Despite its unrivalled popularity as a contraceptive, the Pill remains
a variation on a now antiquated theme. Developed in 1951, it has become
the Morris Minor of pharmaceuticals. Yet compared to other contraceptives,
this ageing product of postwar chemistry looks positively high-tech. The
condom was invented in the 16th century and the only significant improvement
since then has been the vulcanisation of rubber in the 19th century.
But the lack of progress cannot be blamed on the indifference of scientists.
If anything, there has been a flurry of acti-vity in recent years with researchers
dev-eloping new hormone-based methods that could revolutionise birth control,
offering contraceptives that would be safer and more pleasant to use than
today’s options. A ‘male pill’ is now a real possibility. In low doses,
the compound RU486, or mifepristone, famous as the controversial ‘abortion
pill’, looks promising as a new contraceptive for women. And both men and
women could benefit from novel contraceptive pills that work by interfering
with gonadotro-phin, a hormone released inside the brain which acts to
control fertility.
There is even cautious speculation about using gene therapy to control
fertility. By 2020, for example, it might be possible to introduce genes
so men could produce their own gonadotrophin-blocking chemicals, thereby
achieving a form of hormonal castration.
Advertisement
But without the wholehearted backing of pharmaceuticals companies, none
of these developments will ever reach the market. And therein lies the
rub. Just as scientists seem poised to conquer a whole new frontier, most
of the world’s leading pharmaceuticals companies have stopped investing
in contraceptive research and development. ‘There has been a massive reduction
over the past 15 years in research related to contraception in many of
the countries with the most money to spend on research,’ says Dennis Lincoln,
director of the Medical Research Council’s Reproductive Biology Unit in
Edinburgh.
Nowhere is that more obvious than in the US, where companies have been
scared off contraception research by the vigorous campaigning of pro-life
activists and the prospect of having to pay out millions of dollars to women
who claim that a contraceptive product made them ill. The powerful ‘right
to life’ movement in the US has already provided a rough ride for those
advocating RU486 as an abortion pill. Many scientists fear that the controversy
has so tarnished the drug’s image that it may never see the light of day
there as a contraceptive.
Medical mishap
‘The public little realises how sparsely stocked will be the shelves
of an American contraceptive supermarket by the turn of the century,’ says
Carl Djerassi, a Stanford University chemist and one of the architects of
the first contraceptive pill. In 1970, Djerassi wrote that ‘birth control
choices in 1984 would not differ much from those of 1970’ unless something
drastic was done to prevent the pharmaceuticals industry from leaving the
field, such as introducing no-fault compensation for medical mishaps.
The same could be said of 1994. Industry angst about litigation is still
fuelled by painful memories of the reaction to the ‘combined oral contraceptive’
that was introduced more than forty years ago. This cocktail of oestrogen
and progestogen – a synthetic version of natural progesterone – prevents
the monthly release of a fertilisable egg and has been taken by millions
of women.
But over the years it has been repeatedly, albeit controversially, linked
to potentially fatal blood clots and cancers. The spectre of a fresh spate
of lawsuits, this time inspired by a male hormonal contraceptive or a new
female one, fills drugs companies with horror. ‘They’re scared,’ says Bill
Bremner, director of the Center for Population Research at the University
of Washington in Seattle. ‘They’re worrying about profit and about lawsuits.’
But there is an irony here. If scientists are right about the contraceptives
waiting in the wings, these new methods may not only be safer than the
old ones but may even enhance health by reducing the risk of cancers or
heart disease. This is what most frustrates biologists about the loss of
nerve in the drugs industry. It is also the reason why many of them are
persevering.
Optimists see the withdrawal of the richest drugs companies, especially
those in the US, as an opportunity for smaller companies in Europe or Asia
to make an impact. Whether that happens could depend on RU486 and other
compounds that function as ‘antigestogens’. Will scientists be able to realise
the potential of these compounds as contraceptives? This would require generating
a ‘new vision of what antigestogens are all about’, says Lincoln. Critics
fear that women given RU486 as a contraceptive could use it to induce abortions
instead. But advocates of RU486 are sceptical. ‘You would have to take one
heck of a load of pills to induce a do-it-yourself abortion,’ says Lincoln.
Natural steroids
Antigestogens work by blocking the action of progesterone, the hormone
of pregnancy. ‘Their discovery has been the most promising development in
the field of control of human fertility since the oral contraceptive pill,’
says David Baird, professor of obstetrics and gynaecology at the University
of Edinburgh. The breakthrough came in the early 1980s when a group of chemists
at the French company Roussel UCLAF synthesised an artificial version of
the natural steroid progesterone. The compound turned out to block the actions
of both progesterone and the glucocorticoid hormone cortisol. Etienne-Emile
Baulieu, an endocrinologist at INSERM, the French national health and medical
research institute, in Paris and a consultant to Roussel, immediately recognised
the significance of this compound and encouraged its development. Two years
later, he had helped to demonstrate its potential as an abortion pill.
