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Use of vitamin D supplements during infancy in an international feeding trial
- Eveliina Lehtonen, Anne Ormisson, Anita Nucci, David Cuthbertson, Susa Sorkio, Mila Hyytinen, Kirsi Alahuhta, Carol Berseth, Marja Salonen, Shayne Taback, Margaret Franciscus, Teba González-Frutos, Tuuli E Korhonen, Margaret L Lawson, Dorothy J Becker, Jeffrey P Krischer, Mikael Knip, Suvi M Virtanen, , Thomas Mandrup-Poulsen, Elias Arjas, Åke Lernmark, Barbara Schmidt, Jeffrey P. Krischer, Hans K. Åkerblom, Mila Hyytinen, Mikael Knip, Katriina Koski, Matti Koski, Eeva Pajakkala, Marja Salonen, David Cuthbertson, Jeffrey P. Krischer, Linda Shanker, Brenda Bradley, Hans-Michael Dosch, John Dupré, William Fraser, Margaret Lawson, Jeffrey L. Mahon, Mathew Sermer, Shayne P. Taback, Dorothy Becker, Margaret Franciscus, Anita Nucci, Jerry Palmer, Minna Pekkala, Suvi M. Virtanen, Jacki Catteau, Neville Howard, Patricia Crock, Maria Craig, Cheril L. Clarson, Lynda Bere, David Thompson, Daniel Metzger, Colleen Marshall, Jennifer Kwan, David K. Stephure, Daniele Pacaud, Wendy Schwarz, Rose Girgis, Marilyn Thompson, Shayne P. Taback, Daniel Catte, Margaret L. Lawson, Brenda Bradley, Denis Daneman, Mathew Sermer, Mary-Jean Martin, Valérie Morin, Lyne Frenette, Suzanne Ferland, Susan Sanderson, Kathy Heath, Céline Huot, Monique Gonthier, Maryse Thibeault, Laurent Legault, Diane Laforte, Elizabeth A. Cummings, Karen Scott, Tracey Bridger, Cheryl Crummell, Robyn Houlden, Adriana Breen, George Carson, Sheila Kelly, Koravangattu Sankaran, Marie Penner, Richard A. White, Nancy King, James Popkin, Laurie Robson, Eva Al Taji, Irena Aldhoon, Pavla Mendlova, Jan Vavrinec, Jan Vosahlo, Ludmila Brazdova, Jitrenka Venhacova, Petra Venhacova, Adam Cipra, Zdenka Tomsikova, Petra Krckova, Pavla Gogelova, Ülle Einberg, Mall-Anne Riikjärv, Anne Ormisson, Vallo Tillmann, Päivi Kleemola, Anna Parkkola, Heli Suomalainen, Anna-Liisa Järvenpää, Anu-Maaria Hämälainen, Hannu Haavisto, Sirpa Tenhola, Pentti Lautala, Pia Salonen, Susanna Aspholm, Heli Siljander, Carita Holm, Samuli Ylitalo, Raisa Lounamaa, Anja Nuuja, Timo Talvitie, Kaija Lindström, Hanna Huopio, Jouni Pesola, Riitta Veijola, Päivi Tapanainen, Abram Alar, Paavo Korpela, Marja-Liisa Käär, Taina Mustila, Ritva Virransalo, Päivi Nykänen, Bärbel Aschemeier, Thomas Danne, Olga Kordonouri, Dóra Krikovszky, László Madácsy, Yeganeh Manon Khazrai, Ernesto Maddaloni, Paolo Pozzilli, Carla Mannu, Marco Songini, Carine de Beaufort, Ulrike Schierloh, Jan Bruining, Margriet Bisschoff, Aleksander Basiak, Renata Wasikowa, Marta Ciechanowska, Grazyna Deja, Przemyslawa Jarosz-Chobot, Agnieszka Szadkowska, Katarzyna Cypryk, Malgorzata Zawodniak-Szalapska, Luis Castano, Teba Gonzalez Frutos, Mirentxu Oyarzabal, Manuel Serrano-Ríos, María Teresa Martínez-Larrad, Federico Gustavo Hawkins, Dolores Rodriguez Arnau, Johnny Ludvigsson, Malgorzata Smolinska Konefal, Ragnar Hanas, Bengt Lindblad, Nils-Osten Nilsson, Hans Fors, Maria Nordwall, Agne Lindh, Hans Edenwall, Jan Aman, Calle Johansson, Margrit Gadient, Eugen Schoenle, Dorothy Becker, Ashi Daftary, Margaret Franciscus, Carol Gilmour, Jerry Palmer, Rachel Taculad, Marilyn Tanner-Blasiar, Neil White, Uday Devaskar, Heather Horowitz, Lisa Rogers, Roxana Colon, Teresa Frazer, Jose Torres, Robin Goland, Ellen Greenberg, Maudene Nelson, Holly Schachner, Barney Softness, Jorma Ilonen, Massimo Trucco, Lynn Nichol, Erkki Savilahti, Taina Härkönen, Mikael Knip, Outi Vaarala, Kristiina Luopajärvi, Hans-Michael Dosch
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- Journal:
- Public Health Nutrition / Volume 17 / Issue 4 / April 2014
- Published online by Cambridge University Press:
- 24 June 2013, pp. 810-822
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Objective
To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial.
