Reduced gonadotropin secretion in postmenopausal women during treatment with a stimulatory LRH analogue.

The potent and long-acting LRH agonist D-Ser(TBU)6-EA10-LRH was administered in a daily subcutaneous dose of 5 microgram to 5 postmenopausal women for a period of 10 days. The LRH analogue produced a significant decrease in both the basal FSH and LH levels and the gonadotropin responses to the agonist. The estrogen levels in serum remained unchanged during the study period. The results suggest that D-Ser(TBU)6-EA10-LRH has a direct inhibitory effect at the pituitary level.     

Serum concentrations of gonadotrophins in hypergonadotrophic patients following stimulation by a long-acting analogue of luteinizing hormone-releasing hormone

The effect of D-Ser(TBU)6-EA10-LRH, a long-acting analogue of luteinizing hormone-releasing hormone (LRH), was studied in patients with hypergonadotrophism due to orchidectomy (n = 8) or due to Klinefelter's syndrome (n = 6). Patients orchidectomized less than 7 days prior to the administration of the compound presented with maximum concentrations of LH (63.8 +/- 29.9 mIU/ml) within 60 min following iv injection of the LRH-analogue (10 micrograms). This behaviour of LH was qualitatively similar to that seen in healthy men. In patients orchidectomized more than 40 days prior to the administration of the LRH-analogue and in patients with Klinefelter's syndrome the occurrence of maximum serum LH-concentrations (115.0 +/- 39.4 and 149.4 +/- 134.5 mIU/ml, respectively) was delayed up to 240-360 min following iv LRH-analogue. This pattern of LH secretion is similar to that of healthy women. No qualitative differences in stimulated FSH-concentrations were observed between the described groups of hypergonadotrophic patients. These findings demonstrate a time-dependent increase in the 'second pool' of LH following orchidectomy. The similar behaviour of stimulated LH-release in healthy women and in male patients with long-term hypergonadotrophic hypogonadism could indicate an augmented production of endogenous LRH in these individuals as compared to healthy men, providing an explanation for the sexually related differences in the LH-response upon the administration of the LRH-analogue.     

CONTRACEPTION WITH AN LHRH AGONIST: EFFECT ON GONADOTROPHIN AND STEROID SECRETION PATTERNS

Chronic treatment with the LHRH agonist D-Ser(TBU)6-LHRH (1-9)-EA (buserelin) has been suggested as a contraceptive method since it has been shown to inhibit ovulation. To elucidate the mechanism of this paradoxical action, we investigated the pattern of gonadotrophin and steroid secretion after the daily intranasal application of 300 micrograms of the agonist. Ten volunteers with ovulatory cycles received the analogue from Day 1 to Day 22 and 5 mg norethisterone acetate from Day 16 to Day 22. Blood samples were taken on Day 1, 15, and 21 every 15 min for 6 h after the application of the agonist. LH secretion was increased nine-fold on the first treatment day as compared to Day 2 of the preceding control cycle. Thereafter, it decreased slowly but was still elevated five-fold on Day 21 of treatment. FSH release increased three-fold on Day 1 but decreased thereafter to values similar to those of the controls. During treatment with the analogue, the LH/FSH ratio changed from 1.3 (controls) to 3.8 on Day 1 and to 5.5 on Day 15 and 21 of treatment. Although the ovary retained follicular activity, ovulation was inhibited in every treatment cycle. This seemed to be due to an impairment of follicular steroid synthesis as indicated by a significant increase of 17 alpha-hydroxyprogesterone and testosterone levels for several hours after the application of the analogue. It appears that at least during the first treatment cycle of daily administration of buserelin the abolishment of pulsatile gonadotrophin release, and the abnormally increased ratio of LH/FSH secretion may possibly impair follicular maturation and thus contribute to the inhibition of ovulation.     

The effect of D-Trp6-LRH upon secretion of gonadotrophin--a possible therapeutic application in anorexia nervosa

