Department of Obstetrics and Gynecology, Hopital de Nyon, 1260 Nyon, Switzerland
1 To whom correspondence should be addressed. e-mail: ddeziegler{at}bluewin.ch
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New drugs in gynaecology |
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In the current issue of Human Reproduction, Mitwally and Casper (2003) report a pilot trial providing encouraging results for the possible use of letrozole in the treatment of unexplained infertility. This new report complements prior reports relating clinical experience with aromatase inhibitors in COH, alone (Mitwally and Casper, 2001
; Biljan et al., 2002
; Fischer et al., 2002
) or in combination with exogenous FSH (Mitwally and Casper, 2002
; 2003) in women suffering from chronic oligo-anovulation (Mitwally and Casper, 2001
; Fischer et al., 2002
) or ovulating spontaneously (Mitwally and Casper, 2002
; 2003; Biljan et al., 2002
). These studies provide positive proof of principle and should serve as groundwork for future prospective trials assessing the true merit of these new approaches. Let us, therefore, take the time to muse over those possible uses and how best to challenge them.
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Induction of ovulation and COH |
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The recruitment and development of small antral follicles followed by ovulation of one of them obey the dual concept of FSH threshold (Brown, 1978) and FSH window (Van Santbrink et al., 1995
; Schipper et al., 1998
). The FSH threshold implies that the levels of circulating FSH must rise above a threshold value in order to initiate the development of antral follicles.
The FSH window concept states that the duration of the FSH signal is normally of short duration because the ovarian response to FSH (E2 and inhibin B) feeds back negatively on FSH levels, which secures the single follicular dominance and ovulation. As the sensitivity of ovarian follicles to FSH increases with size, only the largest continues to grow and ultimately ovulates in the face of declining FSH levels (Schipper et al., 1998). Moreover, the largest follicle acquiring LH receptors when its size is >13 mm in diameter, the last steps of follicular maturation and growth of the dominant follicle are LH- rather than FSH-driven (Sullivan et al., 1999
).
Treatments provided in COH consist of artificially generating and/or augmenting the FSH signal and expanding the window of exposure to FSH in order to rescue a fraction or all the smaller follicles of the cohort from their predestined atresia. Typically, this is achieved by enhancing the endogenous FSH signal, providing exogenous FSH or, a combination of both.
Until now, all products that enhance the endogenous FSH signal and extend its duration belonged to the family of anti-estrogens, with clomiphene citrate (CC) remaining the lead compound. Typically, the common 5-day CC treatment (50250 mg/day, from cycle day 37) suffices for elevating FSH levels for longer than the normal FSH window. This results in COH of moderate magnitude and consequently, moderate risk. Over the years, CC has been extensively prescribed because of its great ease of use and efficacy at inducing ovulation in women whose ovulatory disorders stem from chronic oligo-anovulation of polycystic ovary syndrome (PCOS) type. Successes at inducing ovulation are classically 75%. This efficacy is tempered, however, by pregnancy rates noticeably less fulfilling (10%). CC has also been used in normally ovulating women with the intent of improving fecundity. The primary constraint limiting CCs use stems from its anti-estrogenic properties on the endometrium and cervical mucus (Massai et al., 1993
; Nakamura et al., 1997
). Recently, Elkind-Hirsh et al. (2002
) indicated that administration of exogenous E2 in the late follicular phase normalized the endometrial response to progesterone.
The availability of specific aromatase inhibitors is sending out ripples, disrupting years of habits associated with our current COH protocols. The new aromatase inhibitors offer the possibility of increasing and extending the endogenous FSH signal using a simple (CC-like) oral treatment, but without fearing the anti-estrogenic effects of CC on the endometrium.
Like CC, the aromatase inhibitors require an intact hypothalamo-pituitary axis and consequently like CC, aromatase inhibitors are likely to be inefficient in hypothalamic amenorrhoea (HA) when GnRH production is partially or completely absent and when gonadotrophin secretion is blocked by GnRH agonists.
Exogenous gonadotrophins are extensively used for COH, either alone or in combination with CC. Preliminary data indicate that aromatase inhibitors can also be used in combination with exogenous hMG/FSH with the intent of decreasing the risk of OHSS, high rank multiple pregnancy, hMG/FSH needs and ultimately, costs (Fischer et al., 2002; Mitwally and Casper, 2003
).
Thus, three possible advantages are seen in using aromatase inhibitors such as letrozole in COH: (i) simplicity of CC cycles without anti-estrogenic effects on endometrium and mucus; (ii) increased responsiveness to FSH leading to better responses in poor responders and (iii) Decreased tendency for premature luteinization.
