ICMR BULLETIN VOL. 28-No.-10-OCTOBER-1998

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Title
ICMR BULLETIN VOL. 28-No.-10-OCTOBER-1998
extracted text
ISSN 0377-4910

® Vol. 28, No. 10

October, 1998

CONTRACEPTIVE RESEARCH AND DEVELOPMENT DURING THE
FIFTY YEARS OF INDEPENDENCE IN INDIA:
ACHIEVEMENTS AND DESIRED GOAL
The Family Welfare Programme of India is to be
complimented for substantially reducing the burden of
reproductive ill-health of people during the last fifty years.
Marked reduction in the infant and maternal mortality
rates, decrease in the total fertility rate and increase in
life expectancy for both men and women are testimo­
nies to the achievements of the Programme. However,
in spite of these achievements we are far away from the
desired goals. The population of India has increased by.
over 600 million people since independence. Moreover,
' there is a visible large inbuilt momentum for continued
growth of the population over the next several decades
as over 45% of the women in India today are in the re­
productive age group of 15-44 years. At the present growth
rate of a little over 2%, the population will cross the one
billion mark by the turn of the century. The coming years
are thus very crucial for the survival of the people of
India. The actions taken now to improve the reproduc­
tive health (RH) of people and particularly to control
population growth will determine the quality of life in
the years to come.
Numerous factors have contributed to the increase
in population. Some of these are low age at marriage;
unmet needs for contraception including poor access to
health facilities; low status of women; low female literacy;
perceiving children as assets for old age and not taking

risk due to high infant mortality. Low contraceptive
prevalence was probably the most killing factor responsible
for high population growth and this in turn had a bearing
on other components of RH such as high incidence of
unwanted pregnancies and induced abortions, high infant
and maternal mortality and increasing incidence of
sexually transmitted diseases (STDs).

The Programme of Action of the International Con­
ference on Population and Development (ICPD) held in
Cairo in 1994 has acknowledged the advances made in
developing a greater range of safe and effective modem
contraceptive technologies and has also emphasized that
many people, particularly men, still cannot find a family
planning method that suits their needs. The ICPD has
emphasized the need for a wider range of safe and effec­
tive methods.
Indian scientists have played a commendable role in
the development of contraceptive technologies over the
last five decades. The Indian Council of Medical Research
(ICMR) and some other national agencies including the
Department of Biotechnology, Department of Science
and Technology and Council of Scientific and Industrial
Research have provided enormous technical and financial
inputs for the success of research programmes in these
areas.

Division of Publication & Information, ICMR, New Delhi - 110029

This article is a tribute to the Indian scientists for
their endeavours during the post independence era to
develop contraceptive technologies to improve the RH
of people. The article also addresses some of the de­
sired changes in the expression and perception of needs
for fertility regulating technologies, especially in rela­
tion to the new concepts of RH expressed at the ICPD
and the Fourth World Conference on Women held in
Beijing.
ACHIEVEMENTS

The research contributions by Indian scientists have
led to evaluating and improving the safety, efficacy and
acceptability of a number of contraceptive methods, and
the development of new methods of fertility regulation.
In addition, the studies elucidating the intricate mecha­
nisms regulating fertility and the new hypothesis pro­
posed by them have provided the fundamental base for
the development of contraceptive technologies.

Evaluation of the safety and efficacy of
CONTRACEPTIVE METHODS

The ICMR through a series of multicentric clinical
trials and many scientists at their own initiative have carried
out a number of studies evaluating newer contraceptive
methods for their safety, efficacy, side effects and
continuation rates. The information derived from such
studies on the Indian population suggests that a number
of contraceptives, in particular the use of oral pills and
copper (Cu)-bearing intrauterine devices (IUDs), are safe,
effective and reversible in preventing pregnancy. Some
of the copper IUDs, such as CuT 220C and CuT 380A,
are effective for as long as 12 years after insertion, thereby
suggesting that the couples need not resort to terminal
methods to control their fertility. Improved counselling
and better quality of services are essential to improve
the acceptance of the available methods and their continued
use.

Vasectomy and its Long-term Sequelae
Vasectomy is used by approximately 40 million
men world-wide as the preferred method of fertility
regulation1. In India almost 2% men of reproductive
age rely on vasectomy for fertility regulation. It is highly
effective and has a low complication rate. However,
there have been sporadic reports about possible
development of cardiovascular sequelae and an
increased risk of prostate and testicular cancer among
vasectomized men. Studies carried out under the aegis
90

of the ICMR have shown that vasectomy had no adverse
effects on the cardiovascular system2. Similarly, a
review by the ICMR has concluded that there was no
consensus about an increased risk of prostate cancer
among vasectomized men3. The overall morbidity and
mortality rates due to cancer in vasectomized men are
equal to or lower than those of community-matched
controls. Regarding the association between vasectomy
and testicular cancer, follow up of a study funded by
the WHO in Denmark involving some 65,000 men who
had had vasectomy demonstrated that there was no such
association1. These observations are quite reassuring
to dispel any fear which vasectomized men or those
thinking of opting for this approach for fertility
regulation might have.

Oral Contraceptives
Oral contraceptives (OCs) containing estrogen and
progestin were introduced over 35 years ago. During
this period the content of these steroids in OCs has been
considerably reduced to curtail the associated side effects
without compromising the contraceptive efficacy4. The
two most widely used OCs contain either a combination
of ethinyl estradiol and levonorgestrel or norethisterone
(COC) or only levonorgestrel (minipills). More recently
OCs containing newer progestins such as norgestimate,
gestodene or desogestrel have been developed which help
to further reduce the side effects due to the intrinsic
androgenic activity of levonorgestrel or norethisterone.

Indian scientists have undertaken a number of stud­
ies evaluating the contraceptive safety and efficacy of
available preparations. Multicentre studies carried out
by the ICMR have shown that OCs are generally safe
and highly effective in preventing pregnancy 5-6. Some
of these studies have shown that the progestogen-only
contraceptives have an advantage over the combination
pills in that they can be used safely by lactating women
and by those in whom the use of estrogens is contrain­
dicated. However, the incidence of breakthrough bleed­
ing and method failure rate was slightly more in the minipill
users compared to the COC. Studies on the long-term
follow up of infants and children exposed for short or
long periods to low dose progestins in infancy through
their mother's milk did not show any obvious adverse
effects on the infants' or children's anthropometric mea­
surements or major systems7. However, subtle effects
that could go unnoticed cannot be ruled out8.
In addition to evaluating some of the oral contracep­
tives, the Central Drug Research Institute, Lucknow, has

developed a nonsteroidal antiestrogen centchroman [3,4trans-2,2-dimethyl-3-phenyl-4-p-(P-pyrrolidinoethoxy)phenyl-7-methoxychroman], the postcoital or
weekly use of which provides acceptable pregnancy
protection. Centchroman is being marketed in India as
a weekly contraceptive. A dose of 30 mg administered
biweekly for the first three months and thereafter at weekly
intervals to 377 women volunteers, covered for 3,932
months of use, provided excellent pregnancy protection.
No drug related side effects were observed or reported9.
Babies bom to user-failures presented normal milestones.
The contraceptive effect was readily reversible and sub­
sequent pregnancies were normal.

In addition to providing contraceptive protection, the
use of OCs also provides protection against some of the
life threatening diseases and conditions that impair the
quality of life. Their use has been shown to be associ­
ated with decrease in the incidence of epithelial ovarian
cancer, endometrial cancer, pelvic inflammatory disease,
ectopic pregnancy, benign breast disease, iron deficiency
anaemia and formation of functional ovarian cysts10,11.
However, there are some concerns and controver­
sies about the long-term effects of the OCs on the devel­
opment of neoplasia and on the cardiovascular system.
A number of studies have found no overall association
between OC use and the risk of breast cancer12,13. How­
ever, some14 have reported a weak association between
long-term use of OCs and breast cancer in young women
in general who had early menarche and those who have
used the combination pill for long periods of time. The
WHO supported multinational case-control study found
that women who had ever used OCs had an overall rela­
tive risk of 1.15 of developing breast cancer compared
with women who had never used OCs14. This issue of
the possible association of breast cancer with OC use is
still controversial and can possibly be resolved by fur;
ther research in this area. However, considering that the
risk of breast cancer in these age groups is low and that
such cancers represent a very small proportion ofall breast
cancers, the association if real is not of significant pub­
lic health importance. Similarly, it is still not resolved
whether the use of OCs, particularly the third generation
OCs, have any association with increased incidence of
venous thromboembolism, myocardial infarction or
stroke15'17. It is, however, very clear that if women with
risk factors for coronary heart disease are excluded from
taking OCs, the incidence of myocardial infarction in
healthy women who are taking the pill is not increased.

