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Estradiol and Dydrogesterone

A Review of Their Combined Use as Hormone Replacement Therapy in Postmenopausal Women

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Abstract

Synopsis

The focus of this review is hormone replacement therapy (HRT) with continuous oral 17β-estradiol (herein referred to as estradiol) 2 mg/day plus sequential oral dydrogesterone 10 or 20 mg/day for 14 days of each 28-day cycle. According to data from nonblind trials, this regimen relieves climacteric symptoms, preserves bone mineral density (BMD) and improves the cardiovascular risk profile in postmenopausal women.

Increases in mean BMD in the lumbar spine of 2.4 to 6.4% have been reported after 2 years’ treatment. The effect on BMD of oral estradiol plus sequential dydrogesterone was similar to that achieved with transdermal estradiol plus sequential oral dydrogesterone or with oral tibolone.

Good protection against endometrial hyperplasia and cancer is provided by the dydrogesterone component. Cyclical vaginal bleeding occurs in most treatment cycles, but is generally light to moderate and the time of onset is highly predictable. Noncyclical bleeding occurs in <10% of cycles.

Mean serum high density lipoprotein-cholesterol levels are increased and low density lipoprotein-cholesterol levels are decreased during treatment with oral estradiol plus sequential dydrogesterone. Insulin resistance appears to be improved. Blood pressure and bodyweight are not generally affected to any clinically important extent. Serum homocysteine levels were reported to decrease in postmenopausal women with high pretreatment levels.

No data are available on the general tolerability profile of this regimen. However, the adverse events that most commonly led to discontinuation of treatment in clinical trials were typical of those associated with HRT, including vaginal bleeding, headache, bloating and breast tenderness. Although the risk of breast cancer has not been specifically assessed for this regimen, it is unlikely to carry a greater risk than that of other HRT regimens.

In summary, available data indicate that treatment with continuous oral estradiol plus sequential dydrogesterone is effective in relieving climacteric symptoms and preserving BMD in postmenopausal women. The dydrogesterone component provides good endometrial protection and cycle control without negating the cardiovascular benefits of estradiol. Comparisons with other standard HRT regimens and long term data (including clinical end-points) are needed. In the meantime, this regimen can be regarded as an acceptable HRT option.

Pharmacological Properties

This review concerns hormone replacement therapy (HRT) in the form of continuous oral 17β-estradiol (herein referred to as estradiol) 2 mg/day with the sequential addition of oral dydrogesterone 10 or 20 mg/day for 14 days of each 28-day cycle.

Estradiol secreted from the ovaries is the major source of estrogen in premenopausal women. Administration of oral estradiol 2 mg/day to postmenopausal women increases serum/plasma estradiol levels to those that are typical of the early to mid-follicular phase in premenopausal women, and reduces follicle-stimulating hormone and luteinising hormone levels. Similar effects are seen when estradiol is administered concomitantly with dydrogesterone.

The micronised estradiol contained in commercially available HRT preparations is well absorbed after oral administration. It is rapidly metabolised in the intestinal mucosa and liver. The primary metabolites produced are estrone and estrone sulphate, which are less active than estradiol. However, interconversion can occur; thus, estrone and estrone sulphate effectively provide an estrogen reservoir. Estrone is inactivated to catecholestrogens or estriol. Estrogen conjugates are formed during phase II metabolism. Glucuronide products are excreted in the bile or urine, while the sulphates are mainly hydrolysed and reabsorbed. Estradiol has a plasma elimination half-life (t½β) of approximately 1 hour.

Dydrogesterone is an orally active 6-dehydro retroisomer of progesterone. It has potent progestogenic and antiestrogenic activity, but no significant estro-genic, androgenic or antiandrogenic activity. When administered to pregnant rats or rabbits, it does not cause feminisation of male fetuses or masculinisation of female fetuses. The drug is not associated with glucocorticoid, anti-mineralocorticoid, anti-inflammatory or thymolytic effects.

