FSH/LH Agonists & Prolactin Antagonists
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Prolactin
Dopamine
- Dopamine tonically inhibits lactotroph release of prolactin, hence it's alternative name: prolactin-inhibiting hormone.
- It ensures that prolactin secretion is low in males and non-pregnant/non-breastfeeding females; whereas, in pregnant and breastfeeding women, dopamine's effects are inhibited, and lactotrophs release prolactin, which stimulates breast development and lactogenesis (milk formation). To learn about the role of suckling in promoting prolactin release during breast-feeding, see the links in our notes.
Indications
- We use prolactin antagonism to treat hyperprolactinemia, which can manifest as galactorrhea, irregular menstrual cycles, and gynecomastia.
- Parkinson's disease, which we discuss in detail elsewhere.
- Acromegaly, because dopamine reduces GH production in patients with acromegaly (note that it can have the opposite effect in normal individuals).
Bromocriptine
- Here, we highlight bromocriptine because it was the first dopamine agonist used for prolactin inhibition, note, however, that many dopamine agonists exist.
Side Effects
- Importantly, dopamine agonists can produce multiple potential side effects, namely:
- Psychosis – think of D2 activation in the positive symptoms of schizophrenia, as well as the surprising impulsivity that can occur with ropinirole and pramipexole¬
- Gastrointestinal (GI) upset – in part, for this reason, non-oral methods of administration have been developed to try to regulate dopamine surges and mitigate GI side effects.
- There are also complicated blood pressure (elevation/lowering) and, of course, motor effects.
Gonadotropin-releasing hormone (GnRH)
- Gonadotropin-releasing hormone (GnRH) from the hypothalamus promotes gonadotroph release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which act on the gonads (ovaries and testes) to produce, in short: spermatogenesis in the testes and produce key ovarian hormonal effects.
In the testes:
- FSH promotes spermatogenesis via multiple actions on Sertoli cells.
- LH promotes testosterone synthesis in Leydig cells.
In the ovaries:
- The hormonal effects are more complicated and phase-dependent:
- FSH promotes granulosa cell growth, follicle maturation, and aromatase synthesis; aromatase is the enzyme that converts androgens to estrogens.
- LH has multiple effects:
- It promotes thecal cell secretion of androgens, which are then converted to estrogens by the nearby granulosa cells;
- The LH surge induces ovulation;
- And, post-ovulation, LH promotes the development and functioning of the Corpus Luteum (notice that "luteinizing" hormone promotes the "luteum").
Assisted Reproductive Technology (ART)
- Ovulation induction via assisted reproduction technology can be performed via a variety of complicated protocols, but let's review some basic principles as a primer for this next section:
- Steady GnRH agonism or GnRH antagonism are used to inhibit gonadotropin production.
- FSH analogs stimulate follicle development (follicular phase), pre-ovulation phase.
- LH/hCG analogs simtulate oocyte maturation (luteal phase), post-ovulation phase.
Indications
- FSH & LH analogs are used in combination to treat infertility in hypogonadotropic, hypogonadal men and women.
- Specifically, they are used to:
- Induce spermatogenesis in the testes.
- Stimulate ovarian follicle development and ovulation (particularly in anovulatory women who are unresponsive to simpler treatments, like Clomiphene).
Key Examples
- The FSH analogs (recombinant/engineered forms of medication): follitropin alfa and beta – these are recombinant (engineered) forms of medication;
- The LH analog lutropin
- And rhCG, recombinant hCG.
- Note that hCG and LH act on the same receptor so we lump them together here, but LH acts on gonadal steroidogenesis and ovulation regulation, whereas hCG is produced by the placenta and secreted during pregnancy.
- Next, indicate menotropin (hMG – human menopausal gonadotropin), which is a combination of FSH & LH; instead of being a recombinant engineered medication, it is a purified extraction from urine.
- Similarly, urofollitropin is a purified urine extraction but of FSH, only – it was withdrawn from the US market.
Side Effects
- Ovarian hyperstimulation syndrome, which is now rare, but is characterized by:
- Ovarian edema and related edematous changes (pulmonary edema, ascites) with loss of volume in the intravascular space, causing electrolyte imbalances and kidney failure, and potentially causing thromboembolism (DVT, PE).
- FSH & LH analog infertility treatment also increases the likelihood of multiple pregnancies and related complications.
- In men, these gonadotropin analogs can cause gynecomastia.