Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot.

Hormonally induced azoospermia induced by weekly im injections of testosterone enanthate provides effective and reversible male contraception, but more practical regimens are needed. Given our previous findings that six 200-mg pellets implanted subdermally produced more stable, physiological T levels and reduced the delivered T dose by more than 50% while maintaining equally effective suppression of sperm output with fewer metabolic side-effects than weekly 200-mg testosterone enanthate injections, we sought in this study to determine 1) whether further dose-sparing could be achieved by lower testosterone doses while maintaining efficacy and 2) the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose as a model depot progestin/androgen combination male contraceptive. Healthy volunteers were randomized into groups (n = 10) who received either of two lower T doses (two or four 200-mg T pellets) or four 200-mg T pellets plus a single im injection of 300 mg depot medroxyprogesterone acetate (DMPA). Two T pellets (400 mg, 3 mg/day) had a negligible effect on sperm output. Four T pellets (800 mg, 6 mg/day) suppressed sperm output between the second to fourth postimplant months; output returned to normal by the seventh postimplant month, although only 4 of 10 men became azoospermic or severely oligozoospermic (< 3 mol/L/mL). The addition of a depot progestin markedly increased the extent, but not the rate, of sperm output suppression, with 9 of 10 becoming azoospermic and 10 of 10 becoming severely oligozoospermic. There were no serious adverse effects during the study. Plasma total and free testosterone levels remained within the eugonadal range at all times with each treatment. Plasma epitestosterone was suppressed by all 3 regimens, consistent with a dose-dependent inhibition of endogenous Leydig cell steroidogenesis. Plasma LH and FSH measured by a two-site immunoassay were suppressed in a dose-dependent fashion by T and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either T dose. Prostate-specific antigen and lipids (total, low or high density lipoprotein cholesterol, and triglycerides) were not significantly changed in any group. Thus, a depot testosterone preparation with zero order release must be delivered at between 6-9 mg/day to provide optimal (but not uniform) efficacy at inducing azoospermia. The addition of a single depot dose of a progestin to a suboptimal testosterone dose (6 mg/day) markedly enhances the extent, but not the rate, of spermatogenic suppression, with negligible biochemical androgenic side-effects. These findings provide a basis for the use of a progestin/androgen combination depot for hormonal male contraception.

PIP: Clinical research conducted in Australia suggests that a progestin-androgen combination depot has potential for hormonal male contraception. The authors' previous research had indicated that 6 200-mg testosterone enanthate pellets implanted subdermally produced substantial reductions over injections in the delivered testosterone dose while maintaining equally effective suppression of spermatogenesis with few metabolic side effects. The present study sought to determine whether lower testosterone doses would maintain efficiency and to assess the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose (6 mg/day). 10 volunteers received either 2 or 4 200-mg testosterone pellets or 4 200-mg pellets plus a single intramuscular injection of 300-mg depot medroxyprogesterone acetate (DMPA). The testosterone implants alone achieved inadequate suppression of spermatogenesis for a male contraceptive; 400 mg of testosterone (3 mg/day) had a negligible effect on sperm output, while 800 mg (6 mg/day) produced azoospermia or severe oligozoospermia in only 4 of 10 men. However, the addition of DMPA markedly increased the extent, but not the rate, of sperm output suppression: azoospermia was achieved in 9 men and oligozoospermia in all 10 subjects, and sperm suppression persisted for 3 months. Epitestosterone concentrations, used as a marker of Leydig cell steroidogenesis, were decreased in a time- and dose-dependent manner, reaching castrate levels in the combined group. Plasma luteinizing hormone and follicle-stimulating hormone levels were suppressed in a dose-dependent fashion by testosterone and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either testosterone dose. Prostate-specific antigens and lipids were not significantly altered by any regimen. There were no discontinuations or reports of side effects.

Depo-Provera in adolescents: effects of early second injection or prior oral contraception.

