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Different HRT treatment choices for the menopause

Nuttan Tanna
MRPharmS PhD ACPP
Specialist Pharmacist - Menopause and Osteoporosis
Associate Director
Pharmacy Practice
Northwick Park Menopause Clinical and Research Unit
NW London Hospitals NHS Trust
Harrow, Middlesex
Honorary Lecturer
MSc/Women's Healthcare Module
Department of Pharmacy
University of Cardiff
Wales
E:nuttan.tanna@nwlh.nhs.uk

Individualised risk-benefit evaluation based on currently available evidence(1-4) precedes the prescription of a suitable hormone replacement therapy (HRT) regimen. Treatment choice depends on symptoms, medical history, family history, lifestyle and preferences. 
Patient symptom assessment charts, where women are asked to score for severity of their symptoms at the time of presentation, are useful in assessing initial symptoms and progress with time, with or without treatment.(5) Table 1 details the absolute and relative contraindications to taking HRT. Treatment is given for 2-4 years if the main aim of treatment is symptom control, but will have to be taken for five years at least if the main aim is to maintain bone mass and prevent osteoporosis.(5)

[[NIP05_table1_39]]
 
Women pose numerous questions, depending on what stage they are at in their reproductive lifespan (Table 2). The role of the practice nurse includes the provision of information, care and monitoring of menopausal women on HRT and alternative therapies and in promoting health in the postmenopausal population.(4,5)

[[NIP05_table2_41]]
 
This article considers the range of HRT preparations available. An understanding of the rationale behind each regimen, with appropriate advice on what to expect in the settling in phase, will help nurses support patients with the initiation of and ongoing compliance to treatment.

HRT regimens
There are some 50 different HRT preparations currently licensed in the UK, with new product launches scheduled for later this year. The regularly updated Monthly Index of Medical Specialities (MIMS) HRT list (Box 1) forms an easily accessible information tool, providing details on hormonal components and doses, NHS costings, prescription charges, and expected bleed profiles for all regimens (see April 2002 issue). What is advantageous both from the clinical and patient's point of view are the various administration options; these include the oral route, transdermally absorbed patches and gels, the vaginal and intranasal route, and subcutaneously administered implants. Table 3 presents the advantages and disadvantages of these different administration routes.

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[[NIP05_table3_41]]

When menopausal patients are prescribed HRT, the aim is to achieve the naturally circulating endogenous hormone levels of the premenopausal stage. It is the deficiency of oestrogen that is the cause of menopausal symptoms, and therefore oestrogens are the mainstay of treatment. HRT treatments can be divided into six different groups, namely the sequential combined and continuous combined HRT preparations, gonadomimetics, unopposed oestrogen preparations prescribed for hysterectomised patients, with adjunctive progestogen if the patient has an intact uterus, vaginal oestrogen treatments for local symptom relief and finally implants.

Sequential combined HRT
Oestrogen is taken from 21 to 31 days each month, depending on the regimen prescribed, with a progestogen course for part of the month. Original packs of monthly HRT based on a 28-day cycle are the prescription norm; with continuous oestrogen, progestogen is added in from between 12 (eg, Elleste Duet: Pharmacia) and 14 days (eg, Prempak-C: Wyeth; Femoston 2/10: Solvay) per month. Taking progestogen is important for endometrial protection in patients on oestrogen and with an intact uterus.(1-6) Progestogen must be added in for at least 10 days per month.(6) These regimens should result in women having monthly bleeds. Tridestra (Orion) is an exception. Here oestrogen is taken continuously with a two-weekly progestogen course every three months. This tricyclic regimen results in a three-monthly bleed profile. Careful assessment of the patient's bleeding pattern before prescription is important to avoid a high incidence of breakthrough bleeding. Patients at the postmenopausal border, with an erratic bleed pattern ranging around three months or more, should do well on Tridestra. Original HRT packs, which by law include a patient information leaflet and clear instructions on how the preparation is to be taken, are considered "patient-friendly" packs. Here the onus to remember the cyclical sequence in which the tablets or patches are to be administered is not on the patient.

