HRT: contained in the advanced world provide chain behind a $20bn market | Prescription drugs business

In the centre of the manufacturing unit stand 31 reactors: large steel globes that may maintain as much as 10,000 litres of liquid every. Each week, gleaming chrome steel drums arrive by truck at this plant on the outskirts of Oss, within the Netherlands. Their contents are poured into the reactors by a funnel, dissolved, after which heated to boiling level. Standing by one of many huge containers, the manufacturing unit supervisor, Robert Dam, compares it to a “cooking pot”. Peering inside, we are able to see the sunshine liquid effervescent away.

At Dam’s manufacturing unit, a white powder distilled from soya beans and shipped from China is become a valuable commodity: sturdy artificial oestrogen. The plant at Oss, owned by the Dutch subsidiary of South Africa’s largest drugmaker Aspen Pharmacare, produces essentially the most potent variant of oestrogen, often called oestradiol, destined for the UK market. It is going to be added to gels, sprays and patches utilized by greater than 1 million ladies in Britain to handle the signs of menopause.

Stretching from the fields of Heilongjiang in north-east China to the cabinets of British pharmacies, the chain of agricultural, industrial and chemical labour concerned in producing medicines for hormone substitute remedy (HRT) is as advanced and world as for the manufacture of iPhones or vehicles. And like all provide chains, it’s susceptible to disruption.

In Might of this 12 months, stories of a scarcity of HRT medicines, particularly oestradiol gel, started to floor. As economies reopened after the pandemic, transport routes grew to become jammed, compounded by shortages of supplies, lorry drivers and lots of different staff. On the identical time, demand in Britain surged, following a 2021 documentary produced by the TV presenter Davina McCall, which debunked considerations concerning the security of utilizing hormones to deal with menopause.

The “Davina impact” induced NHS prescriptions to peak at almost 700,000 in Might, up from 380,000 a 12 months earlier, representing a month-to-month spend of £9.4m, in accordance with OpenPrescribing. With many pharmacies out of inventory, ladies depending on a day by day dose to alleviate among the extra extreme signs of menopause – which might vary from debilitating nervousness to insomnia – discovered themselves driving a whole lot of miles to seek out merchandise, paying giant sums on-line, and even swapping private provides with strangers in automotive parks.

HRT: contained in the advanced world provide chain behind a bn market | Prescription drugs business
Penny Lancaster, left, and Davina McCall with protesters outdoors the Homes of Parliament demonstrating towards prescription fees for HRT. {Photograph}: Steve Parsons/PA

In April 2022, Madelaine McTernan, the previous director basic of the Covid-19 vaccine taskforce, was appointed HRT tsar to assist handle the shortages. She was tasked with making use of classes realized from the profitable procurement of vaccines to enhancing the availability chain. Aspen API’s manufacturing unit within the Netherlands is a key a part of that chain. The Observer was given unique entry to the power to watch a course of about which little or no has been revealed outdoors the pages of scientific journals.

The location produces 900 batches of hormones and different key components for medicine yearly, together with oestradiol, one other oestrogen variant known as oestriol, and progesterone, which is commonly utilized in mixture with oestrogen within the therapy of menopause.

Dirkjan van Zoelen, Aspen API’s supervisor of improvement and technical help, explains the method for making oestradiol. It begins with the mashing of soya beans to provide cooking oil in China. The beans are transported from the farm to a crushing plant.

A byproduct of this course of is an oil wealthy in compounds corresponding to stigmasterol, which happen naturally in crops and make good uncooked supplies for the manufacturing of steroid hormones. The stigmaserol is then reworked, by way of a chemical course of or by way of pure fermentation, into oestrone. The oestrone, a weak type of oestrogen, is decreased to a white powder and shipped to the Aspen manufacturing unit.

Right here, contained in the reactors, its chemical construction is modified by including sodium borohydride, a white powder, and methanol, which acts as a solvent to allow the response.

As soon as it has executed its job, the solvent is faraway from the crude oestradiol together with every other overseas supplies like mud, utilizing a filter dryer. In a last step, water is added to crystallise the oestradiol right into a pure powder. “Oestradiol doesn’t like water,” explains Van Zoelen. “It kinds a cluster of molecules. Any impurities that don’t match into the orientation of molecules keep within the answer.”

