Hormone cycles rule the lives of women during their reproductive years. Fluctuating hormone levels subject us to a monthly roller-coaster of mood and emotion, as well as bleeding, which can be both reassuring and irritating. Periods are the visible signs of a complex hormonal fertility dance, orchestrated from puberty by the brain. Although the menstrual cycles are popularly thought to be inflexible, one following another in a rigorous 28-day march, the reality is actually far more elastic than people imagine and relatively easily perturbed by external influences.
Hormones are blamed for so much during these years. Whatever the problem – mood swings, bloating, infertility, heavy periods – the answer is always ‘It’s your hormones’. This chapter aims to tell you the truth about these cyclical hormones and also lifts the lid on a cultural hormone phenomenon – the pill.
Hormonally Yours
Let me introduce you – or reintroduce you – to the key players in the wondrous system that runs your reproductive life. From the hypothalamus, we have gonadotrophin releasing hormone, GnRH, and from the anterior pituitary, two key hormones, follicle stimulating hormone (FSH) and luteinising hormone (LH). In an elegantly orchestrated pas de trois, the three of them persuade the ovary to produce oestrogens (of several varieties), androgens (ditto) and progesterone. This is how they do it.
Every month, your body gears you up for pregnancy. An egg – not just any old egg, but the pick of the bunch, must be selected for release. Meanwhile, your womb must be prepared for pregnancy, its lining turned from something like a parquet floor into a shag pile carpet, all within the space of a month. This is because if a fertilized egg should appear, it will need that thick and luxurious lining to sink into, settle and implant. If there is no embryo, then the womb lining must be shed, rather than be allowed to continue getting thicker.
There are two parts of your cycle: before and after ovulation. The ‘before’ section is called the follicular phase, and the ‘after’ is the luteal phase. Even as you start your period, the level of FSH is beginning to rise. This hormone takes the role of the clerk of the course that waves the flag before horse races. He must get all the runners and riders under starter’s orders. Effectively, this is what FSH is doing, for the rising levels have triggered the growth of several wannabe follicles within the ovary.
Every single day of your reproductive life, up to twenty potential follicles are recruited from the store of eggs that you were born with. After a six-month maturing period, just a few will be brought to the finishing line each month by FSH, and only one will win the race to be the dominant follicle that gets to release an egg. Sometimes there is a dead heat, and two eggs are released – which may result in twins.
The chosen follicle becomes exquisitely sensitive to FSH and then to LH. This is enabled by the sudden appearance of a rash of LH receptors. The follicle looks like a ball, containing a small pond of liquid, within which the egg sits. The outer layers of the ball are a steroid-producing factory, pouring out oestrogens, particularly the very potent sort called oestradiol, as well as oestrone. As you will now know from your bluffer’s guide (Chapter 1), oestrogens are the final destination steroid, and to make them, you have to make testosterone first. Inside that ultimately girly product, an egg follicle, the male hormone testosterone is being manufactured, before being passed over to different sets of cells within the follicle to be further processed into oestrogens.
These oestrogens escape into the bloodstream. Their effect on the lining of the womb, currently looking thin and pathetic about a week after your period started, is miraculous. Like mustard and cress on a wet flannel, it begins to proliferate and grow. The rising levels of oestrogen in the blood trigger the pituitary to produce a huge whoosh of LH, plus a smaller slosh of FSH. Ovulation will follow within thirty-six hours.
Ovulation predictor kits are over-the-counter mini-laboratories which do the chemical testing necessary to pick up this big increase in LH. You are then supposed to go away and bonk madly. But the kits are not necessarily the key to successful conception. First because, if you are restricting your love-making to just once a month, you will have less chance of getting pregnant, not more. Second, there is nothing that wrecks love-making more effectively than having to do it; and third, just because you have a spike of LH doesn’t always mean that you release an egg, as you will see. It’s normal not to occasionally. Save your money and buy exotic underwear instead – it’s far more likely to be effective.
When the egg is released, the follicle is a bit like a pricked balloon. But LH engineers some reconstructive work and the busted follicle turns into a corpus luteum (yellow body). By now, you are three weeks into your cycle and the corpus luteum is secreting progesterone. It needs to do this for two reasons. First, in order to complete the work on the womb lining that oestrogen has already begun: progesterone will add structure by initiating curious spiral blood vessels, secretory cells and so on, which will ensure the lining is ready for pregnancy. The second task of the corpus luteum is to be the principal supplier of hormones to support pregnancy in its first ninety days.
If you haven’t got pregnant by around day 26, the corpus luteum gives up, folding in on itself. There is a sudden drop in oestrogen and progesterone levels. Because progesterone was maintaining the secretions within the womb lining, they suddenly stop too and fluid is sucked from the lining back into the veins. The tissue collapses and the spiral arteries buckle and then rupture, haemorrhaging blood. They are swiftly closed at source (otherwise you would bleed to death) but the blood and the tissue built up so carefully are sloughed off and expelled through the vagina.
Then the whole thing starts all over again. It is downright miraculous – and happening in a body near you, every month.
This cyclical hormonal change also affects the consistency and acidity/alkalinity (the pH) of the cervical mucus. Trying to get through the mucus in the ‘after’ phase of the cycle is tough for a sperm because, thanks to progesterone, it is not only like swimming in treacle, but highly acidic treacle at that. By contrast, the mucus in the ‘before’ phase is watery, abundant and clear and the perfect pH for a sperm with an eye to the main chance. The progesterone-only pill exploits this effect, making the cervical mucus so hostile that fertilization is unlikely.
The ‘before’ part of the cycle is of more variable length than the ‘after’. Once ovulation has occurred, it is pretty consistently 14 days to your period – but 12–17 is still normal. Quite a number of cycles – and this is especially the case at the beginning and end of your reproductive life – are anovular. No egg is released. You will still have a period because oestrogen will still have started the growth of the womb lining. When, because there is no egg, its levels fall, menstruation is initiated. Anovular cycles mean that there is no progesterone (because there is no corpus luteum). As it is principally progesterone that initiates period pain (but does not causes it), anovular cycles are painless. There’s an explanation of this seeming contradiction later.
The average woman in Britain will have approximately 400 periods in her lifetime. Amongst the Dogon tribe of Mali (who have on average eight babies each), only 110 periods will be experienced, which is just as well since during their menses they are banished to a menstrual hut. There is still much folklore attached to menstruation. Even in Britain, some mothers still tell their daughters not to wash their hair during a period, pursuing a long held and mistaken belief that women are more vulnerable to infection at this time.
An extraordinary American, R. F. Vollman, made menstruation his life’s work, compiling a classic volume called simply The Menstrual Cycle, which was published in 1977. He based his book on 691 women born between 1875 and 1951, aged from 4 to 63. Age at first period ranged from 9 to 21, with 55 per cent of them aged 13–14. He noted the similarities in menstrual onset between sisters and mothers and noted that the average cycle drops from 35.1 days at 12 to 27.1 by 43. It then rises to 51.9 at age 55.
