Pharmacodynamics OHPC has progestogenic activity, some antimineralocorticoid activity, and no other important hormonal activity. Progestogenic activity OHPC, also known as 17α-hydroxyprogesterone<unk> , is closer to progesterone in terms of structure and pharmacology than most other progestins, and is essentially a pure progestogen – that is, a selective agonist of the progesterone receptor (PR) with minimal or no other hormonal activity. However, OHPC has improved pharmacokinetics compared to progesterone, namely a much longer duration with intramuscular injection in oil solution. Administered by intramuscular injection, the endometrial transformation dosage of OHPC per cycle is 250 to 500 mg, and the weekly substitution dosage of OHPC is 250 mg, while the effective dosage of OHPC in the menstrual delay test (Greenblatt) is 25 mg per week. An effective ovulation-inhibiting dosage of OHPC is 500 mg once per month by intramuscular injection. However, the dose of OHPC used in once-a-month combined injectable contraceptives is 250 mg, and this combination is effective for inhibition of ovulation similarly. For comparison, the dose of medroxyprogesterone acetate (MPA; 6α-methyl-17α-hydroxyprogesterone acetate), a close analogue of OHPC, used by intramuscular injection in microcrystalline aqueous suspension in once-a-month combined injectable contraceptives, is 25 mg. It has also been said that given by intramuscular injection, 250 mg OHPC in oil solution is equivalent in progestogenic potency to 50 mg medroxyprogesterone acetate in microcrystalline aqueous suspension. Although the elimination half-life of intramuscular OHPC in oil solution in non-pregnant women is about 8 days, the elimination half-life of intramuscular medroxyprogesterone acetate in microcrystalline aqueous suspension in women is around 50 days. OHPC is also to some degree less potent than the more closely related ester hydroxyprogesterone acetate (OHPA; 17α-hydroxyprogesterone acetate). 17α-Hydroxyprogesterone (OHP) has weak progestogenic activity, but C17α esterification results in higher progestogenic activity. Of a variety of different esters, the<unk>  (hexanoate) ester was found to have the strongest progestogenic activity, and this served as the basis for the development of OHPC, as well as other<unk>  progestogen esters such as gestonorone<unk> . OHPC is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high of affinity for the PR as progesterone. OHPC has about 26% and 30% of the affinity of progesterone for the human PR-A and PR-B, respectively. The medication was no more efficacious than progesterone in activating these receptors and eliciting associated gene expression in vitro. Antigonadotropic effects Due to activation of the PR, OHPC has antigonadotropic effects, or produces suppression of the hypothalamic–pituitary–gonadal axis, and can significantly suppress gonadotropin secretion and gonadal sex hormone production at sufficiently high doses. One study found that OHPC by intramuscular injection at a dosage of 200 mg twice weekly for the first two weeks and then 200 mg once weekly for 12 weeks did not significantly influence urinary excretion of estrogens, luteinizing hormone, or follicle-stimulating hormone in men with benign prostatic hyperplasia. In another study that used an unspecified dosage of intramuscular OHPC, testosterone secretion was assessed in a single man and was found to decrease from 4.2 mg/day to 2.0 mg/day (or by approximately 52%) by 6 weeks of treatment, whereas secretion of luteinizing hormone remained unchanged in the man. Yet another study found that 3,000 mg/week OHPC by intramuscular injection suppressed testosterone levels from 640 ng/dL to 320–370 ng/dL (by 42–50%) in a single man with prostate cancer, which was similar to the testosterone suppression with cyproterone acetate or chlormadinone acetate. Gestonorone<unk> , a closely related progestin to OHPC with about 5- to 10-fold greater potency in humans, was found to suppress testosterone levels by 75% at a dosage of 400 mg/week in men with prostate cancer. For comparison, orchiectomy decreased testosterone levels by 91%. In general, progestins are able to maximally suppress testosterone levels by about 70 to 80%. The antigonadotropic effects of OHPC and hence its testosterone suppression are the basis of the use of OHPC in the treatment of benign prostatic hyperplasia and prostate cancer in men. Suppression of luteinizing hormone levels by OHPC has also been observed in women. Glucocorticoid activity OHPC is said not to have any glucocorticoid activity. In accordance, OHPC has been found not to alter cortisol levels in humans even with very high doses by intramuscular injection. This is of relevance because medications with significant glucocorticoid activity suppress cortisol levels due to increased negative feedback on the hypothalamic–pituitary–adrenal axis. OHPC has been studied in humans at doses as high as 5,000 mg per week by intramuscular injection, with safety and without glucocorticoid effects observed. The medication does interact with the glucocorticoid receptor however; it has about 4% of the affinity of dexamethasone for the rabbit glucocorticoid receptor. But it acts as a partial agonist