Vol. 28, No.8, August 1977 Printed in U.S.A.
FERTILITY AND STERILITY Copyright' 1977 The American Fertility Society
PREGNANCY FOLLOWING THYROID HORMONE TREATMENT IN A PATIENT WITH AMENORRHEA-GALACTORRHEA DUE TO PRIMARY HYPOTHYROIDISM
TOSHIHIRO AONO, M.D.* TAKENORI SHIOJI, M.D. TOSHIO ONISHI, M.D. HIROHISA KURACHI, M.D. KIYOSHI MIYAI, M.D. KEIICHI KURACHI, M.D. Departments of Obstetrics and Gynecology, Medicine, and Geriatrics, and Central Laboratory for Clinical Investigation, Osaka University Medical School, Fukushimaku, Osaka 553, Japan
A 32-year-old female with amenorrhea-galactorrhea due to primary hypothyroidism was treated with thyroid hormones, and serum levels of thyrotropin (TSH), prolactin (PRL), triiodothyronine (T:J, thyroxin (T.J, and T3 resin sponge uptake (RT3U) were measured throughout the course of treatment. The elevated serum levels ofTSH and PRL fell into the normal range following T3 treatment. Subsequently, the menstrual cycle was restored within 1 month, and galactorrhea completely ceased and conception was achieved within 3 months. Desiccated thyroid was administered during pregnancy, and the patient gave birth to a female infant. Impaired secretion of PRL during pregnancy and poor milk secretion with blunted response of PRL to the suckling stimulus during the puerperium were noted.
Since the first description in 1956 by Jackson! of a patient with primary hypothyroidism and galactorrhea, more than 25 cases of primary hypothyroidism with galactorrhea have been reported. Although improvement of galactorrhea and amenorrhea has been often reported following treatment with thyroid hormone, conception has occurred in only three cases, but PRL levels were not assayed. 2 ,3 We report here a patient with primary hypothyroidism and amenorrhea-galactorrhea who successfully conceived and delivered a baby following thyroid hormone treatment. Serum levels of thyrotropin (TSH), prolactin (PRL), triiodothyronine (T3), thyroxin (T4 ), and T3 resin sponge uptake (RT3U) were measured throughout the course of therapy.
CASE REPORT
S. K., a 32-year-old gravida 2, para 1 female was referred to our hospital in May 1975 because of amenorrhea-galactorrhea and infertility. Her menses had been sporadic since menarche, which had occurred at 16 years of age. Lactation persisted after the birth of her first baby in August 1968, and she underwent an induced abortion in January 1969. She had been amenorrheic since April 197 4 and had complained of cold intolerance during recent years. Physical examination revealed a myxedematous face with cold, dry skin. The thyroid gland was not palpable. Both breasts were active, and spontaneous secretion of milk was observed. Pituitary tumor was excluded on the basis of normal visual field examination and negative skull x-ray studies. Investigations. Serum levels of TSH, PRL, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and T3 were determined by radioimmunoassay (RIA) methods as previously de-
Received February 17, 1977; revised March 21, 1977; accepted March 22, 1977. *Reprint requests: Toshihiro Aono, M.D., Department of Obstetrics and Gynecology, Osaka University Medical School, 1-1-50 Fukushima Fukushimaku, Osaka 553, Japan.
