Progesterone perils

A lot of women are prescribed progesterone for the treatment of threatened abortion and staining during early pregnancy – with the ostensible purpose of saving the pregnancy. Unfortunately some doctors use progesterone as a kind of insurance against miscarriage and this practice is becoming increasingly common. The progesterone levels in the body are naturally higher during early pregnancy. So several doctors think that adding a bit of exogenous progesterone for support will have little or no adverse effects. However not all adverse events are immediately apparent.
A recent paper by Reinisch et al, in Archives of sexual behaviour had a provocative argument. The intake of synthetic progestin by the mother, called lutocyclin was associated with a higher risk of bisexuality in the child. As sexual behaviour and preference can only be discerned after puberty, this intriguing signal is very interesting. Several animal studies show that exposure to progesterone in the prenatal period can cause weird sexual behaviour in the offspring.However animals are largely free of the societal pressures that humans have to face – so the data cannot be directly extrapolated to humans.
The determinants of human sexuality are fiendishly complex. Many are unknown. It is conceivable that exposure of the developing fetal brain to exogenous hormones can have effects that are very hard to predict. To make matters worse, the long latent period between prenatal exposure and the first sexual behaviour makes it very hard to pin any adverse event on a particular drug / event. People with bad experience tend to remember the details that they feel might be related to the issue – the recall bias. Furtheremore it is impractical and unethical to round up a group of mothers, randomly split them into two groups and given one group progesterone and see what happens to their kids later on.So how can we investigate the possible link , between prenatal progesterone exposure and sexual preference in the child?
One way is to have a natural birth cohort. To identify the women who were given progesterone and track the children from birth and compare them with the children of women who were not given progesterone. As long as the children are of the same social background and have good follow up, we might be able to compare them. That’s what the authors did in the study.
They had tracked 34 individuals and found that the tendency for bisexuality (being attracted to both sexes) is higher in the children of mothers treated with progesterone. There was also a dose response effect – crucial in determining casuality. The Bradford hill criteria are commonly used to assess causality


The children of mothers who were treated with higher doses for longer duration were more likely to have bisexuality. The sexual preferences were self reported. Interestingly heterosexual attraction was not diminished in those who reported bisexuality – it ‘s as if they had developed additional attraction to the same sex as well. This is different from a shift to homosexuality – thus showing that a bidimensional model where in both homo and heterosexuality exists in the same individual, with each one having high and low poles.

What do we make of this research?

As we all know , it takes a lot more than a single study to come to conclusions. However a single study which shows consistent findings, with a dose response effect, should raise some alarm. There are some doubts, whether the trade name lutocyclin ( made in late 1950’s, the time the birth cohort was established) was actually progesterone. However the author seems certain. The magnitude of effect and the numbers are small, but the effect itself appears concerning.
In the mean time, it is vitally important that we acknowledge the uncertainty surrounding the effects of prenatal hormone exposure. Studying the effects of such hormone use is very hard.
Hormones are to be used with care – a lot of things like metabolism, receptor affinity,distribution and post receptor mechanisms can result in varying effects in different individuals.

The most important question to ask before taking a hormone is – do I really need it?

Further reading

  1. Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans

The God in small things

Name the decisive war that Napoleon lost?

Most of us would answer Waterloo. In fact , Waterloo is almost a synonym for final comeuppance. The reality though is a little different. Napoleon actually won Waterloo. Yet, he managed to snatch defeat from the jaws of victory.

When Napoleon escaped from Elba in 1815 and the Hundred Day Campaign begun, the capitals of Europe instantly sprang to activity. The political uncertainty was profound , as everyone was well aware of Napoleon’s military genius. To put it mildly, the future of Europe and thus of the world was at stake. As fate would have it, it fell upon Colonel Cornelius Frazier,battalion commander of Wellington to face Napoleon. The British had cleverly planned to fight from high ground at Mont Saint-Jean. Napoleon was least bothered -he had the best of men, horses and lances -commanded by the mighty Napoleon himself. He decided to mount a deadly cavalry attack and separate the enemy forces from their cannons. Facing Napoleon’s marauding army, the British forces tried their best to avert disaster. There was only so much they could do and before long they started abandoning their cannons and ran for life. Napoleon beamed -he had defeated Wellington at Waterloo. He thought he would dine in Brussels that night.

