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Pharmacodynamics of progesterone

December 15, 2023

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.[1][2]

Progesterone is a naturally occurring and bioidentical progestogen, or an agonist of the progesterone receptor, the biological target of progestogens like endogenous progesterone.[1] Progesterone also has antimineralocorticoid and inhibitory neurosteroid activity, whereas it appears to have little or no glucocorticoid or antiandrogenic activity and has no androgenic activity.[1] Because of its progestogenic activity, progesterone has functional antiestrogenic effects in certain tissues such as the uterus, cervix, and vagina.[1] In addition, progesterone has antigonadotropic effects due to its progestogenic activity and can inhibit fertility and suppress sex hormone production.[1] Progesterone differs from progestins (synthetic progestogens) like medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety.[1]

Progesterone can be taken by mouth, in through the vagina, and by injection into muscle or fat, among other routes.[1] A progesterone vaginal ring and progesterone intrauterine device are also available as pharmaceutical products.[3][4]

Mechanism of action edit

See also: Progesterone § Biological activity, and Progestin § Pharmacology

Progesterone is a progestogen, or an agonist of the nuclear progesterone receptors (PRs), the PR-A, PR-B, and PR-C.[1] In one study, progesterone showed EC50 values of 7.7 nM for the human PR-A and 8.0 nM for the human PR-B.[5] In addition to the PRs, progesterone is an agonist of the membrane progesterone receptors (mPRs), including the mPRα, mPRβ, mPRγ, mPRδ, and mPRϵ.[6][7] It is also a potent antimineralocorticoid (antagonist of the mineralocorticoid receptor (MR)),[8][9] as well as a very weak glucocorticoid (agonist of the glucocorticoid receptor).[10][11] Progesterone does not interact significantly with the androgen receptor (AR) or with the estrogen receptor (ER).[1] In addition to its activity as a steroid hormone, progesterone is a neurosteroid.[12] Specifically, it is an antagonist of the sigma σ1 receptor,[13][14] a negative allosteric modulator of nicotinic acetylcholine receptors,[12] and, via its active metabolites allopregnanolone and pregnanolone, a potent positive allosteric modulator of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[15]

Relative affinities (%) of progesterone
Compound PR AR ER GR MR SHBG CBG
Progesterone 50 0 0 10 100 0 36
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG. Sources: [1]
Parenteral potencies and durations of progestogens[a][b]
Compound Form Dose for specific uses (mg)[c] DOA[d]
TFD[e] POICD[f] CICD[g]
Algestone acetophenide Oil soln. - – 75–150 14–32 d
Gestonorone caproate Oil soln. 25–50 – – 8–13 d
Hydroxyprogest. acetate[h] Aq. susp. 350 – – 9–16 d
Hydroxyprogest. caproate Oil soln. 250–500[i] – 250–500 5–21 d
Medroxyprog. acetate Aq. susp. 50–100 150 25 14–50+ d
Megestrol acetate Aq. susp. - – 25 >14 d
Norethisterone enanthate Oil soln. 100–200 200 50 11–52 d
Progesterone Oil soln. 200[i] – – 2–6 d
Aq. soln. ? – – 1–2 d
Aq. susp. 50–200 – – 7–14 d
Notes and sources:
  1. ^ Sources: [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]
  2. ^ All given by intramuscular or subcutaneous injection.
  3. ^ Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OID of OHPC is 250 to 500 mg/month.
  4. ^ Duration of action in days.
  5. ^ Usually given for 14 days.
  6. ^ Usually dosed every two to three months.
  7. ^ Usually dosed once monthly.
  8. ^ Never marketed or approved by this route.
  9. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Antimineralocorticoid activity edit

Progesterone is a potent antimineralocorticoid.[8][9][35] It has 1000% of the affinity of aldosterone, the major endogenous agonist, for the human MR, and 100% of the affinity of aldosterone for the rat MR.[36][1][8] Progesterone produces antimineralocorticoid effects such as natriuresis (excretion of sodium in the urine) at normal physiological concentrations.[9] A 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of the potent antimineralocorticoid spironolactone, which itself is a derivative of progesterone.[37] Doses of progesterone of 50 to 200 mg by intramuscular injection, which are similar to progesterone exposure in the third trimester of pregnancy, have also been reported to produce antimineralocorticoid-like effects.[35] The antimineralocorticoid effects of progesterone underlie its ability to lower blood pressure and reduce water and salt retention and its potential application in the treatment of hypertension.[38][1][39][35] An active metabolite of progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone), is a precursor of aldosterone and has strong mineralocorticoid activity (i.e., is a strong agonist of the MR).[37] However, it is formed in relatively small amounts, and any such effects produced by it are usually outweighed by the antimineralocorticoid activity of progesterone.[37] Progesterone may be a relatively weak antimineralocorticoid in vivo.[40]

Glucocorticoid activity edit

Progesterone is a partial agonist of the glucocorticoid receptor (GR).[1][10][11][41][42] It has about 35% of the affinity of dexamethasone, a corticosteroid, for the human GR, and about 3 to 11% of the affinity of dexamethasone for the rat GR.[36] However, progesterone appears to show weak or no glucocorticoid activity and no antiglucocorticoid activity in vitro and in animals.[42] Nonetheless, progesterone has been found to upregulate the thrombin receptor in vascular smooth muscle cells in vitro, a glucocorticoid effect, and this could have clinical relevance in relation to risk of blood clots.[1][43]

Glucocorticoid activity of selected steroids in vitro
Steroid Class TR (↑)a GR (%)b
Dexamethasone Corticosteroid ++ 100
Ethinylestradiol Estrogen – 0
Etonogestrel Progestin + 14
Gestodene Progestin + 27
Levonorgestrel Progestin – 1
Medroxyprogesterone acetate Progestin + 29
Norethisterone Progestin – 0
Norgestimate Progestin – 1
Progesterone Progestogen + 10
Footnotes: a = Thrombin receptor (TR) upregulation (↑) in vascular smooth muscle cells (VSMCs). b = RBA (%) for the glucocorticoid receptor (GR). Strength: – = No effect. + = Pronounced effect. ++ = Strong effect. Sources: [44]

Androgenic and antiandrogenic activity edit

The binding and activity of progesterone at the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT) in the body, is controversial.[45] Some studies have found progesterone to bind to the AR, with agonistic and antagonistic activity exerted, whereas other studies have found very low or no affinity for the AR at all.[45] In animal studies, no androgenic effects have been observed, but weak antiandrogenic effects have been reported.[45] The weak antiandrogenic activity has been attributed not to antagonism of the AR by progesterone, but rather to its weak 5α-reductase inhibition and consequent inhibition of the conversion of testosterone into the more potent DHT.[45] There is no clinical evidence of AR-mediated androgenic or antiandrogenic activity with progesterone.[45] Progesterone has not been associated with any classical androgenic effects in clinical studies in women, including no changes in the blood lipid profile or sex hormone-binding globulin levels, acne, oily skin, hirsutism, or voice deepening, nor with virilization of female fetuses.[46][47][48][49][50] As such, the scientific consensus is that progesterone is clinically neither androgenic nor antiandrogenic.[1][51][52] This is in contrast to many progestins, such as 19-nortestosterone derivatives (e.g., norethisterone, levonorgestrel, dienogest) and 17α-hydroxyprogesterone derivatives (e.g., cyproterone acetate, medroxyprogesterone acetate), which do bind to the AR and have been associated with significant androgenic or antiandrogenic effects depending on the progestin in question.[1][52] Due to its lack of androgenic and antiandrogenic activity, and hence lack of masculinizing and feminizing effects, progesterone is one of the few progestogens that is suitable for use during pregnancy in women at risk for preterm birth or recurrent miscarriage.[53][54]

 
Steroidogenesis, showing progesterone as an intermediate in the biosynthesis of the androgens.[55]

Although progesterone does not have significant AR-mediated androgenic or antiandrogenic activity, it is a precursor and intermediate, albeit distant, in the biosynthesis of androgens from cholesterol.[55][56] For this reason, there has been some speculation that exogenous progesterone could be transformed into androgens by certain tissues that express the requisite enzymes.[56][57] Progesterone is converted by 17α-hydroxylase into 17α-hydroxyprogesterone; 17α-hydroxyprogesterone is converted by 17,20-lyase into androstenedione; and androstenedione is converted by 17β-hydroxysteroid dehydrogenases into testosterone.[55] CYP17A1, the cytochrome P450 gene that encodes 17α-hydroxylase and 17,20-lyase, is expressed mainly in the gonads (ovaries and testes) and the adrenal glands.[58] However, while it is theoretically possible that progesterone could be transformed in the body into androgens, no androgenic effects have been observed in animal studies.[45] In addition, clinical studies, in which women were treated with 100 to 300 mg/day oral progesterone, have found no or only a small increase in levels of 17α-hydroxyprogesterone, and no change in androgen levels, including of dehydroepiandrosterone, androstenedione, and testosterone.[50][59][46] In these studies, levels of estradiol and cortisol, which progesterone is also a precursor of, did not change either, although levels of 11-deoxycorticosterone increased significantly.[59][46] Levels of androgens, like testosterone and dihydrotestosterone (DHT), also do not increase going from the follicular phase to the luteal phase of the menstrual cycle in premenopausal women (progesterone levels being high in the luteal phase).[60]

5α-Reductase inhibition edit

Progesterone is a substrate for 5α-reductase, and has been found to act as a competitive inhibitor of this enzyme in vitro in a variety of studies.[1] In one study, it showed IC50 values of 1,375 nM and 88 nM (in the presence of 50 nM androstenedione as the substrate) for 5α-reductase types 1 and 2, respectively.[61] 5α-Reductase is highly expressed in skin, hair follicles, and prostate gland, and is responsible for the transformation of testosterone into the several-fold more potent androgen DHT in such tissues.[62][63] As such, it has been suggested that progesterone might possess some antiandrogenic effect via acting as a 5α-reductase inhibitor.[1] However, inhibition of 5α-reductase by progesterone is described as a weak effect that has only been demonstrated in vitro and at supraphysiological concentrations.[64][65] In accordance, physiological levels of circulating progesterone have not been found to importantly influence circulating DHT concentrations.[60][66]

Congenital 5α-reductase 2 deficiency is a rare intersex condition which is associated with ambiguous genitalia in male fetuses due to a deficiency in DHT production during genital differentiation.[63] Experimental prenatal exposure to established 5α-reductase inhibitors like finasteride has been found to produce similar feminized genital defects in male animals including rodents and monkeys.[67] In contrast, exogenous administration of progesterone to pregnant rodents and monkeys has resulted in minimal abnormality in either male or female pups.[68][69][70][71] In addition, endogenous progesterone levels naturally increase to extremely high concentrations during pregnancy, yet genital defects do not occur.[72] In accordance, while total concentrations of progesterone in pregnant women at term are around 150 ng/mL (~500 nM), free or unbound and hence bioactive concentrations of progesterone are only about 3 ng/mL (~10 nM) due to the high plasma protein binding of progesterone, and these concentrations are still well below the aforementioned IC50 values for inhibition of 5α-reductase types 1 and 2.[73][74] As with endogenous progesterone during pregnancy, exogenous supplemental progesterone during pregnancy has been found not to increase the risk of hypospadias in male infants.[75]

Although systemic progesterone does not appear to be an effective 5α-reductase inhibitor, topical progesterone may produce potent inhibition of 5α-reductase in the skin due to the very high local concentrations that occur.[76][77] A study found that topical progesterone applied to the pubic area in men inhibited 5α-reductase in the skin in this region by 75%.[77][78] In addition to inhibition of 5α-reductase, progesterone is metabolized by 5α-reductase into 5α-dihydroprogesterone (5α-DHP), a compound reported to have some antagonistic activity at the AR.[78][79] However, this compound appears to have no systemic antiandrogenic activity.[80] In spite of its apparent 5α-reductase inhibition, the effectiveness of topical progesterone in the treatment of pattern hair loss has been poor.[79][81][82]

Other activity edit

Certain progestins have been found to stimulate the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[83] Progesterone, nomegestrol acetate, and chlormadinone acetate act neutrally and do not stimulate proliferation, whereas norethisterone, desogestrel, levonorgestrel, and drospirenone strongly stimulate proliferation and medroxyprogesterone acetate, dienogest, and dydrogesterone weakly stimulate proliferation.[83][84] As such, progesterone differs from some but not all progestins in the activity mediating this PGRMC1-dependent effect.[83] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies.[85]

Effects in the body and brain edit

See also: Progesterone § Biological function, and Progestogen § Biological function

The PRs are expressed widely throughout the body, including in the uterus, cervix, vagina, fallopian tubes, breasts, fat, skin, pituitary gland, hypothalamus, and elsewhere throughout the brain.[1][86] Through activation of the PRs (as well as the mPRs), progesterone has many effects, including the following:[1][86]

Many of the effects of progesterone require estrogen, as estrogens prime tissues for progesterone by inducing expression of the PRs.[1][86] The PRs are induced in the breasts by estrogens, and for this reason, it is assumed that progestogens cannot mediate breast changes in the absence of estrogens.[101]

Progesterone also lowers blood pressure and reduces water and salt retention among other effects via its antimineralocorticoid activity.[1][39]

Progesterone can produce sedative, hypnotic, anxiolytic, euphoric, cognitive-, memory-, and motor-impairing, anticonvulsant, and even anesthetic effects via formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain.[38][102][103][104]

