Jorge Martínez-Manautou

Low Doses of Progestogen as an Approach to Fertility Control

A clinical program was undertaken to establish the contraceptive effectiveness of minimal hormonal supplementation with chloramadinone acetate .5 mg given daily in both a cyclic and continuous pattern. Nonlactating women of proven fertility 36 years and under were given the drug daily as a contraceptive. They were all involved in an intensive study of the reproductive system. With the cyclic use of .5 mg chlormadinone acetate there were 2 pregnancies on of which was due to failure of the patient to continue the regimen. The principal side effect was intramenstrual bleeding and spotting in about 20-25% studied. Endometrial biopsies showed that the drug did not prevent the development of a normal secretory endometrium this was seen in 80 of the 109 specimens. Of 122 urinary pregnanediol determinations done 33(27%) had concentrations at ovulatory levels. In culdoscopic findings follicular activity or corpora lute were found in 18 of 19 patients studied. Contraceptive protection was also afforded with continuous administration of the drug. With continuous administration of the drug approximately 60% of the women had cycles of 24-34 days the longer cycle being more common and 80-90% had 7 or less days of bleeding per month. The endometrium showed less evidence of normal secretory activity than that seen with cyclic administration of the same drug. Preliminary studies of ovarian biopsy specimens suggest that ovulation occurs as in cyclic treatment.

THE ROLE OF PROGESTOGENS IN THE HORMONAL CONTROL OF FERTILITY.

The role of progestogens in the hormonal control of fertility was studied in women of proven fertility. Compounds and dosages evaluated were 10-mg norethindrone with .07-.074% mestranol 2.5-mg norethynodrel .5- or 1-mg chlormadinone 250- or 500-mg progesterone 2.5-mg norethindrone .5-mg chlormadinone with 80-mcg mestranol and 2.5-mg norethyndrel with 100-mcg mestranol. The compounds were administered for 20 days starting on Day 5 of the menstrual cycle. 24-hour pregnanediol excretion was measured on Day 19 or 20. Progestogens as well as estrogens were able to inhibit ovulation. However ovulation may occur on a random basis with estrogens progestogens and combinations of both agents. Progestogens in addition to their antiovulatory action may confer other antifertility effects such as the production of a state of maturation of the endogenous or exogenous estrogen-stimulated endometrium which is out of phase with ovulation if it did occur and changes in the cervical mucus incompatible with vital and motile spermatozoa. It is concluded that in constructing an oral contraceptive agent of the progestogen-estrogen type these effects of the progestogen may be lost with the consequence that estrogen effects predominate.(AUTHORS MODIFIED)

Incidence of side effects with contraceptive placebo

147 Mexican women, of low socioeconomic level, who had aborted spontaneously and desired pregnancy, were subjected to trial of placebo oral contraceptive. In 424 months there were 72 pregnancies, a Pearl index of 203.8 pregnancies per 100 couple-years. Menstrual cycles lasted 21-24 days in 30 women (9.8%), 25-35 days in 235 (76.8%), and 36-59 days in 38 (12.4%). 18 cycles (5.8%) were marked by intermenstrual bleeding. Incidence of 31 side effects is listed. Most common were: decreased libido 125 months (29.5%), headache 66 (15.6%), lower abdominal pain and bloating 58 (13.7%), dizziness 47 (11.1%). Common complaints were nervousness, increased libido, dysmenorrhea, nausea, epigastric pain, leg pain, leukorrhea, somnolence. Oral contraceptive-like side effects reported in fewer than 1% of months included acne, mastalgia, increased appetite, weight gain, painful varicose veins. Nausea (here 4.2% of months) was the only side effect with markedly different incidence from other studies with active oral contraceptives.

Inhibition of human sperm motility by calcium and zinc ions

Abstract Calcium and zinc chloride were effective in impairing the motility and viability of human spermatozoa at high molar concentrations. The effect of these ions on several enzymatic activities and on oxygen uptake was measured in order to explain the mechanism by which immobilization was produced. The possibility of using these salts in fertility regulation is suggested.

