Hormonal Therapy Part 1

Let's start by zooming all the way out to the HPO axis.

The hypothalamus releases GnRH, which drives the pituitary to release luteinizing hormone, or LH, and follicle-stimulating hormone, or FSH, which then signal the ovary to produce estrogen and progesterone.

These two steroid hormones, estrogen and progesterone, maintain homeostasis in normal tissues but can also drive proliferation in hormone receptor-positive tumors.

Progesterone is produced mainly by the ovary, specifically by thecal cells and the corpus luteum during the luteal phase and in high concentrations by the placenta during pregnancy.

Estrogen is primarily produced in the ovary in premenopausal patients, where it's converted from androstenedione and testosterone in the granulosa cells.

In postmenopausal patients, estrogen is produced in several peripheral tissues, as well as in multiple sites in the brain.

Overproduction of estrogen in peripheral tissues, primarily due to aromatization from testosterone, is another major source of estrogen in the body, occurring in both pre- and postmenopausal patients.

So there are really two levels we can discuss with these agents, broadly with the endocrine axis itself or the up-close level of the receptor or its downstream pathway.

How do these hormones work on a cellular pathway level?

Great and tough question.

Progesterone signaling is very complex.

It works through multiple mechanisms to promote cellular proliferation and cell survival, with downstream signaling effects on cyclin D1 and RANKL, MAPK, and AKT, WNT1, and EGFR.

The estrogen receptor can be activated directly by estrogen binding, which is the classic ligand-dependent pathway, but the estrogen receptor is also a downstream target of growth factor pathways.

The PI3K/AKT/mTOR axis, as well as the RAS/RAF/MEK and MAP kinase axis, both feed into the estrogen receptor activity.

These multiple pathways of activation and activity provide mechanisms for resistance to hormonal therapy and contribute to the failure of single-agent hormonal treatments.

Many gynecologic cancers are hormone receptor-positive, making these therapies promising.

Hormonal agents are generally cytostatic, not cytotoxic, meaning they halt cells at a specific phase of the cell cycle.

This explains why we don't generally use these drugs in combination with chemotherapy.

Since most chemotherapies target rapidly dividing cells and the hormonal therapy is parking the cells in the quiescent phase, the combination would be counterproductive.

The cytostatic effect of these therapies also reframes what, quote, "response" means.

With these drugs, prolonged stable disease is often the win, not shrinkage.

Let's walk through the therapies class by class.