Women with premature ovarian insufficiency (POI) after cancer treatments are affected by the consequences of low oestrogen, as are women with POI from other aetiologies. There are no preparations of hormone replacement therapy (HRT) designed for women with POI as preparations were developed for naturally menopausal, and therefore older, women. The basic principles of treatment are the same as for post-menopausal women: those without a uterus only require oestrogen but those with a uterus require a progestogen in addition. This is to protect the endometrium from the effects of unopposed oestrogen, which could otherwise lead to endometrial cancer. Progesterone receptors have been described in tissues as diverse as the gut and brain, but currently the indication to replace progesterone remains endometrial protection only. Breast cancer risk in untreated women with (all cause) POI is thought to be lower than that in the general population. HRT has not been found to increase the risk compared to normal when used before the average age of menopause.1 It is expected—but not proven—that HRT use by women with POI up to the average age of menopause reduces the risks associated with this diagnosis.
WHAT ARE THE OPTIONS FOR OESTROGEN REPLACEMENT?
There are various formulations of oestrogen available for hormone replacement, which is required continuously. Oestradiol is the main ovarian oestrogen. The most widely available preparations contain oestradiol as the hemihydrate or as an esterified pro-drug (e.g. oestradiol valerate) to increase bioavailability of the physiological hormone. It is also available as an intramuscular injection or topical spray (but only in some countries). An implant is available although its usefulness is limited by the development of tachyphylaxis and it is rarely indicated now. Oral delivery requires once daily dosing, but the transdermal route can be via patches changed once or twice a week or as a gel applied daily from a single dose sachet or a metered pump. Since the transdermal route avoids first-pass hepatic metabolism, there are no extra metabolites of oestrogen formed. These have uncertain significance but may have unwanted additional actions to oestradiol that may contribute to side-effects. Thus transdermal delivery is more physiological and this may be an important consideration for some women.
Conjugated equine oestrogens are derived from the urine of pregnant mares. These are potent oestrogens that can be administered orally. However, the consensus has moved towards providing physiological hormone replacement, which has become less expensive and more readily available.
Ethinyl oestradiol is a synthetic oestrogen that has high bioavailability orally and is used in combined hormonal contraception (CHC). It may be less beneficial for bone health than oestradiol and when combined with progestogens for contraception, has higher risks of venous thromboembolism and cardiovascular disease than HRT. There is no reason to believe that these risks are any different for women with POI compared to those with normal ovarian function.