Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women.

BACKGROUND: Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation. STUDY DESIGN: This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated. RESULTS: Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%). CONCLUSION: In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.

Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

CONTEXT: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. OBJECTIVE: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. DESIGN AND SETTING: The randomized, unblinded clinical trial was conducted at two academic medical centers. PARTICIPANTS: A total of 140 healthy male volunteers participated. INTERVENTIONS: One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. MAIN OUTCOME VARIABLE: Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. RESULTS: A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. CONCLUSION: Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis.

Hormone therapy effects on social behavior and activity levels of surgically postmenopausal cynomolgus monkeys.

The purpose of the experiments reported here was to investigate central nervous system effects of commonly prescribed postmenopausal hormone therapies in a primate model, the cynomolgus monkey (Macaca fascicularis). The results of two experiments are reported. In the first, ovariectomized adult cynomolgus monkeys were treated for eight weeks each with oral micronized 17beta-estradiol (E2) (n=23), E2+medroxyprogesterone acetate (MPA) (n=23), E2+progesterone (P4) (n=23), and placebo (n=23) using a crossover design. In the second, ovariectomized adult cynomolgus monkeys were treated for eight weeks with oral micronized E2+oral micronized P4 (n=10), or E2+intravaginal micronized P4 delivered via a Silastic ring (n=8), or oral placebo and intravaginal placebo (n=5), using a parallel arm design. Behavior was recorded during weeks two through four. Cerebrospinal fluid (CSF) and blood were sampled, and 24h heart rate recorded by telemetry during weeks five through seven. Monoaminergic metabolites were assayed in CSF, and cortisol was assayed in serum. There were no significant effects of treatment on CSF monoaminergic metabolites or heart rate. E2+MPA increased cortisol concentrations. While there were some differences in effects between experiments, both progestogens and both routes of administration increased time spent resting, particularly resting in body contact, resulting in increased passive affiliative interaction. Thus, synthetic progestogens appear to be as sedating as progesterone, and the ring delivery system does not appear to protect the central nervous system from effects of progestogens. Further research is needed to explore social context as an important feature of behavioral response to steroid hormone regimens and to verify and extend knowledge of systemic effects of vaginal ring-delivered progestogens.

Effects of estradiol with oral or intravaginal progesterone on risk markers for breast cancer in a postmenopausal monkey model.

OBJECTIVE: To evaluate the effects of oral estradiol given with either oral or intravaginal micronized progesterone (P4) on risk biomarkers for breast cancer in a postmenopausal monkey model. DESIGN: This experiment was a two-way crossover study in which 20 ovariectomized adult female cynomolgus macaques were treated (in equivalent doses for women) with oral estradiol (1 mg/d) + oral micronized P4 (200 mg/d) or intravaginal P4 delivered by Silastic rings (6- to 10-mg/d release rate). Hormone treatments lasted 2 months and were separated by a 1-month washout period. The primary outcome measure was breast epithelial proliferation. RESULTS: Serum P4 concentrations were significantly greater in subjects receiving oral P4 (10.9 ng/mL) compared with intravaginal P4 (3.8 ng/mL) at 2 to 3 hours after oral dosing (P<0.0001) but not at 24 to 28 hours after oral dosing (2.9 ng/mL for oral P4 vs 3.2 ng/mL for intravaginal P4 at 2 months, P=0.19). Serum estradiol concentrations were significantly lower after oral P4 than after intravaginal P4 (P<0.05 for all time points). Oral P4 resulted in significantly decreased body weight (-2.5%) compared with intravaginal P4 (+3.6%) (P=0.0001). Markers of breast proliferation, sex steroid receptor expression, and endometrial area did not differ significantly between oral P4 and intravaginal P4 treatments (P>0.1 for all). CONCLUSIONS: Despite different pharmacodynamic profiles, oral and intravaginal P4 had similar effects on biomarkers in the postmenopausal breast.

Immune complex deposition in adult male Sprague-Dawley rats chronically immunized with GnRH.

PROBLEM: This study was undertaken to evaluate whether the anti-GnRH antibodies and immune complexes (IC) generated by immunization with GnRH-TT cause cellular damage within the animal. METHOD OF STUDY: Chronic immunization of rats with GnRH-TT injected i.m. was followed by tissue/organ analysis for immune complex deposition by immunofluorescence microscopy. Two groups were studied: (1) those immunized throughout the experiment until their ultimate demise, and (2) those given a chance to recover from the effects of chronic immunization before final analysis. RESULTS: GnRH-TT was effective in stopping spermatogenesis, which resumed after withdrawal of the immunogen. Most tissues from chronically immunized animals were not significantly different than controls, however the kidneys of treated animals exhibited a higher accumulation of IC. Despite increased IC deposition, pathologic effects were not detected at the cellular level. CONCLUSIONS: GnRH-TT is an effective immunocontraceptive although the accumulation of glomerular IC represents a potential deleterious side effect.

