e-19th century

Papers from the early 19th century

Inspired by Cloquet, Sarlandière, Pelletan, Carraro, and Pouillet, on Acupuncture. Edinburgh Med Surg J 1827;27:190–200.

On the 25th October 2018 three rather unusual papers appeared on my PubMed search.[1–3] They were remarkable because they were nearly two centuries late! So I guess there is an ongoing process of digitising journal archives, and it happens that the word ‘acupuncture’ or ‘acupuncturation’ appeared in the titles of these old papers. I often use the search term ‘acup*’, where the asterisk is a wild card – meaning it can stand for any letter or combination of letters. Generally, that means I will get ‘acupuncture’ or ‘acupressure’… I never expected, in the modern era to get ‘acupuncturation’!

I was very pleased to find that the full text of these papers was hosted on PubMed Central (PMC), although they are reasonably big files since they are page images. The oldest of the three was published in 1827, and it is this paper to which the following extracts and comments are attributed.

The Edinburgh Medical and Surgical Journal was published in Edinburgh from 1805 to 1855, and was described as: …exhibiting a concise view of the latest and most important discoveries in medicine, surgery, and pharmacy.

EMSJ 1805

It was clearly a quite prestigious and conservative journal, as the opening paragraph of the earliest paper reveals:[1]

Those of our readers who have perused the essay of Mr Churchill on acupuncture and his papers in the London Medical Repository, and who are aware that investigations have been lately made on the same subject in various parts of the Continent, may be surprised that hitherto no notice has been taken of it in this Journal. Our reason has been, that the first accounts given of the virtues of the new remedy were so marvellous, and therefore seemed to savour so much of quackery, that, coming, as they did, from persons not of the highest authority, we could not but follow the general example, and decline giving implicit credit to their assertions.

The same paragraph goes on to describe the editors’ change of heart – dare I say u‑turn on the matter:

But these assertions have been re-echoed from almost every quarter of Europe; observations have been made on the subject at many continental schools of eminence; the several accounts given by unconnected writers agree very remarkably in every essential particular; the alleged facts have at length been put to the test of a full and minute train of experiments by one of the most scientific of the Parisian physicians, in a great public hospital, and under the eyes of its pupils; the results of these experiments, as published by his hospital assistants, harmonize exactly with the statements made by those who introduced the remedy into Europe; and under such circumstances we cannot any longer delay presenting a summary of the interesting information which has been accumulated in its favour.

So how about that then?

The acuphiles jump for joy…
(my neologism – ‘acupuncture lovers’) 

But wait:

It must be confessed, however, that after all we cannot approach this singular topic without hesitation.

What now? I love the use of the term ‘singular’ here, meaning remarkable, which has fallen out of common use. It is the word I have noticed jumping out with great regularity from the text of Conan Doyle’s Sherlock Holmes, as reanimated by the wonderfully expressive voice of Stephen Fry.

It is true, that, in the hands of M. Cloquet, the remedial virtues of acupuncture have passed triumphantly through an ordeal, to which no remedy, whose claims were false, could be submitted without detection. But, at the same time, the utmost ingenuity of its favourers has been unable to discover, in a long course of minute inquires, any rational way of accounting for its effects; and, what is perhaps of more consequence, they have been unable to detect any physiological change or phenomenon co-ordinate with its operation. There is in short a total want of every sort of evidence in its favour as a remedy, except that most treacherous kind, the evidence of succession; and consequently, a philosophical mind, especially considering the diseases in which the greatest success has been obtained, will naturally feel inclined to attribute the cures which have been accomplished to the influence of the imagination, and to sentence acupuncture to banishment from regular practice, as being nothing else than a variety of animal magnetism.

…a total want of every sort of evidence in its favour as a remedy, except that most treacherous kind, the evidence of succession!

Could it be:

…nothing else than a variety of animal magnetism!

Well the piece goes on to say that the journal is not the place to discuss evidence, and proceeds to describe the experiences of the fellows who have written about the technique. It is interesting to note the common opinion of where the technique works best, or should I say, where it doesn’t!

It is applied to all manner of maladies; but those in which it is accounted most applicable and is in reality most successful, are evidently such as do not belong to the active inflammatory disorders.

