Reduced gonadotropin secretion in postmenopausal women during treatment with a stimulatory LRH analogue.

The potent and long-acting LRH agonist D-Ser(TBU)6-EA10-LRH was administered in a daily subcutaneous dose of 5 microgram to 5 postmenopausal women for a period of 10 days. The LRH analogue produced a significant decrease in both the basal FSH and LH levels and the gonadotropin responses to the agonist. The estrogen levels in serum remained unchanged during the study period. The results suggest that D-Ser(TBU)6-EA10-LRH has a direct inhibitory effect at the pituitary level.

Increased bone turnover during gonadotropin-releasing hormone superagonist-induced ovulation inhibition.

Superactive stimulatory analogs of GnRH inhibit ovulation in women. This investigation was done to assess bone turnover during GnRH agonist-induced anovulation. Particular interest was directed to the effects of smoking, since smokers have an increased risk of osteoporosis. Fasting serum calcium, phosphate, PTH, and bone Gla-protein (osteocalcin) levels, as well as urinary calcium, cAMP, and hydroxyproline excretion and the renal tubular threshold for phosphate were determined before and after 6 months of GnRH superagonist contraceptive treatment in 47 women, 22 of whom smoked more than 10 cigarettes daily. Before treatment the women who smoked had significantly higher serum phosphate concentrations and lower serum PTH concentrations than the women who did not smoke. Fasting serum calcium and the urinary calcium to creatinine ratio increased after treatment in all women, especially in the nonsmokers. The nonsmokers also had more pronounced increases in serum phosphate and osteocalcin concentrations. A decrease in serum PTH during treatment was confined to the nonsmokers. These results suggest increased bone resorption and turnover during GnRH agonist-induced anovulation and indicate that smoking habits should be taken into account in the evaluation of bone disease.

Development of a new method for the determination of immune responses in the human stomach.

The discovery of the gastric pathogen Helicobacter pylori has created a need for accurate methods to study immune responses locally in the human stomach. Therefore, we have developed a quick and easy method for extraction of antibodies from gastric biopsies using saponin and compared this method with the more laborious analysis of antibody-secreting cells (ASCs) from gastric biopsies. We have also analyzed the antibody content in gastric aspirates, saliva and plasma. There was a strong correlation between the total IgA levels in the biopsy extracts and the frequencies of IgA-secreting cells. In addition, the IgA and IgG levels against a H. pylori whole membrane preparation and purified urease in the biopsy extracts correlated well with the frequencies of specific IgA and IgG secreting cells. However, the antibody levels in gastric aspirates, saliva and plasma specimens did not correlate with the frequencies of corresponding ASC in the gastric biopsies. Thus, the saponin extraction method is suitable for monitoring local antibody responses in the stomach, while analyses of gastric aspirates, saliva or plasma are not appropriate for this purpose.

Antibody responses in serum and lung to intranasal immunization with Haemophilus influenzae type b polysaccharide conjugated to cholera toxin B subunit and tetanus toxoid.

AIM: Cholera toxin B subunit (CTB) has previously been used as a mucosal carrier for various vaccine candidate antigens. The objective of this study was to see if coupling a bacterial polysaccharide, Haemophilus influenzae type b capsular polysaccharide (HibCPS), to CTB, either directly or through prior coupling to tetanus toxoid (TT), would improve the immunogenicity of HibCPS after nasal immunization. METHODS: HibCPS was conjugated to CTB, TT or via TT to CTB, using glutaraldehyde or 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide (EDAC) and N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The conjugates were characterized and used for intranasal (IN) and subcutaneous (SC) immunizations of mice. The anti-Hib, -TT and -CTB antibody titers in serum and lungs after the immunizations were measured with ELISA. RESULTS: The HibCTB was poorly immunogenic both given IN and SC compared with HibTT and HibTTCTB, probably because of inefficient coupling. In contrast, the conjugation of CTB to the HibTT conjugate resulted in a preparation which was superior both to the HibTT and the HibCTB conjugates in inducing local IgA and IgG anti-HibCPS antibodies in the lungs. The anti-HibCPS serum IgG titers after IN immunization with the HibTTCTB conjugate were similar to the titers after IN immunization with HibTT, or SC immunization with a commercial HibCRM conjugate vaccine. In contrast to the other conjugates, the HibTTCTB conjugate also gave rise to anti-Hib serum IgA titers. CONCLUSION: We conclude that appropriate conjugation to CTB increases the mucosal immunogenicity of HibCPS, and that intranasal immunization with such a conjugate can give rise to both local and systemic anti-HibCPS antibody responses.

