Regulatory perspective on clinical trials and end points for female sexual dysfunction, in particular, hypoactive sexual desire disorder: formulating recommendations in an environment of evolving clinical science.

This article examines the history, current status, and potential future challenges in the development of drugs for female sexual dysfunction (FSD) from the perspective of the United States Food and Drug Administration. In particular, the article focuses on testosterone therapy for hypoactive sexual desire disorder (a component of FSD), and the role of the Division of Reproductive and Urologic Products in facilitating the development of safe and effective therapies for this indication.

Dose-related suppression of serum luteinizing hormone in women by a potent new gonadotropin-releasing hormone antagonist (Ganirelix) administered by intranasal spray.

OBJECTIVE: To determine if the GnRH antagonist (GnRH-a) Ganirelix (Syntex Research, Palo Alto, CA), administered by intranasal (IN) spray to normal women, is absorbed into the systemic circulation and suppresses LH secretion. DESIGN: A single center, open label, nonrandomized, dose-escalation study. SETTING: Academic research environment. PATIENT(S): Normal female volunteers ages 23 to 43 years. INTERVENTION(S): Ganirelix was administered as a single dose by IN spray. The administered doses and the number of women receiving each of them were 0.1 mg (n = 1), 0.3 mg (n = 1), 1 mg (n = 2), 3 mg (n = 5), and 6 mg (n = 5). Blood samples were collected from -15 minutes to 24 hours after dosing. MAIN OUTCOME MEASURE(S): Serum concentrations of Ganirelix and LH. RESULT(S): Ganirelix was absorbed rapidly. The mean time to maximal serum levels in the 3- and 6-mg groups was 0.67 and 0.53 hour, respectively. Mean serum LH levels were suppressed by > or = 35% relative to baseline from 2 to 12 hours after dosing in both groups. The mean maximal percent decrease in serum LH was -62% (at 8 hours after dosing) and -74% (at 6 hours after dosing) in the 3- and 6-mg groups, respectively. CONCLUSION(S): Single dose IN administration of 3 or 6 mg of Ganirelix suppressed serum LH levels in women, further enhancing the potential clinical utility of this potent GnRH-a. This is the first clinical report of a GnRH-a reducing the secretion of a pituitary gonadotropin when administered by an IN delivery system. Based on the duration and extent of LH suppression observed in this study, Ganirelix, administered by twice daily IN spray, may be effective for the treatment of gonadal hormone-dependent disorders in women.

Effects of a gonadotropin-releasing hormone agonist on the calcium-parathyroid axis and bone turnover in women with endometriosis.

OBJECTIVE: Our purpose was to investigate the effects of nafarelin on bone turnover and mass (bone mineral density, in grams per square centimeter) in women with endometriosis. STUDY DESIGN: We monitored 22 young women with endometriosis during and 6 months after 6 months of nafarelin treatment. We compared the bone mineral density status of these women with that of healthy controls undergoing sequential bone mineral density measurement. RESULTS: Subjects had a 2.2% loss in L2-4 bone mineral density by 6 months, increasing 3 months later to 3% and returning toward baseline by 6 months after treatment. Radius bone mineral density did not change in the treatment group. Bone mineral density did not change in controls. Serum and urinary calcium levels rose during treatment. Hydroxyproline excretion increased and remained elevated 6 months after treatment. A rise in serum osteocalcin persisted 3 months after therapy but normalized by 6 months. CONCLUSIONS: Bone mineral density deficits with nafarelin are reversible. Increased bone turnover persists 6 months beyond treatment, demonstrating the need for careful monitoring of women receiving prolonged or repeated treatment.

Suppression of follicular phase pituitary-gonadal function by a potent new gonadotropin-releasing hormone antagonist with reduced histamine-releasing properties (ganirelix).

