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Glossary

HRT/Osteoporosis

[last updated 21 Aug 2006]

Note: Please seek the advice of your doctor regarding HRT. We are not medically qualified. This information is provided as a general guide only.

Index to this Page

What Influences Bone Mass?

Bone mass is referred to in terms of bone density. Our genetic inheritance plays a large part in determining the size of our skeleton and hence our bone mass. Diet, reproductive hormones and exercise are also important. Bone tissue is constantly being broken down (absorbed) and built up. Achieving an adequate bone density is a matter of these processes being in balance.

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Diet

A teenager needs a minimum of 1200 mg of calcium per day (equivalent to three 8 oz glasses of milk), but 1500 mg may be better. Vitamin D is also needed to help the absorption of calcium by the gut. At least 800 units per day is recommended, preferably 1000 units. 400 units is not enough.

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Hormones

Oestrogen is the major hormonal factor that influences bone, in both men and women. Oestrogen causes bones to grow and it also causes them ultimately to stop growing. An oestrogen surge at the end of puberty normally causes the ends (epiphyses) of the long bones to fuse, thus halting growth. Testosterone results in a widening of bones. In girls the growth goes into the centre of the bone. In boys it goes into the width. Later in life women get more Colles fractures (wrist fractures) than men.

The National Osteoporosis Society (UK) advises that the minimum daily dose to maintain bone density in normal adult post-menopausal women is thought to be 0.625mg conjugated oestrogen (e.g. Premarin) or 2 mg oestradiol by mouth, or 50 micrograms oestradiol skin patch.

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Exercise

The mechanical environment (bone-loading exercise) is important in maintaining bone density. People undergoing complete bed rest can lose a maximum of 40% of their bone mass.

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Monitoring Bone Density

Bone density, or more accurately, bone mineral density (BMD), is measured using scanning equipment and is the process is referred to as bone densitometry. It is a completely painless experience that just involves lying on a platform while a mechanical arm scans the hip and spine region using a low dose ‘X-ray’. It is usually repeated at one or two year intervals.

The important measurement on the bone density printout is the T-score. This is what gives an estimate of the fracture risk.

If you have a T-score of -2 this means you are in the 5% of patients that have the lowest BMD.

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Hormone Replacement Therapy

This section essentially covers the use of HRT by regular XX women. It is recommended that you read this material before going on to read the later sections on bone health and HRT in AIS women.

History, Ancient and Modern

In the 1940s and 1950s oestrogens were only given to post-menopausal women if they exhibited symptoms, e.g. hot flushes. Later it was found that the incidence of heart disease and osteoporosis seemed to decrease in these women, so this supported the idea of replacement therapy, to actually replace the hormones lost, even if there were no symptoms.

Animal studies then showed that oestrogens might cause breast cancer. So could progestins (progesterone-like compounds) protect against this? The downside would be that it causes a menstrual period (not welcome in post-menopausal women) although not if given continuously as opposed to cyclically.

The Women's Health Initiative was a US National Institute of Health (NIH) sponsored study of 100,000 women during 1992 - 1997. Women were given either HRT or a placebo (50/50). Women who had a uterus were given oestrogen and progestin. Those without a uterus were given oestrogen only. The preparations used were Premarin 0.625mg and a progestin 0.25mg manufactured by Wyeth.

However Wyeth had in the meantime conducted their own trial (the ?Herr's trial) on women who already had some heart disease which showed a 30-50% increase in their heart disease. So the WHI trial got stopped prematurely, at 7 years.

The WHI's oestrogen/progestin group also showed an early increase in heart attacks but it was not statistically significant. So the conclusion was that this form of HRT does not lower the risk of heart attack (and also the risk of stroke was increased). In the oestrogen-only group there was no increase in heart attack, but again it cannot be said to lower the risk (and again the risk of stroke went up).

The risk of leg thrombosis went up by 2-3 times, therefore a similar risk to that of oral contraceptives. Regarding breast cancer, the oestrogen/progestin group showed an increased risk. The oestrogen-only group showed no increase in breast cancer risk. But the researchers concluded that it is certainly wrong to say that HRT protects against breast cancer.

Both WHI groups showed an increase in bone mineral density, a decrease in hot flushes, an increased rate of dementia (Alzheimer's), and (surprisngly) an increase in the incidence of stress-related urinary incontinence (urinary leakage from bladder when you cough, laugh or jump up and down - that sort of 'stress').

Panic then set in, with many women stopping their HRT. However in 75% of these women there no problems as a result of this (in 25% there were hot flushes).

The Million Women Study, a European/UK study, suggested no difference between transdermal (patches) and pills. But it was not a double-blind trial. It did show that patches result in lower incidence of deep vein thrombosis (DVT) than pills.

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Current Recommendations

For post-menopausal XX women the experts recommend HRT for symptom control and for bone health, but suggest that treatment should be limited to 3-5 years. Patients should use the lowest dose that gives symptom control (freedom from flushes, moodiness etc.), bearing in mind that strictly-speaking the WHI findings can only really be applied to a single dosage level (0.625mg oestrogen/0.25mg progestin).

