The efficacy of estrogen replacement therapy (estrogen replacement therapy) in relieving vasomotor and urogenital symptoms associated with the menopause is well established. Estrogen supplementation also provides additional long-term clinical benefits by reducing postmenopausal bone loss and bone fractures”, and may have beneficial effects on cardiovascular and neuro-cognitive functions.

The two most widely used forms of estrogens are conjugated equine extracts and 17β-estradiol. Currently, the oral and transdermal routes are the most commonly used in the administration of estrogen replacement therapy. Both routes are effective in relieving menopausal symptoms but are associated with a number of clinical disadvantages. Orally administered estrogen is subject to first-pass hepatic and intestinal effects and consequently this route requires high doses to be effective (1-2 mg/day), with significant intra- and interpatient variability. Although transdermal patches have circumvented some of the drawbacks of oral therapy, they present additional problems, such as wide interindividual variations in absorption rate (including the presence of poor absorbers), the loss of 4-8% of patches due to poor adhesion, and local skin reactions. Furthermore, this route provides a relatively constant delivery of hormone but at least 2-10 mg must be applied to the skin to obtain the passage of 50 µg of estradiol per day.

Despite the benefits of estrogen replacement therapy, its use is currently limited to a minority of postmenopausal women and among those treated, the average duration of treatment is no greater than 18-24 months. This problem of compliance is mainly due to undesirable and uncomfortable side-effects such as mastalgia and bleeding.

A better understanding of the mechanism of estrogen action has allowed the development of compounds with specific action according to the tissue, such as specific estrogen receptor modulators (selective estrogen receptor modulators) or tibolone, but these compounds are less effective than estrogen in alleviating climacteric symptoms or preventing postmenopausal bone loss. Progress in endocrinology has also shown that due to the complex cellular machinery, differences in the kinetics of stimulation of estrogen receptors may also result in different reactions at the tissue level. The nasal mucosa offers a large surface for absorption, which avoids first-pass intestinal and hepatic metabolism and allows a rapid increase of drug concentration in plasma, resulting in a rapid diffusion at the tissue level. Several hormones such as calcitonin and luteinizing hormone-releasing hormone (LHRH) analogs are already administered successfully using this route.

S21400 (Aerodiol ®, 17β-estradiol) with its original pharmacokinetic profile leading to transient hormonal exposure and brief stimulation of estrogen receptors, introduces a new concept in hormone replacement therapy: the ‘pulsed estrogen therapy’ (PET).

Pharmacokinetics

Aerodiol ® is an aqueous formulation of 17β- estradiol for nasal administration, which uses randomly methylated P-cyclodextrin, a novel polysaccharide excipient, which increases steroid aqueous solubility about 1000 fold. The estradiol-cyclodextrin complex easily dissociates when in contact with the nasal mucosa. Estradiol is readily absorbed whereas the cyclodextrin component is swallowed and eliminated in the faeces.

The pharmacokinetic profile of Aerodiol ® was characterized in a study including 36 postmenopausal women. It differs from that of oral or transdermally administered estradiol. The intranasal route provides a ‘pulsed’ plasma concentration profile, characterized by high, rapidly-achieved maximal plasma concentrations of estradiol, 10-30 min after administration, followed by a relatively quick return to levels of untreated postmenopausal women within 8-12 hours. For example, Cmax of estradiol after 300 µg of Aerodiol ®, administered as a single daily dose, is more than 10-fold than after transdermal and oral dosing.

Systemic exposure following Aerodiol ® treatment is dose-dependent and does not differ whether given as a single dose or as two doses split over a day. Compared with oral (2 mg/day) and transdermal (50 µg/day) estradiol, which give sustained plasma levels over the day, a similar estimated 24-hour exposure to estradiol (measured as area under curve) was provided by all three formulations.

The bioavailability of Aerodiol ® is 25%, seven times greater than that following oral administration as a consequence of the first-pass effect. This enables the administration of lower doses, and above all ensures particularly small variations in absorption.

Avoiding this first-pass metabolism, in tra nasally administered 17β-estradiol is particularly well-tolerated, and the estrone/estradiol (E1/E2) ratio is close to 1, the physiologic ratio, compared with the oral route, which has an E1/E2 ratio of 4.

