Download should treatment with clomiphene citrate continue?

Should Treatment with Clomiphene Continue?
H.J. Out
Organon Laboratories, Cambridge, United Kingdom
Introduction
Forty years have passed now after the first description of a ”chemically” induced ovulation with
clomiphene citrate (CC, Greenblatt, 1961). This created great enthousiasm because it made it
possible to induce follicular development without using pituitary extracts. Since then, its
popularity has increased tremendously. In the United States, the number of prescriptions for CC
has increased from 390,000 in 1973 to 731,000 in 1991 or 14.6 cycles per thousand women
between 15 and 44 years of age, which accounts for the largest proportion of the market of
fertility drugs during this time period (Wysowski, 1993).
Disadvantages of Clomiphene Citrate
The cause for the popularity of this drug is obvious: it is easy to administer (orally), no close
monitoring is needed, it is highly effective in the induction of ovulation and, above all, it is
cheap. However, based on a recent review of the latest literature on CC (Out and Coelingh
Bennink, 1998), we would like to challenge the role of this compound in the next decade.
We see the following disadvantages of CC:
1. The compound is a mixture of two “isomers”, Zu and En, with different pharmacokinetic and
-dynamic profiles. The active isomer is the En isomer, and the relatively inactive Zu isomer
has a very long half-life. As a result, the half-life of CC is estimated to be between 5 and 7
days and, therefore, accumulation of CC takes places every 28-40 days when a trial of CC is
given.
2. There are no published data on the multiple-dose pharmacokinetics of CC. In view of
experiences with the structurally related compound diethylstilbestrol (DES), this is amazing.
The assessment of the impact of chemical agents circulating during early embryonic life is a
major issue nowadays for pharmaceutical companies active in the field of reproductive
medicines. This has never been investigated for CC. It is therefore highly unlikely that CC
would be allowed to enter the market if registration would be sought for nowadays.
3. Because many couples successfully have been treated the last 30 years with CC and therefore
extensive experience has been gained, its use is considered to be safe. However, this
conclusion is empirical, rather than the result of properly designed follow-up studies
(Greenland et al., 1995). Negative side-effects therefore should not be excluded, especially in
view of the extensive teratogenic and toxic effects that have been described in animals. In
addition, because CC displays a tendency for prolonged nuclear receptor occupancy, in
contrast to native oestrogens which are known to clear the cell within 24 hours, a progressive
nuclear accumulation upon repetitive administration may occur, possibly leading to lingering
blastocystotoxic or teratogenic effects.
4. Its mechanism of action is unclear and is a mixture of effects on the hypothalamus, pituitary
and the ovaries. The following variables can be mentioned that will influence the final
activity of CC: (1) the En/Zu-isomer ratio in the tablet, (2) the En/Zu- isomer ratio in the
circulation, (3) individual metabolism, (4) route of administration, (5) dosage regimen, (6)
administration period relative to the cycle, if present, (7) cause of anovulation, (8) estrogenic
state of the patient, (9) carry-over effects from previous CC cycle(s), and, (10) effects of
unknown metabolites.
15 Out
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5. There is a well-known discrepancy between the high ovulation rates after CC treatment, and a
relatively low pregnancy rate. The following causes for this phenomenon have been described
in (recent) literature: (1) Anti-estrogenic effects on the endometrium (2) anti-estrogenic
effects on the cervical mucus, (3) decrease of uterine blood flow, (4) impairment of placental
protein 14 synthesis, (5) subclinical pregnancy loss, (6) effect on tubal transport, (7)
detrimental effects on oocyte.
Alternative Strategies
It is generally agreed upon that the therapeutic effect of CC in anovulatory patients is related to
the increase of circulating gonadotropins, especially FSH (Glasier, 1990). Usually, an initial rise
in the early follicular phase is followed by a decrease in the midfollicular phase. However, the
LH rise after CC treatment is not needed and might contribute to low quality eggs and increased
abortion rates (Balen et al., 1993). The overall increase of FSH levels during CC treatment seems
to be 50-60% from baseline (Polson et al., 1989; Butzow et al., 1995).
If the goal of CC administration is to temporarily increase FSH levels, it seems that from a
pharmacological point of view, it makes much more sense to administer recombinant FSH,
nearly 100% pure and indistinguishable from pituitary FSH, instead of using a racemic mixture
with accumulating isomers and an unknown mechanism of action. The impopularity of
gonadotropins in the treatment of WHO group II women as experienced in the sixties, is not
justified nowadays using the low-dose protocols. In three recently reported studies, ovulation
rates were between 72 and 95%, and pregnancy rates between 40 and 48% (Homburg et al.,
1995; Balasch et al., 1996; White et al., 1996). In these studies, a multiple pregnancy rate of 015% was observed in more than 1500 cycles, and only one (!) case of severe OHSS. It should
therefore be questioned whether clomiphene-resistance always should be a condition prior to
proceed to gonadotropin treatment.
In addition, it might be speculated that a single-shot of 200-300 IU of recombinant FSH on day 3,
4, or 5 after a spontaneous or progestagen withdrawal bleeding will do the same job as CC. With
baseline FSH levels between 0.11 and 1.63 IU/l, the mean peak FSH concentrations after a
single-dose of 300 IU of recombinant FSH in eight gonadotropin-deficient volunteers was 4.3
IU/l (SD 1.7) with a Tmax of 27 ± 5 hours (Mannaerts et al., 1993). In most women, the return to
baseline values was seen after 11 days. The 50-60% increase from baseline of FSH levels as seen
in PCO patients after the administration of 100-150 mg of CC can therefore easily be achieved
and it can be speculated that a single administration of exogenous FSH might induce the
development of one or more ovulatory follicles.
Conclusion
Current ideas on the future of ovarian stimulation emphasize the need for optimalization rather
than maximalization. In other words, lower number of eggs but with a higher quality will
minimize agressive and potentially detrimental stimulation regimens (Edwards et al., 1997).
In our view, lowering the dosage presentations of gonadotropins (from 75 to 50 IU ampoules)
and the introduction of GnRH-antagonists as ganirelix (Orgalutran) will contribute to this
concept. We fail to see how CC pharmacologically will contribute to a more rational approach of
hormonal treatment in the infertile couple and to optimalization and simplification of treatment
protocols. Its wanted action, a transient FSH rise, can easily and more reliably be achieved using
exogenous (recombinant) FSH. Clomiphene citrate might cost less, but that does not make it the
best treatment.
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