Christer Bergquist

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.

INTRANASAL GONADOTROPIN-RELEASING HORMONE AGONIST AS A CONTRACEPTIVE AGENT

The stimulatory luteinising hormone-releasing hormone (LRH) analogue D-Ser(TBU)6-EA10-LRH was administered intranasally once daily to twenty-seven regularly menstruating women to determine its efficacy as a contraceptive agent. Ovulation was inhibited during all but 2 of the 89 treatment months. The failures were due to initial technical problems with the nasal spray. Twenty-one of the twenty-seven women had slight menstrual-like anovulatory bleeds during the 3--6 month trial. The remaining six women were amenorrhoeic. Ovulatory menstrual cycles rapidly returned after discontinuation of treatment. There were no serious side-effects.

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.

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.

Luteolysis induced by a luteinizing hormone-releasing hormone agonist is prevented by human chorionic gonadotropin

The superactive stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser(TBU)6-EA10-LRh was administered intranasally to five healthy women in a daily dose of 600 microgram during two successive days of the mid-luteal phase. Both the basal serum progesterone levels and the length of the luteal phase were reduced, i.e. luteolysis occurred. Three women who were given additional treatment with human chorionic gonadotropin (HCG) in a daily intramuscular dose of 1500 IU for 10 days, had increased basal progesterone levels and a prolongation of the luteal phase. Thus, HCG prevented the luteolytic effect caused by the LRH agonist.

Human gonadotropin therapy. II. Serum estradiol and progesterone patterns during nonconceptual cycles

Hormone patterns during 113 nonconceptual gonadotropin-induced cycles of 65 infertile anovulatory women were analyzed. All but one women ovulated, i.e., the ovulation rate was 98%. Signs of defective corpus luteum function were observed during 8 cycles, and anovulation occurred in 11 treatment cycles. The duration of the active phase of the follicular stimulation was shorter during cycles with defective luteal phases and anovulatory cycles. The mean estradiol level at induction of ovulation by human chorionic gonadotropin did not differ between the groups. Premature ovulation was observed in six treatment cycles. No case of severe hyperstimulation was encountered. The hormone pattern during gonadotropin-induced conceptual cycles did not differ in comparison with gonadotropin-induced nonconceptual ovulatory cycles.

INTRANASAL LHRH AGONIST TREATMENT FOR INHIBITION OF OVULATION IN WOMEN: CLINICAL ASPECTS

Daily intranasal administration of the potent stimulatory LHRH analogue D‐Ser(TBU)6‐EA10‐LHRH was given to fifty healthy women for 3 months. Twenty‐six women received 400 μg LHRH agonist/day and twenty‐four women received 600 μg/day. Inhibition of ovulation occurred during 147 of the 150 treatment months. The three presumptively ovulatory cycles were probably the result of initial technical problems with the nasal spray. No pregnancies occurred. Reactivation of corpus luteum with slightly raised progesterone levels in serum at initiation of treatment was observed in six women. During 20 months of treatment the serum progesterone levels were slightly raised, indicating luteinization of follicles or defect luteal phases. Most of the women had menstrual‐like bleeding during treatment. Seventeen volunteers had regular bleeding and twenty‐three women had oligomenorrhoea. No dysfunctional uterine bleeding occurred, but three women reported spotting. The remaining ten women had amenorrhoea during treatment without any symptoms of oestrogen deficiency. After discontinuation of treatment the women regained ovulatory menstrual cycles after 31 days on average. The treatment was very well accepted by all the women.

Inhibition of ovulation by intranasal nafarelin, a new superactive agonist of GnRH

Thirty healthy female volunteers used a new superactive stimulatory analog of the hypothalamic gonadotropin-releasing hormone (GnRH) for inhibition of ovulation and contraception during 3 months. The potent GnRH agonist nafarelin (D-Nal(2)6-GnRH) was administered intranasally in a daily dose of 125 micrograms to 15 women and 250 micrograms to 15 women. The treatment inhibited ovulation in all women during the 89 months of therapy. No pregnancies occurred during 59 treatment months in which no additional contraceptives were used. The mean estradiol concentration decreased during the 3-month treatment within the normal range for the early to mid-follicular phase of the menstrual cycle. The results suggest that the GnRH agonist nafarelin has a potential for contraception by inhibition of ovulation in women.

Effects of a luteinizing hormone-releasing hormone agonist on luteal function in women

The potent stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser(TBU)6-EA10-LRH was administered once daily during the luteal phase of the human menstrual cycle. The treatment was instituted in the early or mid-luteal phase of the cycle. Early luteal phase institution of intranasal treatment with 600 micrograms of the LRH agonist once daily reduced the basal progesterone levels during the luteal phase in 4 women but did not cause premature onset of menstruation. Mid-luteal phase institution of subcutaneous treatment with 10 micrograms of the LRH agonist once daily did not affect the progesterone levels or reduce the length of the luteal phase in 5 women. Thus, daily postovulatory administration of the LRH agonist D-Ser(TBU)6-EA10-LRH did not cause luteolysis in normally cycling women.