British Journal of Obstetrics and Cynaecology March 1979. Vol. 86. pp 238-242
ACUTE MENOPAUSAL TRANSITION ASSOCIATED WITH CLOMIPHENE THERAPY: TWO CASE REPORTS BY
ELIZABETH A. LENTON,Senior Biochemist University Department of Obstetrics and Gynaecology Jessop Hospital for Women, Shefield S3 7RE R. M. BURTON,Consultant Obstetrician and Gynaecologist HiIlingdon Hospital, Uxbridge, Middlesex AND
I. D. COOKE, Professor University Department of Obstetrics and Gynaecology Jessop Hospital for Women, Shefield S3 7RE Summary Two patients presenting with anovulation and secondary infertility were treated with clomiphene citrate. Intermittent blood samples were obtained for the first three months of therapy in each case. One patient failed either to ovulate or menstruate in response to clomiphene and the other patient had only two episodes of cyclical bleeding before she too became amenorrhoeic. Hormonal analyses revealed that both women had undergone a rapid and precocious menopausal transition which has persisted throughout the subsequent three years. METHODS Blood samples were obtained daily or every other day throughout the first three courses of clomiphene treatment. Plasma was separated within 60 minutes and stored at -20°C until assayed for LH, FSH, oestradiol and progesterone. Plasma concentrations of prolactin (PRL), androstenedione and testosterone, in addition to the above hormones, were estimated in one pre-treatment sample from each patient. All the hormones were measured by radioimmunoassays described elsewhere (Lenton et al, 1978). Antibodies were kindly provided by the National Pituitary Agency (anti-LH, anti-PRL), Dr W. Butt (anti-FSH), Dr R. Scaramuzzi (anti-oestradiol) or were obtained commercially. Results were expressed as U/1 of the reference
SINCEclomiphene citrate was first described in 1960 for ovulation induction (Kistner and Smith, 1960) it has been used extensively for the treatment of patients with all types of infertility although possibly its greatest potential is in the treatment of secondary amenorrhoea or oligomenorrhoea (Garcia et al, 1977). Unfortunately not all these patients respond successfully by ovulating (Poliak et al, 1973) and conceiving for reasons which are largely unknown. The present report describes two patients from a consecutive series of 20 women who were carefully monitored following ovulation induction with clomiphene. Treatment in these two patients appeared to precipitate a precocious or premature menopause (ovarian failure, WHO Consultative Document, 1976). 238
MENOPAUSAL TRANSITION WITH CLOMIPHENE
preparation 2nd IRP-HMG (LH and FSH) and mU/l of the research standard 71/222 (PRL), both supplied by the National Institute for Biological Standards and Control, London.
cytology showed little 'evidence of oestrogenic activity (as assessed by the karyopyknotic index) and no endometrium was obtained at curettage. The haemoglobin was 1 3 . 3 g/dl and 17 oxoand oxogenic steroids were normal at 7.4 mg/24 hours and 15.4 mg/24 hours respectively. Pretreatment hormone levels were as follows: LH 40.5 U/l; FSH 73.0 U/1; PRL 275 mU/l; oestradiol 194 pmol/l; androstenedione 3 - 3 nmol/l and testosterone 3 -9 nmol/l. Despite the already elevated gonadotrophin concentrations, ovulation induction was attempted. Clomiphene (50 mg daily) was given for five days and when
CLINICAL HISTORIES Patient 1 The patient, aged 29, presented with oligomenorrhoea and infertility of three years duration following the birth of her first child. Routine investigations (including hysterosalpingography, thyroid function tests and her husband's semen analysis) were all within normal limits. Vaginal
1
5
10
15
20
25
30
35
40
45
50
239
55
60
65
70
75
80
85
90
95
115
120 125 130
Days
FIG.1 The plasma concentrations of LH, FSH, oestradiol and progesterone during treatment of Patient 1. The shaded bars show the duration and timing of clomiphene administration and the filled block indicates menstruation.
