Medical Pharmacology

April 16, 2003

Doug Bayliss

HYPOTHALAMIC-PITUITARY-GONADAL AXIS
I. OVERVIEW
The major physiological function of this hormonal axis in both males and females is the development of
primary and secondary sexual characteristics, and the control of gametogenesis and reproduction. The
major uses of pharmacological agents that target this axis are:
• contraception
• treatment of infertility
• treatment of hormone-dependent disorders (e.g. prostate and breast cancer, endometriosis)
• hormone replacement
• to promote normal development and maintain normal structures (e.g., hypogonadism)
• to alleviate symptoms of menopause
• to arrest premature development (e.g., precocious puberty)

II. HORMONES AND DEVELOPMENT

The hypothalamic-pituitary-gonadal axis is active in males and females during three main periods of life: [1]
in the midtrimester of the fetal period; [2] early in the neonatal period; and [3] from puberty throughout the
reproductive years. During the fetal period, testosterone secretion is essential for sexual differentiation in
boys and elevated levels of FSH may contribute to folliculogenesis in girls. The increased activity in the
neonatal period results from the abrupt decrease in steroid levels at birth and the resultant disinhibition of the
hypothalamo-pituitary system. In both boys and girls, increased pulsatile release of GnRH occurs mostly at
night early in puberty; later, pulsatile release of GnRH occurs throughout the 24 hour day. The increased
GnRH release, along with enhanced pituitary responsiveness to GnRH triggers elevated gonadotropin
secretion, gonadal steroidogenesis and development of secondary sexual characteristics. In men, testosterone
levels peak following puberty, are maintained at those levels throughout adulthood and drop slightly in old
age. In women, ovulatory cycles begin and last until menopause, when ovarian function ceases.

MALES FEMALES
plasma gonadotropins

Schematic diagram of phases of male sexual behavior Pattern of gonadotropin secretion during different
as indicated by mean plasma testosterone level and stages of life in women. Secretory patterns of LH
sperm production at different phases of life. during waking (clear) and sleep (stippled).

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 Overview

III. HORMONAL CONTROL OF THE MENSTRUAL CYCLE

We will briefly consider the general mechanisms involved with hormonal control of the menstrual cycle as this
will illustrate many of the important features of the hypothalamic-pituitary-gonadal axis. Details regarding
individual hormonal components, cognate drugs and their uses will be provided later.
Follicular (Proliferative) Phase
By convention, menstruation marks the beginning of a cycle. Withdrawal of estrogen and progesterone at the
end of the previous cycle triggers menstruation and removes negative feedback at the hypothalamus and
pituitary, thereby increasing LH and FSH release in response to GnRH pulses. Higher concentrations of FSH
trigger the recruitment of a cohort of follicles to begin to grow and mature. Follicular cells multiply and express
steroidogenic enzymes that synthesize estrogen under the joint control of LH and FSH. Synthesis and release of
estrogen occurs predominantly from a single dominant follicle (Graafian follicle) around the mid-to-late follicular
phase. Estrogen acts throughout this phase to rebuild the endometrium that was shed during menses by
stimulating mitotic proliferation
and a thickening of the
endometrium. Estrogen induces
expression of progesterone
receptor in the endometrium,
preparing the cells to respond to
progesterone in the luteal phase.
Prolonged, elevated concentrations
of estrogen inhibit FSH secretion,
but together with rising
progesterone levels stimulate
further GnRH and LH secretion
through a positive feedback
mechanism. An LH (and FSH)
surge ensues, which triggers
follicular rupture and ovulation.
Luteal (Secretory) Phase
After ovulation, the luteinized
follicle (corpus luteum) responds
to LH by synthesizing large
amounts of progesterone (and
estrogen). Progesterone limits the
proliferative effects of estrogen on
the endometrium and triggers
differentiation and glandular
secretions that are necessary for
implantation of the blastocyst.
High levels of progesterone and
estrogen inhibit LH and FSH
secretion, whose levels decrease.
Average daily values of LH, FSH, estradiol (E2) and progesterone in plasma If the ovum is fertilized, hCG from
samples from women exhibiting normal 28-day menstrual cycles. Changes the blastocyst maintains luteal
in ovarian follicle and endometrium are depicted. Also shown are the function. If not, luteolysis occurs
pulsatile patterns of LH release at two points in the cycle. and steroid synthesis decreases,
the endometrium is shed and the
process begins again.

