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Contraception and its significance in

Traditional System of Medicines

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Contraception and its significance in Traditional System of Medicines

V.Ravichandran1, G. Arunachalam2, N.Subramanian3 and B.Suresh4.

1
School of Pharmaceutical Sciences, Vels University, Chennai- 600 035, Tamilnadu, India.
2
PGP College of Pharmaceutical Science and Research Institute, NH-7, Namakkal - Karur Main Road, Namakkal
– 637207, Tamilnadu, India.
3
Bharathidasan Institute of Technology, Anna University Tiruchrappalli, Tiruchirappalli - 620 024, Tamilnadu,
India.
4
J S S University, Karnataka, Mysore, India.

Introduction assist in the majority of births. In

Traditional medicine refers to health
practices, approaches, knowledge and
beliefs incorporating plant, animal and
mineral based medicines, spiritual
therapies, manual techniques and
exercises, applied singularly or in
combination to treat, diagnose and
prevent illnesses or maintain well-being.
Countries in Africa, Asia and Latin
America use traditional medicine (TM)
to meet some of their primary health
care needs. In Africa, up to 80% of the
population uses traditional medicine for
primary health care. In industrialized
countries, adaptations of traditional
medicine are termed
“Complementary“or “Alternative”
(CAM).TM has maintained its
popularity in all regions of the
developing world and its use is rapidly
spreading in industrialized countries. In
China, traditional herbal preparations
account for 30%-50% of the total
medicinal consumption. In Ghana, Mali,
Nigeria and Zambia, the first line of
treatment for 60% of children with high
fever resulting from malaria is the use of
herbal medicines at home. WHO
estimates that in several African
countries traditional birth attendants
1
Europe, North America and other
industrialized regions, over 50% of the
population have used complementary or
alternative medicine at least once. In San
Francisco, London and South Africa,
75% of people living with HIV/AIDS
use TM/CAM. 70% of the population in
Canada has used complementary
medicine at least once. In Germany, 90%
of the population has used a natural
remedy at some point in their life.
Between 1995 and 2000, the number of
doctors who had undergone special
training in natural remedy medicine had
almost doubled to 10,800. In the United
States, 158 million of the adult
population use complementary
medicines and according to the USA
Commission for Alternative and
Complementary medicines, US $17
billion was spent on traditional remedies
in 2000. In the United Kingdom, annual
expenditure on alternative medicine is
US$ 230 million. The global market for
herbal medicines currently stands at over
US $ 60 billion annually and is growing
steadily.
Scientific evidence from randomized
clinical trials is very strong for many
uses of acupuncture, some herbal
medicines and for some of the manual
therapies. Further research is needed to
ascertain the efficacy and safety of
several other practices and medicinal
plants. Unregulated or inappropriate use
of traditional medicines and practices
can have negative or dangerous effects.
In addition to patient safety issues, there
is the risk that a growing herbal market
and its great commercial benefit might
pose a threat to biodiversity through over
harvesting of the raw material for herbal
medicines and other natural health care
products. These practices, if not
controlled, may lead to the extinction of
endangered species and the destruction
of natural habitats and resources.
Another related issue is that at present,
the requirements for protection provided
under international standards for patent
law and by most national conventional
patent laws are inadequate to protect
traditional knowledge and biodiversity.
Tried and tes ted methods of
products
25% of modern medicines are made
from plants first used traditionally.
Acupuncture has been proven effective
in relieving postoperative pain, nausea
during pregnancy, nausea and vomiting
resulting from chemotherapy, and dental
pain with extremely low side effects. It
can also alleviate anxiety, panic
disorders and insomnia. Yoga can reduce
asthma attacks while Tai Ji techniques
can help the elderly reduce their fear of
falls. TM can also have impact on
infectious diseases. For example, the
Chinese herbal remedy Artemisia annua,
used in China for almost 2000 years has
been found to be effective against
resistant malaria and could create a
breakthrough in preventing almost one
million deaths annually, most of them
2
children, from severe resistant malaria.
In South Africa, the Medical Research
Council is conducting studies on the
efficacy of the plant Sutherlandia
microphylla in treating AIDS patients.
Traditionally used as a tonic, this plant
may increase energy, appetite and body
mass in people living with HIV.
Priorities for prom oting th e use
of traditional medicines
Over one-third of the population in
developing countries lack access to
essential medicines. The provision of
safe and effective TM/CAM therapies
could become a critical tool to increase
access to health care. Like China, the
Democratic People’s Republic of Korea,
the Republic of Korea and Vietnam have
fully integrated traditional medicine into
their health care systems and many
countries are yet to collect and integrate
standardized evidence on this type of
health care.70 countries have a national
regulatory body on herbal medicines but
the legislative control of medicinal
plants has not evolved around a
structured model. This is because
medicinal products or herbs are defined
differently in different countries and
diverse approaches have been adopted
with regard to licensing, dispensing,
manufacturing and trading (http:// www.
who.int/medicentre/factsheets/fs134/en/)
.
Indian traditional medicine
India has an ancient heritage of
traditional medicine. The Materia
Medica of India provides a great deal of
information on the folklore practices and
traditional aspects of therapeutically
important natural products. Indian
traditional medicine is based on various
systems including Ayurveda, Siddha,
and Unani. The evaluation of these drugs
is primarily based on phytochemical,
pharmacological, and allied approaches
including various instrumental
techniques such as chromatography,
microscopy and others. These traditional
systems of Indian medicine are unique in
their way but there is a common thread
in their fundamental principles and
practices. With the emerging worldwide
interest in adopting and studying
traditional systems and exploiting their
potential based on different health care
systems, the evaluation of the rich
heritage of traditional medicine is
essential. The government and the
private sector are exploring all of the
possibilities for the perfect evaluation of
these systems in order to effectively
adopt the therapeutic approaches
available in original systems of medicine
as well as to help in generating data to
put these products on the national health
program.