Uterine effects edit

Under normal physiological circumstances, progesterone secreted by the corpus luteum during the luteal phase of the menstrual cycle produces endometrial transformation of the estrogen-primed uterus in preparation for implantation and pregnancy.[105] Normal progesterone production during the luteal phase is 25 mg/day on average with a range of 15 to 50 mg/day.[106][71] Progesterone levels during the luteal phase range from 7 ng/mL to 22 ng/mL using liquid chromatography–tandem mass spectrometry (LC–MS/MS) per one source.[107] Sustained progesterone levels of more than 5 ng/mL, perhaps approximately 10 ng/mL, are required for full endometrial transformation.[87][108] Progesterone levels of more than 10 ng/mL are rarely associated with luteal-phase defect on the basis of endometrial biopsy.[109]

Luteal-phase levels of progesterone are said to be produced by 25 mg/day progesterone in oil solution by intramuscular injection or by 100 mg/day progesterone by vaginal or rectal administration.[71][110] Progesterone by intramuscular injection in oil solution has been found to produce endometrial transformation at a dose of 10 or 20 mg/day for 14 days (total dose per cycle of 200 mg), whereas a single intramuscular injection of 200 mg progesterone in microcrystalline aqueous suspension provides endometrial transformation after 10 to 14 days.[111] A study found full and equivalent endometrial transformation with subcutaneous injection of 25 mg/day versus 50 mg/day progesterone in aqueous solution.[112] Due to a uterine first-pass effect and markedly higher uterine progesterone levels than with other routes, 45 mg/day vaginal progesterone, a dosage that achieves circulating progesterone levels of only 1 to 5 ng/mL, provides complete endometrial transformation.[113][110] Conversely, intranasal administration of progesterone achieving progesterone levels of 2 to 5 ng/mL was ineffective.[113] Transdermal progesterone achieves very low progesterone levels and is considered to be ineffective for endometrial protection.[113][114][115]

The endometrial transformation dosage of oral micronized progesterone in women has been listed as 200 to 300 mg/day or 4,200 mg total per cycle.[116][1] However, a clinical study found that 300 mg/day oral micronized progesterone was insufficient for full endometrial transformation.[117] Similarly, 600 to 1,000 mg/day oral micronized progesterone has been reported to be ineffective for achieving complete endometrial transformation.[113][112] Despite inadequate endometrial transformation with oral progesterone, continuous 100 mg/day oral micronized progesterone or cyclic 200 mg/day oral micronized progesterone is effective for protection of the endometrium against estrogen-induced endometrial hyperplasia.[118] On the other hand, and in contrast to progestins, typical clinical doses of oral micronized progesterone have been associated with failure to prevent increased endometrial cancer risk caused by estrogen therapy.[119]

Antiestrogenic effects edit

Progesterone, like all progestogens, has antiestrogenic effects in certain tissues such as the uterus, cervix, vagina, and breasts, and possibly also the brain.[1][120][121] These effects are mediated by activation of the PR in these tissues.[1] Progesterone does not have antiestrogenic effects in the more conventional sense of binding to and antagonizing the ER or binding to and inhibiting enzymes involved in estrogen biosynthesis.[1] Instead, for instance in the endometrium, progesterone causes downregulation of the ER and upregulation of the estrogen-inactivating enzymes 17β-hydroxysteroid dehydrogenase 2 (converts estradiol into estrone) and estrone sulfotransferase (converts estrone into estrone sulfate).[1] The antiestrogenic effects of progesterone and other progestogens form the basis for their only approved indication in menopausal hormone therapy: prevention of long-term unopposed estrogen-induced endometrial hyperplasia and increased endometrial cancer risk in women with intact uteruses.[1]

In the breasts, progesterone and other progestogens downregulate the ER as well as the estrogen-activating enzymes steroid sulfatase (converts estrone sulfate into estrone) and 17β-hydroxysteroid-dehydrogenase 1 (converts estrone into estradiol) and upregulates estrone sulfotransferase.[120][121] However, other studies suggest that progestogens do not downregulate ER expression in the breasts.[122][123] When applied directly to the breasts in women, progesterone can block the proliferative effects of estradiol.[124][101][125][126][127][128][129][85] However, the concentrations were supraphysiological and the same may not be the case with more physiological concentrations.[127][85] Cellular proliferation in the breasts is greatest in the luteal phase of the menstrual cycle, when progesterone levels are highest.[85]

It has been hypothesized that progestogens may counteract various effects of estrogens in the brain such as stimulatory and excitatory effects on neuronal activity.[1] Progesterone moreover has a special position among progestogens concerning such actions due to its inhibitory neurosteroid metabolites and their central depressant effects.[1] It has been suggested that these actions of progestogens may explain unfavorable effects on mood that have been reported with these medications in some women.[1] However, the mutual interactions of estrogens and progestogens in the brain in general are controversial and require more research.[1]

Progesterone can produce body-wide antiestrogenic effects at very high doses in both women and men via its antigonadotropic effects and consequent suppression of gonadal estrogen production (see below).[1][130] These antigonadotropic effects are mediated by hyperactivation of the PR.[1][130]

Effects on the HPG axis edit

Antigonadotropic effects edit

Progestogens have antigonadotropic effects at sufficiently high doses via activation of the PR and consequent negative feedback on and hence suppression of the hypothalamic–pituitary–gonadal axis (HPG axis).[130] This results in suppression of gonadotropin secretion and by extension interference with fertility and gonadal sex hormone production.[130] Progesterone prevents ovulation by suppressing the mid-cycle surge in gonadotropin secretion during the menstrual cycle.[131][94]

The ovulation-inhibiting (i.e., contraceptive) dosage of oral crystalline (non-micronized) progesterone in women is 300 mg/day or greater.[71][132][1][133][134] However, this figure is based on limited clinical data.[71] In the clinical research in the 1950s that determined this dosage, ovulation inhibition occurred in 50 to 100% of women when assessed via measures including urinary pregnanediol excretion, daily basal body temperatures, endometrial biopsies, and vaginal smears.[132][135][136][137][138] Another study found that ovulation inhibition with 300 mg/day oral non-micronized progesterone occurred in a "proportion of the cases" when assessed via laparotomy.[137] A third study found that ovulation was inhibited in only 38% of women treated with 1,000 mg/day oral non-micronized progesterone.[133] A fourth publication stated that even 750 to 1,000 mg/day oral non-micronized progesterone had weak effects as evidenced by poor thermogenic effect, weak endometrial effect, and lack of production of withdrawal bleeding in amenorrheic women.[139][140] Neumann and colleagues listed the ovulation-inhibiting dosage of oral non-micronized progesterone in women as 300 to 500 mg/day or as 400 mg/day but provided no other details.[134][141][142][143]

In a study of a progesterone vaginal ring alone or in combination with estradiol that released 1.5 to 3 mg/day progesterone and achieved mean progesterone levels varying between 0.7 and 1.6 ng/mL (mean 0.9 ng/mL) during anovulatory cycles, ovulation occurred in 18 of 30 (60%) menstrual cycles.[144] A study of a vaginal progesterone ring that released almost 10 mg/day progesterone and maintained mean progesterone levels of 4.4 ng/mL (range 2.4–6.5 ng/mL) found that ovulation was inhibited in some but not all women.[145][146] In another study, a progesterone vaginal ring that released about 10 mg/day progesterone and produced progesterone levels of around 4 ng/mL (range 3–5.2 ng/mL) resulted in ovulation occurring in 25% of treated breastfeeding women compared to a rate of 56% in a control group of breastfeeding women.[147] A study in rhesus monkeys found that a vaginal ring delivering 0.235 or 1.77 mg/day progesterone inhibited ovulation in all monkeys at the higher dose and in a proportion of monkeys at the lower dose.[68][148] A dose of progesterone of 5 to 10 mg/day by intramuscular injection has been found to prevent ovulation in women and has been considered effective as a progestogen-only injectable contraceptive.[149][150][151]

Short-term therapy with 300 mg/day oral progesterone had no effect on luteinizing hormone pulse frequency in women.[152] Treatment with a high dosage of oral progesterone of 100 mg four times per day (or 400 mg/day total) in men for 10 days did not cause any change in testosterone levels, suggesting that oral progesterone has little or no antigonadotropic effect in males at typical clinical dosages.[38][153] In addition, a study found that administration of 1,000 mg/day oral progesterone for 3 months had no significant effect on urinary gonadotropin excretion.[71] On the other hand, a single 50 mg intramuscular injection of progesterone, which is associated with high progesterone levels of approximately 50 ng/mL (or early- to mid-pregnancy levels),[154][155][156] resulted in substantial (50–60%) suppression of luteinizing hormone, follicle-stimulating hormone, and testosterone levels in men.[157][158] Similarly, continuous or intermittent intravenous injections of 100 to 400 mg/day progesterone for 10 days significantly decreased urinary gonadotropin excretion.[71][159] Progestogens in general are able to suppress gonadal testosterone production in men by a maximum of about 70 to 80% or to just above castrate levels when used at sufficiently high doses.[160][161]

A study using 50 mg/day progesterone by intramuscular injection in five men found that the medication produced azoospermia or severe oligozoospermia in all within 10 weeks, suppressed libido, erectile function, and ejaculate volume to minimal levels, produced slight gynecomastia in two of the men, moderately decreased testicular size, and impaired testicular morphology.[149][162][163][158][164][165][166] Upon discontinuation, sperm counts returned to normal in the men within 14 to 17 weeks.[149][162][158][164][166] In another study, 100 mg rectal suppositories of progesterone given five times per day for 9 days resulted in progesterone levels of 5.5 to 29 ng/mL and suppressed circulating testosterone and growth hormone levels by about 50% in men, but did not affect libido or erectile potency with this short duration of therapy.[149][167]

Progonadotropic effects edit

Progesterone can have progonadotropic effects under certain circumstances.[131]

Neurosteroid effects edit

Progesterone, through the actions of neurosteroid active metabolites such as allopregnanolone and pregnanolone, is a potent positive allosteric modulator of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[15] It can produce sedative, hypnotic, anxiolytic, euphoric, cognitive-, memory-, and motor-impairing, anticonvulsant, and even anesthetic effects with formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain.[38][102][103][104] These actions and effects are characteristically similar to those of other GABAA receptor positive allosteric modulators like alcohol, barbiturates, and benzodiazepines.[104]

Similarly to other GABAA receptor positive allosteric modulators like alcohol, barbiturates, and benzodiazepines, tolerance has been found to develop with exposure to increased levels of allopregnanolone and related inhibitory neurosteroids.[168][169] This includes downregulation and desensitization of the GABAA receptor, reduced effects of allopregnanolone and other GABAA receptor activators (e.g., GABA and benzodiazepines), and rebound or withdrawal effects upon falls in allopregnanolone levels.[168][169] In addition, changes in allopregnanolone levels have been implicated in adverse neuropsychiatric effects associated with the menstrual cycle (e.g., dysphoria, depression, anxiety, irritability) and postpartum period (e.g., postpartum depression), as well as in catamenial epilepsy (seizures).[170][171] Low and high levels of allopregnanolone seem to have a neutral effect on mood, whereas moderate levels have a negative effect, which may underlie the symptoms of premenstrual syndrome and premenstrual dysphoric disorder that are observed in 30 to 40% of premenopausal women.[170][171][172] This U-shaped effect on mood appears to be a common property of GABAA receptor positive allosteric modulators.[170][171]

