Centchroman is a novel, nonsteroidal chemical that is marketed in India, where it was
developed, as a once-a-week contraceptive pill. Based on limited studies, Centchroman
appears to be a highly effective, safe and easy to use oral contraceptive. Also, because
it is free of the side effects commonly associated with oral contraceptives containing
both estrogen and progestin, Centchroman could become an extremely important new oral
contraceptive. In India, Centchroman is marketed under the trade names Centron® and
Saheli®.
Chemical Structure
The chemical structure of Centchroman is depicted in Figure 1.
Figure 1. Structural Formula
Structurally it is the hydrochloride salt of a chroman derivative that is
a colorless, crystalline compound with a molecular weight of 493.5. Its melting point is
163°C. It is stable under normal conditions (Nityanand et al 1990). Because of its
aromatic ring structure, it is highly lipophilic, and dissolves most readily in nonpolar
solvents such as hexane and ether. This is a physical characteristic shared by most sex
steroids.
How Does Centchroman Prevent
Pregnancy
In animal studies with rats and mice, a single dose of Centchroman (1.25 mg/kg)
prevented 100% of pregnancies when given 1, 2 or 3 days postcoitally (Kamboj et al 1971).
Similar findings were reported in rhesus monkeys given a single dose of 2.5 mg/kg within
24 hours of mating (Kamboj 1977).
In humans Centchroman behaves as a potent antiestrogen but also has weak estrogenic and
antiprogestational actions. These effects are similar to those of the ovulation-inducing
drug, clomiphene citrate. For example, it has been reported by Roy et al (1976) that
Centchroman can induce ovulation when given chronically in daily doses of 15, 30 or
60 mg for 10 to 20 days to women who are not ovulating. When only a single dose
(30–60 mg) is given weekly to healthy, ovulating women for contraception, however,
Centchroman does not alter basal or peak gonadotropin (FSH/LH) secretion or production of
estradiol and progesterone (Roy et al 1976). In addition, it does not block ovulation. At
this dosage and frequency of administration the only remaining reproductive endocrine
effects of the drug are:
- to slightly increase the transport of the zygote through the oviducts,
- to accelerate blastocyst formation, and
- to suppress uterine endometrial proliferation and decidualization.
Apparently, the combined effect of these actions is capable of creating sufficient
asynchrony between the developing zygote and endometrial maturation to prevent
implantation (Singh et al 1986).
Effectiveness of
Centchroman as a Contraceptive Pill
Contraceptive effectiveness data from two multicenter, Phase III clinical trials are
presented in Tables 1 and 2. In the first trial (Table
1), 898 women took a single 30 mg dose of Centchroman weekly for a total pregnancy
exposure of 13,483 months (12,085 actual menstrual cycles). The pregnancy rate as
calculated by the Pearl Index (PI) was 2.84. The only reported adverse effect was delayed
menstruation (bleeding interval > 45 days), which occurred in 8% of the users (Puri et
al 1988).
Table 1. Effectiveness of Centchroman
| STUDY DESIGN |
| Phase III clinical trial |
10 centers |
| Schedule |
weekly |
| Dose of Centchroman |
30 mg |
| Number of women |
898 |
| Duration of use |
13,483 months |
| Pregnancy rate (Pearl Index) |
2.84 |
Source: Centchroman 1991.
In the second Phase III trial (Table 2) the
schedule for administering the Centchroman was changed in an attempt to improve the
effectiveness of the method. In this study women initiallytook a single 30 mg pill
twice-a-week for 3 months, and thereafter they took a single 30-mg pill once-a-week.
Table 2. Effectiveness of Centchroman
| STUDY DESIGN |
| Phase III clinical trial |
11 centers |
| Schedule |
twice weekly/weekly |
| Dose of Centchroman |
30 mg twice weekly (3 months) 30 mg
weekly thereafter |
| Number of women |
376 |
| Duration of use |
3,959 months |
| Pregnancy rate (Pearl Index) |
183 |
| Cumulative pregnancy rate at 12 months |
1.63 ± 0.74 |
Source: Centchroman 1991.
Three hundred and seventy-six women enrolled in 11 centers participated in this study
and had a total pregnancy exposure of 3,959 months (3,397 actual menstrual cycles). Here
the pregnancy rate calculated by the Pearl Index was only 1.83 per woman-years, and the
cumulative pregnancy rate based on life table analysis at 12 months was 1.63 (Centchroman
1991). Compared with the typical use effectiveness rate for combined oral contraceptives
(COC), which ranges from 0.1 to eight (Trussell et al 1990), the rate for Centchroman in
this second clinical trial is very encouraging. Again, delayed menstruation was the only
adverse effect reported and occurred in only 6% of cycles compared to the 8% in the first
trial (Centchroman 1991).