PURPOSE: To examine the effects of an early second injection or prior use of oral contraceptive pills (OCP) on side effects of Depo-Provera during the early months of use in adolescents. METHODS: Thirty-six girls, gynecologic age 4.2 +/- 0.3 years, and body mass index (BMI) 23.2 +/- 0.8, received the currently recommended injection of 150 mg every three months. Twenty-seven girls (gynecologic age 3.9 +/- 0.5 years, BMI 24.0 +/- 0.8) received the second injection six weeks after the first injection. Fifteen girls (gynecologic age 5.0 +/- 0.5, BMI 25.4 +/- 1.3) switched directly from an OCP to Depo-Provera. The patients were periodically assessed by their care providers. RESULTS: Early administration of the second injection of Depo-Provera did not alter the bleeding episodes, onset of bleeding, or total days of bleeding (14.3 +/- 3.7 vs. 17.1 +/- 4.0, p = 0.62) during the three months interval following injection, compared with the standard second injection interval. Moreover, an excessive BMI gain (BMI increase 0.99 +/- 0.22 vs. 0.40 +/- 0.14, p = 0.03) was observed in these girls. Girls who switched directly from OCP showed no difference in the rate of BMI gain when compared to those not previously on OCP (BMI increase 0.38 +/- 0.3). Bleeding duration of these girls, however, was markedly reduced; the total number of days of bleeding was 5.7 +/- 1.9 (p = 0.0003) during the first three month interval, and 5.7 +/- 2.3 (p = 0.019) during the three month period following the second injection. This reduction did not persist beyond the first six months. CONCLUSIONS: Early second Depo-Provera injection does not alter the experience of menstrual abnormalities, and predisposes to greater weight gain; OCP use prior to Depo-Provera results in a decrease in the duration of bleeding with no change in the weight gain rate.

PIP: The capability of an early second injection or prior use of oral contraceptives (OCs) to improve satisfaction and long-term continuation of Depo-Provera in adolescents was investigated in a clinical trial involving 78 females 12-20 years of age (average, 15.9 years) recruited from a hospital-based adolescent health clinic. 36 subjects received injection of 150 mg of Depo-Provera every three months (Group 1), 27 received the second injection after only six weeks (Group 2), and 15 switched directly from OCs to the standard Depo-Provera regimen (Group 3). There was no difference between Groups 1 and 2 in terms of duration or frequency of menstrual bleeding; however, prior OC users experienced a significant reduction in the duration and intensity of bleeding in the first six months of Depo-Provera use (when estrogen was still present in the women's systems). Overall, 64% of study subjects reported less dysmenorrhea while on Depo-Provera. A slightly greater change in body mass index was observed among girls in Group 2 than in Groups 1 and 3; moreover, 70% of those in the early injection group reported increased appetite and weight gain compared to 39% of those on the standard schedule. The most commonly reported side effects included initial pain and soreness at the injection site (27%), decreased libido (56%), mood changes (31%), depression (26%), frequent headache (25%), fatigue (24%), and increase in acne (15%); there were no significant differences by group. 17 adolescents (22%) discontinued Depo-Provera, generally after two injections and due to bleeding irregularities or weight gain. 87% of adolescents who were prior OC users, 52% of those on the regular schedule, and 39% of those who received an early injection stated they were very satisfied with Depo-Provera. These findings indicate that early second Depo-Provera injection offers no advantages; use of OCs immediately prior to Depo-Provera should be further investigated, however, given its potential to minimize bleeding problems.

Effects of intermittent antiprogestin RU486 combined with cyclic medroxyprogesterone acetate on folliculogenesis and ovulation.

The results of several studies have suggested an inhibitory effect of the antiprogestin RU486 on late stages of folliculogenesis and ovulation. To assess the feasibility of using this property to inhibit ovulation without losing cycle control, an intermittent administration of RU486 alternated with medroxyprogesterone acetate (MPA) was tested in a phase I study. RU486 at a dose of 50 mg/day was given on menstrual cycle days 9-11 and 27-29, and 10 mg/day of MPA was given on cycle days 17-26 for three consecutive cycles to six Finnish and five Chilean women. Blood samples were collected two to three times a week for serum progesterone and oestradiol assays in three treatment cycles. One control cycle and one post-treatment recovery cycle were also monitored by serum samplings. Ultrasonography was carried out to measure follicular diameters in the treatment cycles. In 29 of 32 cycles, bleeding commenced within 3 days after the last MPA pill intake. Out of 32 treatment cycles, 20 were without luteal activity (serum progesterone < 9 nmol/l). Although 12 treatment cycles showed luteal activity (serum progesterone > or = 9 nmol/l), a clear rupture of a pre-ovulatory follicle > 15 mm, verified by ultrasonography, was seen in only one treatment cycle. During the treatment cycles with luteal activity (serum progesterone levels > or = 9 nmol/l), serum oestradiol concentrations were significantly higher on cycle days 9-18 and significantly lower at the end of the cycle compared with the cycles without luteal activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Pilot trial of a gonadotropin hormone agonist with replacement hormones as a prototype contraceptive to prevent breast cancer.

