Estrogens and antiestrogens

Chapters:

Watch video only

Introduction0:00–0:43

Synthetic estrogens are a class of medications that act like natural estrogens and are mainly used for primary hypogonadism, primary amenorrhea, estrogen deficiency, and as contraceptives.
Now, antiestrogens, or estrogen antagonists include full antagonists, which antagonize natural estrogens in all tissues, and selective estrogen receptor modulators, or SERMs, which act as estrogen antagonists in some tissues but also act as estrogen agonists in others.
Full antagonists and SERMs are used for breast cancer, and SERMs are also used for osteoporosis. But first let’s talk a bit about natural estrogen, which plays a big role in the menstrual cycle.

Physiology0:43–3:38

The hypothalamus, which is part of the brain, secretes gonadotropin-releasing hormone, or GnRH, which travels to the nearby pituitary gland and stimulates it to secrete two hormones follicle stimulating hormone, or FSH, and luteinizing hormone, or LH.
FSH and LH make the ovarian follicles, which are scattered throughout the ovaries, develop and secrete the female sex hormones, estrogens and progesterone.
These hormones gradually increase during the first 2 weeks of the cycle, called the follicular phase, but estrogen is the main hormone synthesized during this phase.
The high estrogen levels stimulate the thickening of the endometrium, the growth of endometrial glands, and the emergence of spiral arteries from the basal layer.
The high estrogen levels also make the pituitary more sensitive to the actions of hypothalamic GnRH, acting as a positive feedback signal, and at the end of the follicular phase, it leads to a massive surge of FSH and LH that leads to ovulation where one of the follicles releases an ovocyte.
Okay, now the 2 weeks following ovulation is called the luteal phase, where the follicle that released the oocyte becomes the corpus luteum.
This structure mainly synthesizes progesterone which helps maintain the uterine lining so a fertilized oocyte can implant.
Other than the menstrual cycle, estrogen along with progesterone are also responsible for the maturation of the female reproductive organs during fetal development.
These hormones trigger the growth of the fallopian tubes, uterus, cervix, and vagina. Estrogens are also responsible for the development of female secondary sex characteristics during puberty, like the growth of breasts and widening of the hips, as well as distribution of fat on the buttocks, hips, and thighs.
Alright, now estrogens also act on a systemic level. They have a protective effect on the cardiovascular system by keeping the blood vessels’ walls flexible, and by lowering the levels of LDL-cholesterol.
Now, in the skeleton, estrogens decrease the action of osteoclasts which break down bone, and increase the action of osteoblasts which build up bone.
So, they help sustain bone density. The bad news is that during menopause, which usually happens around age 50, the ovaries run out of functional ovarian follicles.
That leads to a decrease in estrogen levels, accounting for many of the symptoms preceding menopause, like hot flashes, night sweats, vaginal atrophy, and bone fractures due to osteoporosis.
However, a small amount of estrogen is still being synthesized by the adrenal glands and the fat cells in the woman’s body.

Synthetic Estrogens3:38–6:04

Synthetic estrogens are estrogen receptor agonists, and include ethinyl estradiol; diethylstilbestrol, or DES; and mestranol.
They can be given orally, via transdermal patches, vaginal creams, or intramuscular injection. Okay, now synthetic estrogens have various indications.
First, they are used for primary hypogonadism, or primary gonadal dysfunction, in which low gonadal activity leads to low levels of estrogen in the body, resulting in delayed puberty, or delayed sexual maturation.
So, synthetic estrogens can stimulate the development of secondary sexual characteristics and accelerate growth. Now when estrogens are given in girls with hypogonadism, if the dose is not adjusted carefully, they can cause premature closure of the epiphyses of the long bones resulting in short stature.
They’re also indicated for primary amenorrhea where menses fails to occur by the age of 16 in the presence of normal growth and secondary sexual characteristics.
In this case, synthetic estrogens can be given cyclically to mimic the natural menstrual cycle and trigger menses. Alright, now after menopause, estrogens are also indicated to replace the loss of estrogens and relieve menopausal symptoms, which is referred to as hormone replacement therapy, or HRT.
Another indication is estrogen deficiency resulting from surgical removal of the ovaries or from premature ovarian failure, where the ovaries stop ovulating and producing hormones before the age of 40.
Estrogens are also indicated as hormonal contraceptives along with a progestogen. Alright, now let’s move on to side effects which include vaginal bleeding, nausea, and breast tenderness.
They also increase the risk of thromboembolic events like deep vein thrombosis in postmenopausal women. There is also an increased risk for endometrial cancer when given without progesterone to counteract their effects on the endometrium, as well as a small increase in the risk for breast cancer.
Finally, a super important side effect of diethylstilbestrol is that females that were exposed to DES in utero, meaning that they are daughters of women who were treated with DES during pregnancy, can develop vaginal adenosis, and clear cell adenocarcinoma, which is a type of vaginal cancer.