OBJECTIVE: To determine if daily subcutaneous doses of ganirelix will suppress and maintain E2 < or = 30 pg/mL (conversion factor to SI unit, 3.671), the serum profiles of LH and FSH during and after cessation of treatment, the time-course of the resumption of normal ovarian function after ganirelix cessation, and to identify side effects of daily treatment. DESIGN: Open-label nonrandomized clinical study. SETTING: Normal human volunteers in an academic research center. PATIENTS: Women 21 to 45 years of age, with documented ovulatory menstrual cycles. INTERVENTIONS: Ganirelix was administered subcutaneously daily for 8 days. Blood samples were obtained during dosing as well as before and after cessation of dosing. MAIN OUTCOME MEASURES: Changes in serum E2, LH, FSH, P, and ganirelix. RESULTS: Ganirelix treatment rapidly decreased serum levels of gonadotropins and E2 after both 1 and 2 mg administration. Twenty-four hours after the first dose of ganirelix, E2 decreased from a mean +/- SEM of 50 +/- 8 and 67 +/- 11 pg/mL at baseline to 25 +/- 4 and 20 +/- 3 in the 1 mg and 2 mg groups, respectively. Estradiol remained suppressed (mean levels < 26 pg/mL) on all subsequent 7 days of ganirelix dosing in both groups. After the final dose of ganirelix, there was a rapid return of ovarian function in all volunteers. All women had P levels indicative of ovulation in the subsequent cycle, and the mean number of days from the final ganirelix dose to the next menses was 25.8 +/- 2.1 and 27.3 +/- 1.6 in the 1 and 2 mg groups, respectively. CONCLUSIONS: Daily ganirelix administration is effective in suppressing the pituitary-gonadal axis and has a side effect profile that should be well tolerated.

Contrasting effects of a gonadotropin-releasing hormone agonist and antagonist on the secretion of free alpha subunit.

Gonadotropin-releasing hormone agonists and antagonists have initial divergent effects on the pituitary secretion of intact biologically active gonadotropins and long-term divergent effects on the secretion of free alpha-subunit. The antagonists appear to function as true competitive inhibitors, blocking the stimulatory effects of endogenous GnRH without evoking any known postreceptor activity. The agonists, in contrast, initially stimulate pituitary secretion and then incompletely desensitize the gonadotrope, resulting in suppression of intact gonadotropin, but not free alpha-subunit, secretion. The mechanisms by which GnRH-a produce this incomplete gonadotrope desensitization and facilitate limited postreceptor activity remain to be elucidated.

Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (Ganirelix) with minimal histamine-releasing properties: studies in postmenopausal women.

A potent and safe GnRH antagonist has been sought unsuccessfully for the last 2 decades. The recently developed GnRH antagonist RS-26306 or Ganirelix ([N-Ac-D-Nal(2)1,D-pClPhe2,D-Pal(3)3,D-hArg(Et2)6,L-++ +hArg(Et2)8,D-Ala10]GnRH ; Syntex Research, Palo Alto, CA), exhibited high antiovulatory potency and low histamine-releasing properties in preclinical studies. Therefore, we determined the extent to which single sc injections of three doses of RS-26306 (1, 3, and 6 mg) decreased serum concentrations of LH and FSH, the free alpha-subunit of LH/FSH/TSH, PRL, and testosterone in five healthy postmenopausal women. We also examined the pharmacokinetic characteristics of RS-26306 by quantifying serum levels of the drug by RIA. RS-26306 rapidly suppressed serum concentrations of LH, FSH, and free alpha-subunit. RS-26306 (6 mg) maximally decreased serum concentrations (mean +/- SEM) of LH, FSH, and free alpha-subunit by 70.1 +/- 3.6%, 42.3 +/- 2.5%, and 74.6 +/- 3.5%, respectively. RS-26306 also decreased serum testosterone, but not serum PRL, concentrations. RS-26306 concentrations reached peak serum levels at 1.2 +/- 0.3, 1.9 +/- 0.4, and 1.8 +/- 0.5 h, respectively, after 1-, 3-, and 6-mg sc injections. The mean serum half-life values based on the terminal portion of the disappearance curves were 22.8 +/- 2.5 and 26.9 +/- 1.0 h, respectively, after 3- and 6-mg s.c. doses. No systemic side-effects were noted after the administration of RS-26306. Our results demonstrate that the GnRH antagonist RS-26306 has favorable pharmacokinetic characteristics and is a potent suppressor of pituitary gonadotropin secretion in postmenopausal women. These attributes and the lack of systemic side-effects make RS-26306 a promising candidate for future clinical applications.