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Questions remaining about using aromatase inhibitors in COH |
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Understandably, the first pilot trials followed a path paved by a long experience with CC: 5 days of treatment, starting on cycle day 3 of spontaneous or induced menses. The favourable results reported in anovulatory (Mitwally and Casper, 2001) and ovulatory patients (Fischer et al., 2002
) support the clinical soundness of this simple approach. Yet in certain women, FSH rises earlier or later in relation to menses with consequences on the ovarian response to letrozole that still need to be clarified. Hence, the patho-physiological groundwork remains to be done for possibly optimizing COH regimens by synchronizing letrozole treatments to the timing of the endogenous FSH signal (Roseff et al., 1989
; le Nestour et al., 1993
).
That letrozole was not continued beyond cycle day 7 in trials published to date may have been well inspired. More prolonged treatments might further hamper the E2 rise and carry negative consequences on follicular maturation, oocyte quality and the endometrium. Conversely, further extending letrozole treatment, for example until day 9, might yield a larger oocyte crop by further extending the duration of the FSH window.
A distinct objective of aromatase inhibitors is to improve the ovarian response in the so-called poor responders by lowering intra-ovarian E2, increasing intra-ovarian androgens and enhancing the sensitivity of FSH receptors (Vendola et al., 1998; Weil et al., 1999
). Here, the optimal timing of aromatase inhibitor treatment may markedly differ from what has already been tested. If the objective is to enhance the sensitivity of FSH receptors by increasing intra-ovarian androgens, the optimal timing of letrozole treatment may well be before rather than when the ovary is exposed to FSH (endogenous and/or exogenous). Hence, aromatase inhibitor treatments may possibly be more efficient for this objective if given in a priming manner when FSH levels and follicular recruitment are still inhibited by endogenous or exogenous E2 (de Ziegler et al., 1992
; 1999). Further trials are evidently needed to map out the best treatment paradigms for using letrozole in poor ovarian responders.
Dosing letrozole
The dose of letrozole used in most COH trials, 2.5 mg/day, is efficacious in breast cancer patients (Cohen et al., 2002), leading to near complete suppression of E2 production and undetectable E2 levels (Cohen et al, 2002). This dose should therefore suffice for maximizing the stimulating signal sent to the hypothalamo-pituitary axis. Yet, higher doses may more profoundly inhibit the ovarian response and thus further extend the FSH window by impairing the ovarian production of E2. The recent data, Biljan et al. (2002) support this concept, with more mature follicles seen in women who received a higher dose of letrozole (5 mg/day) despite lower levels of circulating E2. On the contrary, a lower dose of letrozole (<2.5 mg) or a decreasing one (starting with 2.5 mg/day and decreasing thereafter) could potentially permit a longer therapy (beyond day 7) with possibly, lesser needs for exogenous FSH in combined letrozole/FSH COH protocols. Here again, further trials are urgently needed.
Risk of premature LH surge and need for GnRH antagonists
An observed effect of aromatase inhibitors used in CC-like protocols is a decrease in E2 production with approximately a 50% diminution in E2/mature follicle in peripheral blood on the day of hCG administration (Mitwally and Casper 2001; 2002, 2003; Fischer et al., 2002
). As LH surge is induced by a late follicular rise in E2 levels that feeds back positively on the hypothalamo-pituitary axis (Hoff et al., 1983
), we would anticipate that letrozole delays LH elevation. Yet, actual findings may differ because the onset of LH elevation reflects a balance between the dose-dependent stimulation of E2 and an antagonizing action of follicular proteins (Danforth et al., 1987
). Thus, the lower E2 per follicle levels observed in letrozole cycles will delay the LH surge only if it is not accompanied by a parallel decline in follicular protein(s) that antagonize(s) LH elevation.
From the report of Mitwally and Casper (2003), we learn that women having an LH surge in letrozoleFSH cycles have higher E2/mature follicles (600 pmol/l) than those who did not surge (460 pmol/l), which is consistent with our expectations. Yet these E2 values were markedly lower than those seen in women who surged in CCFSH and FSH-only COHs (1193 and 1514 pmol/l, respectively). Hence, the data of Mitwally and Casper (2003
) suggest that letrozole not only lowers E2 but also the follicular protein(s) that antagonize(s) the LH surge, because the E2 levels that triggered an LH surge were lower than in non-letrozole COH.
Quality of oocytes
The worthy pregnancy rates reported in the pilot trials published to date augur well for the oocyte quality in letrozole and letrozolehMG/FSH cycles. Reports of human IVF data in letrozole cycles are however urgently needed for a definitive answer to this question.
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Other possible uses of aromatase inhibitors in gynaecology |
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The concept of add-back therapy coined for GnRH agonists may find its ultimate meaning in combining aromatase inhibitors with a hormonal preparation such as possibly, tibolone (Livial®; Organon Pharmaceuticals, Oss, The Netherlands). As with GnRH agonists, hormonal add-back will prevent the side effects of oestrogen deprivation but not interfere with the suppression of the estrogenic stimulation of endometriosis implants by the high E2 levels of follicular fluid released at the time of ovulation (as with GnRH agonists) or the local production of E2 (specific to aromatase inhibitors).