HRT tablets
HRT tablets have been commercially produced since about 1960. {Photograph}: Realimage/Alamy

A lot of the course of is automated. However the last stage is completed by hand. Oestradiol, now a high quality white powder with an outlined particle measurement distribution, is weighed and disbursed inside sterile “glove packing containers” – glass packing containers that employees attain into by putting their fingers by two holes and into arm-length gloves. As soon as packaged, oestradiol is transported to factories in different international locations corresponding to Germany the place it’s added to patches, gels or tablets, earlier than being packaged and shipped to Britain.

Till 2013, when Aspen acquired the Oss plant from US group Merck, the power produced oestrone on-site. However the manufacturing of oestrone and different components was shifted to Asia to maintain costs of generic medicines low. Van Zoelen says: “It’s a continuing search to seek out methods to lower value: for some merchandise it’s preventing for each penny.”

To make sure towards shortages, Aspen has two suppliers in several areas of China. Manufacturing unit closures imposed throughout the Covid pandemic, or below China’s Blue Skies initiative to curb air pollution, can abruptly disrupt the circulate of uncooked supplies for medicine to Europe. “That is one in all a number of elements which have induced the HRT shortages being skilled within the UK,” says Van Zoelen.


In a scene from the in any other case forgettable film spin-off Intercourse and the Metropolis 2, Samantha Jones pleads with airport customs in Abu Dhabi to not confiscate her HRT medicine. “I want to talk to an envoy, or an embassy, or somebody in menopause,” she insists. The customs officer is unmoved. Disadvantaged of her medicines, she spends her vacation ordering platefuls of yams from the resort kitchens. They don’t appear to assist a lot.

“It’s not that if we eat numerous yams we’re going to have the quantity of hormones in our physique – it does need to be transformed appropriately by a laboratory course of,” says Dr Theodora Kalentzi, a menopause specialist at Medical Prime clinic in London.

Throughout menopause, ranges of oestrogen, progesterone and testosterone start to fluctuate, and fall, producing bodily and psychological side-effects. Soya and wild yams include a comparatively excessive quantity of the plant hormones stigmasterol and diosgenin respectively, and these are each comparable in chemical construction to human hormones. Nevertheless, whereas naturopaths might suggest consuming soya milk or ingesting wild yam powder, there’s little proof to counsel these meals can do a lot to stabilise hormone ranges. Vegetation must be altered within the lab to provide the so-called body-identical hormones utilized in HRT.

“Most crops include steroid substrates known as phyto-oestrogens – take into account them plant hormones – which have a really, very weak oestrogenic impact when consumed by people,” says Michael Buckley, medical director on the Australian agency Lawley Prescription drugs, which buys soya-based testosterone powder from the US to make testosterone lotions.

“Immediately, most pharmaceutical-grade hormone manufacturing begins with soya because the uncooked supply materials for extracting stigmasterol, as it’s simpler to develop for large-scale industrial functions than yams,” he says. “The conversion is pure chemistry and molecular manipulation.”

The invention and distillation of intercourse hormones dates to the early twentieth century. In 1929, the American biochemist Edward Doisy succeeded in isolating oestrone, unveiling his discovery at a symposium in Boston. Fuller Albright, an endocrinologist (a health care provider specialising in glands and hormones) who was observing his presentation, went on to reveal that oestrogen may very well be used to deal with scorching flushes, bone density loss, and finally to dam ovulation. In different phrases, as a contraceptive.

A Premarin HRT therapy ad from the 50s and 60s.
A Premarin HRT remedy advert from the 50s and 60s.

The primary commercially produced contraception tablet was accredited by regulators within the US in 1960. The usage of hormones to deal with menopause was popularised at across the identical time, if not just a little earlier.

The Brooklyn gynaecologist Robert Wilson was a serious affect. His now infamous 1966 e book, Female Eternally, conjured the thought of menopause as a illness, describing it as a “dwelling decay”, which may destroy a lady’s “character in addition to her well being”. Running a blog concerning the impression of Wilson’s e book, his son Ron picked out a very startling passage: “The unpalatable fact should be confronted that every one postmenopausal ladies are castrates. A person stays a person till the very finish.”

Probably the most in style oestrogen manufacturers on the American market was Premarin. Produced from 1942 by the Pennsylvanian firm Wyeth, the identify is an acronym: it stands for Pregnant Mares’ Urine. In his weblog, Ron Wilson describes in unflinching element the circumstances through which the horses that produced it had been stored. “To gather the urine, farmers in the USA and Canada confine some 75,000 mares to tiny stalls for six months at a stretch. A few of the horses obtain train each few weeks, however most don’t see the sunshine of day for months.