878
Vol. 28, No.8
879
COMMUNICATIONS·IN-BRIEF
scribed in detail. 4 The serum concentration of T4 was measured by competitive protein-binding analysis, and RTaU was performed with a Triosorb kit. The thyroid function was impaired as judged by the following findings: basal metabolic rate (BMR), 20%; RTaU, 23%; T 4 , 1.8ILg/dl; T a, 74 ng/dl; TSH, 341 IL U/ml; and cholesterol, 272 mg/dl. Tests for thyroid autoantibodies to thyroglobulin and micro somes were negative. The serum level ofPRL was moderately elevated (33.6 ng/ml). The responses of TSH and PRL to an intravenous injection of 500 ILg of thyrotropin-releasing hormone (TRH) were supranormal (i.e., TSH, from 341 to 1100 ILU/ml; PRL, from 32 to 182 ng/ml). The serum PRL level was suppressed from 30.0 to 8.3 ng/ml 150 minutes after the oral administration of I-dopa in a 500-mg dose. Serum LH (4.8 mIU/ml) and FSH (11.3 mIU/ml) levels responded well to 100 ILg of intravenous LH-releasing hormone, reaching peak values of 70.0 and 28.5 mIU/ml, respectively. The intravenous injection of 20 mg of conjugated estrogen (Premarin) did not provoke an LH surge, which is
usually seen 48 to 72 hours after the injection. Serum levels of estradiol (31.6 pg/ml) and progesterone (0.4 ng/ml) were similar to those found during the early follicular phase. These data suggested that the cause of the amenorrheagalactorrhea in this patient was primary hypothyroidism. Course of Treatment. Treatment with Ta was started on June 28, 1975, and the dose of Ta was increased gradually from 10 ILg/day to 75 ILg/day, as is shown in Figure 1. The serum level of T a rapidly increased to normal, and the TSH level was undetectable by July 28. Serum PRL levels decreased gradually and reached the normal range by August 4; galactorrhea then decreased gradually and ceased completely by the middle of October. A TRH stimulation test performed on August 18 revealed no TSH response and a normal PRL response. By continuous administration of T a, the BMR and RTaU returned to normal and a biphasic basal body temperature (BBT) was recorded, followed by a menstrual period. Twentyfour days after the last menstrual period, on September 12, continuous elevation of the BBT
TSH (!'u mi)
400 TSH
300 200 100
o~----------~~~~~======~====~==~~~==~==~==~~====~o T,
9,
,
,0,.
("II dR)
200
T.
, 'b- __
--"'- ,
_ _ ..0...._ .....
- - - -
-
-0--
""'0--.0--
(!'g dR)
,,
20 '0---0.
,
10
/
/
~~====~~~~~~======~==~~----------------------~o +20 BMR (%)
10 BMR
~~
--
o
-- -- --
-20
1 ..."",-__Ga_Iactorrhea _ _ _~_ _ ~
~~:
~
1
~.5~----A~~~~2-~~~~~~---~-----------~----~
Menses
~.0~_~~_~~_~_~~_~~_~~_~~~{~_~~_7-~_~~~~_7-~~ 15 15 15 1 15 15 15 1 May
1975
..An.
.Jul.
Aug.
Sept.
Oct.
Nov.
Dec.
-Jan.
M....
May.
.Jul.
Sept.
1976
FiG. 1. Serum levels of TSH, PRL, Ta, and T.; RTaU; BMR; and clinical course during treatment with thyroid hormones in a patient with galactorrhea-amenorrhea due to primary hypothyroidism who conceived and delivered a baby.
August 1977
COMMUNICATIONS-IN-BRIEF
880
was observed, and pregnancy was confirmed by an immunologic human chorionic gonadotropin test. On December 1 the daily thyroid hormone treatment was changed from 50 ILg ofT3 to 100 mg of desiccated thyroid, resulting in an increase in serum T4 levels. As the patient complained of palpitation and sweating, the dose of desiccated thyroid was gradually decreased. During the course of pregnancy, the levels of T3, T4, and TSH remained within the normal range, whereas a decrease in RT3U levels was observed. No increase in PRL levels was observed during the pregnancy. On June 21,1976, the patient delivered a female infant weighing 3720 gm by cesarean section because of cephalopelvic disproportion. With the interruption of thyroid hormone treatment during the early postpartum period, decreases in T3and T 4 levels with concomitant elevations ofTSH and PRL were noted. The suckling reflex seemed not to have been established as judged by a total milk yield of only 20 ml after 7 days' suckling. An impaired PRL response (from 25.0 to 30.0 ng/ml) to a 20-minute suckling was observed; the test was conducted on the 7th postpartum day. The concentrations of T4. T 3, and TSH in cord blood obtained from the newborn infant (5.6ILg/dl , 60 ngl dl, and 8.8 ILUlml, respectively) were within the normal range. DISCUSSION
