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Color Atlas of Physiology 2003 thieme

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A. Menstrual cycle

 

 

 

 

 

 

 

 

 

Anterior

 

Ovulation

 

 

 

Cycle

 

 

 

pituitary

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Units/L

 

 

 

 

 

 

 

 

 

 

 

 

Menstrual

 

 

 

50

 

 

LH

 

 

 

 

 

 

 

 

FSH

 

 

1

 

 

 

 

 

 

 

 

 

 

0

 

 

 

 

 

and the

ng/mL

ng/mL

 

 

 

 

 

 

8

 

0,4

 

 

 

Progesterone

11.17 Oogenesis

 

6

 

0.3

Estrogens,

 

 

Progesterone

 

 

 

(P)

 

 

 

 

chiefly estradiol

 

 

 

4

Estrogens

0.2

(E2)

 

 

 

 

2

0.1

 

 

 

 

 

0

0

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

1

7

14

21

Day

28

Plate

 

 

 

 

 

 

 

 

 

 

 

 

3

 

 

 

 

Rises

 

 

 

 

 

 

 

ca. 0.5°C

 

 

 

 

Basal body

 

 

 

 

 

 

 

temperature

 

 

 

 

 

 

 

 

 

1

7

14

21

Day

28

 

4

 

 

 

 

 

 

 

 

 

Ovarian follicle

 

 

 

 

 

 

development

 

 

 

 

 

 

 

 

 

 

 

Ovum

 

 

 

 

 

 

 

Follicle

Dominant

Rupture of follicle

Corpus

Degenerating

 

 

 

 

selection

follicle

(ovulation)

luteum

corpus luteum

 

5

 

 

Discharge

Regeneration

Ischemia

 

 

Endometrium

 

 

 

 

 

 

 

 

 

1

7

14

21

Day

28

 

 

 

 

Menstruation

 

 

 

 

 

 

 

 

 

 

Follicular phase

 

Luteal phase

 

 

299

 

 

 

 

 

 

 

 

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

Hormonal Control of the Menstrual

Cycle

 

In sexually mature women, gonadoliberin or

 

gonadotropin-releasing hormone (Gn-RH) is

 

secreted in one-minute

pulses

every

 

60–90 min in response to signals from various

 

neurotransmitters. This, in turn, induces the

 

pulsatile secretion of FSH and LH from the

Reproduction

anterior pituitary. If the rhythm of Gn-RH

secretion is much faster or continuous, less

FSH and LH will be secreted, which can result

in infertility. The LH : FSH secretion ratio

changes during the course of the menstrual

cycle. Their release must be therefore subject

and

to additional factors besides Gn-RH.

 

The secretion of LH and FSH is, for example, subject

Hormones

to central nervous effects (psychogenic factors,

stress) mediated by various transmitters circulating

in the portal blood in the hypothalamic region, e.g.,

norepinephrine (NE) and neuropeptide Y (NPY) as

11

well as by ovarian hormones,

i.e., by

estrogens

(estrone, estradiol, estriol, etc.), progesterone and

 

 

inhibin. Ovarian hormones affect Gn-RH secretion in-

 

directly by stimulating central nerve cells that acti-

 

vate Gn-RH-secreting neurons by way of neu-

 

rotransmitters such as norepinephrine and NPY and

 

inhibit Gn-RH secretion by way of GABA and opioids.

 

FSH production again increases toward the

 

end of the luteal phase (! p. 299, A1). In the

 

early follicular phase (!A1), FSH induces the

 

proliferation of the stratum granulosum in

 

about 20 follicles and stimulates the secretion

 

of aromatase in their granulosa cells. Aro-

 

matase catalyzes the conversion of the andro-

 

gens testosterone and androstenedione to

 

estradiol (E2) and estrone

(E1) (!p. 295 A,

 

steps r and o). Estrogens are synthesized in

 

theca cells and absorbed by granulosa cells. Al-

 

though relatively small amounts of LH are

 

secreted (!A1 and p. 299 A1), this is enough

 

to activate theca cell-based enzymes (17!-hy-

 

droxysteroid dehydrogenase and C17/C20-

 

lyase) that help to produce the androgens

 

needed for estrogen synthesis. The follicle-

 

based estrogens increase their own FSH recep-

 

tor density. The follicle with the highest estro-

 

gen content is therefore the most sensitive to

 

FSH. This loop has a self-amplifying effect, and

300

the follicle in question is selected as the domi-

nant follicle around the 6th day of the cycle

(!A2). In the mid-follicular phase, estrogens

restrict FSH and LH secretion (via negative feedback control and with the aid of inhibin; !A2) but later stimulate LH receptor production in granulosa cells. These cells now also start to produce progesterone (start of luteinization), which is absorbed by the theca cells (!A3) and used as precursor for further increase in androgen synthesis (!p. 295 A, steps f and l).

