The first of these stories concerns a synthetic steroid hormone known as 17-Hydroxyprogesterone caproate or 17-OHPC. It is in the news because the US company KV Pharmaceutical had paid some $7.5 million to secure the world distribution rights, with another $77.5 million to follow once the drug had been given a licence by the US Food and Drugs Administration, the FDA. It was to be marketed under the name Makena (originally Gestiva) for the prevention of premature birth in women with a history of at least one previous pre-term delivery. The FDA had hesitated to grant approval initially, but are now reported to have done so.
The money invested can be considered a marker for the anticipated profits to be achieved via KV’s 300-strong sales force with direct access to American obstetrician/gynaecologists. Why should we be uneasy about this? Surely, with this level of investment, this must be a new wonder drug, offering hope to the estimated 500,000 women who experience premature births in the USA each year, suffering anxiety, grief or despair due to the complications, illness and even death that may overtake such babies?
Well, not exactly, because this drug was in fact originally marketed by another company under a different name in 1956 (!), before being voluntarily withdrawn from the market in 1999. Doctors continued to use it ‘off label’ as it could be, and still is, made up by compounding pharmacies. However, both the effectiveness and the safety of this hormone have been uncertain. The Cochrane review in 2006 concluded that ‘information regarding the potential harm of this therapy is limited’, with ‘maternal and infant outcomes being poorly reported’. One study from the NIH (National Institutes of Health) has shown a reduction in risk of pre-term birth, with no apparent risk to the foetus, but several others actually showed a trend to increased risk of miscarriage and stillbirth. In addition to this, a toxicology study in rhesus monkeys resulted in the deaths of all foetuses exposed to doses of the hormone between 1 and 10 times the human dose equivalent.
All this for a drug that was thought to have the very opposite effect! And yet, in spite of serious uncertainty about its safety and even its effectiveness, it is again being granted a licence under a new name.
It gets worse. For many years compounding pharmacies have been able to produce this formula at a cost of $10-20 per dose (by weekly injection, over a minimum of 15-20 weeks in the second and third trimesters of pregnancy). KV, justifying this against the cost of potential intensive care for a seriously premature baby, set the price of a single dose at $1500! After the inevitable furore, and the fact that the FDA then announced that compounding pharmacies could continue to make up the same compound at their usual cost, KV relented, and reduced their price to just $690 per dose. This is Alice in Wonderland stuff, but I would tentatively suggest that they are on a loser here.
What about the good news?
If we take this further, and look for the nearest equivalent to 17-OHPC in the human steroid hormone biosynthesis pathways, we find 17-Hydroxyprogesterone, similarly named (without the caproate) and similar in structure up to a point. Both molecules are made out of carbon, hydrogen and oxygen, but the natural form has 21 carbon, 30 hydrogen, and 3 oxygen atoms, while the synthetic form has 27 carbon, 40 hydrogen and 4 oxygen atoms per molecule. Regular readers of this site will know it takes only very small changes in molecular structure to bring about significant changes in properties and effects, – the synthetic medroxyprogesterone known as Provera, for instance, has 24 carbon, 34 hydrogen and 4 oxygen atoms in each molecule, a sort of halfway structure between the natural form and 17-OHPC.
Provera has been extensively assessed, in combination with Premarin (a mixture of equine estrogens), by the Women’s Health Initiative. In this study, it was found that the apparent benefits of this form of HRT – reduced risk of hip fracture and endometrial cancer – was offset by an increased risk of coronary heart disease, breast cancer, strokes and pulmonary embolism. Very good reasons to be extremely cautious about taking any of these synthetic progestins.
What about the natural form in the human body, 17-hydroxyprogesterone, you may well ask? Could this have potential ill-effects? Probably not, as the body has had hundreds of thousands of years to iron out any glitches, but even if it does, in the biosynthesis pathway the natural 17-hydroxyprogesterone appears as an intermediate form in the conversion of progesterone (which as you know all of us on this site are much in favour of), to the stress hormone cortisol, both hormones of vital importance in our metabolism. As such, the 17-OHP molecule is not in existence for very long, so that any harmful potential will hardly come into play.
Now at last for the good news, and some welcome common sense. A new study published in the journal ‘Ultrasound in Obstetrics and Gynaecology’ from Dr Sonia Hassan and her team at the National Institutes of Health assigned 458 pregnant women with a diagnosis of ’short cervix’ (a risk factor for premature delivery) to receive either a once-daily dose of vaginal bio-identical progesterone, or a daily dose of a placebo gel, during their second and third trimesters. 16% of the women in the placebo group had premature births before the 33rd week of pregnancy, while this figure was only 8.9% in the natural progesterone group, a reduction of nearly half.
Besides this, the infants in the progesterone group were three times less likely to develop RDS, Respiratory Distress Syndrome, a common and difficult complication in premature babies.
Dr Roberto Romero, head of the Perinatal Research Branch of the NIH said “This study offers hope to women, families and children. Worldwide, more than 12 million premature babies are born each year, and the results are often tragic. Our clinical study clearly shows that it is possible to identify women at risk and reduce the rate of pre-term delivery by nearly half, simply by treating women who have a short cervix with a natural hormone, progesterone.”
As bio-identical progesterone can also relieve nausea in early pregnancy, reduce the risk of miscarriage before 16 weeks, and prevent the development of ‘baby blues’ or more serious depression after the birth, I am very much in favour of extending the use of progesterone to include all these indications.
In conclusion, you can have Makena from KV Pharmaceutical, with an uncertain pedigree and effects, for $690 per 1 week’s dose.
Or the same synthetic hormone from a compounding pharmacy, for $10-20 per dose.
Or bio-identical natural progesterone which is safer, more effective, and costs approx $30 (£25) for a 4-6 week supply.
We live in a very strange world.