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The symptomatology of progestogen intolerance
Maturitas 18 (1994) 87-91
The symptomatology
of progestogen intolerance
R.N.J. Smith*, E.F.N. Holland, J.W.W. Studd Department
of Obstetrics
and Gynaecology,
Chelsea and Westminster
Hospital,
Fulham
Road, London,
UK
(Received 8 March 1993; revision received 26 April 1993; accepted 27 April 1993)
Abstract
It is common for women receiving oestrogen replacement therapy to experience adverse symptoms whilst taking cyclical progestogen. This study highlights the similarity of these symptoms to those experienced in pre-menstrual syndrome and confirms that the Moos Menstrual Distress Questionnaire is an appropriate tool for future research. The data also indicate that progestogens vary in the type of symptoms they cause. Norethisterone is more likely to cause symptoms from the Moos pain symptom cluster than either medroxyprogesterone or dydrogesterone, but is less likely to cause negative affect symptom cluster symptoms. The relative levels of oestrogen and progestogen may influence the severity of progestogenic symptoms. Key words: Progestogen; Side effects; Hormone replacement therapy
1. Introduction It is a common clinical experience that women receiving oestrogen replacement therapy to treat either menopausal problems or pre-menstrual syndrome (PMS) suffer a variety of symptoms whilst taking cyclical progestogen. The potential severity of the problem is highlighted by a long-term study in which such symptoms led to hysterectomy in 10% of PMS patients [ 11, and by the view that progestogenic sideeffects are one of the two major problems resulting in poor compliance in women taking hormone replacement therapy [2]. The fact that these symptoms are due to * Corresponding author, Fertility and Endocrinology Centre, The Lister Hospital, Chelsea Bridge Road, London SWIW 8RH, UK. 0378-5122/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0378-5122(93)00766-C
88
R.N.J. Smith et al. / Maturitas
18 (1994) 87-91
the progestogen component of the treatment and not oestrogen has been demonstrated in a placebo-controlled study [3]. Although there is a general clinical impression that these progestogenic symptoms are similar to those of PMS, there has been no systematic characterisation of their precise nature, which is reflected in the differing research tools used to assess the problem [4-61. The Moos Menstrual Distress Questionnaire (MMDQ) was derived from a comprehensive study of menstrual cycle-related symptomatology, and is widely regarded as the most appropriate research tool for the investigation of PMS-type symptoms [7]. It enquires after 35 unpleasant symptoms which are divided into 6 adverse symptom clusters: pain, concentration, behavioural change, autonomic reactions, water retention and negative effect (Appendix). The main purpose of this study was to determine what proportion of the symptoms associated with progestogen intolerance would be detected by the MMDQ, in order to decide whether or not the MMDQ is an appropriate tool for the further study of progestogenic side-effects. 2. Patients and methods All 35 symptoms from the 6 adverse MMDQ symptom clusters were included in the questionnaire used. In addition there were 10 blank lines at the bottom on which the women were instructed to record any symptoms not listed in the questionnaire. Symptoms were scored as 0 = none, 1 = mild, 2 = moderate or 3 = severe on a daily basis for 6 consecutive weeks. Each symptom experienced was individually assessed using Triggs trend analysis [8]. A symptom was deemed to be progestogenic if a significant positive trend was present for at least 2 days whilst taking progestogen but before the onset of menstruation, and at no other time, together with a significant negative trend after progestogen was discontinued. The questionnaire was given to women receiving oestrogen treatment for PMS or menopausal problems who were experiencing moderate or severe unpleasant symptoms whilst taking cyclical progestogen. The progestogen was either norethisterone (NET) 5 mg, medroxyprogesterone acetate (MPA) 5 mg or dydrogesterone 10 mg daily. Progestogens were prescribed for 10 days per month, except when severe symptoms persisted despite changing progestogen type, in which circumstance they were given for only 7 days. 3. Results Sixty-five women returned questionnaires. Eight were completed incorrectly and 5 women had no progestogenic symptoms on Triggs trend analysis. Of the remaining 52 women 31 were PMS patients of mean age 37.5 years and 21 were menopause patients of mean age 51 years. The ten most commonly encountered symptoms of progestogen intolerance are all included in the MMDQ and are listed in Table 1. There was a total of 328 instances in which a symptom was determined to be progestogenic. In 97% of these instances the symptom was included in the MMDQ, in 46.7% amongst the 10 most commonly encountered symptoms, and in only 3% was the symptom not one of the MMDQ symptoms.