See also edit

References edit

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  47. ^ Zutshi (2005). Hormones in Obstetrics and Gynaecology. Jaypee Brothers, Medical Publishers. pp. 74–75. ISBN 978-81-8061-427-9. It has been observed that micronized progesterone has no suppressive effects on high-density lipoprotein-cholesterol (HDL-C). Jensen et al have proved that oral micronized progesterone has no adverse effect on serum lipids. These preparations have the same antiestrogenic and antimineralocorticoid effect but no androgenic action. It does not affect aldosterone synthesis, blood pressure, carbohydrate metabolism or mood changes. No side effects have been reported as far as lipid profile, coagulation factors and blood pressure are concerned.
  48. ^ Levy T, Yairi Y, Bar-Hava I, Shalev J, Orvieto R, Ben-Rafael Z (2000). "Pharmacokinetics of the progesterone-containing vaginal tablet and its use in assisted reproduction" (PDF). Steroids. 65 (10–11): 645–9. doi:10.1016/s0039-128x(00)00121-5. PMID 11108871. S2CID 9627000. Natural progesterone is devoid of any androgenic activity and is thus extensively used in assisted reproduction, sometimes for long periods of time.
  49. ^ Samsioe, Göran; Dören, Martina; Lobo, Rogerio A (2006). "Hormone replacement therapy – the agents". Women's Health Medicine. 3 (5): 213–216. doi:10.1053/S1744-1870(06)70207-4. ISSN 1744-1870. Progestogens differ in their relative metabolic and androgenic effects; for example MPA is minimally androgenic, but does counteract the rise in HDL-cholesterol caused by oestrogen therapy. In contrast, oral micronized progesterone does not mitigate against increased HDL-cholesterol levels.
  50. ^ a b Woods KS, Reyna R, Azziz R (2002). "Effect of oral micronized progesterone on androgen levels in women with polycystic ovary syndrome". Fertil. Steril. 77 (6): 1125–7. doi:10.1016/s0015-0282(02)03119-9. PMID 12057716. The mean values of TT, FT, SHBG, DHEAS, A4, and 17-OHP did not change with OMP administration. However, a higher 17-OHP level was observable at the completion of OMP administration (week 2).
  51. ^ Sitruk-Ware R (2002). "Progestogens in hormonal replacement therapy: new molecules, risks, and benefits". Menopause. 9 (1): 6–15. doi:10.1097/00042192-200201000-00003. PMID 11791081. S2CID 12136231.
  52. ^ a b Sumino, Hiroyuki; Ichikawa, Shuichi; Kasama, Shu; Takahashi, Takashi; Kumakura, Hisao; Takayama, Yoshiaki; Minami, Kazutomo; Kanda, Tsugiyasu; Kurabayashi, Masahiko; Murakami, Masami (2011). "Hormone Therapy and Blood Pressure in Postmenopausal Women". Journal of Experimental & Clinical Medicine. 3 (3): 112–115. doi:10.1016/j.jecm.2011.04.005. ISSN 1878-3317. Natural progesterone, such as micronized progesterone, has no androgenic properties, whereas some synthetic progestins, such as MPA and norethisterone acetate, possess androgenic side effects, which raise the concern of potentially harmful effects on blood pressure.
  53. ^ Walch KT, Huber JC (April 2008). "Progesterone for recurrent miscarriage: truth and deceptions". Best Pract Res Clin Obstet Gynaecol. 22 (2): 375–89. doi:10.1016/j.bpobgyn.2007.08.009. PMID 17964858.
  54. ^ Rode L, Langhoff-Roos J, Andersson C, Dinesen J, Hammerum MS, Mohapeloa H, Tabor A (2009). "Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies". Acta Obstet Gynecol Scand. 88 (11): 1180–9. doi:10.3109/00016340903280982. PMID 19900136. S2CID 556588.
  55. ^ a b c Häggström, Mikael; Richfield, David (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-4436.
  56. ^ a b Samuel B. Frank (1971). Acne Vulgaris. Thomas. p. 131. ISBN 9780398006020. The chemical structure of progesterone and testosterone are remarkably similar; they differ only in the side chain at the 17-carbon position. The possibility that progesterone can be transformed to testosterone has been considered good by many. If true, it could then be a source of androgens in women. [...] Laboratory evidence exists that progesterone can be converted to testosterone in vitro by human and animal ovarian and testicular tissue.44-47 Although the role of progesterone in acne and its effect on sebaceous gland activity is not fully established, the possibility that endogenous progesterone is a precursor of testosterone or of another androgenic substance invites further exploration.48,49
  57. ^ Vermorken, A. J. M.; Houben, J. J. G. (2016). "Topical Androgen Treatment for ACNE a Review". Drug Intelligence & Clinical Pharmacy. 12 (3): 151–157. doi:10.1177/106002807801200302. ISSN 0012-6578. S2CID 74413605. The only concern Voigt and Hsia expressed about the use of progesterone as an anti-androgen was the possibility that the small amount of hormone which reached the circulation could be converted into testosterone by the sexual organs, mainly the testes.
  58. ^ Shufeng Zhou (6 April 2016). Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism. CRC Press. pp. 52–. ISBN 978-1-4665-9788-4.
  59. ^ a b Whitehead MI, Townsend PT, Gill DK, Collins WP, Campbell S (1980). "Absorption and metabolism of oral progesterone". Br Med J. 280 (6217): 825–7. doi:10.1136/bmj.280.6217.825. PMC 1600943. PMID 7370683. Plasma concentrations of oestradiol were unchanged by giving progesterone.
  60. ^ a b Dewis P, Newman M, Anderson DC (October 1984). "The effect of endogenous progesterone on serum levels of 5α-reduced androgens in hirsute women". Clin. Endocrinol. (Oxf). 21 (4): 383–92. doi:10.1111/j.1365-2265.1984.tb03225.x. PMID 6542470. S2CID 72895292. These studies suggest that [...] a rise in serum progesterone has only a minimal effect on circulating levels of the active 5α‐reduced androgen metabolites. [...] Progesterone has been shown to be a potent in vitro inhibitor of cutaneous 5α-reductase (Mauvais-Jarvis et al., 1974). However we found only a small reduction in serum DHT levels in the late luteal phase in ovulatory women and no change in serum 3α-diol. Hence the rise in serum progesterone in ovulatory women has only a minimal effect on the circulating levels of the major active 5α-reduced androgens in vivo.
  61. ^ Rižner TL, Brožič P, Doucette C, Turek-Etienne T, Müller-Vieira U, Sonneveld E, van der Burg B, Böcker C, Husen B (May 2011). "Selectivity and potency of the retroprogesterone dydrogesterone in vitro". Steroids. 76 (6): 607–15. doi:10.1016/j.steroids.2011.02.043. PMID 21376746. S2CID 31609405.
  62. ^ Swerdloff RS, Dudley RE, Page ST, Wang C, Salameh WA (2017). "Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels". Endocr. Rev. 38 (3): 220–254. doi:10.1210/er.2016-1067. PMC 6459338. PMID 28472278.
  63. ^ a b Marks LS (2004). "5α-reductase: history and clinical importance". Rev Urol. 6 Suppl 9 (Suppl 9): S11–21. PMC 1472916. PMID 16985920.
  64. ^ Golub MS, Kaufman FL, Campbell MA, Li LH, Donald JM (October 2006). ""Natural" progesterone: information on fetal effects". Birth Defects Research Part B: Developmental and Reproductive Toxicology. 77 (5): 455–70. doi:10.1002/bdrb.20089. PMID 17066418. Progesterone has been shown to inhibit 5α-reductase, another important enzyme in steroid hormone metabolism, (Dean and Winter, 1984; Beckmann et al., 1993; Cassidenti et al., 1991; Kadohama et al., 1983; Mauvais-Jarvis et al., 1974; Dube et al., 1975). However, this is a weak effect that has only been demonstrated at supra-physiological concentrations and in vitro conditions.
  65. ^ Kincl, Fred A. (1990). "Control of Reproductive Function in the Adult". Hormone Toxicity in the Newborn. Monographs on Endocrinology. Vol. 31. pp. 5–120. doi:10.1007/978-3-642-83794-4_2. ISBN 978-3-642-83796-8. ISSN 0077-1015. PMID 1965221. Progesterone (and other progestational agents) inhibit testosterone from expressing its activity at the target sites (Kincl, 1971a). Mice and rats are the test animals of choice (Dorfman, 1963a,b). Inhibition of 5α-reductase activity of binding to cytosol and nuclear receptors has been shown to be the steps at which antiandrogens express their activity (Neumann and Steinbeck, 1974). Relatively high amounts are needed to achieve a significant effect (Table 2.16).
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Further reading edit

  • Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P (October 1987). "Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review". Contraception. 36 (4): 373–402. doi:10.1016/0010-7824(87)90088-6. PMID 3327648.
  • Simon JA (December 1995). "Micronized progesterone: vaginal and oral uses". Clinical Obstetrics and Gynecology. 38 (4): 902–14. doi:10.1097/00003081-199538040-00024. PMID 8616985.
  • Ruan X, Mueck AO (November 2014). "Systemic progesterone therapy--oral, vaginal, injections and even transdermal?". Maturitas. 79 (3): 248–55. doi:10.1016/j.maturitas.2014.07.009. PMID 25113944.