India's indigenous systems of medicine,
such as Ayurveda, Siddha, and Unani,
are more than 5000 years old, but they
have steadily lost ground to the power of
modern medicine. An all-India
household survey found that 80% of the
households in urban areas used
allopathic medicine and only 4% used
Ayurvedic drugs. The survey also found
that people spent more on allopathic
medicine than Ayurvedic. In urban and
rural areas alike, low-income groups in
particular were spending a substantial
amount on allopathic medicine. During
the 19th and first half of the 20th century
the traditional systems were gradually
replaced by modern medicine. From the
1920s to the mid-1940s, provincial
3
governments and popular leaders like
Mahatma Gandhi made various efforts to
reverse this trend. However, in 1946,
when India's first national health care
policy was outlined by the Bhore
Committee, traditional practices were
completely ignored. The World Bank
has recently recommended that tertiary
curative health care should be left to the
private sector, concentrating only on
primary health care in rural areas. This
would ensure the death of these systems.
A sound national health policy, on the
other hand, would put the indigenous
systems of medicine back on the map. A
case in point is Sri Lanka's
comprehensive policy to sustain
indigenous medicine by setting out a
comprehensive national policy. It has
nearly 13,000 Ayurvedic physicians (1
per 1400 population). India has about
380,000 practitioners (1 per 2200
population). India's policies on
indigenous medicine could go a long
way towards solving the problems. A
much larger proportion of the central
government's health budget should be
allocated to indigenous systems of
medicine. At present they receive only
4.8% of it.
Herbal contraception
For centuries herbal preparations have
been connected with the goal of
preventing, and or disrupting pregnancy.
It is impossible for us to say how
effective they were as much of the
information remains scarce and
fragented, most recipes are very old and
were transmitted orally and information
was closely guarded to avoid persecution
during the burning times. Some
historical information remains
unresolved to this day. However, exact
recipes are rare, and effectiveness rates
are untested in our modern society.
Scientific researchers have done some
research on botanical anti-fertility
agents; some findings have been very
interesting and promising.
Unfortunately, there is not a lot of
money to be made from herbal drugs
unless botanical compounds can be
extracted, refined, patented and proven
safe, so pharmaceutical companies can
make a profit from marketing the
discovery to the general public. China
and India are two countries that have
done quite a bit of research on herbal
contraceptives.
Numerous herbs have been used
historically to reduce fertility, and
modern scientific research has confirmed
anti-fertility effects in at least some of
the herbs tested. Herbal contraception
may never reach the level of
contraceptive protection as the pill, but it
offers alternatives for women who have
difficulty with modern contraceptive
options or who just want to try a
different way. Very little is known about
many of the herbs, or about long term
side effects or safety concerns.
There's not much information available
on using herbs for contraception, but
there are historical references with clues
to what ancient women did, and the
scientific community has published
some studies, mostly on animals,
showing some of the herbs do seem to
have contraceptive effects. There have
also been informal studies where the
herbs were tested by women for
contraception. Each herb has its own
way of being taken; some are taken
daily, while others are used on need
based manner, after potential exposure to
sperm during a fertile time. Generally,
herbs that are taken on a daily basis need
4
some time to take effect; an alternative
method of birth control should be used
during the waiting period to provide
protection. So it’s important to know
how they are used, when to take them
and how much to use [1].
Herbal contraceptives
Herbal contraceptives are a category of
herbs that have an anti-fertility effect.
There are many different ways in which
herbs can impair fertility. Some herbs
may affect the ovary, while others act
upon the uterus, affect normal hormone
production or block certain hormones.
For several of these we don't really
understand their action or how they got
their reputation. Some herbs have the
ability to interfere with implantation,
these herbs can be taken on as needed
basis, and are useful as an emergency
contraceptive. There are also some herbs
that have been found to interfere with
normal sperm production, or mobility.
Each herb is used in its own way, so it’s
important to have some idea of how they
are used, or could be used.
Daily herbal contraceptives
Some herbal contraceptives have a
cumulative effect in the body, they need
to be taken regularly (usually daily) to
maintain the contraceptive effect. They
often need a period of time to establish
their effectiveness and have a barrier
method should be employed; examples
are wild yam and neem.
Wild Ya m is a good example of a
typical herbal contraceptive, taken daily,
needing a period of time to establish
effectiveness and mixed results reported.
There is absolutely no scientific
documentation is available. Doses must
be taken twice daily, and never
forgotten. The herb needs to be taken for
a minimum of one month to allow it time
to take effect, waiting two months, may
even be better before
relying on it for birth control [2].
Neem (Azadirachta indica) a tree from
India, with numerous uses, used for just
about anything and everything. Quite a
bit of scientific research is available
about this herb, for both general uses as
well as for contraceptive uses. Most of
the research has been conducted in India.
There are commercial preparations
available that can be used for
contraception for both men and women.
For women it is used vaginally as a
spermicide, and men use it orally as a
daily contraceptive to induce temporary
sterility.
Queen Anne's Lace Seeds can also be
used as a daily contraceptive or only
during fertile times as an implantation
inhibitor.
Pomegranate (Punica granatum), a fruit
is used by ancient women to prevent
conception. The seeds of the fruit
contain an oestrone identical to the
natural hormone estrogen.
Implantation inhibitors
Some herbal contraceptives have the
ability to interfere with implantation, the
actual effect in the body can vary from
herb to herb, but the end result makes it
difficult for the egg to implant or
maintain its grip on the uterine wall.
Implantation occurs about 6 days after
the egg has been fertilized. If the egg is
unable to get a grip on the uterine wall, it
5
cannot survive, it begins to break down,
and menstruation will arrive as usual.
The seeds of Queen Anne's lace (QAL)
(Daucus carota) also known as Wild
Carrot, seem to have the best reputation
for contraception. Women from the
Appalachian Mountains to India have
used the mature seeds to reduce their
fertility. This herb is in use today, and
has some documentation to its
effectiveness, both in scientific studies
and through individuals who have used
it. QAL seed seems like a good
reliable option. It does not need to be
used daily to be effective. If a woman
knows she was exposed to sperm during
a fertile time, QAL seeds can be used
like an emergency contraceptive, an after
the fact preventive. One of its biggest
advantages is that it can be taken on as
needed basis, making it useful for
women who have sex in frequently
(http://www. sisterzeu.com/index.html).