Mode Of Action

Although a plateau of estradiol plasma level has been claimed to be necessary for estrogen replacement therapy efficacy, no clear link between estradiol concentration and symptoms has ever been demonstrated. There is no clear threshold value above which estradiol concentrations should be maintained and total systemic exposure to estradiol may be a more reliable index of estrogenic impregnation and activity. Indeed, the pharmacokinetic profile of Aerodiol ®, with a pulsed exposure, is consistent with the current understanding of the mechanism of action of estradiol. After estradiol enters the cell, the binding to specific nuclear receptors triggers a cascade of events leading to a delay in protein synthesis and to physiologic effects occurring 12-48 hours after tissue exposure. The PET provided by Aerodiol ® may take advantage of this inertia in biologic response. In fact, the better tolerance observed with PET could be explained by the influence of a short duration of exposure to estradiol on biologic response. Thanks to its unique pharmacokinetic profile, producing a brief stimulation of estrogens receptors, Aerodiol ® acts in a distinctive way on cofactors and alters the response of breast and uterine tissue. The beneficial clinical consequences of this different mode of action have been observed in two well-designed trials comparing Aerodiol ® 300 µg/day with oral estradiol 2 mg/ day or transdermal estradiol 50 µg/day.

Because of the pulsed pharmacokinetic profile of plasma estradiol, the efficacy of Aerodiol ® on climacteric symptoms is thought to be related to total daily hormonal exposure rather than to estradiol serum concentration. The sustained efficacy of the estradiol pulse seen with Aerodiol ® over a 24-hour dosing interval is supported by the finding that PET is effective against night sweats, despite being administered in the morning. When the treatment could be administered either in the morning or in the evening, vasomotor symptoms were similarly alleviated, regardless of time of intake.

Efficacy

Efficacy on climacteric symptoms

The efficacy of PET on climacteric symptoms has been established versus placebo and compared to that of transdermal and oral estradiol.

Two large studies including 418 and 659 postmenopausal women compared Aerodiol ® with oral estradiol and placebo, and showed that Aerodiol ® reduced postmenopausal symptoms in a dose-dependent manner as shown by the significant reduction in the Kupperman Index (KI)

The change in KI was chosen as the primary efficacy criterion because this index quantifies both the incidence and severity of postmenopausal symptoms in a weighted manner and has been extensively validated.

The 300 µg/day d osage, one spray in each nostril once daily, appeared to be at least as effective as oral estradiol 2 mg/day.

A further double-blind study including 165 patients confirmed the efficacy and safety of the PET on climacteric symptoms in highly symptomatic postmenopausal women. Aerodiol ® 300 µg/day had a faster onset of therapeutic activity than the lower dose (150 µg/day), significantly decreasing the number of moderate-to-severe vasomotor symptoms compared with placebo from the second week of treatment; Aerodiol ® 150 µg/day s ignificantly decreased symptoms from week 8 compared with placebo. No change in the efficacy of Aerodiol ® was found during episodes of infectious rhinitis.

A randomized crossover study involving 358 women compared Aerodiol ® 300 µg/day with transdermal 17β-estradiol (delivering 50 µg/day). Efficacy was compared between groups using the KI and vasomotor symptoms at week 12. The two dosage systems produced significant reductions in KI and in the occurrence of hot flushes and night sweats at week 12. Alleviation of climacteric symptoms was statistically equivalent in the two groups (p<0.001).

Efficacy on bone turnover and bone mineral density

Osteoporosis affects women after menopause and results from an accelerated rate of bone loss mainly due to the effects of estrogen deficiency on the bone remodeling system.

Estrogen supplementation, using either oral or transdermal routes, has been shown to decrease bone turnover, prevent postmenopausal bone loss, and significantly reduce fracture risk in both early and late postmenopausal women.

The effect of Aerodiol ® in normalizing bone turnover was demonstrated in randomized studies versus placebo and oral or transdermal estradiol treatment.

After 1 year of treatment with intranasal estradiol (300 µg/day), both resorption (urinary type I collagen C telopeptides) and formation (osteocalcin, serum bone alkaline phosphatase (BAP) and serum type I collagen N-terminal extension propeptide (PINP)) markers decreased, reaching the levels in premenopausal women.

The effect of Aerodiol ® in preventing postmenopausal bone loss was shown in a study versus patch, on bone mineral density (bone mineral density) measured after 1 year at the lumbar spine and hip. Dual energy X-ray absorptiometry (dual energy X-ray absorptiometry) values increased on average by 2.1% at the lumbar spine and by 1.2% at the hip without any difference between the two treatments — E2 patch 50 µg and Aerodiol ® 300 µg.

Very recent data from a 2-year randomized placebo controlled study has demonstrated the efficacy of Aerodiol ® 150 or 300 µg/day in the prevention of bone loss in early postmenopausal women at the spine, hip and forearm. At the lumbar spine, the increase in bone mineral density was 2.2 and 4% respectively with Aerodiol ® 150 µg and 300 µg/day, respectively, compared with a decrease of 3.4% in the placebo group for the patients who received the treatment over 2 years.

Safety And Tolerance

Breast tolerance and safety

In the intranasal/oral estradiol comparison trial, the incidence of mastalgia was significantly lower with Aerodiol ® 300 µg/day than with oral estradiol 2 mg/day (by a mean of 13%; 90% confidence interval (CI): -19.5 to -6.5).