Antiestrogens6:04–8:27

Okay, next we have antiestrogens. Let’s start by looking at the selective estrogen receptor modulators, or SERMS, which include tamoxifen, raloxifene, and clomiphene.
Remember SERMS have estrogen agonist effects in some tissues, but act as estrogen antagonists in others. Okay, but let’s be more specific.
Tamoxifen acts as an estrogen antagonist in breast tissue, and so, it can be used to prevent and treat estrogen receptor, or ER, positive breast cancer.
On the other hand, tamoxifen acts as a partial estrogen agonist in bones and thus, it can also be used to prevent osteoporosis in postmenopausal women.
Moving on to side effects. Tamoxifen also acts as an agonist in the endometrium which can result in the formation of polyps, endometrial hyperplasia and increase the risk of endometrial cancer.
Other side effects include thromboembolic events and hot flashes. Alright, now let’s move on to raloxifene, which like tamoxifen, acts as an estrogen antagonist in breast tissue and as a partial agonist in bones.
Raloxifene is the medication of choice to prevent and treat osteoporosis in postmenopausal women. The good news is that raloxifene, unlike tamoxifen, has no estrogenic effect on the endometrium and so it does not increase the risk of endometrial cancer.
Side effects include hot flashes and an increased risk of thromboembolic events. Okay, next we have clomiphene which acts as an estrogen antagonist in the hypothalamus, preventing the normal negative feedback, and thus increases FSH and LH output from the pituitary and ultimately stimulates ovulation.
It is used to induce ovulation and treat infertility in women who wish to become pregnant but have anovulatory cycles. Moving on to side effects.
Clomiphene may cause hot flashes, ovarian enlargement, multiple pregnancies due to multiple ovulation, and visual disturbances.
Okay, finally, let’s move on to full estrogen receptor antagonists like fulvestrant. Unlike SERMs, full antagonists have antiestrogenic effects in all tissues.
Fulvestrant is used for breast cancer that is resistant to tamoxifen. Side effects include endometrial hyperplasia which can lead to endometrial cancer, and also an increased risk for thromboembolic events.

Memory Palace8:27–10:37

Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts. So first let’s go to an office where there’s a big pile of paper with the letter “E” on them, and this is where we’ll put the estrogen receptor agonists, or synthetic estrogens.
On the other side of the room, there’s a paper shredder which represents estrogen receptor full antagonists. Between the paper and the shredder, we have a recycling bin where we’ll put the SERMs that act as both agonist and antagonist.
For the indications of synthetic estrogens let’s put an office lady in front of the stack of paper. Someone dropped an egg on the paper and it’s cracked open, and this will represent hypogonadism.
The papers are ruined, so the lady’s quite angry. She’s praying for patience, going “Amen” to represent primary amenorrhea.
She got a bit heated over the situation, and is fanning herself to help you remember these drugs can be used for hormone replacement therapy.
Finally, she’s wearing a t-shirt with a baby on it that’s crossed out to help you remember their use as contraceptives. For the SERMs, let’s look at the recycling bin.
Another lady is about to throw away a tambourine, and this represents tamoxifen. Around her waist, she’s wearing a giant counterfeit watch that says “Ralox,” for raloxifene.
Finally she’s stomping the ground impatiently with her giant boots, going “clomp, clomp,” for clomiphene. For the indications, the tambourine has a picture of a crab wearing a bra to represent breast cancer, the hands on the Ralox are little bones to represent osteoporosis, and there’s a bunch of little baby boots scattered around the ground since clomiphene treats infertility.
Okay, finally, we have the estrogen receptor antagonists like fulvestrant, so we can say the paper shredder is broken since someone dropped a vest in it.
It’s literally full of vest. There’s also a bra with a little crab pinching onto it since this drug is also used to treat breast cancer.

Review10:37–11:26

Remember both tamoxifen and fulvestrant only treat breast cancer that is estrogen receptor positive. All right, as a quick recap… Synthetic estrogens include ethinyl estradiol, diethylstilbestrol, and mestranol.
They are used in the treatment of primary hypogonadism, primary amenorrhea, as hormone replacement therapy and as contraceptives.
Selective estrogen receptor modulators act like estrogen agonists in some tissues and as estrogen antagonists in others..
SERMs include tamoxifen, raloxifene, and clomiphene. Tamoxifen is used for ER positive breast cancer, raloxifene is the medication of choice for osteoporosis, and clomiphene is used to treat infertility.

Mind Map11:26–11:47

Full antagonists include fulvestrant which is used for breast cancer that is resistant to tamoxifen. But wait, there’s more: Here’s a mind map with all of the mnemonics.
Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.