December 15, 2023
pharmacodynamics, progesterone, pharmacology, progesterone, progestogen, medication, naturally, occurring, steroid, hormone, concerns, pharmacodynamics, pharmacokinetics, various, routes, administration, progesterone, naturally, occurring, bioidentical, proges. The pharmacology of progesterone a progestogen medication and naturally occurring steroid hormone concerns its pharmacodynamics pharmacokinetics and various routes of administration 1 2 Progesterone is a naturally occurring and bioidentical progestogen or an agonist of the progesterone receptor the biological target of progestogens like endogenous progesterone 1 Progesterone also has antimineralocorticoid and inhibitory neurosteroid activity whereas it appears to have little or no glucocorticoid or antiandrogenic activity and has no androgenic activity 1 Because of its progestogenic activity progesterone has functional antiestrogenic effects in certain tissues such as the uterus cervix and vagina 1 In addition progesterone has antigonadotropic effects due to its progestogenic activity and can inhibit fertility and suppress sex hormone production 1 Progesterone differs from progestins synthetic progestogens like medroxyprogesterone acetate and norethisterone with implications for pharmacodynamics and pharmacokinetics as well as efficacy tolerability and safety 1 Progesterone can be taken by mouth in through the vagina and by injection into muscle or fat among other routes 1 A progesterone vaginal ring and progesterone intrauterine device are also available as pharmaceutical products 3 4 Contents 1 Mechanism of action 1 1 Antimineralocorticoid activity 1 2 Glucocorticoid activity 1 3 Androgenic and antiandrogenic activity 1 4 5a Reductase inhibition 1 5 Other activity 2 Effects in the body and brain 2 1 Uterine effects 2 2 Antiestrogenic effects 2 3 Effects on the HPG axis 2 3 1 Antigonadotropic effects 2 3 2 Progonadotropic effects 2 4 Neurosteroid effects 3 See also 4 References 5 Further readingMechanism of action editSee also Progesterone Biological activity and Progestin Pharmacology Progesterone is a progestogen or an agonist of the nuclear progesterone receptors PRs the PR A PR B and PR C 1 In one study progesterone showed EC50 values of 7 7 nM for the human PR A and 8 0 nM for the human PR B 5 In addition to the PRs progesterone is an agonist of the membrane progesterone receptors mPRs including the mPRa mPRb mPRg mPRd and mPRϵ 6 7 It is also a potent antimineralocorticoid antagonist of the mineralocorticoid receptor MR 8 9 as well as a very weak glucocorticoid agonist of the glucocorticoid receptor 10 11 Progesterone does not interact significantly with the androgen receptor AR or with the estrogen receptor ER 1 In addition to its activity as a steroid hormone progesterone is a neurosteroid 12 Specifically it is an antagonist of the sigma s1 receptor 13 14 a negative allosteric modulator of nicotinic acetylcholine receptors 12 and via its active metabolites allopregnanolone and pregnanolone a potent positive allosteric modulator of the GABAA receptor the major signaling receptor of the inhibitory neurotransmitter g aminobutyric acid GABA 15 Relative affinities of progesterone Compound PR AR ER GR MR SHBG CBGProgesterone 50 0 0 10 100 0 36Notes Values are percentages Reference ligands 100 were promegestone for the PR metribolone for the AR E2 for the ER DEXA for the GR aldosterone for the MR DHT for SHBG and cortisol for CBG Sources 1 vte Parenteral potencies and durations of progestogens a b Compound Form Dose for specific uses mg c DOA d TFD e POICD f CICD g Algestone acetophenide Oil soln 75 150 14 32 dGestonorone caproate Oil soln 25 50 8 13 dHydroxyprogest acetate h Aq susp 350 9 16 dHydroxyprogest caproate Oil soln 250 500 i 250 500 5 21 dMedroxyprog acetate Aq susp 50 100 150 25 14 50 dMegestrol acetate Aq susp 25 gt 14 dNorethisterone enanthate Oil soln 100 200 200 50 11 52 dProgesterone Oil soln 200 i 2 6 dAq soln 1 2 dAq susp 50 200 7 14 dNotes and sources Sources 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 All given by intramuscular or subcutaneous injection Progesterone production during the luteal phase is 25 15 50 mg day The OID of OHPC is 250 to 500 mg month Duration of action in days Usually given for 14 days Usually dosed every two to three months Usually dosed once monthly Never marketed or approved by this route a b In divided doses 2 125 or 250 mg for OHPC 10 20 mg for P4 Antimineralocorticoid activity edit Progesterone is a potent antimineralocorticoid 8 9 35 It has 1000 of the affinity of aldosterone the major endogenous agonist for the human MR and 100 of the affinity of aldosterone for the rat MR 36 1 8 Progesterone produces antimineralocorticoid effects such as natriuresis excretion of sodium in the urine at normal physiological concentrations 9 A 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of the potent antimineralocorticoid spironolactone which itself is a derivative of progesterone 37 Doses of progesterone of 50 to 200 mg by intramuscular injection which are similar to progesterone exposure in the third trimester of pregnancy have also been reported to produce antimineralocorticoid like effects 35 The antimineralocorticoid effects of progesterone underlie its ability to lower blood pressure and reduce water and salt retention and its potential application in the treatment of hypertension 38 1 39 35 An active metabolite of progesterone 11 deoxycorticosterone 21 hydroxyprogesterone is a precursor of aldosterone and has strong mineralocorticoid activity i e is a strong agonist of the MR 37 However it is formed in relatively small amounts and any such effects produced by it are usually outweighed by the antimineralocorticoid activity of progesterone 37 Progesterone may be a relatively weak antimineralocorticoid in vivo 40 Glucocorticoid activity edit Progesterone is a partial agonist of the glucocorticoid receptor GR 1 10 11 41 42 It has about 35 of the affinity of dexamethasone a corticosteroid for the human GR and about 3 to 11 of the affinity of dexamethasone for the rat GR 36 However progesterone appears to show weak or no glucocorticoid activity and no antiglucocorticoid activity in vitro and in animals 42 Nonetheless progesterone has been found to upregulate the thrombin receptor in vascular smooth muscle cells in vitro a glucocorticoid effect and this could have clinical relevance in relation to risk of blood clots 1 43 vte Glucocorticoid activity of selected steroids in vitro Steroid Class TR a GR bDexamethasone Corticosteroid 100Ethinylestradiol Estrogen 0Etonogestrel Progestin 14Gestodene Progestin 27Levonorgestrel Progestin 1Medroxyprogesterone acetate Progestin 29Norethisterone Progestin 0Norgestimate Progestin 1Progesterone Progestogen 10Footnotes a Thrombin receptor TR upregulation in vascular smooth muscle cells VSMCs b RBA for the glucocorticoid receptor GR Strength No effect Pronounced effect Strong effect Sources 44 Androgenic and antiandrogenic activity edit The binding and activity of progesterone at the AR the biological target of androgens like testosterone and dihydrotestosterone DHT in the body is controversial 45 Some studies have found progesterone to bind to the AR with agonistic and antagonistic activity exerted whereas other studies have found very low or no affinity for the AR at all 45 In animal studies no androgenic effects have been observed but weak antiandrogenic effects have been reported 45 The weak antiandrogenic activity has been attributed not to antagonism of the AR by progesterone but rather to its weak 5a reductase inhibition and consequent inhibition of the conversion of testosterone into the more potent DHT 45 There is no clinical evidence of AR mediated androgenic or antiandrogenic activity with progesterone 45 Progesterone has not been associated with any classical androgenic effects in clinical studies in women including no changes in the blood lipid profile or sex hormone binding globulin levels acne oily skin hirsutism or voice deepening nor with virilization of female fetuses 46 47 48 49 50 As such the scientific consensus is that progesterone is clinically neither androgenic nor antiandrogenic 1 51 52 This is in contrast to many progestins such as 19 nortestosterone derivatives e g norethisterone levonorgestrel dienogest and 17a hydroxyprogesterone derivatives e g cyproterone acetate medroxyprogesterone acetate which do bind to the AR and have been associated with significant androgenic or antiandrogenic effects depending on the progestin in question 1 52 Due to its lack of androgenic and antiandrogenic activity and hence lack of masculinizing and feminizing effects progesterone is one of the few progestogens that is suitable for use during pregnancy in women at risk for preterm birth or recurrent miscarriage 53 54 nbsp Steroidogenesis showing progesterone as an intermediate in the biosynthesis of the androgens 55 Although progesterone does not have significant AR mediated androgenic or antiandrogenic activity it is a precursor and intermediate albeit distant in the biosynthesis of androgens from cholesterol 55 56 For this reason there has been some speculation that exogenous progesterone could be transformed into androgens by certain tissues that express the requisite enzymes 56 57 Progesterone is converted by 17a hydroxylase into 17a hydroxyprogesterone 17a hydroxyprogesterone is converted by 17 20 lyase into androstenedione and androstenedione is converted by 17b hydroxysteroid dehydrogenases into testosterone 55 CYP17A1 the cytochrome P450 gene that encodes 17a hydroxylase and 17 20 lyase is expressed mainly in the gonads ovaries and testes and the adrenal glands 58 However while it is theoretically possible that progesterone could be transformed in the body into androgens no androgenic effects have been observed in animal studies 45 In addition clinical studies in which women were treated with 100 to 300 mg day oral progesterone have found no or only a small increase in levels of 17a hydroxyprogesterone and no change in androgen levels including of dehydroepiandrosterone androstenedione and testosterone 50 59 46 In these studies levels of estradiol and cortisol which progesterone is also a precursor of did not change either although levels of 11 deoxycorticosterone increased significantly 59 46 Levels of androgens like testosterone and dihydrotestosterone DHT also do not increase going from the follicular phase to the luteal phase of the menstrual cycle in premenopausal women progesterone levels being high in the luteal phase 60 5a Reductase inhibition edit Progesterone is a substrate for 5a reductase and has been found to act as a competitive inhibitor of this enzyme in vitro in a variety of studies 1 In one study it showed IC50 values of 1 375 nM and 88 nM in the presence of 50 nM androstenedione as the substrate for 5a reductase types 1 and 2 respectively 61 5a Reductase is highly expressed in skin hair follicles and prostate gland and is responsible for the transformation of testosterone into the several fold more potent androgen DHT in such tissues 62 63 As such it has been suggested that progesterone might possess some antiandrogenic effect via acting as a 5a reductase inhibitor 1 However inhibition of 5a reductase by progesterone is described as a weak effect that has only been demonstrated in vitro and at supraphysiological concentrations 64 65 In accordance physiological levels of circulating progesterone have not been found to importantly influence circulating DHT concentrations 60 66 Congenital 5a reductase 2 deficiency is a rare intersex condition which is associated with ambiguous genitalia in male fetuses due to a deficiency in DHT production during genital differentiation 63 Experimental prenatal exposure to established 5a reductase inhibitors like finasteride has been found to produce similar feminized genital defects in male animals including rodents and monkeys 67 In contrast exogenous administration of progesterone to pregnant rodents and monkeys has resulted in minimal abnormality in either male or female pups 68 69 70 71 In addition endogenous progesterone levels naturally increase to extremely high concentrations during pregnancy yet genital defects do not occur 72 In accordance while total concentrations of progesterone in pregnant women at term are around 150 ng mL 500 nM free or unbound and hence bioactive concentrations of progesterone are only about 3 ng mL 10 nM due to the high plasma protein binding of progesterone and these concentrations are still well below the aforementioned IC50 values for inhibition of 5a reductase types 1 and 2 73 74 As with endogenous progesterone during pregnancy exogenous supplemental progesterone during pregnancy has been found not to increase the risk of hypospadias in male infants 75 Although systemic progesterone does not appear to be an effective 5a reductase inhibitor topical progesterone may produce potent inhibition of 5a reductase in the skin due to the very high local concentrations that occur 76 77 A study found that topical progesterone applied to the pubic area in men inhibited 5a reductase in the skin in this region by 75 77 78 In addition to inhibition of 5a reductase progesterone is metabolized by 5a reductase into 5a dihydroprogesterone 5a DHP a compound reported to have some antagonistic activity at the AR 78 79 However this compound appears to have no systemic antiandrogenic activity 80 In spite of its apparent 5a reductase inhibition the effectiveness of topical progesterone in the treatment of pattern hair loss has been poor 79 81 82 Other activity edit Certain progestins have been found to stimulate the proliferation of MCF 7 breast cancer cells in vitro an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component 1 PGRMC1 83 Progesterone nomegestrol acetate and chlormadinone acetate act neutrally and do not stimulate proliferation whereas norethisterone desogestrel levonorgestrel and drospirenone strongly stimulate proliferation and medroxyprogesterone acetate dienogest and dydrogesterone weakly stimulate proliferation 83 84 As such progesterone differs from some but not all progestins in the activity mediating this PGRMC1 dependent effect 83 It is unclear if these findings may explain the different risks of breast cancer observed with progesterone dydrogesterone and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies 85 Effects in the body and brain editSee also Progesterone Biological function and Progestogen Biological function The PRs are expressed widely throughout the body including in