Low LH Levels Research Articles

Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women.

To elucidate the possible role of genetic variation in androgen receptor (AR), estrogen receptor alpha (ER alpha), and ER beta on serum androgen levels in premenopausal women, the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ER alpha gene, and the CA repeat polymorphism of the ER beta gene were studied in a population-based cohort of 270 women. Total testosterone, free testosterone, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, 3 alpha-androstanediol glucuronide, 17 beta-estradiol, LH, FSH, and sex steroid hormone-binding globulin (SHBG) were measured in serum samples obtained in the follicular phase of the menstrual cycle. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH, than women with longer CAG repeat sequences. The CA repeat of the ER beta gene also was associated with androgen and SHBG levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ER alpha gene was not associated with the levels of any of the hormones measured. Our results suggest that the serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ER beta gene, respectively.

Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.

Several point mutations in the GnRH receptor gene have been described in an autosomal recessive form of congenital isolated hypogonadotropic hypogonadism (HH). We investigated 17 Brazilian patients (10 males and 7 females) from 14 different families, with HH and normal olfaction. The diagnosis of HH was based on absent or incomplete sexual development after 17 yr of age associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. The coding region of the GnRH receptor gene was amplified by PCR and directly sequenced. A novel missense mutation, Arg(139)His, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified in the homozygous state in one female with complete HH. The Arg(139)His mutation completely eliminated detectable GnRH-binding activity and prevented GnRH-induced stimulation of inositol phosphate accumulation in vitro. In another family, a new compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) was identified in four siblings (two males and two females) with partial HH. The Gln(106)Arg mutation, located in the first extracellular loop, has been previously described, and in vitro analysis indicated that the mutant receptor was able to bind GnRH, but with a reduced affinity. The Asn(10)Lys mutation in the extracellular amino-terminal domain of the receptor also reduced the affinity for GnRH in vitro. In this family we also identified a previously described silent polymorphism at amino acid residue 151 in the second intracellular loop that segregated with the two inactivating mutations of the GnRH receptor. This polymorphism was also found in two unrelated patients with sporadic HH without GnRH receptor loss of function mutations. No mutations were identified in the remaining cases. A good correlation between genotype and phenotype was found in our patients. The woman, who is homozygous for the completely inactivating Arg(139)His mutation, has complete HH with undetectable serum basal LH and FSH levels that failed to respond to GnRH stimulation. In addition, the affected patients who are compound heterozygotes for the Asn(10)Lys/Gln(106)Arg mutations, have partial HH with low serum basal LH levels that were responsive to GnRH stimulation. No clinical or hormonal differences were found between HH patients with and without mutations in the GnRH receptor gene, indicating that these data do not contribute to the identification of HH patients with GnRH receptor mutations. In conclusion, we report the first naturally occurring mutation within the conserved DRS motif of the GnRH receptor in a female with complete HH and a novel compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) in a family with partial HH, increasing the repertoire of the inactivating mutations of the GnRH receptor.

How Common Are Polycystic Ovaries and the Polycystic Ovarian Syndrome in Women With Cushing’s Syndrome?

Kaltsas, G. A.; Korbonits, M.; Isidori, A. M.; Webb, J. A. W.; Trainer, P. J.; Monson, J. P.; Besser, G. M.; Grossman, A. B.

Melatonin hypersecretion in male patients with adult-onset idiopathic hypogonadotropic hypogonadism

Increased melatonin secretion observed in male patients with congenital isolated hypogonadotropic hypogonadism and its normalization during testosterone treatment had suggested that melatonin and the reproductive hormones are inter-related. Since these patients have a congenital form of hypogonadism, it is likely that hypermelatoninemia is the consequence of hypogonadism. To further study the relations between the pineal and the reproductive axis in humans, we evaluated melatonin secretion in two men (aged 35 and 50 yrs.) with acquired adult-onset hypogonadotropic hypogonadism. The diagnosis was based on the findings of normal testicular volume, azoospermia, low serum testosterone, normal LH and FSH levels, but apulsatile LH secretion, and intact anterior pituitary hormones secretion, normal findings on skull radiographic imaging, prior sexual maturation and paternity. Melatonin secretion was assessed as urinary 24 h 6-sulphatoxymelatonin excretion (aMT6s) prior to and during the administration of 250 mg testosterone enanthate per month for 4 months. Pretreatment melatonin production was markedly increased in both patients: 427-915 ng/kg/24 h vs. 204+/-81 [mean+/-SD] in 16 age-matched male controls. During testosterone treatment, aMT6s levels were normalized in one patient (range: 81-287 ng/kg/24 h) and remained elevated in the other patient (range: 830-1280 ng/kg/24 h). These data indicate that male patients with acquired GnRH deficiency have increased melatonin secretion. Melatonin hypersecretion in these patients may reflect a functional association.

