John Studd1 and Rossella E. Nappi2
(1)
London PMS and Menopause Centre, 46 Wimpole St, London, W1G8SD, UK
(2)
Department of Obstetrics and Gynaecology, Research Centre for Reproductive Medicine, University of Pavia, Pavia, Italy
John Studd
Email: studd@me.com
23.1 Introduction
It is probable that the first quantitative account of the incidence of depression in women and men came from Charles Dickens [1] who went through the books of St. Luke’s hospital for the insane reporting in his journal Household Words the increase of admission for depression in women. He claimed that this increase in depression occurred particularly in “women of the servant class” thus indicating the effect of both gender and social deprivation on mental illness. The excess of depression in women compared with men can be the result of social and environmental factors but most convincingly it occurs at times of hormonal fluctuation and is a result of these endocrine changes.
23.2 Reproductive Depression and Ovarian Hormones
Depression in women commonly occurs at times of hormonal changes [2], most commonly seen with depression in the premenstrual days. There is also a peak of depression in the postnatal months, often following a pregnancy characterised by a good mood with less depression. Later in life, depression occurs at its most severe in the 2 or 3 years before the periods cease in the menopausal transition. Together, these three components of premenstrual depression, postnatal depression and climacteric depression with its probable endocrine aetiology mostly influenced by changes in ovarian hormones are best termed “Reproductive Depression” as originally suggested by Nappi et al. [3]. This name gives emphasis to the fact that it is a hormone-mediated mood change, which may well be most effectively treated by correction of these hormonal changes [4, 5].
These peaks of depression often occur in the same woman. The typical story is one who has mild-to-moderate PMS as a teenager, which may become worse with age with fewer good days per month. When pregnancy occurs, they are normally in a good mood throughout pregnancy in spite of possible common problems such as nausea, pre-eclampsia or other obstetric complications. After delivery, they develop postnatal depression for many months and it is at this point that women often have their first “nervous breakdown”. They are treated with various antidepressants which are barely effective. When the periods return the depression becomes cyclical and more severe but improves with subsequent pregnancies. They still have cyclical depression in their 1940s and the depression becomes worse in the 2 or 3 years of the menopause transition [6]. If they develop vasomotor symptoms of flushes and sweats, they may be given oestrogens which will cure these symptoms and usually often helps the depression.
With this history in mind, it is important to realise that hormone responsive depression cannot be diagnosed by any blood test. Too frequently, women who believe that their depression is related to her hormone visit their family doctor, their gynaecologist or psychiatrist who measures their hormone levels, which are normal and the association with hormonal changes is dismissed. These are all premenopausal women who will have normal FSH and oestradiol levels, which may not be optimal for the individual but they are normal. It is a huge mistake to exclude hormone responsive depression because of normal blood levels [2]. The clue to the diagnosis is in the history and even then psychiatrists will often regard the association of depression with periods and postpartum changes as irrelevant.
23.3 Premenstrual Depression
Most women will be aware of physical and mood changes a day or two before the periods which indicates that they are premenstrual but this is not a severe abnormality. Perhaps 10 % of women suffer severe premenstrual syndrome for 10–14 days a month with severe depression, behavioural changes, anxiety, aggression, loss of energy, loss of libido and somatic symptoms of headaches, abdominal bloating and mastalgia.
The American Association of Psychiatrists in their DSM IV publication has termed this premenstrual dysphoric disorder. The word dysphoric strongly indicates a psychiatric origin of a condition we can now view as incorrect. The motive behind this renaming by psychiatrists is one done for a reason of territory and of course reimbursement in the American system. “Ovarian Cycle Syndrome” would be a better name as it clearly establishes the cyclical and hormonal aetiology of the condition and the fact that the ovary being the architect of these changes [7], but this has not found favour with psychiatrists involved in the treatment of “PMDD”.