The paper describes the fine needles used, the fact that they simply do not hurt at all to insert, and that they are often retained for only 5 to 6 minutes; but a chap called Cloquet describes having left them in for over an hour.

Sewing needles could be used apparently, but only after passing a thread through the eye so that the needle did not get lost inside the body. Longer needles are also described – three inches in length and one fortieth of an inch in diameter (the latter is just over 0.6mm, so not too fat).

Louis Berlioz, the father of the famous composer, is credited as having first written about its use in the contemporary practice of the time as a ‘memoire to the Parisian Society of Medicine’. Berlioz is also credited as being the first to use electrical stimulation of needles in the form of galvanism.

Rather alarming is the description of how there is no damage to tissues or organs, including the heart and lungs, followed immediately by a description of a fatality that seems to have resulted from the terror caused by the accidental disappearance of needles into the abdomen.

In regard to the accidents arising from acupuncture, it is only necessary to add, that in a few cases the operation has been followed by a tendency to fainting, and that in one instance, which occurred at the Hotel-Dieu of Paris, the accidental disappearance of the needles in the skin of the belly was followed by such extreme and uncontrollable terror, that the patient expired soon after.

After a long description of the effects observed in patients, this paper finishes with some conjecture over the mechanism. They include the possibility that it ‘operates through the mind’, but my favourite idea of theirs is that it acts by:

…rectifying an aberration of the nervous fluid.

References

  1. Cloquet, Sarlandière, Pelletan, Carraro, and Pouillet, on Acupuncture. Edinburgh Med Surg J 1827;27:190–200.http://www.ncbi.nlm.nih.gov/pubmed/30330050 (accessed 25 Oct2018).
  2. Renton J. Observations on Acupuncture. Edinburgh Med Surg J 1830;34:100–7.http://www.ncbi.nlm.nih.gov/pubmed/30330219 (accessed 25 Oct2018).
  3. Banks JT. Observations on Acupuncturation. Edinburgh Med Surg J 1831;35:323–8.http://www.ncbi.nlm.nih.gov/pubmed/30329900 (accessed 25 Oct2018).

Declaration of interests MC

Rewiring the brain with acupuncture

– does sophisticated MRI data point us to optimal treatment?

This blog was first published on 25th January 2018 on https://blogs.bmj.com/aim/

rewiring

For some time, a group on the US east coast have been quietly scanning brains with functional magnetic resonance imaging (fMRI) and related techniques to examine the effects of acupuncture. They hit the headlines in rather a dramatic manner in 2017.[1,2]

At the beginning of the fMRI story we saw some extraordinary claims concerning point specificity in acupuncture from a famous name in the development of fMRI, but these were later retracted.[3] I was relieved to see the retraction, as the claims did not seem mechanistically credible from a neurophysiological point of view. The authors retracted their paper because the results were not in line with the body of developing evidence that acupuncture with typical deep tissue sensation (I prefer this term, but it equates to de qi) seems to cause a general deactivation of limbic structures,[4,5] rather than very specific and targeted functional activations.

So why am I a year behind the headlines? Well I was asked to discuss the research for a television programme, so I read the paper thoroughly in preparation and discovered an interesting observation that had previously escaped my notice. Then there was a mix-up with storyboards and we discussed other research instead. So I thought I had better put all those hours of preparation to good use by describing my thoughts on this rather complex area of research.

The team concerned here first came to my attention when they demonstrated a change in cortical mapping of the second and third fingers (D2/D3) in patients with carpal tunnel syndrome (CTS) treated with acupuncture.[6] This was a departure from the fMRI studies prior, which had tended to simply watch what happened in the brain after acupuncture or control procedures in healthy subjects. Whilst it was an interesting finding, the study was observational rather than a strict RCT, and I felt that the change in cortical mapping was likely to be downstream of the main effects of acupuncture rather than a direct effect, ie a consequence of the acupuncture mechanism rather than part of the mechanism. This is always the problem with observational data – is the observed association causal or consequential?

The team continued to study CTS, and the research published in 2017 was a three-armed study of 80 patients with CTS [2] – a relatively large study in fMRI terms, but small and underpowered in terms of standard clinical trials of acupuncture in pain. The 3 different interventions principally involved electroacupuncture (EA): local EA (PC7–TE5), distant contralateral EA (SP6–LR4) and ipsilateral regional sham EA (non-points on the flexor aspect of the mid forearm). Manual points were included in the same regions as the EA in each group.