How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing's syndrome?

Women with Cushing's syndrome (CS) may present with menstrual irregularity and symptoms/signs of hyperandrogenism, a phenotype similar to that of the polycystic ovarian syndrome (PCOS); however, currently there are no data on the prevalence of either polycystic ovaries (PCO) and/or PCOS in patients with CS. The aim of this study was to investigate their presence among women of reproductive age presenting with CS by analysing clinical, endocrinological and ultrasonographic features. Prospective study of all women within the reproductive age (range 18-40 years) who presented with CS between August 1994 and January 2000. Thirteen women (median age 32 years, range 18-39 years) with CS were evaluated. The diagnosis of CS was based on the presence of appropriate clinical features and an elevated serum midnight cortisol with failure to suppress 0900 hours serum cortisol to less than 50 nmol/l following a formal low-dose dexamethasone suppression test (LDDST). All women had their clinical features relevant to possible hyperandrogenism, menstrual disorder and infertility recorded, and circulating gonadotrophins, oestradiol, androgens and SHBG levels measured; ovarian ultrasonography was performed during their initial assessment. Relevant MR/CT imaging of the pituitary and/or adrenal glands was performed. Eleven women had ACTH-dependent CS [nine Cushing's disease (CD), one ectopic ACTH syndrome due to a bronchial carcinoid, one periodic CS of unknown origin); two patients had ACTH-independent CS (adrenal adenomas). All women with CS had at least one symptom/sign of hyperandrogenism (13 hirsutism, seven acne, five male-pattern alopecia). Nine women (70%) had menstrual disturbances (four oligomenorrhoea, four amenorrhoea, one polymenorrhoea) while four women (30%) had a normal menstrual pattern. Serum oestradiol levels for the group as a whole were similar to those observed in the early follicular phase of normally menstruating women; however, seven women had low oestradiol, LH and FSH levels suggestive of hypogonadotrophic hypogonadism. Serum androgen levels (testosterone, androstendione and DHEAS), even in the presence of symptoms/signs of hyperandrogenism, were within the normal reference range but SHBG levels were uniformly decreased even in women with normal menstrual cycles. There was a negative correlation between urinary free cortisol, but not mean serum cortisol, and serum oestradiol, testosterone and SHBG levels (r = - 0.8, r = - 0.86 and r = - 0.66, P<0.02, P<0.01 and P<0.05, respectively), but not LH or FSH levels. Despite the fact that seven of these 13 patients lacked normal gonadotrophin stimulation, ovarian volumes of both ovaries were relatively preserved: right 7.3 ml, range 2.8-12.8 ml, and left 5.3 ml, range 2.3-13 ml. Women who were defined as oestrogen sufficient (E2 > 140 pmol/l) had higher serum androstenedione, and lower urinary free cortisol levels, than women who were oestrogen deficient (E2 < 140 pmol/l). Six of the 13 women (46%) had ovarian morphology suggestive of PCO, four of six oestrogen sufficient women and two of seven oestrogen deficient women. The results did not differ according to the underlying cause of CS. PCO and PCOS are common in women with Cushing's syndrome; women with Cushing's syndrome and only moderately elevated cortisol secretion maintain gonadotrophin stimulation to the ovary with normal oestradiol levels, in contrast to women with Cushing's syndrome and higher cortisol secretion who develop hypogonadotrophic hypogonadism. However, even in the latter group, high ovarian volumes were maintained and some had ovarian morphology suggestive of PCO.

Functional compensation by Egr4 in Egr1-dependent luteinizing hormone regulation and Leydig cell steroidogenesis.

