Luteinizing hormone-releasing hormone (LH-RH) as a diagnostic and research tool in gynecologic endocrinology

A study is reported on the effects of 150 mcg. of luteinizing hormone-releasing hormone (LH-RH), administered iv to 48 women with 5 types of secondary oligoamenorrhea, on the serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) Levels. At Time 0, patients with pituitary disease showed a markedly diminished LH response and patients with polycystic ovarian disease with enlarged ovaries showed a brisk, elevated LH response. FSH levels in patients with pituitary disease and polycystic ovarian disease showed a negligible rise at Time 0. 9 of 10 patients with pituitary disease and 5 of 9 patients with dietary amenorrhea had a low LH response 30 minutes after LH-RH administration. FSH response 60 minutes after injection in patients with pituitary disease and polycystic ovarian disease seemed to be lowered though too much overlap prevented a complete diagnosis. The conclusion of this initial study is that through baseline determinations of FSH and LH, along with a LH-RH stimulation test, useful data are provided for determining whether amenorrhea is due to ovarian or pituitary failure. A 2nd study evaluated the effects of 150 mcg of LH-RH administered iv before and after the im administration of various dosages of estrogen and progesterone to anovulatory women. A vigorous response in pituitary gonadotropin, particularly LH, was observed with LH-RH administered only. The effect with estrogen and progesterone was diminished pituitary response in terms of LH production. It is concluded that estrogen and progesterone exert a negative feedback effect on gonadotropin secretion at the hypothalamic and pituitary levels.     

Pseudocyesis: pituitary function before and after resolution of symptoms

Pseudocyesis was clinically established in a 39-year-old woman. Pituitary function was assessed with the use of hypothalamic peptides and dopamine receptor agonists. Basal serum concentrations of anterior pituitary and ovarian hormones were normal. An exaggerated rise in luteinizing hormone (LH) and prolactin levels was seen following the administration of luteinizing hormone-release hormone and thyrotropin-releasing hormone (TRH), respectively. A paradoxic rise in growth hormone (GH) levels followed TRH administration, whereas the response to dopamine receptor agonists was normal. Pituitary hormone secretion after deflation remained similar to that before deflation, although a normal response of GH to apomorphine was reestablished. These data indicate that the amenorrhea of pseudocyesis is associated with normoprolactinemia and a readily releasable pituitary LH pool, which suggests a suprahypophyseal etiology of the amenorrhea. The abnormalities in GH secretion may also support this contention.     

Effects of opioid antagonism with naltrexone on pulsatile luteinizing hormone secretion in women with hypothalamic amenorrhea in basal conditions and after discontinuation of treatment with pulsatile LHRH.

Although endogenous opioids seem to play an important role in the inhibition of luteinizing hormone releasing hormone (LHRH) secretion in women with hypothalamic amenorrhea, opioid antagonism does not always cause an increase of pituitary luteinizing hormone (LH) secretion. The effect of the long-acting oral opiate antagonist naltrexone on pulsatile LH secretion was studied in eight women with weight loss and exercise-related hypothalamic amenorrhea. LH pulse studies and LHRH tests were performed in basal conditions and after 4 days of naltrexone treatment, 50 mg q.d. Naltrexone caused a slight, but significant increase of LH pulse frequency. Six weeks later, a second experiment was performed. The response to naltrexone was studied after enhancement of the pituitary sensitivity. Patients were pretreated with pulsatile LHRH during 4 days, followed by naltrexone 50 mg q.d. during 4 days. An increased LH response to LHRH, but no response to naltrexone, were seen after discontinuation of pulsatile LHRH. It is concluded that the limited pituitary response to opioid antagonism, observed in weight loss-related forms of hypothalamic amenorrhea, is not caused by pituitary insensitivity to LHRH.     

Evaluation and treatment of patients with prolactin-secreting pituitary tumors

Six women with secondary amenorrhea and hyperprolactinemia, four of whom had associated galactorrhea, were studied. Four were found to have prolactin-secreting pituitary microadenomas and two had macroadenomas. Suppression of prolactin secretion and stimulation of prolactin, serum growth hormone and thyroid-stimulating hormone secretion were studied, and gonadotropin and adrenocorticotropic hormone reserves were evaluated. The most sensitive techniques available for the diagnosis of pituitary adenomas in patients with amenorrhea and hyperprolactinemia appear to be the measurement of the magnitude of plasma prolactin elevation and hypocycloidal tomography of the sella turcica. The dynamic function tests proved to be of little diagnostic, but of great prognostic, value for patients with small pituitary tumors.     