Combination oral contraceptive (COC) users have reduced risks of ovarian and endometrial cancer, but COCs have not reduced breast cancer risk. We have previously argued that a hormonal contraceptive with substantially lower doses of sex-steroids should reduce breast cancer risk by decreasing the breast epithelial cell proliferation below usual premenopausal levels. We report here the preliminary results of a pilot trial with such a prototype contraceptive consisting of an agonist of gonadotropin releasing hormone (GnRHA) administered with low doses of an oral estrogen (0.625 mg of conjugated estrogen, CE, for 6 days every week) and intermittent oral progestogen (10 mg of medroxyprogesterone acetate, MPA, for 13 days every 4 months). Eighteen subjects at five-fold or greater increased breast cancer risk were entered and randomized -12 to the contraceptive arm and 6 to a control arm. The principal endpoints included tolerance of the regimen, vaginal bleeding patterns, and the regimen's effect on the endometrium, bone metabolism, and lipids. A symptom questionnaire was used to assess tolerance; the contraceptive subjects had fewer symptoms following initiation of the regimen. This results from the elimination of symptoms associated with the luteal phase of the menstrual cycle, commonly referred to collectively as premenstrual syndrome, PMS. The few occurrences of hot flushes or vaginal dryness that did occur were eliminated by small increases in estrogen dose (0.9 mg CE). Scheduled vaginal bleeding occurred associated with most periods of progestogen administration. Unscheduled bleeding or spotting was infrequent and decreased with time on the regimen. A beneficial rise in high-density lipoprotein cholesterol was evident in the contraceptive subjects. Despite the use of an estrogen dose which is known to prevent loss of bone mineral density in normal postmenopausal women, an annualized loss of 1.9% was seen in contraceptive subjects. It is hypothesized that this is secondary to inhibition of ovarian androgen production by the GnRHA, which may additionally account for changes in libido occasionally reported with GnRHA. The study continues with the addition of a small dose of androgen to replace that lost by the action of the GnRHA.

Use of injectable progestin (medroxyprogesterone acetate) in adolescent health care.

To assess medroxyprogesterone acetate (DMPA) prescription practices in adolescent health care practices, an anonymous questionnaire was distributed to 160 American and Canadian physicians attending the 1991 meetings of either the Society for Adolescent Medicine or the North American Society for Pediatric and Adolescent Gynecology. Of 54 (33.7%) physicians who responded, 33 (61.1%) reported prior prescription of an injectable progestin (DMPA) as a form of birth control. Of those, 15 (45.5%) had prescribed it to 10 or more adolescents. Twelve (57%) pediatricians but only 3 (25%) gynecologists reported prescribing DMPA to 10 or more adolescents (p = 0.074). Female physicians were more likely to have prescribed DMPA to adolescents than male physicians (p = 0.009). Mental retardation was considered the strongest "potential indication" for DMPA administration by 48 physicians responding to a 5-point Likert scale. The study suggests that physicians with interest or expertise in Adolescent Medicine are using DMPA as a form of birth control for selected young women in spite of the lack of Food and Drug Administration approval. A centralized DMPA registry is suggested to monitor adverse outcomes in users.

PIP: To assess medroxyprogesterone acetate (DMPA) prescription practices in adolescent health care practices, an anonymous questionnaire was distributed to 160 American and Canadian physicians who attended 1991 meetings of either the society for Adolescent Medicine or the North American Society for Pediatric and Adolescent Gynecology. Of 54 (33.7%) physicians who responded, 33 (61.1%) reported prior prescription of an injectable progestin (DMPA) as a form of birth control. Of those, 15 (45.5%) had prescribed it to 10 or more adolescents. 12 (57%) pediatricians, but only 3 (25%) gynecologists, reported prescribing DMPA to 10 or more adolescents (p = 0.074). Female physicians were more likely to have prescribed DMPA to adolescents than male physicians (p = 0.009). Mental retardation was considered the strongest "potential indication" for DMPA administration by 48 physicians who responded to a 5-point Likert scale. This study suggests that physicians with interest or expertise in adolescent medicine are using DMPA as a form of birth control for selected women in spite of the lack of FDA approval. A centralized DMPA registry is suggested to monitor adverse outcomes in users.

Effect of long-acting progestagen-only injectable contraceptives on carbohydrate metabolism and its hormonal profile.

Two groups, each composed of 20 women, who used depomedroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) injectable contraceptives were investigated for changes in 75-g OGTT and in the fasting and two-hour post oral glucose load (2-hours) levels of serum insulin, growth hormone, glucagon, cortisol and blood pyruvate. Samples were taken before and 3, 6 and 12 months after use of injectables. DMPA and NET-EN caused significant changes in mean blood glucose and pyruvate and in mean serum insulin, growth hormone and glucagon, but not in mean fasting cortisol. Changes with NET-EN started after 3 months, became maximal after 6 months and reverted to normal after 12 months of use, due to more frequent administration during the first 6 months of use (every 60 +/- 5 days) and to more spacing of the injections (every 84 +/- 5 days) after that. Changes with DMPA started after 3 months, and increased with the duration of use to become maximal after 12 months. Maximal changes were similar with DMPA and NET-EN and consisted of: a significant increase in fasting blood glucose and pyruvate and serum insulin; a significant increase in 2-hour blood glucose and pyruvate, serum insulin, growth hormone and glucagon. Although significant changes in blood glucose levels occurred with both DMPA and NET-EN, yet they did not reach the lower cut-off levels for impaired glucose tolerance in any user. With the same spacing of injections, i.e. every 84 +/- 5 days for NET-EN and every 90 +/- 5 days for DMPA, the effects on various parameters studied were less with NET-EN.

