Int J Gynaecol Obstet 16: 53-55, 1978
Gonadotropic Patterns in Psychogenic Amenorrhea Michael Groll Department of Obstetrics and Gynecology, Abington Memorial Hospital, Abington, Pennsylvania, USA
ABSTRACT Groll M (Dept of Obstetrics and Gynecology, Abington Memorial Hospital, Abington, PA, USA). Gonadotropic patterns in psychogenic amenorrhea. Int J Gynaecol Obstet 16: 53-55, 1978 Sixteen patients with estrogen-deficient amenorrhea of psychogenic origin were studied to determine whether or not radioimmunoassays of their gonadotropin levels would provide any information not available with earlier bioassay techniques. The radioimmunoassays performed in this study corroborate the data produced by the earlier studies. Additionally, the data in the paper demonstrate that psychogenic stress can induce a variety of gonadotropic patterns without the modulating effect of estrogen.
gonadotropin levels. They were hoping that the ability to measure L H and FSH separately would shed more light on the mechanism of amenorrhea. In 1972, Boon and Schalch (2) used radioimmunoassay to measure serial L H and FSH in seven patients with functional amenorrhea not clearly associated with a history of severe stress. Like Rakoff, they noted a variety of gonadotropic patterns. O n the other hand, Vandekerckhove et al (8) correlated the gonadotropin level with the estrogen level in 1975. T h e purpose of this report is to study L H and FSH patterns in patients with psychogenic amenorrhea and to determine whether or not these patterns corroborate the earlier work and further illuminate the mechanism of estrogen deficiency.
INTRODUCTION MATERIALS A N D M E T H O D S During the past decade, radioimmunoassay has allowed us to measure precisely the concentration of gonadotropic hormones in blood. This accomplishment has enhanced our understanding of normal menstrual physiology and some of its aberrations. There has, however, been a paucity of studies dealing with the gonadotropic patterns found in psychogenic amenorrhea. Earlier studies were hampered by the inability of bioassay to distinguish between luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In 1943, Klinefelter et al (4) first noted normal gonadotropic titers associated with estrogen-deficient psychogenic amenorrhea. Subsequent studies have revealed high, normal and low total urinary gonadotropic excretion patterns associated with estrogen deficiency due to psychic stress (5, 6). Rakoff (6), in his study of 61 patients, found that 54% had low gonadotropin levels, 10% had normal levels and 18% had high levels and that all of these patients were estrogendeficient. T h e remaining 18% of the patients studied showed normal gonadotropin and estrogen levels. Early investigators were unable to explain estrogen deficiency in patients with normal or high
A retrospective study was made of 16 patients with estrogen-deficient secondary amenorrhea of at least one year's duration. Each patient gave a history of profound emotional stress. Only those patients who had not taken medication for at least six months and whose weights fell within normal range (without significant fluctuation) were selected for study. All patients were diagnosed as being estrogen deficient, both by vaginal hormonal cytology with a maturation index having 10% or greater parabasal cells and by failure of withdrawal bleeding after taking 10 mg of medroxyprogesterone acetate daily for five days. All patients had a thorough endocrine evaluation which included several radioimmunoassays for L H and FSH using a double antibody technique. T h e samples were taken at six-month intervals. T h e L H assay used rabbit antisera against h u m a n luteinizing hormone (HLH), 125I-h uman chorionic gonadotropin (HCG) and H L H as standard. T h e interassay coefficient of variation was 6.4% and the intraassay coefficient of variation was 5.0%. T h e FSH assay used rabbit antisera against h u m a n follicle stimulating hormone (HFSH), 1 2 5 I-HFSH and H F S H as
Int J Gynaecol Obstet 16
54
Groll
standard. T h e interassay coefficient of variation was 12.2% a n d the intraassay coefficient of variation was 3.4%. Serum concentrations of L H and FSH are expressed as second International Reference Preparation-human menopausal gonadotropin (IRPH M G ) units ( m l U / m l ) . T h e relative potency of the second I R P - H M G compared to the L E R 907 pituitary standard used is 1 m I U / 3 0 ng for FSH and 1 m I U / 5 ng for L H . All patients in this study had normal levels of thyroxine by column, prolactin, testosterone, 24hour urine for 17-ketosteroids a n d normal skull xrays.
