Progestin Group Research Articles

Menopausal hormone therapy informed consent

A little over a year ago now, the large hormone therapy clinical trial of the Women’s Health Initiative came to an abrupt halt. The publication of the results rocked the medical community and our patients because a class of drugs once thought to be associated overwhelmingly with benefit was found to cause more harm than good. Now doctors have the dilemma of how to inform patients of the results of the Women’s Health Initiative in a way that will help them make the best decision for themselves of whether they should use of these agents for hot flashes, night sweats, vaginal dryness, or prevention of osteoporosis. In the thousands of daily conversations on this topic, the scenario used to look like this: The patient came to the office asking questions about menopause. When the practitioner determined the patient was going through the menopausal transition, the doctor wrote a prescription for hormone pills or patches, saying they would address her concerns by replacing the hormones her body used to make. They would abolish her hot flashes, slow her bone loss, and reduce her risk of a heart attack. The patient asked if the pills caused breast cancer. Probably in some women, the doctor would acknowledge, but argued that the benefits to the heart and bones were worth taking the chance. Now the patient comes to the office and asks about the confusing information she has been reading on the increased risk of heart attack, strokes, blood clots, and dementia with hormone use. The doctor acknowledges the information has changed and is very important, but the decision to use or not to use hormones is up to her. She has menopausal symptoms and wants a solution. However, she is looking for something safe that does not cause more problems than it solves.

Oestrogen plus progestin was not effective for long term secondary prevention of coronary heart disease in postmenopausal women

(2002) JAMA 288, 49; Grady D, Herrington D, Bittner V, et al. . , for the HERS Research Group. . Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart...

Effects of two oral contraceptives on plasma levels of insulin-like growth factor I (IGF-I) and growth hormone (hGH)

In 18 healthy women, the effect of two oral contraceptives (OCs) on insulin-like growth factor (IGF-I) and its binding protein-3 (IGFBP-3) and growth hormone (hGH) plasma level were studied before and after intake of either of two OC formulations over 21 days, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). There was a reduction of the mean IGF-I concentration of 30% (p = 0.008) in the women receiving dienogest-containing pills and 12% (p = 0.006) in women taking the levonogestrel-containing preparation. This difference between drug groups was statistically significant (p = 0.002). A correlation between the control values and the basal-treatment difference (r = 0.945; p = 0.000) was observed only in women of group A. Between basal and treatment cycles the mean plasma levels of hGH remained unchanged in both groups tested, but the 23.5-h integrated mean hGH plasma concentrations (AUC 0–23.5h) were significantly elevated by 36% (p = 0.016) in comparison to basal values before treatment only in women receiving the levonorgestrel-containing pills. Also, in the women who received the dienogest-containing preparation, the changes of integrated mean plasma level were inversely associated with the control values (r = −0.723; p = 0.025). Neither in group A nor in group B was the mean plasma level of IGFB-3 changed. In conclusion: the results of the present analysis indicate that hormonal contraceptives can modulate the GH and IGF-I-axis in the reproductive age. Probably the androgenic progestogen levonorgestrel (0.125 mg/day) opposes the estrogen-induced action. In the women who took the dienogest-containing formulations (anti-androgenic progestogen—group A), the extent of individual changes (hGh and IGF-I) depends on the basal level prior to pill intake. Further studies, especially of long-term intake of OCs, are necessary to confirm these results and to assess the practical relevance for possible effects on connective tissue and bone.

A randomized study of the effects of tibolone and transdermal estrogen replacement therapy in postmenopausal women with uterine myomas

Objective: To evaluate the effects of two types of hormone replacement therapy, an estrogen–progestin combination and tibolone, on uterine myomas in menopausal women. Study design: Thirty-eight menopausal women with one or more uterine myomas were randomized to treatment with a transdermal system continuously releasing estradiol 50 μg/day combined with oral medroxyprogesterone acetate (MPA) 10 mg/day for 12 days/month or tibolone tablets 2.5 mg/day. The scheduled duration of both treatments was 12 months. Physical examination and abdominal/transvaginal ultrasonography were performed before entering the study and at 3, 6 and 12 months of treatment. At each ultrasonography the overall uterine volume was determined as well as the size of each myoma and the endometrial thickness and characteristics. Results: No statistically significant difference was detected between the two groups at any time during treatment. However, within-group analysis showed a significant increase of uterine volume and of myoma number and size in the estrogen–progestin group, whereas no such increase occurred in the patients treated with tibolone. Also, the mean endometrium width increased significantly from baseline to the end of treatment in the estrogen–progestin group, but not in the tibolone group. Conclusions: Tibolone seems a valid alternative in menopausal patients with uterine myomas as it provides adequate relief from menopausal symptoms and avoids volume increase of the uterus and myomas.