Inhibin and estrogens secreted by the dominant follicle increasingly inhibit FSH secretion, thereby decreasing the estrogen production in other follicles. This leads to an androgen build-up in and apoptosis of the unselected follicles.

Increasing quantities of LH and FSH are released in the late follicular phase (!A3), causing a sharp rise in their plasma concentrations. The FSH peak occurring around day 13 of the cycle induces the first meiotic division of the ovum. Estrogens increase the LH secretion (mainly via the hypothalamus), resulting in the increased production of androgens and estrogens (positive feedback) and a rapid rise in the LH conc. (LH surge). The LH peak occurs around day 14 (! A2). The follicle ruptures and discharges its ovum about 10 hours later (ovulation). Ovulation does not take place if the LH surge does not occur or is too slow. Pregnancy is not possible in the absence of ovulation.

Luteal phase (!A4). LH, FSH and estrogens transform the ovarian follicle into a corpus luteum. It actively secretes large quantities of progesterone (progestational hormone), marking the beginning of the luteal phase (!A). Estrogens and progesterone now inhibit the secretion of FSH and LH directly and indirectly (e.g., through inhibition of Gn-RH; see above), causing a rapid drop in their plasma conc. This negative feedback leads to a marked drop in the plasma conc. of estrogens and progesterone towards the end of the menstrual cycle (approx. day 26), thereby triggering the menses (!p. 299, A2). FSH secretion starts to rise just before the start of menstruation (!A4).

Combined administration of estrogens and gestagens during the first half of the menstrual cycle prevents ovulation. Since ovulation does not occur, pregnancy cannot take place. Most contraceptives work according to this principle.

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

A. Hormonal control of the menstrual cycle

 

 

 

Cycle

1

 

Hypothalamus

 

 

 

 

 

 

 

 

 

 

 

 

End of cycle,

 

 

 

2

 

 

 

 

 

 

 

 

 

Menstrual

early

 

 

Gn-RH,

Mid-

 

 

follicular phase

 

follicular

 

 

 

 

 

transmitter

phase

 

Gn-RH,

 

Pituitary

 

 

 

 

 

transmitter

 

gland

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

the

 

FSH

LH

 

 

 

 

 

 

 

 

 

 

 

 

 

of

 

 

 

 

 

 

FSH

LH

 

 

 

 

 

FSH receptor

 

 

Control

 

 

 

 

 

 

 

 

 

 

 

 

LH receptor

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Androgens

 

 

 

 

Hormonal

 

 

 

 

Aroma-

 

 

 

Androgens

 

 

 

 

tase

Theca

 

 

Aroma-

 

 

 

 

 

 

Inhibin

tase

 

 

 

 

 

cells

 

 

 

 

 

 

 

 

 

11.18

 

 

 

 

 

Granulosa

 

 

Progesterone

 

 

cells

 

 

 

Estrogens

 

 

 

 

Oocyte

 

Estrogens

Plate

 

 

New

 

Estrogens

 

 

 

 

 

 

 

 

 

 

 

group of follicles

 

 

 

Dominant

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

follicle

Uterus, etc.

 

4

 

 

 

 

 

 

 

3

 

Luteal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Late

 

phase

 

 

 

 

 

 

 

 

 

Gn-RH,

 

 

 

 

 

follicular phase,

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gn-RH,

ovulation

 

 

 

transmitter

 

 

 

 

 

 

 

 

 

transmitter

 

 

 

 

 

 

 

 

 

FSH

LH

 

 

 

FSH

LH

Day 14:

 

 

 

 

 

 

 

 

 

 

 

 

LH peak

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Androgens

 

 

Corpus luteum

 

 

 

 

Aroma-

 

 

 

 

 

 

 

 

 

tase

 

 

 

 

 

 

 

 

 

 

Progesterone

 

Estrogens

Progesterone

 

 

 

 

Ovulation

 

 

 

 

 

 

 

 

Uterus, etc.

