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Comparisons of the potential utility of LHRH agonists and antagonists for fertility control.

Prospects for the use of LHRH analogs for human fertility control have been reviewed with particular reference to two highly potent representatives. Nafarelin acetate, the LHRH agonist, has a potency about 200 X that of LHRH and is consistently effective in suppressing gonadal function in females through a desensitization of LHRH receptors in the pituitary. Such agents show promise as ovulation inhibitors for women although concern has been expressed over the dangers of unopposed estrogen or alternatively hypoestrogenemia. Although early studies indicated luteolysis in women and interceptive action in baboons it is now clear that the LHRH agonists will not be useful clinically to terminate pregnancy. Wide species differences in the male response to LHRH agonists exist. Unfortunately azoospermia has not been achieved in men. The LHRH antagonists, typified by [N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10]LHRH, require high doses to competitively inhibit responses to endogenous LHRH. Their advantages include a rapid induction of the hypogonadal state with apparently little species or sexual variation in response. Based on animal studies, preferable utility of the antagonists would lie in male contraception and pregnancy interception.

Abortion, Induced↗

Hyposexuality and epilepsy: a community survey of hormonal and behavioural changes in male epileptics.

A survey of five group practices in South London identified 60 male patients currently undergoing treatment for epilepsy. Fifty-four agreed to participate in a detailed enquiry into aspects of their sexual activity and behaviour. Anterior pituitary and sex-hormone levels were measured. The epileptic patients were characterized by low levels of sexual activity and interest. Temporal-lobe and non-temporal-lobe epileptics were indistinguishable in these respects, but when the latter group was further subdivided into primary generalized epilepsy and focal non-temporal lobe epilepsy, the focal groups (both temporal lobe and non-temporal lobe) were more impaired. Hormonal analysis confirmed earlier hospital-clinic-based reports. In the epilepsy group, plasma free testosterone and percentage free testosterone values were decreased, sex hormone binding globulin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were increased compared to values in a normal healthy population. As association between the behavioural and hormonal indices of hyposexuality was shown, particularly for LH, but this was less apparent than in previous work.

Adolescent↗

Synthesis and biological activity of luteinizing hormone-releasing hormone and related peptides.

Syntheses of the decapeptide luteinizing hormone-releasing hormone, less thanGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 are described. The basic properties of arginine can provide a simple repetitive isolation procedure for arginine-containing peptides. The biological activities of the decapeptide, of a range of fragments and modified fragments, and of two analogs with alteration in the series at position 4 were measured by in vitro incubation with sheep pituitary slices, measuring the liberated LH by bioassay. None of the compounds of shortened sequence were active, with the exception of less thanGlu-His-Trp which showed 1% of the decapeptide in one of four experiments. Neither [Ser(But)4]-LH-RH-nor [Leu4]-LH-RH showed significant activity indicating (despite the known activity of [Ala4]-LH-RH) the importance of this part of the structure for full biological activity.

Amino Acid Sequence↗

An inexpensive method for assessing pituitary response to luteinizing hormone releasing hormones: analysis of serum gonadotropins in pooled samples.

Sixty-two children, aged 2-18 years, suspected of an endocrine disorder were given one of several IM injections of the LHRH and the blood was drawn prior to and at 30, 60, 90, 120, 240 minutes after the injection. An aliquot of .2 ml of serum was taken from each post-LHRH specimen and pooled. The gonadotropins were measured in all the individual and pooled samples. A high correlation (r = .974, LH; r = .981, FSH) between the peak and the pooled sample suggests that the analysis of gonadotropins in a pooled sample gives information comparable to that obtained by the gonadotropin analysis in multiple serum samples. A formula to calculate the peak LH and FSH from the pooled specimen taken from only four post-LHRH injections is: peak LH = 3.015 + 1.049 times the pooled LH; peak FSH = 3.153 + 1.072 times the pooled FSH value. The correlation coefficient between the observed and the calculated LH was .98; the same for the FSH was .987. I suggest that the pooled sample, due to it's integrated response, is a better reflection of the pituitary response to the LHRH.

Adolescent↗

[Rational hormonal diagnosis of secondary amenorrhea].

