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Biomedical subjects

M Haukkamaa

Publications and source records attributed to M Haukkamaa.

At least 19 recordsLinked to original sources
PubMed1994

The progestin ST 1435--rapid metabolism in man.

Parenterally administered ST 1435 (Nestorone) is highly potent for contraception, and ovulation can be inhibited with very low serum levels of ST 1435. Orally administered ST 1435 is ineffective in various laboratory animals, presumably due to extensive first-pass metabolism. Thus, ST 1435 has been proposed for lactational contraception, to be metabolized by the suckling infant. We have studied the metabolism of ST 1435 in female volunteers following oral (10 mg), intravenous (iv) (0.1 mg) and transdermal (4.5-9.0 mg) routes of ST 1435 administration. Preliminary studies using rats were performed to develop the methodology of high performance-liquid chromatography (HPLC) fractionation and ST 1435-RIA detection. Rat portal serum revealed 4 distinct peaks of immunoreactive material with the retention times (Rt's) of 7.5, 10, 14.5 and 17.5 min (ST 1435 = 10 min). In systemic serum, only the peak with the Rt of 7.5 min could be detected. Therefore, orally administered ST 1435 is very effectively metabolized by the rat liver; this also explains the previously observed lack of biological effects of oral ST 1435. Following oral administration of ST 1435 to two women, the Rt of the major peak was 10 min. The magnitude of the ST 1435 peak decreased rapidly, and at 24h following ingestion, no ST 1435 could be detected by this method. The t1/2 of ST 1435 was approximately 1-2h. In addition, two minor peaks with Rt's of 4.5 and 16 min could be detected with the ST 1435 RIA at 1-4h following oral ingestion. Competitive receptor binding assays using the human uterine progesterone receptors (hPR) revealed that the ST 1435 fraction exhibits strong binding affinity towards the hPR; thus, in the human, a small fraction of biologically active ST 1435 seems to escape from the first-pass metabolism following oral intake. Following iv and transdermal administration of ST 1435, the only detectable peak with ST 1435-RIA was that of ST 1435. Similar magnitude of the ST 1435 peaks following oral administration of 10 mg and iv administration of 0.1 mg indicated that the bioavailability of ST 1435 is low. These data seem to confirm the suspicion that orally administered ST 1435 is also rapidly metabolized in the human, therefore encouraging further evaluation of ST 1435 during lactation. However, the rapid metabolism seen after oral intake can be successfully circumvented by sustained parenteral administration of ST 1435.

Administration, Cutaneous↗
PubMed1992

Contraception with subdermal implants releasing the progestin ST-1435: a dose-finding study.

A new modified subdermal implant releasing the potent progestin ST-1435 was studied in eleven fertile-aged women. These implants have been developed for contraception and they have a life-time of two years. Three implant lengths of 4, 6 and 8 cm were tested to find the optimal steroid dose for inhibition of ovulation. Serum samples were collected twice per week during a six-week period every six months. The concentrations of serum ST-1435, estradiol and progesterone were determined by RIA. Ovulation was inhibited by all ST-1435 doses tested. The concentration of serum progesterone was below 6 nmol/l in all samples tested showing the absence of luteinization. The concentration of serum ST-1435 increased with increasing ST-1435 dose. Serum estradiol concentrations were quite variable, showing wide range and occasional high peak values typical of progestin treatment; the mean value of serum estradiol concentrations measured did not differ with different ST-1435 doses. The results of steroid determinations led to the conclusion that a single 4 cm subdermal implant is optimal for contraception. With this dosage level, ovulation is inhibited and side effects are minimized. Bleeding control was variable. No hormonal side effects due to the progestin ST-1435 were reported. This method, using a single 4 cm subcutaneous implant releasing the progestin ST-1435 with a life-time of two years, represents a promising alternative for inhibition of ovulation and contraception.

Adult↗
PubMed1992

Intrauterine progestin induces continuous insulin-like growth factor-binding protein-1 production in the human endometrium.

The effect of local intrauterine progestin on endometrial insulin-like growth factor-binding protein-1 (IGFBP-1) production was studied in 60 women using a levonorgestrel-releasing intrauterine device (IUD). Intrauterine progestin was a potent stimulator of stromal cell IGFBP-1 production, with 97% of endometrial specimens showing positive staining by immunohistological methods. After 5 yr or more of intrauterine progestin exposure, 100% (n = 20) of the tissues remained strongly positive for IGFBP-1. The IGFBP-1 content in endometrial tissue homogenates reached values as high as 10 micrograms/mg protein when measured by immunoradiometric assay. In contrast to the continuous endometrial IGFBP-1 production induced by local progestin, no such effect could be found in endometria from subjects with sc progestin-releasing implants or copper IUDs. Although the levonorgestrel-releasing IUD had a striking effect on local endometrial IGFBP-1 production, it had no effect on serum IGFBP-1 levels. By Western ligand blot analysis, the domainating IGF-binding species in endometria exposed to intrauterine progestin was of 28K mol wt, corresponding to IGFBP-1, whereas no IGFBP species of 31-43K, corresponding to IGFBP-2 or IGFBP-3, were detected.

