Why are estrogens rarely used for the treatment
of depression in women?
John Studd, DSc, MD, FRCOG
July 2007
The short answer to this question could be that they do not work, but that is not true. It is much more likely that a turf war is developing between psychiatrists and gynaecologists/endocrinologists for this common disorder. This is not surprising as we are all products of our training, with hormones and vaginal bleeding an unchartered country for some. As depressed women would normally gravitate to their family doctor and to psychiatrists, it is usual that psychiatric intervention including anti-depressants would be the first line of therapy. However, there are depressed women with particular features in their history which make them very suitable for estrogen therapy as an excellent clinical response can be expected. These are currently being neglected.
Depression is more common in women than men, whether these data come from hospital admissions, community studies, suicide attempts or a prescription of anti-depressants (1). There will always be debate whether this is genetic, environmental or hormonal with psychiatrists, and no doubt feminists, supporting the view that it is the lifestyle, domestic problems and career limitations which is an essential factor in this excess. Nobody would doubt the social aspects of depression, but the role of hormones is inadequately recognised in spite of good evidence that this is an aetiological factor in many women.
The increase of depression in women occurs at times of hormonal fluctuation. It begins at puberty and adolescence, and the difference is no longer present five years after the menopause. Depression occurs in the pre-menstrual phase, sometimes lasting for as long as 14 days each month, is rare during pregnancy when there are stable and high levels of estradiol, only to occur post-partum. Such post-partum depression occurs in up to 15% of women, may last for years, and becomes more cyclical when the periods recur.
Climacteric depression is at its worst in the 2-3 years before the periods cease. Indeed, if the 45-year old depressed woman is asked when she was last well, the frequent reply is that it was during the last pregnancy, several years previously. Then post-natal depression occurred, followed by cyclical pre-menstrual depression which then became more constant as the menopause approached. Such patients respond well to moderately high doses of transdermal estrogens. Unfortunately, the association of depression with these reproductive events is rarely sought in a history taking by psychiatrists. Similarly, the enquiry about how many good days a month a woman experiences, reveals not only the severity of her distress with the premenstrual syndrome, menstrual headaches and heavy, painful periods, but also reinforces the cyclical and hormonal nature of the problem. This is another very appropriate question for psychiatrists (and gynaecologists!) to ask.
Thus, this triad of hormone-related depression – premenstrual depression, post-natal depression and peri-menopausal depression often occur in the same vulnerable woman. Perhaps the correct name should be “reproductive depression”.
The earliest double-blind study by Klaiber (2) using huge daily doses of 5-25mg of Premarin in a mixed group of patients with severe recurrent depression showed an impressive significant response to the active therapy. However, this somewhat bizarre but valuable high-dose estrogen study has not been replicated. Montgomery et al (3), using 100mg estradiol implants, which would produce plasma estradiol levels of approximately 600p.mols/l, had a significant beneficial effect on depression on peri-menopausal women but not on those women after the menopause. This improvement was not transient, lasting for the 23 months’ duration of the study.
Schmidt and colleagues (4) have repeatedly shown the association of premenstrual depression and climacteric depression, and recorded the improvement which occurs with treatment by transdermal estrogens. (5) This is not the “domino-effect” of relief of vasomotor symptoms as the patients studied were without hot flushes and night sweats. Also Soares, (6) in several studies has reported the beneficial effects of 100mcg transdermal estrogens on peri-menopausal depression regardless of the precise DSM IV diagnosis.
Transdermal estrogens in a dose of 200mcg twice weekly have been shown to be more effective than placebo in post-natal depression. (7) It is incomprehensible that this study of 1996 has not been repeated. Either it was perfect and didn’t need confirmation, or psychiatrists who deal with post-natal depression prefer their own Mother and Baby Units, psychoanalysis or anti-depressant therapy rather than consider the logical causative factor of decreasing estrogens. The hormonal aetiology of post-natal depression has been supported by an experiment by Bloch et al (8) who created a pseudo-pregnancy by hormonal manipulation in women with and without a history of post-natal depression.
5 out of 8 of those women with a history of post-natal depression developed depression when estrogens were withdrawn, compared with no patients who did not have a history of post-natal depression.
The common condition of premenstrual syndrome (PMDD), with its psychiatric problems of depression, irritability and irrational behaviour, together with the somatic symptoms of mastalgia and bloating are clearly related to undetermined hormonal changes which follow ovulation. It follows that the essential tenant of treatment is to suppress ovulation and the cyclical hormonal changes responsible for the cyclical symptoms of PMDD. This can be done by GnRH analogues (9) creating a temporary medical menopause or by transdermal estrogens in a dose of 200mcg twice-weekly has been shown in a cross-over trial to improve every cluster of Moos symptoms against placebo (10). This treatment is as effective as it is logical, but not used by psychiatrists. This treatment, based upon suppression of ovulation and cyclical symptoms, is safe, simple and successful. It would be, in the view of many gynaecologists, first choice therapy if one was looking for a pharmacological treatment. Once again, this Lancet study has not been repeated. Is it perfection or fear of the findings?
Most “menopausologists” see many women with recurrent, cyclical or climacteric depression who have been on the full gamut of psychiatric interventions, when estrogen therapy would have been a more logical and more effective therapy. These women are still having electro-convulsive therapy, the majority are having SSRI medication with its unfortunate effect upon weight and libido.
It is true that the beneficial effects of estrodial on depression is not universally accepted and advisory bodies will state that estrogens are useful for depressed mood, but not depression (11). Indeed, it will be difficult for a gynaecologist to claim to make a precise diagnosis of depression in scientific papers, and it is for this reason that all of the studies referenced above included psychiatrists, expert in their field, to assess the clinical condition and response. But still there remains doubt in the minds of many practitioners or advisory bodies as to whether estrogens are effective for depression.