Hypothalamic-pituitary-gonadal axis in thalassemic patients with secondary amenorrhea

Eight thalassemic patients, aged 24-35 years, who developed amenorrhea 2-15 years after menarche, were studied. Mean basal serum LH and FSH levels and the peak levels after gonadotropin-releasing hormone were significantly less than corresponding values in normal controls. All patients showed low basal serum levels of estradiol and six had a poor or absent response to human menopausal gonadotropin. One subject had intact pituitary-gonadal function and one patient had an impaired LH and FSH response to gonadotropin-releasing hormone in the presence of a significant increase of estradiol after human menopausal gonadotropin stimulation. The findings regarding pituitary hormones other than gonadotropins suggest that iron overload damages tropic cells unequally and inconsistently. We conclude that both pituitary and gonadal damage may be responsible for the secondary amenorrhea in thalassemic patients.     

A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia

The return of menses in amenorrheic normoprolactinemic women after treatment with bromocriptine is well documented. To determine whether an increased pituitary prolactin-secreting capacity may be the underlying mechanism, 14 women with amenorrhea were studied. None complained of galactorrhea, but in all 14 it was possible to express a few drops of milk from the nipple. All women were normoprolactinemic and had normal sellar tomography. A standard thyrotropin-releasing hormone (TRH) test was performed and bromocriptine (2.5 mg twice daily) was administered. Within 8 weeks, 9 of 14 patients had return of menses. The second group of five patients did not respond to bromocriptine. The mean prolactin response to TRH was significantly greater in those women who experienced return of menses, although there was individual overlap between both groups. This finding suggests that enhanced prolactin secretory capacity may account for amenorrhea is some apparently normoprolactinemic patients. The TRH test may serve to identify those patients who may benefit from bromocriptine.     

Growth hormone deficiency as the only identifiable cause for primary amenorrhea

Background: There is much evidence that growth hormone plays an important role in the development and function of the reproductive system of both males and females. Growth hormone exerts its effects on the ovarian follicular cycle directly or by local production of insulin-like growth factor 1 (IGF-1). It is known that growth hormone deficiency during childhood may delay pubertal development, but there is limited data about primary amenorrhea in GH-deficient girls with sufficient stimulated gonadotropin levels.Methods: Case series.Results: In the evaluation of primary amenorrhea and delayed puberty, 3 cases of adolescent females aged 17-19 years were identified as isolated GH-deficiency. Among the 3 patients, 2 had history of intracranial surgery due to hydrocephalus (shunt operation) or prolactin-secreting pituitary macro-adenoma (transphenoidal surgery, one year before). 17-year-old patient with shunted hydrocephalus and 19-year-old patient with primary amenorrhea showed short statue (< 5%) and delayed bone maturation. The patient undertaken transphenoidal surgery for prolactinoma showed normal height and bone maturation. There was no familial history of delayed puberty. On physical examination, 3 patients showed variable degree of breast development from Tanner stage II to IV without sex-steroid replacement. In sella MRI, small pituitary gland were identified in 2 patients with short statue and delayed bone maturation. All of the 3 patients underwent combined pituitary function test. After insulin-induced hypoglycemia, peak growth hormone levels of the 3 patients were 0.08, 1.4 and 1.4 ng/ml and were compatible with growth hormone deficiency. Peak LH after intravenous gonadrelin (FACTREL) were 19.0 to 56.1 mIU/ml and LH % responses were 217 to 1100% and were hence defined as not being gonadotropin deficiency. Other anterior pituitary functions were normal in all of the 3 patients.Conclusions: We found isolated growth hormone deficiency as the only identifiable cause for primary amenorrhea in three patients with sufficient gonadotropins secretion. These findings suggest a complementary role of GH to gonadotropins in the occurrence of menarche.     