The Egr family of zinc finger transcription factors, whose members are encoded by Egr1 (NGFI-A), Egr2 (Krox20), Egr3, and Egr4 (NGFI-C) regulate critical genetic programs involved in cellular growth, differentiation, and function. Egr1 regulates luteinizing hormone beta subunit (LHbeta) gene expression in the pituitary gland. Due to decreased levels of LHbeta, female Egr1-deficient mice are anovulatory, have low levels of progesterone, and are infertile. By contrast, male mutant mice show no identifiable defects in spermatogenesis, testosterone synthesis, or fertility. Here, we have shown that serum LH levels in male Egr1-deficient mice are adequate for maintenance of Leydig cell steroidogenesis and fertility because of partial functional redundancy with the closely related transcription factor Egr4. Egr4-Egr1 double mutant male mice had low steady-state levels of serum LH, physiologically low serum levels of testosterone, and atrophy of androgen-dependent organs that were not present in either Egr1- or Egr4-deficient males. In double mutant male mice, atrophic androgen-dependent organs and Leydig cell steroidogenesis were fully restored by administration of exogenous testosterone or human chorionic gonadotropin (an LH receptor agonist), respectively. Moreover, a normal distribution of gonadotropin-releasing hormone-containing neurons and normal innervation of the median eminence in the hypothalamus, as well as decreased levels of LH gene expression in Egr4-Egr1-relative to Egr1-deficient male mice, indicates a defect of LH regulation in pituitary gonadotropes. These results elucidate a novel level of redundancy between Egr4 and Egr1 in regulating LH production in male mice.

Development of time-resolved immunofluorometric assays for rat follicle-stimulating hormone and luteinizing hormone and application on sera of cycling rats.

The aim of this study was to develop time-resolved immunofluorometric assays (TR-IFMA) for measuring rat (r)FSH and rLH. The advantages of these IFMAs are higher sensitivity due to lower background values, higher specificity as only intact molecules of FSH and LH can be measured, and a very long shelf life of the nonradioactive biotin antigens compared with radiolabeled iodine antigens. For rFSH, IFMAs are lacking, while for rLH, if present, the resources for antibodies are scarce or the mouse monoclonal antibodies (mMAbs) against LHalpha are inactive with FSH. Thus specific antibodies need to be obtained. With the final TR-IFMAs, rFSH and rLH levels were assessed during the estrous cycle and compared with those obtained with the more classical RIAs and fluoroimmunoassays (FIAs). Two IFMAs for rFSH were developed with mMAbs against the recombinant human (rec h)FSHbeta subunit (FSH56A) attached to the wall and two different rabbit polyclonal antibodies (PAbs) against the alpha subunit of rec hFSH (R93-2705) or recombinant rat (rec r)LH (R95-2715) conjugated with biotin as signal antibody. With both IFMAs, rFSH holo-molecules can be measured. Rat FSH standards could be assessed between 0.02 and 10 ng/ml with a detection limit of 0.05 and 0.24 ng/ml in buffer and serum, respectively. These detection limits in four IFMAs were 8- to 16-fold lower than those in RIAs and FIAs. This detection level allowed the measurement of FSH levels in serum of hypophysectomized (HYPEX) rats at 0.18 ng/ml. In serum of cycling rats, the FSH levels of the IFMA were 2-fold lower than those of the FIA, while in ovariectomized (OVX) rats the IFMA levels were comparable. A peak level of FSH was found during proestrus of Day 2 and gestation with both RIA and FIA, but with IFMAs at gestation only. An IFMA for rLH was set up with mMAb (hCG77A) reacting with rLHbeta as capture and rabbit PAb to rec rLHalpha (R95-2712) as signal antibody. Rat LH standard could be assessed between 0.001 and 10 ng/ml with a detection limit of 0.012 and 0.1 ng/ml in buffer and serum, respectively, which was 8-fold lower than that in RIA/FIA. In serum of HYPEX rats, LH was undetectable (< 0.04 ng/ml), whereas a high background level of 2.5 ng/ml was measured in the FIA. In serum of cycling rats, only a very low LH level of 0.14 ng/ml was measured, which strongly deviated from the level of 3.46 ng/ml with an FIA. The load of LH in serum of OVX rats was 2.91 ng/ml, which was 12-fold lower than that for the FIA. The peak level of LH was detected on proestrus Day 2 with RIA, FIA, and IFMA. In conclusion, two IFMAs for rFSH and one for rLH have been developed with high sensitivity and specificity for intact gonadotropins. The LH pattern during the estrous cycle was comparable between IFMA, RIA, and FIA, although the overall level in the IFMA was much lower, as were HYPEX levels. The FSH pattern differed only on proestrus Day 2 in the IFMA from that of RIA/FIA, showing a peak level with RIA/FIA and a basal level with the IFMA. This implies that in RIA/FIA measurements, proteins other than intact FSH and LH interfere with the analysis at proestrus Day 2 for FSH and in HYPEX, cycling, and OVX rats for LH.