The symptom scores in all groups declined over the course of treatment with no significant differences, although noticeably bigger change scores in the local and sham groups, where the focus of treatment was in the correct limb. Despite this, the median nerve conduction latency improved in both EA groups and deteriorated in the sham EA group. D2/D3 cortical separation distance improved marginally more (not significant) with local EA than distant EA, and not at all in the sham.

…median nerve conduction latency and D2/D3 cortical separation distance improved in both EA groups

So despite there being no difference between groups in terms of symptoms, there was a clear difference in objective measures of nerve function and brain function. And there is more! The degree of improvement in D2/D3 cortical separation distance immediately after the 8-week 16-session treatment course predicted (correlated with) the symptom score at 3 months follow-up. That is very interesting, and somewhat counters my assumption that the cortical remapping is downstream (ie a consequence rather than a cause) of the effect of EA.

The degree of improvement in D2/D3 cortical separation distance correlated with the symptom score at 3 months follow-up

Another interesting aspect is the rate of deterioration in symptom score of the sham group after they were unmasked, and the continued improvement of the distal group after they learned that they had a genuine treatment. This makes me ponder over the influence of other brain centres – those related to cognition analysis and expectation – and how these can add unwanted noise in group means for subjective outcomes.

And there is still more! The bit I originally missed because it was just too much effort to read and understand. The team studied the microstructure of the white matter adjacent to the relevant areas of the primary somatosensory cortex (S1). I didn’t even know this was possible, but it has been around for about 15 years. Fractional anisotropy is a measure of order in the structure of white matter based on diffusion of water. A perfect isotropic material would have an even pattern of diffusion in all directions, but uniform tracts of myelinated neurones will disturb this, and cause a degree of anisotropy. Got it? Anyway, the team discovered that the changes after real EA (local & distant) in fractional anisotropy near the S1 cortex related to the contralesional hand correlated with latency changes in the median nerve. This was not true of sham. Even more interesting is that this correlation between changes in fractional anisotropy and median nerve latency occurred in different areas of the ipsilesional SI cortex depending on whether the EA was local or distant.

This has to be considered speculative, since it was a bit of a fishing trip, but it is very exciting to speculate that in the future we may be able to develop ways of tracking the course of plastic changes in the central nervous system and design optimal treatment approaches as a result; moving us from ancient philosophy, through neuroscience from the last century (segmental neuromodulation) perhaps to real-time neural remodelling.

References

  1. Ditch the paracetamol and try ACUPUNCTURE. Daily Mail Online 2017. http://www.dailymail.co.uk/health/article-4274898/Ditch-paracetamol-try-ACUPUNCTURE.html (accessed 24 Jan2018).
  2. Maeda Y, Kim H, Kettner N, et al. Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture. Brain 2017;140:914–27. doi:10.1093/brain/awx015
  3. Cho ZH, Chung SC, Lee HJ, et al. Retraction. New findings of the correlation between acupoints and corresponding brain cortices using functional MRI. Proc Natl Acad Sci U S A 2006;103:10527. doi:10.1073/pnas.0602520103
  4. Wu MT, Hsieh JC, Xiong J, et al. Central nervous pathway for acupuncture stimulation: localization of processing with functional MR imaging of the brain–preliminary experience. Radiology 1999;212:133–41.http://www.ncbi.nlm.nih.gov/pubmed/10405732 (accessed 28 Aug2011).
  5. Hui KK, Liu J, Makris N, et al. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects. Hum Brain Mapp 2000;9:13–25.
  6. Napadow V, Liu J, Li M, et al. Somatosensory cortical plasticity in carpal tunnel syndrome treated by acupuncture. Hum Brain Mapp 2007;28:159–71. doi:10.1002/hbm.20261

Declaration of interests MC

EA for stress urinary incontinence

– perhaps via direct pudendal nerve stimulation

This blog was first published on 4th December 2017 on https://blogs.bmj.com/aim/

blue clean clear dew
Photo by Pixabay on Pexels.com

Earlier in 2017 this paper popped up in JAMA.[1] It was from the same group that had published a huge multicentre trial of electroacupuncture (EA) for chronic severe functional constipation,[2] which was featured in a previous blog. This was a large sham controlled trial (n=504) although not as big as the previous one on constipation (n=1075).

