Page 746 - Basic _ Clinical Pharmacology ( PDFDrive )

732 SECTION VII Endocrine Drugs

OTHER OVARIAN HORMONES ■ HORMONAL CONTRACEPTION

The normal ovary produces small amounts of androgens, (ORAL, PARENTERAL, &
including testosterone, androstenedione, and dehydroepian- IMPLANTED CONTRACEPTIVES)
drosterone. Of these, only testosterone has a significant amount
of biologic activity, although androstenedione can be converted A large number of oral contraceptives containing estrogens or pro-
to testosterone or estrone in peripheral tissues. The normal gestins (or both) are now available for clinical use (Table 40–3).
woman produces less than 200 mcg of testosterone in 24 hours, These preparations vary chemically and pharmacologically and
and about one-third of this is probably formed in the ovary have many properties in common as well as definite differences
directly. The physiologic significance of these small amounts of important for the correct selection of the optimum agent.
androgens is not established, but they may be partly responsible Two types of preparations are used for oral contraception:
for normal hair growth at puberty, for stimulation of female (1) combinations of estrogens and progestins and (2) continuous
libido, and, possibly, for metabolic effects. Androgen produc- progestin therapy without concomitant administration of estrogens.
tion by the ovary may be markedly increased in some abnormal The combination agents are further divided into monophasic
states, usually in association with hirsutism and amenorrhea as forms (constant dosage of both components during the cycle) and
noted above. biphasic or triphasic forms (dosage of one or both components
The ovary also produces inhibin and activin. These pep- is changed once or twice during the cycle). The preparations for
tides consist of several combinations of α and β subunits and oral use are all adequately absorbed, and in combination prepara-
are described in greater detail later. The αβ dimer (inhibin) tions the pharmacokinetics of neither drug is significantly altered
inhibits FSH secretion while the ββ dimer (activin) increases by the other.
FSH secretion. Studies in primates indicate that inhibin has Only one implantable contraceptive preparation is available
no direct effect on ovarian steroidogenesis but that activin at present in the USA. Etonogestrel, also used in some oral con-
modulates the response to LH and FSH. For example, simul- traceptives, is available in the subcutaneous implant form listed
taneous treatment with activin and human FSH enhances in Table 40–3. Several hormonal contraceptives are available as
FSH stimulation of progesterone synthesis and aromatase vaginal rings or intrauterine devices. Intramuscular injection of
activity in granulosa cells. When combined with LH, activin large doses of medroxyprogesterone also provides contraception
suppressed the LH-induced progesterone response by 50% of long duration.
but markedly enhanced basal and LH-stimulated aromatase
activity. Activin may also act as a growth factor in other tis- Pharmacologic Effects
sues. The physiologic roles of these modulators are not fully
understood. A. Mechanism of Action
Relaxin is another peptide that can be extracted from the The combinations of estrogens and progestins exert their con-
ovary. The three-dimensional structure of relaxin is related to that traceptive effect largely through selective inhibition of pituitary
of growth-promoting peptides and is similar to that of insulin. function that results in inhibition of ovulation. The combination
Although the amino acid sequence differs from that of insulin, this agents also produce a change in the cervical mucus, in the uterine
hormone, like insulin, consists of two chains linked by disulfide endometrium, and in motility and secretion in the uterine tubes,
bonds, cleaved from a prohormone. It is found in the ovary, pla- all of which decrease the likelihood of conception and implanta-
centa, uterus, and blood. Relaxin synthesis has been demonstrated tion. The continuous use of progestins alone does not always
in luteinized granulosa cells of the corpus luteum. It has been inhibit ovulation. The other factors mentioned, therefore, play a
shown to increase glycogen synthesis and water uptake by the major role in the prevention of pregnancy when these agents are
myometrium and to decrease uterine contractility. In some spe- used.
cies, it changes the mechanical properties of the cervix and pubic
ligaments, facilitating delivery. B. Effects on the Ovary
In women, relaxin has been measured by immunoassay. Chronic use of combination agents depresses ovarian function.
Levels were highest immediately after the LH surge and during Follicular development is minimal, and corpora lutea, larger fol-
menstruation. A physiologic role for this peptide has not been licles, stromal edema, and other morphologic features normally
established. seen in ovulating women are absent. The ovaries usually become
Clinical trials with relaxin have been conducted in patients smaller even if enlarged before therapy.
with dysmenorrhea. Relaxin has also been administered to patients The great majority of patients return to normal menstrual
in premature labor and during prolonged labor. When applied to patterns when these drugs are discontinued. About 75% will
the cervix of a woman at term, it facilitates dilation and shortens ovulate in the first posttreatment cycle and 97% by the third
labor. posttreatment cycle. About 2% of patients remain amenor-
Several other nonsteroidal substances such as corticotropin- rheic for periods of up to several years after administration is
releasing hormone, follistatin, and prostaglandins are produced stopped.
by the ovary. These probably have paracrine effects within the The cytologic findings on vaginal smears vary depending on
ovary. the preparation used. However, with almost all of the combined