Adult↗
PubMed1992

Suppression of ovarian function with the transdermally given synthetic progestin ST 1435.

OBJECTIVE: To study transdermal administration of the synthetic progestin ST 1435 and effectiveness of the steroid in suppression of ovarian function. DESIGN, PATIENTS: The effect of transdermal administration of the synthetic progestin ST 1435 in suppression of ovarian function was studied in a short term (17 to 93 days) study in healthy regularly menstruating women. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: Nine women used the progestin ST 1435 transdermally during a total of 21 menstrual cycles. Treatment was started on the 5th day of the menstrual cycle and continued for 17 to 93 days. Three different daily doses (0.5, 0.8, and 1.0 mg) were tested. The steroid was applied to the periumbical area once a day in a gel. MAIN OUTCOME MEASURES: Serum concentrations of ST 1435, progesterone, and estradiol (E2) were determined during the luteal phase of control cycles and in a total of 16 treatment cycles. Bleeding records were kept and side effects registered. RESULTS: Transdermal absorption of the progestin ST 1435 resulted in relatively constant serum concentrations in each subject, depending on the dose used. All doses caused changes in ovarian function. With the 0.5-mg/d dose, inhibition of ovulation was observed in three of five treatment periods. The 0.8-mg/d dose was high enough to inhibit ovulation in 7 of 10 cycles analyzed. With the 1.0-mg/d dose, the serum concentrations of the progestin were high, and anovulation was seen. Serum E2 concentrations were variable in all cases; occasional high peak values were seen, typical of progestin treatment. Bleeding control was variable; irregular bleeding was seen, especially in anovulatory cases. CONCLUSIONS: A 0.8-mg dose of the progestin ST 1435 administered transdermally once a day appeared to suppress ovulation, if properly applied, and excessive suppression of ovarian function was not seen. The steroid was well accepted. The synthetic progestin ST 1435 given transdermally represents an effective alternative for inhibition of ovulation and for progestin therapy.

Administration, Cutaneous↗
PubMed1992

A contraceptive subdermal implant releasing the progestin ST-1435: ovarian function, bleeding patterns, and side effects.

OBJECTIVE: To study ovarian function, bleeding patterns, and side effects during the 1-year use of a new modified contraceptive subdermal implant releasing the progestin ST-1435 with a lifetime of 2 years. DESIGN, PATIENTS: The effect on ovarian function and bleeding patterns of one contraceptive implant releasing the progestin ST-1435 was studied in 26 healthy women who volunteered. Side effects were recorded. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: One ST-1435 contraceptive implant was inserted subcutaneously into the ventral aspect of left upper arm. MAIN OUTCOME MEASURES: The women attended the clinic at half-year intervals. Records of bleeding were kept. Blood samples were collected from 5 women before insertion of an implant, from 12 women during the first 5 to 6 weeks of use, and from 10 women during the 6th and 12th month of use. Serum concentrations of ST-1435, progesterone, and estradiol were determined. Side effects were reported. RESULTS: The study covered 302 woman-months. The implant gave serum concentrations of ST-1435 high enough to inhibit ovulation in all of the 37 analyzed cycles. No pregnancies occurred. Irregular bleeding or spotting was the main event observed, especially during the 1st year of use. One half of the users had irregular cycles. None of the women's implants was removed during 1 year of use because of irregular bleeding. The implant was well accepted and tolerated by the women; no hormonal side effects were reported. CONCLUSIONS: One single 4-cm subdermal ST-1435 implant with a lifetime of 2 years showed good contraceptive efficacy and led to suppression of ovulation. No hormonal side effects were reported. Irregular bleeding patterns were common but well-tolerated, and the implant had a high continuation rate.

Adult↗
PubMed1992

Endometrial effect of transdermal estradiol and progestin ST-1435 in postmenopausal women.