The usefulness of the guideline recommended in 1976 by the World Health Organization (WHO) for the differential diagnosis of ovarian sterility needs critical reevaluation, since it does not take into account new aspects such as the pulsatility of GnRH secretion, androgen excess, or thyroid disorders and other phenomena related to ovarian dysfunction. In order to demonstrate the relative frequency of such phenomena, the authors examined 183 women with secondary amenorrhea of more than three months' duration (mean +/- SD = 12.7 +/- 18.4 months). The endocrine status of these women was examined under standardized conditions in two clinical endocrinology units in the cities of Hamburg and Berlin. The percentages of abnormal hormonal data (greater than mean +/- SD + gray zone) were as follows: testosterone (T) 39.9%; DHEA sulfate (DS) 29.5%; prolactin (PRL) 18.0%; TSH 11.5%; FSH or LH 26.8%; estradiol (E2) 30.1%. Among 96 patients with increased T and/or DS (52.5% of all patients), 53 patients (55.2%) did not show any clinical signs of androgenization (hirsutism, acne). Retrospective evaluation of all data revealed that a stepwise diagnostic procedure would have resulted in the following cumulative percentages of hormonal abnormalities: (1) T = 39.9%; (2) +DS = 52.5%; (3) +PRL = 60.2%; (4) +LH/FSH = 82.0%; (5) +E2 = 91.2%; (6) +TSH = 92.3%. Only in 7.7% of all patients were all hormonal parameters within normal ranges. Individual case analysis showed that 52.5% of all patients had hyperandrogenemia, while 18% had hypothalamic amenorrhea without any other pathologic condition; 17.5% had hyperprolactinemia and 3.3% primary ovarian insufficiency. Another 4.9% had hypothyroidism only, while 1.1% had exclusively hyperthyroidism. Combined hormonal deviations were found in 24% of all patients. Considering the differential diagnosis of secondary amenorrhea from an economic point of view, one comes to the conclusion that direct and indirect expenditures are similar in magnitude, no matter whether one prefers a conventional stepwise procedure or a one-step hormonal analysis encompassing all potentially relevant hormones (DM 859.00 + 10 weeks waiting time vs. DM 827.50 + 1 week waiting time). Androgen excess is much more frequent than was believed; hirsutism and/or acne by no means necessarily occur in cases of androgen excess. Hyperprolactinemia is less frequent than hyperandrogenemia. Thyroid status should be evaluated in all women with functional amenorrhea. The stepwise diagnostic procedure as recommended by the WHO is time-consuming, complicated, and sometimes incomplete in the diagnostic work-up, with obvious potential disadvantages for therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

Ovarian follicular dynamics in the llama.

Ovarian follicular dynamics were determined in adult llamas by ultrasonography and palpation per rectum and hormone analysis (estradiol-17 beta and estrogen conjugates) of plasma and urine. The relationship of gonadotropin secretion to follicular development was determined by the analysis of plasma FSH and LH concentrations. Progesterone analysis of plasma was used to verify or deny the presence of CL. Final follicular development (from 3 mm) averaged 4.8 days, while the duration of the mature follicle (8-12 mm) averaged 5.0 days; regression of the follicle occurred over about 4 days. The development of a subsequent dominant follicle usually began within 2-3 days after onset of regression of the dominant follicle. While several follicles were present at the time of the demise of the dominant follicle, only one follicle continued to develop. The interval between ovarian follicle waves averaged 11.1 days. Dominant follicle activity alternated between ovaries in 81% of the cycles. The occurrence of dominant follicles was evenly distributed between ovaries. While plasma estradiol and estrogen conjugate concentrations were positively associated (p less than 0.05) with follicular activity, urinary estrogen conjugate concentrations best reflected ovarian follicular dynamics (p less than 0.001). Daily FSH concentrations in plasma were not correlated with follicular activity. LH concentrations in plasma were low in all animals throughout the study, indicating estrogen from developing ovarian follicles does not induce the release of LH. Progesterone values were low during the study, indicating that the llama does not spontaneously ovulate, at least under the conditions of this study. In summary, llamas have overlapping ovarian follicle waves that occur at about 11-day intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Testicular volume, semen profile and serum hormone levels in fertile Thai males.