It would seem appropriate to clarify this by further studies of estrogen, preferably by the transdermal route, in the common problems of premenstrual depression and peri-menopausal depression. Although such studies are desperately required, it is virtually impossible to obtain funding for such an important study. On a personal level, I have requested help from pharmaceutical companies, even offering to complete the study without any cost to the companies. Placebo patches were all that was required. These, incomprehensibly, were not available. Of course, such non-availability is nonsense but on a commercial level there is no reason why a company selling profitable anti-depressants would wish to create competition from small-profit out-of-patent estrodiol patches.
In the meantime, women suffer from inappropriate therapy for their depression which is as misguided as a surgical treatment of the19th centaury. (12)
REFERENCES
Studd J, Panay N
Hormones and Depression in Women
Climacteric 2004, Dec;7(4):338-346
Klaiber E L, Broverman D M, Vogel W, Kobayashi Y
Estrogen therapy for severe persistent depressions in women.
Arch Gen Psychiatry 1979, 36; 550-554.
Montgomery J C., Appleby L., Brincat M., Versi E., Tapp A., Fenwick PB., Studd JW.
Effective Estrogen and Testosterone Implants on Psychological Disorders in the Climacteric
Lancet 1987, 8528; 297-299.
Richards M, Rubinow D R, Daly R C, Schmidt P J
Premenstrual Symptoms and Peri-Menopausal Depression
Am J Psychiatry 2006, 163; 133-137.
Schmidt P J,
Mood, Depression and Reproductive Hormones in the Menopausal Transition
Am J Med, 2005 118; 54-58.
Soares C N, Joffe H, Steiner M
Menopause and Mood
Clin Obstet Gynecol 2004, 47; 576-591.
Gregoire A J, Kumar R, Everitt B, Henderson A F, Studd J W
Transdermal Estrogen for the Treatment of Severe Post-Natal Depression
Lancet 1996, 347; 930-933.
Bloch H, Schmidt P J, Rubinow D R,
Effects of gonadal steroids in women with a history of Post-Partum Depression
Am J Psychiatry 2000; 157: 924-930.
Leather A T, Studd J W, Watson N R, Holland EF
The treatment of severe premenstrual syndrome with goserelin, with and without 'add-back' estrogen therapy.
Gynecol Endocrinol 1999; (1) 48-55.
Watson N R, Studd J W, Savvas M, Garnett T, Baber R J
Treatment of severe premenstrual syndrome with estrodiol patches and cyclical oral norethisterone.
Lancet 1989, 2; 30-732.
RCP (Edin) Consensus conference on HRT. Oct. 2003
Studd, JW., Ovariotomy for menstrual madness and premenstrual syndrome--19th century history and lessons for current practice. Gynecol Endocrinol. 2006 Aug;22(8):411-5.
John Studd, DSc, MD, FRCOG
Consultant Gynaecologist, Chelsea & Westminster Hospital, London
On Boxing Day 1851, Charles Dickens attended the patients Christmas dance
at St Luke's Hospital for the insane. On describing his visit in an article
for Household Words,. He commented that the experience of the asylum proved
that insanity was more prevalent amongst women than men. Of the 18,759
inmates over the century, 11,162 had been women. He adds "it is well
known that female servants are more frequently affected lunacy than any
other class of persons."
Charles Dickens was as great an observer as any Nobel
prize winner and indeed this passage is one of the very few references
in Victorian literature that make the point between gender and depression
but there are none to my knowledge relating reproductive function to depression.
Jane Eyre's red room and Berthe Mason's monthly madness may be coded examples
of this from Charlotte Bronte's pen. Modern epidemiology confirms that
depression is more common in women than men whether we look at hospital
admissions, population studies, suicide attempts or the prescription of
antidepressants (1). The challenge remains to determine whether
this increase in depression is environmental reflecting women perceived
role in contemporary society or whether it is due to hormonal changes.
It is clear that this excess of depression in women starts at puberty
and is no longer present in the 6th and 7th decade. The peaks of depression
occur at times of hormonal fluctuation in 1) the premenstrual phase, 2)
the postpartum phase and 3) the climacteric perimenopausal phase, particularly
in the one or two years before the periods cease. This triad of hormone
responsive mood disorders, (HRMD) often occur in the same vulnerable woman.
The 45 year old depressed peri-menopausal woman who is still menstruating
will often give a history of previous postnatal depression and depression
before periods. They will often be in very good mood during pregnancy
and also have systemic manifestations of hormonal fluctuation in the form
of menstrual headaches or menstrual migraine. Such a woman will often
say that she last felt well during her last pregnancy. She then developed
post natal depression for several months. When the periods returned, the
depression became cyclical and as she approached the menopause the depression
became more constant. Reproductive events also affect the course of bipolar
disorder in women. 67% of such women had a history of postpartum depression.
Of these, all had episodes of depression after subsequent pregnancies.
Subsequently women who were not using hormone replacement therapy were
significantly more likely than those who were using HRT to report worsening
of the depression symptoms during the perimenopause/menopause. The authors
Freeman et al conclude that hormonal fluctuations are associated with
increased risk of affective disregulation and mood episodes in women with
bipolar disorders.
The depression of these patients can be usually treated effectively by
oestrogens, preferably by the transdermal route and in a moderately high
dose. Transdermal oestrogen patches of 200 mcgs has been the dose used
in published placebo controlled studies but the 100 mcg dose is frequently
effective.