OBJECTIVE: To study the endometrial effect of the transdermal synthetic progestin ST-1435. DESIGN: Prospective. SETTING: City Maternity Hospital, Helsinki, Finland. PATIENTS: Eleven postmenopausal women used transdermal estradiol (E2) patches for 6 weeks immediately before a vaginal operation for prolapse. For the last 10 days, 1 mg of ST-1435 transdermally in a gel was combined to the treatment. MAIN OUTCOME MEASURES: Blood samples were taken to follow serum concentrations of E2, follicle-stimulating hormone, and ST-1435. Endometrial samples for histologic examination were collected during the operation to evaluate the effect of the progestin. RESULTS: Transdermal absorption of ST-1435 resulted in reasonably constant serum concentrations of ST-1435 in each subject. A progestin effect on the endometrium was seen in 9 of 10 samples obtained. One sample did not show any progestin effect in spite of adequate ST-1435 levels, but this patient's E2 concentrations were low. CONCLUSIONS: When the estrogen stimulation was adequate, the transdermal ST-1435 induced a progestin effect on the endometrium, i.e., it had an end-organ effect.

Administration, Cutaneous↗
PubMed1991

Transdermal absorption of the progestin ST-1435: therapeutic serum steroid concentrations and high excretion of the steroid in saliva.

The synthetic progestin ST-1435 was administered transdermally to six healthy women during the late luteal phase. The steroid was applied to the periumbilical area in a commercial gel ("Progestogel"), also containing progesterone. Single doses of 2.3, 4.5 and 9.0 mg of ST-1435 were given in three experiments and repeated doses of 2.3 mg of ST-1435 for five days were given in another three experiments. Samples of serum and saliva were collected and the concentrations of ST-1435 and progesterone were determined by radioimmunoassays. Transdermal absorption of the synthetic progestin ST-1435 was shown to result in serum steroid concentrations high enough for therapeutic purposes. The concentration of ST-1435 in serum was still high 24 hours after application, reflecting sustained release of the steroid from the skin. In the five-day experiments, relatively constant serum levels were achieved in different individuals, and a single dose per day seems sufficient. High excretion of ST-1435 in saliva was found two hours after gel application. However, the concentrations of serum and salivary ST-1435 were not directly correlated in different individuals. Transdermal application of ST-1435 might offer a good alternative for systemic progestin treatment.

Administration, Cutaneous↗
PubMed1990

A contraceptive vaginal ring releasing ethinyl estradiol and the progestin ST-1435: bleeding control, serum steroid concentrations, serum lipids and serum chemistry.

Four women used vaginal rings releasing the synthetic progestin ST-1435 and ethinyl estradiol for at least three 21-day cycles with a 7-day treatment-free period between intervals of use. Patterns of bleeding were evaluated and serum concentrations of ST-1435, estradiol, progesterone and ethinyl estradiol were measured by radioimmunoassay. Total serum cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and serum chemistry were determined before ring use and during the first and third treatment cycles. The women experienced no difficulties in using the vaginal ring and all continued to use the ring after the first three cycles. Bleeding control was good and hormonal side effects were minimal. Serum steroid concentrations were: ST-1435, 289 +/- 117 pmol/l (mean +/- SD); ethinyl estradiol, 172 +/- 108 pmol/l; and estradiol, 184 +/- 107 pmol/l. Concentrations of serum progesterone were low, indicating complete suppression of ovulation during treatment. Total serum cholesterol increased slightly during use of ring. However, this increase could be accounted for by an increase in serum HDL-cholesterol. Liver function tests were in the normal range during ring use and values of serum chemistry showed no significant changes. This contraceptive vaginal ring presents a good method of contraception, showing good bleeding control and no harmful metabolic effects.

Adult↗
PubMed1990

Interference with ovulation by sequential treatment with the antiprogesterone RU486 and synthetic progestin.

Seven healthy women were treated with the antiprogesterone RU486, 25 mg/d, on days 1 to 14 of the follicular phase of the menstrual cycle, followed by the synthetic progestin NET in the luteal phase of the cycle. Venous blood samples were collected twice per week. Serum E2, P, and RU486 concentrations were determined by RIAs, and FSH and LH by immunofluorometric assays. Ultrasonography was used to measure the sizes of the follicles. Serum concentrations of FSH and LH were not suppressed during the treatment. Ovulation was apparently suppressed during RU486 treatment according to E2 and P concentrations and ultrasonography findings. During NET treatment, some evidence of ovulation and follicle growth were found during the first treatment periods. During the third treatment cycle, there was no evidence of ovulation (n = 2). Estradiol concentrations were sufficient to stimulate normal proliferative growth of the endometrium during the treatment. Control of bleeding was good. The exact mechanism of action of RU486 on steroid synthesis and ovulation is not clear, but it appears to act at the ovarian level. The evidence indicates that sequential RU486/progestin treatment could be developed to result in suppression of follicular growth and ovulation.

