Effect of hypothyroidism on pituitary cytoplasmic concentrations of messenger RNA encoding thyrotrophin beta and alpha subunits, prolactin and growth hormone

Thyroid hormones may directly regulate gene expression in the anterior pituitary. In order to examine this possibility we have studied the effect of hypothyroidism in the rat on pituitary cytoplasmic concentrations of messenger RNA (mRNA) encoding thyrotrophin (TSH) beta and alpha subunits, prolactin and GH. We demonstrated a marked increase in TSH beta and alpha subunit mRNA, accompanied by a decrease in GH mRNA, in the hypothyroid state, changes largely reversed by thyroid hormone replacement. We have thus shown a direct influence of thyroid status on the pretranslational events occurring in pituitary hormone synthesis. The simultaneous rise in cytoplasmic TSH beta and alpha mRNA levels and fall in GH mRNA in hypothyroidism suggests that thyroid status exerts a differential effect on the expression of these genes.     

AMIODARONE AND THYROID HORMONE EFFECTS ON ANTERIOR PITUITARY HORMONE GENE EXPRESSION

Amiodarone therapy results in marked changes in circulating thyroid hormone and TSH concentrations in man. In the present study we have demonstrated that amiodarone treatment of the rat increases serum TSH and pituitary cytoplasmic concentrations of TSH beta and alpha subunit messenger RNAs (mRNAs) and reduces PRL mRNA as measured by cytoplasmic dot hybridization with specific complementary (c) DNA probes. The fall in circulating TSH and TSH mRNA resulting from thyroid hormone treatment was less marked in animals receiving amiodarone in addition to T3 and T4. In contrast, in the hypothyroid state, increases in serum TSH, TSH beta and alpha mRNA, and reductions in PRL and GH mRNA were less marked in rats treated with amiodarone. In studies of rat anterior pituitary cells in primary monolayer culture we demonstrated a direct effect of amiodarone on PRL gene expression which was antagonized by T3. Changes in circulating thyroid hormone concentrations and deiodination of T4 and T3 induced by amiodarone in vivo may be important in the regulation of pituitary hormone gene expression but we have, in addition, shown a direct interaction between amiodarone and T3 effects on the anterior pituitary cell.     

The effect of altered thyroid status on pituitary hormone messenger ribonucleic acid concentrations in the rat

To study the effects of altered thyroid status on pretranslational control of pituitary hormones, adult male rats were given propylthiouracil for 6 weeks and underwent the following studies. 1) Rats were injected with T3 at 10 micrograms/100 g BW daily for 10 days. 2) Rats were given T3 injections at 0, 0.01, 0.1, 1.0, or 10 micrograms/100 g BW for 10 days. 3) Rats were killed 0, 1, 6, or 24 h after a single injection of T3 at 10 micrograms/100 g BW or after 5 or 10 days of daily T3 injections. Pituitary mRNA concentrations of TSH beta, alpha-subunit, PRL, GH, POMC, FSH beta, and LH beta were determined for individual animals. Marked increases in TSH beta and alpha-subunit mRNAs occurred after PTU treatment, and these changes were reversed by 1.0 microgram/100 g BW T3 and within 24 h of a single T3 injection of 10 micrograms/100 g BW. Further increases in the dose or time course of T3 administration led to a relatively greater suppression of TSH beta mRNA levels than alpha-subunit mRNA levels. In contrast, GH and PRL mRNA levels were low in hypothyroid animals, and both rose toward control levels with 0.1 microgram/100 g BW T3 and by 24 h after a single T3 dose. Induction of hyperthyroidism did not further increase GH mRNA levels above control, but increased PRL mRNA levels 2-fold over control. No changes were seen in FSH beta, LH beta, or POMC mRNA levels with any treatment. Thus, studies of altered thyroid status in the rat reveal dose-response and time-course variability in the pretranslational control of TSH beta, alpha-subunit, GH, and PRL by thyroid hormone.     

