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Home , Quingestanol, Quingestanol acetate, Retroprogesterone

HORMONAL CONTROL OF CONCEPTION

S. TEJUIA Indian Council of Medical Research, New De/hi-16

Prologue

Prior to 1938 no form of oral was possible as none of the then availablehormones were active when given orally. The era of oral contraception commenced withthe reports of Pincus et al (3). The contraceptive pills used today contain a synthetic oestrogenand a synthetic progestational agent. Oestrone and oestradiol were available prior to 1938 as esters but these were active only when injected. Impure injectables indicated then that they could prevent pregnancy.

The oestrogens used now and which are active orally are either which is 3 methylether of 17 ethinyl oestradiol or ethinyl oestradiol itself. These two synthetic oestro- gensretain most of the biological properties of oestradiol.

Progesterone is primarily, a secretory of the corpus luteum. The name is derivedin part from progestin, first proposed in 1930 by Corner and Allen (1) for the active substance present in their extracts of the corpus luteum. Literally, the word 'progestin' indicatesa hormone which supports or assists pregnancy. The relationship between progest- erone and oral contraceptives is intimate but "the pill" is not a , but contains a progestational agent which has many of the biological properties of progesterone. The proges- tational agents in the pills are not naturally occuring .

The most characteristic effect of progesterone is the induction of progestational change in the endometrium. The histological evidence of this change is quite variable from one speciesto another but in all species, the endometrial changes induced by progesterone are essentialfor the normal growth and implantation of the fertilized egg. An associated and equallyimportant effect is exerted on the myometrium. This is generally manifested by myometrial quiescence and refractoriness to oxytocin. These functional alterations in the myometrium enable the uterus to adapt to the growing conceptus. - The biological effect of oestradiol on target organs is quite different from that of pro- gesterone. Oestradiol is primarily a growth-promoting hormone. It induces growth of the

Lecture delivered at the XVI Annual Conference of the Association of Physiologists and Pharmacologists of India, on December 28, 1970 in Bangalore. January 1972 Volume 16 16 Tejuja Ind. J. Physiol. Pharmac. Number 1 ledge into practice. These sythel uterus, vagina, and breasts and brings these organs to sexual maturity. Tn the process, it such was not soluble in water, w brings about a subtle change which permits them to respond to progesterone. Without pre- only when progesterooe was obta liminaryexposure to oestrogen, progesterone generally has no demonstrable effect. called "Black Head" in Mexico version into orally active compc Agents and their biological properties : potency and biological activity 0 It is remarkable that the numerous -oestrogen combinations have similar basic effects despite the varied pharmacological properties of the individual ingredients. Table I shows the groups from which these compounds are derived. Common derivatives of progesterone which are active orally and have been used for contraceptive purposes are Delay-o/-mensl like medroxy progesterone , megesterol acetate and acetate. test (mg.)

Changes in the molecule give rise to compounds with properties compara- Med roxyprogesterone 30 ble to (Table I). acetate Chlormadinone 4 TABLE I: Synthetic components in contraceptive pills Natural Structural Group added Generic name orethindrone 10 change 3 6 17a 17b orethindreone 7.5 acetate Oestradiol None Ethinyl Ethinyl Ethyoodiol diacetate

None Methyl Ethinyl Mestranol Norethynodrel 13.8 Progesterone None Methyl Acetyl Medroxy-pro------gesterone acetate

Methyl Acetyle Megesterol acetate L Combined regimens: 6 dehydro Chloro Acetyle A. Containing vari gens. Testosterone None Methyl Propynyl Dimesthisterone 19-nor Ethinyl Norethindrone 1. 20 or 21 day scheme (start! 2. 20 or 21 day scheme with I 19-nor Ethinyl Acetyl orethindrone 3. "Lunar scheme" starting a acetate 4. "Post ovulatory" day 16-25 19-nor Acetyl Ethinyl Acetyl Ethynodiol 5. One-pill-a-month: on day diacetate metyl-6-, oestrogen (3 cyclopentyl e 19-nor -OH 6. One-pill-a-month: Starting 19-nor 5-10 - Ethinyl Norethynodrel progestogen and oestrogen (instead of 4) B. Containing administration.