Impaired Adrenocorticotropin-Adrenal Axis in Combined Pituitary Hormone Deficiency Caused by a Two-Base Pair Deletion (301–302delAG) in the Prophet of Pit-1 Gene1

The Prophet of Pit-1 gene (PROP1) encodes a paired-like homeodomain protein, which is expressed early in pituitary gland development. When mutated, it is responsible for combined pituitary hormone deficiency (CPHD) in humans, as well as in Ames dwarf mice (df/df). Several independent mutations in the homeodomain of PROP1 have been identified as causative for the human CPHD phenotype, which has been characterized, thus far, as absence or low levels of GH, PRL, TSH, LH, and FSH. Here, we report 10 CPHD cases, 9 of which were born to consanguineous marriages occurring in a large family living in an isolated area in the Southeast of Brazil. All affected patients present complete absence of puberty and low GH, PRL, TSH, LH, and FSH associated with severe hypoplasia of the pituitary gland, as seen by MRI. All 3 exons of the PROP1 genes of these patients were sequenced. The 301-302delAG frameshift mutation was found in both alleles of each affected case. Surprisingly, we observed ACTH/cortisol insufficiency associated with the PROP1 phenotype. The patients' ages varied between 8 and 67 yr, and cortisol response impairment was identified in 5 of 6 of the older patients and in an 11-yr-old patient. Previous studies have not fully characterized patients at advanced ages, leading us to conclude that the phenotype of this PROP1 mutation includes late-onset adrenal insufficiency. We present an extensive clinical analysis of all of these patients. The presence of ACTH/cortisol deficiency in this family bearing the PROP1 301-302delAG mutation indicates the importance of a complete endocrine characterization and of life-long monitoring of PROP1 patients.

Serum Dihydrotestosterone and Testosterone Concentrations in Human Immunodeficiency Virus‐Infected Men With and Without Weight Loss

Weight loss is an important determinant of disease outcome in human immunodeficiency virus (HIV)-infected men. Others have suggested that a defect in dihydrotestosterone (DHT) generation contributes to weight loss in HIV-infected men. To determine whether DHT levels correlate with weight loss independently of changes in testosterone levels, we prospectively measured serum total- and free-testosterone and DHT levels in 148 consecutive HIV-infected men and 42 healthy men. Thirty-one percent of HIV-infected men had serum testosterone levels less than 275 ng/dL, the lower limit of the normal male range; of these, 81% had normal or low LH and FSH levels (hypogonadotropic), and 19% had elevated LH and FSH levels (hypergonadotropic). Overall, serum testosterone, free-testosterone, and DHT levels were lower in HIV-infected men than in healthy men, but serum DHT-to-testosterone ratios were not significantly different between the two groups. Serum total- and free-testosterone levels were lower in HIV-infected men who had lost 5 lb or more of weight in the preceding 12 months than in those who had not lost any weight. Serum DHT levels and DHT-to-testosterone ratios did not differ between those who had lost weight and those who had not. Serum testosterone and free-testosterone levels, but not DHT levels, correlated with weight change and with Karnofsky performance status. We also performed a retrospective analysis of data from a previous study in which HIV-infected men with serum testosterone levels less than 400 ng/dL had been treated with placebo or testosterone patches designed to nominally release 5 mg testosterone over 24 hours. Serum testosterone-to-DHT ratios did not change after testosterone treatment. Changes in fat-free mass were correlated with changes in both serum testosterone (r = 0.42, P = 0.018) and DHT (r = 0.35, P = 0.049) levels. Serum total- testosterone and DHT levels were highly correlated with one another, and when the change in serum testosterone was taken into account, serum DHT levels no longer showed a significant correlation with change in fat-free mass. We conclude that DHT levels are lower in HIV-infected men than in healthy men but that neither DHT levels nor DHT-to-testosterone ratios correlate with weight loss. During testosterone treatment, serum DHT levels increase proportionately, but the increments in serum testosterone correlate with the change in fat-free mass. Our data do not support the hypothesis that a defect in DHT generation contributes to weight loss in HIV-infected men independently of changes in testosterone levels; it is possible that such a defect might exist in HIV-infected men with more severe weight loss.