 

 

 

 

Uterus, etc.

 

 

 

 

 

 

 

 

 

 

 

 

Becomes/goes to

Stimulates

Inhibits

 

301

(In part after H.-P. Leichtweiß)

 

 

 

 

 

 

 

 

 

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

11 Hormones and Reproduction

302

Estrogens

Estrogens are steroid hormones with 18 carbon atoms. Estrogens are primarily synthesized from the 17-ketosteroid androstenedione, but testosterone can also be a precursor (!p. 295 A). The ovaries, (granulosa and theca cells), placenta (!p. 304), adrenal cortex, and in Leydig’s cells (interstitial cells) of the testes (!p. 306) are the physiological sites of estrogen synthesis.. In some target cells for testosterone, it must first be converted to estradiol to become active.

Estradiol (E2) is the most potent estrogen

(E). The potencies of estrone (El) and estriol (E3) are relatively low in comparison (E2 : E1 : E3 = 10 : 5 : 1). Most estrogens (and testosterone) circulating in the blood are bound to sex hor- mone-binding globulin (SHBG). Estriol (E3) is the chief degradation product of estradiol (E2).

Oral administration of estradiol has virtually no effect because almost all of the hormone is removed from the bloodstream during its first pass through the liver. Therefore, other estrogens (with a different chemical structure) must be used for effective oral estrogen therapy.

Actions. Although estrogens play a role in the development of female sex characteristics, they are not nearly as important as the androgens for male sexual development (!p. 306). The preparatory action of estrogen is often required for optimal progesterone effects (e.g., in the uterus; see below). Other important effects of estrogens in human females are as follows.Menstrual cycle. Estrogens accelerate maturation of the ovarian follicle during the menstrual cycle (!p. 298 and table). In the uterus, estrogen promotes the proliferation (thickening) of the endometrium and increases uterine muscle contraction. In the vagina, estrogen thickens the mucosal lining, leading to the increased discharge of glycogen-containing epithelial cells. The liberated glycogen is used for an increased production of lactic acid by Döderlein’s bacillus. This lowers the vaginal pH to 3.5–5.5, thereby reducing the risk of vaginal infection. In the cervix, the mucous plug sealing the cervical os functions as a barrier that prevents sperm from entering the uterus. Estrogens change the consistency of

the cervical mucus, making it more conducive to sperm penetration and survival, especially around the time of ovulation.

Fertilization. In the female body, estrogens prepare the sperm to penetrate and fertilize the ovum (capacitation) and regulate the speed at which the ovum travels in the fallopian tube.

Extragonadal effects of estrogen. During puberty, estrogens stimulate breast development, induces changes in the vagina and in the distribution of subcutaneous fat, and (together with androgens) stimulate the growth of pubic and axillary hair. Since estrogens increase the coagulability of the blood, the administration of estrogens (e.g., in contraceptives) increases the risk of thrombosis and leads renal salt and water retention. Estrogens slow longitudinal bone growth, accelerate epiphyseal closure (in men and women) and increase osteoblast activity. Estrogen deficiencies in menopause consequently lead to the loss of bone mass (osteoporosis). Estrogens induce a decrease in LDL and a rise in VLDL and HDL concentrations (!p. 254ff.), which is why arteriosclerosis is less common in premenopausal women than in men. Estrogen also makes the skin thinner and softer, reduces the sebaceous glands, and increases fat deposits in subcutaneous tissue. Lastly, estrogen influences a number of central nervous functions, e.g., sexual response, social behavior, and mood.

Plasma concentrations of estradiol and progesterone (ng/mL)

Phase

Estradiol

Progesteron

 

 

 

Women

 

 

Early follicular phase

0.06

0.3

Midand late follicular

0.1 ! 0.4

1.0

phase

 

 

Ovulation

0.4

2.0

Mid-luteal phase

0.2

8–16

Pregnancy

7–14

40 ! 130

Day 1 after parturition

 

20

 

 

 

Men

0.05

0.3

 

 

 

Progesterone

Progesterone, the most potent progestational (pregnancy-sustaining) hormone, is a steroid hormone (21 C atoms) synthesized from

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

cholesterol via pregnenolone (!p. 295). It is produced in the corpus luteum, ovarian follicles and placenta (!p. 304) of the female, and in the adrenal cortex of males and females. Like cortisol, most circulating progesterone is bound to cortisol-binding globulin (CBG = transcortin). Like estradiol (E2), most progesterone is broken down during its first pass through the liver, so oral doses of progesterone are almost completely ineffective. Pregnanediol is the most important degradation product of progesterone.