This most common component of reproductive depression is an endocrine problem due to the hormonal changes that occur following ovulation and it is logical that effective treatment should be one which suppresses ovulation and suppresses the ovarian hormonal changes (whatever they are) that produce the cyclical symptoms of the premenstrual syndrome. The most logical and easiest way to suppress ovulation is the birth control pill [8], but these women are usually progesterone/progestogen intolerant [9] and hence the birth control pill even when taken “back to back” will suppress cycles and even suppress bleeding if taken back to back but they may have depressive and somatic symptoms most of the time without having the usual 10–14 good days a month that even the most severe cases enjoy.
Suppression of ovulation by transdermal oestradiol in the form of oestradiol patch 200 mcgs twice weekly has been shown to be effective [10] and transdermal oestrogen in the form of oestradiol gels, Oestrogel 2 measures daily or Sandrena 2 g/day will also be effective. It is necessary to give cyclical progestogen by some route to prevent endometrial hyperplasia, but it is common for the PMS symptoms to reoccur during these days; hence, a minimum duration of progestogen is recommended for the first 7 days of each calendar month with a withdrawal bleeding occurring on about day 10 of each calendar month. Alternatively, a Mirena IUS is usually very effective although perhaps 10 % of women do have absorption of the D-norgestrol and suffer almost continuous PMS symptoms [11]. These symptoms disappear within 24 h of the removal of the Mirena IUS.
Alternatively, ablation of ovulation by the use of GnRH analogues is most effective [12] and indeed is a useful diagnostic tool if a hysterectomy and bilateral salpingo oophorectomy is contemplated [13]. There is a risk of distressing menopausal symptoms and even osteopenia so add-back HRT is essential if prolonged treatment is required. This will usually be in the form of transdermal oestradiol and cyclical oral progestogen [14], which may produce a return of PMS symptoms or the insertion of a Mirena IUS. Using Livial as Add Back is an effective way of avoiding bleeding and progestogenic side effects [15].
Women with severe PMS who respond partially to treatment because of progestogenic side effects or bleeding problems should be offered a hysterectomy and bilateral salpingo oophorectomy. A hysterectomy alone is not effective because the ovaries will still produce the cyclical hormonal changes and the cyclical symptoms although menstruation has been abolished the cyclical symptoms have not.
There are now many studies showing the very beneficial effect of surgery and long-term replacement therapy for the most severe PMS [16, 17]. This is a further example to indicate that the condition is endocrine and not psychiatric.
The great danger to women with severe PMS who do not respond to antidepressants is that they are given a higher dose then a second or third antidepressant, which also do not work. By then they can be labelled as bipolar disorder and the scene is set for mood stabilising drugs, antiepileptics and even electroconvulsive therapy. After 10 or more years of this therapy, it is difficult but not impossible to wean them off these psychotropic drugs by transdermal oestradiol, which they should have had in the first place. The clues of course are in the history.
There are eight vital questions to diagnose PMS and to exclude bipolar disorder [18]:
1.
2.
3.
4.
5.
6.
7.
8.
23.4 Postnatal Depression
The seriousness of this condition cannot be overstated as both the mother and the child can be in great danger. It occurs in 10 % of healthy women and can last for months or years. It is not the “baby blues” occurring in the week after delivery. It is usually treated with varying success with antidepressant drugs, psychotherapy or admission to mother and baby units, but once again the association with profound, abrupt hormone changes after childbirth should point to a hormonal aetiology. Prolonged breast feeding which is associated with lower oestradiol levels often produces more severe and prolonged depression.
Depression has been reproduced experimentally in women with a history of postnatal depression by creating a pseudo pregnancy with excess doses of oestradiol and progesterone, which is then suddenly discontinued [19]. Depression occurred in women with a history of postnatal depression but not in the women in the study without a previous history of postnatal problems. Transdermal oestradiol is effective in the treatment of postnatal depression even in those women who have inadequately responded to antidepressants [20]. Unfortunately, psychiatrists rarely use this therapy preferring antidepressants, psychotherapy or admission to mother and baby units. Formerly, progesterone and progestogen have been recommended, but there is no evidence that they are effective. On the contrary, studies have shown them to be ineffective, and the Cochrane report has agreed that oestrogen improves mood and postnatal depression and norethisterone makes depression worse [21].