Programming ovulation in the menstrual cycle by a simple innovative approach: back to the future of assisted reproduction

Objective: To synchronize the intercycle FSH elevation with exogenous E 2 for programming ovulation in the menstrual cycle. Design: Open single-arm study. Setting: Teaching hospital. Patient(s): Twenty-six patients with infertility whose menstrual cycles normally lasted 25–35 days and who underwent our routine programming method for postcoital tests and ovulation evaluations. Intervention(s): Participants received estradiol valerate (2 mg) twice a day from day 25 of the previous cycle until 1–15 days after the onset of menses. Women had ultrasonography on the last day of E 2 treatment or on functional day 0 and 13 days later or on functional day 13. Hormones were determined on functional days 0, 3, 9, and 13. The increase in FSH in response to E 2 withdrawal was defined as ΔFSH. Main Outcome Measure(s): LH surge and other ovulatory indices on functional day 13. Result(s): On functional day 13, 73% of the women had an LH surge. Fifteen percent had evidence of previous ovulation with low LH and elevated plasma P levels, and the remaining 12% had low LH levels and no evidence of past or imminent ovulation. Women with evidence of early ovulation were older and had higher FSH signal amplitude. Conclusion(s): It is feasible and practical to program ovulation in the menstrual cycle with exogenous E 2. In 73% of women, the true duration of the follicular phase (intercycle FSH elevation to LH surge interval) remained constant (13 days). Hence, common fluctuations in menstrual cycle length mainly result from variations in the timing of the intercycle FSH elevation. Although rare, truly short follicular phases also exist (15%). This simple and practical system for programming natural ovulation offers new possibilities for using the menstrual cycle in assisted reproductive technology, at least in selected individuals.

Requirements for human chorionic gonadotropin and recombinant human luteinizing hormone for follicular development and maturation.

Our purpose was to evaluate the requirements for human chorionic gonadotropin (hCG) and recombinant luteinizing hormone (rec-LH) for follicular development and maturation in mice. We carried out ovarian stimulation of immature mice. Output parameters were the preembryos created in vivo and frequency of blastocyst formation in vitro. hCG at 0 to 1 IU resulted in a dose-dependent recovery of preembryos (0 to 39.7 +/- 4.3; mean +/- SE) per mouse. hCG at 1 and 10 hCG gave similar results, whereas higher doses significantly reduced the number of preembryos. Potential for blastocyst formation was independent of hCG dose. hCG and rec-LH together exerted a synergistic effect on the recovery of preembryos. Optimal follicular development required a combination of 20 IU follicle stimulating hormone and 1-10 IU hCG. The potency of hCG was higher than that of rec-LH, but a synergistic effect of rec-LH and hCG was observed. The results may be pertinent for the development of strategies for ovarian stimulation of women with low levels of endogenous LH.

The Effect of Food Intake from 2 to 24 Weeks of Age on LHRH-I Content in the Median Eminence and Gonadotrophin Levels in Pituitary and Plasma in Female Broiler Breeder Chickens

