Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Unsafe sex: treat the whole condition!
- veronique verhoeven, Dirk Avonts, Paul Van Royen (23 July 2004)
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Hazards of isotretinoin
- Javier Borja, David Rigau, Eva Arnaiz (23 July 2004)
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POM to P in the UK
- John S Watts (23 July 2004)
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Drugs with high dose of Vitamin A should not be available
- Umesh Kapil, NIL (24 July 2004)
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isotretinoin
- Sonya M Havill (28 July 2004)
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Dr
- Robert R. Fenichel (29 July 2004)
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The answer is simple. All drugs should be available over the counter.
- N Portman (10 August 2004)
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..simple. All drugs should be available .. to competent adults
- Sam Lewis (11 August 2004)
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In Mexican "pharmacias" one can buy Thalidomide over the counter.
- Dr. Herbert H. Nehrlich (11 August 2004)
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Levonorgestrel is hazardous
- Ellen C G Grant (15 August 2004)
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recent travels
- Robert R. Fenichel (17 August 2004)
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Hormonal contraceptives should not be OTC
- Ellen C G Grant (18 August 2004)
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Chaos and control
- Phillip J. Colquitt (18 August 2004)
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To travel does not mean one has arrived
- Dr. Herbert H. Nehrlich (19 August 2004)
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questions and answers
- Robert R Fenichel (26 August 2004)
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OTC progesterones are dangerous
- Ellen C G Grant (27 August 2004)
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veronique verhoeven, researcher University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, BELGIUM, Dirk Avonts, Paul Van Royen
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There is no doubt that women are able to diagnose themselves with exposure to unsafe sex, but emergency contraception is only part of the therapy! The risk of pregnancy, following a single act of mid-cycle unprotected sexual intercourse is estimated at 8%(1). On the other hand, the reported prevalence of Chlamydia trachomatis in young women in UK ranges from 3.4 to 17.6%(2) and the transmission rate is estimated at 50%(3); thus the risk of chlamydial infection may be as high as the risk of unwanted pregnancy. Furthermore, unprotected sex often is not a once-only event:in a chlamydia prevalence study, carried out in 2001-2002 in Antwerp, Belgium in 819 general practice attendants aged 14-35, a history of emergency contraception use was positively associated with present/past sexually transmitted infection(OR 1.69, 95%CI: 1.05-2.73, p=0.032) and with current risky sexual behaviour (OR for having had multiple sexual partners in the present year without consistent condom use: 2.11, 95%CI: 1.46-3.07, p<0.001). Women exposed to unsafe sex may primarily be concerned with avoiding pregnancy, but they also need counselling and a test for chlamydia; if not, future reproductive health is compromised. Over the counter delivery of levonorgestrel is only safe if it is followed by referral to a health care provider. (1)World health organization. Task Force on Post-Ovulatory Methods for Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998;352:428-33 (2) Pimenta JM, Catchpole M, Rogers PA, et al. Opportunistic screening for genital chlamydial infection. II: Prevalence among healthcare attenders, outcome, and evaluation of positive cases. Sex. Transm. Inf., Feb 2003; 79: 22 - 27 (3)Lycke E, Lowhagen GB, Hallhagen G, et al. The risk of transmission of genital Chlamydia trachomatis infection is less than that of genital Neisseria gonorrhoeae infection. Sex Transm Dis. 1980;7:6-10 Competing interests: None declared |
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Javier Borja, Drug Safety Manager J. Uriach y Compañía, S.A. 08184 Palau-solità i Plegamans. Barcelona.Spain, David Rigau, Eva Arnaiz