Artificial insemination with fresh donor semen using the cervical cap technique: a review of 278 cases.

Two hundred twenty-six patients received artificial insemination with fresh donor semen (AID) using the cervical cap technique; 52 patients underwent the procedure for 2 conceptions. Using life-table analysis to adjust for uneven patient follow-up, the cumulative pregnancy rate was 62.5% after 6 months of AID, and 82.4% after 10 months. Moreover, using a mathematical model of cumulative pregnancy following AID, the estimated cure rate was not significantly different from 100%, and the estimated monthly probability of pregnancy among those cured was 15.5%. Age was found to be inversely related to pregnancy success, while parity had no effect. For those who continued to undergo AID beyond 6 months, the monthly probability of pregnancy did not decline. Patients can be advised that their chance of conception with AID should approach that of normal fertile couples.

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.

Intranasal peptide contraception by inhibition of ovulation with the gonadotropin-releasing hormone superagonist nafarelin: six months' clinical results.

Forty-seven woman volunteers used a new highly potent stimulatory analog of the hypothalamic gonadotropin-releasing hormone (GnRH) for contraception. The superagonist nafarelin acetate, D-Nal(2)6-GnRH, was administered intranasally in one daily dose of 125 micrograms to 25 women and 250 micrograms to 22 women. Ovulation was consistently inhibited during 261 of 262 treatment months. No pregnancy occurred during 222 months in which no additional contraceptives were used. The mean plasma estradiol level after 6 months of treatment was 162 pmol/l. The predominant bleeding pattern was oligomenorrhea. Three women on the lower dose and six women on the higher dose discontinued the trial prematurely, mainly because of hot flushes. No serious side effects were reported. Ovulatory menstruations returned after a median time of 43 days after discontinuation of therapy. Daily intranasal nafarelin treatment for inhibition of ovulation proved to be an effective and rapidly reversible method of contraception.

Human gonadotropin therapy. I. Serum estradiol and progesterone patterns during conceptual cycles.

Hormone patterns during 43 conceptual cycles induced by human gonadotropins in 37 women with anovulatory infertility were analyzed. The treatment was monitored by daily determinations of estradiol (E2) in serum. The incidence of both multiple pregnancies and abortions during the gonadotropin therapy was high (30%). When the hormone patterns during the human menopausal gonadotropin-induced conceptual cycles were compared with spontaneous conceptual cycles, it became evident that the ovaries were hyperstimulated during the follicular and luteal phases of the induced cycle. The mean serum E2 level at induction of ovulation did not differ between treatment courses resulting in single or multiple pregnancies. The endogenous estrogen secretion at the initiation of treatment was lower in the multiple pregnancy group than in the single pregnancy group. The active phase, i.e., when the estrogens progressively increase during the late follicular phase of the induced cycle, was found to be prolonged in the multiple pregnancy group. The prolonged follicular stimulation by human menopausal gonadotropin might explain why multiple ovulations and pregnancies occur. Thus, both the duration of the active phase of follicular stimulation and the E2 level at the day of induction of ovulation by human chorionic gonadotropin should be determined for optimal monitoring of human gonadotropin therapy.

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.

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.

PIP: The risk of endometrial hyperplasia during long-term inhibition of ovulation by luteinizing hormone-releasing hormone (LH-RH) agonist was investigated in 17 endometrial biopsy specimens from 12 22-36 year old women (mean age 29.6 years). The volunteers were treated for 13-55 weeks with a single daily 400 or 600 mcg dose of the the LH-RH agonist, D-Ser(TBU)6-EA10-LH-RH, administered intranasally. Endometrial biopsies were done after 78-380 days of treatment. Half of the women had amenorrhea and the other half had one or more episodes of uterine bleeding during treatment, but there was no dysfunctional bleeding. Biopsy specimens showed 6 inactive endometria and 9 weak proliferative endometria with slightly atrophic stoma. There were no signs of hyperplasia, glandular cysts, or atypia of the epithelium. Mean estradiol levels during treatment corresponded well with estradiol levels during the earlier follicular phases of the normal menstrual cycles. No pregnancies occurred. Ovulatory menstrual cycles rapidly returned after discontinuation of treatment; menstrual bleeding began an average of 45.3 days after treatment.