Evaluation of a 1-year levonorgestrel-releasing contraceptive implant: side effects, release rates, and biodegradability.

OBJECTIVE: To determine the release rates, effects on ovulation, and side effects of two lengths of a biodegradable, subdermal contraceptive implant containing levonorgestrel in a caprolactone capsule. DESIGN: Phase II randomized clinical trial. SETTING: Public family planning clinic at an urban general hospital. PARTICIPANTS: Forty-eight healthy, parous, ovulating volunteers. INTERVENTION: Subjects were randomly assigned either a 2.5- or a 4.0-cm contraceptive capsule that was worn under the skin of the upper arm for 1 year if not removed earlier for other reasons. MAIN OUTCOME MEASURES: Serum concentrations of levonorgestrel, progesterone, estradiol, and lipoproteins were measured as were metabolic parameters. Vaginal bleeding and other side effects were recorded. After implant removal, remaining levonorgestrel, capsule viscosity, and molecular weight were measured. RESULTS: The 4-cm implant provided serum concentrations of levonorgestrel ranging from 0.65 ng/mL shortly after insertion to 0.20 ng/mL at 12 months, but the 2.5-cm implant resulted in levels too low for contraception. The 4-cm implant suppressed ovulation in approximately 80% of cycles over 1 year of use, but the 2.5-cm implant failed to suppress ovulation. The implants were rapidly and easily inserted and removed. They retained structural integrity through 1 year of use. Of 48 subjects, 32 had abnormal bleeding patterns; the mean number of days of bleeding per month was 7 with 23 days between episodes. Women using capronor maintained normal metabolic parameters except that low-density lipoprotein decreased slightly. CONCLUSIONS: The 4.0-cm implant is a promising contraceptive. There were no important metabolic effects, but there were bothersome minor side effects typical of progestin-only contraception.

Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, alpha subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix).

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P less than 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix.(ABSTRACT TRUNCATED AT 400 WORDS)

First-trimester aneuploidy screening using serum human chorionic gonadotropin (hCG), free ahCG, and progesterone.

Immunochemical serum assays for human chorionic gonadotropin (hCG), the free ahCG subunit, and progesterone (P) were considered separately and in combination for their ability to screen for chromosomally abnormal pregnancies in the first trimester. Maternal serum was collected from 141 women undergoing chorionic villus sampling at 9-12 menstrual weeks. Trisomy 21 pregnancies had significantly higher hCG levels, while trisomy 18 and 13 pregnancies had markedly lower hCG and progesterone levels than those of chromosomally normal pregnancies. However, the discrimination of normal from aneuploid pregnancies was poor with either hCG alone, progesterone alone, or free ahCG alone. Much improved discrimination was obtained by combining hCG, free ahCG, and P into an aneuploidy index [(P/hCG)(free ahCG/hCG)]. This index distinguished 9 out of 17 (53 per cent) of the trisomy 21 pregnancies, while only misidentifying 5 out of 112 (4.5 per cent) of the normal pregnancies. The aneuploidy index thus appears promising as a first-trimester biochemical screen for aneuploid pregnancies.

Variable ovarian response to gonadotropin-releasing hormone antagonist-induced gonadotropin deprivation during different phases of the menstrual cycle.