In spite of the fact that the OCs are quite safe and
effective, less than 2% of the Indian women use oral pills

to prevent a pregnancy. The issue of compliance deserves
closer attention by family planning care providers. Proper
counselling and providing balanced information on sig­
nificant contraceptive and noncontraceptive benefits/risks
associated with OCs and services should help improve
compliance.
Long-acting Methods
Indian scientists have also made significant contri­
butions to the development of contraceptives which once
administered provide pregnancy protection for a long time.
Such injectables include subdermal silastic implants, and
intramuscular depot preparations containing either onlyprogestogen or estrogen-progestogen preparations.

Silastic implants

After evaluating silastic implants of varying length,
wall thickness, the amount of progestin contained in them
and the release rate, Srivastava and associates identified
an implant (Implant D) which released norethindrone
acetate at an average release rate of 128 pg/day and
calculated functional life of 1 Omonths18. Administration
of these implants to 876 women, who were followed up
for 3,975 woman-months, showed high contraceptive
efficacy. The pregnancy rates at 7 and 8 months of use
were 2.3 and 3.9 per 100 woman-months, respectively19.
The cumulative removal rate, for medical and personal
reasons, at the end of 8 months was 7.5%. These studies
revealed that development of slow-releasing devices was
an attractive option for long-term contraception.
The ICMR has also evaluated levonorgestrel-releasing NorplantR, consisting of six capsules, and Norplant II,
consisting of two covered rods which were developed
by the Population Council, New York20. No method fail­
ure was reported by the 172 women who had used these
devices for a period of up to 2 years. The continuation
rates with both devices were similar and were 80 and 65
per 100 users at the end of the first and second years of
use, respectively. Norplant II was preferred as it was
easier to insert two rods as compared to the six. In an­
other phase III multicentre clinical trial NorplantR-lI was
evaluated over a 5-year of use. A total of 1,466 women
were observed for 52,849 woman-months. The cumula­
tive method failure rate was 0.8 per 100 users and con­
tinuation rate at 5 years was 42.1%21.

Over the years, clinical studies with NorplantR have
involved 55,000 women, the device has been registered
in 60 countries and the method has been used by some
6 million women world-wide22. The cumulative pregnancy
rate at the end of 5 years is approximately one per 100

women. Ectopic pregnancy rates are correspondingly low,
0.3 per 1,000 woman-years. The major advantage of this
method is its long-term effectiveness. However, by the
end of 5 years, almost 25% of the Norplant* users had
requested for its removal because of bleeding problems
and another 15% for medical problems including head­
ache and weight gain. Difficult removal of the implant
is another associated problem of implant use. In addi­
tion to the levonorgestrel releasing implants, implants
releasing 3-keto-desogestrel, nomegestrel or nestorone
are being developed in an endeavour to further reduce
the incidence of side effects and the number of implants
to be inserted in a woman's body.

The use of subdermal implants form a good option
for fertility regulation for programmes which have ad­
equate service facilities including counselling and pro­
vision for training for the providers.
Progestogen-only injectables

A three-monthly injectable depot-medroxyprogesterone
acetate (DMPA) has been approved for use as a contra­
ceptive in over 100 countries where an estimated 10 mil­
lion women have used this method. DMPA is highly
effective in preventing pregnancy. In India, studies have
been undertaken to assess its utility in the family plan­
ning programme. In a study in which 138 women partici­
pated for a total of 907 woman-months no pregnancy
occurred23. However, the discontinuation rates due to se­
vere menstrual disturbances were very high. Almost 32%
of women discontinued after the first injection and an­
other 38.8% before receiving the third dose.
Similar observations were made in a multicentre study
conducted by the World Health Organization (WHO) in
13 countries24. A total of 1,587 women were observed
for 20,550 woman-months over a 2 year period in which
only 3 pregnancies occurred. The discontinuation rate in
the 13 participating countries ranged between 33.3 to 75.0
and 49.5 to 91.3 per 100 women at one and two years of
- use, respectively. The major reasons for discontinua­
tion were menstrual irregularities, weight gain, and head­
ache.

A recent survey of first users of DMPA from the USA
reported a continuation rate of 28.6% at one year of use25.
It seems that women who have wider choice of alternative
contraception do not prefer to continue using DMPA.
The Ministry of Health and Family Welfare, Government
of India has not yet approved DMPA for the National
Family Planning Programme but has approved its use by
private physicians.
92

Norethisterone enanthate (NET-OEN, 200 mg) given
at two or three-monthly interval has also been extensively
evaluated for its efficacy and side effects in multicentre
studies conducted by the ICMR26-27. The method is as
effective as DMPA. The discontinuation rates for bleed­
ing disturbances and due to other medical and personal
reasons were very high in NET-OEN users and seemed
comparable to those with the use of DMPA.

Estrogen-progestogen combination
To overcome the problems of irregular bleeding
observed with the progestogen-only injectables, combined
estrogen-progestogen preparations have been developed.
Several dose finding studies have been carried out in
India to determine the optimum dose of the two steroids
in the combination regimen28. The two preparations which
have undergone extensive clinical evaluation are Cyclofem
(25 mg DMPA and 5 mg estradiol cypionate) and Mesigyna
(50 mg NET-OEN and 5/mg estradiol valerate)29. A phase
III randomized clinical trial, on 849 subjects observed
for 7,817 woman-months, comparing Mesigyna given
at monthly or two monthly intervals showed that the
pregnancy rates with one monthly injections (0.2 per 100
users) were less than with the two monthly injections
(1.1 per 100 users)26. Moreover, the subjects using the
monthly preparation had a better bleeding pattern.
Phase III clinical trials carried out by the WHO and
other agencies in some 9,793 women for 1,02,058 womanmonths of use have also confirmed the high contracep­
tive efficacy of Cyclofem and Mesigyna29. More than
65% of women had predictable regular cycles. Discon­
tinuation due to bleeding related problems were less than
half of those seen with progestogen only injectable. Both
Cyclofem and Mesigyna are thus safe and effective con­
traceptives. With proper counselling and service deliv­
ery it should be possible to add these combination regi­
mens to the existing range of contraceptive methods.
Vaginal rings

The use of a vaginal ring releasing small quantities
of contraceptive steroids offers an attractive method of
contraception. The device is long-acting, under user's
control and is not limited by the constraints of daily
administration or coitus related such as the use of con­
dom. Silastic rings impregnated with either combina­
tion of estrogen and progestins or only progestins have
undergone extensive evaluation. However, menstrual
disturbances, vaginal irritation and lesions in some cases
have so far hampered the widespread use of vaginal rings.

In a large multicentre study carried out by the WHO on
1005 women the rate of intrauterine pregnancy in
levonorgestrel-releasing contraceptive ring was 4.5 per
100 women. The discontinuation rate at one year was
66%. Since the vaginal lesions and irritation was thought
to be due to the texture of the silastic ring, the WHO is
considering the possible development of a new vaginal
ring with higher dose of levonorgestrel30.
Vaginal ring releasing levonorgestrel has also been
evaluated in India. Menstrual irregularity (36%), vagi­
nal irritation or increased vagina] discharge (23%) and
expulsion (6%) were the most common reasons for
discontinuation31. Since most women find this method
more suitable for their contraceptive needs, efforts to
develop more safe, effective and acceptable rings need
to be pursued.
Intrauterine devices

A number of studies have been conducted in India to
develop new intrauterine devices (IUDs), to evaluate the
contraceptive efficacy of available IUDs and to improve
their utilization. Soonawala's CuY and Merchant's CuR
are two devices developed by Indian scientists during
1970s. CuT 200 which is offered in the National Family
Planning Programme has in particular been extensively
investigated for its efficacy and side effects. A multicentre
study initiated in early 1970s on 4,357 women, observed
over 32,709 woman-months, showed high contraceptive
efficacy of the device. The discontinuation rate at the
end of two years due to expulsion and medical reasons
were 9.4 and 15%, respectively. Almost 22% ofthe women
had the device removed for non-medical reasons32. The
discontinuation rates due to pregnancy and medical rea­
sons including bleeding disorders and pain were less than
those observed with the Lippes loop33.

In a more recent study, CuT 200 was evaluated in
comparison to CuT 220C, CuT 380Ag and a levonorgestrel
releasing device 34. In a multicentre study 1905 women
were randomly allocated to one of these four types of
IUDs and observed for 45,683 woman-months of use.
While no method failure was reported with the
levonorgestrel IUD, the cumulative failure rate per 100
users, at 36 months of use, was least with CuT 200C
(0.3) as compared to CuT 380Ag (1.0) or CuT 220C (1.6).
Continuation rates were significantly lower with the
levonorgestrel IUD as compared to the other devices,
which were primarily due to higher menstrual disturbances
and amenorrhoea. The risk of expulsion ranged between
8.3 to 10.6 per 100 users and was comparable for the
four devices.