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 Overview

IV. PREVIEW OF HORMONES, MAJOR EFFECTS & THERAPEUTIC AGENTS

Hypothalamus
GnRH released in pulses from the hypothalamus stimulates LH and FSH release from the pituitary
• synthetic agonists of GnRH either mimic (gonadorelin) or inhibit (leuprolide, goserelin) effects of
GnRH. They are used in assisted fertility, to induce chemical castration (e.g. for treatment of breast
or prostate cancer and endometriosis) and to treat precocious puberty.
Pituitary
LH & FSH from the pituitary gonadotropes; hCG from the placenta stimulate gonadal development,
gametogenesis and gonadal steroid hormone synthesis
• preparations of human LH, FSH (menotropins) and hCG are obtained from the urine of menopausal
and pregnant women (recombinant forms may soon be available for use). They are used primarily in
the treatment of infertility.
Gonads
Estradiol and progesterone from ovaries and testosterone from testis are required for development and
maintenance of secondary sexual characteristics and for gametogenesis.
• Estrogens, estrogen receptor antagonists and estrogen synthesis inhibitors are available.
• natural and synthetic estrogens (e.g., ethinyl estradiol, estrone sulfate), as well as non-steroidal
estrogens may be used therapeutically, most commonly in contraceptive pills and in hormone
replacement therapy in postmenopausal women.
• antiestrogens in common use are estrogen receptor antagonists: clomiphene (for assisted
fertility) and tamoxifen (for prevention and treatment of breast cancer).
• synthesis (aromatase) inhibitors such as aminoglutethimide have been used in treatment of
breast cancer (as second-line therapy following tamoxifen). New aromatase inhibitors that are
far more potent and specific are now available (e.g., anastrozole, a.k.a. Arimidex).
• SERMs, such as raloxifene, to prevent osteoporosis and improve lipoprotein profiles in
postmenopausal women.
• A number of progestins have been developed. A receptor antagonist, mifepristone (RU 486), has
been available in Europe for the termination of pregnancy; it was recently approved in the U.S.
• agonists include natural and synthetic progestins (e.g., norgestrel, medroxyprogesterone
acetate, norethindrone). They are used alone or combined with estrogens in contraceptive
pills, and together with estrogens for hormone replacement in postmenopausal women.
• Androgen preparations, receptor antagonists and synthesis inhibitors are available.
• natural (testosterone in a transdermal patch) and synthetic androgens (e.g. testosterone
enanthate) are used principally to treat hypogonadism and delayed puberty; some are used by
athletes (e.g. stanozolol) in an attempt to enhance performance.
• receptor antagonists (e.g. flutamide) are used with GnRH analogs to treat prostate cancer.
• synthesis inhibitors that block testicular production of testosterone (e.g. ketoconazole) or inhibit
conversion of testosterone to its more active, 5α-dihyroxy metabolite (e.g. finasteride), are used
to treat prostatic hyperplasia.

Reading List
Katzung, Basic & Clinical Pharmacology, 6th Edition (Chapters 36,39)

Additional Reading
Goodman & Gilman’s, The Pharmacological Basis of Therapeutics, 9th edition (Chapters 55,57,58)
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 Overview

LIST OF DRUGS

GnRH Preparations
gonadorelin hydrochloride
leuprolide acetate, histrelin acetate, nafarelin acetate, goserelin acetate

Gonadotropin Preparations
Menotropins, also called human menopausal gonadotropins (hMG)
Urofollitropin
Human chorionic gonadotropin

Gonadal Steroid Preparations

Estrogens and Antiestrogens
Natural estrogens:
Synthetic steroidal estrogens:
estradiol esters:
conjugated estrogens:
alkyl estrogens:
Synthetic non-steroidal estrogens:
Antiestrogens:
receptor antagonists:
synthesis inhibitor:
Selective Estrogen Receptor Modulators (SERMs):
estradiol, estrone, estriol
estradiol valerate, estradiol cypionate
estrone sulfate, equilin sulfate
ethinyl estradiol, mestranol
diethylstilbestrol
clomiphene citrate, tamoxifen citrate
aminoglutethimide, anastrozole
raloxifene

Progestins and Antiprogestins

Natural Progestins: progesterone, 17α-hydroxyprogesterone
Synthetic Progestins (C21 deriv.): medroxyprogesterone acetate, hydroxyprogesterone caproate
Synthetic Progestins (C19 deriv.): norethindrone, norethynodrel
Gonanes norgestrel, norgestimate, desogestrel
Antiprogestins: mifepristone (RU 486)

Androgens and Antiandrogens

Natural Androgens:
Synthetic Androgens:
unmodified 17β β -esters: testosterone enanthate, testosterone propionate,
modified 17β β -esters:
17αα -alkyl compounds:
Antiandrogens:
receptor antagonists:
synthesis inhibitors:
5αα -reductase inhibitor:
α -dihydrotestosterone
testosterone, 5α
testosterone cypionate
methenolone acetate
danazol
cyproterone acetate, flutamide
ketoconazole, spironolactone
finasteride

N.B. only those given in bold are required