THYROID Volume 13, Number 10, 2003 © Mary Ann Liebert, Inc.
Prolactin Dysregulation in Women with Subclinical Hypothyroidism: Effect of Levothyroxine Replacement Therapy Christian Meier,1,* Mirjam Christ-Crain, 1,* Merih Guglielmetti,1 Peter Huber, 2 Jean-Jacques Staub,1 and Beat Müller1
This study investigated the effect of levothyroxine treatment on serum prolactin (PRL) levels in women with subclinical hypothyroidism. Sixty-six women (mean age, 58.5 6 1.3 years) with confirmed subclinical hypothyroidism (mean thyrotropin [TSH], 11.7 6 0.8 mIU/L) were randomly assigned to receive levothyroxine or placebo for 48 weeks. Based on blinded TSH monitoring, physiologic levothyroxine replacement (85.5 6 4.3 mg/d; TSH, 3.1 6 0.3 mIU/L) was ascertained throughout the study. PRL levels were measured before and after administration of thyrotropin-releasing hormone (TRH) at baseline, after 24 and 48 weeks. Sixty-three of the 66 women completed the study. At baseline, basal PRL levels were elevated in 19% of the patients. None of the patients reported menstrual disturbances, infertility, or galactorrhea. In the levothyroxine group (n 5 31) basal and peak PRL levels were significantly reduced after 24 and 48 weeks (p 5 0.03 and p 5 0.001). Mean changes in PRL levels differed significantly between the two treatment groups after 24 weeks (p 5 0.03 and p 5 0.01). The treatment effect was more pronounced in patients with PRL and TSH levels above the median at baseline (i.e., PRL . 16 ng/mL; TSH . 11 mIU/L). Based on this double-blinded, placebo-controlled study we demonstrate that in subclinical hypothyroidism PRL regulation is altered with elevated basal and stimulated PRL levels, and that physiologic levothyroxine treatment restores PRL concentrations.
Introduction
E
(PRL) levels of variable magnitude have been reported in patients with overt primary hypothyroidism (1–6). Because of the effects of hyperprolactinemia on the pituitary gland and the ovary, untreated hypothyroidism may be associated with ovulatory dysfunction (7), causing infertility (3,8) and menstrual disturbances (9–11), with restoration after levothyroxine (LT4) therapy (8,12). However, based on a recent study, menstrual disturbances were not more common in hyperprolactinemic than in normoprolactinemic hypothyroid patients (13). Because of the widespread use of thyrotropin (TSH) measurements subclinical hypothyroidism (SCH) has been detected with increasing frequency. This syndrome, characterized by the finding of elevated TSH levels in the presence of normal circulating thyroid hormones (14), is causing major controversy concerning management and treatment. Published data on presence and extent of basal hyperprolactinemia in SCH are controversial (15–17). Furthermore, LEVATED SERUM PROLACTIN
PRL levels after thyrotropin-releasing hormone (TRH) stimulation were increased in subclinical and overt hypothyroidism compared to euthyroid controls (6,18,19), demonstrating the stimulating effect of TRH on pituitary lactotroph cells. Although it has been shown that thyroid hormone replacement may be beneficial in patients with SCH, controlled data investigating its potential role on PRL regulation are scarce. We therefore sought to investigate the PRL-lowering effect of physiologic LT4 treatment on basal and stimulated PRL levels in patients with SCH using a prospective, doubleblinded, placebo-, and TSH-controlled study design. Materials and Methods
Study population The present analysis was part of a prospective, doubleblinded, placebo-controlled study, the design of which and patient characteristics have been described previously (20).
1 Division of Endocrinology, Diabetology, and Clinical Nutrition, Department of Internal Medicine and 2Department of Central Laboratories, University Hospitals, Basel, Switzerland. *These authors contributed equally to this work. Abstract presented at 84th Annual Meeting of the Endocrine Society, San Francisco, June 19–22, 2002.