Modulation by oestrogen of thyroid hormone effects on thyrotrophin gene expression

The role of oestrogen in the regulation of TSH gene expression is unclear. We have examined the effect of administration of oestrogen in the rat on serum TSH, pituitary TSH content and pituitary cytoplasmic concentrations of mRNA encoding the TSH beta and alpha subunits, thus deriving measures of hormone release and synthesis. In addition, we have examined the effect of oestrogen on the binding of tri-iodothyronine (T3) to nuclear receptors in the anterior pituitary. Administration of oestrogen did not affect serum concentrations of TSH in euthyroid or untreated hypothyroid rats, but did augment the effects of T3 (1 and 2 micrograms) on serum TSH in hypothyroid animals 6 h after injection of T3. No influence of oestrogen or of thyroid status on pituitary content of TSH was seen. A marked increase in the concentrations of TSH beta and alpha mRNA in pituitary cytoplasm was found in hypothyroidism, compared with those in the euthyroid state. No effect of oestrogen on TSH mRNA was seen in euthyroid animals but concentrations of TSH beta and alpha mRNA were lower in hypothyroid animals than in vehicle-treated controls. A stimulatory influence of T3 on TSH mRNA was seen 6 h after injection of T3; this stimulation was absent in oestrogen-treated rats. No effect of oestrogen on the action of T3 was evident 72 h after beginning treatment with T3. In addition to effects on serum TSH and TSH mRNA, an increase in the number of pituitary nuclear receptors for T3 was seen after oestrogen treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of thyroid hormones on growth hormone gene expression in vivo in rats

Thyroid hormones are important regulators of GH synthesis and secretion. In this study we have made a detailed examination of the time-course of the effects of hypothyroidism and tri-iodothyronine (T3) replacement in the intact rat on GH gene expression in the anterior pituitary gland. Changes in pituitary cytoplasmic GH messenger (m)RNA levels were compared with total pituitary GH content and serum GH concentration during the development of hypothyroidism and following short-term T3 replacement in vivo. Hypothyroidism was associated with a fall in pituitary GH mRNA levels. Treatment of hypothyroid animals with T3 rapidly stimulated GH mRNA levels to values above those seen in euthyroid controls. The reduction in GH mRNA levels seen during the development of hypothyroidism was accompanied by a fall in serum GH and pituitary GH content, both of which were partially restored by T3 replacement. Thus thyroid hormone replacement in hypothyroidism rapidly stimulates GH mRNA synthesis, which is followed by the gradual restoration of pituitary GH stores and serum GH concentration.     

Induction of hypothyroidism and hypoprolactinemia by growth hormone producing rat pituitary tumors.

The GH3 rat pituitary tumor cell line which secretes both growth hormone (GH) and prolactin (PRL) stopped releasing PRL when transplanted to animals; furthermore, it suppressed PRL production by the hosts' pituitary glands. When the same tumor was transferred back to cell culture, PRL production resumed. The PRL to GH ratio in cell culture medium and cells ranged from 5 to 1 while in the tumor and serum of the host animals it averaged 0.09 and 0.001, respectively. To investigate further this phenomenon, female rats were transplanted with GH3 tumors (T) and compared to intact normal (N) and to thyroidectomized (Tx) rats. T animals were larger and had splanchnomegaly but smaller pituitaries and thyroids. Serum PRL concentrations in the basal state were decreased, as were levels of triiodothyronine (T3), thyroxine (T4), and free T4 index. Despite reduced serum thyroid hormone concentrations, and in contrast to Tx animals, the serum thyrotropin (TSH) level in T rats was not elevated and they did not show a supranormal TSH response to thyrotropin-releasing hormone (TRH) administration. The PRL response to TRH in T animals was completely abolished while all N and Tx animals responded by a significant increase in serum PRL. Serum corticosteroids and estrogens were normal in T rats. Pituitary content of PRL was decreased and that of TSH increased in T rats. Tx animals, however, had a reduced pituitary content of PRL, TSH, and GH. When GH3 cells were grown in cell culture media containing serum from T animals, there was a reduction of PRL content in cells and released in the medium. Addition of T3 to the T serum did not alter its suppressive effect on PRL nor did rat GH added to N serum alter PRL production and release in vitro. In a preliminary experiment, rats injected ip with 50 mug hGH in two divided doses for eighteen days, suppressed serum T4 and T3 concentrations; pituitary content of TSH was significantly increased and that of PRL slightly decreased. Injection with 250 mug oPRL or saline, on the same schedule and for the same length of time, had no significant effect on the levels of serum thyroid hormones. Thus, GH, but also possibly other substance(s) secreted by GH3 tumors in vivo a) suppress the production of tumor and pituitary PRL; b) suppress the release of TSH, causing mild hypothyroidism; c) inhibit the PRL and TSH responses to TRH; and d) decrease the production of PRL in tissue culture. Although no simple and unifying theory could explain these findings, an hypothesis implicating somatomedin is presented.     