One of the things admirably shown by his work is the huge variation that is ‘normal’. The ‘monthlies’ are well named, recurring as they do at approximately four-week intervals, yet somewhere along the line it has become an article of faith that a normal cycle is 28 days long. The obsession with 28 is perpetuated with the pill, where women are programmed to bleed at 28-day intervals. Actually, as Vollman showed, only 12.4 per cent of women regularly have cycles of this length, so how has it come to be the gold standard?
In the seventeenth and eighteenth centuries, meddling philosophers liked to translate four weeks as 28 days and very soon numbers were more important than biology. Four times seven for the menstrual cycle and ten times twenty-eight for the duration of pregnancy (forty weeks) became the ‘official’ length. Thus it is that women, who have come to believe, not surprisingly, that pregnancy is nine months in duration, find when they reach the ninth month, that they still have another month to go. Obstetricians wonder why they do not have a reputation for high-quality research. Given that they are a group of people who, to get the duration of pregnancy, divide forty by four and consistently come up with nine as an answer, it’s hardly surprising.
The Moon and You
The length of a woman’s cycle is a reflection of her hormones and of her fertility. Those women with cycles of 29.5 days have the highest likelihood of fertile cycles and both short and long cycles are associated with infertility. Is it a coincidence that this happens to be the length of the lunar cycle? For centuries, the moon and menstrual cycles were believed to be linked. When an obsessive Frenchman called Clos actually collected details of the periods of a woman for 289 successive cycles between 1807 and 1834, he claimed, after some complicated sums, that he had proved the link. However, he rather holed his own theory below the waterline by remarking, ‘a woman does not always menstruate regularly. Every so often the intervals are shorter or longer.’ The one thing that you can guarantee is that a new moon will appear every month – but it is not so with periods.
Since then there have been many more studies, most disproving the theory. But in 1987, an American researcher, Winnifred Cutler, collected cycle details from nearly 1,000 Philadelphia college students, publishing her data in the Journal of Human Biology, which showed that the highest density of menstrual onset appeared at the full moon. This means that ovulation would occur at around the time of the new moon, fifteen days before. There was no variation in this with season. A study published around the same time of 826 female volunteers, confirmed these findings; 28 per cent of periods started on the day of the full moon, compared to no more than 12 per cent for any other day of the lunar cycle. In an intriguing adjunct, the levels of melatonin in menstrual blood were recorded in just three of the women and found to peak just before menstruation. Melatonin, the hormone of sleep, is also the slave of the body clock, helping it to coordinate activity in response to changes in day length. Disturbances of melatonin production, for example because of shift work, can play havoc with your cycles, because, in order to maintain your monthly rhythm, the body needs to set its clock each day. It does this with light. If it can’t do this, or becomes confused, your rhythms – daily and monthly – become altered.
If all this moon thing seems a bit fanciful and new ageish, perhaps we need to think again. Many animals coordinate their reproductive rhythms, via their hormones, with the moon, and not just those sea creatures like crabs or other marine life dependent on the tides. Flatworms, frogs, hamsters and the monkey species Ceropithecus have been shown to do so too. Hormones are the messengers dispatched in response to environmental cues, like day length and phase of the moon, which require appropriate behaviours, like courtship, to be set in motion. Humans are likely to be entrained to some extent by the same environmental cues as other animals, although I doubt, with the night-time light pollution we experience in our own age, that moonlight is still a factor in our lives, as with the Dogon, for whom no reports of moon menstrual phasing have been noted. It has to be said that most scientists are deeply suspicious about the moon having any sort of link with menstruation, thinking the data sets are comparable to those recording itching palms and sprouting hair at the full moon.
But the environment isn’t the only thing that can knock our cycles off course.
We have talked mainly of LH and FSH, which depend for their production on gonadotrophin releasing hormone (GnRH) being sent from the hypothalamus to the anterior pituitary where messages to increase production of LH and FSH are handed over. GnRH is released not just as one continuous stream, but in little pulsed doses every ninety minutes or so. The effect of stress – in particular, rising levels of the stress hormone cortisol – on the hypothalamus can weaken the strength of the GnRH message, usually through a reduction in the pulsing of GnRH. Many women will notice that during time of stress, their periods – the visible sign of their reproductive cycle and of their fertility – either disappear or become less regular. Certainly extreme stress such as war, burns, sudden bereavement or a serious accident can result in periods disappearing for months. We’ve already covered the relationship between decreasing levels of body fat and complete loss of periods (a condition called amenorrhoea).
There appears to be a close response relationship between the type and severity of stress and the proportion of individuals whose periods stop. Elevated cortisol levels are also found in women with depression, women athletes and those with anorexia, but not in women with bulimia. These women, including bulimics, all experience problems with their periods. However, you shouldn’t think of stress and GnRH purely in terms of levels of cortisol (or of its ultimate master, corticotrophin releasing hormone), or purely in terms of single stressors. Neuroendocrine effects are incredibly complex and multiple, and it might be that seemingly minor psychogenic and metabolic stressors are likely to be more harmful to reproductive function than a single stressor in those that are susceptible. What are these stressors? How long have you got? Commuting, money worries, bullying, uncertain future, long hours, poor relationships – the list goes on and on.
It could be any or none of these, and not just because none of these things might apply to you personally. We each have a very individual response to stress and what’s energizing for some brings others down. Our challenges – the metabolic ones (like exercise, nutrition, our level of activity) together with the psychogenic ones (perhaps including performance pressure, negative attitudes, unrealistic expectations, all of which have been specifically associated with missing cycles) – are fed to the brain, which responds by modulating levels of neurotransmitters. The hypothalamus then translates these into altered secretion of its hormones, which in turn affect the pituitary hormones, and through them the endocrine glands. What this means for your periods is nigh on impossible to quantify in relation to a single external force.
There is an equivalent stress effect in men, where the end point is reduction in sperm count. It has always been assumed – on the basis of not very much evidence – that women have a hypothalamus fragilis as it’s called, while men have a hypothalamus robustus. In other words, women are more susceptible to stress. But when US Army researchers actually looked at it, they found that combining a metabolic stressor (fasting) with a psychogenic stressor (a war drill) appeared to suppress GnRH production more profoundly in men than in women.
Stress acting on the hypothalamus can cause many diverse effects, acting through many different hormonal systems – becoming thin for instance, or alternatively, over-eating. Perhaps the bottom line here is that women who miss their periods will pretty soon go to their doctor seeking an explanation. Men have no such visible signs of stress, and if their sperm counts are lower they are unlikely to know unless actively trying to conceive.
It is often said that stress is the reason why couples fail to conceive, and everyone, but everyone, has an example of a couple they know who, having had years of infertility treatment, went away on holiday and conceived – or had two children with IVF and then another quite unexpected one naturally. The implication is that stress must have been the cause all along. It has some influence, but getting pregnant mainly requires two things: time and opportunity for sex.
If a stressed lifestyle means that opportunities for sex are limited to once or twice a month, your chances of pregnancy are immediately diminished. Frequent sex is the cure and going away on holiday is one of the best recipes I know for it. How else do you fill the time between lunch and dinner when it’s too hot to lie in the sun?