The fertility profile of 307 Thai male volunteers whose wives were currently in early pregnancy was established by genital examination, semen analysis and serum hormone analysis. Ninety percent of the subjects had testicular volumes of 12-25 ml (mean 17.2 ml) which was found to relate to body weight, height and the ponderal index as well as to the sperm count. However, values for semen analysis were significantly below the recognised standard for Caucasian males. There was an inverse relationship between testicular volume and the serum concentration of FSH, LH and prolactin. It is suggested that a common protocol for male fertility assessment should be used to establish standard parameters for racially different male populations.

Adolescent↗

Hormone studies in females with androgenic hairloss.

Reports on hormone analysis in androgenic hairloss in the female show partly contradicting results. Elevated as well as normal-range androgen levels have been found. The present study aimed at the investigation of a possibly more differentiated hormonal constellation by hormone analysis and additional determination of the hypophyseal level by the thyrotropin-releasing hormone (TRH) test. In 46 female patients with androgenic hairloss blood sampling for hormone analysis was performed. Determination of the androgens testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxy-progesterone acetate (17-OHP) and free testosterone (FT), of sex-hormone-binding globulin (SHBG), estradiol (E2), cortisol (F) and the hypophyseal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was performed by standard radioimmunoassay methods. The TRH-test is based on feedback mechanisms between the hypothalamic TRH which stimulates hypophyseal TSH and PRL release. Thus, even mild forms of hypothyroidism or hyperprolactinaemia can be detected. The control group for the TRH test consisted of 45 volunteer females without hairloss or any other hormonal or menstrual disturbances. Statistical analysis was performed according to the Wilcoxon two-sample test. The results of the study show no significant elevation of androgens in females with androgenic hairloss, but a more complex condition with involvement of the glandula suprarenalis and the hypophyseal level. Significantly elevated TSH levels prior to and after TRH stimulation in the hairloss group indicate that hypothyroidism may be an important hormonal disturbance in androgenic hairloss. Interactions between hypothyroidism and androgen metabolism are possible at various links.(ABSTRACT TRUNCATED AT 250 WORDS)

17-alpha-Hydroxyprogesterone↗

Hormone serum levels and hormone receptor contents of endometria in women with normal menstrual cycles and patients bearing endometrial carcinoma.

Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (HPRL), 17 beta-estradiol (E2) and progesterone (P) were estimated in 46 subjects with normal menstrual cycles in whom hysterectomies were performed. Estrogen (ER) and progesterone receptor (PgR) levels in endometrial samples of these patients were estimated, and histological dating of the cycle day was carried out. Similarly, hormone serum levels and ER as well as PgR were estimated in 17 patients with endometrial carcinoma. No correlation between LH, FSH, HPRL and ER as well as PgR was noted in the normal subjects. Correlation between P and ER was observed in this group. Parallel variations between E2 and PgR were recorded in the normal females. In the carcinoma group no correlations between hormone serum levels and receptor contents were found, but ER and PgR correlated with each other. Receptor levels was highest in the well-differentiated group of endometrial carcinoma. The present experiments provide a rationale for progestagen therapy of carcinoma of the endometrium.

Endometrium↗

Plasma levels of adrenocorticotropin and cortisol in women receiving oral contraceptive steroid treatment.

The secretion rate and plasma concentration of the adrenocortical steroid cortisol is modified in subjects treated with estrogenic and/or progestational steroids. The effects of contraceptive steroids on the secretion of ACTH are poorly documented, however, In the current investigation, we found that concentrations of ACTH and cortisol in plasma obtained at 0800--0900 h from a group of women with normal cyclic menses (n = 4) ranged from 78--120 pg/ml and 77--137 ng/ml, respectively. Although significant cyclic changes in the plasma levels of LH, FSH, 17 beta-estradiol, and progesterone occurred during the ovarian cycle, no obvious cyclic fluctuations in plasma levels of ACTH or cortisol were observed. In women treated with Norinyl 1 + 80 (1.0 mg norethindrone plus 0.08 mg mestranol), plasma concentrations of LH, FSH, 17 beta-estradiol, and progesterone were significantly lower (P less than 0.001) than plasma levels of these hormones in normal women during the ovarian cycle. The mean daily plasma concentrations of ACTH were significantly lower (P less than 0.001), whereas plasma cortisol levels were significantly higher (P less than 0.001) in women treated with oral contraceptive steroids compared to the levels of these hormones in the untreated ovulatory women.

Adrenocorticotropic Hormone↗

Influence of suckling and of suckling followed by TRH or LH-RH on plasma prolactin, TSH, GH and FSH.

