Preliminary experience with steroidal ovarian suppression for prevention of severe ovarian hyperstimulation syndrome in IVF patients.

The purpose of the study was to evaluate the efficiency of administration of high dose progesterone in combination with oestradiol during the luteal phase for the prevention of ovarian hyperstimulation syndrome in a high-risk population of patients undergoing in vitro fertilization. An observational study was carried out involving 21 women (mean age 28.6 years) undergoing controlled ovarian stimulation for in vitro fertilization. The women were identified as at risk of ovarian hyperstimulation syndrome as they had suffered from the condition when hCG was used for luteal phase support in previous cycles. Steroidal suppression of the stimulated ovary on days 2, 6, 10 and 14 after embryo transfer was achieved by intramuscular injections of 500 mg hydroxyprogesterone caproate and 10 mg oestradiol valerate. The incidence of moderate and severe ovarian hyperstimulation syndrome under steroidal ovarian suppression, serum progesterone concentration and pregnancy rates were compared with those in cycles in which human chorionic gonadotrophin was used for luteal phase support. No cases of moderate or severe ovarian hyperstimulation syndrome occurred under steroidal ovarian suppression. Despite low progesterone concentrations (mean 10.7 nmol l(-1), range 2.6-24.5), indicating almost complete ovarian suppression, the pregnancy rate was not impaired. These preliminary results indicate that steroidal ovarian suppression during the luteal phase is a promising tool for reducing the incidence and severity of ovarian hyperstimulation syndrome in a high-risk population, without compromising the pregnancy rate.

Immunoreactive inhibin in human follicular fluid in an ovarian hyperstimulation programme for in vitro fertilization: correlations and different forms.

UNLABELLED: The inhibin concentration in 131 samples of human follicular fluid obtained from 31 women undergoing ovarian hyperstimulation for in vitro fertilization was measured using specific double antibody radioimmunoassay. We used the synthetic 1-32-alpha-inhibin as standard and radioiodinated 1-32-Tyr-alpha-inhibin as tracer. Antibodies were raised in rabbits by immunization with the synthetic peptide. Estradiol and progesterone concentrations were measured using commercial radioimmunoassays. RESULTS: The inhibin concentration correlated with the estradiol (r = 0.57, N = 88, p < 0.0001) and progesterone (r = 0.82, N = 88, p < 0.0001) concentrations in human follicular fluid. The dosage of human menopausal gonadotropin given to individual patients correlated with the average inhibin concentration measured in their follicles (r = 0.72, N = 23, p < 0.0001). Similarly, the size of follicles correlated with their inhibin content (r = 0.75, N = 131, p < 0.0001). Nineteen samples of human follicular fluid originating from follicles of different size and volume were examined using gel-chromatography. In each human follicular fluid the main form of inhibin (32 kDa) was recovered. In small follicles (3 ml) we found 12.8 +/- 9.1% (mean +/- SD) of the whole immunoreactive inhibin eluting in the area of Vo (> or = 80 kDa). In the larger follicles (4-7 ml), however, only 4.4 +/- 4.2% of this large inhibin form could be found. CONCLUSIONS: Our data confirm that human menopausal gonadotropin stimulates ovarian inhibin production. In addition to the estradiol and progesterone concentrations, the inhibin concentration may be an index of granulosa cell function and follicular maturation. The occurrence of large molecular weight forms of inhibin in small follicles remains unclear. They may represent large precursor molecules which are proteolytically cleaved in more mature follicles.

[Value of nuclear magnetic resonance tomography in the diagnosis and therapy outcome of prolactinomas]. / Aussagekraft der Kernspintomographie über Diagnose und Therapieerfolg bei Prolaktinomen.