240 LENTON, BURTON AND COOKE been no spontaneous resumption of menses in the subsequent three years.
there was no apparent response (flat basal temperature recording and no period), a second course (100 mg daily for five days) was commenced 49 days after the first. There followed an apparently normal menstrual period after an interval of only eight days (Fig. 1) which hormonal analysis subsequently showed was because the second course of clomiphene had inadvertently been given during a preceding luteal-like phase. A third course of clomiphene (100 mg daily) was accordingly given from Day 5 to 9 of this cycle and another episode of bleeding occurred after an apparently normal cycle lasting 27 days. However the next and all subsequent courses of treatment at the same dose level were without further clinical effect and there has
1
5
10
15
20
25
Patient 2 The patient, a 37-year-old Indian lady presented with a history of irregular cycles and secondary infertility of 18 months duration. She had had one normal pregnancy nine years previously. Again, routine investigations were within normal limits and only a small amount of non-secretory slightly hyperplastic endometrium was obtained at curettage. Pre-treatment hormone concentrations were as follows: LH 14.0 U/1; FSH 10.5 U/1; PRL 450 mU/l; oestradiol 445 pmol/l; androstenedione 0.43 nmol/l; testosterone 0 . 8 nmol/l and progesterone 1.78
30
118 123 128 133 138
35 Davs
FIG.
2
Plasma concentrations of LH, FSH, oestradiol and progesterone during treatment of Patient 2. The shaded bar representsthe timing of clomiphene administration and the filled block indicates menstruation.
MENOPAUSAL TRANSITION WITH CLOMIPHENE
nmol/l. The patient started menstruating spontaneously the day before clomiphene treatment (at 50 mg daily for five days) began. Her previous two cycles had been of 27 and 25 days duration and the above pre-treatment blood sample corresponded to Day 18 of a 25 day cycle (Fig. 2). Both the hormone concentrations and basal temperature recording suggested that these cycles were anovulatory. There was no clinical response to clomiphene, the basal temperature recording was consistent with anovulation and there were no further episodes of bleeding. Amenorrhoea has persisted for the subsequent three years.
ENDOCRINE RESULTS AND INTERPRETATION Patient 1 Patient 1 had not menstruated for several months before treatment was initiated and the finding of slightly elevated peripheral concentrations of both LH and FSH suggested that some degree of ovarian failure was already present. The first course of clomiphene was associated with an exaggerated response by FSH but not by LH. There was however, no increase in oestradiol secretion and no evidence of any follicular development (Fig. 1). However, after about 45 days some luteal-like activity was observed with simultaneous elevation of both oestradiol and progesterone concentrations. This phase lasted about 10 days and was followed by an episode of bleeding. There did not appear to be an LH surge associated with the start of the luteal phase, although LH levels subsequently rose and parallelled the changes seen in oestradiol and progesterone concentrations. Unfortunately a second course of clomiphene was given at this time which may have been responsible for the elevation in LH and the dissociation between LH and FSH concentrations. The third course of clomiphene in this patient produced smaller alterations in both L H and FSH but stimulated apparently normal follicular development with oestradiol secretion. This follicular phase was followed by a probable ovulatory surge of both LH and FSH (although the latter was greatly exaggerated), and a luteal phase lasting 14 days. The basal temperature recording also showed normal appearances. The fourth course of clomiphene
241
produced marked increases in both LH and FSH but there was no concomitant ovarian response and gonadotrophin concentrations continued to rise until within a week they had reached menopausal levels. Steroid secretion by the ovary was, and has remained, low.
