Sven Johan Nillius

Inhibition of ovulation in women by chronic treatment with a stimulatory lrh analogue — A new approach to birth control?

A stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser(TBU)6-EA10-LRH was administered subcutaneously once daily in a dose of 5 microgram to four regularly menstruating women. Treatment was instituted within the first three days of the menstrual bleeding and continued for 22--30 days. Ovulation was inhibited in all the women during the treatment cycle. The treatment resulted in disturbances in the pituitary gonadotropin secretion which presumably led to disordered follicular menuration and anovulation. The maximum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to the LRH analogue were obtained during the first few days of treatment. The gonadotropin responses then rapidly decreased during the prolonged treatment. This change in the pituitary responsiveness probably prevented the release of a normal preovulatory LH surge. After the treatment, all the women resumed normal ovulatory menstrual cycles. The results suggest that it might be possible to use stimulatory LRH analogues for birth control.

VARIATION IN LH AND FSH RESPONSE TO LH-RELEASING HORMONE DURING THE MENSTRUAL CYCLE

Synthetic luteinizing hormone‐releasing hormone (LRH) was injected intravenously in a dose of 100 μg. to test the capacity of the pituitary to respond to LRH with a release of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) in 16 healthy regularly menstruating women. A total of 28 LRH tests were performed during different stages of the menstrual cycle. Venous blood was obtained before and at frequent intervals during the first two hours after the LRH injection and assayed for LH, FSH and in five tests also for thyrotrophic (TSH) and growth hormone (GH). No consistent change of TSH or GH was observed after LRH. In all the 28 LRH tests there was a significant increase of LH and in tests also of FSH. The mean LH and FSH increase was 292 and 40 per cent, respectively. The maximum response was usually observed after 30 to 45 minutes. There was a pronounced variation in the response to LRH in the course of the menstrual cycle. During the late follicular phase the average LH response was 4‐ to 6‐fold that obtained in the early and mid‐follicular phase. An increased pituitary responsiveness was also found in the luteal phase. It was suggested that this variation in the response to LRH is due to the changes of the ovarian secretion of oestrogens during the menstrual cycle. In one amenorrhoeic woman exogenous oestrogen was found to enhance the LH response to LRH.

Clinical course and outcome of pregnancies in amenorrhoeic women with hyperprolactinaemia and pituitary tumours

Seventeen term pregnancies occurred in 14 amenorrhoeic women with hyperprolactinaemia and radiological evidence of pituitary tumour. The abortion rate was high (32%). All but one of the term pregnancies occurred after ovulation-inducing treatment with human gonadotrophins and bromocriptine (four and 12 pregnancies respectively). Two of the 14 women had visual complications during pregnancy, but neither had serious residual visual impairment. Two patients had possible pituitary enlargement during pregnancy. Bromocriptine may be the most suitable primary treatment for many infertile women with prolactin-secreting tumours. Tumour complications during pregnancy are a definite risk, but most pregnancies went uneventfully to term. Patients with pituitary tumour should be carefully evaluated before starting ovulation-inducing treatment with bromocriptine alone, and they should be told of the possible risks and of the advantages and disadvantages of pretreatment with irradiation or surgery. Patients should be carefully monitored during pregnancy and have their visual fields checked frequently. If visual complications due to tumour enlargement occur during a pregnancy, reinstituting bromocriptine may be the treatment of choice. If this fails, other forms of treatment such as induction of labour, high-dose corticosteroid treatment, pituitary implantation of yttrium-90, or surgery may be effective.

Successful induction of follicular maturation and ovulation by prolonged treatment with LH-releasing hormone in women with anorexia nervosa.

Four women with anorexia nervosa were treated with synthetic LH-releasing hormone (LRH) in an attempt to induce ovulation. All the women had very low pretreatment levels of gonadotropins and estrogens. Administration of LRH resulted in significant gonadotropin increases. The FSH response to LRH in relation to the LH response was higher than in regularly menstruating women. LRH (500 mug) was administered parenterally three times daily over about 4 weeks. During this period there were no significant effects on mood, eating behavior, weight, or libido. All the women responded with follicular maturation and ovulation to the prolonged LRH treatment.

INHIBITION OF OVULATION IN WOMEN BY INTRANASAL TREATMENT WITH A LUTEINIZING HORMONE-RELEASING HORMONE AGONIST

39 healthy women, aged 22-37 years, tested the efficacy of an intranasal dose of a potent and long-acting stimulatory luteinizing hormone-releasing hormone LRH analogue D-Ser(TBU)6-EA10-LRH once daily. Doses ranged from 87-600 mcg. All 8 women who were treated with daily intranasal doses of 87 or 174 mcg had signs of follicular growth during the treatment, and 6 of them had raised premenstrual progesterone (P) levels in blood. The P values were low during 4/6 presumptively ovulatory cycles, indicating defective corpus luteum function. 3/5 women treated with 348 mcg daily had anovulatory cycles, and the other 2 had very low P values, indicating again insufficient luteal function. Anovulation occurred in all but 2 of the 26 women who received 400 or 600 mcg daily. None of the women had dysfunctional uterine bleeding. 10/26 women treated with 400 or 600 mcg did not have any bleeding during the 5-week study period. The remaining 16 women experienced a menstrual-like bleeding after 26 days on average (range 21-34 days). 32/39 women have discontinued intranasal treatment with the analogue, and all of them ovulated within 4 weeks after discontinuation.