Serum Nestorone and ethinyl estradiol levels, and ovulation inhibition in women using three different dosage combinations of a Nestorone progestogen-ethinyl estradiol contraceptive vaginal ring on a bleeding-signaled regimen.

OBJECTIVES: This trial tested the hypothesis that menstrually signaled use of contraceptive vaginal rings ("rings") releasing low-dose combinations of Nestorone (NES) and ethinyl estradiol (EE) would reliably suppress luteal activity and ovulation, and prevent unintended pregnancy, while controlling the incidence of menstrual bleeding episodes and bleeding days. METHODS: Nestorone/ethinyl estradiol rings releasing 50/10, 50/20 and 150/15 mug/day were studied through 6 months. A ring was to be used continuously, until its removal was signaled by menstrual bleeding. Reinsertion was required 96 h after removal. Serum for NES, EE and progesterone were collected and assayed, and vaginal ultrasound scans were performed in three 5-week periods to examine luteal activity, follicular growth, ovulation and their correlates. In 10 subjects using the 150/15 ring, six samples were drawn in the 24-h period after ring removal to examine serum levels of NES and EE. RESULTS: One hundred sixty subjects at three doses provided blood samples. Median serum concentrations of NES and EE demonstrated dose ratios slightly below the nominal dose ratios expected. Serum NES concentrations declined 19-22% from weeks 3 to 25. Changes in EE levels depended on dose. Nestorone levels fell 81% by 24 h after ring removal and EE levels fell by 50%. Luteal activity was completely suppressed in 94-95% of cycles and in 90% of subjects. Three pregnancies occurred in subjects participating in this serum sampling study. CONCLUSION: Satisfactory serum levels of NES and EE, and a high level of ovulation suppression were achieved. Irregular ring use, however, permitted pregnancies to occur.

Clinical performance and menstrual bleeding patterns with three dosage combinations of a Nestorone progestogen/ethinyl estradiol contraceptive vaginal ring used on a bleeding-signaled regimen.

OBJECTIVE: We examined the clinical performance of contraceptive vaginal rings (rings) delivering Nestorone (NES) progestin and ethinyl estradiol (EE). Ring removal times were signaled by menstrual events. Bleeding patterns, adverse events, patterns of use and continuation rates were the principal parameters evaluated. METHODS: In a two-stage 6-month trial, subjects were randomized to use rings releasing 50 microg/day of NES and either 10 (50/10) or 20 (50/20) microg/day of EE. Subjects were to keep rings continuously in situ until menstrual bleeding or prolonged spotting-signaled removal. Reinsertion was to occur 96 h later. After the randomized stage, an open-label 6-month trial of rings releasing 150 microg/day of NES and 15 microg/day of EE (150/15) began with the same menstrually signaled regimen. RESULTS: Two-hundred forty-six subjects participated in the trial. Six-month pregnancy rates ranged by ring dose from 1.3 to 3.9 per 100. For each ring dose combination, 6-month continuation rates were above 80 per 100. Bleeding and spotting (B+S) days in women with the 50 microg/day NES rings were similar in number to those experienced by cycling women not using contraception. Nevertheless, in the initial 90 days, fewer B+S days were reported by subjects with the 50/20 ring than by subjects with the 50/10 ring (p < .05). Throughout the trial, subjects using the 150/15 ring reported significantly fewer B+S episodes than did subjects with either 50 microg/day NES ring. CONCLUSION: Combined contraceptive rings used with a bleeding-signaled regimen led to few terminations attributed to bleeding problems and to acceptable continuation rates. The 150/15 ring appeared to induce fewer bleeding problems than did the lower-dose NES combination rings, but no important difference in 6-month continuation rates among the three doses was noted.

Nestorone: clinical applications for contraception and HRT.

The 19-nor derivatives of progesterone are referred to as "pure" progestational molecules as they bind almost exclusively to the progesterone receptor (PR) without interfering with receptors of other steroids. In this category is Nestorone, which has strong progestational activity and antiovulatory potency with no androgenic or estrogenic activity in vivo. These properties make it highly suitable for use in contraception and hormonal therapy (HT). Due to its high potency, very low doses of Nestorone may be delivered via long-term sustained-release delivery systems. Nestorone, 75 or 100 microg per day, released by vaginal ring has suppressed ovulation in women, with inhibition of follicular maturation. A vaginal ring releasing both 150 microg of Nestorone and 15 microg of ethinyl estradiol per day has effectively suppressed ovulation for 13 consecutive cycles. Nestorone has also been used effectively in a single implant for contraception in breastfeeding women and shows promise for use in transdermal systems as a contraceptive or for HT when combined with estrogen.