A furore ensued, fuelled by opponents of abortion who argued that RU486
would encourage the widespread use of abortion as a means of contraception
– something a woman could administer herself. In the end, the drug has remained
firmly in the hands of the medical profession. Women seeking an early abortion
through RU486 must make two visits to a licensed clinic, first to receive
600 milligrams of RU486 and then, two days later, to receive another compound,
a synthetic version of prostaglandin.
Baird hopes that the fact doctors have remained in control will clear
the way for developing RU486 as a contraceptive. In clinical trials, RU486
has already shown its worth as a morning-after contraceptive. The standard
approach to ’emergency contraception’ is to give a woman who has had unprotected
sex a high dose of oestrogen and progestogen, taken twice, 12 hours apart.
The result is usually severe nausea and vomiting as the woman is exposed
to a massive dose of potent hormones.
Such suffering may be unnecessary. Anna Glasier and her colleagues at
the MRC in Edinburgh have shown that a 600 milligram dose of RU486 within
72 hours of sexual intercourse may be more effective at preventing pregnancy,
and is much less likely to cause gastrointestinal side effects. The researchers
studied 800 women seeking emergency contraception at the Family Planning
Centre in Edinburgh. Half these women were given the traditional combination
of oestrogen and progestogen, and while the other half received RU486.
There were four pregnancies in the group treated traditionally, but none
among those given RU486.
The morning after
‘This is an exciting, absolutely new strategy for emergency contraception,’
says Lincoln. ‘Unfortunately, it is a bit expensive at the moment and we
do not yet know whether we could safely reduce the dose of RU486 to, say,
100 milligrams, which would make it very much cheaper.’ What is more, both
RU486 and the traditional morning-after pill disturb the pattern of menstrual
bleeding, making them unsuitable for anything more than occasional use.
This is why some researchers are hoping RU486 might prove to be the
elusive ‘once-a-month’ pill. While a single monthly dose can act as a routine
contraceptive, there are problems with the timing of the single dose: it
will only work if it is taken just before ovulation. Could women use hormone
test-kits to analyse their urine and so time the dose of RU486? In recent
Swedish trials, 21 volunteers used the kits to detect a sudden rise in
a hormone released by the pituitary gland – known as luteinising hormone
– which signals the release of a mature egg from the ovary. A relatively
small dose of RU486, some 200 milligrams, taken two days after this surge
of luteinising hormone, proved to be effective as a contraceptive in the
Swedish study.
Naturally, this DIY approach would be unlikely to work well with less
motivated women, and it could also prove too complicated or costly for some
women. Even so, Djerassi foresees an era of ‘fertility awareness’ in which
women in affluent societies will regard the determination of the time of
ovulation as a routine item of health information.
For the time being, most enthusiasts for antigestogens are backing the
contraceptive potential of a simpler regimen – a small, daily dose of RU486
or a similar compound. Several groups, including Baird’s in Edinburgh and
Horacio Croxatto and his colleagues at the Chilean Institute of Reproductive
Medicine in Santiago, have shown that a continuous low dose of RU486 – as
low as two milligrams a day – can prevent ovulation. No one is quite sure
how the compound manages to do this, although the evidence to date suggests
it blocks the surge of luteinising hormone.
The good news is that a low, daily dose of RU486 does not seem to interfere
with natural oestrogen levels, and so does not put women at risk of developing
premature osteoporosis or other signs of oestrogen deficiency. But there
could be other dangers. High levels of oestrogen can encourage the uncontrolled
growth of cells lining the endometrium – something normally prevented by
the progesterone also secreted by the ovaries. According to Baird, however,
studies in monkeys suggest that for some reason RU486 can block this cell
growth, even in the presence of oestrogen. If this is also true for women,
he argues that it would be possible to use RU486 as an oestrogen-free contraceptive.
Cancer connection
Other possibilities include taking low doses of RU486 for 10 days or
so and then switching to a progestogen for 12 days to produce a light menstrual
period. ‘The strategies here are absolute magic, absolutely novel,’ says
Lincoln. ‘We could take them to the marketplace very quickly.’ Drugs like
RU486 might even prove to guard against breast cancer, he speculates. A
woman’s risk of developing breast cancer is now thought to be governed not
so much by her lifelong exposure to oestrogen but rather by the combined
actions of oestrogen and progesterone during the second half of the menstrual
cycle. This implies that antigestogens such as RU486 might act to retard
the development of breast tumours.