The gonadotropin dependence of ovarian follicular maturation and corpus luteum function can now be examined in women using antagonistic analogs of GnRH. We studied the responses of three groups of women throughout a control cycle and during the administration of a potent GnRH antagonist, detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] GnRH, Syntex Research). Detirelix (10 mg, sc) was administered for 3 consecutive days during the midfollicular phase (n = 4), preovulatory phase (n = 4), and early luteal phase (n = 4). The pituitary response to detirelix was similar throughout the three phases of the menstrual cycle. Immunoreactive LH concentrations decreased to 35% (mean +/- SEM) of pretreatment values within 8 h after the initial injection and remained suppressed for 72 h after discontinuance of treatment. Immunoreactive FSH concentrations decreased to 73 +/- 3% of pretreatment levels within 8 h and returned to baseline within 24 h after the third injection. In contrast, the ovarian response to detirelix varied markedly during different phases of the cycle. Midfollicular phase treatment was associated with a decline in estradiol (E2) levels from pretreatment values of 246 +/- 48 to 81 +/- 15 pmol/L within 24 h of the last injection. Vaginal bleeding ensued in three of four women. Follicular recruitment was then reinitiated, and an ovulatory LH surge occurred 18.2 +/- 2.9 days after the last injection. Similarly, treatment during the early luteal phase produced a decline in E2 concentrations from 286 +/- 29 to 70 +/- 7 pmol/L and a decline in progesterone concentrations from 20 +/- 1.6 to 1.9 +/- 0.3 nmol/L within 24 h after the last injection. Luteolysis was associated with menstrual bleeding in all four women. The subsequent ovulatory LH surge occurred 16.5 +/- 1.0 days after discontinuance of treatment. In contrast, treatment during the preovulatory phase resulted in a decline in E2 concentrations from 844 +/- 66 to 429 +/- 132 pmol/L during the first 48 h of treatment. Gonadotropin and E2 concentrations subsequently recovered from suppression, growth of the dominant follicle resumed, and a LH surge occurred 5.8 +/- 1.4 days after the last injection. These data indicate that the GnRH antagonist detirelix produces rapid and consistent suppression of pituitary gonadotropin secretion. The magnitude of suppression and preferential suppression of LH vs. FSH are similar throughout the cycle. In contrast, the ovarian response to gonadotropin deprivation varies during the menstrual cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of follicular development by a potent antagonistic analog of gonadotropin-releasing hormone (detirelix).

The ability of a potent long-acting antagonistic analog of GnRH to suppress gonadotropin secretion, disrupt follicular development, and inhibit ovulation was studied in six women with normal menstrual cycles. The GnRH antagonist detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] GnRH; Syntex Research) was administered to six women by sc injection on alternate days during a 27-day period. Six additional women underwent blood sampling only, without receiving detirelix. Within 8 h after the initial injection of detirelix, mean (+/- SEM) serum LH and FSH concentrations decreased by 74 +/- 2% and 26 +/- 3%, respectively. Mean immunoreactive FSH levels, however, returned to baseline after the first 72 h despite continued administration of detirelix. Mean estradiol (E2) concentrations decreased from 165 +/- 15 to 70 +/- 11 pmol/L in the first 24 h. During the treatment period follicular development was inhibited, and none of the six volunteers showed evidence of ovulation, as assessed by serum progesterone (P) levels. Maximal suppression of serum LH and E2 was observed approximately 24 h after each injection of detirelix. Compared to the control volunteers, those receiving detirelix had significantly lower mean serum LH (P less than 0.001), E2 (P less than 0.001), and P (P less than 0.001) levels during treatment; mean FSH concentrations, however, were not statistically different in the treatment and control groups. Rapid recovery of pituitary-ovarian function occurred after completion of treatment. In all six volunteers receiving detirelix, a LH surge occurred 10-16 days after the final injection, followed by increased P levels (greater than 32 nmol/L), indicating ovulation and a luteal phase of normal duration (12-14 days). Detirelix injections elicited local skin reactions (erythema and pruritus), but no systemic side-effects were observed. Thus, this long-acting GnRH antagonist can rapidly suppress gonadotropin secretion, inhibit follicular development, and prevent ovulation.

Treatment of uterine leiomyomas and hirsutism with nafarelin.

Nafarelin treatment reduces both uterine and myoma volume, induces amenorrhea and improves blood indices in women with uterine leiomyomas. The gonadotropin releasing hormone analog is also effective in decreasing hair growth in women with hirsutism that is associated with excess ovarian androgen production.