The longer the period of time that you have been having unprotected sex, the more likely you are to conceive. It is estimated that, with time, a third of the women attending infertility clinics would have got pregnant without treatment. Clearly, if you are thirty-eight, the clock is ticking on, reducing the chances of successful fertility treatment. You’re not going to risk it, and hope that you’re one of that third who will get there by yourself. You opt for treatment.
Having said this, levels of stress hormones are regulated differently in men and women because oestrogens tend to intensify and prolong the response of the adrenal glands (producers of cortisol). Interestingly, if men are given a short course of oestrogen, they have an increased response to stress. It’s possible that testosterone and oestrogen are what determines the body’s exact response to stress and perhaps this is why diseases associated with increased amounts of emotional pressure, like post traumatic stress disorder (PTSD), are more common in women than men. Remember, too, that oestrogens have a direct effect on neurons in the brain, not just through the hypothalamus.
The ‘Hot Romance’ Effect
There have always been anecdotal reports that cycles change during an intense romance (typically that periods intrude early, so ruining your plans for a dirty weekend). Many animals ovulate in response to copulation – cats, for instance, and rabbits. It’s called reflex ovulation. For other animals, the mere sight of a male strutting his stuff is enough. It’s called the Ram Effect (if you are a sheep). Then there’s smell. Young female possums have been shown recently to come into heat simply in response to aromas in male scent trails. So are human menstrual cycles as exposed to outside influence? There are several studies showing that exposure to men has the capacity to shorten menstrual cycles and increase ovulation. In one, researchers showed that women who spent at least two or more nights with men during a forty-day period showed a significantly higher rate of ovulation than those spending one or no nights. This was more the ram effect than the rabbit effect, because ovulation rates were unaffected by the number of times sex took place. There’s clearly something about men that literally turns women on. But could there be something about women too?
All Girls Together?
In 1971 a study appeared in journal Nature confirming what many women already suspected, that women who share close quarters come to menstruate in synchrony. The author, Martha McClintock, then just twenty-three, based her paper on what she had observed in a dormitory in the exclusive Wellesley College, Massachusetts. Her contemporary and dorm mate was another observant woman, now a US Senator, Hillary Rodham Clinton.
The research came about because when Martha was an undergraduate she had been invited with some other students to a conference about pheromones. Pheromones are airborne chemical signals that are released by an individual into an environment and which affect the physiology or behaviour of other members of the species, without them being consciously detected as odours. The delegates were discussing how they cause female mice to ovulate. In a scene straight out of Legally Blonde, Martha tentatively put up her hand and said that the same things happened all the time in humans. When the incredulous scientists said ‘where’s your proof?’, Martha replied that it was what happened in her dormitory.
Her faculty adviser got her to enrol 135 women in her dorm in a study and Martha wrote up the results as her senior thesis. She went on to Harvard and was persuaded by the legendary sociobiologist, E. O. Wilson, who worked on signalling systems in ants, to submit her findings to Nature. Nearly thirty years later, Martha, by now Professor of Psychology at the University of Chicago, had another paper published in Nature which, she claimed, proved the existence of pheromones.
In the 1971 paper, McClintock considers whether shared light /dark patterns (in other words, room mates sharing the same time for lights out) might be a possible mechanism, with synchrony initiated by melatonin, but rejects this. She noted that synchrony was most noticeable amongst best friends and concludes the paper with ‘this indicates that in humans there is some interpersonal biological process which affects the menstrual cycle’.
Although there were mutterings about McClintock’s statistical analysis and also about the inclusion of women on the pill, some better designed studies showed much the same thing. That menstrual synchrony was most likely among best friends and women with intensive social contact with each other. However, there were an equal number of other studies showing no such thing and most tellingly, no such correlation was found among lesbian couples.
In 1998, again in Nature, McClintock claimed to have proved that pheromones were that ‘interpersonal process’, which altered the hormones affecting onset of menstruation. In a blinded controlled trial, women were asked to sniff pads taken from the armpits of women in the latter half of their cycle. The sniffers’ cycles were accelerated, bringing on their periods earlier than anticipated. Pads taken from women around the time of ovulation had the opposite effect. It was a spectacular paper.
Game, set and match? Well, it’s all very curious. This is a cherished notion which women want to believe, but as most women’s periods last five days, and the length between periods is only a month, overlap among a group of women living together is therefore not only possible but highly likely. This is not synchrony, is it? An equally insurmountable problem with this theory is, what would be the purpose of this team menstruation? Not being synchronous with your best mate surely makes having a baby by the best guy around (which is your body’s gameplan, if not yours) more rather than less likely. After all, if you are both ovulating, will he sleep with both of you? Not if he values his life he won’t. Amongst the cliff-dwelling Dogon, the nearest we have to representatives of early humans, there is no evidence of synchrony, though surely, if it conferred some sort of biological advantage, you’d see it among these women. There is no doubting the existence of human pheromones, but it’s hard to be convinced that menstrual synchrony really exists. If it does, it is a very weak effect.
Bleedin’ Awful
In a huge collaborative study on periods, sponsored by the World Health Organization, and involving fourteen different socio-cultural groups across ten countries, including Pakistan, Egypt, the UK and the Philippines, menstruation was associated with youth and sexuality. Overwhelmingly, women do not want to see any changes in their cycles, regarding them as a sign of health, not ill-health. But it does not stop them complaining about ‘the curse’ – too heavy, too long, too short, too painful, too irregular, too frequent and too awful. Frequently these problems are laid at the door of hormones.
Most periods last between five and six days, with average blood loss of 35 ml. That’s seven teaspoonsworth. Heavy periods are defined as blood loss of more than 80 ml but it’s what’s heavy for you that counts. Women are notoriously bad at estimating blood loss and what’s fine for one woman is a catastrophe for another. There are lots of reasons for increased blood loss that have no direct link with hormones – fibroids and endometriosis to name but two. Still most cases of menorrhagia, as it’s known in the trade, are unexplained. Prostaglandins – pre-hormones – are usually blamed, along with elevated levels of an enzyme that affects fibrinogen, a party to blood clotting. Despite hormones not being guilty as charged, heavy periods were treated for decades with a synthetic progesterone, norethisterone. It was literally worse than useless. Meanwhile, time and time again, one of the best and most effective treatments was shown to be an anti-fibrinolytic (so an anti- anti-clotting agent) called tranexamic acid. A big clue, you might have thought, yet prescriptions of the synthetic hormone continued. However, using a progestogen-releasing IUD (coil) which slowly releases hormone into the womb cavity does work. Here there is a direct hormonal effect on the lining, which prevents its build-up, and cuts down blood loss that way.
With regard to painful periods, you’d think, given that anovular periods (ones where no progesterone is produced) are painless and that women on the pill don’t have painful periods, that hormones – and specifically progesterone – were the villains. Actually that is not the case, at least not directly. Remember, too, that by the time the period actually starts, progesterone levels have been falling for a couple of days. But within all that tissue that is built up during the second half of the cycle are various prostaglandins. Some women develop high concentrations of these, which seem to cause the womb to contract a lot (causing pain). No one knows why this should be so. True, they wouldn’t be there if it had not been for progesterone’s message to the womb lining to proliferate, but it isn’t progesterone causing the pain – honestly.