The aim of this study was to evaluate the effect of the agonistic LRH analogue (D-Trp6-LRH) on LH, FSH and prolactin secretion, and its possible efficacy in female patients with anorexia nervosa. The study included 18 female patients with anorexia nervosa and 7 healthy women in the same age group. The patients with anorexia nervosa were divided into two groups of 9 women each. The first group consisted of patients in the weight loss phase of the disorder and the second of 9 women who had achieved normal body weight. Additionally, in 6 women with anorexia nervosa serum LH concentration was determined in response to native LRH before and 14 days after the treatment with D-Trp6-LRH. Serum LH, FSH, prolactin concentrations were determined before and 5, 10, 24 and 48 h after administration of D-Trp6-LRH in a dose of 5 micrograms. The serum LH response to D-Trp6-LRH in the second group did not differ from that of the control group. However, in women with anorexia nervosa in the weight loss phase, LH release in response to administration of the analogue was significantly lower. FSH release after LRH analogue administration in both groups of patients with anorexia nervosa did not differ from that in the control group. The increased LH secretion in response to native LRH after treatment indicates that D-Trp6-LRH in low doses did not inhibit pituitary responsiveness. A dose of 5 micrograms of D-Trp6-LRH was administered in a therapeutic regimen every 48 h from 1 to 3 months to 7 of 9 patients with anorexia nervosa who exhibited amenorrhoea in spite of normalization of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of renal transplantation on pituitary gonadal function.

Twelve adult male patients who had undergone successful renal transplantation were investigated. The gonadotropin responses to 100 microgram luteinizing hormone-releasing hormone (LRH) were studied, and basal serum testosterone and prolactin assayed. Significantly elevated mean basal levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were found, associated with a correspondingly excessive LH and FSH response to LRH. Mean basal serum testosterone levels in the posttransplant patients were significantly lower than in normal controls, while the mean basal prolactin levels were similar in the two groups. The results were not influenced by the varying degrees of renal function found in the posttransplant patients.     

男性慢性肝病患者下丘脑－垂体－性腺轴功能的研究

用放射免疫法检测６１例男性慢性肝病患者血清睾酮（Ｔ）、雌二醇（Ｅ２）、泌乳素（ＰＲＬ）、促黄体生成素（ＬＨ）和卵泡刺激素（ＦＳＨ）的浓度，并对部分病例进行促黄体生成素释放激素（ＬＲＨ）垂体兴奋试验和绒毛膜促性腺激素（ＨＣＧ）刺激试验。结果示，肝硬化基础血清Ｔ显著降低（Ｐ＜０．０１）；对ＬＲＨ垂体兴奋试验ＬＨ多数呈正常反应，部分呈延迟反应或低反应；而对ＨＣＧ刺激试验均呈正常反应。提示肝硬化患者有下丘脑－垂体－性腺轴功能障碍。     

Half-life of FSH and LH in the ferret

Anoestrous and oestrous ferrets were injected with luteinizing hormone-releasing hormone (LRH) or a long-acting analogue and subsequently hypophysectomized. Spayed ferrets were hypophysectomized without prior treatment with gonadotrophin releasing factor, and serial blood samples collected from all animals in order to follow the rate of decline in plasma gonadotrophin concentration. The half-life of LH in the spayed female (around 2 h) was much longer than that of the hormone released from the hypophysis of anoestrous females by LRH (25 min) or by the analogue (19 min). The half-life of FSH released by LRH or analogue in anoestrous females was approximately 65 min, while that discharged by the analogue in oestrous females was about 4 h. The fall in plasma FSH concentration in spayed females after hypophysectomy was too slow to allow calculation of a half-life.     

Effects of castration or testosterone implants upon pituitary function in hypogonadal mice bearing normal foetal preoptic area grafts

Grafts of normal mouse preoptic area (POA) tissue into the third ventricle of gonadotrophin-releasing hormone (GnRH)-deficient hypogonadal (hpg) mice resulted in an elevation of pituitary GnRH receptors, an increased synthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland, an elevation of gonadal LH receptors and in the stimulation of steroidogenesis and spermatogenesis in the testis. In normal mice both castration or the subcutaneous implantation of testosterone capsules for 10 days reduced GnRH receptors, pituitary LH and FSH content, and the latter treatment also caused a 50% reduction in testicular LH receptors. In hpg mice bearing POA grafts testosterone implants failed to affect any of the above parameters, and castration failed to affect pituitary gonadotrophin hormone content, although there was a slight reduction in pituitary GnRH receptors after castration. These experiments suggest that neither the pituitary gonadotroph, nor the GnRH neurone represent major sites for the direct negative feedback of testosterone upon gonadotrophic hormone secretion in male mice.     

Gonadotrophin release during chronic administration of D-ser (TBU)6 LH-RH-EA in functional amenorrhoea.

