Intrauterine application of progestins in hormone replacement therapy: a review

Abstract

The intrauterine application of progestins as endometrial protection against hyperstimulation by estrogen replacement therapy has been investigated in clinical trials since the early 1990s and one product has become available for this indication. This review considers the available published and presented reports on intrauterine use of progestin to date. Reports of 19 studies were reviewed. These studies included both peri- and postmenopausal women (826 in total), treated with different types of estrogens administered via various routes. Progesterone was used in two small studies, while all other studies used different doses of levonorgestrel for periods ranging from 6 months to more than 5 years. Endometrial effects, bleeding profiles, systemic effects (symptoms and metabolic), as well as clinical experience, were considered and were comparable to other forms of continuous combined hormone replacement therapy (HRT). It is concluded that the current evidence supports complete endometrial protection and a good safety profile. The observed bleeding profiles appear favorable but have not yet been directly compared with other forms of continuous combined HRT. A favorable effect on serum lipids has been observed and also awaits direct comparative confirmation. Progestin-attributable side-effects, effects on bone and breast tissues and other systemic effects have not yet been studied. Acceptance by patients has been good, while insertion did not present undue problems for the investigating physicians. Retention of the studied intrauterine systems has been very good. Intrauterine use of progestins, especially levonorgestrel, by purpose-designed systems as part of combined HRT, is a new way of administration and carries good benefits, while some aspects require more clinical evidence.

Hormonal contraception and risk of endometrial cancer: a systematic review

“…Mean plasma levels of levonorgestrel can be assessed to be in the range of about 150-200 pg/ml (0.4-0.6 nmol/l), whereas endometrial tissue levels more than tenfold higher are obtained (Riphagen 2000). Thus, side effects similar to those seen with orally or parenterally administered progestin-only preparations have been observed in the studies, but are very rare.…”

“…However, the main effect of LNG-IUS is to decrease the local endometrial response to estrogen, as with the use of systemically administered progestins when added to estrogen therapy (Pike & Spicer 2000, Riphagen 2000. During progestogen action, cell proliferation ceases despite continuous exposure to estrogen levels (as in the luteal phase).…”

“…The use of the LNG-IUS to protect from endometrial cancer is one of the most important issues regarding cancer risk and contraception (Hubacher & Grimes 2002) as well as HRT (Riphagen 2000). However, studies on primary risk reduction in general populations are still lacking, although in 2008, at least three studies and two case reports for effective treatment of endometrial hyperplasia (including even atypical or complex histology) were published (Haimovich et al 2008, Oerbo et al 2008, Qi et al 2008, Varma et al 2008, in addition to a series of earlier reports (Vereide et al 2003, Giannopoulos et al 2004, Wildemeersch et al 2007).…”

New developments in HRT: low-dose therapy

“…It has, however, also been used increasingly in menopausal women as the progestogen component of HRT, together with oral, transdermal or subcutaneously implanted oestrogen. 13 These combinations have been shown to be equally effective as longer established cyclic or continuous combined oestrogen and progestogen regimens. They produce an atrophic endometrium after the first few months of treatment, during which breakthrough bleeding and spotting are common.…”

Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence

“…Hence an estimate of free testosterone is thought to be the most useful measure of endogenous testosterone levels. However, commonly available direct free testosterone assays are notoriously imprecise (Wells et al 2002), and it is generally agreed that free testosterone is most reliably calculated by the laboratory using the Sodergard equation if both total testosterone and sex hormone binding globulin are known (Riphagen 2000).…”