WHO sponsored clinical research in multicentric,
randomized studies have shown that CuT 220C and CuT
380A are effective for at least 12 years of use3S. The
cumulative 12-year intrauterine pregnancy rate per 100
women, with CuT 380A was less (1.9 + 0.5) as com­
pared to the CuT 22.0C (7.0 + 0.6). However, the overall
continuation rate at all intervals since insertion was higher
with the CuT 220C device, mainly due to higher removal
rates for nonmedical reasons with the CuT 380A.
These studies suggest that IUDs provide a revers­
ible non-surgical alternative to sterilization for women
requiring very long-term pregnancy protection. How­
ever, its use must be properly counselled and the device
carefully applied.

Development of New Methods of Fertility
Regulation
Approaches for Male Fertility Regulation
Hormonal methods
Testosterone which is essential for the maintenance of
spermatogenesis and libido when given in pharmacologi­
cal doses has inhibitory effects on gonadotrophin secretion
and consequently on spermatogenesis. These observations
led Reddy and Rao in 1972 to evaluate the effects of long­
term treatment with testosterone propionate on spermato­
genesis in adult men36. Daily intramuscular treatment of
men, aged 23-38 years, with testosterone propionate (25
mg/day) resulted in complete suppression of spermatoge­
nesis by 60 days. The libido and potency ofthese men were
not affected. The inhibitory effects oh spermatogenesis were
reversed within 150 days ofthe stoppage oftreatment. This
study demonstrated the feasibility 'of a hormonal method
for fertility regulation in normal men.
The lead established by the Indian scientists was taken
up by many research centres in the world to develop male
hormonal methods of fertility control. The major em­
phasis of the research programme was to develop more
potent androgens so that the need for daily administra­
tion of the drug could be avoided. Using a relatively longer
acting androgen, testosterone enanthate, the WHO has
completed two clinical multicentric trials and has con­
firmed the contraceptive potential of androgens in men37*38.
A total of 670 adult men from 9 countries volunteered
for the two studies. Weekly administration of 200 mg
testosterone enanthate caused azoospermia in 425 men
and oligospermia in another 81. The 506 men started
relying only on testosterone enanthate as a contracep­
tive after the treatment had induced either azoospermia
93

or oligospermia in them. Only five pregnancies occurred
in the partners of these men. The overall pregnancy rate
in the two studies was 1.2 per 100 person years which
was superior to that achieved with condoms or the with­
drawal method. The fertility or sperm production was
restored within 7 months after the treatment was stopped.
High level of acceptability was found in both the recipi­
ents and their partners in spite of the need for weekly
injections.
In addition, studies are on to evaluate androgen in
combination with progestogen as a male contraceptive39.
In the combination strategy, progestogen is to primarily
block gonadotrophin release and consequently steroido­
genesis whereas low doses of androgens are to maintain
libido. Studies have shown that oligospermia and azoosper­
mia are achieved much faster and in more number of
subjects using a combination regimen as compared to
androgens alone. The combination regimen may be pre­
ferred over the androgen only regimen as it may reduce
the potential for lipid, behavioural and prostate changes
that could arise from the continued exposure to andro­
gen alone.

These studies supported the idea that androgens
either alone or in combination with progestins could be
used as male contraceptives. However, availability of a
longer acting preparation will be a distinct improvement
and more attractive. Studies carried out with testosterone
buciclate have shown that a single injection can provide
sustained levels of testosterone for 3-4 months40,41.
Alternatively there is a need to develop formulations and
delivery systems such as slow-release biodegradable
implant; testosterone incorporated into sustained-release
delivery systems such as the biodegradable copolymer
microspheres; and long-acting testosterone esters which
on hydrolysis release the biologically active form of
testosterone in the body which can help obviate the need
for frequent systemic administration.

Vas occlusion
Vasectomy is highly effective and has a low
complication rate but its more widespread acceptability
is affected by the need for a surgical intervention; and
that the procedure must be considered permanent as
reversal is difficult and the success rate, as determined
by subsequent fertility, is low. Although the advent of
no-scalpel vasectomy has considerably reduced these
concerns, and the success rates of vasovasectomy are
improving, an approach is needed that is easier to perform
and more predictably reversible if a greater number of
men and couples are to find this type of method attractive.
94

Guha and associates have shown that injection of
styrene maleic anhydride (SMA, 60 mg) in a solvent
system of dimethylsulphoxide into the vas deferens
induces complete azoospermia42. The phase I clinical
trial and continuing follow up of the subjects over a
period of seven years have demonstrated that the pro­
cedure does not lead to any clinical complications in
the urogenital system and other parts of the body. In
the phase II study, 12 adult healthy men were admin­
istered the drug and followed up for a period of one
year. These volunteers and their wives did not use any
other form of contraception during the study period.
Regular monthly semen examination showed azoosper­
mia in all 12 men. The treatment was safe and provided
pregnancy protection during the one year study period.
The results of recent preliminary studies carried out in
non-human primates and men have shown that the process can be reversed by flushing out the SMA plug into
the urethra43. Hopefully, vas occlusion using SMA will
develop into an acceptable method of male contracep­
tion.

More recently, liquid silicone is also being tried to
form cured-in-place plugs following injection in the vas.
However, the results of the initial studies carried out in
Indonesia and China have shown high frequency of vas
rupture following percutaneous intravasal injection of
silicone44 and the studies carried out in the Netherlands
have shown poor occlusion rate as evidenced by a rela­
tively high number of sperm in the ejaculate compared
to vasectomy cases1. These studies need to be extended
to determine the optimum volume and pressure charac­
teristics needed to achieve complete vas occlusion without
causing any damage to the vas.

Immunological methods
The antigenic nature of hormones, spermatozoa,
secretory products of accessory glands and tissues of the
reproductive system have been utilized to target them
for contraception by using actively or passively induced
antibodies to these substances. Rao and associates at
the Institute for Research in Reproduction (IRR), Mumbai,
showed that antibodies to spermatozoa could block fer­
tility. These investigators proposed in early 1960s that
the presence of autoantibodies to spermatozoa in men or
iso-antibodies in some women could be the cause of
infertility45. These authors further demonstrated that the
buffalo seminal plasma contained at least 16 antigens,
and spermatozoa at least 7, of which 4 were common to
seminal plasipa. These pioneering observations by the

Indian scientists have provided leads to develop a sperm
vaccine based on identification of suitable surface-expressed epitopes that are sperm-specific, adequately
immunogenic and involved in fertilization.
Sperm-surface antigens
The IRR scientists have identified a 80 kDa protein
on the sperm surface using circulating antisperm antibod­
ies from infertile women as probes46. The preliminary studies
show that active immunization with this protein results in
infertility in both male and female rats. This protein has
been sequenced and studies are being extended to deter­
mine the N-terminal or internal fragment of the native 80
kDa protein, immunization against which might have
contraceptive potential.

Scientists at IRR have also generated a panel of mono­
clonal antibodies (MAb) to identify sperm membrane
antigens which may play a role in sperm function47. One
of the MAbs, D,G, was found to react with the 26 kDa
protein present on the acrosomal region of mouse and human
spermatozoa. This 26 kDa antigen is also present in the
cauda epididymis and is regulated by androgens. The
antibodies directed to the 26 kDa protein had antifertility
effects in both male and female mice48. These studies suggest
that sperm maturation antigens are particularly suitable
for immunocontraception as in the male the antibodies
inhibit post testicular modulation and are not expected to
interfere with testicular function. The gene encoding the
26 kDa epididymal protein has been cloned using a mon­
key epididymal cDNA library and is being sequenced.
Working on similar approaches, Shaha and Seshadri at
the National Institute of Immunology (Nil), New Delhi,
have identified two proteins of 94-96 kDa and 40 kDa on
the sperm surface, the antibodies against which blocked
sperm-oocyte interaction in rodents49.

which bound and neutralized bioactive human FSH. The
antibody produced was specific for FSH and no signifi­
cant changes in the values of related glycoprotein hor­
mones (LH/testosterone and TSH/thyroxine) were recorded.
Seminal plasma transferrin, a marker of Sertoli cell as well
as of seminiferous tubular function, showed reduction (3090%) following immunization with oFSH. Preclinical and
clinical toxicology studies revealed that oFSH vaccine at
the doses tested was free from toxicity. Adopting such an
approach for male contraception appeared attractive, as it
had no effect on serum testosterone and libido, the prob­
lem that besets other steroid-based male contraceptive
procedures.
Inhibin and related peptides
Inhibin was initially thought to be a protein of tes­
ticular origin and having a specific function of inhibit­
ing the secretion of FSH. However, over the years, a
number of inhibin and inhibin-like substances have been
identified with multiple effects. Some of the inhibins have
also been suggested to be secreted by the prostate or other
male accessory reproductive organs51. Sheth and col­
leagues from IRR have undertaken extensive work on
the human seminal plasma inhibin (HSPI)52. Following
isolation and purification the primary structure of HSPI
was determined. Further, HSPI (10.4 kDa) was shown
to be sperm-coating protein of prostatic origin having
potential for immunocontraception. This prompted the
group to further identify and synthesize sequence seg­
ments that might mimic the immunobiological activity
of the native protein. The N-terminal 1-17 (R-17) and
C-terminal 67-94 (R-28) sequences are two such pep­
tides. Studies (IRR-unpublished observations) have shown
that active immunization with R-17 induced infertility
in male rats.