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Risks/Benefits

As mentioned above, the risk of breast cancer from oestrogen-only treatment in the Women's Health Initiative study was not elevated. The study did not find any beneficial effect of estrogen on the risk of heart attack.

The cardiovascular effects seem to be mixed. There is good evidence that oestrogen improves the lipid profile, by lowering the total cholesterol and LDL ("bad" cholesterol) levels, while increasing the HDL ("good" cholesterol) levels. However, there may also be an increase in triglyceride levels and in levels of an inflammatory marker called C-reactive protein. So overall, the effect on the parameters related to cardiovascular health seems to be neutral. Estratest (an HRT that combines oestrogen and testosterone) causes a worse profile of lipid changes than oestrogen alone.

Oestrogen appears to improve insulin sensitivity. So women with diabetes who take estrogen may need to use less insulin.

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Dosage

There is no "one size fits all" in oestrogen treatment. This is because the effects of hormones (or other treatments for that matter) depend not only on the dose, but on the specific individual's responsiveness to the treatment. Two people may respond quite differently to the same dose of a medication. The best approach is to aim for the lowest dose that prevents or controls symptoms. This has to be worked out between you and your physician on a personal basis.

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Bone Health in AIS

Low Bone Density in AIS

It is oestrogen that closes the ends of the long bones and stops their elongation after the pubertal growth spurt. CAIS women who have a late gonadectomy/orchidectomy (removal of the testes), and women with XY Gonadal Dysgenesis (Swyer's Syndrome) who go onto HRT late, tend to be taller than average. This suggests that although AIS testes 'produce' oestrogen by conversion from testosterone in body tissues (facilitated by an enzyme called aromatase - the process is known as aromatisation) they may not produce enough to close the long bones. In other words, CAIS women with intact testes and no HRT are relatively oestrogen-deficient.

There is anecdotal evidence within the support group that a number of AIS women who have been on HRT since gonadectomy still have a low bone density. However, it's important to realise that charts giving bone density versus age are based on people of average height. Since women with AIS tend on average to be taller, the bone density readings need to be interpreted in the light of this. If their bone density was distributed throughout a smaller (shorter) skeleton it might have been somewhat closer to the reading expected for someone of that age. Also, there are other agents acting on bone besides oestrogen. There might be androgen effects operating in regular XX women which are not able to operate in AIS.

Peak bone mineral density is normally achieved at age 35-40 years. For as long as they retain their testes, people with AIS produce their own oestrogen, but the circulating levels are lower than in XX females. They are sufficient, however, to produce spontaneous pubertal changes, such as an adolescent growth spurt and breast development, but may not be high enough to achieve optimal bone density. This, together with an insensitivity to possible beneficial effects of androgens on bone, means that those AIS patients who retain their testes until after their teenage years - and whose oestrogen levels are thus not boosted by HRT in the period when they should be developing their peak bone mass - are likely to have a low bone density. The same outcome is likely in those young AIS patients who do not comply with their HRT following pre-pubertal gonadectomy. This bone deficit, once established, is seemingly unresponsive to hormone treatment and anti-reabsorptive agents such as bisphosphonates, thus putting the patient at risk of fractures. One AIS patient suffered fractures when stamping her heel in an argument and when being hugged on her wedding day!

An association of osteopenia (low bone density) with AIS has rarely been reported in the medical literature, but Soule et al. (1995) provided evidence for the first time that androgen insensitivity may itself contribute to a low bone density. It was already well established that oestrogens play a major role in achieving and maintaining peak bone mineral density but evidence is given that oestrogen and other treatments may not be effective in reversing low bone density in AIS because the action of androgens on the bone may also required. And this may not be surprising since the actions of adrenal and gonadal steroids (e.g. androgens), thyroid hormone, and Vitamin D (which affects calcium absorption by bone) are mediated by receptors encoded by a family of related genes.

An AISSG member circulated the abstract of a 1998 paper by Bertelloni et al, on bone density in CAIS, to other members. It started:

Androgens have major influences on the regulation of bone mineralization. Because of their unique peripheral metabolism androgens may act on bone via activation of the androgen and/or estrogen receptor. Patients with complete androgen insensitivity syndrome (CAIS) are natural models to assess androgen actions on bone. We studied bone mineral density (BMD) in 10 patient with CAIS; 3 patients were studied before gonadectomy; the others were castrated and 6 were on hormonal replacement therapy. We measured ..... etc. etc....

And concluded:

BMD [bone mineral density] is reduced in CAIS patients, while bone turnover and the fracture risk seem not to be increased. Our data indicate that [the action of] both androgens and estrogens may be required for acquisition of bone density during childhood.