The plant also grows wild in many areas,
though positive identification is a must.
Scoope out patches while the flower is in
bloom in August and return later to
collect the seeds. To the inexperienced,
wild carrot could be confused with other
poisonous members of the carrot/parsley
family. Once familiar with the plant it is
easy to identify, the flower in bloom is
very distinctive, and just remembers
Queen Anne has hairy legs (the stem is
hairy rather than smooth).
Rutin - This is found at local health food
markets. It is also known as Vitamin P.
It can be used to prevent pregnancy,
when taken in tablet form in doses of at
least 500 mg daily for several days
preceeding and following ovulation, or
when taken after intercourse and
continue until menstruation begins.
Neem Oil has also been found to prevent
implantation. Testing so far has involved
rats; the implantation inhibitory effects
were seen in as many as 10 days after
intercourse occurred, although it was
most effective if used within 3 days of
fertilizing intercourse.
Smartweed leaves (Polygonum
hydropiper) - Smartweed grows as a
weed all over the world, and is used
worldwide as a fertility regulator. It
contains rutin, quercitin and gallic acid,
all of which interfere with normal
pregnancy. An infusion can be prepared
using 4 ounces of the fresh leaves or one
ounce of the dried leaves in a quart of
boiled water. Drinking freely until
menstrual bleeding begins. Smartweed
may be used to prevent implantation
after fertilizing intercourse, or to bring
on a missed period. Apricot Kernels
Suspected to have anticancer qualities
which might treat the developing foetus
as a foreign body. 5-10 apricot kernels
three times a day immediately after
following fertilizing intercourse and
continuing until menstruation comes [3].
Neem - herbal contraceptive
Lots of research has been done in India
on neem and its contraceptive effects. It
seems to have several contraceptive
applications, as spermicide and an oral
contraceptive for men, and two other
options which would only be available
through qualified medical research
personal at this time. Neem provides
men with an alternative oral
contraceptive option, Neem leaf tablets.
Research conducted on 20 married
soldiers from the Indian Army over the
course of one year showed that a daily
oral dose of several drops of neem seed
oil placed in gelatin capsules prevented
6
pregnancy in each of the wives during
the period of the study. The effect took 6
weeks to become 100% effective. The
effects were reversed within 6 weeks
after subjects discontinued taking the
capsules. During the study, none of the
men experienced any negative side
effects and retained their normal
capabilities and desires [4]. Neem is
currently being used in India as a
spermicide for contraceptive purposes
for both men and women.
Neem - birth control
Vaginal creams and suppositories made
with neem oil are quickly becoming the
birth control method of choice in India
[5, 6]. They are non-irritating and easy
to use while almost 100 percent
effective. It's important to note,
however, that even toxic spermicides are
not 100 percent effective. When tested
against human sperm, neem extract
(sodium nimbidinate) at 1000 mg was
able to kill all sperm in just 5 minutes
and required only 30 minutes at a 250
mg level. [7, 8, 9]. They have the added
benefit of preventing vaginal and
sexually transmitted diseases [10]. Neem
has a proven ability to prevent
pregnancy. Neem oil has also been
shown to work well both before and
after sex while some purified extracts
only worked before sex as a preventive.
[6]. Neem oil appears to be the most
effective form of neem for birth control,
particularly hexane extracted neem oil.
After a single injection of a minute
amount of neem oil in the uterine horns,
a strong cell-mediated immune response
reaction produced a long term (up to 12
months) and reversible block in fertility
[11,12].
Neem oil has also been found to prevent
implantation and may even have an
abortifacient effect similar to
pennyroyal, juniper berries, wild ginger,
myrrh and angelica. The effects were
seen as many as ten days after
fertilization in rats though it was most
effective at no more than three days [9].
In a study on rats, neem oil was given
orally eight to ten days after
implantation of the fetus on the uterine
wall. In all cases, by day 15, the
embryos were all completely resorbed
by the body. The animals regained
fertility on the next cycle showing no
physical problems. Detailed study of the
rats revealed increased levels of gamma
interferon in the uterus. Years of study in
India by some of the world's leading
scientists resulted in the development of
a neem-based polyherbal vaginal cream
that has both spermicidal and anti-
microbial action. The cream combines
25 per cent neem seed extract with
extracts from the soap nut and quinine
hydrochloride. Based on the success of
these experiments, a neem-based
contraceptive cream was developed by a
pharmaceutical company in India. Tests
of its effectiveness showed that it
compared favorably with the chemical-
based foams and gels. It was safer and
easier to use, caused no irritation or
discomfort, was nearly 100% effective,
and was therefore used more frequently
than the foam or gel spermicides [5].
The effect does not appear to be
hormonal and is considered a safe and
effective alternative to other methods
that use hormones [13, 14].
The studies leading to the development
of these products proved that neem oil
killed sperm in the vagina within thirty
seconds and was effective for up to five
hours. Most spermicide creams must be
7
reapplied at least every hour [9]. An
important effect of neem oil used in the
vagina is that it seems to increase the
antigen presenting ability of the uterine
tract. This activation of the local
immune cell population has a direct
spermicidal effect without apparent side
effect. Neem may become the first truly
effective birth control "pill" for men [8].
Neem leaf tablets ingested for one month
produced reversible male antifertility
without affecting sperm production or
libido [15]. In India and the United
States, exploratory trials show neem
extracts reduced fertility in male
monkeys without inhibiting libido or
sperm production.