R.N.J.
Smirh et al. /Maturitas
18 (1994)
89
87-91
Table I Commonest symptoms of progestogen intolerance Symptom
No. of patients with symptom
Feeling swollen/bloated Painful breasts Mood swings Fatigue Depression Irritability Skin disorders Weight gain Anxiety General aches and pains
I8 16 I6 I6 15 IS 15 I5 I4 I3
All 35 adverse symptoms of the MMDQ were found to be progestogenic in at least one woman. In addition eight other symptoms fitted the criteria of progestogen intolerance. These were diarrhoea, unmanageable hair, increased appetite, constipation, urinary urgency, craving sweets, dry skin and sore eyes. None of these was reported more than twice. Table 2 compares the type of symptoms produced by the three progestogens NET, MPA and dydrogesterone. Dydrogesterone caused significantly more symptoms from the concentration symptom complex than did MPA, and significantly more symptoms from the negative affect symptom complex than did NET. PMS patients reported a mean of 7 progestogenic symptoms each, significantly greater than the mean of 4 reported by menopause patients (Wilcoxon two-sample test P < 0.05). Fifty percent of the 24 women treated with subcutaneous oestradiol implants reported a worsening of progestogenic symptoms as the repeat implant was due.
Table 2 Mean number of symptoms per patient by MMDQ symptom cluster
Pain Concentration Behavioural change Autonomic reaction Water retention Negative affect
NET (n = 10)
MPA (n = 24)
1.8 0.4 0.3 0.1 1.6 0.7*
0.92 0.5* 0.58 0.13 1.13
1.67
Dydrogesterone 18)
(n =
I 1.33* 1.06 0.33 1.22 2.5*
*Significantly different at P < 0.05, Wilcoxon two-sample test.
90
R.N.J.
Smith et al. / Maturitas
18 (1994) 87-91
4. Discussion The main purpose of this study was to determine whether the MMDQ is an appropriate tool for researching the symptoms of progestogen intolerance. Ninety-seven percent of the progestogen symptoms identified in this study were included in the MMDQ, and only 3% were not, these being symptoms occurring only infrequently. These data therefore confirm that the MMDQ is appropriate because it includes all commonly occurring progestogenic symptoms. The use of a shortened form comprising only the 10 most commonly encountered symptoms listed in Table 1 cannot be recommended, however, because such a questionnaire would miss over 50% of symptoms. These data are derived from an unhomogenous group of women. This indicates that the MMDQ will detect progestogenic symptoms across a wide spectrum of clinical circumstances and is suitable for the assessment of progestogenic symptoms complicating both postmenopausal HRT and oestrogen treatment of PMS. The similarity between the adverse symptoms associated with progestogen use and the symptomatology of the spontaneous menstrual cycle identified by Moos is striking [7]. This suggests that progesterone may have a role in the generation of PMS [9]. The data indicate that different progestogens cause different adverse symptoms. Norethisterone is less likely to cause negative effect complex symptoms, and is possibly more likely to cause pain complex symptoms. Dydrogesterone is more likely to produce both concentration and negative effect complex symptoms. These differences are of relevance in the choice of progestogen when managing women who experience symptoms of progestogen intolerance. The observation that 50% of implant patients noticed that progestogenic symptoms were worse when oestradiol levels were dropping suggests that the severity of symptoms may be dependent upon the balance between oestrogen and progesterone. The implication is that higher oestrogen levels may attenuate the severity of cyclical progestogenic symptoms. 5. Appendix
The adverse symptom clusters of the Moos Menstrual Distress Questionnaire Pain
Muscle stiffness Headache Cramps Backache Fatigue General aches and pains Behavioural change
Lowered school or work performance Take naps; stay in bed Stay at home
Avoid social activities Decreased efficiency Water retention
Weight gain Skin disorders Painful breasts Swelling
R.N.J.