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980 Briefly, between September 1993 and May 1997, 66 women with SCH were enrolled in the study. All patients were examined and followed-up in the Thyroid Research Unit of the Division of Endocrinology, Department of Medicine, University Hospital Basel, Switzerland. Patients between the age of 18–75, with TSH levels more than 5.0 mIU/L on two consecutive blood tests, exaggerated TSH response of more than 35 mIU/L after TRH stimulation, free T4 concentration within the normal range, and good general health were included. Exclusion criteria were coronary heart disease, pituitary/hypothalamic disorders or other nonthyroidal illnesses, treatment with drugs known to alter PRL secretion, as well as thyroid hormone medication up to 3 months before enrollment. A total of 63 women (mean age 58.5 6 1.3 years) completed the study according to the study protocol, with no adverse events reported. The study was terminated early in 2 participants because of previously unknown serious medical comorbidities and rapid progression to clinically overt hypothyroidism, respectively. The underlying thyroid disorders leading to SCH consisted of autoimmune thyroiditis (n 5 32), Graves’ disease (n 5 21; treated with radioiodine, surgery, or carbimazole), toxic multinodular goiter (n 5 1, treated with radioiodine), surgically resected goiter (n 5 6), and idiopathic SCH (n 5 3). The frequencies of underlying thyroid disorders were equally distributed in the LT4 and placebo groups.
Study design We used a prospective, double-blinded, placebo-controlled trial design, as previously described (20). Eligible patients were sequentially assigned either to the LT4 treatment group (n 5 33) or to the placebo group (n 5 33) according to a predefined randomization list. The study duration for each patient was 50 weeks, including a 2-week run-in phase before starting treatment. During the first 24 weeks, the LT4 dose was adapted continuously every 6 weeks in order to achieve an optimal physiological hormone replacement with euthyroid basal TSH levels (i.e., basal TSH concentration within the reference range [0.1–4.0 mIU/L]). LT4 (Henning Berlin, Berlin, Germany) was given in the fasting state. The placebo tablets were prepared and packed in the identical way as the LT4 tablets. The dosage was controlled every 6 weeks to ascertain an optimal replacement regimen. To guarantee blinding, patients in the placebo group received tablets with dose adjustments in concordance to their randomly assigned patients in the treatment group. The local Ethics Committee for Human Studies approved the study. All patients gave their written informed consent to participate in the trial.
MEIER ET AL. ments were averaged. All laboratory analyses were conducted at the Department of Central Laboratories at the University Hospital Basel. The TSH level (reference range, 0.1–4.0 mIU/L) was measured using an immunometric assay (Delfia, Wallac, Inc., Turku, Finland). Free T4 (8.0–23.0 pmol/L) and total triiodothyronine (T3) (1.2–3.1 nmol/L) were determined by microparticle enzyme immunoassays (IMx, Abbott Laboratories, Inc., Chicago, IL). Serum concentrations of PRL were measured using an immunometric assay (Elecsys, Roche Diagnostics, Mannheim, Germany; reference range, 3.4–24.1 ng/mL). An intranasal TRH test with measurement of PRL and TSH levels was performed in all patients to evaluate the effect LT4 treatment (21,22). In this test we determined serum PRL and TSH concentrations before and 30 minutes after the intranasal administration of 1 mg of synthetic TRH (Relefact TRH nasal, Aventis, Zurich, Switzerland; mean peak PRL in euthyroid female controls, 96.8 6 8.2 ng/mL [n 5 18, age 50.1 6 7.5 years, premenopausal/postmenopausal 8/10]).
Statistical analyses All data are expressed as the mean 6 standard error of the mean (SEM). Unpaired t test (two-sided) or Mann-Whitney U test in the case of nonparametric distributions was used to identify differences in demographic variables among the treatment groups. Differences of frequencies were tested with the x2 test or Fisher’s exact test, as appropriate. Treatment effects in the LT4 or placebo group were analyzed by paired Student’s t-test or by Wilcoxon signed rank test for nonparametric distributions, respectively. Significance was defined as p , 0.05. Data were analyzed using Statistica for Windows (version 5.0, StatSoft, Inc., Tulsa, OK). Results
Baseline data of the study population Sixty-three women completed the study as predicted by the study protocol. At baseline the two groups of women with subclinical hypothyroidism (LT4, n 5 31; placebo, n 5 32) were well balanced with respect to age, body mass index, estrogen status, and thyroid hormone concentrations. In both groups, basal TSH levels were mildly to markedly elevated (range, 5.0–50 mIU/L) with an exaggerated TSH response of more than 35 mIU/L after TRH stimulation. Peripheral thyroid hormone concentrations (free T4 and T3 ) were within the lower reference range. PRL levels, either before or after TRH stimulation, were comparable in both groups before treatment without significant difference between the treatment groups.