(Another group member commented: "Hey, don’t you just love it when these guys refer to us as having been ‘castrated’. It’s awful. I’ve seen it quite often in relation to AIS. The editors of these publications should outlaw the use of such stigmatizing terms. I think AISSG should award an androgen-induced ‘insensitivity’ prize for this!")

In 2000 a member of the US AISSG co-authored a paper with Dr. Robert Marcus, an osteoporosis expert at Stanford University. Some support group members took part in the study, with measurements being made at the time of a US group meeting in San Diego.

Further studies are needed. The paper of Soule et al. was based on the history of six Complete AIS (CAIS) patients. It would be very interesting to know if those with Partial AIS (PAIS) are better able to achieve and maintain a good bone density by virtue of their ability to respond, to some extent, to androgens. This is certainly the impression that we get within the support group. UK patients could ask their GP to refer them to one of the paper's co-authors, Dr. Gerard Conway (see Recommended Clinicians), if they are interested in helping with this research.

Eric S. Orwoll MD (Chief of Endocrinology and Metabolism and Assoc. Prof. of Medicine, Oregon Health Sciences University, Portland VA Medical Center, 3710 South West US Veterans Hospital Rd., Portland, OR 97201, USA) is interested in working with US support group members to collect information about osteoporosis in AIS, e.g. how often it occurs, what its characteristics are, and what might be done to prevent or treat it.

ALIAS Refs:
"Low Bone Density in AIS" in ALIAS No. 6
"Orchidectomy/HRT" in ALIAS No. 11
"Bone Density" in ALIAS No. 11
"Osteoporosis in AIS" in ALIAS No. 14

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Oestrogen Sensitivity (CAIS vs PAIS)

There is some evidence in regular XX women that early androgen action results in smaller breasts, by opposing oestrogen action. In CAIS the androgens can’t act on the tissues due to their insensitivity, so the oestrogens are unopposed, resulting usually in good breast development.

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Low Bone Density in Carriers

It has been suggested in the medical literature that carriers of the faulty AIS gene (e.g. mothers, XX sisters and XX maternal aunts/cousins of AIS girls/women) might themselves have some slight insensitivity to androgens (as evidenced by reduced density of pubic/axillary hair and delayed onset of menstruation). If low bone density in AIS has any link to the androgen insensitivity itself, as has been suggested by Soule et al., then maybe carriers also have an increased risk of osteoporosis? Therefore it is probably important for carrier women also to be diligent with their HRT and to obtain regular bone density measurements.

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Bone Scans in AIS

Measurement of bone mineral density (BMD) is not routinely offered to pre-menopausal women. But because evidence is emerging that AIS women are a special risk group for osteoporosis, it would make sense for them to ask for their bone health to be monitored in this way, even from a young age. In particular, it might be useful to establish a baseline measurement early in life, perhaps prior to a gonadectomy as a young adult, or maybe even earlier, say in teenage years.

Many doctors will not know much about AIS, let alone that the condition carries a risk of osteoporosis, so you might have to be rather firm in asking for the test. If you have any problems in arranging this, please seek the help of one of our recommended clinicians.

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HRT in AIS

Introduction

AIS women have reasonably high oestrogen levels except when there has been early (childhood) gonadectomy with delayed introduction of HRT at puberty or the testes have been removed later in life followed by a substantial interval without HRT (either because it was not prescribed or because of non-compliance with treatment).

When the testes are removed after puberty in AIS girls/women, immediate long-term female hormone replacement therapy is needed in order to prevent menopausal symptoms and to protect the skeleton from osteoporosis. Oestrogen-only preparations should be used in AIS, as there is no benefit (and possibly some harm) in using a preparation containing a progestin. If the testes have been removed in infancy or childhood, this therapy is usually started at the age of about 10 or 11, in order to initiate puberty.

There seems to be no consensus amongst clinicians as to whether pubertal development in AIS is more 'natural' via oestrogen from testes left in the body (the body converts testosterone to oestrogen) or via hormone replacement therapy (HRT) following early gonadectomy. However, as discussed earlier, some adults with AIS have a low bone density in spite of regular HRT, and some medical experts think this could be a result of early gonadectomy, or maybe an effect of the androgen insensitivity itself.

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XX Women vs AIS women

There are clearly significant differences in physiology between 46,XX women and those with AIS. The majority of 'regular' women have a cyclic pattern of rising and falling oestrogen levels (range 5 - 200 picogram) and progesterone levels every month for about 30 - 40 years. In addition, their bodies are able to respond to the (relatively weak) androgens produced by the adrenal glands and ovaries. (The adrenal glands produce only 1/4 to 1/3 of the oestrogen produced by the ovaries.)

So an XX woman's body is exposed to varying concentrations of a mixture of oestrogens, progesterone and androgens over many years. In contrast, women with AIS produce no progesterone and are partially or completely unable to respond to androgens, so the effect of oestrogens in their bodies (whether produced by their own testes, or provided through medication) is unopposed by any other hormone effects. Nevertheless, based on the information available from various sources, treatment with oestrogen alone during the period between the teens and 40s-50s remains the overall best approach in AIS.