I might have been writing this post in French, instead of English, had Napoleon’s men not forgotten a tiny detail. Those days, the cannons were muzzle loaded and were ‘triggered’ by placing flame in the touchhole. It was customary to destroy enemy cannons after capture by hammering a headless nail into the touchhole, making the cannon useless. Napoleon’s men had forgotten to bring that pack of nails!

As the battle raged on, the British realized the French blunder. This energized the British forces who thought they were staring at death. Eventually the British recaptured the cannons and the tide turned. Napoleon watched in horror as he lost the battle he had just won, all for want of a few nails. He had the best men and weapons, but that didn’t matter. A small detail, overlooked, changed the history of the world.

As doctors, we will see patients and we will make mistakes.Sometimes a mistake will cost the life of a patient. It may not change the history of the world, but it may snuff out the future of someone, who means the world to his loved ones. No one is immune to mistakes, but we take each mistake seriously and learn from them.

For instance,a mortality meeting is one such probe for mistakes. The kind of things we want to avoid. Learning from someone else’s mistakes is easier and less painful than learning from our own. I have made my lion’s share of mistakes. Thinking back, some were as disastrous as Napoleon’s nails and others much less so. But each one taught me that small things matter. As they say God is in the details, but so is the devil.

Our experience is the sum total of our successes and failures. We will only ever truly fail, if we fail to learn from our mistakes. In life or in medicine.

Getting started with case reports

A case report is the perfect starting point for a resident new to scholarly publishing. It is easy to write, requires little creativity (after all it is just a documentation of a patient that came to meet the doctor) and though has limited impact, has good educational value. More than anything else, it lowers the barrier to scientific writing.

There is a catch though – case reports are the low hanging fruits. Accordingly there is quite a bit of competition there – lot of people want to write, very few publishers want to publish. This has created a vacuum which has been fulfilled by speciality case report journals. These journals publish only case reports and therefore have a much higher acceptance rate – somewhere in the range of 30 to 70 %. The increased demand also causes a situation where publishers may resort to questionable practices. In fact, almost half the journals are found to be dubious.

How to identify the genuine journals?

The trick is to find those case report journals which are PubMed Indexed. Only one PubMed Indexed journal(published by Baishideng group) is known to indulge in questionable practices[Refer to the Excel file linked at the end of the article]. So a case report journal that is PubMed Indexed is highly likely to be genuine. For example, my first publication was a case report in BMJ case reports.  BMJ case reports has a decent acceptance rate, but in order to submit one of the authors or the institution must have subscription. Individual subscription costs around 185 GBP (around Rs.15000), but just one subscription in a department is more than enough. Be sure to check if your institution has subscription – in which case, you can contact the librarian to get the submission access code. BMJ case reports doesn’t have an impact factor as such (many case report only journals don’t.). However you can use the scimagojr 2 year citations per article as a reasonable proxy.

Of course, case reports are also published by journals that publish other stuff like reviews and original articles. However the acceptance rate is likely to be lower in these journals. If you are confident of your material, it is best to try in a general journal first before trying a case reports only journal. When in doubt, ask an expert.

A master list of case reports only journals can be accessed in Excel format here. Sadly I couldn’t get a master list of submission fees – if you have details on that, do let me know. If you found this post useful, please share with your friends.

Further reading

New journals for publishing medical case reports

Hope for the “helmet” times

I have shared this one before in social media. Luckily Journal of Social Health and Diabetes was willing to publish it. If you haven’t read about the heroic work of my friends in managing a patient with unusual features of Type 1 Diabetes, you can read it in the link below.

Hope for the “helmet” times

Marriage and the nocebo effect


Today morning, I opened The Lancet, to see an interesting Statin trial that looked at SAMS (Statin associated muscle symptoms). You can read the trial here

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase


Statins are cholesterol lowering drugs that are sometimes associated with muscle pains. Unlike myopathy or myonecrosis, muscle pains have no objective  biochemical or histological component. The authors had analyzed the statin related adverse effects during the blinded(patient doesn’t know he’s taking statin) and the unblinded(patient knows he’s taking statin) phase of ASCOT trial. When the patients knew they were taking statins, they complained of muscle pains. When they didn’t know what they were taking, they had no symptoms !