FSH vaccine

Approaches to Female Fertility Regulation

Another immunological approach being developed by
Indian scientists is based on the bioneutralization of fol­
licle stimulating hormone (FSH). FSH has specific recep­
tors on the Sertoli cell membrane and blockade of FSH
inhibits spermatogenesis without affecting testosterone
biosynthesis. Moudgal and colleagues at the Indian Insti­
tute of Science, Bangalore, have shown that immuniza­
tion of bonnet monkeys with ovine FSH (oFSH) gener­
ates antibodies which disrupt spermatogenesis, leading to
oligospermia and infertility50.

Clomiphene citrate

A limited clinical trial carried out on 5 adult men showed
that active immunization with oFSH produced antibodies

Clomiphene citrate, a non-steroidal agent, was shown
in early 1960s to have gonadotrophin-suppressing, ovula­
tion inhibiting and blastotoxic actions in rats53. These
observations raised hopes of developing clomiphene cit­
rate as a potential antifertility agent. However, subsequent
studies by Roy and associates showed that clomiphene
citrate had estrogenic and antiestrogenic actions which could
be manifested at the same dose levels depending upon the
hormonal milieu54. These investigations also showed that
its antifertility effects were limited to laboratory animals
and could not be confirmed in humans. In none of the
95

11 ovulatory women, who received clomiphene citrate in
doses of 50 to 200 mg per day for varied duration ovula­
tion was suppressed55. On the contrary, administration of
clomiphene citrate induced ovulatioh in women. Clomi­
phene administration to women with inadequate luteal phase
resulted in improvement in luteal phase. It is the result of
these observations that the clomiphene is being widely
used for induction of ovulation in patients desiring preg­
nancy and in several other clinical conditions.
Antiprogestins

Antiprogestins such as RU 486, ZK 98.299 and ZK
98.734, intercept progesterone action at the molecular
level of receptor binding, and have the potential to ter­
minate early pregnancy56. RU 486 which has undergone
extensive clinical evaluation is commonly referred to as
the “abortion pill” as its oral administration, followed
48 h later by a small dose of a prostaglandin analogue,
terminates pregnancy in almost 95% of the women with
an amenorrhoea of less than 63 days.
The studies carried out at IRR have shown that these
antiprogestins have direct inhibitory effects on the en­
dometrium as well as hypothalamo-hypophyseal axis
and therefore have a potential for intercepting a wide
range of progesterone-dependent reproductive pro­
cesses57. Moreover, their effects on the endometrium
and the gonadotrophs are dose-related, the endometrium
being more sensitive than the gonadotrophs. Low doses
of the drugs retard endometrial development and con­
sequently block implantation without affecting ovula­
tion or other menstrual cycle parameters58. These drugs
have therefore shown potential for further development
as a contraceptive where the drug could be taken either
daily like a 'mini pill' or once-a-week throughout the
menstrual cycle or just during the early luteal phase59.
Antiprogestins have also shown potential for use as an
emergency method of contraception. Studies carried
out under the aegis of the WHO have shown that a dose
of 10 mg RU 486 when taken within 72 hours of
unprotected sex averts pregnancy in almost 80% of
instances30. The major advantage of developing
antiprogestins as contraceptive is that the need for
simultaneous administration of estrogens would be
obviated and their use is likely to decrease the risk
of endometrial and breast cancer through their
antiproliferative effects on target organs. Even when
used as an emergency contraceptive method the
side effects were much fewer compared to the Yuzpe
regimen.
96

Gonadal peptides
Nandedkar et al60 at IRR have identified some novel
proteins in the human ovarian follicular fluid which have
shown potential as fertility regulating agents. Extensive
efforts on the purification and characterization have re­
sulted in the isolation of a 4 kDa protein which when
injected into rodents and non-human primates impairs
fertility61. Studies on sequencing of this protein are be­
ing conducted to embark upon extensive preclinical and
clinical evaluation of this protein for its antifertility ef­
fects.
Immunological methods

Rao and Shahani62 from IRR had shown in 1961 that
human chorionic gonadotrophin (hCG) can act as a true
antigen and the antibodies against hCG can neutralise
the parent molecule. Antiserum raised in a rabbit immu­
nized with a mixture of hCG and Freund's adjuvant showed
serological reactions, characteristic of an immune serum
containing specific antibodies. These results provided
evidence that protein hormones mixed with adjuvants
and injected systemically can elicit serologically active
antibodies in the blood which can neutralise the parent
molecule. These observations have given impetus to the
concept of developing immunocontraceptives.

hCG vaccine
Indian scientists have developed a hCG vaccine which
has undergone phase II clinical evaluation63. A vaccine
consisting of a heterospecies dimer of the p subunit of
hCG associated noncovalently with the a subunit of ovine
LH and conjugated to tetanus and diphtheria toxoids as
carriers when injected to 148 women induced antibodies
of high avidity against hCG. In 80% of the women, the
antibody titre was more than 50 ng/ml; with only one
pregnancy occurring in this group. Some of these women
had completed up to 30 menstrual cycles of continuous
exposure to the risk of pregnancy. On the other hand, in
women in whom the antibody titre was less than 50 ng/
ml, 26 pregnancies occurred. The antibody response
declined with time, fertility was regained when the titres
fell to less than 35 ng/ml. This study presents evidence
of the feasibility of a vaccine for control of human fer­
tility.

In this respect the work carried out by Indian scien­
tists to develop a contraceptive vaccine is at the most
advanced stage as compared to laboratories in other parts
of the world engaged in similar studies.

WHO is also developing a synthetic peptide-based
hCG immunocontraceptive64-65. It is envisaged that a further
5-7 years of clinical testing and product improvement
will be required before a first-generation product will be
available. A second-generation, totally synthetic,
bioengineered product is also under development by the
WHO and could become available within a similar or a
slightly more extended time-frame.
Some vaccines originally developed for fertility control
are also being evaluated for treatment of hormone-de­
pendent cancers66. Recombinant hCG vaccine is in clini­
cal trial in Mexico in lung cancer patients carrying a type
of tumour that secretes hCG and its subunits. Similarly,
LHRH vaccine is approved for trials in prostate carci­
noma patients.

Zona pellucida antigens

The zona pellucida has generated considerable inter­
est as a target for developing immunocontraceptive vac­
cine. The advantage of this approach would be of block­
ing pregnancy by acting at the pre-fertilization stage. In
this direction, studies carried out by Gupta and cowork­
ers at the Nil have centred on delineating the epitopes
recognised by MAbs generated against porcine ZP3a and
ZP3P67. The MAbs against these antigens delayed trypsinmediated zona lysis and also inhibited the binding of ZP3
to sperm membrane vesicle. It is hoped that the leads taken
by Indian scientists in this direction will help in the devel­
opment of a new effective contraceptive vaccine.
Riboflavin carrier protein

Scientists at the Indian Institute of Science and the
IRR have isolated riboflavin carrier protein, a novel
estrogen-dependent protein, from the hen's egg white6’.
Immunization against this protein has shown antifertil­
ity effects in laboratory animals and non-human pri­
mates69-7'. Scientists at IRR have also identified some
epitopes with potential antifertility effects. A synthetic
peptide, based upon this epitope, was shown to have
antifertility effects in rodents71.

Herbal Preparations
Indian scientists have identified a number of plants
that possess antifertility effects. The ICMR had published
a special report on “Plants with antifertility activity”
way back in 1966 emphasing the need to explore the
antifertility potential of herbal preparations72'73. The
Central Drug Research Institute, Lucknow has screened

about 3,300 plant materials for antifertility activity of
which some 67 have shown potential74. The plants which
have demonstrated interesting antifertility activity in
clinical trials include Hibiscus rosa-sinensis and Embelia
ribes. The extract of red petals of the plant
Rudrapushpaka, collected between October and
December, when given orally from day 7 to day 22 of
the menstrual cycle prevented pregnancy in all the 22
women75. Embelia ribes is being used in combination
with Piper longum and borax as a contraceptive by
practitioners ofthe traditional systems ofmedicine. When
given in high doses for ten days in a cycle, Embelia
ribes prevented pregnancy in 95% ofthe women observed
for 2,051 cycles over 4 years76. In addition, there are a
large number of other plants, such as seeds of Daucus
carota, Butea monosperma and Sapindus trifoliatis, which
have demonstrated antifertility effects in rodents77 and
there are some, such as Vicoa indica known as banjhauri,
which are being used by people in rural areas at their
own initiative and risk to prevent pregnancy7’. The
groundwork done by the Indian scientists in screening
a large number of plants with antifertility effects and
in identifying the few which need further testing has
thus become extremely valuable. However, research
in this area has not received continued support.

