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progestogens

progestogens

introduction

  • by far the main progestin is progesterone, but small amounts of 17-alpha-OH progesterone are also secreted;
  • males secrete 1-5mg progesterone per day & level is only slightly higher in females during follicular phase
  • progesterone secretion equals a few milligrams per day (half from ovaries & half from adrenal cortices) in the follicular phase of the menstrual cycle but increases after ovulation to a peak of 20–30 mg/d in the luteal phase (secreted by the corpus luteum) resulting in serum levels ~10x higher in the luteal phase than in the follicular phase. The peak usually occurs 8 days after the LH surge associated with ovulation.
  • there is large amount secreted by the corpus luteum & in pregnancy, esp. after 4th month, very large amounts secreted from placenta, until, towards term, the progesterone:oestrogen ratio plummets
  • The three possible mechanisms by which progesterone affects the function of the brain include:
    • genomic effect via binding to intracellular progesterone receptors (PR), and
    • direct non-genomic effect - oestrogen or progesterone, bound to large molecules, such as albumin or plastic beads, exerts immediate effects on electrophysiologic activity of neurons 1).
    • non-genomic effect via metabolism to GABA(A) receptor-modulating neurosteroids
  • progestins have a very short plasma half life of only several minutes as it is metabolised, esp. by liver, to other steroids that have no genomic progesteronic effect such as pregnanediol which is excreted in urine;
    • HOWEVER, 5 alpha hydroxylase and 3 alpha-hydroxysteroid dehydrogenase produce a neuroactive metabolite, allopregnanolone
    • Among neurosteroids, 3alpha-hydroxylated, 5alpha-reduced metabolites of progesterone (3alpha-hydroxy,5alpha-pregnan-20one/3alpha,5alpha-THP) and deoxycorticosterone (3alpha,21-dihydroxy,5alpha-pregnan-20one/3alpha,5alpha-THDOC) are positive allosteric modulators of gamma-aminobutyric acid (GABA) action at GABA A receptors2)
  • progesterone is synthesized by neurons and glial cells and may have a role in supporting myelination of neurons3).

actions of progestogens can be thought of as having relationships to oestrogens as follows:

  • opposing action of oestrogens to provide a balanced physiologic state:
    • eg. relaxation of uterus opposes oestrogen's uterine muscle contractility
    • thus females may at times be either:
      • oestrogen dominant:
        • hypertensive
      • progesterone dominant:
        • hypotensive with constipation, GOR, venous insufficiency, PMT
        • in high doses, or in those sensitive to progesterone and its metabolites, they may develop symptoms of dysautonomia syndromes
  • acting with oestrogen to attain synergistic effect
  • some actions unrelated to oestrogens

actions of progesterones:

relaxes muscles:

  • venodilatation which may lead to:
    • lower limb oedema
    • varicosities - lower limb, vulval & rectal (ie. haemorrhoids)
    • arteriolar vasodilatation which may lead to:
      • decreased vascular resistance and hypotension
  • GIT smooth muscle relaxation:
    • heartburn
    • constipation via inhibition of both amplitude & frequency of spontaneous colonic muscle activity
    • decreased gallbladder motility may increase incidence of gallbladder disease
    • ureteric dilatation & stasis which may contribute to UTI's & urinary incontinence
  • decreases uterine contractions:
    • prevents implanting blastocyst being expelled
    • prevents premature labour
      • high levels of progesterone in pregnancy upregulates ZEB1 expression (zinc finger E-box binding homeobox protein 1) in myometrial cells (ZEB-dominant state) which results in low levels of miRNA-200 family members, inhibition of key contraction-associated proteins CXN43 and OXTR with resultant low levels of connexin-43 and oxytocin receptors
      • as progesterone levels wane, miRNA-200 family members increase and ZEB levels decrease paving the way for oxytocin-mediated contraction in labour.4)
    • may decrease menstrual cramps
  • skeletal muscle & ligamentous relaxation (esp. during pregnancy when relaxin is present)

increases possibility of pregnancy & its maintenance & subsequent lactation:

  • prepares uterine lining for implantation:
    • promotes secretory endometrium & decreases uterine contractions (& helps protect against uterine cancer)
      • demise of corpus luteum in non-pregnant females thus results in falling progesterone & menstruation
      • low luteal levels of progesterone may lead to dysfunctional uterine bleeding
  • increases secretory changes Fallopian tubes
    • thus allows improved chance of fertilised ovum being carried to uterus
  • helps prevent expulsion of blastocyst:
    • decreases uterine contractions (normally 3-4/min during ovulation)
  • promotes fat deposition
  • helps breasts ready for lactation:
    • increases the levels of the EZH2 molecule which:
      • can induce epigenetic changes in perhaps thousands of genes
      • is vital in the development of normal breast tissue, particularly, the ductal tree, both as the breasts grow during puberty and also as they change during pregnancy
      • NB. EZH2 is also over-produced in many cancers, including breast cancer
    • promotes development of lobules & alveoli of breasts
      • ⇒ secretory, but requires prolactin for secretion
  • prevents premature delivery:
    • inhibits release of oxytocin from posterior pituitary oxytocin neurones via enhancing the inhibitory GABA neurotransmitter's actions
    • decreases sensitivity to oxytocin
    • decreases uterine contractions
  • prevents premature lactation:
    • inhibits actions of prolactin

direct action on neurons:

CNS effects:

