In 2002 the WHI study was prematurely stopped when it confirmed what had been apparent for some time: taking conjugated estrogens plus medroxyprogesterone acetate (CLIMOPAX) increases the risk of heart attacks, strokes, venous thromboembolism and breast cancer (a-t 2002; 33: 81-3). The hormones not only promote the development of breast cancer but at the same time also delay diagnosis, probably due to higher radiodensity of the breast tissue during use (a-t 2003; 34: 72). One year after publication of the WHI study, the Million Women Study, a large cohort study, confirmed the increased breast cancer risk. According to this study, the greatest risk exists when estrogen-progestins combinations are taken. There is no difference between the various progestins. In addition a trend to increased breast cancer mortality is also documented for the first time (a-t 2003; 34: 80).

Now, again one year later, Schering AG obviously regards the time as ripe for marketing ANGELIQ, a new combination for hormone replacement therapy and osteoporosis prevention. The introduction, originally planned for last autumn, was postponed because the company did not want to introduce the drug at a time when potential users had been alarmed by the WHI results (1). ANGELIQ contains 1 mg estradiol plus 2 mg drospirenone, a Schering progestin derived from the aldosterone antagonist spironolactone (ALDACTONE etc.) that is insufficiently tested and which is also contained in the contraceptives PETIBELLE and YASMIN (a-t 2000; 31: 103-4 and 2002; 33: 54).

"Hormone treatment should be performed with the lowest possible dosage", proclaims Schering in an "Adviser" for patients (2). This sounds good but does not apply for ANGELIQ in Germany: in two randomised placebo-controlled studies, in which the effect of 1 mg, 2 mg or 3 mg drospirenone, in each case in combination with 1 mg estradiol, on the frequency of hot flushes and bone density was investigated, all three progestin dosages were superior to the placebo but did not differ from one another (3,4). In the USA, where licensing of the hormone combination had initially been refused in October 2002 under the impression of the results of the WHI study (5), ANGELIQ will now contain 0.5 mg drospirenone according to the FDA letter announcing licensing - only a quarter of the progestin quantity here (6). This dose is said to be sufficient to protect the endometrium (7).

All typical adverse effects of hormone replacement therapy are to be expected with ANGELIQ. However, comparative studies with other HRT products have not been published. Breakthrough bleeding and spotting occur in 59% of users in the first three months, and in 27% in the tenth to twelfth month. About one woman in five complains of breast pain (8). This is the commonest reason for stopping use in phase 3 studies (19.3%), followed by vaginal bleeding (10%) and headache (3.4%) (9). As with other HRT combinations, an increased risk of breast cancer and cardiovascular complications has to be considered as long as suitable long-term studies did not prove the contrary.

Taking ANGELIQ for three months costs 59 Euro and thus almost twice as much as a low-dose hormone combination such as ACTIVELLE (1 mg estradiol plus 0.5 mg norethisterone acetate; 32 Euro).

	With ANGELIQ, Schering is marketing a new hormone combination for postmenopausal women that contains drospirenone, a insufficently tested progestin combined with estradiol.
	The German variant containing 2 mg drospirenone is a high-dose preparation compared with the ANGELIQ planned for the USA, which contains only 0.5 mg drospirenone.
	Hormones should as far as possible not be used in treating climacteric symptoms. Because of major risks such as the increased risk of breast cancer, heart attack and thromboembolism. They should be used for as short as possible and in the lowest possible dosage in case of rare therapeutic need. Combinations with better tested progestins such as norethisterone acetate (in ACTIVELLE etc.) should be preferred.

(R = randomised study)

1

Scrip 2004; No. 2985: 20

2

Schering: ANGELIQ patient brochure, printing code 51001006/8520

3

SCHÜRMANN, R. et al.: Climacteric 2004; 7: 189-96

4

WARMING, L. et al.: Climacteric 2004; 7: 103-11

5

Scrip 2002; No. 2792: 19

6

Schering: Press release of 15th Sept. 2004

7

Scrip 2004; No. 2989: 19

8

Schering: ANGELIQ SPC, May 2004

9

Schering: ANGELIQ Product information, July 2004

WHI = Women's Health Initiative