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The effect of orally given diethystilboestroldiphophate (DES) and 17alpha-ethinyl-oestradiol-3-methylether (EEM) on plasma progesterone levels was studied. Both compounds were administered for 5 days to 5 women in daily doses of 60 mg (DES) and 30 mg (EEM). The fully informed volunteers were found to have a normal menstrual cycle before the study. The mean corpus luteum phase (corpus luteum phase = days between LH surge and onset of menstruation) of all control cycles lasted 12.8 days. Daily plasma samples were collected for radioimmunoassay (RIA) of progesterone, immunoreactive oestrogens and LH. After a control cycle the first treatment was carried out with DES. The third and the fifth cycle were control cycles again. The EEM-treatment was done in the fourth cycle. Although the effect of the two compounds was different, a dependence of the age of the corpus luteum (CL) could be demonstrated for both. DES-treatment lowered plasma progesterone levels during administration. This effect was only demonstrable if the treatment was begun on the day of the LH-peak. The length of the CL-phase remained unaltered. EEM-treatment if started on the day of the LH surge, suppressed corpus luteum function in the late luteal phase. If the treatment was started later, the effect was less pronounced. The administration of both compounds did not shorten the time between ovulation and the next bleeding. After DES-treatment this interval was not altered. After EEM-treatment the subsequent bleeding was even delayed depending on slowly decreasing levels of plasma oestrogens.

Out of 109 hMG stimulations for in vitro fertilization (IVF) 41 cycles (38%) had to be cancelled because of premature endogenous luteinization. Pretreatment with the LH/RH-agonist Buserelin induces selective pituitary suppression and prevents spontaneous LH-surge during hMG stimulation. The pharmacologic hypogonadotropism allows considerable flexibility with respect to the timing of starting gonadotropin stimulation and ovulation induction. In 74 Buserelin/hMG/IVF-cycles no premature luteinization occurred and all started stimulations yielded in follicular puncture. In addition increased oocyte recovery rate, significant higher fertilization rate and significant better pregnancy rate could be achieved as compared with hMG/IVF-cycles. In conclusion pharmacologic hypogonadotropism by administration of LH/RH-analogue reliably prevents endogenous luteinization and improves gonadotropin stimulation as well as IVF results.

In the present paper we examined, whether the combined GnRH-agonist/hMG therapy implies an increased risk of the ovarian hyperstimulation syndrome (OHS). In a retrospective analysis, 525 GnRH-a/hMG cycles were compared with 643 cycles of hMG stimulation, which were simultaneously performed at the Department of Gynecology and Obstetrics of the University of Hamburg. Two different GnRH-agonists were used: Buserelin (Hoechst) given intranasally (410 cycles) and Triptorelin (Ferring) intramuscularly (115 cycles). The clinical results of hMG "only"-therapy revealed an OHS incidence of 7% for grade II and 0.2% for grade III. In contrast, significantly higher incidences were observed after GnRH-a/hMG treatment. In Buserelin/hMG cycles in 23% OHS grade II and in 1.0% OHS grade III occurred, in Triptorelin/hMG cycles in 40% OHS II and in 5.2% OHS III, respectively. The increased incidence of OHS correlated with higher ovarian estrogen production as well as a higher number of follicles following the GnRH-a/hMG stimulation. Furthermore, in GnRH-a/hMG cycles a prolonged duration of follicular maturation occurred due to an increase of the active phase; in addition the amount of hMG-ampoules needed for ovarian stimulation was higher. After GnRH-a/hMG treatment, an endogenous LH-surge was not detected, whereas in 34% of hMG stimulated cycles irregular LH-fluctuations were observed. There was a higher pregnancy rate in GnRH-a/hMG cycles (15%/525 cycles), as compared to hMG stimulation (8%/643 cycles), but the abortion rate was similar (23%, GnRH-a/hMG, versus 13%, hMG). The demonstration of an increased ovarian response leading to better pregnancy rates but also higher risks of OHS is well known from earlier data of hMG stimulation in patients with hypogonadotropic amenorrhoea (WHO group I). This implies that GnRH-agonist pre-treatment shows similar endocrine conditions in normogonadotropic patients.