The etiopathology of the galactorrhea observed in patients with hypothyroidism may be explained as follows: As the low levels of thyroid hormones cause an increase in the TRH secretion from the hypothalamus and enhance the sensitivity of the pituitary to TRH, large amounts of PRL and TSH are secreted from the pituitary. Subsequently,
elevated PRL levels stimulate lactation. The present results are consistent with this theory. We previously reported5 that, following estrogen administration, the impaired LH release observed in amenorrhea-galactorrhea patients with normal thyroid function may be partly responsible for anovulation. Our patient with hyperprolactinemia due to hypothyroidism also had an impaired LH response to an intravenous estrogen injection. Increased levels ofPRL have been reported during pregnancy. However, our patient surprisingly showed no PRL increment throughout her pregnancy. The PRL release following suckling was also impaired during the puerperium. Acknowledgments. The authors are grateful to Dr. K. Matsumoto for reviewing the manuscript. We wish to express appreciation to the National Institute of Arthritis, Metabolism and Digestive Diseases, Bethesda, Md., for the generous gift of the PRL radioimmunoassay kit, and to the National Institute for Biological Standards and Control for supplying the Second International Reference Preparation of human menopausal gonadotropin. REFERENCES 1. Jackson WPU: Post-thyroidectomy hypothyroidism, hypoparathyroidism, exophthalmos and galactorrhea with normal menstruation: metabolic response to probenecid. J Clin Endocrinol Metab 16:1245, 1956 2. Canfield CJ, Bates RW: Nonpuerperal galactorrhea. N Engl J Med 273:897,1965 3. Kinch RAH, Plunkett ER, Devlin MC: Postpartum amenorrhea-galactorrhea of hypothyroidism. Am J Obstet Gynecol 105:766, 1969 4. Aono T, Shioji T, Miyai K, Onishi T, Kurachi K: Effect of triiodothyronine treatment on prolactin secretion in patients with amenorrhea-galactorrhea. J Clin Endocrinol Metab 44:8,1977 5. Aono T, Miyake A, Shioji T, Kinugasa T, Onishi T, K urachi K: Impaired LH release following exogenous estrogen administration in patients with amenorrhea-galactorrhea syndrome. J Clin Endocrinol Metab 42:696, 1976
FERTILITY AND STERILITY Copyright' 1977 The American Fertility Society
PREGNANCY FOLLOWING THYROID HORMONE TREATMENT IN A PATIENT WITH AMENORRHEA-GALACTORRHEA DUE TO PRIMARY HYPOTHYROIDISM
TOSHIHIRO AONO, M.D.* TAKENORI SHIOJI, M.D. TOSHIO ONISHI, M.D. HIROHISA KURACHI, M.D. KIYOSHI MIYAI, M.D. KEIICHI KURACHI, M.D. Departments of Obstetrics and Gynecology, Medicine, and Geriatrics, and Central Laboratory for Clinical Investigation, Osaka University Medical School, Fukushimaku, Osaka 553, Japan
A 32-year-old female with amenorrhea-galactorrhea due to primary hypothyroidism was treated with thyroid hormones, and serum levels of thyrotropin (TSH), prolactin (PRL), triiodothyronine (T:J, thyroxin (T.J, and T3 resin sponge uptake (RT3U) were measured throughout the course of treatment. The elevated serum levels ofTSH and PRL fell into the normal range following T3 treatment. Subsequently, the menstrual cycle was restored within 1 month, and galactorrhea completely ceased and conception was achieved within 3 months. Desiccated thyroid was administered during pregnancy, and the patient gave birth to a female infant. Impaired secretion of PRL during pregnancy and poor milk secretion with blunted response of PRL to the suckling stimulus during the puerperium were noted.
Since the first description in 1956 by Jackson! of a patient with primary hypothyroidism and galactorrhea, more than 25 cases of primary hypothyroidism with galactorrhea have been reported. Although improvement of galactorrhea and amenorrhea has been often reported following treatment with thyroid hormone, conception has occurred in only three cases, but PRL levels were not assayed. 2 ,3 We report here a patient with primary hypothyroidism and amenorrhea-galactorrhea who successfully conceived and delivered a baby following thyroid hormone treatment. Serum levels of thyrotropin (TSH), prolactin (PRL), triiodothyronine (T3), thyroxin (T4 ), and T3 resin sponge uptake (RT3U) were measured throughout the course of therapy.