‘The prospect of a great advance on both the contraceptive front and
breast cancer prevention is very exciting,’ says Lincoln. ‘We need an international
endeavour to take forward the clinical development of these drugs.’ Yet
Baulieu, the father of RU486, is more sceptical of ultimate triumph: ‘Who’s
going to develop this new method? It’s easier and less costly for drugs
companies to play with what they already know about.’
A similar tendency to play safe is holding back the development of a
male hormonal contraceptive. The WHO has doggedly pursued this avenue more
or less on its own and will soon publish the results of its latest trials.
The overall picture is striking: something pharmaceutical companies could
quickly act on. ‘Unfortunately, they don’t see it as a great way of making
money yet,’ says Lincoln.
From trials conducted around the world, it is clear that giving men
testosterone can reduce sperm numbers and fertility, making it every bit
as good as contraceptive pills for women. It works like this: boosting the
body’s natural levels of testosterone sends a biochemical message back to
the hypothalamus and the pituitary gland in the brain, blocking the release
of two important hormones – luteinising hormone and follicle stimulating
hormone. These normally stimulate the testes to produce home-grown testosterone
as well as sperm. The extra injections of testosterone fool the brain into
thinking that the testes are working overtime when they are not.
In the first WHO trials, conducted two years ago at clinics around the
world, hundreds of male volunteers were given a weekly injection of tes-tosterone.
In half of these men, sperm production fell to zero after a few months.
There was only one recorded pregnancy, in China. The second WHO trial, just
completed, focused on men whose sperm production was impaired, but not closed
down, by the injection. The results show that these men also became infertile,
while still producing five million sperm per millilitre of semen (the normal
range is between 50 and 150 million sperm per millilitre). So the good news
for reproductive scientists is a male contraceptive does not have to wipe
out sperm production to be effective.
Giving men extra doses of testosterone has side eff-fects, however.
Some men develop acne, others claim it makes them more aggressive. And it
is possible that long-term treatment might increase the risk of heart disease
or prostate disorders. ‘Ideally, to create positive health care for men,
we would like to reduce circulating levels of testosterone,’ says Lincoln.
An alternative to testosterone, now being pursued by Bremner and his
colleagues, is to use compounds that act directly on the hypothalamus.
Normally, nerve cells in the hypothalamus produce regular pulses of gonadotrophin,
which then act to stimulate the nearby pituitary gland to release luteinising
hormone and follicle stimulating hormone. These hormones in turn stimulate
the testes to make sperm and testosterone. By giving men drugs that block
the production of gonadotrophin, it might be possible to shut down all this
reproductive chemistry.
That would make the men infertile without artificially boosting their
testosterone levels. In fact, the most likely side effects would result
from the opposite problem of testosterone levels falling too low. This could
help to reduce the risk of heart disease, but it might also threaten men’s
sexual prowess or, in the long term, the strength of their bones. Doctors
would probably need to prescribe testosterone supplements to replace some
of the natural supply – HRT for men.
Balancing act
‘We need to sort out the dose that is most appropriate, balancing the
goods and bads as far as possible,’ says Bremner. The evidence to date,
he says, suggests that men given a compound that blocks the production of
gonadotrophin tend to be more grumpy and aggressive, and to experience a
decline in sexual function after two to four weeks. Such side effects could
be avoided by giving moderate doses of testosterone replacement therapy,
he argues.
There is a third possibility for a male hormonal contraceptive: a cocktail
of progestogen and testosterone supplements. Progestogens block the production
of luteinising hormone and follicle stimulating hormone, so wiping out natural
testosterone and sperm production. As with the gonadotrophin blockers,
doctors would have to prescribe a testosterone supplement to offset some
of the side effects. But they may also run into another problem. Giving
people progestogens tends to reduce levels of high-density lipoproteins,
the form of cholesterol that helps to reduce the risk of heart disease.
Recently, researchers have synthesised modified progestogens that are reputed
to be less harmful, but these have yet to be tested on men.
The great advantage with progestogens is that they are relatively cheap
and available as pills or implants that last for months. Gonadotrophin blockers,
by contrast, are expensive and must be injected. Testosterone requires injection
too, but the latest formulations seem to require only one injection every
three months. A recent study in Indonesia found that a combination of long-lasting
progestogen and testosterone caused sperm production to fall to zero in
97 per cent of the male volunteers.
Ten-foot pole
But do men really want a reliable, regular contraceptive? Popular opinion
has it that men will never take one of these agents, yet as Bremner points
out, almost a third of all contraception is done by men. In the US, 16
per cent of men use condoms and 14 per cent have had vasectomies, which
is irreversible for practical purposes.