INDUCTION OF A MIDCYCLE‐LIKE PEAK OF LUTEINIZING HORMONE IN YOUNG WOMEN BY EXOGENOUS OESTRADIOL‐17β

Oestradiol‐17β, given intramuscularly in a dose of 1 mg., was found to increase the serum level of luteinizing hormone (LH) but not of follicle stimulating hormone (FSH) in eight women 48 to 72 hours after the administration. This increase of LH was preceded by a decrease in the serum levels of both FSH and LH. When 5 or 10 mg. of progesterone was administered five days after the injection of oestradiol‐17β, a second increase of LH was observed in two of four women. These results suggest that changes in the ovarian secretion of both oestradiol‐17β and progesterone may be of importance for the appearance of the midcycle surge of LH in women.

THE LH‐RELEASING HORMONE TEST IN 31 WOMEN WITH SECONDARY AMENORRHOEA

Thirty‐one women with secondary amenorrhoea were given 100 μg. of synthetic luteinizing‐hormone‐releasing hormone (LRH) intravenously to test the capacity of the pituitary to respond to LRH with a release of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). The preceding endocrine investigation showed that three of the women had pituitary tumours and two had a premature menopause. The remaining 26 women were classified as functional amenorrhoea. This group included, among others, patients with anorexia nervosa, Chiari‐Frommel syndrome and amenorrhoea after oral contraceptive treatment. All the 26 patients with functional amenorrhoea responded to LRH with a significant increase of LH and, in 16 of them, also of FSH. The mean LH and FSH increase was 351 and 51 per cent respectively. The response to LRH indicates hypothalamic rather than pituitary dysfunction in this group. The smallest LH response to LRH was obtained in the women with anorexia nervosa. Patients with a low endogenous oestrogen production had a significantly smaller LH response than the rest of the group. The LH response to LRH was also significantly related to the pretreatment level of LH. Small but significant increases of LH were obtained in the three patients with pituitary tumours. The two women with premature menopause had LH responses to LRH in relation to their increased pretreatment LH levels while no further increase of their high FSH levels were observed. The LRH test can be performed without side effects in one hour in ambulant patients. It should be useful not only in the investigation of women with amenorrhoea but also as a valuable complement to the thyrotrophin‐releasing hormone (TRH) test in other patients with diseases of the pituitary and hypothalamus.

Gonadotrophin-releasing hormone treatment for induction of follicular maturation and ovulation in amenorrhoeic women with anorexia nervosa.

Follicular maturation and ovulation can be induced in amenorrhoeic women with anorexia nervosa by long-term treatment with 500 mug of luteinizing hormone releasing hormone (LH-RH) every eight hours. In some women, however, treatment with LH-RH alone results in ovulatory menstrual cycles with indications of luteal phase insufficiency. Human chorionic gonadotrophin (HCG) was therefore given with LH-RH during three treatment cycles. This resulted in ovulation and normal corpus-luteum function, as shown by the occurrence of a single pregnancy in the only involuntarily sterile patient. During the prolonged LH-RH treatment the LH response to LH-RH increased in parallel with the increased oestrogen secretion while the follicle-stimulating hormone response to LH-RH decreased. These changes in the pituitary responsiveness to LH-RH may result from modulating effects on the pituitary by the sex steroids.

Long-term intranasal luteinizing hormone-releasing hormone agonist treatment for contraception in women

Fifty-one female volunteers used a superactive stimulatory luteinizing hormone-releasing hormone (LH-RH) analog for suppression of ovulation for 3 to 12 months. The potent LH-RH agonist D-Ser(TBU)6-EA10-LH-RH was administered intranasally once daily in a dose of 400 or 600 micrograms. No pregnancies occurred during the 283 treatment months. Severe bleeding disturbances were not observed during the long-term treatment. No signs of hyperplastic changes were found in endometrial biopsies. There were no serious side effects. Ovulation promptly returned after cessation of treatment even in women with amenorrhea during treatment periods of 1 year or more. Thus, long-term LH-RH agonist treatment proved to be a safe, effective, and rapidly reversible new method for peptide contraception.

Endometrial Patterns in Women on Chronic Luteinizing Hormone-Releasing Hormone Agonist Treatment for Contraception

Endometrial biopsy specimens were obtained from 12 healthy women under chronic intranasal luteinizing hormone-releasing hormone (LH-RH) agonist treatment for evaluation of the risk of endometrial hyperplasia during long-term inhibition of ovulation. A single daily dose of 400 or 600 microgram of the superactive LH-RH agonist D-Ser(TBU)6-EA10-LH-RH was given for 13 to 55 weeks. Treatment was monitored by clinical examination, basal body temperature (BBT) recordings, and frequently taken venous blood specimens for determination of estradiol and progesterone. Ovulation was inhibited during all but 2 of the 102 treatment cycles. No pregnancy occurred. Six of the women had slight menstrual-like bleeding, and six hac amenorrhea during the treatment period. No dysfunctional uterine bleeding occurred. The dominating histologic picture of the 17 endometrial biopsies, obtained after 78 to 380 days of treatment, was inactive or weak proliferative glands with slightly atrophic stroma. There were no signs of hyperplasia. After discontinuation of treatment ovulatory menstrual cycle rapidly returned.