Prescribing HRT is not difficult. The evaluation, discussion, agreement and arriving at a decision to prescribe may be seen as time consuming, but look at it as an investment.
For most women who are sufficiently troubled by their menopausal symptoms to seek help, benefit from HRT will exceed risk (see 10 top tips on menopause). If you get it right they will feel better, not come back until scheduled for review and then thank you for giving them their life back. It is a rewarding aspect of medicine.
The best management option for the individual will vary with what is bothering her most. You will need to consider her symptom profile, her risk profile and her preferences and concerns. You will need to understand where she is in the menopause transition.
When you get to prescribing, ask yourself some simple questions, as follows.
- Are her symptoms general or exclusively urogenital? True menopausal symptoms derive from estrogen deficiency. If the flushes are tolerable but urogenital symptoms are significant, then low dose vaginal estrogens should not only be sufficient but will often be more effective as an initial strategy.
- Has she got a uterus? More strictly, is there possibly any endometrium remaining? If so, then as well as estrogen she will need progestogen to provide opposition and prevent hypertrophy and malignant change, as otherwise risk doubles over 5 years. If she has a levonorgestrel intrauterine system (LNG IUS) which has been in place over five years but is deemed adequate for contraception at her age, she will still need additional progestogen.
- Has she had a period in the last year? If so, she should be offered a cyclical regimen unless she already has an in-date Mirena ® LNG IUS. If so, only estrogen is needed. If she has not had a period in the last year she will need either continuous progestogen and estrogen, or tibolone.
- Does she have any significant cardiovascular risk factors, gallstones, thyroid replacement therapy or other metabolic issues, which indicate a non-oral estrogen is preferable?
- What does she want to use?
- Does she need contraception?
Figure 1 shows a menopause clinical pathway highlighting history, examination, and management including hormonal treatment.
Oral estrogen is available in three formats:
- conjugated equine estrogen which is a complex mixture derived from the urine of pregnant mares,
- estradiol valerate and
- micronised 17β estradiol.
The latter is my oral format of choice, with conjugated equine estrogen as the alternative. Women happy with any one do not need to change. 17β estradiol is the most important systemically active estrogen in vivo, and is the type of estrogen used in non-oral preparations such as patches or gel.
Patches should be changed once or twice a week dependent on brand, while gel has to be applied daily. There are pros and cons to both and the option should ultimately be the choice of the woman. Bioavailability will differ between women but as a rough approximation, 1.5mg estradiol delivered as gel = 50mcg/day from a patch = 2mg oral estradiol 17β.
Progestogens fall into different classes, and the two to familiarise yourself with are the testosterone derivatives (C19 progestogens such as levonorgestrel and norethisterone) and the progesterone derivatives (C21 – progesterone, dydrogesterone and medroxyprogesterone acetate). The activity at the testosterone receptor is one of the factors that result in different responses to different progestogens and if your patient appears intolerant, change class.
It is helpful to work out which types of estrogen and progestogen are available in the marketed products. This enables you to develop a simple formulary to allow low start and standard cyclical combinations, to move to continuous within the same family, and then progressively to drop the dose as women generally can be managed with lower doses over time.
Figure 2 shows the basis of a simple limited oral HRT formulary, although other options are available.
If your patient has previously has had no issues with a first line 30mcg ethinylestradiol/150mcg levonorgestrel combined oral contraceptive, and her cardiovascular risk profile is satisfactory, then a 17β estradiol + norethisterone oral combination is likely to suit. If she has had progestogen-related side effects in the past, a C21 combination could be chosen initially.
Some patch brands offer sequential and continuous regimens with C19 progestogens. Cutaneous absorption of C21 progestogens is limited but there is the option of developing a bespoke regimen using estrogen only with either:
- micronised oral progesterone (200mg cyclically for 12-14 days a month or 100mg daily for continuous use). This has a sedative profile so it can be helpful to take at night
- medroxyprogesterone acetate (10mg cyclically or 5mg continuously).
The general rule is to start with a low estrogen dose (such as 1mg oral) and then increase if needed unless your patient is under 45. Such women often have a higher replacement requirement and should be started at standard doses.
Warn her that if she is given a cyclical preparation, two prescription charges will be levied, and provide three months’ supply. Review before she runs out considering her symptoms, her reaction to the product, bleeding pattern and risk profile. Modify if necessary considering estrogen dose and route and then the progestogen.
Once stable, review annually but aim to move women to a continuous regimen by about five years, as this has been shown to give best protection. With time, dose requirement to manage symptoms does reduce and women can be reassured that the dose needed to maintain bone density is quite low so they will not lose protection.
There is no limit as to how long HRT can be prescribed. It is an individual decision, reviewed annually, with the risks and benefits discussed such that the decision to continue is informed. In women below the typical age of menopause (51-52) replacement can be seen as protective. HRT is not delaying the inevitable, if symptoms return they would have been present anyway and the lowest effective dose is always sought.
Menopause often comes when there are other significant challenges in women’s lives. Helping your patient to cope may not just give her life back but have a cascading effect on those around her. The risks are few, the rewards can be great – do not be afraid to prescribe what she is missing.