Clinical experience in endometriosis was also first gained by proof of principles (Takayama et al., 1998) before embarking in more extensive studies (Zeitoun and Bulun, 1999
). In the same spirit, we pre-treated one patient who suffered from severe recurrent uterine fibroids with letrozole 2.5 mg/day together with tibolone add-back therapy (2.5 mg/day) for 30 days prior to undertaking a repeat myomectomy. In this patient, the observation of an important reduction in fibroid size by a mean of 68% (de Ziegler D. and Brioschi P.A., unpublished observation) and the finding of good cleaving planes at the time of surgery are encouraging for undertaking further trials.
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Approval of new drugs and the practice of medicine |
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The examples of clinical situations in gynaecology where drugs have been successfully used for applications other than those warranting their release on the market, the so-called unapproved indications, are countless. Their list being too long for an exhaustive review here, we will only retrace the most salient ones in our specialty.
One example of unapproved drug use is given by hMGs and CC that were approved for inducing ovulation in anovulatory women. Yet extending their use to enhance the ovulatory signal in women who ovulate normally but in whom multiple ovulation is sought (an unapproved indication) has contributed to the IVF success story (Edwards et al. 1984). Today the new FSH preparations are approved for IVF but that approval lagged, by more than 15 years, behind the unapproved use of the parent hMG preparations in IVF (Edwards et al. 1984
) and COHIUI (Dodson et al. 1987
).
In some European countries soft gelatine capsules of micronized progesterone have been available for over 20 years, being designed and approved for oral administration (Utrogestan®; Besin-Iscovesco Pharmaceuticals). Yet oral progesterone was found inefficient at priming endometrial receptivity (Bourgain et al., 1990) because of its paucity of bioavailability linked to massive metabolism during the first liver pass (Nahoul et al., 1993
; Nahoul and de Ziegler, 1993
). The oral progesterone capsules remained on the market, but the medical community used them vaginally in infertility, years before the manufacturer sought (only in certain countries, not in the USA) and obtained approval for the vaginal route. Here again, the medical practice led the way while industry and regulatory agencies trailed far behind.
An even more extraordinary fate befell GnRH agonist products when they became available for treating prostate cancer. Reports of preliminary results of GnRH agonists in IVF in the USA (de Ziegler et al., 1987) and Europe (Neveu et al., 1987
) sufficed to spark large uses that soon became practically routine in IVF thus constituting the standard of care in the community. The GnRH agonist product most commonly used in IVF protocols, leuprolide acetate (Lupron®; TAP Pharmaceuticals, Chicago, USA) still does not hold formal FDA indication for that use. The various GnRH agonist protocols (short and long) and doses used in COH (reduced from those approved for treating prostate cancer) have nonetheless become the new standard of care, yet remaining unapproved; and we know that before courts of law, physicians are liable for offering treatments according to the standard of care in the community, not to FDA regulations, when these differ.
Some other unapproved indications bear no chance of ever being approved despite being widely adopted in gynaecology and of overt interest for patients, because the drug manufacturer has no intent to pursue these indications. The reasons for shunning new uses for existing drugs can be economical or otherwise. A good example of this is given by the prostaglandin analogue misoprostol (Cytotex®; Searle Pharmaceuticals). This drug that shares the properties of prostaglandins while remaining active orally was found to be an advantageous adjunct to the abortive anti-progesterone, mifepristone (Peyron et al., 1993). But the manufacturer of misoprostol, Searle Pharmaceuticals (now part of Pharmacia), saw no interest in being associated with this particular use of its product. Actually, Searle Pharmaceuticals actively discourage the use of misoprostol in gynaecology, including that in conjunction with mifepristone. Should this company policy deprive us from testing and using misoprostol in gynaecology, including in conjunction with mifepristone, if that appears sound?
In striving for improvement in the quality of treatments, the medical community has made a habit of finding new uses of existing drugs. Medical journals such as Human Reproduction play a crucial role in this process by screening data that become public. Yet assuring the quality of published data cannot be reduced to merely checking that manuscripts comply with sets of buzzwords such as prospective, randomized and double blind. There are studies that need to fulfil these standards and others notably, the preliminary communications and proof of principles such as reported by Mitwally and Casper (2003) that are different in nature. Journals must be shrewd at singling out the latter because they convey true innovations that are necessary groundwork for future prospective trials. Just like the practice of medicine cannot be ruled by the sets of instructions that accompany drugs in the package insert, editorial gauging of manuscripts should keep sight of the big picture. For that, editorial guiding of medical journals just like medicine is, and should remain, an art.
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Acknowledgement |
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References |
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