Hormone measurements
Effect of treatment on thyroid hormone concentrations
Serum samples were collected using an intravenous line in the fasting state after a 15-minute waiting period to allow for any stress-induced changes in PRL to recede, immediately put on ice, and processed within 30 minutes. Thereafter, they were kept frozen at 270°C. Hormone measurements were assessed at baseline visit, after 24 weeks, and at the end of the study after 48 weeks. In order to minimize nonspecific variability, thyroid hormones were evaluated twice in a time period of 2 weeks (before and after treatment); for statistical analysis the results of both measure-
In the treatment group the LT4 dose was adapted in 6week intervals in order to decrease the TSH concentration to the euthyroid reference range (mean dose, 85.5 6 4.3 mg daily, range, 50–125 mg). In all patients, basal TSH concentrations were within the reference range at least for the last 24 weeks. Mean serum TSH level at the end of the study was 3.1 6 0.3 mIU/L (Table 1). No patient had a blunted or absent TSH response to TRH. Peripheral thyroid hormone concentrations increased (free T4) or decreased (T3) significantly within the reference range. As expected, no change in any
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TABLE 1. PARAMETERS BEFORE, AFTER 24 WEEKS , AND AFTER 48 WEEKS OF TREATMENT WITH LT4 (n 5 31) OR PLACEBO (n 5 32) Parameters TSH basal (mIU/L) TSH after TRH (mIU/L) FT4 (pmol/L) T3 (nmol/L) Prolactin basal (ng/mL) Prolactin after TRH (ng/mL) TSH basal (mIU/L) TSH after TRH (mIU/L) FT4 (pmol/L) T3 (nmol/L) Prolactin basal (ng/mL) Prolactin after TRH (ng/mL)
Before treatment
After 24 weeks
Treatment with LT4 (n 5 31) 12.8 6 1.4 82.3 6 9.5 11.6 6 0.3 2.0 6 0.1 18.3 6 2.1 104.1 6 9.5
3.5 24.4 16.6 1.7 15.9 89.6
6 6 6 6 6 6
0.5* 3.0* 0.6* 0.1** 1.7** 8.5***
Treatment with placebo (n 5 32) 10.7 6 0.9 10.2 6 0.7 73.9 6 7.4 65.4 6 6.6 12.0 6 0.3 12.4 6 0.4 1.9 6 0.1 1.8 6 0.1 16.6 6 1.5 16.6 6 1.3 120.9 6 10.9 117.7 6 9.8
After 48 weeks 3.1 21.3 17.8 1.7 16.1 85.2
6 6 6 6 6 6
0.3* 2.3* 0.8* 0.1* 1.8** 9.0***
9.9 61.1 12.3 1.9 16.1 114.3
6 6 6 6 6 6
0.6 5.4 0.4 0.1 1.3 12.6
Analysis was done per protocol; significance was determined by paired t test (two-sided) or by Wilcoxon signed rank test in nonparametric distribution: values at 24 and 48 weeks compared to baseline. Data are mean 6 standard error of the mean (SEM). *p , 0.001; **p , 0.05; ***p , 0.005. LT4 , levothyroxine; TSH, thyrotropin; FT4 , free thyroxine; T3, triiodothyronine; TRH, thyrotropin-releasing hormone.
variable of thyroid function tests could be seen in patients on placebo.