Smith et al. /Maturitas
Concentration Insomnia Forgetfulness Confusion Lowered judgement Difficulty concentrating Distractable Accidents Lowered motor coordination Autonomic reactions Dizziness, faintness Cold sweats
91
18 (1994) 87-91
Nausea, vomiting Hot flushes Negative effect Crying Loneliness Anxiety Restlessness Irritability Mood swings Depression Tension
6. References Watson NR, Studd JWW, Savvas M, Baber RJ. The long-term effects of estradiol implant therapy for the treatment of pre-menstrual syndrome. Gynecol Endocrinol 1990; 4: 99-107. Studd J. Complications of hormone replacement therapy in post-menopausal women. J R Sot Med 1992; 85: 316-378. Magos AL, Brewster E, Singh R, O’Dowd T, Brincat M, Studd JWW. The effects of norethisterone in post menopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome. Br J Obstet Gynaecol 1986; 93: 1290-96. Kirkham C, Hahn PM, Van Vugt DA, Carmichael JA, Reid RL. A randomised, double blind, placebo-controlled, cross over trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy. Obset Gynecol 1991; 78: 93-97. Hammarback S, Backstrom T, Holst J, von Schoultz B, Lyrenas S. Cyclical mood changes as in the pre-menstrual tension syndrome during sequential estrogen-progestogen post menopausal replacement therapy. Acta Obstet Gynecol Stand 1985; 64: 393-397. Marslew U, Riis B, Christiansen C. Progestogens: therapeutic and adverse effects in early postmenopausal women. Maturitas 1990; 13: 7-16. Moos RH. The development of a menstrual distress questionnaire. Psychosom Med 1968; 30: 853-867. Magos AL, Studd JWW. Assessment of menstrual cycle symptoms by trend analysis. Am J Obset Gynecol 1986; 155: 271-7. Studd J. Pre-menstrual tension syndrome. Br Med J 1979; i: 410.
The symptomatology
of progestogen intolerance
R.N.J. Smith*, E.F.N. Holland, J.W.W. Studd Department
of Obstetrics
and Gynaecology,
Chelsea and Westminster
Hospital,
Fulham
Road, London,
UK
(Received 8 March 1993; revision received 26 April 1993; accepted 27 April 1993)
Abstract
It is common for women receiving oestrogen replacement therapy to experience adverse symptoms whilst taking cyclical progestogen. This study highlights the similarity of these symptoms to those experienced in pre-menstrual syndrome and confirms that the Moos Menstrual Distress Questionnaire is an appropriate tool for future research. The data also indicate that progestogens vary in the type of symptoms they cause. Norethisterone is more likely to cause symptoms from the Moos pain symptom cluster than either medroxyprogesterone or dydrogesterone, but is less likely to cause negative affect symptom cluster symptoms. The relative levels of oestrogen and progestogen may influence the severity of progestogenic symptoms. Key words: Progestogen; Side effects; Hormone replacement therapy
1. Introduction It is a common clinical experience that women receiving oestrogen replacement therapy to treat either menopausal problems or pre-menstrual syndrome (PMS) suffer a variety of symptoms whilst taking cyclical progestogen. The potential severity of the problem is highlighted by a long-term study in which such symptoms led to hysterectomy in 10% of PMS patients [ 11, and by the view that progestogenic sideeffects are one of the two major problems resulting in poor compliance in women taking hormone replacement therapy [2]. The fact that these symptoms are due to * Corresponding author, Fertility and Endocrinology Centre, The Lister Hospital, Chelsea Bridge Road, London SWIW 8RH, UK. 0378-5122/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0378-5122(93)00766-C
88
R.N.J. Smith et al. / Maturitas
18 (1994) 87-91