the uterus cervix vagina fallopian tubes breasts fat skin pituitary gland hypothalamus and elsewhere throughout the brain 1 86 Through activation of the PRs as well as the mPRs progesterone has many effects including the following 1 86 Induces endometrial secretory transformation in preparation for pregnancy gt 5 ng mL 87 Prevents estrogen induced endometrial hyperplasia and increased endometrial cancer risk Maintains pregnancy via effects in endometrium with withdrawal resulting in miscarriage Reduces amount and fibrosity of cervical mucus and causes cervix to become firmer and more tightly closed 88 Controls motility and composition of fluid in the fallopian tubes Reduced cornification and maturation of the vaginal lining 89 Causes water retention in the breasts resulting in temporary enlargement during the menstrual cycle 90 91 Mediates lobuloalveolar development of the breasts necessary for lactation Suppresses lactation initiation and triggers lactation upon withdrawal as with parturition Maintains skin health integrity appearance and hydration and slows the rate of aging of the skin 92 93 Modulates brain function with effects on mood emotionality and sexuality as well as cognition and memory Exerts negative feedback on the hypothalamic pituitary gonadal axis HPG axis by suppressing the secretion of the gonadotropins FSH and LH from the pituitary gland including the mid cycle gonadotropin surge thereby inhibiting gonadal sex hormone production as well as ovulation and fertility gt 2 ng mL 94 Increases basal body temperature by 0 3 0 6 C 0 5 1 0 F relative to preovulation via the hypothalamus gt 4 ng mL 95 96 Reduces hot flashes via the hypothalamus 97 98 Stimulates respiration via the hypothalamus and or respiratory center 99 100 Influences the risk and or progression of hormone sensitive cancers including breast cancer and endometrial cancerMany of the effects of progesterone require estrogen as estrogens prime tissues for progesterone by inducing expression of the PRs 1 86 The PRs are induced in the breasts by estrogens and for this reason it is assumed that progestogens cannot mediate breast changes in the absence of estrogens 101 Progesterone also lowers blood pressure and reduces water and salt retention among other effects via its antimineralocorticoid activity 1 39 Progesterone can produce sedative hypnotic anxiolytic euphoric cognitive memory and motor impairing anticonvulsant and even anesthetic effects via formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain 38 102 103 104 Uterine effects edit Under normal physiological circumstances progesterone secreted by the corpus luteum during the luteal phase of the menstrual cycle produces endometrial transformation of the estrogen primed uterus in preparation for implantation and pregnancy 105 Normal progesterone production during the luteal phase is 25 mg day on average with a range of 15 to 50 mg day 106 71 Progesterone levels during the luteal phase range from 7 ng mL to 22 ng mL using liquid chromatography tandem mass spectrometry LC MS MS per one source 107 Sustained progesterone levels of more than 5 ng mL perhaps approximately 10 ng mL are required for full endometrial transformation 87 108 Progesterone levels of more than 10 ng mL are rarely associated with luteal phase defect on the basis of endometrial biopsy 109 Luteal phase levels of progesterone are said to be produced by 25 mg day progesterone in oil solution by intramuscular injection or by 100 mg day progesterone by vaginal or rectal administration 71 110 Progesterone by intramuscular injection in oil solution has been found to produce endometrial transformation at a dose of 10 or 20 mg day for 14 days total dose per cycle of 200 mg whereas a single intramuscular injection of 200 mg progesterone in microcrystalline aqueous suspension provides endometrial transformation after 10 to 14 days 111 A study found full and equivalent endometrial transformation with subcutaneous injection of 25 mg day versus 50 mg day progesterone in aqueous solution 112 Due to a uterine first pass effect and markedly higher uterine progesterone levels than with other routes 45 mg day vaginal progesterone a dosage that achieves circulating progesterone levels of only 1 to 5 ng mL provides complete endometrial transformation 113 110 Conversely intranasal administration of progesterone achieving progesterone levels of 2 to 5 ng mL was ineffective 113 Transdermal progesterone achieves very low progesterone levels and is considered to be ineffective for endometrial protection 113 114 115 The endometrial transformation dosage of oral micronized progesterone in women has been listed as 200 to 300 mg day or 4 200 mg total per cycle 116 1 However a clinical study found that 300 mg day oral micronized progesterone was insufficient for full endometrial transformation 117 Similarly 600 to 1 000 mg day oral micronized progesterone has been reported to be ineffective for achieving complete endometrial transformation 113 112 Despite inadequate endometrial transformation with oral progesterone continuous 100 mg day oral micronized progesterone or cyclic 200 mg day oral micronized progesterone is effective for protection of the endometrium against estrogen induced endometrial hyperplasia 118 On the other hand and in contrast to progestins typical clinical doses of oral micronized progesterone have been associated with failure to prevent increased endometrial cancer risk caused by estrogen therapy 119 Antiestrogenic effects edit Progesterone like all progestogens has antiestrogenic effects in certain tissues such as the uterus cervix vagina and breasts and possibly also the brain 1 120 121 These effects are mediated by activation of the PR in these tissues 1 Progesterone does not have antiestrogenic effects in the more conventional sense of binding to and antagonizing the ER or binding to and inhibiting enzymes involved in estrogen biosynthesis 1 Instead for instance in the endometrium progesterone causes downregulation of the ER and upregulation of the estrogen inactivating enzymes 17b hydroxysteroid dehydrogenase 2 converts estradiol into estrone and estrone sulfotransferase converts estrone into estrone sulfate 1 The antiestrogenic effects of progesterone and other progestogens form the basis for their only approved indication in menopausal hormone therapy prevention of long term unopposed estrogen induced endometrial hyperplasia and increased endometrial cancer risk in women with intact uteruses 1 In the breasts progesterone and other progestogens downregulate the ER as well as the estrogen activating enzymes steroid sulfatase converts estrone sulfate into estrone and 17b hydroxysteroid dehydrogenase 1 converts estrone into estradiol and upregulates estrone sulfotransferase 120 121 However other studies suggest that progestogens do not downregulate ER expression in the breasts 122 123 When applied directly to the breasts in women progesterone can block the proliferative effects of estradiol 124 101 125 126 127 128 129 85 However the concentrations were supraphysiological and the same may not be the case with more physiological concentrations 127 85 Cellular proliferation in the breasts is greatest in the luteal phase of the menstrual cycle when progesterone levels are highest 85 It has been hypothesized that progestogens may counteract various effects of estrogens in the brain such as stimulatory and excitatory effects on neuronal activity 1 Progesterone moreover has a special position among progestogens concerning such actions due to its inhibitory neurosteroid metabolites and their central depressant effects 1 It has been suggested that these actions of progestogens may explain unfavorable effects on mood that have been reported with these medications in some women 1 However the mutual interactions of estrogens and progestogens in the brain in general are controversial and require more research 1 Progesterone can produce body wide antiestrogenic effects at very high doses in both women and men via its antigonadotropic effects and consequent suppression of gonadal estrogen production see below 1 130 These antigonadotropic effects are mediated by hyperactivation of the PR 1 130 Effects on the HPG axis edit Antigonadotropic effects edit Progestogens have antigonadotropic effects at sufficiently high doses via activation of the PR and consequent negative feedback on and hence suppression of the hypothalamic pituitary gonadal axis HPG axis 130 This results in suppression of gonadotropin secretion and by extension interference with fertility and gonadal sex hormone production 130 Progesterone prevents ovulation by suppressing the mid cycle surge in gonadotropin secretion during the menstrual cycle 131 94 The ovulation inhibiting i e contraceptive dosage of oral crystalline non micronized progesterone in women is 300 mg day or greater 71 132 1 133 134 However this figure is based on limited clinical data 71 In the clinical research in the 1950s that determined this dosage ovulation inhibition occurred in 50 to 100 of women when assessed via measures including urinary pregnanediol excretion daily basal body temperatures endometrial biopsies and vaginal smears 132 135 136 137 138 Another study found that ovulation inhibition with 300 mg day oral non micronized progesterone occurred in a proportion of the cases when assessed via laparotomy 137 A third study found that ovulation was inhibited in only 38 of women treated with 1 000 mg day oral non micronized progesterone 133 A fourth publication stated that even 750 to 1 000 mg day oral non micronized progesterone had weak effects as evidenced by poor thermogenic effect weak endometrial effect and lack of production of withdrawal bleeding in amenorrheic women 139 140 Neumann and colleagues listed the ovulation inhibiting dosage of oral non micronized progesterone in women as 300 to 500 mg day or as 400 mg day but provided no other details 134 141 142 143 In a study of a progesterone vaginal ring alone or in combination with estradiol that released 1 5 to 3 mg day progesterone and achieved mean progesterone levels varying between 0 7 and 1 6 ng mL mean 0 9 ng mL during anovulatory cycles ovulation occurred in 18 of 30 60 menstrual cycles 144 A study of a vaginal progesterone ring that released almost 10 mg day progesterone and maintained mean progesterone levels of 4 4 ng mL range 2 4 6 5 ng mL found that ovulation was inhibited in some but not all women 145 146 In another study a progesterone vaginal ring that released about 10 mg day progesterone and produced progesterone levels of around 4 ng mL range 3 5 2 ng mL resulted in ovulation occurring in 25 of treated breastfeeding women compared to a rate of 56 in a control group of breastfeeding women 147 A study in rhesus monkeys found that a vaginal ring delivering 0 235 or 1 77 mg day progesterone inhibited ovulation in all monkeys at the higher dose and in a proportion of monkeys at the lower dose 68 148 A dose of progesterone of 5 to 10 mg day by intramuscular injection has been found to prevent ovulation in women and has been considered effective as a progestogen only injectable contraceptive 149 150 151 Short term therapy with 300 mg day oral progesterone had no effect on luteinizing hormone pulse frequency in women 152 Treatment with a high dosage of oral progesterone of 100 mg four times per day or 400 mg day total in men for 10 days did not cause any change in testosterone levels suggesting that oral progesterone has little or no antigonadotropic effect in males at typical clinical dosages 38 153 In addition a study found that administration of 1 000 mg day oral progesterone for 3 months had no significant effect on urinary gonadotropin excretion 71 On the other hand a single 50 mg intramuscular injection of progesterone which is associated with high progesterone levels of approximately 50 ng mL or early to mid pregnancy levels 154 155 156 resulted in substantial 50 60 suppression of luteinizing hormone follicle stimulating hormone and testosterone levels in men 157 158 Similarly continuous or intermittent intravenous injections of 100 to 400 mg day progesterone for 10 days significantly decreased urinary gonadotropin excretion 71 159 Progestogens in general are able to suppress gonadal testosterone production in men by a maximum of about 70 to 80 or to just above castrate levels when used at sufficiently high doses 160 161 A study using 50 mg day progesterone by intramuscular injection in five men found that the medication produced azoospermia or severe oligozoospermia in all within 10 weeks suppressed libido erectile function and ejaculate volume to minimal levels produced slight gynecomastia in two of the men moderately decreased testicular size and impaired testicular morphology 149 162 163 158 164 165 166 Upon discontinuation sperm counts returned to normal in the men within 14 to 17 weeks 149 162 158 164 166 In another study 100 mg rectal suppositories of progesterone given five times per day for 9 days resulted in progesterone levels of 5 5 to 29 ng mL and suppressed circulating testosterone and growth hormone levels by about 50 in men but did not affect libido or erectile potency with this short duration of therapy 149 167 Progonadotropic effects edit Progesterone can have progonadotropic effects under certain circumstances 131 Neurosteroid effects edit Progesterone through the actions of neurosteroid active metabolites such as allopregnanolone and pregnanolone is a potent positive allosteric modulator of the GABAA receptor the major signaling receptor of the inhibitory neurotransmitter g aminobutyric acid GABA 15 It can produce sedative hypnotic anxiolytic euphoric cognitive memory and motor impairing anticonvulsant and even anesthetic effects with formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain 38 102 103 104 These actions and effects are characteristically similar to those of other GABAA receptor positive allosteric modulators like alcohol barbiturates and benzodiazepines 104 Similarly to other GABAA receptor positive allosteric modulators like alcohol barbiturates and benzodiazepines tolerance has been found to develop with exposure to increased levels of allopregnanolone and related inhibitory neurosteroids 168 169 This includes downregulation and desensitization of the GABAA receptor reduced effects of allopregnanolone and other GABAA receptor activators e g GABA and benzodiazepines and rebound or withdrawal effects upon falls in allopregnanolone levels 168 169 In addition changes in allopregnanolone levels have been implicated in adverse