The problem with this, (to me), clear clinical history of a woman who
will probably respond to oestrogens is that the scientists believe that
such patients are ideal for the use of antidepressants. This is because
they would recognise that they would have had premorbid history of depression
and therefore they would have chronic relapsing depressive illness. The
fact that this depression is postnatal or premenstrual in timing escapes
this. It is sad that both gynaecologists and psychiatrists are victims
and products of their own training with too little overlap in knowledge.
The clue to the use of oestrogens came with the important and somewhat
eccentric paper by Klaiber (2) who performed the placebo controlled
study of very high dose oestrogens in patients with chronic relapsing
depression. They had various diagnoses and were both premenopausal and
postmenopausal. They were given Premarin 5 mgs daily with an increase
in dose of 5 mg each week until a maximum of 30 mg a day was used. There
was a huge improvement in depression on these high doses, (figure 1),
but this work has not been repeated because of anxiety over high dose
oestrogens.
PREMENSTRUAL SYNDROME
This condition is mentioned in the fourth century BC by Hippocratic but
became a medical epidemic in the nineteenth century. Victorian physicians
were aware of menstrual madness, hysteria, chlorosis, ovarian mania, as
well as the commonplace neurasthenia. In the 1870's Maudsley(3),
the most distinguished psychiatrist of the time, wrote "…The
monthly activity of the ovaries which marks the advent of puberty in women
has a notable effect upon the mind and body; wherefore it may become an
important cause of mental and physical derangement…" This and
other female maladies were recognised, rightly or wrongly, to be due to
the ovaries. As a consequence bilateral oophorectomy - (Battey's operation(4))
- became fashionable, being performed in approximately 150,000 women in
North America and Northern Europe in the 30 years from 1870. Longo(5),
in his brilliant historical essay on the decline of Battey's operation,
posed the question whether it worked or not. Of course they had no knowledge
of osteoporosis and the devastation of long-term oestrogen deficiency,
therefore, on balance the operation was not helpful as a long-term solution
but it probably did, as was claimed, cure the "menstrual/ovarian
madness" which would be a quaint Victorian way of labelling severe
PMS. The essential logic of this operation was to remove cyclical ovarian
function but happily this can now effectively be achieved by simpler medical
therapy. Only in 1931 was the phrase 'premenstrual tension' introduced
by Frank(6), who described 15 women with the typical symptoms
of PMS as we know it. Greene and Dalton extended the definition to 'premenstrual
syndrome' in 1953 (7), recognising the wider range of symptoms.
Severe premenstrual syndrome (PMS) is a poorly understood collection
of cyclical symptoms, which cause considerable psychological and physical
distress. The psychological symptoms of depression, loss of energy, irritability,
loss of libido and abnormal behaviour as well as the physical symptoms
of headaches, breast discomfort and abdominal bloating may occur for up
to 14 days each month. There may also be associated menstrual problems,
pelvic pain, menstrual headaches and the woman may only enjoy as few as
7 good days per month. It is obvious that the symptoms mentioned can have
a significant impact on the day-to-day functioning of women. It is estimated
that up to 95% of women have some form of PMS but in about 5% of women
of reproductive age they will be affected severely with disruption of
their daily activities. Considering these figures it is disturbing that
many of the consultations at our specialist PMS clinics start with women
saying that for many years they have been told that there are no treatments
available and that they should simply "live with it". In addition
many commonly used treatments of PMS particularly progesterone or progestogens
have been shown by many placebo controlled trials not to be effective.
In fact they commonly make the symptoms worse as these women are progesterone
or progestogen intolerant.
The exact cause is uncertain but fundamentally it is due to the hormonal
or biochemical changes, (whatever they are with ovulation), and the resulting
complex interaction between ovarian steroids and neuro-endocrine factors
that occur with ovulation. This combination produces these varied symptoms
in women who are somehow vulnerable to changes in their normal hormone
levels. These cyclical chemical changes, probably due to progesterone
or one of its metabolites, produce the cyclical symptoms of PMS.
OESTROGENS
PMS does not occur if there is no ovarian function (8). Obviously,
it does not occur before puberty or after the menopause or after oophorectomy.
It also does not occur during pregnancy. However, it is important to realise
that hysterectomy with conservation of the ovaries does not often cure
PMS (9) as patients are left with the usual cyclical symptoms
and cyclical headaches. This condition, best-called "the ovarian
cycle syndrome" (10) is usually not recognised to be hormonal
in aetiology, as there is no reference point of menstruation. The failure
to make this diagnosis is regrettable because these monthly symptoms of
depression, irritability, mood change, bloating and headaches which might
affect the women for most days in the month with only perhaps a good week
each month can easily be treated with transdermal oestrogens which suppress
ovarian function and thus remove the symptoms.
A medical Battey's operation can be achieved by the use of GnRH analogues
and Leather et al (11) have demonstrated that three months
of Zoladex therapy cures all of the symptom groups of PMS. The women do,
of course, have hot flushes and sweats but these are usually far preferable
to the cyclical depression, irritability and headaches. The long-term
risk of Zoladex therapy is bone demineralisation but the same group showed
that add-back with a product containing 2 mgs of oestradiol valerate and
cyclical levonorgestrel (Nuvelle, Schering Health) maintain the bone density
at both the spine and the hip (12). Most of the PMS symptoms
remain improved with this "add-back" but bloating, tension and
irritability recur - probably due to the cyclical progestogen. Livial
may be a better add-back preparation. In a Scandinavian study, Sundstrom
and colleagues used low-dose GnRH analogues (100 µg buserelin) with
good results on the symptoms of PMS, but the treatment still caused anovulation
in as much as 56% of patients (13). Danazol is another method
to treat PMS by inhibiting pituitary gonadotrophins, but it has side-effects
including androgenic and virilising effects. When used in the luteal phase
only (14) it only relieved mastalgia but not the general symptoms
of PMS even though side-effects were minimal.