In a test of neem's birth control effects
with members of the Indian Army, daily
oral doses of several drops of neem seed
oil in gelatin capsules were given to
twenty married soldiers. The effect took
six weeks to become 100 percent
effective, it remained effective during
the entire year of the trial and was
reversed six weeks after the subjects
stopped taking the capsules. During this
time the men experienced no adverse
side effects and retained their normal
capabilities and desires, there were no
pregnancies of any of the wives during
the period of the study [4]. For long term
birth control for men it appears that a
very minute amount of neem oil injected
in the vas deferens provides up to eight
months of birth control. The tests
revealed no obstructions, no change in
testosterone production and no anti-
sperm antibodies. The local lymph nodes
showed increased ability to respond to
infections indicating an immune
response may be responsible for the birth
control effect in men as it is in women
[16].
Neurohormonal control of the
female reproductive system
At puberty, an increased output of the
hormones of the hypothalamus and
anterior pituitary stimulates secretion of
oestrogenic sex steroids. These are
responsible for the maturation of the
reproductive organs and the
development of the secondary sexual
characteristics, and also or a phase of
accelerated growth followed by closure
of the epiphyses of the long bones. Sex
steroids are there after involved in the
regulation of the cyclic changes
expressed in the menstrual cycle and are
important in pregnancy.
A simplified outline of the inter-
relationship of these substances in the
physiological control of the menstrual
cycle is given in Figure 01 and 02.The
menstrual cycle begins with
menstruation, which lasts for 3-6 days
during which the superficial layer of
uterine endometrium is shed. The
endometrium regenerates during the
follicular phase of the cycle after
menstrual flow has stopped. A releasing
factor, the gonadotrophin-releasing
hormone (GnRH), is secreted from
peptidergic neurons in the hypothalamus
in a pulsatile fashion, the frequency
being about 1 burst of discharges per
hour, and stimulates the anterior
pituitary to release gonadotrophic
hormones, follicle-stimulating hormone
(FSH) and luteininsing hormone (LH).
These act on the ovaries to promote
development of small groups of follicles,
each of which contains an ovum. One
follicle develops faster than the others
and forms the Graafian follicle, and the
rest degenerate. The ripening Graafian
follicle consists of thecal and granulosa
cells surrounding a fluid filled centre
8
within which lies an ovum. Oestrogens
are produced by the granulosa cells
stimulated by FSH, from androgen
precursor molecules derived from thecal
cells stimulated by LH.
Oestrogens are responsible for the
proliferative phase of endometrial
regeneration, which occurs from day 5
or 6 until midcycle. During this phase,
the endometrium increases in thickness
and vascularity, and at the peak if
oestrogen secretion there is a prolific
cervical secretion of mucus of pH 8-0,
rich in protein and carbohydrate, which
facilitates entry of spermatozoa.
Oestrogen has a negative feedback effect
on the anterior pituitary, decreasing
gonadotrophin release during chronic
administration of oestrogen as oral
contraception. In contrast, the high
endogenous oestrogen secretion just
before midcycle sensitises LH-releasing
cells of the pituitary to the action of the
GnRH and causes the midcycle surge of
LH secretion. This, in turn, causes rapid
swelling and rupture of the Graafian
follicle, resulting in ovulation. If
fertilisation occurs, the fertilised ovum
passes down the fallopian tubes to the
uterus, starting to divide as it goes.
Stimulated by LH, cells of the ruptured
follicle proliferate and develop into the
corpus luteum, which secretes
progesterone. Progesterone acts, in turn,
on oestrogen-primed endometrium,
stimulating the secretary phase of the
cycle, which renders the endometrium
suitable for the implantation of a
fertilised ovum. During this phase,
cervical mucus becomes more viscous,
less alkaline, less copious and in general
less welcoming for sperm. Progesterone
exerts negative feedback on
hypothalamus and pituitary, decreasing
the release of LH. It also has a
thermogenic effect, causing a rise in
body temperature of about 0.5C at
ovulation, which is maintained until the
end of the cycle. If implantatin of the
ovum does not occur, progesterone
secretion stops, triggering menstruation.
If implantation does occur, the corpus
luteum continues to secrete
progesterone, which, by its effect on the
hypothalamus and anterior pituitary,
prevents further ovulation.
The chorion (an antecedent of the
placenta) secretes human chorionic
gonadotrophin (HCG), which maintains
the lining of the womb during
pregnancy. For reasons that are not
Figure 01
9
physiologically obvious, HCG has an
additional pharmacological action in
stimulation ovulation. As pregnancy
proceeds, the placenta develops further
hormonal functions and secretes a gamut
of hormone variants (often with post-
translational modification), including
gonadotrophins as well ad progesterone
andoestrogens; Progesterone secreted
during pregnancy controls the
development of the secretory alveoli in
the mammary gland, while oestrogen
stimulated the lactiferous ducts. After
parturition, oestrogens, along with
prolactin, are responsible for stimulating
and maintaining lactation, whereas high
doses of exogenous oestrogen supress
this [17].
Fig.1. Hormonal in ter-relationship in
the control of the female reproductive
system. The Graafian follicle (GF) is
shown developing on the left, then
involuting to form the corpous luteum
(CL) on the right, after the ovum (.) has
been released. , (LH, lutenising
hormone; FSH, follicle-stiulating
hormone; GnRH, gonadotrophin-
releasing hormone).
 Figure 02
Fig.2. Pl asma conc entrations of
ovarian h ormones a nd
gonadotrophinsin women duri ng
normal menstrua l cycles. Values are
mean ± standard deviation of 40 women.
The shaded areas indicate the entire
range of observations. Day 1 is the onset
of menstreuation. E and F show
diagrametically the changesin the
ovarian follicle and the endomerium
during the cycle. Ovulation on day 14 of
the menstrual cycle occurs with the mid
cycle peak of LH, represented by the
vertical dashed line. (LH, lutenising
hormone; FSH, follicle-stimulating
hormone; A, arterioles; V, venules.)

Figure 03

Fig.3. The biosynthetic pathway for the androgens and oestrogens with sites of drug action.
Finasteride is used in benign prostatic hyperplasia and formestane to treat breast cancer in
postmenopausal women.