neuropsychiatric effects associated with the menstrual cycle e g dysphoria depression anxiety irritability and postpartum period e g postpartum depression as well as in catamenial epilepsy seizures 170 171 Low and high levels of allopregnanolone seem to have a neutral effect on mood whereas moderate levels have a negative effect which may underlie the symptoms of premenstrual syndrome and premenstrual dysphoric disorder that are observed in 30 to 40 of premenopausal women 170 171 172 This U shaped effect on mood appears to be a common property of GABAA receptor positive allosteric modulators 170 171 See also editPharmacokinetics of progesterone Pharmacodynamics of estradiol Pharmacokinetics of estradiolReferences edit a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai Kuhl H 2005 Pharmacology of estrogens and progestogens influence of different routes of administration PDF Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 Unfer Vittorio di Renzo Gian Gerli Sandro Casini Maria 2006 The Use of Progesterone in Clinical Practice Evaluation of its Efficacy in Diverse Indications Using Different Routes of Administration Current Drug Therapy 1 2 211 219 doi 10 2174 157488506776930923 ISSN 1574 8855 Whitaker Amy Gilliam Melissa 2014 Contraception for Adolescent and Young Adult Women Springer p 98 ISBN 9781461465799 Chaudhuri 2007 Practice Of Fertility Control A Comprehensive Manual 7Th ed Elsevier India pp 153 ISBN 978 81 312 1150 2 Attardi BJ Burgenson J Hild SA Reel JR March 2004 In vitro antiprogestational antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB 2914 CDB 4124 and mifepristone J Steroid Biochem Mol Biol 88 3 277 88 doi 10 1016 j jsbmb 2003 12 004 PMID 15120421 S2CID 23958876 Soltysik K Czekaj P April 2013 Membrane estrogen receptors is it an alternative way of estrogen action J Physiol Pharmacol 64 2 129 42 PMID 23756388 Prossnitz ER Barton M May 2014 Estrogen biology New insights into GPER function and clinical opportunities Mol Cell Endocrinol 389 1 2 71 83 doi 10 1016 j mce 2014 02 002 PMC 4040308 PMID 24530924 a b c Rupprecht R Reul JM van Steensel B Spengler D Soder M Berning B Holsboer F Damm K October 1993 Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands European Journal of Pharmacology 247 2 145 54 doi 10 1016 0922 4106 93 90072 H PMID 8282004 a b c Elger W Beier S Pollow K Garfield R Shi SQ Hillisch A 2003 Conception and pharmacodynamic profile of drospirenone Steroids 68 10 13 891 905 doi 10 1016 j steroids 2003 08 008 PMID 14667981 S2CID 41756726 a b Attardi BJ Zeleznik A Simhan H Chiao JP Mattison DR Caritis SN 2007 Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone 17 alpha hydroxyprogesterone caproate and related progestins Am J Obstet Gynecol 197 6 599 e1 7 doi 10 1016 j ajog 2007 05 024 PMC 2278032 PMID 18060946 a b Lei K Chen L Georgiou EX Sooranna SR Khanjani S Brosens JJ Bennett PR Johnson MR 2012 Progesterone acts via the nuclear glucocorticoid receptor to suppress IL 1b induced COX 2 expression in human term myometrial cells PLOS ONE 7 11 e50167 Bibcode 2012PLoSO 750167L doi 10 1371 journal pone 0050167 PMC 3509141 PMID 23209664 a b Baulieu E Schumacher M 2000 Progesterone as a neuroactive neurosteroid with special reference to the effect of progesterone on myelination Steroids 65 10 11 605 12 doi 10 1016 s0039 128x 00 00173 2 PMID 11108866 S2CID 14952168 Maurice T Urani A Phan VL Romieu P November 2001 The interaction between neuroactive steroids and the sigma1 receptor function behavioral consequences and therapeutic opportunities Brain Research Brain Research Reviews 37 1 3 116 32 doi 10 1016 s0165 0173 01 00112 6 PMID 11744080 S2CID 44931783 Johannessen M Fontanilla D Mavlyutov T Ruoho AE Jackson MB February 2011 Antagonist action of progesterone at s receptors in the modulation of voltage gated sodium channels American Journal of Physiology Cell Physiology 300 2 C328 37 doi 10 1152 ajpcell 00383 2010 PMC 3043630 PMID 21084640 a b Paul SM Purdy RH March 1992 Neuroactive steroids FASEB Journal 6 6 2311 22 doi 10 1096 fasebj 6 6 1347506 PMID 1347506 S2CID 221753076 Knorr K Beller FK Lauritzen C 17 April 2013 Lehrbuch der Gynakologie Springer Verlag pp 214 ISBN 978 3 662 00942 0 Knorr K Knorr Gartner H Beller FK Lauritzen C 8 March 2013 Geburtshilfe und Gynakologie Physiologie 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ed Pharmacology of the Endocrine System and Related Drugs Progesterone Progestational Drugs and Antifertility Agents Vol II Pergamon Press pp 13 24 ISBN 978 0080168128 OCLC 278011135 Henzl MR Edwards JA 10 November 1999 Pharmacology of Progestins 17a Hydroxyprogesterone Derivatives and Progestins of the First and Second Generation In Sitruk Ware R Mishell DR eds Progestins and Antiprogestins in Clinical Practice Taylor amp Francis pp 101 132 ISBN 978 0 8247 8291 7 Brotherton J 1976 Sex Hormone Pharmacology Academic Press p 114 ISBN 978 0 12 137250 7 Sang GW April 1994 Pharmacodynamic effects of once a month combined injectable contraceptives Contraception 49 4 361 385 doi 10 1016 0010 7824 94 90033 7 PMID 8013220 Toppozada MK April 1994 Existing once a month combined injectable contraceptives Contraception 49 4 293 301 doi 10 1016 0010 7824 94 90029 9 PMID 8013216 Goebelsmann U 1986 Pharmacokinetics of Contraceptive Steroids in Humans In Gregoire AT Blye RP eds Contraceptive Steroids Pharmacology and Safety Springer Science amp Business Media pp 67 111 doi 10 1007 978 1 4613 2241 2 4 ISBN 978 1 4613 2241 2 Becker H Dusterberg B Klosterhalfen H 1980 Bioavailability of cyproterone acetate after oral and intramuscular application in men author s transl Bioavailability of Cyproterone Acetate after Oral and Intramuscular Application in Men Urologia Internationalis 35 6 381 385 doi 10 1159 000280353 PMID 6452729 Moltz L Haase F Schwartz U Hammerstein J May 1983 Treatment of virilized women with intramuscular administration of cyproterone acetate Efficacy of Intra muscularly Applied Cyproterone Acetate in Hyperandrogenism Geburtshilfe und Frauenheilkunde 43 5 281 287 doi 10 1055 s 2008 1036893 PMID 6223851 Wright JC Burgess DJ 29 January 2012 Long Acting Injections and Implants Springer Science amp Business Media pp 114 ISBN 978 1 4614 0554 2 Chu YH Li Q Zhao ZF April 1986 Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol megestrol long acting injectable contraceptive The Chinese Journal of Clinical Pharmacology The results showed that after injection the concentration of plasma MA increased rapidly The meantime of peak plasma MA level was 3rd day there was a linear relationship between log of plasma MA concentration and time day after administration in all subjects elimination phase half life t1 2b 14 35 9 1 days Runnebaum BC Rabe T Kiesel L 6 December 2012 Female Contraception Update and Trends Springer Science amp Business Media pp 429 ISBN 978 3 642 73790 9 Artini PG Genazzani AR Petraglia F 11 December 2001 Advances in Gynecological Endocrinology CRC Press pp 105 ISBN 978 1 84214 071 0 King TL Brucker MC Kriebs JM Fahey JO 21 October 2013 Varney s Midwifery Jones amp Bartlett Publishers pp 495 ISBN 978 1 284 02542 2 a b c Elkik F Mauvais Jarvis P January 1980 Role de la progesterone et des progestatifs sur le metabolisme hydroelectrolytique The role of progesterone and progestins in hydroelectrolytic metabolism Nouv Presse Med in French 9 1 35 8 PMID 6986604 a b Krattenmacher R July 2000 Drospirenone pharmacology and pharmacokinetics of a unique progestogen Contraception 62 1 29 38 doi 10 1016 S0010 7824 00 00133 5 PMID 11024226 a b c Simon JA December 1995 Micronized progesterone vaginal and oral uses Clinical Obstetrics and Gynecology 38 4 902 14 doi 10 1097 00003081 199538040 00024 PMID 8616985 a b c d Goletiani NV Keith DR Gorsky SJ 2007 Progesterone review of safety for clinical studies Exp Clin Psychopharmacol 15 5 427 44 doi 10 1037 1064 1297 15 5 427 PMID 17924777 a b Oelkers W 2000 Drospirenone a new progestogen with antimineralocorticoid activity resembling natural progesterone Eur J Contracept Reprod Health Care 5 Suppl 3 17 24 PMID 11246598 Quinkler M Diederich S November 2002 Difference of in vivo and in vitro antimineralocorticoid potency of progesterone Endocr Res 28 4 465 70 doi 10 1081 erc 120016824 PMID 12530650 S2CID 168394 Zerr Fouineau M Chataigneau M Blot C Schini Kerth VB January 2007 Progestins overcome inhibition of platelet aggregation by endothelial cells by down regulating endothelial NO synthase via glucocorticoid receptors FASEB J 21 1 265 73 doi 10 1096 fj 06 6840com PMID 17116740 S2CID 22679638 a b Fuhrmann U Krattenmacher R Slater EP Fritzemeier KH October 1996 The novel progestin drospirenone and its natural counterpart progesterone biochemical profile and antiandrogenic potential Contraception 54 4 243 51 doi 10 1016 s0010 7824 96 00195 3 PMID 8922878 Drospirenone and progesterone exhibited low binding affinities to the rat GR as is documented by 1 and 11 RBA values compared to the reference dexamethasone respectively Similar results were reported elsewhere 8 In accordance with the low affinity to the GR progesterone and drospirenone showed weak or no detectable agonistic activities respectively in the GR dependent transactivation assay Figure 2A and Figure 2B Furthermore both progestins were devoid of antiglucocorticoid activity in vitro These data are in agreement with in vivo studies carried out with rats where drospirenone and progesterone showed neither glucocorticoid nor antiglucocorticoid activity 8 Wiegratz I Kuhl H August 2004 Progestogen therapies differences in clinical effects Trends Endocrinol Metab 15 6 277 85 doi 10 1016 j tem 2004 06 006 PMID 15358281 S2CID 35891204 Kuhl H 2005 Pharmacology of estrogens and progestogens influence of different routes of administration PDF Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 a b c d e f Yeh YT Chang CW Wei RJ Wang SN 2013 Progesterone and related compounds in hepatocellular carcinoma basic and clinical aspects Biomed Res Int 2013 290575 doi 10 1155 2013 290575 PMC 3581253 PMID 23484104 a b c Ottosson UB 1984 Oral progesterone and estrogen progestogen therapy Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins Acta Obstet Gynecol Scand Suppl 127 1 37 doi 10 3109 00016348409157016 PMID 6596830 S2CID 26138417 Natural progesterone is devoid of any androgenic activity that might compromise lipoprotein metabolism or induce teratogenicity Zutshi 2005 Hormones in Obstetrics and Gynaecology Jaypee Brothers Medical Publishers pp 74 75 ISBN 978 81 8061 427 9 It has been observed that micronized progesterone has no suppressive effects on high density lipoprotein cholesterol HDL C Jensen et al have proved that oral micronized progesterone has no adverse effect on serum lipids These preparations have the same antiestrogenic and antimineralocorticoid effect but no androgenic action It does not affect aldosterone synthesis blood pressure carbohydrate metabolism or mood changes No side effects have been reported as far as lipid profile coagulation factors and blood pressure are concerned Levy T Yairi Y Bar Hava I Shalev J Orvieto R Ben Rafael Z 2000 Pharmacokinetics of the progesterone containing vaginal tablet and its use in assisted reproduction PDF Steroids 65 10 11 645 9 doi 10 1016 s0039 128x 00 00121 5 PMID 11108871 S2CID 9627000 Natural progesterone is devoid of any androgenic activity and is thus extensively used in assisted reproduction sometimes for long periods of time Samsioe Goran Doren Martina Lobo Rogerio A 2006 Hormone replacement therapy the agents Women s Health Medicine 3 5 213 216 doi 10 1053 S1744 1870 06 70207 4 ISSN 1744 1870 Progestogens differ in their relative metabolic and androgenic effects for example MPA is minimally androgenic but does counteract the rise in HDL cholesterol caused by oestrogen therapy In contrast oral micronized progesterone does not mitigate against increased HDL cholesterol levels a b Woods KS Reyna R Azziz R 2002 Effect of oral micronized progesterone on androgen levels in women with polycystic ovary syndrome Fertil Steril 77 6 1125 7 doi 10 1016 s0015 0282 02 03119 9 PMID 12057716 The mean values of TT FT SHBG DHEAS A4 and 17 OHP did not change with OMP administration However a higher 17 OHP level was observable at the completion of OMP administration week 2 Sitruk Ware R 2002 Progestogens in hormonal replacement therapy new molecules risks and benefits Menopause 9 1 6 15 doi 10 1097 00042192 200201000 00003 PMID 11791081 S2CID 12136231 a b Sumino Hiroyuki Ichikawa Shuichi Kasama Shu Takahashi Takashi Kumakura Hisao Takayama Yoshiaki Minami Kazutomo Kanda Tsugiyasu Kurabayashi Masahiko Murakami Masami 2011 Hormone Therapy and Blood Pressure in Postmenopausal Women Journal of Experimental amp Clinical Medicine 3 3 112 115 doi 10 1016 j jecm 2011 04 005 ISSN 1878 3317 Natural progesterone such as micronized progesterone has no androgenic properties whereas some synthetic progestins such as MPA and norethisterone acetate possess androgenic side effects which raise the concern of potentially harmful effects on blood pressure Walch KT Huber JC April 2008 Progesterone for recurrent miscarriage truth and deceptions Best Pract Res Clin Obstet Gynaecol 22 2 375 89 doi 10 1016 j bpobgyn 2007 08 009 PMID 17964858 Rode L Langhoff Roos J Andersson C Dinesen J Hammerum MS Mohapeloa H Tabor A 2009 Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies Acta Obstet Gynecol Scand 88 11 1180 9 doi 10 3109 00016340903280982 PMID 19900136 S2CID 556588 a b c Haggstrom Mikael Richfield David 2014 Diagram of the pathways of human steroidogenesis WikiJournal of Medicine 1 1 doi 10 15347 wjm 2014 005 ISSN 2002 4436 a b Samuel B Frank 1971 Acne Vulgaris Thomas p 131 ISBN 9780398006020 The chemical structure of progesterone and testosterone are remarkably similar they differ only in the side chain at the 17 carbon position The possibility that progesterone can be transformed to testosterone has been considered good by many If true it could then be a source of androgens in women Laboratory evidence exists that progesterone can be converted to testosterone in vitro by human and animal ovarian and testicular tissue 44 47 Although the role of progesterone in acne and its effect on sebaceous gland activity is not fully established the possibility that endogenous progesterone is a precursor of testosterone or of another androgenic substance invites further exploration 48 49 Vermorken A J M Houben J J G 2016 Topical Androgen Treatment for ACNE a Review Drug Intelligence amp Clinical Pharmacy 12 3 151 157 doi 10 1177 106002807801200302 ISSN 0012 6578 S2CID 74413605 