Futhermore, women treated with Aerodiol ® suffered significantly less severe mastalgia than women treated with oral estrogen (1 versus 5.2%, p<0.0l).

Similarly, in the intranasal/transdermal comparative trial, moderate and severe mastalgia was less frequent in the intranasal group (7.2 versus 15.5%, p=0.02).

The mammary safety of PET has been assessed in both in vitro and in vivo studies. Results of the comparison of the in vitro effects of PET and continuous estradiol treatments on gene expression and cell proliferation indicated that the total exposure to estradiol was more important than the total concentration in accounting for the effect of estrogen on gene expression and cell proliferation. Compared with untreated controls, there were no substantial differences between pulsed and continuous estradiol treatment for the same 24-hour period of exposure in: the extent and time-course of genomic responses studied up to 24 hours; the extent of the dose-dependent proliferation of human estrogen-receptor-positive cancer cells and in the proliferation of normal human breast cells.

Mammary safety of PET was studied in vivo in a well-recognized experimental model using mammary tumors chemically induced by 7,12-dimethylbenz[a]anthracene (DMBA) in the rat. Potency of both continuous and pulsed estrogen therapy was assessed by the measurements of uterus weight. Results demonstrated that PET led to a significantly lower tumor incidence (p=0.05) and to lower mammary tumor development rates than continuous estrogen therapy.

Endometrial safety

Endometrial safety was also assessed during the development of S21400 (Aerodiol ®). There were no cases of atypia, hyperplasia or cancer in 311 women treated for 12 months with Aerodiol ® with various progestogens administered at recommended doses (medroxyprogesterone acetate, dydrogesterone, chlormadinone acetate, promegestone and natural progesterone). The endometrium was mostly atrophic (34%) or secretory (39%) leading to an adequate progestational response rate of 97%.

Nasal tolerance and saf ety

Results from studies comparing the acceptability of Aerodiol ® with that of placebo and oral estradiol control groups confirm that Aerodiol ® was well-tolerated locally. The most common effects are minor local symptoms, such as prickling or sneezing lasting only a few minutes after administration and persisting for only a few weeks. Their frequency decreases during treatment, falling to 9% after 1 year. Ear, nose and throat examinations, including rhinoscopy and mucociliary clearance, systematically performed on 304 women after 3 and 6 months of treatment and in cases of premature withdrawal of treatment due to local symptoms (rhinoscopy only) did not show any major alterations of the nasal mucosa.

Overall Tolerability

No clinically relevant changes were observed in laboratory parameters, body weight, or diastolic or systolic blood pressure with S21400 (Aerodiol ®).

Dosage And Administration

The recommended initial dosage of Aerodiol ® is one spray in each nostril per day (300 Hg/day) and can be given cyclically 25-28 days/month or continuously every day. Oral progestogen at recommended doses has to be added for non-hysterectomized women for at least 12 days of each cycle. If there are signs of hyper- or hypoestrogenization, the usual dosage of 300 µg/day can be decreased to 150 µg/day (one spray per day) or increased to up to 600 µg/day (four sprays per day). In that case a delay of 30 minutes should be observed between each administration in the same nostril.

Combined sequential regimens of estrogen and progestin are associated with cyclic withdrawal bleeding, often poorly tolerated by women over 50 years old. This can be avoided by the use of continuous combined hormone replacement therapy (ccHRT), which may result in greater compliance with therapy. Women on sequential Aerodiol ® and progestogen could be switched to a continuous combined regimen after 1 year. They should be informed that initial breakthrough bleeding usually settles after 3-6 months of usage.

Intranasal estradiol retains its efficacy in patients with blocked or streaming noses. If the nasal passages are severely blocked, intranasal estradiol can be administered temporarily buccally (at twice the intranasal dosage), by spraying and rubbing the intranasal estradiol on to the gums.

Conclusions

S21400 (Aerodiol ®) introduces a brand new concept in hormone replacement therapy: pulsed estrogen therapy. PET, a brief once-daily exposure of target tissues to a small dose of natural 17β-estradiol, produces high therapeutic efficacy over 24 hours, thus avoiding continuously elevated plasma estrogen levels. Data collected during the clinical development have shown that Aerodiol ® provides excellent clinical efficacy in relieving climacteric symptoms and in the prevention of postmenopausal bone loss. It is at least as effective as continuous estrogen therapies, but is better tolerated than oral and transdermal treatments with significantly less frequent mastalgia and a lower incidence of uterine bleeding. Initial breast safety data are encouraging.

Aerodiol ®, the first PET, increases acceptability and compliance, offering a new approach to hormone replacement therapy to physicians and women.

Selections from the book: “The Management of the Menopause” (2003).

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