Continuous combined HRT
These "bleed-free" HRT regimens have been available in the UK since 1996. They combine oestrogen and progestogen taken together, daily, with no break. These preparations are licensed for the postmenopausal patient; therefore the woman should have been period-free for a year before starting continuous combined HRT. In addition to offering a bleed-free option to patients, with exposure to lower, continuous doses of progestogen, they are also responsible for fewer premenstrual syndrome symptoms, and for progestogen-sensitive patients, fewer side-effects.(7) The majority are oral formulations, with one transdermal system on the market (Evorel Conti: Janssen-Cilag). More recently, two oral, low-dose, bleed-free regimens have been launched (see MIMS, p.346; Kliovance: Novo Nordisk; Femoston-Conti: Solvay). 
By the age of 54, more than 80% of women can expect to be period-free.(4) Women who don't know when they had their last normal menstrual period because of withdrawal bleeds, and who have previously been on sequentially combined HRT, could start on bleed-free HRT at the age of 55. Patients should be warned that it could take up to six months to settle on continuous combined HRT, and to expect a lower incidence of breakthrough bleeding with time. Endometrial assessment needs to be considered if the bleeding becomes heavier rather than lighter, if it persists beyond six months, or if it occurs after a significant time of amenorrhoea.(4) One in five patients fail to become "bleed free" with time; they may have to consider using the sequential combined treatments instead, or else they can be assessed for a gonadomimetic prescription.

Gonadomimetics
Tibolone (Livial: Organon) is the only preparation in this group. It is a synthetic steroid derivative of norethisterone, with mixed oestrogenic, progestogenic and androgenic activity. It is licensed for use in postmenopausal patients for menopausal symptom control and osteoporosis. Table 4 shows the minimum bone-sparing doses of HRT and tibolone. In addition, tibolone can be used in cases of depressed mood and decreased libido problems. It provides an alternative option to continuous combined, "bleed-free" HRT, for postmenopausal women who wish to have amenorrhoea.

[[NIP05_table4_42]]

Unopposed oestrogen
This is the treatment option for hysterectomised patients, where endometrial protection is not an issue. Oestrogen will be necessary after a total abdominal hysterectomy and bilateral salpingo-oophorectomy. In cases of ovarian conservation at the time of the hysterectomy, it is appropriate to wait until the patient presents with menopausal symptoms indicative of ovarian failure before oestrogen is prescribed. The MIMS list provides information on the types of oestrogen used in HRT; these include oestradiol, conjugated equine oestrogens, oestrone and oestriol. The latter two are less potent metabolites of oestradiol. Delivery routes range from oral to patches and gels and include Aerodiol (Servier), a product which provides patients with oestradiol administered intranasally. There are two patch technologies: alcohol-based reservoir patches with an adhesive outer ring (Estraderm TS range: Novartis); and matrix patches where the hormone is evenly distributed throughout the adhesive (all other patch systems apart from the Estraderm TS range). Skin reactions are less common with matrix than reservoir patches. 
Patients often ask for reassurance on the source of their medication, with a preference for an extraction or manufacturing process free from animal cruelty. Premarin (Wyeth), a conjugated equine oestrogen, is obtained from pregnant mares' urine utilising a catheter. The mares are not slaughtered as is commonly suspected. Conjugated equine oestrogens contain around 50-60% oestrone sulphate. The other major component is equilin sulphate. The conjugated equine oestrogens are normally classified as "natural". All other oestrogens (and the progestogens) used in HRT are sourced from plants (eg, soya beans or yams); to obtain a stable formulation, they undergo some form of chemical synthesis. 
If a clinician wishes to prescribe a particular oestrogen and progestogen for certain patients, rather than use the original packs available, then appropriate combinations could be made up from the oestrogen and progestogen options detailed on the MIMS list.

Adjunctive progestogens
Figure 1 shows the three groups of progestogens currently used for HRT. It is important to remember that norethisterone is available as the progestogen-only pill (Micronor POP: Janssen-Cilag; dose 350mg), which is different from Micronor HRT, where the norethisterone dose is 1mg. The progesterone vaginal gel (Crinone 4%: Serono), prescribed as an original pack containing six applicators, is administered on alternate days. This effectively provides progestogen cover for 12 days of the monthly cycle when used with continuous oestrogen in a sequentially combined HRT regimen. Currently under investigation is an intrauterine device to deliver the progestogen component of HRT. Mirena (Schering Health Care), the intrauterine device that delivers levonorgestrel to the endometrium, is licensed only for contraception in the UK. However, it is licensed for use as the progestogenic component of HRT in Finland.

[[nip05_box1_43]]

Vaginal HRT
For patients requiring treatment for local vaginal atrophic symptoms, the use of vaginally administered oestrogens has been found to be effective. Various administration routes are available (see MIMS list), including creams, pessaries, vaginal tablets and rings. Long-term use of these vaginal preparations may be associated with some absorption and endometrial stimulation; this needs to be borne in mind when considering endometrial safety. With the recently launched vaginal ring, Menoring (Galen), absorption and achievement of systemic levels has been demonstrated. This preparation is licensed for the control of menopausal symptoms in hysterectomised patients.