Maximum plasma concentrations of dydrogesterone and its major metabolite 20α-dihydrodydrogesterone (DHD) are reached after 0.5 to 2.5 hours. After oral administration, 63% of a dydrogesterone dose is excreted in the urine as metabolites. The mean t½β of dydrogesterone is 5 to 7 hours and that of DHD is 14 to 17 hours.

Concomitant administration of dydrogesterone with estradiol significantly decreases the time to attain the maximum plasma estradiol concentration, but this is not likely to be clinically important. Other changes in pharmacokinetic parameters that occur with concomitant administration of the agents are generally within regulatory limits for bioequivalence with administration of the agents alone.

Therapeutic Effects

Effects on Climacteric Symptoms. In 2 noncomparative clinical studies (0.5 or 1 year’s duration), treatment with continuous oral estradiol 2 mg/day plus sequential dydrogesterone 5 to 20 mg/day improved climacteric symptoms, particularly hot flushes, night sweats and other sweating attacks. Vaginal dryness and pain on intercourse were also reduced.

Effects on Bone. Treatment of postmenopausal women with continuous oral estradiol 2 mg/day plus sequential dydrogesterone 10 mg/day preserves bone mineral density (BMD). Increases of 2.4 to 6.4% in mean BMD in the lumbar spine have been reported in 3 nonblind studies after 2 year’ treatment. Women switched from conjugated estrogens 0.625 mg/day plus sequential norgestrel 150 jug/day to oral estradiol 2 mg/day plus sequential dydrogesterone 10 mg/day had further increases in BMD, but there was no control group to indicate whether a similar increase would have occurred if the women had continued on their previous HRT regimen. In a nonblind comparative study, the increase in BMD achieved with oral estradiol 2 mg/day plus sequential dydrogesterone 10 mg/day was not significantly different from that achieved with transdermal estradiol 50 jig/day plus sequential oral dydrogesterone 10 mg/day, or oral tibolone 2.5 mg/day.

Effects on the Endometrium. In noncomparative clinical studies in postmenopausal women treated with continuous oral estradiol 2 mg/day, the addition of sequential dydrogesterone 5 to 20 mg/day produced a satisfactory endometrial response (as shown by the absence of proliferation, hyperplasia and malignancy on biopsy) in 94 to 100% of women. Endometrial hyperplasia developed in <1% of the evaluable women. Cyclical vaginal bleeding was reported to occur in 83 to 93% of treatment cycles. Bleeding lasted for an average of 5 to 6 days and was light to moderate in most women after the first few months of treatment. On average, the day of onset and duration of bleeding for each individual varied by less than 2 days between cycles. Noncyclical bleeding occurred in <10% of cycles.

Effects on the Cardiovascular Risk Profile. Dydrogesterone does not negate the beneficial effects of estradiol on lipid and lipoprotein levels. Mean serum high density lipoprotein-cholesterol levels increased by 7 to 20% and low density lipoprotein-cholesterol levels decreased by 13 to 20%, compared with baseline, in five 1- to 2-year nonblind studies in which 380 postmenopausal women received continuous oral estradiol 2 mg/day plus sequential dydrogesterone 10 mg/day. Mean serum lipoprotein (a) levels decreased by 16 to 32%. Mean serum triglyceride levels tended to increase, but this change was not statistically significant in most studies.

Oral estradiol 2 mg/day plus sequential dydrogesterone 10 mg/day had a more favourable effect overall on the lipid/lipoprotein profile than transdermal estradiol 50 jug/day plus sequential oral dydrogesterone 10 mg/day, or oral tibolone 2.5 mg/day in a nonblind comparative study.

Glucose homeostasis is not adversely affected by oral estradiol plus sequential dydrogesterone, and insulin resistance may be improved. Treatment with this regimen does not generally affect blood pressure to any clinically important extent. In postmenopausal women with raised diastolic blood pressure (>90mm Hg), treatment with estradiol plus dydrogesterone significantly reduced both diastolic and systolic blood pressure. Bodyweight is generally unchanged or only slightly increased, and the increase in abdominal fat mass associated with menopause may be prevented. No clinically important changes in clotting factors have been reported to date. Beneficial reductions in fasting serum total homocysteine levels (an independent risk factor for premature vascular disease) have been reported in postmenopausal women with elevated pretreatment levels.