Effect of treatment on PRL levels In all women, basal and stimulated PRL levels were measured at baseline, after 24 and after 48 weeks of LT4 and placebo treatment, respectively. Significant changes in PRL levels could be observed in LT4-treated patients only, whereas placebo-treated women showed no significant changes during the entire study period (Table 1). At baseline, circulating basal PRL levels were elevated in 12 study participants (19%), with comparable distribution regarding the two treatment groups (LT4 group, n 5 7; placebo group, n 5 5). After 24 and 48 weeks of LT4 therapy, basal PRL levels decreased significantly from 18.3 6 2.1 ng/mL to 15.9 6 1.7 ng/mL (p 5 0.03) and 16.1 6 1.8 ng/mL (p 5 0.01), respectively. Similarly, peak PRL levels after TRH stimulation decreased significantly after 24 and 48 weeks (p 5 0.004). The observed PRL-lowering effect of LT4 was the result of a significant treatment effect in patients with pretreatment PRL concentrations above 16 ng/mL (median, n 5 15). In these patients basal PRL levels decreased from 25.9 6 3.0 to 21.2 6 2.5 ng/mL (p , 0.01) and 21.6 6 2.7 ng/mL (p 5 0.03), whereas the corresponding stimulated PRL levels decreased from 133.1 6 13.9 ng/mL to 110.7 6 12.4 ng/mL (p , 0.01) and 114.1 6 13.4 ng/mL (p 5 0.03), respectively. Patients with pretreatment PRL levels below the median showed no significant effect of T4 treatment. The mean changes in serum concentrations of basal PRL and peak PRL after TRH differed significantly between the two groups (LT4, n 5 31; placebo, n 5 32) after 24 weeks (mean percent change, p 5 0.03 and p 5 0.01, respectively). After 48 weeks, stimulated PRL levels showed a near significant trend toward lower levels in the LT4 group com-
pared to the placebo group (p 5 0.05) (Figs. 1 and 2). Because no menstrual disturbances were reported in premenopausal women, no change in menstrual function could be observed after treatment. In the subgroup of patients with markedly elevated TSH concentrations above 11.4 mIU/L (median, n 5 16), LT4 therapy was associated with a significant decrease of basal PRL from 19.0 6 3.2 ng/mL to 16.6 6 2.7 ng/mL after 24 weeks (p 5 0.04) and 16.6 6 2.8 ng/mL after 48 weeks (p 5 0.04), respectively. Stimulated PRL levels decreased from 103.4 6 12.4 ng/mL to 87.9 6 10.5 ng/mL (p 5 0.02) and 84.0 6 9.1 ng/mL (p 5 0.01), respectively. In contrast, in patients with TSH levels , 11.4 mIU/L (n 5 15) no significant treatment effects could be observed (Fig. 3). Premenopausal women and postmenopausal women on estrogen replacement therapy (n 5 36; serum E2, 474.2 6 77.5 pmol/L) had significantly higher levels of basal and stimulated PRL than postmenopausal women without estrogen supplementation (n 5 27; serum E2, 103.5 6 8.0 pmol/L): basal PRL, 19.3 6 1.8 ng/mL vs. 14.6 6 1.8 ng/mL, p 5 0.05; peak PRL, 126.9 6 10.9 ng/mL vs. 93.9 6 7.5 ng/mL, p 5 0.02. During LT4 treatment significant reductions of PRL levels could be observed mainly in women with adequate estrogen levels at study entry (premenopausal women and postmenopausal women on estrogen replacement therapy, n 5 17; serum E2, 526.8 6 143.8 pmol/L). In these women PRL concentrations decreased from 21.0 6 3.1 ng/mL to 17.4 6 2.4 ng/mL (p 5 0.08) and 16.8 6 2.3 ng/mL (p 5 0.02) after 24 and 48 weeks, respectively. Similar treatment effects were seen for stimulated PRL levels (p 5 0.02, and p 5 0.04). In postmenopausal women without estrogen replacement therapy (n 5 14; serum E2, 101.2 6 13.5), no PRL-lowering effect was found during LT4 replacement therapy. The mean changes in serum concentrations of basal and peak PRL in premenopausal women and postmenopausal
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MEIER ET AL. perprolactinemia in SCH. Importantly, in SCH elevated basal and stimulated PRL levels have been associated with disturbances in female reproductive function (16). Thereafter, relevant effects of T4 treatment can be postulated. The aim of this study was to investigate the effect of thyroid hormone replacement on serum PRL regulation in patients with SCH. It was part of a prospective, double-blinded, placebo- and TSH-controlled trial designed to evaluate clinical and metabolic effects of LT4 replacement in patients with mild thyroid failure. We found a significant reduction in basal PRL levels in LT4-treated patients, whereas serum PRL levels remained unchanged in the control group. This treatment effect was observed not only in women with elevated baseline values, but also in patients with pretreatment PRL levels within the so-called reference range, indicating that the individual reference range is much less wide. Furthermore,
FIG. 1. Changes in serum concentrations of basal prolactin in women with subclinical hypothyroidism treated with levothyroxine or placebo. A: all women (n 5 63). B: Premenopausal women/postmenopausal women with estrogen replacement therapy (n 5 36). Values are expressed as mean (6 standard error of the mean [SEM]) percentage of baseline value. p values are calculated for the treatment effect after 24 and 48 weeks, respectively.