30 MR tomographies were performed in 15 patients suspected of having a prolactinoma on account of clinical examinations and test in the chemical laboratory. The T1 and T2 times of the adenomas were determined quantitatively. In addition, high resolution CT imaging had been performed in all patients. The signal performance of the normal pituitary gland determined in 11 healthy persons on the basis of quantitatively measured T1 and T2 times, was found to largely correspond with that of grey matter of the brain. Of the 14 confirmed prolactinomas, 11 were microadenomas and 3 macroadenoma. Solid adenomas were identified by enhanced T1 values. It was possible to differentiate these from cystic, haemorrhagic and necrotic tumour components by differences in signal performance. 7 patients on drug therapy with dopamine agonists were controlled by means of MR tomography. No measurable size reduction of tumour was seen in 3 patients with cystic or haemorrhagic tumour components. On the other hand, tumour reduction was seen after brief drug therapy in 2 macroprolactinomas and one microprolactinoma. An essential advantage offered by MR is, besides the absence of exposure to radiation, in the first place the better and more precise information on the relative position of the adenoma with reference to the vessels and the optic chiasm, and, secondly, better identification of cystic and haemorrhagic processes within the prolactinoma.

[Treatment of anovulatory patients by pulsatile administration of gonadotropin releasing hormone]. / Die Behandlung anovulatorischer Patientinnen durch pulsatile Gabe von Gonadotropin-Releasing-hormon.

83 anovulatory patients refractory to clomiphene were treated with gonadotropin releasing hormone (GnRH) in pulsatile form (Zyklomat). 146 of 172 treated cycles were ovulatory. A total of 37 pregnancies occurred. The patients were classified into three groups according to the degree of severity of their cyclic disturbance and according to the results of testosterone determinations. In amenorrhoic women with normal testosterone values (group I) the authors found the highest incidence of ovulation and pregnancies. In the patients of group II the ovulation rates were high, whereas the incidence of pregnancies was low (this group comprised anovulatory oligomenorrhoea and normal testosterone values). It was found that about 30% of the anovulatory women with elevated testosterone levels (group III) were refractory to therapy, the proliferation phases being mostly considerably prolonged during the ovulatory cycles. It is concluded from the results of this study that in women with normoandrogenemic amenorrhoea the treatment of first choice should be pulsatile application of GnRH. In many hyperandrogenemic, anovulatory patients treatment with gonadotrophins should be considered as the presently more suitable method.

[Hyperprolactinemic ovarian insufficiency]. / Hyperprolaktinämische Ovarialinsuffizienz.

About 20% of all menstrual cycle disorders are due to a hyperprolactinemia. Although changes in the bony area of the sella indicating intrasellar space-requiring processes have been found in only 30% of these women presenting hyperprolactinemic ovarian insufficiency, an adenoma of the pituitary gland is probably also responsible for the hyperprolactinemia observed in the rest of the cases. Treatment is however not strictly necessary, as long as there are no other endocrine dysfunctions, and a pregnancy is not desired. Side-effects of a therapy of dopamine agonists can be diminished by a gradually increasing dosage.

[Treatment of hyperprolactinemic amenorrhea by pulsatile administration of gonadotropin-releasing hormone]. / Behandlung der hyperprolaktinämischen Amenorrhoe durch pulsatile Gabe von Gonadotropin-Releasing-hormon.

Two patients with hyperprolactinemic secondary amenorrhoea were treated with gonadotropin releasing hormone (GnRH). Both desired children and had an incompatibility to treatment with Dopamin agonists (Zyklomat). Both patients ovulated and had regular follicular maturation in spite of rising prolactin levels. The pregnancies occurred in the first treatment cycles. The pulsatile intravenous administration of GnRH is apparently a viable alternative plan of management in patients with a moderate hyperprolactinemia and incompatibility to Dopamine agonists to the treatment with gonadotropins which was in use up to now.

[Pulsatile GnRH substitution in Kallmann's syndrome in women]. / Pulsatile GnRH-Substitution beim Kallmann-Syndrom der Frau.