Greenblatt et al showed the effects of an anovulatory dose of oestrogen
implants for the use of contraception (15) and the first study
for its use in PMS was by Magos et al (16) using 100 mg oestradiol
implants, the dose that had been shown to inhibit ovulation by using ultrasound
and day 21 progesterone measurements in earlier studies by the same group.
This showed a huge 84% improvement with placebo implants but the improvements
of every symptom cluster was greater in the active oestradiol group (Figure
1). In addition the placebo effect usually waned after a few months compared
with a continued response to oestradiol. These patients, of course, were
also given 12 days of oral progestogen per month to prevent endometrial
hyperplasia and irregular bleeding (17). It was clear that
the addition of progestogen attenuated the beneficial effect of oestrogen.
Subsequently a placebo-controlled trial of cyclical norethisterone in
well oestrogenised hysterectomised women reproduced the typical symptoms
of PMS (18). This study of cyclical oral progestogen in the
oestrogen primed woman is the model for PMS. It is also significant that
progestogen intolerance is one of the principal reasons why older, post-menopausal
women stop taking HRT (19), particularly if they have a past
history of PMS or progesterone intolerance. It is common for progestogens
to cause PMS-like symptoms in these women in the same way endogenous cyclical
progesterone secretion is the probable fundamental cause of premenstrual
syndrome.
Our group still uses oestradiol implants, often with the addition of
testosterone for loss of energy and loss of libido, in our PMS clinics
but we have reduced the oestradiol dose, never starting with 100 mgs.
We will now insert pellets of oestradiol 50 mgs or 75 mgs with 100 mgs
of testosterone. These women must have endometrial protection by oral
progestogen or a Mirena (Schering Healthcare) levonorgestrel-releasing
intra-uterine system (LNG IUS).(20) As women with PMS respond
well to oestrogens but are often intolerant to progestogens and it is
therefore common-place for us to reduce the orthodox 13 day course of
progestogen to 10 or 7 days starting, for convenience, on the first day
of every calendar month. Thus, the menstrual cycle is reset.
The Mirena IUS also plays a vital role in preventing PMS-like symptoms
as it performs its role of protecting the endometrium without systemic
absorption. A recent study has shown a 50% decrease in hysterectomies
in our practice since the introduction of the Mirena IUS in 1995,(17).
With its profound effect on menorrhagia and the possibility of less progestogenic
side-effects, Mirena looks a very promising component of PMS treatment
in the future.
Hormone implants are not licensed in all countries and are unsuitable
for women who may wish to easily discontinue treatment in order to become
pregnant. Oestradiol patches are an alternative and our original double-blind
cross-over study used 200 mcgs of oestradiol patch twice weekly (21).
This produced plasma oestradiol levels of 800 pmol/l and suppressed luteal
phase progesterone and ovulation. Once again this treatment was better
than placebo in every symptom cluster of PMS. Figure 4 shows the response
to oestradiol treatment and placebo in a six month cross-over study. This
is now our treatment of choice in severe PMS.
Subsequently a randomised but uncontrolled observational study from our
PMS clinic indicated that PMS sufferers could have the same beneficial
response to 100 mcg patches as they do with the 200 mg dose. They also
have fewer symptoms of breast discomfort, bloating and there is less anxiety
from the patient or general practitioner about high dose oestrogen therapy.(22)
21 day progesterone assays in the patients receiving 100 mcgs showed low
anovulatory levels prompting the intriguing question that even this moderate
dose might reliably suppress ovulation and be contraceptive. Clearly,
a great deal of work must be done before we can suggest that this treatment
is effective birth control but it is of great importance because many
young women on this therapy for PMS will be pleased if it also was an
effective contraceptive. This is a study which needs to be conducted.
The original studies outlined in this paper are all scientifically valid
placebo-controlled trials showing a considerable improvement in PMS symptoms
with oestrogens. Although this treatment is used by most gynaecologists
in the United Kingdom, its value has not been exploited by psychiatrists
anywhere in the world. We believe that the benefit of this therapy in
severe PMS is due to the inhibition of ovulation but there is probably
also a central mental tonic effect. Klaiber et al (1) in his
study of high dose Premarin showed this and our other psycho-endocrine
studies of climacteric depression(23)and post-natal depression(24)
have shown the benefit of high dose transdermal oestrogens for these conditions.
Ultimately there are some women who, after treatment with oestrogens
and Mirena coils will prefer to have a hysterectomy in order to remove
all cycles with a virtual guarantee of improvement of symptoms. This should
not be seen as a failure or even treatment of last resort as it does carry
many other advantages (25).
It is important that these women who have had a hysterectomy and bilateral
salpingo-oophorectomy have effective replacement therapy, ideally with
replacement of the ovarian androgens. Implants of oestradiol 50 mgs and
testosterone 100 mgs are an ideal route and combination of hormones for
this long-term therapy post-hysterectomy with a continuation rate of 90%
at 10 years (17). We have a study of 50 such patients who have
had a hysterectomy, bilateral salpingo-oophorectomy and implants of oestradiol
and testosterone for severe PMS who have gone through many years of treatment
with transdermal oestrogens and cycle progestogens or Mirena coil. The
symptoms are removed in all patients and all but one was very satisfied
with the outcome.
POSTNATAL DEPRESSION
Postnatal depression is another example of depression being caused by
fluctuations of sex hormones and having the potential to be effectively
treated by hormones. It is a common condition which affects 10-15% of
women following childbirth and may persist for over one year in 40% of
those affected. There does seem to be a lack of any overall influence
of psychosocial background factors in determining vulnerability to this
postpartum disorder although it can be recurrent.
