17-Hydroxyprogesterone
Encyclopedia
17-Hydroxyprogesterone (17-OH progesterone or 17OHP) is a C-21 steroid hormone
produced during the synthesis of glucocorticoid
s and sex steroid
s.
As a hormone, 17OHP also interacts with the progesterone receptor
.
via 17-hydroxylase, a P450c17 enzyme
, or from 17-hydroxypregnenolone
via 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase.
17-Hydroxyprogesterone is a natural progestogen, and in pregnancy increases in the third trimester primarily due to fetal adrenal production.
This hormone is primarily produced in the adrenal gland
s and to some degree in the gonad
s, specifically the corpus luteum
of the ovary
. Normal levels are 3-90 ng/dl in children, and in women, 20-100 ng/dl prior to ovulation
, and 100-500 ng/dl during the luteal phase
.
The use of 17-hydroxyprogesterone caproate in pregnancy to prevent preterm birth has a long history. A 2006 Cochrane Review concluded "...important maternal and infant outcomes have been poorly reported to date... information regarding the potential harms of progesterone therapy to prevent preterm birth is limited". There was a similar conclusion from a review by Marc Keirse. Three clinical studies of 250 mg/week of i.m. 17-hydroxyprogesterone caproate showed a trend for an increase in pregnancy loss due to miscarriage compared to placebo. There had been speculation that the castor oil in some 17-hydroxyprogesterone caproate formulations may not be beneficial for pregnancy.
In contrast, a large NIH study in 2003 looked at the effect of 17OHPC injections in women at risk for repeat premature birth and found that the treated group experienced premature birth in 37% versus 55% in the controls.
A follow-up study of the offspring showed no evidence that 17OHPC affected the children in the first years of life. Based on these NIH data, 17 OHPC was approved by the FDA in 2011 as a drug to reduce the risk of premature birth in selected patients at risk. (v.i.)
17-hydroxyprogesterone caproate is a category B drug according to the FDA.
as the typical enzymes that are defective, namely 21-hydroxylase
and 11β-hydroxylase, lead to a build-up of 17OHP. In contrast, the rare patient with 17α-hydroxylase deficiency will have very low or undetectable levels of 17OHP. 17OHP levels can also be used to measure contribution of progestational activity of the corpus luteum during pregnancy as progesterone but not 17OHP is also contributed by the placenta
.
as Makena, as an orphan drug
in February 2011 to reduce the risk of premature birth in women prior to 37 weeks gestation with a single fetus who had at least one previous premature birth. The drug is not effective in preventing premature birth in women with multiples. With the arrival of Makena as an orphan drug, the price of the drug was to increase from $15 to $1,500 per dose meaning a typical treatment would cost $25-30,000, - a pricing strategy that was strongly criticized. The FDA then announced that pharmacies could continue to compound the drug at their usual cost of $10~20 per dose without fear of legal reprisals., and KV reduced its price to $690 per dose.
s like RIA (radioimmunoassay
) or IRMA (immunoradiometric
assay) were used to clinically determine 17-Hydroxyprogesterone. Today more sophisticated methods use gas or liquid chromatography and mass spectrometry
(e.g. LC-MS/MS).
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
produced during the synthesis of glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s and sex steroid
Sex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
s.
As a hormone, 17OHP also interacts with the progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
.
Production
It is derived from progesteroneProgesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
via 17-hydroxylase, a P450c17 enzyme
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
, or from 17-hydroxypregnenolone
17-Hydroxypregnenolone
17-Hydroxypregnenolone , is a C21 steroid that is obtained by hydroxylation of pregnenolone at the C17α position. This step is performed by the mitochondrial cytochrome P450 enzyme 17α-hydroxylase that is present in the adrenal and gonads. Peak levels are reached in humans at the end of puberty...
via 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase.
17-Hydroxyprogesterone is a natural progestogen, and in pregnancy increases in the third trimester primarily due to fetal adrenal production.
