The perimenopause, the time leading up to the menopause or final menses, has been recognised through the ages as a time of significant change. Symptoms of gradual reduction in female hormone production are common and experienced by many women.
For some these, symptoms can be debilitating, affecting all aspects of daily living. There is little reference to early remedies in the literature; indeed menopause has only become a concern with the increase in lifespan associated with better nutrition and improved healthcare over the past two centuries.
The average age of menopause has been consistently around age 51 whilst average age of death has increased from mid 20s in medieval times to 84 years today. Even when menopausal problems were apparent, there was little help available. Thomas Graham wrote in his book published in 1837, “The
Diseases of Females”, that with the exception for attention to diet and exercise, “little or nothing is required for the management of ordinary cases”.
Women were thought to be ruled by their hormones, and thus inferior to men, making menopause a shameful secret. It was only in the later 19th century that scientists began experimenting with various animal extracts in the search for the “fountain of youth”. The Merck Manual of 1899 describes a preparation known as “Ovariin” which was a coarse brown powder taken orally, essentially the dried and pulverised ovaries of a cow. Research continued; notably Drs Allen and Doisy.
Working together between 1923 and 1938 they identified oestrogen and its effects, followed by the other female hormones and their relationship to each other. Pharmaceutical companies were quick to spot possible market opportunities in menopause, menstruation problems, infertility and contraception and also hoped to address problems such as wrinkles and thinning hair! Scientists were recruited by the drug industry and the first commercial oestrogen was available in 1930. This was “Emmenin”, produced from urine obtained from late-pregnant women in Canada. Although marketed as the first effective oestrogen, an alternative source was quickly required as there were problems with high cost, taste and odour!
A better source was found in pregnant mares urine and this was marketed by the company Ayerst (which became Wyeth) as Premarin, its name derived from the source. This has been available for nearly 70 years now.
Other oestrogens followed with ethinyl oestradiol being synthesised in Germany by the company Schering in 1938, still the leading oestrogen used in contraception, and diethylstilbestrol synthesised in the same year in the UK by Charles Dodds. He made the formulation available freely, believing that pharmaceutical companies should not profit from scientific work. Many companies applied to manufacture DES (diethylstilbestrol) as it was off patent even thought Dodds himself already had concerns about possible cancer and miscarriage risks.
All these preparations to date had been oral formulations with no consideration of alternative delivery methods. Although effective HRT had really been made available in 1941 with DES, prescribing was not widespread until the 1960s when the change in womens role in society brought the menopause and hence the benefits of HRT to the fore.
Several books were written at that time which highlighted the improvement in both emotional and physical wellbeing for middle-aged women, indeed HRT was regarded as a panacea for all midlife issues. The prominent American gynaecologist, Dr Robert Wilson, promoted the use of oestrogen in his book “Feminine Forever” as a means of combating the “living decay” of menopause and advocated the use of oestrogen from “puberty to the grave”, advice which is not recommended now. Drug prescriptions increased steadily with Premarin being the number one drug in the US by 1992 . The use of HRT remained popular despite a significant scare in the 1970s in the USA when the link between unopposed oestrogen and endometrial cancer was demonstrated.
Despite providing an excellent treatment for many women, oral preparations are not without drawbacks. Daily dosing is required, which is a disadvantage for some menopausal women with memory problems! Any oral preparation must be absorbed from the digestive tract, then passes to the liver via the portal system and is metabolised before reaching the target organs. This increases the workload on the liver and affects the dose eventually delivered. The higher total dose required may give rise to oestrogenic side-effects including nausea, breast tenderness, headaches and leg cramps. Women with malabsorption problems may simply not absorb sufficient drug doses to achieve an adequate response.
Other routes of administration have become possible, but obviously need to be convenient and confer advantages over the oral route in order to be worthwhile. Research into transdermal administration had been going on throughout the 1970s but had several difficulties to overcome. Earlier, skin had been thought of as an impermeable protective barrier. However it has been shown that many drugs can diffuse through the thin layer of tissue separating the outside world from the capillary network lying just below the skin surface.
The first transdermal delivery systems were launched in 1979 and the next decade saw the development of ten further transdermal delivery systems (TTDS) containing different drugs. The drug company ALZA in the US led the market with brands including Estraderm, Duragesic, and Transderm-Nitro. They also produced patches for delivery of nicotine and analgesics, and anti-nausea drugs.
The main advantage of transdermal delivery relates to the controlled absorption rate giving predictable, uniform plasma levels, and improved bioavailability. The lower overall dose tends to result in fewer side effects. A transdermal patch is easy and painless to apply and equally simple to discontinue by removing the patch, should administration no longer be required, for example prior to surgery. A simple system tends to improve patient compliance particularly with weekly patches.
In order for a drug to be administered via the passive adhesive transdermal route, it must fulfill several requirements; the drug must be of low molecular weight, non-ionic, have adequate solubility in both oil and water; it must have a low melting point and be potent (dose in mg per day). Oestrogen meets all these requirements and several types of patch have