Thyrotropin-releasing hormone stimulates growth hormone release from the anterior pituitary of hypothyroid rats in vitro

We have examined the interaction of thyroid hormone and TRH on GH release from rat pituitary monolayer cultures and perifused rat pituitary fragments. TRH (10(-9) and 10(-8)M) consistently stimulated the release of TSH and PRL, but not GH, in pituitary cell cultures of euthyroid male rats. Basal and TRH-stimulated TSH secretion were significantly increased in cells from thyroidectomized rats cultured in medium supplemented with hypothyroid serum, and a dose-related stimulation of GH release by 10(-9)-10(-8) M TRH was observed. The minimum duration of hypothyroidism required to demonstrate the onset of this GH stimulatory effect of TRH was 4 weeks, a period significantly longer than that required to cause intracellular GH depletion, decreased basal secretion of GH, elevated serum TSH, or increased basal secretion of TSH by cultured cells. In vivo T4 replacement of hypothyroid rats (20 micrograms/kg, ip, daily for 4 days) restored serum TSH, intracellular GH, and basal secretion of GH and TSH to normal levels, but suppressed only slightly the stimulatory effect of TRH on GH release. The GH response to TRH was maintained for up to 10 days of T4 replacement. In vitro addition of T3 (10(-6) M) during the 4-day primary culture period significantly stimulated basal GH release, but did not affect the GH response to TRH. A GH stimulatory effect of TRH was also demonstrated in cultured adenohypophyseal cells from rats rendered hypothyroid by oral administration of methimazole for 6 weeks. TRH stimulated GH secretion in perifused [3H]leucine-prelabeled anterior pituitary fragments from euthyroid rats. A 15-min pulse of 10(-8) M TRH stimulated the release of both immunoprecipitable [3H]rat GH and [3H]rat PRL. The GH release response was markedly enhanced in pituitary fragments from hypothyroid rats, and this enhanced response was significantly suppressed by T4 replacement for 4 days. The PRL response to TRH was enhanced to a lesser extent by thyroidectomy and was not affected by T4 replacement. These data suggest the existence of TRH receptors on somatotrophs which are suppressed by normal amounts of thyroid hormones and may provide an explanation for the TRH-stimulated GH secretion observed clinically in primary hypothyroidism.     

Hypothyroidism increases substance P concentrations in the heterotopic anterior pituitary

The regulatory effects of thyroid hormone on adenohypophysial substance P (SP) were studied in heterotopically implanted anterior pituitaries. Three or four anterior pituitaries from 21-day-old rat pups were implanted under the renal capsule in 175- to 200-g adult rats. The donor and recipient animals were sex matched. One week after implantation, animals were thyroidectomized or sham operated. A separate group of animals received daily T4 treatment (1.5 g/100 g, ip). After 2 weeks, the native and heterotopic pituitaries were assayed for SP, TSH, PRL, and LH. Thyroidectomy resulted in a 3- to 10-fold increase in the SP concentration in both the heterotopic and native pituitaries compared to euthyroid values. T4 treatment suppressed the SP levels in the heterotopic pituitaries of the thyroidectomized rats. In contrast to the reduction of TSH concentrations in native pituitaries in thyroidectomized animals vs. controls, TSH concentrations in the heterotopic pituitaries of thyroidectomized rats were approximately 10 times greater than those in euthyroid animals. PRL concentrations were unaffected by hypothyroidism in native and heterotopic pituitaries. Thyroidectomy resulted in a decrease in LH concentrations in the native anterior pituitary, without affecting LH concentrations in the implanted pituitary. These findings indicate that a direct link from the hypothalamus to the anterior pituitary is not required for the pituitary SP response to hypothyroidism.     