Comparison of the operating microscope and loupe for microsurgical tubal anastomosis: a randomized clinical trial.

Reversal of sterilization was performed by microsurgical tubal anastomosis in 72 women using either loupe (n = 36) or microscope (n = 36). The study design called for the randomization of patients within pairs, which were matched for method of sterilization and site of anastomosis. A significant difference between methods could not be demonstrated at 12 months (P = 0.39) or 24 months (P = 0.37) after the procedure.

PIP: This paper describes a randomized, controlled clinical trial to compare the efficacy of the loupe and the microscope in performing a microsurgical anastomosis of tubal segments other than the cornual-isthmic region. 72 women evaluated at the Johns Hopkins Hospital in Baltimore between January 1, 1978 and December 31, 1980, for reversal of sterilization met the criteria for entry into the trial: under 36 years of age and at least 5 cm of oviduct remaining. The surgeon was informed of which device to use for magnification just prior to the procedure. The study design called for the randomization of patients within pairs, which were matched for method of sterilization and site of anastomosis. No significant differences were observed between the loupe and microscope groups in age, parity, or interval from sterilization to reversal. 75% of each group had had an ampullary-isthmic anastomosis, 22% of the loupe and 20% of the microscope group had had an amupllary-ampullary anastomosis, and 3% of the loupe and 6% of the microscope group had had an isthmic-isthmic anastomosis. At 12 and 24 months after the reversal procedures, no differences could be demonstrated between the groups with respect to total pregnancies, term pregnancies, spontaneous abortions, or ectopic pregnancies. 23 of 36 loup patients and 19 of 36 microscope patients had term pregnancies, but the differences were not significant.

Endometrial morphology after 6 months of continuous treatment with a new gonadotropin-releasing hormone superagonist for contraception.

Light and electron microscopic studies were performed on endometrial curettage specimens from 27 women after 6 months of contraceptive treatment with continuous intranasal gonadotropin hormone-releasing hormone (GnRH) superagonist. The GnRH superagonist nafarelin acetate (D-Nal[2]6-GnRH) was used in single daily doses of 125 or 250 micrograms. Ovulation was inhibited during all but one of the 159 treatment months. No pregnancies occurred. In 6 women with fairly regular bleedings, the endometrium displayed weak to normal proliferation. Twenty women developed oligomenorrhea or amenorrhea, 16 of them had inactive endometrium, 1 had weakly proliferative endometrium, and 3 endometrial biopsies were too sparse for adequate evaluation. One woman reported repeated episodes of heavy uterine bleedings. The endometrial biopsy from this woman showed weak proliferation. No signs of endometrial hyperplasia were observed. Generally, the electron microscopy showed signs of low metabolic activity and weak protein synthesis. Thus, long-term continuous treatment with nafarelin acetate for inhibition of ovulation does not appear to have untoward effects on the endometrium.

Cul-de-sac fluid in women with endometriosis: fluid volume and prostanoid concentration during the proliferative phase of the cycle--days 8 to 12.

Cul-de-sac fluid from women with histologically confirmed endometriosis (n = 45) or with no evidence of endometriosis (n = 17) was removed during the proliferative phase of the menstrual cycle (days 8 to 12) and analyzed for prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), 15-keto-13,14-dihydroprostaglandin F2 alpha (PGFM), and thromboxane B2 (TXB2). The fluid volume was recorded. Peripheral blood was also obtained to determine the concentration of PGFM. Prostanoid concentrations (PGE2, PGF2 alpha, PGFM, TXB2) in women with endometriosis were not significantly different from a comparable group of disease-free women. Furthermore, a meaningful elevation of prostanoid with increasing severity of disease could not be demonstrated. Plasma PGFM was not significantly different from controls. There was, however, an elevation of PGFM with severity of disease, although this increase was not statistically significant (P = 0.11). An increase in fluid volume was not demonstrated in women with endometriosis, as compared with controls.