If painful periods are not quite the fault of hormones, that is not the case with irregular or no periods. As I’ve outlined earlier, anything that affects the release of GnRH, such as severe stress or anorexia, can cause problems. The commonest endocrine disorder affecting ovulation and causing irregular and disrupted periods is polycystic ovary syndrome (PCOS).
This condition was first described by B. A. Stein and S. E. Leventhal in 1935 (and indeed was once known as Stein–Leventhal syndrome). Women who have PCOS have a triad of symptoms: very irregular periods, obesity and problems associated with too many male hormones, like excess body hair, acne and male-pattern baldness. They also have polycystic ovaries. These are ovaries so packed with follicles, at all stages of development, that they look rather like someone has stuffed them with as many marbles as they could. Although, in fact, ovaries like this are rather common, with around one in five women of reproductive age having them, those with associated symptoms of PCOS are less so, but they still affect around 10 per cent of women.
Problems with another hormone, insulin, add to the misery. Women with PCOS are insulin-resistant – their tissues don’t hear the signals from insulin as well as they should. Also, more insulin than normal is secreted, which has a double-jeopardy effect on those androgens. Normally steroids are chaperoned in the bloodstream by steroid hormone binding globulins (SHBG), which mop up all but a small amount of sex steroids. Insulin not only prompts greater production of male hormones by the ovary, but also decreases the number of SHBGs. This means more androgens free to roam about causing trouble. Thus the male hormone effect is enhanced, resulting in greasy skin and acne, hirsutism and even male-pattern baldness.
Not surprisingly, the pituitary becomes thoroughly confused. Its response to this mayhem is to attempt to regulate it with higher than normal levels of LH. But the effect of this is to make ovulation less frequent. One of the consequences of fewer ovulations is a cruel one. Progesterone is released only after ovulation, so women with PCOS who ovulate far fewer times a year than normal are exposed to less of it. Some think that this lack of progesterone predisposes women with PCOS to lay down fat around their middles, rather than other sites in the body. In itself, this fat pattern is associated with Type 2 diabetes.
The consequences on the cycle are very apparent. Great long gaps between periods, or none at all. Meanwhile, obesity further compounds the hormonal problems. In fat cells, circulating male hormones get converted into weak oestrogens. Their effect is to make the womb lining grow and grow, resulting in not just shag pile carpet linings to the womb, but something more akin to a mattress. Because there is no progesterone in anovular cycles, it doesn’t get shed as normal. When the woman does eventually have a period and all this lining is lost, her period can be catastrophically heavy.
Infertility is very common although still some women conceive spontaneously, since there are still between two and six ovulatory cycles a year. But inducing ovulation in women with PCOS – who, remember, already have an ovary full to bursting with follicles – is very hazardous, with multiple pregnancy (and we are talking quads and above) a serious risk.
Hairy, fat and infertile. Thanks, or no thanks, to their hormones, these women have been dealt a very poor hand. What used to be a tragedy has now, in the last decade, turned into an endocrine success story. It has been realized that losing weight and taking more exercise in themselves result in an 80 per cent ovulation rate. Combining this with drugs normally given to diabetics increases this further. For those that need ovulation induction, there is now a cunning protocol of gonadotrophins, which are used in carefully stepped doses to just tip the threshold for producing FSH. This allows only a few follicles to be recruited, instead of the many that would have resulted had there been too big a blast of FSH. We’ll return to the subject of fertility and infertility anon, but let’s now examine the variations in female physiology imposed by variations in hormone levels.
The variation in hormones levels over the cycle causes far-reaching effects throughout the body. For instance, hormones can affect the way that women’s bodies process drugs. Sometimes women with epilepsy will have a seizure just before or during the first days of their period, something called catamenial epilepsy. This is not just variation in the condition across a cycle as used to be thought, but also a reflection of the fact that many anti-epileptic drugs are metabolized through an enzyme pathway called CYP 3A4. The activity of this system is accelerated by progesterone in the second half of the cycle, so that drugs are cleared more quickly from the body and may be temporarily less effective in preventing fits. Much the same thing happens with the asthma medication methylpredinsolone, which is metabolized differently at different times of the cycle. Many women with asthma may need to alter their medication in line with their cycles. Another example of a drug hormone interaction is the anti-coagulant drug warfarin, which competes for the same blood-binding proteins as oestrogen. This means anti-coagulation may be more marked in the first half of the cycle when oestrogen diminishes warfarin’s ability to bind, so freeing more of it to work.
Women report many other conditions which seem to fluctuate across their cycles, particularly autoimmune diseases, which affect far more women than men. For instance, rheumatoid arthritis and MS symptoms both appear to be worse at the beginning of a period. This is because ovarian hormones modulate autoimmune illness. Hormones are clearly not the whole story here, because those women who have specific hormone problems affecting their ovaries don’t have a higher than normal incidence of these illnesses. Also, while rheumatoid arthritis and MS tend to get better in hormone-awash pregnancy, lupus (another autoimmune disease) gets worse. What’s going on here? Autoimmune diseases occur because the immune system becomes unable to distinguish what is you from what is foreign in you. It then starts attacking you, instead of the foreign invaders it is supposed to deal with. One suggestion – of many – as to why autoimmune diseases are more common in women, is that female sex hormones influence the development of the thymus gland. This is an important site for the production of those bits of the immune system that tell self from non-self.
Whatever the reason for the disparity in autoimmune disease between the sexes, there is definitely a difference between the day-to-day working of men’s and women’s immune systems. Testosterone dampens the immune system and oestrogen boosts it. Viral infections are less severe in women than in men; parasitic infections are more common in male animals than female ones and so on. Variations in oestrogen across the cycle are likely to be the reason why women report a greater rate of infection of cold sores, for example, just before a period.
Something else that is modulated by hormones is pain. Oestrogen influences the size of the ‘field’ of nerves activated in response to a painful stimulus. Oestrogen stimulates release of the body’s own opioid painkillers. Pain is least noticeable, then, when progesterone as an anaesthetic is at its highest level in the second half of your cycle. This may be an important piece of scheduling knowledge if you are set on having a Brazilian. Does it mean that women are more sensitive to pain than men? No. Whatever our cultural beliefs about tough men, there is no variation between the genders, but a huge individual variation both in response to pain and to pain relief. You see this most dramatically after surgery when patients are able to set levels of pain relief for themselves using what are called patient-controlled analgesia (PCA) pumps. There is a fourfold variation in the ‘right’ level of pain relief, and there is no correlation with gender, race, age, weight or type of operation.
It’s Your Time of the Month, Isn’t It?