The present study describes the effect of long-term food restriction on hypothalamopituitary function in the broiler breeder hen during the period prior to sexual maturity. From 1 week of age onward, chickens were divided into 3 groups: one group received foodad libitum(Ad lib); a second group was fed a restricted quantity of food (Res); and a third group was restricted to obtain an intermediate body weight (Int) in between groups one and two. The effects of these feeding regimes on hypothalamopituitary function were assessed by measuring the amounts of cLHRH-I stored in the median eminence (ME) and the pituitary content and plasma levels of gonadotrophins. The Res group had significantly lower levels of cLHRH-I in the ME compared to the Ad lib animals. In all groups, there was a major increase in cLHRH-I in the median eminence about 3 weeks before onset of lay. The age of first oviposition was delayed by 2 and 6 weeks in the Int and Res groups, respectively, compared to the Ad lib animals, indicating that body weight gain patterns are not directly related to the appearance of the first egg. The attainment of sexual maturity may be associated with a threshold value of cLHRH-I stored in the ME in the Ad lib and Int birds. The pituitary LH and FSH contents (after week 16) were positively related to the amount of cLHRH-I in the ME. Plasma FSH concentrations in Ad lib and Int chickens peaked about 3 weeks before the first oviposition and this prepubertal peak was associated with increased pituitary FSH and ME cLHRH-I. There were however no relationships between plasma LH concentrations and pituitary LH content and between plasma LH and cLHRH-I amounts in the ME. The present study demonstrates that the delayed sexual maturation, caused by a chronic food restriction, may be associated with (1) delayed ovarian and oviductal growth, (2) decreased cLHRH-I storage in the ME, and (3) lower levels of LH and FSH in the pituitary. These hormones were however not directly related to levels of food restriction.

Progesterone implants delay age-related declines in regular estrous cyclicity and the ovarian follicular reserve in Long-Evans rats.

The present study examined the effects of progesterone (P4) treatments on estrous cyclicity and the loss of ovarian follicles during aging. Young rats received repeated treatments with P4 or empty implants between 3.5 and 8 mo of age. At 8 mo, ovaries were obtained from some animals to determine the numbers of resting follicles, and estrous cycle patterns and hormone levels were determined from other groups of treated females. In contrast to the cyclic increases in P4, estradiol (E2), LH, and FSH in control animals, P4-implanted rats exhibited elevated serum P4 but low E2, LH, and FSH levels. After implant treatments, the follicular reserve was significantly (p < 0.05) larger in P4-treated females (2012 +/- 297 resting follicles per ovary, n = 5 rats per group) than in regularly cyclic control rats (713 +/- 226 follicles per ovary, n = 7). The effects of P4 implants on the follicular reserve were associated with a subsequently higher incidence of regular estrous cycles after P4 treatment. These results demonstrate that P4 prevents cyclic increases in E2 secretion and is associated with a conservation of the ovarian follicular reserve and the maintenance of regular estrous cycle patterns, indicating a protective effect of P4 on the age-related loss of ovarian follicles.

Neonatal immunization against gonadotropin-releasing hormone (GnRH) results in diminished GnRH secretion in adulthood.

The effects of neonatal immunization against GnRH were studied in sheep after they had reached adulthood (3-4 yr) and the antibody titers had fallen to undetectable levels. The immunized animals had small gonads, and the females did not have large follicles (>3 mm) or corpora lutea in their ovaries. Compared with controls, the immunized animals had low or nondetectable levels of LH and FSH in peripheral plasma, and the immunized animals generally failed to respond to a single i.v. GnRH challenge. After ovariectomy, the control ewes, but not the immunized ewes, showed an elevation in plasma LH and FSH levels. The sampling of hypophysial portal blood, with a newly described method, showed that the secretion of GnRH was reduced in the immunized animals, but the amount of GnRH in the median eminence was similar in the control and immunized ewes. The pituitary content of LH and FSH was reduced in the immunized ewes as was messenger RNA for the gonadotropin subunits and the GnRH receptor. These data indicate that neonatal immunization does not affect the synthesis of GnRH in adulthood but reduces the secretion of GnRH, causing long-term sterility in these animals.