Six women with long-standing functional amenorrhoea were treated with 5 microgram of D-Ser (TBU)6 LH-RH-EA twice daily for 14 days. The functional states of the gonadostats, as assessed by a 25 microgram LH-RH test dose, varied widely before the treatment was started whereas at the end of it they were uniformly low. In all patients D-Ser (TBU)6 LH-RH-EA induced gonadotrophin release, the peak values occuring between day 1 and 3 of therapy. Despite further injections mean gonadotrophin levels declined rapidly therafter and remained in the basal range for the rest of the study. Release of oestradiol was very uncharacteristic. No consistent ovarian response pattern was observed during the analogue administration. It is obvious that chronic stimulation with D-Ser (TBU)6 LH-RH-EA leads to a decreased responsiveness of the pituitary gland.     

Effect of clomiphene citrate on the in vitro release of LH and FSH by the pituitary gland of the long-term ovariectomized rat pretreated with LRH or with LRH and oestradiol benzoate

The effect of a combined in vivo pre-treatment with luteinizing hormone-releasing hormone (LRH) and either oestradiol benzoate (OB), clomiphene (-citrate) or OB plus clomiphene on the autonomous and the supramaximally LRH-stimulated in vitro secretion of LH and FSH by pituitary glands of long-term ovariectomized (OVX) rats was studied using a hemipituitary perifusion system. The concentration of LRH in the perifusion medium was 1 microgram/ml. Pre-treatment with LRH during 5 days was effected by means of sc implanted Alzet osmotic minipumps; control rats received a piece of silastic with the dimensions of a minipump. OB, 3 micrograms/injection, clomiphene 100 micrograms/injection or solvent were given on days 2 and 4 (day of perifusion: day 5). In rats not pre-treated with LRH neither OB, nor clomiphene changed the content of the pituitary gonadotropin stores. There was only a small but significant positive effect of the combined treatment with OB and clomiphene on the pituitary FSH content. LRH (partly) depleted the gonadotropin stores. This effect of LRH was potentiated by OB, but not by clomiphene. Clomiphene prevented the depletion-potentiating effect of OB. OB raised the LRH-stimulated secretion of LH and FSH as well as the autonomous secretion of LH. Clomiphene raised the LRH-stimulated (not the autonomous) secretion of LH and FSH. OB plus clomiphene had the same effect as OB alone. Clomiphene also raised the LRH-stimulated secretion of LH and FSH after pre-treatment with LRH, but OB did not do so: LRH prevented the stimulatory effect of OB but not of clomiphene. OB plus clomiphene had the same effect as OB alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary-testicular interrelationships during germinal involution in the vitamin A deficient rat

Pituitary-testicular relationships in mature male rats were investigated during the period of germinal involution after the induction of vitamin A deficiency (VAD). Vitamin A deficiency caused a decrease in testicular weight, a gradual increase in the incidence of delayed spermiation, increased phagocytosis of spermatids and pyknosis of germ cell nuclei in rats aged 80 to 110 days. Both basal and gonadotrophin releasing hormone (GnRH)-stimulated serum FSH concentrations were increased by 100 days of age. During the same period, the per cent increment in GnRH-stimulated FSH secretion, pituitary FSH concentration and LH secretion remained unchanged. These results suggest that the increased serum FSH may mark specifically an alteration in the germinal epithelium. By 140 days of age, spermatogenic activity in the rats with VAD was limited to the spermatogonial proliferations so that only Sertoli cells, spermatogonia and preleptotene spermatocytes remained. At this time hypersecretion of FSH persisted while the per cent increment of GnRH-stimulated FSH secretion decreased. Concomitantly, basal and GnRH-stimulated LH concentrations were also increased in the presence of normal serum testosterone. These results indicate that a complete cessation of spermatogenesis beyond preleptotene spermatocytes is associated with a change in the secretion of both FSH and LH. The relationship between serum LH and testosterone was normal until at least 110 days of age. By 140 days the ratio between basal LH and basal testosterone, and between total LH and total testosterone, after GnRH administration, increased in the rats with VAD.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of cyproterone acetate on pituitary-ovarian function and clinical symptoms in hirsute women

