If the uterus is still present and oestrogen is being used to manage symptoms and protect against long term consequences of oestrogen shortage, progesterone needs to be added to protect the uterus from abnormal changes/ pre-cancer (hyperplasia) or cancer.
Risk of uterine cancer - 2.6 women/10,000 per year
Lifetime risk for developing uterine cancer – Approximately 3 in 100 women
Endometrial cancer risk is 22% lower in ever-users of continuous combined HRT (oestrogen and progesterone taken together ), versus non-users, a meta-analysis of observational studies showed
Both synthetic progestogens and bioidentical progesterone will reverse abnormal cells in the endometrium/uterine lining and reduce the risk of developing uterine cancer.
The protective effect of progesterone does not relate to the withdrawal bleed but to the duration of progesterone as this gradually reverses the tendency for abnormal cell division over the month. Therefore, women who take progesterone continuously for 30 to 31 days per month have an almost zero chance of developing uterine cancer with HRT. Women who take it cyclically have a reduced risk of developing uterine cancer compared to the background population, but a very slightly higher risk than with continuous progesterone.
Progestogens/progesterone can be taken by mouth (tablets), through the skin (patches), by injection –slow-release depo injections or targeted within the uterus as an intrauterine progesterone coil.
All of these different methods of delivering progesterone into the bloodstream and uterus have advantages and disadvantages compared to other types and can depend upon individual preference, side effects associated with different types of progestogens and progesterone, and the response to those.
Pure micronised progesterone - Utrogestan
This is the most common form of progesterone used in HRT as this has largely superseded synthetic progestogens which previously were used. Both the metabolic effects and physical side effects are much fewer with pure bioidentical progesterone. It can be taken orally or inserted vaginally although vaginal administration usually results in fewer progestogen-based side effects.
Duration of use: In the perimenopausal years when the cycle is still occurring, it is usually advised to take progesterone cyclically to match in with the progesterone phase of the individual’s cycle. This usually therefore means taking the progesterone for 2 weeks commencing around 14 days after the menstrual bleed and thereafter moving into a regular cycle of 2 weeks of progesterone and 2 weeks without progesterone.
Continuous progesterone: This is usually when a woman has moved into the post menopause and is usually taken on a daily basis, increasing to two per day if there is breakthrough bleeding.
Dosages: 100mg – 200mg per capsule
Synthetic progestogens
Synthetic progestogens include:
· Desogestrel (Cerelle,Cerazette) – this is a non-androgenic (non-male) hormone progestogen which can be slightly more effective for suppression of the endometrium – bleeding and endometrial protection than Utrogestan. However, pure progesterone is usually the first choice due to having less metabolic effects than synthetic progestogens. Dosage: 5mcg per day, can increase to twice daily temporarily if breakthrough bleeding.
· Norethisterone – norethisterone is a C19 synthetic progestogen. It is extremely strong and therefore very effective at reversing abnormal cells within the uterus and also suppressing bleeding. It is often used if there is dysfunctional uterine bleeding which is retractable and unresponsive to the more gentle progestogens and pure progestogens. Dosages: 5mg up to 4 per day depending on heaviness of bleeding, reducing gradually once the bleeding has subsided to a maintenance dose of 2.5mg per day. Side effects include PMS type symptoms such as low mood, facial spots, weight gain and fatigue.
This is therefore a balance between the effectiveness and safety of the uterine protection and prevention of bleeding versus side effects. Please note not all women experience side effects in the long term synthetic progestogens are not as safe as pure progesterone.
Mirena/Kyleena/Jaydess
These are intrauterine progesterone devices which deliver levonorgestrel directly into the endometrium – lining of the uterus. For this reason, because of the target progestogen directly into the uterus, they can be much more effective than oral progestogens which require higher doses to achieve penetration and reversal of any abnormal cells in the endometrium. This is useful therefore, not only for switching off the cycle and depression of bleeding, but also for reversal of any abnormal cells especially in the early stages (secretory transformation of the endometrial cells.)
Dosages:
Mirena = 20mcg levonorgestrel over 24 hours; lasts five years.
Kyleena = 17mcg levonorgestrel over 24hours; lasts five years.
Jaydess = 13mcg levonorgestrel over 24 hours; lasts 3 years.
Progesterone side effects are similar to those experienced with premenstrual syndrome including breast discomfort, bloating, carbohydrate and sugar cravings, brain fog, headaches and mood changes. It is not clear whether the side effects are related to the progesterone itself or to the blocking effect on the oestrogen resulting in exaggerated low oestrogen symptoms. Sometimes supplementing with oestrogen during the progestogen phase of cyclical regimens can offset this effect.
References:
1. Lifetime risk estimates calculated by the Cancer Intelligence Team at Cancer Research UK 2023
2. Estève J, Benhamou E, Raymond L. Statistical methods in cancer research. Volume IV. Descriptive epidemiology. IARC Sci Publ. 1994;(128):1-302.
3. Brinton LA, Felix AS. Menopausal hormone therapy and risk of endometrial cancer J Steroid Biochem Mol Biol. 2014 Jul;142:83-9.
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