Actions of progesterone. The main functions of progesterone are to prepare the female genital tract for implantation and maturation of the fertilized ovum and to sustain pregnancy (!see table). Progesterone counteracts many of the effects induced by estrogens, but various effects of progesterone depend on the preparatory activity or simultaneous action of estrogens. During the follicular phase, for example, estrogens increases the density of progesterone receptors, while simultaneous estrogen activity is needed to induce mammary growth (see below).

The uterus is the chief target organ of progesterone. Once estrogen induces endometrial thickening, progesterone stimulates growth of the uterine muscle (myometrium), restructures the endometrial glands (! p. 298), alters the blood supply to the endometrium, and changes the glycogen content. This represents the transformation from a proliferative endometrium to a secretory endometrium, with a peak occurring around day 22 of the cycle. Progesterone later plays an important role in the potential implantation (nidation) of the fertilized ovum because it reduces myometrial activity (important during pregnancy), narrows the cervical os, and changes the consistency of the cervical mucous plug so that it becomes virtually impregnable to sperm.

Progesterone inhibits the release of LH during the luteal phase. The administration of gestagens like progesterone during the follicular phase inhibits ovulation. Together with its effects on the cervix (see above) and its inhibitory effect on capacitation (!p. 302), progesterone can therefore have a contraceptive effect (“mini pill”).

High levels of progesterone have an anesthetic effect on the central nervous system. Progesterone also increases the susceptibility

to epileptic fits and exerts thermogenic action, i.e., it raises the basal body temperature (!p. 298). In addition, a decrease in the progesterone concentration is also believed to be responsible for the mood changes and depression observed before menstruation (premenstrual syndrome, PMS) and after pregnancy (postpartum depression).

In the kidneys, progesterone slightly inhibits the effects aldosterone, thereby inducing increased NaCl excretion.

Prolactin and Oxytocin

The secretion of prolactin (PRL) is inhibited by prolactin-inhibiting hormone (PIH = dopamine) and stimulated by thyroliberin (TRH) (!p. 270). Prolactin increases the hypothalamic secretion of PIH in both men and women (negative feedback control). Conversely, estradiol (E2) and progesterone inhibit PIH secretion (indirectly via transmitters, as observed with Gn-RH; see above). Consequently, prolactin secretion rises significantly during the second half of the menstrual cycle and during pregnancy. Prolactin (together with estrogens, progesterone, glucocorticoids and insulin) stimulate breast enlargement during pregnancy and lactogenesis after parturition. In breast-feeding, stimulation of the nerve endings in the nipples by the suckling infant stimulates the secretion of prolactin (lactation reflex). This also increases release of oxytocin which triggers milk ejection and increases uterine contractions, thereby increasing lochia discharge after birth. When the mother stops breast-feeding, the prolactin levels drop, leading to the rapid stoppage of milk production.

Hyperprolactinemia. Stress and certain drugs inhibit the secretion of PIH, causing an increase in prolactin secretion. Hypothyroidism (!p. 288) can also lead to hyperprolactinemia, because the associated increase in TRH stimulates the release of prolactin. Hyperprolactinemia inhibits ovulation and leads to galactorrhea, i.e., the secretion of milk irrespective of pregnancy. Some women utilize the anti-ovulatory effect of nursing as a natural method of birth control, which is often but not always effective.

Estrogens

303

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

Hormonal Control of Pregnancy and

Birth

 

Beside its other functions, the placenta pro-

 

duces most of the hormones needed during

 

pregnancy (!p. 220). Ovarian hormones also

 

play a role, especially at the start of pregnancy

 

(!A).

 

Placental hormones. The primary hormones

Reproduction

produced by the placenta are human chorionic

gonadotropin (hCG), corticotropin-releasing

 

 

hormone (CRH), estrogens, progesterone,

 

human placental lactogen (hPL), and pro-

 

opiomelanocortin (POMC; !p. 280). hCG is

 

the predominant hormone during the first

and

trimester of pregnancy (3-month period calcu-

lated from the beginning of the last menses).