Ten hirsute women in fertile age were given 50 mg cyproterone acetate (CA) on day 5--14 and 50 micrograms ethinyl oestradiol (EE2) on day 5--21 except during the first treatment cycle when EE2 was given on day 15--21. The treatment lasted for 12 months. Clinical examination and hormone analysis were undertaken every third month. LRH tests were performed prior to treatment with CA in late follicular phase and after one week of administration of the drug. Subjective improvement of hypertrichosis was reported in 7 women, objectively a significant decrease in hair scores was observed. Short-term effects of CA alone included significantly decreased serum levels of oestrogens while FSH, LH, 4-androstene-3,17-dione and testosterone remained unaffected. Long-term administration of CA and EE2 resulted in significantly decreased serum levels of FSH, LH and oestrogens whereas 4-androstene-3,17-dione and testosterone were not affected. The gonadotrophin response to LRH did not reveal any significant difference before and after treatment. 4-Androstene-3,17-dione and testosterone did not change during the LRH tests but increased levels of oestrogens were observed at the end of the test during the CA treatment. Since CA alone causes decreased oestrogen levels without any suppression of the basal gonadorrohin levels, it is speculated that CA directly affects the ovarian steroid biosynthesis. On the other hand the adrenal androgens seem to be unaffected by the drug.     

HORMONAL CHANGES IN PATIENTS WITH POLYCYSTIC OVARIAN DISEASE AFTER OVARIAN ELECTROCAUTERY OR PITUITARY DESENSITIZATION

Eleven patients with polycystic ovarian disease (PCO) were treated by laparoscopic ovarian electrocautery and nine with a long-acting luteinizing hormone releasing agonist (LHRH-A) for 8 weeks. Both groups showed equivalent significant decreases in their 6-h mean values of luteinizing hormone (LH) and testosterone (T) measured in 25 samples collected every 15 min. Patients treated with ovarian electrocautery showed significant increases in their 6-h mean values of follicle stimulating hormone (FSH) and insulin with variable oestradiol (E2) responses. The magnitude of change following treatment was significantly greater for LH than for FSH. Buserelin medication did not cause persistent significant changes in the levels of insulin or FSH but it did cause a significant reduction in the 6-h mean values of E2. We conclude that LH is the gonadotrophin primarily affected after pituitary desensitization and ovarian electrocautery. Furthermore, there is no direct correlation between the levels of circulating insulin and testosterone in patients with PCO.     

Inhibition of gonadotropic and ovarian function by intranasal administration of D-Ser (TBU)6-EA10-LHRH in normo-ovulatory women and patients with polycystic ovary disease

We investigated the effectiveness of D-Ser (TBU)6-EA10-LHRH (Buserelin) intranasally 600 micrograms/day given 6 times daily in desensitizing normal ovulatory women and patients with polycystic ovarian disease (PCOD) before initiation of ovarian stimulation for in vitro fertilization. We found that this regimen was sufficient to suppress the gonadotrophs in the normal women and in 8 out of 10 PCOD patients. In PCOD ovarian hormones became normal after Buserelin administration. Adrenal steroidogenesis was not affected by the GnRH agonist. We suggested that the frequency of administration of Buserelin was important to achieve a constant receptor binding and consequently a rapid desensitization. The choice of a monoclonal immunoradiometric assay for luteinizing hormone (LH) and follicle stimulating hormone (FSH) in association with the estradiol-benzoate provocation test were essential in evaluating desensitization.     

EFFECTS OF SYNTHETIC ORAL OESTROGENS IN NORMAL MEN AND PATIENTS WITH PROSTATIC CARCINOMA: LACK OF GONADOTROPHIN SUPPRESSION BY CHLOROTRIANISENE

The effects of the oral synthetic oestrogens, diethylstiboestrol and chlorotrianisene, have been studied in healthy male volunteers and in patients with prostatic carcinoma. The plasma levels of follicle stimulating hormone, luteinizing hormone and testosterone decreased significantly during treatment with diethylstilboestrol. Although plasma levels of testosterone decreased during treatment with chlorotrianisene, levels of follicle stimulating and luteinizing hormones were not significantly suppressed. This pattern of response was observed both in healthy males and in patients with prostatic carcinoma, regardless of whether chlorotrianisene was used as the primary therapy in the latter group or following therapy with diethylstilboestrol or orchidectomy. The capacity of the sex steroid binding globulin for testosterone was increased following prolonged administration of both agents. It is concluded that suppression of plasma testosterone levels observed during chlorotrianisene therapy is the result of a direct effect on the testis and that this agent may be of value in studies of gonadotrophin physiology. Although the palliative effect of treating prostatic carcinoma with synthetic oestrogens such as diethylstilboestrol (DES) and chlorotrianisene (CTA) has been known for many years, the mechanism of this action is obscure. It is generally believed that reduction of circulating androgens secondary to suppression of pituitary gonadotrophin secretion is the main effect, but it is possible such drugs have direct effects both on the testis and the carcinoma. During investigations designed to evaluate the mode of action of these two drugs, an interesting difference emerged between their effects on serum levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). An earlier study had demonstrated that when a patient who had been previously treated with DES was given CTA, plasma levels of testosterone remained low despite rising levels of FSH and LH (Burger et al., 1972). This paper reports the results of more detailed investigations of the effects of DES and CTA in healthy volunteers and in patients with carcinoma of the prostate.     