Conservation of free but not total or non-sex-hormone-binding-globulin-bound testosterone in serum from Nagase analbuminemic rats.

Nagase analbuminemic rats have normal reproductive capacity, normal apparent libido, and normal serum concentrations of LH and FSH. Therefore, it is reasonable to assume that intracellular sex steroid hormone concentrations are normal or at least adequate to maintain normal reproductive function in these rats. To test whether intracellular testosterone concentrations in these rats are maintained by the circulating concentration of free or free-plus-weakly-bound testosterone, we measured the concentrations of total testosterone, free testosterone, and non-sex-hormone-binding-globulin-bound testosterone in sera from five adult male Nagase analbuminemic rats and from five age- and sex-matched controls. We found that the analbuminemic rats had markedly decreased serum concentrations of total and non-sex-hormone-binding-globulin-bound testosterone, but normal serum concentrations of free testosterone. These results suggest that intracellular concentrations of testosterone in biologically relevant organs of the rat are maintained by the concentration of free rather than free-plus-weakly-bound testosterone in plasma, in accord with the free hormone hypothesis.

Clinical evaluation of the Capronor contraceptive implant: preliminary report.

Capronor, a single-capsule, biodegradable, subdermal contraceptive that releases levonorgestrel over a 12- to 18-month period, has been evaluated in 48 healthy women, ages 18 to 40 years. Sixteen participants received a 2.5 cm capsule (12 mg of levonorgestrel), and 32 received a 4.0 cm capsule (21.6 mg of levonorgestrel). Serum levonorgestrel levels were significantly lower in the 2.5 cm group. Ovulation occurred in all cycles in the 2.5 cm group and in 26.3% of cycles in the 4.0 cm group. Levonorgestrel levels with the shorter capsule were too low for reliable contraception in all users, and 4 cm may be a minimal functional length. Bleeding patterns were regular in most women who ovulated and irregular in most remaining subjects. It is assumed that changes in cervical mucus and the endometrium contributed to effective contraception despite the frequency of ovulation.

PIP: Capronor, a single-capsule, biodegradable, subdermal contraceptive that releases levonorgestrel over a 12-18 month period, has been evaluated in 48 healthy women, ages 18 to 40 years. 16 participants received a 2.5 cm capsule (12 mg of levonorgestrel), and 32 received a 4.0 cm capsule (21.6 mg of levonorgestrel). Serum levonorgestrel levels were significantly lower in the 2.5 cm group. Ovulation occurred in all cycles in the 2.5 cm group and in 26.3% of cycles in the 4.0 cm group. Levonorgestrel levels with the shorter capsule were too low for reliable contraception in all users, and 4 cm may be a minimal functional length. Bleeding patterns were regular in most women who ovulated and irregular in most remaining subjects. It is assumed that changes in cervical mucus and the endometrium contributed to effective contraception despite the frequency of ovulation.

Low-dose dopamine infusions do not ablate luteinizing hormone pulses in women.

The effect of dopamine on the secretion of luteinizing hormone in 15 euprolactinemic and 15 hyperprolactinemic women was investigated using infused doses of dopamine that achieved circulating levels from 2 to 100 times basal physiologic concentrations. The normal women were studied in the early follicular phase of the cycle. Different concentrations of dopamine were maintained at each dose level for 2 hours. Blood samples were obtained every 15 minutes and concentrations of dopamine, luteinizing hormone, follicle-stimulating hormone, and prolactin quantified. Mean basal concentrations of estradiol were 53 +/- 19 pg/ml in the euprolactinemic and 33 +/- 12 pg/ml in the hyperprolactinemic women; mean prolactin levels were 8.1 +/- 3.9 ng/ml in euprolactinemic and 183 +/- 174 ng/ml in hyperprolactinemic women; mean basal dopamine concentrations were 323 +/- 308 pg/ml in euprolactinemic and 337 +/- 232 pg/ml in hyperprolactinemic women. All doses of dopamine achieved some degree of prolactin suppression, but doses that achieved nanomolar circulating concentrations did not significantly affect luteinizing hormone secretion. Eight of the women in each group exhibited high-amplitude luteinizing hormone pulses, which persisted during the dopamine infusions. Neither the amplitude nor frequency of luteinizing hormone release correlated with basal estradiol, luteinizing hormone, or prolactin levels. We conclude that low doses of dopamine infused into the peripheral circulation do not achieve significant suppression of luteinizing hormone release. In some women during the early follicular phase of the menstrual cycle and in some amenorrheic hyperprolactinemic women, luteinizing hormone is secreted in a pulsatile manner characterized by high-amplitude low-frequency bursts. These bursts of luteinizing hormone were not influenced by elevations in circulating dopamine concentrations sufficient to suppress prolactin.