Reversible azoospermia induced by an androgen-progestin combination regimen in Indonesian men.

The suppression of spermatogenesis by a combination of depot medroxyprogesterone acetate (DMPA) and testosterone enanthate (TE) was studied in Indonesian men. Twenty healthy, fertile volunteers were allocated randomly to either of two treatments each consisting of four intramuscular injections at monthly intervals. Group I (n = 10 men) received 100 mg DMPA plus 100 mg TE monthly while group II (n = 10 men) received 200 mg DMPA plus 250 mg TE monthly. Sperm concentration was suppressed markedly, with all men attaining azoospermia between the third and fourth month after the start of treatment. There was no significant difference in the suppression of spermatogenesis between the two dosage regimens. The median time to reaching azoospermia was 2.5 months from the onset of injections and the median time to recovery of sperm in the ejaculate was 2.0 months after cessation of treatment. Both steroid regimens were equally effective in suppressing LH, FSH and testosterone levels. Testosterone levels returned to baseline by the fourth post-treatment month while LH and FSH demonstrated significant rebound above baseline levels from 3 to 5 months after cessation of treatment. No serious clinical side effects were observed. Weight gain and increases in libido were reported during treatment by most volunteers. A transient decrease in libido was noted in 5/20 (25%) men between 1-2 months after cessation of injections, presumably due to the prolonged effects of DMPA relative to TE. These results indicate that uniform induction of reversible azoospermia with minimal side effects can be achieved in a non-Caucasian population.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of depot-medroxyprogesterone acetate on lipoprotein metabolism.

To assess the effects of depot-medroxyprogesterone acetate (DMPA) upon serum lipids and lipoproteins, a comparative study in chronic users and new acceptors was undertaken. Two groups of women of reproductive age were included in the study; group I (n = 8) was formed by new acceptors whereas, group II (n = 14) constituted DMPA users of more than five continuous years (7.0 + 2.1 years). Blood samples were taken on the day of injection and 15, 29, 57 and 92 days after the i.m. administration of 150 mg of DMPA for the measurement of total triglycerides (TG), cholesterol (CHOL) and phospholipids (PHL). In addition, the TG and CHOL content in the very low density (VLDL), low density (LDL) and high density (HDL) lipoprotein fractions obtained by ultracentrifugation were also determined. The results demonstrated a moderate increase in the serum total TG concentrations at the expense of the VLDL fraction in the group of chronic DMPA users. In both groups, the administration of DMPA induced a moderate, though not significant, decrease in total CHOL and HDL-chol, an effect that was noticed at the end of the treatment interval; the serum LDL-chol content remained unchanged. In addition, a decrease in the total serum phospholipids content was noticed after DMPA injection in both groups, which resembled the fluctuations observed in the luteal phase of normal ovulating women. The overall data indicate that acute and/or chronic DMPA administration at the dose currently employed for contraception does not induce major abnormalities in lipoproteins in serum.

Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.

Combination of 19-nortestosterone-hexyloxyphenylpropionate (Anadur) and depot-medroxyprogesterone-acetate (Clinovir) for male contraception.

Because monotherapy with 19-nortestosterone hexyloxyphenylpropionate (Anadur, Pharmacia Arzneimittel, Ratingen, Federal Republic of Germany) suggested improved results for male contraception compared with available testosterone esters, it was tested for induction of complete azoospermia when combined with depot-medroxyprogesterone acetate (DMPA, Clinovir, Upjohn GmbH, Heppenheim, Federal Republic of Germany). Twelve men were treated for 7 weeks with weekly intramuscular (IM) injections of 200 mg Anadur followed by 3-weekly IM injections of Anadur up to week 15. Clinovir (250 mg) IM was administered at the start of treatment and during weeks 6 and 12. Anadur and Clinovir suppressed serum gonadotropins. Although serum testosterone declined steeply, in general, libido and potency were not impaired. Sperm concentrations were reduced significantly after 3 weeks of treatment. Lowest sperm counts were seen during week 8 of follow-up, when only 2 volunteers showed measurable sperm counts of 2.1 and 3.0 X 10(6)/ml, with a declining tendency. After 43 weeks, sperm concentrations were still below pretreatment range in 2 men, but later returned to pretreatment values. Computerized sperm motion analysis revealed that motility parameters in the residual sperm were reduced. In vitro analysis excluded a direct effect of medroxyprogesterone acetate in seminal plasma on sperm motion. The data indicate that the combination of Anadur with Clinovir increases the rate of azoospermia in normal volunteers seen under Anadur monotherapy, although the goal of azoospermia in all participants was not quite achieved.

