Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 25The Gonads: Development & Function of the Reproductive System 419

cortex. About 2% of the circulating progesterone is free (Table
25–5), whereas 80% is bound to albumin and 18% is bound to
corticosteroid-binding globulin. Progesterone has a short
half-life and is converted in the liver to pregnanediol, which is
conjugated to glucuronic acid and excreted in the urine.

Secretion

In men, the plasma progesterone level is approximately 0.3 ng/mL
(1 nmol/L). In women, the level is approximately 0.9 ng/mL
(3 nmol/L) during the follicular phase of the menstrual cycle
(Figure 25–25). The difference is due to secretion of small
amounts of progesterone by cells in the ovarian follicles; theca
cells provide pregnenolone to the granulosa cells, which con-
vert it to progesterone. Late in the follicular phase, progester-
one secretion begins to increase. During the luteal phase, the
corpus luteum produces large quantities of progesterone
(Table 25–7) and plasma progesterone is markedly increased
to a peak value of approximately 18 ng/mL (60 nmol/L).
The stimulating effect of LH on progesterone secretion by the
corpus luteum is due to activation of adenylyl cyclase and
involves a subsequent step that is dependent on protein synthesis.

Actions

The principal target organs of progesterone are the uterus, the

breasts, and the brain. Progesterone is responsible for the

progestational changes in the endometrium and the cyclic

changes in the cervix and vagina described above. It has an

antiestrogenic effect on the myometrial cells, decreasing their

excitability, their sensitivity to oxytocin, and their spontaneous

electrical activity while increasing their membrane poten-

tial. It also decreases the number of estrogen receptors in the

endometrium and increases the rate of conversion of 17β-

estradiol to less active estrogens.

In the breast, progesterone stimulates the development of

lobules and alveoli. It induces differentiation of estrogen-pre-

pared ductal tissue and supports the secretory function of the

breast during lactation.

The feedback effects of progesterone are complex and are

exerted at both the hypothalamic and pituitary levels. Large

doses of progesterone inhibit LH secretion and potentiate the

inhibitory effect of estrogens, preventing ovulation.

Progesterone is thermogenic and is probably responsible for

the rise in basal body temperature at the time of ovulation. It

stimulates respiration, and the alveolar PCO 2 (see Chapter

35) in women during the luteal phase of the menstrual cycle is

lower than that in men. In pregnancy, the PCO 2 falls as

progesterone secretion rises. However, the physiologic signifi-

cance of this respiratory response is unknown.

Large doses of progesterone produce natriuresis, probably

by blocking the action of aldosterone on the kidney. The hor-

mone does not have a significant anabolic effect.

Mechanism of Action

The effects of progesterone, like those of other steroids, are

brought about by an action on DNA to initiate synthesis of new

mRNA. The progesterone receptor is bound to a heat shock

protein in the absence of the steroid, and progesterone binding

releases the heat shock protein, exposing the DNA-binding do-

main of the receptor. The synthetic steroid mifepristone (RU

486) binds to the receptor but does not release the heat shock

protein, and it blocks the binding of progesterone. Because the

maintenance of early pregnancy depends on the stimulatory ef-

fect of progesterone on endometrial growth and its inhibition of

uterine contractility, mifepristone combined with a prostaglan-

din can be used to produce elective abortions.

There are two isoforms of the progesterone receptor—PRA

and PRB—that are produced by differential processing from a

single gene. PRA is a truncated form, but it is likely that both

isoforms mediate unique subsets of progesterone action.

Substances that mimic the action of progesterone are some-

times called progestational agents, gestagens, or progestins.

They are used along with synthetic estrogens as oral contra-

ceptive agents.

FIGURE 25–29 Biosynthesis of progesterone and major
pathway for its metabolism. Other metabolites are also formed.

HO

HO

CH 3

C O

Cholesterol

Sodium pregnanediol-20-glucuronide

Pregnenolone

CH 3

CHOH

Pregnanediol

O

CH 3

C O

Progesterone