10
Behavioral ef fects of s ex
hormones
As well as controlling the menstrual
cycle, sex steroids affect sexual
behaviour. Two types of control are
recognized, namely organizational and
activation. The former refers to the fact
that sexual differentiation of the brain
can be permanently altered by the
presence or absence of sex steroids at a
key stage in development. In rats,
administration of androgens to females
within a few days of birth results in
long-term virilisation of behavior.
Conversely, neonatal castration of male
rats causes them to develop behaviorally
as females. Brain development in the
absence of sex steroids follows female
lines, but it is switched to the male
pattern by exposure of the hypothalamus
to androgen at a key stage of
development. Similar but less-complete
behavioural virilisation of female
offspring has been demonstrated
following androgen administration in
non-human primates and probably also
occurs in humans if pregnant women
secrete or are treated with androgens.
The activational effect of sex steroids
refers to their ability to modify sexual
behaviour after brain developments
complete. In general, oestrogens and
androgens increase sexual activity in the
appropriate sex. Oxytocin, which is
important during parturition, also has
roles in mating and parenting
behaviours, its action in the central
nervous system being regulated by
oestrogen.
Oestrogens
Oestrogens are synthesized by the ovary
and placenta, and, in small amounts, by
the testis and adrenal cortex. As for other
11
steroids the starting substance for
oestrogen synthesis is cholesterol. The
immediate percursors to the oestrogens
are androgenic substances-
androstenedione or testosterone. There
are three main endogenous oestrogens in
humans-oestradiol, oestrone and oestriol.
Oestradiol is the most potent and is the
principal oestrogen secreted by the
ovary. At the beginning of the menstrual
cycle, the plasma concentration is 0.2
nmol/l rising to 2.2 nmol/l in mid
cycle.
Oestrogen acts in concert with
progesterone and induces synthesis of
progesterone receptors in uterus, vagina,
anterior pituitary and hypothalamus.
Conversely, progesterone decreases
oestrogen receptor expression in the
reproductive tract, by reducing their
synthesis. Prolactin also influences
oestrgen action by increasing the
numbers of oestrogen receptors in the
mammary gland but has no effect on
oestrogen receptor expression in the
uterus.
Effects of exogenous oestrogen depend
on the state of sexual maturity when the
oestrogen is administered:
 In primary hypogonadism:
oestrogen stimulates
development of secondary sexual
characteristics and accelerates
growth
 In adults with primary
amenorrhoea: oestrogen, given
cyclically with a progestogen,
induces an artificial cycle
 In sexually mature women:
estrogen (with a progestagen) is
contraceptive
 At or after the menopause
oestrogen replacement prevents
menopausal symptoms and bone
loss.
Oestrogens have several metabolic
actions, including mineral corticoid
(retention of salt and water) and mild
anabolic actions. They increase plasma
concentrations of high density
lipoproteins, a potentially beneficial
effect that may contribute to the
relatively low risk of atheromatous
disease in premenopausal women
compare with men of the same age.
Oestrogens increase the coagulability of
blood, and contraceptive pills containing
high oestrogen content increase the risk
of thromboembolism. This effect is dose
related.
As with other steroids, oestrogen binds
to intracellular receptors. There are at
least two types of oestrogen receptors,
termed ER, and ERβ the roles of which
are currently being investigated using
mice in which the gene coding one or
other of these has been “knocked out”.
Binding is followed by interaction of the
resultant complexes with nuclear sites
and subsequenct genomic effects-either
gene transcription (i.e. DNA-directed
RNA and protein synthesis) or gene
repression (inhibition of transcription).
In addition to these “classical”
intracellular receptors evidence is
emerging that some oestrogen effects, in
particular rapid vascular actions, may be
mediated via membrane receptors. Acute
vasodilation caused by 17--oestrodial is
mediated by nitric oxide, and a plant-
derived (phyto) oestrogen called
genistein (which is selective for ER, as
well as having quite distinct effects from
inhibition of protein kinase) is a potent
17--oestrodial in this regard. There is
12
considerable therapeutic interest in
receptor-selectable oestrogen agonists or
antagonists for different indications.
One drug, raloxifene, has been dubted in
“Selective oestrogen receptor
modulator” (SERM). It has
antioestrogenic effects on breast and
endometrial tissue but oestrogenic
effects on bone, lipid metabolism and
blood coagulation. It is licensed in the
UK for treatment and prevention of
postmenopausal osteoporosis. Unlike
hormone replacement treatment (HRT),
raloxifene does not improve menopausal
flushing; however, among
postmenopausal women drug, terpatide,
is being developed for osteoporosis in
men as well as women. Other agents
with different specifications are in
development, and oestrogen receptor
pharmacology is a space worth
watching!
Many preparation (oral, transdermal,
intramuscular, implantation and topical)
of oestrogens are available are for a wide
range indications. These preparations
include natural (e.g. estradiol, estriol)
and synthetic (e.g. mestranol,
ethinylestradiol, Stilbosterol) oestrogens.
Oestrogens are presented either as single
agents or combined with progestogen.
Very different doses of oestrogen are
used for different conditions, for
example ethinylestradiol is used in a
dose of 10—20 μg/day for
postmenopausal hormone replacement
therapy. 20—50 µg/day in the combined
contraceptive pill, 1-3 mg/day for breast
cancer. The clinical use of oestrogens
and anti-oestrogens is given in the box.
Unwanted effects of oestrogens include
tenderness in the breasts, nausea,
vomiting, anorexia, retention of salt and
water with resultant oedema, and
increased risk of thromboembolism.
Used intermittently for postmenopausal
replacement therapy, estrogens cause
menstruation-like bleeding. Oestrogen
causes endometrial hyperplasia unless
given cyclically with a progestogen.
When administered to males, oestrogens
result in feminization.
Oestrogen administration to pregnant
women can cause genital abnormalities
intheir offspring. Carcinoma of the
vagina was more common in young
women whose mothers were given
stilboestrol in early pregnancy in a
misguided attempt to prevent
miscarriage.
Anti-oestrogens
Anti-oestrogens compete with natural
oestrogens for receptors in target organs.