the progestogen component of the treatment and not oestrogen has been demonstrated in a placebo-controlled study [3]. Although there is a general clinical impression that these progestogenic symptoms are similar to those of PMS, there has been no systematic characterisation of their precise nature, which is reflected in the differing research tools used to assess the problem [4-61. The Moos Menstrual Distress Questionnaire (MMDQ) was derived from a comprehensive study of menstrual cycle-related symptomatology, and is widely regarded as the most appropriate research tool for the investigation of PMS-type symptoms [7]. It enquires after 35 unpleasant symptoms which are divided into 6 adverse symptom clusters: pain, concentration, behavioural change, autonomic reactions, water retention and negative effect (Appendix). The main purpose of this study was to determine what proportion of the symptoms associated with progestogen intolerance would be detected by the MMDQ, in order to decide whether or not the MMDQ is an appropriate tool for the further study of progestogenic side-effects. 2. Patients and methods All 35 symptoms from the 6 adverse MMDQ symptom clusters were included in the questionnaire used. In addition there were 10 blank lines at the bottom on which the women were instructed to record any symptoms not listed in the questionnaire. Symptoms were scored as 0 = none, 1 = mild, 2 = moderate or 3 = severe on a daily basis for 6 consecutive weeks. Each symptom experienced was individually assessed using Triggs trend analysis [8]. A symptom was deemed to be progestogenic if a significant positive trend was present for at least 2 days whilst taking progestogen but before the onset of menstruation, and at no other time, together with a significant negative trend after progestogen was discontinued. The questionnaire was given to women receiving oestrogen treatment for PMS or menopausal problems who were experiencing moderate or severe unpleasant symptoms whilst taking cyclical progestogen. The progestogen was either norethisterone (NET) 5 mg, medroxyprogesterone acetate (MPA) 5 mg or dydrogesterone 10 mg daily. Progestogens were prescribed for 10 days per month, except when severe symptoms persisted despite changing progestogen type, in which circumstance they were given for only 7 days. 3. Results Sixty-five women returned questionnaires. Eight were completed incorrectly and 5 women had no progestogenic symptoms on Triggs trend analysis. Of the remaining 52 women 31 were PMS patients of mean age 37.5 years and 21 were menopause patients of mean age 51 years. The ten most commonly encountered symptoms of progestogen intolerance are all included in the MMDQ and are listed in Table 1. There was a total of 328 instances in which a symptom was determined to be progestogenic. In 97% of these instances the symptom was included in the MMDQ, in 46.7% amongst the 10 most commonly encountered symptoms, and in only 3% was the symptom not one of the MMDQ symptoms.
R.N.J.
Smirh et al. /Maturitas
18 (1994)
89
87-91
Table I Commonest symptoms of progestogen intolerance Symptom
No. of patients with symptom
Feeling swollen/bloated Painful breasts Mood swings Fatigue Depression Irritability Skin disorders Weight gain Anxiety General aches and pains
I8 16 I6 I6 15 IS 15 I5 I4 I3
All 35 adverse symptoms of the MMDQ were found to be progestogenic in at least one woman. In addition eight other symptoms fitted the criteria of progestogen intolerance. These were diarrhoea, unmanageable hair, increased appetite, constipation, urinary urgency, craving sweets, dry skin and sore eyes. None of these was reported more than twice. Table 2 compares the type of symptoms produced by the three progestogens NET, MPA and dydrogesterone. Dydrogesterone caused significantly more symptoms from the concentration symptom complex than did MPA, and significantly more symptoms from the negative affect symptom complex than did NET. PMS patients reported a mean of 7 progestogenic symptoms each, significantly greater than the mean of 4 reported by menopause patients (Wilcoxon two-sample test P < 0.05). Fifty percent of the 24 women treated with subcutaneous oestradiol implants reported a worsening of progestogenic symptoms as the repeat implant was due.
Table 2 Mean number of symptoms per patient by MMDQ symptom cluster
Pain Concentration Behavioural change Autonomic reaction Water retention Negative affect
NET (n = 10)
MPA (n = 24)
1.8 0.4 0.3 0.1 1.6 0.7*
0.92 0.5* 0.58 0.13 1.13
1.67
Dydrogesterone 18)
(n =
I 1.33* 1.06 0.33 1.22 2.5*
*Significantly different at P < 0.05, Wilcoxon two-sample test.