Immunodiagnostics
Scientists at IRR were the first in the world to de­
velop a simple enzyme-linked immunosorbent assay
(ELISA) for the detection ofestrone-glucuronide and preg­
nanediol glucuronide7’-*0. The assay methods for steroid
hormones are of considerable diagnostic value in repro­
ductive endocrinology. Similarly, they were the first to
develop a pregnancy detection test based on ELISA tech­
nology’1. This test allows detection of pregnancy within
30-35 days from the last menstrual period. The scien­
tists at IRR have also done considerable work on the early
pregnancy factor (EPF) which has been observed to be
a promising biomarker of pregnancy, and allows detec­
tion of pregnancy even before the missed period or 48
hour after fertilization’2. This method also has immense
clinical value in assessing pregnancy wastage and in
assisted reproductive technologies where it can be used
for detection of fertilization.

DESIRED GOAL
The desired goal of contraceptive research and
development should be to empower couples to control
their fertility by choice rather than by chance. More and

97

more people should therefore be provided with a greater
range of safe, effective and affordable methods of fertility
regulation. They should also be provided with information
about the use of contraceptives and services to manage
the possible side effects and contraceptive failure, if any.
This will enable the couples to have a satisfying and safe
sex life, the capacity to reproduce and the freedom to
decide, if, when and how often to do so - the essential
ingredients of good RH. Fertility regulation in turn will
also have bearing on other aspects of RH. The timely
use of appropriate contraceptive technologies will help
prevent unwanted pregnancy and its consequences, STDs,
infertility, and will ensure infant survival and safe
motherhood.

Research Needs
New research on developing safe and effective meth­
ods of fertility regulation must be guided by the user's
needs and perspectives and after assessing the feasibil­
ity of product development and service delivery. The
prevailing RH indicators should he Ip identify the condi­
tions or problems responsible for creating an unneces­
sary burden on the RH and decide on the research agenda
to address those unresolved problems.

In our country, the infant and maternal mortality rates
are still very high. The infant mortalilty rate is approxi­
mately 74 per 1,000 live births83 which is almost ten times
of that in many developed countries. Similarly, in India,
1 in 57 women has the chance of dying from complica­
tions of pregnancy, childbirth or unsafe abortion during
her life time as compared to 1 in more than 17,000 in some
of the developed countries84. At the prevailing maternal
mortality rate of 437 deaths per 100,000 live births more
than 100,000 women in India die every year from causes
related to pregnancy and child birth83. It is estimated that
15,000-20,000 abortion-related deaths occur annually among
married, multiparous women in India. Similarly, the inci­
dence of reproductive tract infections (RTIs) and STDs is
very high85-86. Almost 20% of the eligible couples who do
not want children or want to space their children are not
using any method of contraception83. Moreover, in south­
east Asia only 57% of eligible couples have access to con­
traception at an affordable price as compared to 90% in
east Asia.

The above mentioned RH indicators point to the need
of integrating technology development with provision
of services. Expanding family planning services is an
important strategy for reducing the population growth
rate, spacing the children and consequently decreasing
98

the infant and maternal mortality rates and reducing the
incidences of RTIs and STDs. High priority should be
given to the development of male methods of fertility
regulation; emergency contraception; and vaginal meth­
ods that provide dual protection against pregnancy and
STDs. In addition, there is a need to promote basic re­
search to understand the reproductive processes which
may eventually lead to the development of newer treat­
ments and technologies.

Expanding family planning options
Male Methods

In spite of the fact that a number of methods have
been developed to allow women to control her fertility,
the options available to men are rather limited. The male
reproductive system, particularly the process of gametogenesis, maturation of spermatozoa and the sperm-egg

®/

interaction, is so complex that it has not so far been possible
to find an effective intervention that can be converted
into a product. Reversible hormonal method has shown
promising results but still needs to be developed into a
viable product. Antifertility vaccine directed against FSH
has entered clinical trial and basic research is being
continued on vaccines directed against specific molecules
on the spermatozoa or the epididymal secretions. De­
velopment of a reversible male method which will help
control fertility without affecting the potency will en­
rich the field of contraceptive research and development.
The approaches targeting maturation of spermatozoa in
the epididymis or sperm-egg interaction, without inter­
fering with sperm production or secretion of testoster­
one, may be more acceptable to men.
In addition to the development of male methods of
fertility regulation, it is essential to formulate strategies to increase male participation and responsibility
in reproductive health. It will help to improve accep­
tance of available male methods and eventually the
wellbeing of the entire family. Some of the ongoing
studies at IRR show that lack of initiative, misconcep­
tions about family planning methods, wives and family
members objection, fear of surgery in case of vasec­
tomy, lack of knowledge about the methods and poor
quality of services contribute to low acceptance of male
methods87. Further research needs to be undertaken to
study the attitude and sexual behaviour of men about
fertility regulation, and the factors inhibiting their role
and participation in reproductive health so that appro­
priate intervention studies could be planned to enhance
their involvement and responsibility.

r

Emergency Contraception

Currently available emergency contraceptive meth­
ods when used shortly after unprotected coitus can pre­
vent 75% or even more pregnancies88. Unfortunately,
however, these methods have not been used to their full
potential. Research needs to be directed to assess the
reasons why these methods are not available to or used
by the potential users. This also necessitates research on
the risk taking behaviour of people, determinants and
consequences of induced abortion including its effects
on subsequent fertility, reproductive and mental health
and contraceptive practices.

In addition, more biomedical research is needed to
overcome the limitations of the most commonly used
emergency contraceptives (estrogen-progestin combina­
tion, levonorgestrel or danazol) such as: (i) effective only
when started within 48 or 72 hours after unprotected in­
tercourse; (ii) two doses must be taken; (iii) relatively
high incidence of nausea and vomiting; and (iv) prevents
only about 75% of unplanned pregnancies that would
have occurred otherwise. Research should be aimed to
increase the window of effectiveness of the available
methods of emergency contraception, and to increase their
contraceptive efficacy to almost 100%. The development
of better methods for emergency contraception is there­
fore a challenging task requiring high priority.

methods of contraception so that they could be incorpo­
rated in the National Family Planning Programme; the
development of newer methods of fertility regulation for
both men and women; and understanding of the repro­
ductive processes and proposing new hypothesis which
may lead to the development of newer technologies.
Achievements in these areas have helped in improving
the RH of the people and have made us more optimistic
for further development of newer contraceptive technolo­
gies. It is time that we review our research activities and
orient ourselves to meet new challenges resulting from
the paradigm shift from a narrow focus on family plan­
ning and population control to the broader, holistic con­
cept of RH. Contraceptive research should be viewed in
relation to the overall health, social and service context
and should have the involvement of potential users in
determining the research needs and priorities. Moreover,
high priority contraceptive research should be decided
after assessing the feasibility of product development and
service deliveries.
Author's Note
A sincere and unbiased attempt has been made in this article
to acknowledge all those efforts which have contributed
substantially to contraceptive development. In view of
the large body ofdata available on this subject, omission
of any other significant contribution from this article is
inadvertent.

Barrier Methods

The incidences of STDs including HIV/AIDS are
gradually increasing in India. It has necessitated devel­
opment of methods that not only protect against preg­
nancy but also against STDs. Moreover, increasing
emphasis is being placed upon the interrelationship be­
tween methods of fertility regulation and STD infection.
Areas that need increased attention include barrier methods,
both male and female, for fertility control and the pre­
vention of STDs including HIV/AIDS. The interim re­
sults of studies supported by the WHO suggest that pro­
moting condom use among couples for dual protection
against pregnancy and STDs may be more successful than
for prevention of STDs alone.

References
1.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction. Technology development and assessment. In: Annual
Technical Report 1996. World Health Organization, Geneva, p
37, 1997.

2.

Indian Council of Medical Research, Task Force on Male Fer­
tility Regulation. Long-term effects of vasectomy. Part I: Bio­
chemical parameters. Contraception 28: 423, 1983.

3.

Tripathy, S.P., Ramachandran, C.R. and Ramachandran, P. Health
consequences of vasectomy in India. Bull WHO 72:779,1994.

4.

Puri, C.P. Steroids as contraceptives. In: Steroidal Contracep­
tion. Eds. C.P. Puri and R.P. Soonawala. The Federation of
Obstetrics and Gynaecological Societies of India, Mumbai, p 4,
1993.

CONCLUSIONS

5.

The contributions of Indian scientists over the past
50 years have enriched the field of contraceptive research
and product development. Some of their contributions
were targeted towards the evaluation and improvement
of the safety, efficacy and acceptability of promising

Indian Council of Medical Research, Task Force on Hormonal
Contraception. Randomized clinical trial with triquilar-ED and
low-dose combination pill. J Obstet Gynaecol India 42: 71,
1992.

6.

Indian Council of Medical Research, Task Force on IUD and
Hormonal Contraceptives. Improved utilization of spacing
methods - Intrauterine devices (IUDs) and low dose combined

99

oral contraceptives (OCs) - through reorientation training for
improving quality of services. Contraception 50: 215, 1994.
7.