Superovulatory response following ablation-induced follicular wave emergence at random stages of the oestrous cycle in cattle.

Based on the premise that superovulation in cattle is optimal when superstimulation is initiated at the time of follicular wave emergence, the present study was done in beef heifers to determine if the superovulatory response following a single bolus of gonadotrophin treatment after follicle ablation (induced wave) at random stages of the oestrous cycle is comparable to the same gonadotrophin treatment at mid-dioestrus (spontaneous wave). In Experiment 1, heifers were assigned to nonablation (n = 18) and ablation (n = 20) groups. In nonablated heifers, superstimulatory treatment was given as a single subcutaneous injection (Folltropin-V, 400 mg) at mid-di-oestrus to coincide with emergence of the spontaneous follicular wave 8 to 12 days after oestrus. In ablated heifers, the same superstimulatory treatment was given 1 day after ablation of all follicles > or = 5 mm at random stages of the oestrous cycle to coincide with emergence of the ablation-induced wave. In both the nonablation and ablation groups, PGF2 alpha (Estrumate, 500 micrograms) was given 48 h after the superstimulatory treatment and artificial insemination was done 60 and 72 h later. Reproductive tracts were collected at the time of slaughter 6 or 7 days after insemination. Observations made in Experiment 1, indicated that some ablated heifers had only partial luteal regression at the time of insemination, while some others exhibited behavioral oestrus as early as 24 h after PGF2 alpha treatment. The design was amended in Experiment 2 to address these problems. Heifers were assigned to nonablation (n = 17), ablation-alone (n = 20) or ablation plus progestogen (n = 20) groups. Follicle ablation, superstimulatory treatment, artificial insemination and collection of reproductive tracts were done as in Experiment 1. However, all heifers were given two doses of PGF2 alpha (500 micrograms/dose) 48 and 60 h after superstimulatory treatment to ensure complete luteal regression, and heifers in the ablation plus progestogen group received a norgestomet ear implant at the time of follicle ablation to prevent early ovulations. The implant was removed at the time of the second PGF2 alpha treatment. In Experiments 1 and 2, the means for the ovarian and superovulatory responses were not significantly different between groups. Averaged over the nonablation and all ablation groups for Experiments 1 and 2, the mean number. of corpora lutea, fertilized ova and transferable embryos were 22.9 vs 18.6, 7.3 vs 7.8 and 5.4 vs 5.6, respectively. In summary, follicle ablation at random stages of the oestrous cycle followed by a single bolus of gonadotrophin treatment 1 day later resulted in a superovulatory response that was comparable to the same superstimulatory treatment administered around the time of spontaneous wave emergence at mid-dioestrus. The ablation/superstimulation method described herein offers the advantage of initiating superstimulatory treatment forthwith and assuring that treatment is concomitant with wave emergence to achieve an optimal superovulatory response. Moreover, the full extent of the oestrous cycle is available for superstimulation and the need for detecting oestrus or ovulation and waiting 8 to 12 days to initiate treatment is eliminated.

Effects of low-dose oral contraceptive oestrogen and progestin on lipid peroxidation in rats.

Groups of six female rats were treated with low-dose oral contraceptive (0.667 mg progestin [norethisterone acetate] and 0.02 mg oestrogen [ethinyloestradiol]/kg body-weight), or its components, separately, at the same doses, for 6 weeks. Changes in liver and kidney levels of lipid peroxides (as indicated by malondialdehyde production), free fatty acids, superoxide dismutase, and catalase liver glutathione and serum ceruloplasmin compared with the untreated control group were studied. Combined oral contraceptive treatment produced a significant increase in the activity of catalase in the kidneys (P < 0.05). The levels of lipid peroxides, free fatty acids and glutathione in the liver, and of serum ceruloplasmin increased significantly with oestrogen treatment (P < 0.05). Lipid peroxides (in the liver only), and serum ceruloplasmin decreased significantly when progestin was administered (P < 0.05). The activities of superoxide dismutase and catalase decreased significantly in the oestrogen group (except for catalase in the kidney) but increased in the progestin group (P < 0.05). The results indicate that the components of the low-dose oral contraceptive may alter liver and kidney metabolism.