Presence of corpus luteum as evidence of ovulation in women treated with low doses of chlormadinone acetate

50 women under continuous treatment for 1-31 months with 500 mcg chlormadinone acetate daily were studied. Culdoscopy was performed between Day 14 and 23 of their menstrual cycles. A corpus luteum was thought to be observed in 37 cases. In 18 with suspected corpus luteum a wedge resection of the ovary was done. Examination of patients 10 days after operation revealed no complications. In 4 cases subsequent culdoscopic examinations revealed no traces of biopsy damage. In 5 an endometrial biopsy was obtained the same day as the ovarian one or shortly thereafter. The 18 ovarian biopsies showed recent corpora lutea in 12, old corpus luteum in 1, follicular and theca-lutein cysts in 2, and normal follicles without corpus luteum in 3. Endometrial biopsies revealed 2 instances of normal secretory endometrium and 1 case of irregular endometrium with corpora lutea. Evidence of ovulation occurred in 70%. The reported pregnancy rate with low-dose progestogen therapy has been 3.7/100 years of woman exposure. The exact mechanism of contraception by chlormadinone acetate has not been determined.

Cyclic changes in salivary activity of N-acetyl-beta-D-glucosaminidase. A possible efficient indicator for predicting ovulation and pregnancy.

Salivary activity of N-acetyl-beta-D-glucosaminidase showed a characteristic pattern of changes during the normal menstrual cycle with a distinct peak on Day 13, 14, or 15 before the next menstruation. This peak of enzyme activity occurred withing one day of the nadir of basal body temperature and was absent in women with spontaneous or iatrogenic anovulatory cycles. These results are stongly suggestive that the salivary determination of this activity may be convenient indicatior for determining the day of ovulation.

Effect of the intrauterine contraceptive device upon the biochemical composition of human endometrium

Abstract Biochemical composition of human endometrium was studied during the secretory and proliferative phases of 14 untreated normal young women and of 23 users of a large Lippes loop placed between 2 and 65 months previously. In the non-intrauterine contraceptive device (IUD) users, protein and potassium contents of the endometrium were higher and the sodium concentration and the fucose/sialic acid ratio were lower during the luteal than the proliferative phase. The main changes produced by the IUD were a significant decrease of ribonucleic acid (RNA) and sodium, and a 5 times increase in calcium during the proliferative phase and an increase of calcium, sodium, and fucose and in the fucose/sialic acid ratio in the secretroy phase. Secretory phase endometrium of IUD users has amounts of RNA, protein, and potassium lower than those of the control group. The observed changes are discussed in relation to the mechanism of action of the IUD.

In vitro autoradiographic study of the endometrium from women treated with low-dose chlormadinone acetate for contraception.

Abstract An autoradiographic study of the in vitro DNA synthesis of endometrium of women on a continuous low dose of chlormadinone acetate and a control group was carried out in order to assess the degree of endogenous estrogen production of the women in contraceptive treatment. The index of labeled nuclei in both groups of endometria did not show a significant statistical difference, from which it is concluded that normal proliferative endometrium can result from endogenous estrogenic stimulation during the cycles studied. The integrity of the hypothalamic-pituitary ovarian axis would therefore appear to be demonstrated.

Metabolic Changes in Human Spermatozoa Related to Capacitation*†*Supported in part by a Grant from the Ford Foundation (66-334).†Presented in part at the 27th Annual Meeting of The American Fertility Society, New Orleans, Louisiana, March 24-27, 1971.

Metabolic changes in human spermatozoa related to capacitation were investigated. Glycolysis, motility, oxygen uptake, survival time, and c hanges in tetracycline-binding capacity were studied in spermatozoa expo sed to the following possible capacitating agents: 1) human cervical mucus, 2) human serum, 3) hydroxalpinx fluid, and 4) follicular cyst fluid. Mucus and serum did not produce marked changes. Hydrosalpinx fluid produced an increase in oxygen uptake in the presence of citrate and succinate while follicular cyst fluid produced modifications that could be related to capacitation such as increase in oxygen uptake, increase in motility, and release of bound tetracycline. Similar changes were seen with cyclic adenosine monophosphate and adenosine triphosphate treatment but not with other related nucleotides. The parameters studied in this work are suggestive of functional capacitation.