  • increases GABA-A receptor actions (probably via its metabolites including allopregnanolone):
    • drowsiness, tiredness, depression, decreased coordination, slowed reflexes, impaired memory & reasoning skills
    • decreased seizures
    • increased appetite & food intake
    • high progesterone levels during the luteal phase might be the cause of decreased anesthetic requirement when measured using spectral BIS rather than MAC which is a spinally-determined anaesthetic phenotype 5)
    • falling progesterone levels may thus induce a withdrawal syndrome similar to benzodiazepine, barbiturate or alcohol withdrawal (eg. immediate pre-menstrual phase):
      • irritability, anxiety
  • increases medulla oblongata's sensitivity to carbon dioxide resulting in hyperventilation & resp. alkalosis
  • lowers pain threshold thus women are more sensitive to pain in the luteal phase than in the follicular or ovulation phase - women are most sensitive to ischemic, thermal, and pressure pain during the luteal phase
  • negative feedback actions of progesterone include rapid PR(A/B)-independent effects on GnRH release that may in part be mediated by mPR proteins6), and involve the opioid peptide, dysnorphin7).
  • progesterone and oestrogen appear to induce nitric oxide production in neurons via a genomic mechanism, which appears to be neuroprotective 8)

other effects

  • competes with aldosterone on renal tubules
    • ⇒ increased Na/water excretion with subsequent elevated aldosterone levels to compensate
  • mild catabolic effect similar to glucocorticoids:
    • raises body temperature by ~0.5deg C
  • decreases insulin sensitivity ⇒ insulin resistance & hyperglycaemia & gestational diabetes
  • decreased libido
  • stimulates osteoblasts to increase bone building activity via direct effect & via increased IGF-1
  • high levels without combined use of oestrogen (eg. progesterone-only mini pills) cause 10-fold reduction in levels of interferon epsilon potentially raising the risk of sexually transmitted infections (STDs/STIs)9)

effects of the neuroactive metabolite, allopregnanolone

  • it would appear than allopregnanolone and other neuroactive metabolites are the prime mechanism for progesterone's actions on GABA A receptors.
  • in pregnant rats, induces opioid inhibition over the hypothalamus–pituitary–adrenal axis responses to immune challenge10).
  • potentiation of GABA(A)-mediated inhibition of dorsal raphe nucleus serotonergic neurons. This effect on 5-HT neurotransmission may have relevance for mood disorders commonly associated with reproductive hormone events, such as premenstrual dysphoric disorder and postpartum depression11).
  • certain neurons may produce these neurosteroids to produce a local paracrine action, in particular, targetting extra-synaptic GABA A receptors12)

Progesterone-only contraception:

formulations:

  • “mini-pill”
  • depo-provera (medroxyprogesterone acetate) injection:
    • long-acting injection requiring repeat doses every 3 months
  • subdermal levonorgestrel implants

mechanism of action:

  • prevent pregnancy through a combination of actions:
    • disturbance of hypothalamic-pituitary function, including partial suppression of ovulation (as for combined OCP):
      • the amount of progestin in progestin-only oral contraceptives is much less than in combined oral contraceptives; therefore progestin-only oral contraceptives do not prevent ovulation consistently
      • ovarian response to progestin-only oral contraceptives varies widely among individual women. Approximately 40% of women using progestin-only oral contraceptives ovulate, in other cases follicular activity occurs without any corpus luteum development or with signs of insufficient luteal function and in some users ovarian function is completely suppressed.
    • alteration of the cervical mucus to prevent sperm penetration:
      • cause a cervical mucus that is “hostile” to sperm, similar to mucus of the postovulatory phase
      • greatly reduce the volume of mucus, increase its viscosity and cell content, and alter its molecular structure. These changes result in little or no sperm penetration. Even in the rare cases when penetration does occur, sperm motility is reduced and fertilization is unlikely to take place.
    • endometrial changes which may prevent implantation:
      • these changes differ, depending on the amount of endogenous ovarian hormones produced; this effect is superimposed on the direct endometrial effect of the exogenous progestin.
      • varies between atrophy, suppressed proliferation, irregular secretion, and, sometimes, apparently normal secretory activity.
    • actions in lactating women:
      • during the amenorrhea associated with breast-feeding, ovarian function is largely suppressed, ovulation is unlikely to occur, and the cervical mucus is hostile to the sperm. These effects greatly potentiate the contraceptive effect of progestin-only oral contraceptives during lactation.

other effects of progestin only contraception:

missed mini-pill:

  • delay > 3hr then use other contraception for next 14 days

progestogens for Rx of endometriosis

  • these act by reducing oestradiol production and preventing growth of the endometrium
  • dienogest
1)
Archives of Sexual Behavior. New York: Oct 2002. Vol. 31, Iss. 5; pg. 401:
2)
Critical Reviews in Neurobiology. 16(1-2):67-74, 2004.
3)
Endocrine Reviews 28 (4): 387-439
4)
NEJM 364:10 March 10, 2011. p972-973
5)
Anesth Analg 2005;101:1007–11
6)
Endocrinology. 150(8):3833-44, 2009 Aug.
7)
Reproductive Sciences. 16(8):781-7, 2009 Aug.
8)
Steroids. 74(8):650-6, 2009 Aug
10)
The Journal of Neuroscience, May 20, 2009, 29(20):6449-6460;
11)
European Neuropsychopharmacology. 17(2):108-15, 2007 Jan 15.
12)
Psychoneuroendocrinology. 34 Suppl 1:S48-58, 2009 Dec.
progestogens.txt · Last modified: 2017/12/23 16:07 (external edit)