Expression of the Xenopus laevis prolactin and thyrotropin genes during metamorphosis.

The cDNAs encoding Xenopus laevis prolactin (PRL) and the alpha and beta subunits of thyroid-stimulating hormone (TSH alpha and TSH beta, respectively) have been cloned from a pituitary library. Results of developmental RNA blot analysis contradict the long-held biological role for PRL as a juvenilizing hormone in amphibia. The pituitary gland of a premetamorphic tadpole expresses PRL mRNA at very low levels. The abundance of PRL mRNA increases late in metamorphosis as a response to thyroid hormone (TH), suggesting that PRL is more likely to have a function in the frog than in the tadpole. TSH alpha and -beta mRNA levels increase through prometamorphosis; this rise does not appear to be regulated directly by TH. At climax, both TH and TSH mRNA levels drop. The sequential morphological changes that characterize prometamorphosis depend upon the gradual increase of endogenous TH, which peaks at climax. This increase in TH in turn depends upon the lack of a traditional thyroid-pituitary negative-feedback loop throughout prometamorphosis.     

The paraventricular nucleus of the hypothalamus has a major role in thyroid hormone feedback regulation of thyrotropin synthesis and secretion

The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.     

The influence of dexamethasone on serum thyrotrophin and thyrotrophin synthesis in the rat

Glucocorticoid hormones suppress circulating concentrations of thyrotrophin (TSH), but their effect on synthesis of TSH in the pituitary gland is unclear. We have examined the influence of the glucocorticoid dexamethasone on serum TSH, pituitary TSH content and TSH beta- and alpha-subunit mRNA concentrations in pituitary cytoplasm in both the euthyroid and hypothyroid rat, and following triiodothyronine (T3) treatment in the hypothyroid rat. The rise in serum TSH in hypothyroidism was attenuated in animals treated with dexamethasone; in addition the suppression of serum TSH 6 h after T3 administration to hypothyroid rats was enhanced by dexamethasone. In contrast to the changes in serum TSH, pituitary TSH content was unaffected by dexamethasone. Furthermore dexamethasone had no significant effect on changes in pituitary cytoplasmic TSH beta- and alpha-subunit mRNA levels with thyroid status. These findings demonstrate that dexamethasone exerts differential effects on serum TSH levels and TSH biosynthesis which contrast with those of thyroid hormones.     

PERSISTENT TRH-INDUCED GROWTH HORMONE RELEASE AFTER SHORT-TERM AND LONG-TERM L-THYROXINE REPLACEMENT THERAPY IN PRIMARY CONGENITAL HYPOTHYROIDISM

No appreciable changes in plasma GH levels after TRH stimulation have been observed in normal subjects, whereas acute GH release has been reported in primary hypothyroidism and other pathophysiological states. To evaluate the effect of the T4 replacement therapy on TRH-induced GH release, 28 patient volunteers with primary congenital hypothyroidism (PCH), were studied before (11 subjects), after 1 month (nine subjects) and after long-term T4 replacement therapy (eight subjects). All patients underwent a TRH test with measurement of TSH, PRL and GH levels, and were compared to 28 age-matched normal subjects. An increase of plasma GH after TRH was found in 46% of patients without any therapy, in 67% of patients after one month of T4 administration and in 75% of patients after long-term therapy. No changes were observed in plasma GH levels in controls. The TSH response to TRH was inhibited and the response of PRL was reduced step by step by T4 replacement therapy in our patients with PCH. Our results suggest that: (i) Replacement T4 therapy in PCH does not abolish the paradoxical GH response to TRH, in spite of inhibiting the TSH response and reducing the exaggerated PRL response; (ii) the GH response to TRH in PCH seems to be unrelated to low thyroid hormone levels and/or to high TSH levels, but it could be due to changes in hypothalamic-pituitary regulation which are not improved by T4 replacement therapy.     