EA can influence symptoms in overactive bladder

We have known for some time that EA can influence symptoms in overactive bladder, albeit under another name.[3] These are mainly urge symptoms, and a similar mechanism that reduces pain perception might be postulated to explain the results. Urinary stress incontinence (SUI) seems entirely different, and so the results of this trial were rather unexpected (by me at least).

I revisited the paper to examine the intervention in more detail and consider the anatomy involved. The active EA intervention involved just two points on each side (I love the simplicity!) – BL33 and BL35. 75mm needles were employed, and inserted 50 to 60mm. At BL33 the angulation (oblique inferiomedial) aimed to have the needle tip entering the S3 foramina. At BL35 (just lateral to the coccyx) the needle was angled superiolateral. In terms of safety, the structure to be avoided in this area is the rectum, and a paper in Acupuncture in Medicine studied the position of needle tips relative to the rectum when inserted into sacral foramina,[4] but not BL35. Needles inserted into S4 got close to the rectum (4-8mm), but there was a bigger margin in S2 and S3 (19-29.5mm). At BL35, a sufficient lateral angulation would avoid getting close to the rectum, but this angulation would be critical.

joi170065f1
Figure 1 from Lui et al JAMA 2017[1]

In terms of physiological effects the needle placement at the S3 foramina would certainly stimulate the dorsal ramus of S3, and possibly the ventral ramus, depending on depth. A superiolateral angulation at BL35 might approach the pudendal nerve as it passes over the sacrospinous ligament, lateral to the sacrum at about the level of S4 (sacral hiatus). Direct stimulation of the pudendal nerve has been described in a small case series of patients with spinal stenosis refractory to less invasive EA,[5] and nerve stimulation was confirmed by perineal sensation. The study in JAMA on SUI does not mention perineal sensation but just mentions mild shivering of the skin around the points, presumably secondary to muscle contraction. EA at 50Hz was applied at a current of 1-5mA. If either needle tip was close to motor fibres, the relevant muscle would have contracted quite strongly for the entire period of stimulation (30 minutes). The authors do not report such effects, but they do discuss the possibility of S3 and pudendal nerve stimulation. If direct electrical nerve stimulation occurred, the effect may have been in some part attributed to pelvic floor muscle contraction induced by motor nerve stimulation. With this in mind it is interesting to note that the effect observed after 18 sessions of acupuncture over 6 weeks was similar to 12 weeks of a pelvic floor exercise programme.

18 sessions of acupuncture over 6 weeks was similar to 12 weeks of a pelvic floor exercise programme

I should note that the sham technique involved no skin penetration and no electrical output, so if there was direct motor nerve stimulation in the active group, there would have been quite a considerable difference in terms of the physiological stimulation applied between the groups.

References

  1. Liu Z, Liu Y, Xu H, et al. Effect of Electroacupuncture on Urinary Leakage Among Women With Stress Urinary Incontinence: A Randomized Clinical Trial. JAMA 2017;317:2493–501. doi:10.1001/jama.2017.7220
  2. Liu Z, Yan S, Wu J, et al. Acupuncture for Chronic Severe Functional Constipation: A Randomized Trial. Ann Intern Med 2016;165:761–9. doi:10.7326/M15-3118
  3. Peters KM, Carrico DJ, Perez-Marrero R a, et al. Randomized Trial of Percutaneous Tibial Nerve Stimulation Versus Sham Efficacy in the Treatment of Overactive Bladder Syndrome: Results From the SUmiT Trial. J Urol 2010;183:1438–43. doi:10.1016/j.juro.2009.12.036
  4. Katayama Y, Kamibeppu T, Nishii R, et al. CT evaluation of acupuncture needles inserted into sacral foramina. Acupunct Med 2016;34:20–6. doi:10.1136/acupmed-2015-010775
  5. Inoue M, Hojo T, Nakajima M, et al. Pudendal nerve electroacupuncture for lumbar spinal canal stenosis – a case series. Acupunct Med 2008;26:140–4.pm:18818559

Declaration of interests MC

EA for chronic severe functional constipation

– it seems to work after an intensive course…

This blog was first published on 28th November 2017 on https://blogs.bmj.com/aim/

adult attic bathroom bathtub
Photo by Pixabay on Pexels.com

About a year ago I was surprised to see a sham controlled RCT of electroacupuncture (EA) published in Annals of Internal Medicine.[1] I was surprised for several reasons: I review for Annals, and I had not seen the paper for review; it was on chronic severe functional constipation – a subject with few previous RCTs of acupuncture; it was positive; it was the biggest 2 arm RCT in the acupuncture literature to date (n=1075).