Anosmia and primary amenorrhoea are guiding symptoms of Kallmann's syndrome (olfacto-genital syndrome) in which agenesis of the olfactory lobe is associated with congenital defects in the mediobasal region of the hypothalamus, thus preventing a sufficient GnRH synthesis. In three patients with Kallmann's syndrome, the secretion of gonadotropins on bolus injection of 25 micrograms GnRH was comparable with prepubertal reaction. In one patient, the hypophyseal function was normalized, and ovulatory cycles were induced by pulsatile GnRH substitution via a portable computerized pump (Zyklomat). Pregnancy occurred. The duration of treatment required to induce ovulation was identical during two subsequent treatment cycles, contrary to observations in functional hypothalamic amenorrhoeas. The marked ovarian reaction shows that even if there is no endogenous GnRH secretion, a pulsatile dose of less than 20 micrograms seems to be sufficient.

Ovulation and pregnancy after pulsatile administration of gonadotropin releasing hormone.

Twenty-seven patients with primary or secondary amenorrhea were treated with gonadotropin releasing hormone (GnRH). They were given 20 micrograms of GnRH in 50 microliter solution i.v. every 90 min by means of a peristaltic pump (Zyklomat, Ferring GmbH, Kiel). Two days after a rise in basal body temperature and when a ferning test on cervical mucus was negative the Zyklomat was removed and injections of hCG (2,500 IU) were given on alternate days until three injections had been administered. Ovulation occurred in 32 out of 40 treatment cycles and 11 patients conceived. Three of them miscarried at 6, 8, and 15 weeks of gestation. There were no severe complications of treatment and we did not encounter ovarian hyperstimulation and multiple pregnancy.

Spontaneous development of hyperprolactinaemia.

Spontaneous development of hyperprolactinaemia was investigated by measuring prolactin levels in 34 hyperprolactinaemic females with a normal sella turcica, in 19 females with a radiologically proven prolactinoma, and in 19 females with a histologically proven prolactinoma after transsphenoidal surgery. Prolactin levels remained unchanged or declined in 69 patients followed over a period of up to 6 years. In one patient with a normal sella turcica, prolactin levels increased accompanied by the development of a radiologically detectable microprolactinoma. In one patient with a radiologically proven macroprolactinoma the increase of human prolactin (hPrl) levels was accompanied by infiltrative and parasellar prolactinoma growth. One patient showed a dramatic increase of post-operative persisting elevated hPrl levels without radiological changes. These findings suggest that prolactinomas in general have a limited growth potential which should be considered in the management of hyperprolactinaemic patients.

Influence of pregnancies on prolactinomas.

Hyperprolactinaemic patients desiring pregnancy with a normal sella turcica or radiological evidence for a microprolactinoma without suprasellar extension were treated with bromocriptine. Females desiring pregnancy with large adenomas or suprasellar extension were treated by transsphenoidal surgery and in most instances post-operatively with bromocriptine. This differentiated management allowed the outcome of 65 pregnancies with delivery at term without complications related to the sella turcica. Considerable variations of prolactin levels during pregnancy suggesting different oestrogen sensitivity of the prolactinoma cells were encountered. However, a rapid fall of the prolactin levels in 60 patients after termination of pregnancy indicated that oestrogen stimulation does not cause persisting growth of the adenoma. In contrast, in 10% of pregnancies of hyperprolactinaemic patients a reduction of the prolactin levels has been observed leading to spontaneous ovulatory cycles in 5 patients.

[Hyperprolactinemia in the male: clinical aspects and therapy]. / Die Hyperprolaktinämie beim Mann: Klinik und Therapie.