This hormone is primarily produced in the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s and to some degree in the gonad
Gonad
The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries. The product, gametes, are haploid germ cells. For example, spermatozoon and egg cells are gametes...
s, specifically the corpus luteum
Corpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...
of the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
. Normal levels are 3-90 ng/dl in children, and in women, 20-100 ng/dl prior to ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
, and 100-500 ng/dl during the luteal phase
Luteal phase
The luteal phase is the latter phase of the menstrual cycle or the estrous cycle . It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis...
.
17-Hydroxyprogesterone caproate
17-Hydroxyprogesterone (17OHP) is not the same compound as 17-hydroxyprogesterone caproate (17OHPC), the latter being the caproic acid of 17-Hydroxyprogesterone that was first clinically introduced as an injectable version of the steroid under the name of Delalutin in 1956.The use of 17-hydroxyprogesterone caproate in pregnancy to prevent preterm birth has a long history. A 2006 Cochrane Review concluded "...important maternal and infant outcomes have been poorly reported to date... information regarding the potential harms of progesterone therapy to prevent preterm birth is limited". There was a similar conclusion from a review by Marc Keirse. Three clinical studies of 250 mg/week of i.m. 17-hydroxyprogesterone caproate showed a trend for an increase in pregnancy loss due to miscarriage compared to placebo. There had been speculation that the castor oil in some 17-hydroxyprogesterone caproate formulations may not be beneficial for pregnancy.
In contrast, a large NIH study in 2003 looked at the effect of 17OHPC injections in women at risk for repeat premature birth and found that the treated group experienced premature birth in 37% versus 55% in the controls.
A follow-up study of the offspring showed no evidence that 17OHPC affected the children in the first years of life. Based on these NIH data, 17 OHPC was approved by the FDA in 2011 as a drug to reduce the risk of premature birth in selected patients at risk. (v.i.)
17-hydroxyprogesterone caproate is a category B drug according to the FDA.
Measurement
Measurements of levels of 17-hydroxyprogesterone are useful in the evaluation of patients with suspected congenital adrenal hyperplasiaCongenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
as the typical enzymes that are defective, namely 21-hydroxylase
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency , in all its forms, accounts for over 95% of diagnosed cases of congenital adrenal hyperplasia, and "CAH" in most contexts refers to 21-hydroxylase deficiency...
and 11β-hydroxylase, lead to a build-up of 17OHP. In contrast, the rare patient with 17α-hydroxylase deficiency will have very low or undetectable levels of 17OHP. 17OHP levels can also be used to measure contribution of progestational activity of the corpus luteum during pregnancy as progesterone but not 17OHP is also contributed by the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
.
Medication
17OHPC was first introduced in 1956 as Delalutin to reduce pregnancy loss. After decades of use, Squibb, the manufacturer, voluntarily withdrew the brand, however, physicians continued to use 17OHPC "off label". Renewed interest was sparked with a large NIH-sponsored study in 2003 that found that 17OHPC reduced the risk of premature birth in selected at-risk pregnant women. With follow-up data showing no evidence of harmful effects on the offspring, the FDA approved the drug, as sponsored by KV PharmaceuticalKV Pharmaceutical
KV Pharmaceutical Company is an American drug company that brings generic and non-branded pharmaceutical products to the market. Headquartered in St...
as Makena, as an orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
in February 2011 to reduce the risk of premature birth in women prior to 37 weeks gestation with a single fetus who had at least one previous premature birth. The drug is not effective in preventing premature birth in women with multiples. With the arrival of Makena as an orphan drug, the price of the drug was to increase from $15 to $1,500 per dose meaning a typical treatment would cost $25-30,000, - a pricing strategy that was strongly criticized. The FDA then announced that pharmacies could continue to compound the drug at their usual cost of $10~20 per dose without fear of legal reprisals., and KV reduced its price to $690 per dose.
Determination
Earlier immunoassayImmunoassay
An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods...
s like RIA (radioimmunoassay
Radioimmunoassay
Radioimmunoassay is a very sensitive in vitro assay technique used to measure concentrations of antigens by use of antibodies...
) or IRMA (immunoradiometric
assay) were used to clinically determine 17-Hydroxyprogesterone. Today more sophisticated methods use gas or liquid chromatography and mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
(e.g. LC-MS/MS).