Patient 2 Patient 2 had experienced irregular cycles for some months before treatment. Her basal temperature recording showed these to be anovulatory cycles separated by episodes of heavy bleeding. Her final period occurred one day before the first course of clomiphene (Fig. 2). Pre-treatment gonadotrophin levels were within the normal range and gave no suggestion that this woman was peri-menopausal. However, following 50 mg of clomiphene, gonadotrophin concentrations rose rapidly and after 10 days oestradiol secretion decreased abruptly. By this time the gonadotrophins were within the menopausal range where they have remained since. DISCUSSION The hormonal changes occurring during the transition from the peri-menopausal to the menopausal state have not been extensively documented and we could find only two other examples of what was probably the final menstrual cycle in a woman’s reproductive life (Sherman et al, 1976; Van Look et al, 1977). These authors have, however, analysed a number of cycles from peri-menopausal women and the profiles they have obtained are similar to the hormone patterns initially observed in Patient 1 (Sherman and Korenman, 1975). It would appear that most women experience cycles with bizarre hormonal relationships during the peri-menopausal period (Adamopoulos et al, 1971), which may last several years (Keettel and Bradbury, 1964). Our two patients apparently did not have long peri-menopausal phases and it seems likely that clomiphene, by stimulating ovarian function (via increased gonadotrophin secretion) may have precipitated ovarian failure and thus the onset of true menopause. The dissociation between the secretion of L H and FSH is very obvious in the first cycle of
242
LENTON, BURTON AND COOKE
Patient 1 and supports the hypothesis put forward by Sherman and Korenman (1975) that there may be an ovarian regulatory hormone analogous to the ‘inhibin‘ thought to exist in men. This factor would reduce progressively with age and would be important in the regulation of FSH secretion. It is possible that clorniphene may accelerate the age-related reduction in ‘inhibin’. The transition to the menopausal state occurred very rapidly in both our patients with gonadotrophin levels rising simultaneously to the menopausal range over the space of a few days. Final concentrations of FSH were about twice the concentration of LH and the whole pattern was very similar to the acute onset menopause following oophorectomy (Monroe ef al, 1972). Despite the abruptness of the transition, neither of these two women experienced any menopausal symptoms. It is doubtful whether, once the true menopausal state has been reached, ovarian function is restorable (Keettel and Bradbury, 1964) although it is possible to see from our data how a woman on the verge of the menopause may still have occasional apparently normal cycles (Patient I) and could possibly conceive. Clinically these patients would have been classed as treatment failures although the actual cause of this failure would not have been apparent without a certain amount of endocrine information. Early recognition of the menopausal state prevents
undue prolongation of treatment and unnecessary distress to the patient.
ACKNOWLEDGEMENTS We are indebted to Mrs L. Sexton and Miss L. Brook for skillful technical assistance. REFERENCES Adamopoulos, D. A., Loraine, J. A., and Dove, G. A. (1971): Journal of Obstetrics and Gynaecology of the British Commonwealth, 78,62. Garcia, J., Seegar Jones, G., and Wentz, A. C. (1977): Fertility and Sterility, 28,707. Keettel, W. C., and Bradbury, J. T. (1964): American Journal of Obstetrics and Gynecology, 89,83. Kistner, R. W., and Smith, 0.W. (1960): Surgical Forum, 10,725. Lenton, E. A., Adams, M., and Cooke, I. D . (1978): Clinical Endocrinology, 8,241. Monroe, S. E., Jaffe, R. B., and Midgley, A. R. Jr. (1972) : Journal of Clinical Endocrinology and Metabolism, 34,420. Poliak, A., Smith, J. J., and Seymour, L. R. (1973): Fertility and Sterility, 24,921. Sherman, B. M., and Korenman, S. G. (1975): Journalof Clinical Investigation, 55,699. Sherman, B. W., West, J. H., and Korenman, S. G. (1976): Journal of Clinical Endocrinology and Metabolism, 42,629. Van Look, P. A., Lothian, H., Hunter, W. M., Michie, E. A., and Baird, D. T. (1977): Clinical Endocrinology, 7,13. WHO Consultative Document (1976): The Diagnosis and Treatment of Endocrine Forms of Female InfertiIity.