women on estrogen replacement therapy differed between the two groups (LT4, n 5 17; placebo, n 5 19) (Figs. 1 and 2). Discussion In this randomized placebo-controlled study of women with subclinical hypothyroidism, physiologic LT4 treatment reduced basal and stimulated PRL concentrations after 24 and 48 weeks of replacement therapy. The PRL-lowering effect was most pronounced in premenopausal women and women with TSH levels greater than 11 mIU/L at baseline. Hyperprolactinemia of variable magnitude has been reported in both, overt and subclinical hypothyroidism (1,5,6,16,18,23,24). The prevalence of hyperprolactinemia in overt hypothyroidism in women is reported as 39% to 57% (1,10). According to several case-control studies, normalization of serum PRL levels has been observed after LT4 replacement of patients with overt thyroid failure (2,4,25,26). In contrast, no data are available on the prevalence of hy-
FIG. 2. Changes in serum concentrations of peak prolactin after thyrotropin-releasing hormone (TRH) in women with subclinical hypothyroidism treated with levothyroxine or placebo. A: All women (n 5 63). B: Premenopausal women/ postmenopausal women with estrogen replacement therapy (n 5 36). Values are expressed as mean (6 standard error of the mean [SEM]) percentage of baseline value. p values are calculated for the treatment effect after 24 and 48 weeks, respectively.
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FIG. 3. Effect of levothyroxine treatments on serum prolactin in relation to median thyrotropin (TSH) levels at baseline. Free thyroxine (FT4) and (T3) levels were comparable in both TSH groups (p 5 ns). Data are given as mean (6 standard error of the mean).
peak PRL levels after TRH stimulation were significantly reduced in LT4-treated women confirming earlier reports (18,19,27). Supporting the concept that hypothyroidism is a graded phenomenon, patients with markedly elevated TSH levels at baseline were most likely to benefit from LT4 treatment. Significant reduction of PRL levels could be observed in women with TSH levels higher than 11.4 mIU/L, whereas patients with lower values showed no beneficial effect. Of special interest is the observation that basal and stimulated PRL levels decreased significantly only in premenopausal women. As this women may present with menstrual irregularities or occasionally infertility, thyroid hormone replacement could be advocated in these patients. However, as in accordance with a recently published study (13) none of our premenopausal women reported menstrual irregularities, further work is needed to investigate if hyperprolactinemia is only the result of stimulated pituitary regulatory feedback mechanism or if it has a clinical consequence, also. The mechanism by which hypothyroidism causes hyperprolactinemia is not completely understood. It is well known that TRH is a physiologic mediator of both PRL and TSH release, and thus, elevated hypothalamic TRH levels increase PRL secretion in hypothyroid patients. However, PRL levels in hypothyroid males have been shown to be normal in mag-