The most noticeable effect of your menstrual cycle is on mood – which, as a woman, it rather irks me to have to admit. It is true, there is nothing more irritating, or more likely to make you pick up the bread knife and plunge it into the man in your life, than him saying, as you make some perfectly sensible point, ‘It’s your time of the month, isn’t it?’ Men have a nasty habit, particularly if they live with you or know you well, of being spot on with this observation. By the way, it is perfectly acceptable for a woman to lie through her teeth when challenged in this way. On interrogation, several men of my acquaintance claimed that their ability to tell whether a woman is hormonal is akin to that of being able to tell whether there is an elephant in the sitting room. I have of course rejected this information as being prejudiced nonsense. Why? Because I say so.
On a more serious note, pre-menstrual syndrome is a classic model of the way that hormones affect mood and emotion. It is also a fascinating model of fluctuating medical beliefs, swayed by prevailing medical dogma.
Only 10–25 per cent of women between the ages of eighteen and forty-five experience no fluctuations in mood or physical symptoms through their cycle. About two thirds report changing mood and bloating, and of these 10 per cent think this is troublesome enough to consult a doctor. About 3 per cent are severely handicapped by their symptoms for fourteen days a month. Thus there is a continuum from nothing to awful. Also, as you will know, even if PMS isn’t something that normally affects you, there are some months when you can be unaccountably ambushed by quite irrational premenstrual irritation.
Symptoms occur during the second half of the cycle only, with any one or all of the following: depression, anxiety, rapid mood change or anger, which may also be accompanied by a great range of physical symptoms, including sleepiness or insomnia, bloating, headache, and succumbing to comfort-eating or fatigue. Symptoms tend to increase with age and may start after childbirth or post-natal depression. Nearly half of those with severe PMS have a prior history of depression, and in those with bipolar disorder (manic depression) their condition is exacerbated with their cycle.
Doctors argue about the name for this condition. Pre-menstrual tension (PMT) is out. PMS tends to be used for more moderate symptoms while, post-menstrual dysphoric disorder (PMDD) is favoured by psychiatrists for those severely affected. We’ll use PMS here.
Right from the time that the ovarian steroids were isolated, that is to say, in the 1920s and 1930s, PMS was characterized as a condition of either hormone excess or deficiency, with either oestrogen or progesterone or both taking prime responsibility. One of the best-known theories was the low progesterone hypothesis of Greene and Dalton in the 1970s. The fly in the ointment has always been that studies of PMS have consistently failed to identify any difference in progesterone levels between women with PMS and those without it. Thus women with PMS have hormones within the normal range and have no abnormality of reproductive endocrine function. Recently attention has focused on neurosteroids – steroids that are synthesized in the brain and have acute effects on some of the brain’s chemical systems and in particular, the breakdown products of progesterone.
Let’s work through PMS, piece by piece. First of all, removing the womb does not stop PMS whereas removing the ovaries (oophorectomy) does. If you have no ovaries, there are no ovarian hormones and no ovulation. Since symptoms appear after ovulation has occurred, in the luteal phase, it suggests that it is something about the hormone cocktail in this part of the cycle that causes PMS.
Symptoms disappear in anovular cycles, and if you banish the cycle, for instance by shutting off GnRH at source with what are called GnRH-agonists (agents chemically similar to GnRH that block its action, and hence also block production of FSH and LH and, because ovulation is shut down, oestrogen and progesterone too), you banish the PMS problem. But significantly, if you then add back progesterone and oestrogen, in the same amounts and regimes, in women who’ve never had PMS and in those who have, only those who have had it before get it again when you restore ovarian steroids. In other words, women who get PMS seem to be especially sensitive to these hormones.
Progesterone gets a particularly bad press, and this is intensified by what happens when post-menopausal women take combined HRT. During the oestrogen-only phase, they are fine. When they take a progestogen, they get cranky and complain of PMS. Compare levels of oestrogen within groups of women with PMS and those with the highest levels have the most severe symptoms, even though oestrogen alone doesn’t provoke symptoms. This suggests that there is some sort of additionality effect with oestrogen and progesterone. The sum is more than the parts.
For women with mild PMS, taking the pill, which banishes ovulation, seems to help. But for those with more severe PMS, the pill worsens their condition. No matter how the culprit hormones are presented to the body, naturally or synthetically, they are symptom-provoking in those prone to PMS.
Neurosteroids
Now we come to the brain, certain parts of which are awash with sex steroid receptors. Oestrogen receptors in the brain modulate memory and learning, as well as balance and pain perception. Of greater interest here are the breakdown products of progesterone (pregnenolone and allopregnenolone) which bind to receptors of the GABA system. GABA (which stands for gamma aminobutyric acid) is a neurotransmitter, a brain chemical which facilitates messages across neurons. It acts as an inhibitor. Low levels of GABA plus low levels of serotonin (another neurotransmitter) are associated with violence and aggression. High levels of both produce passive behaviour and a sunny mood. Interestingly, the pharmaceutical drugs that also bind to GABA receptors are tranquillizers and barbiturates. But progesterone’s breakdown products are even better at binding to GABA receptors than barbiturates are. So here, in progesterone, you have an on-board, in-house tranquillizing system: progesterone can also be used as an anaesthetic in large quantities. Instead of being calmed, however, women with PMS seem to experience a less sedating effect if given pregnenolone than women without PMS.
Low levels of the neurotransmitter serotonin are associated with depression. Insufficient intake of the amino acid from which the body makes serotonin – tryptophan (found in protein foods like cheese, chicken and beef) – worsens PMS symptoms. There is now a large amount of evidence pointing to a serotonin dysfunction in women with PMS, so that drugs that promote serotonin release and prevent its reuptake improve PMS.
So hormones in the brain, hormones from the ovaries, serotonin – how do they all fit together? Numerous animal studies demonstrate that the serotonin system and ovarian steroids are linked. The evidence is harder to find in humans, but oestrogen given to post-menopausal women is known to increase serotonin. Also women undergoing assisted conception, who experience a decrease in oestrogen, have a simultaneous rise in depression and anxiety, a feature of falling serotonin levels. Thus it’s not just the stress of their treatment causing them to feel miserable and low, but a physiological response to lowered oestrogen. Women with PMS become as sensitive to pregnenolone as women without PMS who are being treated with Sselective Serotonin Reuptake Inhibitors (SSRIs) such as Prozac. If serotonin levels are increased, women with PMS are able to experience the sedating effect of pregnenolone that is felt by women who do not suffer from PMS.
This is hard science but there are two things to take away from it. It shows why taking SSRIs like Prozac, normally prescribed for depression, can help what is seen as a hormone problem. Women are rather suspicious of anti-depressants for PMS because they think that it ‘relegates’ PMS from a hormone problem to one that is in the mind and confected by the mind. A friend of mine with PMS was deeply upset and hurt when she was prescribed SSRIs. ‘Don’t they believe me?’ she kept saying. ‘I’m not a depressed neurotic, just premenstrual for heaven’s sake, this is a hormone problem.’ A prescription for an anti-depressant SSRI isn’t a value judgement. It’s an acknowledgement of the mechanics of PMS. The second thing I hope I’ve demonstrated – and this is the only time you are going to read this phrase in this book – is that you haven’t got a hormone imbalance. Your hormones are balanced just fine – you’ve just got rather enthusiastic receptors.