Arginine-GnRH-TRH test in patients with primary hypothalamic amenorrhea

In 8 patients with hypothalamic primary amenorrhea aged from 16 to 23 years (average age 19,4 years) a sequential stimulations test was performed with 0,5 g arginine hydrochloride per kg body weight, 25 micrograms gonadotropin-releasing hormone (GnRH) and 200 micrograms thyreotropin-releasing hormone (TRH). The response of the lactotropic, gonadotropic, thyreotropic and somatotropic cells of the pituitary was investigated. Serum levels of PRL, LH, FSH, TSH and HGH were determined by RIA. In all women hypoplastic ovaries were found by laparoscopy. In 7 patients tissue biopsies showed primordial follicles or primordial and secondary follicles, respectively. Investigations point to, that in hypothalamic primary amenorrhea at first the function of the gonadotropic and lactotropic cells of the pituitary is injured. The somatotropic cells could not be stimulated in 3 of 8 patients, the function of hypothalamo-pituitary-thyroid-axis in the stimulations test was normal in all women.     

Pituitary hormone response to thyrotropin-releasing hormone in secondary amenorrheic women associated with simple weight loss

OBJECTIVE: To investigate endocrine dysfunction in simple weight loss amenorrhea. DESIGN: We studied pituitary hormone responses to thyrotropin-releasing hormone (TRH) in 10 women with simple weight loss amenorrhea. SETTING: Department of Obstetrics and Gynecology, University Hospital, University of Tokushima at Tokushima, Japan. PATIENTS, PARTICIPANTS: Secondary amenorrheic women associated with simple weight loss who did not have anorexia nervosa. INTERVENTIONS: Intravenous injection of 500 micrograms of synthetic TRH. MAIN OUTCOME MEASURE: Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin, and prolactin were measured before and 15, 30, and 60 minutes after TRH injection. RESULTS: In normally menstruating women on day 7 of the cycle TRH did not affect serum LH and FSH levels. In women with simple weight loss amenorrhea, however, TRH raised serum LH and FSH levels significantly (P less than 0.01, respectively). Prolactin response to TRH was significantly (P less than 0.05) lower in women with simple weight loss amenorrhea than in normally menstruating women. CONCLUSIONS: These results indicate that TRH causes a significant rise in serum LH and FSH and the impaired prolactin response in women with simple weight loss amenorrhea.     

The induction of ovulation in amenorrheic patients with synthetic luteinizing hormone-releasing hormone: the significance of pituitary responsiveness.

The pituitary reserve of gonadotropins was evaluated with intravenous injections of 25 mug of synthetic luteinizing hormone-releasing hormone (LH-RH) in 32 patients with secondary amenorrhea. An obvious individual difference in the magnitude of the serum LH response was noted in these patients. Thus the patients were classified into four groups according to their pituitary responsiveness as expressed by the ratio of the serum LH stimulated peak to the basal level. Patients with values within the range of, or higher than, that of the normal follicular phase were classified as having high response (750% and above); within the range of that of the normal luteal phase as having moderate response (500 to 740%); between that of the normal luteal phase and that of postmenopausal women as having low response (250 to 490%); and within the range of, or lower than, that of postmenopausal women as having no response (240% and below). Among 26 clomiphene-failed patients in this series who were treated again with clomiphene and subsequent injection of LH-RH; 10 of 12 patients (25 or 35 cycles) with high response, 6 of 10 patients (12 of 28 cycles) with moderate response, and 1 of 4 patients (1 of 13 cycles) with low response ovulated. Five patients became pregnant. The results of this study indicate that in amenorrheic women the higher the pituitary response to LH-RH the greater the chance of inducing ovulation. Patients with secondary amenorrhea may thus be classified by assessing their pituitary response to LH-RH, which may be useful in predicting the chance for the successful induction of ovulation.     