Acceptability of injectable contraceptives in Assiut, Egypt.

The present work was a randomized comparative study of two injectable progestogen-only contraceptives. The first group (200 subjects) received 150 mg of depotmedroxyprogesterone acetate (Depoprovera) every 84 +/- 7 days and the second (200 subjects) received 200 mg of norethisterone enanthate (Noristerat) every 56 +/- 7 days. Acceptors of injectable contraceptives in Assiut, Egypt, were mainly women looking for fertility termination. Menstrual disruption was the main side effect among both treatment groups. Amenorrhoea was the commonest menstrual complaint and was the main reason for discontinuation in both groups. Only one pregnancy occurred during NET-EN use; two more pregnancies occurred, one in each of the two groups but there were indications that conception preceded the first injection. Menstrual irregularities were generally more frequent with DMPA users. However, DMPA had better one-year continuation rates than NET-EN (68.8 +/- 3.5 and 57.1 +/- 3.6 per 100 women, respectively).

Depo-Provera in the treatment of recurrent vulvovaginal candidiasis.

The long-acting injectable progestogen Depo-Provera appears to substantially reduce women's susceptibility to recurrent vulvovaginal candidiasis. Pregnancy and exogenous estrogen appear to counteract this effect of the drug. Evidence was derived from 15 patients studied for up to six years.

PIP: Patients with a history of recurrent candidiasis and who were using Depo-Provera (medroxyprogesterone acetate, DMPA) for contraception were reviewed in order to determine the time relationship between episodes of proven candidiasis, episodes of pruritus vulvae suggestive of this infection (but unproven), and injection of DMPA. Recently, patients were included in the study who had been given DMPA specifically to prevent recurrences of candidiasis even when the drug's contraceptive action was unnecessary, such as after sterilization. In all cases, the infection was initially treated with a vaginal candidacide, most commonly 1 week of an imidazole. The patients ranged in age from 19-37 years at the time of the 1st injection. Diabetes had been eliminated in all the cases. DMPA was given intramuscularly at a dose of 150 mg every 12 weeks. Prior to 1983, an estrogen supplement was prescribed in most cases in an effort to produce monthly menstrual periods. Estrogen supplementation is no longer used routinely, with amenorrhea the aim, although it is occasionally given to women who experience breakthrough bleeding. Candidal infection was considered proven when the branching filaments of the species were seen on a stained vaginal smear or when the species were cultured in a laboratory from a vaginal swab taken a symptomatic patient. With the exception of 2 patients, clinical candidiasis did not occur within the time in which 150 mg of intramuscular DMPA is known to suppress ovulation in all women, i.e., 12 weeks -- except in the presence of exogenous estrogen (cases 1, 2, and 14) and in one case (15) in which the patient had an unplanned conception prior to the injection. Both patients who experienced clinical despite the use of DMPA alone (cases 8 and 13) asked remain on the drug because believe it was responsible for their longest remissions in the past few years. The study seemed to provide evidence that DMPA will prevent a recurrence of clinical candidiasis in many women who are prone to this condition. The study further indicated that estrogens may predispose women to this infection.

Inhibition of ovulation during discontinuous intranasal luteinizing hormone-releasing hormone agonist dosing in combination with gestagen-induced bleeding.

Four groups of eight or nine normal cycling volunteers with regular menstrual cycles had daily blood sampling during two pretreatment, two treatment, and two posttreatment cycles. Intranasal doses of 100, 200, and 300 micrograms of (D-Ser[TBU]6-des-Gly-NH210) luteinizing hormone-releasing hormone (LH-RH) ethylamide were administered every 12 hours and compared with a 400-micrograms dose given every 24 hours during two periods of 21 days followed by a drug-free interval of 7 days. Five milligrams of medroxyprogesterone acetate was taken orally on days 17 to 21. Serum luteinizing hormone was elevated during the first 2 weeks of treatment, and serum follicle-stimulating hormone was increased only during the first 2 days of treatment. At 100 to 300 micrograms/12 hours serum estradiol was stimulated up to preovulatory levels, whereas at 400 micrograms/24 hours most values were in the early follicular phase range. Ovarian ultrasonography revealed the transient development of preovulatory-like follicles in 8 of 12 studied cycles. Serum progesterone values were less than 2 ng/ml in 57.3%, between 2 and 5 ng/ml in 27.9%, and greater than 5 ng/ml in 14.7%. Withdrawal bleeding occurred during the pause in 97% of treatment cycles. Nine of 13 breakthrough bleedings happened in the groups given 100-micrograms and 300-micrograms/12 hours. Recovery cycles showed slightly prolonged follicular phases with normal luteal phases. No changes were observed in routine laboratory measurements. In conclusion, intermittent administration of appropriate LH-RH agonist dosing in combination with a progestogen would effectively block ovulation while preserving adequate cyclic estradiol secretion and could be an alternative contraceptive approach.