Assessment of the Role of Serum Luteinizing Hormone and Estradiol Response to Follicle-Stimulating Hormone on In Vitro Fertilization Treatment Outcome

Objective: To analyze the role of serum LH and of E 2 secretion on IVF-ET outcome in patients stimulated with FSH. Design: Using data from three studies, we analyzed ovarian response to FSH and IVF-ET outcome from two standpoints: [1] serum LH and [2] serum E 2 on the day of hCG administration divided by the number of retrieved oocytes. Setting: Twenty-six academic and private clinical centers. Patient(s): Three hundred twenty-three ovulatory patients eligible for IVF-ET. Intervention(s): Patients were treated with a GnRH agonist and FSH and underwent IVF-ET. Main Outcome Measure(s): Follicular development, embryos, and pregnancy rate (PR). Result(s): Serum LH levels did not correlate significantly with number of oocytes retrieved, E 2-oocyte ratio, fertilization rate, or PR. Five patient subpopulations were identified on the basis of E 2-oocyte ratios: 0 to 70 (A), 70 to 140 (B), 140 to 210 (C), 210 to 280 (D), and >280 (E) pg/mL per oocyte (conversion factor to SI unit, 3.671). Pregnancy rates were significantly different, i.e., 5.3%, 31.3%, 18.1%, 23.9%, and 20.4% for groups A, B, C, D, and E, respectively. Groups were not different in terms of baseline characteristics, number of follicles, fertilization rates, and number of embryos transferred. Conclusion(s): Patients with very low levels of LH respond to FSH alone as well as those with higher LH. The E 2-oocyte ratio is a strong index of success rate.

Relation of Luteinizing Hormone Levels to Body Mass Index in Premenopausal Women

Objective: To assess the relationship between body mass index (BMI) and basal LH and the LH-FSH ratio in normally menstruating women. Design: Cross-sectional analysis. Setting: A teaching hospital clinic. Patient(s): Premenopausal women without cancer, not currently using oral contraceptives, selected from a familial ovarian cancer clinic or the general population. Intervention(s): None. Main Outcome Measure(s): Early follicular phase plasma LH and FSH. Result(s): Luteinizing hormone increased slightly and nonsignificantly ( P = 0.44) from the first to the second quintile of BMI and decreased over all subsequent quintiles. Women in the highest quintile of BMI (>27.1) had significantly lower LH levels than women in the lowest quintile of BMI (≤20.4; P = 0.003). Compared with women in the second quintile of BMI who had the highest LH levels, women in the highest quintile of BMI had LH levels that were 40% lower. The relationship between BMI and the LH-FSH ratio was similar, though not as strong. Conclusion(s): Over most of the range of BMIs observed in this study, BMI was inversely associated with LH. These results suggest that the upper limits of normal for LH may need to be shifted downward for heavier women.

Ovarian Steroidogenesis in Congenital Adrenal Hyperplasia (CAH) 30

Amenorrhea and menstrual disorders are frequent in women with CAH, and have been attributed to excessive androgen and/or progestin production. With the aim of analyzing the ovarian steroidogenesis in CAH, 8 young women with 21-OHlase deficiency on corticoid treatment (CA 21.8±3.3 y.), 4 amenorrheic(Am) and 4 with spontaneous menstrual cycles(SC) were studied. Serum LH, FSH, Estradiol (E2), Androstenedione (A), Testosterone (T), 17-hydroxyprogesterone (17OHP) and Progesterone (P) were determined in the basal state(b). Then 150 IU/day purified FSH was given and the same hormone levels were daily measured until an E2 level ≥150 pg/ml was reached or up to a 5 days maximum FSH administration. FSH levels increased under treatment from (x ± SD) 3.0 ±1.8 to 9.0±2.3 IU/L(p<0.0002) and the E2 increase (ΔE2) was 278±158 pg/ml. A significant positive correlation was observed betweenΔ E2 and: bE2(p<0.05), bT(p<0.02), and bA(p<0.02). Basal hormonal levels of the 4 Am patients compared to those of the 4 SC patients showed higher P levels, 4.4±3.9 vs 1.2±0.4 ng/ml (p < 0.01), lower LH levels, 4.1±1.7 vs 7.7±2.6 IU/l (p< 0.05) and a tendency to lower FSH, 1.8±1.4 vs 4.1±1.3 IU/l(p = 0.06). Conclusion: 1)The ovarian ability to secrete E2 in response to exogenous FSH seems not to be impaired in CAH 2)The E2 response was better in those patients with higher basal estrogen and androgen levels 3)The higher P concentration found in amenorrheic patients suggests a role of this steroid in the menstrual abnormality, probably through an inhibition of gonadotropin secretion.