Tamoxifen has anti-oestrogenic action
on mammary tissue but oestrogenic
actions on plasma lipids, endometrium
and bone. It produces mild oestrogen-
like adverse effects consistent with
partial agonist activity. The tamoxifen—
oestrogen receptor complex does not
readily dissociate, so there is
interference with the recycling of
receptors. Tamoxifen up regulates
transforming growth factor-13 (TGF-
decreased function of which is
associated with the progression of
malignancy; this may play a part in its
anticancer action. The anti osteoporotic
action of tamoxifen may also be related
to up regulation of TGF-t3 since this
cytokine h a role in controlling the
balance between bone-producing
osteoblasts or bone-resorbing
osteoclasts.
Clomiphene inhibits oestrogen binding
in the anterior pituitary, so preventing
13
the normal modulation by negative
feedback and causing increased secretion
of GnRH and gonadotrophins. This
results in a marked stimulation and
enlargement of the ovaries and increased
oestrogen secretion. The main effect of
their anti-oestrogen action in the
pituitary is that they induce ovulation.
These compounds are used in treating
infertility caused by lack of ovulation.
Twins are common, but multiple
pregnancies are unusual.
Progestogens
The natural progestational hormone
(‘progestogen’) is progesterone (Figuer
02 and 03). This is secreted by the
corpus luteum in the second part of the
menstrual cycle, and by the placenta
during pregnancy. Small amounts are
also secreted by testis and adrenal
cortex.
Progestogens act, as do other steroid
hormones, on intracellular receptors.
The density of progesterone receptors is
controlled by oestrogens.
There are two main groups of
progestogens.
 The naturally occurring hormone
and its derivatives (e.g.
hydroxyprogesterone,
medroxyprogesterone,
dehydrosterone). Progesterone
itself is virtually inactive orally
because after absorption it is
metabolised in the liver and
hepatic extraction is nearly
complete. Other preparations are
available for oral administration,
intramuscular injection or via the
vagina or rectum.
 Testosterone derivatives (e.g.
norethisterone, norgestrel, and
ethynodiol) can be given orally.
The first two have some
androgenic activity and are
metabolised to give oestrogenic
products. Newer progestogens
used in contraception include
desogestrel and gestodene; they
may have less adverse effects on
lipids than ethynodiol and may
be considered for women who
experience side-effects such as
acne, depression or breakthrough
bleeding with the older drugs.
However, these newer drugs have
been associated with higher risks
of venous thromboemboric
disease.
The pharmacological actions of the
progestogens are in essence the same as
the physiological actions of
progesterone.
Unwanted effects of progestogen include
weak androgenic actions of some of the
progestogens derived from testosterone.
Other unwanted effects include acne,
fluid retention, weight change,
depression, change in libido, breast
discomfort, premenstrual symptoms,
irregular menstrual cycles breakthrough
bleeding. There is an increased incidence
of thromboembolism.
Antiprogestogens
Mifepristone is a partial agonist at
progesterone receptors It sensitizes the
uterus to the action of prostaglandins.It
is given orally and has a plasma half-life
of 21 hours. Mifepristone is used as a
medical alternative to surgical
termination of pre box. If given in the
late follicular phase of the menstrual
14
cycle mifepristone inhibits ovulation and
hence has potential as a postcoital
contraceptive agent.
Postmenopausal Hormone
Replacement Therapy
At the menopause, both natural or
surgically induced ovarian function
decreases and oestrogen levels fall.
Gonadoropin secretion increases because
of loss of negative feed back. Oestrogen
replacement (HRT) has sonic clear-cut
benefits;
 Improvement of symptoms
caused by reduced oestrogen for
example vasomotor symptoms
(hot flushes) and vaginitis.
 Prevention and treatment of
osteoporosis.
Additional possible benefits of oestrogen
replacement have been suggested.
 A possible reduction in the risk
of coronary heart diseases, the
commonest cause of death in
postmenopausal women.
epidemiological studies suggest
that there is a 50% reduction, but
a large randomized controlled
trial of secondary prevention
was negative. Further
randomized trials of primary
prevention somewhat younger
postmenopausal women are
under way.
 Some observational studies have
raised the possibility that women
on HRT have a reduced
incidence and/or a delayed onset
of Alzheimer’s disease, but other
studies have not. There are no
 data so far from randomized
trials.
The us e of HRT has some
definite drawbacks.
 Uterine bleeding; this occurs if
withdrawal of oestrogen and
cyclical progestogens are
included in the HRT regimen as
is needed unless the woman has
had a hysterectomy.
 Mood changes and other, usually
mild, adverse effects related to
progestogen
 An increased risk of endometrial
cancer if oestrogen is given
unopposed by progestogen.
Progestogens are, therefore,
given, usually for 10 days each
month, to women with an intact
uterus.
 An increase in the risk of breast
cancer, related to the duration of
HRT use and disappearing within
5 years of stopping. The
epidemiological evidence
suggests that about 45 women in
1000 aged 50 and not using HRT
will have breast cancer diagnosed
during the next 20 years; this is
creased by 2 cases (in 1000)
among those using HRT for 5
years, by 6 for those using it for
10 years and by 12 for those
using it for 15 years. This
contrasts dramatically with
raloxifene, which prevents
postmenopausal osteoporosis
without improving vasomotor
symptoms of oestrogen
deficiency but reduces the risk of
breast cancer.
15
 An increased risk of venous
thromboembolism. This is not so
great as to affect the overall
positive balance of benefit to risk
of HRT for most women, but
shifts this unfavorably in women
who have other risk factors for
venoi’s thrombosis.
Oestrogens used in HRT can be given
orally (conjugated estrogens, estradiol,
estriol), vaginally (estriol), by
transdermal patch (estradiol) or by
subcutaneous implant (estradiol).
Tiholone is marketed for the treatment of
postmenopausai symptoms and
prevention of osteoporosis. It has
oestrogenic, progestogenic and weak
androgenic activity and can be used
continuously without cyclical
progesterone (avoiding the
inconvenience of withdrawal bleeding).
