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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↗

[Inhibition of ovulation with 17-alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol plus ethinylestradiol].

A combined oral application of 30 micrograms ethinylestradiol with 50 micrograms 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol (a newly developed progestagen) -- for 21 days resulted in a distinct antigonadotrophic effect, shown by hormone analysis (LH, FSH, estradiol and progesterone) in serum samples of three healthy and fertile women. A final recommendation on the daily dosage, however, depends on the results of clinical experimental investigation still in progress.

Estradiol↗

[The clinical and hormonal effects of laparoscopic multiple punch resection (MPR) of the ovary in polycystic ovary syndrome].

Eleven women with polycystic ovary syndrome (PCO) were treated with Laparoscopic Multiple Punch Resection (MPR) of the ovarian follicle and capsule and studied by hormone analysis before and after MPR. In 90.9% of the patients, ovulation appeared to occur within 9 weeks and 63.6% conceived within 26 weeks. No changes in serum LH and FSH levels were seen before and after MPR, but testosterone levels which were in the upper normal range or slightly elevated before treatment were reduced after MPR. Endocrine responses to MPR were similar to those described previously after wedge resection. Laparoscopic MPR is a simple and least invasive method and makes it unnecessary to worry about periovarian adhesion after operation. Furthermore, other causes of infertility can be examined by laparoscopy. MPR appeared to be a promising alternative treatment for patients with PCO.

Adult↗

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↗

Cystogenesis of the ovarian antral follicle of the rat: ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone.

Immature 27-day-old female Sprague-Dawley rats were administered daily subcutaneous injections of dehydroepiandrosterone (DHEA, 5 mg/100 g BW) to induce the formation of ovarian follicular cysts. Groups of rats were killed on days 0, 10, 15, 20, 25, and 30. Ovaries from each group of rats were processed for light and electron microscopy and for follicular or cystic fluid hormone analysis. Normal antral follicle fluid, PMSG-treated preovulatory follicular fluid, and cystic fluids were analyzed for progesterone (P), estrone (E1), estradiol (E2), testosterone (T), delta 4-androstenedione (delta 4-A), 5 alpha-dihydrotestosterone (DHT), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PRL). DHEA induced anovulation, acyclicity, and the formation of follicular cysts. In certain antral follicles, there was a dramatic increase in the quantities of smooth endoplasmic reticulum (SER) in the granulosa cells and many mitochondria had tubular cristae. Further depletion of granulosa cell number was associated with intense blebbing of the cytoplasm into the follicle antrum. Formation of the ovarian follicular cyst was completed when the entire cyst was lined by a single layer of transformed granulosa cells in contact via adhering, gap, and tight junctions. These cells had little cytoplasm, mitochondria with lamellar cristae, vast basal and apical bands of microfilaments, and an extensive array of smooth-surfaced endocytotic invaginations on the basal plasma membrane. These endocytotic pits may subsequently form smooth-surfaced vesicles and thereby serve as one mechanism for moving fluid from the ovarian interstitium into the cyst. Theca interna cells were rarely observed in the peripheral regions of the cyst. Abundant smooth muscle cells were located beneath the basement membrane of the epithelial cells comprising the cyst wall. These acquired morphological and physiological features may ensure persistence of the ovarian cyst and thus potentiate a chronic pathological condition. In this study it was also shown that progesterone, estrone, and estradiol as well as androgen concentration increased in the follicle after PMSG treatment. With DHEA treatment, the follicular cystic fluid concentrations of these steroids progressively increased to extremely high levels concurrent with the development of the follicular cysts.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Experimental studies on the positive feedback effect of progesterone, 17 alpha-hydroxyprogesterone and 20 alpha-dihydroprogesterone on the pituitary release of LH and FSH in the human female. The estrogen priming of the progesterone feedback on pituitary gonadotropins in the eugonadal woman.