Worldwide frequency of a common genetic variant of luteinizing hormone: an international collaborative research

Objective: To determine the worldwide frequency of a common immunological LH variant because of two point mutations in the LH β-subunit gene (Trp8Arg and Ile15Thr). Design: Cross-sectional study on LH status (variant and wild-type) in serum (or DNA) samples from Finland (Finns and Lapps), Estonia, Poland, Sweden, The Netherlands, United Kingdom, Italy, South Africa (blacks), Thailand, China, Japan, and the United States (Hispanics and blacks). Setting: Academic research environment. Patient(s): Ambulatory adult men and women (n = 2,936) with minor illnesses and no known endocrinological disorders. Intervention: A single blood sample was collected from each subject. Main Outcome Measure(s): The LH status was determined by two immunofluorometric assays using monoclonal antibodies. One (assay 1) only recognizes the wild-type LH, the other (assay 2) recognizes equally variant and wild-type LH. The ratio of assay 1 to assay 2 indicates the LH status: wild-type, >0.9; heterozygote, 0.2 to 0.9; and homozygote, < 0.15. One population (Lapps) was studied by DNA analysis using polymerase chain reaction and allele-specific oligonucleotide hybridization. Result(s): The carrier frequency of the variant LHβ allele varied from 7.1% in U.S. Hispanics to 41.9% in Lapps of northern Finland. The variant LHβ allele tended to be more common in populations from Northern Europe as compared with those from Asia. Conclusion(s): The high frequency of the LHβ variant worldwide makes it an important confounding factor when obtaining disproportionately low LH levels with some immunometric assays. The LH variant may contribute to some pathologies of the pituitary-gonadal function.

Unilateral cryptorchidism corrected in prepubertal age: evaluation of sperm parameters, hormones, and antisperm antibodies in adult age

Objective: To evaluate whether prepubertal orchidopexy for unilateral cryptorchidism can reduce adult dysspermia. Design: Patient follow-up comparison with control groups. Setting: Surgical and endocrinologic sections of a children's hospital and a university infertility-care center. Patient(s): Seventy-one patients with unilateral cryptorchidism who underwent orchidopexy in prepubertal age (6.4 ± 2.8 years) were followed up as adults (20.0 ± 2.8 years). Main Outcome Measure(s): Patients underwent testicular examination and hormonal evaluation; 49 of these had semen analysis and antisperm antibody tests. Semen results were compared with those of two age-matched control groups: a group of 20 healthy, randomly selected subjects and a group of 20 patients operated on in postpubertal age for cryptorchidism. Result(s): Unilateral reduced testis size was found in 30.1% of patients, eight patients had a low LH level, eight had a low T level, and none had abnormal FSH values. Antisperm antibodies were found in 1 of 49 cases. Cluster analysis of sperm parameters showed that the mean values of patients were worse than those of the healthy controls but better than those of the subjects operated on in postpubertal age. Conclusion(s): This study indicates that prepubertal orchidopexy can give better results than postpubertal correction.

Estradiol, gonadotropins, and tumor markers in ovarian cyst fluid.

The study was designed to improve the discrimination between functional and neoplastic ovarian cysts in order to avoid unnecessary surgery. Concentrations of tumor markers (CA 125, CEA, CASA, CA 72-4) and hormones (estradiol, FSH, LH) in cyst fluid were detected by enzyme immuno- or immunoradiometric assays. Wilcoxon test was used to evaluate the correlation of cyst fluid markers and histology. One hundred and thirty-eight ovarian cyst aspirates were investigated. Seventy-one patients (51.5%) had functional cysts whereas 67 (48.5%) had benign (n=59) or malignant (n=8) cystic tumors. Statistically significant correlations of CA 125 (p<0.0005) and CASA (p<0.02) with neoplastic histology were found. No significant correlation could be detected between CA 72-4, CEA, or hormone values and histology. Elevated estradiol concentrations are suspicious for functional cysts in premenopausal age. Low FSH and LH levels seem to be an indicator for functional cysts in peri- and postmenopausal age. The assessed analytes could not reliably distinguish between functional and neoplastic ovarian cysts. Our results indicate that CA 125 is a marker for neoplastic histology in a proportion of ovarian cysts. The use of FSH and LH in the diagnosis of postmenopausal blastomas needs further investigation.