Reproductive Depression and the response to Estrogen Therapy
Professor John Studd DSc MD FRCOG1
Professor Rossella E. Nappi MD PhD2
- Director London PMS and Menopause Centre, 46 Wimpole St London W1G8SD UK
- Professor Gynecological Endocrinology Research Centre for Reproductive Medicine, Dept Obstetrics and Gynaecology, University of Pavia, Italy
- Many cases of depression in women are due to endocrine factors and treatment by antidepressants or mood stabilizing drugs is inappropriate
- Reproductive Depression includes Premenstrual Depression (PMDD), Postnatal Depression and Climacteric Depression
- Climacteric Depression is more severe in the transitional phase, two or three years before the periods cease rather than in the years after the menopause.
- The diagnosis can not be made by measuring hormone levels but by a careful history relating depression to monthly cycles and the postnatal state.
- Treatment should be by transdermal estrogens possibly with testosterone if available
- The syndrome of Reproductive Depression consists or postnatal depression, premenstrual depression and climacteric depression.
- These women are often progesterone / progestogen intolerant.
- This depression usually responds to estrogen therapy.
Although this treatment is supported by many placebo controlled trials it is not accepted by psychiatrists who would prefer to use many changes of antidepressants and even Lithium or worse when severe PMS is misdiagnosed as Bipolar Disorder .This is seen as a serious territorial threat but gynaecologists have no desire to take over patients but wish to encourage psychiatrists to learn the simple practice of prescribing estrogens .
It is probable that the first quantitative account of the incidence of depression in women and men came from Charles Dickens1 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 occured 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.
Reproductive depression and ovarian hormones
Depression in women commonly occurs at times of hormonal changes2, 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 two or three 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 etiology 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
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 forties and the depression becomes worse in the two or three years of the menopause transition5. 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 associationwith hormonal changes is dismissed. These are all premenopausal women who will have normal FSH and estradiol 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 levels2. The clue to the diagnosis is in the history and even then psychiatrists will often regard the association of depression with periods and post partum changes as irrelevant.
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 ten to fourteen days a month with severe depression, behavioral 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 etiology of the condition and the fact that the ovary being the architect of these changes6 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 7 but these women are usually progesterone/progestogen intolerant8 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 ten to fourteen good days a month that even the most severe cases enjoy.
Suppression of ovulation by transdermal estradiol in the form of estradiol patch 200 mcgs twice weekly has been shown to be effective9 and transdermal estrogen in the form of estradiol gels, Oestrogel 2 measures daily or Sandrena 2.grams per 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 seven days of each calendar month with a withdrawal bleeding occurring on about day ten 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 10. These symptoms disappear within twenty four hours of the removal of the Mirena IUS.
Alternatively ablation of ovulation by the use of GnRH analogues is most effective11 and indeed is a useful diagnostic tool if a hysterectomy and bilateral salpingo oophorectomy is contemplated12. 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 progestogen13 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 effects14.
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 PMS15,16. 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, anti epileptics and even electroconvulsive therapy. After 10 or more years of this therapy it is difficult but not impossible to wean them off these psychotrophic drugs by transdermal estradiol 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 disorder17.
- Relating earlier depressive episodes to the menstrual cycle
- The relief of depressive symptoms during pregnancy
- The recurrence of depression post partum
- Premenstrual depression on menstruation recurs after delivery
- The premenstrual depression becoming worse with age blending into the menopausal transition
- Often the co-existence of somatic symptoms such as menstrual migraine , abdominal bloating or cyclical mastalgia
- These patients usually have seven to ten good days per month
- Although depression can be cyclical they rarely have highs.
Post Natal 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 etiology. 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 discontinued18. 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 antidepressants19. 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 worse20].
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 improved2. 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 transition21. 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 oestrogens22,23. In fact, the evidence for the benefit of oestrogens on perimenopausal depression is more convincing than the beneficial effects in the depression of the post menopausal woman24. This treatment is best done by transdermal oestrogens in the form of gels or patches continuously with cyclical progestogen if the woman has a uterus2. 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.
It may seem odd to include a section of hysterectomy but there is much evidence from psychiatrists that depression is less common after hysterectomy25. 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 break up. 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 beneficial26. 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 procedure27 This should not be seen as a radical last choice – or never choice option.