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EDITOR-In his article about which drugs should be available over the counter, Fenichel affirm that isotretinoin, used to treat acne, presents no special hazards to men or not pregnant women (1). This sentence is, in our opinion, risky. As pointed in a recent review by Charakida and colleagues (2), although the most important issue concerning isotretinoin safety is teratogenicity, its use is associated with many adverse reactions affecting almost all systems and some of these reactions can be very serious. A few of the examples mentioned by the authors (2) are severe forms of erosive and exfoliative cheilitis, diffuse interstitial skeletal hyperostosis, xerophtalmia that can lead to significant blepharoconjunctivitis, exposure keratitis and, in extreme cases, corneal ulceration, neurological effects including seizures, stroke and pseudotumor cerebri, and the impact of isotretinoin on liver function and lipid metabolism. Moreover, there have been serious concerns about the possible association between isotretinoin and depression, suicidal ideation and suicide. Although no causal link has yet been established between isotretinoin and depression, dermatologists should be aware of this possible serious adverse reaction, and if such symptoms occur, isotretinoin treatment should be discontinued and if necessary specialist psychiatric support should be obtained (2). Isotretinoin therapy should be initiated in patients after obtain a writing informed consent/patient agreement form to comply with the clinician instructions on the use of the drug (3). Thus it seems that isotretinoin is not devoid of significant hazards in male patients and non pregnant women. 1.Fenichel R R. Which drugs should be available over the counter?. Br Med J 2004; 329: 182-3. 2.Charakida A, Mouser P E, Chu A C. Safety and side effects of the acne drug, oral isotretinoin. Expert Opin Drug Saf 2004; 3: 119-29. 3.American Society of Health-System Pharmacists. AHFS Drug Information, Bethesda, 2003. Competing interests: None declared |
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John S Watts, Locum Associate Specialist CAMHS, 1 Twisleton Court, Priory Hill, Dartford. DA1 2EN
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Editor - I agree with Fenichel (1) that there is a wide variation between countries when it comes to medicines available "over-the-counter". In the UK, there are three legal classifications of medicines - Prescription Only Medicine (POM); Pharmacy Medicine (P); and General Sales List (GSL)(2). By definition, a POM medicine requires a prescription, a P medicine is available under pharmacist supervision, and GSL medicines are available from other shops, including supermarkets. These are legal categories as defined in the (UK) Medicines Act 1968 and an EC directive (Directive 2001/83/EC). Interestingly, all medicines are presumed to be P unless they meet the criteria for POM or GSL. The POM Criteria are: 1. Likely to present a danger either directly or indirectly, even when used correctly, if utilised without medical supervision. 2. Frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health. 3. Contain substances or preparations thereof the activity and/or side-effects of which require further investigation. 4. Are normally prescribed by a doctor or dentist to be administered parenterally. These criteria are mirrored in the directive (2001/83/EC). Therefore, for a medicinal product to be reclassified from POM to P, it must no longer fulfil the POM criteria (2). For reclassification of a drug in the UK, the normal route is POM to P, then P to GSL. Some examples of non-POM medicines in the UK are (3): Nicotine Replacement Therapies; Zovirax (cold sores); Opticrom eye drop products (hayfever); Canesten (thrush); Nurofen (pain relief); Zantac (heartburn); Buccastem (migraine); Lamisil (fungal infection). Yet again we see an important medical issue that is dealt with in different regions of the world. Is it time for the International Conference on Harmonisation (ICH) to start harmonising? References: 1. Robert R Fenichel Which drugs should be available over the counter? BMJ 2004; 329: 182-183 2. Changing the legal classification in the United Kingdom of a medicine for human use. London: MCA, 2002. Accessed via the MHRA website 23-Jul-04 3. MHRA press release: Wider access to medicines to allow patients to manage their own healthcare. Accessed via the MHRA website 23-Jul-04 Competing interests: None declared |
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Umesh Kapil, Professor, Public Health Nutrition All India Institute of Medical Sciences, New Delhi, India, NIL