nitude, pulsatility and circadian pattern (28), suggesting that hypothyroidism per se is not sufficient to cause hyperprolactinemia. Rather another stimulus, such as estrogen, is required. Estrogens are known to increase the PRL response to TRH (29,30) with the effect that TRH-induced PRL response in hypothyroidism in women is greater than in men (31–33). This indicates that the presence of estrogens augments the TRH-induced PRL release in hypothyroidism. Accordingly, we found significantly higher PRL levels in premenopausal women or women with estrogen replacement therapy compared to postmenopausal women without estrogen replacement therapy. Sixty-seven percent of the women with PRL levels higher than the upper reference limit, had estrogen levels in the premenopausal range. In our study population of women with SCH no menstrual disturbances have been reported. In infertile women, the reported incidence of subclinical hypothyroidism is comparable to what is expected in the younger female population (12). However, as subclinical hypothyroidism may progress to overt disease, and, as ovulatory dysfunction with reversible menstrual disturbances has been reported in hypothyroid women (9,10,34), screening for thyroid dysfunction in women presenting ovulatory dysfunction with infertility has been advocated (12,14). In conclusion, we demonstrate that SCH has negative ef-
984 fects on PRL regulation with altered basal and stimulated PRL levels, especially in premenopausal women. Using a randomized double-blinded placebo-controlled study we show that physiologic, TSH-guided LT4 treatment restores this hyperprolactinemic state. Further studies are needed to elucidate the clinical impact of hyperprolactinemia in subclinical hypothyroidism. Acknowledgments We thank Prof. Christian De Geyter for critical review of the manuscript. Supported by grants from the Swiss National Science Foundation (32.27866.89, 32.37792.93, and 32.37792.98) and unconditional research grants from Henning Berlin, Sandoz Research, and Roche Research Foundations, Nora van Meeuwen-Häfliger, and the “Sonderprogramm zur Förderung des akademischen Nachwuchses der Universität Basel” (to B.M.) References 1. Honbo KS, van Herle AJ, Kellett KA 1978 Serum prolactin levels in untreated primary hypothyroidism. Am J Med 64:782–787. 2. Onishi T, Miyai K, Aono T, Shioji T, Yamamoto T 1977 Primary hypothyroidism and galactorrhea. Am J Med 63:373– 378. 3. Fish LH, Mariash CN 1988 Hyperprolactinemia, infertility, and hypothyroidism. A case report and literature review. Arch Intern Med 148:709–711. 4. Grubb MR, Chakeres D, Malarkey WB 1987 Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 83:765–769. 5. Semple CG, Beastall GH, Teasdale G, Thomson JA 1983 Hypothyroidism presenting with hyperprolactinaemia. Br Med J (Clin Res Ed) 286:1200–1201. 6. Staub JJ, Althaus BU, Engler H, Ryff AS, Trabucco P, Marquardt K, Burckhardt D, Girard J, Weintraub BD 1992 Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 92:631–642. 7. del Pozo E, Wyss H, Tollis G, Alcaniz J, Campana A, Naftolin F 1979 Prolactin and deficient luteal function. Obstet Gynecol 53:282–286. 8. Louvet JP, Gouarre M, Salandini AM, Boulard C 1979 Hypothyroidism and anovulation. Lancet 1:1032. 9. Edwards CR, Forsyth IA, Besser GM 1971 Amenorrhoea, galactorrhoea, and primary hypothyroidism with high circulating levels of prolactin. BMJ 3:462–464. 10. Thomas R, Reid RL 1987 Thyroid disease and reproductive dysfunction: A review. Obstet Gynecol 70:789–798. 11. Krassas GE, Pontikides N, Kaltsas T, Papadopoulou P, Paunkovic J, Paunkovic N, Duntas LH 1999 Disturbances of menstruation in hypothyroidism. Clin Endocrinol (Oxf) 50:655–659. 12. Lincoln SR, Ke RW, Kutteh WH 1999 Screening for hypothyroidism in infertile women. J Reprod Med 44:455–457. 13. Raber W, Gessl A, Nowotny P, Vierhapper H 2003 Hyperprolactinaemia in hypothyroidism: Clinical significance and impact of TSH normalization. Clin Endocrinol (Oxf) 58:185–191. 14. Cooper DS 2001 Clinical practice. Subclinical hypothyroidism. N Engl J Med 345:260–265.