One of the noticeable features of PMS is carbohydrate craving – particularly for chocolate. Taking in carbs will certainly up your serotonin – incidentally the biggest serotonin hit is estimated to be from a white bagel and jam. But it’s a short-term solution and sets up a vicious cycle as your blood sugar alternately plunges and soars. Low blood-sugar levels also prompt the release of glucocorticoids, which, as their name suggests, help control glucose. Eating little and often seems to help and choosing foods wisely so that you include complex carbohydrates rather than quick-hit ones may be all you need to do to alleviate your problem. There are a number of books to help you, principally available from the Women’s Nutritional Advisory Service.
Stress Again
Before leaving PMS, let me mention stress again. It is always said that stress is a trigger for PMS – certainly its worst aspects always seem to coincide with domestic disaster or travel hell. Actually there isn’t a natural variation in stress response with the menstrual cycle, nor is there any difference in stress hormones between women who have PMS and those who don’t. However, in women who are affected, there is an increased stress response in the luteal phase. Learning how to manage stress and not let your kids/partner/life wind you up so much is likely to help alleviated the worst symptoms if you have PMS.
The stress response and depression share much in common. In some ways, depression can be understood as an endocrine disease, although it is not often recognized as such. What the stress response does is prepare body and mind for fight or flight. Heart rate goes up, body fuel is mobilized, while anything surplus to immediate requirements (sleep, reproduction, feeding, growth) gets put on hold. There is preferential access to stored memories involving similar experiences, which might help in dealing with the current situation. Behaviour is modified from the normal, cognitively complex exploration of novel circumstances, to well-worn, get-out-of-here-now behaviour. These responses are induced by nor-adrenaline and by cortisol, both produced by the adrenal glands in huge quantity. While short-term stress can be life-saving (and often life-enhancing), chronic stress is almost always bad news, the sufferer experiencing a wide range of symptoms including becoming withdrawn, jumpy, having problems with sleep, losing sex drive or appetite.
Compare this with depression. A person becomes withdrawn, jumpy, has problems with sleep, loses sex drive or appetite. In depression, anxiety is directed at yourself, not at a tiger trying to eat you. The depressed person also has preferential access to memory – but to those memories of past loss and failure. Equally, people with major depression have sustained high levels of cortisol, just as those with chronic stress do, putting them at risk of premature heart disease and diabetes in just the same way as those exposed to constant stress. The realization of the relationship between stress hormones and psychiatric disease opens up a whole new field for diagnosis, treatment and prevention of depression, plus an understanding of the endocrine abnormalities that underlie it.
Contraception – A Brief History
The story of how people have attempted to control a woman’s cycle and with it fertility is a fascinating one, and like most of hormoneology, driven by larger than life people, no doubt driven by their hormones.
Dr Ludgwig Haberlandt was an Austrian doctor who, in 1908, expressed what many doctors felt at the time – that there must be a better method of contraception than the Dutch cap, a simple circle of material which fitted over the cervix, which was all that was available. When in 1916, two German researchers showed that ovulation could be prevented in female animals if they were injected with an extract from the corpus luteum, Haberlandt saw that hormones might be a way of providing safe, temporary, sterilization. In 1919, he transplanted the ovary of a pregnant animal to one that had readily become pregnant before. The rabbit became infertile. He successfully and temporarily sterilized five out of eight rabbits. By 1927 Haberlandt was suggesting that women might be also be temporarily sterilized if they were given extracts of ovaries of pregnant animals. He was vilified in the German press, with one eminent doctor saying that it was a highly immoral act which would permit a few drones of society to indulge in love games – adding for good measure that every scientist knew that there were no such things as hormones of the ovary.
In 1930, the possibility of hormonal contraceptives was raised at the Seventh International Birth Control Conference held in Zurich, but it was all theory because it was still not understood which hormones they were actually talking about. But seven years later, there was the first breakthrough with progesterone. Scientists from the University of Pennsylvania tested progesterone, then a fabulously expensive commodity, for its contraceptive effect in rabbits. It worked like a charm, but this research was never taken up. Perhaps this was because, during the war years, almost all endocrine research was directed towards the function of the adrenal glands, so important in shock and battlefield injury. Another important factor at the time was that research was mainly concerned with improving fertility, rather than restricting it.
The Indiana Jones of the Hormone World
Russell Marker was a maverick chemist. He walked out on his Ph.D., choosing not to complete his thesis, then went into hydrocarbons research, where he developed the octane rating system for petrol. This also failed to inspire him and he drifted into yet another field of research. Finally, in 1938, when he was approaching forty, he decide to work on steroids at Pennsylvania State University.
At this time progesterone was available, but the production process was so involved and laborious that it was prohibitively expensive. Marker knew that certain plants contained a substance called saponin, which foams in water, hence their use by primitive peoples as soap. Saponins are also steroids. The one known source of saponins was the plant used to make the drink sarsaparilla, but again this was extremely expensive. Marker read up on botany before going on an expedition to Mexico where he found his steroid source in the wild yam, Dioscorea. He collected two sacks full, and then promptly lost them. He apparently had to bribe a policeman in order to get them back. Once back in his lab, he isolated the yam’s saponin, diosgenin. From this, he was able to make testosterone in eight steps, or progesterone in just five. He took his discovery to two different drug companies, who turned him down flat – a move reminiscent, in terms of commercial opportunities missed, of the record company Decca turning down the Beatles.
So Marker withdrew all his savings, resigned his job and moved to Veracruz, Mexico. He harvested ten tons of yams from the jungle and set up a lab in his bedroom to make steroids from them. He offered to sell some progesterone to a Mexican businessman, who offered him $80 a gram, no doubt expecting a few grams at most. Marker then handed him over 3 kg, worth $240,000 at 1943 prices – the equivalent of several million today.
Marker formed a company called Syntex with a German scientist and a Hungarian businessman, finding both his associates from the phone book. There was a dispute over profits and Marker pulled out, taking the secret of a crucial step in the process with him. Syntex eventually managed to work it out, making first testosterone and then finally oestrone from diosgenin. The price of progesterone plummeted to $1 per gram.
By 1949, Marker, surely the Indiana Jones of the hormone world, had retired from research altogether, but his discovery led directly to a synthetic hormone used in 50 per cent of today’s contraceptives.
Marker’s place at Syntex was taken by a young American chemist called Carl Djerassi, who was recruited to Mexico as director of steroid research. Djerassi and his boss George Rosenkranz discovered a synthetic variant of progesterone, norethisterone, which they were to patent in 1951. Both this product and a later one produced by Searle, norethynodrel, were not, however, marketed as contraceptives – which is what they were – but as products to treat menstrual disturbance.
By the late 1940s, there were perhaps only a dozen people clinically testing contraceptive methods, most in the employ of pharmaceutical companies. The direct impetus to do more came from two extraordinary American women, Margaret Sanger, an American woman’s rights activist, and Katherine Dexter McCormick, a science-trained philanthropist.