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Vitamin A is a chemical that is essential to sustain human life and must be provided in adequate amounts through food or other dietary supplements. However, excessive consumption of vitamin A can cause birth defects. Recently, birth defects have been observed in children born to mothers taking synthetic vitamin A drugs used to treat acne. These observations raised concerns that high vitamin A intake during pregnancy could cause birth defects in unborn children. The California Environmental Protection Agency (CAL/EPA) has identified retinol or retinyl esters (types of pre-formed vitamin A) as developmental toxins when administered at doses greater than 10,000 International Units (IU). The Food and Drug Administration has established a daily recommended allowance (RDA) of 5,000 IU for vitamin A. Because vitamin A is required to ensure reproductive health, it has been recommended that pregnant woman maintain their intake around 8,000 IU and that vitamin A be taken in the form of beta-carotene, which is not considered toxic. The following list contains recommendations from the Teratology Society (Teratology Society; 1987): Supplementation of 8,000 IU vitamin A (as retinol/retinyl esters) per day should be considered the recommended maximum prior to or during pregnancy until further evaluations can be performed in the human population. It is important to determine the type of vitamin A consumed, since beta-carotene has not been associated with vitamin A toxicity in animals or man. Manufacturers of vitamin A (as retinol or retinyl esters) should lower the maximum amount of vitamin A per unit dosage to 5,000-8,000 IU (1,500-2,400 RE) and identify the source of the vitamin A. High dosages of vitamin A as retinol/retinyl esters (25,000 IU or more) are not recommended. Labeling of products containing vitamin A supplements (as retinol/retinyl esters) should indicate (a) that consumption of excessive amounts of vitamin A may be hazardous to the embryo/fetus when taken during pregnancy; and (b) that women of childbearing potential should consult with their physicians before consuming these products. The drugs with high dose of VA should not be available over the couinter as nearly 30% of the mothers are niot even aware that they are pregnant during first three months of the pregnancy Dr. Umesh Kapil MD, DNB, FAMS ,FIPHA,FIAPSM Professor Public Health Nutrition Department of Human Nutrition All India Institute of Medical Sciences, New Delhi 110 029, INDIA Tel No: (Off) 91-11- 26593383 ; (R) 91-11-26195105 Mobile:. 9810609340 Fax : 91-11-26588641 , 91-11-26588663 kapilumesh@hotmail.com Competing interests: None declared |
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Sonya M Havill, Dermatologist North Shore hospital, Auckland, New Zealand
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You comment in your article that isotretinoin presents no special hazards to men or non pregnant women.This is a false statement. Isotretinoin has a wide range of adverse effects other than teratogenicity that must be clearly explained to the patient before treatment commences.This is why isotretinoin must be prescribed by a doctor with full knowledge and experiece of treating patients with this medication. Competing interests: None declared |
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Robert R. Fenichel, consultant 3922 Ingomar Street; Washington, DC 20015-1916; USA
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In naming isotretinoin, I was trying to illustrate the notion that prescription status might be retained because of a drug's special hazards, even if the drug were hazard-free in most patients. The notion is useful, and perhaps I need not have tried to illustrate it. However that may be, Havill and Borja et al. are certainly correct: isotretinoin was not a well-chosen example. Depending on how strictly one wishes to define "hazard-free," perhaps no actual example exists. Competing interests: see note accompanying editorial |
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N Portman, Patient Tunbridge Wells, Kent
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It always amazes me that when the medical community debates a subject such as this, every possible issue gets mentioned except personal freedom. The answer to R Fenichel's question is actually very simple. All medicines should be available to adults without the need for a prescription. Of course ideally patients should consult their doctor before taking a new drug but it shouldn't be a requirement. Medicines should be (and generally are) supplied with clear instructions and for many patients this is protection enough. We pride ourselves on living in a 'free society'. An adult in Britain is able to join the army, vote, marry, have children, drive a car (once a licence has been obtained), engage in hazardous sports etc. Basically our society operates on the premise that on the whole individuals can be relied upon to behave rationally and responsibly. Yet sick people do not have the right to choose, without the permission of a doctor, what medicines they can take in order to alleviate their suffering. This is surely an anachronism in the 21st century. Basically the medical profession assumes (somewhat patronisingly) that once people develop a medical condition they somehow regress into an infantile state where they can't be trusted to make decisions for themselves. If this assumption is true (and there is no evidence to support it) then