Post-menopause, the ovaries in XX women still produce oestrone (another form of oestrogen compared to oestradiol) as well as adrenal oestrogen. This is somewhat similar to the situation in an AIS woman post-gonadectomy, except that there are no androgens in the latter case.

The Women's Health Initiative study, mentioned earlier, did not find any beneficial effect of estrogen on risk of heart attack. However this was a study of 46,XX women, so may not directly apply to AIS. What is the risk of breast cancer for a woman with AIS taking long-term oestrogen? The risk of breast cancer from oestrogen-only treatment in the WHI study was not elevated. Again, the results may or may not be relevant to AIS women. That said, we are not aware of any evidence of an increased risk of breast cancer in women with AIS who take oestrogen. There is even a speculation that such women may have an inherently low risk of breast cancer but there are no studies to prove or disprove this.

Data have not been collected in any kind of systematic fashion in AIS, so there is no real evidence either way on many HRT-related questions. There are probably about 7,500 AIS women in the USA but, as of 2006, only about 200 are known to the US AISSG so we won't really get reliable data on AIS. AIS women have the additional complication of needing to take HRT for a very much longer period of their lives than most women. There is virtually no information on the risks of such long-term use.

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Dosage in Children

With regard to the dosage for HRT in young AIS patients, Zachmann et al (1986) cite one AIS patient who had undergone gonadectomy and in whom oestrogen administration was started at the earliest estimated pubertal age of 10.3 years in the form of Premarin 0.625 mg three times weekly. It was found, however, that this stopped growth of the girl prematurely and the authors felt that it would have been better to have given the patient 0.005 - 0.01 mg ethinyloestradiol daily, instead. From studies of patients with Turner syndrome it has been suggested that to ensure normal pubertal growth, physiologic oestrogen replacement should be started at the appropriate bone age of about 11 years and should not be delayed in the hope of achieving a greater mature height. Batch et al suggest a regime of 5 micrograms of ethinyloestradiol daily for the first 6 months, increasing to 20 micrograms daily by the end of puberty.

Soule et al. (1995) suggest that the best course of action in AIS, assuming diagnosis in infancy/childhood, may be to perform a gonadectomy just before puberty (at 11 years in a case quoted) followed by oestrogen therapy (ethinyl oestradiol 2 micrograms daily, gradually increasing to 20 micrograms over 2 years, in the case quoted) with regular bone density measurements. This policy, it is suggested, reduces any slight risk of malignant transformation of the gonads and ensures adequate oestrogen activity throughout the critical years of bone accretion. They suspect, however, that the androgen resistance may compromise attainment of full adult bone density irrespective of the oestrogenic milieu of the developmental years.

Prof. Ieuan Hughes (Dept. of Paediatrics, New Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ) told a UK group meeting that oestrogen levels are higher in XX girls than in boys, even in childhood, and it is thought that XY girls with AIS have lower levels than XX girls with ovaries. Dr. Richard Stanhope (see Recommended Clinicians) tells us that XX girls start producing oestrogen at 8 or 9 (i.e. a year or two before breast development). Both clinicians therefore recommend oestrogen supplements in AIS children, even if the gonads are still in place. Dr. Stanhope suggests 1 microgram ethinyloestradiol per day from age 8-9, with an increase at about 11-12 years.

The teenage years are when the bulk of bone tissue is laid down. Peak of oestrogen production is normally age 16-24, so it also makes sense to give young adult women a higher than usual HRT dose following gonadectomy, although oral oestrogen passes through the liver so presents a risk of thrombosis at very high doses (e.g. the 10 times normal dose used by some male to female transsexuals).

ALIAS Refs:
"Low Bone Density in AIS" in ALIAS No. 6
"Orchidectomy/HRT" in ALIAS No. 11
“Childhood HRT?” in ALIAS No. 18

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Dosage in Adults

For adult AIS women, most physicians these days would recommend using the lowest effective dose that keeps symptoms such as hot flushes at bay, and for the shortest period of time. However this is an extrapolation from the situation in XX women, because there are other factors at work in AIS, a) the androgen receptor normally helps to bind oestrogen (helps it to have an effect in the tissues) and b) the level of aromatisation (conversion of testosterone to oestrogen in the body) changes during life.

Dr. Garry Warne's 2005 paper (see General Refs at foot of page) says:

Some women with CAIS have argued that the testes are a valuable source of oestrogen precursors and should be retained, but in fact they probably need oestrogen supplementation to prevent osteoporosis even with the testes still present [Ref: Mizunuma et al, 1998]. This is because oestrogen levels in women with CAIS who still have testes never reach the levels found in 46,XX women with ovaries [Ref: Melo et al, 2003].