Use of an agonistic analog of gonadotropin-releasing hormone (nafarelin) to treat leiomyomas: assessment by magnetic resonance imaging.

The purposes of this study were to investigate the effect of a superactive agonistic analog of gonadotropin-releasing hormone, nafarelin, on uterine leiomyomas and to assess the use of magnetic resonance imaging in monitoring uterine and myoma size. Eleven women with uterine leiomyomas were treated with 800 micrograms of nafarelin per day for 6 months. Serum gonadotropin and estradiol concentrations were suppressed during treatment. The mean +/- SEM serum luteinizing hormone level decreased from 11.1 +/- 1.4 to 5.6 +/- 0.42 mlU/ml and follicle-stimulating hormone from 9.5 +/- 0.66 to 7.5 +/- 0.72 mlU/ml by 3 months of treatment (p less than 0.01). The estradiol level decreased from a pretreatment follicular phase mean +/- SEM of 43 +/- 8.3 to 19.8 +/- 3.1 (p less than 0.05) and 14.8 +/- 2.2 pg/ml (p less than 0.01) at 3 and 6 months of treatment, respectively. Mean pretreatment androgen levels (testosterone, androstenedione, and dehydroepiandrosterone sulfate) were low in these women and did not change significantly during treatment. Ten women had magnetic resonance imaging, which provided excellent resolution of individual uterine myomas. As assessed by magnetic resonance imaging, the largest myoma decreased in size in nine of 10 women; the mean decrease was 46% +/- 9%. Uterine volume decreased in all 10 patients; the mean decrease was 57% +/- 7%. In several women myomas reenlarged after discontinuance of nafarelin treatment. Posttreatment myomectomy was carried out in four women; there was minimal blood loss and no surgical complications. These data indicate that suppression of ovarian estrogen production with nafarelin is associated with a decrease in uterine myoma size in many women but that myomas may regrow with reinstitution of ovarian function. Magnetic resonance imaging is an excellent method by which to monitor treatment as changes in the size of the uterus, as well as individual myomas, can be assessed. The optimal use of gonadotropin-releasing hormone analogs may be in perimenopausal women or as presurgical treatment to decrease uterine and myoma size to facilitate myomectomy.

Optical characteristics of a deformable-mirror spatial light modulator.

Some of the optical characteristics of a recently developed solid-state deformable-mirror spatial light modulator have been investigated. The device is composed of an array of 128 x 128 pixels, with each pixel consisting of four hinged reflective rectangular surfaces. Modulation at video frame rates has been achieved, providing real-time displays in coherent light, which may be useful for a variety of optical processing and computing applications.

Dose-dependent inhibition of pituitary-ovarian function during administration of a gonadotropin-releasing hormone agonistic analog (nafarelin).