Margaret Sanger was born in 1883 into an Irish working-class family. She witnessed her mother’s slow death, worn out by eighteen pregnancies and eleven live births. Margaret worked as a nurse and midwife in the poorest parts of New York City. What information about contraception there was, was suppressed by the Church and doctors, although the rich and educated could use subterfuge to buy ‘French’ products (condoms) and ‘feminine hygiene products’ (spermicides). Sanger defied Church and State, writing a series of articles entitled ‘What every girl should know’ in her own newspaper, The Woman Rebel. She was effectively exiled to Europe in order to avoid the severe criminal penalties she incurred for violating postal obscenity laws. Her case was eventually dismissed and she founded the Planned Parenthood Federation of America. She organized population conferences and mobilized scientists and politicians. H. G. Wells said of her ‘When the history of our civilization is written, it will be a biological history and Margaret Sanger will be its heroine.’ He was right.
Katherine Dexter McCormick graduated from America’s premier science and technology university, Massachusetts Institute of Technology (MIT), in 1904, with a degree in biology. Women students accounted for less than 3 per cent of students. She made many contributions to women’s equality, helping to achieve the right to vote for women in 1919. Having inherited a considerable fortune from her husband, she espoused the cause of women in science and when in the 1950s women were still just 3 per cent of students at MIT, she paid for an on-campus residence for women. It helped open the science and engineering professions to them and today MIT has 40 per cent women undergraduates. But it was her funding of the pill, which so significantly advanced women’s health and independence, for which she is best remembered.
Sanger was so convinced of the need for simple, reliable birth control that in the 1920s she founded two journals to provide a forum in which scientists could present their research findings. The German doctor Haberlandt had effectively committed professional suicide simply by speaking about contraception, and with his vilification still fresh in their minds scientists were reluctant to work in such a controversial area. In 1951 Sanger was sixty-eight and time was running out, but then she found her scientist, Gregory Pincus. He was an endocrinologist who had fallen foul of the authorities at Harvard, following the publication of a controversial paper on parthenogenesis (virgin birth). He had built a major research organization, the Worcester Foundation, outside Boston, but always had trouble attracting grants. He approached the pharmaceutical company G. D. Searle and persuaded them to go into the hormone business, but their interest was not in contraception.
Sanger visited Pincus and persuaded him of the need for hormonal contraceptives. Equally important, she persuaded her very rich friend, Katherine Dexter McCormick, to bankroll Pincus. Sanger must have been an extraordinarily persuasive woman, for she also managed to convince Searle, who were deeply sceptical that there was any future in this area, to provide the compounds they were developing for use in other areas of medicine, for testing as contraceptives. Without Sanger and the women’s movement, there is no doubt that the development of chemical contraception would have been delayed by many years.
The next stage was clinical testing, and Pincus formed a collaboration with John Rock, professor of gynaecology at Harvard. There was a serious problem, however. Progesterone was far more active if given by daily injection, which clearly wasn’t a practical option. Given orally, a very large dose was required, which would make it too expensive. Pincus then asked all the pharmaceutical companies to send him synthetic compounds to test, which could be given by mouth without losing their efficacy. Over 200 arrived and he whittled it down to two companies: Searle (with whom he already had a working relationship) and Syntex. Later he worked with Searle alone using their norethynodrel.
Pincus was the pivot between clinic and pharmaceutical company. All of this was carried out in the state of Massachusetts, where birth control was outlawed. Rock’s fertility clinic provided the perfect cover for something that was strictly illegal. Their first trial was known as the pee, pee, pee project because of all the urine samples they required women to give for testing (actually PPP stood for Pincus Progesterone Project). The first public presentation of this work by Pincus in 1955 was received with yawns. Concern was raised too about side effects, such as headache.
No trials could be organized in Massachusetts, so the first were carried out amongst medical students in Puerto Rico. They were pretty disastrous, as the students dropped out when they graduated. Subsequent tests on psychotic prisoners weren’t helpful either.
In 1956, trials moved back to Rio Piedras, a slum area of Puerto Rico. the pill was considered a technological fix for the burgeoning population problem, then a greater world concern than it is now, and limiting of family size was thought to be a necessary requisite to economic development. Puerto Rico was the perfect testbed. Hormones thus became slaves to a political ideology.
The first trials worked well until the chemists removed ‘impurities’ from the pill – which turned out to be oestrogen. The consequence was breakthrough bleeding and some pregnancies. Putting oestrogen back solved the problem. Thus the combined oral contraceptive was created.
So how does the pill actually work? By adding oestrogen to your system, the pituitary thinks that it doesn’t need to produce FSH, and because this isn’t produced there is no recruitment of follicles. If there are no follicles, there is no feedback of oestrogen to initiate a surge of LH which would induce ovulation. Even if there were, the pill is a combined contraceptive containing a progestogen which also acts to stop that whoosh of LH from being produced. No LH surge, no ovulation. No ovulation, no egg. No egg, no pregnancy.
The original dose had, frankly, been a guess. Second-generation pills halved the dose, and then halved it again. Early pills gave as much progestogen a day as is now dispensed in a month. A pill-free interval was created to imitate periods. In effect these are caused by stopping the pill and they are technically hormone-withdrawal bleeds, not periods. There were concerns about side effects then, particularly nausea, and from the start there were worries about breast cancer and thrombosis.
Taking the pill does increase your risk of breast cancer by a very small amount while you use it. But the risk disappears within ten years of having stopped taking it. Since women’s risk of breast cancer rises with age, this finding is much more significant for older women than for the younger women who would normally use the pill. The advice would be to consider another contraceptive method from the age of thirty-five. There is no relation between duration of use and breast cancer risk. It is thought that the oestrogen element of the pill may promote existing cancer, rather than initiating new ones. Incidence of breast cancer is not the same as deaths from breast cancer. Deaths from breast cancer, in both current and past pill users, are no different from those in non-pill users.
Professor John Guillebaud has translated the most recent epidemiological studies into real numbers. Think of two concert halls each filled with 10,000 women aged forty-five. One lot have taken the pill for varying lengths of time, but stopped when they reached thirty-five (which is very common). The other group have never been pill users. In the never-used group there are ten cases of breast cancer, in the pill user hall, eleven cases.
On the other hand, the pill protects against both ovarian cancer (a 50 per cent reduction after five years which persists for at least ten years after the pill is stopped) and endometrial cancer (protection for about fifteen years after stopping).
There have been many scares about use of the pill. Those concerning deep vein thrombosis perhaps best illustrate the duality of thought and the separation of act and consequence that the pill has created. In 1995, there was a flight from so-called third-generation pills when research revealed that they doubled the risk of deep vein thrombosis (DVT). The consequence was that a lot of women got pregnant. As it happens, DVT is also a well-known complication of pregnancy, caused by blood becoming more sticky. It affects 60 out of every 100,000 pregnant women. But surely it was still safer than being on the pill? Actually no. The chances of getting DVT on those ‘high-risk’ pills was less than half that of pregnancy at 25 cases per 100,000 women. Women forgot why they were taking the pill. To prevent pregnancy. There was incidentally also a 9 per cent jump in terminations, which, as with any surgical procedure, carry risks associated with anaesthesia – including, of course, DVT.