why are sick people still entitled to vote? [For the purposes of this argument I'm ignoring the handful of medical conditions that cause genuine mental impairment] The argument that 'vulnerable' patients need to be protected doesn't really stand up to close scrutiny and is inconsistent with the way we choose to operate our society as a whole. Any adult can go and purchase rat poison, drain cleaner, or any number of other substances that are extremely toxic if ingested. So why aren't they prescription only? And many non-prescription drugs such as Paracetamol are lethal if taken in overdose. No, the prescription system has little to do with protecting patients and everything to do with protecting the power and status of the medical profession. If wholesale scrapping of the prescription system is too radical for some then I can suggest an alternative. A mechanism could be developed to enable individual 'expert' patients to opt out of the prescription system if they so wished. Perhaps the patient could obtain some sort of prescription-exemption certificate, maybe signed by a psychiatrist, confirming that he was of sound mind, and understood the implications of what he was doing. This certificate would then be used in place of a prescription and would release the patient's doctor/pharmacist from any responsibility for inappropriate prescribing. Of course if something went wrong the patient would have no redress. But that would be his choice. Competing interests: None declared |
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Sam Lewis, GP Surgery, Newport, Pembs, SA42 0TJ
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I find that every instinct within me wants to agree with N Portman.. So why am I anxious ? With some caveats, might we be in agreement :- 1. The Adult should be mentally competent. 2. That competent Adult should have been 'fully informed' - by a competent informer ( - doctor ? ). 3. That fully-informed competent Adult should pay the full cost for the drug ( converse: an HMO or NHS should be allowed to 'ration' its funds) . 4. And take full reponsibility for his choice of drug ( converse: the doctor should be absolved of all responsibility except the quality of his advice). I now feel more at ease, except that :- 5. The drug itself should not undermine premise 1, 2 , 3 etc ( eg: addictive drugs ) Competing interests: None declared |
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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Excuse me N. Portman ! Assuming that your doctor has your best interests at heart and is in possession of the proper skills and certifications attesting to them, I cannot for the life of me imagine a scenario where ANYONE but your doctor ought to be the final decision maker over what medication you ought to take.(Of course you can take part in the decision making.) How many "qualified" patients do you know that could take on that kind of responsibility? It should be obvious, even to you, that the purpose of a medical education is to enable the future doctor to act as the expert in matters concerning these chemicals. While there are undoubtedly doctors among us who place their own economics above the interests of their patients that in itself is not reason enough to establish a type of 'pharmaceutical anarchy'. All of us know the old saying "A doctor who treats himself has a fool for a patient". What would you call a patient who treats himself? No, I find NOTHING useful or practical in your comments. We know over-the-counter drugs, under-the-counter drugs and some more exotic ones. A medicine is placed on prescription not for the benefit of the doctor but for the protection of the patient. Even though the system can create some frustrating situations I personally wouldn't want the inmates to run the asylum. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist 20 Coomeb Ridings, Kingston-upon-Thames, KT2 7Ju, UK
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Editor- Your Editorial author Robert Fenichel has served as a consultant to a large number of drug companies, some of whom manufactured synthetic progesterones.1 He says none of them have made the levonorgestrel preparation which was rejected by the FDA as an “over the counter” drug. He mentions Schering which made Anovlar, the first synthetic progesterone we tested in 1962. Anovlar contained norethisterone acetate. Like all progesterone dominant preparations, side-effects included severe migraine, clotting and mood changes.2,3 Micronised levonorgestrel is about ten times more powerfully progestogenic than norethisterone acetate. Schering have produced a variety of products containing levonorgestrel, such as Microgynon, Eugynon, Neogest, Logynon and Norgeston and an emergency contraceptive pill containing levonorgestrel. Where has Dr Fenichel been? Has he missed the studies finding that progesterones are more powerful breast carcinogens than oestrogens? Progesterones are among the most immunosuppressive, teratogenic and carcinogenic drugs in existence. How can he possibly claim therefore that the medical hazards of levonorgestrel are minimal? I attach my previous Rapid Response the BMJ news item on this subject4 as a reminder of the serious implications of exposures to progesterones seems to be needed for everyone. 