Adult↗
PubMed1989

Distribution of RU 486 and its demethylated metabolites in humans.

The concentrations of RU 486 and its demethylated metabolites were determined by RIA in samples of myometrium, abdominal adipose tissue, and serum, which were collected at hysterectomies performed 12-15 h after oral administration of 200 mg RU 486. The RU 486 concentrations in myometrium were similar in the five women studied, with a mean of 148 +/- 58 (+/- SD) ng/g (344 +/- 135 pmol/g). The adipose tissue RU 486 levels varied more, the mean concentration being 447 +/- 191 ng/g (1041 +/- 445 pmol/g). The serum RU 486 concentrations ranged from 175-899 ng/ml [mean, 396 +/- 259 ng/mL (922 +/- 603 nmol/L)]. In these women the nonprotein-bound fraction of [6,7-3H]RU 486 varied from 1.4-3.1% (mean, 2.3%). The approximate concentrations of the combined mono- and didemethylated metabolites of RU 486 were 1.4, 3.1, and 5.2 times higher in adipose tissue, myometrial tissue, and serum, respectively, than those of the parent RU 486. In vitro, rapid and nonsaturable accumulation of [6,7-3H]RU 486 from phosphate buffer into adipose tissue was inhibited by the addition of alpha 1-acid glycoprotein, the specific serum transport protein for RU 486, to the buffer medium. Accumulation of [6,7-3H]RU 486 in myometrial specimens was poor. The enterohepatic cycling of RU 486 was assessed in four normal subjects by repetitive intake of charcoal subsequent to ingestion of 200 mg RU 486. Compared to other normal subjects, the serum levels and areas under the concentration curves were lower and t1/2 values shorter in the group given charcoal, suggesting that in vivo RU 486 may be partly pooled in the enterohepatic cycle. Our studies suggest that despite the low volume of distribution and the effective serum binding of RU 486, the myometrial and adipose tissue concentrations of RU 486 and its metabolites were similar (approximately 10(-9)-10(-10) mol/g) after oral intake of RU 486.

Adipose Tissue↗
PubMed1988

Inhibition of folliculogenesis and ovulation by the antiprogesterone RU 486.

Healthy, regularly menstruating women were treated with the antiprogesterone RU 486, Mifepristone (Roussel-Uclaf, Romainville, France) during the follicular phase of the cycle. Three women were given 25 mg of RU 486 on days 1 to 14 of the cycle and five received 25 mg on days 1 to 21 of the cycle. Venous blood samples were collected three times per week during a control cycle and during one treatment cycle in each subject. Serum concentrations of estradiol (E2), progesterone (P), and RU 486 were determined by radioimmunoassays. No drug-related side effects and no spotting or bleeding during RU 486 treatment were observed. Menstrual bleeding was delayed by 8.7 +/- 3.8 days (mean +/- SD) after treatment over days 1 to 14 and by 12.6 +/- 3.2 days after treatment over days 1 to 21. During the treatment with RU 486, the serum concentrations of E2 remained low, indicating effective inhibition of folliculogenesis. After cessation of RU 486 treatment, serum E2 levels rose to similar values as in the control cycle, and subsequently serum P concentrations also reached ovulatory levels in six out of the eight volunteers. The results showed that the antiprogesterone RU 486 delayed folliculogenesis and luteinization even at low doses when given during the follicular phase of the menstrual cycle. It is speculated that this property of RU 486 could be utilized in the design of an estrogen-free combined oral contraceptives.

Adult↗
PubMed1987

Bacterial flora of the cervix in women using an intrauterine device.

The cervical bacterial flora of 18 healthy, parous, sexually active women was analysed before, and 3-5 months after insertion of a copper-releasing intrauterine device (IUD) and after long-term use of an IUD for 3-5.5 years in another nine women. No significant differences were found in the number of aerobic bacteria isolated before or after IUD insertion or after long-term use of an IUD. In contrast to aerobic bacteria, significantly more anaerobes were isolated in the cervix of women having used an IUD for several years when compared to those using barrier contraception with a condom. None of the women had clinical signs of pelvic infection and a cervical bacterial flora rich in anaerobes can be regarded as a normal finding in healthy sexually active women using an IUD for contraception.

Adult↗
PubMed1987

Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study.

