Hypothyroidism and amenorrhea due to hypothalamic insufficiency

Hypothyroidism and Amenorrhea Due to Hypothalamic lnsuff iciency A Study in Four Young Women

PAUL D. WOOLF, M.D. Rochester, New York

From the Endocrine Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York. This study was supported in part by NINCDS Grant No. NS-11642, General Research Support Grant RR-05403 and USPHS Grant (NIH) RR00044. Requests for reprints should be addressed to Dr. Paul D. Woolf, Endocrine Unit, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642. Manuscript accepted December 8, 1976.

Four women, aged 17 to 23, were evaluated for secondary amenorrhea of 12 to 36 months’ duration. All were considered to have hypothalamic hypothyroidism on the basis of low thyroxine (T4) concentrations, inappropriately low thyrotropin (TSH) levels, with a normal TSH response to thyrotropin-releasing hormone (TRH, 500 pg intravenously) in three, and absence of a pituitary lesion. Nevertheless, menses did not resume after adequate replacement with thyroid hormone. Investigation of the pituitary-gonadal axis revealed a normal increase in both luteinizing hormone (LH) and folllclestimulating hormone (FSH) following the intravenous administration of gonadotropin-releasing hormone (GnRH). Three subjects received clomiphene citrate, 100 mg/day for five days, but a normal menstrual cycle was not induced. It is concluded that the amenorrhea was not due to thyroid hormone deficiency but, like the hypothyroidism, to a hypothalamic abnormality involving secretion of the appropriate releasing hormone. It has only been possible to document hypothalamic insufficiency as a clinical entity for the past few years [ 11. For reasons which are not clear, it appears that hypopituitarism in a majority of children is due to a failure of the hypothalamus to secrete the appropriate releasing hormone [2,3], whereas the etiology in adults is varied [4-131. Nevertheless, normal responsivity to thyrotropin-releasing hormone (TRH) and/or gonadotropin-releasing hormone (GnRH) may persist despite many years of pituitary hypofunction [5-7,l l-131. Both single [ 12- 151 and multiple hormonal deficiencies [4-l l] have been documented, but because of poor responsivity to GnRH in patients with hypogonadotropic hypogonadism and associated primary amenorrhea [ 141, a hypothalamic cause of primary amenorrhea due to GnRH deficiency has been difficult to document. Reported in this study is the evaluation of four young women who presented with secondary amenorrhea and who were found to have hypothyroidism on a hypothalamic basis. The normal luteinizing hormone (LH) and folliclestimulating hormone (FSH) response to GnRH combined with an absent response to clomiphene citrate suggests that the amenorrhea, like the hypothyroidism, was caused by an abnormality of hypothalamic secretion of the appropriate releasing hormone.

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HYPOTHYROIDISM

Age (yr)

1 2 3 4 Normal

INSUFFICIENCY-WOOLF

Clinical and Base Line Hormonal Data

TABLE I

Patient

AND AMENORRHEA DUE TO HYPOTHALAMIC

Age at Menarche LMP (mo) (yr) 12 15 14 15 6112

23 18 17 23

18 12 18 36

Total T4 (pg/dl)

Free Tr (ng/dl)

TSH (j.Wml)

PRL (ng/ml)

4.3 2.7 4.8 4.5 5.0-13.7

1.0 0.6 0.8 1.0-2.3

3.0 3.7 3.3 1.5 2.1-10.0

13 16 16 13 (25

(ml:ml)

(m:vs/Hml)

1.5 8.6 5.0 5.0 5-15

(;;b”/“m;)

4.5 9.9 4.5 4.0 5-20

Xortisol” (Fg/dl)