Ten women were studied during the first post-partum week. Suckling for 20 min induced a marked increase in plasma prolactin, reaching a maximum within 0-25 min after the end of suckling and then returning to pre-suckling levels after 120 min. Suckling induced no changes in plasma thyrotrophin (TSH), growth hormone (GH) or follicle stimulating hormone (FSH). The iv injection of 200 mug of thyrotrophin releasing hormone (TRH) immediately after suckling resulted in an additional increase in plasma prolactin and a rise in TSH. When given 120 min after suckling TRH was followed by increased plasma levels of prolactin and TSH, which for both hormones were of a magnitude comparable to the TRH induced increment seen immediately after suckling. Thus, suckling did not inhibit the effect of TRH on the release of TSH. These studies indicate that TRH is probably not involved in the suckling induced increase in prolactin secretion. The mean plasma FSH level was below the limit of detection before and after suckling. Neither plasma FSH nor prolactin showed any appearant changes following the iv injection of 25 mug of luteinizing hormone releasing hormone (LH-RH), when given immediately after and 120 min after suckling. When given after suckling as indicated above, TRH induced no changes in plasma GH or FSH and similarly LH-RH was without influence on plasma GH and TSH.

Adult↗

Evidence for the action of bovine follicular fluid factor(s) other than inhibin in suppressing follicular development and delaying oestrus in heifers.

The aim of this study was to investigate the importance of inhibin in the delay in return to oestrus in heifers induced by steroid-stripped bovine follicular fluid (bFF). Oestrous activity was synchronized in 18 Hereford x Friesian heifers with two injections of prostaglandin (PG) 12 days apart. At the time of the second PG injection (time 0), the animals were assigned at random to one of three experimental groups and received i.v. injections of 20 ml saline (controls, n = 6), whole bFF (FF group, n = 6) or bFF in which the bioactive inhibin content had been reduced by > 95% by immunoaffinity chromatography (-INH group, n = 6; inhibin content approximately 0.8 ml whole bFF) every 8 h for 2 days. In a dose-response study, 2.5 ml whole bFF was insufficient to delay oestrus consistently following a similar synchronization regimen. Blood samples were taken every 8 h, initially before each injection and then subsequently for a further 9 days for hormone analysis. Animals were observed every 8 h throughout the experiment for signs of behavioural oestrus. The ovaries of all animals were examined using real-time ultrasonography about 30 h after the second PG injection. Treatment failed to suppress peripheral follicle-stimulating hormone (FSH) concentrations, although a significant increase was observed in both treatment groups after cessation of injections. Progesterone concentrations fell immediately after the second PG injection in all animals and remained below minimum detectable concentrations in all treated animals for the remainder of the experiment. In control animals, progesterone rose above minimum detectable concentrations by day 6 and continued to rise until the end of the experiment. Analysis of samples taken from treated animals several days after observed oestrus revealed that all had apparently ovulated. Mean daily luteinizing hormone (LH) concentrations did not differ between treatment groups before ovulation, but after ovulation, mean daily LH was significantly reduced in control animals as progesterone concentrations rose. Follicular development, as assessed by the mean antral diameter of the largest follicle on a pair of ovaries at ultrasound examination, was significantly suppressed in treated animals compared with controls (P < 0.01) and there was no significant difference (P = 0.397) between the two treatment groups. Control animals displayed oestrus 68 h (+/- 8 SEM) after the second PG injection, but oestrus was delayed in treated animals to 186h +/- 5 (FF group) and 191 h +/- 6 (-INH group).

Analysis of Variance↗

Evaluation of danazol as an oral contraceptive.

The effect of Danazol as an oral contraceptive in doses of 50, 100, and 200 mg daily for 6 months was studied in 3 groups of 10 women. Both 50 and 100 mg Danazol daily were well tolerated, but one pregnancy occurred among the women receiving 50 mg daily, and 2 pregnancies occurred in women receiving 100 mg daily. There were no pregnancies in women taking 200 mg Danazol daily; however, the side effects were frequent and 5 of the 10 patients withdrew from the study prior to 6 months of therapy. Six patients in this study were followed intensively with blood hormone analysis, vaginal cytology, and pathologic evaluation, and these findings are detailed.

Acne Vulgaris↗

[Experimental endocrinological studies in gilts near the time of ovulation using Gn-RH vet. "Berlin Chemistry"].