Although common, the disease is often not reported to the health care
professional, particularly the general practitioner or the visiting midwife
as the exhaustion and depression is regarded as normal. Indeed the symptoms
of postnatal depression may be confused with the normal sequelae of childbirth.
The symptoms can consist of depressed mood with lack of pleasure with
the baby or any interest in her surroundings. There may be sleep disturbance,
either insomnia or hypersomnia. There may be loss of weight, loss of energy
and certainly loss of libido together with agitation, retardation and
feelings of worthlessness or guilt. Frequent thoughts of death and suicide
are common.
Postnatal depression is not more common after a long labour, difficult
labour, caesarean section, separation from the baby after birth, nor is
it determined by education or socio-economic group. The only environmental
factor which seems to be important is the perceived amount of support
given by the partner. There is no doubt that the first 6 or more months
after delivery can be an exhausting time, full of anxiety and insecurity
in mothers with the new responsibility of the baby. Even allowing for
that, there does seem to be a clear hormonal aspect to this condition.
Postnatal depression is severe and more prolonged in women who are lactating
and lower oestradiol levels are found in depressed women following delivery
than with controls. It is probable that the low oestradiol levels with
breast feeding and the higher incidence of depression are related in a
causative way.
We studied the effect of high dose transdermal oestrogens in this condition
in an attempt to close the circle of studies treating this triad of hormone
responsive depressions - premenstrual depression climacteric depression
and postnatal depression. This was a double blind placebo controlled trial
of 60 women with major depression which began within 3 months of childbirth
and persisted for up to 18 months postnatally.(24) They had
all been resistant to antidepressants and the diagnosis of postnatal depression
was made by two psychiatrists who are expert in the field. We excluded
breast feeding women from the study. They were given either placebo patches
or transdermal oestradiol patches 200 mcgs daily for 3 months without
any added progestogen. After 3 months, cyclical Duphaston 10 mgs daily
was added for 12 days each month. The women were assessed monthly be a
self-rating of depressive symptoms on the Edinburgh postnatal depression
score, "EPDS" and by clinical psychiatric interview. Both groups
were severely depressed with a mean EPDS score of 21.8 before treatment.
During the first month of therapy the women who received oestrogen improved
rapidly and to a greater extent than controls. None of the other factors,
age, psychiatric, obstetric or gynaecological history, severity and duration
of current episode of depression and concurrent antidepressant medication
influenced the response to treatment.
The study showed that the mean EPDS score was less with the active group
at one month and then maintained for eight months and that the percentage
with EPDS scores over 14, (diagnostic of postnatal depression) was reduced
by 50% at one month and 90% at 5 months. This was much better than the
placebo response. Fig
Not only did this study show that transdermal oestrogens were effective
for the treatment of postnatal depression but a subsequent study by Lawrie
et al(26) showed that depot-progestogen was worse than placebo causing
deterioration in the severity of postnatal depression. Thus we have again
the picture of the mood elevating effect of oestrogens and the depressing
effect of progestogen.
An uncontrolled study showed similar improvements using sublingual oestradiol
in 23 women with major postnatal depression. (26) These women
had plasma levels of 79.0 pmol/l before the treatment with sublingual
oestradiol. The oestradiol levels were 342 pmol/l at one week and 480
pmol/l at 8 weeks.. There was improvement in 12 out of the 23 patients
at one week and after two weeks there was recovery in 19 of the 23 patients.
The mean Montgomery Asberg depression rating scale was 40.7 before treatment,
11 at one week and 2 at eight weeks. At the end of the second week of
treatment the MADRS scores were compatible with clinical recovery in 19
out of the 23 patients. This study stressed the rapidity of response to
the oestradiol therapy and this was our observation also. However, it
must be stressed that this is an uncontrolled study in women with a very
low almost postmenopausal level of oestradiol. Another placebo controlled
study is required together with information about bleeding patterns to
support or refute our original paper.(24)
It would support the hormonal pathogenesis of this condition if we could
mimic postnatal depression by hormonal manipulation. This was done by
a study by Bloch,(27) who studied 16 women, 8 with a history
of postnatal depression. They induced hypogonadism with leuprolide acetate
and stimulated pregnancy by "add back" supraphysiological doses
of oestradiol and progesterone for 8 weeks and then withdrawing both steroids.
Five of the eight women, 62.5% with a history of postnatal depression
and none of the women without a prior history developed significant mood
symptoms during the withdrawal period.
This study supported the view that there was an involvement of the reproductive
hormones, oestrodiol and progesterone in the development of postpartum
depression in a set group of women. Furthermore, the study showed that
women with a history of postpartum depression are differentially sensitive
to the mood destabilising effects of gonadal steroids.
CLIMACTERIC DEPRESSION
Like many aspects of depression in women, the diagnosis of climacteric
depression and its treatment remains controversial. Whereas gynaecologists
who deal with the menopause have no difficulty in accepting the role of
oestrogens in the causation and the treatment of this common disorder,
psychiatrists seem to be implacably opposed to it. This may be because
there is no real evidence of an excess of depression occurring after the
menopause, nor any evidence that oestrogens help postmenopausal depression
or what used to be called "involutional melancholia". This is
quite true and indeed many women with longstanding depression improve
considerably when the periods stop. This is because the depression created
by premenstrual syndrome, heavy painful periods, menstrual headaches and
the exhaustion that attend excess blood loss disappears. Therefore, the
longitudinal studies of depression carried out by many psychologists,
particularly those as notable as Hunter(28), have shown no
peak of depression in a large population of menopausal women. The depression
that occurs in women around the time of the menopause is at its worst
in the two or three years before the periods stop. This, of course, is
perimenopausal depression and is no doubt, related to premenstrual depression
as it becomes worse with age and with falling oestrogen levels.