Toddywalla, V.S., Patel, S.B., Betrabet, S.S. and Saxena, B.N.
Low-dose progestogen contraception and the nursing mother.
Adv Contracep 11: 285, 1995.

8.

Toddywalla, V.S., Patel, Z.M., Patel, S.B., Betrabet, S.S and
Saxena, B.N. Long-term effects of maternal low-dose progestogenic contraceptives on their nurslings. JObstet Gynaecol India
44: 426, 1994.

9.

Nityanand, S., Kamboj, V.P., Chandravati, K.D., Gupta K.,
Rohtagi, P., Baveja, R., Jina, R., Mitra, R. and Sharma, U.
Contraceptive efficacy and safety of centchroman with biweeklycum-weekly schedule. In: Current Concepts in Fertility Regu­
lation and Reproduction. Eds. C.P. Puri and P.F.A. Van Look,.
Wiley Eastern Ltd, New Delhi, p. 61, 1994.

21.

Indian Council of Medical Research, Task Force on Hormonal
Contraception. Phase 111 clinical trial with Norplant* 2 (two covered
rods): Report on five years of use. Contraception 48:120,1993.

22.

Fraser, I.S., Tiitinen, A., Affandi, B., Brache, V., Croxatto, H.B.,
Diaz, S., Ginsburg, J., Gu, S., Holma, P., Johansson, E., Meirik,
O., Mishell, D.R., Nash, H.A., Schoultz, B. V. and Sivin, I.
Norplant*: Consensus statement and background review. Con­
traception 57: 1, 1998.

23.

Mukherjee, M., Mukherjee, P. and Biswas, R. Long-term con­
traception with depo-provera: A clinical evaluation. IntJFertil
25: 122, 1980.

24.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction. Multinational comparative clinical trial of long-acting
injectable contraceptive: Norethisterone given in two dosage
regimens and depot-medroxyprogesterone acetate. Final report.
Contraception 28: I, 1983.

10.

Centres for Disease Control, Cancer and Steroid Hormone Study.
Oral contraceptive use and the risk of ovarian cancer. J Am Med
Assoc 249: 1596, 1983.

11.

Centers for Disease Control, Cancer and Steroid Hormone Study.
Oral contraceptive use and the risk of endometrial cancer. J Am
Med Assoc 249: 1600, 1983.

25.

Sangi-Haghpeykar, H., Poindexter, A.N., Bateman, L. and
Ditmore, J.R. Experiences of injectable contraceptive users in
an urban setting. Obstet Gynecol 88: 227, 1996.

12.

Ory, H.W. Contraceptive safety: The need for epidemiologic
research. In: Research on the Regulation of Human Fertility.
Eds. E. Diczfalusy and A. Diczfalusy, Scriptor, Copenhagen,
p 133, 1983.

26.

13.

Thomas, D.B. Do hormones cause breast cancer? Cancer 53:
595, 1984.

Indian Council of Medical Research, Task Force on Hormonal
Contraception. A multicentre phase III comparative study of
two hormonal contraceptive preparations NET-OEN (50 mg) +
E2 valerate (5 mg) given every month and NET-OEN (200 mg)
given every 2 months as intramuscular injection: A report of a
12-months study. Contraception 42: 179, 1990.

14.

UNDP/UNFPA/WHO/World Bank Speical Programme of Re­
search, Development and Research Training in Human Repro­
duction. Oral contraceptives and neoplasia : Report of a WHO
Scientific Group. WHO Tech Rep Ser 817: 1992.

27.

Datey, S., Gaur, L.N. and Saxena, B.N. Vaginal bleeding pat­
terns of women using different contraceptive methods (implants,
injectables, IUDs oral pills) — An Indian experience. Contra­
ception 51: 155, 1995.

15.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction. Effect of different progestogens in low estrogen oral
contraceptives on venous thromboembolic disease. Lancet 346:
1582, 1995.

28.

Indian Council of Medical Research, Task Force on Hormonal
Contraception. Phase-II randomized clinical trial with
norethisterone oenanthate 50 mg alone or in combination with
5 mg or 2.5 mg of either estradiol valerate or cypionate as a
monthly injectable contraceptive. Contraception 32:383,1985.

16.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction. Ischaemic stroke and combined oral contraceptives:
Results of an international, multicentre, case-control study. Lancet
438: 498, 1996.

29.

Facts about once-a-month injectable contraceptives: Memorandum from a WHO meeting. Bull WHO 71: 677, 1993.

30.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction. Developing new methods of fertility regulation. In:
Reproductive Health Research: The New Directions. Eds. J.
Khanna and P.F.A. Van Look, World Health Organization, Geneva,
p 22, 1998.

31.

Buckshee, K., Kumar, S. and Saraya, L. Contraceptive vaginal
ring: A rising star on the contraceptive horizon. Adv Contracep
6: 177, 1990.

32.

Tejuja, S., Saxena, N.C., Malhotra, U., Choudhury, S.D. and
Bhinder, G. Two years experience with the copper T 200 in
India. Contraception 10: 337, 1974.

33.

Phatak, L.V. Comparative study of puerperal and non-puerperal
IUCD insertions. In: Report of the ICMR Seminar on lUCDs:
Review ofResearch Work in India on lUCDs. Ed. K.R. Laumas,
p 189, 1968,

17.

Schwingl, PJ. and Shelton, J. Modeled estimates of myocardial
infarction and venous thromboembolic disease in users of sec­
ond and third generation oral contraceptives. Contraception 55:
125, 1997.

18.

Srivastava, U.K., Bhatnagar, S. and Laumas, K.R. Development
of new long acting contraception for women. Indian J Physiol
Pharmacol 17: 283, 1973.

19.

Bhatnagar, S., Srivastava, U.K., Takkar, D., Chandra, V.L.,
Hingorani, V. and Laumas, K.R. Long-term contraception by
steroid releasing implants. Contraception 11: 505, 1975.

20.

100

Indian Council of Medical Research, Task Force on Hormonal
Contraception. Phase II randomized comparative clinical trial
of Norplant* ( six capsules), with Norplant R-2 (two covered
rods) subderma! implants for long-term contraception: Report
of a 24-month study. Contraception 33: 233, 1986.

A k

j

34.

35.

Indian Council of Medical Research, Task Force on IUD.
Randomized clinical trial with intrauterine devices
[(Levonorgestrel intrauterine device (LNG), CuT 380Ag, CuT
220C and CuT 200B)]: A 36-months study. Contraception 39:
37, 1989.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction. Twelve years of experience with CuT 380A and CuT
220C. Contraception 56: 341, 1997.

maturation antigen of spermatozoa. In: Current Concepts in
Fertility Regulation and Reproduction. Eds. C.P. Puri and P.F.A.
Van Look, Wiley Eastern Ltd, New Delhi, p 237, 1994.

48.

Premchandran, S. and Hegde, U.C. Ontogeny of mouse caudal
protein identified by a monoclonal antibody. Hum Reprod 6:
589, 1991.

49.

Shaha, C. and Seshadri, T. Sperm surface antigens that contain
multiple proteins important for sperm function. In: Current
Concepts in Fertility Regulation and Reproduction. Eds. C.P.
Puri and P.F.A. Van Look, Wiley Eastern Ltd, New Delhi, p
209, 1994.

50.

Moudgal, N.R., Ravindranath, N., Murthy, G.S., Dighe, R.R.
and Aravindan, G.R. On the development of a male contracep­
tive vaccine. In: Perspectives in Primate Reproductive Biology.
Eds. N.R. Moudgal, K. Yoshinaga, A.J. Rao and P.R. Adiga,
Wiley Eastern Ltd, New Delhi, p 297, 1991.

51.

Sheth, N.A. Vanage, G.R., Hurkadli, K.S. and Sheth, A.R. Prostate:
An extragonadal source of inhibin. Demonstration of inhibin in
normal, benign, malignant human prostate and rat prostate by
bioassay, radioimmunoassay, immunocytochemical localization
and biosynthesis. In: Inhibins: Isolation Estimaton and Physi­
ology. Ed. A.R. Sheth. CRC Press, USA (vol 1), p 109, 1987.

36.

Reddy, P.R.K. and Rao, I.M. Reversible antifertility action of
testosterone propionate in human males. Contraception 5:295,
1972.

37.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction, Task Force on Methods for the Regulation of Male
Fertility. Contraceptive efficacy oftestosterone-induced azoosper­
mia in normal men. Lancet 330: 955, 1990.

38.

UNDP/UNFPA/WHO/World Bank Special Programme of Re­
search, Development and Research Training in Human Repro­
duction, Task Force on Methods for the Regulation of Male
Fertility. Contraceptive efficacy of testosterone-induced oligosper­
mia in normal men. Fertil Steril 65: 821, 1996.

39.