Administration of progesterone eugonadal women during the midfollicular phase of the menstrual cycle failed to induce a positive feedback effect on the serum concentrations of LH and FSH. The levels of estradiol in serum decreased following the injection of progesterone without a parallel change in LH and FSH concentrations indicating a direct ovarian effect of the exogenous progesterone. In the late follicular phase of the cycle, when preovulatory levels of estradiol were present in serum, or under a ethinyl estradiol treatment progesterone was able to induce an LH discharge indicating the requirement of an estradiol priming of the positive feedback of progesterone in eugonadal women. In order to establish the time required for a sufficient estrogen priming with preovulatory levels of estradiol in serum 3 mg of estradiol-benzoate were administered i.m. 1, 12 and 24 h prior to the administration of 30 mg of microcristalline progesterone in the midfollicular phase of the menstrual cycle, when progesterone alone did not cause an LH surge. Only when estradiol-benzoate was injected 24 h prior to the progesterone administration an LH surge reproducible in time course and magnitude occurred. Administration of estradiol-benzoate alone under these conditions did not cause an LH surge within the elapse of time after the injection when the progesterone induced LH surge occurred. Thus, these experiments demonstrate that a defined estrogen priming is required for the positive feedback effect of progesterone on the gonadotropin release in eugonadal women. Furthermore, progesterone levels in serum of about only 1--2 ng/ml were required for the induction of an LH surge indicating that under physiological conditions progesterone may have an supplementory effect on the primarily estradiol induced LH midcycle peak. 17-hydroxyprogesterone administered during the mid follicular phase of the menstrual cycle and under pretreatment with ethinyl estradiol failed to induce a positive feedback effect on the serum concentrations of LH and FSH, indicating that this steroid does not play a regulatory role on the midcycle LH release in women. 20alpha-dihydroprogesterone administered under the same experimental conditions as 17-hydroxyprogesterone seems to be able to induce an LH surge in serum provided there is an adequate estrogen priming.

20-alpha-Dihydroprogesterone↗

Exaggerated prolactin response to thyrotropin-releasing hormone in infertile women with the luteinized unruptured follicle syndrome.

Ten cases of luteinized unruptured follicle (LUF) syndrome out of 250 women with unexplained infertility were detected on ultrasonography, giving a frequency of 4%. Hormonal analysis revealed lower serum progesterone levels at mid-luteal phase in LUF cases, suggesting a link between LUF syndrome and inadequate luteal phase. Prolactin response to thyrotropin-releasing hormone was exaggerated in LUF cases as compared with ovulatory cases. Aberrant prolactin release may be a contributory factor in the pathophysiology of the LUF syndrome.

Anovulation↗

Clinical microdose study of gossypol: effect on sperm motility and renal function.

This study is part of a series designed to identify the smallest effective gossypol dose for male fertility control. Three men, aged 31-35 years, were administered gossypol, 10 mg/day, orally for 3 months. Urinalysis and assays for plasma hormone values, including cortisol, beta 2-microglobulin, potassium, and BUN, showed no changes during treatment. Forward sperm motility, however, was severely affected by the end of the treatment period (less than 4% forward motility). Sperm density also showed a marked decrease. The subjects developed no undue side effects.

Adult↗

Gonadotropin suppression with oral contraceptives before in vitro fertilization.

One hundred eighty-one stimulation cycles in which gonadotropin suppression with oral contraceptives (OCs) preceded induction of follicle stimulation (study group) and 113 stimulation cycles without pituitary suppression (control group) were compared. The mean length of ovarian suppression was 35.3 +/- 0.9 days. No spontaneous luteinizing hormone (LH) surges occurred when the use of OC preceded ovarian hyperstimulation, whereas in the control group the incidence of LH surges was 19.5%. The mean amount of human menopausal gonadotropin required was significantly lower in the study group than in the control group (8.9 +/- 0.4 and 10.9 +/- 0.4 ampules, respectively). Significantly more follicles greater than or equal to 1.5 cm in diameter were seen on the day before oocyte retrieval and significantly more oocytes were retrieved per attempt in the group with OC pretreatment. Our data clearly demonstrate that OCs are useful in vitro fertilization stimulation protocols to facilitate scheduling of cycles and to prevent spontaneous LH surges.