of the receptor and has no greater efficacy than progesterone in activating the receptor and eliciting associated gene expression in vitro. Other activities As a pure progestogen, OHPC has no androgenic, antiandrogenic, estrogenic, or glucocorticoid activity. The absence of androgenic and antiandrogenic activity with OHPC is in contrast to most other 17α-hydroxyprogesterone-derivative progestins. Due to its lack of androgenic properties, similarly to progesterone, OHPC does not have any teratogenic effects on the fetus, making it safe for use during pregnancy. Although OHPC has been described as a pure progestogen, there is evidence that it possesses some antimineralocorticoid activity, similarly to progesterone and 17α-hydroxyprogesterone. This includes clinically important diuretic effects and reversal of estrogen-induced fluid retention and edema. Unlike progesterone, OHPC and its metabolites are not anticipated to interact with non-genomic receptors such as membrane progesterone receptors or the GABAA receptor. In accordance, OHPC is not thought to possess the neurosteroid activities of progesterone or its associated sedative effects. In relation to cytochrome P450 enzymes, OHPC has no effect on CYP1A, CYP2D6, CYP2C9, or CYP3A4, but is a modest inducer of CYP2C19. Differences from progesterone There are pharmacodynamic differences between progesterone and OHPC, which may have implications for obstetrical use. These include: * Decreased myometrial activity with progesterone in vitro but no effect or increased myometrial activity with OHPC * Prevention of cervical ripening with progesterone but unknown effect with OHPC * A non-significantly increased rate of stillbirth and miscarriages with OHPC (in one study) * A possibly increased incidence of gestational diabetes with OHPC (increased in two studies, no difference in one study) but no such effect with progesterone * A significantly increased risk of perinatal adverse effects such as fetal loss and preterm delivery in multiple gestations with OHPC (in two studies) Differences in the metabolism of progesterone and OHPC and differences in the formation and activities of metabolites may be responsible for or involved in these observed biological and pharmacological differences. Progesterone is metabolized by 5α- and 5β-reductases, 3α- and 3β-hydroxysteroid dehydrogenases, and 20α- and 20β-hydroxysteroid dehydrogenase in various tissues. In target tissues, particularly the cervix and myometrium, these enzymes regulate local progesterone concentrations and can activate or inactivate progesterone signaling. In addition, these enzymes catalyze the formation of metabolites of progesterone such as 5β-dihydroprogesterone and allopregnanolone, which signal through their own non-genomic receptors such as membrane progesterone receptors and the GABAA receptor and have their own important effects in pregnancy. As examples, 5β-dihydroprogesterone has been found to play an important role in suppressing myometrial activity while allopregnanolone has potent sedative and anesthetic effects in the mother and especially the fetus and is involved in fetal nervous system development. In contrast to progesterone, OHPC is not metabolized by traditional steroid-transforming enzymes and instead is metabolized exclusively via oxidation at the<unk>  side chain by cytochrome P450 enzymes. As such, it is not thought to have the same tissue-specific activation and inactivation patterns that progesterone does nor the same non-genomic actions that progesterone and its metabolites possess. Further clinical research is anticipated to provide additional data to help clarify the issue of safety with OHPC. In any case, it has been recommended by the American College of Obstetricians and Gynecologists that pregnant women treated with OHPC receive counseling about its risks and benefits. Pharmacokinetics + Pharmacokinetics of OHPCa in pregnant women Parameter Singleton Twin (ng/mL) 22.6 (15.8–27.4) 17.3 (12–27) (ng/mL) 16.8 (12.8–22.7) 12.3 (8.4–18.7) (ng/mL) 14.1 (10–18.1) 11.2 (4.8–16.3) (ng/mL/day) 117.3 (89.9–159.1) 86.1 (59–131) (days) 16.2 (10.6–21.0) 10 (6–16) (days) 1.0 (1–3) 1.2 (1–2) (×103) (L) 56 (25.2–69.6) 16.9 (9.1–24.5) (×103) (L) 2.1 (1.5–2.7) 1.2 (0.9–1.7) Footnotes: a = OHPC 250 mg once per week by intramuscular injection. Sources: Absorption In animals, the bioavailability of OHPC with intramuscular injection is nearly 100%, but its oral bioavailability is very low at less than 3%. In women, 70 mg/day oral OHPC has similar endometrial potency as 70 mg/day oral OHPA and 2.5 mg/day oral medroxyprogesterone acetate, indicating that oral OHPC and OHPA have almost 30-fold lower potency than medroxyprogesterone acetate via oral administration. Studies on progestogenic endometrial changes with oral OHPC in women are mixed however, with one finding weak effects with 100 mg/day whereas another found that doses of 250 to 1,000 mg produced no effects. As a result of its low oral potency, OHPC has not been used by the oral route and has instead
Hydroxyprogesterone caproate
Hydroxyprogesterone heptanoate
Hydroxyprogesterone acetate
Estradiol enantate
Estradiol undecylate
Medroxyprogesterone acetate
Estradiol dienantate
Desoxymethyltestosterone