EFFECTS OF PROTRACTED HYPOTHYROIDISM ON PITUITARY FUNCTION AND STRUCTURE IN ENDEMIC CRETINISM

Pituitary function and structure were assessed in 69 endemic cretins from western China. In hypothyroid cretins (TSH greater than 10 mIU/l), CT imaging of the pituitary revealed adenoma in five of 20 (25%) and partially empty sella (PES) in a further eight of 20 (40%). The majority of tumours were microadenomas and showed a relation with higher levels of serum TSH but not with duration of hypothyroidism. Dynamic pituitary testing with TRH and GnRH in four patients with adenoma on CT gave a flat TSH response but significant rises in serum PRL, GH, LH and FSH concentrations. Hyperprolactinaemia (greater than 350 mIU/l) was present in hypothyroid cretins only (13 of 26; 50%) and serum PRL showed a curvilinear relation with serum TSH levels (r = 0.7, P less than 0.0001). Hypogonadism was seen in approximately half the cretins with high PRL levels. Our data suggest that severe protracted thyroid hormone deficiency may result in thyrotrophin adenomas of the pituitary gland. Disturbances of growth, puberty, and sexual function in endemic cretins are explained by the secondary effects of thyroid hormone deficiency on pituitary function.     

Metabolic interfaces between growth and reproduction. II. Characterization of changes in messenger ribonucleic acid concentrations of gonadotropin subunits, growth hormone, and prolactin in nutritionally growth-limited lambs and the differential effects of increased nutrition

Previous studies show that limited nutrition in the ovariectomized lamb results in an impairment of LH and FSH secretion, a phenomenon that is rapidly reversible by increasing the level of nutrition and independent of ovarian steroid feedback. The present study characterizes the biosynthesis of pituitary hormones in the nutritionally growth-limited female lamb by measuring steady state mRNA concentrations. These changes were examined relatively to pituitary and serum hormone concentrations to establish the relationship(s) of synthesis and secretion in response to nutritional manipulation. Ad libitum feeding of nutritionally growth-restricted ovariectomized lambs for 14 days resulted in an increase in the frequency of episodic LH release, thereby increasing mean serum LH concentrations (P less than 0.001). Similarly, mean circulating concentrations of FSH were increased (P less than 0.001). By contrast, serum GH concentrations were lowered significantly as a result of ad libitum feeding (P less than 0.05). Serum PRL concentrations remained unchanged. Although pituitary LH and PRL concentrations were also unchanged in response to increased nutrition feeding, FSH and GH concentrations increased (P less than 0.05). Short-term ad libitum feeding of the chronically food-restricted lamb resulted in significant changes in mRNA concentrations for all hormones except PRL. The concentrations of gonadotropin subunit mRNAs (i.e. alpha, LH beta, and FSH beta) were all significantly higher in response to increased nutrition (P less than 0.001). GH mRNA was also affected; however, feeding decreased concentrations (P less than 0.001). The results demonstrate that an increase in the level of nutrition in the restricted diet lamb produces profound changes in the synthesis, storage, and secretion of LH, FSH, and GH. These changes appear to be coordinated, although the response differs depending upon the hormone.     