Short-term pituitary desensitization to luteinizing hormone-releasing hormone (LH-RH) after pulsatile LH-RH administration in women with amenorrhea of suprapituitary origin

The existence of a short-term pituitary desensitization in luteinizing hormone (LH) release to single doses of luteinizing hormone-releasing hormone (LH-RH) in the ovariectomized rat was recently disclosed. The purpose of the present study was to investigate whether this refractoriness is also present in humans. Blood from six women with amenorrhea of suprapituitary origin was sampled every 10 minutes for 300 minutes for determination of LH and follicle-stimulating hormone (FSH). A pulse of 20 micrograms LH-RH was given intravenously 90 and 210 minutes after the first blood sample, and 2 micrograms LH-RH was given 30, 150, 240, and 270 minutes after t0. The mean maximal increments of LH and FSH were compared. The LH response to a 2-micrograms LH-RH bolus given 30 (t240) or 60 (t150) minutes after a 20-micrograms LH-RH pulse was significantly decreased, compared with the initial response to this dose at t30. For both LH and FSH, the response to 2 micrograms LH-RH given 30 minutes after the 20-micrograms pulse (t240) was almost absent, compared with 60 (t150) minutes after the 20-micrograms dose. We conclude that a short-term pituitary refractoriness to LH-RH is present after administration of single pulses of LH-RH in women with amenorrhea of suprapituitary origin and pulses of LH-RH in the physiologic range (2 micrograms) given to these women do not always generate LH and FSH increments that are identifiable as significant hormone pulses.     

Adrenal adenocarcinoma and empty sella syndrome in a 37-year-old woman.

The case of a 37-year-old woman with secondary amenorrhea and clear signs of hyperandrogenism is reported. The patient underwent hormonal evaluation including circadian rhythm of cortisol, gonadotropin-releasing hormone/thyroid-stimulating hormone (GnRH/TRH) test, corticotropic-releasing hormone (CRH) test and dexamethasone suppression test. She also underwent pelvic and adrenal ultrasound examination, adrenal computed axial tomography (CAT) scan and cranial nuclear magnetic resonance (NMR). A mass about 10 cm in size was detected in the left adrenal region. The sella was empty and the pituitary displaced downward. Suspected adrenal adenocarcinoma was confirmed by histological examination after surgical removal of the mass. This case is of interest for physicians because of the mixed androgen and cortisol secretion of the adenocarcinoma in a hyperprolactinemic patient with empty sella. Moreover, it suggests the need to investigate the adrenal gland in patients with hyperprolactinemia and hirsutism.     

Pituitary responses to synthetic luteinizing hormone-releasing hormone in thirty-four cases of amenorrhea or oligomenorrhea associated with galactorrhea.

Pituitary responses to 100 mcg. of luteinizing hormone-releasing hormone (LH-RH) administered subcutaneously were studied in 34 cases of amenorrhea or anovulatory oligomenorrhea associated with galactorrhea. Twenty-six patients had pituitary prolactin-secreting tumors (group I); eight patients had a normal sella turcica and remission of the syndrome either spontaneously or after thyroid replacement therapy (group 2). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to LH-RH were variable in each group of patients, ranging from poor to exaggerated, and no statistically significant difference could be observed between the groups. A positive correlation was found between FSH pituitary responses and basal FSH levels (r=0.50; P less than 0.01). No positive correlation was observed between either LH responses and basal LH levels or the gonadotropin responses and plasma estradiol levels, serum prolactin concentrations, duration of amenorrhea, or size of the tumor.     

Prolactin-secreting pituitary microadenoma: detection and evaluation

Eleven women with secondary amenorrhea associated with hyperprolactinemia were studied. Base line evaluations, visual field determinations, and routine sella turcica x-rays were normal. Prolactin-secreting pituitary microadenomas were found in all of the patients only after further diagnostic studies were carried out. These studies included polytomography of the sella turcica; dynamic pituitary testing of growth hormone reserve, adrenocorticotropic hormone reserve, and gonadotropin reserve; and prolactin suppression with L-dopa. The early diagnosis of a small prolactin-secreting adenoma may be possible if several diagnostic criteria are utilized. The most sensitive diagnostic indices available are (1) polytomography, (2) the magnitude of the plasma prolactin elevation, and (3) the failure to suppress prolactin secretion with L-dopa. Our findings emphasize the importance of an extensive evaluation of all women with amenorrhea associated with hyperprolactinemia.     

Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.     