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 post partum 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 antidepressants28]. 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 to 4 grams daily throughout the month. Cyclical gestogen 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 thes 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. 100mg testosterone pellets would be ideal but at the time of writing they are no longer available.
- Dickens Charles. Household words 1852;95:385-9.
- Studd J. A Guide To hormone therapy for the treatment of depression in women. Climacteric 2011;14637-42.
- Nappi RE, Tonani S, Santamaria V, Ornati A, Albani F, Pisani C, Polatti F. Luteal phase dysphoric disorder and premenstrual syndrome. It J Psych 2009;28:27-33.
- Panay N, Studd J. Psychotherapeutic effect of oestrogens. Gynecol Endocrinol 1998;12:353-65. Studd J. Why Are Oestrogens Rarely Used In The Treatment Of Depression In Women. Gynaecological Endocrinology 2007;23:63-4
- Burger H G Hale GE, Robertson DN, Dennerstein L. A review of hormonal changes during the menopausal transition. Human Reprod Update 2007;13:559-65.
- Studd J. Ovarian Cycle Syndrome. Gynaecol Endocrinol 2009; 2574
- Rapkin AJ. Yaz in the treatment of premenstrual dysphoric disorder. J Reprod Med 2008;53:729-41
- Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159-71.
- Watson NR, Studd JWW, Savvas M, Garnett T, Baber RJ. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet 1989;8665:730-2
- Elovainio M, Teperi J, Aalto AM. Depressive symptoms as predictors of discontinuation of levonorgestrel releasing intrauterine system. Int J Behav Med 2007;14:70-5.
- Leather AT, Studd JWW, Watson NR, Holland EFN. The prevention of bone loss in young women treated with GnRh analogues with ‘add back’ oestrogen therapy. Obstet Gynecol 1993;81:104-7.
- Wyatt KM, Dimmock PW, Ismail KM, Jones PW, O’Brien PM. The effectiveness of GnRH analogue with and without “addback” therapy in treating premenstrual syndrome: a meta analysis. BJOG 2004;111:585-93.
- Leather AT, Studd JW, Watson NR, Holland EF. The treatment of severe premenstrual syndrome with goserelin with and without ‘add-back’ estrogen therapy: a placebo-controlled study. Gynecol Endocrinol 1999;13:48-55.
- Di Carlo C, Palomba S, Tommaselli GAm, et al. Use of leuprolide acetate plus Tibolone in the treatment of severe premenstrual syndrome. Fertil Steril 2001;76:850-2.
- Casson P, Hahn PM, Van Vugt DA, Reed RL. Lasting response to ovariectomy in severe entractable premenstrual syndrome. MJ Obstet Gynecol 1990;162:99-105.
- Cronje WH, Vashisht A, Studd JW. Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome. Hum Reprod 2004;19:2152-5.
- Studd J. Severe premenstrual syndrome and bipolar disorder; a frequent tragic confusion. Menopause Int 2012;18: 65-7.
- Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 2000;157:924-30.
- Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal estrogen for the treatment of severe post-natal depression. Lancet 1996;347:930-3.
- Dennis CL, Ross LE, Herxheimer A. Oestrogens and progestins for preventing and treating postpartum depression. Cochrane Database Syst Rev 2008;(4):CD001690.
- Dennerstein L, Lehert P, Burger H, et al. Mood and the menopausal transition. J Nerv Ment Dis 1999;187:685-91.
- Brincat M, Magos A, Studd JW, et al. Subcutaneous hormone implants for the control of climacteric symptoms. A prospective study. Lancet 1984;1:16-8.
- Soares CN, Almeida, Joff H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-34.
- Montgomery JC, Brincat M, Tapp A, et al. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet 1987;1:297-9.
- Gath D Rose N Bond A et al. Hysterectomy and psychiatric disorder Psycho Med 1995;25:277-83.
- Khastgir G, Studd J. Patient’s outlook experience and satisfaction with hysterectomy bilateral oophorectomy and subsequent hormone replacement therapy. Am J Obstet Gynecol 2000;183:1427-33.
- Studd J Hysterectomy A life saving as well life enhancing operation. Menopause International 2009;15:2-3.
- Graziottin A, Serafini A. Depression and the menopause:why antidepressants are not enough? Menopause Int 2009; 15:76-81.