Return of Fertility After
Using Centchroman
Of the 37 women who withdrew from the second trial in order to become pregnant, 23
(62%) conceived within 6 months of stopping Centchroman, 10 more during the next 6 months
and 3 after 12 months. All told, 36 women (97%) conceived, and all reportedly delivered a
normal baby. The only woman who did not become pregnant was reported to be 39 years old
with five living children (Centchroman 1991).
Teratogenicity of Centchroman
Only limited data were obtained from both clinical trials to document user failures.
Among the 45 infants (one set of twins) born to 44 mothers, no congenital abnormalities
were reported and their growth and development through 6 months was reported to be normal
(Centchroman 1991; Puri 1988). These findings coupled with the teratogenicity data from
animals studies would suggest that Centchroman is not harmful to mothers or their babies.
As reported in the animal studies, oral administration of Centchroman during organogenesis
to pregnant rats, at doses ranging from 25 to 100 mg/kg, and 20 to 80 mg/kg in pregnant
rabbits did not have anydeleterious effects on either the mother or the litters. In
addition, histologically there was no evidence of any skeletal or visceral malformations
in the fetuses (Centchroman 1977).
Finally, in neither clinical trial were continuation rate data reported and, because of
the small size of both studies—only 1,274 total users—care must be taken in
interpreting the results. Clearly what is needed is a large, multicenter study comparing
Centchroman with at least COC users and perhaps injectable or IUD users as well.
Pharmacokinetics Studies
In 330 women with over 2 years of weekly or biweekly ingestion of Centchroman,
hematologic, liver and other organ function were all within normal limits. At therapeutic
doses, the drug had no measurable effect on cholesterol, triglycerides or HDL and did not
cause any effect on platelet aggregability (Vaidya et al 1977). Also no abnormality of the
human female genital tract (vagina, cervix, uterus and ovaries) was observed, and
ultrasonographic monitoring of the ovaries in 161 women revealed no abnormal change in
their size or volume (Nityanand et al 1990).
Summary
Based on the limited data available for review, this novel nonsteroidal chemical may
become an extremely important, new oral contraceptive. To date, all evidence indicates
that Centchroman:
- is highly effective (only 1.63 pregnancies per 100 women during the first year), safe
and easy to use (requires no pelvic examination prior to starting the drug);
- is free from side effects commonly associated with steroidal oral contraceptives like
nausea, vomiting, weight gain and dizziness;
- does not delay return of fertility;
- has only one adverse effect, delayed menses, but this occurs in less than 10% of cycles
and with good counseling should not decrease compliance and continuation rates;
- maintains normal ovulatory cycles because the low dose and weekly or biweekly
administration schedule minimizes any effect on the hypothalamic-pituitary-ovarian axis;
- has no apparent adverse effects on endocrine, hematologic, liver and lipid function and,
to date, has not been associated with any serious complications (heart attack, stroke or
blood clots) that would limit its use by most women; and
- does not appear to cause congenital anomalies in infants born because of user failure.
References
Centchroman. 1977. Influence of Centchroman on prenatal development in mice and
rabbits. Indian J Exp Biol 15:1183–1184.
Centchroman. 1991. Multicentric trial with biweekly cum weekly dose. Central Drug
Research Institute.
Kamboj VP et al. 1971. Antifertility activity of 3.4-trans-2., -dimethyl-3
phenyl-4-(beta-pyrrolidinoethoxy)-phenyl-7-metoxychroman. Indian J Exp Biol 9:103–104.
Kamboj VP et al. 1977. Biological profile of Centchroman—A new post-coital
contraceptive Indian J Exp Biol 15:1144–1150.
Nityanand S et al. 1990. Clinical evaluation of Centchroman: a new oral contraceptive,
in Hormone Antagonists for Fertility Regulation. Puri CP and Van Look, PFA (eds).
ISSRF: Bombay, India.
Paliwal JK et al. 1989. High performance liquid chromatographic (HPLC) determination of
Centchroman in human serum and application to single-dose pharmacokinetics. Pharmaceut
Res 6:1048–1051.
Puri V et al. 1988. Results of multicentric trial of Centchroman, in Pharmacology
for Health in Asia. Dhawan, BN et al (eds). Allied Publishers: New Delhi, India.
Roy S et al. 1976. Induction of ovulation in the human with Centchroman: a preliminary
report. Fertil and Steril 27(9): 1108–1110.
Trussell J et al. 1990. A guide to interpreting contraceptive efficacy studies. Obstetrics
and Gynecology 76: 558–567.
Vaidya R et al. 1977. Activity profile of Centchroman in healthy female volunteers. Indian
J Exp Biol 15:1173–1176.
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