The optimal dose of oestrogen for HRT in young women is not known [Ref: Zacharin et al, 2000]. The doses of oestrogen that are recommended for the prevention of osteoporosis in women are derived from studies on post-menopausal women [Ref: Togerson et al, 2001] rather than on young women aiming to achieve optimal peak bone mass. For post-menopausal women, the following are the daily doses generally accepted as adequate for the maintenance of bone density: conjugated equine oestrogen 0.625mg; oestradiol valerate 2mg; and estropipate (piperazine estrone sulfate) 1.25mg. As the attainment of peak bone mass is determined by several factors including exercise, calcium intake, genetics, and 1,25-hydroxy vitamin D, these factors also need to be optimized in young women, as well as oestrogen dose.

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Oestrogen HRT

Oestrogenic HRT preparations are covered in more detail lower down on this page.

An expert at a 2006 AISSG meeting said that oestrogen is good for symptoms but is not useful for vaginal dryness unless there are symptoms. It was not clear whether he was saying that regular oestrogen HRT doesn't have an effect on vaginal tissue (we would agree that it's not particularly good at relieving vaginal dryness) or that locally-acting vaginal oestrogen products shouldn't be prescribed solely for this purpose unless there are symptoms. Group members have found vaginal oestrogen treatments (creams, pessaries etc.) to be extremely helpful in a) greatly easing the use of vaginal dilators, b) making intercourse more comfortable, and c) curing cystitis (see Vaginal Hypoplasia).

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Progestins Too?

There is debate about whether women with AIS might also need progesterone even though they do not have a uterus (lowering the risk of uterine cancer is usually the main reason for including progesterone in HRT). Whether there are progesterone receptors in other parts of the body is not known. It has been asked at our meetings whether this hormone not might be important, apart from its effect on the uterus, since it is obviously part of the general hormonal milieu in XX women. It is possible that the hormone has effects in tissues other than the uterus. It is known that is has an effect on the brain, where it acts as a mild anaesthetic.

Ulrich et al. (1995) suggested a possible beneficial effect of weekly high-dose oestrogen-progestogen injections (so-called 'pseudo-pregnancy') for 6 months on bone density in AIS and other conditions.

Dr. Garry Warne's 2005 paper says:

Women with CAIS have no uterus, because during fetal life, fetal Mullerian inhibitory substance suppressed uterine development. Such women therefore have no need of a progestogen, and 'unopposed oestrogen' is safe to administer. There has been some discussion about whether, despite the absence of a uterus, a progestogen might nevertheless have some benefits for women with CAIS, but there is no evidence base to support this hypothesis.

ALIAS Refs:
"Natural Progesterone" in ALIAS No. 10, Winter 1997

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What about Androgens?

Whether CAIS women can respond in some way to androgens such as testosterone is not clear. Testosterone is converted to oestrogen in the body (aromatisation) so it may be that any benefits seen, e.g. an elevation of mood, are due to the resulting oestrogen rather than the testosterone.

Androgens work via the androgen receptor but they also work via other mechanisms, e.g. the cortico-steroid pathway. And a hormone expert has mentioned at several US AISSG meetings that a direct effect testosterone on the membranes of brain cells has been reported (i.e. without the need for an androgen receptor). A number of US AISSG members report feeling good using Estratest (combined oestrogen/androgen HRT). Dr. Gerard Conway at the Middlesex Hospital, London (see Recommended Clinicians) has said at UK group meetings that it might be possible for the brain/body tissues to sense, or react to the actual conversion of testosterone to oestrogen, rather than the resulting levels of hormones in the body. This sort of indirect mechanism of hormone action has apparently been found in other systems in the body. Dr. Conway is currently doing a study of testosterone HRT (by skin patch) in CAIS women (see Research Studies).

Dr. Garry Warne's 2005 paper says:

Women with CAIS have little or no pubic hair and their genitalia are female. Their testes are normal and serum testosterone levels are generally well above those of normal men but serum LH levels [.......]. Serum oestradiol levels are in the normal range for males or higher (and breast development is usually good) but are much lower than in pre-menopausal women with ovaries [Ref: Melo et al, 2003]. Removal of the testes in later adolescence is usually recommended, because there is an increased risk of malignant change. This necessitates life-long HRT.

Some women with CAIS have argued that testosterone is their natural hormone, and that they should therefore be treated with testosterone, not oestrogen. The available evidence, however, suggests that women with CAIS derive no benefits from being treated with testosterone [Ref: Slob et al, 1993], and are better treated with oral or transdermal oestrogen. Even those women whose testes have not been removed should probably have an oestrogen supplement, because without it, they are at risk of osteoporosis [Ref: Bertelloni et al, 1998].

ALIAS Refs:
"Hormones on the Brain?" in ALIAS No. 10, Winter 1997
"Testosterone HRT" in ALIAS No. 13, Autumn 1998

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HRT for Life?

At an AISSG meeting in 2006 an HRT/osteoporosis expert with experience of these issues in AIS recommended that HRT need not be for life, as long as the bones are good and you have the right genes for (lack of) heart disease etc. You need to think of your own individual health needs and monitor a) breasts (mammograms), b) bones (BMD), and c) lipids.