THYROTROPHIN, PROLACTIN AND GROWTH HORMONE RESPONSES TO TRH IN BARBITURATE COMA AND IN DEPRESSION

The effects of 200 microgram thyrotrophin-releasing hormone (TRH) i.v. on thyrotrophin (TSH), prolactin (PRL), growth hormone (GH) and triiodothyronine (T3) were studied in eight patients with barbiturate coma due to attempted suicide, in the same patients after recovery, in eight depressive patients and in eight normal controls. The patients with barbiturate coma presented normal basal TSH and PRL, elevated basal GH and normal PRL but blunted TSH responses to TRH; their GH concentrations varied widely without consistent relation to TRH administration. The same patients after recovery from coma presented normal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a clear-cut rise in GH (i.e. more than 10 ng/ml) occurred after TRH administration. The depressive patients presented normal basal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a moderated rise in GH (less than 10 ng/ml) occurred after TRH administration. The increment in T3 concentrations 120 min after TRH was found reduced in the comatose patients only. Basal cortisol was measured in all the subjects and found elevated in the comatose patients only. It is concluded that the abnormal TSH and GH responses to TRH observed in patients with barbiturate coma are more likely related to depressive illness than to an effect of barbiturates at the pituitary level. Barbiturates might affect thyroid secretion.     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

Measurement of messenger ribonucleic acid for luteinizing hormone beta-subunit, alpha-subunit, growth hormone, and prolactin after hypothalamic pituitary disconnection in ovariectomized ewes

A transnasal, transsphenoidal surgical approach was used to perform hypothalamic pituitary disconnections (HPD) in ovariectomized (OVX) ewes to examine the role of the hypothalamus in regulating the synthesis of anterior pituitary hormones. Ewes were killed at 1-3 days (n = 6), 1 week (n = 5), or 1 month (n = 5) after HPD. Pituitary glands were removed, and hemisected for analysis of hormone or messenger RNA (mRNA) content. Blot hybridization using specific complementary DNA probes was used to quantify the concentration of mRNA for LH beta-subunit, alpha-subunit, GH, and PRL. Concentrations of mRNA for LH beta- and alpha-subunits were lower (P less than 0.01) at 1-3 days after HPD than in OVX ewes. At 1 week and 1 month after HPD, concentrations of mRNA for LH beta- and alpha-subunits were near the lower limit of detection of this assay system. In contrast, for 30 days after HPD, pituitary concentrations of mRNA for GH and PRL were not different (P greater than 0.05) from those in OVX ewes. At 1 week and 1 month after HPD, pituitary content of LH, FSH, and GH was lower (P less than 0.01) than in OXV ewes. Pituitary PRL content in all HPD ewes was lower (P less than 0.05) than in OVX ewes. In a separate group of five ewes that were bled daily for 30 days after HPD, serum concentrations of LH and FSH fell dramatically during the first 3 days after HPD. In contrast, serum concentrations of GH and PRL remained similar to pre-HPD concentrations for 30 days after HPD. Thus, hypothalamic stimulation is essential for maintaining the concentration of mRNA for LH beta- and alpha-subunits within the anterior pituitary gland. Without continued hypothalamic support, pituitary and serum concentrations of LH and FSH rapidly decline. In contrast, concentrations of mRNA for GH and PRL are maintained in the absence of hypothalamic input.     

The interaction between growth hormone and the thyroid axis in hypopituitary patients

Alterations in the hypothalamo‐pituitary‐thyroid axis have been reported following growth hormone (GH) administration in both adults and children with and without growth hormone deficiency. Reductions in serum free thyroxine (T4), increased tri‐iodothyronine (T3) with or without a reduction in serum thyroid‐stimulating hormone secretion have been reported following GH replacement, but there are wide inconsistencies in the literature about these perturbations. The clinical significance of these changes in thyroid function remains uncertain. Some authors report the changes are transient and revert to normal after a few months or longer. However, in adult hypopituitary patients, GH replacement has been reported to unmask central hypothyroidism biochemically in 36–47% of apparently euthyroid patients, necessitating thyroxine replacement and resulting in an attenuation of the benefit of GH replacement on quality of life in those who became biochemically hypothyroid after GH replacement. The group at highest risk are those with organic pituitary disease or multiple pituitary hormone deficiencies. It is therefore prudent to monitor thyroid function in hypopituitary patients starting GH therapy to identify those who will develop clinical and biochemical features of central hypothyroidism, thus facilitating optimal and timely replacement.