The earliest placebo controlled study which defined the precise menopausal
syndrome showed that oestrogens helped hot flushes, night sweats and vaginal
dryness. They also had a mood elevating effect.(29) This work
was further supported by the work of Campbell and Whitehead(30) who used
Premarin and by the study of Montgomery et al(23) using higher
dose oestradiol implants. This study of 90 peri and postmenopausal women
with depression showed considerable improvement in the treatment group
compared with placebo but only in the perimenopausal women. There is no
improvement in the depression in the postmenopausal women with this treatment
when compared with placebo.
At last, after 15 years, psychiatrists, particularly in the USA are coming
round to the view that transdermal oestrogens are effective in the treatment
of depressed perimenopausal women. Soares et al in 2001 studied 50 such
women 26 with major depressive disorder, 11 with dysthymic depression
and 30 with minor depressive illness. They treated them with 100 mcg oestradiol
patches in a 12 week placebo controlled study. There was a remission of
depression in 17 out of 25 of the treatment patients, (68%) and only 5
out of the 25 placebo patients (20%). This improvement occurred regardless
of the DSM-IV diagnosis.
Rasgon et al, (32) studied 16 perimenopausal women with unipolar
major depressive disorder for an 8 week open protocol trial comparing
low dose 0.3 mg Premarin plus Fluoxetine daily. There was a greater response
with oestrogen alone. All but two of the total patients responded but
the response was greater in the ERT patients and it was significant that
the reduction of depression scores began rapidly after the first week
of treatment.
More recently, Harlow(34) studied a large number, (976) of
perimenopausal women with a history of major depression and those without.
The patients with the history of depression had higher FSH levels and
lower oestradiol levels at enrolment to the study and those women with
a history of antidepressant medication had three times the rate of early
menopause. A similar excess rate was found in perimenopausal women who
had had a history of severe depression.
It is reassuring for those "menopausologists" who have been
trying to persuade the world of psychiatry that oestrogens have a place
in the treatment of depressed women and pleasing to read at last the comments
from Soares who states that periods of intense hormonal fluctuations have
been associated with the heightened prevalence and exacerbation of underlying
psychiatric illness, particularly the occurrence of premenstrual dysphoria,
puerperal depression and depressive treatment during the perimenopause.
It is speculated that sex steroids such as oestrogens, progestogens, (SIC),
testosterone and DHEA exert a significant modulation of brain functioning…..
There are preliminary, although promising data on the use of oestradiol,
(particularly transdermal oestradiol to alleviate depression during the
menopause "at last we are getting through".
Progestogen Intolerance
These women having moderately high dose oestrogen therapy must of course
have cyclical progestogen if they still have a uterus in order to prevent
irregular bleeding and endometrial hyperplasia. The problem is that women
with hormone responsive depression enjoy a mood elevating effect with
oestrogens but this is attenuated by the necessary progestogen. This hormone
can produce depression, tiredness, loss of libido, irritability, breast
discomfort and in fact, all of the symptoms of premenstrual syndrome,
particularly in women with a history or previous history of PMS. A randomised
trial of Norethisterone against placebo in oestrogenised hysterectomised
women, already referred to clearly showed this and in fact the paper was
subtitled a "A model for the causation of PMS".(16)
If women become depressed with 10 to 12 days of progestogen, it may be
necessary to halve the dose, decrease the duration or change the progestogen
used.(35) It is our policy to routinely shorten the duration
of progestogen in women with hormone responsive depression because adverse
side-effects with any gestogen are almost invariable. We would therefore
use transdermal oestrogens either 100 mcgs or 200 mcgs of an oestradiol
patch or a 50 mg oestradiol implant and then we would reset the menstrual
bleeding by prescribing Norethisterone 5 mgs for the first 7 days of each
calendar month. This will produce a regular bleed on about day 10 or 11
of each calendar month.
If heavy periods occur, (and they usually do not), to extend the duration
of progestogen to the more orthodox 12 days. At this stage many women
would prefer to have a Mirena coil inserted so there will be no bleeding,
no cycles nor any need to take oral progestogen with its side effects.
It is It is not unusual for women at this stage who understand the benefits
of oestrogens and the problems of their menstrual cycles, to request hysterectomy
and bilateral salpingo-oophorectomy with hormone replacement therapy with
oestradiol and testosterone.(33) This is a fact of medical
life and patient choice but it will be at least another 15 years before
psychiatrists attempt to leap over that hurdle.
Summary:
Oestrogen therapy is effective for the treatment of postnatal depression,
premenstrual depression and perimenopausal depression the triad of hormone
responsive mood disorders.
Transdermal oestradiol 100 mcg or 200 mcg patches producing plasma
levels
approximately of 500 pmol/l and 800 pmol/l respectively should be used.
These patients often require plasma levels of more than 600 pmol/l
for efficacy.
Consider adding testosterone for depression libido and energy.
They require a cyclical progestogen or Mirena IUS if the patient still
has a uterus.
The most effective longterm medical therapy is oestradiol patches
or an implant of oestradiol and testosterone with a Mirena IUS in situ.
Ultimately, a hysterectomy plus bilateral salpingo-oophorectomy and implants
with testosterone may be requested.