Hormones

Maternal conc. of hPL and CRH-controlled

 

 

estrogens rise sharply during the third

 

trimester (!B). Placental hormones are dis-

 

tributed to mother and fetus. Because of the

11

close connection between maternal, fetal and

placental hormone synthesis, they are jointly

 

 

referred to as the fetoplacental unit (!A).

 

Human chorionic gonadotropin (hCG) (a)

 

stimulates the synthesis of steroids like DHEA

 

and DHEA-S by the fetal adrenal cortex (see

 

below); (b) suppresses follicle maturation in

 

the maternal ovaries, and (c) maintains the

 

production of progesterone and estrogen in

 

the corpus luteum (!A1) until the 6th week of

 

gestation, i.e., until the placenta is able to pro-

 

duce sufficient quantities of the hormones.

 

Most pregnancy tests are based on the fact that

 

hCG is detectable in the urine about 6–8 days after

 

conception. Since the levels of estrogen and pro-

 

gesterone greatly increase during pregnancy (see

 

table on p. 302), larger quantities of these hormones

 

and their metabolites estriol and pregnanediol are ex-

 

creted in the urine. Therefore, their conc. can also be

 

measured to test for pregnancy.

In contrast to other endocrine organs, the placenta has to receive the appropriate precursors (cholesterol or androgens, !p. 294) from the maternal and fetal adrenal cortex, respectively, before it can synthesize progesterone and estrogen (!A2). The fetal adrenal cortex (FAC) is sometimes larger than the kidneys and consists of a fetal zone and an adult zone. The

304placenta takes up cholesterol and pregnenolone and uses them to synthesize pro-

gesterone. It is transported to the fetal zone of

the FAC, where it is converted to dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S). DHEA and DHEA-S pass to the placenta, where they are used for estrogen synthesis. Progesterone is converted to testosterone in the testes of the male fetus.

Human placental lactogen (hPL = human chorionic somatomammotropin, HCS) levels rise steadily during pregnancy. Like prolactin (!p. 303), hPL stimulates mammary enlargement and lactogenesis in particular and, like GH (!p. 280), stimulates physical growth and development in general. hPL also seems to increase maternal plasma glucose conc.

Corticotropin-releasing hormone (CRH) secreted by the placenta seems to play a key role in the hormonal regulation of birth. The plasma levels of maternal CRH increase exponentially from the 12th week of gestation on. This rise is more rapid in premature births and slower in post-term births. In other words, the rate at which the CRH concentration rises seems to determine the duration of the pregnancy. Placental CRH stimulates the release of ACTH by the fetal pituitary, resulting in increased cortisol production in the adult zone of FAC; this again stimulates the release of CRH (positive feedback). CRH also stimulates lung development and the production of DHEA and DHEA-S in the fetal zone of FAC.

The maternal estrogen conc. rises sharply towards the end of the pregnancy, thereby counteracting the actions of progesterone, including its pregnancy-sustaining effect. Estrogens induce oxytocin receptors (!p. 303), α1- adrenoceptors (!p. 84ff.), and gap junctions in the uterine musculature (!p. 16ff.), and uterine cells are depolarized. All these effects increase the responsiveness of the uterine musculature. The simultaneous increase in progesterone synthesis triggers the production of collagenases that soften the taut cervix. Stretch receptors in the uterus respond to the increase in size and movement of the fetus. Nerve fibers relay these signals to the hypothalamus, which responds by secreting larger quantities of oxytocin which, in turn, increases uterine contractions (positive feedback). The gap junctions conduct the spontaneous impulses from individual pacemaker cells in the fundus across the entire myometrium at a rate of approximately 2 cm/s (!p. 70).

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

A.Hormone synthesis in placenta, mother and fetus: fetoplacental unit

1Early pregnancy:

Proteohormone synthesis in placenta 2 Later pregnancy:

Steroid hormone synthesis in placenta

Mother

 

Child

Mother

 

Child

 

 

 

 

 

 

Placenta

 

 

 

 

Adrenal cortex

 

Adrenal cortex

 

 

 

 

 

 

Fetal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

zone

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cholesterol,

 

 

 

 

 

pregnenolone

 

 

hCG

 

 

DHEA

 

DHEA

 

 

 

 

 

 

(human chorionic

 

 

DHEA-S

 

DHEA-S

 

 

gonadotropin)