DesignLongitudinal study.
SettingInformation about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months.
SubjectsInfants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia.
ResultsDaily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80 % of the infants), with somewhat lower rates observed in Southern Europe (>60 %). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g. 71 % v. 44 % at 6 months of age). Less than 2 % of infants in the USA and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements.
ConclusionsMost of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the USA and Australia very few were given supplementation.
Drug-Induced Infertility and Sexual Dysfunction
- Robert G. Forman, Susanna K. Gilmour-White, Nathalie H. Forman
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- 30 March 2010
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- 14 March 1996
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This unique source of reference provides the first comprehensive guide to the adverse side-effects of many commonly prescribed drugs on fertility and sexual health. More than 150 drugs are listed in this compilation, and the evidence linking them with infertility and sexual dysfunction is carefully reviewed. The volume is designed to provide a rapid source of reference to alert doctors and pharmacists to these hazardous side-effects. The volume also includes an introductory account of the reproductive process and a review of the mechanisms by which these drugs can interfere with or inhibit reproduction. Another important theme of the volume is the effect of social and recreational drugs and environmental agents on reproductive health.
1 - Sexual and reproductive function
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Sperm production and transport
Male reproductive anatomy
The male reproductive tract consists of the testes, which produce sperm, and a series of ducts and tubes allowing the sperm and seminal plasma to be secreted (see Fig. 1.1). Testicular sperm drain into the epididymis which is a single convoluted tubule opening into the vas deferens. The epididymis is divided into three regions, the caput, corpus and caudum. Sperm concentration and maturative changes occur in the caput and corpus regions and are regulated by the concentrations of hormones and proteins within the epididymis. The cauda acts as a sperm reservoir where sperm may be stored for several weeks before being released into the vas deferens. The vas is approximately 25 cm long and passes into the peritoneal cavity via the inguinal canal before opening into the urethra. Secretions from the accessory glands, the seminal vesicles and prostate, drain into the urethra to form the bulk of the semen or seminal plasma. The bulbourethral glands produce a small amount of seminal fluid.
Anatomy of the testis
The testes are paired organs consisting of an outer capsule, the tunica albuginea, the seminiferous tubules, which form sperm, and the interstitial tissue (see Fig. 1.2). The seminiferous tubules, which occupy most of the volume of the testis, are contained in lobules (of which there are approximately 300), each lobule containing between one and four tubules. The tubules are composed of germ cells and Sertoli cells. The sperm produced in the seminiferous tubules pass into the ductus efferentes and rete testis before reaching the epididymis. The interstitial tissue fills the spaces between the seminiferous tubules and contains the Leydig cells.
7 - Miscellaneous drugs
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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Summary
Gastrointestinal drugs
Cimetidine
Cimetidine was first introduced in the USA for the treatment of duodenal ulcer in 1978. It is a histamine (H2) receptor antagonist that was generally thought to be well tolerated apart from the known occurrence of gynaecomastia. In 1979, however, several case reports appeared in the UK and the USA suggesting that cimetidine was associated with impotence (Wolfe, 1979; Peden et al, 1979). It was suggested that because minor elevations of gonadotrophins, testosterone and prolactin were found this side effect may have an endocrine basis. However, these hormonal disturbances were mild and unlikely to influence sexual function directly. A study in the USA of seven men taking cimetidine reported an average reduction in sperm count of 43% after 6 weeks of therapy, although sperm concentrations remained within the normal range (Van Thiel et al. 1979). Furthermore, although there was no difference in basal FSH or LH before or after cimetidine, testosterone levels were higher after treatment. The authors postulated that as cimetidine is an antiandrogen it might be having an atrophic effect on androgen-dependent tissues (similar findings had been recorded in rats given cimetidine).