In other words, their expectation of what statin might cause (after learning about it from net/other sources) influenced their symptoms. This fascinating phenomenon is called the nocebo effect.It’s the negative cousin of the well known placebo effect. It reflects changes in human psychobiology involving the brain, body, and behaviour rather than drug toxicity.Muscle related adverse effects are often low in randomized trials  compared with observational studies. The strength of this study is that these were the same patients, no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins.

This reminded me of some of the unfortunate posts on marriage I ve been seeing in Facebook and Quora of late. The liberal rants have an unmistakable pattern – they claim that marriage is the worst thing that can happen to a person. There are some sites (such as this one) whose only job appears to “educate” people on the evils of marriage and praise any and every form of decadence. You can see this in present day movies as well – the premise is that if you get married you are screwed. All these sources happen to think the plural of anecdote is data – it’s not.

It’s possible this can have a “nocebo effect” on our youth – for example,some of the fine boys I know appear to have become unusually nervous at the thought of getting married. Such negativity  may even become a self fulfilling doomsday prophecy. At the expense of committing the same sin as the liberals(the plural of anecdotes!), I must say there is nothing to be afraid of about marriage. Sure,occasional mishaps happen – but they are ,thankfully, still not the norm. Of course, our world view is colored by our own atomized experinces. I am also aware that just because,my experience is overwhelmingly positive doesn’t mean everyone’s will be the same. In any case, it’s important to keep an open mind. Negative thoughts are clearly useless.

PS: Here’s a pro tip: Stay away from the leftist/liberal websites that spew constant trash, if you can. You won’t regret it.

How do I know if I have insulin resistance using my glucose curve results?

My answer to How do I know if I have insulin resistance using my glucose curve results?

Answer by Karthik Balachandran:

From the values you have, it appears that you don’t have significant insulin resistance. Several indices can be calculated which look at the relationship between glucose levels and the amount of insulin in your blood. Insulin resistance is said to exist when your body needs to produce more insulin than usual to bring down your blood glucose. By comparing these indices with known normal values, we can tell whether your body has normal insulin sensitivity(a measure of how well your insulin does its job). It is important to note that insulin resistance is not an all or none phenomenon – think of it as a spectrum from good insulin sensitivity to poor insulin sensitivity (aka insulin resistance).

Some important IR indices calculated from your blood glucose and insulin values are

  1. HOMA -1R = 1.96 (less than 2.5 is normal)
  2. Matsuda index – 6.62 ( whole body insulin resistance if less than 2.5)
  3. QUICKI index -0.35
  4. Insulinogenic index – 1.9 ( defect in insulin secretion if less than 0.4)

Several web based calculators are available for calculating these indices and for health professionals downloading the excel file may be useful.

A couple of such online calculators can be accessed at

  1. WEB Calculator for Matsuda Index
  2. calculators (HOMA)

For a more detailed review of how insulin resistance is assessed,( for health care professionals), you can see my presentation below.

Assessing Insulin Resistance

How do I know if I have insulin resistance using my glucose curve results?

virtual journal club–steroid induced osteoporosis

Steroid induced osteoporosis is a common problem which needs to be addressed in patients on long term steroid therapy. The American College of Rheumatology has published guidelines on optimal management of glucocorticoid induced osteoporosis a few days back.

In this edition of the virtual journal club, I will focus on these guidelines. You can get the guidelines (free pdf) here.

Click on the video below to listen to the presentation.

If you don’t have the time, here’s the gist

  • Assess all patients on GC within first 6 months for fracture risk ( clinical


  • Risk stratification is key, adjust FRAX risk for GC use
  • Optimize Calcium (800 to 1000 mg) ,Vitamin D( 600 to 800 IU) and lifestyle
  • Oral bisphosphonates preferred treatment when pharmacological
    management is indicated
  • Follow up every year and reassess fracture risk

You can download the presentation (without author name Smile ) here.

If you like the post/video/presentation, feel free to share with your friends.