RESULTS T h e pattern of a high serum LH and a lownormal F S H is identical with that seen in polycystic ovarian disease. However, the four patients in this group were estrogen deficient and had no clinical or laboratory evidence of hyperandrogenism (Table I). T w o patients had endometrial biopsies demonstrating atrophic endometrium. All four women had marked oligomenorrhea with only one to three menses per year before their secondary amenorrhea. All gave a history of emotional stress frequently brought on by u n h a p p y family life. The history of one
Table I. Gonadotropin data (in mlU/ml) on 16 women with secondary amenorrhea. Years of Secondary Age FSH" Patient LH" Amenorrhea High LH and low-normal FSH pattern 1 17 1 61 76 2 22 3 41 3 18 1 43 4 25 2 High LH and FSH pattern 71 5 32 17 a 6 25 4 40 High-normal LH and FSH pattern 7 20 3 33 8 22 1 31 Normal to low LH and FSH pattern 9 7 29 10 3 18 11 17 18 12 20 6 13 16 9 14 16 16 15 15 9 16 21 6
7 9 9 10 102 83 25 24 11 5 13 13 15 12 10 7
" Wore: Normal range for LH and FSH is 5-25 mlU/ml.
IntJ Gynaecol Obstei 16
patient, for example, included the disintegration of family structure, her brother's suicide and her subsequent depression. In the case of another patient in this group, menstrual function did not become regular until she had graduated from college and married. This is not the natural history of polycystic ovarian disease. T h e laboratory values for the two hypergonadotropic patients are classical for the diagnosis of a premature menopause. These patients, however, presented a history of acute stress followed by estrogen-deficient secondary amenorrhea with atrophic endometrium on biopsy. They subsequently had a return of spontaneous regular menstrual function. One patient experienced amenorrhea and hot flushes after the death of her father. Four years later, regular menses returned and she subsequently became pregnant. Eight women had normal to low gonadotropins and the pattern is what one would expect in patients suffering from acute stress. Six of these patients gave a history of regular menstrual function before the stressful event. O n e patient suffered secondary amenorrhea after she learned of her mother's breast cancer. Seven years later, she is just beginning to develop menstrual function again. Two other patients were obsessive-compulsive young women whose overachieving personalities created sufficient stress to cause severe oligomenorrhea followed by secondary amenorrhea. These findings seem to confirm the findings of earlier investigators who used bioassay and showed the appearance of a wide variety of gonadotropic patterns in connection with estrogen deficiency.
DISCUSSION T o explain the different gonadotropin levels, Dignam et al (3) postulated in 1969 that hypothalamic control was minimal in patients with low gonadotropins and greater in patients with normal gonadotropins. This agrees with the greater responsiveness to clomiphene citrate by the patients with normal gonadotropin levels. It is well accepted that central nervous system (CNS) catecholamines play a central role in the variation of emotional states as well as hypothalamic endocrine function (1). There also are data to suggest that depressive disorders cause an alteration in CNS catecholamine metabolism (7). O n e can conclude, therefore, that emotional stress via the CNS catecholamines can alter gonadotropic function independently of estrogen modulation. Emotional stress can cause secondary amenorrhea
Gonadotropic patterns in amenorrhea
associated with any one of several gonadotropic patterns. L H and FSH levels in these cases may mimic polycystic ovarian disease or the premature menopause, and one must avoid making such diagnoses on the basis of these values alone. These findings reveal no correlation between estrogen levels as determined by vaginal cytology and gonadotropin levels in psychogenic amenorrhea. This is consistent with older bioassay data. The greater specificity a n d sensitivity of radioimmunoassay have not helped the clinician in his ability to diagnose or understand this entity.
4.
5. 6. 7.
8.
55
measurements in the evaluation of menstrual disorders. Am J Obstet Gynecol 105:619, 1969. Klinefelter H F , Albright F, Griswold G C : Experience with quantitative test for normal or decreased amounts of FSH in urine in endocrinological diagnosis. J Clin Endocrinol 3:529, 1943. Loraine J A , Bell E T : Fertility and Contraception in the H u m a n Female. Williams & Wilkins Co, Baltimore, 1968. Rakoff AE: In Endocrinology a n d H u m a n Behavior, (ed R P Michael). Oxford University Press, London, 1968. Sachar EJ: Neuroendocrine abnormalities in depressive illness. In Topics in Psychoendocrinology (ed E J Sachar). G r u ñ e and Stratton, New York, 1975. Vandekerckhove D, Dhont M, VanEyck J : Diagnostic value of L H - R H stimulation test in functional amenorrhea. Acta Endocrinol 75:625, 1975.