23.5 Climacteric Depression
There are many reasons why women become depressed around the time of menopause. Hot flushes and sweats produce insomnia and social embarrassment, headaches are troublesome and the vaginal atrophy producing dyspareunia, recurrent cystitis together with loss of libido are enough to cause some depression. These typical symptoms of oestrogen deficiency can easily be treated with routine HRT and the low mood associated with these problems of sexuality and sleep are improved [2]. However, there is another type of depression not associated with characteristic menopausal symptoms in the 3 or 4 years before the periods cease in the so-called menopausal transition [22]. This is the depression that occurs usually in the absence of vasomotor symptoms or vaginal dryness and has been shown in many studies to be responsive to oestrogens, both oral oestrogens and transdermal oestrogens [23, 24]. In fact, the evidence for the benefit of oestrogens on perimenopausal depression is more convincing than the beneficial effects in the depression of the postmenopausal woman [25]. This treatment is best done by transdermal oestrogens in the form of gels or patches continuously with cyclical progestogen if the woman has a uterus [2]. Gynaecologists are aware that depression occurring in most perimenopausal women respond well to oestrogens given for the depression or associated symptoms although most psychiatrists are unaware of this because they do not use oestrogens. Antidepressants would be there first choice therapy.
23.6 Hysterectomy
It may seem odd to include a section of hysterectomy, but there is much evidence from psychiatrists that depression is less common after hysterectomy [26]. In spite of this virtually all newspaper and magazine articles on this subject stress the belief that hysterectomy causes profound depression, loss of sexuality and marital breakup. The reverse is true. In younger women having persistent cyclical depression as well as other cyclical problems of bleeding, pain and cyclical headaches, hysterectomy with bilateral oophorectomy will usually cure these problems. In the specific case of premenstrual depression in those women with progestogen intolerance, hysterectomy with bilateral oophorectomy and replacement of oestradiol and testosterone have been shown in all studies to be beneficial [27]. Thus, a well-conducted hysterectomy for the correct indication should be seen as a life-enhancing produce and may also remove the need for progestogen and the 4 % of women who die of cancer of the ovary, cervix and uterus should be seen as a life saving as well as a life-enhancing procedure [28]. This should not be seen as a radical last choice—or never choice option.
23.7 General Principles of Hormone Therapy for Reproductive Depression
The use of transdermal oestrogens is recommended to suppress ovulation in women with premenstrual syndrome, or in correcting the profound oestrogen decrease with postpartum depression. It should be the first choice therapy in perimenopausal women with depression whether they have associated vasomotor symptoms or not. But such therapy does not exclude the combined therapy with antidepressants [29]. Most studies looking at hormone responsive depression have used transdermal patches or implants, but there is no reason why oral oestrogen should not be effective although the appropriate studies have yet to be published. However, transdermal oestrogens are preferable because they do not invoke hepatic coagulation factors and are not associated with the higher rates of venous thromboembolism of oral estrogens. The preferred regimen would be oestradiol patches 200 mcgs twice weekly or oestradiol gels 2–4 g daily throughout the month. Cyclical gestagen in women with a uterus should be used for the first 7 days of each calendar month which would produce a scanty withdrawal bleed on approximately day 10 of each calendar month.
The monthly progestogen duration has been reduced from the orthodox 14 days as these women with depression are usually progestogen intolerant and there is now mounting evidence that the major side effects of HRT are related to the progestogen component.
For the women with libido and energy problems which often coexist with depression and treatment by antidepressants, testosterone can be added in the form of testosterone gel in the appropriate dose. This would be approximately 10 % of the average male dose which in practical terms would be one-quarter of a sachet of Testogel alternate days or a quarter of a tube of Testim alternate days. 100 mg testosterone pellets would be ideal, but at the time of writing they are no longer available.
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