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CONTINUOUS COMBINED HRT

Hormone replacement therapy (HRT) for menopausal symptoms consists of oestrogen alone or with progesterone. Women with an intact uterus need to take a combination of oestrogen and progesterone, as taking oestrogen alone can increase the chance of getting cancer of the uterine lining (endometrium). Adding progesterone to oestrogen reduces this risk.

This article was included in issue 74 (autumn 2017) of The Menopause Exchange newsletter.

Continuous combined HRT
Continuous combined HRT (bleed free) involves taking oestrogen and progesterone every day without a break. This is suitable for women who haven’t had periods for over one year. Progestogens, also called progestagens or gestagens, are a class of steroid hormones that bind to and activate the progesterone receptor. Progesterone is the major and most important progestogen in a woman’s body, while progestins are synthetic progestogens. The progestogens used in HRT are largely synthetic and are structurally different from progesterone as they are created from plant sources.

Common forms
Continuous combined HRT is available on prescription in several forms including skin patches, tablets, gel and progestogen-releasing intrauterine coil. The Mirena coil (intrauterine system), which is used for contraception and to control heavy periods, can be used to supply progestogen to the uterus. It means that the woman can have oestrogen through her whole body and progestogen in the only place it’s needed. The coil needs replacing every four years but it provides extremely effective contraception and good bleeding control.

Some common brands of continuous combined HRT in the UK include Evorel Conti, Premique, Kliovance, Kliofem, Femoston Conti and Elleste Duet Conti.

When to switch?
Although progestogens can be used cyclically, the protective effect of cyclical progestogens on the endometrium is less reliable after five years. Consideration should be given to switching HRT to a continuous combined therapy within five years of starting cyclical HRT or once a woman is assumed to be postmenopausal.

Continuous progestogens reduce the risk of endometrial cancer to lower than that in postmenopausal women not taking HRT. Women already on sequential HRT may consider changing to continuous combined HRT after one to two years (if 50 or over) or after four to five years (if under 50). Continuous combined HRT is also suitable as ‘add-back HRT’ for women on long-term gonadotrophin releasing hormone analogues for bone protection. It’s recommended instead of oestrogen-only HRT in women who have had a hysterectomy for oestrogen-responsive conditions, such as severe endometriosis or endometrial cancer.

Tibolone
Tibolone (Livial) is a type of continuous combined HRT that doesn’t contain oestrogen or progestogen. It’s a synthetic steroid compound. On absorption, it is converted in the body to substances with mild oestrogenic, progestogenic and androgenic actions. It has been shown to be helpful in women with endometriosis and fibroids, as it doesn’t appear to stimulate these conditions. Research suggests that libido improves much more in women taking tibolone than in women taking other forms of combined HRT. Tibolone doesn’t increase the risk of endometrial hyperplasia or cancer. It may slightly increase the risk of breast cancer, but less so than combined HRT.

Tissue-selective oestrogen complex
This is a combination of bazedoxifene and conjugated oestrogens. It’s suitable for postmenopausal women who have an intact uterus but are unable to tolerate progestogens. The bazedoxifene prevents oestrogen stimulating the endometrium.

Bio (or body)-identical HRT
Most combined HRT products contain progestogens with progesterone-like actions. Micronised progesterone is a natural progesterone without androgenic and glucocorticoid activity. Early reports suggest this may be the best progesterone in terms of effects on the cardiovascular system, blood pressure and breast tissue. Utrogestan is the only preparation currently prescribed in the UK.

Side effects and risks
Oestrogen-related side effects of continuous combined HRT include breast tenderness, leg cramps, skin irritation, indigestion, nausea and headaches. Progestogen-related side effects include premenstrual syndrome (PMS)-like symptoms, fluid retention, bloating, backache, depression, mood swings and pelvic pain.

Erratic breakthrough bleeding is common in the first three to six months and doesn’t usually warrant further investigations. But you may need to be assessed if the bleeding becomes heavier rather than lighter, persists beyond six months or occurs after a significant length of time without any periods. The incidence of irregular bleeding may be reduced by taking more progestogen and less oestrogen. Adding more progestogen or lowering doses of oestrogen tend to be associated with better bleeding profiles.

If you have significant nausea or migraine headaches with oral products, patches can be an alternative. The patches have a superior safety profile over oral products when there are concerns about the risk of deep vein thrombosis (blood clots). Progestogen-related side-effects can often be minimised if Mirena coil is used as the progesterone arm of HRT.

For most women, the increased risks of taking HRT are very small, but they need to talk to their healthcare professionals to weigh up their individual risks and benefits. The principal risks of HRT are blood clots in veins and lungs, stroke, cardiovascular events, gallbladder disease, breast cancer, ovarian cancer and endometrial cancer. HRT isn’t prescribed in certain conditions such as undiagnosed abnormal vaginal bleeding, blood clots, active heart disease, current or past breast cancer, current or past endometrial cancer, other oestrogen-dependent cancers, active liver disease and uncontrolled high blood pressure. If you have one of these conditions and want to take HRT, seek specialist advice.

 About the author
Dr. Vikram Talaulikar, MD MRCOG PhD is Associate Specialist at the Reproductive Medicine Unit at University College London Hospital.

References:
Gynecol Endocrinol. 2010 Nov; 26 (11): 804-14. doi: 10.3109/09513590.2010.495437. Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials. Biglia N1, Maffei S, Lello S, Nappi RE.

Hum Reprod Update. 2017 Jul 1;23(4):481-500. doi: 10.1093/humupd/dmx011. The management of menopause in women with a history of endometriosis: a systematic review. Gemmell LC, Webster KE, Kirtley S, Vincent K, Zondervan KT, Becker CM.

JAMA. 2017 Sep 12; 318(10): 911-913. doi: 10.1001/jama.2017.11462. Menopausal Hormone Therapy: Understanding Long-term Risks and Benefits. McNeil M1.

Created Autumn 2017

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