There is still some controversy about the
use of HRT- but many authorities
consider that the benefits outweigh the
risks for most women. One 20-year
retrospective study using data from
34,000 women showed a 20% reduction
in overall mortality for HRT users, the
reduction being greater for women with
a higher risk of coronary disease.
Survival benefits decrease with longer
duration of use.
Antifertility research- an update
Literature with regard to fertility control
is well documented throughout the
globe. In this field, the research
activities are mainly targeted against oral
contraceptives, preparation of vaccines
and herbal medications to regulate
fertility.
There are several methods of controlling effect of Aristolic acid from Aristolochia
child birth like, indica (Linn) [20], folk herbal medicines
used in birth control and sexual diseases
Chemical - Hormonal methods by tribal of southern Rajasthan, India,
with steroidal oral showed 53 plants belonging to 33
contraceptive pills families have been reported from the
containing varying study area, which are used to cure sexual
doses of synthetic diseases and for family planning [21].
estrogen and
progestogen. On the other hand studied anti
spermatogenic effect of extract of
Barriers - Condoms for male Aristolochia indica linn on male mice
and diaphrags for [22] that showed a marked decreased in
female. the weight of testis and other accessory
genetal organs of male mice. Badami
Vaccines -Anti-HCG, GnRH,
have reported traditional physician in
FSH
and around Kotagiri village near
Natural methods - Coitus interrupts, safe Ootacamund, use a mixture of powdered
periods. roots of Cassia occidentalis,
Derris brevipes variety coriaceae and
Surgical interventions - Tubectomy Justicia simplex to control female
and vasectomy. fertility [23] ethanol extracts were
screened for antifertility activity in
Devices - IUDs, Vaginal rings proven fertile female rats. Bhandary
Natural products - Azadiracta indica. have reported the medical ethnobotany
of the siddis of uttara Kannada district,
No method, however, is suitably Karnataka, India, showed that 40
accepted without any interventions in hitherto unknown medicinal uses of
physical, psychological or sociological known medicinal plants. Among these,
problems. the use of the stem sap of Calamus
thwaitesii as an antifertility drug, and the
use of the flowers of Ichnocarpus
Plants used as possible frutescens and the rhizome of
antifertility agents Hedychium coronarium in the treatment
of diabetes [24], the aristalic acid from
Literatures in regard to fertility control Aristolia indica showed post coital
using herbal preparations are well pregnancy terminating activity in mouse
documented. Previously reported the [25], antiferility effect on
antifertility chromene from B1 spermatogenesis of ethanolic leaf
Epharispermum subsessile showed that extracts of Azadirachta indica,
isolated active constituent Beaumontia grandiflora, Chordia
desmethyilisoencecalin has anti- dichotoma, Casiarea tomentosa,
implantation activity [18], Diospyros embryopteris and Melia
antiimplantation activity and azedarach [26], hormonal requirement
abortifacient activity of vicolide D for blastocyst implantation and a new
isolated from Vicoa indica DC [19], approach for anti-implantation strategy
antiestrogenic and anti-implantation
16
[27], toxicity of Solanum lycocarpum in
the reproductive system of male mice
and rats the significant weight loss was
observed only in the ventral prostate of
mice receiving the high dose treatment
[28], the Trans-Anethole is an essential
oil showing 100% anti-implantation
activity [29], reproductive toxicity
potentials of Salvia fruticosa (Labiatae)
in rats, showed that the ingestion of
Salvia fruticosa may produce adverse
effects on the fertility of male and
female rats [30].
Estrogenic activity of phenolic
compounds from Nigella damascene
evaluated using a recombinant yeast
screen [31], phytochemical screening
and antifertility evaluations of the
methanolic root extract of Rumex
steudelii [32], potential value of plants
as sources of new antifertility agents and
naturally occurring steroid estrogens,
estrogenic isoflavins, coumestans, and
plants with reported estrogenic activity
and cycto toxicity [1], fractionated
extracts of Taxus baccata leaves for
antifertility activity on female Albino
rats [33] and the extracts of different
parts of 36 plants has tested for anti-
fertility activity in female albino rats by
a method which would detect antizygotic
mastocystotoxic, anti-implantation or
early abortifacient activity [34].
The contraceptive efficacy of praneem
polyherbal creamv can protect against
pregnancy without causing irritation [5],
the extraction of neem seeds by both
mechanical expression and solvent
extraction using a range of polar to non
polar solvents. And conclude that
subsequent fractionation to reach the last
active fraction the hexane extract is the
most useful starting material [12],
immunocontraceptive activity guided
17
fractionation and characterization of
active constituents of neem (Azadirachta
indica) seed extracts showed that active
fraction from neem seeds, responsible
for long and reversible blocking of
fertility after a single intrauterine
administration [35], synergistic
spermicidal activity of neem seed
extract, reetha saponins and quinine
hydrochloride [12], fertility regulatory
effect of root of Jatropha curcas in
pregnancy terminating effect in rats for
varying peroids of time foetal resorption
claimed indicating abortifacient activity
of the fruits [36], antifertility studies of
the root extract of the Barleria prionitis
Linn in male albino rats with special
reference to testicular cell population
dynamics, disturbances in testicular
somatic cells functions (ceydig and
sertoli cells) resulting in the physio-
morphological events of
spermatogenesis [37]. The extracts of
whole plant Striga lutea have been found
to possess significant antifertility activity
in mice [38]. The extracts of whole plant
Acalypha indica L. (Euphorbiaceae)
were tested for post-coital antifertility
activity in female albino rats [39] and
two flavones, apigenin and luteolin
isolated from Striga onobanchioides,
were investigated for endocrine and
contraceptive properties. Graded doses
of these compounds when administered
from day 1 to day 4 of pregnancy
showed dose dependent and significant
anti -implementation activity [40].