90
R.N.J.
Smith et al. / Maturitas
18 (1994) 87-91
4. Discussion The main purpose of this study was to determine whether the MMDQ is an appropriate tool for researching the symptoms of progestogen intolerance. Ninety-seven percent of the progestogen symptoms identified in this study were included in the MMDQ, and only 3% were not, these being symptoms occurring only infrequently. These data therefore confirm that the MMDQ is appropriate because it includes all commonly occurring progestogenic symptoms. The use of a shortened form comprising only the 10 most commonly encountered symptoms listed in Table 1 cannot be recommended, however, because such a questionnaire would miss over 50% of symptoms. These data are derived from an unhomogenous group of women. This indicates that the MMDQ will detect progestogenic symptoms across a wide spectrum of clinical circumstances and is suitable for the assessment of progestogenic symptoms complicating both postmenopausal HRT and oestrogen treatment of PMS. The similarity between the adverse symptoms associated with progestogen use and the symptomatology of the spontaneous menstrual cycle identified by Moos is striking [7]. This suggests that progesterone may have a role in the generation of PMS [9]. The data indicate that different progestogens cause different adverse symptoms. Norethisterone is less likely to cause negative effect complex symptoms, and is possibly more likely to cause pain complex symptoms. Dydrogesterone is more likely to produce both concentration and negative effect complex symptoms. These differences are of relevance in the choice of progestogen when managing women who experience symptoms of progestogen intolerance. The observation that 50% of implant patients noticed that progestogenic symptoms were worse when oestradiol levels were dropping suggests that the severity of symptoms may be dependent upon the balance between oestrogen and progesterone. The implication is that higher oestrogen levels may attenuate the severity of cyclical progestogenic symptoms. 5. Appendix
The adverse symptom clusters of the Moos Menstrual Distress Questionnaire Pain
Muscle stiffness Headache Cramps Backache Fatigue General aches and pains Behavioural change
Lowered school or work performance Take naps; stay in bed Stay at home
Avoid social activities Decreased efficiency Water retention
Weight gain Skin disorders Painful breasts Swelling
R.N.J.
Smith et al. /Maturitas
Concentration Insomnia Forgetfulness Confusion Lowered judgement Difficulty concentrating Distractable Accidents Lowered motor coordination Autonomic reactions Dizziness, faintness Cold sweats
91
18 (1994) 87-91
Nausea, vomiting Hot flushes Negative effect Crying Loneliness Anxiety Restlessness Irritability Mood swings Depression Tension
6. References Watson NR, Studd JWW, Savvas M, Baber RJ. The long-term effects of estradiol implant therapy for the treatment of pre-menstrual syndrome. Gynecol Endocrinol 1990; 4: 99-107. Studd J. Complications of hormone replacement therapy in post-menopausal women. J R Sot Med 1992; 85: 316-378. Magos AL, Brewster E, Singh R, O’Dowd T, Brincat M, Studd JWW. The effects of norethisterone in post menopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome. Br J Obstet Gynaecol 1986; 93: 1290-96. Kirkham C, Hahn PM, Van Vugt DA, Carmichael JA, Reid RL. A randomised, double blind, placebo-controlled, cross over trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy. Obset Gynecol 1991; 78: 93-97. Hammarback S, Backstrom T, Holst J, von Schoultz B, Lyrenas S. Cyclical mood changes as in the pre-menstrual tension syndrome during sequential estrogen-progestogen post menopausal replacement therapy. Acta Obstet Gynecol Stand 1985; 64: 393-397. Marslew U, Riis B, Christiansen C. Progestogens: therapeutic and adverse effects in early postmenopausal women. Maturitas 1990; 13: 7-16. Moos RH. The development of a menstrual distress questionnaire. Psychosom Med 1968; 30: 853-867. Magos AL, Studd JWW. Assessment of menstrual cycle symptoms by trend analysis. Am J Obset Gynecol 1986; 155: 271-7. Studd J. Pre-menstrual tension syndrome. Br Med J 1979; i: 410.