Case study 1
Anne is 48 and has not had a period for three months. This is the first time she has missed two in a row but her periods have become less predictable in the last few years. She took Microgynon 30® for contraception but stopped when she was 40 after her husband had a vasectomy.
She has come to see you as she has dreadful hot flushes and night sweats, cannot sleep and is moody and tearful which is quite out of character. She is a police officer and she is not sure if she can continue to do her job like this. Her two teenage daughters have told her "to get a grip" and none of the products in the health food shop have helped.
What is her best option?
- Microgynon 30®
- Fluoxetine 20mg/day
- Estradiol 50mcg/day + norethisterone continuous twice weekly patch
- Clonidine 50mg bd
- Estradiol 1mg + cyclical norethisterone daily oral regimen
An estradiol 1mg + cyclical norethisterone daily oral regimen would be a very reasonable starting option as the 1mg dose may be sufficient, and if not can be increased at the 3 month review.
Estradiol 50mcg/day + norethisterone continuous twice weekly patch could help symptoms considerably but might result in erratic bleeding that is difficult to assess, and is not recommended within 12 months of the last period.
If Anne has no significant risk factors, Microgynon 30® could be considered and could help but symptoms may return in the pill free week and it is not the best option. Neither SSRIs (such as fluoxetine) or SNRIs are recommended by NICE unless there is overt depression - which is not the case for Anne.
Clonidine may affect flushing, but no other symptoms, and is not recommended by NICE.
Case study 2
Bettina is 51. She has a BMI of 38, diet-controlled type II diabetes and stopped smoking last year. She had a Mirena® coil inserted 8 years ago to manage both her contraception and heavy periods and it was replaced after 5 years. She is suffering greatly from both day time flushes and sweats at night. She sweats profusely and finds this very embarrassing as she has to deal with the public in her job. She bleeds occasionally without warning but it is very light, her blood pressure is 128/76 and she takes no other medication.
What are her best options?
- Estradiol 50mcg/day + norethisterone continuous twice weekly patch
- Estradiol 0.06% gel – two measures = 1.5mg daily
- Estradiol 50mcg/day twice weekly patch
- Estradiol 1mg + 5mg dydrogesterone continuous daily tablet
- Isoflavone phytoestrogens from the health food shop
Her best options are estradiol gel or estradiol patch. As Bettina has cardiovascular risks a non-oral delivery route is recommended, and either estradiol 0.06% gel 1.5mg daily or estradiol 50mcg/day twice weekly patch would be an appropriate dose. Additional progestogen is not needed with an in date Mirena®.. She therefore does not need a norethisterone continuous twice weekly patch.
The option of estradiol 1mg + 5mg dydrogesterone continuous daily tablet would involve an appropriate estrogen dose for initiation, but the oral route is not recommended for a woman at higher cardiovascular risk, and she does not need the progestogen.
Isoflavone phytoestrogens from the health food shop are not recommended as the evidence of efficacy and safety is sparse. Consensus clinical experience is that they are unlikely to help very severe symptoms.
Case study 3
Carol is 55. She has come to see you for her annual review. She has been taking estradiol 2mg with cyclical dydrogesterone 10mg tablets for the last three and a half years. When she started, her periods had become haphazard and up to four months apart. She had started on the lower dose 1mg + 10mg combination but it did not settle her flushes enough.
She has been very well since, is about to become a grandmother and is stepping down to working just three days a week. She would like not to bleed now, although her existing bleeding is not heavy or painful. It now takes 3-4 days into the new pack before it starts and she needs only light protection for 2-3 days. She is slim, active, has never smoked and her blood pressure is 118/74.
What is her best option?
- Estradiol 2mg oral with a LNG IUS
- Estradiol 50mcg/day, twice weekly patch, with a LNG IUS
- Estradiol 1mg with continuous dydrogesterone 5mg oral
- Estradiol 1mg with cyclical dydrogesterone 10mg oral
- Estradiol 0.5mg with continuous dydrogesterone 2.5mg oral
Estradiol 1mg with continuous dydrogesterone 5mg oral is Carol’s best option. This uses the components that she already tolerates well, in a lower dose continuous regimen, and would be appropriate in this scenario.
Estradiol 0.5mg with continuous dydrogesterone 2.5mg oral would use the same well tolerated components in a very low dose continuous regimen. It represents a substantial reduction in dose and the interim 1mg combination would be a more appropriate first step. It may prove possible to step down to this dose after three months.
Estradiol 2mg oral with a LNG IUS would use the same estrogen route and dose, but her bleeding is not so much of a problem as to warrant intrauterine progestogen as the first line suggestion (though it would be an option).
Estradiol 50mcg/day twice weekly patch, with a LNG IUS, would have a similar effect and might be considered if there were cardiovascular risk factors, but Carol has done very well with the oral route and at present there is no overriding reason to change. Her bleeding is not so much of a problem as to lead to intrauterine progestogen as the first line suggestion (though it would be an option).
Estradiol 1mg with cyclical dydrogesterone 10mg oral: Carol may manage with this lower dose combination, but she does not want to bleed and a continuous regimen would offer best protection.
- Dr Sarah Gray is a GP specialist in women’s health in Cornwall