The preliminary study on antifertility
activity of Calotropis procera roots in
female rats, showed a strong
antiimplantation and uterotropic activity
[41], antifertility activity of methanolic
extract of Ferula asafoetida in female rat
claimed 80% termination of pregnancy
was showed [42], chloroform extracts of
the root stem leaf Ruta graveolens
showed significant antifertility activity
in rats [43], antifertility effect of
indigenous drug Arjuna (Termnalia
arjuna W & A) and claimed significant
anti-implantation and abortifacient
activities [44] and antifertility effect of
chronically administered 50% ethanol
extract of Martynia annua root produced
dose related effects on male
reproduction without altering general
body metabolism [45].
Estrogenic activity of Cuminum cymium
(Umbellifera) in rats with Na+-K-
ATPase was experimentally increased in
both endometrium and myometrium at
medium and high doses and also studied
an oestrous cycle uterine weight and on
some of the oestrogen dependent
biochemical parameters in the uterus of
rats [46], the assessment of
oestrogenecity of neem leaf extracts in
rats [14], traditional remedies for fertility
regulation showed that 74 plants have
been screened for their antifertility
potential, 48 plants has been shown to be
effective [47], termination of pregnancy
in rodents by oral administration of
Praneem, a purified neem seed extract.
Dose given orally from day 8 to 10 after
confirming presence and number of
implants significantly on day 7 of
pregnancy. Complete resorption of
embroys was observed on day 15 of
pregnancy in every animal treated with
praneem in contrast to normally
developing embroyos in rats given
peanut oil [48] and antifertility activity
indigenous plant preparation (ROC-
101)I effect on reproduction. ROC-101
herbal preparation composed of a
mixture of three different plants.
Administration of this mixture twice a
day for three days during menstruation
has reported to prevent conception [49].
18
Antifertility activity of the stem bark of
Alangium salviifolium (Linn. F) Wang in
wistar female rats – indicated mainly
abortifacient activity and less anti-
implantation activity [50], traditional
source of various medicinal plants for
antifertility [51], antifertility
investigation and toxicological screening
of the petroleum ether extract of the
leaves of Mentha arvensis L. in male
albino mice showed that the petroleum
ether extract of the leaves possess
reversible antifertility property [52],
ethanol extract of Calotropis root,
Argemone flower and Neem seed oil.
Petroleum ether fraction showed anti-
implantation and abortifacient activity in
female rats [53], oestrogen induced
responses in non-pregnant rats compared
with changes in pair fed and vitamin C
treated pregnant rats [54] and postcoital
antifertility effect of piperinal and also
shown antifertility activities of piperine
did not operate through any hormonal
actions or uterotonic activity [55].
The 32 medicinal plant materials have
extracted with different solvents and
screened for their antifertility [56],
Neem oil, a natural product of
Azadirachta indica for various hormonal
properties in relation to its post-coital
contraceptives action. Neem oil did not
possess any estrogenic, anti-estrogenic
or progestational activity and appeared
not to interfere with action of
progesterone. Since the post coital
contraceptive effect of neem oil seems to
be non-hormonal, neem oil would be
expected to elicit fewer side effects than
the steroidal contraceptives [57], the
male-fertility resulting agents, steroidal,
non steroidal plant-derived,
gonadotropin-related and immunological
agents investigated for control of male
fertility [58], the mechanism of action of
neem oil study showed neem oil exerts
its effect on the endometrium through
absorption into the general circulation
from the vaginal epithelium.Anti
estrogenic quality of neem oil explains
its anti –implantation effect [8] and anti
fertility activity of volatile fraction of
neem oil .NIM-76, odorous and volatile
fraction of neem oil studied for its
antifertility activity in vivo in rats,
rabbits and rhesus monkeys. The drug
was showed effective in precoitus but
not in post coital stages [6].
Hexane extract of Ferula jaeshkeana
(Vatke) effects on oesters cycle in adult
cyclic female rats [59], butanolic extract
of Purarea tuberosa showed 100% anti-
implantation activity [60], the effect of
neonatal androgenization on parturition,
lactation and on subsequent fertility in
rats showed the inability of first
pregnancy in precenting the Impending
an ovulatory syndrome in neonatally
androgenized rats [61] and the
mechanism of action of NIM-76; a novel
vaginal contraceptive from neem oil.
Study shows mechanism of spermicidal
action of NIM-76, a fraction isolated
from neem oil. spermicidal activity of
NIM-76 was confirmed using
fluorescent staining technique it also
shows calcium supplementation did not
relieve the sperm from the spermicidal
action ,it was determined that NIM-76
does not cause any depletion of
intracellular calcium capability of NIM-
76 to selectivity kill sperm without
affecting normal cells makes it a history
desirable potential vaginal contraceptive
agent [7].
The inhibitory effect of hyper
prolactinemia on induction of ovulation
by gonadotropins [62], chemical control
of fertility by different contraceptives
19
such as hormonal methods and non
hormonal methods for male and females
[63], extracts of the aerial parts of the
plant Rivea hypocrateriformis
(convolvulaceae) were tested for
antiimplantation and pregnancy
interruption properties in female albino
rats [64], neem oil as a vaginal
contraceptive and anti- implantation
agent. [9], ethanol extract of
Tabernacemontana heyneana and
isolated alkaloids hejneanine and
voacristine prevented pregnancy, when
administered during the pre-implantation
period in Sprague-dawly rats were found
posses significant uterotrophic activity
[65] and biochemical and histological
studies of reproductive organs in cyclic
and ovariectomized rats supporting a
non hormonal action for neem oil [66].
the antifertility effects of neem
(Azadirachta indica) oil by single
intrauterine administration: a novel
method for contraception [10], in male
rats by single intra-vas administration an
alternate approach to vasectomy, showed
that the testicular effects following intra-
vas applications of neem oil may
possibly be mediated by a local immune
mechanism [17], long-term
contraceptive effects of intrauterine
neem treatment (IUNT) in bonnet
monkeys: an alternate to intrauterine
contraceptive devices (IUCD) [11],
antifertility activity of Quassia amara in
male rats – in vivo study, showed that
Quassin appears to be the antifertility
principle of Quassia amara [67] and
Hong Kong samples of the traditional
Chinese medicine “Fangji” contain
Aristolochic Acid Toxins [68].
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