1 Feichel RR. Which drugs should be available over the counter? BMJ 2004;329:182-183 (24 July), doi:10.1136/bmj.329.7459.182 2 Mears E, Grant ECG. "Anovlar" as an oral contraceptive. BMJ 1962; 2: 75-79. 3 Changing oral contraceptives. BMJ 1969;4:789-91 & Today's Drugs (Grant ECG). 4 Grant ECG Progesterone emergency contraception http://bmj.com/cgi/eletters/328/7450/1219#60340, 23 May 2004 “Janis Hopkins Tanne reports that the rejection by the FDA of over counter status for high dose synthetic progesterone emergency contraception has aroused outrage.1 Are there not sound medical reasons for the FDA's decision? The incidence of underage pregnancies world-wide, like the diagnosis of breast cancer, appears to have increased with increasing promotion of hormones. The USA and the UK have high incidences of both. Progesterone is strongly immuno-suppressive and carcinogenic. It promotes growth in breast glands, ducts and blood vessels in untreated luteal cycles and when women are exposed to exogenous hormones. Several studies including the Million Women Study, the Women's Health Initiative Study and the Nurses Study found progesterones increased the risk of invasive, metastatic breast cancer more than estrogens given alone. The risk increases with repeated or longer use for different reasons, whether for contraception or menopausal symptoms. Haiyhan Pang and colleagues write that progesterone may play a direct role in breast cancer invasion and metastasis.2 While the effects of progesterone on cell cycle progression are well known, its role in spreading and adhesion of breast cancer cells is now receiving attention. Cell adhesion protein desmoplakin is upregulated by progesterone – a process that is suppressed by epidermal growth factor. This appears to be a general but not universal effect in breast cancer cell lines. Randomised trials of HRT have been stopped and older women are being warned not to use hormones because of the unacceptably high risks of invasive and metastatic cancer and vascular diseases. It is unfair to subject teenagers to the dangers of life long autoimmune diseases, such as systemic lupus erythematosus and anti- phosphlipid syndome and increased risks of several cancers. Any use of contraceptive hormones in the previous 20 years doubled the number of breast cancers with over expression of cyclin-D in young women.3 The FDA has made a rational medical decision. Randomised hormone trials have confirmed unacceptable risks for older women but the possible deleterious long-term effects of repeated, large dose hormone exposures on reproduction, and future health, are greatest for younger women. 1 Tanne JH. FDA rejects over the counter status for emergency contraceptive. BMJ 2004; 328: 1219. 2 Pang H, Brian G Rowan, Mariam Al-Dhaheri and Lee E Faber. Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells. Breast Cancer Research 2004, 6:R239-R245. 3 Terry MB, Gammon MD, Schoenberg JB, Brinton LA, Arber N, Hibshoosh H. Oral Contraceptive Use and Cyclin D1 over expression in Breast Cancer among Young Women. Cancer Epidemiol Biomarkers Prev, 2002;11: 1100-1103. Competing interests: Tested oral contraceptives for the Council for the Investigation of Fertility Control in the 1960s |
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Robert R. Fenichel, consultant 3922 Ingomar Street, NW; Washington, DC 20015; USA
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Dr. Grant asks, "Where has Dr. Fenichel been?" and I'm happy to answer. I've been in a world where two drugs in the same class often have different effects, where short- and long-term treatments with the same drug often have different effects, and where mechanistic speculation leads to empiric studies instead of shouted conclusions. That's where I've been. I have never met Dr. Grant. Competing interests: See original editorial |
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Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, kingston-upon-Thames, Surrey, KT2 7JU, UK