18.1 8.5 7.7 20.2 L8

20.4 3.5 19.2 7.3 L5

NOTE:LMP = last menstrual period. After insulin-induced hypoglycemia. l

MATERIALS

AND

METHODS

GnRH (100 gg, Parke Davis) and TRH (500 @g, Abbott Laboratories) were given intravenously as a bolus. Blood was taken 5 minutes and immediately before, and 5, 10, 15, 20, 30, 45, 60, 90, 120 and 180 minutes after, the injection. The heparinized blood was kept at O°C until centrifuged, the plasma was separated within 3 hours and stored at -2O’C until assayed. The samples from each test were run in one assay to minimize assay variability. Clomiphene citrate, 100 mg, was given for five days and blood for the determination of LH was taken prior to and seven days after the start of therapy [ 151. Hypoglycemia was induced by the intravenous administration of regular insulin, 0.1 U/kg [ 161. Plasma LH [ 171, FSH [ 181, TSH [ 191, prolactin (PRL) [20] and growth hormone (GH) [21] were measured by radioimmunoassay, and cortisol and T4 by competitive protein binding [22,23]. The free T4 was determined at Bioscience Laboratories. The LH and FSH concentrations were expressed as mlU/ml. The conversion factor for the expression of the gonadotropins in nanograms of LER 907 are 4.8 for LH and 25 for FSH.

Funduscopic examination was within normal limits, and her visual fields were grossly intact. Her thyroid was soft and of normal size. The breasts were normal, and galactorrhea was absent. Pelvic examination disclosed no abnormalities. The reflexes were normoactive. Resulb of her routine laboratory studies were normal, including a complete blood count, SMA-12 and urinalysis. Formal visual field testing and skull films were within normal limits. The base line endocrine evaluation is shown in Table I, and her responses to TRH and GnRH are shown in Figures 1 and 2, respectively. Her growth hormone concentration remained unchanged

1

TRH

120-i

) ud

PATIENT I--_

(1

23-._.4

CASE REPORTS Patient 1. This 24 year old unmarried white woman was referred for evaluation of secondary amenorrhea. She underwent menarche at age 12 but normal menstrual function was never established. She was treated with Ovulen-Pi@ at age 19 for one year with regular withdrawal bleeding, but she remained completely amenorrheic during the subsequent three years and did not respond to therapy with Provera@. In August 1971, and again in May 1972, she underwent culdocentesis for ruptured ovarian cysts, and an exploratory laparotomy in August 1974, for a presumed ruptured ovarian cyst, revealed appendecial inflammation, multiple peritoneal adhesions, normal fallopian tubes and uterus, and a small cyst of the left ovary. There was no history of headaches, visual difficulties or recent weight change, although she noted long-standing constipation, cold intolerance, skin dryness, deepening of her voice and easy fatigability. Her family history is remarkable for similar menstrual abnormalities in an identical twin who has been amenorrheic for the past three years, one year after a normal pregnancy and delivery, and for secondary amenorrhea in her younger sister (Patient 2). Physical examination revealed a tall, thin, normal-appearing woman. Her height was 69 l/2 inches and her weight 119 pounds. Her skin and hair were of normal consistency.

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-@__-_--O

25

1

-5 0 10

30 45

60

90

120

180

MINUTES .

-.

gure 1. The intravenous administration of TRH (500 pg) caused significant prolactin release in all subjects (top panel) whereas TSH release was normal in Patients 1, 2 and 3 and probably subnormal in Patient 4 (bottom panel).

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following the oral administration of L-dopa, 500 mg, but it increased normally after insulin-induced hypoglycemia. Prolactin increased from 19 to 79 ng/ml after the intramuscular administration of chlorpromazine, 50 mg. The administration of clomiphene citrate, 100 mg/day for five days, resulted in a change in LH concentration from 1.4 to 8.2 mlU/ml, but there was no resumption of menses. Thyroid replacement therapy was then started with levothyroxine, 150 pglday, following which her T4 increased to 7.5 pg/dl, but she discontinued the medication after two months. She has remained amenorrheic for the past year. Patient 2. This patient, the 18 year old unmarried sister of Patient 1, was evaluated for secondary amenorrhea of one year’s duration. She underwent normal puberty with breast development at age 11 and her first menstrual period at age 15. Menses were regular for 15 months but, with the exception of one spontaneous menstrual period, she had been amenorrheic for the 19 months prior to her evaluation. During this time she received Provera twice, having four days of spotting after the first course but no response after the second. With the exception of a 13 pound weight loss over the past two years, she had no significant illnesses, headaches, visual difficulties, galactorrhea or constioation. She noted some cold intolerance.