CASE REPORT
S. K., a 32-year-old gravida 2, para 1 female was referred to our hospital in May 1975 because of amenorrhea-galactorrhea and infertility. Her menses had been sporadic since menarche, which had occurred at 16 years of age. Lactation persisted after the birth of her first baby in August 1968, and she underwent an induced abortion in January 1969. She had been amenorrheic since April 197 4 and had complained of cold intolerance during recent years. Physical examination revealed a myxedematous face with cold, dry skin. The thyroid gland was not palpable. Both breasts were active, and spontaneous secretion of milk was observed. Pituitary tumor was excluded on the basis of normal visual field examination and negative skull x-ray studies. Investigations. Serum levels of TSH, PRL, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and T3 were determined by radioimmunoassay (RIA) methods as previously de-
Received February 17, 1977; revised March 21, 1977; accepted March 22, 1977. *Reprint requests: Toshihiro Aono, M.D., Department of Obstetrics and Gynecology, Osaka University Medical School, 1-1-50 Fukushima Fukushimaku, Osaka 553, Japan.
878
Vol. 28, No.8
879
COMMUNICATIONS·IN-BRIEF
scribed in detail. 4 The serum concentration of T4 was measured by competitive protein-binding analysis, and RTaU was performed with a Triosorb kit. The thyroid function was impaired as judged by the following findings: basal metabolic rate (BMR), 20%; RTaU, 23%; T 4 , 1.8ILg/dl; T a, 74 ng/dl; TSH, 341 IL U/ml; and cholesterol, 272 mg/dl. Tests for thyroid autoantibodies to thyroglobulin and micro somes were negative. The serum level ofPRL was moderately elevated (33.6 ng/ml). The responses of TSH and PRL to an intravenous injection of 500 ILg of thyrotropin-releasing hormone (TRH) were supranormal (i.e., TSH, from 341 to 1100 ILU/ml; PRL, from 32 to 182 ng/ml). The serum PRL level was suppressed from 30.0 to 8.3 ng/ml 150 minutes after the oral administration of I-dopa in a 500-mg dose. Serum LH (4.8 mIU/ml) and FSH (11.3 mIU/ml) levels responded well to 100 ILg of intravenous LH-releasing hormone, reaching peak values of 70.0 and 28.5 mIU/ml, respectively. The intravenous injection of 20 mg of conjugated estrogen (Premarin) did not provoke an LH surge, which is
usually seen 48 to 72 hours after the injection. Serum levels of estradiol (31.6 pg/ml) and progesterone (0.4 ng/ml) were similar to those found during the early follicular phase. These data suggested that the cause of the amenorrheagalactorrhea in this patient was primary hypothyroidism. Course of Treatment. Treatment with Ta was started on June 28, 1975, and the dose of Ta was increased gradually from 10 ILg/day to 75 ILg/day, as is shown in Figure 1. The serum level of T a rapidly increased to normal, and the TSH level was undetectable by July 28. Serum PRL levels decreased gradually and reached the normal range by August 4; galactorrhea then decreased gradually and ceased completely by the middle of October. A TRH stimulation test performed on August 18 revealed no TSH response and a normal PRL response. By continuous administration of T a, the BMR and RTaU returned to normal and a biphasic basal body temperature (BBT) was recorded, followed by a menstrual period. Twentyfour days after the last menstrual period, on September 12, continuous elevation of the BBT
TSH (!'u mi)
400 TSH
300 200 100
o~----------~~~~~======~====~==~~~==~==~==~~====~o T,
9,
,
,0,.
("II dR)
200
T.
, 'b- __
--"'- ,
_ _ ..0...._ .....
- - - -
-
-0--
""'0--.0--
(!'g dR)
,,
20 '0---0.
,
10
/
/
~~====~~~~~~======~==~~----------------------~o +20 BMR (%)
10 BMR
~~
--
o
-- -- --
-20
1 ..."",-__Ga_Iactorrhea _ _ _~_ _ ~
~~:
~
1
~.5~----A~~~~2-~~~~~~---~-----------~----~
Menses
~.0~_~~_~~_~_~~_~~_~~_~~~{~_~~_7-~_~~~~_7-~~ 15 15 15 1 15 15 15 1 May
1975
..An.