The effects of intranasal application of low dose buserelin in women with hypothalamic amenorrhea]

Low doses of the Gn-RH agonist (buserelin, 30 micrograms) were given intranasally to 14 women with clomiphene ineffective hypothalamic amenorrhea three times daily for three weeks in order to study pituitary responses and to induce follicular maturation and ovulation. Clomiphene ineffective hypothalamic amenorrhea patients were classified into two groups by LH-RH stimulation test before the treatment. Group 1 was defined as having basal serum LH and FSH levels lower than 1.5 mIU/ml, LH and FSH peaks lower than 3mIU/ml by LH-RH stimulation test. Group 2 consisted of cases other than those in Group 1. While a significant increase in basal LH and FSH (p less than 0.01, p less than 0.001) and improvement in pituitary response to LH-RH stimulation test were observed in group 1, the basal levels of LH and FSH did not increase significantly and pituitary response to a LH-RH stimulation test was decreased in group 2. It is suggested that pituitary priming occurred in group 1 and pituitary desensitization occurred in group 2. None of 14 patients showed signs of follicular maturation during or after the treatment. The results demonstrated that the biphasic pituitary response to intranasal buserelin spray and the limit of its therapeutic use for the treatment of hypothalamic amenorrhea.     

A schematic approach to the work-up of amenorrhea.

Amenorrhea is a symptom having many possible causes. Since amenorrhea can result from disturbed function anywhere in the hypothalamic-pituitary-ovarian-uterine axis, a specific etiologic diagnosis must be made if treatment is to be effective. For this purpose, a diagnostic scheme for the differential diagnosis of the etiology of primary and secondary amenorrhea is proposed. This scheme includes a progestin test, a cyclic estrogen and progestin test, a luteinizing hormone-releasing hormone (LH-RH) loading test, and a gonadotropin (human menopausal gonadotropin and human chorionic gonadotropin) loading test. A specific pattern of responses to LH-RH and gonadotropins exists in patients with hypothalamic, pituitary, and ovarian amenorrheas, respectively, and the character of the response may facilitate the etiologic diagnosis of amenorrhea. The clinical usefulness and/or value of the scheme in the diagnosis and treatment of amenorrheas is discussed.     

Stimulatory effect of a traditional herbal medicine, Unkeito on LH-RH release

In order to study the effect of Unkeito (Chinese name, Wen-Jan-Tang), a traditional Chinese herbal medicine and its components on luteinizing hormone-releasing hormone (LH-RH) and LH release, the mediobasal hypothalamus (MBH) alone or the pituitary alone or the pituitary in sequence with the MBH from normal female rats in diestrus was perifused in a sequential double-chamber perifusion system. LH-RH release from MBH increased significantly (p less than 0.05) by 50-100% of the basal level 30-90 min after the beginning of Unkeito administration. Unkeito at 5 micrograms/ml induced significant LH release (60-95% increase) from the pituitary in series with the MBH, but had no effect on LH release from the pituitary perifused alone. One of Unkeito's components Botanpi induced significant LH release, although other five components had no effect on LH release. These data suggest that Unkeito induces LH release from the pituitary through hypothalamic LH-RH, and can be used for the treatment of patients with hypothalamic amenorrhea.     

Opioid regulation of luteinizing hormone in amenorrheic patients after therapy for induction of ovulation

This study evaluated the activity of central opiate receptors modulating luteinizing hormone (LH) secretion before and during treatment with human menopausal gonadotropin (n = 8) or purified human urinary follicle-stimulating hormone (n = 6) in 14 patients with hypogonadotropic hypogonadism (n = 6) or secondary amenorrhea (n = 8). LH response to saline infusion and naloxone administration (4 mg intravenously) was assessed. As control, 6 normal ovulating women were studied. Before therapy, all amenorrheic patients showed no LH increase after naloxone injection. Gonadotropin treatment restored the naloxone-induced LH response at preovulatory and midluteal phases in ovulating patients with secondary amenorrhea. The same response was present in spontaneously ovulating women but was absent in the hypogonadotropic hypogonad patients, despite the gonadotropin therapy's efficiency. In conclusion, when the alteration of gonadotropin-releasing hormone synthesis and/or release is reversible, the opioid system actively participates in the regulation of the hypothalamus-pituitary-gonadal axis.     

Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus

Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge ,while thyroid-stimulating hormone (TSH) response to TRH was diminished ,and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus ,with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.