Endocrinology: The effect of high-dose medium- and long- term progestogen exposure on endometrial vessels

A total of 19 paraffin-embedded endometrial tissue blocks were obtained from high-dose progestogen-exposed patients. A labelled streptavidin-biotin-alkaline phosphatase method was used with antibodies against von Willebrand factor (vWF) and CD34. The density of CD34 and vWF positive (CD34+ and vWF+) vessels in progestogen-exposed endometria (103 +/- 9.6/mm2 and 106 +/- 8.7/mm2) was significantly lower than in endometria from women with normal cycles (169 +/- 9.3/mm2 and 136 +/- 8.0/mm2) (P < 0.05). In women with normal menstrual cycles the concentration of CD34+ vessels was significantly higher than the number of vWF+ vessels (P = 0.0001). By comparison, the concentration of CD34+ vessels was similar to the concentration of vWF+ vessels in progestogen-exposed endometria. The ratios of vascular density as determined by vWF+ and CD34+ staining the control and progestogen groups were 0.81 and 1.05 respectively (P = 0.0001). Dilated venules were seen in the progestogen group. This study has demonstrated firstly that CD34 antibody detected the endothelial cells in a higher proportion of small endometrial vessels than vWF, and secondly that high-dose progestogen exposure significantly decreased the density of microvessels and increased the number of dilated venules in endometrium.

The effect of season and technique on synchronized and induced estrus and the induction of lambing in the ewe in a commercial setting

At 40 day intervals, groups of 87 to 142 commercial ewes of mixed breeding were subjected to a 5 day breeding period, following one of three estrus inducing or synchronizing treatments (intravaginal sponges containing 60 mg of medroxyprogesterone acetate) for 12 days with (progestin P.M.S.G. group) or without pregnant mares serum gonadotropin (P.M.S.G.) (Progestin group) at sponge removal, or a single injection of prostaglandin F 2α (breeding season and early anestrus only) (PGF 2α group)). Mean pregnancy rates (ewes lambing of those treated) and lambing percentages (lambs born per 100 ewes lambing) were 31 ± 4%, 169 ± 6%, 20 ± 5%, 105 ± 2% and 18 ± 8%, 118 ± 3%, respectively, for the three treatment groups above. Pregnancy rates for the progestin, P.M.S.G. group were 52% in late July, prior to the breeding season, 52% in September and declined to 14% in March (early anestrus). The time from the first of two daily injections of estradiol benzoate to lambing was 34.5 ± 4.4 hours in ewes 142 to 146 days pregnant.

Estradiol and progesterone receptors in estrogen-primed endometrium

Estradiol and progesterone receptor levels were measured in endometrial samples obtained from patients who were on different dosages of estradiol therapy and from women in the late proliferative phase of a normal menstrual cycle. Samples of blood were collected at the time of biopsy, and the levels of estradiol, estrone, progesterone, follicle stimulating hormone, and luteinizing hormone were measured in the serum. The patients were divided into five groups. The first group (controls) consisted of patients in their late proliferative phase. The patients in groups two, three, and five were receiving estradiol in various doses by pellet therapy, along with a cyclic progestogen each month. The women in the fourth group also had implantation of estradiol pellets but failed to take the progestogen as advised. In our series, the levels of cytoplasmic estradiol and progesterone receptors were markedly elevated in the no progestogen group compared to the controls. There was no significant difference in the levels of the receptors in the groups which took the progestogen as advised.

Combined cytotoxic and progestogen therapy for advanced breast cancer

Sixty-nine patients with advanced breast cancer treated with cytotoxic chemotherapy were randomized to receive concomitantly either norethisterone acetate (progestogen group) or a placebo (placebo group). Objective responses were seen in 53% of patients in the progestogen group and 61% of patients in the placebo group. The median duration of response was the same for both groups (38 weeks). Three out of ten patients in the placebo group, who received subsequently the progestogen on relapse, had a further objective regression. The overall survival in the two groups was similar, although in a sub-group of patients who had operable tumors, but a subsequent short disease-free interval, survival was significantly better in the placebo group. There was less myelosuppression in the progestogen group, who were able to receive higher doses of cytotoxic drugs. Less nausea and vomiting occurred in the progestogen group, but subjective side effects were similar. It is concluded that there is no advantage therapeutically in combining cytotoxic chemotherapy and progestogen therapy and, in some patients, better results are obtained using the two treatments sequentially.