 

 

 

 

 

 

 

Corpus luteum

 

 

Fetal adrenal

 

 

 

 

 

of maternal

 

 

 

 

 

 

 

ovary

 

 

cortex (FAC)

 

 

 

 

 

 

 

 

 

 

E

 

 

 

E

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

P

E

P

 

DHEA

 

 

 

 

 

 

 

DHEA-S

 

 

 

 

 

Steroid hormones:

P = progesterone; DHEA(-S) = dehydroepiandrosterone (sulfate); E = estrogens

Plate 11.19 Hormonal Control of Pregnancy and Birth

B. Hormone concentrations in plasma during pregnancy

 

 

 

 

 

 

 

 

 

hCG

 

 

 

 

 

 

 

 

 

plasma

 

 

 

 

 

 

Estrogens (E)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

activity

in maternal

 

 

 

 

Progesterone (P)

 

 

CRH

 

 

 

 

 

 

 

 

 

 

 

 

 

Corpus luteum

Concentration

 

 

 

 

 

 

 

 

 

hPL

 

 

 

 

 

 

 

 

 

 

 

 

 

Week

4

8

12

16

20

24

28

32

36

40

305

Trimester

 

1

 

 

2

 

 

3

 

 

 

 

 

 

 

 

 

 

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

Androgens and Testicular Function

 

Androgens (male sex hormones) are steroid

 

hormones with 19 C atoms. This group in-

 

cludes potent hormones like testosterone (T)

 

and 5α-dihydrotestosterone (DHT) and less

 

potent 17-ketosteroids (17-KS) such as DHEA

 

(!p. 294). In males, up to 95% of testosterone

 

is synthesized by the testes (!A2) and 5% by

Reproduction

the adrenal cortex (!Al). The ovaries and

adrenal cortex synthesize testosterone in

 

 

females. The plasma testosterone conc. in

 

males is about 15 times higher than in females,

 

but decreases with age. Up to 98% of testos-

 

terone circulating in blood is bound to plasma

and

proteins (albumin and sex hormone-binding

globulin, SHBG; !A2).

Hormones

terone (via aromatase) by their respective target

 

The testes secrete also small quantities of DHT and

 

estradiol (E2). Larger quantities of DHT (via 5-α-re-

 

ductase) and estradiol are synthesized from testos-

11

cells. A portion of this supply is released into the

plasma. DHT and testosterone bind to the same in-

 

 

tracellular receptor. Estradiol influences many func-

 

tions in the male, e.g., epiphyseal cartilage and

 

ejaculate formation and pituitary and hypothalamic

 

activity.

 

Testosterone secretion is regulated by

 

luteinizing hormone (= LH, also called ICSH,

 

!p. 269), the pulsatile secretion of which is

 

controlled by Gn-RH at 1.5- to 2-hourly inter-

 

vals, as in the female. LH stimulates the release

 

of testosterone from Leydig’s cells (interstitial

 

cells) in the testes (!A2), whereas testos-

 

terone and estradiol inhibit LH and Gn-RH

 

secretion (negative feedback).

 

Gn-RH also induces the release of FSH,

 

which stimulates the secretion of inhibin and

 

induces the expression of androgen-binding

 

protein (ABP) in Sertoli cells of the testes

 

(!A3). Testosterone cannot induce spermato-

 

genesis without the help of ABP (see below).

 

FSH also induces the formation of LH receptors

 

in the interstitial cells of Leydig. Testosterone,

 

DHT, estradiol and inhibin inhibit the secretion

 

of FSH (negative feedback; !A). Activin, the

 

physiological significance of which is still un-

 

clear, inhibits FSH secretion.

 

Apart from the important effects of testos-

306

terone on male sexual differentiation, sper-

matogenesis and sperm growth as well as on

the functions of the genitalia, prostate and seminal vesicle (see below), testosterone also induces the secondary sex characteristics that occur in males around the time of puberty, i.e., body hair distribution, physique, laryngeal size (voice change), acne, etc. In addition, testosterone is necessary for normal sex drive (libido), procreative capacity (fertility) and coital capacity (potentia coeundi) in the male. Testosterone also stimulates hematopoiesis and has anabolic properties, leading to increased muscle mass in males. It also has central nervous effects and can influence behavior— e.g., cause aggressiveness.