The treatment was relatively straightforward – EA to the rectus abdominis muscle bilaterally (ST25—SP14) and manual stimulation of a point in tibialis anterior bilaterally (ST37). The sham control involved shallow needling of points close by, but not on the meridians, avoidance of typical needling sensation (de qi) and sham EA (ie no electrical stimulus, but the power indicator and sound as if it were real EA). The frequency used varied from 10 to 50Hz and the intensity was between 0.1 and 1mA. The frequency covers the best range for autonomic modulation (as judged by visceral blood flow), but the intensity was varied from sub-threshold (in terms of nerve stimulation you generally need 0.3 to 0.5mA for the lowest electrical threshold nerves to respond) to a rather gentle stimulus of 1mA. In my experience, many patients do not perceive sensation until around 1.5mA when needle tips are placed into muscle.

Twenty-eight EA sessions were provided over 8 weeks

Twenty-eight EA sessions were provided over 8 weeks – 5 sessions per week for the first 2 weeks, and 3 sessions per week for the next 5 weeks. So it was quite an intense course of treatment. There was no comment about rotation of needling sites – with such an intense treatment regime it is common to alternate similar protocols so that needle sites do not get sore.

The primary outcome was based on a stool diary and was the number of complete spontaneous bowel movements (CSBM) per week. EA performed significantly better than sham at 8 weeks and the effect was maintained at 12 weeks follow-up.

Lui-Fig-CSBM-2016-1024x660
Figure 2 from Lui et al Ann Int Med 2016[1]

Blinding appears to have been maintained at 4 and 8 weeks from a random sample of 140 participants. At 8 weeks about 90% from each group guessed that they had received the real EA.

The size of the effect appears to be clinically relevant, with a change from baseline in CSBM of greater than 1 per week,[2] although the group average does not exceed 3 per week so most participants in the active group would still be considered to have constipation.

Of interest is a follow-up paper published recently that examines factors associated with the response to acupuncture in this trial. It found that age was inversely related to response to acupuncture (ie younger patients did better), and comorbidities reduced the likelihood of response.[3]

References

  1. Liu Z, Yan S, Wu J, et al. Acupuncture for Chronic Severe Functional Constipation: A Randomized Trial. Ann Intern Med 2016;165:761–9. doi:10.7326/M15-3118
  2. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol 2004;2:796–805. doi:10.1016/S1542-3565(04)00356-8
  3. Yang X, Liu Y, Liu B, et al. Factors related to acupuncture response in patients with chronic severe functional constipation: Secondary analysis of a randomized controlled trial. PLoS One 2017;12:e0187723. doi:10.1371/journal.pone.0187723

Declaration of interests MC

Segmental EA falls short in ovulation induction

…in women with polycystic ovarian syndrome (PCOS)

This blog was first published on 18th November 2017 on https://blogs.bmj.com/aim/

affection beautiful blur couple
Photo by Pixabay on Pexels.com

Finally I have come to address this topic, some months following publication of an eagerly awaited (at least by me) large clinical trial.[1] I have been a colleague and friend of the second author (ES-V) since proofreading her PhD thesis over 20 years ago. In those days I focussed solely on muscle so any suggestion of acupuncture being used to influence visceral function or blood flow was a bit of a conceptual stretch for me. After all my needles were going directly into the target that I wanted to influence, and I was just about comfortable with the idea that the needle alone actually did something useful without the need for injecting a drug. So the idea that acupuncture or electroacupuncture could have any useful effect through indirect influences only really arose when I read Lisa’s thesis.