Tubal anastomosis following unipolar cautery.

Twenty-five of 48 women (52%) sterilized by unipolar cautery techniques conceived following tubal anastomosis, of whom 17 (36%) had a living child. The overall cumulative probability of conception at the end of follow-up as determined by life-table analysis was 76%. Increasing age, parity, and the duration of the interval from sterilization to reversal did not influence pregnancy success. A decreased pregnancy rate was associated with ampullary-isthmic anastomosis; however, a pregnancy was least likely to occur in women with shortened oviducts of less than or equal to 4 cm (P less than 0.01). A decreased pregnancy rate in cautery-sterilized patients undergoing reversal may be related to the destruction of a larger segment of the fallopian tube. Interestingly, 71% of the cautery-sterilized patients were noted to have associated tubal disease such as endometriosis and/or proximal hydrosalpinx. The influence of these findings on subsequent pregnancy success remains to be established.

Immediate postpartum insertion of the norplant contraceptive device.

OBJECTIVE: To determine the safety and efficacy of Norplant (Wyeth-Ayerst Laboratories, Philadelphia, PA) insertion immediately postpartum. DESIGN: Prospective study of 14 women receiving Norplant immediately postpartum compared with controls (n = 6) having a bilateral tubal ligation. Subjects were followed for 3 months postpartum, and data were analyzed by analysis of variance and chi2. SETTING: Academic Health Sciences Center. PATIENTS: Female subjects 18 to 35 years old who had an uncomplicated term pregnancy, normal spontaneous vaginal delivery, and did not breast-feed. INTERVENTION: A brief interview, physical exam, and blood and urine samples were evaluated during a 12-week postpartum period. MAIN OUTCOME MEASURES: Major complaints, serum chemistry panels, hematologic and coagulative measures, serum E2, P, levonorgestrel, PRL, LH, FSH, and urinary estrone-3 conjugates and pregnanediol-3-glucuronide concentrations. RESULTS: Serum levonorgestrel peaked at approximately 2,000 pg/mL (6,400 pmol/L) during the 1st week after Norplant insertion, declining to approximately 250 pg/mL (800 pmol/L) by the 8th week. Significant differences between Norplant and control groups included bleeding irregularities, headaches, alopecia, and abdominal discomfort. Serum electrolytes, metabolic markers, and blood components were within normal limits. Serum E2, P, and urinary steriod biomarkers indicated that steroid secretion was suppressed severely in the Norplant group compared with controls who exhibited normal postpartum ovarian activity. CONCLUSION: Norplant inserted immediately postpartum appears to be a safe and effective method of contraception. However, the long-term hypoestrogenic state and contraceptive efficacy beyond the 3-month postpartum period as observed in this study are concerns that need further clinical evaluation.

PIP: During December 1992 to October 1994, in Texas, clinical researchers conducted a prospective case control study (15 cases receiving Norplant immediately postpartum vs. 6 controls undergoing bilateral tubal ligation immediately postpartum) to determine the safety and efficacy of inserting the contraceptive implant Norplant (6 capsules inserted subdermally, each containing 35 mg levonorgestrel) immediately postpartum. They followed the cases and the controls for three months. The study subjects were 18-35 years old, received prenatal care at one of the Department of Obstetrics and Gynecology's (Texas Tech University Health Sciences Center) community clinics, had an uncomplicated term pregnancy and normal spontaneous vaginal delivery, and did not breast feed. They tended to be poor. During the first week after Norplant insertion, serum levonorgestrel levels peaked at about 2000 pg/ml, then fell abruptly until about the eighth week to about 250 pg/ml. This lower levonorgestrel level concerned the researchers because it is just slightly higher than levels associated with pregnancy. They were also concerned about the possibility of Norplant inducing a hypoestrogenic state in postpartum women. The Norplant group was more likely than the tubal ligation group to experience irregular bleeding (p 0.01), headaches (p 0.01), hair loss (p 0.05), and abdominal discomfort (p 0.05). The various serum metabolic biomarkers, serum electrolytes, and blood components fell into the normal range in both groups. The serum estradiol, progesterone, and urinary steroid biomarkers suggested that the Norplant group experienced very suppressed steroid secretion throughout the three month study period, while the controls had normal postpartum ovarian activity. Thus, ovarian activity was absent in the Norplant group. These findings suggest that postpartum insertion of Norplant is safe and effective. Yet further clinical evaluation is needed to address concerns about the long-term hypoestrogenic state and contraceptive efficacy beyond the three month postpartum period.