Survey after survey reveals that from a third to a half of women taking the pill feel unhappy about doing so, mainly because they think that their health is being damaged by hormones or that they are loading their body with unnecessary chemicals. This is hardly surprising for women have been buffeted by scare after scare about hormones – not just the pill but HRT too. I am curious why women continue to take the pill if they are unhappy. There are plenty of other effective contraceptive methods.
There is particular worry that taking hormones for many years will cause infertility. This worry is buttressed by reports from women whose periods do not return when they stop the pill. In fact, work by Professor Howard Jacobs at University College found that amenorrhoea (no periods) was equally common among non-pill-users as in pill users. In some ways this problem is akin to getting on a bus in London, falling asleep and finding yourself in France. The landscape is different because time has passed and you are now somewhere different. Thus it is that problems with your periods, which were not apparent when you started on the pill some five or ten years before, are revealed when you stop it. If you hadn’t been taking the pill, with its reassuring withdrawal bleeds, you would have noticed something was amiss much earlier. The difficulty here is that doctors often talk about ‘post-pill amenorrhoea’ as if this were an actual condition (which it isn’t) and use this as an excuse to delay investigation. If this is you, your lack of periods is almost certainly down to some other problem, which should be investigated without delay.
Women who find they have no periods after pill use beat themselves up about it, believing that they have caused their problems and will now not be able to conceive. First, you didn’t do this to yourself and second, methods for ovulation induction are now highly successful. As for the pill causing infertility, early studies revealed no difference in fertility for users and non-users, although there was a delay of some three months in conception for pill users having a first baby. However, I suspect that this may be because of widely given advice to ‘clear the pill out of your system’ before conception. In 2002, a large study of over 12,000 by Farrow showed exactly the opposite of what is believed – that prolonged use (more than five years) was associated with decreased risk of delay. The reason for waiting to conceive after coming off the pill, incidentally, is because one of the effects of the pill is to reduce the level of folic acid and other vitamins in the body. Folates are important in preventing the type of handicaps called neural tube defects, which include spina bifida.
Should the side effects put you off? You need to remind yourself why you are taking the pill and ask yourself, what would happen if you fell pregnant. What impact would a baby have on your life and how would you cope? Now compare that with the known risks as you perceive them. We all look at risk through different glasses and for some breast cancer is a major fear despite the risk being a very small one. To me, the concerns about DVT are more puzzling, because if you get pregnant you immediately put yourself naturally, as we have seen, at much greater risk of this complication. It’s a decision that you have to take for yourself, but the bottom line is how important avoiding pregnancy is to you.
One further point, which illustrates a recurring theme throughout this book, is about being uniquely hormoned. If you have side effects when you take the pill – breakthrough bleeding, greasy skin, mood change, breast soreness are the commonest – swap to another brand. Women are very individual and even the tiniest change in the hormones you receive can make a difference to you. A small number of women, however, will never ‘get on’ with the pill and if this is you, just jump ship to an IUD.
The other point about being uniquely hormoned is that missing a pill matters more to some women than others – especially the sort, I suspect, who later says that their husband only had to unzip his trousers for her to get pregnant. What you are doing during the pill-free interval is allowing the ovary to escape from its imposed hormonal straitjacket. In a study from the Margaret Pyke Centre, 23 per cent of women were, by the end of their pill-free period, developing follicles again and two of those women were within two days of ovulation. Had they missed taking the first couple of pills in the new packet and had sex, they would have probably have got pregnant. Lengthening the pill-free interval is a sure way to decrease protection, and in some, a recipe for pregnancy. Beware in particular of missing pills early in the packet.
Despite all the scares, 200 million women are estimated to have taken the pill, which is probably the best-researched pharmaceutical product in the world. It was hailed as giving freedom for women, but fifty years after its introduction one wonders whether the price of freedom has been too high, for there is now an expectation by men that women will control fertility and in some senses, this hormone product for women has been more liberating for men. Some will say that extra breast cancer cases are too high a price to pay for the pill, forgetting that pregnancy leads to birth, something which is still fatal for many women, particularly in those countries without easy access to medical care. There are also those who would say that the pill has caused an explosion in promiscuity and taken innocence from young women. Have you met any young women en masse lately? If I were an adolescent boy, I would be very afraid.
the pill has always been closely entangled with sexual politics. Control of reproduction, and hence of sexuality, has always been a matter for suspicion, if not outright hostility, particularly from those quarters where control has been usurped. It seems to me that news of side effects of the pill, many of which were scares but some of which were accurate (especially those concerning smoking and cardiovascular effects), have always been seized upon with special glee, as if women deserve everything they get for trying to subvert nature. The subverting nature argument is a curious one. Polio vaccinations subvert nature, so do kidney transplants, but we don’t view them as such – but then neither have anything to do with sex as the pill does. That is its great threat.
Infertilty
We have talked of fertility and the pill and covered one of the common, hormonally induced causes of infertility, PCOS. Another hormonal cause of infertility is a luteal phase defect (LPD). Basically the womb lining isn’t in the right place at the right time. To get that wonderful shag-pile effect, progesterone is required. In LPD, either because the follicle isn’t good, or because the corpus luteum packs up before it should, the womb lining hasn’t had the progesterone needed to do its thing, so no implantation will take place. Extra progesterone or other hormones are used as treatment.
Infertility and its treatment is a complex and growing field, which is too large to cover here, but I did want to draw your attention to one fact. Whatever the cause of infertility – and there are many, including straight plumbing problems like blocked tubes – hormones are almost certain to be used in treatment. In fact, without the manufacture of hormone-based drugs, IVF would not be possible, nor would many of the very successful treatments now available.
Let me briefly introduce some of the main hormone treatments used in infertility treatment. Clomiphene (Clomid) is a first-line treatment for ovulation induction – in other words, something that your GP might prescribe. It’s an anti-oestrogen which fools the pituitary into thinking that more FSH is needed, which may be enough to kick-start ovulation. You should not take it for more than six months – for no other reason than if you aren’t pregnant by this time, you and your partner need a more thorough assessment of your needs and there is no point in delaying it.
Human menopausal gonadotrophin (Pergonal, Humegon) is used in a clinic setting, after more detailed investigations, and is a mixture of two hormones, FSH and LH. Injections are given daily, so that the ovaries begin developing follicles. These are followed 7–12 days later by an injection of human chorionic gonadotrophin (the hormone of pregnancy), which tells the ovaries to release the eggs that have been developed. More than 75 per cent of women will ovulate with this regime of drugs.
Initially, these drugs were produced using millions of gallons of human urine. Yet, no matter how refined the processing, the drugs still contained impurities. But in the mid-1980s, bioengineering became possible, and in 1997, the two principal companies in this market, Serono and Organon, announced recombinant DNA versions in which bioengineered cells produce the hormone, rather than nuns. Hormones produced in this way combine very high purity and very specific biological activity. They have fewer side effects and are more effective. Recombinant technology is now the main method of manufacturing hormones.
This chapter has been about the ‘juicy’ hormonal years, those from roughly from thirteen to fifty. What happens when this regular cycle disappears and hormones crash is the subject of our next chapter.
