HRT: inside the complex global supply chain behind a $20bn market

There are giant metal globes that can hold up to 10,000 litres of liquid. The plant on the outskirts of Oss in the Netherlands is home to gleaming steel drums. They are poured into the reactor through a funnel and then heated to boiling point. Robert Dam compared it to a cooking pot while standing by one of the large containers. Light liquid can be seen bubbling away as we peer inside.

A white powder distilled from soya beans is turned into synthetic oestrogen at Dam's factory. The most potent variant of oestrogen, known as oestradiol, is produced at the Oss plant and will be sold in the UK. More than one million women in Britain use gels, sprays and patches to manage the symptoms of menopause.

The chain of agricultural, industrial and chemical labour involved in producing medicines for hormone replacement therapy is as complex and global as the manufacture of phones or cars. It is vulnerable to disruption.

There were reports of a shortage of HRT medicines in May. After the Pandemic, shipping routes became jammed and there were shortages of workers. There was a surge in demand in Britain, following the debunking of fears about the safety of using hormones to treat menopause.

According to OpenPrescribing, the "Davina effect" caused the number of prescriptions to peak at nearly 700,000 in May, up from 360,000 a year earlier. Women dependent on a daily dose to relieve some of the more severe symptoms of menopause found themselves driving hundreds of miles to find products, paying large sums online, and even exchanging personal supplies with strangers in car parks, because many pharmacy out of stock.

HRT tsar Madelaine McTernan was the former director general of the Covid-19 vaccine task force. Lessons learned from the successful procurement of vaccines were to be applied to improve the supply chain. The Netherlands is a key part of the chain. The Observer was given exclusive access to the facility and was able to observe a process in which very little has been published outside of scientific journals.

The site makes 900 batches of hormones and other key ingredients every year, including oestradiol and oestriol, which are used in combination with oestrogen in the treatment of menopause.

The process for making oestradiol is explained by Dirkjan vanZoelen. The mashing of soya beans will lead to the production of cooking oil. The beans are unloaded from the truck.

A good raw material for the production of steroid hormones can be found in the oil rich in compounds such as stigmasterol. The stigmaserol is then transformed into oestrone. The oestrone is sent to the Aspen factory in a white powder.

The reactor's chemical structure is modified by adding a white powder and a solvent to make it react.

The solvent is removed from the crude oestradiol and any other foreign materials using a filter dryer. Water is added to make a pure powder. "Oestradiol doesn't like water" There is a cluster of molecule. The solution has any impurities that aren't in the orientation of the molecule staying in it.

The majority of the process is done manually. The last stage is done by hand. Oestradiol, a fine white powder with a defined particle size distribution, is weighed and put into glass boxes that staff can reach into by putting their hands through two holes. After being packaged, oestradiol is shipped to Britain where it is added to patches, gels, and tablets.

Oestrone was produced at the Oss plant before Aspen acquired it. The manufacturing of oestrone and other ingredients was moved to Asia. There is a constant search to find ways to decrease cost for some products.

Aspen has suppliers in different parts of China. The flow of raw materials for drugs to Europe can be disrupted by factory closings. There are a number of factors that have caused the HRT shortages in the UK.

In the movie Sex and the City 2, there is a scene in whichSamantha Jones pleads with airport customs not to seize her HRT drugs. She wants to speak to an ambassador or someone in menopause. The customs officer is not interested in what's happening. She doesn't have her medicine anymore so she spends her holiday ordering food from the hotel kitchens. They don't seem to help a lot.

If we eat a lot of yams, the hormones in our body have to be converted through a laboratory process.

There are physical and mental side-effects of menopause. The plant hormones stigmasterol and diosgenin are similar to human hormones and are found in soya and wild yams. Naturopaths may recommend drinking soya milk or eating wild yam powder, but there isn't much evidence to suggest these foods can help regulate hormones. Plants need to be changed in the lab to be able to make body-identical hormones.

According to Michael Buckley, medical director at the Australian firm Lawley Pharmaceuticals, most plants have a weak oestrogenic effect when eaten by humans.

As it is easier to grow for large-scale commercial purposes than yams, most pharmaceutical-grade hormone production starts with soya. The conversion is pure chemistry.

Sex hormones were discovered and distilled in the 20th century. The discovery of oestrone was made by Edward Doisy in 1929. The doctor who was watching the presentation showed that oestrogen could be used to treat hot flushes, bone density loss, and eventually to block ovulation. It's also a contraceptive.

In 1960, the first commercially produced birth control pill was approved. At the same time, the use of hormones to treat menopause was popular.

Robert Wilson was a gynaecologist. The idea of menopause being a disease, which could destroy a woman's "character as well as her health", was conjured up in his 1966 book. The unpalatable truth must be faced that all postmenopausal women are castrates, according to a startling excerpt from Wilson's book. A man is a man until the very last moment.

Premarin is one of the most popular oestrogen brands in the United States. The name is an acronym that means "pregnant mares' urine" The conditions in which the horses were kept were detailed in Ron Wilson's post. Farmers in the United States and Canada confine some 75,000 mares to small stalls for six months to collect urine. Most of the horses don't see the light of day for more than a few months.

The mares have to wear urine collection bags that cause their legs to itch and prevent them from lying down. Farmers are encouraged to limit the amount of water that horses are allowed to drink.

Pfizer insists that it works with family-owned equine ranches in Canada to care for their animals, even though it has a 3% market share in the UK. Pfeiffer has a long standing commitment to equine care. Pfizer's ranches are required to comply with a code of practice, which sets forth standards for the care, feeding and exercise of horses.

Premarin was marketed to both men and women in the 1950s and 60s, with magazine ads saying the pills made a woman feel good. One ad claimed that it was no easy thing for a man to take the sting and barbs of business life. There is a photograph of a bus driver with one of the angry female passengers. The reason is she.

Scientists were working to find a way to extract hormones from plants. Russell Marker, an American chemist, went to Mexico to look for a giant tuber that he had read about. The Mexican yam is a perfect raw material for making large quantities of chemicals.

Medical benefits were part of Marker's work. The chair of the British Menopause Society says that body-identical hormones from plants are less likely to cause breast cancer and blood clot than older drugs.

In the last five years, the number of rescriptions of HRT has doubled. In the year to the end of June this year, £85m was spent on the health service. According to Grand View Research, the global market is expected to grow to $36 billion by the end of the decade. The drugs are used to treat other conditions, but menopause is the largest chunk of that spend.

Smaller drugmakers that specialize in women's health are the ones that sell HRT products, with the exception of New York-based Pfizer. Importers are reliant on international supply chains due to manufacturing taking place almost entirely outside the UK.

One of the most popular products is Oestrogel, made by Besins healthcare, a fifth generation family-owned pharmaceutical firm founded in Paris in 1885. The gel is made in two different countries.

Theramex, a private-equity-owned pharmaceutical firm based in London, gets plant-based oestradiol from Hungary.

The new health secretary is being urged to introduce a national list of approved HRT medicines by the British Menopause Society and Carolyn Harris. Theramex said it would encourage them to invest more because it would ensure that all women in the UK have the same access to the newer body-identical drugs.

The HRT task force was wound up at the end of August after only four months. The situation has vastly improved, according toBriggs. Pharmacy are allowed to limit how much a customer can buy or offer a substitute if the stock of some products remains low. The serious shortage protocols limit the amount of time a product can be sold to three months.

Harris says the stock shortages of a number of HRT products are "infuriating". The government has blamed the increase in demand but it should have worked with suppliers to resolve the situation more quickly.