Sexual development and differentiation. The genetic sex (!B) determines the development of the sex-specific gonads (gamete-producing glands). The germ cells (spermatogonia; see below) then migrate into the gonads. The somatic sex is female when the subsequent somatic sex development and sex differentiation occurs in the absence of testosterone (!C). Male development requires the presence of testosterone in both steps (!C) with or without the aid of additional factors (e.g., calcitonin gene-related peptide, CGRP?) in certain stages of development (e.g., descent of testes into scrotum). High conc. of testosterone, either natural or synthetic (anabolic steroids), lead to masculinization (virilization) of the female (!C).

Testicular function. Spermatogenesis occurs in several stages in the testes (target organ of testosterone) and produces sperm (spermatozoa) (! A3). Sperm are produced in the seminiferous tubules (total length, ca. 300 m), the epithelium of which consists of germ cells and Sertoli cells that support and nourish the spermatogenic cells. The seminiferous tubules are strictly separated from other testicular tissues by a blood–testis barrier. The testosterone required for sperm maturation and semen production (!p. 308) must be bound to andro- gen-binding protein (ABP) to cross the barrier.

Spermatogonia (!B) are primitive sex cells. At puberty, a spermatogonium divides mitotically to form two daughter cells. One of these is kept as a lifetime stem cell reservoir (in contrast to oogonia in the female; !p. 298). The other undergoes several divisions to form a primary spermatocyte. It undergoes a first meiotic division (MD1) to produce two secondary spermatocytes, each of which undergoes a second meiotic division (MD2), producing a total of four spermatids, which ultimately differentiate into spermatozoa. After MD1, the spermatocytes have a single (haploid) set of chromosomes.

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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A.Control and transport of androgenic hormones; effects of testosterone on the testes

Hypothalamus

 

ABP = Androgen-binding protein

 

 

 

 

T = Testosterone

 

 

E2 =Estradiol

CRH

 

SHBG = Sex hormone-binding

GnRH

globulin

Adrenal cortex

 

 

 

Seminiferous

tubule

 

 

 

ACTH

 

 

 

 

 

 

 

 

 

Anterior

1

 

 

 

 

LH

FSH

 

3

 

Activin

lobe of

 

 

Leydig

 

 

 

 

 

 

 

 

 

 

pituitary

 

 

 

 

2

 

 

 

Inhibin

 

Sertoli

 

 

 

cells

 

 

 

 

 

 

cell

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lumen

 

 

 

 

 

 

 

 

 

 

ABP

 

 

 

Androgens,

 

E2

 

 

T

 

T

 

 

T

ABP

 

 

SHBG

 

 

 

 

 

 

 

 

17-ketosteroids

 

 

 

 

 

Spermatogenesis

 

 

 

 

 

 

 

 

 

 

 

(DHEA, etc.)

 

 

 

 

 

 

 

 

 

 

E2

 

 

 

 

 

 

 

 

 

 

 

 

 

Blood

T

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sperma-

 

 

 

 

 

 

 

 

 

 

Spermatogonia

tozoa

B. Genetic sex determination

 

 

 

C. Effect of androgens on sexual

 

Oocytes

Primary

Spermatocytes

 

differentiation

 

 

 

 

 

 

 

 

 

 

X X

 

 

 

 

 

X Y

 

X X

 

Genetic

 

 

X Y

Female

Male

 

 

 

sex

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Oogenesis

Spermato-

 

 

 

 

 

 

 

 

 

 

 

 

genesis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ovary

Gonadal

Testis

 

X

X

Each with half set

X

Y

 

sex

 

 

 

 

 

 

 

of chromosomes

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ova

 

 

 

 

Sperm

 

 

 

 

 

 

 

 

 

 

(spermatids)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fertilization

 

 

 

 

 

 

Androgens

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X + X

 

 

X + Y

Female secondary

Somatic

Male secondary

 

 

 

 

 

 

 

 

 

 

 

 

 

 

sex differentiation

sex

sex differentiation

Genetic sex is female

Genetic sex is male

 

 

 

Androgens

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X X

 

 

 

 

 

X Y

 

 

 

 

 

 

 

 

 

Somatic cells

 

 

 

 

Female

Psychological

Male

 

 

 

 

 

 

 

sex

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X,Y = sex chromosomes

 

 

Androgen-related disorders

 

 

 

 

 

 

of female sex differentiation

 

 