.Jul.
Aug.
Sept.
Oct.
Nov.
Dec.
-Jan.
M....
May.
.Jul.
Sept.
1976
FiG. 1. Serum levels of TSH, PRL, Ta, and T.; RTaU; BMR; and clinical course during treatment with thyroid hormones in a patient with galactorrhea-amenorrhea due to primary hypothyroidism who conceived and delivered a baby.
August 1977
COMMUNICATIONS-IN-BRIEF
880
was observed, and pregnancy was confirmed by an immunologic human chorionic gonadotropin test. On December 1 the daily thyroid hormone treatment was changed from 50 ILg ofT3 to 100 mg of desiccated thyroid, resulting in an increase in serum T4 levels. As the patient complained of palpitation and sweating, the dose of desiccated thyroid was gradually decreased. During the course of pregnancy, the levels of T3, T4, and TSH remained within the normal range, whereas a decrease in RT3U levels was observed. No increase in PRL levels was observed during the pregnancy. On June 21,1976, the patient delivered a female infant weighing 3720 gm by cesarean section because of cephalopelvic disproportion. With the interruption of thyroid hormone treatment during the early postpartum period, decreases in T3and T 4 levels with concomitant elevations ofTSH and PRL were noted. The suckling reflex seemed not to have been established as judged by a total milk yield of only 20 ml after 7 days' suckling. An impaired PRL response (from 25.0 to 30.0 ng/ml) to a 20-minute suckling was observed; the test was conducted on the 7th postpartum day. The concentrations of T4. T 3, and TSH in cord blood obtained from the newborn infant (5.6ILg/dl , 60 ngl dl, and 8.8 ILUlml, respectively) were within the normal range. DISCUSSION
The etiopathology of the galactorrhea observed in patients with hypothyroidism may be explained as follows: As the low levels of thyroid hormones cause an increase in the TRH secretion from the hypothalamus and enhance the sensitivity of the pituitary to TRH, large amounts of PRL and TSH are secreted from the pituitary. Subsequently,
elevated PRL levels stimulate lactation. The present results are consistent with this theory. We previously reported5 that, following estrogen administration, the impaired LH release observed in amenorrhea-galactorrhea patients with normal thyroid function may be partly responsible for anovulation. Our patient with hyperprolactinemia due to hypothyroidism also had an impaired LH response to an intravenous estrogen injection. Increased levels ofPRL have been reported during pregnancy. However, our patient surprisingly showed no PRL increment throughout her pregnancy. The PRL release following suckling was also impaired during the puerperium. Acknowledgments. The authors are grateful to Dr. K. Matsumoto for reviewing the manuscript. We wish to express appreciation to the National Institute of Arthritis, Metabolism and Digestive Diseases, Bethesda, Md., for the generous gift of the PRL radioimmunoassay kit, and to the National Institute for Biological Standards and Control for supplying the Second International Reference Preparation of human menopausal gonadotropin. REFERENCES 1. Jackson WPU: Post-thyroidectomy hypothyroidism, hypoparathyroidism, exophthalmos and galactorrhea with normal menstruation: metabolic response to probenecid. J Clin Endocrinol Metab 16:1245, 1956 2. Canfield CJ, Bates RW: Nonpuerperal galactorrhea. N Engl J Med 273:897,1965 3. Kinch RAH, Plunkett ER, Devlin MC: Postpartum amenorrhea-galactorrhea of hypothyroidism. Am J Obstet Gynecol 105:766, 1969 4. Aono T, Shioji T, Miyai K, Onishi T, Kurachi K: Effect of triiodothyronine treatment on prolactin secretion in patients with amenorrhea-galactorrhea. J Clin Endocrinol Metab 44:8,1977 5. Aono T, Miyake A, Shioji T, Kinugasa T, Onishi T, K urachi K: Impaired LH release following exogenous estrogen administration in patients with amenorrhea-galactorrhea syndrome. J Clin Endocrinol Metab 42:696, 1976