Her early work stimulated interest in the use of acupuncture in fertility and augmented reproduction,[2,3] although the subsequent plume of clinical research that occurred in this field seemed to go a little off course from a basic science perspective, with an unwarranted focus on embryo transfer as part of IVF.[4] Lisa observed this, but continued with her research path, which was by then on PCOS. She clearly showed that segmental electroacupuncture (EA) could have positive influences on the condition, both in terms of hormonal and metabolic markers, and apparently in terms of ovulation rates.[5,6]

Lisa regularly runs research updates for the BMAS, and we were all excited to hear of her involvement in this huge clinical trial in China on women with PCOS. With 1000 women to be randomised and treated the trial was a considerable undertaking, and several years passed with no news. Then on the 27th June 2017 the results were out… clomiphene was nearly twice as good as segmental EA, and segmental EA was no better than a very minimal non-segmental sham.

joi170062f2-1024x578
Figure from Wu et al JAMA 2017 [1]

It did not seem to make sense from the basic science perspective! The numbers were big enough to power the comparison with sham (assuming similar size effects to those we see in clinical trials of chronic pain). The intervention appeared sufficient in neurophysiological terms, to generate the effects that had been demonstrated in the basic science experiments that had led up to this trial. Yes it was a penetrating sham, but the physiological stimulus of the sham intervention would not have generated any effect in the laboratory in terms of somatovisceral reflexes. In the clinical realm, with conscious humans, sham always seems to have a substantial context effect, but still I would have expected some physiological effect from the segmental EA.

Well there was a difference between real and sham EA in terms of adverse events. In the segmental EA group the rate of diarrhoea was 3 times that in the sham EA group, perhaps indicating an excess effect in somatovisceral reflexes in a small proportion of women. It should be noted that the absolute rate of diarrhoea was low at 1.6 and 5%, in sham and real segmental EA respectively.

The primary outcome was live birth rate. This is the most valid outcome for trials of this nature, but it is not the same as ovulation induction of course, so it is not a direct measure of the putative physiological effect of segmental EA. This could add noise to the statistics, but even so, there was not even a trend in favour of segmental EA.

The slightly curious thing is that both acupuncture groups seemed to substantially outperform metformin, which, in a large comparative trial with clomiphene resulted in a live birth rate of just 7.2%.[7] The populations are not easily comparable though as there were notable differences in BMI that would favour acupuncture. The Chinese women were normal weight compared with an average BMI of about 35 in the metformin group in the prior comparative trial, and BMI is inversely related to outcome.[8] Could that explain the difference between 7.2 and 15.4%? Well frankly, I’m afraid it probably can!

So where does that leave the acupuncture in the fertility arena? There is little or no high quality clinical data to support its use, just a lot of experimental data that did seem encouraging, although the results of this trial should give pause to the assumptions of advocates that anything demonstrated at the bench should automatically imply useful effects at the bedside.

For now at least we must encourage women with PCOS to consider clomiphene before acupuncture for ovulation induction.

References

  1. Wu X-K, Stener-Victorin E, Kuang H-Y, et al. Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome. JAMA 2017;317:2502. doi:10.1001/jama.2017.7217
  2. Stener-Victorin E, Waldenström U, Andersson SA, et al. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314–7.
  3. Stener-Victorin E. Reproductive medicine: Research projects in acupuncture. Acupunct Med 1998;16:80–2.http://dx.doi.org/10.1136/aim.16.2.80
  4. Carr D. Somatosensory stimulation and assisted reproduction. Acupunct Med 2015;33:2–6. doi:10.1136/acupmed-2014-010739
  5. Stener-Victorin E, Maliqueo M, Soligo M, et al. Changes in HbA1c and circulating and adipose tissue androgen levels in overweight-obese women with polycystic ovary syndrome in response to electroacupuncture. Obes Sci Pract 2016;2:426–35. doi:10.1002/osp4.78
  6. Johansson J, Redman L, Veldhuis PP, et al. Acupuncture for ovulation induction in polycystic ovary syndrome: a randomized controlled trial. Am J Physiol Endocrinol Metab 2013;304:E934-43. doi:10.1152/ajpendo.00039.2013
  7. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. doi:10.1056/NEJMoa063971
  8. Legro RS, Zhang H, Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:1463–4. doi:10.1056/NEJMc1409550

Declaration of interests MC