Suppression and recovery of pituitary gonadotrophin secretion in intact and orchidectomized rats treated neonatally with a gonadotrophin-releasing hormone antagonist

Suppression of neonatal rat pituitary-testis function by gonadotrophin-releasing hormone (GnRH) antagonists results in delayed sexual maturation and infertility. Since the mechanism is not understood, the acute effects of a GnRH antagonist on gonadotrophin secretion in neonatal male rats has been studied in more detail. Treatment with a GnRH antagonist analogue, N-Ac-D-Nal(2)1,D-p-Cl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 -GnRH (2 mg/kg per day) on days 1-10 of life had prolonged effects on gonadotrophin secretion; serum LH and FSH recovered in 1 week, but the pituitary content took 2 weeks to recover. Likewise, LH and FSH responses to acute in-vivo stimulation with a GnRH agonist were still suppressed 1 week after the treatment. Interestingly, a rebound (86% increase) in basal serum FSH was found 16 days after treatment with the antagonist. Whether testis factors influence gonadotrophin secretion during treatment with the GnRH antagonist and/or in the subsequent recovery period was also assessed. Neonatal rats were castrated on days 1, 5 or 10 of the 10-day period of antagonist treatment. Orchidectomy on days 1 and 5 only marginally affected gonadotrophin secretion. When orchidectomy was performed at the beginning of the recovery period, no effects on pituitary recovery were seen within 1 week of castration. After 16 days, serum LH and FSH in the antagonist-treated and control castrated rats were equally increased but the pituitary contents of the antagonist-treated rats were still suppressed. Finally, the effect of testosterone treatment on the recovery of gonadotrophin secretion after antagonist suppression was studied in intact and orchidectomized animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary gonadotrophin secretion during the first weeks of pregnancy.

A longitudinal study of basal plasma LH and FSH and their responses to 25 microng LRH iv as well as basal levels of oestradiol, progesterone, prolatin and HCG was performed every week in 3 women, pregnant after heterologous insemination, from conception until the 6th week of gestation. A comparative study was carried out in 7 women in cycles in which no conception occurred after insemination. All hormones were assayed with radioimmunoassay. LH was measured with a specific assay for native HL, which did not cross-react with HCG. A decrease in basal levels of LH and FSH as well as decreasing responses to LRH was found during the first 2 weeks of gestation. These changes did not differ from what was observed during the luteal phase in the non-conception cycles. One week later the basal FSH levels and the FSH response in the pregnant women showed a further decrease, while in the non-pregnant women, now reaching the early follicular phase, a rise in FSH basal levels occurred. The basal levels of LH and the LH response, however, did not differ from that found in the non-pregnant woment at this time. FSH basal levels remained below the lower normal limit in eumenorrhoic women from the 3rd week of gestation. By this time the FSH response was almost completely inhibited. The LH basal levels, however, remained above the lower normal limit in eumenorrhoic women, but the LH response to LRH progressively decrease and was completely inhibited by the 5th week of gestation. In the non-conception cycles the LH response varied with the levels of oestradiol in plasma. This was not found in the pregnant women as the decrease in gonadotrophin response occurred while oestradiol remained at mid-cycle levels during the first 4 weeks of gestation. Rather it seems that the increasing and continuously elevated level of progesterone, in the presence of appropriate levels of oestradiol, might be the main go nadal steroid responsible for the diminishing pituitary secretion. The contribution of HCG to the further decrease in gonadotrophin secretion after the 2nd week of pregnancy cannot be answered by the present studies. Prolactin remained at non-pregnant levels until the 6th week of gestation, and appeared to have no influence on the secretion of gonadotrophins during early pregnancy.     

Dose-response study with a new LH-RH analogue, D-Ser (TBU)6 LH-RH 1-9 (EA)10 during the follicular phase of the menstrual cycle.

