Androgen replacement in women the present state of the art

Another parallel between androgen replacement in men and in women is seen in the evolving technology of testosterone replacement. Hypogonadal men were initially replaced with potent oral anabolic steroids, then by substantial doses of oral MT. In high doses, however, this preparation has significant hepatic problems, including liver dysfunction (Westabay etal. 1977), hepatic adenomas (Farrell etal. 1975), and possible induction ofhepatic carcinoma (Goldfarb 1976) (see also Chapter 14). The focus of androgen replacement in men shifted to depot intramuscular testosterone enanthate (or other esters), to avoid hepatic issues from first-pass metabolism. The intramuscular depot route of administration was a significant improvement over oral synthetic androgens, but still remained an unphysiological replacement modality, with large day-to-day excursions in androgen effect noted. Attention then shifted to transdermal mechanisms to providing a relatively constant release of testosterone. Reservoir and adhesive matrix patches were developed which, while providing a physiologic replacement, were large and ungainly because of the large amount of delivered testosterone needed to effect replacement in men. The most recent advance in male testosterone replacement is the development of transcu-taneous testosterone gels, which deliver substantial amounts of testosterone in a relatively constant fashion.

The development of female androgen replacement remains several iterations behind its male counterpart. For many years the most common androgenic preparation for females (at least in North America) was a combination of oral MT and oral estrogens (usually conjugated equine estrogen or esterified estrogen), in levels as high as 5 or 10 mg/day of MT (Greenblatt et al. 1950). This has subsequently been replaced by a combination product of oral esterified estrogens 0.625 mg with MT 2.5 or 1.25 mg/day (Estratest®, or Estratest HS®). At these MT doses, which are comparatively low, there have been no cases ofhepatic problems (Simon et al. 2001). This compound is FDA approved for the treatment of climacteric symptoms recalcitrant to conventional therapy, although there is a paucity of data to support this contention. This combination has been demonstrated to have beneficial effects on bone homeostasis and sexual function. Problematically, MT is not assayable with conventional testosterone assays and thus, measurement of excessive androgenization must rest on the development of androgenic symptoms alone. At a dose of 1.25 mg/day of MT, one well controlled two-year study (Watts etal. 1995) demonstrated a 30% incidence of adverse androgenic effects (hirsutism, acne) as well as adverse effects on lipoproteins, confirmed by others in the more recent past (Lobo etal. 2003).

Clearly, oral MT is not an optimal androgen replacement modality for women. Another oral alternative, which is more available outside North America, is testosterone undecanoate, which has recently been shown to have beneficial effects on sexual function and general well-being (Floter et al. 2002). This testosterone ester is apparently absorbed by the gut lymphatic system and thus bypasses hepatic firstpass metabolism. It remains to be seen whether this oral preparation will have similar adverse lipoprotein effects.

Following the lead of male testosterone replacement, female replacement is moving away from the oral route of administration. There is an extensive experience with female preparations of depot intramuscular testosterone enanthate 150 mg monthly in conjunction with a 10 mg dose of estradiol valerate (Sherwin and Gelfand 1987). Unfortunately, this results in serum testosterone levels far above those acceptable in women, with concurrent reports of significant virilization (Urman et al. 1991). This mode of replacement has largely fallen by the wayside in recent years.

Perhaps the best-characterized method of non-oral androgen replacement in women is the testosterone pellet. This form of replacement, pioneered in both the UK and Australia, results in daily delivery of between 250 and 500 |xg of testosterone, a much closer mimic of physiology, where the ovaries produce 250 |xg/day. The 50 mg pellet is normally placed every three months, sometimes with concurrent E2 (40 mg/pellet). It is usually placed in the subcutaneous fat in the right or left lower quadrant of the abdomen, using a specially designed trochar. The delivery of testosterone with this method is well characterized, with demonstrated beneficial effects on bone and sexual function (Davis et al. 1995). Despite the fact that supraphysiologic levels of circulating testosterone are attained with the pellet, there appears to be no adverse effects on lipoproteins, in contrast to MT.

More recently, attempts have been made to replace testosterone in women with a transcutaneous gel (Androgel®, 50 mg of testosterone/packet). This preparation is made for male testosterone replacement; data in women are non-existent. Assuming a 10% nominal absorption, even a quarter packet applied per day would result in daily administration of 1,250 mg of testosterone, far in excess of the physiologic a

48 72

Fig. 17.13 Physiologic serum levels of free testosterone obtained with the investigational testosterone patch, which delivers 150 or 300 ^g of testosterone per day, equivalent to female production rates. The patch is changed twice a week and gives serum testosterone levels in the range of 40-60 ng/dl without perturbation of serum E2 or SHBG levels (Mazer 2002).

48 72

Fig. 17.13 Physiologic serum levels of free testosterone obtained with the investigational testosterone patch, which delivers 150 or 300 ^g of testosterone per day, equivalent to female production rates. The patch is changed twice a week and gives serum testosterone levels in the range of 40-60 ng/dl without perturbation of serum E2 or SHBG levels (Mazer 2002).

production rate. Consequently, serum testosterone levels with administration of this gel, even in that limited dose, are often quite higher than seen with testosterone pellets.

Perhaps the best potential delivery system is the female testosterone patch presently under development. This patch has been well characterized pharma-codynamically and is designed to deliver 150 or 300 |xg of testosterone per day, equivalent to female production rates. The patch is changed twice a week and gives serum testosterone levels in the range of 40-60 ng/dl without perturbation of serum E2 or SHBG levels. The free testosterone levels obtained are quite physiologic, as illustrated in Fig. 17.13 (Mazer 2002). It has been recently tested in a blinded, randomized, controlled trial in surgically menopausal women with decreased libido and found to modestly enhance parameters of sexual function and general well being. Further studies in natural and surgical menopause are presently underway.

As illustrated in Table 17.3, testosterone replacement regimens in women have gradually moved away from oral administration of synthetic androgens towards much more physiologic replacement with transdermal therapies. Only now are these modalities approximating the physiologic androgenic milieu of the naturally post-reproductive woman. Truly, an assessment of the efficacy of testosterone replacement in women can only be made with physiologic replacement after identification of defined deficiency states. Now such studies begin to be possible.

Table 17.3 Current testosterone replacement alternatives for women

Name

Type

Route

Dose

Daily delivery

Ovaries

testosterone

Systemic

250 ^g

250 ^g

Testes

testosterone

Systemic

7mg

7mg

Depot IM

testosterone

Systemic

200 mg Q 3 mos

2 mg

testosterone

enanthate or cypionate

Methyl-

MT

(IM)

1.25,2.5, 5,

? 50 mg/day is

testosterone

10 mg

virilizing

T pellet

testosterone

Oral

50 mg Q 3 mos

250-500 ^g

Male

testosterone

Systemic (SQ)

4, 6 mg q daily

5mg

testosterone

patch

Female

testosterone

Systemic (TD)

150, 300 ^g

testosterone

patch

testosterone gel

testosterone (?DHT)

Systemic (TD)

50, 75, 100 mg/day

? 250-500 mg

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