Supplemental Readings and References
801
Among these, combination pill is the most widely used
and is probably the most effective at > 99%, whereas the
mini pill is the least effective at ~95% because it does not
always prevent ovulation. The rationale for varying the
dose of progestin was that by reducing the total amount of
steroid, it would reduce the risk of myocardial infarction,
hypertension, and stroke, all of which were subsequently
shown not to be altered by varying the dose of progestin.
The rationale for the progestin only protocol was to elim-
inate the risk of endometrial cancer and breast cancer as-
sociated with estrogen; however, some of the health ben-
efits of estrogen (e.g., increased HDL, osteoprotection)
are eliminated and some side effects (e.g., breakthrough
bleeding) are introduced.
In women using the combination pill, the plasma lev-
els of LH, FSH, estradiol, and progesterone were found
to be greatly suppressed and unchanged throughout the
3 week period on the pill. Folliculogenesis did not occur
during treatment but there was no evidence of increased
atresia; when electing to bear a child, former pill users
experienced normal menstrual cyclicity, pregnancy, and
lactation. Long term observations indicated that pill users
experienced menopause within the normal age range, and
had no health problems that could be attributed to the long
term use of the pill, although recent epidemiological stud-
ies suggest that combination pill users may be at increased
risk of developing breast cancer prior to age 45.
Post-coital pharmacologic prevention of implantation
can be achieved by oral administration of a synthetic estro-
gen (25 mg diethylstilbestrol) twice daily for 5 days. This
“morning after pill” treatment stimulates fallopian tube
contractions during the period of conceptus travel toward
the uterus, such that the conceptus is propelled into the
uterus prematurely and is resorbed, or is trapped within
the fallopian tube because of spastic contraction of the
isthmus. Although effective, the high dose estrogen pro-
duces nausea, vomiting, and menstrual problems. Alter-
natively, oral administration of a combination pill (50 /xg
ethinylestradiol + 0.5 mg norgestrol), two tablets within
72 h post-coitum and two tablets 12 h later, is also ef-
fective and does not produce undesirable side effects.
This treatment does not involve an alteration in fallop-
ian tube activity but the treatment may serve to convert
the endometrium into a less receptive tissue for blastocyst
implantation.
Another post-coital treatment is the use of a proges-
terone antagonist, mifepristone (RU-486), which appar-
ently works by reversing the effects of progesterone on
the endometrium, and thereby interferes with implanta-
tion. Administration of the drug two days after the mid-
cycle LH surge prevents implantation by a direct effect
on the endometrium, and has no effect on the circulating
levels of gonadotropins or on luteal function.
Supplemental Readings and References
C. J. Bagatell and W. J. Bremner: Drug therapy: Androgens in men:
Uses and abuses.
New England Journal of Medicine
3 3 4 ,
707
(1996) .
S. Bhasin and W. J. Bremner: Clinical review 85: Emerging issues in
androgen replacement therapy.
Journal of Clinical Endocrinology and
Metabolism
8 2 , 3(1997).
S. Bhasin, T. W. Storer, N. Berman, and others: The effects of supraphysi-
ologic doses of testosterone on muscle size and strength in normal men.
New England Journal of Medicine
335, 1 (1996).
E. G. Biglieri: A prismatic case: 17o(-Hydroxylase deficiency: 1963-
1966.
Journal of Clinical Endocrinology and Metabolism
82, 48
(1997) .
B. C. J. M. Fauser and A. M. Van Heusden: Manipulation of human ovarian
function: physiological concepts and clinical consequences.
Endocrine
Review
18,71 (1997).
A. Gougeon: Regulation of ovarian follicular development in primates: facts
and hypotheses.
Endocrine Review
1 7 , 121(1996).
K. B. Horwitz: The molecular biology of RU486. Is there a role for an-
tiprogestins in the treatment of breast cancer?
Endocrine Review
1 3 , 146
(1992).
J. L. Jameson and A. N. Hollenberg: Regulation of chorionic gonadotropin
(hCG) gene expression.
Endocrine Review
1 4 , 203 (1993).
A. L. Kierszenbaum: Mammalian spermatogenesis
in vivo
and
in vitro',
a
partnership of spermatogenic and somatic cell lineages.
Endocrine Review
1 5 , 116(1994).
C. S. Kovacs and H. M. Kronenberg: Maternal-fetal calcium and bone
metabolism during pregnancy, puerperium, and lactation.
Endocrine
Review
18, 832 (1997).
R. A. Wild: Metabolic and cardiovascular issues in women with androgen
excess.
Endocrinologist
6 , 120 (1996).
J. D. Wilson: Androgen abuse by athletes
Endocrine Review
9, 181 (1988).
J. D. Wilson, J. E. Griffin, and D. W. Russell: Steroid 5a-reductase 2 defi-
ciency.
Endocrine Review
1 4 ,577 (1993).
M. D. Pisarska, S. A. Carson, and J. E. Buster: Ectopic Pregnancy.
The
Lancet
351, 1115 (1998).
D. T. Baird: Amenorrhoea.
The Lancet
350, 275 (1997).
F. Muscatelli, T. M. Strom, A. P. Walker, and others: Mutations
in the DAXC-1 gene give rise to both X-linked adrenal hypopla-
sia congenita and hypogonadtropic hypogonadism.
Nature
3 7 2 , 672
(1994).
A. Swain, V. Narvaez, P. Burgoyne, and others: Daxl antagonizes Sry in
mammalian sex determination.
Nature
3 9 1 , 761 (1998).
H. E. Maclean, G. L. Wame, and J. D. Zajact: Intersex disorders: shed-
ding light on male sexual differentiation beyond SRY.
Clinical Molecular
Endocrinology
4 6 , 101 (1997).
A. Glasier: Emergency postcoital contraception.
New England Journal of
Medicine
3 3 7 , 1058 (1997).
F. Muscatelli, T. M. Strom, A. P. Walker, et al.: Mutations in the DAXC-1
gene give rise to both X-linked adrenal hypoplasia congenita and hypog-
onado. tropic hypogonadism.
Nature
3 7 2 , 672 (1994).
A. Swain, V. Narvaez, P. Burgoyne, et al.: Daxl antagonizes Sry in mam-
malian sex determination.
Nature
3 9 1 ,761 (1998).
H. E. Maclean, G. L. Warne, and Zajact: Intersex disorders: shedding light on
male sexual differentiation beyond SRY.
Clinical Molecular Endocrinol-
ogy
4 6 , 101 (1997).
G. El-Hajj Fuleihan: Tissue-specific estrogens—the promise for the future.
New England Journal of Medicine
3 3 7 , 1686 (1997).
P. D. Delmas, N. H. Bjarnason, B. H. Mitlak, et al.: Effects of raloxifene on
bone mineral density, serum cholesterol concentrations, and uterine en-
dometrium in postmenopausal women.
New England Journal of Medicine
3 3 7 , 1641 (1997).
W. Khovidhunkit and D. M. Shoback: Clinical effects of raloxifene hy-
drochloride in women.
Annals of Internal Medicine
1 3 0 ,431 (1999).