Although it has been known since long. that steriod hormones (oestrogen and pro- 1. Intramuscular each month gesterone) have contraceptive properties, it has taken almost two decades to put this know- thate. January 1972 VolumeJ6 Ind. J. Physiol, Pharmac. Number 1 Hormonal Control of Conception 17

ledge into practice. These sythetic compounds had to be prepared because progesterone as ual maturity. In the process, it such was not soluble in water, was short acting and was terribly expen ive. Also it was d to progesterone. Without pre- only when progesterone was obtained in bulk and very cheap from a tuberous plant root no demonstrable effect. called "Black Head" in Mexico and from other plant sterols that its wide use and its con- version into orally active compounds was thought of. Table II gives the comparative potency and biological activity of these compounds. trogen combinations have similar of the individual ingredients. TABLE II: Progestin potency are derived. Common derivatives for contraceptive purposes are Delay-of-menses Gonadotrophin Anabolic Human foetal Coversion to Anti-oestrogen and chlormadinone acetate. test (mg.) suppression masculinization oestrogen mpound with properties cornpara- 30 0 0 0 0 + acetate Chlormadinone 4 0 0 Unknown 0 + Dimethisterone Unknown 0 0 Unknown Unknown Generic name orethindrone 10 + .. + + + 17b orethindreone 7.5 + + + Unknown + acetate Ethinyl estradiol Ethynodiol diacetate + + Unknown Unknown Mestranol Norethynodrel 13.8 + 0 0 + o Medroxy-pro- gesterone acetate Megesterol acetate REGIMENS I. Combined regimens tyle Chlormadinone acetate A. Containing various combinations of orally active oestrogens and progesto- Dimesthisterone gens.

Norethindrone 1. 20 or 21 day scheme (starting day 5 of menstrual cycle). Acetyl orethindrone 2. 20 or 21 day scheme with placebos in the remaining 7 days. acetate 3. "Lunar scheme" starting a 21 day schedule with each new moon. 4. "Post ovulatory" day 16-25: accompanied by fertile-period abstinence. Acetyl Ethynodiol 5. One-pill-a-month: on day 21 of cycle. A progestogen (Chlorrnadinone, retroprogesterone, 16-17 di- diacetate metyl-ti-retroprogesterone, or the 18 homologue of ) together with a long acting oral Lynestrenol oestrogen (3 cyclopentyl ether of erhiny l oestradiol). 6. One-pill-a-month: Starting on day 1 or 2 of the cycle and every month sybsequently. Long acting N orethynod rei progestogen and oestrogen ( acetate and Quinesterol).

------B. Containing long acting progestogen -l-oestrogen combination for parenteral administration. hormones (oestrogen and pro- I. Intramuscular each month on day 7 or 8: dihydroxy-progesterone acetophenide and oestradiol enan- two decades to put this know- thate. January 1972 Volume 16 18 Tejuja Ind. J. Pnysiol. Pmrrmc. umber 1

H. Sequential regimens There are some indica reduce its sensitivity to gon 1. Clas ical sequential Rudel et al (2) brough -oestrogen alone (i) Day 5 to 20 nece sary to inhibit ovulation (ii) Day 21 to 25 -combined oestrogen and progestogen inhibition of ovulation such perm transport etc. and that 2. Modified sequential began. (i) Day 5 to 16 -oestrogen alone (ii) Day 16 to 25 -combined oestrogen and progestogen Adverse changes in th in the development of endon 3. Step-up sequential and subsequently their (i) Day 1 to 5 -'micro' oestrogen dosage agents act. With formulati (ii) Day 5 to 16 -first oestrogen alevation a prescribed i.e. combinatio -second oestrogen elevation (iii) Day 16 to 20 Pregn ancy rate with sequen (iv) Day 20 to 25 -oestrogen and progestogen case. (v) Day 25 to 30 -'micro' oestrogen