WHO, Geneva.
ACUTE MENOPAUSAL TRANSITION ASSOCIATED WITH CLOMIPHENE THERAPY: TWO CASE REPORTS BY
ELIZABETH A. LENTON,Senior Biochemist University Department of Obstetrics and Gynaecology Jessop Hospital for Women, Shefield S3 7RE R. M. BURTON,Consultant Obstetrician and Gynaecologist HiIlingdon Hospital, Uxbridge, Middlesex AND
I. D. COOKE, Professor University Department of Obstetrics and Gynaecology Jessop Hospital for Women, Shefield S3 7RE Summary Two patients presenting with anovulation and secondary infertility were treated with clomiphene citrate. Intermittent blood samples were obtained for the first three months of therapy in each case. One patient failed either to ovulate or menstruate in response to clomiphene and the other patient had only two episodes of cyclical bleeding before she too became amenorrhoeic. Hormonal analyses revealed that both women had undergone a rapid and precocious menopausal transition which has persisted throughout the subsequent three years. METHODS Blood samples were obtained daily or every other day throughout the first three courses of clomiphene treatment. Plasma was separated within 60 minutes and stored at -20°C until assayed for LH, FSH, oestradiol and progesterone. Plasma concentrations of prolactin (PRL), androstenedione and testosterone, in addition to the above hormones, were estimated in one pre-treatment sample from each patient. All the hormones were measured by radioimmunoassays described elsewhere (Lenton et al, 1978). Antibodies were kindly provided by the National Pituitary Agency (anti-LH, anti-PRL), Dr W. Butt (anti-FSH), Dr R. Scaramuzzi (anti-oestradiol) or were obtained commercially. Results were expressed as U/1 of the reference
SINCEclomiphene citrate was first described in 1960 for ovulation induction (Kistner and Smith, 1960) it has been used extensively for the treatment of patients with all types of infertility although possibly its greatest potential is in the treatment of secondary amenorrhoea or oligomenorrhoea (Garcia et al, 1977). Unfortunately not all these patients respond successfully by ovulating (Poliak et al, 1973) and conceiving for reasons which are largely unknown. The present report describes two patients from a consecutive series of 20 women who were carefully monitored following ovulation induction with clomiphene. Treatment in these two patients appeared to precipitate a precocious or premature menopause (ovarian failure, WHO Consultative Document, 1976). 238
MENOPAUSAL TRANSITION WITH CLOMIPHENE
preparation 2nd IRP-HMG (LH and FSH) and mU/l of the research standard 71/222 (PRL), both supplied by the National Institute for Biological Standards and Control, London.
cytology showed little 'evidence of oestrogenic activity (as assessed by the karyopyknotic index) and no endometrium was obtained at curettage. The haemoglobin was 1 3 . 3 g/dl and 17 oxoand oxogenic steroids were normal at 7.4 mg/24 hours and 15.4 mg/24 hours respectively. Pretreatment hormone levels were as follows: LH 40.5 U/l; FSH 73.0 U/1; PRL 275 mU/l; oestradiol 194 pmol/l; androstenedione 3 - 3 nmol/l and testosterone 3 -9 nmol/l. Despite the already elevated gonadotrophin concentrations, ovulation induction was attempted. Clomiphene (50 mg daily) was given for five days and when
CLINICAL HISTORIES Patient 1 The patient, aged 29, presented with oligomenorrhoea and infertility of three years duration following the birth of her first child. Routine investigations (including hysterosalpingography, thyroid function tests and her husband's semen analysis) were all within normal limits. Vaginal
1
5
10
15
20
25
30
35
40
45
50
239
55
60
65
70
75
80
85
90
95
115
120 125 130
Days
FIG.1 The plasma concentrations of LH, FSH, oestradiol and progesterone during treatment of Patient 1. The shaded bars show the duration and timing of clomiphene administration and the filled block indicates menstruation.