Abortion, Spontaneous↗

Long-term treatment of hirsutism: desogestrel compared with cyproterone acetate in oral contraceptives.

OBJECTIVE: Effectiveness of 2-year treatment of hirsutism with low estrogen oral contraceptives (OCs) containing nonandrogenic or antiandrogenic progestogen. Evaluation of changes in plasma lipids. DESIGN: Ten patients treated with desogestrel 150 micrograms + 30 micrograms ethinyl estradiol, 6 with desogestrel 150 micrograms + 50 micrograms ethinyl estradiol, 10 with cyproterone acetate 2 mg + 35 micrograms ethinyl estradiol. Random allocation. Paired comparisons. CONTROL GROUP: 19 normal women, not treated. SETTING: Academic tertiary care. PATIENTS: Women with hirsutism (idiopathic and/or polycystic ovary), 24 of 26 completed treatment. INTERVENTION: Two-year treatment. MAIN OUTCOME MEASURES: Hirsutism score, plasma testosterone, and lipids. RESULTS: Initial hirsutism scores (11.8 +/- 0.6 SE) declined with treatment (-7.2 +/- 0.4, P less than 0.01) to 4.7 +/- 0.6, almost reaching control (3.6 +/- 0.3). Initial plasma cholesterol (4.33 mmol/L +/- 0.30 SE), similar to control (4.78 +/- 0.24), increased slowly over 2 years (+2.04 +/- 0.34, P less than 0.01). High-density lipoproteins cholesterol (1.05 mmol/L +/- 0.04 SE), similar to control (1.12 +/- 0.07), did not change the 1st year and increased at 2 years (+0.57 +/- 0.11, P less than 0.01). No differences appeared among treatment groups. CONCLUSIONS: Treatment is very effective, 2 years for best results. The OCs tested are equally efficacious. Changes in plasma lipids are of some concern but of difficult interpretation.

Adult↗

Combination of 19-nortestosterone-hexyloxyphenylpropionate (Anadur) and depot-medroxyprogesterone-acetate (Clinovir) for male contraception.

Because monotherapy with 19-nortestosterone hexyloxyphenylpropionate (Anadur, Pharmacia Arzneimittel, Ratingen, Federal Republic of Germany) suggested improved results for male contraception compared with available testosterone esters, it was tested for induction of complete azoospermia when combined with depot-medroxyprogesterone acetate (DMPA, Clinovir, Upjohn GmbH, Heppenheim, Federal Republic of Germany). Twelve men were treated for 7 weeks with weekly intramuscular (IM) injections of 200 mg Anadur followed by 3-weekly IM injections of Anadur up to week 15. Clinovir (250 mg) IM was administered at the start of treatment and during weeks 6 and 12. Anadur and Clinovir suppressed serum gonadotropins. Although serum testosterone declined steeply, in general, libido and potency were not impaired. Sperm concentrations were reduced significantly after 3 weeks of treatment. Lowest sperm counts were seen during week 8 of follow-up, when only 2 volunteers showed measurable sperm counts of 2.1 and 3.0 X 10(6)/ml, with a declining tendency. After 43 weeks, sperm concentrations were still below pretreatment range in 2 men, but later returned to pretreatment values. Computerized sperm motion analysis revealed that motility parameters in the residual sperm were reduced. In vitro analysis excluded a direct effect of medroxyprogesterone acetate in seminal plasma on sperm motion. The data indicate that the combination of Anadur with Clinovir increases the rate of azoospermia in normal volunteers seen under Anadur monotherapy, although the goal of azoospermia in all participants was not quite achieved.

Anabolic Agents↗

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↗

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↗