Pangkahila, W. Reversible azoospermia induced by an androgen-progestin combination regimen in Indonesian men. /nt J
Androl 14: 248, 1991.

52.

Sheth, A.R., Moodbidri, S.B., Garde, S.V. and Vanage, G.R.
Seminal inhibin: Prospects for immunocontraception. Indian J
Exp Biol 30: 1012, 1992.

40.

Rajalakshmi, M. and Ramakrishnan, P.R. Pharmacokinetics and
pharmacodynamics of a new lor.g-acting androgen ester: Main­
tenance of physiological androgen levels for 4 months after a
single injection. Contraception 40: 399, 1989.

53.

Roy, S. Early developmental studies with clomiphene citrate:
Their subsequent validation and extension. Indian J Exp Biol
°30: 931, 1992.

54.

Behre, H.M. and Nieschlag, E. Testosterone buciclate (20AET-1)
in hypogonadal men: Pharmacokinetics and pharmacodynamics
of the new long-acting androgen ester. J Clin Endocrinol Metab
75: 1204, 1992.

Roy, S., Greenblatt, R.B. and Mahesh, V.B. Effects of clomi­
phene on the physiology of reproduction in the rat. II. Its estro­
genic and antiestrogenic actions. Acta Endocrinol Kbh 47: 657,
1964.

55.

Guha, S.K., Singh, G., Ansari, S., Kumar, S., Srivastava, A.,
Koul, V., Das, H.C., Malhotra, R.L. and Das, S.K. Phase II clinical
trial of a vas deferens injectable contraceptive for the male. Con­
traception 56: 245, 1997.

Roy, S., Greenblatt, R.B., Mahesh, V.B. and Jungck, E.C. Clo­
miphene citrate: Further observations on its use in induction of
ovulation in the human and on its mode of action. Fertil Steril
14: 575, 1963.

56.

Puri, C.P. and Van Look, P.F.A. Newly developed competitive
progesterone antagonists for fertility control. Front Horm Res
19: 127, 1991.

57.

Puri, C.P. Antiprogestins: Useful investigative tools and novel
contraceptives. Curr Sci 68: 407, 1995.

58.

Katkam, R.R., Gopalkrishnan, K., Chwalisz, K., Schillinger, E.
and Puri, C.P. Onapristonc (ZK 98.299): A potential antiprogestin
for endometrial contraception. Am J Obstet Gynecol 173: 779,
1995.

59.

Puri, C.P. Effects of antiprogestins on folliculogenesis, corpus
luteum function and endometrium of primates: Emerging con­
traceptive strategies: In: Current Concepts in Fertility Regula­
tion and Reproduction. Eds: C.P. Puri and P.F.A. Van Look.
Wiley Eastern Ltd, New Delhi, p 445, 1994.

60.

Nandedkar, T.D. and Raghavan, V.P. Control of ovarian folli­
cular maturation during menstrual parameters: New approaches
to female contraception. Adv Contracep Del Syst 5: 117, 1989.

41.

42.

43.

Lohiya, N., Manivannan, B. and Mishra, P.K. Non-invasive re­
versible vas occlusion with styrene maleic anhydride: A pos­
sible alternative for vasectomy. In: Reproductive Health. Eds.
C.P. Puri, J.M. Kasonde and P.F.A. Van Look, 1998 (in press).

44.

Zhao, S.C., Zhang, S.P. and Yu, R.C. Intravasal injection of
formed-in-place silicone rubber as a method of vas occlusion.
Int J Androl 15: 460, 1992.

45.

Rao, S.S., Sadri, K.K. and Sheth, A.R. The antigenicity of human
spermatozoa and its significance. Proceedings of Symposium
on Proteins. Wesley Press, Mysore, p 1, 1960.

46.

Bandivdekar, A.H., Koide, S.S., and Sheth, A.R. Antifertility
effects of human sperm antigen in female rats. Contraception
44: 559, 1991.

47.

Hegde, U.C., Premchandran, S.,-Fernandes, J.E.S. and Khole,
V. Immunochemical characterization and antifertility effect of

101
I

61.

Nandedkar, T.D., Parkar, S.G., Iyer, K.S.N., Mahale, S.D.,
Moodbidri, S.B., Mukhopadhyaya, R.R. and Joshi, D.S. Regu­
lation of follicular maturation by human ovarian follicular fluid
peptide. J Reprod Fertil 50 (Suppl): 95, 1996.

62.

Rao, S.S. and Shahani, S.K. The antigenicity of human chori­
onic gonadotrophin. Immunology 4: 1, 1961.

63.

Talwar, G.P., Sharma, N.C., Dubey, S.K., Salahuddin, M., Das,
C., Ramakrishnan, S., Kumar, S. and Hingorani, V. Isoimmu­
nization against human chorionic gonadotropin with conjugates
of processed p-subunit of the hormone and tetanus toxoid. Proc
Natl Acad Sci USA 73: 218, 1994.

75.

Tewari, P.V. Preliminary clinical trial on flowers of Hibiscus
rosa-sinensis as an oral contraceptive. J Res Indian Med Yoga
Homeopath 9: 96, 1974.

76.

Tewari, P.V., Sharma, S.K. and Basu, K. Clinical trial of an
indigenous drug as an oral contraceptive. J Natl Integ Med Assoc
18: 117, 1976.

77.

Chaudhury, R.R. A tale of six plants. In: Lectures in Contra­
ceptive Pharmacology. Ed. R.R. Chaudhury, Arun and Rejive
Printers, Chandigarh, p 36, 1981.

78.

Chaudhury, R.R., Mathur, V.S. and Sankarnarayanan P. Clini­
cal evaluation of plant contraceptives: Translating folklore into
scientific application. In: Pharmacologyfor Health in Asia. Eds.
B.N. Dhawan., K.K. Agarwal., R.B. Arora, and S.S. Parmar.
Allied Publishers, New Delhi, p 432, 1988.

64.

Griffin, P.D. The immunoregulation of fertility: Changes in
perspectives. Am J Reprod Immunol 35'. 140, 1996.

65.

Stevens, V.C. Progress in the development of human chorionic
gonadotropin antifertility vaccines. Am J Reprod Immunol 35:
148, 1996.

79.

Khatkhatay, M.I., Sankoli, G.M., Meherji, P.K., Chowdhary,
V. and Joshi, U.M. Excretion of estrone glucuronide in spon­
taneous and induced ovulatory cycles. Int JFertil 33: 181,1988.

66.

Talwar, G.P., Singh, 0., Rahul, P., Chatterjee, N., Suri, A.K.
and Shaha, C. Vaccines for control of fertility. Indion J Exp
Biol 30: 947, 1992.

80.

Khatkhatay, M.I., Desai, M.P., Meherji, P.K., Sankoli, G.M. and
Joshi, U.M. Screening of infertile women for detection of
occurrence of ovulation and assessment of corpus luteum func­
tion by ELISA of pregnanediol. Eur J Obstet Reprod Biol 38:
213, 1991.

67.

68.

69.

Gupta, S.K., Bagavant, H., Koothan, P.T., Talwar, G.P. Yurewicz,
E.C. and Sacco, A.G. Characteristics of monoclonal antibodies
against porcine zona pellucida-3 and their functional relevance.
Indian J Exp Biol 30: 1000, 1992.

Adiga, P.R., Karade, A.R., Visweswaria, S.S. and Sheshagiri,
P.B. Carrier protein mediated transplacental riboflavin transport
in the primate. In: Perspectives in Primate Reproductive Biol­
ogy. Eds. N.R. Moudgal, K. Yoshinaga, A.J. Rao and P.R.
Adiga, Wiley Eastern Ltd, New Delhi, p 129, 1991.
Natraj, U. Role of riboflavin carrier protein in the maintenance
of pregnancy in common marmosets (Callithrix jacchus). In:
Perspectives in Primate Reproductive Biology. Eds. N.R. Moudgal,
K. Yoshinaga, A.J. Rao and P.R. Adiga, Wiley Eastern Ltd, New
Delhi, p 141, 1991.

70.

71.

72.

73.

74.

102

Mahale, S.D., Kadam, L.R., Pereira, J., Natraj, U. and Iyer, K.S.N.
Studies on the delineation of the antigenic determinants of chicken
riboflavin carrier protein (cRCP): Identification of determinant
in the region of 10-24 of the protein. Int J Pept Protein Res 42:
28, 1993.
Natraj, U., Sabnis, T.M., Mahale, S.D. and Iyer, K.S.N. Termi­
nation of pregnancy in mice following administration of anti­
bodies to the pentadeca peptide 10-24 of chicken riboflavin carrier
protein. Identification of bioneutralysing epitope of chicken
riboflavin carrier protein. Vaccine 12: 431, 1994.
Chaudhury, R.R. Plants with possible antifertility activity. Special
Report Series No. 55. Indian Council of Medical Research, New
Delhi, 1966.