ide Effects Ill. Progestogen alone Variou side-effects 1. 'Micro' doses continuous at 0.5 mg. daily. ing, fatigue, weight gain et 2. One-pill-a-week: 'Sunday Pill' (Norgesterinone). 3. Intramuscular Provera (Medroxy proge terone acetate) 150 mg every 3 months or 400 to 800 mg ever) men es, amenorrhea and brt 4 to 6 month. 4. Intramuscular injection every 3 months: 200 mg. Some symptoms exp 5. Intravaginal placement of silicone ring with medroxy progesterone acetate-inserted early in cycle an related to progestogens. 1 removed on day 27. selection of combinations 6. Subcutaneous silastic implant containing proge togen-continuous doses in micro quantities release ceptive is therefore, very in for over a year. 7. Intrauterine administration of progesterone by a slow releasing device (a silastic capsule containing gnancy, unusual headache, progesterone attached to a Lippes loop). Metabolic and other effects 8. Intracervical administration of progesterone by a slow releasing device (silastic capsule containing

the steroid) placed in the cervical canal. 1. AoRENAL CORTEX

IV. Oestrogens administered post-coital. 2. THYROID

3. HEPTlC EFFECTS MODE OF ACTION 4. INTEGUMENTAL EFFECTS Most of the oral combined/sequential preparations In use at present have their con- 5. HAEMATOLOGICAL CHNGEli traceptive action by preventing ovulation through the suppression of the hypothalarnic-

pituitary axis. 6. CARDIOVASCULAR EFFECTS Both FSH and LH are suppressed. This is brought about by blocking the oestrogen receptor site in the hypothalamus and pituitary and subsequent reduction in gonadotrophi 7 Cf. TRAL ERVOUS SYSTH release and inhibition of ovulation. INCLUDING EMOTIONAL January 1972 Volume16 Hormonal Control of Conception 19 Ind. J. Physiol. P'rirrn ic. Number 1

There are some indications that the contraceptives may directly act on the ovary and reduce its sensitivity to gonadotrophins.

Rudel et al (2) brought out the hypothesis that for the contraceptive action it was not necessary to inhibit ovulation. Search then went on for reproductive processes other than inhibition of ovulation such as fertilization, transport of fertilized ovum, implantation, sperm transport etc. and that is how the era of continuous low dose hormonal began.

Adverse changes in the cervical mucus which hindered sperm survival, subtle changes in the development of endometrium to hinder implantation, rapid transport of fertilized ovum and subsequently their degeneration are some of the other ways by which these agents act. With formulations which are in a high enough dose to inhibit ovulation, if taken as prescribed i.e. combination regimens from day 5-25 etc. effectiveness is 100 per cent. Pregn ancy rate with sequentials is a little higher as failure of ovulation has occurred in some cases.

SideEffects

Various side-effects have been reported which could be general such as nausea, vomit- ing, fatigue, weight gain etc. and others which pertain to menstrual periods such as scanty every3 months or 400 to SOO mg every menses, amenorrhea and breakthrough bleeding. thate 200 mg. Some symptoms experienced by these women are specific for oestrogen and others are roneacetate-inserted early in cycle and related to progestogens. Therefore, depending on the symptoms complained, an appropriate selection of combinations can be made. History of a patient before giving the oral contra- us doses in micro quantities released ceptive is therefore, very important. History of excessive nausea and vomiting during pre- . device(a silastic capsule containing gnancy, unusual headache, visual complaints, tendency to gain weight etc. are important. ingdevice(silastic capsule containing Metabolic and other effects

1. ADRENAL CORTEX Serum bound levels increase. o sign of hyperadreno-corticism.

2. THYROID Slightly elevated PBI, normal thyroxin and J131 uptake. Clinically normal, and BMR normal.

3. HEPTIC EFFECTS Serum transaminase increases, ESP retention increases.

4. lNTEGUMENTAL EFFECTS Melanosis use at present have their con- 5. HAEMATOLOGICAL CHNGE5 Hb increases, MCHC increases, PCV increases, serum Fe increases, and pression of the hypo thalamic- Fe binding capacity increases.

6. CARDIOVASCULAR EFFECfS Hypertension (renin, angiotensin, electrolyte and fluid balance increase about by blocking the oestrogen and also sensitivity of smooth muscle).

nt reduction in gonadotrophin 7. CENTRAL ERVOUS SYSTEM EEG changes variable, thermogenic action, depression, libido decrease f. INCLUDI G EMOTIO AL January 19T 20 Tejuja Ind. J. Physiol. Pharmac Volume 16 umber 1

~. CARBOHYDRATE METABOLISM Related to type and dose of oestrogen, changes more with combined th sequential, increase in cortisol, increase in growth hormone, alteration GT absorption, peripheral tissue utilization of glucose decreased.