Up to the point when peak bone mass is normally attained, oestrogen is needed to increase/maintain the BMD. After that point there are other options for maintaining bone. Oestrogen HRT should be taken by AIS women for the bones, and probably, for overall wellbeing, from the time of gonadectomy (this, in itself, should be challenged - is it really necessary?) and using the attainment of peak bone mass to estimate the duration, i.e. about 40 years. After 50 or so, oestrogen supplementation may be needed by some women to prevent symptoms such as severe hot flushes.

After 50 there are fewer additional benefits than once thought. It is probably best to stop at about 50 years, in order to mimick the situation in XX women. After 50 you can stop HRT as long as your breasts, your bone density and your lipids are all OK.

If you decide to stop HRT you can do it overnight. Hot flushes should not occur until 2-3 months later, so you should wait that long before evaluating the effect of coming off the hormones. If symptoms occur (e.g. hot flushes) you simply start the HRT again. If you are going back onto HRT after a longish break you should have your cardiovascular markers (lipids, C-reactive protein etc.) monitored, and you can take statins, aspirin etc.

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Forms of HRT

Delivery Routes

There are a number of ways of taking hormones (delivery routes):

If using oestradiol (the most common form of oestrogen) then a patch is a good choice (or a lotion, although this is not regulated, not tested to see if gives a reliable dose etc.).

Oral estrogens have to be absorbed through the gastrointestinal tract, which means that they reach the liver in high concentrations. A significant amount of an orally administered hormone will be metabolised there and lost. Oestradiol tablets tend to get converted to oestrone in the gut/liver then get converted back to oestradiol. They also tend to affect the production of the clotting proteins by the liver. This may result in an increase in the risk of venous thromboembolism (blood clots). Transdermal oestrogens avoid this problem by being absorbed directly into the circulation.

Because skin absorption does not involve the liver transit, the doses provided by skin patches are lower than those of tablets. This means that you cannot directly compare the dosage figures on the packets of the two types of preparation. Another reason is that different preparations and delivery methods have different effects on a) the ratio of oestradiol to oestrone in the blood, b) levels of Follicle Stimulating Hormone (FSH) - a brain hormone that stimulates the gonads, and c) liver biochemicals.

Vaginal oestrogen is used to treat local symptoms, i.e. vaginal dryness, and not as a main source of whole-body hormone replacement. See also Vaginal Hypoplasia for information on use of vaginal oestrogen to help with pressure dilation.

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There are many products

There are a lot of HRT products on the market and finding the right one can be difficult. It is a very individual thing. The questionnaire for The Million Women Study (a late 1990s? study of breast cancer in UK women) asked “What is the most recent HRT you have used?” and listed the following UK preparations:

Prempak C 0.625 mg
Prempak C 1.25 mg
Tridesta
Trisequens
Trisequens Forte
Cycloprogynova 1 mg
Cycloprogynova 2 mg
Estrapak
Estracombi
Climaval 1 mg
Climaval 2 mg
Premique Cycle
Premique
Nuvelle
Kliofem
Livial
Premarin 0.625 mg
Premarin 1.25 mg
Evorel 25 mcg/50 mcg
Evorel 75 mcg/100 mcg
Progynova 1 mg (skin patch)
Progynova 2 mg (skin patch)
Estraderm 25 mcg (skin patch)
Estraderm 50 mcg (skin patch)
Estraderm 100 mcg (skin patch)
Zumenon 1 mg
Zumenon 2mg
Ethinyloestradiol (BP tablets in a bottle)
Micronor
Oestrogel (skin gel)

Provera (progesterone)
Duphaston (progesterone)

Implants

There will almost certainly be a lot more on the market by now.

As discussions at AISSG meetings indicate, what suits one person will not suit another. There are really no guidelines other than just to keep trying different preparations until you find one that suits you.

HRT can be in the form of oestrogenic, progestogenic or androgenic agents.

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Oestrogenic Preparations

In terms of the specific biochemicals contained in oestrogen-based HRT preparations, there are five main categories:

Most of the information available in the medical arena is on Premarin, which contains about 40 different types of oestrogen.

HRT preparations often come in two doses. Finding the right dose is a matter of balancing symptomatic relief (hot flushes, mood problems etc.) against the possible risks. The contraceptive pill is sometimes used as HRT but contains higher doses of hormones than HRT preparations.

Most of the preparations that are licensed for use as HRT (these may be conjugated oestrogens, but are usually based on oestradiol valerates) are only available by doctor’s prescription. Oestradiol valerate is the only form of HRT that can be measured in blood, so blood oestrogen measurements are meaningless in someone taking, say, Premarin. Products based on phyto-oestrogens are available in health food shops but are not subject to licensing or standardisation of their active constituents, and are usually of very low, and possibly ineffective dose. A hormone expert told us at the Sept 2000 meeting of the US AISSG that Ogen, which is based on the hormone oestrone (to which all oestrogenic hormones get converted by the body), has less of an effect on breast tissue than other types of HRT.