John Studd, DSc, MD, FRCOG
Consultant Gynaecologist, Chelsea & Westminster Hospital, London
Why is it depression is more common in women than
men? Why is it that twice as many women are prescribed antidepressants
and tranquillisers than men? Perhaps it is the extra stress of life
as a woman coping with family, work, husbands and with the added
social problems of divorce, poor job prospects and general frustration
of life at home. This is the feminists point of view, but it does
not really explain why life should be more stressful or depressing
for a woman than it may be for a man. However, there is a belief
that at times of anxiety and stress, women complain and men misbehave.
That means that women go to their doctors and are prescribed antidepressants
and men go out drinking and worse.
All this may be true but there is also a hormonal
factor and most women will recognise that "hormones" are part of
the problem. This may be the pill, periods, pregnancy or the menopause.
These factors affect greatly mood and behavior. It is very likely
that a decrease in the hormone oestrogen, or changes of hormones
from the ovaries, like oestrogen and progesterone, produce depression.
This is why depression in women occurs at times of great hormonal
change, such as puberty, after a baby is born as post-natal depression,
before a period as pre-menstrual depression and when the periods
eventually stop as menopausal depression. They are often linked.
It is very common for doctors to see a woman of about 45 with severe
depression for years who will say that she was last well when she
was last pregnant 10 or so years ago. She then developed post-natal
depression three months after the baby was born whichÔ lasted for
about nine months, she had anti-depressants and when the periods
returned the depression became worse each month with the period
and she developed pre-menstrual depression. This becomes worse with
age and then she hits depression in her mid forties. People do not
realise that the depression around the menopause is at its worst
in the two or three years before the periods stop. This means that
women will go to their doctor with depression but as they are still
having periods, albeit with fairly low oestrogen levels, the hormonal
cause of the depression is not recognised. They are then treated
with anti-depressants rather than oestrogens.
Although at times pregnancy may be very inconvenient,
both socially and financially, depression and suicide is quite rare
in the last half of pregnancy, but is increased tenfold after birth
because the sudden fall of hormones in part of the cause of post-natal
depression. Post-natal depression occurs in at least one in ten
women after delivery. Most women believe that depression and exhaustion
after pregnancy is normal due to the problems of breatfeeding, lack
of sleep and general exhaustion. That may be so but there is also
a hormonal element, and it is well proven now that oestrogens will
alleviate the depression in most cases of post-natal depression,
even when the more usual anti-depressant drugs have failed.
Recently a woman's magazine had a cover which
said "Does PMS exist or are you just a grumpy old cow". Premenstrual
syndrome is a very real hormonal problem that occurs in both normal
women and also women with other causes of depression or personality
problems. They will complain that for two or more days, sometimes
as many as 14 days each month, they will have irritability, depression,
sore breasts, abdominal bloating, tiredness and loss of sex drive.
They will often have five or six day periods which may be heavy
or painful, thus they may only have about 7 or 10 good days a month.
These women are aware that their hormones are causing the trouble
and unless they can find treatment which works, they find themselves
less successful at work and barely tolerated by the family at home.
There are three sorts of hormone responsive depression
which can be succesfully treated with oestrogens. These are postnatal
depression, premenstrual depression and menopausal
depression.
This work is just about complete in my clinics
and many scientific trials show how helpful it is. There is not
much evidence that oestrogen tablets work, as all the research has
been done with oestrogens applied on or through the skin. The most
straightforward way of treating is to use oestrogen patches. A hormone
implant of oestradiol, or sometimes with testosterone, for poor
sex drive and energy is also effective.
These quite high doses of oestrogen work because
they stimulate the brain into making chemicals to help depression.
There is also another mechanism in premenstrual depression, in that
these doses stop ovulation and stop the cyclical hormonal changes
(whatever they are) in the ovaries and thus stop the symptoms of
PMS. It is brilliant treatment but unfortunately, although used
by most gynaecologists, is hardly used by any psychiatrists. Patches
can be worn on the thigh or the abdomen, and absorption of oestrogen
from the patches is very efficient. The patches are changed twice
a week. This oestrogen treatment works brillantly well for severe
PMS, but strangely enough it is much more difficult to treat mil
PMS because this may merely be the normal symptoms which precede
a period in somebody who has a fairly neurotic and worrying personality.
There is one problem. The women has to have a withdrawal
bleed and will take some sort of progestogen such as Norethisterone,
or Provera, or Duphaston for the first ten days of every month to
produce a regular bleed and prevent overstimulation of the lining
of the womb. These tablets often reproduce a few of the premenstrual
symptoms. This is called progestogen intolerance and most women
with PMS suffer from this so it becomes a problem of treatment.
There are a couple of options for this intolerance to progestogen
tablets. Firstly the progestogen can be put into the cavity of the
uterus in the form of a coil, much like the usual birth control
coils, but one which releases progestone into the cavity having
a local effect on the lining of the womb. The periods will also
stop in about three months. Thus a women will have oestrogens for
her premenstrual depression or menopausal depression. They do not
have to have the progestogen tablets nor will she have any periods.
It seems a good deal and it has certainly transformed the lives
of many thousands of women.
The other choice of course is hysterectomy in women
whose families have been completed. There is no doubt that monthly
premenstrual depression which occurs with heavy, painful periods
and often menstrual headaches is a great burden for any woman to
bear. These can of course be treated with a hysterectomy and HRT
in the form of oestrogen pills, or patches or implants. It does
seem to be a fairly crazy notion that hysterectomy can cure depression
but it certainly can in circumstances. Every single scientific paper
in the last ten years has shown that depression in large groups
of women is less common after hysterectomy than before hysterectomy.