Ultrasonic measurement of ovarian follicles during chronic LRH agonist treatment for contraception.

Ultrasonic examinations of ovarian follicles were performed in seven healthy women on continuous luteinizing hormone-releasing hormone (LRH) agonist treatment for contraception. Four of the women had 1-4 uterine bleedings during the four-month study period and the remaining three women developed amenorrhea. The follicle diameter varied during LRH agonist treatment up to or above the preovulatory size of the normal menstrual cycle in the menstruating group of women. No ovulation occurred as judged by the low progesterone levels in serum. Slightly raised progesterone concentrations (mean 7.6 nmol/l) were observed during four treatment cycles with persistent follicles indicating luteinization of unruptured follicles. No or only small ovarian follicles (8-10 mm) were visualized by ultrasound in the amenorrheic group of women. This study further establish previous reports that chronic LRH agonist treatment effectively inhibits normal ovulation in regularly menstruating 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.

PIP: 30 healthy female volunteers used a new superactive stimulatory anaog of the hypothalamic gonadotropin-releasing hormone (GnRH) for inhibition of ovulation and contraception over a 3 month period. The potent GnRH agonist nafarelin (D-Nal(2)6GnRH) was administered intranasally in a daily dose of 125 mcg to 15 women and 250 mcg 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 months treatment within the normal range for the early to midfollicular phase of the menstrual cycle. Results suggest that the GnRH agonist nafarelin has potential for contraception because of its inhibition of ovulation in women.

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.

PIP: The superactive stimulatory (LHRH) luteinizing hormone-releasing hormone analogue D-Ser (TBU)6-EA10-LRH was administered intranasally to 5 healthy women in a daily dose of 60 mcg during 2 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. 3 women who were given additional treatment with (HCG) human chorionic gonadotropin 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 LHRH antagonist.

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.

PIP: Induction of luteolysis with superactive agonists of luteinizing hormone-releasing hormone (LRH) may provide an effective means of or prevention or interception of implantation. This study examines the effects of daily administration of superactive LRH agonist D-ser (TBU) 6-EA10-LRH during luteal phase of menstrual cycle of 8 healthy regularly menstruating women aged 24 to 32 (mean age, 29 years). 5 women were given daily administration of intranasal treatment with 600 ug of LRH agonist during the early luteal phase of the menstrual cycle. This treatment reduced the basal progesterone levels during the luteal phase in 4 women but did not cause premature onset of menstruation. 5 women self-administered 10 ug of LRH agonist subcutaneously once daily during the mid-luteal phase. This treatment did have any effect on the progesterone levels or length of luteal phase. There were no side effects during or after the treatment period. Daily postovulatory administration of the above LRH agonist did not cause luteolysis in normally cycling women. Further research should be done to determine if LRH agonists are effective as postovulatory contraceptive agents.

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.

PIP: 4 women aged 30-34 years were given the luteinizing hormone-releasing hormone (LH-RH) analog D-Ser(TBU6-EA10-LRH to determine its effects on the pituitary response. 5 mcg/day analog were self-administered sc for 22-30 days beginning within the first 3 days of menstrual bleeding, and serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone were monitored 3 times weekly. In all 4 subjects there was a sharp rise in LH and FSH on Treatment Day 1 that fell to within lower normal follicular phase limits for the remainder of treatment. Estradiol and progesterone responses varied among the subjects, perhaps because premature bleeding caused 2 subjects to begin treatment at a different point in the menstrual cycle. 1 subject stopped treatment after Day 22 because of headache and vertigo. None of the women ovulated during treatment, but 3 of 4 had ovulated within 4 weeks of discontinuation of treatment, and all women ovulated in the following cycle. The anovulatory effect of the analog is thought to be due to a disturbance of pituitary gonadotropin secretion that leads in turn to disordered follicle development. The possibilities for using this analog as a means of birth control are discussed.