This study was subsequently criticised on methodological grounds, specifically that spermatogenesis is known to take over 10 weeks whereas the authors were reporting decreased sperm counts after 6 weeks. (White, Gore & Jewell, 1979). A case report has also described rapid and reversible loss of libido in a woman within 3 days of commencing cimetidine (Pierce, 1983). The authors suggested that, as androgens are thought to stimulate libido in women, the antiandrogenic action of cimetidine might have the opposing effect.
3 - Psychotropic and central nervous system drugs
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Effect of psychiatric disease on sexual function
The relationship between psychotropic medication and sexual dysfunction is complicated by the fact that abnormalities of sexual function are common symptoms of underlying psychiatric illness. For example, impotence in untreated psychiatric patients is estimated to be as high as 70% depending on the diagnosis. In a controlled study of schizophrenic males versus healthy men, significant differences were found in most aspects of human sexuality between the groups. The failure of many studies and reports to include information regarding baseline sexual function makes interpretation of published data difficult. In some situations, the untreated patient cannot be relied upon to give an accurate sexual history even if questioned directly.
Despite these reservations, many data have accumulated, mainly from case reports but also from a handful of controlled trials, to suggest that some psychotropic medication does have a negative effect on sexual function. This may be a significant cause of non-compliance leading to psychiatric relapse.
Antipsychotics (neuroleptics)
Antipsychotic medication is often associated with sexual dysfunction, occurring in over 50% of patients in some studies (Buffum, 1982). The most common form of sexual dysfunction, seen both in male and female patients treated with neuroleptics, is decreased libido. Erectile and ejaculatory dysfunction are also common. Disturbances of orgasmic function occur less commonly. Neuroleptics have been reported to produce abnormalities in sperm morphology compared with the sperm of non-medicated schizophrenics (Nestoros, Lehmann & Ban, 1981).
Priapism has also been described in patients treated with antipsychotic medication. The mechanisms of drug-induced dysfunction with neuroleptics are complicated and may be mediated by hormonal and by both central and peripheral neurological mechanisms.
4 - Cancer chemotherapy
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Factors influencing reproductive toxicity
Chemotherapeutic agents can have significant toxic effects on the gonads and these cause major degrees of reproductive dysfunction. In the early days of cancer chemotherapy, reproductive toxicity was a secondary consideration to attempting to cure the disease. Fertility only became a concern when cancer treatment was associated with disease remission and patient survival. Now that some cancers are 100% curable, future reproductive capacity is of major importance to patients, particularly young men and women. Patients may only agree to chemotherapy that does not harm their ability to become parents.
Early cancer chemotherapy usually consisted of the administration of a single drug, and identification of the agent responsible for reproductive toxicity was obvious. Significant information is available from early studies and follow-up data are now available to assess the possibility of long-term recovery of reproductive function following treatment. More recent trends in cancer chemotherapy are towards combinations of several cytotoxic drugs with different mechanisms of action. The aim is to maximise cytotoxic activity while reducing toxicity to healthy tissues. Consequently, it is often less apparent which of the drugs used is responsible for the toxic effect.
In general, cytotoxic drugs exert the most marked effect on rapidly dividing tissue, and germ cells are particularly sensitive. The reproductive consequence of the treatment depends not only on the dose administered but also the sex of the patient and the stage in reproductive life. The neoplastic process itself may also adversely affect sexual function.
This chapter will review the mechanisms of action of cytotoxic therapy and describe known associated reproductive toxicity.
9 - Fertility and the environment
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Introduction
We live, work, eat and breathe in an environment filled with agents that have the potential for reproductive toxicity. There are over 60 000 chemicals in use in manufacturing processes and over 500 are added each year. Men and women can be exposed to these agents if they work in manufacturing industries producing or utilising the products; however, we all consume and accumulate chemicals because of our position as the terminal link in the food chain. We drink contaminated water. We are in contact with toxic chemicals when we decorate our houses and indulge in our hobbies. We are surrounded by sources of ionising and non-ionising radiation. In short it is impossible to avoid exposure to potential reproductive toxicants.