Plate 11.20 Androgens and Testicular Function

307

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11 Hormones and Reproduction

308

Sexual Response, Intercourse and

Fertilization

Sexual response in the male (!A1). Impulses from tactile receptors on the skin in the genital region (especially the glans penis) and other parts of the body (erogenous areas) are transmitted to the erection center in the sacral spinal cord (S2–S4), which conducts them to parasympathetic neurons of the pelvic splanchnic nerves, thereby triggering sexual arousal. Sexual arousal is decisively influenced by stimulatory or inhibitory impulses from the brain triggered by sensual perceptions, imagination and other factors. Via nitric oxide (! p. 278), efferent impulses lead to dilatation of deep penile artery branches (helicine arteries) in the erectile body (corpus cavernosum), while the veins are compressed to restrict the drainage of blood. The resulting high pressure (!1000 mmHg) in the erectile body causes the penis to stiffen and rise (erection). The ejaculatory center in the spinal cord (L2 –L3) is activated when arousal reaches a certain threshold (!A2). Immediately prior to ejaculation, efferent sympathetic impulses trigger the partial evacuation of the prostate gland and the emission of semen from the vas deferens to the posterior part of the urethra. This triggers the ejaculation reflex and is accompanied by orgasm, the apex of sexual excitement. The effects of orgasm can be felt throughout the entire body, which is reflected by perspiration and an increase in respiratory rate, heart rate, blood pressure, and skeletal muscle tone. During ejaculation, the internal sphincter muscle closes off the urinary bladder while the vas deferens, seminal vesicles and bulbocavernous and ischiocavernous muscles contract rhythmically to propel the semen out of the urethra.

Semen. The fluid expelled during ejaculation (2–6 mL) contains 35–200 million sperm in a nutrient fluid (seminal plasma) composed of various substances, such as prostaglandins (from the prostate) that stimulate uterine contraction. Once semen enters the vagina during intercourse, the alkaline seminal plasma increase the vaginal pH to increase sperm motility. At least one sperm cell must reach the ovum for fertilization to occur.

Sexual response in the female (!A2). Due to impulses similar to those in the male, the erectile tissues of the clitoris and vestibule of the vagina engorge with blood during the erection phase. Sexual arousal triggers the release of secretions from glands in the labia minora and transudates from the vaginal wall, both of which lubricate the vagina, and the nipples become erect. On continued stimulation, afferent impulses are transmitted to the lumbar spinal cord, where sympathetic impulses trigger orgasm (climax). The vaginal walls contract rhythmically (orgasmic cuff), the vagina lengthens and widens, and the uterus becomes erect, thereby creating a space for the semen. The cervical os also widens and remains open for about a half an hour after orgasm. Uterine contractions begin shortly after orgasm (and are probably induced locally by oxytocin). Although the accompanying physical reactions are similar to those in the male (see above), there is a wide range of variation in the orgasmic phase of the female. Erection and orgasm are not essential for conception.

Fertilization. The fusion of sperm and egg usually occurs in the ampulla of the fallopian tube. Only a small percentage of the sperm expelled during ejaculation (1000–10 000 out of 107 to 108 sperm) reach the fallopian tubes (sperm ascension). To do so, the sperm must penetrate the mucous plug sealing the cervix, which also acts as a sperm reservoir for a few days. In the time required for them to reach the ampullary portion of the fallopian tube (about 5 hours), the sperm must undergo certain changes to be able to fertilize an ovum; this is referred to as capacitation (!p. 302).

After ovulation (!p. 298ff.) the ovum enters the tube to the uterus (oviduct) via the abdominal cavity. When a sperm makes contact with the egg (via chemotaxis), species-specific sperm-binding receptors on the ovum are exposed and the proteolytic enzyme acrosin is thereby activated (acrosomal reaction). Acrosin allows the sperm to penetrate the cells surrounding the egg (corona radiata). The sperm bind to receptors on the envelope surrounding the ovum (zona pellucida) and enters the egg. The membranes of both cells then fuse. The ovum now undergoes a second meiotic division, which concludes the act of fertilization. Rapid proteolytic changes in the receptors on the ovum (zona pellucida reaction) prevent other sperm from entering the egg. Fertilization usually takes place on the first day after intercourse and is only possible within 24 hours after ovulation.

Despopoulos, Color Atlas of Physiology © 2003 Thieme

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

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