240 LENTON, BURTON AND COOKE been no spontaneous resumption of menses in the subsequent three years.
there was no apparent response (flat basal temperature recording and no period), a second course (100 mg daily for five days) was commenced 49 days after the first. There followed an apparently normal menstrual period after an interval of only eight days (Fig. 1) which hormonal analysis subsequently showed was because the second course of clomiphene had inadvertently been given during a preceding luteal-like phase. A third course of clomiphene (100 mg daily) was accordingly given from Day 5 to 9 of this cycle and another episode of bleeding occurred after an apparently normal cycle lasting 27 days. However the next and all subsequent courses of treatment at the same dose level were without further clinical effect and there has
1
5
10
15
20
25
Patient 2 The patient, a 37-year-old Indian lady presented with a history of irregular cycles and secondary infertility of 18 months duration. She had had one normal pregnancy nine years previously. Again, routine investigations were within normal limits and only a small amount of non-secretory slightly hyperplastic endometrium was obtained at curettage. Pre-treatment hormone concentrations were as follows: LH 14.0 U/1; FSH 10.5 U/1; PRL 450 mU/l; oestradiol 445 pmol/l; androstenedione 0.43 nmol/l; testosterone 0 . 8 nmol/l and progesterone 1.78
30
118 123 128 133 138
35 Davs
FIG.
2
Plasma concentrations of LH, FSH, oestradiol and progesterone during treatment of Patient 2. The shaded bar representsthe timing of clomiphene administration and the filled block indicates menstruation.
MENOPAUSAL TRANSITION WITH CLOMIPHENE
nmol/l. The patient started menstruating spontaneously the day before clomiphene treatment (at 50 mg daily for five days) began. Her previous two cycles had been of 27 and 25 days duration and the above pre-treatment blood sample corresponded to Day 18 of a 25 day cycle (Fig. 2). Both the hormone concentrations and basal temperature recording suggested that these cycles were anovulatory. There was no clinical response to clomiphene, the basal temperature recording was consistent with anovulation and there were no further episodes of bleeding. Amenorrhoea has persisted for the subsequent three years.
ENDOCRINE RESULTS AND INTERPRETATION Patient 1 Patient 1 had not menstruated for several months before treatment was initiated and the finding of slightly elevated peripheral concentrations of both LH and FSH suggested that some degree of ovarian failure was already present. The first course of clomiphene was associated with an exaggerated response by FSH but not by LH. There was however, no increase in oestradiol secretion and no evidence of any follicular development (Fig. 1). However, after about 45 days some luteal-like activity was observed with simultaneous elevation of both oestradiol and progesterone concentrations. This phase lasted about 10 days and was followed by an episode of bleeding. There did not appear to be an LH surge associated with the start of the luteal phase, although LH levels subsequently rose and parallelled the changes seen in oestradiol and progesterone concentrations. Unfortunately a second course of clomiphene was given at this time which may have been responsible for the elevation in LH and the dissociation between LH and FSH concentrations. The third course of clomiphene in this patient produced smaller alterations in both L H and FSH but stimulated apparently normal follicular development with oestradiol secretion. This follicular phase was followed by a probable ovulatory surge of both LH and FSH (although the latter was greatly exaggerated), and a luteal phase lasting 14 days. The basal temperature recording also showed normal appearances. The fourth course of clomiphene
241
produced marked increases in both LH and FSH but there was no concomitant ovarian response and gonadotrophin concentrations continued to rise until within a week they had reached menopausal levels. Steroid secretion by the ovary was, and has remained, low.