Certain environmental agents (comparatively few) have been proved by rigorous experimentation to have a major deleterous effect on reproductive performance. Many more have been linked to reproductive dysfunction but hard proof is lacking. It is highly likely that several environmental toxicants have as yet undiscovered adverse effects. Furthermore, we are exposed daily to low levels of toxicants, lead and radiation for example, which are known to have serious adverse effects on reproductive functions above certain threshold levels. Maximum permitted exposure levels have been calculated, but it is impossible to predict a level that is not harmful.
Reproductive toxicology is a very new branch of occupational medicine. The first significant report describing the effect of the pesticide dibromochloropropane (DBCP) was only published in 1977. There is now much more consumer interest in environmental issues in general and the importance of toxicants as a cause of infertility is starting to create deep concern in both lay and scientific communities.
Frontmatter
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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6 - Antibiotics
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Sulphonamides
Sulphasalazine
Sulphasalazine has been used in the treatment of inflammatory bowel disease since 1942, although the first reports of sperm toxicity only appeared in 1979. Sulphasalazine is taken orally and reaches the colon intact. As a result of the action of colonic bacteria, the compound is split into its constituents sulphapyridine and 5-aminosalicylic acid. It is useful to follow the sulphasalazine story in some detail. It is one of the few drugs for which clinical observation of reproductive side effects has led to detailed study of the underlying mechanisms responsible for the side effects. This has resulted in identification of the toxic component and a change in the pharmacological formulation.
Two separate reports in 1979 drew attention to men with inflammatory bowel disease presenting with infertility while being treated with long-term sulphasalazine. Levi et al (1979) noted reduced sperm count and motility that improved after withdrawal of the drug. Three of the four men fathered children when sulphasalazine was discontinued. The sperm abnormalities returned when the drug was reintroduced. Toth described 10 subfertile men on sulphasalazine. Six stopped treatment and their wives all conceived. He also noted a particular sperm morphological abnormality consisting of a ballooned enlarged sperm with a pale staining head. This appearance was thought to result from immaturity of the sperm coupled with osmotic damage to the membrane structures (Toth, 1979a,b). Others also described large numbers of immature sperm, suggesting a toxic action on sperm maturation. At this time, it was also postulated that the adverse effect could be related to the antiprostaglandin action of sulphasalazine, as prostaglandins are thought to be implicated in sperm motility (Traub, Thompson & Carville, 1979).
8 - Recreational drugs and drugs of abuse
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Tobacco
Tobacco is the most significant reproductive poison in current use. It is estimated that each year in North America there are 100 000 fetal deaths, 5000 congenital malformations and 200 000 babies who are born growth retarded as a consequence of maternal cigarette smoking (Hughes, 1994). Given this enormous effect on pregnancy outcome, it would be surprising if smoking did not also have some influence on the ability to conceive. However, despite the huge number of smokers it has proved impossible to reach definitive conclusions of the influence of smoking on conception. There are several reasons for this.
Smoking is more likely to be associated with other factors that can influence fertility, such as pelvic infection and the use of alcohol and caffeine. Small retrospective trials are of inadequate statistical power to reach valid conclusions and only a few large prospective studies have been performed. The design of the studies may introduce bias. One, for example, investigating the effect of smoking on sperm count, selected smokers from an infertility clinic whereas non-smoking controls were selected from men of proved fertility (Vine et al.9 1994).
Studies have concentrated on the effects of smoking by men on their sperm parameters, on the chances of conception in women smokers and, more recently, on the influence of smoking on the results of in vitro fertilisation. These areas will be reviewed separately.
Effects on sperm
Several reports mention negative effects of nicotine on sperm. One investigation in fertility clinic patients reported that 41% of smokers had reduced sperm density compared with 26% of non-smokers.
Index
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Contents
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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- 30 March 2010
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- 14 March 1996, pp vii-viii
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2 - Antihypertensive therapy
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Hypertension is one of the most frequent reasons for medical consultations in the developed world. In the USA alone, 35 million people are affected and 2 million die from hypertension and hypertensive-related illnesses each year. Hypertension is frequently asymptomatic and is usually detected only by screening.