Many women instantly feel that this is so and that their hormones
and periods contribute to their ill health. These are the patients
who come to hospital requesting a hysterectomy and are so much better
and lucky to find a gynaecologist sympathetic to their views. There
are so many women "out there" whose depression and misery is the
result of some sort of hormonal imbalance. Their stress is made
worse by the fact that they are usually given anti-depressants and
no attempt is made to manipulate their hormones. It is for this
reason that I started the first clinic in the country at the Chelsea
and Westminster Hospital and at the Lister Hospital in London for
the treatment of hormone related depression. It is called a psycho-endocrine
clinic which is merely a posh name for the recognition that hormones
have a profound effect upon the mood, behaviour and well-being of
women.
Professor John Studd, DSc, MD, FRCOG
Lister Hospital,
Chelsea Bridge Road
London SW1W
Pre-menstrual syndrome (sometimes called PMT, Pre-menstrual
Tension) is a complex severe disorder that affects many women. Almost
all women are aware by some bodily changes that their period is
about to come but that is not PMT. About 40% of women have distressing
symptoms and about 5% are severely incapacitated by pre-menstrual
symptoms.
Typically, women complain of loss of energy, depression,
anxiety, irritability, irrational behaviour or loss of libido in
the pre-menstrual days. Physical symptoms include headaches, breast
discomfort and abdominal bloating. Most women who suffer PMS have
a combination of both psychological and physical symptoms.
They usually start at or after ovulation and last
for 14 days until the periods appears and then they usually have
symptom free days before the next mid cycle.
The ultimate cause of PMS is unknown but it is
clearly associated with ovulation and the cyclical changes (whatever
they are) of ovarian hormones or their metabolites which produce
the cyclical symptoms of PMS. Many treatments, such as oral progesterone,
evening primrose oil and vitamin B6 have been used but for the most
part, no benefit has been shown in scientific randomised placebo
controlled trials. There is certainly a huge placebo respect to
this condition and if an unscientific treatment appears to work
it should not be discouraged in the individual.
There problem with severe PMS is the severe behavioural
and physical problems that can occur lasting for many years. These
can break relationships and destroy a career as the woman suffers
this Jekyll and Hyde change of personality. She may well have antidepressants
or tranquillisers which usually do not help.
Another clue to the hormonal basis of this condition
is that women with severe PMS are normally very well during pregnancy
and frequently have postnatal depression which is in part due to
the sudden change of female hormones after delivery. PMS often becomes
worse with age becoming less cyclical and more constant. After about
the age of 45 these worsening PMS symptoms blend with the worst
part of the climacteric as "menopausal depression" is at its most
severe in the 2-3 years before the periods stop. The depression
in these perimenopausal women can be very well treated with oestrogens.
Transdermal oestrogens are also the best way to treat PMS in younger
women.
The logic of this treatment is that oestradiol
patches in the dose of 100 or 200 mcgs twice weekly suppress ovulation
and the ovarian hormonal changes which cause PMS. 1.2.3. Alternatively,
oestradiol implants can be used to suppress ovulation and ablate
PMS symptoms.
In women who have problems with loss of energy
and libido it is often useful to add testosterone to the oestradiol
implant inserting pellets of oestrogen 50mgs (or 75mgs) and testosterone
100mgs. This is most effective as this dose of oestradiol suppresses
ovarian activity and the testosterone increases the energy, self-confidence
and libido. This treatment has also been pioneered by my research
team and published in the appropriate journals. 4.5.
Women with PMS are very sensitive to their own
progesterone or to synthetic progestogen. But a woman having continuous
oestrogens must have some sort of progestogen to prevent irregular
bleeding and excessive growth of the lining of the womb but this
oral progestogen, may (not always), produce a slight recurrence
of their PMS symptoms. If this happens it may be necessary to change
the progestogen, or reduce the dose. Alternatively, a brilliant
new device, the Mirena progestogen releasing intra-uterine system
enables the lining of the womb to be protected without the woman
having to take oral progestogens with their side-effects.
It follows that the most effective treatment for
PMS is transdermal oestrogens, either by patches or implants in
a dose that usually stops ovulation. It is often advantageous to
insert a Mirena coil to prevent bleeding and the cyclical progestational
symptoms that oral progestogen produces.
Hysterectomy and bilateral salpingo-oophorectomy
may be appropriate for older women. This surgery may seem to be
the last resort but it does work and should be followed through
with long-term HRT so that the women have no cycles and no symptoms
of hormone sufficiency. 6.
JOHN STUDD Professor of Gynaecology
Watson, N.R., Studd, J.W.W., Riddle, A.F., Savvas, M. (1988)
Suppression of ovulation by transdermal oestradiol patches. Br.
Med. J., 297, 900-901.
Watson, N.R., Studd, J.W.W., Savvas, M., Garnett, T., Baber,
R.J. (1989) Treatment of severe pre-menstrual syndrome with oestradiol
patches and cyclical oral norethisterone. Lancet ii: 730-734
Smith, R.N.J., Studd, J.W.W., Zamlera, D., Holland, E.F.N. (1995)
A randomised comparison over 8 months of 100mcgs and 200mcgs twice
weekly doses of transdermal oestradiol in the treatment of severe
premenstrual syndrome. B.J.O.G. 102 475-484
Magos, A.L., Brincat, M., Studd, J.W.W. (1986) Treatment of
the Premenstrual Syndrome by Subcutaneous Oestradiol Implants
and Cyclical Oral Norethisterone: Placebo Controlled Study. B.M.J.
292, 1629-33.
Panay, N., Studd, J.W.W. The psychoterapeutic effect of oestrogens
Gynecol Endocrinol 1998, 12:353-365
Khastgir, G., Studd, J.W.W., Catalan, J. The psychological outcome
of hysterectomy. Gynecol Endocrinol 2000 Apr;14(2):132-41