PIP: 4 groups of 8 or 9 normal cycling volunteers with regular menstrual cycles had daily blood sampling during 2 pretreatment, 2 treatment, and 2 posttreatment cycles. Intranasal doses of 100, 200, and 300 mcg of luteninizing hormone-releasing hormone (LH-RH) ethylamide were administered every 12 hours and compared with a 400-mcg dose given every 24 hours during 2 periods of 21 days followed by a drug-free interval of 7 days. 5 milligrams of medroxyprogesterone acetate was taken orally on days 17 to 21. Serum luteinizing hormone was elevated during the first 2 weeks of treatment and serum follicle-stimulating hormone was increased only during the first 2 days of treatment. At 100-300 mg/12 hours serum estradiol was stimulated up to preovulatory levels, whereas at 400 mcg/24 hours most values were in the early follicular phase range. Ovarian ultrasonography revealed the transient development of preovulatory-like follicles in 8 of 12 studied cycles. Serum progesterone values were less than 2 ng/ml in 57.3%, between 2-5 ng/ml in 27.9%, and greater than 5 ng/ml in 14.7%. Withdrawal bleeding occurred during the pause in 97% of treatment cycles. 9 of 13 breakthrough bleedings happened in the groups given 100-mcg and 300-mcg/12 hours. Recovery cycles showed slightly prolonged follicular phases with normal luteal phases. No changes were observed in routine laboratory measurements. In conclusion, intermittent administration of appropriate LH-RH agonist dosing in combination with a progestogen would effectively block ovulation while preserving adequate cyclic estradiol secretion and could be an alternative contraceptive approach.

Return to ovulation following the use of long-acting injectable contraceptives: a comparative study.

A comparative study was undertaken in twenty-four Mexican women who discontinued the use of depo-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) to assess the time required for the return to menses and ovulation. All subjects were exposed to long-acting injectable contraceptives for at least one year, and were followed prospectively. Serum progesterone levels were determined weekly in all subjects beginning 3 months after the last progestogen injection. Mean time to return to ovulation occurred significantly earlier (p less than 0.001) after NET-EN (2.6 months) as compared with DMPA (5.5 months). No correlation between the return to ovarian function and the duration of steroid exposure was found. The overall data was interpreted as demonstrating a clear-cut difference between the two long-acting progestogens in terms of ovulation suppression.

Long-term follow-up of children breast-fed by mothers receiving depot-medroxyprogesterone acetate.

A long-term follow-up study compared development and health of 128 breast-fed children whose mothers had received depot-medroxyprogesterone acetate (depot-MPA) while lactating and 142 control children whose mothers had used mechanical contraceptives or no contraceptives or had undergone sterilization. The children, who were approximately 4-1/2 years old at follow-up, showed no ill effects on their growth and development and health status from exposure to depot-MPA. Depot-MPA-treated mothers lactated significantly longer than controls and also had greater parity than controls. These factors apparently contributed to a difference in weight at follow-up. Compared with the Sempe-Pedron standard, more of the depot-MPA group were underweight and more controls were overweight.

PIP: A longterm follow-up study compared development and health of 128 breastfed children whose mothers had received depot-medroxyprogesterone acetate (depot-MPA) while lactating and 142 control children whose mothers had used mechanical contraceptives, no contraceptives, or had undergone sterilization. The children, who were approximately 4 1/2 years old at follow-up showed no ill effects with regard to growth and development and health status from exposure to depot-MPA. The treated mothers lactated significantly longer than controls and also had higher parity than controls. These factors apparently contributed to a difference in weight at follow-up. Compared with the Sempe-Pedron standard, more of the depot-MPA group were underweight and more controls were overweight.

Treatment of seizures with medroxyprogesterone acetate: preliminary report.

Medroxyprogesterone acetate (MPA), a synthetic progesterone, was added to the antiepileptic drug regimen of 14 women who had uncontrolled seizures. Of the 11 women who developed amenorrhea, 7 reported fewer seizures during MPA therapy. Overall reductions in seizure frequency averaged 30% (n = 11), declining from a baseline 8.3 +/- 5.8 seizures per month to 5.1 +/- 4.1 seizures per month (p = 0.02). No serious side effects were encountered, but spotting was common. These preliminary data suggest further evaluation of MPA for catamenial seizures.