REFERENCES 1. A x e l r o d J : Relationship between catecholamines and other hormones. Rec Prog Horm Res 31:\, 1975. 2. Boon R C , Schalch DS: Plasma gonadotropin secretory patterns in patients with functional menstrual disorders and Stein-Leventhal syndrome. A m J Obstet Gynecol 112:136, 1972. 3. Dignam W J , Parlow AF, D a a n e T A : Serum FSH and L H
Address for reprints: M. Groll Abington Hospital Medical Office Building 1245 Highland Avenue, Suite 601 Abington, PA 19001 USA
IntJ Gynaecol Obstet 16
Gonadotropic Patterns in Psychogenic Amenorrhea Michael Groll Department of Obstetrics and Gynecology, Abington Memorial Hospital, Abington, Pennsylvania, USA
ABSTRACT Groll M (Dept of Obstetrics and Gynecology, Abington Memorial Hospital, Abington, PA, USA). Gonadotropic patterns in psychogenic amenorrhea. Int J Gynaecol Obstet 16: 53-55, 1978 Sixteen patients with estrogen-deficient amenorrhea of psychogenic origin were studied to determine whether or not radioimmunoassays of their gonadotropin levels would provide any information not available with earlier bioassay techniques. The radioimmunoassays performed in this study corroborate the data produced by the earlier studies. Additionally, the data in the paper demonstrate that psychogenic stress can induce a variety of gonadotropic patterns without the modulating effect of estrogen.
gonadotropin levels. They were hoping that the ability to measure L H and FSH separately would shed more light on the mechanism of amenorrhea. In 1972, Boon and Schalch (2) used radioimmunoassay to measure serial L H and FSH in seven patients with functional amenorrhea not clearly associated with a history of severe stress. Like Rakoff, they noted a variety of gonadotropic patterns. O n the other hand, Vandekerckhove et al (8) correlated the gonadotropin level with the estrogen level in 1975. T h e purpose of this report is to study L H and FSH patterns in patients with psychogenic amenorrhea and to determine whether or not these patterns corroborate the earlier work and further illuminate the mechanism of estrogen deficiency.
INTRODUCTION MATERIALS A N D M E T H O D S During the past decade, radioimmunoassay has allowed us to measure precisely the concentration of gonadotropic hormones in blood. This accomplishment has enhanced our understanding of normal menstrual physiology and some of its aberrations. There has, however, been a paucity of studies dealing with the gonadotropic patterns found in psychogenic amenorrhea. Earlier studies were hampered by the inability of bioassay to distinguish between luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In 1943, Klinefelter et al (4) first noted normal gonadotropic titers associated with estrogen-deficient psychogenic amenorrhea. Subsequent studies have revealed high, normal and low total urinary gonadotropic excretion patterns associated with estrogen deficiency due to psychic stress (5, 6). Rakoff (6), in his study of 61 patients, found that 54% had low gonadotropin levels, 10% had normal levels and 18% had high levels and that all of these patients were estrogendeficient. T h e remaining 18% of the patients studied showed normal gonadotropin and estrogen levels. Early investigators were unable to explain estrogen deficiency in patients with normal or high
A retrospective study was made of 16 patients with estrogen-deficient secondary amenorrhea of at least one year's duration. Each patient gave a history of profound emotional stress. Only those patients who had not taken medication for at least six months and whose weights fell within normal range (without significant fluctuation) were selected for study. All patients were diagnosed as being estrogen deficient, both by vaginal hormonal cytology with a maturation index having 10% or greater parabasal cells and by failure of withdrawal bleeding after taking 10 mg of medroxyprogesterone acetate daily for five days. All patients had a thorough endocrine evaluation which included several radioimmunoassays for L H and FSH using a double antibody technique. T h e samples were taken at six-month intervals. T h e L H assay used rabbit antisera against h u m a n luteinizing hormone (HLH), 125I-h uman chorionic gonadotropin (HCG) and H L H as standard. T h e interassay coefficient of variation was 6.4% and the intraassay coefficient of variation was 5.0%. T h e FSH assay used rabbit antisera against h u m a n follicle stimulating hormone (HFSH), 1 2 5 I-HFSH and H F S H as
Int J Gynaecol Obstet 16
54
Groll
standard. T h e interassay coefficient of variation was 12.2% a n d the intraassay coefficient of variation was 3.4%. Serum concentrations of L H and FSH are expressed as second International Reference Preparation-human menopausal gonadotropin (IRPH M G ) units ( m l U / m l ) . T h e relative potency of the second I R P - H M G compared to the L E R 907 pituitary standard used is 1 m I U / 3 0 ng for FSH and 1 m I U / 5 ng for L H . All patients in this study had normal levels of thyroxine by column, prolactin, testosterone, 24hour urine for 17-ketosteroids a n d normal skull xrays.