PATIENT

25 i

lOi

e’

r-m-7 -50 IO

30 45 60

90

120

180

MINUTES .

--..

igure 2. The Intravenous administration of GnRH (100 p caused significant release of LH (top panel) and of FSH (bottom panel) in all subjects.

September

DUE TO HYPOTHALAMIC

INSUFFICIENCY-WOOLF

On physical examination the patient was a tall, thin woman. Her height was 70 l/2 inches and she weighed 125 pounds. Her thyroid was normal in size and soft. Her breasts were poorly developed (Tanner stage 2-3) and galactorrhea was absent. Pelvic examination disclosed no abnormalities. The skin was slightly coarse and cool; the hair distribution was normal. The reflexes were brisk, but the relaxation phase was delayed. Results of a routine complete blood count, urinalysis and SMA-12 were normal. Skull films and formal visual fields were within normal limits. Her base line endocrine evaluation is given in Table I, and her responses to the administration of TRH and GnRH are shown in Figures 1 and 2, respectively. The 24-hour radioactive iodine uptake was 6 per cent (normal = 10 to 25 per cent). Her prolactin concentration increased normally from 16 to 60 ng/ml after the intramuscular administration of chlorpromazine (50 mg). After the administration of 100 mg clomiphene citrate for five days, her LH increased from 8.7 to 9.7 mlU/ml, but she did not have a menstrual period. She has been receiving levothyroxine, 100 pg/day, for six months and her T4 has increased to 9.2 pgldl, but her menses have not resumed. l

Patient 3. This 17 year old unmarried woman was evaluated for amenorrhea. She noted breast development at age 1 I, the appearance of pubic hair at age 12, and she had her first menstrual period at age 14. However, over the ensuing 18 months, she had only two additional periods, each lasting two weeks, the last 18 months prior to evaluation. She denied any history of headache, visual difficulties, galactorrhea, cold intolerance or constipation. Over the past year she had lost 10 pounds on a diet. Physical examination revealed a normal-appearing woman. Her height was 63 inches and her weight 120 pounds. Funduscopic examination was within normal limits. The thyroid was normal in size. The breasts were normally developed, and galactorrhea was absent. Pelvic examination disclosed no abnormalities. The skin was slightly dry and the palms were yellow. Hair texture was normal. The patient’s reflexes were normoactive. Her skull films were within normal limits. The results of her base line endocrine evaluation are given in Table I, and her responses to the administration of TRH and GnRH are shown in Figures 1 and 2, respectively. She did not have a menstrual period following clomiphene administration although LH increased from 6.3 to 15 0 mlU/ml. Despite thyroid hormone replacement for one year, which increased her T4 to 7.8 lg/dl, menses have not resumed. Patient 4. This 23 year old white married woman was evaluated for secondary amenorrhea of three years’ duration. She noted the appearance of pubic hair at age 13, breast development at age 14 and her first menstrual period at age 15. Her periods were completely regul,ar for one year and were grossly irregular for the next four years before ceasing three years prior to evaluation. She had never used oral contraceptives and did not respond to a five day course of Provera (10 mg/day). She denied a history of headache, visual difficulty, galactorrhea, cold intolerance and constipation, and her weight was stable.

* Performed at Strong Memorial Hospital, Rochester, New York.

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DUE TO HYPOTHALAMIC

INSUFFICIENCY-WOOLF

On physical examination she was a normal-appearing woman. Her height was 68 inches, and she weighed 122 pounds. Funduscopic examination disclosed no abnormalities; her thyroid was of normal size and consistency. Her breasts were well developed and galactorrhea was absent. Pelvic examination was within normal limits. Her skin and hair were of normal texture. Her reflexes were normoactive. Results of routine laboratory tests were normal, including a complete blood count, urinalysis and SMA-12. Results of her base line endocrine evaluation are given in Table I, and her responses to the administration of TRH and GnRH are shown in Figures 1 and 2, respectively. The 24-hour radioactive iodine uptake increased normally from 7.8 per cent (normal = 8.4 to 28.5) to 24 per cent and her T4 level from 4.5 to 12.0 pg/dl after a three day course of bovine TSH (10 U/day). She was treated with dessicated thyroid, 120 mg/day, but noted no change in her feeling of well-being, and menses have not resumed after two years of therapy. Skull films and formal visual field testing have remained within normal limits. Clomiphene citrate was not given. l