The only concern Voigt and Hsia expressed about the use of progesterone as an anti androgen was the possibility that the small amount of hormone which reached the circulation could be converted into testosterone by the sexual organs mainly the testes Shufeng Zhou 6 April 2016 Cytochrome P450 2D6 Structure Function Regulation and Polymorphism CRC Press pp 52 ISBN 978 1 4665 9788 4 a b Whitehead MI Townsend PT Gill DK Collins WP Campbell S 1980 Absorption and metabolism of oral progesterone Br Med J 280 6217 825 7 doi 10 1136 bmj 280 6217 825 PMC 1600943 PMID 7370683 Plasma concentrations of oestradiol were unchanged by giving progesterone a b Dewis P Newman M Anderson DC October 1984 The effect of endogenous progesterone on serum levels of 5a reduced androgens in hirsute women Clin Endocrinol Oxf 21 4 383 92 doi 10 1111 j 1365 2265 1984 tb03225 x PMID 6542470 S2CID 72895292 These studies suggest that a rise in serum progesterone has only a minimal effect on circulating levels of the active 5a reduced androgen metabolites Progesterone has been shown to be a potent in vitro inhibitor of cutaneous 5a reductase Mauvais Jarvis et al 1974 However we found only a small reduction in serum DHT levels in the late luteal phase in ovulatory women and no change in serum 3a diol Hence the rise in serum progesterone in ovulatory women has only a minimal effect on the circulating levels of the major active 5a reduced androgens in vivo Rizner TL Brozic P Doucette C Turek Etienne T Muller Vieira U Sonneveld E van der Burg B Bocker C Husen B May 2011 Selectivity and potency of the retroprogesterone dydrogesterone in vitro Steroids 76 6 607 15 doi 10 1016 j steroids 2011 02 043 PMID 21376746 S2CID 31609405 Swerdloff RS Dudley RE Page ST Wang C Salameh WA 2017 Dihydrotestosterone Biochemistry Physiology and Clinical Implications of Elevated Blood Levels Endocr Rev 38 3 220 254 doi 10 1210 er 2016 1067 PMC 6459338 PMID 28472278 a b Marks LS 2004 5a reductase history and clinical importance Rev Urol 6 Suppl 9 Suppl 9 S11 21 PMC 1472916 PMID 16985920 Golub MS Kaufman FL Campbell MA Li LH Donald JM October 2006 Natural progesterone information on fetal effects Birth Defects Research Part B Developmental and Reproductive Toxicology 77 5 455 70 doi 10 1002 bdrb 20089 PMID 17066418 Progesterone has been shown to inhibit 5a reductase another important enzyme in steroid hormone metabolism Dean and Winter 1984 Beckmann et al 1993 Cassidenti et al 1991 Kadohama et al 1983 Mauvais Jarvis et al 1974 Dube et al 1975 However this is a weak effect that has only been demonstrated at supra physiological concentrations and in vitro conditions Kincl Fred A 1990 Control of Reproductive Function in the Adult Hormone Toxicity in the Newborn Monographs on Endocrinology Vol 31 pp 5 120 doi 10 1007 978 3 642 83794 4 2 ISBN 978 3 642 83796 8 ISSN 0077 1015 PMID 1965221 Progesterone and other progestational agents inhibit testosterone from expressing its activity at the target sites Kincl 1971a Mice and rats are the test animals of choice Dorfman 1963a b Inhibition of 5a reductase activity of binding to cytosol and nuclear receptors has been shown to be the steps at which antiandrogens express their activity Neumann and Steinbeck 1974 Relatively high amounts are needed to achieve a significant effect Table 2 16 Kalund Jensen H Myren CJ December 1984 Vaginal absorption of oestradiol and progesterone Maturitas 6 4 359 67 doi 10 1016 0378 5122 84 90009 4 PMID 6543461 Picut CA Ziejewski MK Stanislaus D February 2018 Comparative Aspects of Pre and Postnatal Development of the Male Reproductive System Birth Defects Res 110 3 190 227 doi 10 1002 bdr2 1133 PMID 29063715 S2CID 3967093 a b Sitruk Ware R August 2018 Non clinical studies of progesterone Climacteric 21 4 315 320 doi 10 1080 13697137 2018 1463982 PMC 6281289 PMID 29790373 Fred A Kincl 6 December 2012 Hormone Toxicity in the Newborn Springer Science amp Business Media p 60 ISBN 978 3 642 83794 4 Kawashima K Nakaura S Nagao S Tanaka S Kuwamura T February 1977 Virilizing activities of various steroids in female rat fetuses Endocrinol Jpn 24 1 77 81 doi 10 1507 endocrj1954 24 77 PMID 558879 a b c d e f g Aufrere MB Benson H June 1976 Progesterone an overview and recent advances J Pharm Sci 65 6 783 800 doi 10 1002 jps 2600650602 PMID 945344 Early studies on its use as an oral contraceptive showed that at 300 mg day 5th to 25th day of the menstrual cycle progesterone was effective in preventing ovulation through four cycles 263 The related effect of larger doses of progesterone on gonadotropin excretion also has been investigated Rothchild 264 found that continuous or intermittent intravenously administered progesterone 100 400 mg day for 10 days depressed the total amount of gonadotropin excreted into the urine However Paulsen et al 265 found that oral progesterone at 1000 mg day for 87 days did not have a significant effect on urinary gonadotropin excretion The efficacy of progesterone as an oral contraceptive was never fully tested because synthetic progestational agents which were orally effective were available Tony M Plant Anthony J Zeleznik 15 November 2014 Knobil and Neill s Physiology of Reproduction Academic Press pp 2289 2386 ISBN 978 0 12 397769 4 Hormones Brain and Behavior Five Volume Set Elsevier 18 June 2002 pp 54 ISBN 978 0 08 053415 2 Heidrich A Schleyer M Spingler H Albert P Knoche M Fritze J Lanczik M February 1994 Postpartum blues relationship between not protein bound steroid hormones in plasma and postpartum mood changes J Affect Disord 30 2 93 8 doi 10 1016 0165 0327 94 90036 1 PMID 8201129 Baek K Rosenwaks Z Poppas D P Palermo G D 2006 P 657 Fertility and Sterility 86 3 S377 doi 10 1016 j fertnstert 2006 07 1033 ISSN 0015 0282 Pharmacology of the Skin I Pharmacology of Skin Systems Autocoids in Normal and Inflamed Skin Springer Science amp Business Media 6 December 2012 pp 249 250 ISBN 978 3 642 73797 8 a b Pharmacology of the Skin II Methods Absorption Metabolism and Toxicity Drugs and Diseases Springer Science amp Business Media 6 December 2012 pp 253 485 ISBN 978 3 642 74054 1 a b Walter P Unger 1 February 1995 Androgenetic alopecia and its treatment A historical overview Hair Transplantation Third Edition Taylor amp Francis pp 1 33 ISBN 978 0 8247 9363 0 a b Sawaya Marty E Shapiro Jerry 2000 Androgenetic alopecia Dermatologic Clinics 18 1 47 61 doi 10 1016 S0733 8635 05 70146 7 ISSN 0733 8635 PMID 10626111 Parthasarathy Saudhamini Chin Andrea Malloy Virginia Matias Jonathan 1988 In Vitro Androgen Receptor Binding Affinity and in Vivo Inhibitory Activity of 5 Pregnane 3 20 Dione Annals of the New York Academy of Sciences 529 1 Fourth Colloq 239 241 Bibcode 1988NYASA 529 239P doi 10 1111 j 1749 6632 1988 tb51470 x ISSN 0077 8923 S2CID 86039350 Price Vera H 1988 Androgenetic alopecia and hair growth promotion state of the art Present and future Clinics in Dermatology 6 4 218 227 doi 10 1016 0738 081X 88 90090 9 ISSN 0738 081X PMID 3063373 Sawaya ME Hordinsky MK January 1993 The antiandrogens When and how they should be used Dermatol Clin 11 1 65 72 doi 10 1016 S0733 8635 18 30283 3 PMID 8435919 a b c Neubauer H Ma Q Zhou J Yu Q Ruan X Seeger H Fehm T Mueck AO October 2013 Possible role of PGRMC1 in breast cancer development Climacteric 16 5 509 13 doi 10 3109 13697137 2013 800038 PMID 23758160 S2CID 29808177 Ruan X Neubauer H Yang Y Schneck H Schultz S Fehm T Cahill MA Seeger H Mueck AO October 2012 Progestogens and membrane initiated effects on the proliferation of human breast cancer cells Climacteric 15 5 467 72 doi 10 3109 13697137 2011 648232 PMID 22335423 S2CID 11302554 a b c d Trabert B Sherman ME Kannan N Stanczyk FZ September 2019 Progesterone and breast cancer Endocr Rev 41 2 320 344 doi 10 1210 endrev bnz001 PMC 7156851 PMID 31512725 a b c P J Bentley 1980 Endocrine Pharmacology Physiological Basis and Therapeutic Applications CUP Archive pp 264 274 ISBN 978 0 521 22673 8 a b Mark A Sperling 10 April 2014 Pediatric Endocrinology E Book Elsevier Health Sciences pp 630 ISBN 978 1 4557 5973 6 Sue Macdonald Gail Johnson 3 June 2017 Mayes Midwifery E Book Elsevier Health Sciences pp 391 ISBN 978 0 7020 6336 7 Kenneth L Becker 2001 Principles and Practice of Endocrinology and Metabolism Lippincott Williams amp Wilkins pp 889 940 ISBN 978 0 7817 1750 2 Lee Ellen C Copstead Kirkhorn Jacquelyn L Banasik 25 June 2014 Pathophysiology E Book Elsevier Health Sciences pp 660 ISBN 978 0 323 29317 4 Throughout the reproductive years some women note swelling of the breast around the latter part of each menstrual cycle before the onset of menstruation The water retention and subsequent swelling of breast tissue during this phase of the menstrual cycle are thought to be due to high levels of circulating progesterone stimulating the secretory cells of the breast 12 Farage MA Neill S MacLean AB 2009 Physiological changes associated with the menstrual cycle a review Obstet Gynecol Surv 64 1 58 72 doi 10 1097 OGX 0b013e3181932a37 PMID 19099613 S2CID 22293838 Raine Fenning NJ Brincat MP Muscat Baron Y 2003 Skin aging and menopause implications for treatment Am J Clin Dermatol 4 6 371 8 doi 10 2165 00128071 200304060 00001 PMID 12762829 S2CID 20392538 Holzer G Riegler E Honigsmann H Farokhnia S Schmidt JB Schmidt B 2005 Effects and side effects of 2 progesterone cream on the skin of peri and postmenopausal women results from a double blind vehicle controlled randomized study Br J Dermatol 153 3 626 34 doi 10 1111 j 1365 2133 2005 06685 x PMID 16120154 S2CID 6077829 a b Leon Speroff Marc A Fritz 2005 Clinical Gynecologic Endocrinology and Infertility Lippincott Williams amp Wilkins pp 211 ISBN 978 0 7817 4795 0 When administered before the estrogen stimulus or in high doses achieving a blood level greater than 2 ng mL progesterone blocks the midcycle LH surge Charles R B Beckmann William Herbert Douglas Laube Frank Ling Roger Smith 21 January 2013 Obstetrics and Gynecology Lippincott Williams amp Wilkins pp 342 ISBN 978 1 4698 2604 2 Quigley MM August 1986 Drugs in the treatment of female infertility Recent advances Drugs 32 2 169 77 doi 10 2165 00003495 198632020 00004 PMID 3527660 S2CID 46972235 In the presence of circulating levels of approximately 4 mg L or greater of progesterone most women experience a 0 5 to 1 F rise in basal body temperature Shanafelt TD Barton DL Adjei AA Loprinzi CL 2002 Pathophysiology and treatment of hot flashes Mayo Clin Proc 77 11 1207 18 doi 10 4065 77 11 1207 PMID 12440557 Sassarini J Lumsden MA 2010 Hot flushes are there effective alternatives to estrogen Menopause Int 16 2 81 8 doi 10 1258 mi 2010 010007 PMID 20729500 S2CID 37505358 Bayliss DA Millhorn DE 1992 Central neural mechanisms of progesterone action application to the respiratory system J Appl Physiol 73 2 393 404 doi 10 1152 jappl 1992 73 2 393 PMID 1399957 Ghada Bourjeily Karen Rosene Montella 21 April 2009 Pulmonary Problems in Pregnancy Springer Science amp Business Media pp 21 ISBN 978 1 59745 445 2 a b Gompel A Plu Bureau G August 2018 Progesterone progestins and the breast in menopause treatment Climacteric 21 4 326 332 doi 10 1080 13697137 2018 1476483 PMID 29852797 S2CID 46922084 a b Wang Cheng R Neuner JM Barnabei VM 2007 Menopause ACP Press p 97 ISBN 978 1 930513 83 9 a b Bergemann N Ariecher Rossler A 27 December 2005 Estrogen Effects in Psychiatric Disorders Springer Science amp Business Media p 179 ISBN 978 3 211 27063 9 a b c Backstrom T Bixo M Johansson M Nyberg S Ossewaarde L Ragagnin G Savic I Stromberg J Timby E van Broekhoven F van Wingen G 2014 Allopregnanolone and mood disorders Prog Neurobiol 113 88 94 doi 10 1016 j pneurobio 2013 07 005 PMID 23978486 S2CID 207407084 Eric J Bieber Joseph S Sanfilippo Ira R Horowitz Mahmood I Shafi 23 April 2015 Clinical Gynecology Cambridge University Press pp 972 ISBN 978 1 107 04039 7 Susan Tucker Blackburn 2007 Maternal Fetal amp Neonatal Physiology A Clinical Perspective Elsevier Health Sciences pp 44 ISBN 978 1 4160 2944 1 J Larry Jameson Leslie J De Groot 25 February 2015 Endocrinology Adult and Pediatric E Book Elsevier Health Sciences pp 1 ISBN 978 0 323 32195 2 Younis JS Simon A Laufer N December 1996 Endometrial preparation lessons from oocyte donation Fertil Steril 66 6 873 84 doi 10 1016 s0015 0282 16 58677 4 PMID 8941049 It seems that progesterone levels of approximately 10 ng mL are sufficient to sustain morphological and functional endometrial development Oral micronized P 100 mg three times was investigated in ovarian failure patients in 12 cycles after adequate E2 priming 84 The serum P levels achieved were subphysiologic and incapable of inducing a normal secretory response in the endometrium Howard Carp 13 June 2007 Recurrent Pregnancy Loss Causes Controversies and Treatment CRC Press pp 79 ISBN 978 0 415 42130 0 a b Gautam N Allahbadia Rita Basuray Das Goral Gandhi Rubina Merchant 17 July 2017 The Art amp Science of Assisted Reproductive Techniques ART JP Medical Ltd pp 145 ISBN 978 93 86322 82 1 Lars Philip Bengtsson M Tausk 30 January 1971 Pharmacology of the endocrine system and related drugs progesterone progestational drugs and antifertility agents Pergamon Press p 449 ISBN 9780080157450 a b de Ziegler D Sator M Binelli D Leuratti C Cometti B Bourgain C Fu YS Garhofer G September 2013 A randomized trial comparing the endometrial effects of daily subcutaneous administration of 25 mg and 50 mg progesterone in aqueous preparation Fertil Steril 100 3 860 6 doi 10 1016 j fertnstert 2013 05 029 PMID 23806850 a b c d de Ziegler D Fanchin R 2000 Progesterone and progestins applications in gynecology Steroids 65 10 11 671 9 doi 10 1016 s0039 128x 00 00123 9 PMID 11108875 S2CID 5867301 Stanczyk FZ 2014 Treatment of postmenopausal women with topical progesterone creams and gels are they effective Climacteric 17 Suppl 2 8 11 doi 10 3109 13697137 2014 944496 PMID 25196424 S2CID 20019151 Stanczyk FZ Paulson RJ Roy S 2005 Percutaneous administration of progesterone blood levels and endometrial protection Menopause 12 2 232 7 doi 10 1097 00042192 200512020 00019 PMID 15772572 S2CID 10982395 Gautam N Allahbadia Yoshiharu Morimoto 15 September 2015 Ovarian Stimulation Protocols Springer pp 137 ISBN 978 81 322 1121 1 Devroey P Palermo G Bourgain C Van Waesberghe L Smitz J Van Steirteghem AC 1989 Progesterone administration in patients with absent ovaries Int J Fertil 34 3 188 93 PMID 2567713 Stute P Neulen J Wildt L August 2016 The impact of micronized progesterone on the endometrium a systematic review Climacteric 19 4 316 28 doi 10 1080 13697137 2016 1187123 PMID 27277331 Davey DA October 