Compliance with antihypertensive medication
Difficulty can be experienced in persuading patients of the need for drug therapy particularly as they are often asymptomatic. Compliance with therapy is frequently poor especially when side effects occur. Trials performed to assess this show that between 8 and 35% of all treated patients discontinue therapy because of adverse effects. Although a few patients withdraw for serious side effects, such as bradycardia, the majority stop treatment for symptoms interfering with the quality of life. Patients may willingly report socially acceptable side effects such as nausea, lethargy or headaches, but there is increasing evidence that they may not volunteer information about sexual dysfunction. It has been known for many years that certain drugs may provoke sexual dysfunction, but many medical practitioners are unaware of the number of therapeutic classes of antihypertensive drug that have been reported to modify sexual function and behaviour. It is also important during the monitoring of antihypertensive therapy that prescribers directly question men and women on whether they are experiencing sexual problems.
Gender differences
There is certainly a gender difference in reports of sexual dysfunction related to antihypertensive therapy. For example, in the Hypertension Detection and Follow-up Programme in the USA, 8.3% of men but only 0.4% of women stopped their antihypertensive drug because of sexual side effects (Curb et al, 1985).
5 - Hormone therapy
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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Summary
Sex hormones
Oestrogens
Combined oral contraceptive pill
In 1993, a National Opinion Poll was carried out on behalf of a pharmaceutical company that manufactures contraceptive pills. This poll surveyed 1000 women in the 16 to 44 year age range. The combined oral contraceptive pill (OCP) was the most popular form of contraception used: 90% of women had used it at some time in their sexual history and 33% of women were current users.
The pill is designed to produce reversible infertility. The oestrogen component inhibits ovulation and the progestogen both balances the oestrogen (oestrogen unopposed by progestogen can induce endometrial cancer) and has contraceptive properties. As the therapeutic effect of the pill is to produce infertility, it is not relevant to discuss this aspect further. However, there have been a few reports linking OCP use to reduced libido. In a 1976 review of psychological effects of pill use, Kane reported that between 10 and 40% of users of OCPs suffered mild to moderate depressive syndromes, many also experiencing loss of libido (Kane, 1976). This figure does seem very high but these studies, which were all performed in the late 1960s and early 1970s, were concerned with hormone formulations that used much higher doses of oestrogen and different progestogens from those in current use. However, even a recent placebo-controlled study using modern triphasic contraception has shown that women using these pills reported significantly decreased sexual interest during the menstrual and post-menstrual phases of the cycle. This effect was unrelated to any influence of the pill on mood (Graham & Sherwin, 1993).
Preface
- Robert G. Forman, Guy's and St Thomas' Hospital, London, Susanna K. Gilmour-White, Guy's Hospital, London, Nathalie H. Forman
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- Drug-Induced Infertility and Sexual Dysfunction
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- 30 March 2010
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- 14 March 1996, pp ix-x
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Summary
The idea for this book originated from the professional frustration experienced by the authors in the face of apparently simple enquiries from patients or health care colleagues. Questions on the possibility that patients’ fertility or sexual problems could be drug related resulted in extensive literature searches, discussions with pharmaceutical companies and, sometimes, contact with the Committee on Safety of Medicines. These endeavours generated a collection of academic papers requiring time-consuming analysis before a reply could be given.
The desirability for a comprehensive reference text which included much of this information in a readily accessible form was all too evident.
One of the difficulties in a project of this type is the source of data. We were only able to access information in the public domain. Two important sources of valuable data are not available to the public. These are the databases collated by the Committee on Safety of Medicines via the yellow card notification scheme and those held by pharmaceutical manufacturers. Manufacturers have a reporting obligation to notify the Committee on Safety of Medicines about serious or life-threatening adverse effects. Infertility and sexual dysfunction do not come into this category.
Academic journals are the major reference source for much of the information in this book. Adverse drug effects may be published as case reports, which can be useful early warnings of a potential problem but do not necessarily represent general experience. Controlled clinical trials of adverse reproductive effects are few and far between but have been included where available. Many drugs are given for diseases which can themselves affect reproductive function and this is highlighted in the relevant sections.