RESULTS Thyroid

function

studies revealed

mild hypothyroidism

in all the patients. Both the total and free T4 concentrations were low (Table I). In Patients 2 and 4, the thyroidal accumulation of 13’1at 24 hours was low (with no history of exogenous iodine loading), but it increased normally in Patient 4 following exogenous TSH administration indicating that her hypothyroidism was caused by a TSH deficiency and not by intrinsic thyroid disease. Despite low thyroid hormone concentrations, TSH levels were low but increased briskly following TRH administration in three subjects. The response in Patient 4 was poor but possibly normal [24] (Figure 1). None of the patients ovulated after clomiphene administration, although the LH concentrations increased in Patients 1 and 3. All subjects had brisk releases of both LH and FSH after GnRH administration (Figure 2). Secretion of the remaining pituitary hormones was intact in all patients. Prolactin increased normally following the administration of TRH (Figure 1) and after the administration of chlorpromazine (50 mg intramuscularly) in Patients 1 and 2. GH increased appropriately after insulin-induced hypoglycemia in all subjects, whereas cortisol release was abnormal only in Patient 2 (Table I). However, she responded appropriately to the administration of metyrapone. COMMENTS

In our patients the abnormalities in thyroid function tests (low total and free Tq, inappropriately low TSH which increased normally after the administration of TRH) seem to indicate mild hypothyroidism on a hypothalamic Performed Virginia.

346

at the Naval

September 1977

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Center,

Portsmouth,

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basis; i.e., an inability to secrete TRH normally because of disordered synthesis, secretion or altered set point. However, because of the mildness of the symptoms, these results are also compatible with euthyroidism maintained by normal triiodothyronine (Ta, unfortunately, not measured) levels. This condition, however, is rare and has been reported with iodine deficiency [25,26] and following treatment for hyperthyroidism [27], neither of which was present in our patients. Furthermore, the 13’1uptake was low in the two patients in whom it was measured, providing further support for the diagnosis of hypothalamic hypothyroidism. Hypothalamic hypothyroidism may be quite profound [5] or mild [4], as it was in our patients. The etiology may be idiopathic [6-81, as in our patients, due to trauma [4-61, tumor [6,7], irradiation [9] or stalk section [6]. TSH deficiency may be an isolated phenomenon [l] or part of multiple pituitary deficiencies [ 2- 111. However, the combination of hypothalamic hypothyroidism and secondary amenorrhea in the absence of an obvious pituitary or hypothalamic lesion has rarely been reported [lo]. The cause of our patients’ amenorrhea is unclear. Although hypothyroidism is known to cause menstrual irregularity, complete amenorrhea is unusual [ 281. Moreover, in our patients, menses did not resume after thyroid hormone replacement. The fact that their sexual development was normal and that a normal menstrual pattern was established, albeit for only a short period of time, suggests that tonic and cyclic gonadotropin secretion was initially normal. Our patients’ normal LH and FSH responses to exogenous GnRH administration and failure to respond completely to clomiphene administration support an acquired abnormality within the hypothalamus [29,30]. We cannot determine from our data whether this abnormality is due to an inability to synthesize or secrete GnRH, to an acquired defect of the positive feedback effects of estrogen-a condition which is present in prepubertal children [31]-or to some other abnormality within the central nervous system. However, it is tempting in the face of the apparent lack of TRH to attribute our patients’ amenorrhea to failure of GnRH secretion. ACKNOWLEDGMENT I wish to thank Dr. S. Zane Burday for his critical comments, Mrs. Louyse Lee for her technical assistance, Dr. William Peck for his encouragement and, especially, Dr. J. H. Cho for referring Patients 1 and 2 and Dr. R. Pincus for the referral of Patient 3. The reagents for the PRL and TSH assays were generously provided by the National Pituitary Agency. GnRH was generously supplied by Parke, Davis & Co. and TRH by Abbott Laboratories.

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