‘Men who had been on our trial for a year wanted to stay on it,’ says
Bremner. So far, recovery of normal fertility has not been a problem either.
‘Lots of men have had children after coming off the contraceptive,’ he adds.
But it takes some time to turn on and off fertility – between two and three
months.
A more urgent question is whether men will ever be offered a wider choice.
‘Drugs companies are not interested. They won’t touch it with a ten-foot
pole,’ says Bremner. ‘There is no real excuse for such an enormous discrepancy
between the energy and money put into the study of male versus female contraception.’
That said, the scope of contraceptives that target gonado-trophin is
by no means limited to men. One of the most ambitious ideas involves using
compounds to shut down the reproductive systems of women. A chemical cocktail
would then be given to the women, both to control fertility and perhaps
to reduce the risk of cancers and other illnesses. Researchers speak of
the concept of ‘block and replace’. In practice, women could be given drugs
that block or boost the effects of gonadotrophin, as both would act to suppress
ovarian activity.
Malcolm Pike at the University of Southern California School of Medicine
in Los Angeles and his colleagues have recently reported the results of
a two-year pilot trial of this highly complex approach. Once a month, women
in the trial received an injection of a drug that boosts the effects of
gonadotrophin. Six days out of seven they took a low dose of oestrogen,
and for 13 days, once every four months, they took a progestogen pill. The
rationale for such a cocktail? The drug induces menopause, so it is necessary
to give the women oestrogen to reduce hot flushes and bone loss. But this
oestrogen supplement, in turn, raises the risk of cancers in the uterine
lining, making a further supplement necessary, this time of progestogen.
The results of the trial look promising so far. Women taking the contraceptive
seem to show a lower than normal rate of cell division in the breasts during
the second half of the menstrual cycle. Perhaps that would reduce the risk
of breast cancer in the long term. Despite the oestrogen supplement, however,
the women were losing bone and so needed a low dose of testosterone.
Block and replace
Enthusiasts talk of the prospect of the ‘complete suppression of ovarian
function through most of a woman’s reproductive life’, with the ‘judicious
and timed replacement’ of oestrogen and progesterone. But is that a good
idea?
Fellow researchers such as Hamish Fraser of the MRC’s Edinburgh unit
point out that it will be decades before anyone can be sure that this form
of contraceptive really does reduce cancer risks and does not create other
health haz-ards. What’s more, cancers of the reproductive system are at
the moment really a problem only in the West – limiting the potential market
for this novel contraceptive. Yet this may change rapidly if diets become
more Westernised and the average size of families in developing countries
continues to shrink, says Olivia Judson of the University of Oxford. Enthusing
about the prospects of a new gonadotrophin-blocking pill, she concludes:
‘A path towards healthy infertility will be welcome worldwide.’
* * *
The vaccine alternative
Will contraceptive vaccines ever replace pills and condoms? Plenty
of teams are working on vaccines that may eventually prove effective in
stopping pregnancy. But sceptics point to the dangers of possible side effects.
One approach in men might be to immunise them against their follicle
stimulating hormone. Scientists have kept male macaques infertile for as
long as seven years through injections that make the monkeys hyperimmune
to a segment of their own luteinising hormone molecule. An alternative idea
would be a male vaccine capable of blocking, or neutralising, gonadotrophin.
One prototype vaccine for women, now being tested in several countries,
acts against a hormone produced by the early embryo, a compound known as
human chorionic gonadotrophin, or hCG. Normally, this hormone tells the
body to block the onset of menstruation. It is the target of pregnancy testing
kits on sale in the high street. A vaccine that could produce antibodies
against hCG might also prevent pregnancy.
Another strategy, being pursued by John Aitken and his colleagues at
the MRC’s unit at the University of Edinburgh, is to develop a vaccine that
acts to prevent fertilisation. This kind of vaccine would have to stimulate
antibodies against proteins found on the surface of the sperm or egg, which
are crucial for normal fertilisation. With this in mind, molecular biologists
are now isolating these proteins and trying to characterise their molecular
structures.
Yet the idea of contraceptive vaccines remains controversial. ‘Classical
immunologists would prefer to avoid imm-unisation against hormones (such
as gonadotrophin and hCG) so central in endocrine control, for fear of creating
autoimmune reactions,’ says Geoff Waites of the WHO in Geneva. Bremner,
too, is sceptical about the prospects of a vaccine against sperm, suspecting
that circulating antibodies might form dangerous immune complexes or set
off an autoimmune response while also creating an infertility that would
be difficult to turn off again. ‘That’s where I fall off the bandwagon,’
he says. ‘I’m not convinced that any vaccine can be used as a reversible
³¦´Ç²Ô³Ù°ù²¹³¦±ð±è³Ù¾±±¹±ð.’