2018 Menopausal hormone therapy a better and safer future Climacteric 21 5 454 461 doi 10 1080 13697137 2018 1439915 PMID 29526116 S2CID 3850275 a b Pasqualini JR 2007 Progestins and breast cancer Gynecol Endocrinol 23 Suppl 1 32 41 doi 10 1080 09513590701585003 PMID 17943537 S2CID 46634314 a b Pasqualini JR 2009 Breast cancer and steroid metabolizing enzymes the role of progestogens Maturitas 65 Suppl 1 S17 21 doi 10 1016 j maturitas 2009 11 006 PMID 19962254 Kopernik G Shoham Z June 2004 Tools for making correct decisions regarding hormone therapy Part II Organ response and clinical applications Fertil Steril 81 6 1458 77 doi 10 1016 j fertnstert 2003 09 080 PMID 15193461 Gorins A Denis C 1995 Effects of progesterone and progestational hormones on the mammary gland Arch Anat Cytol Pathol in French 43 1 2 28 35 PMID 7794024 de Lignieres B September 2002 Effects of progestogens on the postmenopausal breast Climacteric 5 3 229 35 doi 10 1080 713605271 PMID 12419080 Barrat J de Lignieres B Marpeau L Larue L Fournier S Nahoul K Linares G Giorgi H Contesso G 1990 Effet in vivo de l administration locale de progesterone sur l activite mitotique des galactophores humains resultat d une etude pilote The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue Results of a pilot study J Gynecol Obstet Biol Reprod Paris in French 19 3 269 74 PMID 2345268 Chang KJ Lee TT Linares Cruz G Fournier S de Lignieres B April 1995 Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo Fertil Steril 63 4 785 91 doi 10 1016 S0015 0282 16 57482 2 PMID 7890063 a b Spicer DV Ursin G Pike MC May 1996 Progesterone concentrations physiologic or pharmacologic Fertil Steril 65 5 1077 8 doi 10 1016 s0015 0282 16 58295 8 PMID 8612843 J M Foidart C Colin X Denoo J D Desreux S Fournier B de Lignieres 1996 Influence of percutaneous administration of estradiol and progesterone on the proliferation of human breast epithelial cells In F Calvo M Crepin H Magdelenat eds Breast Cancer Advances in Biology and Therapeutics John Libbey Eurotext pp 329 334 ISBN 9782742001385 Foidart JM Colin C Denoo X Desreux J Beliard A Fournier S de Lignieres B May 1998 Estradiol and progesterone regulate the proliferation of human breast epithelial cells Fertil Steril 69 5 963 9 doi 10 1016 s0015 0282 98 00042 9 PMID 9591509 a b c d de Lignieres B Silberstein S April 2000 Pharmacodynamics of oestrogens and progestogens Cephalalgia An International Journal of Headache 20 3 200 7 doi 10 1046 j 1468 2982 2000 00042 x PMID 10997774 S2CID 40392817 a b Shaw RW November 1978 Neuroendocrinology of the menstrual cycle in humans Clin Endocrinol Metab 7 3 531 59 doi 10 1016 S0300 595X 78 80008 5 PMID 365398 a b Endrikat J Gerlinger C Richard S Rosenbaum P Dusterberg B December 2011 Ovulation inhibition doses of progestins a systematic review of the available literature and of marketed preparations worldwide Contraception 84 6 549 57 doi 10 1016 j contraception 2011 04 009 PMID 22078182 Table 1 Publications on ovulation inhibition doses of progestins Progestin Progesterone Reference Pincus 1956 Method Urinary pregnanediol Daily dose mg 300 000 Total number of cycles in all subjects 61 Total number of ovulation in all subjects 30 of ovulation in all subjects 49 a b Stone Abraham Kupperman Herbert S 1955 The Effects of Progesterone on Ovulation A Preliminary Report The Fifth International Conference on Planned Parenthood Theme Overpopulation and Family Planning Report of the Proceedings 24 29 October 1955 Tokyo Japan International Planned Parenthood Federation p 185 The results of testing the effects of progesterone on ovulation in 13 patients at the Margaret Sanger Research Bureau are presented The patients had normal menstrual cycles and showed clear evidence of ovulation Each patient was given 1000 mg of oral progesterone daily during the midperiod for 10 or 12 days during 16 cycles Ovulation was inhibited in 6 cycles No disturbance in menstrual rhythm was observed 3 of 12 patients with longstanding infertility histories became pregnant within 2 4 months after the cessation of progesterone therapy a b S Beier B Dusterberg M F El Etreby W Elger F Neumann Y Nishino 1983 Toxicology of Hormonal Fertility Regulating Agents In Giuseppe Benagiano Egon Diczfalusy eds Endocrine Mechanisms in Fertility Regulation Raven Press pp 261 346 ISBN 978 0 89004 464 3 Pincus G 1956 Some effects of progesterone and related compounds upon reproduction and early development in mammals Acta Endocrinol Suppl Copenh 23 Suppl 28 18 36 doi 10 1530 acta 0 023S018 PMID 13394044 Pincus G December 1958 The hormonal control of ovulation and early development Postgrad Med 24 6 654 60 doi 10 1080 00325481 1958 11692305 PMID 13614060 Table 1 Effects of oral progesterone on three indexes of ovulation Medication Progesterone Number 69 Mean cycle length 25 5 0 59 Per cent positive for ovulation by Basal temperature 27 Endometrial biopsy 18 Vaginal smear 6 we settled on 300 mg per day oral progersterone as a significantly effective ovulation inhibition dosage and this was administered from the fifth day through the twenty fourth day of the menstrual cycle We observed each of 33 volunteer subjects during a control nontreatment cycle and for one to three successive cycles of medication immediately following the control cycle As indexes of the occurrence of ovulation daily basal temperatures and vaginal smears were taken and at the nineteenth to twenty second day of the cycle an endometrial biopsy Although we thus demonstrated the ovulation inhibiting activity of progesterone in normally ovulating women oral progesterone medication had two disadvantages l the large daily dosage 300 mg which presumably would have to be even larger if one sought 100 per cent inhibition1 a b Pincus Gregory 1959 Progestational Agents and the Control of Fertility Vitamins amp Hormones Vol 17 pp 307 324 doi 10 1016 S0083 6729 08 60274 5 ISBN 9780127098173 ISSN 0083 6729 Ishikawa et al 1957 employing the same regime of progesterone administration also observed suppression of ovulation in a proportion of the cases taken to laparotomy Although sexual intercourse was practised freely by the subjects of our experiments and those of Ishikawa el al no pregnancies OCcurred Since ovulation presumably took place in a proportion of cycles the lack of any pregnancies may be due to chance but Ishikawa et al 1957 have presented data indicating that in women receiving oral progesterone the cervical mucus becomes impenetrable to sperm Rock J Garcia CR Pincus G 1957 Synthetic progestins in the normal human menstrual cycle Recent Prog Horm Res 13 323 39 discussion 339 46 PMID 13477811 Tyler ET Olson HJ April 1959 Fertility promoting and inhibiting effects of new steroid hormonal substances J Am Med Assoc 169 16 1843 54 doi 10 1001 jama 1959 03000330015003 PMID 13640942 Haller J 1968 Die antikonzeptionelle Therapie Die Gestagene pp 1125 1178 doi 10 1007 978 3 642 99941 3 8 ISBN 978 3 642 99942 0 Neumann FW Elger Y Nishino Y Steinbeck H 1977 Probleme der Dosisfindung Sexualhormone Problems of Dose Finding Sex Hormones Arzneimittel Forschung Drug Research 27 296 318 ISSN 0004 4172 Neumann F 1978 The physiological action of progesterone and the pharmacological effects of progestogens a short review Postgrad Med J 54 Suppl 2 11 24 PMID 368741 Neumann F 1987 Pharmacology and Clinical Uses of Cyproterone Acetate In Furr BJA Wakeling AE eds Pharmacology and Clinical Uses of Inhibitors of Hormone Secretion and Action London Bailliere Tindall pp 132 159 ISBN 9780702011368 OCLC 925173670 OL 20778637M Victor A Jackanicz TM Johansson ED December 1978 Vaginal progesterone for contraception Fertil Steril 30 6 631 5 doi 10 1016 S0015 0282 16 43688 5 PMID 729823 Croxatto HB Diaz S 1987 The place of progesterone in human contraception J Steroid Biochem 27 4 6 991 4 doi 10 1016 0022 4731 87 90179 8 PMID 3320572 Backstrom T von Schoultz B Toivonen J 1979 Plasma progesterone concentrations after administration via intravaginal rings Acta Obstet Gynecol Scand 58 2 211 2 doi 10 3109 00016347909154585 PMID 452876 S2CID 34956863 Shaaban MM 1991 Contraception with progestogens and progesterone during lactation J Steroid Biochem Mol Biol 40 4 6 705 10 doi 10 1016 0960 0760 91 90294 F PMID 1835650 S2CID 25152238 Wadsworth PF Heywood R Allen DG Hossack DJ Sortwell RJ Walton RM October 1979 Treatment of rhesus monkeys Macaca mulatta with intravaginal rings impregnated with either progesterone or norethisterone Contraception 20 4 339 51 doi 10 1016 s0010 7824 79 80044 x PMID 116799 a b c d Janet Brotherton 1976 Sex Hormone Pharmacology Academic Press pp 220 341 342 ISBN 978 0 12 137250 7 Hans Dieter Taubert Herbert Kuhl 1981 Kontrazeption mit Hormonen Contraception with Hormones 1 ed Stuttgart New York Goerg Thieme Verlag p 86 ISBN 9783136088012 OCLC 612130880 Daily intramuscular injection of 5 to 10 mg of progesterone from days 7 to 23 suppresses LH and FSH and prevents ovulation 569 Progestogens also lead to a reduction in gonadotropin levels Netter A Gorins A Thomas K Cohen M Joubinaux J 1973 Blocage du pic d ovulation de LH et de FSH par la progesterone a faibles doses chez la femme Blockade of LH and FSH peaks by low doses of exogenous progesterone in the human female Ann Endocrinol Paris in French 34 4 430 5 ISSN 0003 4266 PMID 4779738 Lobo Rogerio A Stanczyk Frank Z 1994 New knowledge in the physiology of hormonal contraceptives American Journal of Obstetrics and Gynecology 170 5 1499 1507 doi 10 1016 S0002 9378 12 91807 4 ISSN 0002 9378 PMID 8178898 Tollan A Oian P Kjeldsen SE Eide I Maltau JM 1993 Progesterone reduces sympathetic tone without changing blood pressure or fluid balance in men Gynecol Obstet Invest 36 4 234 8 doi 10 1159 000292636 PMID 8300009 Progesterone Drugs com retrieved 2015 08 23 Josimovich J 11 November 2013 Gynecologic Endocrinology Springer Science amp Business Media pp 9 25 29 139 ISBN 978 1 4613 2157 6 Jerome Frank Strauss Robert L Barbieri 2009 Yen and Jaffe s Reproductive Endocrinology Physiology Pathophysiology and Clinical Management Elsevier Health Sciences pp 807 ISBN 978 1 4160 4907 4 Brady BM Anderson RA Kinniburgh D Baird DT 2003 Demonstration of progesterone receptor mediated gonadotrophin suppression in the human male Clin Endocrinol Oxf 58 4 506 12 doi 10 1046 j 1365 2265 2003 01751 x PMID 12641635 S2CID 12567639 a b c Heller CG Moore DJ Paulsen CA Nelson WO Laidlaw WM December 1959 Effects of progesterone and synthetic progestins on the reproductive physiology of normal men Fed Proc 18 1057 65 PMID 14400846 Archived from the original on 2018 12 18 Retrieved 2018 12 18 Rothchild I June 1957 Effect of large doses of intravenously administered progesterone on gonadotropin excretion in the human female J Clin Endocrinol Metab 17 6 754 9 doi 10 1210 jcem 17 6 754 PMID 13428841 Wein AJ Kavoussi LR Novick AC Partin AW Peters CA 25 August 2011 Campbell Walsh Urology Expert Consult Premium Edition Enhanced Online Features and Print 4 Volume Set Elsevier Health Sciences pp 2938 ISBN 978 1 4160 6911 9 Kjeld JM Puah CM Kaufman B Loizou S Vlotides J Gwee HM Kahn F Sood R Joplin GF 1979 Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men Clinical Endocrinology 11 5 497 504 doi 10 1111 j 1365 2265 1979 tb03102 x PMID 519881 S2CID 5836155 a b Neumann F Diallo F A Hasan S H Schenck B Traore I 1976 The Influence of Pharmaceutical Compounds on Male Fertility Andrologia 8 3 203 235 doi 10 1111 j 1439 0272 1976 tb02137 x ISSN 0303 4569 PMID 793446 S2CID 24859886 Heller CG Laidlaw WM Harvey HT Nelson WO July 1958 Effects of progestational compounds on the reproductive processes of the human male Ann N Y Acad Sci 71 5 649 65 doi 10 1111 j 1749 6632 1958 tb54641 x PMID 13583821 S2CID 32637425 a b Neumann F 1985 Steroidal contraception experimental background Future Aspects in Contraception 129 144 doi 10 1007 978 94 009 4910 2 2 ISBN 978 94 010 8675 2 Bain J 1980 Androgen Progestin Combinations Clinical Trials Regulation of Male Fertility 85 91 doi 10 1007 978 94 009 8875 0 9 ISBN 978 94 009 8877 4 a b Petry R Pfizenmayer K 1973 Moglichkeiten der medikamentosen Fertilitatshemmung beim Mann Deutsche Medizinische Wochenschrift 98 38 1775 1779 doi 10 1055 s 0028 1107127 ISSN 0012 0472 PMID 4742513 Sundsfjord JA Aakvaag A Norman N August 1971 Reduced plasma testosterone and LH in young men during progesterone administration J Reprod Fertil 26 2 263 5 doi 10 1530 jrf 0 0260263 PMID 5558416 a b Turkmen S Backstrom T Wahlstrom G Andreen L Johansson IM 2011 Tolerance to allopregnanolone with focus on the GABA A receptor Br J Pharmacol 162 2 311 27 doi 10 1111 j 1476 5381 2010 01059 x PMC 3031054 PMID 20883478 a b Follesa P Concas A Porcu P Sanna E Serra M Mostallino MC Purdy RH Biggio G 2001 Role of allopregnanolone in regulation of GABA A receptor plasticity during long term exposure to and withdrawal from progesterone Brain Res Brain Res Rev 37 1 3 81 90 doi 10 1016 s0165 0173 01 00125 4 PMID 11744076 S2CID 362309 a b c Schiller CE Schmidt PJ Rubinow DR 2014 Allopregnanolone as a mediator of affective switching in reproductive mood disorders Psychopharmacology 231 17 3557 67 doi 10 1007 s00213 014 3599 x PMC 4135022 PMID 24846476 a b c Backstrom T Haage D Lofgren M Johansson IM Stromberg J Nyberg S Andreen L Ossewaarde L van Wingen GA Turkmen S Bengtsson SK 2011 Paradoxical effects of GABA A modulators may explain sex steroid induced negative mood symptoms in some persons Neuroscience 191 46 54 doi 10 1016 j neuroscience 2011 03 061 PMID 21600269 S2CID 38928854 Andreen L Sundstrom Poromaa I Bixo M Andersson A Nyberg S Backstrom T February 2005 Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone Psychoneuroendocrinology 30 2 212 24 doi 10 1016 j psyneuen 2004 07 003 PMID 15471618 S2CID 29760633 Further reading editSitruk Ware R Bricaire C De Lignieres B Yaneva H Mauvais Jarvis P October 1987 Oral micronized progesterone Bioavailability pharmacokinetics pharmacological and therapeutic implications a review Contraception 36 4 373 402 doi 10 1016 0010 7824 87 90088 6 PMID 3327648 Simon JA December 1995 Micronized progesterone vaginal and oral uses Clinical Obstetrics and Gynecology 38 4 902 14 doi 10 1097 00003081 199538040 00024 PMID 8616985 Ruan X Mueck AO November 2014 Systemic progesterone therapy oral vaginal injections and even transdermal Maturitas 79 3 248 55 doi 10 1016 j maturitas 2014 07 009 PMID 25113944 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Pharmacodynamics of progesterone amp oldid 1186027005, wikipedia, wiki, book, books, library,

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