Tolerability

The incidence of drug-related adverse events cannot be established for oral estradiol plus sequential dydrogesterone because clinical trials to date have not been placebo controlled and have not reported the incidences of general adverse events. Five to 19% of women participating in clinical trials discontinued treatment because of adverse events. As would be expected with an HRT regimen, the most commonly reported adverse events leading to treatment discontinuation included vaginal bleeding, headache, bloating and breast tenderness. Nausea and skin reactions are also reported to occur occasionally.

The incidence of breast cancer has not been specifically assessed in women treated with oral estradiol plus sequential dydrogesterone. The general consensus is that HRT use for <5 years is not associated with an increased risk of breast cancer, but that there may be a 25 to 50% increase in risk with long term use (i.e. >10 to 20 years).

Dosage and Administration

This information refers specifically to the use of FemostonR, which is the only commercially available preparation that provides continuous oral estradiol plus sequential dydrogesterone as a single oral daily tablet. Tablets contain estradiol 2mg alone for the first 14 days, and estradiol 2mg plus dydrogesterone 10 or 20mg for the remaining 14 days, of each 28-day cycle. Ideally, treatment should be initiated on the first day after onset of menstruation in women who are still menstruating. A 10- to 14-day course of progestogen monotherapy is recommended before initiation of treatment for women who are menstruating irregularly. Women who have not menstruated for ≥12 months can start treatment at any time.

Contraindications to the use of oral estradiol plus sequential dydrogesterone include carcinoma of the breast or endometrium or any other hormone-dependent neoplasia, acute or chronic liver disease or ongoing liver function test abnormalities, acute venous thromboembolic disorders, abnormal genital bleeding of unknown cause, pregnancy and lactation. Discontinuation of treatment should be considered in the case of trauma, illness or impending surgery that carries a risk of thrombosis. Caution is required in patients with a past history of deep vein thrombosis, thromboembolic disorders, cerebrovascular accident, present or incipient cardiac failure, epilepsy, migraine, hypertension, porphyria, haemoglobinopathies, otosclerosis or uterine leiomyomata or a history of endometriosis.

A physical examination (including a gynaecological examination) and a mam-mogram are recommended before, and periodically during, therapy. Hyper-stimulation of the endometrium in women who have received unopposed estrogen replacement therapy should be excluded before starting combination therapy.

Concomitant administration of drugs that induce liver enzymes may reduce the estrogenic effect of estradiol.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Rachel H. Foster & Julia A. Balfour

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  1. Rachel H. Foster
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  2. Julia A. Balfour
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Correspondence to Rachel H. Foster.

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Various sections of the manuscript reviewed by: D. Burch, Department of Obstetrics & Gynaecology, Royal Lancaster Infirmary, Lancaster, England; S.J. Gallacher, Department of Medicine, Southern General Hospital NHS Trust, Glasgow, Scotland; W. Hänggi, Frauenklinik, Universitätsspital Bern, Inselspital, Bern, Switzerland; T.C. Hillard, Department of Obstetrics and Gynaecology, Poole Hospital NHS Trust, Poole, England; N. Pattison, Department of Obstetrics & Gynaecology, University of Auckland, Auckland, New Zealand; I. Persson, Institutet för Medicinsk Epidemiologi, Karolinska Institutet, Stockholm, Sweden; M. J. van der Mooren, Academisch Ziekenhuis, Vrije Universiteit, Amsterdam, The Netherlands.

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Foster, R.H., Balfour, J.A. Estradiol and Dydrogesterone. Drugs & Aging 11, 309–332 (1997). https://doi.org/10.2165/00002512-199711040-00006

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