RESULTS T h e pattern of a high serum LH and a lownormal F S H is identical with that seen in polycystic ovarian disease. However, the four patients in this group were estrogen deficient and had no clinical or laboratory evidence of hyperandrogenism (Table I). T w o patients had endometrial biopsies demonstrating atrophic endometrium. All four women had marked oligomenorrhea with only one to three menses per year before their secondary amenorrhea. All gave a history of emotional stress frequently brought on by u n h a p p y family life. The history of one
Table I. Gonadotropin data (in mlU/ml) on 16 women with secondary amenorrhea. Years of Secondary Age FSH" Patient LH" Amenorrhea High LH and low-normal FSH pattern 1 17 1 61 76 2 22 3 41 3 18 1 43 4 25 2 High LH and FSH pattern 71 5 32 17 a 6 25 4 40 High-normal LH and FSH pattern 7 20 3 33 8 22 1 31 Normal to low LH and FSH pattern 9 7 29 10 3 18 11 17 18 12 20 6 13 16 9 14 16 16 15 15 9 16 21 6
7 9 9 10 102 83 25 24 11 5 13 13 15 12 10 7
" Wore: Normal range for LH and FSH is 5-25 mlU/ml.
IntJ Gynaecol Obstei 16
patient, for example, included the disintegration of family structure, her brother's suicide and her subsequent depression. In the case of another patient in this group, menstrual function did not become regular until she had graduated from college and married. This is not the natural history of polycystic ovarian disease. T h e laboratory values for the two hypergonadotropic patients are classical for the diagnosis of a premature menopause. These patients, however, presented a history of acute stress followed by estrogen-deficient secondary amenorrhea with atrophic endometrium on biopsy. They subsequently had a return of spontaneous regular menstrual function. One patient experienced amenorrhea and hot flushes after the death of her father. Four years later, regular menses returned and she subsequently became pregnant. Eight women had normal to low gonadotropins and the pattern is what one would expect in patients suffering from acute stress. Six of these patients gave a history of regular menstrual function before the stressful event. O n e patient suffered secondary amenorrhea after she learned of her mother's breast cancer. Seven years later, she is just beginning to develop menstrual function again. Two other patients were obsessive-compulsive young women whose overachieving personalities created sufficient stress to cause severe oligomenorrhea followed by secondary amenorrhea. These findings seem to confirm the findings of earlier investigators who used bioassay and showed the appearance of a wide variety of gonadotropic patterns in connection with estrogen deficiency.
DISCUSSION T o explain the different gonadotropin levels, Dignam et al (3) postulated in 1969 that hypothalamic control was minimal in patients with low gonadotropins and greater in patients with normal gonadotropins. This agrees with the greater responsiveness to clomiphene citrate by the patients with normal gonadotropin levels. It is well accepted that central nervous system (CNS) catecholamines play a central role in the variation of emotional states as well as hypothalamic endocrine function (1). There also are data to suggest that depressive disorders cause an alteration in CNS catecholamine metabolism (7). O n e can conclude, therefore, that emotional stress via the CNS catecholamines can alter gonadotropic function independently of estrogen modulation. Emotional stress can cause secondary amenorrhea
Gonadotropic patterns in amenorrhea
associated with any one of several gonadotropic patterns. L H and FSH levels in these cases may mimic polycystic ovarian disease or the premature menopause, and one must avoid making such diagnoses on the basis of these values alone. These findings reveal no correlation between estrogen levels as determined by vaginal cytology and gonadotropin levels in psychogenic amenorrhea. This is consistent with older bioassay data. The greater specificity a n d sensitivity of radioimmunoassay have not helped the clinician in his ability to diagnose or understand this entity.
4.
5. 6. 7.
8.
55
measurements in the evaluation of menstrual disorders. Am J Obstet Gynecol 105:619, 1969. Klinefelter H F , Albright F, Griswold G C : Experience with quantitative test for normal or decreased amounts of FSH in urine in endocrinological diagnosis. J Clin Endocrinol 3:529, 1943. Loraine J A , Bell E T : Fertility and Contraception in the H u m a n Female. Williams & Wilkins Co, Baltimore, 1968. Rakoff AE: In Endocrinology a n d H u m a n Behavior, (ed R P Michael). Oxford University Press, London, 1968. Sachar EJ: Neuroendocrine abnormalities in depressive illness. In Topics in Psychoendocrinology (ed E J Sachar). G r u ñ e and Stratton, New York, 1975. Vandekerckhove D, Dhont M, VanEyck J : Diagnostic value of L H - R H stimulation test in functional amenorrhea. Acta Endocrinol 75:625, 1975.
REFERENCES 1. A x e l r o d J : Relationship between catecholamines and other hormones. Rec Prog Horm Res 31:\, 1975. 2. Boon R C , Schalch DS: Plasma gonadotropin secretory patterns in patients with functional menstrual disorders and Stein-Leventhal syndrome. A m J Obstet Gynecol 112:136, 1972. 3. Dignam W J , Parlow AF, D a a n e T A : Serum FSH and L H
Address for reprints: M. Groll Abington Hospital Medical Office Building 1245 Highland Avenue, Suite 601 Abington, PA 19001 USA
IntJ Gynaecol Obstet 16