Two oestrogen receptors have been identified. Conjugated oestrogens and the oestradiol valerates are known to work on the brain oestrogen receptors. The phyto-oestrogens are known to work on the bone oestrogen receptors.

SERMS stands for Selective Estrogen Receptor Modulators. These are compounds that have oestrogenic properties in some tissues (e.g. a protective effect on bones) but block oestrogenic action is other tissues (e.g. the breast) thus reducing the risk of cancer in that tissue. While Raloxifene protects the bones from osteoporosis, and does not stimulate breast tissue, its drawback is that it does not treat menopausal symptoms, like hot flushes, so does not strictly come under the category of hormone replacement therapy. Tibolone (Livial) is a synthetic compound that has oestrogenic, and weak androgenic and progestogenic properties, and that started out being licensed only to protect against osteoporosis. It may now be licensed as a full HRT preparation (i.e. to protect against menopausal symptoms and heart disease). It does not stimulate breast tissue as much as some HRTs.

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Progestogenic Preparations

There are some prescription HRTs available that are based on synthetic progestogens (chemicals that have progesterone-like actions), e.g. Provera and Duphaston.

Our attention has been drawn to books by John R. Lee and by Alan Gaby which propose a new syndrome of 'oestrogen dominance' or 'unopposed oestrogen' and which suggest that doctors should re-evaluate their HRT treatment. These books make enthusiastic claims for progesterone, in particular the so-called 'natural progesterone', as being safer and more effective in treating menopausal symptoms and osteoporosis, but less remunerative for drug companies. It is available in some health food shops or via the Internet, usually in the form of a skin cream.

'Natural progesterone' is present in certain plant sources in a form that’s the same as that produced by the human body (hence its name). Drug companies cannot patent a natural substance, but by altering the chemical make-up of synthetic compounds (like the oestrogenic chemicals used in most HRT preparations) they can make a lot of money by taking out a new patent. An argument has been advanced that, for this reason, drug companies have no interest in promoting progesterone.

Two UK trials of natural progesterone were started in 1997/98 by a) Beverly and Adam Carey, Chelsea and Westminster Hospital, London, SW10 9NH, and b) Gill Pearson and Wesley McCullough, Osteoporosis Clinical Research Unit, Southampton General Hospital.

A progesterone preparation called Prometrium (possibly only available in the US?) was recommended by specialists attending the Sept 2000 meeting of the US AISSG.

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Androgenic Preparations

There are no health/medical benefits to women in general taking testosterone (androgen) although it is sometimes prescribed in post-menopausal XX women to boost their libido.

The main problem has been the lack of suitable preparations for women (the products are designed for men). Testosterone can be taken by mouth (not a very effective route), by skin patch (e.g. Andropatch, Testoderm, Virormone) or intramuscular injection, say, every two weeks. An HRT preparation (tablets) containing androgen, and called Estratest, is available in the US. However it has been found to be not much better in health terms than other HRTs in a double-blind randomised trial. An androgenic preparation called Forteo was mentioned by specialists attending the Sept 2000 meeting of the US AISSG. There is an androgen gel (Androgel) which enables absorption through the skin.

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Osteoporosis Treatments

If osteoporosis has actually taken hold there are a number of treatments.

Bisphosphonates

This is the general name for a group of synthetic compounds that are used as a treatment for osteoporosis. They act as a kind of cement, plugging the holes in bone so that new bone can be laid down. They effectively prevent the reabsorption of bone.

There are two generations of such products; Etidronate (Didronel) and the newer form, Fosamax. Many endocrinologists do not recommend the use of these preparations in young patients. They are usually a last resort for established osteoporosis in older women when oestrogen HRT has failed to prevent osteoporosis or cannot be tolerated.

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Forsteo (Teriparatide)

In 2003 a treatment for osteoporosis was introduced in the UK that offers a potential cure for the condition by increasing the number and activity of osteoblasts (bone-forming cells). Teriparatide (Forsteo) is administered by self-injection. Drugs available previously were able only to slow the loss of bone.

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Denosumab

In Feb 2006 the New England Journal of Medicine reported on a new drug, Denosumab, for osteoporosis that increases bone mineral density and cuts the bone destruction rate. It is injected only once every several months which should ensure that women keep taking it. Non-compliance with treatment is a serious problem with other drugs for osteoporosis, says its makers Amgen, who designed and funded the study.

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UK Prescription Charge Exemption

Certain medical conditions requiring long-term medication (e.g. HRT for certain medical conditions) qualify for exemption from UK prescription charges. An AISSG member was advised by her consultant to apply for an exemption certificate (although AIS is not one of the qualifying conditions specifically mentioned on the form) and was successful. You have to fill in and submit an FP92A form (although it may now have changed to a PE21 Version 03 form?) which can be obtained from your doctor's surgery or from some chemists (pharmacies). You need to add an extra tick/check-box to the form, write 'hypogonadism' beside it then tick/check the box. Getting it also countersigned by your consultant /specialist may help.

