Unlike previous explanations that always in a surprising number of cases and swept away the claimed that changes in the female genital tract hallowed concepts of long-term ‘word treatments’. brought about by sexual arousal facilitated sperm Erectile dysfunction appeared vanquished and the transport, in my explanation, it occurs to delay pharmaceutical industry’s whetted appetite for new sperm transport allowing the crucial liquefaction of sexual fields to conquer grew. The answer was the semen and capacitation of the sperm to occur.57 obviousFif it could be accomplished for men then Inadequate tenting because of poor arousal may be a why not for women, because there was evidence of a cause of infertility because it allows too rapid growing awareness of sexual dysfunction in wo- transport of incompetent sperm. Thus, even after men53 that needed to be addressed. The focus of 37 years of the description of a basic genital attention was turned to women and magically phenomenon have passed, one can still interpret pharmaceutical companies, old and new, started to its fundamental role in human sexual arousal and

International Journal of Impotence Research A journey through two lumens! RJ Levin 8 fertility. That is the excitement of scienceFit is 14 Levin RJ, Parker AJ. Human vaginal (ectocervix) epithelium in never static (see research apothegm number 2). vitroFa preparation for assessing the acute actions of spermicides and other agents 1. Nonoxynol-9 and dl-propra- nolol. Med Sci Res 1988; 16: 695 – 696. 15 Levin RJ. Actions of spermicidal and viricidal agents on Last words electrogenic transfer across human vaginal epithelium in vitro. Pharmacol Toxicol 1998; 81: 219 – 225. 16 Bechgaard E, Riis KI, Jorgensen L. The development of an In a perceptive article on scientists involved in sex Ussing chamber technique for isolated human vaginal muco- research, Weinrich58 grouped them into three ideal sa, and the viability of the in vitro system. Int J Pharm 1994; 106: 237 – 242. types. In his definitions, ‘Pioneers are the first to 17 Geer J, Quartararo JD. Vaginal blood volume responses during come up with a new idea that eventually replaces masturbation. Arch Sex Behav 1976; 5: 403 – 413. the older one, they are the revolutionaries; Provers 18 Hoon P. The assessment of sexual arousal in women. Prog are the first to prove to sceptics that the idea is true, Behav Mod 1979; 7: 1 – 61. 19 Henson DE, Rubin HB. A comparison of two objectives they are the implementers of the revolution; Critics measures of sexual arousal of women. Behav Res Ther 1978; are the last to hold onto the previous older ideas, 16: 143 – 151. they are the preservers of the revolution.’ Scientists 20 Heiman J. Issues in the use of psychophysiology to need to perform in all three modes. In my career, I assess female sexual dysfunction. J Sex Mar Ther 1976; 2: have had my share of pioneering, proving and 197 – 204. 21 Fox CA, Fox BA. Blood pressure and respiratory criticising but most of all it has been a wonderful patterns during human coitus. J Reprod Fertil 1969; 22: and privileged experience. To the subjects who 587 – 590. volunteered and the colleagues I cooperated withF 22 Gillan P, Brindley GS. Vaginal and pelvic floor responses to and still doFmy heartfelt gratitude. sexual stimulation. Psychophysiology 1979; 16: 471 – 481. 23 Wagner G, Bohr L, Wagner P, Petersen LN. Tampon-induced changes in vaginal oxygen and carbon dioxide tensions. Am J Obstet Gynecol 1984; 148: 147 – 150. References 24 Wagner G, Levin RJ, Bohr L. Diaphragm insertion increases human vaginal oxygen tension. Am J Obstet Gynecol 1988; 158: 1040 – 1043. 1 Bullough B, Bullough VL, Fithian MA, Klein RS. How I Got 25 Edwards F, Levin RJ. The bioelectric parameters of the Into Sex. Prometheus Book: Amherst, New York, 1974. vagina during the oestrus cycle of the rat. J Physiol 1975; 2 Levin RJ. Discussion. In: Christie DA, Tansey EM (eds). 248: 307 – 315. Wellcome Witnesses to Twentieth Century Medicine, Vol. 8, 26 Levin RJ, Wagner G. TRH and vaginal blood flowFeffects in Intestinal Absorption. The Wellcome Trust: London, 2000, pp conscious women and anesthetized sheep. J Physiol 1986; 378: 22 – 26. 83P. 3 Dickinson RL. Atlas of Human Sex Anatomy, 2nd edn. The 27 Wagner G, Levin RJ. Vaginal fluid. In: Hafez ESE, Evans T Williams & Wilkins Company: Baltimore, 1949. (eds). The Human Vagina. North-Holland Publishing Co.: 4 Kinsey AC, Pomeroy WB, Martin CE, Gebhard PH. Sexual Amsterdam, 1978, pp 121 – 138. Behaviour in the Human Female. W.B. Saunders: Philadel- 28 Wagner G, Levin RJ. Electrolytes in vaginal fluid during the phia, 1953, Chapters 14, 15. menstrual cycle of coitaly active and inactive women. 5 Masters WH, Johnson VE. Human Sexual Response. Little, J Reprod Fertil 1980; 60: 17 – 27. Brown: Boston, 1966. 29 Levin RJ, Wagner G. Mechanisms for vaginal ion movement in 6 Levin RJ. The effects of hormones and the oestrous cycle women. J Physiol 1978; 284: 172 – 173P. on the transvaginal potential difference. J Physiol 1968; 194: 30 Levin RJ, Wagner G. Human vaginal fluidFionic composi- 94 – 95P. tion and modification by sexual arousal. J Physiol 1977; 266: 7 Levin RJ, Camfield J. The isolated everted vaginaFa prepara- 62 – 63P. tion for studying vaginal bioelectric phenomena in vitro. Life 31 Geshnizgani AM, Onderdonk AB. Defined medium simulating Sci Oxford 1967; 6: 1871 – 1881. genital tract secretions for growth of vaginal microflora. J Clin 8 Levin RJ, Edwards FE. The transuterine endometrial potential Microbiol 1992; 30: 1323 – 1326. difference, its variation during the oestrous cycle and its 32 Owen DH, Katz DF. A vaginal fluid simulant. Contraception relation to uterine secretion. Life Sci. Oxford 1968; 7: 1019 – 1999; 59: 91 – 95. 1036. 33 Levin RJ, Wagner G. Quantitative analysis of amino acids in 9 Levin RJ. A critique on the relevance of membrane potentials human vaginal fluid during the menstrual cycle. J Physiol to the mechanism of nidation. 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