MEIER ET AL. 15. Bigos ST, Ridgway EC, Kourides IA, Maloof F 1978 Spectrum of pituitary alterations with mild and severe thyroid impairment. J Clin Endocrinol Metab 46:317–325. 16. Olive KE, Hennessey JV 1988 Marked hyperprolactinemia in subclinical hypothyroidism. Arch Intern Med 148:2278– 2279. 17. Bals-Pratsch M, De Geyter C, Muller T, Frieling U, Lerchl A, Pirke KM, Hanker JP, Becker-Carus C, Nieschlag E 1997 Episodic variations of prolactin, thyroid-stimulating hormone, luteinizing hormone, melatonin and cortisol in infertile women with subclinical hypothyroidism. Hum Reprod 12:896–904. 18. Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH 1973 Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone. J Clin Invest 52:2324–2329. 19. Refetoff S, Fang VS, Rapoport B, Friesen HG 1974 Interrelationships in the regulation of TSH and prolactin secretion in man: Effects of L-dopa, TRH and thyroid hormone in various combinations. J Clin Endocrinol Metab 38:450–457. 20. Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, Drewe J, Huber P, Herzog R, Muller B 2001 TSHcontrolled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: A double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab 86:4860–4866. 21. Schurr W, Knoll B, Ziegler R, Anders R, Merkle HP 1985 Comparative study of intravenous, nasal, oral and buccal TRH administration among healthy subjects. J Endocrinol Invest 8:41–44. 22. Ryff-de-Leche AS, Staub JJ, Paul S, Polc B, Girard J 1985 [Intranasal TRH for the stimulation of hypophyseal and thyroid reserves. Preliminary report]. Schweiz Med Wochenschr 115:342–343. 23. Jacobs LS, Snyder PJ, Wilber JF, Utiger RD, Daughaday WH 1971 Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J Clin Endocrinol Metab 33:996–998. 24. Takai T, Yamamoto K, Saito K, Ando K, Saito T, Kuzuya T 1987 Galactorrhea in subclinical hypothyroidism. Endocrinol Jpn 34:539–544. 25. Groff TR, Shulkin BL, Utiger RD, Talbert LM 1984 Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargement as presenting features of primary hypothyroidism. Obstet Gynecol 63:86S-89S. 26. Boroditsky RS, Faiman C 1973 Galactorrhea-amenorrhea due to primary hypothyroidism. Am J Obstet Gynecol 116: 661–665. 27. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC 1984 L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med 101:18–24. 28. Iranmanesh A, Lizarralde G, Veldhuis JD 1992 Robustness of the male lactotropic axis to the hyperprolactinemic stimulus of primary thyroidal failure. J Clin Endocrinol Metab 74:559–564. 29. Carlson HE, Jacobs LS, Daughaday WH 1973 Growth hormone, thyrotropin, and prolactin responses to thyrotropinreleasing hormone following diethylstilbestrol pretreatment. J Clin Endocrinol Metab 37:488–490. 30. Katznelson L, Riskind PN, Saxe VC, Klibanski A 1998 Prolactin pulsatile characteristics in postmenopausal women. J Clin Endocrinol Metab 83:761–764. 31. Bowers CY, Friesen HG, Hwang P, Guyda HJ, Folkers K 1971 Prolactin and thyrotropin release in man by synthetic
PROLACTIN IN SUBCLINICAL HYPOTHYROIDISM pyroglutamyl-histidyl-prolinamide. Biochem Biophys Res Commun 45:1033–1041. 32. Noel GL, Suh HK, Frantz AG 1974 Prolactin release during nursing and breast stimulation in postpartum and nonpostpartum subjects. J Clin Endocrinol Metab 38:413–423. 33. Jacobs LS, Snyder PJ, Utiger RD, Daughaday WH 1973 Prolactin response to thyrotropin releasing hormone in normal subjects. J Clin Endocrinol Metab 36:1069–1073. 34. Krassas GE 2000 Thyroid disease and female reproduction. Fertil Steril 74:1063–1070.
985 Address reprint requests to: Dr. C. Meier Division of Endocrinology Department of Internal Medicine University Hospitals Petersgraben 4 CH-4031 Basel Switzerland E-mail:
[email protected]