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Editor- During the 45 years I have spent studying the effects of hormones on women’s health, I have not previously encountered Dr Robert Fenichel.1 Nor have I inhabited a drug company sponsored world since the 1960s. Between 1961- 1969 companies manufacturing oral contraceptives paid for trials run by the Council for the Investigation of Fertility Control, the research body of the UK Family Planning Association. The results of clinical, pathological and biochemical investigations in pre-treatment, treated, and post treatment cycles, in hundreds of women, taking over 60 oral contraceptive formulations, led me to the conclusion that hormones were too dangerous to use. I also acted as pathology advisor for a trial of different progestogen-only formulations in Yugoslavia. Since then I have attended a few expensive international meetings and paid privately. This year I attended an International Conference on Women’s Health in Florence and previously went to the Harvard/MRC/Lancet conference on HRT in Milan. I was ahead of the news in 1997 when I led the case against prescribing HRT in a debate sponsored by Solgar. Otherwise, 25 years ago I joined a group of like-minded doctors to found the “British Society for Allergy, Environmental and Nutritional Medicine” which has biannual scientific meetings. Instead of using drugs as a first option, nutritional deficiencies and silent infections are monitored and treated, and patients are advised to follow nutritious, low allergy diets and to avoid common social poisons like exogenous hormones, smoking and alcohol. These methods are useful in many conditions including allergies, headaches, migraine and hypertension and are essential for the best preconception care.2 More often than not “establishment” studies are conducted with scant regard for the underlying biochemical upsets that cause conditions “treated” by drugs. Scientific knowledge is the key to recognising and treating reactions to drugs and to hormonal progesterones, however they are administered. Nothing I have learnt in the past 45 years has made me think that taking very large intermittent doses of levonorgestrel is safe. International trials of emergency contraceptives seem to be more concerned with prevention of pregnancy than following up or investigating the effects of the progesterones on the women or future children. Unmonitored “over the counter sales” are unlikely to increase scientific knowledge. Some patients have reported mood changes, breast lumps or severe migraine with acute post viral syndrome. As a grandmother, I welcome the decision of Australia to reverse its decision on morning after pill. BMJ News in brief reported that the Australian government plans to ban sales of the morning-after pill levonorgestrel (Postinor-2) only six months after making it available over the counter at chemists. Federal health minister Tony Abbott said the government wants to make the pill prescription-only because of concerns that girls as young as 13 are using it as emergency contraception.3 I hope the chairman of the Medicines and Healthcare products Regulatory Agency (MHRA), previously the Medicines Control Agency (MCA), Professor Sir Alasdair Breckenridge, who was a fellow student at St Andrews University, can also persuade the UK authorities to follow the US FDA and the Australian government in banning OTC hormones. It is not good enough to hide behind a yellow card system which has always been notoriously underused. 1 Fenichel RR. Which drugs should be available over the counter? BMJ 2004; 329: 182-183 2 Anthony H, Birtwistle S, Eaton K, Maberly J. Environmental Medicine in Clinical Practice BSAENM 1997 ISBN: 0952339722 3 News In brief BMJ 2004;328:1454 (19 June), doi:10.1136/bmj.328.7454.1454 Competing interests: None declared |
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Phillip J. Colquitt, Reader At my PC
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It seems improbable that doctors having control over that which is prescribed, would also mean doctors having control over that which is taken. Life is just not like that. Competing interests: None declared |
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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I found Dr. Fenichel's response to Dr. Grant a trifle flippant. I assume that by not answering her question he is revealing that he is either unwilling or unable to. Makes me wonder what a patient would think after reading these comments. Which doctor would (s)he choose ? Personally, I can do entirely without arrogance in my health professionals, there are other qualities much more appropriate. But, I admit, it is very easy to become an echidna to the world around when one begins to suspect that others are not displaying enough awe and respect. Schoolteachers eventually suffer from the same illness, the cause of which shall remain unsaid. Competing interests: None declared |
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Robert R Fenichel, consultant 3922 Ingomar Street, NW;Washington DC 20015; USA
