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250 Hormones

Follicular Growth and Ovulation, Estrogen and Progestin Production

Follicular maturation and ovulation, as well as the associated production of female gonadal hormones, are controlled by the hypophyseal gonadotropins FSH (follicle-stimu- lating hormone) and LH (luteinizing hormone). In the first half of the menstrual cycle, FSH promotes growth and maturation of ovarian tertiary follicles that respond with accelerating synthesis of estradiol. Estradiol stimulates endometrial growth and increases the permeability of cervical mucus for sperm cells. When the estradiol blood level approaches a predetermined set-point, FSH release is inhibited owing to feedback action on the anterior hypophysis. Since follicle growth and estrogen production are correlated, hypophysis and hypothalamus can “monitor” the follicular phase of the ovarian cycle through their estrogen receptors. Immediately prior to ovulation, when the nearly mature tertiary follicles are producing a high concentration of estradiol, the control loop switches to positive feedback. LH secretion transiently surges to peak levels and triggers ovulation. Within hours after ovulation, the tertiary follicle develops into the corpus luteum, which then also releases progesterone in response to LH. This initiates the secretory phase of the endometrial cycle and lowers the permeability of cervical mucus. Nonruptured follicles continue to release estradiol under the influence of FSH. After two weeks, production of progesterone and estradiol subsides, causing the secretory endometrial layer to be shed (menstruation).

The natural hormones are unsuitable for oral application because they are subject to presystemic hepatic elimination. Estradiol is converted via estrone to estriol; by conjugation, all three can be rendered water-soluble and amenable to renal excretion. The major metabolite of progesterone is pregnanediol, which is also conjugated and eliminated renally.

Estrogen preparations. Depot preparations for i.m. injection are oily solutions of esters of estradiol (3- or 17-OH group). The hydrophobicity of the acyl moiety determines the rate of absorption, hence the duration of effect. Released ester is hydrolyzed to yield free estradiol.

Orally used preparations. Ethinylestradiol

(EE) is more stable metabolically, passes the liver after oral intake and mimics estradiol at estrogen receptors. Mestranol itself is inactive; however, cleavage of the C3 methoxy group again yields EE. In oral contraceptives, one of the two agents forms the estrogen component (p.252). (Sulfate-) Conjugated estrogens (excretory products) can be extracted from equine urine and are used in the therapy of climacteric complaints. Their effectiveness is a matter of debate. Estradiol transdermal delivery systems are available.

Progestin preparations. Depot formulations for i.m. injection are 17-α-hydroxy- progesterone caproate and medroxyprogesterone acetate. Preparations for oral use are derivatives of ethinyltestosterone = ethisterone (e.g., norethisterone, dimethisterone, lynestrenol, desogestrel, gestoden), or of 17α-hydroxyprogesterone acetate (e.g., chlormadinone acetate or cyproterone acetate).

Indications for estrogens and progestins include hormonal contraception (p.252); hormone replacement, as in postmenopausal women for prophylaxis of osteoporosis; bleeding anomalies; menstrual and severe climacteric complaints.

Adverse effects. After long-term intake of estrogen/progestin preparations, increased risks have been reported for breast cancer, coronary heart disease, stroke, and thromboembolism. Although the incidence of bone fractures also decreases, the risk–benefit relationship is unfavorable. Concerning the adverseeffectsoforalcontraceptives,seep.252.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Estrogens and Progestins

251

A. Estradiol, progesterone, and derivatives

 

 

 

 

 

 

 

 

 

Hypothalamus

Hydroxyprogesterone

 

 

O Estradiol

 

 

 

 

 

 

H3C

caproate

 

 

 

 

 

GnRH

O O

 

O

C

 

 

C

 

 

 

 

 

 

17

-valerate

 

 

 

 

O

C

 

 

 

 

 

 

17

 

 

 

 

 

 

 

 

 

 

3 weeks

 

 

Hypophysis

 

 

1 week

O

 

 

 

FSH

LH

 

 

 

C

O

 

 

 

 

 

 

3

 

 

 

Medroxyprogesterone

-benzoate

 

 

 

 

acetate

 

 

 

 

 

 

 

8 – 12 weeks

 

 

1 2 week

 

 

Duration of effect

 

Ovary

Duration of effect

 

 

 

 

 

 

H3C

O

 

 

 

 

 

 

OH

 

C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

17

 

 

 

 

 

3

 

 

 

 

 

 

 

 

HO

 

Estradiol

O

 

 

 

 

 

 

 

Progesterone

 

 

 

 

 

 

 

 

 

CH3

 

 

 

 

 

 

 

 

HC

OH

OH

 

O

 

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

 

 

 

 

 

HO

 

 

 

 

 

 

 

 

 

 

 

 

Estriol

Estrone

Estradiol

 

Pregnanediol

 

 

Conjugation with sulfate, glucuronate

 

Conjugation

 

 

 

 

 

