Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

Disclosures
In This Article

The Symptomatic Menopause: Pathophysiology and Tibolone Therapy

Most menopausal complaints have a complex etiology compounded by lifestyle, environmental factors, aging and, most importantly, the individual's genetic makeup. HT and drugs such as tibolone can only influence the hormonal contribution to the pathogenesis of a given menopausal symptom or condition. It is in this context that the clinical benefits (and potential side effects) of tibolone will be reviewed.

ERalpha and ERbeta have been identified in the brain: ERalpha is the predominant form in the hypothalamus and ERbeta is the predominant form in those areas of the brain concerned with cognition, memory, and motor function.[22] AR immunoreactivity has also been identified in the hypothalamus.[23] SHBG reduces the movement of testosterone across the blood brain barrier.[24]

Hot flushes have been attributed to dysfunction of various physiologic pathways, including: the hypothalamic thermoregulatory threshold to circulating estrogen; destabilization of the thermoregulatory set-point via an alteration in serotonin (5-HT) receptors in favor of the hyperthermic (5-HT2A ) vs the hypothermic (5-HT1A) receptors[25]; and a narrowed peripheral (skin) thermoneutral zone.[26] Estrogen modulates both central and peripheral thermoregulatory control, and is the gold standard against which other agents are judged for the management of hot flushes.[27]

Tibolone decreases the frequency and intensity of hot flushes in a dose-dependent manner.[28] The optimal daily dose is 2.5 mg, with significant benefit noted within 4 weeks and maximal effect at 12 weeks. After 12 weeks of treatment with tibolone 1.25 mg or greater, 86% of the subjects had either no or mild symptoms compared with 55% on placebo. Highly symptomatic women did benefit earlier (4 weeks) with tibolone 1.25 mg daily, but more subjects at this dose dropped out due to an insufficient therapeutic effect -- 10% compared with 1% in the 2.5 mg/daily tibolone group.[28]

In 2 randomized clinical trials, tibolone 2.5 mg daily was either equally effective in controlling hot flushes as the comparative continuous combined hormone therapy (CCHT) (17beta estradiol 2 mg; NETA 1 mg)[29] or slightly less so (CEE 0.625 mg; MPA 5 mg).[30] In both studies, the incidence of unwanted vaginal bleeding was significantly lower in women taking tibolone.

Mood and Cognition. Mood and other dysphoric changes may result from environmental and other nonhormonal factors.[31] Many menopausal women do experience alterations in mood and cognition that are responsive to ET. Oral estrogen may occasionally exacerbate androgen insufficiency by increasing SHBG and reducing free bioavailable testosterone.[32]

Tibolone improves mood in most but not all studies. The available data suggest that its efficacy in this regard is comparable to that achieved with ET, and greater than that seen with placebo. This is attributed to the increase in beta endorphin levels following tibolone, in both the pituitary gland and plasma.[33] It has been postulated that tibolone's effect on mood is mediated via the delta4-isomer metabolite, which can be locally synthesized in the brain by the 3beta-hydroxysteroid dehydrogenase isomerase enzyme.[17]

Postmenopausal ET improves recollection, memory, and some other aspects of cognitive function, including cognitive decline.[31] The latter is closely correlated with free bioavailable plasma E2 but not total E2 levels. Tibolone-treated women had an improvement in long-term semantic memory similar to that of matched cohorts receiving continuous combined 17beta E2 and NETA.[34] As previously noted, tibolone significantly lowers SHBG and may enhance the bioavailability of free E2 and testosterone.[20,21]

Although sexual desire and arousal normally decline with advancing age, many peri- and postmenopausal women list decreased libido as a significant quality-of-life issue. The problem may be central in origin or secondary to peripheral problems, for example, dyspareunia associated with estrogen deficiency conditions such as atrophic vaginitis and the urethral syndrome.

Hormone therapy, especially when testosterone is coadministered with estrogen, has been noted to enhance sexual desire, enjoyment, and frequency more than placebo alone.[35] Tibolone -- because of its combined estrogenic, androgenic, and SHBG-lowering activity -- is also consistently associated with improvement in sexual desire.[36] In some studies,[37] women on tibolone expressed a greater improvement in overall sexuality and sexual function when compared with women on CCHT (E2 2 mg; NETA 1 mg) or estrogen alone (transdermal 17beta E2 50 mcg). Estrogen has a direct effect on vaginal and lower urogenital tract health. Estrogen enhances pelvic blood flow and glycogenization of the vaginal epithelium. Both ERalpha and ERbeta are present in the vaginal epithelium of premenopausal women, but ERbeta is absent from vaginal wall tissue in postmenopausal women. Recently, the vaginal tissue of postmenopausal women was found to have enzymes (17beta - HSD type 2) that oxidized estradiol to the less active estrone and via estrone sulfotransferase to inactive estrone sulfate. The postmenopausal changes in estradiol receptor and enzyme activity may partly explain individual variability in the prevalence and degree of atrophic vaginitis and the nonresponse in some women to oral (as opposed to local) ET.

Tibolone improves vaginal pulse amplitude (a measure of vaginal blood flow) in postmenopausal women,[38] normalizes the vaginal maturation index, and alleviates symptoms of atrophic vaginitis.[39]

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