Patient 2 Patient 2 had experienced irregular cycles for some months before treatment. Her basal temperature recording showed these to be anovulatory cycles separated by episodes of heavy bleeding. Her final period occurred one day before the first course of clomiphene (Fig. 2). Pre-treatment gonadotrophin levels were within the normal range and gave no suggestion that this woman was peri-menopausal. However, following 50 mg of clomiphene, gonadotrophin concentrations rose rapidly and after 10 days oestradiol secretion decreased abruptly. By this time the gonadotrophins were within the menopausal range where they have remained since. DISCUSSION The hormonal changes occurring during the transition from the peri-menopausal to the menopausal state have not been extensively documented and we could find only two other examples of what was probably the final menstrual cycle in a woman’s reproductive life (Sherman et al, 1976; Van Look et al, 1977). These authors have, however, analysed a number of cycles from peri-menopausal women and the profiles they have obtained are similar to the hormone patterns initially observed in Patient 1 (Sherman and Korenman, 1975). It would appear that most women experience cycles with bizarre hormonal relationships during the peri-menopausal period (Adamopoulos et al, 1971), which may last several years (Keettel and Bradbury, 1964). Our two patients apparently did not have long peri-menopausal phases and it seems likely that clomiphene, by stimulating ovarian function (via increased gonadotrophin secretion) may have precipitated ovarian failure and thus the onset of true menopause. The dissociation between the secretion of L H and FSH is very obvious in the first cycle of
242
LENTON, BURTON AND COOKE
Patient 1 and supports the hypothesis put forward by Sherman and Korenman (1975) that there may be an ovarian regulatory hormone analogous to the ‘inhibin‘ thought to exist in men. This factor would reduce progressively with age and would be important in the regulation of FSH secretion. It is possible that clorniphene may accelerate the age-related reduction in ‘inhibin’. The transition to the menopausal state occurred very rapidly in both our patients with gonadotrophin levels rising simultaneously to the menopausal range over the space of a few days. Final concentrations of FSH were about twice the concentration of LH and the whole pattern was very similar to the acute onset menopause following oophorectomy (Monroe ef al, 1972). Despite the abruptness of the transition, neither of these two women experienced any menopausal symptoms. It is doubtful whether, once the true menopausal state has been reached, ovarian function is restorable (Keettel and Bradbury, 1964) although it is possible to see from our data how a woman on the verge of the menopause may still have occasional apparently normal cycles (Patient I) and could possibly conceive. Clinically these patients would have been classed as treatment failures although the actual cause of this failure would not have been apparent without a certain amount of endocrine information. Early recognition of the menopausal state prevents
undue prolongation of treatment and unnecessary distress to the patient.
ACKNOWLEDGEMENTS We are indebted to Mrs L. Sexton and Miss L. Brook for skillful technical assistance. REFERENCES Adamopoulos, D. A., Loraine, J. A., and Dove, G. A. (1971): Journal of Obstetrics and Gynaecology of the British Commonwealth, 78,62. Garcia, J., Seegar Jones, G., and Wentz, A. C. (1977): Fertility and Sterility, 28,707. Keettel, W. C., and Bradbury, J. T. (1964): American Journal of Obstetrics and Gynecology, 89,83. Kistner, R. W., and Smith, 0.W. (1960): Surgical Forum, 10,725. Lenton, E. A., Adams, M., and Cooke, I. D . (1978): Clinical Endocrinology, 8,241. Monroe, S. E., Jaffe, R. B., and Midgley, A. R. Jr. (1972) : Journal of Clinical Endocrinology and Metabolism, 34,420. Poliak, A., Smith, J. J., and Seymour, L. R. (1973): Fertility and Sterility, 24,921. Sherman, B. M., and Korenman, S. G. (1975): Journalof Clinical Investigation, 55,699. Sherman, B. W., West, J. H., and Korenman, S. G. (1976): Journal of Clinical Endocrinology and Metabolism, 42,629. Van Look, P. A., Lothian, H., Hunter, W. M., Michie, E. A., and Baird, D. T. (1977): Clinical Endocrinology, 7,13. WHO Consultative Document (1976): The Diagnosis and Treatment of Endocrine Forms of Female InfertiIity.
WHO, Geneva.