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I was sorry to find that Dr. Nehrlich (and others, presumably) found my response to Dr. Grant’s letter to have been “a trifle flippant,” and not responsive to Dr. Grant’s question. Actually, Dr. Grant asked three questions in her letter. The first was the topic sentence of her second paragraph: “Where has Dr. Fenichel been?” That is not the way I would have chosen to structure this discussion, but I am sometimes willing to go with the flow of other people’s rhetoric. I answered the question. Dr. Grant’s second question asked whether I had missed the studies finding that progesterones are more powerful breast carcinogens than oestrogens. I did not answer this question directly, but I did not ignore it. The hazards of chronic exposure to progesterones must be weighed against the benefits of such exposure; in recent years, most regulators, physicians, and patients have come to a nuanced understanding of this issue. I have (tangentially) commented on this issue elsewhere (see page 491 of [1]). The issues surrounding chronic progesterone exposure are interesting, but they are only distantly relevant to acute exposures, such as those that are involved in emergency contraception. I would be amused to hear that my patient had won a bet by eating 12 eggs at one sitting, but dismayed to learn that he ate 12 eggs every day. Powerful immunosuppressants are routinely used to treat exacerbations of rheumatoid arthritis, psoriasis, and systemic lupus, even though chronic treatment with the same agents is life-threatening. Ionizing radition is immunosuppressive and carcinogenic, but this isolated factoid is not much help in deciding whether or not to travel by air, whether a particular injury should be xrayed, or even whether a particular malignant lesion should be heavily irradiated. I did not think that BMJ readers needed to be reminded of these elementary therapeutic principles, so I merely alluded to them in noting that “short- and long-term treatments with the same drug often have different effects.” Dr. Grant’s third question asked how I could possibly claim that the medical hazards of levonorgestrel were minimal. Her premise to this question was the assertion that “progesterones are among the most immunosuppressive, teratogenic, and carcinogenic drugs in existence.” Put as a positive chain of reasoning instead of a question, Dr. Grant’s argument appears to be (1) Progesterones are among the most immunosuppressive . . . in existence. (2) There are no data other than those alluded to in (1) with which to estimate the hazards of one-off use of levonorgestrel. Assertion (1) seems exaggerated, to say the least. Just focussing on immunosuppression, assume that (1) were true. One might then expect that diseases of immune hyperactivity would be relatively suppressed in premenopausal women, and therefore that rheumatoid arthritis, systemic lupus, and primary biliary cirrhosis would be seen mainly in progesterone- deprived children, men, and elderly people of either sex. Diseases of impaired immune surveillance (e.g., reactivated tuberculosis, herpes zoster, and many cancers) would be hazards of the female reproductive years, seen only rarely in children, men, and the elderly. To reduce the immunosuppressive hazards to progesterone-naïve toddlers, progesterone- containing oral contraceptive medications would not be exempt from laws relating to child-resistant packaging, and inadvertent ingestions of such medications would be considered serious incidents. Patients threatened with immune rejection of transplants would receive progesterones in addition to (or instead of) cyclosporine and tacrolimus. My observations have been different. More importantly, discussion of (1) is inessential, since (2) is simply false. The regulatory evaluation of levonorgestrel for emergency contraception was informed by knowledge of the hazards of chronic use of other progesterones, but the critical trials had to do with the acute effects of levonorgestrel. These specific data were evaluated by regulators in painstaking detail (I have worked in those mills), described at the Advisory-Committee meeting whose transcript is among my original references, and further evaluated (in lesser detail) by the Advisory- Committee members and by various academic groups (the American College of Obstetrics and Gynecology, the American Academy of Pediatrics, the American Public Health Association, and others). In saying that “[t]he medical hazards of [one-off] levonorgestrel appear to be minimal in absolute terms and also relative to those of responses to pregnancy,” I was not describing the result of any personal analysis; I have not seen the detailed data. Of course, Dr. Grant has not made any reference to levonorgestrel-specific data at all. I noted that "two drugs in the same class often have different effects," but again, this will hardly be news to most readers of the BMJ. The original editorial was to have been limited to 800 words (later negotiated upward to 1000), and I may have been overly impressed by the BMJ’s emphasis on brevity. My response to Dr. Grant was deliberately terse, but surely not deliberately flippant, and again, I’m sorry that it was so perceived. In hindsight, I should have written this letter straight away, instead of having it appear reparatively. 1. Fenichel RR, Malik M, Antzelevitch C, et al. Drug-induced torsades de pointes and implications for drug development. J Cardiovasc Electrophysiol 2004; 15(4):475-95. Competing interests: see original editorial |