Oral contraception and platelet aggregation.

93 British women using various oral contraceptives daily were compared with 89 normal and pregnant controls to determine the effect of contraceptives on platelet aggregation. The 93 test subjects were subdivided as follows: 1) 14 used conventional high-dose estrogen-progestogen combinations; 2) 14 used the conventional low-dose Norinyl-1 preparation; 3) 18 used Ortho-Novin a preparation containing twice the hormone dose of Norinyl-1 i.e. 2 mg of norethisterone and .1 mg of mestraniol; 4) 32 used .5 mg of chlormadinone acetate (pure progestogen); and 15 changed to pure progestogen from combined conventional preparations. A slightly modified Chandlers tube technique showed platelet aggregation to be significantly more accelerated in the pregnant controls than in normal controls or any test group. Platelet aggregation was significantly accelerated in the high- and low-dose groups although a comparison of the two low-dose groups failed to show a significant dose-dependent difference between them. The progestogen group without prior experience showed no significant change at 6 months; but there was a significant acceleration normalized after 1 month and remaining normal at 6 months in subjects who had previously used conventional preparations. A follow-up study showed that the progestogen-only preparations caused a significantly smaller acceleration than the combined preparations after 2 years of use and therefore may offer a lesser risk of thrombosis.

Influence of Various Hormonal Contraceptives on Sperm Migration in Vivo

To determine the effect of the cervical mucus in hormonal contraception a standardized postcoital test was designed. Subjects were fertile young women attending contraception and fertility clinics. The control group of 19 women had normal menstrual cycles. Of these 16 had undergone tubal ligation; the other 3 were being treated for secondary infertility. 10 women were using Sequens containing estrogen only for 7 days of the cycle Days 10-16. 44 women were wearing Lippes loops. Oral progestagen microdoses were being given to 50 women who were taking 30 mcg of d-norgestrel daily. Monthly injectable progestogens (norethindrone enanthate) were given to 30 women who received a single dose of 25 mcg without estrogenic addition on Day 6 or 8 of each cycle. Long-acting (depot) injectable progestogens were used by 93 women. Norethindrone enanthate 200 mg had a contraceptive effect for at least 12 weeks. The postcoital tests were made 4-10 hours after coitus following 3 days of abstinence and on 1 of the 7 days from Day 10 to Day 16 of the cycle. Intracervical material was taken from the middle third of the cervical canal. A sample of intrauterine material was then taken. Sperm counts were made. The number of motile sperm were recorded and the number with progressive forward motion noted. Quantity transparency spinnbarkeit and arborization or ferning were observed. Almost all sperm found in the uterine lumen were motile and with good forward motion. Treatment with estrogen alone did not interfere with sperm migration into the uterine lumen. Postcoital test findings for the 44 women wearing IUDs showed marked variations. In the 3 groups treated with progestational contraceptives differences were found between the intracervical and intrauterine specimens. Endocervical specimens were similar to those of the control group but intrauterine findings showed an almost total absence of sperm. Of the 93 patients receiving injections of depoprogestogen at 12-week intervals the postcoital test was done during the 1st postinjection months for 43 during the 2nd month for 18 and on the day they came for the next injection for 32. Total sperm counts were considerably lower at first for the progestogen group at high dosage but no longer at 12 weeks postinjection. At 12 weeks uterine sperm were found in only 7 of 32 patients. Groups treated with progestogens were almost all negative for spermatozoa in the uterus except for those using a low oral microdose. Cervical mucus arborization correlated with the number of sperm showing directional motion. Results show that the estrogens used increased intercervical penetrability but had no action on intrauterine sperm penetration. The IUDs had no uniform effect on sperm ascension. Only high-dose progestogens decreased intracervical penetration but even low doses of progestogens stopped intrauterine penetration of sperm. This lack of entrance of sperm into the uterine cavity may account for the contraceptive effect of low-dose progestational agents.