Fifty-seven male patients with hyperprolactinemia have been investigated. Macroadenomas were found in 49 patients of whom 24 had received pituitary surgery before elevated PRL levels were discovered. In 8 patients radiology of the pituitary fossa revealed either evidence of microadenoma or a completely normal sella turcica. Prolactin levels ranged from 582 to 498 000 microU/ml. All patients with macroprolactinomas, including those who had undergone previous surgery, had PRL levels above 5000 microU/ml. Disturbances of libido and sexual potency were prevalent in the majority of patients, less frequently accompanied by gynacecomastia and galactorrhea. However, visual disturbances were the reason for the first visit to the doctor in the majority of patients. Pituitary surgery led to improvement of visual field defects, though prolactin levels were never normalized. Postoperative radiotherapy had no significant influence on PRL levels. In contrast, bromocriptine therapy led, in the majority of patients, not only to improvement of hypogonadal symptoms but also to normalization of PRL levels.

[The value of alpha-1-fetoprotein determinations in the amniotic-fluid of patients with hydramnios in the diagnosis of fetal anomalies (author's transl)]. / Wertigkeit der Alpha-1-Fetoprotein-Bestimmung im Fruchtwasser für die Diagnose fetaler Missildungen bei Patientinnen mit Hydramnion.

Little is known about the influence of hydramnios on the alphafetoprotein (AFP)-concentration in the amniotic fluid. We therefore investigated in 19 patients with hydramnios the diagnostic value of the sonographic evidence and the AFP-concentration in the amniotic fluid in relation to prenatal diagnosis of fetal malformations in two independent series. An anlysis of the AFP-concentration in the amniotic fluid can corroborate the diagnosis of a malformation made by sonography and influence decisions concerning the management of pregnancy and delivery. If ultra-sonic tests show no anomalies, significantly increased AFP-concentrations in the amniotic fluid of patients with hydramnions can merely confirm a suspicious of an existing malformation and influence decisions on further diagnostic steps.

[Andrological, biochemical and endocrinological studies of subfertile men during kallikrein therapy]. / Andrologische, biochemische und endokrinologische Untersuchungen bei subfertilen Männern während Kallikreintherapie.

31 men with idiopathic oligozoospermia and 23 men with idiopathic asthenozoospermia were treated three months by oral administration of daily 600 units kallikrein. In a greater number of patients apart from the semen analysis different seminal plasma proteins and enzymes as well as hormones in serum (LH, FSH, prolactin, testosterone) and in seminal plasma (LH, prolactin) were determined. There was a significant increase of sperm count and sperm motility in the oligozoospermic group. In asthenozoospermic patients sperm motility was significantly increased, however, sperm count decreased within the normal range. Conception rate was 25% in the oligozoospermic goup and 36% in the asthenozoospermic group. A treatment period of three months showed better results than seven weeks and a dosage of 600 units kallikrein daily was significantly better than daily 300 units. During kallikrein therapy mean concentrations of alpha U,x-antichymotrypsin in seminal plasma and serum LH, prolactin and testosterone increased significantly. Seminal plasma levels of LH and prolactin remained unchanged. The mode of action of systemic kallikrein therapy may be at the level of tissue hormones (kinin liberation), however, an increase of the intratesticular testosterone level and an interference with the blood-seminal plasma barrier has also to be considered.

Persisting suppression of prolactin secretion after long-term treatment with bromocriptine in patients with prolactinomas.

The effect of bromocriptine withdrawal after long-term treatment on prolactin levels has been investigated in thirty-seven patients with prolactinomas. In ten patients with macroprolactinomas and post-operatively excessively high prolactin levels persisting suppression of prolactin secretion after bromocriptine withdrawal has been observed. This effect was not observed in patients with microprolactinomas or macroprolactinomas with only moderately elevated prolactin levels. The degree of persisting suppression correlated to the height of prolactin levels before treatment and to the duration of bromocriptine therapy. No correlation was found between the rise of prolactin levels after bromocriptine withdrawal and withdrawal time. It is suggested that the persisting suppression of prolactin levels is a sequence of reduction in tumour size. This anti-proliferative action of bromocriptine seems to be specific for the prolactin secreting cells in macroprolactinomas with high proliferation rate and high prolactin turn-over. These findings offer new possibilities in the management of patients with macroprolactinomas.