“The mares should additionally put on cumbersome urine-collection baggage which chafe their legs and forestall them from ever mendacity down comfortably. Farmers are inspired to restrict horses’ entry to water in order that their urine will yield extra concentrated oestrogens.”

Pfizer, which acquired Wyeth and nonetheless sells Premarin within the UK (it has a 3% market share), insists that it really works with family-owned equine ranches in Canada “devoted to the care of welfare of their animals”. The agency provides: “Pfizer has a long-standing dedication to equine care. All ranches that Pfizer works with are required to adjust to a code of follow, which units forth requirements for the suitable care, feeding and train in horses.”

A magazine ads from the 1960s advises husbands to keep their wives looking happy and healthy with Premarin.
{A magazine} advertisements from the Nineteen Sixties geared toward husbands. {Photograph}: Ted Eytan/Flickr

Throughout the Fifties and 60s, Premarin was marketed to males in addition to ladies, with journal adverts claiming the drugs made a lady “nice to reside with as soon as once more”. “It’s no straightforward factor for a person to take the stings and barbs of enterprise life,” claimed one advert “then to return residence to the turmoil of a lady ‘going by the change of life.’” In one other, {a photograph} of a bus driver featured alongside one in all an indignant feminine passenger, with the headline: “He’s affected by estrogen deficiency. She is the rationale why.”

Fortunately for pregnant mares, different scientists had been understanding extract hormones from crops. An American chemist known as Russell Marker headed south to Mexico searching for an enormous tuber he had examine in a Texan botany e book. The Mexican yam proved an ideal uncooked materials for extracting giant quantities of the chemical compounds wanted for mass manufacturing.

Marker’s work had medical advantages too. So known as body-identical hormones extracted from crops, notably these made utilizing fashionable strategies, are related to much less threat in relation to breast most cancers and blood clots than older medicine, says Dr Paula Briggs, chair of the British Menopause Society.


Prescriptions of HRT in England have greater than doubled in 5 years. NHS information reveals £85m was spent within the 12 months to the top of June this 12 months. The worldwide market was valued at $20bn final 12 months, in accordance with the market analysis agency Grand View Analysis, and it’s anticipated to develop to $36bn by the top of the last decade. The medicine are used to deal with different circumstances, corresponding to hypothyroidism and progress hormone deficiency, however menopause represents the biggest chunk of that spend.

Regardless of the dimensions of the market, HRT merchandise are primarily offered by smaller drugmakers that concentrate on ladies’s well being, fairly than Large Pharma firms, except for New York-based Pfizer. Manufacturing takes place virtually completely outdoors the UK, that means importers are completely reliant on worldwide provide chains.

Oestrogel, probably the most in style merchandise, is made by Besins Healthcare, a fifth-generation family-owned pharmaceutical agency based in Paris in 1885, and now primarily based in Brussels. The gel is manufactured in Belgium and France.

HRT prescriptions

Theramex, a private-equity-owned pharmaceutical agency primarily based in London, will get plant-based oestradiol from Hungary and progesterone from Italy to make its Bijuve capsules.

Whereas UK shortages have began to ease, the British Menopause Society and campaigners together with the MP Carolyn Harris are calling on the brand new well being secretary, Thérèse Coffey, to introduce a nationwide checklist, or formulary, of accredited HRT medicines. They are saying this might guarantee all ladies within the UK have the identical entry to the newer body-identical medicine, and firms like Theramex say it could encourage them to take a position extra.

The HRT taskforce was wound up on the finish of August, after solely 4 months, following what the federal government mentioned was an enchancment within the provide chain. Briggs agrees the state of affairs has “massively” improved. However shares of some merchandise stay low, and pharmacies are nonetheless allowed to restrict how a lot a buyer should purchase, or supply a substitute. These so-called severe scarcity protocols, which restrict meting out to a few months provide, are nonetheless in place for 9 merchandise.

“This extended fiasco with inventory shortages of quite a lot of HRT merchandise is infuriating,” says Harris. “The federal government has been blaming the rise in demand however months down the road that is no excuse – it ought to have labored with suppliers to get the state of affairs resolved much more rapidly.”

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