D-Ser (TBU)6 LH-RH 1-9 (EA)10 (HOE 766) a highly active LH-RH analogue, was studied with regard to its effects on the release of follicle stimulating hormone (FSH), luteinizing hormone (LH) and oestradiol-17beta (Oe2) during the follicular phase of the menstrual cycle. Forty-two regularly menstruating women were allowed to five different treatment groups with different doses (1.25 microgram; 2.5 microgram; 5.0 microgram; 10.0 microgram; 20.0 microgram) of HOE 766 given as intravenous bolus injections and the plasma concentrations of FSH, LH and Oe2 were measured up to 24 h after injection using specific radioimmunoassays. In the majority of cases, peak values of both FSH and LH occurred 4 h after injection being significantly different from pre-injection levels (P less than 0.02 in the 1.25 microgram treatment group, P less than 0.005 for the other treatment groups). Statistical analysis of maximum values as well as the absolute and relative increase in the different treatment groups revealed a dose-dependent effect of HOE 766. Maximum values of Oe2 occurred 8 h after injection and were found to be significantly different from pre-injection levels (P less than 0.005). However, no dose dependent effect was observed. It was concluded that HOE 766 is a potent and long-acting stimulator of FSH, LH and OE2 release in women. The effect of HOE 766 is dose dependent for FSH and LH but not for Oe2.     

Gonadotrophin-releasing activity of neurohypophysial hormones: I. Potential for modulation of pituitary hormone secretion in rats

Neurohypophysial hormones have been implicated in the control of anterior pituitary function, and oxytocin has been shown to stimulate gonadotrophin excretion and ovarian follicular development in certain species. To determine the role of neurohypophysial peptides in the control of gonadotrophin release, their actions on LH and FSH secretion were analysed in rats in vivo and in vitro. In adult female rats, administration of oxytocin during early pro-oestrus advanced the spontaneous LH surge and markedly increased peripheral LH levels at 15.00 h compared with control animals. In cultured pituitary cells from adult female rats, oxytocin and vasopressin elicited dose-related increases in LH and FSH release. Such responses were not affected by a potent gonadotrophin-releasing hormone (GnRH) antagonist that abolished GnRH agonist-induced release of LH and FSH. Oxytocin did not enhance GnRH agonist-stimulated gonadotrophin release to the same extent as it increased basal secretion, but at low concentrations of GnRH agonist the effects were additive. The gonadotrophin responses to oxytocin and vasopressin were inhibited by the specific neurohypophysial hormone antagonists, [d(CH2)5D-Ile2,Ile4,Arg8]vasopressin and [d(CH2)5Tyr (Me),Arg8]vasopressin. These results provide direct evidence that neurohypophysial hormones can stimulate gonadotrophin secretion through a receptor system distinct from the GnRH receptor. Such a mechanism could represent a complementary hypothalamic control system for long-term modulation of LH and FSH secretion by exerting a basal or tonic influence on gonadotrophin production.     

PRIMARY HYPOTHYROIDISM OF CHILDHOOD: EVALUATION OF THE HYPOTHALAMIC-PITUITARY GONADAL AXIS BEFORE AND DURING L-THYROXINE REPLACEMENT

Hypothyroidism is frequently associated with abnormal sexual development. To determine the longitudinal influence of thyroxine replacement on the hypothalamic pituitary gonadal axis, we studied five prepubertal hypothyroid girls and two boys before, and all the girls six weeks and one year after, thyroxine replacement. All girls showed significantly elevated basal gonadotrophin concentrations before treatment. Following one year of therapy, despite all girls having begun puberty, basal gonadotrophin concentrations were significantly decreased in the four euthyroid girls as compared with our normal pubertal girls. The fifth girl studied at one year was hypothyroid at the time of testing and her gonadotrophin values were increased even above previous basal values. Pretreatment serum TSH values inversely correlated with maximum pretreatment incremental LH (r = -0.54) and FSH (r = -0.52) responses to LHRH. Serum TSH values directly correlated with PRL concentrations (r = +0.82). Of the two hypothyroid boys evaluated, Patient 1 was mildly hypothyroid and showed normal prepubertal basal LH, FSH, testosterone and low normal LHRH responsiveness. Patient 2, who was more severely hypothyroid, had elevated basal gonadotrophin secretion and responsiveness to LHRH but prepubertal testosterone concentrations. These data indirectly show that thyroxine may increase the biological/immunological potency of gonadotrophins. The elevated gonadotrophin values in the hypothyroid state suggest that the metabolic clearance rate of gonadotrophins is prolonged. The more severe the elevation in TSH secretion, the more marked was the alteration in the hypothalamic pituitary axis in respect to PRL secretion and delta max LH and FSH response to LHRH. Replacement with thyroxine was followed by normal pubertal development, and normal pubertal oestradiol and PRL concentrations, despite low immunoreactive gonadotrophin secretion.