Chaudhury, R. R. The quest for a herbal contraceptive. Natl Med
J India. 6: 199, 1993.
Kamboj, V.P. A review of Indian medicinal plants with interceptive
activity. Indian J Med Res 87: 336,1988.

81.

Joshi, U.M., Raghavan, V.P. and Sheth, A.R. Development of
an enzyme linked immunoassay for human chorionic gonadot­
ropin. Indian J Med Res 65: 607, 1977.

82.

Shahani, S.K. and Moniz, C.L. Early pregnancy factor: Mini
review. Indian J Exp Biol 30: 951, 1992.

83.

National Family Welfare Programme: Achievemnts, Challenges
and Strategies. Department of Falmily Welfare, Mnistry of Health
and Family Welfare, Government of India, New Delhi, 1997.

84.

Reproductive Risk: A World-wide Assessment of Women‘s Sexual
and Maternal Health. 1995 Report on Progress Towards World
Population Stabilization. Population Action International, Wash­
ington D.C., 1995.

85.

Joshi, J.V., Mali, B.N., Hazari, K.T., Chitlange, S., Shah, R.S.,
Chadha, U. and Gokral, J. Abnormal cytology indicating sexu­
ally transmitted diseases in women attending family welfare clinic.
J Obstet Gynaecol India 41: 521, 1991.

86.

Mali, B.N., Joshi, J.V., Bhave, G.G. and Wagle, U.D. Cervical
cytology in prostitutes of Bombay, India. Genitourinary Med
68: 62, 1992.

87.

Balaiah, D., Ghule, M., Naik, D.D., Parida, R.C. and Hazari,
K.T. Fertility attitudes of men in an urban setting: A cross sectional
survey analysis. Adv Contracep Del Sys 13: 1, 1997.

88.

Puri, C.P. and Van Look, P.F.A. Editorial. In: Emergency
Contraception. The Federation of Obstetrics and Gynaecological
Societies of India, Mumbai, p 2, 1996.

This write-up has been contributed by Dr. C.P. Puri, Deputy
Director (Sr.Grade), Institute for Research in Reproduction,
Mumbai.

I

FI‘

ICMR NEWS
The following meetings of various technical groups/
committees of the Council were held :

Meetings of the Scientific Advisory Committees :
Institute for Research in
Medical Statistics, Chennai

September 28-29, 1998

ICMR Genetic Research
Centre, Mumbai

October 7, 1998

Institute for Research in
Reproduction, Mumbai

October 8-9, 1998

Regional Medical Research
Centre for Tribals, Jabalpur

October 12-13, 1998

National Institute of Virology,
Pune

October 15-16, 1998

Meetings of the Expert Group/Technical Advisory
Group/Sub-Group and other meetings:

Dr. S.K. Subbarao, Dy. Director (Sr.Grade), MRC,
Delhi, participated in the V meeting of the WHO Com­
mittee on Molecular Entomology at Geneva (September
27-28, 1998).
Dr. Aruna Dewan, Dy. Director, National Institute
of Occupational Health, Ahmedabad, participated in the
meeting of the Expert Group on Women and HealthMainstreaming the Gender Perspective into the Health
Sector at Tunis (September 28 to October 2, 1998).
Dr. Vasantha Thavaraj, Asstt. Director, All India
Institute of Medical Sciences, New Delhi, participated
in the International Conference of the Society of Paedi­
atric Oncology at Yokohama (October 4-8, 1998).
Dr. N.K. Ganguly, Director-General, ICMR, co­
chaired the XII meeting of the Joint Working Group of
the Indo-US Vaccine Action Programme at Washington
D.C. Dr. D.A. Gadkari, Director, National Institute of
Virology, Pune and Dr. P.R. Narayanan, Director, Tu­
berculosis Research Centre, Chennai, also participated
in the meeting.

Expert Group on Argemone
mexicana toxicity

September 19, 1998
(at New Delhi)

Technical Advisory Group
on Pharmacology and
Toxicology including
Traditional Medicine

September 22-23, 1998
(at New Delhi)

Dr. U.M. Donde, Dy. Director, Institute for Research
in Reproduction (IRR), Mumbai, participated in the VIII
Asia-Pacific Congress of Clinical Biochemistry at Kuala
Lampur (October 11-16, 1998).

Sub-Group on Hepatitis

September 25, 1998
(at New Delhi)

Dr. H.S. Juneja, Director, IRR, Mumbai, participated
in the regional symposium on Inter-regional Coopera­
tion on Reproductive Health Research : Asia and Pacific
at Shanghai (October 12-13, 1998).

Meeting of the Principal
Investigators of the district
nutrition project

October 14-15, 1998
(at New Delhi)

Participation of ICMR Scientists in Scientific Events:

Dr. Neeru Singh, Dy. Director, Malaria Research
Centre (MRC), Delhi, participated in the II European
Congress on Tropical Medicine at Liverpool (Septem­
ber 14-18, 1998). .
Dr. A. Roy Chowdhury, Dy. Director, Regional
Occupational Health Centre, Calcutta, participated in the
X International Symposium on Biological Monitoring
in Occupational and Environmental Health at Seoul (Sep­
tember 23-25, 1998).

Dr. A.K. Jain, Senior Research Officer, Institute of
Pathology, New Delhi, participated in the V conference
of the International Society for Trace Element Research
in Humans at Lyon (September 26-30, 1998).

Appointments :

Dr. S.K. Subbarao took over as the Director of the
Malaria Research Centre, Delhi w.e.f. October 9, 1998.
Honours/Awards :

Dr. G.B. Nair, Dy. Director, National Institute of
Cholera and Enteric Diseases, Calcutta, has been awarded
the 1998 Shanti Swarup Bhatnagar Prize in Medical
Science by the Council of Scientific and Industrial Re­
search for his outstanding work in characterizing a novel
toxin in Vibrio cholerae and identifying and characterizing
a new serogroup 0139 causing a cholera pandemic'
Dr. Kalyan Banerjee, former Director of the National
Institute of Virology, Pune and Dr. N.K. Ganguly,
Director-General, ICMR, have been awarded the Om
Prakash Bhasin Awards for Health and Medical Sciences
for the years 1996 and 1997 respectively.
103

ICMR AIDED SYMPOSIA/SEMINARS/WORKSHOPS/COURSES/CONFERENCES
Symposium/Seminar/Workshop/

Contact Address

Date & Place

Course/Conference

Symposium on Alzheimer’s Disease and Neurocognitive
Disorders

October 3-4, 1998;
(at Delhi)

Col. D.S. Goel, Senior Advisor (Psychiatry), Base
Hospital, Delhi Cantt-110010.

International Symposium on Temporomandibular Joint
Disorders and Chronic Orofacial Pain
.

October 30-31, 1998;
(at Mangalore)

Prof. P.K. Dayal, Organising Secretary of the Sym­
posium, KMC College of Dental Surgery, Man­
galore-575001.

Symposium on Current Trends in Autoimmun* ,-piseases
Immunology

October 30-31,1998;
(at Lucknow)

Prof. S. Naik, Department of Immunology, Sanjay
Gandhi Postgraduate Institute ofMedical Sciences,
Lucknow-226014.

XXXI Annual Conference of the Indian Pharmacological
Society

December 17-20,1998;
(at Lucknow)

Dr. V.N. Puri, Organisng Secretary of the Confer­
ence, Division of Pharmacology, Central Drug
Research Institute, Lucknow-226001.

COUNCIL’S TRAINING PROGRAMMES FOR 1998-99
Leprosy

Occupational Health

At the Central JALMA Institutefor Leprosy, Agra:

At the National Institute of Occupational Health,
Ahmedabad:

•

Multidrug Therapy Orientation Course in Leprosy for
Medical Officers (October 26-November 6; and
December 7-18, 1998).

•

Training Course on Environmental Hygiene Practice
(November 16-20,1998).

Reproductive Biology

Biomedical Statistics

At the Institutefor Research in Reproduction, Mumbai:

At the Institutefor Research in Medical Statistics, Chennai:

•

Workshop on Andrology for Clinicians (November 1630, 1998)

•

Basic Course in Statistics for Medical Officers
(November 30-December 6, 1998).

Nutrition

Haematology

At the National Institute of Nutrition, Hyderabad:

At the Institute of Immunohaematology, Mumbai:

•

Postgraduate Certificate Course in Nutrition
(December 1,1998-February 28,1999).

•

Training Course in Advanced Haematology and A.
Immunohaematology (September 21-October 9,1998).

EDITORIAL BOARD
Members
Dr. Padam Singh
Dr. Lalit Kant
Dr. Bela Shah
Dr. R. Ravi
Dr. V. Muthuswamy

Chairman
Dr. N.K. Ganguly
Director-General

Editor
Dr. N. Medappa
Printed and Published by Shri LN. Mathur for the Indian Council of Medical Research, New Delhi
at the ICMR Offset Press, New Delhi-110 029
R.N. 21813/71
Media
ICMR BULLETIN VOL. 28-No.-10-OCTOBER-1998.pdf

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