After 15 years of clinical experiences with Clomiphen treatment it seemed desirable to investigate the efficiency of this kind of therapy under routine conditions in a crowded out-patient clinic. 314 patients treated from 1972--1974 have been included in this study. From 242 sterility patients 730 cycles could be followed. 80.2% were ovulatory, but 23.5% had an insufficient luteal phase and 11.9% of these cycles ended with an anovulatory bleeding. The overall pregnancy rate was 30%. Side-effects were recorded in 4.5% but all of them were harmless, no overstimulation occurred. After discontinuation of Clomiphen therapy 8% of all patients had spontaneous cycles. In 36 patients with eugonadotropic secondary amenorrhea with a total of 115 treatment cycles ovulation was recorded in 58%. Pregnancy rate was 25%, the intensity of treatment 3.1. In 54 patients with anovulatory cycles 156 cycles (72,3%) became ovulatory, pregnancy rate was 24%, the intensity of treatment 3.5. In another group of 19 patients with oligomenorrhea ovulation occurred in 39 of 42 cycles, 4 patients became pregnant. In 108 patients with luteal phase defects in 338 cycles ovulation was found in 90.2%, with 26.6% of these cycles being still insufficient. The pregnancy rate was 18.5%, the intensity of treatment 3.7. 9.8% of these 338 cycles became anovulatory during clomiphen treatment. In 27 patients with "insufficient cycles" in 104 treatment cycles nearly all of them were ovulatory but 20% of them were found to have an insufficient corpus luteum phase. The pregnancy rate was 30%. The highest pregnancy rate was found during the first 3 treatment cycles (26%). It is consequently our policy to treat patients 4 to 6 times with clomiphen and when no pregnancy can be achieved, these patients should be treated with HMG/HCG. 65 of 73 pregnancies were followed, 52 patients were delivered with healthy babies, 12 patients aborted. Of the total number of 54 babies born, 47 were single, 6 were twins, 2 babies were stillborn. The sex ratio (male to female) was 2.2. No malformations were found. In our group of patients other factors besides ovarian dysfunction contributed to the relatively low pregnancy rate. Thus, in 116 out of 244 patients one tube was occluded, while adhesions were found in 99 treated with clomiphen as a diagnostic step to convince the patient, that stimulation of ovarian function will be possible whenever the patient desires to become pregnant. The ovulation rate in this group was 38% in addition 37% responded with anovulatory bleeding, thus, 74% of all patients experienced a positive reaction from their point of view. After discontinuation of clomiphen administration 18% of these patients continued to bleed with (7.5%) or without (10.6%) clinical signs of ovulation. A further observation is the obvious fact that clomiphen therapy free intervals can be interposed without risk of a lower success rate, compared to patients receiving continuous cycle to cycle treatment.

For sensitive assessment of thyroid function a TRH stimulation test using 200 micrograms TRH i.v. was routinely performed in 304 women admitted for evaluation and treatment of infertility. In 37 cases (12.2%) the reaction of TSH 30 min after injection of TRH i.v. was enhanced (by definition of a peak TSH level greater than 25 mIU/l), according to mild or subclinical hypothyroidism. Approximately 14 (14/37 = 37.8%) of these patients were found to have slightly elevated serum PRL values (mean PRL greater than 15 ng/ml). Cycle analysis by means of basal body temperature and evaluation of progesterone and oestradiol values, supplied evidence of luteal phase deficiency in 8 and anovulation in 3 cases. Another group of 11 patients with hypothyroidism involved oligo-/amenorrhoea, hirsutism and hyperandrogenaemia. After treatment with 50-150 micrograms l-thyroxine daily for at least 4 to 6 weeks, elevated PRL values significantly decreased (mean level less than 15 ng/ml, p less than 0.01) in 9 out of 12 patients and testosterone levels slightly decreased in 5 out of 8 patients. An improvement of the cyclical ovarian function could be observed by the significant increase of the average progesterone concentration in the luteal phase. During therapy with l-thyroxine, 4 pregnancies occurred. From these results we conclude, that mild hypothyroidism may cause ovarian insufficiency. Assessment of thyroid function should be mandatory in infertile patients with elevated prolactin levels or chronic anovulation.

Serum hCG was determined in 231 infertility patients in the late luteal phase of spontaneous and therapeutic cycles. The aim was to establish whether the discrepancy between the high number of induced ovulation cycles and the far lower cycle-related pregnancy rate can be explained by subclinical abortion. In 16.7% of spontaneous cycles hCG was positive; in 16.8% of these cases clinical pregnancy subsequently occurred. The rate of biochemically detectable pregnancies was no higher under endocrine therapy. However, under treatment with clomiphene, epimestrol, prolactin inhibitors and glucocorticoids the rate of clinical pregnancies was almost twice as high, and after hMG/hCG therapy clinically demonstrable pregnancies developed from biochemically identified ones in 76% of the cycles. The investigations show that a stimulation therapy leading to ovulatory cycles after multifollicular development increases the clinical pregnancy rate without resulting in a higher rate of very early abortions.

During a period of 17 months 61 couples without pathological tubal factors were treated by follicular puncture and gamete intra-Fallopian transfer (GIFT) at the department of Obstretrics and Gynaecology, University of Hamburg. The combination GnRH-antagonist (GnRH-A)/hMG was administered in 69 stimulation cycles. Two different GnRH-A application forms were used (daily intranasal spray/monthly depot injection). In all cases mature oocytes were collected after ovulation induction, and gamete transfer was performed. None of the cycles had to be cancelled. Twenty-two clinical pregnancies were achieved (32% by stimulation cycle). The highest pregnancy rate was observed in the group of cervical infertility (58%), lowest rate in cases of pathological male factors (15%). In addition, pregnancy rate correlated with the number and maturity of transfered oocytes. The combined GnRH-A/hMG stimulation therapy allows for a prolonged active follicular development without the occurrence of endogenous, premature luteinization. Besides a more flexible and effective strategy of ovarian stimulation, the number of follicles/oocytes was L, increased which provided a better condition for GIFT.