Knowledge of endocrine processes in pro-oestrus and oestrus in conjunction with physiological alterations is of greatest importance to biotechnological control of follicular maturation and ovulation. Methods of hormonal analysis and ovarian diagnosis were used to check on the effectiveness of Gn-RH vet. "Berlin-Chemie" for induction of the luteinising hormone (LH) peak and ovulation. Release in gilts of LH was found to depend on dosage, after 100, 300, and 900 micrograms Gn-RH had been administered at 3 p.m. on the 4th day after synchronisation of ovulation. LH release and induction of ovulation due to these variants were insufficient in some of the animals. Ovulation was then decisively improved in animals with LH peak by subsequent injection of 300 or 900 micrograms Gn-RH at 8 a.m. on the 5th day. Repetitive injections of 300 micrograms Gn-RH at 8 and 8.45 a.m. on the 5th day did not trigger off increased LH release from the pituitary gland. The Gn-RH effect was substantially improved by use of an absorption-retarding preparation (polystyrene sulphonic acid).

Animals↗

[Therapeutic results with tamoxifen in oligospermia. II. Hormonal analysis and semen parameters].

During a five months lasting treatment with tamoxifen (2 X 10 resp. 2 X 20 mg daily) a significant increase of testosterone, LH, FSH, estradiol, free testosterone and SHBG was found. The prolactin levels diminished. In semen analysis the values of pH and fructose decreased within the normal range. The sperm density increased significantly, but we could not ascertain whether a dosage of 2 X 20 mg/die will provide better therapeutic results. Furthermore the hormonal and seminal investigations described in this paper did not allow to predict those patients who would be good responders on tamoxifen therapy. Tamoxifen seems to be effective in normo-, but also in hypo- and hypergonadotropic patients.

Estradiol↗

Bovine cystic ovarian disease: plasma hormone concentrations and treatment.

Ovarian function in 91 dairy cows with cystic ovarian disease was assessed by rectal palpation and by plasma hormone analysis before and after treatment. Plasma analysis showed that 84% of the cysts were correctly classified clinically and only these cows are considered further. Luteinised cysts occurred in 59 cows whereas only 18 had non-luteinised cysts. The mean plasma concentrations of luteinising hormone (LH), follicular stimulating hormone (FSH), progesterone, oestradiol and testosterone were not significantly different when compared with values at relevant stages of the oestrous cycle in normal cows. Success of treatment with progesterone, a synthetic prostaglandin, human gonadotrophin (HCG), or gonadotrophin releasing hormone (GnRH) was not dependent upon prior hormone concentrations, except for the prostaglandin which required active luteal tissue. LH and FSH concentrations in cows with luteinised cysts were not significantly different before and after successful treatment with GnRH or progesterone. Normal luteal function was not always established after treatment of non-luteinised cysts with GnRH.

Animals↗

Changes of serum testosterone and of LH-RH test after treatment of cryptorchidism by intranasal LH-RH.

The aim of the present investigation was to study, in a collaborative double-blind study, the treatment with intranasal LH-RH application of boys aged 1 1/2 to 12 years, who suffered from unilateral or bilateral cryptorchidism. A total of 88 subjects were randomly and blindly allocated to LH-RH and placebo therapy. Before and after 4 weeks of treatment basal testosterone serum levels were estimated and LH-RH tests were performed. Intranasal treatment with LH-RH resulted in partial or complete descents of testes in 23 out of 88 patients, whereas the position of testes remained unchanged in 17 subjects. 42 boys did not respond to placebo therapy, but complete descents were observed in 6 boys of the placebo group. Hormone analysis data of 4 different laboratories were recorded and statistically evaluated. No changes of LH, FSH and testosterone were found in the placebo groups. Only patients of the Frankfurt group responded to LH-RH test with augmented LH release after therapy (P less than 0.05). All patients treated with intranasal LH-RH showed a significant decrease of FSH release after therapy (P less than 0.05 to P less than 0.01). Basal testosterone serum levels were found to be increased after therapy only in the patients treated at Zürich (P less than 0.05). Data of the present study combine to suggest that chronic application of LH-RH may result in an overstimulation phenomenon, and that LH-RH test as well as basal testosterone levels cannot be used as prognostic index of therapy efficacy.

Administration, Intranasal↗