PIP: In Connecticut, physicians followed 19 women with tractable epilepsy for 3-5 months to determine baseline seizure frequency. 14 women agreed to enter a clinical trial evaluating synthetic medroxyprogesterone acetate's (MPA) ability to reduce seizure frequency by adding MPA to the usual antiepileptic drug regimen. They all received 10 mg MPA pills 2-4 times each day. 6 women who did experience amenorrhea later received 120-150 mg intramuscular MPA injections (Depo-Provera) every 6-12 weeks instead of oral MPA. The physicians followed the women for 12 months. 11 women eventually experienced amenorrhea and always had low levels of serum progesterone ( or = ng/ml). Seizure frequency fell significantly from a mean of 8.3 seizures/month before MPA administration to 5.1 seizures/month after MPA administration, equaling 39% fewer seizures (p = .02). 7 women who experienced obvious improvement had 52% fewer seizures on average (25-71%) reduction. All women who had fewer seizures did experience partial seizures, however. MPA did not affect the steady state levels of antiepileptic drugs. MPA levels were higher in women receiving oral MPA than they were in those receiving MPA injections (5.2 ng/ml vs. 2.6 ng/ml). Most women had some spotting, particularly during the first few months of the study. Some of these women discontinued treatment because of this side effect, especially women who did not appear to benefit from the treatment. Menstruation returned in 6-12 months in women receiving MPA injections. Further research on MPA's effect on catamenial seizures is needed.

Return of ovulation following a single injection of depo-medroxyprogesterone acetate: a pharmacokinetic and pharmacodynamic study.

The effect of a single dose of 150 mg of depo-medroxyprogesterone acetate (DMPA) on pituitary, ovarian and endometrial function was assessed in relation to the peripheral levels of the compound in 8 women. The levels of medroxyprogesterone acetate (MPA), follitropin (FSH), lutropin (LH), prolactin, estradiol (E2) and progesterone ( Prog .) were measured 3 times a week during a pretreatment (control) cycle and then daily during postinjection weeks 14-17, 22-25 and 30-33. An endometrial biopsy specimen was obtained during postinjection weeks 17, 25 and 33. In three out of 8 subjects the daily hormone assays carried out during postinjection weeks 30-33 indicated anovulatory periods; in these subjects peripheral blood was drawn daily during postinjection weeks 46-49 and a fourth endometrial biopsy was taken during week 49.

PIP: The effect of a single dose of 150 mg depomedroxyprogesterone acetate (DMPA) on pituitary, ovarian, and endometrial function was assessed in relation to the peripheral levels of the compound in 8 women. The levels of DMPA, follitropin (FSH), lutropin (LH), prolactin, estradiol (E2), and progesterone (P) were measured 3 times/week during a pretreatment (control) cycle and then daily during postinjection weeks 14-17, 22-25, and 30-33. An endometrial biopsy specimen was obtained during postinjection weeks 17, 25, and 33. In 3 of 8 subjects the daily hormone assays carried out during postinjection weeks 30-33 indicated anovulatory periods; in these subjects, peripheral blood was drawn daily during postinjection weeks 46-49 and a 4th endometrial biopsy was taken during week 49. Plasma DMPA levels during the 14th postinjection week varied between 0.90 and 2.24 nmol/1, declined gradually, and became undetectable between weeks 17-24 (4 cases) or some time after week 33 (the other 4 cases). No correlation was found between the time when DMPA levels became undetectable and the obesity index.

Reversible inhibition of sperm production and gonadotrophin secretion in men following combined oral medroxyprogesterone acetate and percutaneous testosterone treatment.

Six men requesting male contraception received a daily oral dose of 20 mg medroxyprogesterone acetate (MPA) in combination with 50 or 100 mg percutaneous testosterone for 1 year. From the third month the sperm concentration was less than 10(6)/ml for all the men at one time or another during treatment, and usually less than 5 X 10(6)/ml, with an average reduction of 95% with respect to pre-treatment values. The sperm count returned to previous values 3-6 months after cessation of the treatment. While FSH and LH secretion was inhibited throughout the treatment period, plasma testosterone levels were not reduced. Oestradiol levels were unaffected while dihydrotestosterone was elevated. The secretory activity of the prostate and seminal vesicles was not appreciably affected; seminal carnitine concentration was reduced during the treatment with a subsequent return to pretreatment values. No pregnancies occurred during treatment. There was no impairment of libido in the subjects, nor any incidence of gynaecomastia, or increase in average body weight. The only observed metabolic side-effect was a moderate increase in glycaemia. A synergistic action of MPA and testosterone is proposed to explain the inhibition of gonadotrophin secretion.