 

Inactivation

 

Inactivation

 

 

 

 

 

 

Estradiol

 

Progesterone

OH

 

 

 

OH

 

 

 

 

 

C

CH

 

 

 

 

 

 

 

 

 

 

 

 

C

CH

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

Ethinylestradiol (EE)

 

Ethinyltestosterone,

 

 

 

 

 

 

 

a gestagen

 

 

 

 

 

 

 

3

Mestranol =

 

 

 

 

 

 

 

3-Methylether of EE

 

 

 

Conjugated

 

H3C

O

 

 

 

 

 

 

 

 

 

estrogens

 

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

252 Hormones

Oral Contraceptives

Inhibitors of ovulation. Negative feedback control of gonadotropin release can be utilized to inhibit the ovarian cycle. Administration of exogenous estrogens (ethinylestradiol or mestranol) during the first half of the cycle permits FSH production to be suppressed (as it is by administration of progestins alone). Owing to the reduced FSH stimulation of tertiary follicles, maturation of follicles and hence ovulation are prevented. In effect, the regulatory brain centers are deceived, as it were, by the elevated estrogen blood level, which signals normal follicular growth and a decreased requirement for FSH stimulation. If estrogens alone are given during the first half of the cycle, endometrial and cervical responses, as well as other functional changes, will occur in the normal fashion. By adding a progestin (p.250) during the second half of the cycle, the secretory phase of the endometrium and associated effects can be elicited. Discontinuance of hormone administration would be followed by menstruation.

The physiological time course of estrogenprogesterone release is simulated in the socalled biphasic (sequential) preparations

(A). In monophasic preparations, estrogen and progestin are taken concurrently. Early administration of progestin reinforces the inhibition of CNS regulatory mechanisms, prevents both normal endometrial growth and conditions for ovum implantation, and decreases penetrability of cervical mucus to sperm cells. The two latter effects also act to prevent conception. According to the staging of progestin administration, one distinguishes (A): one-, two-, and three-stage preparations. Even with one-stage preparations, “withdrawal bleeding” occurs when hormone intake is discontinued (if necessary, by substituting dummy tablets).

Unwanted effects. An increased risk of thromboembolism is attributed to the estrogen component in particular but is also associated with certain progestins (gestoden

and desogestrel). The risk of myocardial infarction, stroke, and benign liver tumors is elevated. Nonetheless, the absolute prevalence of these events is low. Predisposing factors (family history, cigarette smoking, obesity, and age) have to be taken into account. The overall risk of malignant tumors does not appear to be increased. In addition, hypertension, fluid retention, cholestasis, nausea, and chest pain, are reported.

Minipill. Continuous low-dose administration of progestin alone can prevent pregnancy. Ovulations are not suppressed regularly; the effect is then due to progestininduced alterations in cervical and endometrial function. Because of the need for constant intake at the same time of day, a lower success rate, and relatively frequent bleeding anomalies, these preparations are now rarely employed.

“Morning-after” pill. This refers to administration of a high dose of estrogen and progestin, preferably within 12–24 hours, but no later than 72 hours after coitus. The mechanism of action is unclear.

Stimulation of ovulation. Gonadotropin secretion can be increased by pulsatile delivery of GnRH (p.238). Regarding clomifene, see p.254; whereas this substance can be given orally, the gonadotropins presented below must be given parenterally. HMG is human menopausal gonadotropin extracted from the urine of postmenopausal women. Owing to the cessation of ovarian function, gonadotropins show elevated blood levels and pass into urine in utilizable quantities. HMG (menotropins) consists of FSH and LH. HCG is human chorionic gonadotropin; it is obtained from the urine of pregnant women and acts like LH. Recombinant FSH (follitropin) and LH are available.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

 

 

Oral Contraceptives

253

A. Oral contraceptives

 

 

 

 

 

 

 

 

Hypophysis

 

 

 

 

 

 

Hypophysis

 

FSH

LH

 

1

7

14

21

28

Inhibition

 

 

 

 

 

 

 

 

 

 

 

 

Minipill

 

 

 

 

 

 

 

 

 

 

 

Ovulation

 

 

 

 

Ovary

 

 

 

 

 

 

 

 

 

Ovulation

 

 

 

 

 

Ovary

 

 

 

 

 

 

 

 

 

 

 

Estradiol

Progesterone

 

 

 

 

Intake of

Intake of

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

estradiol

progestin

 

Estradiol

 

 

 

 

 

 

 

derivative

 

 

 

 

 

Penetrability

 

 

 

 

 

 

Progesterone

 

by sperm cells

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1

7

14

21

28

 

 

Readiness

 

 

 

 

 

 

 

 

 

 

for

 

 

 

 

Day of cycle

 

 

nidation

No ovulation

 

Biphasic preparation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Days of cycle

7

14

21

28

Monophasic preparations

One-stage regimen

Two-stage regimen

Three-stage regimen

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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