To determine if treatment with the GnRH agonistic analog nafarelin could reliably block ovulation while only partially disrupting ovarian estrogen production, three degrees of pituitary-ovarian inhibition were investigated. Thirty-two women with ovulatory menstrual cycles were given 125 micrograms (group (Gp) I), 250 micrograms (Gp II), or 1000 micrograms (Gp III) nafarelin daily by intranasal spray. Twenty-seven women completed 6 months of treatment. Basal serum FSH concentrations decreased (P less than 0.01) in all groups. Suppression of serum LH was dose dependent and significant (P less than 0.01) only in Gps II and III. Pituitary desensitization to nafarelin developed in all groups. Peak LH responses to nafarelin decreased by about 70% (Gps I and II) and 95% (Gp III). Basal serum estradiol levels after 1 month of treatment were approximately 70 pg/ml (Gp I) and 25 pg/ml (Gps II and III). Serum estradiol levels increased acutely in Gps I and II, but not in Gp III, in response to each dose of nafarelin. Thus, average daily estradiol levels in Gp II were higher than those in Gp III. Serum testosterone and androstenedione levels decreased slightly (P less than 0.05; Gp II) or by 50% (P less than 0.01; Gp III) during treatment. The effects of nafarelin on ovulatory function also were dose-dependent. In Gp I there were four ovulations (progesterone, greater than 4 ng/ml) and seven instances of luteinization (progesterone, 2-4 ng/ml) during 73 months of nafarelin administration. In contrast, there were no ovulations during 58 and 44 months in Gps II and III, respectively. After discontinuance of nafarelin, ovulatory menstrual function returned rapidly in all women. In summary, inhibition of pituitary-ovarian function by daily intranasal nafarelin administration is dose dependent. Gonadotroph sensitivity to 125 micrograms is variable, and there is inconsistent inhibition of ovulation. Daily doses of 250 or 1000 micrograms analog reliably inhibit ovulation, but are associated with either moderate (Gp II) or marked (Gp III) reduction of ovarian estradiol secretion. The effects of these reduced levels of circulating estradiol on bone are not known. Further investigation, with dosage adjusted according to individual patient sensitivity, may lead to the development of a clinically acceptable contraceptive which consistently inhibits ovulation while maintaining serum estradiol levels sufficient to prevent osteoporosis.

Treatment of hirsutism with a gonadotropin-releasing hormone agonist (nafarelin).

GnRH analogs inhibit the secretion of gonadotropins and, therefore, that of estrogens and androgens of ovarian origin. The purpose of this study was to investigate the use of one superactive agonistic GnRH analog, nafarelin, in the treatment of hirsutism. Six hirsute women were treated with nafarelin (1 000 micrograms/day) for 6 months. An acute rise in serum gonadotropin levels occurred in response to nafarelin administration initially, but it lasted less than 2 weeks. Serum gonadotropin, testosterone, free testosterone, and androstenedione concentrations decreased significantly during treatment. Mean serum LH levels decreased from 17.9 +/- 4.6 (+/- SE) to 5.0 +/- 0.5 mIU/ml (P less than 0.01), and FSH decreased from 9.3 +/- 0.7 to 7.2 +/- 0.9 mIU/ml (P less than 0.05) after 1 month of treatment. The total testosterone concentration fell from 0.77 +/- 0.10 to 0.40 +/- 0.14 ng/ml (P less than 0.01) after 1 month of therapy, and free testosterone decreased from 10.7 +/- 2.7 to 4.1 +/- 1.6 pg/ml (P less than 0.01) after 3 months. Androstenedione levels decreased from 2.4 +/- 0.4 to 1.2 +/- 0.2 ng/ml (P less than 0.01) after 1 month of treatment. The mean concentrations of all of the above hormones remained suppressed throughout treatment. Serum 5 alpha-androstane-3 alpha,17 beta-diol glucuronide levels did not decrease significantly during treatment, nor did dehydroepiandrosterone sulfate levels. The mean estradiol concentration during treatment was 34.8 +/- 3.1 pg/ml. The clinical response was very good; hair growth was slower, and new hair was less coarse compared to the pretreatment period. Hirsutism scores (determined by Ferriman-Gallwey assessment of extent and quality of body hair) improved in four of the six patients. In the six patients, the mean score decreased significantly from 19.3 +/- 3.3 to 13.2 +/- 2.8 (P less than 0.05) at the end of treatment. These data demonstrate that by suppressing ovarian androgen production, nafarelin may be useful for the treatment of hirsutism associated with either increased ovarian androgen production or increased sensitivity of the hair follicle to normal concentrations of circulating androgens.