PIP: 6 men requesting male contraception received a daily oral dose of 20 mg medroxyprogesterone acetate (MPA) in combination with 50 or 100 mg percutaneous testosterone for 1 year. From the 3rd month, the sperm concentration was 1 million ml for all the men at 1 time or another during treatment, and usually 5x1 million/ml, with an average reduction of 95% with respect to pretreatment values. The sperm count returned to previous values 3-6 months after cessation of the treatment. While follicle stimulating hormone and luteinizing hormone secretion was inhibited throughout the treatment period, plasma testosterone levels were not reduced. Estradiol levels were unaffected while dihydrotestosterone was elevated. The secretory activity of the prostate and seminal vesicles was not appreciably affected; seminal carnitine concentration was reduced during the treatment with a subsequent return to pretreatment values. No pregnancies occurred during treatment. There was no impairment of libido in the subjects, nor any incidence of gynecomastia, or increase in average body weight. The only observed metabolic side effect was a moderate increase in glycemia. A synergistic action of MPA and testosterone is proposed to explain the inhibition of gonadotropin secretion.

Ultrastructure of endometrium of postmenopausal patients on two modes of hormonal therapy: estrone sulfate with or without MPA.

The response of human postmenopausal endometrium to standard, oral doses of an estrogen alone (estrone sulfate) and to an estrogen plus a progestin (medroxyprogesterone acetate; MPA) was evaluated by scanning electron microscopy and transmission electron microscopy. Endometrial biopsies were obtained over a 4-year period from 12 patients with well-established ovarian failure. Biopsies were taken before the initiation of therapy and during each mode of hormonal treatment. The ability of estrone sulfate alone to stimulate growth of the endometrium was shown during the 1st treatment cycle when the atrophic epithelial cells transformed into tall columnar cells which synthesized and released some secretory products. Unopposed estrogen therapy led to excessive ciliation and breakthrough bleeding. Addition of MPA to the estrone sulfate regimen produced a progestational endometrium. The epithelial cells had ultrastructural features of those in normal postovulatory endometrium, including nucleolar channel systems. MPA elicited deciliation and transformation of ciliated cells into secretory cells. Stromal cells hypertrophied, the vascular endothelium thickened, and bleeding subsided. Estrogen-progestin therapy as tremendously more physiological than unopposed estrogen therapy.

Statement on injectable contraception.

PIP: Injectable hormonal contraception with 2 longacting steroidal preparations--norethisterone enanthate (NET-EN) and depot medroxyprogesterone acetate (DMPA)--provides an effective means of fertility regulation and has become an important method of family planning. DMPA and NET-EN have several advantages which make them particularly appropriate for some women and acceptable in family planning programs. A single injection can provide highly effective contraception for 2 or more months, delivery is simple, independent of coitus, and ensures periodic contact with medical or other trained health personnel. Currently, DMPA is registered as a therapeutic agent in nearly all countries and as a contraceptive agent in over 80 developed and developing countries. NET-EN is registered as a contraceptive in 40 countries. Administered by intramuscular injection in an aqueous microcrystalline suspension, DMPA exerts its contraceptive effect primarily by suppression of ovulation, but its effects on the endometrium, the uterine tubes, and the production of cervical mucus may also play a role in reducing fertility. DMPA as a contraceptive agent is generally given at a dosage of 150 mg every 90 days. NET-EN when administered as an intramuscular injection of an oil preparation at a dose of 200 mg inhibits ovulation. It should be administered at 8 weekly intervals for the 1st 6 months of use, then at intervals of 8 or 12 weeks. Longterm animal studies with DMPA have been completed mainly on beagle bitches and rhesus monkeys, and similar studies with NET-EN are nearing completion. None of the findings in beagles is considered applicable to human populations because the beagle responds differently than humans to steroidal hormones. None of the deaths among rhesus monkeys was attributable to effects of the drug. Endometrial carcinoma was found in 2 of the replacement monkeys but the number of animals was too small for statistically significant studies, and it is not possible to conclude whether DMPA or NET-EN caused these cancers or instead failed to prevent them. Despite more than 18 years of use and an estimated 13 million women who have ever used DMPA or NET-EN, no case has been recorded of an endometrial malignancy in women so exposed. There is no evidence at this stage of a causal association, either anecdotal or scientific. No evidence of an increased risk of malignant and premalignant disease of the uterine cervix has been found in DMPA users. There is sufficient evidence from investigations in several countries that DMPA and NET-EN may increase both milk production and the duration of lactation. The only clinical metabolic effect attributed to DMPA is weight gain. NET-EN and DMPA are associated with disruption of the menstrual cycle and irregular bleeding.^ieng