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Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, KT2 7JU, UK
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EDITOR - Bob Fenichel says I did not refer to the levonorgestrel emergency contraceptive studies. I had previously expressed my concerns about the study comparing combined and single levonorgestrel as emergency contraceptives in 2002.1,2 My studies included 6 different doses of unmicronised norgestrel given with a constant dose of oestrogen. I also tested the effect of norgestrel given alone. Today’s levonorgestrel is twice as powerful as it contains only the active isomer and micronisation also doubles the effect. This means that dose for dose modern levonorgestrel is four times more powerfully progestogenic than the norgestrel tested in the 1960s. A very large dose of levonorgestrel is used for emergency contraception but women often developed migraine with the first few lower dose oral pills. Both blood vessels and monoamine oxidase levels change immediately in response to progestogenic stimulation. This also happens in an untreated menstrual cycle when there is a tenfold increase in monoamine oxidase levels in the late secretory phase. Some women realise adverse reactions warn of serious risks and decide sensibly against further use of hormonal contraceptives. In many studies, such women are classified as never users so data is missing about the effects of acute exposures.3 As further use of immunosuppressive effect of progesterone dominant contraceptive or HRT hormones suppresses warning symptoms, women and their doctors have been lulled into claiming unjustified benefits and withdrawal symptoms have been excuses for further exposures to hormones.4 Emergency contraception is not merely taken once but is increasingly used repeatedly for failed contraception among condom and oral contraceptive users. The average exposure from “chronic” use is very short for a carcinogen, being only two or three years in contraceptive and menopausal hormone studies. No one knows how much exposure is needed to induce breast cancer in susceptible women and a carcinogenic effect of acute exposures cannot be ruled out. As we are suffering from an epidemic of breast cancer we cannot be sanguine about any large or small dose use in such widely exposed populations.5,6 Progesterone is an immune system modifier, acting by inducing a switch during pregnancy from cellular to humoural balance.7 The RCGP oral contraception study found an increase in over 60 conditions. These included systemic and genital viral, bacterial and fungal infections, also vascular, mental and gynaecological conditions and cancers.8 Conditions associated with SLE such as erythema nodosum, rosacea, migraine and mental changes were increased in oral contraceptive users and increases in SLE have also found in HRT users.9 Both progesterones and oestrogens are immune system modulators but progesterone is more immunosuppressive. This effect was described at the Florence Conference on Women’s Health this year as being more powerfully immunosuppressive than cortisol. Irrespective of minor differences (related to chemical structure or the addition of oestrogen) the predominant class action of all hormonal contraceptives, including “the morning after pill”, is that of progesterone. 1 Grant ECG. “Mega” dose emergency contraception http://bmj.com/cgi/eletters/324/7347/1179#22450, 23 May 2002 2 Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998; 352: 428-33. 3 Grant ECG. Poor quality research http://bmj.com/cgi/eletters/328/7430/39#45531, 4 Jan 2004 4 Grant ECG. HRT Addiction http://bmj.com/cgi/eletters/328/7436/371#50825, 19 Feb 2004 5 Grant ECG. Increases in breast cancer incidence http://bmj.com/cgi/eletters/328/7445/921#55298, 1 Apr 2004 6 Grant ECG. Re: Rapid Responses; Authors' reply. http://bmj.com/cgi/eletters/328/7445/921#55843, 6 Apr 2004 7 Grant ECG. Re: Hormornal Balance switches from Th1 to Th2 during Pregnancy http://bmj.com/cgi/eletters/329/7457/112-b#69006, 28 Jul 2004 8 The Royal College of General Practitioners Oral Contraceptives and Health. London: Pitman Medical, 1974 9 Grant ECG. Systemic lupus erythematosus. Lancet 2001 358:586. Competing interests: None declared |
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