Page 688 - Basic _ Clinical Pharmacology ( PDFDrive )

674 SECTION VII Endocrine Drugs

development in women. The early extraction techniques were very and rhCG can be administered by subcutaneous or intramuscular
crude, requiring around 30 L of urine to manufacture enough injection.
hMG needed for a single treatment cycle. These initial prepara-
tions were also contaminated with other proteins; less than 5% of Pharmacodynamics
the proteins present were bioactive. The FSH-to-LH bioactivity
ratio of these early preparations was 1:1. As purity improved, The gonadotropins and hCG exert their effects through
it was necessary to add hCG in order to maintain this ratio of G protein-coupled receptors. LH and FSH have complex effects
bioactivity. on reproductive tissues in both sexes. In women, these effects
change over the time course of a menstrual cycle as a result of
B. Follicle-Stimulating Hormone a complex interplay among concentration-dependent effects of
Three forms of purified FSH are available. Urofollitropin, also the gonadotropins, cross-talk of LH, FSH, and gonadal steroids,
known as uFSH, is a purified preparation of human FSH extracted and the influence of other ovarian hormones. A coordinated
from the urine of postmenopausal women. Virtually all the LH pattern of FSH and LH secretion during the menstrual cycle
activity has been removed through a form of immuno-affinity (see Figure 40–1) is required for normal follicle development,
chromatography that uses anti-hCG antibodies. Urofollitropin ovulation, and pregnancy.
was withdrawn from the US market in 2015. Two recombinant During the first 8 weeks of pregnancy, the progesterone and
forms of FSH (rFSH) are also available: follitropin alfa and estrogen required to maintain pregnancy are produced by the
follitropin beta. The amino acid sequences of these two products ovarian corpus luteum. For the first few days after ovulation, the
are identical to that of human FSH. They differ from each other corpus luteum is maintained by maternal LH. However, as mater-
and urofollitropin in the composition of carbohydrate side chains. nal LH concentration falls owing to increasing concentrations of
The rFSH preparations have a shorter half-life than preparations progesterone and estrogen, the corpus luteum will continue to
derived from human urine but stimulate estrogen secretion at least function only if the role of maternal LH is taken over by hCG
as efficiently and, in some studies, more efficiently. Compared produced by syncytiotrophoblast cells in the placenta.
with urine derived gonadotropins, rFSH preparations have little
protein contamination, much less batch-to-batch variability, and Clinical Pharmacology
may cause less local tissue reaction. The rFSH preparations are
considerably more expensive. A. Ovulation Induction
The gonadotropins are used to induce follicle development and
ovulation in women with anovulation that is secondary to hypo-
C. Luteinizing Hormone gonadotropic hypogonadism, polycystic ovary syndrome, and
Lutropin alfa, the first and only recombinant form of human other causes. Because of the high cost of gonadotropins and the
LH, was introduced in the United States in 2004 but withdrawn need for close monitoring during their administration, they are
in 2012. When given by subcutaneous injection, it has a half-life generally reserved for anovulatory women who fail to respond
of about 10 hours. Lutropin has only been approved for use in to other less complicated forms of treatment (eg, clomiphene;
combination with follitropin alfa for stimulation of follicular see Chapter 40). Gonadotropins are also used for controlled ovar-
development in infertile hypogonadotropic hypogonadal women ian stimulation in assisted reproductive technology procedures.
with profound LH deficiency (<1.2 IU/L). Lutropin alfa with Currently, a number of different protocols use gonadotropins in
follitropin alfa may also be of benefit in certain subgroups of nor- ovulation induction and controlled ovulation stimulation, and
mogonadotropic women (eg, those with an inadequate response new protocols are continually being developed to improve the
to prior follitropin alfa monotherapy). It has not been approved rates of success and to decrease the two primary risks of ovulation
for use with the other preparations of FSH or for induction of induction: multiple pregnancies and the ovarian hyperstimula-
ovulation. tion syndrome (OHSS; see below).
Although the details differ, all of these protocols are based
D. Human Chorionic Gonadotropin on the complex physiology that underlies a normal menstrual
Human chorionic gonadotropin is produced by the human cycle. Like a menstrual cycle, controlled ovulation stimulation
placenta and excreted into the urine, whence it can be extracted is discussed in relation to a cycle that begins on the first day of
and purified. It is a glycoprotein consisting of a 92-amino-acid a menstrual bleed (Figure 37–3). Shortly after the first day (usu-
α subunit virtually identical to that of FSH, LH, and TSH, and ally on day 2), daily injections with one of the FSH preparations
a β subunit of 145 amino acids that resembles that of LH except (hMG, urofollitropin, or rFSH) are begun and continued for
for the presence of a carboxyl terminal sequence of 30 amino acids approximately 8–12 days. In women with hypogonadotropic
not present in LH. Choriogonadotropin alfa (rhCG) is a recom- hypogonadism, follicle development requires treatment with
binant form of hCG. Because of its greater consistency in biologic a combination of FSH and LH because these women do not
activity, rhCG is packaged and dosed on the basis of weight rather produce the basal level of LH that is required for normal follicle
than units of activity. All of the other gonadotropins, including development. The dose and duration of gonadotropin treatment
rFSH, are packaged and dosed on the basis of units of activity. are based on the response as measured by the serum estradiol
Both the hCG preparation that is purified from human urine concentration and by ultrasound evaluation of ovarian follicle