9. LIPID METABOLISM Serum cholestrelol increa es, triglycerides increase and athero c1eroi .

10. BLOOD COAGULATION AND Definite oestrogen dependent relationship reported, i.e. state of hype THROMBOPHLEBITIS coagulability as a result of changes in level of various clotting facto platelet function, physical state of vessels.

11. CARCINOGENIC EFFECT Incidence of cervical cancer has not shown to be increased with the use these contraceptives. ICMR LI T

12. MENSTRUAL DISORDERS Combined preparations have better control. Associated with skipping tablets and present in first few days. 1. Sequential -less controlled withdrawal. Low-dose -greater variability.

13. SUBSEQUENT FERTILITY Much. needs to be done. 2. N orinyl-I ( All these effects need to be tu died and evaluated among women taking these pre· parations in our country. Available data on the effect of continuous low dose progesteron on these metabolic and other processes i not sufficient. Therefore, it is suggested that fo the use of hormones as a contraceptive measure, the following be kept in mind:

I. proper selection of cases 2. good follow up 3. orle trin 3. change of when indicated 4. picking up of complications soon enongh 4. Ovral A total of 14 million women are using the e drugs all 0 er the world for the purpo of contraception. There is no reason why this should not increase with new lower do schedules, long acting pills (one-pill-a-month) injectables containing long acting oestrogen an progestogen, subcutaneous implants for three years, hormone for low release in ide a 5. Eugynon . I am sure, re earch which i now in progress to find out the minimu dose and combination for our women, will lead to the development of a method which simple, has maximum effectiveness. safety, least side-effect and therefore, a high acceptabili 6. 0\ ulen-50 index among our women.

REFERE 'CES 7. Lyndiol-E 1. Corner, G.W. and W.M. Alien. Physiology of corpus luteum: 11. Production of pecial uterine reacti (proge tational proliferation) by extracts of corpu luteum. Am. J. Physiol. 88: 326-39, 1930. 2. Rudel, H.W., J. Martinez-Manaulou and M. Maqueo-Topete. The role of progestogens in the hormo control of fertility. Fertility and Sterility, Vol. 16, o. 2, 158, 1965. 3. Pincus, G., J. Rock, C.R. Garcia, E. Rice-Wray, M. Paniagua and T. Rodriguez. Fertility control with 0 , AlIler. J. Obstet. Gynec., 75: 1333. 1958. ---

January 1972 Ind. J. Physiol. Pharmac. Volume 16 Hormonal Control of Conception 21 Number 1

~trogen, changes more with combined than Increase in growth hormone, alteration in utilization of glucose decreased.

iglycerides increase and atherosclerois.

~Iationship reported, i.e. state of hyper- ~es in level of various clotting factors. of ve sels.

not shown to be increased with the use of ICMR LI T OF APPROVED OR L CO T CEPTIVES

~tter control. Associated with skipping of days. thdrawal, 1. Minovlar-2 Ethinyl oestradiol 0.05 mg. orethisterone acetate 1 mg.

2. Norinyl-I (Norid) 21 plain tablets, each containing among women taking these pre- Mestranol 0.05 mg. continuous low dose progesterone orethindrone 1 mg. ~herefore, it is suggested that for ~ing be kept in mind : 7 coloured tablets, each containing inert ingredients

3. orlestrin Etbinyl oestradiol SO mug, orethinsterone acetate I mg. ngh all over the world for the purpose 4. Ovral Ethinyl oestradiol 0.05 mg. not increase with new lower dose orgestre! 0.5 mg. ~ntaining long acting oestrogen and ~mone for slow release inside an 5. Eugynon Ethinyl oestradiol 0.05 mg. progress to find out the minimum orge trel 0.5 mg. velopment of a method which is ~sand therefore, a high acceptability 6. Ovulen-Sf Ethinyl oestradiol 0.05 mg. Ethyndiol diacetatc I mg,

Ethinyl oestradiol RP. 50 mug, Il. Production of special uterine reaction 7. Lyndiol-E Lynestrenol 2.5 mg, J. Physiol. 88: 326-39, 1930. RP. The role of progestogens in the hormonal ~5. ~d 1. Rodriguez. Fertility control with oral