Implants
Oestradiol implants are crystalline pellets of oestradiol that are inserted subcutaneously under local anaesthetic. They release oestradiol over many months. Once they are inserted, the patient does not have to remember to take medication. An important concern is tachyphylaxis, defined as a recurrence of menopausal symptoms while the implant is still releasing adequate levels of oestradiol.(4) It is recommended that patients continue to take progestogen courses after their last implant in a cyclical pattern until withdrawal bleeds stop, to ensure endometrial protection from ongoing implant activity.(8) Patient concerns include scarring each time an implant is inserted, and having a plasma oestradiol blood test each time, before implant insertion. This usually occurs every 4-8 months.(8) Generally implants are inserted within specialist units rather than within the primary care setting. Patients can also be assessed for a testosterone implant, to be inserted at the same time as an oestradiol implant, used for libido and loss of energy in appropriate cases.

Management of side-effects

Oestrogen-related side-effects

Patients often suffer from initial transient side-effects, which should resolve with time. They should be advised to persist with treatment for at least three months before a change of regimen or dose is considered. Appropriate advice in certain cases include: use of evening primrose oil for mastalgia or breast tenderness; leg cramps can improve with lifestyle changes; if nausea or gastric upset occurs when taking oral oestrogens, the patient can be advised to try taking the tablet after food and at night; the patient could have lactose intolerance if these symptoms are present.
Management options include reducing the dose, changing the oestrogen (for example, conjugated equine oestrogen or oestradiol preparation), or changing the route of delivery.

Progestogen-related side-effects
These will usually be related to the type, duration and dose of progestogen. Figure 1 gives the three groups used within HRT preparations in the UK. Management strategies include changing the progestogen type, reducing the dose (taking care not to go below the recommended doses for endometrial protection), or changing the route of administration, duration of therapy or frequency by using the tricyclic preparation (Tridestra, discussed above).

Conclusion
With the wide range of HRT preparations currently available, menopausal women have many choices. Newer preparations include patches, gels, the nasal spray and vaginal rings. In addition, there are different oestrogen and progestogen options available within each formulation. Which regimen is most appropriate will depend on the woman's menopause stage and the indication for treatment. Practice nurses are in an ideal position, working with the multidisciplinary health professional team, to help women gain the most from their HRT. This includes menopause symptom control and, in the long term, osteoporosis protection.

References

  1. Grady D, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.
  2. Barrett-Connor E. Hormone replacement therapy. BMJ 1998;317:457-61.
  3. Hormone replacement therapy -1: the benefits and risks. WeMeReC Bulletin. Welsh Medicines Resource Centre May 2001;8(2).
  4. Rees M, Purdie DW, editors. Management of the menopause. The handbook of the British Menopause Society. London: BMS Publications, 2002.
  5. The Sheffield protocol for the management of the menopause and the prevention and treatment of osteoporosis. 7th ed. 2001.
  6. Beresford SA, et al. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458-61.
  7. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159-71.
  8. British Medical Association and The Royal Pharmaceutical Society of Great Britain. British National Formulary. Volume 42. September 2001.

Resources
British Menopause Society
36 West Street
Marlow Buckinghamshire SL7 1AB
T:01628 890199
W:www.the-bms.org
National Osteoporosis Society
PO Box 10
Radstock
Bath BA3 3YB
T:01761 471771
Helpline:01761 472721
F:01761 471104
W:www.nos.org.uk
E:info@nos.org.uk
The Northwick Park Menopause Clinical and Research Unit
The NW London Hospitals NHS Trust
Watford Road
Harrow HA1 3UJ
Health Professional Linkline:0208 869 2937
Patient Adviceline: 0208 869 2877/3965
Osteoporosis 2000
47 Wilkinson Street
Sheffield S10 2GB
Helpline:0114 272 2000
F:0114 263 4420
E:anyone@osteoporosis2000.freeserve.co.uk
The Northwick Park Menopause Unit Patient Symptom Assessment Chart is part of the Sheffield Protocol (ref 5; p.57), and is available from Osteoporosis 2000
Amarant Trust
1st Floor
Sycamore House
Sycamore Street
London EC1Y 0SG
T:09068 660620
F:020 7490 2296
The Pennell Initiative c/o JM Associates
13 Grove Street
Summertown Oxford OX2 7JT
T:01865 558000
Publications orderline: 0800 550220
W:www.pennellwomenshealth.org

Forthcoming events
The Royal College of Nursing and the National Osteoporosis Society run regular menopause and osteoporosis study days for nurses.See the following websites for more details: W:www.rcn.org.uk
W:www.nos.org.uk