The use-effectiveness of an intrauterine contraceptive device releasing 20 mcg of levonorgestrel daily (Lng-IUD), and of a Nova T copper-releasing IUD, were studied in a randomized, comparative multicenter trial. The Lng-IUD was inserted in 1821, and the Nova T in 937 women. The 12-month net pregnancy rate with the Lng-IUD (0.1 per hundred women) was significantly lower than that with the Nova T (0.9 per hundred). Removal rates for menstrual problems and/or pain were similar for the two methods (net rates 7.5 and 8.7, respectively). The 12-month continuation rates were 82.2 for the Nova T and 79.7 for the Lng-IUD. The reduction of the bleeding led to oligomenorrhea and amenorrhea in users of the Lng-IUD; the removal rate for these reasons was 1.4. The removal rate for hormonal side effects with the Lng-IUD was 2.4. Blood hemoglobin concentrations increased among users of the Lng-IUD and decreased among users of the Nova T. The results show that the Lng-IUD was a highly effective contraceptive method which reduced menstrual bleeding. It is a promising alternative for women desiring a highly effective method for long-term use.

Adult↗
PubMed1986

Bacterial flora of the cervix in women using different methods of contraception.

Bacteriologic culture samples were taken from the cervix in three groups of 10 healthy, sexually active women using barrier contraception, oral contraceptives, or a levonorgestrel-releasing intrauterine contraceptive device. Culture samples for Candida albicans and Trichomonas vaginalis were taken, a cytologic vaginal smear was obtained, and an amine sniff test was performed; these were in addition to a routine gynecologic examination. Multiple bacteria were isolated from the cervix in women using oral contraceptives or an intrauterine contraceptive device, whereas lactobacilli alone dominated the flora of women using barrier contraception. Significantly more anaerobic bacteria were isolated from the cervix in oral contraceptive and intrauterine contraceptive device users when compared with the barrier method users. Symptoms and findings evident of anaerobic vaginosis were associated with the occurrence of anaerobic bacteria in the cervix of three patients using the intrauterine contraceptive device. The results showed that the cervical bacterial flora in sexually active healthy women is rich in anaerobes that can be regarded as a normal finding in women using oral contraceptives or intrauterine contraceptive devices. Barrier contraception with a condom prevents this anaerobic shift and maintains a lactobacilli-dominated flora in the cervix.

Adolescent↗
PubMed1986

Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment.

The contraceptive efficacy of progestin-only contraception was studied in epileptic patients using NORPLANT subdermal capsules. The effect of anticonvulsants on levonorgestrel plasma levels was determined. NORPLANT subdermal capsules were inserted into nine epileptic women, and ten control women using no medication. Venous blood samples were taken at 0, 1, 3, 6, 9 and 12 months after insertion and the concentration of levonorgestrel was determined by radioimmunoassay. At 3 to 12 months, the overall mean concentration of plasma levonorgestrel was significantly lower in the six epileptics taking phenytoin alone or in combination with other anticonvulsants (203 +/- 128 pg/ml, mean +/- SD) than in the controls (325 +/- 135 pg/ml, p less than 0.01). After one year, nine of the control patients continued the use of NORPLANT and no pregnancies occurred. Two of the nine epileptics became pregnant during contraception by NORPLANT. They both used phenytoin and their plasma concentrations of levonorgestrel were low near the time of conception. Levonorgestrel released from the capsules had no apparent harmful effects on epilepsy and none of the patients reported an increase in seizure frequency. The results show that contraception by the progestin levonorgestrel is not reliable in epileptic patients using anticonvulsants known to induce metabolizing enzymes of the liver.

Adult↗
PubMed1986

Five years' experience with levonorgestrel-releasing IUDs.

Two levonorgestrel-releasing IUDs and a copper-releasing IUD of the same shape were studied in a randomized comparative study over five years. The levonorgestrel-releasing IUDs released 20 micrograms or 30 micrograms per day. The Pearl index during the 10,600 woman-months of LNG-IUD use was 0.11. The control device releasing copper had a Pearl index of 1.6. The amount and duration of menstrual bleeding was greatly reduced, leading to a high incidence of oligo- or amenorrhea. The continuation rate in this pioneer trial was 53 per 100 users for the levonorgestrel-releasing IUD (LNG-IUDs) and 50 per 100 users for the copper-releasing IUD (Nova T). The removal rates for reasons other than amenorrhea were not significantly different. Discontinuation because of amenorrhea occurred during the first two years, the cumulative termination rate for this reason was 11.6 per 100 users at five years. The LNG-IUDs removed for investigation after five years of use revealed that the devices contained about 40 percent of the original load. The effective lifespan of the device has been demonstrated by this study to be five years; the residual steroid gives an additional safety period of two more years. The LNG-IUD is a highly effective reversible contraceptive method, which strongly reduced the amount and duration of bleeding. During the first two months there is scanty but frequent spotting which, like the high incidence of oligo- and/or amenorrhea, requires counselling of health personnel and women using LNG-IUDs.

Adult↗