Prof. John Studd. Women's Health Clinic
clinical gynaecologist
clinical gynaecologist

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Guidelines for Hormone
Implantation

The simple technique described by Thom and Studd in 1980 (1) should be used which is a clinic procedure under local anaesthetic using a small 5 mm incision and no suture. The trocar should be inserted to its full length into the fat of the abdominal wall or upper outer quadrant of the buttock. The muscle and old surgical scars must be avoided as this causes pain and bleeding. As the testosterone pellet is occasionally rejected, this should be inserted after (i.e. on top of) the oestradiol pellet. The procedure is usually repeated every six months.

Oestradiol implants can be used in 25 mg, 50 mg and 75 mg doses. 100 mg dose should never be used as the initial starting dose. Testosterone can be added and is available as 25 mg, 50 mg and 100 mg pellets.

Indications for use
Implants are, for many women, a very convenient way of taking HRT. There is better continuation with good symptomatic improvement due to the higher plasma oestradiol levels obtained than from oral preparations. It is particularly convenient for women after hysterectomy and for those women who have also had bilateral oophorectomy and need testosterone. Implants of oestradiol 50 mg and testosterone 100 mg are the most effective method for these patients and a 10-year continuation rate of more than 85% can be achieved.

Women with hormone responsive depression, loss of libido, loss of energy, loss of bone density and an inadequate response to oral oestrogens should be considered for implant therapy even though they may still have a uterus.

As the incremental increase in bone density is proportional to the plasma oestradiol level obtained after hormone therapy, oestradiol implants are the most effective way of increasing bone density. This is particularly true in older women with low bone density and the lowest dose of oestradiol ie 25 mg, should be used. The increase in the lumbar spine bone density of the younger postmenopausal woman after one year is 4% with a 25 mg implant, 5% with 50 mgs and 7% with the 75 mg oestradiol implant. The mean plasma oestradiol levels for these doses at one year is 320 pmol/l, 360 pmol/l and 520 pmol/l respectively.(2)

It is usual for the climacteric symptoms to improve within two weeks and to begin to return at approximately five months although in some patients the symptoms may return as early as three months or as late as eighteen months after the last implantation.

The relationship of plasma oestradiol levels and symptoms is complex. There is good evidence that a plasma oestradiol level of 300 pmol/l is necessary to ensure the improvement of bone density in nearly all women.(2) There is also evidence that plasma oestradiol levels of 800 pmol/l may be necessary for the improvement of depression in the climacteric woman or in pre-menstrual depression or in post-natal depression.(3) It is in these depressed patients that we can justify using the higher starting dose of 75 mg of oestradiol.

All patients with a uterus must of course have the protection of a progestogen. This can be done by oral progestogen for the first 10 or 12 days of each calendar month or by the insertion of a Mirena coil. The combination of oestradiol implants with or without testosterone together with a Mirena coil is a good regimen for women with hormone responsive depression and in those women with a history of unsatisfactory oral transdermal therapy that may have been complicated by the PMS type symptoms of progestogen intolerance.

Routine Surveillance

Mammography should be performed according to National Guidelines although some patients may wish to have more frequent reassurance. A transvaginal ultrasound scan of the pelvis should be performed if and when indicated.

There is no reason for routine plasma oestradiol measurements before a reimplantation if the patient is on an appropriate dose and the intervals between reimplantation are not less than 6 months. Conversely, if patients come back for repeat implants more frequently than every 5 months, or are having repeated implants of more than 50 mgs, the plasma oestradiol should be measured because the clinical response is inappropriate. Similarly, if apparently oestrogen responsive symptoms are not suppressed there will be a need for measurement of plasma oestradiol levels. In these cases, oestradiol levels should be measure every year but it is not necessary to make these measurements before each implant.

Tachyphylaxis

Too frequent implantation or too high doses of oestrogen leads to supra-physiological oestradiol levels and the recurrence of symptoms even at these high levels.(4) It is not easy to treat and it must be said that the secret is to avoid it happening by using the correct dose of hormones in the first place. The normal range of plasma oestradiol during the ovarian cycle is between 100-1500 pmol/l but plasma oestradiol levels greatly exceeding these values can be found in patients with tachyphylaxis.

The symptoms that these women suffer are real, not imaginary although they are not always typical menopausal symptoms.(5) In fact many of these women have a history of psychological disorders.(6) Because of this potential problem, the implants should be used with caution in women with a known history of chronic anxiety or stress disorders. The recurrence of apparently oestrogen deficiency symptoms at these levels are no doubt due to the change of oestradiol levels from "very high" to "high" and they become accustomed to a higher threshold. These high levels may be unnecessary and avoidable but sometimes women with convincing oestrogen responsive depression need even higher oestradiol levels but there is little or no evidence that they are harmful.

There would rarely be an indication for repeat implant if the oestradiol levels are above 1000 pmol but sometimes women with convincing oestrogen responsive depression need even higher oestradiol levels and a repeat implant should not, after very careful consideration, be prohibited.(3) It is wrong to deny women further oestrogen therapy thus making them suffer many months or years of symptoms, particularly depression, anxiety and loss of energy. They can be given a low dose oestradiol implant of 25 mg usually with testosterone 100 mg, with explanation that this must last for six months. Alternatively this period can be covered by patches, gel or oral therapy. The oestradiol levels will fall to more acceptable levels within one or two years without the patient suffering greatly from oestrogen deficiency symptoms.(7) The "cold turkey" treatment is not acceptable as profound depression is very common in these patients denied further oestrogen therapy.

Prolonged duration of implants

Although symptoms return at six months, the implant is usually still active and producing pre-menopausal hormone levels up to two years after the last implant. This may be seen as a huge advantage and no doubt is responsible for the usual beneficial effect upon wellbeing and bone density. It can also be a disadvantage for women who change their mind and want to discontinue implants and bleeding. They need progestogen courses for about two years after the implant or until the progestogen no longer produces a withdrawal bleed. The increasing use of the Mirena intra-uterine system has solved many of these problems, although it is not yet licensed for this indication. The patient should be warned that this is a potential problem.

If response to therapy is considered, oestrogen implants are the most efficient way of delivering oestrogens. This does not mean they are necessarily first choice or the best treatment for an individual patient but this route does have a particular place in women after hysterectomy, women with libido problems or depression or women with severe osteoporosis and those who have suffered side-effects with oral therapy.

1.(1) Thom, M., Studd, JWW., (1980) Procedures in Practice:Hormone Implantation. Brit. M. J. I, 648-50.
2.Studd, J., Holland, EPN., Leather A., Smith, R. (1994) The dose-response of percutaneous oestradiol implants on the skeletons of postmenopausal women. BJOG 101, 7878-791
3.Panay N, Studd, J W, The Psychotherapeutic effects of oestrogens Gynaecol, endocrinol, 1998, 12, 353-65.
4.Ganger K, Whitehead M I. Hormone implants and tachyphylaxis. BritishJ Obstets Gynaecol 1991 - 98 - 607-9.
5.Brincat M, Magos A, Studd J W, Cardozo L D Subcutaneous Hormone Implants for the Control of Climacteric Symptoms. A prospective study.
6.Pearce, J., Horton, K., Blake, F., Barlow DH. (1997) Psychological effect of continuation versus discontinuation of HRT by oestrogen implants; a placebo-controlled study. J. Psychosomat. Res. 42,177-186.
7.Garnett, T., Studd, JWW, Henderson, AF., Watson, NR., Savvas, M., Leather, A. (1990) Hormone implants and tachyphylaxis. BJOG 97,917-921

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