Some group members have been granted exemption certificates with no problem (in one case almost by return post), others have been refused even after lengthy correspondence. It seems to depend on which Area Health Authority (AHA) you come under. Certificates have been granted to group members by Cornwall & Isles of Scilly AHA, East London & The City AHA, East & West Surrey AHA and West Midlands AHA (and maybe others that we don't know about?). One member was finally successful after enlisting the help of her Member of Parliament. Another member held a certificate for a number of years, with automatic renewals being granted without her having to do anything, but then she was suddenly told that she no longer qualified, so it seems the Prescription Pricing Authority is tightening up on the regulations. Please let the UK support group know if you have been successful - and if you are having difficulty.

ALIAS Refs:
"HRT For Free?" in ALIAS No. 7
"Free Prescriptions" in ALIAS No. 8
"Free HRT" in No. ALIAS 10
"FP92A Success" in No. ALIAS 11
"Free Prescription Quest" in ALIAS No. 12

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Further Reading

One of our recommended books is The Menopause, HRT and You written by Caroline Hawkridge, a women’s health educator and writer who collaborated closely with several support groups in writing the book. She covers the much neglected areas of 'HRT in younger women' and 'HRT in women with unusual reproductive problems'. See Literature page for details of how to obtain this and other publications from the support group. Dr. Gerard Conway (adult endocrinologist, Middlesex Hospital, UCLH Trust, London) maintains a useful web site at http://www.endocrineonline.org that includes an HRT Reference Sheet.

See Links to Other Sites for access to further information about HRT preparations.

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General Refs:

See Medical Literature Sites on our 'Links to Other Sites' page for ways of accessing journal articles.

Demetriou E., Emans S.J., Crigler J.F Jr: Final height in estrogen-treated patients with Turner syndrome. Obstet. Gynaecol. 1984; 64:459.

Zachmann M., Prader A., Sobel E.H. et al: Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls. J. Paediatr. 1986:108:694-7.

Meyer L. et al: Ein Fall with Testicularer Feminizierung und Osteoporose. Ber. Gyn. 1990; 127:1001.

Batch J.A., Patterson M.N., Hughes I.A: Androgen insensitivity syndrome. Reproductive Medicine Review 1992, 1: 131-150.

Boning Up, Newsletter of the National Osteoporosis Society (UK), December 1993, p 9.

Slob A.K. et al: Psychosexual functioning in women with complete testicular feminization: is androgen replacement therapy preferable to oestrogen? J. Sex & Marital Therap. 1993; 19: 201-9.

Preventing and Treating Osteoporosis by Dr. Alan Gaby, Prima Publishing, 1994, ISBN 076150027.

Soule S.G., Conway G., Prelevic G.M., Prentice M., Ginsburg J., and Jacobs, H.S.: Osteopenia as a feature of the Androgen Insensitivity Syndrome. Clinical Endocrinology (1995) 43, 671-675.

Ulrich et al: High-dose estrogen-progesten injections in gonadal dysgenesis, ovarian hypoplasia and androgen insensitivity syndrome. Adolesc. Pediatr. Gynecol. (1995) 8:20-23.

Natural Progesterone - The Multiple Roles of a Remarkable Hormone by John R. Lee, MD, Jon Carpenter Publishing, 1996, ISBN 1 897766 19 X.

What your Doctor may not tell you about Menopause, by John R. Lee and Virginia Hopkins, Warner Books, 1996, ISBN 0-446-67144-4.

Bertellonia et al: Altered Bone Mineral Density in Patients with Complete Androgen Insensitivity Syndrome. Hormone Research 1998, 50:6:309-314.

Mizunuma H. et al: Changes in bone mineral density after orchidectomy and hormone replacement therapy in idividuals with androgen insensitivity syndrome. Hum. Reprod. 1998; 13: 2816-8.

Noble B., Routledge J., Stevens H., Hughes I. and Jacobson W: Androgen Receptors in Bone-Forming Tissue. Hormone Research (1999) 51: 31-36.

Marcus R, Leary D, Schneider D. L, Shane E, Favus M, Quigley C. A: The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. J. Clin. Endocrinol. Metab., 2000 Mar, 85(3):1032-7.

Zacharin M: Use of androgens and oestrogens in adolescents: a review of hormone replacement therapy. J. Pediatr. Endocrinol. Metab. 2000; 13: 3-11.

Melo K.F., Mendonca B.B. and Billerbeck A.E.C: Clinical, hormonal, behavioural and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations of the androgen receptor gene. J. Clin. Endocrinol. Metab. 2003; 88: 3241-50.

Warne G.L., Grover S. and Zajac J.D: Hormonal treatment for individuals with intersex conditions. Treatments in Endocrinology, 4 (1), Jan 2005.


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